Biodosimetry for a radiation worker using multiple assays.

Four state-of-the-art biodosimeters--GPA mutations, chromosome translocations, micronuclei, and dicentrics--were used to evaluate a radiation worker who believed that the official dosimetry records substantially underestimated his actual dose. Dosimetry records indicated that the worker received 0.56 Sv during a 36-y employment history, always within the dose limits. In contrast, the worker believed that his dose equivalent may have been more than 2.5 Sv because much of the exposure was received during the early days of health physics when dosimetry capabilities and practices were not as good as they are today. Because there are no biodosimetric assays that have been fully validated for the long-term low-level exposures received by the worker, we did not expect to obtain particularly useful point-estimates of dose. However, because the discrepancy between the dosimetry records and the worker's belief was so large, we believed that biodosimetry using multiple assays together with probabilistic assessment of the uncertainties would provide useful insight. Results showed that the frequencies of chromosome translocations and GPA mutations (stable biodosimeters) were significantly elevated when compared with those for unexposed controls. Our analysis suggests that dose-equivalent estimates in the approximately 0.4 to approximately 2 Sv range (which include the value in the dosimetry records) cannot be confidently excluded at this time based on biodosimetry; however, a value greater than 2.5 Sv appears unlikely. Important new information on the temporal stability of chromosome translocations is also presented.     

A series of potent HIV-1 protease inhibitors containing a hydroxyethyl secondary amine transition state isostere: synthesis, enzyme inhibition, and antiviral activity.

A series of HIV-1 protease inhibitors containing a novel hydroxyethyl secondary amine transition state isostere has been synthesized. The compounds exhibit a strong preference for the (R) stereochemistry at the transition state hydroxyl group. Molecular modeling studies with the prototype compound 11 have provided important insights into the structural requirements for good inhibitor-active site binding interaction. N-Terminal extension of 11 into the P2-P3 region led to the discovery of 19, the most potent enzyme inhibitor in the series (IC50 = 5.4 nM). 19 was shown to have potent antiviral activity in cultured MT-4 human T-lymphoid cells. Comparison of analogs of 19 with analogs of 1 (Ro31-8959) demonstrates that considerably different structure-activity relationships exist between these two subclasses of hydroxyethylamine HIV-protease inhibitors.     

Evaluation of BioCorkscrew and Bioknotless RC suture anchor rotator cuff repair fixation: an in vitro biomechanical study

This in vitro biomechanical study used cadaveric specimens to compare the rotator cuff repair fixation provided by BioCorkscrew and Bioknotless RC suture anchors. Three cm wide by 1-cm long full-thickness supraspinatus defects were repaired using either two BioCorkscrew suture anchors with combined vertical and horizontal mattress sutures (n = 7) or three Bioknotless RC suture anchors with simple sutures (n = 7). Therefore, the BioCorkscrew suture anchor group had two sutures per anchor (four total sutures), while the Bioknotless RC suture anchor group had one suture per anchor (three total sutures). Two-phase cyclic (5–100 N, 1,000 cycles and 5–180 N, 2,000 cycles) and load to failure tests (31 mm/s) were performed. Non-parametric statistics were used to compare group differences (P < 0.05). All of the BioCorkscrew group specimens (seven of seven) completed the two phase cyclic test regimen without failure or gapping ≥ 5 mm, compared to only three of seven of the Bioknotless RC group (Fisher’s Exact test = 0.03). Groups did not differ for repair site gapping during the 5–100 N cyclic test phase (Fisher’s Exact test = 0.77), however more of the Bioknotless RC group displayed gapping ≥ 5 mm during the 5–180 N cyclic test phase than the BioCorkscrew group (P = 0.02). The BioCorkscrew group also displayed greater yield load during load to failure testing (492.2 ± 204 N vs. 296.4 ± 155 N, P = 0.03). In this in vitro biomechanical study, the BioCorkscrew group with combined vertical and horizontal mattress sutures displayed greater cyclic test survival, less repair site gapping, and superior yield load compared to the Bioknotless RC group with simple sutures. These results in human cadaveric rotator cuff-humerus specimens suggest better immediate post-operative repair site strength and a reduced need for post-operative restrictions. Clinical studies are needed to determine how these rotator cuff repair modes withstand the forces of early rehabilitation and activities of daily living that potentially influence patient outcomes.     

