Estimation of the number of hematopoietic precursor cells during fetal mouse development by covariance analysis

Differentiation of hematopoietic precursor cells results in the formation of clonally related descendent cells. Using the mosaic expression of beta-galactosidase in female mouse fetuses heterozygous for an X-linked lacZ transgene, we analyzed the clonal relationship of the hematopoietic progeny. The proportion of beta-galactosidase positive cells for different T- and B-lymphoid and myeloid cell populations was determined at different stages of fetal development. We found excellent correlations of the proportion of beta-galactosidase expressing cells for all hematopoietic lineages confirming that they share a common ancestry. Therefore, it was possible to estimate the number of common precursor cells (PC) based on binomial distribution and covariance analysis of pairs of different hematopoietic cell populations. Our results obtained from hematopoietic cells at 15.5 to 18.5 days of gestation indicated the presence of 15 to 18 lymphoid and 18 to 22 myeloid/lymphoid specific precursor cells. Statistical analysis of the precursor cell numbers showed a trend of increasing numbers that was highly significant. The precursor cell number was inversely related to maturity of the cell populations analyzed; ie, the lowest number of lymphoid and lymphoid/myeloid precursors was calculated when the most mature CD3+ T-cell population was used for comparison. Determination of PC numbers can therefore be used to assess the relative maturity and developmental potential of individual cell populations.     

MISDIAGNOSES IN A CHINESE NARCOLEPTIC PATIENT WITH DELAYED ONSET OF CATAPLEXY

Narcolepsy is a chronic condition that usually afflicts the patient for decades. It is more common than is generally appreciated. However, it is likely to be misdiagnosed because doctors are unfamiliar with some of the symptoms. Its significant socioeconomic impact on the patient's quality of life warrants prompt medical attention.     

Effects of using a computer in a doctor's office on patient attitudes toward using computerized prompts in routine care

BACKGROUND: We undertook this investigation to understand the effect of using a computer in a primary care setting on attitudes toward using computers to improve health services delivery. METHODS: In this analysis, we compared the acceptability data from the group of primary care patients from 10 community-based practices who did not use a computer program, and answered the questions hypothetically, with data from a group of patients who actually used a program such as one proposed in the survey taken by the first group of patients. Attitudes toward three uses of the program, screening, counseling and changing treatments were measured, as well as attitudes toward specific aspects of the program, such as security. RESULTS: The great majority of patients who used the program believed that the program was not too long (80.1%), was easy to use (82.3%) and that the questions were not hard to answer (75.7%). Also, on average only 20% of patients had concerns about the privacy and confidentiality of using the program. Patients who had used the computer program were significantly less likely to favor its use for screening [odds ratio (OR)=0.09, 95% confidence interval (CI)=0.04-0.19], counseling [OR=0.13 (95% CI=0.05-0.31)] and changing treatments for chronic conditions, such as hypertension [OR=0.12 (95% CI=0.07-0.23)]. Patients who felt that the computer took too long to use were less likely to favor its use for each of the three uses. CONCLUSIONS: Despite acceptability ratings that were high and consistent with ratings observed in other studies, exposure to the program significantly diminished support for using it in routine care. These findings highlight the need for measuring overall program acceptability in the context of a realistic use scenario and for correlating overall acceptability with acceptability of individual program components and attitudes, as a means for identifying opportunities for program improvement.     

Generalized CNS disease and massive GM1-ganglioside accumulation in mice defective in lysosomal acid beta-galactosidase

Human GM1-gangliosidosis is caused by a genetic deficiency of lysosomal acid beta-galactosidase (beta-gal). The disease manifests itself either as an infantile, juvenile or adult form and is primarily a neurological disorder with progressive brain dysfunction. A mouse model lacking a functional beta-gal gene has been generated by homologous recombination and embryonic stem cell technology. Tissues from affected mice are devoid of beta-gal mRNA and totally deficient in GM1-ganglioside- hydrolyzing capacity. Storage material was already conspicuous in the brain at 3 weeks. By 5 weeks, extensive storage of periodic acid Schiff- positive material was observed in neurons throughout the brain and spinal cord. Consistent with the neuropathology, abnormal accumulation of GM1-ganglioside in the brain progressed from twice to almost five times the normal amount during the period from 3 weeks to 3.5 months. Despite the accumulation of brain GM1-ganglioside at the level equal to or exceeding that seen in gravely ill human patients, these mice show no overt clinical phenotype up to 4-5 months. However, tremor, ataxia and abnormal gait become apparent in older mice. Thus, the beta-gal- deficient mice appear to mimic closely the pathological, biochemical and clinical abnormalities of the human disease.      

What can we learn from the recent blood glucose lowering megatrials?

In the past two decades, we have acquired an enormous amount of knowledge regarding the epidemiology, diagnosis, pathophysiology and treatment of type 2 diabetes and its comorbidities. In addition to the earlier landmark blood lipid and blood pressure lowering trials, the latest blood glucose lowering megatrials represent the zenith of this global effort to prevent and control diabetes, and its devastating consequences. Although many of these latter trials have yielded negative results and have shown the narrow risk‐benefit ratio of intensive treatment in patients with advanced disease, the exceedingly low event rates in these high‐risk patients who were carefully monitored and intensively managed made possible in these clinical trial settings have not been emphasized enough. The heterogeneity of the clinical outcomes in these studies further highlight the complexity of diabetes, which is more than managing a disease, but the multiple needs of a patient with multisystem dysfunction. In the final analysis, what transpires from these megatrials is the need to translate the key components of these studies, namely, protocol, team, documentation and monitoring, into our daily clinical practice to enable the care team to stratify risk, define needs, individualize therapy, monitor progress and reinforce compliance in order to achieve positive outcomes. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00063.x, 2010)