Some light from the heat: implications of rave parties for clinicians.
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Adolescent↗
Biomedical subjects
M J Rieder
Publications and source records attributed to M J Rieder.
Compliance with prescription filling in the pediatric emergency department.
OBJECTIVES: To determine the rate of compliance with filling of prescriptions written in a pediatric emergency department and to examine the reasons for not filling the prescriptions. DESIGN: Compliance with filling prescriptions was determined using a follow-up standardized telephone questionnaire, designed so that it was not obvious that assessing prescription filling was the major reason for the study. Compliance herein was defined as having the prescription filled on the same or next day of the pediatric emergency department visit. SETTING: Pediatric emergency department of a tertiary care hospital. SUBJECTS: Pediatric patients discharged home with a drug prescription. MAIN OUTCOME MEASURE: The proportion of prescriptions written in the pediatric emergency department that were filled on either the same or next day as determined by telephone follow-up. This outcome is expressed as a proportion with 95% confidence interval. RESULTS: Follow-up was completed in 1014 (83%) of the 1222 children, aged 4.5 +/- 4.2 (mean +/- SD) years. Compliance with prescription filling was 92.7% (940/1014). Parental reasons for not filling the prescription included medication unnecessary (27%), financial (6.8%), and not enough time (6.8%). Dissatisfaction with the explanation of the medical problem, instructions for treatment, and instructions for follow-up treatment were significantly associated with noncompliance by univariable logistic regression (P<.05). CONCLUSION: The rate of prescription nonfilling in children seen in a pediatric emergency department is at least 7%, although lower than that in adults in a similar setting.
Child, Preschool↗
Palatability of oral antibiotics among children in an urban primary care center.
OBJECTIVE: To evaluate the palatability of antimicrobial agents effective against beta-lactamase-producing bacteria in American children. DESIGN: In a taste test of 4 antimicrobial agents, azithromycin (cherry flavored), cefprozil (bubble gum flavored), cefixime (strawberry flavored), and amoxicillin-clavulanic acid (banana flavored) were compared. SETTING: An urban inner-city primary care clinic. SUBJECTS: A volunteer sample of 30 healthy children (aged 5-8 years). INTERVENTION: Palatability was determined using a single-blind taste test of 4 flavored antimicrobial agents. The 4 antimicrobial agents used were azithromycin, cefprozil, cefixime, and amoxicillin-clavulanic acid. MAIN OUTCOME MEASURES: After each antimicrobial test dose, subjects rated the taste on a 10-cm visual analog scale incorporating a facial hedonic scale. Preference assessments for the best-tasting and worst-tasting agent were also conducted. RESULTS: Of the 20 children who expressed a preference, significantly more children (9 [45%], P<.05) selected the cefixime preparation as the best-tasting formulation compared with the other preparations. The cefixime preparation was also significantly the least likely to be selected as the worst-tasting preparation (2 [10%], P<.05). There were no significant differences between the other 3 preparations with respect to being selected as either the best or worst tasting. The mean (+/- SD) visual analog scale score for cefixime was highest (8.53 [2.49]) compared with the scores for azithromycin (6.78 [3.45]), cefprozil (6.26 [4.04]), and amoxicillin-clavulanic acid (6.24 [4.01]). CONCLUSION: The cefixime preparation was most commonly rated as best tasting by children.
Administration, Oral↗
Multiple antibiotic sensitivity syndrome in children.
