Multiple vitamin deficiencies additively increase the risk of incident fractures in Japanese postmenopausal women.

The associations of multiple vitamin deficiencies on incident fractures were uncertain, the relationships between serum vitamin markers and incident bone fractures were investigated in Japanese postmenopausal women. The number of deficiencies was additively associated with incident fracture after adjustment for possible confounding factors including the treatment of osteoporosis. INTRODUCTION: To evaluate the associations of multiple vitamin deficiencies on incident fractures, the relationships between serum vitamin markers and incident bone fractures were investigated in Japanese postmenopausal women. METHODS: This analysis used a subset of the ongoing cohort maintained by a primary care institution. Inclusion criteria of the present study were postmenopausal women aged ≥ 50 years, without vitamin supplementation and secondary osteoporosis. Baseline serum concentrations of 25-hydroxyvitamin D (25(OH)D), undercarboxylated osteocalcin (ucOC), and homocysteine (Hcy) were measured to assess vitamin D, vitamin K, and vitamin B, respectively. Since 25(OH) D positively relates to vitamin D, ucOC and Hcy negatively relate to vitamin K and vitamin B nutrients, respectively, the subjects with lower (25(OH)D) or higher (ucOC or Hcy) values than each median value was defined as subjects with the corresponding vitamin deficiency. Subjects were divided into four groups according to the number of deficiency: no deficiency, single deficiency, double deficiencies, and triple deficiencies. Relationships between the vitamin deficiencies and incident fractures were evaluated by Cox regression analysis. RESULTS: A total of 889 subjects were included in this analysis; their mean and SD age was 68.3 ± 9.5 years, and the follow-up period was 6.3 ± 5.1 years. The numbers of subjects in the four groups were 139 (15.6%), 304 (34.2%), 316 (35.5%), and 130 (14.6%) for the groups with no, single, double, and triple deficiencies, respectively. Incident fractures were observed in 264 subjects (29.7%) during the observation period. The number of deficiencies was significantly associated with incident fracture (hazard ratio 1.25, 95% confidence interval 1.04-1.50, P = 0.018) after adjustment for possible confounding factors including the treatment of osteoporosis. CONCLUSION: Accumulation of vitamin deficiencies was related to incident fractures.

High and pointed type of femoral localized reaction frequently extends to complete and incomplete atypical femoral fracture in patients with autoimmune diseases on long-term glucocorticoids and bisphosphonates.

Once a localized reaction (beaking) was detected, discontinuation of bisphosphonates (BPs) and switching to vitamin D supplementation or teriparatide therapy effectively improved its shape. When the localized reaction was high, of the pointed type, and/or accompanied by prodromal pain, the risks of complete and incomplete atypical femoral fracture increased and consideration of prophylactic fixation for such patients was required. INTRODUCTION: Femoral localized reaction (localized periosteal thickening of the lateral cortex, beaking) is reported to precede atypical femoral fractures (AFFs) and to develop in 8-10% of patients with autoimmune diseases taking BPs and glucocorticoids. The aims of the present study were to retrospectively investigate the shapes of localized reaction to consider how to manage the condition. METHODS: Twenty femora of 12 patients with autoimmune diseases who were on BPs and glucocorticoids exhibited femoral localized reaction. The heights of localized reaction were measured and the shapes classified as pointed, arched, and other. Localized reaction changes were divided into three categories: deterioration, no change, and improvement. A severe form of localized reaction was defined; this was associated with prodromal pain, de novo complete AFF, or incomplete AFF with a fracture line at the localized reaction. RESULTS: The mean height of localized reaction was 2.3 ± 0.8 mm (range, 1.0-3.7 mm) and the pointed type was 35%. Localized reaction was significantly higher (3.3 ± 0.8 vs. 2.1 ± 0.7 mm; p = 0.003) and the pointed type more common (78 vs. 27%; p = 0.035) in those with the severe form of localized reaction. Seven patients with localized reactions discontinued BPs just after localized reaction was detected, but five continued on BPs for 2 years. Localized reaction deterioration was more common in patients who continued than discontinued BPs (100 vs. 29%; p = 0.027). After 2 years, all patients had discontinued BPs and localized reaction did not deteriorate further in any patient. CONCLUSIONS: Once a localized reaction was detected, discontinuation of BPs and switching to vitamin D supplementation or teriparatide therapy effectively improved it. When the localized reaction was high, of the pointed type, and/or accompanied by prodromal pain, the risks of complete and incomplete AFF increased and consideration of prophylactic fixation for such patients was required.

Changes in the contents of enzymatic immature, mature, and non-enzymatic senescent cross-links of collagen after once-weekly treatment with human parathyroid hormone (1-34) for 18 months contribute to improvement of bone strength in ovariectomized monkeys.

