Patient-derived xenotransplants can recapitulate the genetic driver landscape of acute leukemias.

Genomic studies have identified recurrent somatic mutations in acute leukemias. However, current murine models do not sufficiently encompass the genomic complexity of human leukemias. To develop preclinical models, we transplanted 160 samples from patients with acute leukemia (acute myeloid leukemia, mixed lineage leukemia, B-cell acute lymphoblastic leukemia, T-cell ALL) into immunodeficient mice. Of these, 119 engrafted with expected immunophenotype. Targeted sequencing of 374 genes and 265 frequently rearranged RNAs detected recurrent and novel genetic lesions in 48 paired primary tumor (PT) and patient-derived xenotransplant (PDX) samples. Overall, the frequencies of 274 somatic variant alleles correlated between PT and PDX samples, although the data were highly variable for variant alleles present at 0-10%. Seventeen percent of variant alleles were detected in either PT or PDX samples only. Based on variant allele frequency changes, 24 PT-PDX pairs were classified as concordant while the other 24 pairs showed various degree of clonal discordance. There was no correlation of clonal concordance with clinical parameters of diseases. Significantly more bone marrow samples than peripheral blood samples engrafted discordantly. These data demonstrate the utility of developing PDX banks for modeling human leukemia, and emphasize the importance of genomic profiling of PDX and patient samples to ensure concordance before performing mechanistic or therapeutic studies.

Early-onset GH deficiency results in spatial memory impairment in mid-life and is prevented by GH supplementation.

GH levels increase to high concentrations immediately before puberty then progressively decline with age. GH deficiency (GHD) originating in childhood is treated with GH supplementation to foster somatic development during adolescence. It is not clear if or how early GH replacement affects memory in adulthood, or whether it can prevent the cognitive deficits commonly observed in adults with childhood-onset GHD. Rats homozygous for the Dw-4 mutation (dwarf) do not exhibit the normal increase in GH at 4 weeks of age when GH levels normally rise and are used to model childhood or early-onset GHD (EOGHD). One group of these rats was injected with GH from 4 to 14 weeks of age to model GH supplementation during adolescence with GHD beginning in adulthood (adult-onset GHD; AOGHD). Another group received GH from 4 weeks throughout the lifespan to model normal lifespan GH (GH-replete). Age-matched, Dw-4 heterozygous rats (HZ) do not express the dwarf phenotype and were used as controls. At 8 and 18 months of age, spatial learning in the water maze was assessed. At 8 months of age all experimental groups were equally proficient. However, at 18 months of age, the EOGHD group had poor spatial learning compared to the AOGHD, GH-replete, and HZ groups. Our data indicate that GHD during adolescence has negative effects on learning and memory that emerge by middle-age unless prevented by GH supplementation.

Measured versus estimated glomerular filtration rate in the Calvert equation: influence on carboplatin dosing.

PURPOSE: Carboplatin is frequently dosed to achieve a desired area under the plasma concentration-time curve (AUC) by using the Calvert or Chatelut equations to estimate carboplatin clearance. Accurate determination of glomerular filtration rate (GFR) is necessary to correctly calculate carboplatin clearance using the Calvert equation. In clinical practice, the Cockcroft-Gault formula is frequently used to estimate GFR, but this practice has been reported to under- and overestimate carboplatin clearance. The purpose of this trial was to compare determinations of carboplatin clearance using the Chatelut equation and four separate GFR determinations, including 99mTc-DTPA, the Cockcroft-Gault formula, a 24-h urine collection and a 2-h urine collection. METHODS: Carboplatin clearance was estimated in 21 previously untreated extensive-stage small-cell lung cancer patients. GFR was determined using 99mTc-DTPA, the Cockcroft-Gault formula, 24-h urine collection and 2-h urine collection. Serum and urine creatinine concentrations were measured using enzymatic assays. The carboplatin clearance was then calculated by individually adding 25 to the four GFR determinations based on the Calvert equation, which states that carboplatin clearance equals GFR + 25 (nonrenal clearance). The carboplatin clearance was also estimated using the Chatelut equation. The five determinations of carboplatin clearance were compared using Friedman's test and post-hoc Wilcoxon signed rank tests. Precision and bias for each carboplatin clearance determination were calculated assuming that 99mTc-DTPA provided the most accurate measure of GFR. RESULTS: A statistically significant difference was found between the five methods of estimating carboplatin clearance (P < 0.001). No difference was found between carboplatin clearance calculated using 99mTc-DTPA and the Chatelut equation, the Cockcroft-Gault formula or the 2-h urine collection. The Chatelut equation provided more precision and less bias than the 2-h urine collection (median precision 20% and 30%, median bias -1% and -18%, respectively). CONCLUSION: Compared to 99mTc-DTPA, the Chatelut equation more accurately estimates carboplatin clearance than the Cockcroft-Gault formula, the 2-h urine collection and the 24-h urine collection. The greater negative bias found for the latter three estimates of carboplatin clearance could result in underdosing of carboplatin.

