Geriatric nutritional risk index as the prognostic factor in older patients with fragility hip fractures.

This study investigated the long-term survival and incidence of secondary fractures after fragility hip fractures. The 5-year survival rate was 62%, and the mortality risk was seen in patients with GNRI < 92. The 5-year incidence of secondary fracture was 22%, which was significantly higher in patients with a BMI < 20. BACKGROUND: Malnutrition negatively influences the postoperative survival of patients with fragility hip fractures (FHFs); however, little is known about their association over the long term. OBJECTIVE: This study evaluated the ability of the geriatric nutritional risk index (GNRI) as a risk factor for long-term mortality after FHFs. METHODS: This study included 623 Japanese patients with FHFs over the age of 60 years. We prospectively collected data on admission and during hospitalization and assessed the patients' conditions after discharge through a questionnaire. We examined the long-term mortality and the incidence of secondary FHFs and assessed the prognostic factors. RESULTS: The mean observation period was 4.0 years (range 0-7 years). The average age at the time of admission was 82 years (range 60-101 years). The overall survival after FHFs (1 year, 91%; 5 years, 62%) and the incidence of secondary FHFs were high (1 year, 4%; 5 years, 22%). The multivariate Cox proportional hazard analysis revealed the risk factors for mortality as older age (hazard ratio [HR] 1.04), male sex (HR 1.96), lower GNRI score (HR 0.96), comorbidities (malignancy, HR 2.51; ischemic heart disease, HR 2.24; revised Hasegawa dementia scale ≤ 20, HR 1.64), no use of active vitamin D3 on admission (HR 0.46), and a lower Barthel index (BI) (on admission, HR 1.00; at discharge, HR 0.99). The GNRI scores were divided into four risk categories: major risk (GNRI, < 82), moderate risk (82-91), low risk (92-98), and no risk (> 98). Patients at major and moderate risks of GNRI had a significantly lower overall survival rate (p < 0.001). Lower body mass index (BMI) was also identified as a prognostic factor for secondary FHFs (HR 0.88 [p = 0.004]). CONCLUSIONS: We showed that older age, male sex, a lower GNRI score, comorbidities, and a lower BI are risk factors for mortality following FHFs. GNRI is a novel and simple predictor of long-term survival after FHFs.

Evaluation of skin cancer chemoprevention potential of sunscreen agents using the Epstein-Barr virus early antigen activation in vitro assay.

In our continuing search for novel cancer chemopreventive compounds of natural and synthetic origin, we have evaluated 14 commonly used ultraviolet (UV) sunscreen agents (designated UV-1 to UV-14) for their skin cancer chemoprevention potential. They belong to 8 different chemical categories: aminobenzoate (UV-5, UV-7, UV-8 and UV-14), benzophenone (UV-1, UV-2, UV-3 and UV-13), benzotriazole (UV-10), benzyloxyphenol (UV-9), cinnamate (UV-6), quinolone (UV-4), salicylate (UV-11) and xanthone (UV-12). In the in vitro assay employed, the sunscreens were assessed by their inhibition of the Epstein-Barr virus early antigen (EBV-EA) activation induced by the tumour promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in human lymphoblastoid Raji cells. All sunscreens tested were found to exhibit anti-tumour promoting activity: listed in decreasing order, moderate (UV-11, UV-2, UV-7, UV-12, UV-3, UV-9 and UV-14) to weak (UV-1, UV-6, UV-8, UV-16, UV-5, UV-4 and UV-10) with octyl salicylate (UV-11) as the most potent and drometrizole (UV-10) as the least potent among the compounds evaluated. A plausible relationship between the antioxidant property of sunscreens and their ability to promote anti-tumour activity was noted. The results call for a comprehensive analysis of skin cancer chemoprevention potential of currently used UV sunscreen agents around the globe to identify those with the best clinical profile.

Revascularization by percutaneous transluminal angioplasty improved abruptly deteriorated ischaemic symptoms in cutaneous polyarteritis nodosa.

We report a patient with cutaneous polyarteritis nodosa, who had a 3-year history of recurrent leg and foot ulcers. Symptoms of ischaemia in the left foot, including severe pain, coldness, paraesthesia and violaceous discoloration, deteriorated abruptly, because of complete occlusion of the left anterior tibial artery. The occluded segment was revascularized by percutaneous transluminal angioplasty, resulting in a dramatic improvement in the ischaemic symptoms.