UNLABELLED: Improvements in total content of enzymatic cross-linking, the ratio of hydroxylysine-derived enzymatic cross-links, and non-enzymatic advanced glycation end product cross-link formation from once-weekly administration of hPTH(1-34) for 18 months in OVX cynomolgus monkeys contributed to the improvement of bone strength. INTRODUCTION: Parathyroid hormone (PTH) is used for the treatment of osteoporosis. To elucidate the contribution of material properties to bone strength after once-weekly treatment with hPTH(1-34) in an ovariectomized (OVX) primate model, the content of collagen and enzymatic immature, mature, and non-enzymatic cross-links, collagen maturity, trabecular architecture, and mineralization in vertebrae were simultaneously estimated. METHODS: Adult female cynomolgus monkeys were divided into four groups (n = 18-20 each) as follows: SHAM group, OVX group, and OVX monkeys given once-weekly subcutaneous injections of hPTH(1-34) either at 1.2 or 6.0 µg/kg (low- or high-PTH groups) for 18 months. The content of collagen, enzymatic and non-enzymatic cross-linking pentosidine, collagen maturity, trabecular architecture, mineralization, and cancellous bone strength of vertebrae were analyzed. RESULTS: Low-PTH and high-hPTH treatments increased the content of enzymatic immature and mature cross-links, bone volume (BV/TV), and trabecular thickness, and decreased pentosidine, compared with the OVX group. Stepwise logistic regression analysis revealed that BV/TV, the content of total enzymatic cross-links, and calcium content independently affected ultimate load (model R (2) = 0.748, p < 0.001) and breaking energy (model R (2) = 0.702, p < 0.001). BV/TV was the most powerful and enzymatic cross-link content was the second powerful determinant of both ultimate load and breaking energy. The most powerful determinant of stiffness was the enzymatic cross-link content (model R (2) = 0.270, p < 0.001). CONCLUSION: Once-weekly preventive administration of hPTH(1-34) increased the total contents of immature and mature enzymatic cross-links, which contributed significantly to vertebral cancellous bone strength.

Novel, potent, and selective phosphodiesterase-4 inhibitors as antiasthmatic agents: synthesis and biological activities of a series of 1-pyridylnaphthalene derivatives.

The structural requirements for potent and selective PDE4 inhibition were revealed in a 1-pyridylnaphthalene series, and the best compound (3kg, T-2585.HCl) was chosen for further biological evaluation (PDE4 inhibition IC50 = 0.13 nM, selectivity PDE3/4 ratio = 14 000). Compound 3kg showed potent antispasmogenic activities (ED50 = 0.063 mg/kg for reduction of antigen-induced bronchoconstriction, intravenously; ED50 = 0.033 mg/kg for reduction of histamine-induced bronchoconstriction, intraduodenally) in guinea pigs with little cardiovascular effects. Furthermore, 3kg induced significantly weaker emetic effects than RP73401 after oral administration in ferrets and intravenous administration in dogs (3kg, none of 4 ferrets vomited at a dose of 10 mg/kg, po and none of 8 dogs vomited at a dose of 0.3 mg/kg, iv; RP73401, 4 of 8 ferrets vomited at a dose of 3 mg/kg, po and 6 of 8 dogs vomited at a dose of 0.3 mg/kg, iv); that is compatible with the lower affinity for the high-affinity rolipram binding site (3kg, 2.6 nM; RP73401, 0. 85 nM). This may imply that 3kg has an improved therapeutic ratio because of a broad margin between the Ki value of binding affinity and the IC50 value of PDE4 inhibition (ratio = 0.050).

Hepatoma-derived growth factor belongs to a gene family in mice showing significant homology in the amino terminus.

Hepatoma-derived growth factor (HDGF) is an acidic polypeptide with mitogenic activity for fibroblasts performed outside the cells despite the presence of a putative nuclear localization signal (NLS). We have now cloned three related mouse cDNAs: one for a mouse homologue of human HDGF and two for additional HDGF-related proteins provisionally designated HDGF-related proteins 1 and 2 (HRP-1 and -2). Their deduced sequences have revealed that HDGF belongs to a new gene family with a highly conserved 98-amino-acid sequence at the amino terminus (hath region, for homologous to the amino terminus of HDGF). HRP-1 and HRP-2 proteins are 46 and 432 amino acids longer than mouse HDGF, respectively, and have no conserved amino acid sequence other than the hath region. HRP-1 is a highly acidic protein (26% acidic) and also has a putative NLS. HRP-2 protein carries a mixed charge cluster, a sharp switch of positive-to negative-charge residues, which is often found in some nuclear proteins. Northern blotting shows that mouse HDGF and HRP-2 are expressed predominantly in testis and skeletal muscle, to intermediate extents in heart, brain, lung, liver, and kidney, and to a minimal extent in spleen. HRP-1 is expressed specifically in testis. These findings suggest that the HDGF gene family might play a new role in the nucleus especially in testis.

[The relationship between TSH response to TRH and GH response to dopaminergic agents in patients with acromegaly].

