Biomedical subjects
Publications and source records attributed to H Britton.
[reaction: see text] A key structural feature of the Neocarzinostatin chromophore is a reactive epoxydiyne. We present here a new method for the preparation of epoxydiynes by the addition of an allenyl zinc bromide to a propargylic ketone.
The development of inhibitors to factor VIII is the most serious adverse event associated with the treatment of haemophilia A, predisposing patients to uncontrollable haemorrhage, disability and premature death. Eradication of inhibitors via immune tolerance induction (ITI) is effective in the majority of patients, but may require months to years to achieve success. In the interim, the treatment and prevention of acute bleeding episodes are primary foci of care. Regrettably, there is a paucity of information regarding management of bleeding episodes in inhibitor patients undergoing tolerization. Until specific data from ongoing clinical trials are available to provide more guidance in this patient group, it is reasonable and useful to rely on the broader base of medical literature pertaining to patients not being tolerized to deduce strategies for controlling acute and perioperative bleeding episodes in inhibitor patients during ITI.
Crohn's disease is a chronic inflammatory disorder of the gastrointestinal tract, which is thought to result from the effect of environmental factors in a genetically predisposed host. A gene location in the pericentromeric region of chromosome 16, IBD1, that contributes to susceptibility to Crohn's disease has been established through multiple linkage studies, but the specific gene(s) has not been identified. NOD2, a gene that encodes a protein with homology to plant disease resistance gene products is located in the peak region of linkage on chromosome 16 (ref. 7). Here we show, by using the transmission disequilibium test and case-control analysis, that a frameshift mutation caused by a cytosine insertion, 3020insC, which is expected to encode a truncated NOD2 protein, is associated with Crohn's disease. Wild-type NOD2 activates nuclear factor NF-kappaB, making it responsive to bacterial lipopolysaccharides; however, this induction was deficient in mutant NOD2. These results implicate NOD2 in susceptibility to Crohn's disease, and suggest a link between an innate immune response to bacterial components and development of disease.
OBJECTIVE: The primary aim was to develop a simple scale to quantify indices of emotional distress during the rectal-genital (anogenital) phase of a child sexual abuse examination. METHOD: A scale successfully developed to measure reactions of children to painful procedures, in particular bone marrow aspirations, was used as a model (Elliot, Jay, & Woody, 1987). This new scale was developed to have a simplified rating format, more relevant operational definitions and possibly a different set of behavioral categories. This new scale was developed using 300 children being examined for possible child sexual abuse. Intraclass correlation coefficients identified reliable items to use. Factor analysis and Cronbach alpha were employed to understand the internal structure of the scale. Paired t-tests, Pearson correlations and hierarchical regression were used to explore validity. RESULTS: A simple 7-item scale was developed along with two subscales representing agitated and verbally mediated distress. Ratings of distress were significantly greater during the anogenital phase than the general physical part of the examination. Increased distress was associated with positive physical findings. Ratings by the children that they disliked the physician looking at their bodies provided discriminant validity by correlating with increased scores for emotional distress during the anogenital segment of the examination. CONCLUSION: The Genital Examination Distress Scale (GEDS) has been developed for measuring the emotional distress of children during the anogenital component of child sexual abuse examinations. The GEDS has been provided for prudent use. Descriptive data offer a comparative standard for other programs and research.
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OBJECTIVE: To characterize accidental pediatric rectal/genital trauma in males and compare these physical findings to a cohort of boys evaluated for sexual abuse. DESIGN: Retrospective chart review. SETTING: Tertiary pediatric trauma center/sexual abuse clinic. PARTICIPANTS: Male patients evaluated in the emergency department for rectal/genital trauma from 9/1/89 through 10/31/93 ("accidental group"). Male patients referred to Child Protection Services for suspected sexual abuse from 1/1/93 through 12/31/95 who had abnormal genital physical findings ("sexual abuse group"). MAIN OUTCOME MEASURES: Outcomes measured included age, mechanism of injury, category of diagnosis, location of injury, and type of injury. RESULTS: Forty-four male patients comprised the accidental group, aged six months to 17 years. The most common mechanism was a fall onto an object (34%). The most common injuries were lacerations/perforations of the scrotum (36%) followed by penile lacerations/perforations (25%). No patient had an isolated rectal laceration. Forty-four male patients with positive physical findings comprised the sexual abuse group. Ages ranged from seven months to 18 years. All patients had rectal lesions. Penile lacerations/perforations were the only other injuries documented, occurring in two patients. CONCLUSIONS: Accidental rectal/genital trauma in the pediatric population is uncommon; scrotal trauma occurs much more frequently than rectal trauma. Rectal/genital injury in the sexual abuse group typically involves only the rectal area. Sexual assault should be considered in patients with isolated rectal injury or whenever the alleged history does not correlate with physical findings.
