Boerhaave's syndrome - rapidly evolving pleural effusion; a radiographic clue.

Boerhaave's syndrome is the rare and often fatal condition of spontaneous esophageal rupture. Meckler's triad of vomiting, pain and subcutaneous emphysema are characteristic features of Boerhaave's syndrome. When these symptoms are absent, diagnosis is frequently late and often occurs as the result of incidental investigation. This contributes to the observed high morbidity and mortality. Unless specifically considered in the differential diagnosis, this rare disease is frequently overlooked. The authors described the case of a patient in whom the diagnosis was made several days following presentation by observing that a large pleural effusion had evolved rapidly on chest radiographs. This uncommon radiological sign has relatively few causes and prompted a review of the history and diagnosis, followed by the initiation of additional investigations that confirmed Boerhaave's syndrome.

Five strategies of successful part-time work.

Nearly one in ten professionals now works part-time. But all too often, part-time work creates as many problems as it solves. At best, many part-timers work more hours than they intended. At worst, they see their importance to their organizations dwindle. Two generations have wrestled with such arrangements, and today some part-time professionals have found ways to overcome the challenges, with shining results. Drawing on two years of research investigating part-time engineers, financial analysts, IT specialists, and consultants, the authors present five strategies used by successful part-timers to make their unique position work for themselves and their companies. To begin with, successful part-time professionals take pains to make their work-life priorities, their schedules, and their plans for the future transparent to the organization. Second, they broadcast the business case for their arrangement, being careful to demonstrate that the arrangement has not disrupted the business and may even have a positive impact. Third, they establish routines to protect their time at work and rituals to protect their time at home. Fourth, they cultivate champions in senior management who protect them from skeptics and advocate for their arrangements up and down the ranks. And last, they gently but firmly remind their colleagues that, despite their part-time status, they're still major players in the organization who cannot be ignored. Taken together, these strategies not only help the part-timer deal with the organization but also make the organization itself more receptive to the possibilities of part-time work.

Immunosensitization of melanoma tumor cells to non-MHC Fas-mediated killing by MART-1-specific CTL cultures.

The discovery of human melanoma rejection Ags has allowed the rational design of immunotherapeutic strategies. One such Ag, MART-1, is expressed on >90% of human melanomas, and CTL generated against MART-1(27-35) kill most HLA A2.1(+) melanoma cells. However, variant tumor cells, which do not express MART-1, down-regulate MHC, or become resistant to apoptosis, will escape killing. Cytotoxic lymphocytes kill by two main mechanisms, the perforin/granzyme degranulation pathway and the TNF/Fas/TNF-related apoptosis-inducing ligand superfamily of apoptosis-inducing ligands. In this study, we examined whether cis-diaminedichloroplatinum (II) cisplatin (CDDP) sensitizes MART-1/HLA A2.1(+) melanoma and melanoma variant tumor cells to non-MHC-restricted, Fas ligand (FasL)-mediated killing by CTL. MART-1(27-35)-specific bulk CTL cultures were generated by pulsing normal PBL with MART-1(27-35) peptide. These CTL cultures specifically kill M202 melanoma cells (MART-1(+), HLA A2.1(+), FasR(-)), and MART-1(27-35) peptide-pulsed T2 cells (FasR(+)), but not M207 melanoma cells (MART-1(+), HLA A2.1(-), FasR(-)), FLU(58-66) peptide-pulsed T2 cells, or DU145 and PC-3 prostate cells (MART-1(-), HLA A2.1(-), FasR(+)). CDDP (0.1-10 microg/ml) sensitized non-MART-1(27-35) peptide-pulsed T2 to the CD8(+) subset of bulk MART-1-specific CTL, and killing was abolished by neutralizing anti-Fas Ab. Furthermore, CDDP up-regulated FasR expression and FasL-mediated killing of M202, and sensitized PC-3 and DU145 to killing by bulk MART-1-specific CTL cultures. These findings demonstrate that drug-mediated sensitization can potentiate FasL-mediated killing by MHC-restricted CTL cell lines, independent of MHC and MART-1 expression on tumor cells. This represents a novel approach for potentially controlling tumor cell variants found in primary heterogeneous melanoma tumor cell populations that would normally escape killing by MART-1-specific immunotherapy.