The role of dopaminergic agents (DA) in the regulation of growth hormone (GH) secretion was investigated in patients with untreated acromegaly. TRH (0.5 mg iv), bromocriptine (Br) (2.5 mg orally) or L-Dopa (500 mg orally) loading tests were performed, and serum levels of TSH, GH and prolactin (PRL) were measured. Patients were defined as responders to TRH when peak TSH level after TRH test was higher than 5 microU/ml. Br or L-Dopa was considered to be effective when serum GH or PRL levels were suppressed more than 50% of the basal value. The patients were classified into large adenoma group with suprasellar extension or cisternal herniation (L group, n = 7) and intrasellar small adenoma group (S group, n = 11) which was further divided into TRH responder (Sr group, n = 4) and TRH non-responder with suppressed TSH (Ss group, n = 7). Br was effective in 7 or 100% of 7 patients in the Ss group but only in one or 25% of 4 patients in the Sr group. Br was also effective in 5 or 71% of 7 patients in the L group, although most of them were responders to TRH. Percent inhibition of serum GH levels by Br was significantly higher in the Ss group (82.3 +/- 12.3%, p less than 0.001) and in the L group (64.7 +/- 20.5%, p less than 0.05) compared with that in the Sr group (29.3 +/- 21.6%). Suppression of serum GH level by L-Dopa was also observed in the Ss group. In contrast to the difference in the response of GH, serum PRL level was equally suppressed by Br or L-Dopa in each group. Suppression of TSH by administration of exogenous T4 had no effect on the GH suppression effect of Br in the Sr group. Considering the dual effects of DA to enhance growth hormone-releasing hormone (GHRH) secretion in the hypothalamus and to suppress GH secretion in the pituitary gland, these findings suggest that the paradoxical effect of DA to suppress serum GH level is observed when the hypothalamo-pituitary axis is disturbed mechanically by large adenoma in the L group or functionally in the Ss group probably due to enhanced secretion of somatostatin which suppresses TSH secretion and impairs the effect of GHRH.

[Usefulness of subcutaneously implanted reservoir for postoperative therapy in hepatocellular carcinoma and liver metastases of colorectal carcinoma].

Hepatectomy has been a treatment of choice for hepatocellular carcinoma and metastatic liver carcinoma. Recurrence in residual liver after hepatectomy is clinically a serious problem. Since 1987, postoperative hepatic arterial infusion chemotherapy using subcutaneously implanted reservoir has been undertaken to improve the prognosis after hepatectomy in hepatocellular carcinoma and liver metastasis of colorectal carcinoma. The indications for reservoir implantation were determined for high-risk cases in hepatocellular carcinoma and all cases in liver metastasis. The tip of a catheter was placed at the root of the common hepatic artery via gastroduodenal artery. Lipiodol-ADM was injected for hepatocellular carcinoma every 2 months and MMC-5-FU was injected for liver metastasis of colorectal carcinoma every one or two weeks. Complications of this procedure in every 2 cases of reservoir infection proved to be catheter obstruction and hepatic artery obstruction. In the process of this treatment, we observed 3 recurrences in residual liver of hepatocellular carcinoma and one case of peritoneal dissemination and 3 recurrences in residual liver of liver metastasis of colorectal carcinoma. All are still alive.

Immunopharmacological actions of the new antiallergic drug butyl 3'-(1H-tetrazol-5-yl)oxanilate. 2nd communication: inhibitory effects on histamine release from rat mast cells and lung fragments.

The effects of butyl 3'-(1H-tetrazol-5-yl)oxanilate (WP-833), a new antiallergic drug, on its ability to inhibit histamine release from both peritoneal mast cells and lung fragments of rats were investigated. WP-833 inhibited in a dose-dependent fashion immunoglobulin E (IgE)-mediated histamine release from mast cells. Such potent inhibition was observed in glucose-free as well as complete Tyrode's solution but neither in Ca2+-free nor D2O-supplemented Tyrode's solution. In addition, WP-833 significantly increased intracellular cyclic adenosine monophosphate (AMP) levels in purified mast cells. On the other hand, WP-833 inhibited compound 48/80-but not calcium ionophore A23187-induced histamine release from normal mast cells. Also both IgE- and IgG-mediated histamine release from lung fragments were inhibited by WP-833. WP-833 showed non-competitive inhibition of cyclic AMP-dependent phosphodiesterase derived from lung preparations.

Pharmacokinetic studies on pharmacologic response of captopril in rats.

After administration of captopril, a decrease in mean arterial blood pressure was observed in low sodium rats which were used as animal models of hyper-renin-active pathema. In normal rats, however, this marked decrease in blood pressure was not observed, even with high dose levels. In spite of the fact that captopril does not lower the blood pressure in normal rats, it was demonstrated that converting-enzyme activity was inhibited by captopril. No differences were observed between low sodium rats and normal rats in characteristics of angiotensin-converting enzyme. It was concluded that disposition of captopril might be different in the respective rats.