BACKGROUND: Multiple antibiotic sensitivity syndrome with adverse drug reactions to multiple classes of antibiotics has been described in adults but is not well characterized in children. PATIENTS AND METHODS: Charts of children referred to the adverse drug reaction clinic at the Children's Hospital of Western Ontario, London, Ontario, with adverse drug reactions to multiple antibiotics were reviewed to determine the number of patients with adverse drug reactions to multiple classes of antibiotics and the clinical characteristics of the adverse events. RESULTS: The records of 97 children who were selected as possible candidates for multiple antibiotic sensitivity were studied. These records constituted 11% of referrals to a highly specialized adverse drug reaction clinic, suggesting that in usual clinical practice, this entity, if it does indeed constitute a distinct clinical entity, is quite uncommon. Age at time of the first adverse drug reaction was 26.1+/-26.3 (mean +/- SD) months. Among the 97 children, adverse reactions to five classes of antibiotic were noted in 3.1%, to four in 10.3%, to three in 47. 4% and to two in 39.2%. Most children (85.6%) experienced an adverse reaction to a penicillin, while 71.1% reacted to a cephalosporin, 80. 4% to a sulphonamide and 35.1% to a macrolide. Clinical presentations of the adverse reactions included urticaria or pruritus, other rash, serum sickness-like reaction, angioedema or anaphylaxis, erythema multiforme or Stevens-Johnson syndrome. CONCLUSIONS: There are children who have what appears to be immunologically mediated adverse drug reactions to antibiotics of multiple classes. These reactions, which most commonly manifest as urticaria or other rashes, follow drug use patterns. It remains to be defined whether this is a distinct clinical syndrome or a manifestation of a more fundamental problem in dealing with xenobiotics in the setting of infection. Further work on the immunological and/or biochemical determinants of the multiple antibiotic sensitivity syndrome (MASS) is needed to understand the pathophysiology and determinants of MASS and whether MASS constitutes a distinct clinical entity.
Anti-Bacterial Agents↗
The cytotoxicity of clozapine metabolites: implications for predicting clozapine-induced agranulocytosis.
BACKGROUND: Therapy of schizophrenia with clozapine is associated with the unpredictable development of severe neutropenia and agranulocytosis in 1% to 2% of patients. The mechanism of this effect is unknown but may involve reactive products of clozapine generated by either hepatic metabolism or oxidation by the peroxidase-peroxide system of activated neutrophils. METHODS: Involvement of reactive metabolites was tested with in vitro cytotoxicity assays with use of peripheral blood mononuclear cells isolated from 3 groups of subjects: normal control subjects, patients with schizophrenia who tolerated clozapine therapy (control patients), and patients with schizophrenia in whom agranulocytosis developed while taking clozapine (patients with agranulocytosis). Cell viability was determined after incubations with clozapine and rat liver microsomes or clozapine and horseradish peroxidase-peroxide (HRP-H2O2). RESULTS: In microsomal incubations, clozapine significantly increased the cell death in all groups: control subjects (8.8%+/-1.6%), control patients (7.4%+/-0.4%), and patients with agranulocytosis (9.1%+/-1.5%). However, differences between mean values were not statistically significant. In similar incubations with HRP-H2O2, clozapine significantly increased toxicity (P < .05) in cells from patients with agranulocytosis (22%+/-4.6%) compared with those from normal control subjects (7.7%+/-4.1%) or control patients (6.5%+/-4.4%). CONCLUSIONS: These results suggest that both generating systems metabolized clozapine to toxic products. Some products may play a role in clozapine-induced agranulocytosis. Of diagnostic relevance is the observation the HRP-H2O2 produces significantly greater toxicity in cells from patients with agranulocytosis than in cells from control patients. Although the exact mechanism(s) of drug activation in vivo remains unclear, the bioactivation of clozapine by HRP-H2O2 may be a useful in vitro tool for predicting which patients are at risk for agranulocytosis before initiation of therapy.
Agranulocytosis↗
An alternate mechanism of glucocorticoid anti-proliferative effect: promotion of a Th2 cytokine-secreting profile.
Glucocorticoids (GCs) are used as immunosuppressive and anti-inflammatory agents in organ transplantation and in treating autoimmune diseases and inflammatory disorders and they exert their effects by several mechanisms, the most significant of which is inhibition of cytokine production and action. Recent reports suggested that GCs inhibit cytokine expression indirectly through promotion of a T helper cell type 2 (Th2) cytokine-secreting profile, thereby resulting in preferential blockade of pro-inflammatory monokine and T helper cell type 1 (Th1) cytokine expression. The target of GCs appeared to be monocytes macrophages, whereby altered regulation of interleukin (IL)-1/IL-1 receptor antagonist (IL-1ra), coupled with profound blockade of IL-12 synthesis and inhibition of interferon (IFN)-gamma-induced major histocompatibility complex (MHC) class II expression, lead to a preferential cognate stimulation of Th2 cells at the expense of Th1 cells. It is possible that this may have involved the expansion of a Th2-cell pool or, in addition, frank stimulation of uncommitted naive CD4 + T cells toward the Th2 lineage. In addition, GCs may have blocked Th1 cytokine expression, thereby inhibiting ongoing Th1 cytokine secretion, and consequently provided for the unimpeded production of Th2 cytokines. Collectively, this indicates that, in exerting their anti-proliferative effects, GCs act indirectly by altering Th1/Th2 cytokine balance, blocking the (pro-inflammatory) Th1 program and favoring the (anti-inflammatory) Th2 program.
