Adaptive gene expression changes on the healthy side of parkinsonian rats.

Parkinson's disease (PD) is an asymmetric neurodegenerative disorder, and secondary adaptive mechanisms of the less-affected side could potentially compensate for parkinsonian symptoms. Here, we analyzed gene expression changes on the healthy side of a unilateral PD rat model and correlated these changes with locomotor velocity, which is known to be decreased in PD. Four weeks after a unilateral 6-hydroxydopamine lesion, the spontaneous locomotor velocity of rats was recorded just prior to brain extraction. We then analyzed the gene expression levels of markers of the direct (dynorphin and D1-class dopamine receptors) and indirect (enkephalin and D2-class dopamine receptors) pathways in the contralateral healthy striatum by in situ hybridization histochemistry. In addition, we analyzed the expression of several striatal and cortical glutamatergic markers, as well as nigral tyrosine hydroxylase (TH) and nigral dopamine transporter (DAT). We found a significant positive correlation between the mRNA expression levels of contralateral D1-class dopamine receptors and the mean locomotor velocity, at 4 weeks after surgery in parkinsonian rats but not in controls. Moreover, we observed a significant increase in the level of dynorphin mRNA in the lateral part of the contralateral striatum of parkinsonian rats compared to the controls. In contrast, no contralateral changes were observed in the striatal indirect pathway. We also did not find any significant contralateral modifications of TH, DAT or glutamatergic markers in PD animals, indicating that changes in direct pathway genes are not due to nigrostriatal dopaminergic or corticostriatal glutamatergic innervation. In conclusion, our results suggest a role of the healthy striatal direct pathway in counteracting dopaminergic denervation effects on motor symptoms.

Incidence of intracranial hemorrhage complicating treatment with glycoprotein IIb/IIIa receptor inhibitors: a pooled analysis of major clinical trials.

PURPOSE: The major risk of therapy with platelet glycoprotein IIb/IIIa receptor inhibitors is bleeding. We reviewed trials using these agents to determine if bleeding risks include an increased incidence of intracranial hemorrhage. METHODS: A Medline search identified 14 randomized trials of intravenous platelet glycoprotein IIb/IIIa receptor inhibitors for patients undergoing percutaneous coronary intervention or who had an acute coronary syndrome. We compared the incidence of intracranial hemorrhage among 15,850 patients treated with glycoprotein IIb/IIIa inhibitors with that among 12,039 patients treated with placebo. RESULTS: The incidence of intracranial hemorrhage with heparin plus any IIb/IIIa inhibitor was similar to placebo with heparin (0.12% vs 0.09%, odds ratio = 1.3, 95% confidence interval: 0.6 to 3.1, P = 0.59). The incidence of intracranial hemorrhage with glycoprotein IIb/IIIa drugs alone was similar to that with heparin alone (0.07% vs 0.06%), albeit with a wide confidence interval (odds ratio = 1.2, 95% confidence interval: 0.1 to 16, P = 1.0). CONCLUSIONS: Intravenous glycoprotein IIb/IIIa receptor inhibitors alone or in combination with heparin do not cause a statistically significant excess of intracranial hemorrhage as compared with heparin alone. Because of small numbers, the data do not exclude the possibility of an excess of intracranial hemorrhage in some groups of patients treated with glycoprotein IIb/IIIa receptor inhibitors.

Thrombocytopenia complicating treatment with intravenous glycoprotein IIb/IIIa receptor inhibitors: a pooled analysis.

