Uroporphyria in Hfe mutant mice given 5-aminolevulinate: a new model of Fe-mediated porphyria cutanea tarda

Porphyria cutanea tarda (PCT), a liver disease with skin lesions caused by excess liver production of uroporphyrin (URO), is associated with consumption of alcoholic beverages or estrogens, and moderate iron overload. Recently, it has been shown that many PCT patients carry mutations in the HFE gene, which is responsible for hereditary hemochromatosis. Mice homozygous for either the null mutation in the Hfe gene or the C282Y missense mutation rapidly accumulate hepatic parenchymal iron similar to patients with hemochromatosis. Here we investigated whether disruption of the murine Hfe gene would result in hepatic uroporphyria. Mice homozygous for the Hfe-null mutation accumulated high levels of hepatic URO when fed 5-aminolevulinate (ALA). Hfe (+/-) mice also accumulated hepatic URO when fed ALA, but at a much slower rate. The amount of accumulated URO in the null mutant mice was similar to that in wild-type mice treated with iron carbonyl in the diet, or injected with iron dextran. Iron in both wild-type and Hfe (+/-) mice was mostly in Kupffer cells. In contrast, Hfe (-/-) mice had considerable parenchymal iron deposition as well, in a pattern similar to that observed in wild-type mice treated with iron carbonyl. URO accumulation was accompanied by 84% and 33% decreases in hepatic uroporphyrinogen decarboxylase activities in Hfe (-/-) and Hfe (+/-) mice, respectively. No increases in CYP1A2 or other cytochrome P450s were detected in the Hfe-null mutant mice. We conclude that this experimental model of uroporphyria is a valid model for further investigations into the mechanism of PCT.     

Ageing: definitions, mechanisms and the magnitude of the problem

All multi-cellular organisms undergo change with time. Conception heralds the onset of growth and development, leading to reproductive competence and propagation of the species. With time, organisms age, leading to death as a final end-point. Whilst our knowledge and definitions of growth and reproduction are firmly established, the concept of ageing remains less well understood. One of the reasons for the lack of a singular definition of ageing is that it can be considered in many different ways, according to social, behavioural, physiological, morphological, cellular and molecular changes. Research has led to a number of theories being proposed that may explain the ageing process. In this chapter, we will review some of these theories and address some of the following fundamental questions: What is ageing? How can ageing be measured? When does ageing begin? When is an organism defined as old?     

Agalactosyl IgG: an aid to differential diagnosis in early synovitis

Sixty consecutive patients presenting with early-onset synovitis were studied by measuring rheumatoid factor (RF) titers and the percentage of oligosaccharide chains attached to the C gamma 2 domain of IgG that lack galactose (GAL[0]). After 2 years of followup, 39 patients (65%) had developed rheumatoid arthritis (RA), and 21 had developed a variety of other inflammatory joint diseases. A combination of RF positivity and GAL(0) levels above the age-corrected mean gave a positive predictive value for a diagnosis of RA in 94% of these patients. These observations may well have clinical utility.     

A randomized trial comparing omeprazole, ranitidine, cisapride, or placebo in helicobacter pylori negative, primary care patients with dyspepsia: the CADET-HN Study

BACKGROUND: The management of Helicobacter pylori negative patients with dyspepsia in primary care has not been studied in placebo-controlled studies. METHODS: H. pylori negative patients with dyspepsia symptoms of at least moderate severity (> or =4 on a seven-point Likert scale) were recruited from 35 centers. Patients were randomized to a 4-wk treatment of omeprazole 20 mg od, ranitidine 150 mg bid, cisapride 20 mg bid, or placebo, followed by on-demand therapy for an additional 5 months. Treatment success was defined as no or minimal symptoms (score < or = 2 out of 7), and was assessed after 4 wk and at 6 months. RESULTS: Five hundred and twelve patients were randomized and included in the intention-to-treat (ITT) analysis. At 4 wk, success rates (95% CI) were: omeprazole 51% (69/135; 43-60%), ranitidine 36% (50/139, 28-44%), cisapride 31% (32/105, 22-39%), and placebo 23% (31/133, 16-31%). Omeprazole was significantly better than all other treatments (p < 0.05). The proportion of patients who were responders at 4 wk and at 6 months was significantly greater for those receiving omeprazole 31% (42/135, 23-39%) compared with cisapride 13% (14/105, 7-20%), and placebo 14% (18/133, 8-20%) (p= 0.001), but not ranitidine 21% (29/139, 14-27%) (p= 0.053). The mean number of on-demand study tablets consumed and rescue antacid used was comparable across groups. Economic analysis showed a trade-off between superior efficacy and increased cost between omeprazole and ranitidine. CONCLUSION: Treatment with omeprazole provides superior symptom relief compared to ranitidine, cisapride, and placebo in the treatment of H. pylori negative primary care dyspepsia patients.     