Radiographic appearances in lumbar disc prolapse

The pre-operative lumbar spine radiographs of 200 consecutive patients who had undergone discectomy for prolapsed intervertebral disc were reviewed. Prolapse was recognized as bulging or sequestration of the disc with consequent root compromise. Measurement of the lumbar level of the interiliac line was shown to correlate with the level of disc prolapse and the incidence of transitional vertebrae at the lumbosacral junction was significantly higher than normal. A pathological value for the lumbosacral angle could not be identified.     

Clinical and laboratory observations in a lymphoma-prone family

Three sisters developed non-Hodgkin's lymphoma (NHL). Thirteen maternal relatives had adenocarcinomas of various types, predominantly breast and large bowel. Detailed laboratory assessment of this family revealed a variety of immunologic abnormalities. Two lymphoma patients had elevated anti-early antigens (EA) Epstein-Barr virus (EBV) titers. One of the two also had a markedly elevated anti-viral capsid antigen (VCA) EBV titer. The two lymphoma patients were human leukocyte antigen (HLA)-identical, but two unaffected siblings shared the same HLA haplotypes. One of the lymphoma patients and four unaffected family members were anergic; and three unaffected family members had a decreased percentage of T-cells. These data suggest that a subtle disturbance in cellular immune functions may play a causal role in some familial aggregations of malignant lymphoma.     

Radical prostatectomy: anatomical predictors of success or failure

A total of 143 patients underwent radical prostatectomy. Surgical specimens were evaluated with respect to local extent of disease, Gleason grade of the primary and relative nuclear roundness of the surgical specimen. The probability of disease control in the total population was 88 per cent at 5 years. Only 8 per cent of the patients who had disease confined to the specimen failed compared to 14 per cent of those who demonstrated extension outside of the surgical margins. The incidence of failure increased as a function of seminal vesicle involvement. Seminal vesicle involvement was greatest among patients with a Gleason grade greater than 7. Postoperative radiation did not offer any apparent advantage in patients with positive margins.     

Rurality, remoteness and the change process: evidence from a study of maternity services in the north of Scotland.

There is a wealth of material on 'how to do' change plus empirical work revealing change process complexity. In health care, the relevance of context is highlighted, but studies of rural health-care change have focused on community impacts. There is little to inform health-care managers of how remoteness and rurality impact upon change processes. This study considered Scottish maternity units and aimed to identify issues in the change process associated with rurality and remoteness. Six units were purposively selected and 131 interviews were conducted with managers, staff and community members over 15 months. Analysis induced themes pertinent to remoteness and rurality. These included: perceived 'distance' between senior managers imposing change and the wider community of staff and residents; perceptions of community vulnerability; and tensions arising from working in small teams and living in small communities. The study provides useful insights for rural managers at a time of considerable service reconfiguration.     

In vitro thermo-chemosensitivity screening of spontaneous human tumors: significant potentiation for cisplatin but not adriamycin

The in vitro thermal enhancement of Adriamycin (ADR) and Cisplatin (CDDP) was investigated in 18 surgical biopsy specimens of human tumors cultured in the Adhesive Tumor Cell Culture System. Experimental conditions were adopted to simulate "therapeutic" trials: (a) temperature of 37.0 degrees C, 40.5 degrees C or 42.5 degrees C; (b) hyperthermic duration of 30, 60, or 120 min; and (c) 4-dose drug range normalized to human bone marrow toxicity. Drug concentrations that inhibited 90% of tumor growth (IC90) at 37.0 degrees C were compared to the IC90 at 40.5 degrees C and 42.5 degrees C, adjusted for the effect of heat alone. CDDP plus heat was a better combination than ADR plus heat, regardless of the temperature and the exposure duration: significant synergism (p less than 0.001) occurred in 37% of heat-CDDP combinations, as compared with 15% of heat-ADR combinations, and antagonism was significantly lower (p less than 0.001) for heat-CDDP than for heat-ADR (4.4% versus 21% of combinations, respectively). Within the CDDP group, higher temperature and longer heat exposure resulted in an increased incidence of chemosensitivity. No specific pattern of synergism was evident within the ADR group, but a trend toward a higher incidence of antagonistic effects with increasing hyperthermic duration was observed.