Lactate flux during carotid endarterectomy under general anesthesia: correlation with various point-of-care monitors.

PURPOSE: The ability to assess the brain-at-risk during carotid endarterectomy (CEA) under general anesthesia remains a major clinical problem. Point-of-care monitoring can potentially dictate changes to management intraoperatively. In this observational study, we examined the correlation between a series of point-of-care monitors and lactate flux during CEA. METHODS: Both neurosurgeons and vascular surgeons participated in the study. The patients underwent arterial-jugular venous blood sampling for oxygen, carbon dioxide, glucose, and lactate, n = 26; bispectral index (BIS) monitoring ipsilateral to side of surgery, n = 26; raw and processed electroencephalogram (EEG), n = 22; and bi-frontal cerebral oximetry using the Fore-Sight monitor, n = 20. RESULTS: One patient experienced a new neurological deficit when assessed at 24 hr following surgery. Lactate flux into the brain was correlated with the greatest decrease in cerebral oximetry with carotid cross-clamping; lactate efflux was correlated with the least. The most noticeable changes in processed EEG (density spectral analysis) were also seen with lactate influx, but at a slower time resolution than cerebral oximetry. Loss of autoregulatory behaviour was demonstrated with lactate influx; however, no correlation was seen between lactate flux and BIS monitoring. CONCLUSION: There was a correlation between cerebral oximetry and lactate flux during carotid cross-clamping. The Fore-Sight monitor may be of value as a point-of-care monitor during CEA under general anesthesia. A novel finding of this study is lactate flux into the brain in the presence of a large difference in cerebral oxygenation during cross-clamping of the carotid artery. Registered at clinicaltrials.gov: NCT000737334.

Hybrid open and endovascular therapy for a proximal subclavian artery aneurysm.

A 57-year-old male presented with a large proximal right subclavian artery aneurysm that had been the source of upper extremity emboli on two occasions. A combined open and endovascular approach was undertaken involving a common carotid to vertebral artery autogenous bypass via a supraclavicular incision and endovascular repair of the aneurysm from a transbrachial approach. The patient did well postoperatively and recovered fully following a short hospitalization.

Ruptured mycotic abdominal aortic aneurysm secondary to Mycobacterium bovis after intravesical treatment with bacillus Calmette-Guérin.

Bacillus Calmette-Guérin (BCG) is a live attenuated strain of Mycobacterium bovis that has proven effective in the treatment of early-stage bladder cancer. Although intravesical therapy with BCG is generally considered safe, serious complications including hematuria, granulomatous pneumonitis, hepatitis, and life-threatening BCG sepsis are well known. BCG-related vascular infections are rarely reported. We present a case of a ruptured abdominal aortic aneurysm secondary to M bovis infection 2 years after intravesical instillation of BCG and review the related literature.

Determination of functional outcome following upper extremity arterial trauma.

Upper extremity arterial trauma may lead to significant disability with a poor functional outcome. This study represents a retrospective review of all trauma patients presenting to a university-affiliated medical center. Patients suffering from upper extremity arterial injuries requiring treatment were identified. The injured vessels were identified along with the mechanism of injury and method of repair. The degree of functional disability was evaluated by using a previously validated questionnaire, the Disabilities of the Arm, Shoulder, and Hand (DASH) Outcome Measure. Between September 1999 and December 2004, 17 patients presented with traumatic arterial injury to the upper extremity, with 9 and 8 patients suffering from blunt and penetrating traumas, respectively. One patient required amputation representing a limb salvage rate of 94%. The mean length of hospitalization was significantly shorter for penetrating trauma (5.1 vs 12 days, P = .03), with blunt trauma victims being more prone to coexisting orthopedic injuries (P = .009). Length of follow-up did not differ between the 2 groups and ranged from 1-60 months. Patients with blunt trauma tended, although not statistically significant, to have higher DASH scores (61.8 vs 22.8, P = .08), indicating a greater degree of disability. By utilizing a validated disability questionnaire, this study confirms that patients suffering from blunt injuries to upper extremity arteries are more likely to have greater degrees of disability affecting everyday activities.

Osteopontin localizes to the nucleus of 293 cells and associates with polo-like kinase-1.

Osteopontin (OPN) is a secreted phosphoprotein involved in cellular proliferation and associated with tumor progression. Although an intracellular form of OPN has been described, its function remains unknown. In this study, a novel nuclear location for intracellular OPN and a correlation with cell division were demonstrated. OPN distinctly localized to the nucleus in a subset of transiently transfected human embryonic kidney 293 cells. Immunoblotting confirmed the nuclear location of native OPN, and results from immunofluorescence studies suggested an association between nuclear OPN and cell cycle progression. Flow cytometry revealed that nuclear and cellular OPN content rose significantly during the S and G(2)/M phases, respectively. Treatment of cells with the DNA polymerase inhibitor aphidicolin prevented cell cycling and greatly reduced cellular OPN content. The intracellular location of OPN coincided with polo-like kinase-1 (Plk-1), a member of the polo-like kinase family, which, in part through their regulation of centrosome-related events, are integral to successful cellular mitosis. OPN and Plk-1 were coimmunoprecipitated from nuclear, but not cystoslic, extracts, demonstrating an interaction that is limited to the nucleus, presumably during mitosis. Deletion of the COOH terminus of OPN militated against nuclear localization and Plk-1 interaction. Elevated expression of OPN was also associated with an increase in the number of multinucleate 293 cells, whereas transfection of the COOH-terminal-deleted OPN decreased the percentage of multinucleate cells below basal levels. These findings implicate intranuclear OPN as a participant in the process of cell duplication.

