Rapid EPA and DHA incorporation and reduced PGE2 levels after one week intervention with a medical food in cancer patients receiving radiotherapy, a randomized trial.

BACKGROUND & AIMS: In cancer patients, metabolic alterations, reduced immune competence and anti-cancer treatment can increase the risk of infections. A rapid-acting nutritional intervention might reduce this risk and support overall treatment. The present study investigated whether one week of intervention with a specific medical food led to fatty acid incorporation and functional immunological changes. METHODS: In a randomized, double-blind study, 38 cancer patients receiving radiotherapy consumed daily for one week 400 ml of specific medical food, which is high in protein and leucine, and enriched with fish oil and specific oligosaccharides (Active group), or iso-caloric/iso-nitrogenous product (Control group). Blood samples were taken at day 0 (baseline) and day 7. RESULTS: After one week of intervention, the incorporation of EPA and DHA in white blood cells was significantly higher in the Active group (2.6% and 2.6% of total fatty acids) compared to the Control group (1.0% and 2.2% of total fatty acids) (p < 0.001 and p < 0.05). Serum PGE2 levels decreased in the Active group and increased in the Control group (p < 0.01). No differences were observed on cytokine production in LPS-stimulated whole blood cultures. CONCLUSIONS: In cancer patients receiving radiotherapy, nutritional intervention with a specific medical food rapidly increased the percentage EPA and DHA in white blood cell phospholipids and reduced serum levels of the inflammatory mediator PGE2 within one week. CLINICAL REGISTRATION NUMBER: NTR2121.

Sexual differences in onset of disease and response to exercise in a transgenic model of ALS.

Transgenic mice that overexpress the mutant human SOD1 gene (hSOD1) serve as an animal model for amyotrophic lateral sclerosis (ALS). Age and sex are recognized as risk factors for ALS, but physical activity remains controversial. Therefore, we investigated the effect of exercise on the phenotype of male and female hSOD1 mice. Onset of disease, progression of disease and survival were measured in low-copy and high-copy hSOD1 mice that were randomized to an exercise or sedentary group. We found that onset of disease was different for the two sexes: significantly earlier in male than in female hSOD1 mice. Exercise delayed the onset of disease in female but not in male hSOD1 mice. Also, exercise delayed the total survival time in female high-copy hSOD1 mice. Muscle morphometry and motor neuron counts were similar in all experimental groups at the end of training. Sedentary female hSOD1 mice showed more frequently irregular estrous cycles suggesting a higher estrogen exposure in exercising female mice. These results suggest a possible neuroprotective effect of female sex hormones and support the view that ALS patients should not avoid regular exercise.

Awareness and attitudes concerning BRCA gene testing.

BACKGROUND: The availability of a commercial test for the breast cancer susceptibility genes, BRCA1 and BRCA2, has generated interest in both the medical community and the general public. METHODS: Patients and family members were approached in the waiting room and asked to fill out an anonymous questionnaire about their awareness of breast cancer genes and breast cancer gene testing, and their desire to be tested. chi2 analysis was used to analyze frequencies between groups. RESULTS: A total of 354 women completed a questionnaire concerning the breast cancer genes BRCA1 and BRCA2. The very young, the very old, and African-Americans were the least informed in terms of awareness of the genes and the availability of testing for the breast cancer susceptibility genes. Jewish people, people with a college education or beyond, people earning more than $30,000 a year, and Caucasians were more aware of the genes and of testing for these genes. Interest in being tested was similar in all groups, except for participants over 60 and those who had only an elementary-school education. CONCLUSIONS: Information concerning the breast cancer susceptibility genes has not reached the general public uniformly. A concerted effort is needed if this information is to be passed on to those people at risk.

Optimal treatment of Helicobacter pylori with ranitidine bismuth citrate (RBC): a randomized comparison between two 7-day triple therapies and a 14-day dual therapy.

OBJECTIVE: We investigated two promising 1-wk RBC-triple therapies in comparison to the already well investigated 2-wk RBC dual therapy. METHODS: We conducted two randomized, open, parallel group studies in 13 hospitals in the Netherlands. H. pylori-positive patients without active ulceration were randomized to 14-day RBC 400 mg b.i.d. plus clarithromycin 500 mg b.i.d. (n = 56) or to either 7-day RBC 400 mg b.i.d. plus tetracycline 500 mg q.i.d. plus metronidazole 500 mg t.i.d. (n = 63) in study 1, or to 7-day RBC 400 mg b.i.d. plus amoxycillin 1000 mg b.i.d. plus clarithromycin 500 mg b.i.d. (n = 49) in study 2. At least 6 wk later patients were reendoscoped with antral and corpus biopsies for CLOtest, culture, and histology, and cure was assumed if all tests were negative. RESULTS: Results from the studies were pooled. All regimens were well tolerated with only 1 drop-out because of side effects. Cure rates per protocol/intention to treat were 96%/95% for RBC-CLA dual therapy, 89%/86% for RBC-TET-MET triple therapy, and 93%/92% for RBC-AMO-CLA triple therapy. From 126 patients, a pretreatment antibiogram was available. Metronidazole resistance did not affect the performance of RBC-CLA or RBC-AMO-CLA. In the RBC-TET-MET group, 97% (32/33) with a metronidazole sensitive strain were cured vs 57% (four of seven) with a resistant strain. Of three patients with a pretreatment clarithromycin resistant strain; one failed RBC-CLA dual therapy and two failed RBC-AMO-CLA triple therapy. CONCLUSIONS: All regimens were well tolerated and achieved comparable and very high cure rates. Statistical or clinical relevant differences were not detected. All three regimens can be used as initial anti-Helicobacter therapy and can compete with 7-day PPI-triple therapies. More data are needed on the influence of antimicrobial resistance on the performance of individual triple therapies. The local prevalence of antimicrobial resistance will determine which regimen should be chosen for a certain geographical area.

