Non-invasive therapy to reduce the body burden of aluminium in Alzheimer's disease

There are unexplained links between human exposure to aluminium and the incidence, progression and aetiology of Alzheimer's disease. The null hypothesis which underlies any link is that there would be no Alzheimer's disease in the effective absence of a body burden of aluminium. To test this the latter would have to be reduced to and retained at a level that was commensurate with an Alzheimer's disease-free population. In the absence of recent human interference in the biogeochemical cycle of aluminium the reaction of silicic acid with aluminium has acted as a geochemical control of the biological availability of aluminium. This same mechanism might now be applied to both the removal of aluminium from the body and the reduced entry of aluminium into the body while ensuring that essential metals, such as iron, are unaffected. Based upon the premise that urinary aluminium is the best non-invasive estimate of body burden of aluminium patients with Alzheimer's disease were asked to drink 1.5 L of a silicic acid-rich mineral water each day for five days and, by comparison of their urinary excretion of aluminium pre-and post this simple procedure, the influence upon their body burden of aluminium was determined. Drinking the mineral water increased significantly (P<0.001) their urinary excretion of silicic acid (34.3 +/- 15.2 to 55.7 +/- 14.2 micromol/mmol creatinine) and concomitantly reduced significantly P=0.037) their urinary excretion of aluminium (86.0 +/- 24.3 to 62.2 +/- 23.2 nmol/mmol creatinine). The latter was achieved without any significant (P>0.05) influence upon the urinary excretion of iron (20.7 +/- 9.5 to 21.7 +/- 13.8 nmol/mmol creatinine). The reduction in urinary aluminium supported the future longer-term use of silicic acid as non-invasive therapy for reducing the body burden of aluminium in Alzheimer's disease.     

Plasma nitrendipine concentrations in elderly hypertensive patients after single and multiple dosing.

Twenty-three elderly hypertensive subjects received nitrendipine 10mg daily by mouth for 8 days. Plasma nitrendipine concentrations were measured after the first and last dose. There was no significant difference in plasma concentrations at any time point between the two days nor in derived pharmacokinetic measurements. Drug accumulation was not observed.     

Respiratory function in the prune-belly syndrome

Respiratory function was evaluated in 11 patients with prune-belly syndrome. Nine had evidence of gas trapping and six of restrictive lung disease. These abnormalities of lung function appear to be secondary to the musculoskeletal disorder associated with prune-belly syndrome rather than parenchymal lung disease.     

Dummies and the sudden infant death syndrome

The association between dummy use and sudden infant death syndrome (SIDS) was investigated in 485 deaths due to SIDS in the postneonatal age group and compared with 1800 control infants. Parental interviews were completed in 87% of subjects. The prevalence of dummy use in New Zealand is low and varies within New Zealand. Dummy use in the two week period before death was less in cases of SIDS than in the last two weeks for controls (odds ratio (OR) 0.76, 95% confidence interval (CI) 0.57 to 1.02). Use of a dummy in the last sleep for cases of SIDS or in the nominated sleep for controls was significantly less in cases than controls (OR 0.44, 95% CI 0.26 to 0.73). The OR changed very little after controlling for a wide range of potential confounders. It is concluded that dummy use may protect against SIDS, but this observation needs to be repeated before dummies can be recommended for this purpose. If dummy sucking is protective then it is one of several factors that may explain the higher mortality from SIDS in New Zealand than in other countries, and may also explain in part the regional variation within New Zealand.     

Prognostic value of tissue protein expression levels of MIB‐1 (Ki‐67) in Danish ovarian cancer patients. From the ‘MALOVA’ ovarian cancer study

The primary objective of this study was to assess the expression of MIB‐1 (Ki‐67) in tumour tissues from 808 patients with epithelial ovarian tumours. The second was to evaluate, whether MIB‐1 (Ki‐67) tissue expression levels correlate with clinicopathological parameters and prognosis of the disease. Using tissue arrays (TA), we analysed the MIB‐1 (Ki‐67) expression levels in tissues from 202 women with borderline ovarian tumours (BOT) (177 stage I, 5 stage II, 19 stage III, 1 stage IV) and 606 ovarian cancer (OC) patients (177 stage I, 64 stage II, 311 stage III, 54 stage IV). Using a 10% cut‐off level for MIB‐1 (Ki‐67) overexpression, 12% of the BOTs and 51% of the OCs were positive for MIB‐1 (Ki‐67) expression. The frequency of MIB‐1 (Ki‐67) expression‐positive OC increased with increasing FIGO stage (p = 0.003), increasing histological grade (p ≤ 0.0001), and a significantly different distribution of MIB‐1 (Ki‐67) positive and negative tumours were found in adenocarcinoma NOS, serous adenocarcinomas, mucinous adenocarcinomas, endometrioid adenocarcinomas, non‐epithelial and clear‐cell carcinomas (p = 0.016). Univariate Kaplan–Meier survival analysis performed on all OC cases showed a significant shorter disease specific survival in patients with positive MIB‐1 (Ki‐67) expression in the tumour tissue (p ≤ 0.0001). In a Cox survival analysis including 606 FIGO stages I to IV OC cases, FIGO stage (II vs I: HR = 3.00, 95% CI: 1.81–4.99, III–I: HR = 6.41, 95% CI: 3.90–10.50, IV vs I: HR = 12.69, 95% CI: 7.21–22); age at diagnosis pr.10 years (HR = 1.27, 95% CI: 1.15–1.40), residual tumour after surgery (HR = 1.95, 95% CI: 1.40–2.73) and MIB‐1 (Ki‐67) expression (HR = 1.31, 95% CI: 1.08–1.60) had a significant independent impact on survival. Histological grade (p = 0.14) and histological tumour type (p = 0.35) had no significant independent impact on survival. In conclusion, our results predict that an increased level of MIB‐1 (Ki‐67) expression in tumour tissue, points to a less favourable outcome for OC patients.     

