Meyer, Fredric B.

Object The causes of epileptic events remain unclear. Much in vitro and in vivo experimental evidence suggests that gap junctions formed by connexins (Cxs) between neurons and/or astrocytes contribute to the generation and maintenance of seizures; however, few experiments have been conducted in humans, and those completed have shown controversial data. The authors designed a study to compare the level of expression of Cxs in hippocampi from epileptic and nonepileptic patients to assess whether an alteration of gap junction expression in epileptic tissue plays a role in seizure origin and propagation. Methods The expression of Cxs32, -36, and -43 was studied in 47 consecutive samples of hippocampi obtained from epileptic patients who had undergone an amygdalohippocampectomy for the treatment of intractable seizure. These expression levels were compared with those in hippocampi obtained in nonepileptic patients during postmortem dissection. Immunostaining was performed to create one slide for each of the three Cxs. Each slide demonstrated multiple cells from each of six regions (CA1, CA2, CA3, CA4, dentate gyrus, and subiculum). Two independent reviewers rated each Cx–region combination according to an immunoreactive score. Across all three measures—that is, staining intensity, percentage of positively stained cells, and immunoreactive score—Cx32 appeared to be expressed at a significantly lower level in the epileptic patients compared with controls (p < 0.001 for each measure), whereas Cx43 appeared to be expressed more among the epileptic patients (p < 0.001 for each measure). There was no evidence of any differential expression of Cx36. There was, however, regional variation within each Cx subtype. For Cx36, the staining intensity was higher in the CA2 region in the epilepsy group. Conclusions The increase in Cx43, decrease in Cx32, and preservation of Cx36 expression in hippocampi from epileptic persons could play a role in the development of seizures in patients with temporal sclerosis. Additional studies must be completed to understand this mechanism better.

AbstractBackgroundCushing’s syndrome (CS), due to multiple etiologies, is a disorder associated with the ravages of cortisol excess. The purpose of this review article is to provide a historical synopsis of surgery for CS, review a recent 10‐year period of operative management at a tertiary care facility, and to outline a practical approach to diagnosis and management.Materials and MethodsFrom 1996 to 2005, 298 patients underwent 322 operative procedures for CS at Mayo Clinic, Rochester, Minnesota. A retrospective chart review was carried out. Data was gathered regarding demographics, preoperative assessment, procedures performed, and outcomes. Data are presented as counts and percentages. Five‐year survival rates were calculated where applicable by the Kaplan‐Meier method. Statistical analysis was carried out with SAS, version 9 (SAS Institute, Inc., Cary, NC).ResultsTwo‐hundred thirty‐one patients (78%) had ACTH‐dependent CS and 67 patients (22%) had ACTH‐independent CS. One‐hundred ninety‐six patients (66%) had pituitary‐dependent CS and 35 patients (12%) had ectopic ACTH syndrome. Fifty‐four patients (18%) had cortisol‐secreting adenomas, 10 patients (3%) had cortisol‐producing adrenocortical carcinomas, and 1% had other causes. Cure rates for first time pituitary operations (transsphenoidal, sublabial, and endonasal) were 80% and 55% for reoperations. Most benign adrenal processes could be managed laparoscopically. Five‐year survival rates (all causes) were 90%, 51%, and 23% for adrenocortical adenomas, ectopic ACTH syndrome, and adrenocortical carcinomas, respectively.ConclusionsSurgery for CS is highly successful for pituitary‐dependent CS and most ACTH‐independent adrenal causes. Bilateral total adrenalectomy can also provide effective palliation from the ravages of hypercortisolism in patients with ectopic ACTH syndrome and for those who have failed transsphenoidal surgery. Unfortunately, to date, adrenocortical carcinomas are rarely cured. Future successes with this disease will likely depend on a better understanding of tumor biology, more effective adjuvant therapies and earlier detection. Clearly, IPSS, advances in cross‐sectional imaging, along with developments in transsphenoidal and laparoscopic surgery, have had the greatest impact on today’s management of the complex patient with CS.

The use of the transseptal transsphenoidal approach to the pituitary gland has gained acceptance as a safe, relatively atraumatic means of removing pituitary tumors. The outcome in adult patients has been successful; however, the outcome in pediatric patients whose noses may still be developing is not well described. We reviewed the outcomes in 41 patients younger than age 18 years who underwent transseptal transsphenoidal pituitary surgery at our institution between 1986 and 1997 (20 boys and 21 girls; age, 3 to 17 years; mean age, 13.4 years). The most common diagnosis was prolactin-secreting adenoma (14 patients), followed by craniopharyngioma (7 patients). Presenting symptoms included headache (20 patients), galactorrhea (13 patients), and menstrual irregularities (11 patients). The most common early complication was transient diabetes insipidus (20 patients). No patient experienced serious bleeding at pack removal and no patient developed a cerebrospinal fluid leak postoperatively. Follow-up ranged from 3 months to 12.7 years, with 7 patients experiencing recurrent or residual disease between 6 days and 2 years after their original transseptal procedure. The most common long-term surgical complication was nasal obstruction in 5 patients, 3 of whom also complained of seasonal allergies. Four patients complained of recurrent sinus infections, and 4 patients noted an external nasal deformity as a result of the surgery.

