A systematic review on the use of daily subcutaneous administration of teriparatide for treatment of patients with osteoporosis at high risk for fracture in Asia.

This systematic review aimed to examine the evidence for teriparatide in Asia for osteoporosis with a high fracture risk and for exploratory (unapproved) bone-related indications. MEDLINE (1946+), EMBASE (1966+), and ClinicalTrials.gov (2008+) were searched (16 August 2013); all studies of daily subcutaneous teriparatide 20 µg for bone-related conditions from China, Hong Kong, Japan, Republic of Korea, Philippines, Singapore, and Taiwan were included. Evidence on efficacy/safety was retrieved primarily from randomized controlled trials (10 publications) of postmenopausal women from Japan and China. In these studies, teriparatide was well tolerated; subjects had significantly greater increases in lumbar spine bone mineral density (BMD) from baseline compared with placebo, antiresorptive agents, or elcatonin/calcitonin; bone turnover markers increased from baseline and were sustained at elevated levels during teriparatide treatment. Few studies reported fracture risk, pain, or quality of life; one study showed a lower incidence of new-onset vertebral fracture with teriparatide versus antiresorptive agents. Nonrandomized studies (nine publications, one unpublished trial) conducted mainly in Taiwan, Japan, and the Republic of Korea provided supporting data for efficacy. The exploratory (unapproved) use of teriparatide (17 publications) for fracture healing and osteonecrosis of the jaw was described primarily in case reports. The clinical effectiveness of teriparatide for treatment of postmenopausal women with osteoporosis who are at high risk of fracture in Asia is focused primarily on improvements in BMD and tolerability. Recommended additional studies may include assessment of fracture risk and the effect of teriparatide on pain, quality of life, and mortality in Asia.

Statin suppresses apoptosis in osteoblastic cells: role of transforming growth factor-beta-Smad3 pathway.

Statins possess pleiotropic effects in several tissues. Among them, their bone anabolic actions have been recently noted. We have proposed that Smad3, a TGF-beta-signaling molecule, is a promoter of bone formation. However, whether statins would affect TGF-beta-Smad3 pathway in osteoblasts is still unknown. The present study was performed to examine the effects of statin on Smad3 expression and cell apoptosis by employing mouse osteoblastic MC3T3-E1 and rat osteoblastic UMR-106 cells. Statins (pitavastatin, mevastatin, and simvastatin) as well as alendronate increased the levels of Smad3 in MC3T3-E1 cells. The effects of pitavastatin on Smad3 levels were observed from 3 hours and later. Pitavastatin induced the expression of TGF-beta, and cycloheximide, a protein synthesis inhibitor, antagonized the increased levels of pitavastatin on Smad3. On the other hand, pitavastatin antagonized dexamethasone- or etoposide-induced apoptosis in a dose-dependent manner, and Smad3 inactivation by dominant negative Smad3 or an inhibition of endogenous TGF-beta action by SB431542 antagonized anti-apoptotic effects of pitavastatin, indicating that pitavastatin suppressed osteoblast apoptosis partly through TGF-beta-Smad3 pathway. In conclusion, the present study has demonstrated for the first time that statin suppressed cell apoptosis partly through TGF-beta-Smad3 pathway in osteoblastic cells.

Serum soluble factors induce the proliferation, alkaline phosphatase activity and transforming growth factor-beta signal in osteoblastic cells in the patient with hepatitis C-associated osteosclerosis.

Hepatitis C-associated osteosclerosis (HCAO) is a rare syndrome characterized by severe, acquired, generalized osteosclerosis and hyperostosis in adults who are infected with the hepatitis C virus. However, the detail of the pathogenesis of HCAO is still unknown. We examined the effects of serum of the HCAO patient on the proliferation, alkaline phosphatase (ALP) activity and transforming growth factor (TGF)-beta-Smad signaling in mouse osteoblastic cells. The patient was compatible with HCAO, characterized by high bone mass, bone thickening and bone pain with normal lamelar bone. The serum from the HCAO patient increased the levels of TGF-beta and Smad3 expression in osteoblastic MC3T3-E1 cells, compared with the control subject. Moreover, the serum from the HCAO patient significantly augmented TGF-beta-induced transcriptional activity with luciferase assay using 3TP-Lux with a Smad3-specific responsive element. In addition, the serum from the HCAO patient significantly stimulated the MTT intensity, the level of proliferating cell nuclear antigen expression, a proliferation marker, and ALP activity in MC3T3-E1 cells, compared with that from the control subject. In conclusion, the present study indicated that the serum from the HCAO patient stimulated TGF-beta-Smad signaling, as well as the proliferation and ALP activity in osteoblastic cells. Some soluble factors other than parathyroid hormone might be related to the pathogenesis of HCAO.

