Vitamin K and Osteoporosis

Vitamin K acts as a coenzyme of carboxylase, catalyzing the carboxylation of several vitamin K dependent proteins. Beyond its well-known effects on blood coagulation, it also exerts relevant effects on bone and the vascular system. In this review, we point out the relevance of an adequate vitamin K intake to obtain sufficient levels of carboxylated (active form) vitamin K dependent proteins (such as Osteocalcin and matrix Gla protein) to prevent bone health. Another bone-related action of Vitamin K is being a ligand of the nuclear steroid and xenobiotic receptor (SXR). We also discuss the recommended intake, deficiency, and assessment of vitamin K. Furthermore, we review the few available studies that have as pre-specified outcome bone fractures, indicating that we need more clinical studies to confirm that vitamin K is a potential therapeutic agent for bone fractures.     

Individual radiation exposure from computed tomography: a survey of paediatric practice in French university hospitals, 2010–2013

Objectives

To describe computed tomography (CT) scanning parameters, volume CT dose index (CTDIvol) and dose-length product (DLP) in paediatric practice and compare them to current diagnostic reference levels (DRLs).

Methods

The survey was conducted in radiology departments of six major university hospitals in France in 2010–2013. Data collection was automatised to extract and standardise information on scanning parameters from DICOM-header files. CTDIvol and DLP were estimated based on Monte Carlo transport simulation and computational reference phantoms.

Results

CTDIvol and DLP were derived for 4,300 studies, four age groups and 18 protocols. CTDIvol was lower in younger patients for non-head scans, but did not vary with age for routine head scans. Ratios of 95th to 5th percentile CTDIvol values were 2–4 for most body parts, but 5–7 for abdominal examinations and 4–14 for mediastinum CT with contrast, depending on age. The 75th percentile CTDIvol values were below the national DRLs for chest (all ages) and head and abdominal scans (≥10 years).

Conclusion

The results suggest the need for a better optimisation of scanning parameters for routine head scans and infrequent protocols with patient age, enhanced standardisation of practices across departments and revision of current DRLs for children.

Key points

?? CTDIvol varied little with age for routine head scans. ?? CTDIvol was lowest in youngest children for chest or abdominal scans. ?? Individual and inter-department variability warrant enhanced standardisation of practices. ?? Recent surveys support the need for revised diagnostic reference levels. ?? More attention should be given to specific protocols (sinuses, neck, spine, mediastinum).

     

Effect of DMPPO,a phosphodiesterase type 5 inhibitor,on hypoxic pulmonary hypertension in rats

1. Cyclic guanosine 3′–5′-monophosphate (cyclic GMP) is the second messenger of important physiologically active mediators controlling the pulmonary vascular tone. To potentiate the effects of cyclic GMP on the pulmonary vasculature, we used DMPPO, a new selective PDE-5 inhibitor, and examined its action in a rat model of hypoxic pulmonary hypertension.
2. Levels of cyclic GMP measured during baseline conditions at 5 and 60 min of perfusion were similar in the perfusate of isolated lungs from normoxic and chronically hypoxic rats and did not differ with time. Pretreatment with DMPPO (1 μM) induced a larger increase in cyclic GMP concentration in the perfusate from chronically hypoxic rat lungs (319±36 at 5 min to 1821±83 pmol ml⁻¹ at 60 min) than in normoxic rat lungs (329±20 to 1281±127 pmol ml⁻¹, P<0.05).
3. In isolated lungs preconstricted with U-46619, pretreatment with DMPPO (1 μM) potentiated the vasodilator effects of atrial natriuretic peptide (100 pM–10 nM) and sodium nitroprusside (1 pM–10 nM), but did not alter vasodilation to isoproterenol.
4. In conscious rats previously exposed to 15 days hypoxia and studied under 10% O₂, DMPPO (0.01, 0.05 and 0.1 mg kg⁻¹, i.v. bolus) caused a dose-dependent decrease in pulmonary arterial pressure (Pap) with no change in systemic artery pressure (Sap) and cardiac output.
5. Continuous infusion of DMPPO (0.1 mg kg⁻¹ h⁻¹ i.v. by osmotic pumps) in rats exposed to 10% O₂ during 2-weeks reduced the Pap (P<0.05) and the degree of muscularization of pulmonary vessels at the alveolar wall (P<0.01) and alveolar duct levels (P<0.05) despite no significant change in right ventricular hypertrophy.
6. These results suggest that cyclic GMP phosphodiesterase inhibition may selectively dilate pulmonary circulation during chronic hypoxia.