Excitatory synaptogenesis between identified Lymnaea neurons requires extrinsic trophic factors and is mediated by receptor tyrosine kinases.

Neurotrophic factors have well established roles in neuronal development and adult synaptic plasticity, but their precise role in synapse formation has yet to be determined. This paper provides the first direct evidence that neurotrophic factors in brain conditioned medium (CM) differentially regulate excitatory and inhibitory synapse formation. Somata of identified presynaptic and postsynaptic neurons were isolated from the CNS of Lymnaea and were cultured in a soma-soma configuration in the presence (CM) or absence [defined medium (DM)] of trophic factors. In DM, excitatory synapses did not form. When they were paired in CM or in DM containing Lymnaea epidermal growth factor (EGF); however, all presynaptic neurons reestablished their specific excitatory synapses, which had electrical properties similar to those seen in vivo. CM-induced formation of excitatory synapses required transcription and de novo protein synthesis, as indicated by the observations that synapse formation was blocked by the protein synthesis inhibitor anisomycin and the protein transcription blocker actinomycin D; the CM factor was inactivated by boiling. They were also blocked by receptor tyrosine kinase inhibitors (lavendustin A, genistein, K252a, and KT5926) but not by inactive analogs (genistin and lavendustin B), suggesting that the effect was mediated by receptor tyrosine kinases. These results, together with our previously published data, demonstrate that trophic factors are required for excitatory, but not inhibitory, synapse formation and extends the role of EGF from cell proliferation, neurite outgrowth, and survival to excitatory synapse formation.

A statistical mechanical analysis of the effect of long-chain alcohols and high pressure upon the phase transition temperature of lipid bilayer membranes.

Long-chain n-alcohols decrease the main phase-transition temperature of lipid vesicle membranes at low concentrations but increase it at high concentrations. The nonlinear phenomenon is unrelated to the interdigitation and is analyzed by assuming that alcohols form solid solutions with solid as well as liquid phases. The biphasic response originates from the balance of the free energy difference of alcohols in the liquid and solid membranes (delta gA) and the alcohol-lipid interaction free energy difference (delta u) between the two phases. When delta gA less than 0 and delta u greater than 0, or delta gA less than delta u less than 0, the transition temperature decreases monotonously according to the increase in the alcohol concentration. When delta gA greater than 0 and delta u less than 0, or delta gA greater than delta u greater than 0, it increases monotonously. Biphasic response occurs with a minimum temperature when delta u greater than delta gA greater than 0, and with a maximum temperature when delta u less than delta gA less than 0. When the alcohol carbon-chain length becomes closer to the lipid carbon-chain length, delta u is equalized by delta gA, and the temperature minimum of the main transition is shifted to extremely low alcohol concentrations. Hence, long-chain alcohols predominantly elevate the main transition temperature and lose their anesthetic potency. High pressure decreased both delta gA and delta u. Presumably, high pressure improves the packing efficiency of liquid membranes and decreases the difference between the solid and liquid membrane properties.

Monocarboxylic acids enhance the anesthetic action of procaine by decreasing intracellular pH.

Sodium monocarboxylates are known to enhance the anesthetic action of procaine, and also decrease intracellular pH (pHi). We studied the effect of 30 mM Na monocarboxylates (formate, acetate, propionate, butyrate, and salicylate) on the pHi and on the anesthetic action of procaine HCl using giant axons of crayfish (Procambarus clarkii). The pHi was measured using pH sensitive microelectrode method and the anesthetic action was evaluated by the change in the action potential (AP) amplitude. The tested acids except for formate showed apparent decrease in pHi and enhancement of the action of 2 mM procaine. Other organic acids (maleate and benzensulfonate) did not affect pHi and anesthetic action of procaine. In the bicarbonate free solution, pHi increased and the anesthetic action was weakened. The EC25 values (the concentration of procaine which depresses the AP amplitude by 25%) of acetate, propionate, and bicarbonate free solution were coincided with the predicted EC25 values from the simple simulation on intracellular procaine increase according to the pHi change. But the EC25 value of salicylate group was less than half of the predicted. These results suggested that the enhancing action of straight chain monocarboxylic acids is due to pHi decrease, and salicylate has other additional mechanisms.