Smad3 differently affects osteoblast differentiation depending upon its differentiation stage.

Smad3, a critical component of the TGF-beta signaling pathways, plays an important role in the regulation of bone formation. However, how Smad3 affects osteoblast at the different differentiation stage remains still unknown. In the present study, we examined the effects of Smad3 on osteoblast phenotype by employing mouse bone marrow ST-2 cells and mouse osteoblastic MC3T3-E1 cells at the different differentiation stage. Smad3 overexpression significantly inhibited bone morphogenetic protein-2 (BMP-2)-induced ALP activity in ST-2 cells, indicating that Smad3 suppresses the commitment of pluripotent mesenchymal cells into osteoblastic cells. Smad3 increased the levels of COLI and ALP mRNA at 7 day cultures in MC3T3-E1 cells, and its effects on COL1 were decreased as the culture periods progress, although its effects on ALP were sustained during 21 day cultures. Smad3 overexpression enhanced the level of Runx2 and OCN mRNA at 14 day and 21 day cultures. Smad3 increased the levels of MGP and NPP-1 mRNA, although the extent of increase in MGP and NPP-1 was reduced and enhanced during the progression of culture period, respectively. Smad3 did not affect the level of ANK mRNA. On the other hand, Smad3 enhanced the level of MEPE mRNA at 14 and 21 day cultures, although Smad3 decreased it at 7 day cultures. In conclusion, Smad3 inhibits the osteoblastic commitment of ST-2 cells, while promotes the early stage of differentiation and maturation of osteoblastic committed MC3T3-E1 cells. Also, Smad3 enhanced the expression of mineralization-related genes at the maturation phase of MC3T3-E1 cells.

Menin and TGF-beta superfamily member signaling via the Smad pathway in pituitary, parathyroid and osteoblast.

PITUITARY: Menin is a Smad3-interacting protein; inactivation of menin blocks transforming growth factor (TGF)-beta and activin signaling, antagonizing their growth-inhibitory properties in anterior pituitary cells. Menin is also required for the activin-induced inhibition of prolactin expression mediated by the Smads and the transcription factor, Pit-1. The interaction between menin and Smad3 is direct. PARATHYROID: In cultured parathyroid cells from uremic hemodialysis patients, in which the menin signaling pathways are probably still intact, menin inactivation achieved by menin antisense oligonucleotides leads to loss of TGF-beta inhibition of parathyroid cell proliferation and parathyroid hormone (PTH) secretion. Moreover, TGF-beta does not affect the proliferation and PTH production of parathyroid cells from multiple endocrine neoplasia type 1 (MEN1) patients. OSTEOBLAST: Men1-null mouse fetuses that die at day 12 or earlier have cranial/facial hypoplasias implicating menin in bone development. Menin is required for the commitment of multipotential mesenchymal stem cells into the osteoblast lineage. This is achieved by menin interacting physically and functionally with bone morphogenetic protein (BMP)-2 regulated Smads, such as Smad1 and Smad5, and the key osteoblast regulator, Runx2. These interactions are lost as the committed osteoblasts differentiate further at which time menin interacts with Smad3, mediating the negative regulation of Runx2 by TGF-beta. Menin also suppresses osteoblast maturation, partly by inhibiting the differentiation actions of JunD.

On the density of homogeneous sphere packings.

For some types of sphere packing with typical one- and two-dimensional parameter regions, the sphere-packing density as a function of the free parameters is discussed. In addition, some sphere-packing types with extraordinary density properties are presented. Until now, it was generally assumed that sphere packings with minimal density are also those of highest inherent symmetry. An example to prove the opposite is given.

A transition path for the pressure-induced wurtzite- to NaCl-type transformation described in Pna2(1).

Quite recently, two further mechanisms for the pressure-induced transition from the wurtzite to the NaCl type were proposed [Shimojo et al. (2004). Phys. Rev. B, 70, 184111-1-6] but no symmetry information was given. It will be shown that a slight modification of one of the assumed transition pathways allows a crystallographic description on the basis of a deformation of a heterogeneous 4-connected sphere packing in Pna2(1). All investigations were done with the help of the corresponding homogeneous packing in Pnma where the transition may be described as a deformation of a lonsdaleite configuration into a cubic primitive lattice cP. During the transformation, all sphere contacts are maintained. The new transition model is compared with the well known Cmc2(1) mechanism. Further related mechanisms can also be derived.

Hexagonal and trigonal sphere packings. III. Trivariant lattice complexes of hexagonal space groups.