Differential effects of ethanol on the expression of cyclo-oxygenase in cultured cortical astrocytes and neurons.

The developing central nervous system is a primary target of ethanol toxicity. The teratogenic effect of ethanol may result from its action on prostaglandins. Prostaglandins are generated through the release of arachidonic acid (AA) by the action of cytosolic phospholipase A(2) (cPLA(2)) on membrane-bound phospholipids and the catalytic conversion of AA to prostaglandin E(2) (PGE(2)) by cyclo-oxygenase (COX). COX is expressed in two isoforms, constitutive COX1 and inducible COX2. Cultured astrocytes and neurons from immature cerebral cortex were used as in vitro models to investigate the effect of ethanol on PGE(2) synthesis. In both cell types, neither the activity nor the expression of cPLA(2) was affected by ethanol. PGE(2) was synthesized by astrocytes and neurons. Ethanol (200-400 mg/dL for 24 h) significantly increased PGE(2) production in both cell types and the ethanol-induced increase in PGE(2) accumulation in astrocytes was significantly greater than in neurons. These increases resulted from the effects of ethanol on COX. Overall COX activity was up-regulated by ethanol in astrocytes and neurons, and indomethacin, a nonselective blocker for COX, eliminated the ethanol-induced increases of COX activity in both cell types. Increased COX activity in astrocytes resulted from an increase in COX2 expression. NS-398, a selective COX2 blocker, completely inhibited ethanol-induced alterations in COX activity. In neurons, however, ethanol had a direct effect on COX activity in the absence of a change in COX expression. NS-398 only partially blocked ethanol-induced increases in neuronal COX activity. Thus, astrocytes are a primary target of ethanol and ethanol-induced increases in glial PGE(2) synthesis are mediated by COX, principally COX2. Ethanol toxicity may be mediated through PGE(2) in immature cortical cells.

Performance of two rapid, single-use immunoassays for the detection of Clostridium difficile toxin A.

Two rapid, single-use immunoassays for C. difficile toxin A, the Clearview C. DIFF A (Wampole Laboratories, Cranbury, N.J.) and the ImmunoCard Toxin A assays (Meridian Diagnostics Inc., Cincinnati, Ohio) were compared to the cytotoxin assay for their ability to detect C. difficile toxin in fecal specimens. A total of 537 specimens were tested and 47 (8.8%) were positive by the cytotoxin assay. The sensitivity, specificity, positive predictive value, and negative predictive value of the toxin A assays were as follows: 70.2% (95% CI, 57.1 to 83.3), 98.8% (95% CI, 97.8 to 99.8), 84.6% (95% CI, 73.3 to 95.9), and 97.2% (95% CI, 95.7 to 98.6) respectively for the Clearview assay; and 74.5% (95% CI, 62.0 to 86.9), 99.0% (95% CI, 98.1 to 99.9), 87.5% (95% CI, 77.3 to 97.8), and 97.6% (95% CI, 96.2 to 98.9) respectively for the ImmunoCard assay. Both toxin A assays are less sensitive than the cytotoxin assay, however, these assays offer a rapid and easy-to-perform test that may be used in conjunction with the cytotoxin assay for laboratory confirmation of C. difficile-associated disease.