Two different dose regimens of cisapride in the treatment of reflux oesophagitis: a double-blind comparison with ranitidine.

We conducted a double-blind study comparing two dosage regimens of a prokinetic drug, cisapride (10 mg q.d.s. and 20 mg b.d.), with a low dose of a H2-receptor antagonist (150 mg ranitidine b.d.) in the treatment of 155 patients with reflux oesophagitis as determined by endoscopy. The active treatment took 8 to 12 weeks depending on whether complete healing was found at endoscopy. Improvement in oesophagitis grades from baseline to endpoint was observed in 68% of patients in the 10 mg cisapride q.d.s. group, 83% in the cisapride 20 mg b.d. group and 81% in the ranitidine group (N.S.). At endpoint, the percentages of endoscopically cured patients with initial grades I or II were 52% for 10 mg cisapride q.d.s., 71% for 20 mg cisapride b.d. and 80% for ranitidine (N.S.). The proportional improvement of the overall reflux symptom score (60%) also showed no significant difference between the three groups. In the treatment of mild reflux oesophagitis (grades I and II) similar results can be expected from 20 mg cisapride b.d. and 150 mg ranitidine b.d. As the results of the two dosage regimens of cisapride were not different, the 20 mg twice daily regimen is preferred because it will improve patient compliance. It is concluded that in reflux oesophagitis grades I and II, the efficacy of 20 mg cisapride b.d. and 150 mg ranitidine b.d. are broadly similar.

Epidemic poliomyelitis in The Gambia following the control of poliomyelitis as an endemic disease. I. Descriptive findings.

An epidemic of type 1 poliomyelitis involving 305 cases occurred in The Gambia (estimated 1986 population, 768,995) from May through November 1986, following a 6-year period when only five cases were reported. Cases were identified by physician reporting during the epidemic and by a national village-to-village search conducted after the epidemic. The national attack rate was 40 cases per 100,000 people. Cases lived in all parts of the country except the capital, Banjul. The peak month of the epidemic was August (139 cases). The highest attack rate by year of age was in 1-year-old children (394 cases per 100,000 persons), and 75% of cases were 3 years of age or less. A vaccination coverage survey showed that 64% (95% confidence interval 60-68) of 1- to 2-year-old children were vaccinated with at least three doses of trivalent oral polio vaccine at the beginning of the epidemic. Fifty-seven cases became paralyzed more than 2 weeks after a national mass campaign in which 95% of children 1-7 years old were reported to have received a dose of trivalent oral polio vaccine. Experience in The Gambia shows that a several-year period of excellent control of endemic poliomyelitis by a vaccination program can be followed by a major epidemic and that a mass vaccination campaign may be only partially successful in ending the epidemic.

Premature mortality related to HIV infection in California 1981-1993.

The number of years of potential life lost (YPLL) before age 65 was used to compare the effects of HIV on premature mortality versus other causes of death in California from 1981 to 1993. Using California AIDS case surveillance data, YPLL associated with HIV rose from 629 in 1981 to 120,721 in 1989, and is projected to reach 188,000 in 1993 (plausible range, 155,000-285,000). In 1989, HIV ranked fourth in YPLL behind all malignant neoplasms, traffic-related motor vehicle accidents, and all heart diseases. By 1993, if current mortality trends continue, HIV is projected to be the leading single cause of YPLL in California ahead of all malignant neoplasms (184,597 in 1989), motor vehicle-related YPLL (163,038 in 1989), and all heart diseases.

The effect of known risk factors on the excess mortality of black adults in the United States.

We compared the mortality rate ratios, before and after adjustment for different risk factors, of black vs white adults in the National Health and Nutrition Examination Survey I Epidemiologic Follow-up Study. For persons 35 to 54 years old, the rate ratio of mortality for blacks vs whites decreased from 2.3 (unadjusted) to 1.9 when adjusted simultaneously for six well-established risk factors (smoking, systolic blood pressure, cholesterol level, body-mass index, alcohol intake, and diabetes) and decreased from 1.9 to 1.4 when adjusted for the six risk factors plus family income. Thus, approximately 31% of the excess mortality can be accounted for by six well-established risk factors and a further 38% by family income. This leaves 31% unexplained. Broader social and health system changes and research targeted at the causes of the mortality gap, coupled with increased efforts aimed at modifiable risk factors, may all be needed for egalitarian goals in health to be realized.

