Intraneural malignant granular cell tumor - report of an extremely rare tumor in a child.

We report a case of intraneural malignant granular cell tumor of the upper extremity occurring in a child. This is an exceedingly rare tumor and the incidence has so far been reported only in adults. The tumor was successfully treated surgically and the patient has remained tumor free to date. We describe our approach to the problem so that it will serve as an index case for similar encounters in the future.

Assessing sources of inconsistencies in genotypes and their effects on genome-wide association studies with HapMap samples.

The discordance in results of independent genome-wide association studies (GWAS) indicates the potential for Type I and Type II errors. We assessed the repeatibility of current Affymetrix technologies that support GWAS. Reasonable reproducibility was observed for both raw intensity and the genotypes/copy number variants. We also assessed consistencies between different SNP arrays and between genotype calling algorithms. We observed that the inconsistency in genotypes was generally small at the specimen level. To further examine whether the differences from genotyping and genotype calling are possible sources of variation in GWAS results, an association analysis was applied to compare the associated SNPs. We observed that the inconsistency in genotypes not only propagated to the association analysis, but was amplified in the associated SNPs. Our studies show that inconsistencies between SNP arrays and between genotype calling algorithms are potential sources for the lack of reproducibility in GWAS results.

Use of diagnostic accuracy as a metric for evaluating laboratory proficiency with microarray assays using mixed-tissue RNA reference samples.

Effective use of microarray technology in clinical and regulatory settings is contingent on the adoption of standard methods for assessing performance. The MicroArray Quality Control project evaluated the repeatability and comparability of microarray data on the major commercial platforms and laid the groundwork for the application of microarray technology to regulatory assessments. However, methods for assessing performance that are commonly applied to diagnostic assays used in laboratory medicine remain to be developed for microarray assays. A reference system for microarray performance evaluation and process improvement was developed that includes reference samples, metrics and reference datasets. The reference material is composed of two mixes of four different rat tissue RNAs that allow defined target ratios to be assayed using a set of tissue-selective analytes that are distributed along the dynamic range of measurement. The diagnostic accuracy of detected changes in expression ratios, measured as the area under the curve from receiver operating characteristic plots, provides a single commutable value for comparing assay specificity and sensitivity. The utility of this system for assessing overall performance was evaluated for relevant applications like multi-laboratory proficiency testing programs and single-laboratory process drift monitoring. The diagnostic accuracy of detection of a 1.5-fold change in signal level was found to be a sensitive metric for comparing overall performance. This test approaches the technical limit for reliable discrimination of differences between two samples using this technology. We describe a reference system that provides a mechanism for internal and external assessment of laboratory proficiency with microarray technology and is translatable to performance assessments on other whole-genome expression arrays used for basic and clinical research.

Predictions and associations of fatigue syndromes and mood disorders that occur after infectious mononucleosis.

BACKGROUND: Certain infections can trigger chronic fatigue syndromes (CFS) in a minority of people infected, but the reason is unknown. We describe some factors that predict or are associated with prolonged fatigue after infectious mononucleosis and contrast these factors with those that predicted mood disorders after the same infection. METHODS: We prospectively studied a cohort of 250 primary-care patients with infectious mononucleosis or ordinary upper-respiratory-tract infections until 6 months after clinical onset. We sought predictors of both acute and chronic fatigue syndromes and mood disorders from clinical, laboratory, and psychosocial measures. FINDINGS: An empirically defined fatigue syndrome 6 months after onset, which excluded comorbid psychiatric disorders, was most reliably predicted by a positive Monospot test at onset (odds ratio 2.1 [95% CI 1.4-3.3]) and lower physical fitness (0.35 [0.15-0.8]). Cervical lymphadenopathy and initial bed rest were associated with, or predicted, a fatigue syndrome up to 2 months after onset. By contrast, mood disorders were predicted by a premorbid psychiatric history (2.3 [1.4-3.9]), an emotional personality score (1.21 [1.11-1.35]), and social adversity (1.7 [1.0-2.9]). Definitions of CFS that included comorbid mood disorders were predicted by a mixture of those factors that predicted either the empirically defined fatigue syndrome or mood disorders. INTERPRETATION: The predictors of a prolonged fatigue syndrome after an infection differ with both definition and time, depending particularly on the presence or absence of comorbid mood disorders. The particular infection and its consequent immune reaction may have an early role, but physical deconditioning may also be important. By contrast, mood disorders are predicted by factors that predict mood disorders in general.

Aliphatic and aromatic carbon-fluorine bond activation with Cp*(2)ZrH(2): mechanisms of hydrodefluorination.

Cp*(2)ZrH(2) (1) (Cp* = pentamethylcyclopentadienyl) reacts with primary, secondary, and tertiary monofluorinated aliphatic hydrocarbons to give Cp*(2)ZrHF (2) and/or Cp*(2)ZrF(2) and alkane quantitatively through a radical chain mechanism. The reactivity of monofluorinated aliphatic C-F bonds decreases in the order 1 degrees > 2 degrees > 3 degrees. The rate of hydrodefluorination was also greatly reduced with -CF(2)H and -CF(3) groups attached to the hydrocarbon. An atmosphere of H(2) is required to stabilize 1 against C-H activation of the Cp*-methyl groups and subsequent dimerization under the thermal conditions employed in these reactions. Reaction of 1 with fluorobenzene cleanly forms a mixture of Cp*(2)ZrHF, benzene, and Cp*(2)Zr(C(6)H(5))F. Detailed studies indicate that radicals are not involved in this aromatic C-F activation reaction and that dual hydrodefluorination pathways are operative. In one mechanism, hydridic attack by Cp*(2)ZrH(2) on the aromatic ring and fluoride abstraction is involved. In the second mechanism, an initial ortho C-H activation occurs, followed by beta-fluoride elimination to generate a benzyne complex, which then inserts into the zirconium-hydride bond.

Investigation of the mechanism of alkane reductive elimination and skeletal isomerization in Tp'Rh(CNneopentyl)(R)H complexes: the role of alkane complexes.

Experiments are described that provide indirect evidence for the involvement of alkane sigma-complexes in oxidative addition/reductive elimination reactions of Tp'Rh(L)(R)H complexes (Tp' = tris-3,5-dimethylpyrazolylborate, L = CNCH(2)CMe(3)). Reductive elimination rates in benzene-d(6) were determined for loss of alkane from Tp'Rh(L)(R)H, where R = methyl, ethyl, propyl, butyl, pentyl, and hexyl, to generate RH and Tp'Rh(L)(C(6)D(5))D. The isopropyl hydride complex Tp'Rh(L)(CHMe(2))H was found to rearrange to the n-propyl hydride complex Tp'Rh(L)(CH(2)CH(2)CH(3))H in an intramolecular reaction. The sec-butyl complex behaves similarly. These same reactions were studied by preparing the corresponding metal deuteride complexes, Tp'Rh(L)(R)D, and the scrambling of the deuterium label into the alpha- and omega-positions of the alkyl group monitored by (2)H NMR spectroscopy. Inverse isotope effects observed in reductive elimination are shown to be the result of an inverse equilibrium isotope effect between the alkyl hydride(deuteride) complex and the sigma-alkane complex. A kinetic model has been proposed using alkane complexes as intermediates and the selectivities available to these alkane complexes have been determined by kinetic modeling of the deuterium scrambling reactions.

Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease transgenic mice.

Inhibition of neocortical beta-amyloid (Abeta) accumulation may be essential in an effective therapeutic intervention for Alzheimer's disease (AD). Cu and Zn are enriched in Abeta deposits in AD, which are solubilized by Cu/Zn-selective chelators in vitro. Here we report a 49% decrease in brain Abeta deposition (-375 microg/g wet weight, p = 0.0001) in a blinded study of APP2576 transgenic mice treated orally for 9 weeks with clioquinol, an antibiotic and bioavailable Cu/Zn chelator. This was accompanied by a modest increase in soluble Abeta (1.45% of total cerebral Abeta); APP, synaptophysin, and GFAP levels were unaffected. General health and body weight parameters were significantly more stable in the treated animals. These results support targeting the interactions of Cu and Zn with Abeta as a novel therapy for the prevention and treatment of AD.

Characterization of copper interactions with alzheimer amyloid beta peptides: identification of an attomolar-affinity copper binding site on amyloid beta1-42.

Cu and Zn have been shown to accumulate in the brains of Alzheimer's disease patients. We have previously reported that Cu(2+) and Zn(2+) bind amyloid beta (Abeta), explaining their enrichment in plaque pathology. Here we detail the stoichiometries and binding affinities of multiple cooperative Cu(2+)-binding sites on synthetic Abeta1-40 and Abeta1-42. We have developed a ligand displacement technique (competitive metal capture analysis) that uses metal-chelator complexes to evaluate metal ion binding to Abeta, a notoriously self-aggregating peptide. This analysis indicated that there is a very-high-affinity Cu(2+)-binding site on Abeta1-42 (log K(app) = 17.2) that mediates peptide precipitation and that the tendency of this peptide to self-aggregate in aqueous solutions is due to the presence of trace Cu(2+) contamination (customarily approximately 0.1 microM). In contrast, Abeta1-40 has much lower affinity for Cu(2+) at this site (estimated log K(app) = 10.3), explaining why this peptide is less self-aggregating. The greater Cu(2+)-binding affinity of Abeta1-42 compared with Abeta1-40 is associated with significantly diminished negative cooperativity. The role of trace metal contamination in inducing Abeta precipitation was confirmed by the demonstration that Abeta peptide (10 microM) remained soluble for 5 days only in the presence of high-affinity Cu(2+)-selective chelators.