All types of homogeneous sphere packing and interpenetrating sphere packings and layers were derived that correspond to point configurations of the 15 trivariant hexagonal lattice complexes. The respective sphere packings are assigned to 147 types. In total, sphere packings of 170 types can be realized with hexagonal symmetry. 103 types of sphere packing refer exclusively to trivariant hexagonal lattice complexes. For 23 of these types, the corresponding sphere packings can be generated only in hexagonal lattice complexes with less than three degrees of freedom or with trigonal or lower symmetry. In addition, seven types of interpenetrating sphere packings and two types of interpenetrating sphere layers were found. Interpenetrating 4.8(2) nets of spheres with 120 degrees angles between the nets were assumed to be not possible, so far. The sphere packings belonging to 85 of the 170 hexagonal types can be split up into parallel layers of spheres with mutual contact and can be characterized by symbols derived from those for the Shubnikov nets. The sphere packings of 135 hexagonal types may be subdivided into rod-like subsets of spheres with mutual contact. Such rods may be described by rolling up a plane net. Only 23 types of sphere packing cannot be symbolized on the basis of layers or rods of spheres with mutual contact. Examples are given for crystal structures that can be described by means of sphere packings.

Exceptional properties of some sphere packings in the general position of P6(2)22.

Three types of sphere packing are described which show properties that have never been observed before: a certain set of generating symmetry operations corresponds to a parameter range in P6(2)22 that is not simply connected, but disintegrates into two disjoint non-congruent regions; the minimal sphere-packing density is different for these two regions; two sphere packings from different regions cannot be deformed into each other without opening sphere contacts although their sphere-packing graphs are isomorphic in the graph-theoretical sense. Two heterogeneous crystal nets with different symmetry described by Delgado-Friedrichs & O'Keeffe [Acta Cryst. (2003), A59, 351-360] show a similar behaviour. They are related to a type of tetragonal sphere packing with likewise unusual properties.

Hexagonal and trigonal sphere packings. II. Bivariant lattice complexes.

All homogeneous sphere packings were derived which correspond to point configurations of the 26 bivariant lattice complexes belonging to the hexagonal crystal family. They may be assigned to 109 sphere-packing types. Among these, there is a type of sphere packing with contact number 10 that was not described before. For seven of the 109 types, the inherent symmetry of the sphere packings with minimal density is cubic. In addition, three types of interpenetrating sphere packings were found and one type of interpenetrating 6(3) sphere layers. Such an arrangement was unknown so far. Some frequently occurring structure types that can be related to sphere packings are described as examples.

Hexagonal and trigonal sphere packings. I. Invariant and univariant lattice complexes.

All homogeneous sphere packings and all interpenetrating sphere packings have been derived that refer to the seven invariant and the 23 univariant lattice complexes belonging to the hexagonal crystal family. The respective sphere packings may be assigned to 66 types. In addition, one case of interpenetrating sphere packings was found. For five types, the inherent symmetry of some sphere packings with specialized metrical and coordinate parameters may become cubic. For two further types, namely 8/4/c1 (body-centered cubic lattice) and 12/3/c1 (face-centered cubic lattice), the inherent symmetry is cubic for all corresponding sphere packings. By means of a large number of examples, the applicability of sphere packings for the comparison and description of simple crystal structures is demonstrated.

Relations between the zinc-blende and the NaCl structure type.

A new model for the transformation from the zinc-blende to the NaCl type is developed on the basis of the deformation of a 4-connected heterogeneous sphere packing in space group P3(2). The geometrical features of this transition are discussed by investigating the analogous deformations of a 4-connected homogeneous sphere packing in the supergroup P3(2)21 of P3(2). In this space group, the atomic arrangement corresponds to a diamond configuration. During the phase transition, it is deformed under preservation of all sphere contacts until a cubic primitive lattice is reached, the analogue of the NaCl arrangement formed by like atoms. The intermediate structure that occurs between the zinc-blende and the NaCl type is compared with the cinnabar type.

Group-theoretical and geometrical considerations of the phase transition between the high-temperature polymorphs of quartz and tridymite.

A model was derived for the temperature-dependent phase transition between the high-temperature polymorphs of quartz (P6(4)22) and tridymite (P6(3)/mmc). Only the Si framework is considered, and the transformation can be described as a deformation of a homogeneous sphere packing with three contacts per sphere (type 3/10/h1) in the common subgroup P6(1)22 of P6(4)22 and P6(3)/mmc. The proposed model guarantees the three-dimensional connection of the crystal structure during the whole transformation process.

A proposal for a transition mechanism from the diamond to the lonsdaleite type.

