Nitric Oxide and -Arginine Cause an Accumulation of Utrophin at the Sarcolemma: A Possible Compensation for Dystrophin Loss in Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD), a severe X-linked recessive disorder which results in progressive muscle degeneration, is due to a lack of dystrophin, a membrane cytoskeletal protein. An approach to treatment is to compensate for dystrophin loss with utrophin, another cytoskeletal protein with over 80% homology with dystrophin. Utrophin is expressed, at the neuromuscular junction, in normal and DMD muscles and there is evidence that it may perform the same cellular functions as dystrophin. So, the identification of molecules or drugs that could up-regulate utrophin is a very important goal for therapy. We show that in adult normal and mdx mice (an animal model of Duchenne myopathy) treated with -arginine, the substrate of nitric oxide synthase (NOS), a pool of utrophin localized at the membrane appeared and increased, respectively. In normal and mdx myotubes in culture, -arginine, nitric oxide (NO), or hydroxyurea increased utrophin levels and enhanced its membrane localization. This effect did not occur with -arginine, showing the involvement of NOS in this process. The NO-induced increase in utrophin was prevented by oxadiazolo-quinoxalin-1-one, an inhibitor of a soluble guanylate cyclase implicated in NO effects. These results open the way to a potential treatment for Duchenne and Becker dystrophies.     

Some puzzles in the microscopic structure of the stroma

The mammalian corneal stroma has some intriguing features related to its lamellar structure. OPTICAL LAMINATION: Stromal sections under the polarizing microscope show birefringent bands that are about 5 times less numerous than the collagenous lamellae seen in transmission electron microscopy (TEM). Scattered light reveals similar laminae in the intact fresh tissue. COHESION: Very thin sections of stroma do not fall apart under water, indicating the presence of a structural framework that holds the collagen fibrils together. SHEAR DISTORTION: The stroma shears very readily in its plane; the shear amplitude increases and then decreases as the tissue hydrates. This suggests that the structural framework is coiled at physiological hydration and can expand about 10 times. FOLDING: When the stroma swells, the lamellae are thrown into waves that lie both in the plane of and perpendicular to its surface. It is difficult to understand how the latter are packed.     

Phenotypic differences in survival to an experimental acute carbon monoxide intoxication

Male and female 45-day-old mice of two inbred (CBA and C57B1) and of one outbred (OF₁), SPF (specific pathogen free), strains, LD_12:12 (L = 150 lx) synchronized, were submitted to an acute carbon monoxide challenge giving an overall survival close to 50%. Under these conditions significantly (P < 0.001) less CBA survived than the two other strains. A sex-related significant (P < 0.001 difference was observed in OF₁. Strain survival differences are independent of body weights and of respiratory and displacement activity, but appear to be related to behavior reactions towards environmental stresses. These phenotypic differences are similar to previous findings obtained with these three strains of mice submitted to a 50% survival acute hypoxic hypoxia (M. Stupfel, A. Perramon, P. Merat, J. M. Faure, and H. Masse, 1979, Comp. Biochem. Physiol., 64A, 317–323).     

Reconstruction of male external genitalia with elephantiasis

The surgical rehabilitation of a patient with severely deformed and functionally disabled genitalia due to long-standing lymphedema and infection is described and illustrated. The term "elephantiasis" has been applied to such gross lesions. Appropriate surgery to the penis, scrotum, and perineum has yielded a gratifying result. The principles and techniques of the surgical approach in such an undertaking are presented and discussed.     

The need to embrace molecular profiling of tumor cells in prostate and bladder cancer.

PURPOSE: Current treatment strategies for urological cancer are still based on empirical formulae as opposed to treatment tailored for each cancer patient. To individualize treatment, the multiple molecular abnormalities within tumor cell populations needs to be mapped out. The aim of this article is to explain molecular profiling (MP) and its associated techniques so that the process is not purely seen as a research tool but as a future adjunctive measure in patient diagnosis and treatment. EXPERIMENTAL DESIGN: A Medline search of publications relating to MP of prostate and bladder cancer was carried out. A review article was written combining the relevant published literature along with the clinical and scientific experience of both centers. RESULTS: The advent of MP now provides a strategy by which these molecular abnormalities can be assessed. As well as being of diagnostic and prognostic use, these molecular profiles will identify putative molecular abnormalities within tumor cells that may be appropriate for therapeutic modulation. CONCLUSIONS: In prostate and bladder cancer, mapping out the molecular abnormalities could be translated into a valuable tool to help solve difficult issues regarding patient management decisions.     

Expression of class III {beta}-tubulin is predictive of patient outcome in patients with non-small cell lung cancer receiving vinorelbine-based chemotherapy.

PURPOSE: To determine the prevalence and the prognostic value of microtubule component expression in tumors of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Expression of microtubular components was immunohistochemically examined in 93 tumor samples from untreated patients with stage III and IV NSCLC. All patients received vinorelbine-based chemotherapy. Response to chemotherapy, progression-free survival, and overall survival were correlated with the expression of microtubule proteins. RESULTS: The response rate was 27.3% (21 partial responses among 77 valuable patients). Although expression of microtubule components was not associated with the response rate, high class III beta-tubulin expression was correlated with resistance to vinorelbine, defined as disease progression under treatment. Patients whose tumors expressed high levels of class III beta-tubulin isotype had shorter progression-free survival and overall survival (P = 0.002 and 0.001, respectively). High Delta2 alpha-tubulin expression was associated with a shorter overall survival (P = 0.018). Tubulin II levels were not found to be correlated with patient outcome. A multivariate analysis, taking into account sex, age, histology, stage, weight loss, and class II beta-tubulin, class III beta-tubulin, and Delta2 alpha-tubulin levels, confirmed that class III beta-tubulin expression was independently correlated with progression-free survival (P = 0.04) and overall survival (P = 0.012). CONCLUSIONS: These findings suggest that a high level of expression of class III beta-tubulin in tumor cells is associated with resistance to vinorelbine and a poor prognosis in patients with NSCLC receiving vinorelbine-based chemotherapy.     

Follow-up of women after a first episode of postmenopausal bleeding and endometrial thickness greater than 4 millimeters

OBJECTIVE: To estimate the incidence of recurrent postmenopausal bleeding among women who were diagnosed with an endometrial thickness greater than 4 mm. METHODS: We designed a prospective cohort study and included consecutive women not using hormone replacement therapy, presenting with a first episode of postmenopausal bleeding. We evaluated patients who had an endometrial thickness greater than 4 mm at transvaginal ultrasonography and benign endometrial sampling; presence of carcinoma was ruled out by office endometrial sampling, hysteroscopy, and/or dilation and curettage. Time until recurrent bleeding was measured, and diagnosis at recurrent bleeding was recorded. RESULTS: Among 318 patients who had an endometrial thickness greater than 4 mm, 222 patients had benign histology results and were available for follow-up. During follow-up, 47 (21%, 95% confidence interval 16-27%) patients had recurrent bleeding, with a median time to recurrent bleeding of 49 weeks (interquartile range 18 to 86 weeks). There was no difference with respect to recurrence rate between patients with polyp removal, patients with a normal hysteroscopy, and patients with office endometrial sampling alone at the initial workup. Two patients were diagnosed with atypical endometrial hyperplasia upon recurrent bleeding. CONCLUSION: The recurrence rate of postmenopausal bleeding in women with endometrial thickness greater than 4 mm is 20%. This recurrence rate is not related to incorporation of hysteroscopy or polyp removal at the initial workup. LEVEL OF EVIDENCE: II.