New agents in the Treatment of Myeloma Bone Disease

Patients with multiple myeloma develop a devastating bone disease driven by the uncoupling of bone remodelling, excess osteoclastic bone resorption and diminished osteoblastic bone formation. The bone phenotype is typified by focal osteolytic lesions leading to pathological fractures, hypercalcaemia and other catastrophic bone events such as spinal cord compression. This causes bone pain, impaired functional status, decreased quality of life and increased mortality. Early in the disease, malignant plasma cells occupy a niche environment that encompasses their interaction with other key cellular components of the bone marrow microenvironment. Through these interactions, osteoclast-activating factors and osteoblast inhibitory factors are produced, which together uncouple the dynamic process of bone remodelling, leading to net bone loss and focal osteolytic lesions. Current management includes antiresorptive therapies, i.e. bisphosphonates, palliative support and orthopaedic interventions. Bisphosphonates are the mainstay of treatment for myeloma bone disease (MBD), but are only partially effective and do have some significant disadvantages; for example, they do not lead to the repair of existing bone destruction. Thus, newer agents to prevent bone destruction and also promote bone formation and repair existing lesions are warranted. This review summarises novel ways that MBD is being therapeutically targeted

Outcome After Occlusion of Infrainguinal Bypasses in the Dutch BOA Study: Comparison of Amputation Rate in Venous and Prosthetic Grafts

AbstractObjectiveTo compare the consequences of occlusion of infrainguinal venous and prosthetic grafts.MethodsIn total, 2690 patients were included in the Dutch BOA study, a multicenter randomised trial that compared the effectiveness of oral anticoagulants with aspirin in the prevention of infrainguinal bypass graft occlusion. Two thousand four hundred and four patients received a femoropopliteal or femorodistal bypass with a venous (64%) or prosthetic (36%) graft. The incidence of occlusion and amputation was calculated according to graft material and the incidence of amputation after occlusion was compared with Cox regression to adjust for differences in prognostic factors.ResultsThe indication for operation was claudication in 51%, rest pain in 20% and tissue loss in 28% of patients. The mean follow up was 21 months.After venous bypass grafting 171 (15%) femoropopliteal and 96 (24%) femorodistal grafts occluded. After prosthetic bypass grafting 234 (30%) femoropopliteal and 25 (38%) femorodistal grafts occluded. Patients with occlusions in the venous group had more severe ischemia, less runoff vessels and were older than the patients with prosthetic grafts. In the venous occlusion group 54 (20%) amputations were performed compared to 42 (16%) in the prosthetic occlusion group; crude hazard ratio 1.17 (95% CI 0.78–1.75). After adjustment for above mentioned differences in patient characteristics the hazard ratio was 0.86 (95% CI 0.56–1.32).ConclusionThe need for amputation after occlusion is not influenced by graft material in infrainguinal bypass surgery

NOD/SCID-GAMMA Mice Are an Ideal Strain to Assess the Efficacy of Therapeutic Agents Used in the Treatment of Myeloma Bone Disease

Animal models of multiple myeloma vary in terms of consistency of onset, degree of tumour burden and degree of myeloma bone disease. Here we describe five pre-clinical models of myeloma in NOD/SCID-GAMMA mice to specifically study the effects of therapeutic agents on myeloma bone disease. Groups of 7–8 week old female irradiated NOD/SCID-GAMMA mice were injected intravenously via the tail vein with either 1x106 JJN3, U266, XG-1 or OPM-2 human myeloma cell lines or patient-derived myeloma cells. At the first signs of morbidity in each tumour group all animals were sacrificed. Tumour load was measured by histological analysis, and bone disease was assessed by micro-CT and standard histomorphometric methods. Mice injected with JJN3, U266 or OPM-2 cells showed high tumour bone marrow infiltration of the long bones with low variability, resulting in osteolytic lesions. In contrast, mice injected with XG-1 or patient-derived myeloma cells showed lower tumour bone marrow infiltration and less bone disease with high variability. Injection of JJN3 cells into NOD/SCID-GAMMA mice resulted in an aggressive, short-term model of myeloma with mice exhibiting signs of morbidity 3 weeks later. Treating these mice with zoledronic acid at the time of tumour cell injection or once tumour was established prevented JJN3-induced bone disease but did not reduce tumour burden, whereas, carfilzomib treatment given once tumour was established significantly reduced tumour burden. Injection of U266, XG-1, OPM-2 and patient-derived myeloma cells resulted in less aggressive longer-term models of myeloma with mice exhibiting signs of morbidity 8 weeks later. Treating U266-induced disease with zoledronic acid prevented the formation of osteolytic lesions and trabecular bone loss as well as reducing tumour burden whereas, carfilzomib treatment only reduced tumour burden. In summary, JJN3, U266 or OPM-2 cells injected into NOD/SCID-GAMMA mice provide robust models to study anti-myeloma therapies, particularly those targeting myeloma bone disease