Structural characteristics of the N-glycans of two isoforms of prostate-specific antigens purified from human seminal fluid.

Prostate-specific antigen (PSA) is a glycosylated chymotrypsin-like serine protease and is found mainly in prostatic tissue and seminal fluid. We purified two forms of PSA (PSA-A and PSA-B) from human seminal fluid with pI values of approx. 7.2 and approx. 6.9, respectively. To characterize the N-glycans of the two isoforms, the sugar chains were liberated by hydrazinolysis followed by N-acetylation, and derivatized with 2-aminobenzamide. Both PSA-A and PSA-B contained mono- and disialylated sugar chains, although PSA-B had a much higher content of the latter. After removal of sialic acid residues by sialidase digestion, mono- and biantennary N-glycans and three outer chain moieties (Galbeta1-4GlcNAcbeta1-, GlcNAcbeta1-, GalNAcbeta1-4GlcNAcbeta1-) were found in both samples. However, the ratios of each N-glycan were different. These results indicate that PSA-A and PSA-B differ not only in their sialic acid contents, but also in their outer chain features.

The POU domain gene, XlPOU 2 is an essential downstream determinant of neural induction.

The POU domain gene, XlPOU 2, acts as a transcriptional activator during mid-gastrulation in Xenopus. Overexpression or misexpression of VP16-POU-GR, a fusion protein consisting of the strong activator domain of VP16 and the POU domain of XlPOU 2, results in ectopic expression of the neural-specific genes, nrp-1, en-2, and beta-tubulin. In contrast, overexpressing a dominant-inhibitory form of XlPOU 2 inhibits the chordin-induced neuralization of uncommitted ectoderm, and results in a loss of nrp-1 and en-2 expression in embryos. Furthermore, in uncommitted ectoderm, XlPOU 2 regulates the developmental neural program that includes a number of pre-pattern genes and at least one proneural gene, X-ngnr-1, thus playing a key role during neural determination.

Cloning and expression of a novel zinc finger gene, Fez, transcribed in the forebrain of Xenopus and mouse embryos.

We have identified and cloned a novel zinc finger gene, Fez (forebrain embryonic zinc-finger), as a potential downstream determinant of anterior neural plate formation in Xenopus. Fez was isolated as one of several neural-specific genes that was induced by the neuralizing factor, noggin (Smith and Harland, 1992. Cell 70, 829-840), in uncommitted ectoderm. Fez has an open reading frame comprising 466 amino acids, and contains six C(2)H(2) type zinc finger domains, which are highly conserved among Drosophila, zebrafish, mouse, and human. In Xenopus, the expression of Fez begins at stage 12 in the rostral end of the neural plate, and by stage 45, it is localized to several telencephalic regions, including the olfactory bulbs, nervus terminalis, and ventricular zone. The mouse homologue of Fez is similarly expressed in the mouse forebrain by embryonic day 11.

Differential regulation of Dlx gene expression by a BMP morphogenetic gradient.

Three members of the vertebrate Distal-less gene family, Dlx3, 5 and 6, are transcribed in early gastrula embryos of Xenopus laevis. This expression is confined to ectoderm and is excluded from the presumptive neural plate region. Expression of all three genes is dependent upon BMP signaling, with significant differences in how the three genes respond to the BMP antagonist chordin. This correlates with the different expression domain boundaries in vivo for Dlx3 compared to Dlx5 and 6, suggesting that BMP signal attenuation could be the primary factor in determining these different patterns in the gastrula ectoderm.

Cooperative effects of exercise training and genistein administration on bone mass in ovariectomized mice.