Efficacy of 3 commonly used hearing aid circuits: A crossover trial. NIDCD/VA Hearing Aid Clinical Trial Group.

CONTEXT: Numerous studies have demonstrated that hearing aids provide significant benefit for a wide range of sensorineural hearing loss, but no carefully controlled, multicenter clinical trials comparing hearing aid efficacy have been conducted. OBJECTIVE: To compare the benefits provided to patients with sensorineural hearing loss by 3 commonly used hearing aid circuits. DESIGN: Double-blind, 3-period, 3-treatment crossover trial conducted from May 1996 to February 1998. SETTING: Eight audiology laboratories at Department of Veterans Affairs medical centers across the United States. PATIENTS: A sample of 360 patients with bilateral sensorineural hearing loss (mean age, 67.2 years; 57% male; 78.6% white). INTERVENTION: Patients were randomly assigned to 1 of 6 sequences of linear peak clipper (PC), compression limiter (CL), and wide dynamic range compressor (WDRC) hearing aid circuits. All patients wore each of the 3 hearing aids, which were installed in identical casements, for 3 months. MAIN OUTCOME MEASURES: Results of tests of speech recognition, sound quality, and subjective hearing aid benefit, administered at baseline and after each 3-month intervention with and without a hearing aid. At the end of the experiment, patients ranked the 3 hearing aid circuits. RESULTS: Each circuit markedly improved speech recognition, with greater improvement observed for soft and conversationally loud speech (all 52-dB and 62-dB conditions, P

Riding the mental health pendulum: mixed messages in the era of neurobiology and self-help movements.

Whereas professional disagreement about optimum mental health treatment is commonly understood, recognized, and discussed, the influence of opposing philosophies on patients is less often addressed. This article examines the long-term distress created for the author, battling severe, recurrent depression, as she received advice from practitioners who offered widely varying treatment theories as the basis for differing recommendations. Medical knowledge based on advancing research in neurobiology has led to greater understanding of brain chemistry, more reliance on the use of pharmaceuticals, and an emphasis on other "physical" approaches to mental illness. At the same time, growing "self-help" recovery initiatives, with underlying theories analogous to cognitive therapy, continue a focus on emotional and behavioral self-direction. These messages can appear dramatically opposed in terms of expectations on the patient, when presented from separate perspectives that are not described in a context of the whole. The resulting confusion is an unfair imposition of the personal differences of philosophy among practitioners on patients in crisis seeking help.

Electroconvulsive therapy and memory loss: a personal journey.

The cause for the significant gap between research and anecdotal evidence regarding the extent of some memory loss after electroconvulsive therapy (ECT) has never been adequately explained. A patient's development of awareness and self-education about her severe side effects from ECT raises questions regarding many current assumptions about memory loss. ECT-specific studies, which conclude that side effects are short term and narrow in scope, have serious limitations, including the fact that they do not take into account broader scientific knowledge about memory function. Because of the potential for devastating and permanent memory loss with ECT, informed consent needs significant enhancement until advancing research on both improved techniques and on better predictive knowledge regarding memory loss progresses to making a greater impact on clinical applications. Follow-up care and education in coping skills need to be a regular part of ECT practice when patients do experience severe effects.

An epidemiologic method for assessing the effectiveness of hearing conservation programs using audiometric data.

A hearing conservation program (HCP) must include audiometric monitoring. In keeping with this requirement, enormous bodies of audiometric data have been accumulated. However, only a limited number of methods are available for using audiometric data to assess HCP effectiveness. This study illustrates an epidemiologic method. The risk of developing hearing loss (measured by the standard threshold shift) was compared between study and reference populations using the risk ratio. The study population had an increased risk of nearly 3-fold. Epidemiologic risk comparison methods, using reference populations, offer an alternative to current methods for HCP evaluation using audiometric data.

