Atherogenesis and the homocysteine-folate-cobalamin triad: do we need standardized analyses?

BACKGROUND: Bioscientists, physicians and nutritionists are newly interested in the homocysteine-folate-cobalamin triad, in part because homocysteine may be important both in atherogenesis and thrombogenesis. Homocysteine imbalance may be an early marker for cobalamin disorders because cobalamin is a cofactor in remethylation of homocysteine to methionine. METHODS: In 139 men and 32 women of similar mean age of 65 years, we measured markers which have been cited as risk for atherosclerosis: serum homocysteine, folate, total cobalamin, holotranscobalamin I and II, (TCI and TCII), total serum cholesterol (SCHOL), high density lipoprotein cholesterol (HDLC), triglycerides (STG) as well as red blood cell (RBC) folate, food records and body composition by whole body counting of potassium-forty (40K). RESULTS: Statistical relationships among the data showed healthy women had lower mean serum homocysteine and their mean RBC folate and TCI and TCII were higher than men. Eighty-three subjects had TCII much lower than 60 pg/ml (subnormal), yet only 11 of these men and two women had total cobalamin < 200 pg/ml (abnormal). Fifty-two subjects with serum homocysteine greater than 17.5 nmol/ml had TCII less than 60 pg/ml, suggesting serum homocysteine may be a marker for early cobalamin negative balance. None of the subjects in the study had serum folate below abnormal values, i.e., less than 1.6 mg/ml. All subjects had RBC folate within normal range. Serum homocysteine showed inverse relationship with RBC folate and serum total cobalamin, TCI and TCII. CONCLUSIONS: 1) importance of using serum holotranscobalamin TCI and TCII as markers of cobalamin deficiency, 2) necessity to use documented quantitative components of dietary intake if strong comparisons are to be made among quantitative values of serum or plasma homocysteine, folate, cobalamin, and nutrients in food intake.     

Dipyridamole thallium-201 imaging very early after uncomplicated acute myocardial infarction in patients treated with thrombolytic therapy

The aim of this study was to assess the safety and prognostic value of dipyridamole 201T1 imaging very early after acute myocardial infarction in patients treated with thrombolytic therapy. Fifty-two consecutive patients with an uncomplicated clinical course underwent quantitative planar dipyridamole 201T1 imaging 2 5 days after acute myocardial infarction. The patients were followed for 14 +/- 7 months after discharge. No major complications occurred during the test. Of the 30 patients with redistribution, five (16.6%) developed in-hospital unstable angina as against none of the 22 patients without redistribution. During follow-up, a total of live late cardiac events were observed: two deaths and two cases of unstable angina in the group with reversible defects and one reinfarction in the group with fixed defects. The 1-year actuarial probability of being free of cardiac events was, respectively, 66 +/- 10% and 94 +/- 5% in the patients with and without redistribution (P < 0.01). In conclusion, in patients treated with thrombolysis, dipyridamole-201T1 imaging very early after uncomplicated acute myocardial infarction is a feasible and safe test. Patients with fixed defects appear to be at low risk and may be candidates for early discharge; the presence of redistribution identifies a subgroup of patients who may benefit from further careful clinical evaluation.     

Rationale for development of immunotherapies that target mucoid Pseudomonas aeruginosa infection in cystic fibrosis patients

Despite a complex sputum bacteriology, the progressive decline in pulmonary function that is the hallmark of the genetic disease cystic fibrosis (CF) is attributable to a single infecting pathogen, mucoid Pseudomonas aeruginosa. Therefore, active and passive immunotherapies that target this particular variant of the bacterium should be of value in attenuating infection and interfering with the decline in pulmonary function. The major surface antigen of mucoid P. aeruginosa is referred to as either mucoid exopolysaccharide (MEP) or alginate, a random polymer of D-mannuronic and L-guluronic acid residues linked beta 1-4. During chronic infection CF patients make antibodies to MEP that fail to mediate opsonic killing of bacteria in vitro. These antibodies can be elicited by vaccination in 35-40% of plasma donors given a preparation of MEP comprised of only the highest molecular-weight polymers; inclusion in human vaccines of smaller polymers normally produced by the bacterium fails to elicit opsonic antibodies, just like in infected CF patients. Opsonic, but not non-opsonic, antibodies to MEP protect animals against chronic endobronchial infection. CF patients do produce opsonic antibodies to mucoid P. aeruginosa that are in a planktonic or suspended state, but these antibodies are not directed at the MEP antigen and they fail to kill P. aeruginosa growing in a biofilm. This is the state that the bacteria grow in the lung. Therefore immunoglobulin G preparations with opsonic antibodies to MEP could provide CF patients with antibodies that they normally do not produce during chronic lung infection and may improve their clinical course.     