Anti-Inflammatory Agents↗
Sequence variation in the human angiotensin converting enzyme.
Angiotensin converting enzyme (encoded by the gene DCP1, also known as ACE) catalyses the conversion of angiotensin I to the physiologically active peptide angiotensin II, which controls fluid-electrolyte balance and systemic blood pressure. Because of its key function in the renin-angiotensin system, many association studies have been performed with DCP1. Nearly all studies have associated the presence (insertion, I) or absence (deletion, D) of a 287-bp Alu repeat element in intron 16 with the levels of circulating enzyme or cardiovascular pathophysiologies. Many epidemiological studies suggest that the DCP1*D allele confers increased susceptibility to cardiovascular disease; however, other reports have found no such association or even a beneficial effect. We present here the complete genomic sequence of DCP1 from 11 individuals, representing the longest contiguous scan (24 kb) for sequence variation in human DNA. We identified 78 varying sites in 22 chromosomes that resolved into 13 distinct haplotypes. Of the variant sites, 17 were in absolute linkage disequilibrium with the commonly typed Alu insertion/deletion polymorphism, producing two distinct and distantly related clades. We also identified a major subdivision in the Alu deletion clade that enables further analysis of the traits associated with this gene. The diversity uncovered in DCP1 is comparable to that described for other regions in the human genome. The highly correlated structure in DCP1 raises important issues for the determination of functional DNA variants within genes and genetic studies in humans based on marker association.
Alu Elements↗
Cytotoxicity of sulfonamide reactive metabolites: apoptosis and selective toxicity of CD8(+) cells by the hydroxylamine of sulfamethoxazole.
Treatment with sulfonamide antibiotics in HIV-infected patients is associated with a high incidence (> 40%) of adverse drug events, including severe hypersensitivity reactions. Sulfonamide reactive metabolites have been implicated in the pathogenesis of these adverse reactions. Sulfamethoxazole hydroxylamine (SMX-HA) induces lymphocyte toxicity and suppression of proliferation in vitro; the mechanism(s) of these immunomodulatory effects remain unknown. We investigated the cytotoxicity of SMX-HA via apoptosis on human peripheral blood mononuclear cells and purified cell subpopulations in vitro. CD19(+), CD4(+), and CD8(+) cells were isolated from human peripheral blood by positive selection of cell surface molecules by magnetic bead separation. SMX-HA induced significant CD8(+) cell death (67 +/- 7%) at 100 microM SMX-HA, with only minimal CD4(+) cell death (8 +/- 4%). No significant subpopulation toxicity was shown when incubated with parent drug (SMX). Flow cytometry measuring phosphatidylserine externalization 24 h after treatment with 100 microM and 400 microM SMX-HA revealed 14.1 +/- 0.7% and 25. 6 +/- 4.2% annexin-positive cells, respectively, compared to 3.7 +/- 1.2% in control PBMCs treated with 400 microM SMX. Internucleosomal DNA fragmentation was observed in quiescent and stimulated PBMCs 48 h after incubation with SMX-HA. Our data show that CD8(+) cells are highly susceptible to the toxic effects of SMX-HA through enhanced cell death by apoptosis.
Apoptosis↗
Selection of treatment of cefaclor-associated urticarial, serum sickness-like reactions and erythema multiforme by emergency pediatricians: lack of a uniform standard of care.