Individual differences in metacognition: evidence against a general metacognitive ability.

Individual differences in metacognitive accuracy are generally thought to reflect differences in metacognitive ability. If so, memory monitoring performance should be consistent across different meta-cognitive tasks and show high test-retest reliability. Two experiments examined these possibilities, using four common metacognitive tasks: ease of learning judgments, feeling of knowing judgments, judgments of learning, and text comprehension monitoring. Alternate-forms correlations were computed for metacognitive accuracy (with a 1-week interval between tests). Although individual differences in memory and confidence were stable across both sessions and tasks, differences in metacognitive accuracy were not. These results pose considerable practical and theoretical challenges for metacognitive researchers.

Sensitization of immunoresistant prostate carcinoma cell lines to Fas/Fas ligand-mediated killing by cytotoxic lymphocytes: independence of de novo protein synthesis.

BACKGROUND: We recently reported that drug-resistant prostate tumor cells (DU145, PC-3) are resistant to Fas-mediated killing by cytotoxic lymphocytes, and that this resistance can be overcome by treatment with subtoxic concentrations of chemotherapeutic drugs. Fas belongs to the tumor necrosis factor (TNF) family of receptors. Since resistance to TNF-alpha-mediated killing has been shown to be due, in part, to the presence of protective factors and that inhibitors of protein synthesis can sensitize cells to TNF-alpha killing, we hypothesized that resistance to Fas-mediated killing may be due to similar mechanisms. Since sensitization is achieved with chemotherapeutic drugs, and some chemotherapeutic drugs can also inhibit protein synthesis, we tested whether sensitization of prostate tumor cells to Fas ligand (Fas-L) occurred through inhibition of protein synthesis in a manner analogous to that of TNF-alpha. METHODS: The effect of chemotherapeutic drugs on protein synthesis in DU145 and PC-3 cells was characterized by (3)H-leucine incorporation assays. We also determined the ability of inhibitors of protein synthesis and chemotherapeutic drugs to sensitize Fas and TNF-resistant DU145 cells to killing. The ability of RNA (actinomycin-D, Act-D) and protein synthesis inhibitors (cyclohexamide (CHX), emetine) to block drug-mediated sensitization to Fas-L killing was analyzed. Sensitivity to Fas-L killing was determined by the (51)Cr-release assay using human lymphokine-activated killer cells (LAK) and tumor-infiltrating lymphocyte (TIL) effector cells and the murine Fas-L-expressing PMMI cells. RESULTS: The drugs cis-diamminedichloroplatinum (II) (CDDP), adriamycin (ADR), and etoposide (VP-16) sensitized DU145 and PC-3 cells to Fas killing. CDDP and ADR, which sensitized DU145 and PC-3 cells to Fas-L- and TNF-mediated killing, inhibited de novo protein synthesis in both cell lines, while VP-16 only inhibited protein synthesis in DU145 cells. Further, neither CHX nor emetine sensitized DU145 or PC-3 cells to Fas-L-mediated killing, despite blocking >90% de novo protein synthesis. In contrast, CDDP, VP-16, and the protein synthesis inhibitors, Act-D and CHX sensitized DU145 cells to TNF-alpha killing. Finally, pretreating cells with protein synthesis inhibitors (CHX, emetine) did not abrogate drug-mediated sensitization to Fas-mediated killing. CONCLUSIONS: These findings demonstrate that downregulation of protective factors by protein synthesis inhibition may not be the primary mechanism of drug-mediated sensitization to Fas-L killing in prostate cell lines. These findings also suggest that drug-mediated sensitization to Fas-L killing may be due to modifications of preexisting gene products that participate in Fas-L-mediated apoptosis.

Radiotherapy for atypical or malignant intracranial meningioma.

