Identification of an oncogenic form of the thrombopoietin receptor MPL using retrovirus-mediated gene transfer

Thrombopoietin and its receptor (MPL) are important regulators of megakaryopoiesis. We have identified an activating mutation of MPL using a combination of a retrovirus-mediated gene transfer and polymerase chain reaction-driven random mutagenesis. This point mutation causes a single amino acid substitution from Ser498 to Asn498 in the transmembrane region and abrogates factor-dependency of all interleukin-3-dependent cell lines tested. Murine interleukin-3- dependent Ba/F3 cells expressing the mutated but not the normal form of MPL were tumorigenic when transduced into syngeneic mice. Analysis of intracellular signaling pathways indicated that the mutant MPL protein constitutively activated two distinct signaling pathways, SHC-Raf-MAPK and JAK2-STAT3/STAT5.     

Presence of bile in the oesophagus is associated with less effective oesophageal motility

BACKGROUND/AIMS: Reflux of bile to the oesophagus has been shown to be of importance in the development of gastro-oesophageal reflux disease. This study aims to assess oesophageal motility patterns in relation to acid and bile reflux to the oesophagus. METHODS: Forty-nine subjects with and without reflux disease underwent 24-hour ambulatory recordings of oesophageal pH, bile and 3-channel manometry. Gastroscopy was performed to assess severity of oesophagitis. The percentage of effective peristaltic contractions (oesophageal contractions with a peristaltic pattern and a pressure >30 mm Hg) were correlated to the degree of acid and bile reflux. Ten subjects were re-evaluated within 2 years post-fundoplication. RESULTS: Acid and bile reflux were associated with fewer effective contractions (R(2) = 0.07, p = 0.06 and R(2) = 0.21, p = 0.008, respectively). However, in a multivariate model including acid, bile, age and gender dependency, only bile could show a systematic effect on the variation in percentage of effective peristaltic contractions (R(2) = 0.22, p = 0.001). One year after laparoscopic fundoplication, 24-hour oesophageal motility was unchanged. CONCLUSION: Reflux of duodenal juice to the oesophagus is associated with less effective oesophageal motility, which in turn can perpetuate the disease by less effective oesophageal clearance of bile and acid. The reduced oesophageal motility is not reversed by fundoplication.     

Elevated platelet count and megathrombocyte number in sickle cell anemia.

Eight adult patients with sickle cell anemia were followed over a 6-mo period. During this time all patients had elevated plateletcounts, 1.7-fold (mean, 438,398 +/- 86,223), and megathrombocyte numbers, 2.3-fold (mean, 79,535 +/- 38,907), during asymptomatic periods. These data are interpreted as suggesting that the elevated platelets and megathrombocytes in asymptomatic sickle cell patients result from lack of splenic sequestration. During three crises in two patients, both megathrombocyte number and platelet count fell significantly. It is speculated that platelets may be associated with the pathology in this disease. Platelet function studies performed during crises, therefore, must take into account the number of megathrombocytes.     

TEMPORALLY GRADED SEMANTIC MEMORY LOSS IN ALZHEIMER'S DISEASE: CROSS-SECTIONAL AND LONGITUDINAL STUDIES

Abstract

Semantic knowledge of famous names and words that entered popular North American culture at different times in the 20th century was examined in 16 patients with mild-to-moderate Alzheimer's disease (AD), 12 of whom were re-tested 1 year later. All patients showed evidence of temporally graded memory loss, with names and words from the remote past being relatively better preserved than recent names and words. There was considerable between-patient variability with respect to severity of semantic impairment. Most patients exhibited losses extending back 30-40 years; however, two mildly impaired (MMSE >28) patients showed deficits restricted to the last 10-15 years. At the 1-year follow-up, patients not only exhibited more severe deficits overall, but the temporally graded period of loss extended further back in time, suggesting that this deficit reflects a loss of previously intact knowledge and not merely faulty encoding or lack of exposure to the material. The extensive period of graded semantic loss exhibited by most patients contrasts with the temporally limited retrograde semantic loss typical of medial temporal lobe amnesia. We propose that short periods of temporally graded semantic memory loss can be explained by damage to medial temporal structures, but that extensive periods of graded loss occur only with additional damage to neocortical tissue. This pattern contrasts with that of autobiographical memory loss, which is often ungraded and extends for the person's entire lifetime, even when damage is restricted to the medial temporal lobes.     

The prediction of body fatness by BMI and skinfold thicknesses among children and adolescents

Background: Although the body mass index (BMI, kg?m^?2) is widely used as a measure of adiposity, it is a measure of excess weight, rather than excess body fat. It has been suggested that skinfold thicknesses be measured among overweight children to confirm the presence of excess adiposity.

Objective: The present study examined the additional information provided by skinfold thicknesses on body fatness, beyond that conveyed by BMI-for-age, among healthy 5- to 18-years old (n?=?1196).

Methods and procedures: Total body dual-energy X-ray absorptiometry (DXA) provided estimates of % body fat, and the sum of two skinfolds (triceps and subscapular) was used as an indicator of the overall skinfold thickness.

Results: As assessed by the multiple R²s and the residuals of various regression models, information on the skinfold sum significantly (?p?<?0.001) improved the prediction of body fatness beyond that obtained with BMI-for-age. For example, the use of the skinfold sum, in addition to BMI-for-age, increased the multiple R²s for predicting % body fat from 0.81 to 0.90 (boys), and from 0.82 to 0.89 (girls). The use of the skinfold sum also reduced the overall prediction errors (absolute value of the residuals) for % body fat by 20–30%, but these reductions varied substantially by BMI-for-age. Among overweight children, defined by a BMI-for-age ≥95th percentile, the skinfold sum reduced the predication errors for % body fat by only 7–9%.

Conclusions: Although skinfold thicknesses, when used in addition to BMI-for-age, can substantially improve the estimation of body fatness, the improvement among overweight children is small.