Citations

ABSTRACT OBJECTIVE To determine the clinical presentation, imaging characteristics, microscopic and ultrastructural characteristics, and treatment outcomes of patients with clinically silent pituitary corticotroph adenomas. METHODS All silent corticotroph adenomas diagnosed at the Mayo Clinic during the years 1975 through 1997 were selected from the files of the Mayo Tissue Registry. RESULTS We studied 23 cases, occurring in 16 male and 7 female patients (age range, 11–79 yr; mean age, 48 yr), who presented with headaches (50%), visual field defects (61%), extraocular muscle paresis (13%), hypopituitarism (26%), and galactorrhea/amenorrhea (43%/29% of the female patients). No patients exhibited clinical hypercortisolism. All tumors were macroadenomas (2.4 ± 0.8 cm; range, 1.5–4.0 cm) and exhibited suprasellar extension in 87% of the cases and hemorrhage, necrosis, and/or cystic changes in 61%. All tumors stained were variably periodic acid-Schiff-, adrenocorticotropic hormone-, and β-endorphin-positive, particularly Subtype I lesions. Ultrastructural classification was performed in 19 cases. In a comparison of Subtype I and II tumors, differences were observed with respect to sex (male/female, 1.4:1 versus 6:1), preoperative hyperprolactinemia (5 of 16 versus 0 of 6 cases), preoperative hypopituitarism (9 of 16 versus 5 of 7 cases), radiographic or gross invasion (7 of 16 versus 5 of 7 cases), and partial or total postoperative pituitary failure (6 of 16 versus 6 of 6 cases). The overall median postoperative follow-up period was 4.9 years (range, 0.3–16.6 yr); 54% of the patients had persistent or recurrent tumors. CONCLUSION Clinically silent corticotroph adenomas behave in an aggressive manner and are characterized by the following: lack of clinical signs or symptoms of Cushing's syndrome and normal cortisol levels; no or only minor elevations of serum adrenocorticotropic hormone levels; macroadenomas with hemorrhagic infarction; and presentation dominated by mass effect symptoms. The high persistence/recurrence rate underscores the need for long-term follow-up.

Background and Purpose— Circulating endothelial progenitor cells (EPCs) play an important role in repair of injured vascular endothelium and neovascularization. The present study was designed to determine the effect of EPCs transplantation on the regeneration of endothelium and recovery of endothelial function in denuded carotid arteries. Methods— Isolated mononuclear cells from rabbit peripheral blood were cultured in endothelial growth medium for 7 days, yielding EPCs. A rabbit model of common carotid artery denudation by passage of a deflated balloon catheter was used to evaluate the effects of EPCs on endothelial regeneration and vasomotor function. Immediately after denudation, autologous EPCs (10 5 cells in 200 μL saline) or 200 μL saline alone (control) were administered into the lumen of injured artery. Results— Four weeks after transplantation, fluorescence-labeled colonies of EPCs were found in the vessel wall. Local transplantation of EPCs as compared with saline administration accelerated endothelialization and significantly improved endothelium-dependent relaxation when assessed 4 weeks after denudation (n=4 to 5, P <0.05). Transplantation of EPCs did not affect vasomotor function of arterial smooth muscle cells. Protein array analysis of conditioned media obtained from cultured EPCs demonstrated the ability of these cells to produce and release a number of proangiogenic cytokines. Conclusions— We conclude that local delivery of cultured circulating EPCs into the lumen of denuded carotid arteries accelerates endothelialization and improves endothelial function. Paracrine effects of EPCs may contribute to regenerative properties of EPCs.

Background and Purpose— Following publication of concerns about the results of the National Institute of Neurological Disorders and Stroke (NINDS) intravenous tissue plasminogen activator (t-PA) in acute stroke treatment trial, NINDS commissioned an independent committee “to address whether there is concern that eligible stroke patients may not benefit from t-PA given according to the protocol used in the trials and, whether the subgroup imbalance (in baseline stroke severity) invalidates the entire trial.” Methods— The original NINDS trial data were reanalyzed to assess the t-PA treatment effect, the effect of the baseline imbalance in stroke severity between the treatment groups on the t-PA treatment effect, and whether subgroups of patients did not benefit from receiving t-PA. Results— A clinically important and statistically significant benefit of t-PA therapy was identified despite subgroup imbalances in baseline stroke severity and an increased incidence of symptomatic intracerebral hemorrhage in t-PA treated patients. The adjusted t-PA to placebo odds ratio (OR) of a favorable outcome was 2.1 (95% CI, 1.5 to 2.9). Although these exploratory analyses found no statistical evidence that the t-PA treatment effect differed among patient subgroups, the study was not powered to detect subgroup treatment differences. Conclusions— These findings support the use of t-PA to treat patients with acute ischemic stroke within 3 hours of onset under the NINDS t-PA trial protocol. Health professionals should work collaboratively to develop guidelines to ensure appropriate use of t-PA in acute ischemic stroke patients.

