The impact of peptic ulcer disease and infection with Helicobacter pylori on life expectancy

OBJECTIVE: Knowledge about the influence of H. pylori-related disease on life expectancy might affect physician behavior in dealing with such disease. The aim of this study was to assess how life expectancy is influenced by H. pylori infection and peptic ulcer disease. METHODS: The declining exponential approximation of life expectancy was used to model the effects of H. pylori and various peptic ulcer disease conditions on life expectancy. Deaths from peptic ulcer and gastric cancer were determined from the Vital Statistics of the United States. H. pylori prevalence rates were derived from the existing literature. RESULTS: Cure of active peptic ulcer increases life expectancy by 2.3 yr in persons aged 40-44 yr and 121 days in persons aged 70-74 yr. More substantial impact occurs in complicated ulcer, with increases in life expectancy ranging between 26.1 and 6.3 yr. Primary prevention of H. pylori could increase life expectancy by 190 days in those aged 40-44 yr and 26 days in 70-74-yr-old subjects. CONCLUSION: The benefit of ulcer cure or H. pylori prevention diminishes as age advances. Cure of ulcers in young patients or in those who have sustained complications results in an appreciable increase in life expectancy. Successful primary prevention of H. pylori in selected populations could substantially increase life expectancy.     

Crystal structure at 1.95 A resolution of the breast tumour-specific antibody SM3 complexed with its peptide epitope reveals novel hypervariable loop recognition

The anti-breast tumour antibody SM3 has a high selectivity in reacting specifically with carcinoma-associated mucin. SM3 recognises the core repeating motif (Pro-Asp-Thr-Arg-Pro) of aberrantly glycosylated epithelial mucin MUC1, and has potential as a therapeutic and diagnostic tool. Here we report the crystal structure of the Fab fragment of SM3 in complex with a 13-residue MUC1 peptide antigen (Thr1P-Ser2P-Ala3P-Pro4P-Asp5P-Thr6P -Arg7P-Pro8P-Ala9P-Pro10P-Gly11P- Ser12P-Thr13P). The SM3-MUC1 peptide structure was solved by molecular replacement, and the current model is refined at 1.95 A resolution with an R-factor of 21.3% and R-free 28.3%. The MUC1 peptide is bound both by non-polar interactions and hydrogen bonds in an elongated groove in the antibody-combining site through interactions with Complimentarity Determining Regions (CDRs), three of the light chain (L1, L2, L3) and two of the heavy chain (H1 and H3). The conformation of the peptide is mainly extended with no discernable standard secondary structure. There is a single non-proline cis-peptide bond in H3 (Val95H-Gly96H-Gln97H-Phe98H-Ala101H-Ty r102H) between Gly96H and Gln97H, which appears to play a role in SM3-peptide antigen interactions, and represents the first such example within an antibody hypervariable loop. The SM3-MUC1 peptide structure has implications for rational therapeutic and diagnostic antibody engineering.     

Beneficial effect of vitamin E administration on nitric oxide function in subjects with hypercholesterolaemia

Study of the solubilization of commercial grades of soya phosphatidylcholine (SPC) with different purities by bile salts (BS) indicated that only highly pure grades of SPC are suitable for the preparation of clear solutions of BS/SPC-mixed micelles (BS/SPC-MM). The solubilizing capacity of different BS towards SPC increased in the following order; Sodium cholate (SC) < sodium deoxycholate (SDC) < sodium glycocholate (SGC). Moreover, egg phosphatidylcholine (EPC) was solubilized to a higher extent than SPC. Furthermore, the solubility study of different drugs in the prepared MM showed substantial enhancement of solubility, the extent of which is essentially affected by the chemical nature of the drug and the composition of MM. Benzodiazepine drugs such as clonazepam, tetrazepam, diazepam, and lorazepam displayed higher affinity for MM compared with BS alone, whereas steroidal drugs, such as estradiol, prednisolone and progesterone, compared with benzodiazepines, displayed relatively higher affinity for BS alone. The solubilizing capacity of MM for the different drugs was increased to different degrees by the addition of benzyl alcohol which was comparable to the solubility of the drug in pure benzyl alcohol. The interaction between benzyl alcohol and the drug in MM could be proved by NMR.     

Layer-specific dendritic regression of pyramidal cells with ageing in the human prefrontal cortex

Huntingtin is the protein product of the gene for Huntington's disease (HD) and carries a polyglutamine repeat that is expanded in HD (>36 units). Huntingtin-associated protein (HAP1) is a neuronal protein and binds to huntingtin in association with the polyglutamine repeat. Like huntingtin, HAP1 has been found to be a cytoplasmic protein associated with membranous organelles, suggesting the existence of a protein complex including HAP1, huntingtin, and other proteins. Using the yeast two-hybrid system, we found that HAP1 also binds to dynactin P150(Glued) (P150), an accessory protein for cytoplasmic dynein that participates in microtubule-dependent retrograde transport of membranous organelles. An in vitro binding assay showed that both huntingtin and P150 selectively bound to a glutathione transferase (GST)-HAP1 fusion protein. An immunoprecipitation assay demonstrated that P150 and huntingtin coprecipitated with HAP1 from rat brain cytosol. Western blot analysis revealed that HAP1 was enriched in rat brain microtubules and comigrated with P150 and huntingtin in sucrose gradients. Immunofluorescence showed that transfected HAP1 colocalized with P150 and huntingtin in human embryonic kidney (HEK) 293 cells. We propose that HAP1, P150, and huntingtin are present in a protein complex that may participate in dynein-dynactin-associated intracellular transport.     

Intracellular diadenosine polyphosphates: a novel second messenger in stimulus-secretion coupling

In pancreatic beta-cells, stimulatory glucose concentrations increase cytosolic diadenosine polyphosphates ([ApnA]i) to concentrations sufficient to block ATP-sensitive K+ (KATP) channels. High-performance liquid chromatography and patch clamp techniques were used to study the metabolic pathways by which pancreatic beta-cells synthesize ApnA and the mechanism through which ApnA inhibit KATP channels. ApnA show a glucose- and time-dependent cytosolic concentration increase parallel, though 30- to 50-fold higher, to changes observed in adenine nucleotides. Other fuel secretagogues, leucine and 2-ketoisocaproate, raise [ApnA]i as efficiently as 22 mM glucose. Blockade of glycolysis or Krebs cycle decreases glucose-induced [ApnA]i. No significant increase in cytosolic ApnA concentrations is induced by nonnutrient secretagogues or nonmetabolizable nutrient secretagogues. Inorganic pyrophosphatase inhibition with sodium fluoride blocks 22 mM glucose-induced [ApnA]i increase. ApnA inhibition of KATP channel resembles that of ATP in efficacy, but shows clear functional differences. Unlike ATP, Ap4A does not restore channel activity after rundown. Furthermore, these compounds do not compete with each other for the same site. These features suggest a prominent role for Ap4A in beta-cell function, comparable to ATP. We conclude that nutrient metabolism through pyrophosphatase activation is necessary to induce ApnA synthesis, which in turn constitutes a new, ATP-independent, metabolic regulator of KATP channel activity.