PURPOSE: To study the natural history of intracranial atypical and malignant meningiomas, and the role of radiotherapy in the treatment of these tumors. METHODS AND MATERIALS: The records of the 59 patients who were treated at the Princess Margaret Hospital between 1966 and 1990 with histologically confirmed intracranial atypical or malignant meningiomas were retrospectively reviewed. The median age was 58 years. Twenty-four patients were referred for radiation immediately after diagnosis and the remainder after at least one recurrence. The extent of the most recent surgery prior to radiation was gross total excision in 17, subtotal excision in 35, biopsy in 3, and none or unknown in 4. Seventeen had atypical meningiomas, defined as the presence of mitoses, nuclear atypia, or necrosis. Forty-two had malignant meningiomas on the basis of brain invasion (60%) or a pathologist's designation of malignant or hemangiopericytic meningioma. All patients received megavoltage radiation to a median dose of 50 Gy. RESULTS: Disease progressed in 39 patients (66%) after radiation. Of these, 36 died of meningioma and 3 were alive after further surgery. The 5-year actuarial overall and cause-specific survivals were 28 and 34%, respectively. Age less than 58, treatment after 1975, and a radiation dose of 50 Gy or more were independently associated with higher cause-specific survival by multivariate analysis. CONCLUSIONS: Young age, modern imaging and treatment planning techniques, and a postoperative radiation dose of at least 50 Gy contribute to improved outcome in patients with atypical or malignant meningiomas. We recommend that all patients receive radiotherapy immediately after initial surgery.

Medulloblastoma in adults.

PURPOSE: To assess the outcome and prognostic factors for adult patients with medulloblastoma managed by postoperative radiotherapy between 1958 and 1988 at the Princess Margaret Hospital. METHODS AND MATERIALS: A retrospective review was undertaken of 48 patients age 16 years or older who received radiotherapy for medulloblastoma. The median age at diagnosis was 25 years, with 36 male and 12 female patients. Sixteen tumors were confined to midline structures, and 32 were localized to a cerebellar hemisphere or involved midline and lateral structures. The desmoplastic variant was reported in 12 cases. Complete macroscopic removal was achieved in 22 patients, subtotal removal in 23, and biopsy only in 3. Forty-six patients received craniospinal radiation and 2 patients received local irradiation only. RESULTS: Median overall survival was 7.9 years, and 5- and 10-year overall survival was 62% and 41%, respectively. Significant factors for disease-free survival were M stage (M0 vs. M1-4, p = 0.0005), functional state at the time of radiotherapy (1-2 vs. 3-5, p = 0.005), and the absence or presence of hydrocephalus preoperatively (p = 0.02). Twenty-four patients developed recurrent disease, with 14 relapsing first in the posterior fossa. Subtotal removal of tumor (p = 0.04) was the only factor predictive of posterior fossa relapse. CONCLUSIONS: Patients with disease outside the posterior fossa at diagnosis, symptomatic patients (neurologic functional state 3-5) at the time of radiotherapy, and those who present with hydrocephalus have poorer disease-free survival. Gross total resection improved posterior fossa control.

Effects of nicotine on cellular function in UMR 106-01 osteoblast-like cells.

We examined the effect of nicotine on cellular proliferation, as measured by [3H]thymidine (TdR) incorporation and cell count, and on alkaline phosphatase activity in UMR 106-01 rat osteoblastic osteosarcoma cells. The cells were cultured with varying concentrations of nicotine in serum-free medium for 2 to 72 hours. Nicotine produced a dose-dependent suppression of TdR incorporation, with maximum suppression seen at 10 mM (7% of control); the EC50 for suppression of TdR incorporation was 10 microM. 1 microM nicotine decreased cell number by 20% to 30%. The time course of the effect of 100 microM nicotine on DNA synthesis was measured by TdR incorporation. TdR uptake was measured at 2, 4, 6, 24, 48, and 72 hours. After the addition of nicotine, the following biphasic response in TdR incorporation was observed: a 15% decrease at 2 hours, recovery to near control value at 6 hours, a 27% decrease by 24 hours, and a maximum decrease of 88% by 48 hours. Over a dose range of 1 nM to 10 mM, nicotine produced a dose-dependent increase in alkaline phosphatase activity with maximum stimulation seen at 1 microM (189% of control). We conclude that nicotine suppresses cellular proliferation and stimulates alkaline phosphatase activity in UMR 106-01 osteoblast-like cells. These results may be of significance in the development of osteoporosis and alveolar bone loss associated with the use of tobacco.