BACKGROUND: Serum sickness-like reactions (SSLR) and erythema multiforme are common adverse effects of cefaclor therapy and can be associated with significant morbidity. No standardized evidence-based protocol for the optimal treatment of drug-induced SSLR exists. OBJECTIVES: To define the standard of care used by physicians treating adverse reactions associated with cefaclor. METHODS: A retrospective review of the medical records of children discharged from a pediatric emergency room with a diagnosis of adverse events to cefaclor was conducted. Charts of patients were reviewed to determine which therapy was prescribed. RESULTS: During the study period, 74 cases of adverse events attributed to cefaclor presented to the emergency department. SSLR were the most common pattern of adverse events seen (31 cases, 42%), followed by urticarial reactions (26 cases, 35%) and erythema multiforme (17 cases, 23%). An antihistamine was the treatment most often prescribed (88%) for erythema multiforme. Significantly more children with SSLR than with erythema multiforme or urticaria were treated with prednisone, either alone or in combination (P<0.05). CONCLUSIONS: The treatment most often prescribed for serious cefaclor-associated erythema multiforme was an antihistamine. In the case of SSLR, an antihistamine and prednisone were most commonly used. Prospective randomized, controlled trials are needed to define the role of various therapeutic agents and to determine the optimal therapy for SSLR and other serious adverse drug reactions.
Cefaclor↗
Significance of enhanced cytokine receptor expression by glucocorticoids.
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Cells, Cultured↗
Automating the identification of DNA variations using quality-based fluorescence re-sequencing: analysis of the human mitochondrial genome.
Diagnostic re-sequencing plays a central role in medical and evolutionary genetics. In this report we describe a process that applies fluorescence-based re-sequencing and an integrated set of analysis tools to automate and simplify the identification of DNA variations using the human mitochondrial genome as a model system. Two programs used in genome sequence analysis (Phred, a base-caller, and Phrap, a sequence assembler) are applied to assess the quality of each base call across the sequence. Potential DNA variants are automatically identified and 'tagged' by comparing the assembled sequence with a reference sequence. We also show that employing the Consed program to display a set of highly annotated reference sequences greatly simplifies data analysis by providing a visual database containing information on the location of the PCR primers, coding and regulatory sequences and previously known DNA variants. Among the 12 genomes sequenced 378 variants including 29 new variants were identified along with two heteroplasmic sites, automatically detected by the PolyPhred program. Overall we document the ease and speed of performing high quality and accurate fluorescence-based re-sequencing on long tracts of DNA as well as the application of new approaches to automatically find and view DNA variants among these sequences.
Base Sequence↗
Serum sickness-like reaction to cefaclor: lack of in vitro cross-reactivity with loracarbef.
OBJECTIVES: A lymphocyte-based in vitro rechallenge technique was used to examine the potential for cross-reactivity between loracarbef and cefaclor in children who had had adverse reactions to cefaclor. STUDY DESIGN: The study cohort included 10 patients (2.2 +/- 1.1 years old) with a serum sickness-like reaction to cefaclor, five patients (4.1 +/- 4.6 years old) with immediate-type hypersensitivity reactions to the drug, and five patients (1.5 +/- 0.9 years old) who had a delayed hypersensitivity reaction to cefaclor without joint involvement (i.e., not a serum sickness-like reaction). Peripheral blood mononuclear cells were isolated from each patient and were exposed to cefaclor, loracarbef, and the metabolites of each generated with phenobarbital-induced murine hepatic microsomes. RESULTS: Among patients with cefaclor-associated serum sickness-like reactions, lymphocyte killing (expressed as percentage cell kill above baseline) in the presence of cefaclor metabolites (83.6% +/- 42.2%) was significantly (p < 0.02) higher than that observed among the patients with either immediate-type (1.1% +/- 2.4%) or delayed hypersensitivity (0%) reactions. In contrast, loracarbef did not produce significant in vitro cytotoxicity among any of the patient subgroups. Our in vitro evidence was supported at therapeutic rechallenge with loracarbef among three children with cefaclor-associated serum sickness-like reactions who tolerated a full course of therapy without adverse reactions. CONCLUSION: The metabolite-mediated cytotoxicity associated with cefaclor among patients who had had serum sickness-like reactions after therapeutic administration of the drug was not shared with loracarbef. The extent to which the apparent lack of in vitro cross-reactivity between cefaclor and loracarbef may be predictive of clinical cross-reactivity is not known.
Cefaclor↗
Gender-specific protection from microvessel rarefaction in female hypertensive rats.
