Predicting the safety and efficacy of butter therapy to raise tumour pHe: an integrative modelling study

Background: Clinical positron emission tomography imaging has demonstrated the vast majority of human cancers exhibit significantly increased glucose metabolism when compared with adjacent normal tissue, resulting in an acidic tumour microenvironment. Recent studies demonstrated reducing this acidity through systemic buffers significantly inhibits development and growth of metastases in mouse xenografts.\ud \ud Methods: We apply and extend a previously developed mathematical model of blood and tumour buffering to examine the impact of oral administration of bicarbonate buffer in mice, and the potential impact in humans. We recapitulate the experimentally observed tumour pHe effect of buffer therapy, testing a model prediction in vivo in mice. We parameterise the model to humans to determine the translational safety and efficacy, and predict patient subgroups who could have enhanced treatment response, and the most promising combination or alternative buffer therapies.\ud \ud Results: The model predicts a previously unseen potentially dangerous elevation in blood pHe resulting from bicarbonate therapy in mice, which is confirmed by our in vivo experiments. Simulations predict limited efficacy of bicarbonate, especially in humans with more aggressive cancers. We predict buffer therapy would be most effectual: in elderly patients or individuals with renal impairments; in combination with proton production inhibitors (such as dichloroacetate), renal glomular filtration rate inhibitors (such as non-steroidal anti-inflammatory drugs and angiotensin-converting enzyme inhibitors), or with an alternative buffer reagent possessing an optimal pK of 7.1–7.2.\ud \ud Conclusion: Our mathematical model confirms bicarbonate acts as an effective agent to raise tumour pHe, but potentially induces metabolic alkalosis at the high doses necessary for tumour pHe normalisation. We predict use in elderly patients or in combination with proton production inhibitors or buffers with a pK of 7.1–7.2 is most promising

The use of vouchers for reproductive health services in developing countries: Systematic review

Objectives: To identify where vouchers have been used for reproductive health (RH) services, to what extent RH voucher programmes have been evaluated, and whether the programmes have been effective. Methods: A systematic search of the peer review and grey literature was conducted to identify RH voucher programmes and evaluation findings. Experts were consulted to verify RH voucher programme information and identify further programmes and studies not found in the literature search. Studies were examined for outcomes regarding targeting, costs, knowledge, utilization, quality, and population health impact. Included studies used cross-sectional, before-and-after and quasi-experimental designs. Results: Thirteen RH voucher programmes fitting established criteria were identified. RH voucher programmes were located in Bangladesh, Cambodia, China, Kenya (2), Korea, India, Indonesia, Nicaragua (3), Taiwan, and Uganda. Among RH voucher programmes, 7 were quantitatively evaluated in 15 studies. All evaluations reported some positive findings, indicating that RH voucher programmes increased utilization of RH services, improved quality of care, and improved population health outcomes. Conclusions: The potential for RH voucher programmes appears positive; however, more research is needed to examine programme effectiveness using strong study designs. In particular, it is important to see stronger evidence on cost-effectiveness and population health impacts, where the findings can best direct governments and external funders

Bisphosphonate-induced zebra lines in fibrous dysplasia of bone: histo-radiographic correlation in a case of McCune-Albright syndrome

This study was funded by Telethon (Grant number: GGP15198), and, in part, by the Division of Intramural Research, National Institute of Dental and Craniofacial Research, a part of the Intramural Research Program, National Institutes of Health, Department of Health and Human Services (ZIA DE000380)

Osteoblasts and stromal cells isolated from femora in rheumatoid arthritis (RA) and osteoarthritis (OA) patients express IL-11, leukaemia inhibitory factor and oncostatin M

We investigated both in vitro and ex vivo the role of mature osteoblasts (OB) and bone marrow stromal cells (BMSC) in RA and OA by analysing the expression of the following IL-6-type cytokines: IL-11, leukaemia inhibitory factor (LIF), oncostatin M (OSM) and IL-6. OB and BMSC were isolated from femora of RA, OA and post-traumatic (PT) patients, cultured in vitro in the presence or absence of IL-1β and tumour necrosis factor-alpha (TNF-α), and assessed for the production and mRNA expression of IL-6-type cytokines. Trabecular bone biopsies were obtained from the inner portions of femoral heads and used for cytokine in situ immunostaining. Cultured OB and BMSC from different patients constitutively secreted IL-11 and IL-6 but not OSM. LIF was secreted only by BMSC, at very low levels. Interestingly, IL-11 basal production was significantly higher in BMSC than in OB in all three groups tested. IL-1β and TNF-α strongly stimulated IL-6-type cytokine release (except for OSM) by both OB and BMSC. OSM was expressed only at mRNA levels in all groups studied. Cytokine immunostaining on bone biopsies confirmed the data obtained on cultured cells: IL-11, IL-6 and LIF proteins were detected both in mesenchymal (BMSC and OB) and mononuclear cells; OSM was found only in mononuclear cells. These data demonstrate that IL-6-type cytokines are constitutively expressed in the bone compartment in RA, OA and PT patients and can be secreted by bone cells at different stages of differentiation (BMSC and OB). This suggests that these cytokines may be involved in the mechanisms of bone remodelling in OA and RA