Immunohistochemical analysis of intratumoral heterogeneity of [131I]cG250 antibody uptake in primary renal cell carcinomas

In previous studies, highly heterogeneous uptake of 131I-labelled chimeric monoclonal antibody G250 ([131I]cG250) in primary renal cell carcinomas has been observed (intratumoral differences > factor 100). In this study, we investigated a possible correlation between intratumoral antibody uptake and four immunohistochemically determined parameters: G250 antigen expression, blood vessel density, neovascularization and percentage of viable tumour cells. Whole tumour slices of four different tumours were cut into 1-cm3 cubes, and in each cube the [131I]cG250 uptake was determined. The correlation between [131I]cG250 uptake and each individual parameter was determined in a multiple regression analysis. Additionally, the data were reanalysed after introducing arbitrary cut-off values for each parameter. If a sample showed expression of a parameter above the introduced threshold value, this sample fulfilled one condition. Subsequently, the Pearson correlation coefficients were calculated from [131I]cG250 uptake and the number of fulfilled conditions (0-3). All tumour samples with high [131I]cG250 uptake [> 0.1% of the injected dose per gram (ID g(-1))] showed high antigen expression (> 50%). However, not all samples with high antigen expression displayed high uptake. A statistically significant correlation between [131I]cG250 uptake and antigen expression was found (beta = 0.44, 0.69 and 0.74) in three out of four tumours analysed. Of the other determined parameters, no consistent correlation with [131I]cG250 uptake was found; only the percentage of viable tumour cells correlated significantly in two out of four tumours (beta = 0.80 and 0.26). Calculation of the Pearson correlation coefficients showed a statistically significant correlation between [131I]cG250 uptake and an increased number of fulfilled conditions in all tumours, indicating that each of the individual parameters contribute to the uptake of [131I]cG250. These observations indicate that high antigen expression is a prerequisite for high antibody uptake. However, regional differences in antibody uptake within a tumour cannot be explained by antigen expression alone.     

Heterocycle-containing bisphosphonates cause apoptosis and inhibit bone resorption by preventing protein prenylation: evidence from structure-activity relationships in J774 macrophages

Recent evidence suggests that bisphosphonates (BPs) may inhibit bone resorption by mechanisms that lead to osteoclast apoptosis. We have previously shown that BPs also reduce cell viability and induce apoptosis in the macrophage-like cell line J774. To determine whether BPs inhibit osteoclast-mediated bone resorption and affect J774 macrophages by the same molecular mechanism, we examined the potency to reduce J774 cell viability of pairs of nitrogen-containing BPs that differ slightly in the structure of the heterocycle-containing side chain but that differ markedly in antiresorptive potency. In all cases, the most potent antiresorptive BP of each pair also caused the greatest loss of J774 viability, while the less potent antiresorptive BPs were also less potent at reducing J774 cell viability. Similarly, the bisphosphinate, phosphonoalkylphosphinate and monophosphonate analogs of BPs (in which one or both phosphonate groups are modified, giving rise to much less potent or inactive antiresorptive agents) were much less potent or inactive at reducing J774 cell viability. Thus, the structure-activity relationships of BPs for inhibiting bone resorption match those for causing loss of cell viability in J774 cells, indicating that BPs inhibit osteoclast-mediated bone resorption and reduce J774 macrophage viability by the same molecular mechanism. Loss of J774 cell viability after treatment with BPs was associated with a parallel increase in apoptotic cell death. We have recently proposed that nitrogen-containing BPs reduce cell viability and cause J774 apoptosis as a consequence of inhibition of enzymes of the mevalonate pathway and hence loss of prenylated proteins. In this study, the BPs that were potent inducers of J774 apoptosis and potent antiresorptive agents were also found to be effective inhibitors of protein prenylation in J774 macrophages, whereas the less potent BP analogs did not inhibit protein prenylation. This provides strong evidence that BPs with a heterocyclic, nitrogen-containing side chain, such as risedronate, inhibit osteoclast-mediated bone resorption and induce J774 apoptosis by preventing protein prenylation.     

The market for occupational medicine managed care

The metamorphosis of the health care market has opened a window of opportunity for occupational medicine programs and practices to assume a critical role in the delivery of managed occupational and personal health care services. This chapter offers practical suggestions and tips.     

