Multiple Myeloma

The clinical, biochemical and immunochemical features of 52 patients suffering from multiple myelomatosis are reported. Three major criteria were used to establish the diagnosis: serum and urine protein chemistry, bone marrow morphology and the radiological appearances of bone. The fact that abnormalities of gamma globulin synthesis were present in 49 of the 52 patients indicates the importance of adequate examination of urine by electrophores's and immunochemical techniques in the early diagnosis of multiple myeloma. Bradshaw's test, which is a simple screening test for fence-Jones proteinuria, was positive in 63% of patients.S. Afr. Med. J., 48, 1023 (1974)

Multiple Myeloma

The results of the use of melphalan in 52 patients with multiple myeloma have been analysed. The median survival of the whole group of patients was 30 months, and of those w:th renal insufficiency only 12,5 months. Bence-lones proteinuria was also a poor prognostic finding,. but only because of its association with renal failure. Patients with Bence-Jones protcinur;a and normal renal function had a median survival of 41 months. Responsiveness to therapy by criteria based on those of the Chronic Leukemial Multip!e Myeloma Task Force could be assessed in 25 patients. Dramatic symptomatic relief occurred in all but one of the responsive patients, but in only one-fifth of those who did not respond to therapy.S. Afr. Med. J., 48, 1026 (1974

Differential regulation of a MYB transcription factor is correlated with transgenerational epigenetic inheritance of trichome density in Mimulus guttatus

This is the peer reviewed version of the following article: Scoville, A. G., Barnett, L. L., Bodbyl-Roels, S., Kelly, J. K. and Hileman, L. C. (2011), Differential regulation of a MYB transcription factor is correlated with transgenerational epigenetic inheritance of trichome density in Mimulus guttatus. New Phytologist, 191: 251–263. doi:10.1111/j.1469-8137.2011.03656.x, which has been published in final form at http://doi.org/10.1111/j.1469-8137.2011.03656.x. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.Epigenetic inheritance, transgenerational transmission of traits not proximally determined by DNA sequence, has been linked to transmission of chromatin modifications and gene regulation, which are known to be sensitive to environmental factors. Mimulus guttatus increases trichome (plant hair) density in response to simulated herbivore damage. Increased density is expressed in progeny even if progeny do not experience damage. To better understand epigenetic inheritance of trichome production, we tested the hypothesis that candidate gene expression states are inherited in response to parental damage. Using M. guttatus recombinant inbred lines, offspring of leaf-damaged and control plants were raised without damage. Relative expression of candidate trichome development genes was measured in offspring. Line and parental damage effects on trichome density were measured. Associations between gene expression, trichome density, and response to parental damage were determined. We identified M. guttatus MYB MIXTA-like 8 as a possible negative regulator of trichome development. We found that parental leaf damage induces down-regulation of MYB MIXTA-like 8 in progeny, which is associated with epigenetically inherited increased trichome density. Our results link epigenetic transmission of an ecologically important trait with differential gene expression states – providing insight into a mechanism underlying environmentally induced ‘soft inheritance’

Transient peak-strain matching partially recovers the age-impaired mechanoadaptive cortical bone response

Mechanoadaptation maintains bone mass and architecture; its failure underlies age-related decline in bone strength. It is unclear whether this is due to failure of osteocytes to sense strain, osteoblasts to form bone or insufficient mechanical stimulus. Mechanoadaptation can be restored to aged bone by surgical neurectomy, suggesting that changes in loading history can rescue mechanoadaptation. We use non-biased, whole-bone tibial analyses, along with characterisation of surface strains and ensuing mechanoadaptive responses in mice at a range of ages, to explore whether sufficient load magnitude can activate mechanoadaptation in aged bone. We find that younger mice adapt when imposed strains are lower than in mature and aged bone. Intriguingly, imposition of short-term, high magnitude loading effectively primes cortical but not trabecular bone of aged mice to respond. This response was regionally-matched to highest strains measured by digital image correlation and to osteocytic mechanoactivation. These data indicate that aged bone’s loading response can be partially recovered, non-invasively by transient, focal high strain regions. Our results indicate that old murine bone does respond to load when the loading is of sufficient magnitude, and bones’ age-related adaptation failure may be due to insufficient mechanical stimulus to trigger mechanoadaptation

Edible crabs “Go West”: migrations and incubation cycle of Cancer pagurus revealed by electronic tags

Crustaceans are key components of marine ecosystems which, like other exploited marine taxa, show seasonable patterns of distribution and activity, with consequences for their availability to capture by targeted fisheries. Despite concerns over the sustainability of crab fisheries worldwide, difficulties in observing crabs’ behaviour over their annual cycles, and the timings and durations of reproduction, remain poorly understood. From the release of 128 mature female edible crabs tagged with electronic data storage tags (DSTs), we demonstrate predominantly westward migration in the English Channel. Eastern Channel crabs migrated further than western Channel crabs, while crabs released outside the Channel showed little or no migration. Individual migrations were punctuated by a 7-month hiatus, when crabs remained stationary, coincident with the main period of crab spawning and egg incubation. Incubation commenced earlier in the west, from late October onwards, and brooding locations, determined using tidal geolocation, occurred throughout the species range. With an overall return rate of 34%, our results demonstrate that previous reluctance to tag crabs with relatively high-cost DSTs for fear of loss following moulting is unfounded, and that DSTs can generate precise information with regards life-history metrics that would be unachievable using other conventional means