Protection against aspirin-induced human gastric mucosal injury by bosentan, a new endothelin-1 receptor antagonist

BACKGROUND: Gastric ulceration induced by aspirin and by non-steroidal anti-inflammatory drugs (NSAIDs) is a major clinical problem. The mechanism of injury is unclear. There is evidence that NSAID-induced injury may cause endothelin activation. Endothelin-induced vasoconstriction has been shown to be capable of causing gastric ulceration. AIM: To investigate whether acute gastroduodenal injury induced in humans by aspirin can be prevented by the endothelin-1 antagonist, bosentan. METHODS: Eighteen healthy volunteers each received 5 x 900 mg aspirin every 12 h on three separate occasions (with either placebo, bosentan 700 mg or misoprostol 400 mg). Treatment order was randomized by Latin square design. Subjects were endoscoped and erosions counted before and 90 min after the first and last dose of aspirin. Plasma concentrations of bosentan were measured up to 5 h post-dose. RESULTS: There was a significant reduction in the mean number of erosions in the aspirin plus bosentan and aspirin plus misoprostol groups after the first dose of aspirin, compared with controls (aspirin plus placebo) (P<0.05). This was not sustained after the fifth dose of aspirin in the aspirin plus placebo and aspirin plus bosentan groups, but was still present in the aspirin plus misoprostol group. The mean plasma concentration of bosentan measured 3.5 h post-dose fell from 4510 (95% CI: 2791-6230) ng/mL after the 1st dose to 2508 (95% CI: 1733-3283) ng/mL after the 5th dose (P = 0.02). CONCLUSION: Endothelin receptor antagonism by bosentan can protect the gastric mucosa against aspirin damage. After five doses, bosentan levels fell, possibly because of enzyme induction, and protection was no longer evident. Further investigation is needed to assess whether higher doses would be effective.     

Isolation and characterization of a trisulfide variant of recombinant human growth hormone formed during expression in Escherichia coli

A new variant of human growth hormone was recently found [Pavlu, B. & Gellerfors, P. (1993) Bioseparation 3, 257-265]. We report here the identification and the structural determination of this variant. The variant, which is formed during the expression of human growth hormone in Escherichia coli, was found to be more hydrophobic than rhGH as judged by its prolonged elution time by hydrophobic interaction chromatography. The rhGH hydrophobic variant (rhGH-HV) was isolated and subjected to trypsin digestion and RP-HPLC analysis, resulting in an altered retention time of one single tryptic peptide as compared to the corresponding fragment of rhGH. This tryptic peptide constitutes the C-terminus (aa 179-191) of hGH and contains one of the two disulfide bridges in hGH, viz. CySl82-Cys189. Amino acid sequences and composition analyses of the tryptic peptide from rhGH-HV (T^v_{18 + 19}) and the corresponding tryptic peptide from rhGH (T_{18 + 19}) were identical. Electrospray mass spectrometry (ES/MS) of T^v_{18 + 19} isolated from rhGH-HV revealed a monoisotopic mass increase of 32.7, as compared to T_{18 + 19} from rhGH. A synthetic T_{18 + 19} peptide having a trisulfide bridge between Cys182 and Cys189 showed identical fragments in ES/MS compared to T^v_{18 + 19} isolated from rhGH-HV, i.e. m/z 617.7 and 682.9. These fragments are formed through a unique cleavage in the trisulfide (Cysl82-SSS-Cys189) bridge not found in the corresponding T_{18 + 19} disulfide peptide. Furthermore, the synthetic T^v_{18 + 19} co-eluted in RP-HPLC with T_{18 + 19} isolated from rhGH-HV. Two-dimensional NMR spectroscopy of the synthetic T_{18 + 19} and T^v_{18 + 19} peptides were performed. Using these data all protons were assigned. The major chemical shift changes (δ§>0.05 ppm) observed were for the β-protons of Cys182 and Cys189 in T^v_{18 + 19} as compared to T_{18 + 19}. CD spectroscopy data were also in agreement with the above results. Based on these physico-chemical data, rhGH-HV has been structurally defined as a trisulfide variant of rhGH. The receptor binding properties of rhGH-HV was studied by a biosensor device, BIAcore^TM. The binding capacity of rhGH-HV was similar to rhGH with a binding stoichiometry to the rhGHBP of 1:1.6 and 1:1.5, respectively, indicating that the trisulfide modification did not affect its receptor binding properties. © Munksgaard 1996.