Clinical and immunophenotypic (IP) data are presented on three children with choroid plexus (CP) tumors. Two children ages 0.2 and 2 years old with histologically proven malignant tumors had subtotal tumor resections and were treated with ten monthly cycles of eight-drugs-in-1-day chemotherapy without radiation therapy (XRT). Both are free of tumor 4 and 7 years later. The literature on survival of children with CP carcinomas after chemotherapy and XRT is reviewed. Monoclonal antibodies to 17 neuroectodermal, neuronal, glial, and leukocytic markers on frozen sections were used to IP the two malignant tumors and a CP papilloma. All tumors expressed two neuroectodermal markers (PI-153/3 and UJ 223.8), cytokeratin 19, and a neural and leukocyte marker (Thy-1). Two of three expressed neurofilament protein (NF-H) and glial fibrillary acidic protein (GFAP) and one expressed NF-M and common leukocyte antigen. None had strong expression for the panneuroectodermal antigen UJ13/A. There was variable expression of the other markers. The most common IP profile for CP tumors (cytokeratin 18+, PI-153/3+, Thy-1+, UJ 223.8+, and GFAP+ and UJ13A-, UJ 127.11-, and NF-L-) is discussed in the context of the current knowledge of the ontogenetic origin of the CP. It was concluded that chemotherapy for malignant CP tumors can be associated with long-term survival in young children and that the unique IP profile of CP tumors with coexpression of three intermediate filaments suggests new and provocative evidence of their cellular complexity and heterogeneity.
The effect of ketoconazole on adrenal cortical function was studied in 10 prepubertal children receiving long-term (3 to 52 months) high-dose (10 to 23 mg/kg/d) orally administered ketoconazole treatment because of systemic coccidioidomycosis. Four hours after the once daily morning dose of ketoconazole, the patients had significantly elevated baseline desoxycorticosterone (DOC) and precursor/product ratios, and blunted cortisol and aldosterone responses to ACTH stimulation. Twenty-four hours after ketoconazole ingestion, both DOC and DOC/corticosterone ratio were approaching normal; the cortisol response to ACTH was normal in all but two of the 10 study patients, and these two had significantly improved response compared with their own 4-hour values. There appeared to be no differential adrenal response related to either duration of treatment (greater than 12 vs less than 12 months) or dose of medication per kilogram (greater than 18 or less than 18 mg/kg/d). Our data suggest that ketoconazole impairs production of cortisol and aldosterone by imposing a partial and temporary block at the 11-beta-hydroxylase step of steroid hormone synthesis. None of the patients required adrenal steroid replacement therapy in times of acute illness or surgery, and none had clinical evidence of adrenal insufficiency.
The mortality related to coccidioidal meningitis (CM) has been reduced since the introduction of amphotericin B therapy, but children with CM continue to suffer significant morbidity. Some of this is related to the toxicity of the drug. We report nine children with CM treated with orally administered ketoconazole and intraventricularly administered miconazole. Four of them had been treated initially with amphotericin B with resultant failure in one and severe toxicity in all four. The other five children were treated only with imidazoles. All nine children had evidence of ventriculitis at the time of diagnosis and had ventriculoperitoneal shunts inserted for control of increased intracranial pressure. There was no relapse or recrudescence of CM in a follow-up period of 32 to 90 months on imidazole therapy. The coccidioidal complement-fixation antibody titers in the cerebrospinal fluid of the lateral ventricle became negative in all children 3 to 51 months after diagnosis (mean, 17 months). The serum antibody titers demonstrated a 16- to 256-fold decrease from their maximal levels. Four children are still receiving intraventricular miconazole whereas the others have not received miconazole for an average of 51 months. Therapy with the imidazoles was well-tolerated. The main morbidity was related to the shunts required for control of increased intracranial pressure. There was no evidence of hepatic toxicity and no clinical evidence of adrenal insufficiency although transient adrenal suppression was demonstrated at 4 but not at 24 hours after ketoconazole administration.
A 4-year-old female with acute promyelocytic leukemia (APL) was found to have a variant form of the 15;17 translocation, which is diagnostic of APL. The karyotype of the malignant cells was 47,XX,t(1;11)(q25;q21),t(1;17)(p36;q21), + 8. This case is additional evidence that the breakpoint of #17 at q21 is the characteristic chromosomal aberration of APL. The present case is also unusual because of the young age of the patient.
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We undertook a pilot study to determine whether infusion of gonadotropin-releasing hormone (GnRH) might improve the distinction of hypogonadotropinism from the normal state and might permit gonadotropin deficiency to be diagnosed in the prepubertal child. Normal prepubertal and pubertal boys had a greater luteinizing hormone (LH) reaction (delta LH 54 +/- 15 [SD] ng/ml and 165 +/- 23 ng/ml, respectively) to a 4-hour infusion (100 microgram/hour) than to a 100-microgram bolus of GnRH (19 +/- 9 and 52 +/- 35 ng/ml). These augmented responses were observed in boys with delayed puberty, but not in apparently hypogonadotropic males greater than or equal to 12 years old. LH (delta LH 445 to 1602 ng/ml) and FSH (delta FSH 718 to 2112 ng/ml) surges were induced consistently by GnRH infusion only in normal, postmenarchial females. In all, of 13 hypopituitary cases classified as hypogonadotropic on the basis of a subnormal response to GnRH infusion, 31% had a normal response to the GnRH bolus (P = 0.05). Thus, GnRH infusion testing seems to improve the distinction of hypogonadotropic patients from normal individuals, including boys with delayed puberty.
A 10-month-old male infant had keratosis follicularis spinulosa decalvans, an X-linked dominant disorder. His cutaneous abnormalities consisted of generalized hyperkeratosis, spiny follicular papular lesions, universal alopecia, and hypoplastic nails. Ocular changes characteristic of the disease were also present. Unusual findings included deafness, failure to thrive, predisposition to bacterial infections without demonstrable immune defect, and transient hepatomegaly with abnormal liver function studies.