     

Aneurysmal bone cyst,a study of ultrastructure and malignant transformation

Summary Four cases of aneurysmal bone cyst, of which one became malignant 7 years after irradiation, were studied by electron microscopy. The aneurysmal bone cyst was composed of four different types of stromal cells — fibroblasts, myofibroblasts, osteoblasts, and histiocytes — and osteo-clastlike multinucleated giant cells. The surface of blood spaces was devoid of specialized endothelium, which may explain the presence of large quantities of extravasated erythrocytes. Some histiocytes contained siderosomes. The malignant lesion consisted of two main types of stromal cells, of which one had electron lucent and the other electron dense cytoplasm. The stromal cells produced osteoid and the tumour was regarded as an osteosarcoma. The multinucleated giant cells resembled those observed in aneurysmal bone cysts, but the nuclei seemed to be more often spherical. It is concluded that irradiation of the aneurysmal bone cyst may cause sarcomatous transformation in a cell capable of producing osteoid.     

Expression of FcγRIII defines distinct subpopulations of fetal liver B cell and myeloid precursors

We have isolated four distinct fetal liver (FL) populations based on the expression of AA4.1 and the low-affinity Fcγ receptors type II and III (FcγRII/III), and characterized them with respect to B cell, T cell, and myeloid precursor content. Polymerase chain reaction analysis revealed that the prevalent FcγR isoform at this stage of FL development (day 12 of gestation) was FcγRIII. Two of the four populations, one which expressed AA4.1 but little if any FcγRII/III (AA4.1⁺), and one which expressed abundant levels of both markers (AA4.1⁺/ FcR⁺), contained B cell precursors that grew and differentiated to generate V_HDJ_H-rearranged B-lineage cells on S-17 stromal cells in the presence of IL-7. When cultured on FLST2 stromal cells only the AA4.1⁺ cells generated V_HDJ_H-rearranged B-lineage cells. T cell precursors as assayed by their ability to repopulate fetal thymi in organ culture were found only in the AA4.1⁺ fraction. In contrast to the lymphoid precursors, myeloid precursors able to generate colonies in methyl cellulose cultures were found in all four fractions including the one which expressed FcγRII/III but no AA4.1 (FcR⁺) and the one which expressed neither marker (AA4.1^?/FcR^?). The AA4.1⁺ population which contained both B cell and T cell precursors was enriched for precursors from many myeloid lineages including the most immature ones which generated multilineage colonies. In contrast, the AA4.1⁺/FcR⁺ population, which also contained B cell precursors, was almost devoid of myeloid precursors and the few that were detected were committed to the macrophage lineage. The population defined as FcR⁺ was also enriched for precursors; however, the majority of these were committed to the erythroid, the macrophage and the mast cell lineage. The fourth population which expressed neither marker (AA4.1^?/FcR^?) was enriched for relatively mature erythroid precursors which were not present in any of the other fractions. Together, these findings demonstrate that fractionation of FL cells on the basis of AA4.1 and FcγRII/III expression distinguishes subpopulations of B cell and myeloid precursors and suggests that the low-affinity FcγRIII could play a role in the development of early hematopoietic cells at this stage of ontogeny.     

Cystic osteolysis induced by silicone rubber prosthesis

Synovitic symptoms and radiologically documented cystic lesions in several carpal bones and distal radius developed two years after the implantation of silicone rubber scaphoid prosthesis for pseudoarthrosis. Open biopsy revealed granulomatous synovitis and osteitis and foreign material in carpal tissues. Ultrastructurally dense material was found in the cytoplasm of histiocytic, often multinucleated cells. Electron-probe analysis of the material showed a definite peak for silicon, proving the causal relationship of symptoms and signs to the silicone rubber prosthesis.     

A stretch-activated anion channel is up-regulated by the malaria parasite plasmodium falciparum