Development of approaches to improve the healing following muscle contusion

Muscle injuries are a challenging problem in traumatology, and the most frequent occurrence in sports medicine. Muscle contusions are among the most common muscle injuries. Although this injury is capable of healing, an incomplete functional recovery often occurs, depending on the severity of the blunt trauma. We have developed an animal model of muscle contusion in mice (high energy blunt trauma) and characterized the muscle's ability to heal following this injury using histology and immunohistochemistry to determine the level of muscle regeneration and the development of scar tissue. We have observed a massive muscle regeneration occurring in the first 2 wk postinjury that is subsequently followed by the development of muscle fibrosis. Based on these observations, we propose that the enhancement of muscle growth and regeneration, as well as the prevention of fibrotic development, could be used as approach(es) to improve the healing of muscle injuries. In fact, we have identified three growth factors (bFGF, IGF-1, and NGF) capable of enhancing myoblast proliferation and differentiation in vitro and improving the healing of the injured muscle in vivo. Furthermore, the ability of adenovirus to mediate direct and ex vivo gene transfer of beta-galactosidase into the injured site opens possibilities of delivering an efficient and persistent expression of these growth factors in the injured muscle. These studies should help in the development of strategies to promote efficient muscle healing with complete functional recovery following muscle contusion.     

D-xylose test of resorption as a method to determine radiation side effects in the small intestine

Microscopic papillary carcinoma of the thyroid gland (MPC) measuring < or = 1.0 cm in diameter has a generally benign outcome, but is often overtreated with additional surgery. Ninety cases of MPC and 77 cases of nonmicroscopic papillary carcinoma of the thyroid gland (non-MPC) from 1970 to 1980 were retrieved from the Endocrine Registry of the Armed Forces Institute of Pathology (AFIP), Washington, D.C. Histologic features and patient follow-up were analyzed. Twenty-one patients with MPC had multifocal disease within the affected thyroid lobe, while a further 15 had either bilateral or intraglandular spread. Four of 10 patients who had additional surgery were found to have additional foci of tumor. Fourteen patients with lymph node metastases at initial surgery had no subsequent nodal metastases. All patients were either alive without disease or had died of unrelated causes after an average follow-up period of 17.3 years. Of the 77 non-MPC patients, 13 developed lymph node metastases or local recurrences, and one died of metastatic disease. Sixty-four of these patients were alive without evidence of disease after an average follow-up of 22 years. Present findings show that while MPC may present with perithyroidal lymph node metastases (15.56%), patients do not develop clinical tumors in the remaining thyroid tissue. Our experience indicates that close clinical follow-up without additional surgery is the preferable management for patients with MPC.     

Induction of pulmonary fibrosis in organ-cultured rat lung by cadmium chloride and transforming growth factor-beta1

Cadmium chloride (CdCl2) exposure has been reported to induce pulmonary fibrosis in rats. Accumulating evidence has shown that cytokines play a pivotal role in the excessive production of connective tissue components in pulmonary fibrosis. In this report, rat lung slice cultures were used to study the synergistic involvement of transforming growth factor-beta1 (TGF-beta1) in CdCl2-induced alveolar fibrosis. Rat lung slices were maintained at the interphase of air and medium on a polyester mesh stretched on a plastic scaffold. Treatment of lung slices with 2.5, 5 or 10 microM CdCl2 for 7 days resulted in 85, 40 and 6% respectively for relative survival. Under these culture conditions, CdCl2 alone did not induce alveolar fibrosis in rat lung slices. However, in the presence of 0.5 ng/ml TGF-beta1, CdCl2 at a dose ranging from 1 to 5 microM increased the thickness of alveolar septa. Furthermore, the thickness of alveolar septa in lung slices treated with CdCl2 was dose-dependently increased by the presence of TGF-beta1. The thickened alveolar septa were apparently due to the deposition of excessive extracellular matrix, as revealed by trichrome stain and ultrastructural examination. Our results also show that fibrogenic activity induced by the combined treatment with CdCl2 and TGF-beta1 can be reduced by co-treatment with 200 microg/ml lambda-carrageenan, a TGF-beta1 inhibitor. Therefore, the present results indicate that TGF-beta1 can synergistically stimulate the fibrogenic activity in lung tissue subsequent to CdCl2 injury.     