A phase transition between the diamond (Fd3;m) and the lonsdaleite types (P6(3)/mmc) may be described as a deformation of a homogeneous sphere packing with three contacts per sphere (type 3/10/o1) in the common subgroup Pnna of Fd3;m and P6(3)/mmc. The frequently observed transition between the zinc-blende (F4;3m) and the wurtzite types (P6(3)mc) may be described in an analogous way as a deformation of a heterogeneous sphere packing in the subgroup Pna2(1). The proposed model guarantees the three-dimensional connection during the whole transformation process. By this property it is distinguished from other models.

On the transition from the wurtzite to the NaCl type.

A crystallographic interpretation of a possible transition mechanism from the wurtzite to the NaCl type is given. For this purpose, different atoms in the structures of both types are replaced by like ones, resulting in lonsdaleite-type configurations and in cubic primitive lattices, respectively. The atomic arrangements of both types correspond to homogeneous sphere packings. It is shown that a lonsdaleite configuration may be deformed into a cubic primitive lattice within the Wyckoff position Cmcm 8(f) m. 0,y,z. Such a transition is displacive since no bonds have to be broken. The corresponding phase transformation from the wurtzite to the NaCl type can be described as a deformation of a heterogeneous sphere packing. The intermediate structure would have the symmetry Cmc2(1).

Factors associated with problem behaviors in Turkish immigrant children in The Netherlands.

BACKGROUND: The objective of this study was to examine the relationship between child, parent, family/support, and stress variables and problem behaviors in Turkish immigrant children in the Netherlands. METHODS: Parents of 833 children were interviewed and administered a Turkish version of the Child Behavior Checklist for ages 4 through 18 and a Turkish immigrant assessment questionnaire. RESULTS: Increased integration (i.e., children belonging to a second generation of immigrants, older children) generally reduced the risk for problem behaviors, while frequent arguments, divorce, psychological problems, and convictions/incarcerations increased the risk for problem behaviors. CONCLUSIONS: Results indicate that problem behaviors are associated with the high level of separation faced by Turkish immigrant families and that more integration leads to lower levels of problem behavior. Additionally, migration history alone does not contribute to problem behavior. Factors in the family (e.g., quarrels, divorce, conviction) associated with problem behaviors in Turkish immigrants are similar to those found in Dutch and American populations. Future studies could examine predictors of problem behaviors in other culturally separated immigrant groups in the Netherlands, and in Turkish immigrant groups in other countries.

The NaCl- to CsCl-type phase transition discussed on the basis of the cP to cI deformation with the symmetry Cmcm 4(c) m2m

A structure forming a cubic primitive lattice cP may be deformed into a structure forming a cubic body-centred lattice cI in the space group Cmcm at position 4(c) m2m 0,y,1/4. If in related structures the sites are alternately occupied by unlike atoms, the NaCl and the CsCl types occur, respectively. The corresponding phase transition can be described as a deformation of a heterogeneous sphere packing in the subgroup Pmmn (a,-c,b) of Cmcm. All sphere configurations with symmetry Cmcm 4(c) m2m were derived. On the basis of this information, further possibilities for phase transitions that also correspond to sphere-packing deformations were found with this symmetry. Two of them possibly may take place in metals. The first one leads from a primitive hexagonal lattice to a hexagonal close packing, the other from a cubic body-centred lattice also to a hexagonal close packing.

A unique case of central diabetes insipidus (DI) associated with transient pituitary stalk enlargement: close observation over several years using magnetic resonance imaging (MRI) and hypophysial endocrine tests.

We had the opportunity to closely observe a unique case of central diabetes insipidus (DI), in which dramatic changes in both radiological findings and hypophysial functions were seen. A 63-year-old female developed central DI, and magnetic resonance imaging (MRI) revealed a mild thickening of the pituitary stalk and lack of hyperintense signal associated with normal neurohypophysis on T1-weighted images. About three months later, the stalk was found to be remarkably expanded like neoplasm; however, anterior pituitary functions were almost normal on that occasion, except for the absence of GH response to an insulin tolerance test. About nine months after the onset of DI, secondary hypoadrenalism and hypothyroidism, which required replacement therapy, developed transiently, but recovered about one year later. Results of hypophysial endocrine tests during this period showed that the dysfunction was predominantly suprapituitary in nature. As time passed, the stalk lesion began to shrink spontaneously and another MRI, obtained five years after the onset of DI, disclosed normal findings for the infundibulo-hypophysial system, except for lack of the hyperintense signal of the neurohypophysis. The patient has since been healthy, except for the DI, which has been controlled by treatment with vasopressin. We report here a unique case of central DI associated with transient pituitary stalk enlargement.