Novel tricyclic poly(ADP-ribose) polymerase-1 inhibitors with potent anticancer chemopotentiating activity: design,synthesis, and X-ray cocrystal structure

A series of novel compounds have been designed that are potent inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1), and the activity and physical properties have been characterized. The new structural classes, 3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-ones and 3,4-dihydropyrrolo[4,3,2-de]isoquinolin-5-(1H)-ones, have conformationally locked benzamide cores that specifically interact with the PARP-1 protein. The compounds have been evaluated with in vitro cellular assays that measure the ability of the PARP-1 inhibitors to enhance the effect of cytotoxic agents against cancer cell lines.     

Comparing frequent and average users of elementary school-based health centers in the Bronx,New York City

This study analyzed health care utilization at three school-based health centers (SBHCs) in the Bronx, New York City, and compared characteristics of "frequent" and "average" service users. Encounter form data for visits by 2,795 students who received services at least once between September 7, 1998, and June 30, 1999, were reviewed. Demographic comparisons between clinic users and the total school population, and between "frequent" (five or more visits/year) and "average" (one to four visits/year) users were made. The two groups also were compared after primary diagnoses were classified into five general categories. Some 96% (3,469/3,614) of students were registered in the SBHCs, of whom 81% (2,795/3,469) used clinic services at least once during the school year. Clinic users did not differ from the general school population by gender, but were younger (p < 0.01). "Frequent" users were more likely than "average" users to be older (p < 0.01), but they did not differ by gender, race/ethnicity, or insurance status. "Frequent" users comprised 28% of the clinic-using population, but accounted for 72.5% of all visits. Similarly, "average" users comprised 72.4% of the clinic-using population, but accounted for 27.5% of all visits. "Frequent" users generated most visits for mental health and chronic medical conditions, while "average" users generated most visits for preventive care, acute medical care, and injuries/emergencies (p < 0.01 for all). Important challenges for elementary SBHCs include developing new approaches that meet children's needs while protecting clinic resources, like scheduling group interventions for those with on-going health care needs who require frequent use of school health services.     

Osteopenia in survivors of Wilms tumor

Diminished bone mass (osteopenia) is recognized increasingly as a consequence of therapy in survivors of cancer in childhood. It has been reported in two small series of survivors of Wilms tumor. The objectives of this study were to explore, in a larger sample of such subjects, the prevalence of osteopenia and a possible relationship between osteopenia of the lumbar spine and abdominal irradiation. All survivors of Wilms tumor (n=49) in a single institution were considered eligible for study. Thirty-one agreed to participate; the non-participants were not notably different in their demographic characteristics and diseases/treatment experience. Information was obtained about prior treatment, and usual diet, sun exposure and physical activity. Bone mineral content was measured by dual energy X-ray absorptiometry, and biochemical markers of bone turnover, calciotropic hormones and minerals were assessed in a single blood sample. By Z-scores of whole body bone mineral content, 8 subjects were osteopenic. This was unrelated to milk intake or sun exposure and was not more common in the lumbar spine of those who had been irradiated (15/31 subjects). Physical activity correlated positively with bone mineral density Z-scores (p<0.005). Normal bone formation was reflected in normal blood levels of osteocalcin. C-telopeptide levels, reflecting bone resorption, were high but approximately correlated inversely with maturity. Low serum magnesium and parathyroid hormone levels were detected in a minority of subjects. Osteopenia is present in a large minority (27%) of survivors of Wilms tumor, and an imbalance of bone turnover (with excessive resorption) may be common. Irradiation does not appear to play a causal role. It is possible that a subtle renal tubular defect exists in these individuals; a prospect worthy of further exploration.     

Accuracy of tuned aperture computed tomography in the diagnosis of radicular fractures in non-restored maxillary anterior teeth--an in vitro study

