The effect of lucanthone on sublethal radiation damage, in vivo

The capacity of the Chinese hamster jejunal crypt cell to accumulate and repair sublethal radiation damage was determined by analyzing the return of the shoulder of the radiation dose-crypt microcolony survival curve (Dr) after a priming dose of 1250 rad. The control split dose crypt cell survival curve exhibited a D0, Dr and "n" of 179 +/- 3 rad, 261 +/- 3 rad and 4.3 respectively; repair of sublethal radiation damage was completed by two hours post-irradiation. The effect of lucanthone (an antischistosomal DNA intercalating agent) on the crypt cell's capacity to accumulate and repair sublethal radiation damage was determined by injecting the drug (100 mg/kg, i.p.) at intervals before irradiation with a priming dose of 1250 rad, followed two hours later by graded doses. Injection coincident with the priming dose of radiation resulted in a 22 rad reduction of the Dr (compared to control Dr). Injection eight hours before the priming dose almost completely inhibited the accumulation and repair of sublethal radiation damage so that the resultant Dr two hours later was only 29 rad (a 232 rad reduction). At no time was the D0 of the crypt cell survival curve affected by lucanthone. These data confirm previous results from whole crypt analysis and LD50/7 analysis that non-toxic concentrations of lucanthone reversibly inhibit the accumulation and repair of sublethal radiation damage in a time-dependent manner with complete inhibition approximately eight hours post-injection. This drug is useful for the study of sublethal radiation damage in vivo and may be beneficial in radiation therapy of cancer when it is desirable to inhibit the repair of sublethal radiation damage.     

Software compensation for lung volume in assessment of inspiratory muscle strength and endurance.

BACKGROUND--To increase the sensitivity of measurements of maximal inspiratory pressure (MIP) as a test of inspiratory muscle strength and endurance, software was developed to correct for variation in lung volume. METHODS--Using a body plethysmograph to determine absolute lung volume during each manoeuvre, values for MIP were expressed as a percentage of the pressure "expected" from the unfatigued MIP/lung volume relation in each subject. RESULTS--The method reduced the variance in peak and average pressure during a series of 18 MIP manoeuvres of 10 seconds duration separated by rest intervals of 10 seconds. CONCLUSIONS--The correlation between average pressure and contraction number was improved significantly by the MIP/lung volume correction. This simple correction has many applications in measurements of the MIP.     

Evidence for an S-phase checkpoint regulating DNA replication after heat shock: a review.

Exposure of cells to heat inhibits a number of nuclear activities associated with semi-conservative replication of DNA including the incorporation of radiolabelled precursors into acid-insoluble DNA, the initiation of new replicons, the elongation of the DNA fibre at the replication fork, the synthesis and deposition of new histones into chromatin and the reorganization of nascent DNA into mature chromatin. These effects are likely to underlie the heat sensitivity of S-phase cells and may contribute to the radiosensitization observed in this phase of the cell cycle. While some of these effects may be explained as 'passive' consequences of heat-induced damage on chromatin structures experiments reviewed here point to the activation of a checkpoint as a contributing factor to the observed inhibition of DNA replication. Activation of a heat responsive S-phase checkpoint targets the activity of RPA via interaction with nucleolin. Nucleolin, a major nucleolar protein, is found normally sequestered in the nucleolus. Exposure of cells to heat causes a rapid translocation of nucleolin from the nucleolus into the nucleoplasm that enables RPA/nucleolin interaction. This interaction inhibits functions of RPA associated with the initiation of DNA replication and contributes to the immediate inhibition of DNA synthesis observed after heat shock. The results suggest that the nucleolus serves as a sequestration centre for the temporary inactivation of regulatory molecules, such as nucleolin, capable of regulating essential cellular functions after heat shock. It is speculated that this regulatory process is integrated in the network of responses that determine cell sensitivity to heat and that it may be involved in heat radiosensitization to killing as well.     

Quercetin sensitizes cells in a tumour-like low pH environment to hyperthermia.

Quercetin has been shown to act as a hyperthermia sensitizer by inhibiting the synthesis of heat shock protein 70 (HSP70) in a variety of tumour cell lines. It is most effective under conditions of low pH. This study was designed to test the hypothesis that quercetin suppresses thermotolerance development in cells adapted to growth at low pH and renders them as responsive as acutely acidified cells to hyperthermia-induced cytotoxicity. Chinese hamster ovarian carcinoma cells (OvCa) were exposed to 42 degrees C hyperthermia and/or quercetin (50-200 mm) at their growth pH of either 7.3 or 6.7 or after acute acidification from 7.3 to 6.7. Thermotolerance development was measured by colony survival. HSP70 synthesis and total protein synthesis were measured by radioactive precursor pulse labelling techniques. Quercetin, in a concentration-dependent manner, reduced the rate of total protein synthesis and increased cytotoxicity equally after acute acidification to pH 6.7 or growth at pH 6.7 at 37 degrees C, and to a greater extent than it did in cells at pH 7.3. At 42 degrees C, 100 mm quercetin inhibited total protein synthesis, HSP70 synthesis and thermotolerance development to a similar extent in cells grown at pH 6.7 or acutely acidified to pH 6.7. In contrast, quercetin reduced but did not completely inhibit HSP70 synthesis and thermotolerance development in cells grown and heated at pH 7.3. These results support the hypothesis that quercetin can specifically reduce thermotolerance development in tumour cells adapted to growth at pHe 6.7 so that they respond similarly to acutely acidified cells. Since many tumours are adapted to growth at low pH and may resist a wide variety of therapeutic modalities, inhibition of thermotolerance expression by quercetin may not only enhance the response to hyperthermia but the response to commonly used therapies such as chemotherapy and radiation.     

Physicians for Rural America: The Role of Institutional Commitment Within Academic Medical Centers

CONTEXT: Prior study suggests that contextual characteristics of medical schools (e.g., state demographics, public vs private, NIH research effort) predict output of rural physicians without also considering the effects of the medical schools' own policies and programs. PURPOSE: This study examines medical school commitment to rural policies and programs and its relationship to contextual characteristics and rural physician output. METHODS: A survey of 122 U.S. allopathic medical schools provided data to construct a 32-item Rural Commitment Index for each medical school. Data for other characteristics were linked from published sources. Correlations, t tests, and multiple regression analysis were used to study the association between variables and percentage of medical school graduates (1988-1996) who were in rural primary care practice in 2000. FINDINGS: Among 90 medical schools (response rate, 73.8%), the Rural Commitment Index correlated with the percentage of the state population that is rural and whether the school is public or private, and it joined percentage state population rural, public vs private, and National Institutes of Health support in correlating with percentage of graduates in rural primary care. In a regression model that explained 48.4% of variation in the percentage of graduates in rural primary care, the Rural Commitment Index explained most variation, followed by percentage state population rural, public vs private, National Institutes of Health support, and the interaction between the Rural Commitment Index and public vs private. CONCLUSIONS: The findings support the proposition that observable institutional commitment affects rural physician output and provide justification for a definitive study to verify that a change in medical school commitment to rural medicine produces a change in rural physician output.