Comparison of renal function after endovascular aneurysm repair with different transrenally fixated endografts.

OBJECTIVE: Transrenal fixation of abdominal aortic endografts may provide a more secure proximal attachment with few deleterious effects with respect to renal function. This study's purpose was to determine whether different metals used in two commercially available endografts (Cook Zenith and Medtronic Talent) result in different effects on renal function when placed across renal ostia. METHODS: A total of 140 consecutive patients, between August 2003 and April 2005, who underwent elective endovascular repair of an aortic aneurysm with a nitinol or stainless steel-based endograft with transrenal fixation were reviewed with a mean follow-up period of 5.5 months (range, 1-22 months). The main outcome variable was the percentage change in creatinine clearance (CrCl), which was determined before surgery and at the most recent follow-up. Multiple regression analysis was performed to analyze the contribution of various factors to any deterioration in renal function. RESULTS: The 140 patients were predominantly male (86%), with a mean age of 75 years (range, 56-92) and a mean aneurysm diameter of 62 mm (range, 42-110 mm). The mean intraoperative contrast use was 67 mL (range, 45-160 mL), and after surgery these patients received a mean of 3 surveillance computed tomographic scans (range, 1-7). Nineteen cases (13.6%) required deliberate accessory renal artery coverage. CrCl did not change significantly after surgery; the mean change in CrCl at the end of follow-up was a 2.5% decrease. There was no difference in the reduction in CrCl between endograft types. Only 14.3% of patients experienced a greater than 20% decrease in CrCl. Multiple regression analysis failed to show a relationship between change in renal function and age, sex, aneurysm diameter, infrarenal neck dimensions, endograft type, coverage of accessory renal arteries, intraoperative contrast volume, preoperative CrCl, and postoperative computed tomographic scans. Length of follow-up was an independent predictor (P = .04). CONCLUSIONS: Transrenal endograft fixation results in little deterioration in renal function during intermediate follow-up. The few patients who do experience a decline in renal function do so independently of any features related to the initial endovascular repair, and there is no difference in renal deterioration between endografts with nitinol and stainless steel transrenal bare metal stents.

Endovascular repair of Salmonella-infected abdominal aortic aneurysms: a word of caution.

Over the last several years, treatment modalities have changed for infected aortic aneurysms. Surgical treatment has undergone a paradigm shift from débridement and extra-anatomic bypass to direct reconstruction to, most recently, endovascular repair. Although many reports of endovascular repair of such aneurysms are favorable, the following two cases highlight some of the concerns with endografts in an infected field. Specifically, we urge caution when considering endovascular repair of Salmonella-infected arterial pathologies.

Effects of local pressure and vibration on muscle pain from eccentric exercise and hypertonic saline.

In human subjects the triceps surae of one leg was exercised eccentrically by asking subjects to walk backwards on an inclined treadmill. Before the exercise controlled local pressure, applied to the muscle with an electromagnet, produced mild soreness, which was reduced when the pressure was combined with vibration. When delayed-onset muscle soreness (DOMS) had set in, 24-48 h after the exercise, vibration increased pain from local pressure. Vibrating at different frequencies suggested 80 Hz as the optimal frequency. During 2-h testing post-exercise, evidence of a change in character of the effects of vibration was first detected at 6 h. It persisted up to 72 h post-exercise. When muscle pain was generated in an unexercised triceps by injection of hypertonic (5%) saline, controlled local pressure applied to the sore area increased pain levels by 32% while pressure plus vibration reduced this to 11%. In a subject with DOMS, local pressure again increased pain from saline by 32% but combining it with vibration increased pain further by an additional 20%. The effect of vibration on DOMS could be abolished with a large nerve fibre block applied to the sciatic nerve. It is concluded that the vibration effects are the result of stimulation of large-diameter mechanoreceptive afferents in the muscle which, it is speculated, play a role in generating DOMS.

Nineteen-millimeter prosthetic aortic valves allow normalization of left ventricular mass in elderly women.