OBJECTIVES: This study compared the accuracy of three radiographic imaging modalities for the detection of artificially induced radicular fractures on maxillary anterior teeth. METHODS: Fractures were induced in 28 of 54 maxillary incisors in 15 cadaver specimens using a distally directed force. Radiographs evaluated included conventional two-dimensional direct digital radiographs (DDI), unprocessed Tuned Aperture Computed Tomography (TACT-U) and iteratively restored TACT (TACT-IR). Eight observers recorded their findings using a five-point confidence-rating scale. Receiver Operating Characteristic (ROC) analyses were done, followed by ANOVA to test for significant effects of observers, imaging modality and fracture location. Post hoc tests were carried out in instances where ANOVA indicated significance. RESULTS: The areas under the ROC-curves (A(z)) were, respectively: DDI: 0.53; TACT-U: 0.83 and TACT-IR: 0.97. TACT-IR and TACT-U performed significantly better than DDI (P < 0.001) with TACT-IR providing a higher detection accuracy than TACT-U (P < 0.033). A difference in detection accuracy was also noted based on fracture location (P < 0.001). Tukey's post hoc analyses revealed that fractures extending beyond the middle third of the root were more accurately detected. Inter-observer agreement was 0.68, and intra-examiner agreement, 0.87 (kappa analysis). CONCLUSIONS: TACT performed significantly better than direct digital images in detecting trauma-induced radicular fractures in unrestored, maxillary anterior teeth.     

Virtual radiographs computed from TACT volume data as a gold standard for image registration prior to subtraction

OBJECTIVE: To develop a three-dimensional (3D) model for quantitative analysis of image subtraction methods simulating clinical conditions and relevant to dental radiology. METHOD: A high-resolution volume representation of a formalin-preserved segment of a human maxilla was synthesized from a set of 51 digital radiographs equidistantly covering the entire sampling aperture by means of Tuned-Aperture Computed Tomography (TACT). Two-dimensional (2D) projection renderings of a 3D model were generated yielding arbitrary but well-known 2D projections with, and without, structured noise producing 'virtual radiographs'. RESULTS: Virtual radiographs were found to be similar to actual clinical images with respect to appearance, structure, and texture. Because the TACT reconstruction process allows all possible positions and orientations of source, specimen, and image plane to be simulated with negligible under sampling over a reasonable range of solid angles (sampling aperture), the resulting 3D model provided a rigorous method for establishing a truly objective gold standard (ground truth) for testing different registration techniques. CONCLUSIONS: TACT image registration can be assessed quantitatively by comparing actually observed vs theoretically professed parameters that presumably constrain the underlying projection geometries. Other attributes that vary from one method to the next, such as the use of nonlinear or region-specific techniques to facilitate registration, likewise, now can be rigorously measured by context-based methods such as quantitative determination of image similarity. Hence, a 3D model that renders idealized virtual radiographs from any desired projection geometry makes possible truly objective comparison of various digital subtraction techniques.     

Endometrial carcinoma with laparotomy wound recurrence: complete remission following surgery and chemotherapy consisting of paclitaxel and carboplatin

We present a patient with surgical stage I endometrial cancer who experienced laparotomy wound recurrence 4 years after primary treatment. She was treated successfully by complete surgical resection of recurrent tumors and chemotherapy. A 62-year-old white female with laparotomy wound recurrence of endometrial carcinoma with small-bowel involvement and concomitant subcutaneous metastasis in the abdominal wall underwent complete surgical resection of metastatic tumors followed by six cycles of chemotherapy consisting of paclitaxel (175 mg/m2) and carboplatin (area under the curve 5). Since 24 months after resection of recurrence, she has no evidence of disease recurrence. Endometrial carcinoma with laparotomy wound recurrences, especially those with concomitant metastases, can be successfully treated by complete surgical resection followed by chemotherapy consisting of paclitaxel and carboplatin.     

Double-blind placebo-controlled trial of corticosteroids in children with postpericardiotomy syndrome

Summary The objective of this study was to assess the efficacy of corticosteroids in hastening the recovery of children with postpericardiotomy syndrome, using a randomized double-blind placebo-controlled trial in a tertiary care referral center for pediatric cardiology and cardiac surgery. Twenty-one children, 6 months of age or older (mean age 3.9 years) with postpericardiotomy syndrome following open or closed heart surgery were administered either prednisone 2 mg/kg/day reducing to zero over 14 days (n=12) or placebo (n=9). Progress was monitored by daily clinical assessment and alternate day cross-sectional echocardiograms. The primary measures of efficacy were the number of patients in remission at 72 h and at 1 week. No difference in remission rates were found at 72 h, but at 1 week significantly more children treated with prednisone were in remission (placebo 3/9; prednisone 10/12,p=0.03). A trend to faster resolution of all symptoms and signs was seen in the prednisone-treated group but this was not associated with earlier hospital discharge. Enlargement of pericardial effusion was seen in two children treated with steroids. No complications of treatment were encountered. Prednisone hastens the recovery of children with postopericardiotomy syndrome. Pericardial effusions may increase in size despite the use of corticosteroids.Presented in part at the Society for Pediatric Research, New Orleans, May 1991.