Transcriptional noise and cellular heterogeneity in mammalian macrophages.

Transcriptional noise is known to play a crucial role in heterogeneity in bacteria and yeast. Mammalian macrophages are known to exhibit cell-to-cell variation in their responses to pathogens, but the source of this heterogeneity is not known. We have developed a detailed stochastic model of gene expression that takes into account scaling effects due to cell size and genome complexity. We report the results of applying this model to simulating gene expression variability in mammalian macrophages, demonstrating a possible molecular basis for heterogeneity in macrophage signalling responses. We note that the nature of predicted transcriptional noise in macrophages is different from that in yeast and bacteria. Some molecular interactions in yeast and bacteria are thought to have evolved to minimize the effects of the high-frequency noise observed in these species. Transcriptional noise in macrophages results in slow changes to gene expression levels and would not require the type of spike-filtering circuits observed in yeast and bacteria.

Evolution of 'design' principles in biochemical networks.

Computer modelling and simulation are commonly used to analyse engineered systems. Biological systems differ in that they often cannot be accurately characterised, so simulations are far from exact. Nonetheless, we argue in this paper that evolution results in recurring, dynamic organisational principles in biological systems, and that simulation can help to identify them and analyse their dynamic properties. As a specific example, we present a dynamic model of the galactose utilisation pathway in yeast, and highlight several features of the model that embody such 'design principles'.

Short-term methotrexate administration by low-dose infusion--does it influence clearance of psoriasis?

Twenty-four patients between them received 86 low-dose methotrexate infusions (given over 36 or 48 h) delivered by a Graseby syringe pump in addition to conventional topical therapy during hospital admission for treatment of severe psoriasis (either erythrodermic or severe widespread plaque-type). The average length of hospital stay, usually the time taken to achieve complete clearance, and the average relapse time in the group of patients overall showed no differences from a control group of 25 patients (matched for age and sex) having a similar severity of psoriasis treated without methotrexate. However, separation of the patients into three sub-groups (erythrodermic, severe and 'unstable' widespread plaque-type, and severe and 'stable' widespread plaque-type disease) revealed that erythrodermic patients, as expected, cleared significantly quicker when receiving methotrexate although severe and 'unstable' widespread plaque-type patients had their clearance times possibly prolonged by short-term methotrexate administration. Although methotrexate is commonly used for long-term management of patients with severe psoriasis, short-term methotrexate administered in this manner cannot necessarily be recommended for severe widespread plaque-type disease. Measurement of methotrexate levels in a further 24 patients with severe psoriasis receiving 47 low-dose infusions revealed relatively constant and predictable methotrexate concentrations. Acute side-effects of methotrexate given by the infusion method were minor and uncommon, the infusion being well tolerated by patients. However, the low-dose infusion technique did not, apparently, offer any advantage over conventional methotrexate administration.

A study of enocrine function in protein-energy malnutrition.

Serum concentration of cortisol, growth hormone, thyroxine, thyroid stimulating hormone, follicle stimulating hormone and luteinising hormone, together with triiodothyronine uptake have been measured in Nigerian children with kwashiorkor and marasmus and compared with controls. In both types of malnutrition the cortisol and growth hormone concentrations are raised, whereas those of thyroxine and thyroid stimulating hormone are lowered compared with the controls. Triiodothyronine uptake is lowered in malnutrition but there is no apparent effect on follicle stimulating hormone or luteinising hormone in this age group.

The preparation of trimethylsilyl derivatives of sodium salts of organic acids.

Evidence is presented to confirm that N,O-bis(trimethylsilyl)acetamide does not form trimethylsilyl derivatives of sodium salts of many organic acids. Further evidence suggests that such derivatives are formed when either hydroxylamine hydrochloride or trimethylchlorosilane are also present. This presents a useful technique of reducing losses of organic acids due to evaporation during lyophilisation by converting them to sodium salts and preparing volatile derivatives for gas chromatography directly from the salt residue.

Ovarian failure following abdominal irradiation in childhood.

Ovarian function was studied in 18 female patients treated for abdominal tumours during childhood. All received abdominal radiotherapy as part of their treatment and were studied between 1 and 26 years after irradiation. The serum gonadotrophins and oestradiol levels were consistent with ovarian failure in each case but there was a disproportionate elevation in serum follicle stimulating hormone (FSH) when compared to serum luteinizing hormone (LH) in 16. In 2 patients, the radiotherapeutic field extended downwards only as far as the sacral promontory. However, these 2 girls show similar evidence of ovarian failure to that in the other 16.

PIP: 18 female patients who had received treatment for abdominal lesions in childhood were studied for ovarian function. All had had abdominal surgery and irradiation and 7 had chemotherapy. The dose of irradiation ranged from 2000 to 3000 rad over 25-44 days. Serum follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels were measured by double antibody radioimmunoassay using Medical Research Council standard 69/104, and serum estradiol was measured by radioimmunoassay. 12 of the patients were 13-years-old or over and none was menstruating. The basal serum FSH and LH levels were elevated in all 12. In the 6 patients below age 13, the serum FSH concentration was raised, but the serum LH was elevated in only 3 of the above. The serum LH levels were significantly higher (p less than .02) in the patients aged over 11 years or less. The probable cause of ovarian failure in these patients is abdominal irradiation. A similar hormonal pattern to the other 16 cases was seen in the 2 patients who had received abdominal irradiation with a field extending only as far as the sacral promontory.