Correlation between serum lipoprotein (a) and angiographic coronary artery disease in non-insulin-dependent diabetes mellitus

Abstract. Comlekqi A, Biberoglu S, Kozan 0, Bahqeci 0, Ergene 0, Nazli C, Kinay 0, Guner G (Dokuz Eylul University, Medical School, Inciralti, Izmir, Turkey). Correlation between serum lipoprotein(a) and angio-graphic coronary artery disease in non-insulin-dependent diabetes mellitus. J Intern Med 1997; 242:449-54.
Objectives: To examine the impact of diabetic state on the concentrations of lipoprotein(a) [Lp(a)] in patients with non-insulin-dependent diabetes mellitus (NIDDM) and the correlation between angiographic coronary artery disease (CAD) and serum Lp(a) concentrations in NIDDM.
Design: In this cross-sectional study of 26 patients with NIDDM and 19 nondiabetic sex- and agematched patients who underwent coronary angiography, CAD was assessed visually using coronary artery score (CAS), and plasma Lp(a) was measured by an enzyme-linked immunosorbent assay.
Setting: The study was performed in an internal medicine clinic at a university hospital.
Subjects: Twenty-six age- and sex-matched patients with NIDDM and 19 control patients without diabetes.
Results: There was no significant difference between the Lp(a) concentrations of patientswith NIDDM and nondiabetic subjects (P > 0.05). When patients with NIDDM were stratified by absence or presence of CAD, patients with CAD had higher levels of Lp(a) (P < 0.05). However, there was no significant correlation between the concentrations of Lp(a) and CAS (P > 0.05).
Conclusions: Diabetic state does not have any impact on Lp(a) concentrations. Lp(a) excess seems to be atherogenic in patients with NIDDM as shown in nondiabetic patients in previous studies. Although diabetic patients with CAD have higher Lp(a) concentrations than the diabetic patients without CAD, Lp(a) levels were not correlated with CAS.     

Isolation and characterisation of microsatellite loci for the ancient cephalopod,Nautilus pompilius

Conservation Genetics Resources - A microsatellite-enriched genomic library was created from a single Nautilus pompilius individual and clones/fragments sequenced using Sanger and Illumina MiSeq...     

Characterization of non-human primate antisera to acute lymphoblastic leukemia (ALL): evidence for unique antigen(s) on childhood ALL of "T" phenotype

A non-human primate antiserum was prepared to acute lymphoblastic leukemia of T-cell phenotype (T-ALL) and, after absorptions with normal blood elements, reacted by immunofluorescence and microcytotoxicity to all the T-ALL tested. In addition, the antiserum reacted with cells from about 70% of the common ALL studied and immunoprecipitated the common ALL antigen of 100,000 daltons. However, when the anti-T-ALL serum was absorbed with with lymphoblasts from common ALL, it failed to react with common ALL lymphoblasts, yet reacted significantly with cells from patients with T-ALL phenotype and defined a 100,000-dalton membrane component not found on common ALL lymphoblasts. In addition, sequential immunoprecipitation of 125I-labeled T-ALL membranes by anti- common-ALL serum followed by anti-T-ALL serum detected the T-ALL membrane component of 100,000 daltons that was not found on common ALL. Thus, our results demonstrate the presence of of a unique human T-ALL antigen present on all T-ALL distinct from the common ALL antigen.