We reported that genistein, a soybean isoflavone, prevents bone loss caused by estrogen deficiency, without undesirable effects on the uterus. In this study, we examined cooperative effects of genistein administration and running exercise on bone mass in ovariectomized (OVX) mice. Female mice aged 7 weeks were either sham-operated or OVX and divided into six groups: (1) sham; (2) OVX; (3) OVX, treated with genistein at a submaximal dose (0.4 mg/day) subcutaneously (G); (4) OVX, exercised on a treadmill daily for 30 minutes/day at 12 m/minute on a 10 degree uphill slope (Ex); (5) OVX, given genistein and exercised (ExG); and (6) OVX, treated with 17beta-estradiol (0.03 microg/day) in the same manner as genistein (E2). Four weeks after intervention, bone mass was estimated by dual-energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT). Bone mineral density (BMD) of the whole femur measured by DXA was higher in both the G and the Ex groups than in the OVX group. Furthermore, BMD in the ExG group was significantly higher than that in the groups receiving either intervention alone. Bone area in distal region of the femur was significantly higher in Ex and ExG groups as compared with those in the OVX and G groups. pQCT analysis showed that the cross-sectional areas (CSAs) and periosteum perimeter at midshaft of the femur did not differ in the sham and OVX groups but were significantly higher in Ex and ExG groups. Histomorphometric analysis showed that bone formation rate/bone surface (BFR/BS) was significantly higher in both Ex and ExG groups as compared with that in non-exercised groups. The bone volume (BV/TV) in the distal femoral cancellous bone was lower in the OVX than that in the sham group, and it was restored completely in the ExG group, as in the E2 group. Thickness of the trabecular bone (Tb.Th) was higher in Ex and ExG groups than that in the OVX and G groups. These results indicate that the combined intervention of moderate exercise and the submaximal dose of genistein administration show a cooperative effect in preventing bone loss in OVX mice.

Simultaneous activation of N-methyl-D-aspartate and neurokinin-1 receptors modulates c-Fos and Zif/268 expression in the rat trigeminal nucleus caudalis.

We examined the acute expression of c-Fos or Zif/268 by simultaneous activation of N-methyl-D-aspartate receptor and neurokinin-1 receptor of the trigeminal nucleus caudalis in anesthetized rats. A selective N-methyl-D-aspartate receptor agonist, N-methyl-D-aspartate, and/or a selective neurokinin-1 receptor agonist, substance P, was applied topically to the dorsal surface of the spinal trigeminal tract. Immunohistochemically stained nuclei for c-Fos and Zif/268 at laminae I and II of the trigeminal nucleus caudalis were counted. Ipsilateral c-Fos and Zif/268 were increased significantly dose-dependently by N-methyl-D-aspartate (at 136 and 340 microM, and at 68, 136 and 340 microM, respectively). On the contralateral side, only Zif/268 increased significantly (at 68, 136 or 340 microM). These increases were abolished by D-2-amino-5-phosphonovaleric acid (at 25 mM), a selective N-methyl-D-aspartate receptor antagonist. Substance P (at 3.7 or 7. 4 microM) significantly increased dose-dependently ipsilateral c-Fos and Zif/268. On the contralateral side, only c-Fos was significantly increased (at 3.7 and 7.4 microM). These increases were abolished by D-2-amino-5-phosphonovaleric acid (at 25 mM) and L-703,606 (at 10 microM), a selective neurokinin-1 receptor antagonist. The combined application of N-methyl-D-aspartate 340 microM + substance P (at 0.74 or 3.7 microM) significantly increased ipsilateral c-Fos compared to either agent alone. Combined application of N-methyl-D-aspartate 340 microM + substance P at 0.74, 3.7 or 7.4 microM significantly increased ipsilateral Zif/268 expression compared to either drug alone. Other combinations did not increase c-Fos and Zif/268. Our results indicate that activation of N-methyl-D-aspartate or neurokinin-1 receptor of the trigeminal nucleus caudalis contributes to the acute induction of both c-Fos and Zif/268 on the ipsilateral superficial layer of this nucleus and simultaneous activation of both receptors by their agonists with specific concentrations produces a marked expression of these proteins. Simultaneous activation of N-methyl-D-aspartate and neurokinin-1 receptors under some specific conditions may augment synaptic transmission, contributing to long-term neuronal change.

Donepezil hydrochloride preserves regional cerebral blood flow in patients with Alzheimer's disease.

UNLABELLED: The aim of this SPECT study was to investigate the effects of donepezil on regional cerebral blood flow (rCBF) in patients with mild to moderate Alzheimer's disease (AD) using statistical parametric mapping. METHODS: rCBF was noninvasively measured using (99m)Tc-ethyl cysteinate dimer in 35 AD patients with a Mini-Mental State Examination score > 16 on initial evaluation. Baseline and follow-up SPECT studies with a mean interval of 12 mo were performed on these patients. We used the adjusted rCBF images in the relative flow distribution (normalization of global cerebral blood flow for each patient to 50 mL/100 g/min with proportional scaling) to compare these groups through statistical parametric mapping. RESULTS: In the follow-up study, the adjusted rCBF was significantly preserved in the right and left anterior cingulate gyri, right middle temporal gyrus, right inferior parietal lobules, and prefrontal cortex of donepezil-treated AD patients, compared with placebo-treated AD patients. CONCLUSION: Treatment with donepezil for 1 y appears to reduce the decline in rCBF, suggesting preservation of functional brain activity.

Longitudinal evaluation of early Alzheimer's disease using brain perfusion SPECT.

UNLABELLED: The aim of this SPECT study was to determine the initial abnormality and longitudinal changes in regional cerebral blood flow (rCBF) in early Alzheimer's disease (AD) using statistical parametric mapping (SPM). METHODS: rCBF was noninvasively measured using (99m)Tc-ethyl cysteinate dimer SPECT in 32 patients complaining of mild cognitive impairment, with a Mini-Mental State Examination score more than 24 at the initial study, and 45 age-matched healthy volunteers. All patients satisfied the diagnostic criteria of AD during the follow-up period of at least 2 y. Follow-up SPECT studies were performed on the patients at a mean interval of 15 mo. We used the raw data (absolute rCBF parametric maps) and the adjusted rCBF images of relative flow distribution (normalization of global cerebral blood flow [CBF] for each subject to 50 mL/100 g/min with proportional scaling) to compare these groups with SPM. RESULTS: In the baseline study, the adjusted rCBF was significantly and bilaterally decreased in the posterior cingulate gyri and precunei of patients compared with healthy volunteers. In the follow-up study, selected reduction of the adjusted rCBF was observed in the left hippocampus and parahippocampal gyrus. These areas showed the most prominent reduction in absolute rCBF on each occasion. Moreover, further decline of the absolute rCBF was longitudinally observed in extensive areas of the cerebral association cortex. CONCLUSION: SPM analysis showed the characteristic early-AD rCBF pattern of selective decrease and longitudinal decline, which may be overlooked by a conventional region-of-interest technique with observer a priori choice and hypothesis. This alteration in rCBF may closely relate to the pathophysiologic process of this disease.

Cancer chemopreventive activity of an iridoid glycoside, 8-acetylharpagide, from Ajuga decumbens.

In the course of our continuing search for novel cancer chemopreventive agents from natural sources, several kinds of Labiatae plants were screened. Consequently, the iridoid glycoside derivative, 8-acetylharpagide (8-AcHarp), was obtained from the flowering whole plant of Ajuga decumbens as an active constituent. This glycoside exhibited the remarkable inhibitory effect on two-stage carcinogenesis test of mouse skin tumors induced by nitric oxide (NO) donor, (+/-)-(E)-methyl-2-[(E)-hydroxyimino]-5-nitro-6-methoxy-3-hexen eamide (NOR 1) as an initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as a promoter. Further, 8-AcHarp exhibited potent anti-tumor-promoting activity on two-stage carcinogenesis test of mouse hepatic tumor using N-nitrosodiethylamine (DEN) as an initiator and phenobarbital (PB) as a promoter.

Cancer chemopreventive activity of phenylpropanoid esters of sucrose, vanicoside B and lapathoside A, from Polygonum lapathifolium.

To search for cancer chemopreventive agents from natural resources, many phytochemicals have been screened using the in vitro synergistic assay indicated by the inhibitory effects on the induction of Epstein-Barr virus early antigen (EBV-EA) by 12-O-tetradecanoylphorbol-13-acetate (TPA). Two phenylpropanoid esters of sucrose, vanicoside B and lapathoside A, were isolated from the aerial part of Polygonum lapathifolium as inhibitors on the EBV-EA induction. These compounds also exhibited significant anti-tumor-promoting effects on mouse two-stage skin carcinogenesis induced by 7,12-dimethylbenz[a]anthracene (DMBA, as an initiator) and TPA as a promoter. Further, vanicoside B exhibited the remarkable inhibitory effect on two-stage carcinogenesis test of mouse skin tumors initiated with an NO donor, NOR-1.

Anti-tumor-promoting activity of lignans from the aerial part of Saussurea medusa.

In the course of our continuing search for novel cancer chemopreventive agents from natural sources, several kinds of Compositae plants were screened. Consequently, the lignans, arctiin (ARC) and arctigenin (ARC-G), were obtained from the aerial part of Saussurea medusaas active constituents. These compounds exhibited the remarkable anti-tumor-promoting effect on two-stage carcinogenesis test of mouse skin tumors induced by 7, 12-dimethylbenz[a]anthracene as an initiator and 12-O-tetradecanoyl phorbol-13-acetate as a promoter by both topical application and oral administration. Furthermore, ARC-G exhibited potent anti-tumor-promoting activity on two-stage carcinogenesis test of mouse pulmonary tumors induced by 4-nitroquinoline-N-oxide as an initiator and glycerol as a promoter.

Cancer chemopreventive activity of euglobal-G1 from leaves of Eucalyptus grandis.

In the course of our continuing search for novel cancer chemopreventive agents from natural sources, several kinds of Eucalyptus plants were screened. Consequently, the phlorogrucinol-monoterpene derivative, euglobal-G1 (EG-1), was obtained from the leaves of Eucalyptus grandis as an active constituent. EG-1 exhibited the remarkable inhibitory effect on two-stage carcinogenesis test of mouse skin tumors induced by 7, 12-dimethylbenz[a]anthracene (DMBA) as an initiator and fumonisin-B1, which has been known as one of mycotoxins produced by Fusarium monifliforme, as a promoter. Further, EG-1 exhibited potent anti-tumor-promoting activity on two-stage carcinogenesis test of mouse pulmonary tumor using 4-nitroquinoline-N-oxide (4-NQO) as an initiator and glycerol as a promoter.

Inhibition of epstein-barr virus early antigen activation promoted by 12-O-tetradecanoylphorbol-13-acetate by the non-steroidal anti-inflammatory drugs.

As part of our screening program for cancer inhibitory agents effective specifically in the promotion stage of cancer development, we have evaluated the possible inhibitory effects of 36 non-steroidal anti-inflammatory drugs (NSAIDs) on the Epstein-Barr virus early antigen (EBV-EA) activation which was induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. All the drugs were observed to inhibit the EBV-EA activation at low doses with low toxicity. The two most active anti-tumor promoting agents were the arylacetic acid derivatives, etodolac and sulindac. We also report for the first time the activities of 14 new NSAIDs belonging to different classes as potential cancer chemopreventive agents. A structure-activity relationship study showed that among the salicylic acid derivative tested, the oxidation of the thiol group to dithiol derivatives results in the reduction of the activity. Introduction of amino group on the salicylic acid molecules also results in the reduction of activity in the EBV-EA assay. The results are of great interest in the development of NSAIDs as cancer chemopreventive agents, which halt cancer progression in multistage carcinogenesis, where successive activities are required to evolve into fully-fledged and metastatic cancer.

Anti-tumor promoting activity of Dryopteris phlorophenone derivatives.

As a part of screening studies for cancer chemopreventive agents (anti-tumor promoters) 33 Dryopteris phlorophenone derivatives have been evaluated. The compounds tested comprised of monomeric acylphloroglucinols (e.g. desaspidinol, aspidinol) as well as dimeric (e.g. aspidin, desaspidin), trimeric (e.g. filixic acids), and tetrameric (e.g. dryocrassin) phlorophenone, wherein hexacyclic rings are bound together by a methylene bridge. These compounds were examined for their in vitro anti-tumor promoting effect on Epstein-Barr virus antigen activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). The two dimeric compounds aspidin and desaspidin, which were found to be the most active among the tested phlorophenones, were also examined in vivo on two stage mouse skin carcinogenesis, and found to show significant inhibitory effect on 7,12-dimethylbenz[alpha]anthracene (DMBA)-TPA tumor promotion.