Cationic polypeptides are released by activated leukocytes and may play an important role in the regulation of vascular tone. Effects of cationic polypeptides on cerebral vascular tone have not been studied. The present experiments were designed to determine if synthetic cationic polypeptides, poly-L-arginine and poly-L-lysine, affect the function of cerebral arteries. Rings of canine basilar arteries with and without endothelium were suspended for isometric force recording. Poly-L-arginine (10 –8 –10 –7 M) and poly-L-lysine (10 –8 –10 –7 M) caused endothelium-dependent relaxations. A nitric oxide synthase inhibitor, N G -nitro-L-arginine methyl ester (10 –4 M), and a nitric oxide scavenger, oxyhemoglobin (3 × 10 –6 M), inhibited relaxations in response to cationic polypeptides. Negatively charged molecules, heparin (1 U/ml) and dextran sulfate (10 mg/ml), also inhibited relaxations to poly-L-arginine or poly-L-lysine. Higher concentrations of poly-L-arginine (10 –6 –10 –5 M) and poly-L-lysine (10 –6 –10 –5 M) induced endothelium-independent contractions. A protein kinase C inhibitor, staurosporine (10 –8 M), abolished these contractions. Heparin (10 U/ml) and dextran sulfate (100 mg/ml) inhibited the contractile effect of cationic polypeptides but did not affect contractions to phorbol 12,13-dibutyrate. Poly-L-arginine (10 –6 M) and poly-L-lysine (10 –6 M) abolished endothelium-dependent relaxations in response to bradykinin (10 –10 –10 –6 M) or calcium ionophore A23187 (10 –9 –10 –6 M). Heparin (50 U/ml) and dextran sulfate (200 mg/ml) restored endothelium-dependent relaxations to bradykinin (10 –10 –10 –6 M) in arteries exposed to poly-L-arginine (10 –6 M) or poly-L-lysine (10 –6 M). These studies demonstrate that in the lower concentration range (10 –8 –10 –7 M), poly-L-arginine and poly-L-lysine induce endothelium-dependent relaxations by production of nitric oxide via charge-dependent activation of endothelial nitric oxide synthase. In the higher concentration range (10 –6 –10 –5 M), cationic polypeptides cause endothelium-independent contractions as well as impairment of endothelium-dependent relaxations in response to bradykinin and A23187. These contractions and inhibition of endothelium-dependent relaxations are also mediated by a charge-dependent mechanism and may involve activation of protein kinase C.

Background Septic shock is associated with vasopressin deficiency and a hypersensitivity to its exogenous administration. The goal of the current study was to determine whether short-term vasopressin infusion in patients experiencing severe septic shock has a vasopressor sparing effect while maintaining hemodynamic stability and adequate end-organ perfusion. Methods Patients experiencing septic shock that required high-dose vasopressor support were randomized to a double-blinded 4-h infusion of either norepinephrine (n = 11) or vasopressin (n = 13), and open-label vasopressors were titrated to maintain blood pressure. To assess end-organ perfusion, urine output and creatinine clearance, gastric mucosal carbon dioxide tension, and electrocardiogram ST segment position were measured. Results Patients randomized to norepinephrine went from a median prestudy norepinephrine infusion of 20.0 microg/min to a blinded infusion of 17.0 mug/min at 4 h, whereas those randomized to vasopressin went from a median prestudy norepinephrine infusion of 25.0 microg/min to 5.3 microg/min at 4 h (P < 0.001). Mean arterial pressure and cardiac index were maintained in both groups. Urine output did not change in the norepinephrine group (median, 25 to 15 ml/h) but increased substantially in the vasopressin group (median, 32.5 to 65 ml/h; P < 0.05). Similarly, creatinine clearance did not change in the norepinephrine group but increased by 75% in the vasopressin group (P < 0.05). Gastric mucosal carbon dioxide tension and electrocardiogram ST segments did not change significantly in either group. Conclusions The authors conclude that short-term vasopressin infusion spared conventional vasopressor use and improved some measures of renal function in patients with severe septic shock.