Women's health: a national plan for action.

Women's health is a central item on the national health agenda for the 1990s. Renewed attention to the health needs of women has led to a national plan for action with interventions in research, prevention, treatment, training, public information, and public policy. Since research and training are pivotal to the promulgation of any national health agenda, this has particular importance for dental research and dental education. The 38-goal PHS Action Plan for Women's Health, which directs resources of the U.S. Public Health Service (PHS) toward women's health is coordinated by the Office on Women's Health and implemented through the PHS agencies and offices including the National Institutes of Health (NIH), Centers for Disease Control and Prevention (CDC), and Food and Drug Administration (FDA). It encompasses large scale research interventions like the NIH "Women's Health Initiative" as well as other biomedical, biobehavioral, and health services research programs.

Assessment of the proposed Draft American National Standard method for evaluating the effectiveness of hearing conservation programs.

Using audiometric data, this study assessed the Draft American National Standard ANSI S12.13-1991 (DANS) method for evaluating the effectiveness of hearing conservation programs by comparing it against a standard epidemiologic method. Although the hearing conservation program of the study population was rated as "acceptable" (scale: acceptable, marginal, unacceptable) using the DANS method, the epidemiologic method found a 130% increased risk of hearing loss (relative risk = 2.3, 95% confidence interval = 0.8 to 6.5). In addition, study workers who were excluded from analyses for failing to comply with the DANS criteria were found to be at significantly increased risk of hearing loss (relative risk = 9.1, 95% confidence interval = 3.4 to 24.2). These data indicate that the DANS method may overestimate the effectiveness of hearing conservation programs and systematically exclude workers at high risk of hearing loss from analyses.

Comparison of amplification systems in an auditorium.

Intelligibility of speech at two positions in a large auditorium was compared for the public address system (PA) and two assistive listening systems: Frequency modulation of radio frequencies (FM) and modulation of infrared light waves (IR). Listening groups were: normal-hearing adults, hearing-impaired, hearing aid users, elderly, and non-native. Word-identification scores were obtained with the Modified Rhyme Tests. Analysis of variance indicated that the main effects of systems, groups, and listening position were significant. Also significant were the two-way interactions. For all groups, the assistive listening systems provided better scores than the PA system. The difference between the two systems was statistically significant, but very small. It can be concluded that both listening systems provide improved speech intelligibility for various types of listeners.

Comparison of amplification systems in a classroom.

"Listening systems" are used for hearing impaired listeners as an alternative to public address systems (PA) used for the general public. These listening systems allow individual control of sound pressure level and minimize the effects of background noise and room reverberation. Three listening systems, based on an audio induction loop (AL), frequency modulation of radio frequencies (FM), and modulation of infrared light (IR) were compared among themselves and with a PA system in a medium-size classroom. Listening groups were normal hearing, hearing impaired, hearing aid users, and elderly. Word identification scores were obtained with the Modified Rhyme Test at two conditions: with a babble of 12 voices at a speech-to-noise ratio (S/N) of + 8 dB, and without the babble at S/N of +20 dB. Analysis of variance indicated that the main effects of systems, groups and room S/N were significant. Also significant were interactions of systems by groups, and systems by S/N. For all groups, the three listening systems provided better scores than the PA system. It can be concluded that all three of the tested listening systems are suitable for listeners with various degrees of hearing losses.

Induction loop listening system designed for a classroom.

The principles of designing an induction loop listening system are discussed. Step-by-step procedures for building an induction loop are presented. The loop described was installed in a medium-size classroom and listening tests were performed comparing the loop and loudspeakers. Two groups of hearing impaired listeners were used. One group of listeners wore hearing aids while the other group did not. Result indicated that for both groups, speech perception was enhanced with the loop system.

Vibrotactile performance by normal and hearing-impaired subjects using two commercially available vibrators.

