The impact of vitamin D status on changes in bone mineral density during treatment with bisphosphonates and after discontinuation following long-term use in post-menopausal osteoporosis

BACKGROUND: It is still unclear whether addition of calcium/vitamin D supplements leads to an incremental benefit in patients taking bisphosphonates and whether achievement of serum level of 25 (OH) vitamin D of at least 70 nmol/L has an impact on the skeletal response to bisphosphonates. Moreover the maintenance of BMD after bisphosphonates withdrawal with the continuation of calcium/vitamin D supplements only, remains uncertain. The aims were to assess the impact of vitamin D status on changes in bone mineral density (BMD) in firstly patients with post-menopausal osteoporosis on bisphosphonates and secondly following discontinuation of bisphosphonates after long-term use. METHODS: Two patient groups were recruited. The first study population comprised of 112 women treated with a bisphosphonate. The second study population consisted of 35 women who had been on bisphosphonates for > 5 years in whom the treatment agent was discontinued. Baseline BMD, changes in BMD following treatment, duration of treatment, serum 25 (OH) vitamin D, parathyroid hormone (PTH), urine C-terminal telopeptides of type 1 collagen (CTX) were obtained on the study participants. RESULTS: In the first study group, subjects with serum vitamin D concentrations (> 70 nmol/L) had a significantly lower serum PTH level (mean [SEM] 41 [2] ng/L). PTH concentrations of 41 ng/L or less was associated with a significantly higher increase in BMD at the hip following treatment with bisphosphonates compared to patients with PTH > 41 ng/L (2.5% [0.9] v/s -0.2% [0.9], P = 0.04). In the second study group, discontinuation of bisphosphonate for 15 months after long-term treatment did not result in significant bone loss at the lumbar spine and total hip, although a trend towards gradual decline in BMD at the femoral neck was observed. CONCLUSION: the data suggest that optimal serum 25 (OH) vitamin D concentration may lead to further reduction in bone loss at the hip in patients on bisphosphonates. A prospective controlled trial is needed to evaluate whether the response to bisphosphonates is influenced by vitamin D status. BMD is preserved at the lumbar spine and total hip following discontinuation of bisphosphonate for a short period following long-term treatment, although a gradual loss occurs at the femoral neck

Neoconservatism as Discourse:Virtue, Power and US Foreign Policy

Neoconservatism in US foreign policy is a hotly contested subject, yet most scholars broadly agree on what it is and where it comes from. From a consensus that it first emerged around the 1960s, these scholars view neoconservatism through what we call the ‘3Ps’ approach, defining it as a particular group of people (‘neocons’), an array of foreign policy preferences and/or an ideological commitment to a set of principles. While descriptively intuitive, this approach reifies neoconservatism in terms of its specific and often static ‘symptoms’ rather than its dynamic constitutions. These reifications may reveal what is emblematic of neoconservatism in its particular historical and political context, but they fail to offer deeper insights into what is constitutive of neoconservatism. Addressing this neglected question, this article dislodges neoconservatism from itsperceived home in the ‘3Ps’ and ontologically redefines it as a discourse. Adopting aFoucauldian approach of archaeological and genealogical discourse analysis, we trace itsdiscursive formations primarily to two powerful and historically enduring discourses ofthe American self — virtue and power — and illustrate how these discourses produce aparticular type of discursive fusion that is ‘neoconservatism’. We argue that to betterappreciate its continued effect on contemporary and future US foreign policy, we needto pay close attention to those seemingly innocuous yet deeply embedded discoursesabout the US and its place in the world, as well as to the people, policies and principlesconventionally associated with neoconservatism

Extreme disorder in an ultrahigh-affinity protein complex

Molecular communication in biology is mediated by protein interactions. According to the current paradigm, the specificity and affinity required for these interactions are encoded in the precise complementarity of binding interfaces. Even proteins that are disordered under physiological conditions or that contain large unstructured regions commonly interact with well-structured binding sites on other biomolecules. Here we demonstrate the existence of an unexpected interaction mechanism: the two intrinsically disordered human proteins histone H1 and its nuclear chaperone prothymosin-α associate in a complex with picomolar affinity, but fully retain their structural disorder, long-range flexibility and highly dynamic character. On the basis of closely integrated experiments and molecular simulations, we show that the interaction can be explained by the large opposite net charge of the two proteins, without requiring defined binding sites or interactions between specific individual residues. Proteome-wide sequence analysis suggests that this interaction mechanism may be abundant in eukaryotes