Characterization of primitive subpopulations of normal and leukemic cells present in the blood of patients with newly diagnosed as well as established chronic myeloid leukemia

Elevated numbers of primitive Philadelphia chromosome-positive (Ph+) progenitors, including long-term culture-initiating cells (LTC-IC) as well as colony-forming cells (CFC), have been previously described in the blood of patients with chronic myeloid leukemia (CML) in chronic phase with high white blood cell counts. In the present study, which focused primarily on an analysis of circulating progenitors present in such patients at diagnosis, we discovered the frequent and occasionally exclusive presence of circulating normal (Ph-) LTC-IC, often at levels above those seen for LTC-IC in the blood of normal individuals. The presence of detectable numbers of circulating Ph- LTC-IC was independent of the fact that the same peripheral blood samples also contained elevated numbers of predominantly or exclusively Ph+ CFC. Interestingly, both the Ph+ and Ph- LTC-IC in these samples were CD34+CD71- and variably CD38- and Thy-1+, as previously documented for LTC-IC in normal marrow. Thus, neither CD38 nor Thy-1 expression was useful for discriminating between Ph+ and Ph- LTC-IC in mixed populations. Nevertheless, an association of these phenotypes with LTC- IC function did allow highly enriched (> 5% pure) suspensions of either Ph+ or Ph- LTC-IC to be obtained from selected samples of CML blood in which the initial LTC-IC population was either predominantly Ph+ or Ph- , respectively. These findings suggest that the mechanisms causing mobilization of leukemic stem cells in untreated CML patients may affect their normal counterparts. They also indicate a possible new source of autologous cells for the support of intensive therapy of CML patients. Finally, they provide a method for obtaining the most highly purified populations of Ph+ LTC-IC described to date. This method should be useful for further analyses of the molecular activities of these very primitive neoplastic cells.     

Predictors of survival in very low birth weight infants at the University Hospital of the West Indies, Jamaica

The use of prenatal steroids is an effective, simple clinical intervention that can be implemented in developing countries to help decrease mortality in very low birth weight infants.     

Community-based group exercise improves balance and reduces falls in at-risk older people: a randomised controlled trial

BACKGROUND: recent studies have found that moderate intensity exercise is an effective intervention strategy for preventing falls in older people. However, research is required to determine whether supervised group exercise programmes, conducted in community settings with at-risk older people referred by their health care practitioner are also effective in improving physical functioning and preventing falls in this group. OBJECTIVES: to determine whether participation in a weekly group exercise programme with ancillary home exercises over one year improves balance, muscle strength, reaction time, physical functioning, health status and prevents falls in at-risk community-dwelling older people. METHODS: the sample comprised 163 people aged over 65 years identified as at risk of falling using a standardised assessment screen by their general practitioner or hospital-based physiotherapist, residing in South Western Sydney, Australia. Subjects were randomised into either an exercise intervention group or a control group. Physical performance and general health measures were assessed at baseline and repeated 6-months into the trial. Falls were measured over a 12-month follow-up period using monthly postal surveys. RESULTS: at baseline both groups were well matched in their physical performance, health and activity levels. The intervention subjects attended a median of 23 exercise classes over the year, and most undertook the home exercise sessions at least weekly. At retest, the exercise group performed significantly better than the controls in three of six balance measures; postural sway on the floor with eyes open and eyes closed and coordinated stability. The groups did not differ at retest in measures of strength, reaction time and walking speed or on Short-Form 36, Physical Activity Scale for the Elderly or fear of falling scales. Within the 12-month trial period, the rate of falls in the intervention group was 40% lower than that of the control group (IRR=0.60, 95% CI 0.36-0.99). CONCLUSIONS: these findings indicate that participation in a weekly group exercise programme with ancillary home exercises can improve balance and reduce the rate of falling in at-risk community dwelling older people.     

Age-associated changes in head jerk while walking reveal altered dynamic stability in older people

Many older people have impaired dynamic stability, and up to one in three people over 65 fall each year. It is thought that older people walk more slowly to compensate for reduced capabilities. Here, we investigate whether head jerk, the first time derivative of acceleration, can further our understanding of age-associated changes in dynamic stability while walking. Gait parameters including cadence, step length, walking speed, harmonic ratios, step time variability, and jerk were measured in 43 young and 100 older people using accelerometers securely attached to the head and pelvis. Older people presented significantly (p ≤ 0.004) more mediolateral (ML) head jerk, but significantly less vertical (VT) head jerk. The dimensionless ratio, ML/VT jerk, demonstrated superior ability (89 % accuracy) in differentiating older from younger people. Principal component analysis indicated that ML/VT jerk was a distinct gait construct. ML/VT jerk was highly reliable, normally distributed, independent of stature or gender, and relatively unaffected by walking speed. In older people, reduced VT head jerk may indicate reduced gait vigour, and increased ML head jerk may indicate age-associated changes to dynamic stability. The smoother head movements evident in our younger group may be because they were more able to rely on automatic control and the dynamic (pendulum-like) stability of their systems.     

Copy number variants in patients with short stature

Height is a highly heritable and classic polygenic trait. Recent genome-wide association studies (GWAS) have revealed that at least 180 genetic variants influence adult height. However, these variants explain only about 10% of the phenotypic variation in height. Genetic analysis of short individuals can lead to the discovery of novel rare gene defects with a large effect on growth. In an effort to identify novel genes associated with short stature, genome-wide analysis for copy number variants (CNVs), using single-nucleotide polymorphism arrays, in 162 patients (149 families) with short stature was performed. Segregation analysis was performed if possible, and genes in CNVs were compared with information from GWAS, gene expression in rodents'' growth plates and published information. CNVs were detected in 40 families. In six families, a known cause of short stature was found (SHOX deletion or duplication, IGF1R deletion), in two combined with a de novo potentially pathogenic CNV. Thirty-three families had one or more potentially pathogenic CNVs (n=40). In 24 of these families, segregation analysis could be performed, identifying three de novo CNVs and nine CNVs segregating with short stature. Four were located near loci associated with height in GWAS (ADAMTS17, TULP4, PRKG2/BMP3 and PAPPA). Besides six CNVs known to be causative for short stature, 40 CNVs with possible pathogenicity were identified. Segregation studies and bioinformatics analysis suggested various potential candidate genes.     

A 3-base pair deletion,c.9711_9713del,in DMD results in intellectual disability without muscular dystrophy

We have identified a deletion of 3 base pairs in the dystrophin gene (DMD), c.9711_9713del, in a family with nonspecific X-linked intellectual disability (ID) by sequencing of the exons of 86 known X-linked ID genes. This in-frame deletion results in the deletion of a single-amino-acid residue, Leu3238, in the brain-specific isoform Dp71 of dystrophin. Linkage analysis supported causality as the mutation was present in the 7.6 cM linkage interval on Xp22.11–Xp21.1 with a maximum positive LOD score of 2.41 (MRX85 locus). Molecular modeling predicts that the p.(Leu3238del) deletion results in the destabilization of the C-terminal domain of dystrophin and hence reduces the ability to interact with β-dystroglycan. Correspondingly, Dp71 protein levels in lymphoblastoid cells from the index patient are 6.7-fold lower than those in control cell lines (P=0.08). Subsequent determination of the creatine kinase levels in blood of the index patient showed a mild but significant elevation in serum creatine kinase, which is in line with impaired dystrophin function. In conclusion, we have identified the first DMD mutation in Dp71 that results in ID without muscular dystrophy.