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.     

CASE MANAGEMENT FOR OLDER PEOPLE AT HOME: REVIEW OF AN ‘AT RISK’ REGISTER

‘At risk’ registers have been proposed as a means of improving the case management of older disabled people living at home. An ‘at risk’ register in an outer urban area of Sydney was reviewed through a survey of 34 service providers who were attending ‘at risk’ committee meetings. The opinions of the service providers regarding the case management system were examined. The details of 108 clients of community support services placed on the register from July 1991 to June 1992 were analysed. The system effectively identified clients at risk of death and institutionalisation. It was perceived as worthwhile by service providers but changes were needed to maximise its efficiency.     

Management of bisphosphonate‐related osteonecrosis of the jaw: a literature review

Osteonecrosis of the jaw (ONJ) is a serious side effect of bisphosphonate use in patients with osteoporosis, Paget's disease, hypercalcemia of malignancy, metastatic bone disease and multiple myeloma, although recently this complication has also been reported in patients under non‐bisphosphonate medication, such as denosumab and bevacizumab. The occurrence of ONJ is higher in oncology patients treated with high‐dose iv bisphosphonates than in osteoporosis patients treated with oral bisphosphonates. Although multiple hypotheses have been proposed, the exact pathogenic mechanism of ONJ still remains unclear. As treatment protocols based on randomized controlled trials (RCTs) do not exist, we critically reviewed the existing data concerning the management of bisphosphonate‐related osteonecrosis of the jaw, including the most recent data for the use of teriparatide and hyperbaric oxygen.     

Long-term protection of hematopoiesis against the cytotoxic effects of multiple doses of nitrosourea by retrovirus-mediated expression of human O6-alkylguanine-DNA-alkyltransferase

A human O6-alkylguanine-DNA-alkyltransferase (ATase) cDNA-containing retrovirus was used to infect murine long-term primary bone marrow cultures. High levels of ATase expression were obtained, and colony- forming cells of the granulocyte-macrophage lineage from the cultures transduced with the human ATase retrovirus were three times more resistant to the alkylating agent, N-methyl-N-nitrosourea (MNU), than control cultures. Furthermore, expression of the human ATase protected long-term hematopoiesis, measured as the output of progenitor cells to the nonadherent fraction of the culture, against the cytotoxic effects of repeated exposures to MNU. These results clearly show that a human ATase cDNA-containing retrovirus can be used to infect long-term primary bone marrow cultures and that this attenuates their sensitivity to nitrosoureas.     

The management of trauma victims with head injury: a study by the national confidential enquiry into patient outcome and death

Introduction

In 2006 the National Confidential Enquiry into Patient Outcome and Death undertook a large prospective study of trauma care, which revealed several findings pertaining to the management of head injuries in a sample of 493 patients.

Methods

Case note data were collected for all trauma patients admitted to all hospitals accepting emergencies in England, Wales, Northern Ireland and the Channel Islands over a three-month period. Severely injured patients with an injury severity score (ISS) of ≥16 were included in the study. The case notes for these patients were peer reviewed by a multidisciplinary group of clinicians, who rated the overall level of care the patient received.

Results

Of the 795 patients who met the inclusion criteria for the study, 493 were admitted with a head injury. Room for improvement in the level of care was found in a substantial number of patients (265/493). Good practice was found to be highest in high volume centres. The overall head injury management was found to be satisfactory in 84% of cases (319/381).

Conclusions

This study has shown that care for trauma patients with head injury is frequently rated as less than good and suggests potential long-term remedies for the problem, including a reconfiguration of trauma services and better provision of neurocritical care facilities.     

Tracheal Stenting has Minimal Impact on Survival in Anaplastic Thyroid Carcinoma

Background

Anaplastic thyroid carcinoma (ATC) is the most aggressive form of thyroid cancer and it has an extremely poor prognosis. Rapid airway compromise is the main cause of death in patients with ATC.

Methods

The present study is based on a retrospective review of clinical data of patients with ATC treated over the last decade in a tertiary referral center.

Results

Between January 1998 and December 2010, 31 patients (13 males: 18 females) with a mean age of 74 years (range: 54–90 years) had a diagnosis of ATC made on fine-needle aspiration (n = 29) or biopsy (n = 2). Eight patients underwent total thyroidectomy and lymph node dissection, and five patients had attempted surgery but the procedure was abandoned because of inoperability. Airway compromise was clinically apparent in 11 patients. Five patients had tracheal stents inserted, with a median survival of 2 months (range: 1–36 months). In the whole cohort, 29 patients died of the disease, with a mean survival of 7 months (range: 1–36 months).

Conclusions

Survival of patients with undifferentiated thyroid cancer is severely compromised by airway obstruction. Palliation with tracheal stenting can rescue catastrophic airway obstruction but offers minimal survival benefit.     

Spatial MEG Laterality maps for language: Clinical applications in epilepsy

Functional imaging is increasingly being used to provide a noninvasive alternative to intracarotid sodium amobarbitol testing (i.e., the Wada test). Although magnetoencephalography (MEG) has shown significant potential in this regard, the resultant output is often reduced to a simplified estimate of laterality. Such estimates belie the richness of functional imaging data and consequently limit the potential value. We present a novel approach that utilizes MEG data to compute “complex laterality vectors” and consequently “laterality maps” for a given function. Language function was examined in healthy controls and in people with epilepsy. When compared with traditional laterality index (LI) approaches, the resultant maps provided critical information about the magnitude and spatial characteristics of lateralized function. Specifically, it was possible to more clearly define low LI scores resulting from strong bilateral activation, high LI scores resulting from weak unilateral activation, and most importantly, the spatial distribution of lateralized activation. We argue that the laterality concept is better presented with the inherent spatial sensitivity of activation maps, rather than being collapsed into a one‐dimensional index. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc.