Relationship between methylmalonic acid,homocysteine, vitamin B12 intake and status and socio-economic indices,in a subset of participants in the British National Diet and Nutrition Survey of people aged 65 y and over

OBJECTIVE: Assessment of functional vitamin B(12) status in a subset of the respondents in the British National Diet and Nutrition Survey of people aged 65 y and over. SETTING: National Diet and Nutrition Survey: a British nationwide cross-sectional sample of people aged 65 y and over, living either in the community or in institutions such as nursing homes, during one calendar year spanning 1994-1995. METHODS: Methylmalonic acid (MMA) concentrations were measured in plasma samples from 313 subjects (ca 14% of those originally enrolled in the survey). The results were compared with those for serum vitamin B(12), vitamin B(12) intakes and other status and intake estimates and with socio-demographic indices. RESULTS: Of the NDNS participants overall, 20% had serum vitamin B(12) concentrations<150 pmol/l. In the subset studied here, 24% of free-living and 46% of institution-living participants had MMA>0.5 micromol/l. Geometric mean MMA increased with age, from 0.25 micro mol/l in people aged 65-74 y to 0.38 micro mol/l in people aged 85+y. There was little evidence for any gender difference in MMA. It was inversely correlated with serum vitamin B(12) and with red blood cell folate; it was positively correlated directly with total homocysteine, but not significantly with serum folate or with vitamin B(12) intake. Among respondents with high MMA, a subgroup had normal serum vitamin B(12) but higher-than-average plasma urea and creatinine. Socio-demographic co-variates of MMA included receipt of State income benefits, social class of head of household, and educational attainment. These indices were not correlated with serum vitamin B(12). CONCLUSIONS: The progressive increase in MMA with age is metabolic evidence for increasing risk of functional vitamin B(12) deficiency with increasing age in older people. There is evidence that renal function is linked to high MMA in some older people. Age and renal function are thus both important when establishing upper reference limits for MMA. The socio-demographic observations suggest a link between poverty and poor functional vitamin B(12) status in older British people.     

New cytotoxic sesterterpenoids and norsesterterpenoids from two sponges of the genus Sarcotragus

New norsesterterpenoids (3 and 4), a sesterterpenoid (6), pyrroloterpenoids (7-10), and a stereoisomer of kurospongin (5) were isolated, along with known furanosesterterpenes (11-15), from two marine sponges of the genus Sarcotragus. The gross structures were established on the basis of NMR and MS analysis. The stereochemistry was defined by combined use of NMR and CD spectroscopy. The compounds were evaluated for cytotoxicity against five human tumor cell lines and were found to exhibit marginal to moderate activity.     

Potentiation of the antiproliferative activity of MKT-077 by loperamide, diltiazem and tamoxifen

MKT-077, a delocalized lipophilic cation, selectively targets cancer cells. MKT-077 has been reported to inhibit the growth of several tumor types and has undergone phase I clinical testing. We have examined the effect of MKT-077, alone and in combination with the antidiarrheal drug loperamide. Ten human cancer cell lines, four prostate (PC3, DU145, LNCaP, MDA-PCA-2B), two breast (MCF-7 and MDA-MB-231) and four colon (LoVo, Colo320DM, SW1116 and LS174t) were tested in vitro. Cells were grown to confluency prior to treatment. Loperamide potentiated the antiproliferative effect of MKT-077 in all ten cell lines, in a dose-dependent manner. The sensitivity of MDA-PCA-2B cells, the two breast and four colon cancer cell lines to MKT-077 was relatively low (>2.5 microg/ml MKT-077 required to inhibit growth by 95%). In these cell lines, 0.5-5 microg/ml (1-10 microM) loperamide caused a marked increase in the response to MKT-077. Loperamide is known to activate micro-opioid receptors at nanomolar concentrations and block voltage-gated calcium channels at micromolar doses. We found that calcium channel-blockers diltiazem and nifedipine (10-20 microg/ml), as well as tamoxifen (1.5-2.5 microg/ml) can also potentiate the growth-inhibitory effects of MKT-077. These synergistic interactions could be exploited for therapeutic benefit.     

Functional characterisation of nucleoside transport in rat brain endothelial cells

Multiple nucleoside transport systems exist in the body yet the subtypes functional at the blood-brain barrier (BBB) have not been fully investigated. We have employed RBE4 immortalised rat brain endothelial cells to functionally identify the carrier subtypes involved in nucleoside transfer between blood and brain. Uptake in RBE4 cells was partially sodium dependent, indicating the presence of both equilibrative and concentrative systems. Uptake of adenosine via equilibrative transporters was sensitive to nitro-benzylmercaptopurine riboside, which showed biphasic inhibition. Uptake of [3H]-adenosine via concentrative transporters was studied using the subtype-specific inhibitors thymidine (cit), formycin-B (cif) and tubercidin (cib) and was significantly reduced by thymidine and formycin-B but not by tubercidin. This study suggests that nucleoside transport at the in situ BBB may be mediated by ei and es equilibrative transporters and by cit and cif concentrative transporters.     

Homocysteine concentrations and methionine loading in patients on antiepileptic drugs

OBJECTIVES: A few reports have shown elevated fasting total plasma homocysteine (tHcy) in patients taking antiepileptic drugs (AEDs). In this study we determined the influence of AEDs on plasma tHcy levels prior to and following methionine loading. MATERIAL AND METHODS: Thirty-four patients on different AEDs and 34 matched controls were recruited. Blood samples were drawn prior to and 6 h post-methionine loading (6h-PML). RESULTS: The patients on AEDs inducing the cytochrome P450 (carbamazepine, phenytoin, phenobarbital, primidone), had higher fasting and 6h-PML plasma tHcy concentrations than the controls (P = 0.01 and P<0.001). Patients on AED inhibiting the cytochrome P450 (valproate [VPA]), had lower 6h-PML p-tHcy concentrations than controls (P = 0.01). CONCLUSIONS: Our data indicate that not only fasting but also 6h-PML tHcy levels should be determined in order to identify hyperhomocysteinemia among patients on AEDs. Inducer AEDs seem to have an opposite effect than the inhibitor VPA on plasma tHcy, erythrocyte folate and serum folate levels.     

Identification of a novel mutation in the paired domain of PAX3 in an Iranian family with Waardenburg syndrome Type I

Background: Intravenous etoposide is widely used in multiagent chemotherapy regimens for intraocular retinoblastoma despite the lack of phase II data documenting its efficacy. Because oral etoposide has been found to be highly effective in patients with relapsed medulloblastoma and neuroblastoma who had previously received intravenous etoposide, we investigated its use for intraocular retinoblastoma. Procedure: A pilot trial of oral etoposide (50mg/m 2 /day for 21 days) in five children (6 eyes) with relapsed refractory intraocular retinoblastoma was performed. All had previously received chemotherapy, including intravenous etoposide in four patients, and all had received radiation therapy. Three patients (3 eyes) had vitreous seeds. Response was evaluated after one cycle. Results: No serious acute toxicity was encountered, and no responses were noted. Four patients (5 eyes) had progressive disease. Stable disease was noted in one eye without vitreous disease. One patient developed secondary acute myeloid leukemia 30 months after exposure to oral etoposide. Conclusions: Oral etoposide was not an effective agent in this population. The role of etoposide in the treatment of higher risk intraocular retinoblastoma deserves further study.     

Online Monitoring of PLGA Microparticles Formation Using Lasentec Focused Beam Reflectance (FBRM) and Particle Video Microscope (PVM)

Knowledge of the effects of different product and process variability on microparticle characterization is essential for the successful development, optimization, and scale-up of an encapsulation process. In the current research, the qualitative application of the Lasentec focused beam reflectance (FBRM) system for online monitoring of microparticle size distribution was demonstrated. lasentec particle vision and measurement (PVM) images were also employed to follow up the steps of microparticle formation and ripening. The drug entrapment efficiency and drug release characteristics were found to be dependent on the polymer, drug, and surfactant concentrations. DSC, FTIR, and XRD data revealed that the drug was compatible with the matrix forming polymer in the solid state. As indicated from the chord count data, FBRM was sensitive to the amount of the solid materials and the number of microparticles formed. Linear relationships with good correlations were obtained between polymer, drug, and surfactant levels and the disappearance rate of 5 to 36.8, 18.4 to 135.9, and 63 to 398 µm chord length fractions. Upon organic solvent evaporation, PVM imaging detected various stages of microemulsion droplets, sheath formation, and solidification with subsequent microparticle hardening. This study illustrated the utility of FBRM and PVM in monitoring the progress of particle formation during drug encapsulation.     

Neoadjuvant treatment of advanced stage esophageal adenocarcinoma increases survival.

Sophisticated surgical approaches have a definite but limited role in esophageal cancer. The majority have systemic disease at presentation, minimal residual disease following resection or co-morbid conditions that preclude extensive surgery. This paper examines whether neoadjuvant therapy is effective in advanced-stage disease. A randomized trial, closing September 1995, was followed up to determine results at 5 years. All patients were followed up for more than 5 years. Median survival, based on intention-to-treat, was 17 months for multimodal therapy vs. 12 months for surgery alone (P=0.002). Survival based on treatment received was 27 months vs. 14 months (P=0.0006). Multimodal therapy enhances survival for patients with minimal residual disease. This is consistent with the literature. Under-powered trials cannot prove a real difference to be significant. Future trials should target patients with minimal residual disease.