Objectives

In the UK, the treatment of patients with mycosis fungoides using total skin electron (TSE) beam therapy is undertaken using a number of different irradiation techniques. As part of a review of these techniques, a comparative set of measurements would be useful to determine how the techniques differ in terms of dose distribution. A dose penetration intercomparison method that could be used as part of such a study is presented here.

Methods

The dose penetrations for six treatment techniques currently or recently used in four centres in the UK were measured. The variation of dose with skin depth was measured in a WT1 solid water mid-torso phantom. The phantom is portable and suitable to be used in all the techniques. It is designed to hold four small radiochromic film dosemeters to investigate the variation in dose around the mid-torso. For each treatment technique, the phantom was irradiated using the clinical set-up.

Results

The phantom performed well and was able to measure dose penetration and the uniformity of penetration for several treatment techniques.

Conclusion

These preliminary results demonstrate that there is some variation in dose distribution between different TSE treatment techniques and that the phantom could be used in a more comprehensive intercomparison. The results are not intended to demonstrate comprehensively the range of penetration that can be achieved in clinical practice as, for one of the treatment techniques, the penetration is customised for the extent of the disease.

Cystic Fibrosis (CF) is a genetic disease characterised by a deficit in epithelial Cl− secretion which in the lung leads to airway dehydration and a reduced Airway Surface Liquid (ASL) height. The endogenous lipoxin LXA4 is a member of the newly identified eicosanoids playing a key role in ending the inflammatory process. Levels of LXA4 are reported to be decreased in the airways of patients with CF. We have previously shown that in normal human bronchial epithelial cells, LXA4 produced a rapid and transient increase in intracellular Ca2+. We have investigated, the effect of LXA4 on Cl− secretion and the functional consequences on ASL generation in bronchial epithelial cells obtained from CF and non-CF patient biopsies and in bronchial epithelial cell lines. We found that LXA4 stimulated a rapid intracellular Ca2+ increase in all of the different CF bronchial epithelial cells tested. In non-CF and CF bronchial epithelia, LXA4 stimulated whole-cell Cl− currents which were inhibited by NPPB (calcium-activated Cl− channel inhibitor), BAPTA-AM (chelator of intracellular Ca2+) but not by CFTRinh-172 (CFTR inhibitor). We found, using confocal imaging, that LXA4 increased the ASL height in non-CF and in CF airway bronchial epithelia. The LXA4 effect on ASL height was sensitive to bumetanide, an inhibitor of transepithelial Cl− secretion. The LXA4 stimulation of intracellular Ca2+, whole-cell Cl− currents, conductances and ASL height were inhibited by Boc-2, a specific antagonist of the ALX/FPR2 receptor. Our results provide, for the first time, evidence for a novel role of LXA4 in the stimulation of intracellular Ca2+ signalling leading to Ca2+-activated Cl− secretion and enhanced ASL height in non-CF and CF bronchial epithelia.

Recent improvements in health and an increased standard of living in Oman have led to a reduction in environment-related and infectious diseases. Now the country is experiencing an epidemiological transition characterised by a baby boom, youth bulge and increasing longevity. Common wisdom would therefore suggest that Omanis will suffer less ill health. However, a survey of literature suggests that chronic non-communicable diseases are unexpectedly becoming common. This is possibly fuelled by some socio-cultural patterns specific to Oman, as well as the shortcomings of the ‘miracle’ of health and rapid modernisation. Unfortunately, such new diseases do not spare younger people; a proportion of them will need the type of care usually reserved for the elderly. In addition, due to their pervasive and refractory nature, these chronic non-communicable diseases seem impervious to the prevailing ‘cure-oriented’ health care system. This situation therefore calls for a paradigm shift: a health care system that goes beyond a traditional cure-orientation to provide care services for the chronically sick of all ages.

Pleural fluid analysis yields important diagnostic information in pleural effusions in combination with clinical history, examination, and radiology. For more than 30 years, the initial and most pragmatic step in this process is to determine whether the fluid is a transudate or an exudate. Light's criteria remain the most robust in separating the transudate-exudate classification which dictates further investigations or management. Recent studies have led to the evaluation and implementation of a number of additional fluid analyses that may improve the diagnostic utility of this method. This paper discusses the current practice and future direction of pleural fluid analysis in determining the aetiology of a pleural effusion. While this has been performed for a few decades, a number of other pleural characteristics are becoming available suggesting that this diagnostic tool is indeed a work in progress.

Vancomycin is a glycopeptide antibiotic which is commonly used to treat methicillin-resistant staphylococcal infections. It is commonly used in pediatric oncology wards for children with febrile neutropenia. We report a very rare side effect of vancomycin induced myopathy in a child with acute lymphoblastic leukemia. To the best of our knowledge, this is the first case reported from Oman.

