Marilyn M. Li

Dexamethasone in salbutamol-treated inpatients with acute bronchiolitis: a randomized, controlled trial.

OBJECTIVEnTo determine the clinical benefit of oral dexamethasone in children admitted to the hospital with bronchiolitis treated with nebulized salbutamol.nnnMETHODSnRandomized, double-blind, placebo-controlled trial in the inpatient wards of a pediatric tertiary care hospital. The participants, children aged 6 weeks to 15 months, admitted with first-time wheezing, were eligible if their oxygen saturation was less than 95% on admission to the hospital and their Respiratory Distress Assessment Instrument (RDAI) score was greater than 6. Patients were excluded if they had any one of the following: an underlying disease that might affect cardiopulmonary status, asthma, recent treatment with steroids (within 2 weeks), or any history of adverse reaction to steroids. Patients were randomly assigned to receive either orally administered dexamethasone with 0.5 mg/kg as the first dose and 0.3 mg/kg for the next 2 mornings, or an equal volume of an orally administered placebo with an identical appearance. All patients received nebulized salbutamol at 0.15 mg/kg every 4 hours for the first 24 hours. The primary outcome measure was the change from baseline in the RDAI score at 24 hours. Secondary outcome measures were oxygen saturation, respiratory rate, RDAI measurement twice daily for the first 4 days, and the length of hospitalization.nnnRESULTSnAt 24 hours the mean change (SD) from baseline in the RDAI score was 1.6 (2.3) in the placebo group (n = 28) and 1.4 (2.0) in the dexamethasone group (n = 33; p = 0.74). There were no significant differences between the two groups in change in oxygen saturation, respiratory rate, and RDAI score at any assessment period. The median length of stay (95% confidence interval) for the placebo group was 48 (42, 54) hours compared with 57 (38, 76) hours in the dexamethasone group (p = 0.19).nnnCONCLUSIONSnOral dexamethasone therapy does not affect the clinical course of children hospitalized with bronchiolitis and therefore cannot be recommended in this clinical situation.

Genome-Wide Oligonucleotide Array Comparative Genomic Hybridization for Etiological Diagnosis of Mental Retardation: A Multicenter Experience of 1499 Clinical Cases

To assess the clinical utility of genome-wide oligonucleotide arrays in diagnosis of mental retardation and to address issues relating to interpretation of copy number changes (CNCs), we collected results on a total of 1499 proband patients from five academic diagnostic laboratories where the same 44K array platform has been used. Three of the five laboratories achieved a diagnostic yield of 14% and the other two had a yield of 11 and 7%, respectively. Approximately 80% of the abnormal cases had a single segment deletion or duplication, whereas the remaining 20% had a compound genomic imbalance involving two or more DNA segments. Deletion of 16p11.2 is a common microdeletion syndrome associated with mental retardation. We classified pathogenic CNCs into six groups according to the structural changes. Our data have demonstrated that the 44K platform provides a reasonable resolution for clinical use and a size of 300 kb can be used as a practical cutoff for further investigations of the clinical relevance of a CNC detected with this platform. We have discussed in depth the issues associated with the clinical use of array CGH and provided guidance for interpretation, reporting, and counseling of test results based on our experience.

Clinical Application of Microarray-Based Molecular Cytogenetics: An Emerging New Era of Genomic Medicine

G eneticists have long recognized the role of genomic imbalances (eg, deletions or duplications of chromosomal material) in the pathogenesis of human disorders. Numerous methods have been developed to detect genomic alterations since the discovery of the correct chromosome number in human cells in 1956. In 1959, Lejeune et al discovered that an extra copy of chromosome 21 (trisomy 21) caused Down syndrome, the first evidence linking genomic imbalances with human disease. Soon after, new clinical syndromes were delineated on the basis of the identification of multiple patients with the same cytogenetic abnormality, such as trisomy 13 in Patau syndrome and trisomy 18 in Edwards syndrome. The identification of the Philadelphia chromosome, which was later showed to be caused by a translocation between chromosomes 9 and 22, and its association with chronic myelocytic leukemia in 1960 marked the beginning of cancer cytogenetics. The invention of chromosome banding techniques in 1970 led to the discovery of numerous structural chromosome aberrations and their association with human diseases. By optimizing culture conditions to arrest cellular division at prometaphase, high-resolution banding could detect chromosomal changes to a resolution of 3 to 5 Mb. The next breakthrough in cytogenetics was the development of fluorescent in situ hybridization (FISH) technology, which laid the foundation for molecular cytogenetics. The technology not only allows the detection of small genomic alterations of 50 Kb to 100 Kb, but also permits the direct visualization of these alterations in uncultured cells. These features made FISH testing ideal not only in detecting microdeletion/microduplication syndromes, but also for prenatal aneuploidy screens, where a fast turnaround time is highly desirable, and for cancer genetics studies, where metaphase chromosomes may not be obtainable. Although FISH allows the detection of genomic imbalances with great