Epidemiologic studies reveal that women have a significantly lower age-adjusted morbidity and mortality from cardiovascular disease than men, suggesting that gender is a cardiovascular disease risk factor. The mechanism of the "gender protection" is unknown. In this study, we investigated the microvascular remodeling in reduced renal mass plus a high salt (4.0% NaCl) diet model of hypertension (RRM + HS). We hypothesized that women would be protected from the increase in blood pressure and from the microvascular rarefaction associated with RRM + HS hypertension. Studies were designed to determine whether female rats were less susceptible to changes in microvessel density during RRM + HS. Microvessel density was measured in male and female low salt (0.4% LS) sham-operated controls (Sham + LS) and after 3 days or 4 weeks of RRM + HS hypertension. The microcirculation of hind limb (medial and lateral gastrocnemius, plantaris, soleus) muscles was visualized using rhodamine-labeled Griffonia simplicifolia I lectin. Tissue sections were examined by videomicroscopy and microvessel density was determined by quantitative stereology. As shown previously, mean arterial pressure increased to 160 +/- 8 mm Hg and microvessel density decreased (>30% decrease in all beds) in male RRM + HS. In contrast, mean arterial pressure of female RRM + HS rats was modestly increased from 101 +/- 2 to 118 +/- 4 mm Hg. Despite previous results showing a reduction in microvessel density of both normotensive and hypertensive male rats on a high salt diet, microvessel density of female RRM + HS rats was not reduced at either time. These results suggest that gender protection in the RRM rat extends beyond an attenuation of the increase in pressure to an immunity from microvascular rarefaction.
Animals↗
Physicians' attire as perceived by young children and their parents: the myth of the white coat syndrome.
OBJECTIVE: To determine if young children have a preference regarding whether physicians do or do not wear a white coat. METHODS: One hundred one children, ages four to eight years, and their parents were recruited from the outpatient setting of a pediatric referral center. Two pairs of photographs, the same man with and without a white coat and the same woman with and without a white coat, were shown to the children and their parents, and both were asked which of each pair they would like to have as their or their child's doctor, respectively. Parents filled out a questionnaire rating the appropriateness of various aspects of a physician's attire and appearance. RESULTS: The children selected the person in the white coat 69% of the time. The parents also selected the white coat more often (66%). On the questionnaire parents identified a name tag as the most appropriate item of dress followed by a white coat. A groomed mustache and groomed beard were also rated favorably. Open-toed sandals, clogs, and shorts were rated negatively, while parents were neutral with respect to hospital greens, blouse and skirt or dress, and shirt and tie. CONCLUSIONS: Physicians may wear a white coat without fear that they are negatively affecting their relationship with their pediatric patients four to eight years of age. The appropriateness of wearing a name tag is confirmed.
Adult↗
A review of common dental treatments during pregnancy: implications for patients and dental personnel.
In general, pregnant females tend to over estimate the risk of teratogenicity in the foetus resulting from medical and dental procedures and/or drugs. This may cause them to avoid necessary treatment, leading to detrimental health effects for both the foetus and themselves. In this review, the concerns of pregnant dental patients and personnel will be discussed, including the perceived risks associated with amalgam restorations, radiation, local anesthetics, nitrous oxide gas, antibiotics and analgesics administered in a dental setting. Pregnant dental personnel have special concerns related to their daily occupational exposure to mercury and nitrous oxide. After assessing the potential risks of undergoing dental treatment during pregnancy, it can be stated that necessary treatment should not be with-held. In addition, dental treatments are best performed in the second trimester for the benefit of the foetus, and optimal comfort for the pregnant woman.
Analgesics↗
Assessment of the palatability of beta-lactamase-resistant antibiotics in children.