BACKGROUND: Despite the increasingly prevalent role of platelet glycoprotein (GP) IIb/IIIa receptor inhibitors in acute coronary syndromes and percutaneous coronary interventions, the incidence and clinical relevance of thrombocytopenia occurring with their use remain unclear. METHODS: We identified 8 placebo-controlled, randomized, large trials of GP IIb/IIIa receptor inhibitors reporting the incidence of thrombocytopenia, grouped by severity. The clinical courses of 42 patients with GP IIb/IIIa-related thrombocytopenia in these studies and other case reports were reviewed for bleeding complications. RESULTS: Abciximab increased mild thrombocytopenia compared with placebo (4.2% vs 2.0%; P <.001; odds ratio 2.14) and increased severe thrombocytopenia compared with placebo (1.0% vs 0.4%; P =.01; odds ratio 2.48). Small-molecule IIb/IIIa inhibitors did not significantly increase mild or severe thrombocytopenia compared with placebo. Mild thrombocytopenia occurred more frequently in acute coronary syndrome trials than in coronary intervention trials, even in patients not receiving any IIb/IIIa inhibitors. No major bleeding sequelae were reported in 23 patients with severe thrombocytopenia or in 19 patients with profound thrombocytopenia. CONCLUSIONS: Abciximab, but not eptifibatide or tirofiban, increases the incidence of thrombocytopenia compared with placebo in patients also treated with heparin. Thrombocytopenia associated with GP IIb/IIIa inhibition does not routinely lead to severe bleeding complications.

A medicolegal curriculum for internal medicine residents.

Many residents lack knowledge about medicolegal issues. To assess the ability of 64 primary care residents to learn legal medicine, we studied the impact of a medicolegal curriculum in a randomized, controlled study. We measured residents' medicolegal knowledge using a novel test, the Legal Medicine Evaluation (LME). We found that the mean LME score of residents exposed to the curriculum increased 15.5 points (on a 100-point scale) to 65.9 ( p <.01), while the mean LME score of control residents increased only 3.5 points, to 53.5 ( p =. 05). Clearly, residents can learn basic medicolegal principles. Thus, observed deficiencies in medicolegal knowledge most likely arise from inadequate medicolegal instruction.

Telephone reporting of the results of cardiac procedures: feasibility and primary care physician preferences.

PURPOSE: We evaluated the feasibility and time required for routine telephone communication with primary care physicians after cardiac procedures and surveyed primary care physicians as to their preferences for the method and content of reports of cardiac procedures. SUBJECTS AND METHODS: A phone call was made within 1 day of the procedure during normal working hours to the primary care physician for all 414 patients who underwent cardiac catheterizations or interventions during a 1-year period. Subsequently, all 211 primary care physicians were mailed a questionnaire on the effectiveness of phone calls as compared with other communication methods. RESULTS: The primary care physician was reached with one call for 51% of patients and could not be contacted with up to five calls to office, clinic, or hospital for 32% of patients. Mean (+/- SD) phone time per patient was 4.1 (+/- 2.0) minutes. Surveys were returned by 119 (56%) of 211 referring physicians. Telephone communication was rated as "very helpful" by 69%. Most primary care physicians (86%) were "very" or "a little pleased" to receive phone calls. Survey respondents identified the summary of the results and the recommendations for treatment as the most important parts of the report. Respondents preferred personal phone calls or faxed reports to phone messages left with office staff, reports sent by electronic mail, or mailed written reports. CONCLUSIONS: Most primary care physicians find personal phone calls helpful and desirable, but the effectiveness of routine phone calls is limited by the availability of primary care physicians during working hours and the time required for phonereporting.

Normothermia is protective during infrarenal aortic surgery.