Sigmoid volvulus is a common cause of large bowel obstruction in western countries and Africa. It accounts for 25% of the patients admitted to the hospital for large bowel obstruction. The acute management of sigmoid volvulus is sigmoidoscopic decompression. However, the recurrence rate can be as high as 60% in some series. Recurrent sigmoid volvulus in elderly patients who are not fit for definitive surgery is difficult to manage. The percutaneous endoscopic placement of two percutaneous endoscopic colostomy tube placement is a simple and relatively safe procedure. The two tubes should be left open to act as vents for the colon from over-distending. In our opinion, this aspect is key to its success as it keeps the sigmoid colon deflated until adhesions form between the colon and the abdominal wall.

The cytoplasmic protein tyrosine kinase Syk has two amino-terminal SH2 domains that engage phosphorylated immunoreceptor tyrosine-based activation motifs in the signaling subunits of immunoreceptors. Syk, in conjunction with Src family kinases, has been implicated in immunoreceptor signaling in both lymphoid and myeloid cells. We have investigated the role of Syk in Fcγ receptor (FcγR)-dependent and -independent responses in bone marrow-derived macrophages and neutrophils by using mouse radiation chimeras reconstituted with fetal liver cells from Syk−/− embryos. Chimeric mice developed an abdominal hemorrhage starting 2 to 3 months after transplantation that was ultimately lethal. Syk-deficient neutrophils derived from the bone marrow were incapable of generating reactive oxygen intermediates in response to FcγR engagement but responded normally to tetradecanoyl phorbol acetate stimulation. Syk-deficient macrophages were defective in phagocytosis induced by FcγR but showed normal phagocytosis in response to complement. The tyrosine phosphorylation of multiple cellular polypeptides, including the FcγR γ chain, as well as Erk2 activation, was compromised in Syk−/− macrophages after FcγR stimulation. In contrast, the induction of nitric oxide synthase in macrophages stimulated with lipopolysaccharide and gamma interferon was not dependent on Syk. Surprisingly, Syk-deficient macrophages were impaired in the ability to survive or proliferate on plastic petri dishes. Taken together, these results suggest that Syk has specific physiological roles in signaling from FcγRs in neutrophils and macrophages and raise the possibility that in vivo, Syk is involved in signaling events other than those mediated by immunoreceptors.

Cellular growth control requires the coordination and integration of multiple signaling pathways which are likely to be activated concomitantly. Mitogenic signaling initiated by thyrotropin (TSH) in thyroid cells seems to require two distinct signaling pathways, a cyclic AMP (cAMP)-dependent signaling pathway and a Ras-dependent pathway. This is a paradox, since activated cAMP-dependent protein kinase disrupts Ras-dependent signaling induced by growth factors such as epidermal growth factor and platelet-derived growth factor. This inhibition may occur by preventing Raf-1 protein kinase from binding to Ras, an event thought to be necessary for the activation of Raf-1 and the subsequent activation of the mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinases (MEKs) and MAP kinase (MAPK)/ERKs. Here we report that serum-stimulated hyperphosphorylation of Raf-1 was inhibited by TSH treatment of Wistar rat thyroid cells, indicating that in this cell line, as in other cell types, increases in intracellular cAMP levels inhibit activation of downstream kinases targeted by Ras. Ras-stimulated expression of genes containing AP-1 promoter elements was similarly inhibited by TSH. On the other hand, stimulation of thyroid cells with TSH resulted in stimulation of DNA synthesis which was Ras dependent but both Raf-1 and MEK independent. We also show that Ras-stimulated DNA synthesis required the use of this kinase cascade in untreated quiescent cells but not in TSH-treated cells. These data suggest that in TSH-treated thyroid cells, Ras might be able to signal through effectors other than the well-studied cytoplasmic kinase cascade.

The regulation of the GTPase activity of the Ras proteins is thought to be a key element of signal transduction. Ras proteins have intrinsic GTPase activity and are active in signal transduction when bound to GTP but not following hydrolysis of GTP to GDP. Three cellular Ras GTPase-activating proteins (Ras-gaps) which increase the GTPase activity of wild-type (wt) Ras but not activated Ras in vitro have been identified: type I and type II GAP and type I NF1. Mutations of wt Ras resulting in lowered intrinsic GTPase activity or loss of response to cellular Ras-gap proteins are thought to be the primary reason for the transforming properties of the Ras proteins. In vitro assays show type I and type II GAP and the GAP-related domain of type I NF1 to have similar biochemical properties with respect to activation of the wt Ras GTPase, and it appears as though both type I GAP and NF1 can modulate the GTPase function of Ras in cells. Here we report the assembling of a full-length coding clone for type I NF1 and the biological effects of microinjection of Ras and Ras-gap proteins into fibroblasts. We have found that type I GAP, type II GAP, and type I NF1 show markedly different biological activities in vivo. Coinjection of type I GAP or type I NF1, but not type II GAP, with wt Ras abolished the ability of wt Ras to induce expression from an AP-1-controlled reporter gene. We also found that serum-stimulated DNA synthesis was reduced by prior injection of cells with type I GAP but not type II GAP or type I NF1. These results suggest that type I GAP, type II GAP, and type I NF1 may have different activities in vivo and support the hypothesis that while type I forms of GAP and NF1 may act as negative regulators of wt Ras, they may do so with differential efficiencies.

Images