OBJECTIVES: To evaluate the palatability of antibiotics effective against beta-lactamase-producing bacteria in children and to compare the results obtained with those obtained in adults. DESIGN: A taste test of 4 antibiotic suspensions: a combination of amoxicillin and clavulanic acid (banana), azithromycin (cherry), clarithromycin (wild fruit), and a combination of erythromycin and sulfisoxazole (strawberry-banana). SETTING: Outpatient setting. SUBJECTS: A volunteer sample of 50 healthy children (mean +/- SD age, 6.3 +/- 1.3 years) and 20 adults. MAIN OUTCOME MEASURES: After each antibiotic test dose, subjects rated its taste on a 10-cm visual analog scale incorporating a facial hedonic scale. RESULTS: The mean +/- SD taste scores of the antibiotics as rated by the children were as follows: amoxicillin-clavulanic acid, 5.7 +/- 3.6 cm; azithromycin, 6.8 +/- 3.2 cm; clarithromycin, 3.7 +/- 3.6 cm; and erythromycin-sulfisoxazole, 4.9 +/- 3.5 cm. The mean +/- SD taste score for erythromycin-sulfisoxazole (ie, 2.7 +/- 2.3) assigned by the adults was significantly different than that given by the children (P = .01) with no difference noted for the other 3 drugs. Children and adults both selected azithromycin most often as best tasting. There was a significant difference in the proportions selecting each antibiotic as worst tasting, with the children tending to dislike clarithromycin and the adults tending to dislike erythromycin-sulfisoxazole (P = .03). CONCLUSIONS: The taste of azithromycin was rated most highly by both children and adults, who also selected this antibiotic most often as best tasting. Differences in taste-testing results between children and adults suggest that evaluation of the palatability of medications intended for use in pediatrics should be conducted in children.
Anti-Bacterial Agents↗
In vivo and in vitro testing for adverse drug reactions.
The goal of providing an accurate and reliable diagnostic test for the evaluation of adverse drug reactions remains elusive. Rechallenge remains a truly conclusive method for determining the contribution of drugs to adverse effects, but there are significant disadvantages in exposing patients to drugs that may have caused serious adverse effects. Skin tests are useful for the assessment and predictive risk of serious adverse reactions for a small number of drugs, but skin tests are limited in their utility to adverse drug reactions mediated by Type 1 hypersensitivity. Skin tests must be performed with care and rigor as well. There are a number of in vitro assays that have been used for the assessment of adverse drug reactions, but many of these assays are primarily research tools and have little utility in the clinical setting. Although in vitro tests are not yet readily available for the diagnosis of adverse drug reactions, our increasing understanding of the biology of adverse drug reactions and interactions between the immune system and xenobiotics offers promise that more clinically relevant assays can be developed. At the present time, the primary diagnostic tools for the assessment of adverse drug reactions remain a careful history and physical examination and an astute, insightful physician.
Adverse Drug Reaction Reporting Systems↗
Suppression of pokeweed mitogen-driven human IgM and IgG responses by the hydroxylamine of sulfamethoxazole.
OBJECTIVE: To determine the effect(s) of reactive sulfonamide metabolites on antibody production by human lymphocytes. METHODS: Human peripheral blood cells (PBMCs) were isolated from control volunteers and incubated with the hydroxylamine of sulfamethoxazole (SMX H/A), a reactive metabolite of the most commonly used sulfonamide, in increasing concentrations. PBMCs were then stimulated to produce antibody with pokeweed mitogen. After incubation for 8 days, concentrations of IgG and IgM were determined in supernatant using an ELISA assay. RESULTS: Production of both IgG and IgM was significantly suppressed by sub-lethal concentrations of SMX H/A in a concentration-dependent fashion (p < 0.05). Suppression was more marked for IgM production (maximal decline to 80% of baseline antibody production) than for IgG production (maximal decline to 57% of baseline antibody production). No suppression was seen when cells were incubated with sulfamethoxazole in concentrations up to 400 microM. This suppression was not related to changes in cell viability; at a concentration of 25 microM of SMX H/A, IgM and IgG concentration were reduced by 47 +/- 8.7% and 73 +/- 7.2%, while cell viability (percentage of live cells) was 93 +/- 5%. Suppression was time-dependent, increasing over the incubation periods to reach a plateau after 2 h of incubation. CONCLUSION: Sulfonamide reactive metabolites, in concentrations which are achieved during therapy, suppress antibody production by PWM-stimulated human cells. This may explain, in part, the alterations in immunity associated with hypersensitivity reactions to the sulfonamides. This may also have implications for patients receiving sulfonamide therapy and concurrent immunosuppressive therapy.
Anti-Infective Agents↗