PURPOSE: Mild hypothermia has been suggested to be protective against tissue ischemia during aortic operations. However, recent studies have documented detrimental cardiac effects of hypothermia during a variety of operative procedures. The influence of different warming methods and the impact of hypothermia during standard aortic procedures was assessed. METHODS: One hundred patients who underwent repair of infrarenal aortic aneurysms or aortoiliac occlusive disease were prospectively randomized into 2 groups, receiving either a circulating water mattress or a forced air warming blanket. Adjuvant warming methods were standardized. The day before surgery, 48-hour Holter monitors were applied and interpreted by a cardiologist blinded to the treatment. Randomization resulted in equivalent groups with regard to patient history, indications for surgery, body mass index, length of surgery, and fluid requirements. RESULTS: Core temperatures were significantly warmer during surgery (36.3 degrees C +/- 0.7 degrees C vs 35.4 +/- 0.8 degrees C) and after surgery (36.4 degrees C +/- 0.7 degrees C vs 35.6 degrees C +/- 0.9 degrees C) in patients with forced air warming (P <.001). The circulating water mattress group had significantly more metabolic acidosis perioperatively (P =.03). Postoperative length of stay, cardiac complications, and death rates were not significantly different. Subgroup analysis of 83 aneurysm patients comparing normothermia with hypothermia (temperature less than 36 degrees C) on arrival to the recovery room identified decreased cardiac output (P =.02), thrombocytopenia (P =.02), elevated prothrombin time (P =.04), and inferior Acute Physiology and Chronic Health Evaluation (APACHE) II scores (P <.001) in the hypothermic group. Holter analysis revealed more sinus tachycardia (ST) segment changes and ventricular tachycardia in hypothermic aneurysm patients (P =.05). CONCLUSION: Patients treated with forced air blankets had significantly less metabolic acidosis and were kept significantly warmer than those treated with circulating water mattresses. Patients with aneurysms that were kept normothermic had a significantly improved clinical profile, with fewer cardiac events on the Holter recordings. We therefore conclude that (1) normothermia is protective for infrarenal aortic surgical patients; and (2) forced air warming blankets provide improved temperature maintenance compared with circulating water mattresses.

Americans' knowledge of cancer risk and survival.

BACKGROUND: There are more than 500,000 deaths from cancer each year in the United States. This study examines Americans' knowledge of risk factors for breast, cervical, colon, and prostate cancers, which account for over 130,000 of these deaths, and their knowledge of the prospects of surviving these cancers following early detection. METHODS: Data were obtained from 12,035 subjects who completed the 1992 National Health Interview Survey Cancer Control Supplement which includes questions about cancer risk factors and survival. RESULTS: The majority of respondents were unable to identify major cancer risk factors when prompted with a list. Approximately two-thirds did not recognize that age increased the risk for breast and colon cancer, that diet increased the risk for colon cancer, or that multiple sex partners increased the risk for cervical cancer. Knowledge about survival was also poor. Only about half thought they had a good chance of survival following early detection of colon and cervical cancers, for which 5-year relative survival exceeds 90%. CONCLUSIONS: Americans lack knowledge about major risk factors for common cancers and about the prospects of survival following early detection. Knowledge about risk factors and about survival from cervical and colon cancers was poor at all ages, among all races, at all income levels, and at all educational levels. It was poorest among blacks and Hispanics and among those with the lowest income and least education. Americans need education about cancer risk factors and survival.

Penetration of chemotherapy into vitreous is increased by cryotherapy and cyclosporine in rabbits.

OBJECTIVE: To investigate whether cryotherapy, which induces a serous effusion in retina, might increase access of systemic chemotherapy into the vitreous. METHODS: The right eyes of 18 rabbits were treated with triple or single freeze-thaw cryotherapy at 1 or 2 locations, 1 day before administering intravenous carboplatin with or without cyclosporine. Control left eyes received no cryotherapy. The rabbits were killed 2 or 24 hours after chemotherapy, and carboplatin concentrations were measured in the vitreous of each eye and in blood. RESULTS: A significant increase was found in intravitreal carboplatin concentrations when cryotherapy was applied (P < .001) or high-dose cyclosporine was administered (P < .001) and if 2 locations were frozen compared with 1 location frozen (P = .02). Intravitreal carboplatin concentrations were always significantly greater after cryotherapy, either when the corresponding blood carboplatin concentrations were high (2 hours after completing treatment) or when they had dropped to much lower levels (at 24 hours). The triple freeze-thaw technique did not yield significantly better results than a single freeze-thaw technique. CONCLUSION: Cryotherapy administered 24 hours before chemotherapy significantly increased the intravitreal penetration of carboplatin, and this strategy may enhance the capacity of chemotherapy to cure intraocular retinoblastoma, particularly avascular tumors such as vitreous seeds.