Objective—The ubiquitin-proteasome system is the principal degradation route of intracellular and oxidized proteins, thus regulating many cellular processes conceivably important for atherosclerosis. The aim of this study was to evaluate the activity of ubiquitin-proteasome system in human carotid artery plaques in relation to oxidative stress and clinical manifestation.Methods and Results—In carotid endarterectomy specimens from 83 asymptomatic and 94 symptomatic patients, content of ubiquitin, ubiquitin conjugates, matrix metalloproteases, and NADPH-oxidase-p67 was evaluated by immunoblotting; proteolytic proteasome activity by fluorometric assay; single and double immunostaining for ubiquitin conjugates, 3-nitrotyrosine, apoptosis, smooth muscle α-actin, and macrophage CD-68, as well as Sirius Red staining for collagen were performed. Compared with asymptomatic patients, symptomatic patients showed a more unstable plaque phenotype, an increased degree of apoptosis, a significantly higher ubiquitin conjugates content (17.72±1.36 versus 10.99±1.04;P<0.001), and lower proteasome activity (5.01±0.70 versus 9.41±1.19 nmol AMC/mg protein/min;P<0.01). Ubiquitin conjugates content was directly correlated to NADPH-p67 and degree of apoptosis. Immunostaining revealed colocalization of ubiquitin conjugates and 3-nitrotyrosine, and accumulation of ubiquitin conjugates in smooth muscle cells and macrophages.Conclusions—In human carotid plaques increased oxidative stress is associated with inhibition of the proteasome activity and accumulation of ubiquitin conjugates, particularly in symptomatic patients. These results suggest a possible role of the ubiquitin-proteasome system in influencing plaque stability.

Abstract Objective: Spontaneous intracranial hypotension is typically caused by a spontaneous spinal cerebrospinal fluid (CSF) leak. The configuration of the related dural defects can be complex. We describe our experience with the surgical anatomy of these defects. Methods: Thirteen consecutive patients with spontaneous spinal CSF leaks who underwent surgical exploration at Mayo Clinic between 1994 and 2003 were studied. All patients' records, imaging studies, detailed intraoperative findings, and outcomes were reviewed. Results: There were four men and nine women with an average age of 40 years (range, 12–62 yr). Preoperative imaging studies revealed a single site of CSF leak in eight patients, two sites in three patients, and multiple sites in two patients. Intraoperatively, the exact site of leakage could not be found in four patients. Among the other nine patients, primary closure of a meningeal diverticulum was achieved in one patient. Significant regional attenuation of the dura prevented primary repair of the leak site in eight patients. Muscle, fibrin glue, and Gelfoam (Upjohn Co., Kalamazoo, MI) soaked in patient's own blood were commonly used to pack the epidural space in an attempt to seal the site of the leak. Ligation of two nonappendicular nerve roots allowed closure of the leak in one of these patients. Postoperatively, resolution of symptoms occurred in eight patients, significant improvement was noted in three patients, and only transient resolution in two. The mean duration of follow-up was 20.5 months. Conclusion: Surgery for closure of spontaneous spinal CSF leaks may not be straightforward. Even when extradural CSF leakage is discovered preoperatively by imaging studies, it may not always be possible to identify the exact site of the leakage intraoperatively. Furthermore, the anatomy of the dural defects may be complex and not amenable to primary closure. In such cases, the use of adjuvant techniques during surgical exploration may be effective.

Background and Purpose— The local renin-angiotensin system (RAS) and cyclooxygenase-2 contribute to the activation of nuclear factor κB (NFκB) and C-reactive protein (CRP). We hypothesized that the combination of RAS blockers (RASb) and ASA reduces NFκB and CRP within atherosclerotic plaques. Methods— Patients undergoing carotid endarterectomy were divided into groups according to treatment (RASb–acetylsalicylic acid [ASA], ASA, RASb, and control). The expression of NFκB, CRP, and CD40L was analyzed through Western blots in the obtained plaques. Results— Plaques from patients treated with the combination of RASb and ASA showed lower expression of NFκB (25.4±9.8 densitometric units [DU]) than those of the control group (57.6±13.2 DU, P =0.03) as well as lower expression of CRP (20.9±9.6 DU) than those of the other treatment groups (ASA 86.1±13 DU, RASb 88.4±31 DU, controls 67.8±18.6, P =0.004). A negative expression of NFκB was associated with a reduced incidence of symptoms compared with a positive expression (5/33 [15.1%] versus 14/35 [40%], P =0.031). Conclusions— The combined treatment with RASb and ASA decreases the expression of inflammatory markers in atherosclerosis in humans. This study supports the role of the local RAS and cyclooxygenase-2 in the progression of atherosclerosis.

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.