Circadian temperature variation in healthy aged and in Alzheimer's disease

Circadian temperature variation was monitored in healthy older adults and in health-, age-, and sex-matched Alzheimer's dementia patients. Oral and rectal temperatures were analyzed for mean level, amplitude, and phase using cosinor analyses. Mean 24-hour temperature level was not altered by dementia. A significant sex effect, however, was observed among dementia patients with women exceeding men in mean 24-hour temperatures and across daytime time periods. Cosinor-derived phase and amplitude measures were unaffected by dementia or by sex. This indicates that the primary neuronal degeneration characteristic of Alzheimer's disease in its early stages does not disable the neural pathway(s) controlling circadian temperature regulation. Some impairment in temperature homeostatic regulation may be present, however, because a greater intrasubject temperature variability was observed in Alzheimer men than in control men.     

Modulation of in vitro proliferation kinetics and primitive hematopoietic potential of individual human CD34+CD38-/lo cells in G0

Whether cytokines can modulate the fate of primitive hematopoietic progenitor cells (HPCs) through successive in vitro cell divisions has not been established. Single human marrow CD34+CD38-/lo cells in the G0 phase of cell cycle were cultured under 7 different cytokine combinations, monitored for proliferation on days 3, 5, and 7, then assayed for long-term culture-initiating cell (LTC-IC) function on day 7. LTC-IC function was then retrospectively correlated with prior number of in vitro cell divisions to determine whether maintenance of LTC-IC function after in vitro cell division is dependent on cytokine exposure. In the presence of proliferation progression signals, initial cell division was independent of cytokine stimulation, suggesting that entry of primitive HPCs into the cell cycle is a stochastic property. However, kinetics of proliferation beyond day 3 and maintenance of LTC-IC function were sensitive to cytokine stimulation, such that LTC-IC underwent an initial long cell cycle, followed by more synchronized shorter cycles varying in length depending on the cytokine combination. Nonobese diabetic/severe combined immunodeficiency (NOD/SCID) transplantation studies revealed analogous results to those obtained with LTC-ICs. These data suggest that although exit from quiescence and commitment to proliferation might be stochastic, kinetics of proliferation, and possibly fate of primitive HPCs, might be modulated by extrinsic factors.     

Aggregation and disaggregation of senile plaques in Alzheimer disease

We quantitatively analyzed, using laser scanning confocal microscopy, the three-dimensional structure of individual senile plaques in Alzheimer disease. We carried out the quantitative analysis using statistical methods to gain insights about the processes that govern Aβ peptide deposition. Our results show that plaques are complex porous structures with characteristic pore sizes. We interpret plaque morphology in the context of a new dynamical model based on competing aggregation and disaggregation processes in kinetic steady-state equilibrium with an additional diffusion process allowing Aβ deposits to diffuse over the surface of plaques.     

Patterns of Schistosoma haematobium egg distribution in the human lower urinary tract. II. Obstructive uropathy

In a series of 32 unselected consecutive autopsies of Egyptian male adults, we found a significant prevalence of schistosomal obstructive uropathy (SOU) and of precursor lesions of stenosis, fibrosis and induration of the ureters (62.5%). Lower urinary tracts with obstructive uropathy had a significantly higher total egg burden (TEB) than did lower urinary tracts with any other type of gross lesion (i.e., benign prostatic hypertrophy, other urethral outlet obstruction, or SOU precursor lesions). In turn, lower urinary tracts with any type of gross change had higher egg burdens than did tracts which appeared grossly normal. Lower urinary tracts with any type of gross lesion had significantly larger seminal vesicles than did tracts which were grossly normal. Moreover, relative weight of seminal vesicles could be correlated with the S. haematobium egg burdens in the seminal vesicles. In a series of lower urinary tracts taken from unselected consecutive American autopsies, seminal vesicle weight could be correlated with increase in prostatic weight in those tracts with prostatic hypertrophy; the same correlation could not be found in tracts without prostatic hypertrophy. Thus, seminal vesicle hypertrophy appears to correlate with obstructive uropathy in general, not solely obstructive uropathy of schistosomal origin. Digital evaluation of seminal vesicle size may be useful in the clinical evaluation of such patients.     

A comparison of the reproducibility and the sensitivity to change of visual analogue scales, Borg scales, and Likert scales in normal subjects during submaximal exercise

OBJECTIVE: To assess which subjective scale, the visual analogue scale (VAS), the Borg CR10 (Borg) scale, or the Likert scale (LS), if any, is decidedly more reproducible and sensitive to change in the assessment of symptoms. DESIGN: Prospective clinical study. SETTING: Exercise laboratory. PARTICIPANTS: Twenty-three physically active male subjects (mean +/- SD age of 30 +/- 4 years old) were recruited. INTERVENTION: Each subject attended the exercise laboratory on four occasions at intervals of 1 week. Three subjective scales were used: (1) the VAS (continuous scale); (2) the Borg scale (12 fixed points); and (3) the Likert scale (LS; 5 fixed points). Four identical submaximal tests were given (2 min at 60% maximum oxygen uptake [VO(2)max] and 6 min at 70% VO(2)max). Two tests were undertaken to assess the reproducibility of scores that were obtained with each subjective scale. Two other tests were undertaken to assess the sensitivity of each scale to a change in symptom perception: a double-blind treatment with propranolol, 80 mg, (ie, active therapy; to increase the sensation of breathlessness and general fatigue during exercise) or matching placebo. The subjective scale scores were measured at 1 min 30 s, 5 min 30 s, and 7 min 15 s of exercise. Reproducibility was defined as the proportion of total variance (ie, between-subject plus within-subject variance) explained by the between-subject variance given as a percentage. Sensitivity was defined as the effect of the active drug therapy over the variation within subjects. RESULTS: Overall, the VAS performed best in terms of reproducibility for breathlessness and general fatigue, with reproducibility coefficients as high as 78%. For sensitivity, the VAS was best for breathlessness (ratio, 2.7) and the Borg scale was most sensitive for general fatigue (ratio, 3.0). The relationships between the respective psychological and physiologic variables were reasonably stable throughout the testing procedure, with overall typical correlations of 0.73 to 0.82 CONCLUSION: This study suggests that subjective scales can reproducibly measure symptoms during steady-state exercise and can detect the effect of a drug intervention. The VAS and Borg scales appear to be the best subjective scales for this purpose.     