High resolution depth profile analysis by elastic recoil detection with heavy ions.

Elastic recoil detection (ERD) with energetic heavy ions (e.g. 60-120 MeV(127)I) is a suitable method to measure depth profiles of light and medium heavy elements in thin films. The advantages of this method are reliable and quantitative results and elementally and isotopically resolved depth profiles. A relative energy resolution of 0.07% has been measured in real ERD-experiments using the Q3D magnetic spectrograph at the Munich tandem accelerator and a large solid angle of detection of 5 msr. The good energy resolution allows atomic depth resolution near to the surface which has been obtained at flat and smooth carbon samples. A large solid angle of detection is necessary to measure a depth profile with the desired accuracy before the sample is significantly altered by the ion beam. As an example carbon profiles of thin carbon layers, prepared by a laser plasma ablation deposition process, have been investigated revealing the high depth resolution and its power to resolve elemental profiles at gradiated interfaces.

Coronary dissection resulting from angioplasty with slow oscillating vs. rapid inflation and slow vs. rapid deflation.

To determine if slow inflation or slow deflation (compared to standard rapid inflation/deflation) would minimize coronary arterial dissection, we randomized 162 lesions from 136 patients undergoing coronary angioplasty with polyolefin copolymer balloons to slow oscillating (1 atmosphere/20 sec) vs. rapid (over 30 sec) inflation and slow (over 15 sec) vs. rapid deflation. The incidence of any dissection was nearly identical in the four inflation/deflation groups. The incidence of severe dissection, however, was significantly higher for the slow inflation/slow deflation group compared to the other three groups (38% vs. 15%, P = .024). For angioplasty performed with polyolefin copolymer balloons, slow deflation combined with slow oscillating inflation is associated with more frequent severe dissections.

Projection of incidence rates to a larger population using ecologic variables.

There is wide acceptance of direct standardization of vital rates to adjust for differing age distributions according to the representation within age categories of some referent population. One can use a similar process to standardize, and subsequently project vital rates with respect to continuous, or ratio scale ecologic variables. We obtained from the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) programme, a 10 per cent subset of the total U.S. population, country-level breast cancer incidence during 1987-1989 for white women aged 50 and over. We applied regression coefficients that relate ecologic factors to SEER incidence to the full national complement of county-level information to produce an age and ecologic factor adjusted rate that may be more representative of the U.S. than the simple age-adjusted SEER incidence. We conducted a validation study using breast cancer mortality data available for the entire U.S. and which supports the appropriateness of this method for projecting rates.

Differences in reported food frequency by season of questionnaire administration: the 1987 National Health Interview Survey.

We assessed seasonal reporting bias in a 59-item food frequency questionnaire (FFQ) administered throughout 1 year using data from the 1987 National Health Interview Survey (N = 20,143 adults). Few meaningful differences were found in the proportion of individuals reporting rarely or never consuming a food by season of questionnaire administration. Seasonal reporting bias is evident in FFQs, however, and appears to be due to reporting most recent consumption. Using gender-specific median servings per week, an analysis using logistic regression showed that the estimated proportion of individuals reporting food intake at greater than the yearly median differed between any two seasons by at least 5% of the population for 22 foods. We compared gender-specific quintiles of selected nutrients/food groups for the whole year and each season; these showed that quintile assignment never varied by more than one adjacent quintile. The most frequent shift in quintile assignment, involving as many as 18.5% of women in the summer, occurred for citrus fruits. The intake biases are small and do not greatly affect population estimates if the FFQ is administered in all seasons, but they may somewhat affect classification of individuals into quantiles for some foods/nutrients.

After a treatment breakthrough: a comparison of trial and population-based data for advanced testicular cancer.