Influence of thyroid function on theophylline kinetics.

Theophylline kinetics were examined in five patients with hyperthyroidism before and after treatment with carbimazole. Theophylline clearance fell after carbimazole, but the apparent volume of distribution did not change. There was a correlation between reduction in theophylline clearance and decreased thyroxine serum concentration. Data suggest that maximum induction is reached at a specific level of thyroxine beyond which no further increase in drug metabolizing activity takes place. In 15 subjects treated with aminophylline for acute bronchial obstruction, there was a positive correlation between thyroxine concentration and total body theophylline clearance (r = 0.72 for nonsmokers; r = 0.44 for smokers and nonsmokers).

Isolation of a DNA polymerase alpha-associated regulatory protein from calf thymus.

A regulatory protein for DNA polymerase alpha, responsive to noncomplementary deoxyribonucleoside triphosphates, has been isolated from calf thymus. The regulatory protein was separated from DNA polymerase alpha using Affi-Gel Blue and gel filtration. The regulatory protein had a molecular weight of approximately 70,000 as determined by gel filtration, and its activity was nondialyzable, heat labile, and abolished by pronase treatment. In the presence of regulatory protein, DNA polymerase alpha activity, measured by using polydeoxyadenylate-oligodeoxythymidylate as template primer, was inhibited by 2'-deoxyguanosine 5'-triphosphate in a parabolic-competitive fashion [Ki = 15 +/- 1 (S.E.) microM] and by 2'-deoxycytidine 5'-triphosphate in a linear-competitive manner (Ki = 162 +/- 23 microM). Neither the four natural ribonucleoside triphosphates nor 2'-deoxyadenosine 5'-triphosphate inhibited the DNA polymerase-regulatory protein system to any significant extent. The regulatory protein by itself had no effect on either DNA polymerase alpha activity or the Km for template primer. These results indicate that deoxyribonucleoside triphosphate pools may be involved in the regulation of cellular DNA synthesis through a direct effect on DNA polymerization.

Evaluation of ribonucleoside and deoxyribonucleoside triphosphate pools in cultured leukemia cells during exposure to methotrexate or methotrexate plus thymidine.

Continuous exposure to inhibitory concentrations of methotrexate produces distinct rates of steady-state growth of murine leukemia L1210 and human leukemia CCRF-CEM cells in culture. Addition of thymidine to the medium produces reversal (6 to 40%) of this steady-state growth rate inhibition. This study utilized combinations of methotrexate and thymidine for an evaluation of the accompanying relationship between steady-state growth rate and changes in the ribo- and deoxyribonucleoside triphosphate pools. In L1210 cells exposed to methotrexate alone, the deoxythymidine 5'-phosphate (dTTP) pools decreased, whereas deoxyadenosine 5'-triphosphate, deoxyguanosine 5'-triphosphate, and deoxycytidine 5'-triphosphate (dCTP) remained relatively constant up to 70% inhibition of growth rate, with dCTP at a constant 112% of controls. The corresponding ribonucleoside triphosphates decreased only slightly. With the combination of methotrexate and thymidine resulting in up to 40% inhibition of growth rate, there was also a decrease in the dTTP pool while the other deoxyribonucleoside triphosphates remained relatively constant, and the corresponding ribonucleoside triphosphates again decreased only slightly. The dCTP pool was reduced to a constant 42% of control comparable to that produced by thymidine alone. With greater than 40% (with thymidine) or 70% (without thymidine) inhibition of growth rate, all pools decreased, but only dTTP was substantially reduced in proportion to the growth rate inhibition caused by methotrexate. The dTTP pool became depleted in spite of the presence of exogenous thymidine. Evaluation of CCRF-CEM cells indicated that inhibition of growth rate and nucleotide pool perturbations by methotrexate were similar to those observed in L1210 cells. However, in the presence of thymidine, inhibition of growth rate appeared related to decreased pools of dCTP, deoxyadenosine 5'-triphosphate, and deoxyguanosine 5'-triphosphate, rather than dTTP as was observed for L1210 cells. Hence, mammalian cells were capable of responding in a differential fashion to pharmacological perturbations, and this capacity may play a role in determining therapeutic selectivity. Since the ribonucleoside triphosphate decreases were slight and relatively uniform during methotrexate-induced perturbations, the deoxyribonucleoside triphosphate pools appear to be more directly related to inhibition of growth rate. The results are consistent with the concept that slight imbalances in the deoxyribonucleoside triphosphate pools dramatically inhibit DNA synthesis, as mediated through their interaction with DNA polymerase.