Are all cases of paediatric essential thrombocythaemia really myeloproliferative neoplasms? Analysis of a large cohort

Sporadic essential thrombocythaemia (ET) is rare in paediatrics, and the diagnostic and clinical approach to paediatric cases cannot be simply copied from experience with adults. Here, we assessed 89 children with a clinical diagnosis of ET and found that 23 patients (258%) had a clonal disease. The JAK2 V617F mutation was identified in 14 children, 1 child had the MPL W515L mutation, and 6 had CALR mutations. The monoclonal X-chromosome inactivation pattern was seen in six patients (two with JAK2 V617F and two with CALR mutations). The other 66 patients (742%) had persistent thrombocytosis with no clonality. There were no clinical or haematological differences between the clonal and non-clonal patients. The relative proportion of ET-specific mutations in the clonal children was much the same as in adults. The higher prevalence of nonclonal cases suggests that some patients may not have myeloproliferative neoplasms, with significant implications for their treatment

Advances in tenascin-C biology

Tenascin-C is an extracellular matrix glycoprotein that is specifically and transiently expressed upon tissue injury. Upon tissue damage, tenascin-C plays a multitude of different roles that mediate both inflammatory and fibrotic processes to enable effective tissue repair. In the last decade, emerging evidence has demonstrated a vital role for tenascin-C in cardiac and arterial injury, tumor angiogenesis and metastasis, as well as in modulating stem cell behavior. Here we highlight the molecular mechanisms by which tenascin-C mediates these effects and discuss the implications of mis-regulated tenascin-C expression in driving disease pathology

PART III. ASSESSING IRRITATION: Sensory Irritation: Relation to Indoor Air Pollution

All mucosae of the body possess chemical sensitivity provided by the common chemical sense (CCS). Airborne chemicals can stimulate the CCS through the ocular, nasal, and respiratory mucosae, evoking different pungent sensations, e.g., stinging, irritation, burning, piquancy, prickling, freshness, tingling. Pungent sensations elicited in the nose differ from odor sensations in various characteristics. They are achieved at considerably higher concentrations than those necessary to elicit odor, but they increase with the concentration of the stimulus in a steeper fashion than odor. Pungent sensations from mixtures of compounds show a higher degree of addition - relative to the pungency of the individual components - than that of odor sensations. Pungency is more resistant to adaptation than odor, and, unlike it, displays considerable temporal integration with continuous stimulation. Measurement of a reflex, transitory apnea produced upon inhalation of pungent chemicals holds promise as an objective indicator of the functional status of the CCS. Results from the measurement of this reflex have agreed quantitatively with sensory data in a number of studies, showing higher common chemical sensitivity in nonsmokers - compared to smokers -, in females - compared to males -, and in young adults - compared to elderly. Research issues mentioned here include the following:      - We can rarely validate the symptoms putatively caused by indoor air pollution objectively. Without such means, we will always have the potential problem of over-reporting and embellishment. Although one person may seem more sensitive than another, the difference may lie in a greater proclivity to complain.      - Studies of anosmic persons offer a simple means to understand the functional characteristics of the nasal CCS.   Studies of chemical series in such subjects should eventually allow construction of quantitative structure-activity models for human pungency perception. The human data can be compared with relevant animal data when possible.      - The rules of additivity of pungency in mixtures need explication. Regarding the possible role of VOCs in the creation of irritation, we need to ask whether subthreshold levels add up or even amplify each other to produce noticeable irritation. Do repetitive or continuous exposures to subthreshold concentrations increase sensitivity to those substances, so that they evoke pungency when they otherwise would not? Do the various mucosae - ocular, nasal, throat - differ in their sensitivity?      - Modulation of CCS sensitivity by long-term and short-term inhalation of various agents (e.g., environmental tobacco smoke) would seem a suitable topic for further research

The antiketogenic effect of alanine in normal man: evidence for an alanine-ketone body cycle.

The effect of alanine on ketone body levels, independent of hormonal changes, in normal man has been investigated. Five normal subjects were given somatostatin infusions (200 micrograms/hour) for 3 hr. After 1 hr alanine or isotonic saline was infused for 2 hr. With saline blood beta-hydroxybutyrate and acetoacetate levels rose steadily to a peak of 0.230 plus or minus 0.053 and 0.112 plus or minus 0.023 mmole/l respectively. With alanine beta-hydroxybutyrate and acetoacetate levels plateaued at 0.099 plus or minus 0.020 and 0.055 plus or minus 0.006 mmole/l respectively. Alanine levels reached nearly 1 mmole/l but a significant effect on ketone body levels was apparent at physiologic levels (less than 0.6 mmole/l). Plasma fatty acid and glycerol levels did not change significantly. Insulin C-peptide and glucagon levels were suppressed to a similar extent in both experiments. These results support the view that alanine suppresses ketogenesis in man by a direct hepatic effect independent of insulin and glucagon. It is suggested that this forms part of a negative feedback substrate cycle between alanine and ketone bodies