PURPOSE: To determine to what extent the benefits of cisplatin-based combination chemotherapy have been disseminated to all American men diagnosed with advanced testicular cancer. PATIENTS AND METHODS: One hundred seventy-two advanced testicular cancer cases from five population-based registries of the Surveillance, Epidemiology, and End Results (SEER) Program diagnosed from 1978 to 1984 were compared with 133 diagnostically comparable cases from the Memorial Sloan-Kettering Cancer Center (MSKCC) vinblastine, dactinomycin, and bleomycin (VAB) regimens 7 through 9. Exclusions were made in both series for cases with elevated markers only, abdominal disease only, or extragonadal tumors. Ratings of extent of disease using the Indiana University system (minimal/moderate or advanced) were available for the MSKCC cases, and were determined retrospectively on the SEER cases based on information abstracted from medical records. RESULTS: Among the SEER cases, 89% reported receiving chemotherapy, and 95% of these received cisplatin-containing regimens. Survival among the MSKCC patients was significantly better than for the SEER cases in the minimal/moderate extent of disease category (95% and 73% 3-year survival rate, respectively); however, the difference for advanced cases was only marginally significant (52% and 40% 3-year survival rates, respectively). Survival did not vary significantly by year of diagnosis in either series. CONCLUSION: Although most of the patients in the SEER series received cisplatin-based chemotherapy, this alone did not produce results equivalent to that in the MSKCC series. Since the patients were selected to be as diagnostically comparable as possible at baseline, remaining differences in survival may be due to adherence to a fixed regimen and level of dose-intensity, adequacy of diagnostic work-up, implementation of salvage therapies and debulking surgery, and unknown factors related to who is willing and able to travel to a tertiary care center for treatment. Whatever the reason for not achieving optimal results in the SEER series, the very modest survival improvements over the time period 1978 to 1984 indicates that the differences in outcome between the two series were basically stable over the study period.

Importance of supplemental vitamin C in determining serum ascorbic acid in controls from a cervical cancer case-control study: implications for epidemiological studies.

Classification of individuals by their vitamin C intake was investigated in 493 control subjects from a cervical cancer case-control study. The influence of dietary and supplemental sources of vitamin C, as well as demographic and life-style factors, on serum ascorbic acid were examined. Usual dietary intakes of vitamin C were determined from a food frequency questionnaire and recent intakes from a 24-hour recall taken at the time of blood collection. Vitamin supplement information was obtained at both times. In a regression analysis, the factors found to predict serum ascorbic acid were total recent vitamin C intake, an indicator variable for supplement use, body mass index, number of cigarettes smoked per day, race, education, and age. Higher levels of serum ascorbic acid were found among older nonsmoking highly educated leaner white women. Consideration of supplements, in addition to dietary sources of vitamin C, improved correlation coefficients between serum ascorbic acid and usual vitamin C intake from 0.19 to 0.32 and between serum ascorbic acid and recent intake from 0.36 to 0.56. Furthermore, whereas only a twofold difference between the first and fourth quartiles of serum ascorbic acid was observed using recent dietary vitamin C without supplements, this range increased to sixfold with addition of supplement data. Epidemiological studies should consider use of total vitamin C intakes from supplement and food sources to permit accurate classification of individuals.

The bioavailability to humans of ascorbic acid from oranges, orange juice and cooked broccoli is similar to that of synthetic ascorbic acid.

The relative bioavailability of ascorbic acid from several sources was compared in 68 male non-smokers. Subjects underwent two 8-wk ascorbic acid depletion-repletion cycles. In repletion, subjects were randomized to receive 108 mg/d ascorbic acid as tablets with or without iron, as orange segments or juice, or as raw or cooked broccoli with a crossover within each major treatment group (e.g., cooked to raw broccoli) for the second repletion. Relative ascorbic acid bioavailability was estimated based on the slope obtained from linear regression of plasma ascorbic acid on time during each repletion. In the first repletion, slopes for all groups were similar except for the group consuming raw broccoli (20% lower response, P < 0.01). Second repletion responses were attenuated, but were similar to the first repletion. Ascorbic acid ingested as cooked broccoli, orange juice or fruit, or in synthetic form seems to be equally bioavailable. The lower relative bioavailability of ascorbic acid from raw broccoli is unlikely to be of practical importance in mixed diets.