New quinoline di-Mannich base compounds with greater antimalarial activity than chloroquine, amodiaquine, or pyronaridine

We have compared the ex vivo antimalarial activity of 12 new quinoline di-Mannich base compounds containing the 7-dichloroquinoline or 7-trifluoromethylquinoline nucleus with amodiaquine, chloroquine, and pyronaridine using the Saimiri-bioassay model. Each compound was administered orally (30 mg/kg of body weight) to three or more noninfected Saimiri sciureus monkeys, and serum samples were collected at various times after drug administration and serially diluted with drug-free (control) serum. In vitro activity against the multidrug-resistant K1 isolate of Plasmodium falciparum was determined in serum samples by measuring the maximum inhibitory dilution at which the treated monkey serum inhibited schizont maturation in vitro. Of the 12 Mannich bases tested, 8 were associated with levels of ex vivo antimalarial activity in serum greater than those of amodiaquine, chloroquine, or pyronaridine 1 to 7 days after drug administration. Further studies were carried out with four of these compounds, and the results showed that the areas under the serum drug concentration-time curves for the four compounds were between 7- and 26-fold greater than that obtained for pyronaridine. Activity against four multidrug-resistant strains of P. falciparum was also much greater in serum samples collected from monkeys after administration of these four compounds than in serum samples collected after administration of pyronaridine or chloroquine. These findings suggest that these four quinoline Mannich base compounds possess a very marked and prolonged antimalarial activity and that further studies should be performed to determine their value as antimalarial drugs.     

A model of the posttetanic efficiency of a neuron dendritic spine

A model of postsynaptic processes leading to a prolonged posttetanic modification (potentiation and depression) in the efficacy of the excitatory and inhibitory inputs to the neuron CA3 of the hippocampus was developed. The model enables one to estimate changes in postsynaptic potentials depending on the extent of receptor phosphorylation, which is determined by Ca(2+)-dependent changes in secondary messengers.     

Can adrenal incidentalomas be safely observed?

We currently recommend excision of adrenal incidentalomas > or = 4 cm in size and all hormonally active tumors. The optimal management and follow-up of smaller nonfunctioning tumors are controversial. The aim of this study was to determine the clinical outcome of a well defined population of patients with incidentalomas followed without operative intervention. The study group comprised 231 patients, identified from the records of abdominal or thoracic computed tomographic (CT) scans performed between 1985 and 1989. The primary outcome variable analyzed was survival. Follow-up was obtained by office records, telephone contact, or letter. There were 101 male and 130 female patients with a mean age at diagnosis of 64 years (range 5-86 years). Most adrenal tumors were unilateral (right 113; left 98); 20 were bilateral. Mean tumor size was 2 cm (range 1-6 cm). In nine (4%) patients the tumor was > or = 4 cm. Follow-up [mean 7 years; range 1 month (patient died) to 11.7 years] was complete in 224 (97%) patients. Ninety-one (39%) patients had one or more additional CT scans performed during the follow-up period, with only four patients demonstrating a > 1 cm increase in the size of the adrenal mass. Surgical excision of these four lesions identified benign pathology. Eighty-one (35%) patients died of conditions unrelated to adrenal pathology. No patient developed subsequent adrenal hyperfunction or adrenal malignancy. Within the context of our guidelines, conservative management of adrenal incidentalomas considered benign or nonfunctioning at diagnosis is appropriate. Additional information provided by repeat CT scanning appears to confer limited benefit. This study does not support laparoscopic removal of small, nonfunctional adrenal tumors, as has been suggested.