Clinical reasoning and decision making in the practice. A woman with abdominal complaints

A female patient aged 28 years suffered from recurrent episodes of diarrhoea. Giardia lamblia was isolated once. By rigorous application of basic clinical skills, such as thorough history taking and physical examination, together with laboratory tests the correct diagnosis was established (in this patient systemic lupus erythematosus). Two important aspects of clinical reasoning, viz. returning to the patient when new information becomes available (cyclic way of working) and pattern recognition ensured a fruitful diagnostic process.     

Children with minimal sensorineural hearing loss: prevalence, educational performance, and functional status

OBJECTIVE: This study was designed to determine the prevalence of minimal sensorineural hearing loss (MSHL) in school-age children and to assess the relationship of MSHL to educational performance and functional status. DESIGN: To determine prevalence, a single-staged sampling frame of all schools in the district was created for 3rd, 6th, and 9th grades. Schools were selected with probability proportional to size in each grade group. The final study sample was 1218 children. To assess the association of MSHL with educational performance, children identified with MSHL were assigned as cases into a subsequent case-control study. Scores of the Comprehensive Test of Basic Skills (4th Edition) (CTBS/4) then were compared between children with MSHL and children with normal hearing. School teachers completed the Screening Instrument for Targeting Education Risk (SIFTER) and the Revised Behavior Problem Checklist for a subsample of children with MSHL and their normally hearing counterparts. Finally, data on grade retention for a sample of children with MSHL were obtained from school records and compared with school district norm data. To assess the relationship between MSHL and functional status, test scores of all children with MSHL and all children with normal hearing in grades 6 and 9 were compared on the COOP Adolescent Chart Method (COOP), a screening tool for functional status. RESULTS: MSHL was exhibited by 5.4% of the study sample. The prevalence of all types of hearing impairment was 11.3%. Third grade children with MSHL exhibited significantly lower scores than normally hearing controls on a series of subtests of the CTBS/4; however, no differences were noted at the 6th and 9th grade levels. The SIFTER results revealed that children with MSHL scored poorer on the communication subtest than normal-hearing controls. Thirty-seven percent of the children with MSHL failed at least one grade. Finally, children with MSHL exhibited significantly greater dysfunction than children with normal hearing on several subtests of the COOP including behavior, energy, stress, social support, and self-esteem. CONCLUSIONS: The prevalence of hearing loss in the schools almost doubles when children with MSHL are included. This large, education-based study shows clinically important associations between MSHL and school behavior and performance. Children with MSHL experienced more difficulty than normally hearing children on a series of educational and functional test measures. Although additional research is necessary, results suggest the need for audiologists, speech-language pathologists, and educators to evaluate carefully our identification and management approaches with this population. Better efforts to manage these children could result in meaningful improvement in their educational progress and psychosocial well-being.     

Effects of CO2 laser in treatment of cervical dentinal hypersensitivity

The effectiveness of CO2 laser therapy in the reduction and elimination of dentinal hypersensitivity in vivo and its thermal effects on tooth surfaces in vitro were investigated. Twenty-three patients with 91 sensitive teeth participated in this study and were followed for 3 months. The parameters used with CO2 laser were 1 W in a continuous wave mode and irradiation time ranging from 5 to 10 s. Hypersensitivity was assessed by thermal stimulus (a blast of air from a dental syringe). Thermal effects were measured by thermography using 10 extracted human teeth. After laser treatment, all patients were immediately free from sensitive pain. Over 3 months, the CO2 laser treatment reduced dentinal hypersensitivity to air stimulus by 50%. All teeth remained vital with no adverse effects. Thermography revealed no temperature increase on irradiated tooth surfaces subjected to water coolant. These results show that the CO2 laser is useful in the treatment of cervical dentinal hypersensitivity without thermal damage to pulp.     

Failure of ketoprofen and interferon combination therapy to improve interferon-resistant chronic hepatitis C

Previous studies have documented the effectiveness of magnetic resonance imaging for evaluating and following up the development of avascular necrosis of the femoral head. One of the limitations of this technique, however, is the distortion that is encountered with ferromagnetic screws. A traumatic fracture to the femoral head is a risk factor for avascular necrosis. The addition of internal fixation, which is often required in Pipkin-type fractures of the femoral head, creates significant image distortion on magnetic resonance scans used for postoperative follow-up. The artifact and field distortion present in magnetic resonance imaging when ferromagnetic screw fixation is used has been avoided at our institution by the use of titanium hardware. The authors, therefore, recommend the use of titanium screws in the fixation of Pipkin-type fractures in the hip joint.