Imatinib (STI571) Provides Only Limited Selectivity for CML Cells and Treatment Might Be Complicated by Silent BCR-ABL Genes

Very promising results have been obtained in clinical trials on chronic-phase chronic myeloid leukemia (CP-CML) patients treated with imatinib mesylate (IM; Gleevec®, STI571), a BCR-ABL tyrosine kinase inhibitor. However, we found that IM caused considerable inhibition of normal hematopoietic progenitor cells upon treating control bone marrow (BM) cultures. In vitro IM treatment gave a decrease in the yield and size of colonies from BM of untreated CP-CML patients that was only two to three times that from the normal samples. Moreover, about 30% of myeloid progenitors (CFU-GM) from CML BM still formed colonies in the presence of IM, most of which had BCR-ABL RNA. About half of these treated colonies also displayed methylation of the internal ABL Pa promoter, a CML-specific epigenetic alteration, which was used in this study as a marker for BCR-ABL translocation-containing cells. However, ~5-8% of the treated or the untreated CML BM-derived colonies had no detectable BCR-ABL RNA by two or three rounds of RT-PCR despite being positive for the internal standard RNA and displaying hallmarks of CML, either t(9;22)(q34;q11) or ABL Pa methylation. Our results indicate that IM is only partially specific for CML progenitor cells compared to normal hematopoietic progenitor cells and suggest that some CML cells may have a silent BCR-ABL oncogene that could interfere with therapy.

Paradoxical postural cerebrospinal fluid leak–induced headache: report of two cases

We report two patients with a history of dural puncture who developed paradoxical postural cerebrospinal fluid leak-induced headache. The patients headache worsened when they were in the recumbent position, and it improved when they were placed upright. Both patients had a history of migraine headache. The patients were successfully treated with autologous epidural blood patch. The mechanism for PPCLH is to be elucidated.

Trisomy 4 as the sole cytogenetic abnormality in a Waldenström macroglobulinemia.

We report a case of Waldenström macroglobulinemia with trisomy 4 as the sole cytogenetic abnormality. Trisomy 4 has been reported previously in Waldenström macroglobulinemia, but only in conjunction with multiple chromosomal aberrations. Trisomy 4 has been reported in other hematologic malignancies including acute myeloid and lymphoid leukemias.

Clinical cytogenetics and molecular cytogenetics

The short report will be focused on helping our students to understand commonly used conventional and cutting edge cytogenetic techniques and their clinical applications, the advances and drawbacks of each technique, and how to pick the right test(s) for a specific patient in order to achieve a proper diagnosis efficiently and economically.

Fluorescence in situ hybridization using an old world monkey Y chromosome specific probe combined with immunofluorescence staining on rhesus monkey tissues.

To date, there is no commercially available Y chromosome probe that can be used for fluorescence in situ hybridization (FISH) for the male rhesus monkey. We have recently generated a probe for FISH with high specificity to the short arm of the rhesus monkey Y chromosome. In this study, we further describe a method that keeps the integrity of tissue-specific antigenic structures for immunofluorescence staining subsequent to FISH on paraffin-embedded rhesus monkey tissues. We have examined this technique in combination with an epithelial cell—specific marker, cytokeratin 8/18 (CK8/18), on various tissues, including jejunum, liver, kidney, and pancreas. CK8/18 and Y chromosome signals were distinctly seen simultaneously on epithelial cells from the same tissue section from male but not female monkeys. These studies indicate that our FISH immunofluorescence technique can be reliably used to identify and phenotype male cells in paraffin-embedded rhesus monkey tissues.

Human cancer genetics

The short report will be focused on the genetic basis and possible mechanisms of tumorigenesis, common types of cancer, the importance of genetic diagnosis of cancer, and the methodology of cancer genetic diagnosis. They will also review presymptomatic testing of hereditary cancers, and the application of expression profiling to identify patients likely to benefit from particular therapeutic approaches.