The aim of this study was to measure vibrotactile sensitivity and stress pattern recognition of untrained normal-hearing and hearing-impaired subjects. Vibrotactile thresholds were measured as a function of frequency with two vibrators at three body placements. Stress pattern recognition was tested with two vibrators at two body placements. Vibrotactile threshold results indicate that wrist placements were less sensitive than fingertip placement and the hearing-impaired subjects were equally or less sensitive than the normal-hearing subjects. Vibrator plunger size had the greatest effect on threshold in the most sensitive frequency range of the skin. Stress pattern recognition results indicate that subject performance is a function of body placement but not a function of plunger size. Moreover, stress pattern recognition curves obtained in this study had lower plateaus for the hearing-impaired subjects than for the normal-hearing subjects. Implications for vibrotactile training are discussed.

Occurrence of multiple dentigerous cysts in a patient with the Maroteaux-Lamy syndrome (mucopolysaccharidosis, type VI).

The mucopolysaccharidoses (MPS) are a group of genetic lysosomal storage diseases. These diseases result from a defect in specific lysosomal enzymes required for the degradation of specific mucopolysaccharides. These incompletely degraded saccharides accumulate in tissues and are excreted in the urine. A general characteristic of these diseases is dysostosis multiplex. Dental complications can be severe and include unerupted dentition, dentigerous cystlike follicles, malocclusions, condylar defects, and gingival hyperplasia. This report examines multiple dentigerous cysts in a patient with a deficiency in N-acetylgalactosamine-4-sulfatase, Maroteaux-Lamy syndrome (MPS VI). The inability to hydrolyze the sulfate group from N-acetylgalactosamine-4-sulfate residue of dermatan sulfate due to a deficiency in this enzyme results in the accumulation of dermatan sulfate in tissues and its excretion in the urine. Examination of dentigerous cyst fluid revealed glycosaminoglycan content of 397 microgram per milliliter. Compositional analyses revealed 60% hyaluronic acid, 30% chondroitin 4- and -6-sulfate, and only 10% dermatan sulfate. This was consistent with dentigerous cyst fluid derived from persons without mucopolysaccharide-storage disorders but distinctly different from glycosaminoglycans assayed from other body fluids of this patient.

Jaw involvement in American Burkitt's Lymphoma.

A total of 100 patients with American Burkitt's lymphoma (AMBL) (mean age, 15 years; M:F ratio 3:1; 3% black) have been treated at the National Cancer Institute since 1964. Eighteen of these had jaw involvement, 16 at presentation and 2 at relapse (mean age, 16 years; M:F ratio 1.6:1). None of these 18 patients was black. Of the 16 patients presenting initially with jaw tumors, 14 were first evaluated by their dentist; 8 were 16 years of age or older (adults) and 6 were younger than 16 years of age (children). Toothache and perioral numbness were the most frequent findings in adults, whereas toothache, loose teeth, intra-oral and extra-oral swelling were the most common complaints in children. Ten patients were treated with antibiotic therapy and/or dental extractions for presumed tooth infection. The distribution of jaw lesions was: unilateral mandibular (7), unilateral maxillary (4), bilateral mandibular (5), and four quadrants (2). Radiologic evaluation was abnormal in all 17 cases evaluated. Only three patients (all children) had disease limited to the jaw. Four of eight children and 3 of 10 adults are long-term survivors with a median follow-up of seven years (range, 2-15 years). American Burkitt's lymphoma with jaw involvement differs from African Burkitt's lymphoma (AFBL) with jaw involvement in a number of ways: (1) the incidence of jaw tumors in adults is similar to that in children; (2) the incidence of jaw tumors is not greater in males; (3) tumor is considerably more limited in extent with a single quadrant mandibular lesion being the most common presentation; and (4) clinical presentation also differs, with toothache and perioral numbness, uncommon in AFBL, being the most frequent complaints. These marked differences in the frequency and clinical characteristics of jaw tumor of AMBL and AFBL are consistent with other findings indicating that these diseases may differ phenotypically.