Faculty Bibliography

PURPOSE: We examined preoperative factors that could predict successful microdissection testicular sperm extraction in men with azoospermia and nonmosaic Klinefelter's syndrome. We also analyzed the influence of preoperative hormonal therapy on the sperm retrieval rate. MATERIALS AND METHODS: A total of 91 microdissection testicular sperm extraction attempts were done in 68 men with nonmosaic Klinefelter's syndrome. Men with serum testosterone less than 300 ng/dl received medical therapy with aromatase inhibitors, clomiphene or human chorionic gonadotropin before microdissection testicular sperm extraction. Preoperative factors of patient age and endocrinological data were compared in those in whom the procedure was and was not successful. The sperm retrieval rate was the main outcome. Clinical pregnancy (pregnancy with heartbeat) and the live birth rate were also calculated. RESULTS: Testicular spermatozoa were successfully retrieved in 45 men (66%), representing 62 (68%) attempts. Increasing male age was associated with a trend toward a lower sperm retrieval rate (p = 0.05). The various types of preoperative hormonal therapies did not have different sperm retrieval rates but men with normal baseline testosterone had the best sperm retrieval rate of 86%. Patients who required medical therapy and responded to that treatment with a resultant testosterone of 250 ng/dl or higher had a higher sperm retrieval rate than men in whom posttreatment testosterone was less than 250 ng/dl (77% vs 55%). For in vitro fertilization attempts in which sperm were retrieved the clinical pregnancy and live birth rates were 57% and 45%, respectively. CONCLUSIONS: Microdissection testicular sperm extraction is an effective sperm retrieval technique in men with Klinefelter's syndrome. Men with hypogonadism who respond to medical therapy may have a better chance of sperm retrieval.

Background: Ectopic beats are frequently associated with morphologic repolarization alterations of ensuing sinus beats. Less is known about repolarization duration alterations of post-ectopic sinus beats. In one patient who developed long QT and torsades de pointes upon exposure to a class III antiarrhythmic drug, and was later genotyped as being a carrier for long QT syndrome (LQTS) type 1, review of a pre-drug Holter monitor study revealed marked QT prolongation of post-ectopic sinus beats. In wondering whether this might be a common clue to "concealed" unexpressed LQTS, we realized that we must first characterize the range of post-ectopic QT prolongation present in normals. Prolongation beyond the upper limit of this range might then raise suspicion of possible LQTS and alter the antiarrhythmic drug selection process for the suppression of atrial fibrillation or other arrhythmias. Methods: Accordingly, we assessed the presence/degree of repolarization prolongation following premature ectopic impulses in 166 subjects with normal conduction intervals and normal repolarization on their resting 12-lead ECG, 75 of whom had no known associated cardiovascular disorder of any kind. That is, in our subjects, the maximal prolongation of the QT interval of the sinus beat following isolated ventricular and atrial premature complexes was characterized. Results: QT prolongation is common in post ectopic sinus beats. However, in our subjects the uncorrected QT interval of post-ectopic sinus beats never exceeded 480 ms in duration [which was much shorter than that seen (510-590 ms) in our gene carrier]. CONCLUSIONS: The QT interval in normal subjects may prolong following premature complexes but not to a value in excess of 480 ms.

A 66-year-old male with lower extremity ischemia underwent femoral-posterior tibial bypass with composite vein graft from the arm. Ten days later, he presented to the emergency department with pain, wound erythema, and drainage. Despite a prolonged course of intravenous antibiotics and serial operative debridements, the wound edges repeatedly necrosed after each procedure. The vein graft remained viable. Punch biopsies of wound edges were consistent with pyoderma gangrenosum (PG). The patient's condition improved on immunosuppressive therapy. Although a rare clinical entity, postsurgical PG is a well-described phenomenon whose diagnosis is often delayed. Clinical suspicion is imperative to ensure timely treatment and minimize morbidity.

BACKGROUND: Tissue engineering is often limited by the time required for culture expansion of cells necessary for scaffold seeding. Cell cycle regulators control entry and exit into the cell cycle and as such regulate cellular proliferation rates. The authors hypothesized that transient alteration in cell cycle regulators can be utilized as a means to accelerate stem cell proliferation. METHODS: Mesenchymal stem cells were harvested from wild-type mice and mice deficient in the cell cycle regulator p21. Wild-type cells were treated with small interfering RNA against p21 in two- or three-dimensional cultures in vitro. Cellular proliferation and the potential for cellular differentiation into the bone or fat lineage were assessed. RESULTS: Mesenchymal stem cells treated with small interfering RNA targeting p21 demonstrated a significant decrease in p21 protein and mRNA expression 96 hours after treatment. They also proliferated significantly faster than control cells (2.5 to three times) in both two- and three-dimensional culture. Similarly, cells harvested from p21-deficient mice demonstrated a significant acceleration in cellular proliferation. Inhibition of p21 expression was not associated with significant changes in spontaneous cellular differentiation. However, transient p21 inhibition promoted both osteoblastic and adipogenic differentiation when cells were exposed to differentiation medium. CONCLUSIONS: Transient inhibition of the cell cycle regulator p21 results in significant acceleration of mesenchymal stem cell proliferation without promoting spontaneous cellular differentiation. Exposure to differentiation medium results in increased cellular differentiation toward the osteoblast and fat lineage. Manipulation of cell cycle regulators may represent a novel means by which stem cell proliferation can be accelerated, thereby decreasing the time required for scaffold synthesis in tissue engineering.

BACKGROUND: Response assessment in advanced pancreatic cancer (APC) is difficult and predictive markers are needed. There are insufficient data on the value of carbohydrate antigen 19-9 (CA 19-9) and cytostatic-targeted therapies. Axitinib, a selective vascular endothelial growth factor (VEGF) receptors 1, 2, 3 inhibitor, may increase overall survival (OS) in APC. METHODS: We assessed serum CA 19-9, clinical outcomes and diastolic blood pressure (dBP) in APC patients receiving gemcitabine plus axitinib (Gem+A) or gemcitabine alone. RESULTS: In the total population (N=95), median OS was significantly longer in patients with baseline CA 19-9 values at or below the median than in those with values above it (12.2 months [95% confidence interval (CI), 8.6-16.6%] vs 5.0 months [95% CI, 3.9-5.7%]; P<0.0001). This also reached significance in the Gem+A arm (median OS, 12.5 months [95% CI, 8.6-16.6%] vs 4.9 months [95% CI, 3.6-5.6%]; P<0.0001). Patients with any dBP>90 mmHg had significantly longer OS than those who did not. However, there was no predictive significance of CA 19-9. CONCLUSION: Baseline CA 19-9 levels had prognostic value for OS, but caution is advised in interpreting CA 19-9 as a predictive biomarker for novel cytostatic agents such as VEGF-targeted therapies in phase II studies.