Synergy between T cell Receptor and Fas (CD95/APO-1) signaling in mouse thymocyte death

Both extracellular and intracellular calcium (Ca2+) play important roles in hypoxic pulmonary vasoconstriction (HPV) and the vasoconstrictor responses to endogenous pulmonary vasoconstrictor substances, as evidenced by the effect of calcium-channel blockers on these vasoconstrictor responses and the measurement of changes in Ca2+ flux or intracellular Ca2+ concentrations in isolated cells. The more vasoselective the calcium-channel blocker, the greater its effect on pulmonary vasoconstriction. However, these drugs are not selective for the pulmonary vascular bed and are not as potent as pulmonary vasodilators when compared with other vasodilator drugs, including prostaglandin E1, isoproterenol, prostacyclin, or nitroglycerin. Moreover, the primary effect of vasoselective calcium-channel blockers on pulmonary vascular resistance is secondary to the effects of these agents on systemic vascular resistance and cardiac output. Although there is improvement in oxygen delivery, exercise tolerance, and survival in patients with primary pulmonary hypertension who respond to calcium-channel blockers, the response of individual patients to these drugs is difficult to predict because the extent of reversible versus irreversible changes in the pulmonary vasculature is not known. The use of these drugs in patients with chronic hypoxia-induced pulmonary vasoconstriction may be associated with a worsening of ventilation-perfusion mismatching secondary to inhibition of HPV.     

Mortality and neurologic morbidity after repair of traumatic aortic disruption

BACKGROUND: Traumatic disruption of the thoracic aorta frequently results in death before operative repair. The determinants of mortality after repair, however, are uncertain. In addition, intraoperative strategies for reducing the incidence of spinal cord injury remain controversial. METHODS: The records of 45 consecutive patients undergoing repair of traumatic disruption of the thoracic aorta at a single institution during a 9-year period were reviewed in a retrospective fashion. Patient age ranged from 15 to 81 years (mean age, 33.9 years). Twenty-two patients (49%) had multiple associated injuries, and 8 (18%) had isolated aortic injuries. Nine patients (20%) experienced preoperative hypotension (systolic blood pressure of less than 90 mm Hg). Repair was performed with partial bypass in 22 patients, a heparinized shunt in 2, and no distal perfusion (clamp and sew technique) in 21. RESULTS: Nine patient (20%) died after operation. Multivariate logistic regression analysis of preoperative and intraoperative variables identified advancing age and preoperative hypotension as independent predictors of operative death. The presence of associated injuries was not an independent predictor of operative death. All 4 patients with injuries proximal to the aortic isthmus died. Ten patients were excluded from analysis of spinal cord injury either because of preoperative neurologic deficit or because of death before postoperative evaluation. Six (17%) of the remaining 35 patients had development of paraplegia: 5 of the 15 patients having the clamp and sew technique, 1 of the 2 with a shunt, and 0 of the 18 patients with bypass (p < 0.05, clamp and sew versus bypass). In the clamp and sew group, patients in whom paraplegia developed had significantly longer aortic clamp times than those without neurologic injury (40.6 +/- 4.4 minutes versus 28.7 +/- 2.9 minutes, respectively; p < 0.05). CONCLUSIONS: Advancing age, preoperative hypotension, and perhaps injury location are important determinants of death after repair of traumatic disruption of the thoracic aorta. Adjunctive perfusion with partial bypass should be used during repair to reduce the incidence of spinal cord injury.     

The role of androgen receptor gene mutations in male breast carcinoma

Certain germline mutations (607Arg-Gln, 608Arg-Lys) in the androgen receptor gene have been associated with the occurrence of breast cancer in males suffering from partial androgen insensitivity. To assess whether somatic mutations in this gene could be detected in breast carcinoma, archival tumor tissue of males without clinical evidence of androgen insensitivity was screened for point mutations in the androgen receptor gene. DNA was retrieved by chloroform-phenol extraction from formalin-fixed, paraffin-embedded tissues. Exons 2-8 of the androgen receptor gene, encoding the DNA- and hormone-binding regions of the receptor, were amplified by polymerase chain reaction and subjected to nonisotopic single strand conformation assay (SSCA) to screen for point mutations. In the tumor DNA, no variations suggestive of mutations were encountered on SSCA. However, in a control patient with partial androgen insensitivity and predominantly female phenotype, the germline mutation 607Arg-Gln was identified in blood leukocyte DNA. Our results indicate that somatic mutations of the androgen receptor are not required for the development of male breast cancer. This, however, does not exclude an increased risk of breast carcinoma in patients with androgen insensitivity.     