The role of lymphocytes in human dermal wound healing.

BACKGROUND: Animal experimental data indicate a requirement for functionally active T lymphocytes to allow optimal healing of dermal wounds. Little evidence exists to confirm that this is the case in humans. Lymphocyte involvement in regulation of healing is probably mediated by release of secreted cytokines/growth factors, and we hypothesize that the cytokine profile requirement will be modulated as healing progresses. OBJECTIVES: As this is likely to be reflected in lymphocyte subset changes over the course of normal healing, we investigated the immunophenotype of lymphocyte subpopulations during wound healing. METHODS: Sequential biopsies were taken over 42 days from the margin of 12 wounds healing by secondary intention after pilonidal sinus excision. Serial biopsy sections were analysed by immunohistochemistry using lymphocyte-specific monoclonal antibodies, and lymphocytes were counted microscopically. RESULTS: Within 42 days, the mean decrease in wound volume was 87.5%. This was accompanied by significant changes in the wound margin lymphocyte population. Total numbers (mean +/- SEM) of T lymphocytes decreased from 36.8 +/- 9.8 cells per field at inclusion in the study to 25.9 +/- 3.0 immediately prior to wound closure, with a concomitant increase in B lymphocytes from 1 +/- 0.4 to 9.5 +/- 3.6 cells per field. The CD4/CD8 T-lymphocyte ratio fell from an initial level of 3.6 +/- 0.3 to 2.1 +/- 0.3 (mean +/- SEM) prior to closure. CONCLUSIONS: These data indicate that human wound-associated lymphocyte populations are modulated during healing; the increase in numbers of CD8+ T-suppressor lymphocytes is in accordance with previous animal data, indicating a role for these cells in downregulating healing as the wound closes. This study also documents an associated increase in B lymphocytes and healing of human wounds, with an as yet undefined role.

Evidence for nitric oxide regulation of hamster sperm hyperactivation.

Involvement of reactive oxygen species has been implicated in the process of hyperactivation and capacitation of sperm. Nitric oxide has recently been found to function both as an intracellular and extracellular messenger, with its synthetic enzyme found in several cell types, including male and female genital tract organs. The objective of the present study was to investigate the role of nitric oxide in hamster sperm hyperactivation. Caudal epididymal contents of mature golden hamster sperm were diluted with human tubal medium supplemented with a sperm motility preparation. Inhibitors of nitric oxide synthase (nitro-L-arginine, methyl-L-arginine, and 1,3-phenylene-bis[1,2-ethenediyl]-bis-isothiourea) were added to incubation media in various doses. Alternatively, a nitric oxide donor, sodium nitroprusside, was used. The percentage motile and grade of movement were recorded at intervals encompassing the normal period of capacitation and hyperactivation. Acrosomal status was evaluated by phase contrast microscopy. Inhibition of nitric oxide synthesis did not affect motility during early capacitation but dramatically inhibited later hyperactivation. An inactive stereo-enantomere of the inhibiting drug had no effect. Addition of nitric oxide to nonstimulated sperm induced hyperactivation in a similar time course. In conclusion, nitric oxide plays a significant role in hyperactivation of hamster epididymal sperm.

A simple method for coupling aldehydes to solid support.

A new method for attaching aldehydes to solid supports has been developed employing a 2,2-bis(hydroxymethyl)propionic acid (DMPA) functionalized resin. High loading levels are obtained for both aryl and alkyl aldehydes protected as their respective acetals. Treatment of the derivatized resin with 95% TFA then cleanly affords the recovered aldehyde in high yield.

Synthesis, structure, and antiproliferative activity of selenophenfurin, an inosine 5'-monophosphate dehydrogenase inhibitor analogue of selenazofurin.