High genetic diversity at the extreme range edge: nucleotide variation at nuclear loci in Scots pine (Pinus sylvestris L.) in Scotland

Nucleotide polymorphism at 12 nuclear loci was studied in Scots pine populations across an environmental gradient in Scotland, to evaluate the impacts of demographic history and selection on genetic diversity. At eight loci, diversity patterns were compared between Scottish and continental European populations. At these loci, a similar level of diversity (θsil=~0.01) was found in Scottish vs mainland European populations, contrary to expectations for recent colonization, however, less rapid decay of linkage disequilibrium was observed in the former (ρ=0.0086±0.0009, ρ=0.0245±0.0022, respectively). Scottish populations also showed a deficit of rare nucleotide variants (multi-locus Tajima's D=0.316 vs D=−0.379) and differed significantly from mainland populations in allelic frequency and/or haplotype structure at several loci. Within Scotland, western populations showed slightly reduced nucleotide diversity (πtot=0.0068) compared with those from the south and east (0.0079 and 0.0083, respectively) and about three times higher recombination to diversity ratio (ρ/θ=0.71 vs 0.15 and 0.18, respectively). By comparison with results from coalescent simulations, the observed allelic frequency spectrum in the western populations was compatible with a relatively recent bottleneck (0.00175 × 4Ne generations) that reduced the population to about 2% of the present size. However, heterogeneity in the allelic frequency distribution among geographical regions in Scotland suggests that subsequent admixture of populations with different demographic histories may also have played a role

Human IL-6R(hi)TIGIT(-) CD4(+)CD127(low)CD25(+) T cells display potent in vitro suppressive capacity and a distinct Th17 profile

To date many clinical studies aim to increase the number and/or fitness of CD4⁺CD127$^{low}$CD25⁺ regulatory T cells (Tregs) in vivo to harness their regulatory potential in the context of treating autoimmune disease. Here, we sought to define the phenotype and function of Tregs expressing the highest levels of IL-6 receptor (IL-6R). We have identified a population of CD4⁺CD127$^{low}$CD25⁺ TIGIT⁻ T cells distinguished by their elevated IL-6R expression that lacked expression of HELIOS, showed higher CTLA-4 expression, and displayed increased suppressive capacity compared to IL-6R$^{hi}$TIGIT⁺ Tregs. IL-6R$^{hi}$TIGIT⁻ CD127$^{low}$CD25⁺ T cells contained a majority of cells demethylated at FOXP3 and displayed a Th17 transcriptional signature, including RORC (RORγt) and the capacity of producing both pro- and anti-inflammatory cytokines, such as IL-17, IL-22 and IL-10. We propose that in vivo, in the presence of IL-6-associated inflammation, the suppressive function of CD4⁺CD127$^{low}$CD25⁺ FOXP3⁺IL-6R$^{hi}$TIGIT⁻ T cells is temporarily disarmed allowing further activation of the effector functions and potential pathogenic tissue damage.This research was supported by the JDRF (9-2011-253/5-SRA-2015-130-A-N), the Wellcome Trust (WT091157/107212 and WT083650/Z/07/Z), the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, and the Cambridge Clinical Trials Unit (CCTU). RCF is funded by a JDRF advanced post-doctoral fellowship (3-APF-2015-88-A-N)

In-depth immunophenotyping data of IL-6R on the human peripheral regulatory T cell (Treg) compartment

We provide in this paper a detailed characterization of the human peripheral CD4$^+$ CD127$^{low}$CD25$^+$ regulatory T cell (Treg) compartment, with a particular emphasis in defining the population expressing higher levels of the IL-6 receptor (IL-6R). We provide a description of the phenotype of this population by assessing both the surface expression by flow cytometry as well as their transcriptional profile and functional features. In addition, we also present functional data describing the responsiveness of these subsets to IL-6 signalling $\textit{in vitro}$ and to IL-2 $\textit{in vivo}$. The data presented in this paper support the research article "Human IL-6R$^{hi}$TIGIT$^-$ CD4$^+$CD127$^{low}$CD25$^+$ T cells display potent $\textit{in vitro}$ suppressive capacity and a distinct Th17 profile" (Ferreira RC et al., 2017; doi: 10.1016/j.clim.2017.03.002) [1]

The Transit Phase of Migration: Circulation of Malaria and Its Multidrug-Resistant Forms in Africa

In the third article in a six-part <I>PLoS Medicine</I> series on Migration & Health, Cally Roper and Caroline Lynch use a case study of migration and anti-malarial drug resistance in Uganda to discuss the specific health risks and policy needs associated with the transit phase of migration