Mboga za Watu wa Pwani: Kilifi Utamaduni Conservation Group

Vegetables of the Coast People of Kenya No region in Kenya boasts of a greater variety of vegetables than the coastal area. Over 100 species are used by the nine linguistically-related groups living here, the Mijikenda. Just as rich is the knowledge associated with these vegetables as seen in the variety of mixtures that may be formed in a single preparation and the delicate art of balancing the quantities of each. This book makes available information on this rich vegetable culture. It provides local names of the vegetables in the different dialects (Mijikenda groups), scientific names, ecological and production information, method of preparation and mixtures involved. Eight plates with over 100 photographs as well as over 60 illustrations are provided for easy identification of the species. This book will be valuable for people interested in Mijikenda vegetables and traditions, scientists, development workers as well as extension agents working in the field of agriculture, anthropology, food and nutrition and ethnobotany, among several others. Maelezo Mboga za Watu wa Pwani Hamna sehemu ya Kenya inayojivunia aina nyingi za mboga kuliko Pwani. Zaidi ya aina mia moja hutumiwa na wakaaji wa sehemu hii waitwao WaMijikenda. Vile kuna wingi wa aina za mboga, ndivyo pia kuna wingi wa ujuzi unaoambatana na hizi mboga. Huu ujuzi tunaushuhudia wakati mboga aina tofauti zinapochangnywa kwa umakini na kupikwa pamoja. Kitabu hiki kinasimulia utamaduni wa kipekee wa mboga za Wamijikenda. Kinaelezea maumbile ya hizi mboga, majina ya mboga kwa lugha za waMijikenda na ya kisayanzi, mazingira ambamo mboga inamea, ukuzaji, utayarishaji na ‘visanganyo’ vinavyotumiwa. Kwa jumla, zimo kurasa nane zilio na zaidi ya picha mia moja na pia kuna zaidi ya michoro sitini, ili kumsaidia msomaji kuzitambua hizi mboga kwa urahisi. Hiki kitabu kitakuwa cha manufaa kwa wale wanaotaka kufahamu utamaduni wa waMijikenda kuhusu mboga, na pia kwa wanasayanzi na wanaoendeleza miradi vijijini hasa katika nyanja za kilimo, mila na desturi, lishe bora pamoja na wanaosoma manufaa ya mimea kwa binadamu na wengine

Simulations of neutron background in a time projection chamber relevant to dark matter searches

Presented here are results of simulations of neutron background performed for a time projection chamber acting as a particle dark matter detector in an underground laboratory. The investigated background includes neutrons from rock and detector components, generated via spontaneous fission and (alpha, n) reactions, as well as those due to cosmic-ray muons. Neutrons were propagated to the sensitive volume of the detector and the nuclear recoil spectra were calculated. Methods of neutron background suppression were also examined and limitations to the sensitivity of a gaseous dark matter detector are discussed. Results indicate that neutrons should not limit sensitivity to WIMP-nucleon interactions down to a level of (1 - 3) x 10^{-8} pb in a 10 kg detector.Comment: 27 pages (total, including 3 tables and 11 figures). Accepted for publication in Nuclear Instruments and Methods in Physics Research - Section

Determinants of children’s oral health-related quality of life following aesthetic treatment of enamel opacities