Changes in radiation sensitivity and steroid receptor content induced by hormonal agents and ionizing radiation in breast cancer cells in vitro

Possible influences of tamoxifen and estradiol on in vitro radiation sensitivity and cellular receptor content after irradiation and/or tamoxifen treatment were studied in breast cancer cell lines; estrogen receptor (ER) and progesterone receptor (PgR) positive cell lines MCF-7 and MCF-7/TAM(R)-1 and the ER and PgR negative cell line MDA-MB-231. The tamoxifen resistant MCF-7/TAM(R)-1 cells were more resistant to ionizing radiation than the MCF-7 and MDA-MB-231 cells. Exposure to tamoxifen made the MCF-7 cells more radiation resistant, while estradiol made the MDA-MB-231 cells more radiation sensitive. A radiation dose of 6 Gy reduced the ER content in cytosol in both MCF-7 and MCF-7/TAM(R)-1 cells, but brought no alterations to the PgR content. In MCF-7/TAM(R)-1 cells tamoxifen exposure significantly increased the ER and reduced the PgR content, an effect not observed in the MCF-7 cells. To conclude, the present study indicates that irradiation and tamoxifen may modify the ER and PgR content in cytosol in breast cancer cells. Hormonal treatment may alter the radiation sensitivity, even in ER negative cells, suggesting that hormonal agents may act both via receptor and non-receptor binding mechanisms.     

Kala-azar: liver fine needle aspiration findings in 23 cases presenting with a fever of unknown origin

OBJECTIVE: To study the role of liver fine needle aspiration (FNA) in the diagnosis of kala-azar with an atypical presentation. STUDY DESIGN: The study group consisted of 23 patients (aged 18-37). All were admitted to Shiraz University Hospitals for the investigation of fever of unknown origin. The immunofluorescent antibody titer for kala-azar was positive (> 1:256 dilution). However, routine abdominal sonography revealed multiple small, hypoechoic lesions in the liver, more suggestive of metastatic tumor or miliary tuberculosis. The lesions were aspirated for cytologic diagnosis. RESULTS: The smears revealed many atypical hepatocytes, groups of epithelioid histiocytes and, in 15 patients, macrophages containing few to many Leishman bodies, allowing a diagnosis of kala-azar. The liver needle biopsy specimens confirmed the cytologic diagnosis of kala-azar and liver cell atypia. The patients were given glucantime therapy, and 21 recovered; 1 patient was lost to follow-up, and 1 died during treatment. CONCLUSION: Liver FNA is a useful procedure for the diagnosis of kala-azar, particularly in cases with atypical clinical presentations.     

GBP, an inhibitor of GSK-3, is implicated in Xenopus development and oncogenesis

Dorsal accumulation of beta-catenin in early Xenopus embryos is required for body axis formation. Recent evidence indicates that beta-catenin is dorsally stabilized by the localized inhibition of the kinase Xgsk-3, utilizing a novel Wnt ligand-independent mechanism. Using a two-hybrid screen, we identified GBP, a maternal Xgsk-3-binding protein that is homologous to a T cell protooncogene in three well-conserved domains. GBP inhibits in vivo phosphorylation by Xgsk-3, and ectopic GBP expression induces an axis by stabilizing beta-catenin within Xenopus embryos. Importantly, antisense oligonucleotide depletion of the maternal GBP mRNA demonstrates that GBP is required for the establishment of the dorsal-ventral axis in Xenopus embryos. Our results define a family of GSK-3-binding proteins with roles in development and cell proliferation.     

Biomechanical evaluation of the medial collateral ligament of the elbow

Anatomical dissection and biomechanical testing were used to study twenty-eight cadaveric elbows in order to determine the role of the medial collateral ligament under valgus loading. The medial collateral ligament was composed of anterior, posterior, and occasionally transverse bundles. The anterior bundle was, in turn, composed of anterior and posterior bands that tightened in reciprocal fashion as the elbow was flexed and extended. Sequential cutting of the ligament was performed while rotation caused by valgus torque was measured. The anterior band of the anterior bundle was the primary restraint to valgus rotation at 30, 60, and 90 degrees of flexion and was a co-primary restraint at 120 degrees of flexion. The posterior band of the anterior bundle was a co-primary restraint at 120 degrees of flexion and a secondary restraint at 30 and 90 degrees of flexion. The posterior bundle was a secondary restraint at 30 degrees only. The reciprocal anterior and posterior bands have distinct biomechanical roles and theoretically may be injured separately. The anterior band was more vulnerable to valgus overload when the elbow was extended, whereas the posterior band was more vulnerable when the elbow was flexed. The posterior bundle was not vulnerable to valgus overload unless the anterior bundle was completely disrupted. The intact elbows rotated a mean of 3.6 degrees between the neutral position and the two-newton-meter valgus torque position. Cutting of the entire anterior bundle caused an additional 3.2 degrees of rotation at 90 degrees of flexion, where the effect was greatest. CLINICAL RELEVANCE: Physical findings in a patient who has an injury of the anterior bundle may be subtle, and an examination should be performed with the elbow in 90 degrees of flexion for greatest sensitivity. As the anterior bundle is the major restraint to valgus rotation, reconstructive procedures should focus on anatomical reproduction of that structure. Parallel limbs of tendon graft placed from the inferior aspect of the medial epicondyle to the area of the sublimis tubercle will simulate the reciprocal bands of the anterior bundle. Temporary immobilization with the elbow in flexion may relax the critically important anterior band of the reconstruction during healing.