A recent study on malaria-infected human red blood cells (RBCs) has shown induced ion channel activity in the host cell membrane, but the questions of whether they are host- or parasite-derived and their molecular nature have not been resolved. Here we report a comparison of a malaria-induced anion channel with an endogenous anion channel in Plasmodium falciparum -infected human RBCs. Ion channel activity was measured using the whole-cell, cell-attached and excised inside-out configurations of the patch-clamp method. Parasitised RBCs were cultured in vitro , using co-cultured uninfected RBCs as controls. Unstimulated uninfected RBCs possessed negligible numbers of active anion channels. However, anion channels could be activated in the presence of protein kinase A (PKA) and ATP in the pipette solution or by membrane deformation. These channels displayed linear conductance (∼15 pS), were blocked by known anion channel inhibitors and showed the permeability sequence I⁻ > Br⁻ > Cl⁻. In addition, in less than 5 % of excised patches, an outwardly rectifying anion channel (∼80 pS, outward conductance) was spontaneously active. The host membrane of malaria-infected RBCs possessed spontaneously active anion channel activity, with identical conductances, pharmacology and selectivity to the linear conductance channel measured in stimulated uninfected RBCs. Furthermore, the channels measured in malaria-infected RBCs were shown to have a low open-state probability ( P _o) at positive potentials, which explains the inward rectification of membrane conductance observed when using the whole-cell configuration. The data are consistent with the presence of two endogenous anion channels in human RBCs, of which one (the linear conductance channel) is up-regulated by the malaria parasite P. falciparum .     

Lung overexpression of angiostatin aggravates pulmonary hypertension in chronically hypoxic mice

Exposure to hypoxia leads to the development of pulmonary hypertension (PH) as a consequence of pulmonary smooth muscle hyperplasia. Hypoxia concomitantly stimulates lung expression of angiogenic factors. To investigate the role of angiogenesis processes in development of hypoxic PH, we examined the effects of lung overexpression of angiostatin, an angiogenesis inhibitor, on development of hypoxic PH and lung endothelial cell (EC) density. Angiostatin delivery was achieved by a defective adenovirus expressing a secretable angiostatin K3 molcule driven by the cytomegalovirus promoter (Ad.K3). Comparison was made with a control vector containing no gene in the expression cassette (Ad.CO1). Treatment with Ad.K3 (300 plaque-forming units [pfu]/cell) inhibited cultured human pulmonary artery EC migration by 100% and proliferation by 50%, but was without effects on human pulmonary artery smooth muscle cells. After intratracheal administration of Ad.K3 (109 pfu) to mice, angiostatin protein became detectable in bronchoalveolar lavage fluid. Mice pretreated with Ad.K3 1 d before a 2-wk exposure to hypoxia (10% O2) showed more severe pulmonary hypertension than Ad.CO1-pretreated controls, as assessed by higher right ventricular systolic pressure (36.5 +/- 2.4 versus 30.2 +/- 1.4, respectively), aggravation of right ventricular hypertrophy (P < 0.05), and muscularization of distal vessels (P < 0.01). Lung factor VIII, CD31 immunostaining, as well as eNOS expression were significantly increased after exposure to hypoxia in Ad.CO1-pretreated controls, but decreased in both normoxic and hypoxic animals after treatment with Ad.K3. The results show that inhibition of hypoxia-induced stimulation of lung angiogenic processes aggravates development of hypoxic PH. This suggests that endogenous lung angiogenesis counteracts development of hypoxic PH.     

Similar network activated by young and old adults during the acquisition of a motor sequence

In this functional MRI (fMRI) study, we investigated ageing effects on motor skill learning. We applied an adapted version of the serial reaction time (SRT) task to extensive groups of young (N=26) and elderly (N=40) subjects. Since indications have been provided for age-related shrinkage of brain regions assumed to be critical to motor skill learning, we tested the hypothesis that age effects on implicit sequence learning are larger on a neurofunctional level than on a behavioural level. The SRT task consisted of two identical scan sessions, in which subjects had to manually trail an asterisk appearing serially in one of four spatial positions by means of button-pressing. Reliable response time reductions were already found in the first session for both the young and the elderly groups, when comparing a fixed sequence condition to a random sequence, but the learning effect was greater for the young subjects. In the second session, though, both groups showed a similar degree of learning. This indicates that implicit sequence learning is still intact in elderly adults, but that the rate of learning is somewhat slower. Reliable learning-related changes in brain activity were also observed. A similar network of brain regions was recruited by both groups during the fixed compared to the random sequence, involving several regions that have been previously associated with implicit sequence learning, including bilateral parietal, and frontal regions, the supplementary motor area (SMA), cerebellum and the basal ganglia. The direct group comparison did not reveal any differences in brain activity. In addition, we did not observe any significant differences in activity when comparing the different sessions either, neither for the young nor for the elderly subjects. Hence, we did not find indications for an age-related functional reorganisation of neural networks involved in motor sequence learning. In view of earlier reports of pronounced ageing effects on the performance on declarative memory tasks, our finding of age-related sparing of processes that sustain motor skill learning, provides further support for the proposition of different memory systems relying on different brain substrates.