Combination cytotoxic effects of cis-diamminedichloroplatinum(II) and 5-fluorouracil with and without leucovorin against human non-small cell lung cancer cell lines.

Both cisplatin (CDDP) and leucovorin (LV) have been shown to enhance cytotoxicity of 5-fluorouracil (FUra) against murine and human neoplasms by increasing intracellular reduced folate concentrations. We were interested in their use in a combination to inhibit non-small cell lung cancer (NSCLC) cell growth and therefore conducted an in vitro study to investigate the cytotoxic activities of combinations of CDDP plus FUra, with and without LV (20 microM), against seven NSCLC cell lines. A tetrazolium assay with application of the classical isobole method was used to test drug combinations. We found that LV enhanced FUra but not CDDP cytotoxicity and that the degree of enhancement was negatively correlated with the effect of FUra. There was an overall additive combination effect of CDDP plus FUra, although there may be synergy at higher effect levels. There was synergy to a combination of CDDP, FUra, and LV, presumably primarily related to the synergistic effects of adding LV to FUra. In summary, LV and CDDP enhanced FUra cytotoxicity in a complementary fashion and there was clear synergy of a combination of CDDP, FUra, and LV against a panel of NSCLC cell lines. Our in vitro results provide a rationale for controlled clinical studies of this three-drug regimen in patients with NSCLC.

Representativeness of the surveillance, epidemiology, and end results program data: recent trends in cancer mortality rates.

BACKGROUND: Mortality, incidence, and survival rates are the primary measures used by the National Cancer Institute (NCI) to monitor cancer in the United States. The Surveillance, Epidemiology, and End Results (SEER) data system collects data on all cancers diagnosed among residents in geographically defined populations, which comprise about 10% of the U.S. population. This data system is the major component of the NCI system for tracking these rates. Thus, it is important to assess the degree to which SEER data are representative of the entire U.S. population. PURPOSE: National data on mortality, but not on incidence or survival, are available from the National Center for Health Statistics. These data provide a census against which mortality data from the subset of the SEER regions may be compared. METHODS: Multivariate regression analyses of age-adjusted mortality rates from 1975 to 1988, computed for the SEER areas and for the entire United States, were performed for race- and sex-specific data from 15 cancer sites. Representativeness was evaluated by testing for differences in trends and levels between the data from the U.S. population and those from the SEER Program. RESULTS: Data from the SEER regions reflected the correct direction of trend for all sites, although some race-, sex-, and site-specific differences existed for the magnitude of the trends and levels of mortality when compared with data from the U.S. population. CONCLUSIONS: The demonstration that data from the SEER population do occasionally yield mortality rates that differ from those for the entire U.S. population suggests that data from the SEER coverage population are, in some cases, not representative of the greater U.S. population. IMPLICATIONS: This issue is of particular relevance to the interpretation of incidence measures, computed from the SEER data, for which there is no national database. Future efforts should be directed at a better understanding of how the SEER population differs from the U.S. population so that SEER rates can be adjusted to be more nationally representative.

Quantitative methods for cross-species mapping (CSM).

Cross-species extrapolation will be defined as prediction from one species to another without empirical vetification. Cross-species mapping (CSM) is the same except empirical vetification is performed. CSM may be viewed as validation of methods for extrapolation. Algorithms for CSM may originate from theory, from empirical observations or a combination of the two. Regardless of their origins, CSM algorithms must be explicated and confidence intervals given around their predictions. This paper offers a quantitative method for constructing CSM equations which is useful in evaluation of the CSM and as an aid in the design of new experiments in CSM and extrapolation. The method requires fitting mathematical models for the physiological or behavioral phenomena to be mapped across species. A CSM equation can then be derived from the models in each species and approximate confidence limits may be obtained for predictions from the equation. The method is useful even when the models in the two species differ in form, implying differences in physiology or behavioral principles between species. The method proposed has a number of remaining uncertainties and possible problems.