Objectives To identify clinical and psychosocial predictors of oral health-related quality of life (OHRQoL) in children with molar incisor hypomineralisation (MIH) following aesthetic treatment of incisor opacities. Methods Participants were 7- to 16-year-old children referred to a UK Dental Hospital for management of incisor opacities. Prior to treatment (To), participants completed validated questionnaires to assess OHRQoL and overall health status (C−OHIP-SF19), and self-concept (Harter’s Self-Perception Profile for Children [SPPC]). Interventions for MIH included microabrasion, resin infiltration, tooth whitening or composite resin restoration. Children were reviewed after six months (T1) when they re-completed the C−OHIP-SF19 and SPPC questionnaires. The relationships of predictors with improvement of children’s OHRQoL (T1-To) and children’s overall health status at T1 were assessed using linear and ordinal logistic regression respectively, guided by the Wilson and Cleary’s theoretical model. Results Of 103 participants, 86 were reviewed at T1 (83.5 % completion rate). Their mean age was 11-years (range = 7−16) and 60 % were female. Total and domain OHRQoL scores significantly increased (improved OHRQoL) following MIH treatment. There was a significant positive change in SPPC physical appearance subscale score between To and T1. A higher number of anterior teeth requiring aesthetic treatment were associated with poor improvement of socio-emotional wellbeing at T1 (Coef =-0.43). Higher self-concept at To was associated with greater improvement of socio-emotional wellbeing at T1 (ß = 3.44). Greater orthodontic treatment need (i.e. higher IOTN-AC score) at T0 was linked to worse overall oral health at T1 (OR = 0.43). Conclusions Psychosocial factors and dental clinical characteristics were associated with change in children’s OHRQoL following minimal interventions for incisor opacities. Clinical significance MIH is a common condition and clinicians should be aware of the negative impacts some children experience, particularly those with multiple anterior opacities, poor tooth alignment and low self-concept. However, simple, minimally invasive treatments can provide good clinical and psychosocial outcomes and should be offered to children reporting negative effects

Application of 13C NMR to investigate the transformations and biodegradation of organic materials by wood- and soil-feeding termites, and a coprophagous litter-dwelling dipteran larva

Solid-state 13C nuclear magnetic resonance spectroscopy has been used to characterize the C in samples of the food (wood), gut contents and faeces from the wood-feeding termite, Microcerotermes parvus; soil in the guts and mound material from the soil-feeding termite, Thoracotermes macrothorax; and the food and faeces from the litter-feeding, coprophagous larvae of the dipteran fly, Bibio marci. Spectra from the wood-feeding termite indicated preferential loss of polysaccharide and accumulation of lignin with some modification to the O-aromatic-C and methoxyl-C (O-methyl-C) components during passage through the gut. Spectra for the soil-feeding termite indicated little change in the distribution of 13C between resonances following passage through the gut, except for some evidence of preferential polysaccharide loss. Interpretation of the spectra from these organisms was restricted by the relatively low C content of the soils and mound material, and by the large contribution to the NMR spectra from the gut tissue rather than the gut contents. Spectra for the litter-feeding dipteran larvae indicated preferential feeding on the polysaccharide-rich component of the litter and then overall loss of polysaccharide-C and accumulation of both aromatic-C and methoxyl-C in the gut. These changes were greater for the second passage than for the first passage through the gut, suggesting that principally mechanical and physical changes occurred initially and that chemical digestion was prevalent during the second passage

4f spin density in the reentrant ferromagnet SmMn2Ge2

The spin contribution to the magnetic moment in SmMn2Ge2 has been measured by magnetic Compton scattering in both the low and high temperature ferromagnetic phases. At low temperature, the Sm site is shown to possess a large 4f spin moment of 3.4 +/- 0.1 Bohr magnetons, aligned antiparallel to the total magnetic moment. At high temperature, the data show conclusively that ordered magnetic moments are present on the samarium site.Comment: 5 pages, 2 figures, transferred from PRL to PRB (Rapid Comm.

Residues and World-Sheet Instantons

We reconsider the question of which Calabi-Yau compactifications of the heterotic string are stable under world-sheet instanton corrections to the effective space-time superpotential. For instance, compactifications described by (0,2) linear sigma models are believed to be stable, suggesting a remarkable cancellation among the instanton effects in these theories. Here, we show that this cancellation follows directly from a residue theorem, whose proof relies only upon the right-moving world-sheet supersymmetries and suitable compactness properties of the (0,2) linear sigma model. Our residue theorem also extends to a new class of "half-linear" sigma models. Using these half-linear models, we show that heterotic compactifications on the quintic hypersurface in CP^4 for which the gauge bundle pulls back from a bundle on CP^4 are stable. Finally, we apply similar ideas to compute the superpotential contributions from families of membrane instantons in M-theory compactifications on manifolds of G_2 holonomy.Comment: 47 page