The synthesis and biological activity of selenophenfurin (5-beta-D-ribofuranosylselenophene-3-carboxamide, 1), the selenophene analogue of selenazofurin, are described. Glycosylation of ethyl selenophene-3-carboxylate (6) under stannic chloride-catalyzed conditions gave 2- and 5-glycosylated regioisomers, as a mixture of alpha- and beta-anomers, and the beta-2,5-diglycosylated derivative. Deprotected ethyl 5-beta-D-ribofuranosylselenophene-3-carboxylate (12 beta) was converted into selenophenfurin by ammonolysis. The structure of 12 beta was determined by 1H- and 13C-NMR, crystallographic, and computational studies. Selenophenfurin proved to be antiproliferative against a number of leukemia, lymphoma, and solid tumor cell lines at concentrations similar to those of selenazofurin but was more potent than the thiophene and thiazole analogues thiophenfurin and tiazofurin. Incubation of K562 cells with selenophenfurin resulted in inhibition of IMP dehydrogenase (IMPDH) (76%) and an increase in IMP pools (14.5-fold) with a concurrent decrease in GTP levels (58%). The results obtained confirm the hypothesis that the presence of heteroatoms such as S or Se in the heterocycle in position 2 with respect to the glycosidic bond is essential for both cytotoxicity and IMP dehydrogenase inhibitory activity in this type of C-nucleosides.

Signal processing and calibration of continuous-wave focused CO(2) Doppler lidars for atmospheric backscatter measurement.

Two continuous-wave (CW) focused CO(2) Doppler lidars (9.1 and 10.6 µm) were developed for airborne in situ aerosol backscatter measurements. The complex path of reliably calibrating these systems, with different signal processors, for accurate derivation of atmospheric backscatter coefficients is documented. Lidar calibration for absolute backscatter measurement for both lidars is based on range response over the lidar sample volume, not solely at focus. Both lidars were calibrated with a new technique using well-characterized aerosols as radiometric standard targets and related to conventional hard-target calibration. A digital signal processor (DSP), a surface acoustic wave spectrum analyzer, and manually tuned spectrum analyzer signal analyzers were used. The DSP signals were analyzed with an innovative method of correcting for systematic noise fluctuation; the noise statistics exhibit the chi-square distribution predicted by theory. System parametric studies and detailed calibration improved the accuracy of conversion from the measured signal-to-noise ratio to absolute backscatter. The minimum backscatter sensitivity is ~3 × 10(-12) m(-1) sr(-1) at 9.1 µm and ~9 × 10(-12) m(-1) sr(-1) at 10.6 µm. Sample measurements are shown for a flight over the remote Pacific Ocean in 1990 as part of the NASA Global Backscatter Experiment (GLOBE) survey missions, the first time to our knowledge that 9.1-10.6-µm lidar intercomparisons were made. Measurements at 9.1 µm, a potential wavelength for space-based lidar remote-sensing applications, are to our knowledge the first based on the rare isotope (12)C (18)O(2) gas.

The effect of social adversity on the fatigue syndrome, psychiatric disorders and physical recovery, following glandular fever.

Two hundred and fifty patients attending primary care with glandular fever or an upper respiratory tract infection were studied prospectively up to 6 months after onset. Of these patients 228 were interviewed with the Life Events and Difficulties Schedule and the Schedule for Affective Disorders and Schzophrenia, giving Research Diagnostic Criteria for psychiatric disorders. The experience of severe social adversity (provoking agents) had a significant association with psychiatric disorder at 2 months (odds ratio = 5.3) and 6 months (odds ratio = 5.8) after onset of infection. This association was especially significant for depressive illness (odds ratio = 9.1 at 2 months and 11.9 at 6 months). In contrast, social adversity had little association with the development of the post-infectious fatigue syndrome, or delayed physical recovery. Social adversity may be an important maintaining factor for psychiatric disorders, especially depressive illness, following acute infections.

Tuberculosis in a correctional facility.

BACKGROUND: After the identification of five suspected cases of tuberculosis (TB) in a Nassau County (New York) jail during a 3-week period, an epidemiologic investigation was begun to document the number of cases of TB infection and disease associated with the jail, the characteristics of current or former inmates with TB disease, and the factors contributing to TB transmission in the jail. METHODS: The county TB register was matched against the inmate files of the jail. Medical records from hospitals, the health department, and the jail were then reviewed. All inmates in the jail were skin tested during a mass screening. RESULTS: From January 1, 1988, through March 16, 1990, of 205 TB cases in the county, 49 (24%) were associated with the jail. Forty of the cases occurred among current or former inmates, one in a corrections officer, and eight among community contacts of inmates. The 40 inmates with TB were predominantly nonwhite (75%), unmarried (80%) men (90%), with a median age of 32 years. Twenty-three (58%) had a history of injecting drug use, and 14 (35%) were known to be seropositive for the human immunodeficiency virus. Thirty (75%) of the inmates had culture-confirmed pulmonary TB. Five (29%) of 17 Mycobacterium tuberculosis isolates had the same phage type and DNA fingerprint, which was consistent with transmission of infection within the jail. The mass screening revealed that 374 (20%) of 1855 inmates were tuberculin positive. CONCLUSIONS: Without an effective program of TB control, jails can act as reservoirs of disease for inmates and staff, and for the community into which the inmates are released.