A common variation in deiodinase 1 gene DIO1 is associated with the relative levels of free thyroxine and triiodothyronine

INTRODUCTION: Genetic factors influence circulating thyroid hormone levels, but the common gene variants involved have not been conclusively identified. The genes encoding the iodothyronine deiodinases are good candidates because they alter the balance of thyroid hormones. We aimed to thoroughly examine the role of common variation across the three deiodinase genes in relation to thyroid hormones. METHODS: We used HapMap data to select single-nucleotide polymorphisms (SNPs) that captured a large proportion of the common genetic variation across the three deiodinase genes. We analyzed these initially in a cohort of 552 people on T(4) replacement. Suggestive findings were taken forward into three additional studies in people not on T(4) (total n = 2513) and metaanalyzed for confirmation. RESULTS: A SNP in the DIO1 gene, rs2235544, was associated with the free T(3) to free T(4) ratio with genome-wide levels of significance (P = 3.6 x 10(-13)). The C-allele of this SNP was associated with increased deiodinase 1 (D1) function with resulting increase in free T(3)/T(4) ratio and free T(3) and decrease in free T(4) and rT(3). There was no effect on serum TSH levels. None of the SNPs in the genes coding for D2 or D3 had any influence on hormone levels. CONCLUSIONS: This study provides convincing evidence that common genetic variation in DIO1 alters deiodinase function, resulting in an alteration in the balance of circulating free T(3) to free T(4). This should prove a valuable tool to assess the relative effects of circulating free T(3) vs. free T(4) on a wide range of biological parameters.     

Lipids and CVD management: towards a global consensus.

Cardiovascular disease (CVD) is currently the leading cause of morbidity and mortality worldwide and its incidence is likely to increase. Multiple risk factors contribute to CVD. Elevated LDL-cholesterol (LDL-C) and triglyceride levels, low HDL-cholesterol levels, hypertension, type 2 diabetes, and smoking are key modifiable risk factors. Such risk factors are present in 80-90% of coronary heart disease (CHD) patients. For many factors, modification can significantly reduce CVD incidence. For example, statin-induced LDL-C reductions reduce cardiovascular events by 24-37% and smoking cessation reduces CHD mortality by 36%. The need to identify and treat these risk factors has led many national and local groups to develop clinical practice guidelines for management of CVD. Although the aim of such guidelines is to provide practitioners with a framework to identify, prioritize, and manage patients, the plethora of guidelines can cause confusion. In addition, research indicates that guidelines are not being optimally implemented. This review considers these practical issues, highlights the common goals shared by many guidelines, and focuses on how these can be best achieved. It also highlights areas where the guidelines differ and discusses points to consider when selecting the most appropriate recommendation.     

Efficient T cell repertoire selection in tetraparental chimeric mice independent of thymic epithelial MHC

Nonthymic epithelial cells were compared with thymic epithelial cells for their role in T cell repertoire selection. Tetraparental aggregation chimeras were generated from T and B cell-deficient mice (H-2(d) SCID or H-2(b) Rag-/-) and thymus-deficient nude mice (H-2(b) or H-2(d)). These tetraparental mice showed primary protective CD8(+) T cell responses, after lymphocytic choriomeningitis virus infection, that were peptide-specifically restricted to either thymic or nonthymic epithelial MHC at comparable levels. These chimeras also mounted neutralizing IgG responses dependent on cognate CD4(+) T helper cell activity restricted to nonthymic epithelial MHC. Therefore, in contrast to earlier results with irradiation or thymus chimeras, these relatively undisturbed tetraparental mice reveal that the MHC of nonthymic epithelial cells efficiently selects a functional T cell repertoire.     

Melanoma cells resistant to inhibition of growth by melanocyte stimulating hormone.

Melanocyte stimulating hormone (MSH) enhances melanization but inhibits proliferation of Cloudman S91 melanoma cells in culture. We have isolated variants of these cells that can grow in the presence of MSH. The conclusions we have reached from analyses of these cells are the following: (1) Basal tyrosinase activity (monophenol monooxygenase; monophenol, dihydroxyphenylalanine:oxygen oxidoreductase, EC 1.14.18.1), i.e., the activity that is present in the absence of added MSH, is related through a common biochemical pathway to MSH-mediated control of growth. (2) MSH-inducible tyrosinase activity does not appear to be related to MSH control of growth. (3) The morphological changes that occur following the addition of MSH or cAMP are related to controls of growth and not to those of melanization.