BACKGROUND: Implantation of small aortic valve prostheses has been reported to be associated with impaired left ventricular (LV) mass regression and incomplete resolution of symptoms although these data have been generated largely with male patients. Therefore we sought to determine the clinical and hemodynamic outcomes of female patients who received a 19-mm aortic valve. METHODS: Between May 1995 and December 2000, 38 female patients (average age 73 years, range 42 to 89) underwent isolated aortic valve replacement (AVR; n = 22) or AVR plus coronary artery bypass graft surgery (CABG; n = 16) with a 19-mm aortic prosthesis. The average New York Heart Association (NYHA) class was 3.08 and of the 26 patients who had angina, 47.2% were in CCS class III or IV. Clinical and echocardiographic follow-up was done an average of 33.4 months (8 to 72) after surgery. RESULTS: Operative mortality was 10.5%. Overall survival at an average of 33 months was 71.1%. The average NYHA class was 1.52 +/- 0.34 postoperatively (p < 0.001 versus preoperative) and 95% had no anginal symptoms or were in Canadian Cardiovascular Society class I. The LV mass index showed significant regression (114 +/- 11 g/m2 to 89 +/- 9 g/m2, p = 0.001) despite an effective orifice area index (EOAI) of 0.64 +/- 0.09 cm2/m2. CONCLUSIONS: Despite a very small EOAI, elderly female patients with 19-mm prosthetic aortic valves can experience a satisfactory improvement in symptoms and normalization of LV mass. This finding suggests that small prosthetic aortic valves continue to have an application in contemporary cardiac surgical practice. The current perception of patient-prosthesis mismatch may need to be reconsidered for select populations.

Regulation of the dual function tissue transglutaminase/Galpha(h) during murine neuromuscular development: gene and enzyme isoform expression.

Coagulation Factor XIII (F. VIII), a member of the transglutaminase (TGase) superfamily, is activated by thrombin, cross-links fibrin and stabilizes clots. Another member of this family, tissue TGase (tTG), having similar enzymatic activity, is implicated in neural development and synapse stabilization. Our previous studies indicated that synapse formation and maintenance at the neuromuscular junction (NMJ) involved components of the coagulation cascade in development. Others then showed that either F. XIII or tTG were localized at NMJs in a developmentally-regulated fashion. In the current studies, we addressed the temporal course of skeletal muscle tTG gene expression and found maximal expression at birth and continuing into the immediate postnatal period. Subcellular fractionation revealed a relatively constant particulate isoform of TGase activity which predominated in early embryonic muscle development. In contrast, cytosolic TGase specific activity became the major isoform in the postnatal period. The timing of muscle TGase activity correlated well with expression of tTG mRNA and we now present novel data of Tgm 2 gene expression for tTG in skeletal muscle. Confirming and extending the previous studies, TGase becomes localized at NMJs in the early, further ramifying in the late, neonatal period. These data suggest that the early pulse of particulate activity could coincide with the period of myoblast cell death in embryonic muscle. On the other hand, the peak cytosolic TGase activity occurs in the neonatal period, correlating temporally with muscle prothrombin expression during activity-dependent synapse elimination and possibly the source of the enzyme localized to the NMJ extracellular matrix resulting in synaptic stabilization.

Neural thrombin and protease nexin I kinetics after murine peripheral nerve injury.

We addressed the balance between thrombin and its serpin protease nexin I (PNI) after sciatic nerve injury in the mouse. Prothrombin levels increased twofold 24 h after nerve crush, as measured by a specific chromogenic assay, and peaked at day 3. Thrombin activity also increased 2-4 days after injury in distal sciatic nerve segments. Nerve RNA analysis using reverse transcriptase--polymerase chain reaction (RT-PCR) assay confirmed that prothrombin was synthesized locally. We also monitored PNI levels in these injured nerve samples by complex formation with an 125I-labeled target protease and found peak activity occurring later, 6-9 days after the thrombin induction. These data indicate that nerve injury first induces the synthesis of prothrombin, which is subsequently converted to active thrombin. Nerve crush-induced thrombin is followed by the generation of functionally active PNI and may be directly responsible for its induction. By immunocytochemistry with anti-PNI antibody, we found that activated Schwann cells were the source of induced PNI. These results support the concept that the balance between serine proteases and their serpins is dysregulated during nerve injury and suggests a role for its reestablishment in nerve damage repair.

Cross-linking of beta-amyloid protein precursor catalyzed by tissue transglutaminase.

Alzheimer's disease is characterized by progressive dementia, cortical atrophy with synaptic loss, and the accumulation of neurofibrillary tangles and senile plaques containing beta-amyloid. The beta-amyloid protein precursor (beta-APP), may normally be involved in cell adhesion related to synaptic maintenance. Loss of synapses correlates with dementia, suggesting that synaptic deficits may underlie the disease. Synapse stability may depend on the action of tissue transglutaminase (tTG), an enzyme capable of crosslinking large, multi-domain extracellular glycoproteins, that is active and present at synapses. We now show that beta-APP is a substrate for tTG in vitro that results in dimers and multimers by silver staining and immunoblotting. This novel post-translational modification suggests further roles for beta-APP in synaptic function as well as in Alzheimer's disease.

Selective increase of tetrameric (G4) acetylcholinesterase activity in rat hindlimb skeletal muscle following short-term denervation.

Acetylcholinesterase (AChE; EC 3.1.1.7) isoenzymes in gracilis muscles from adult Sprague-Dawley rats were studied 24-96 h after obturator nerve transection. Results show a selective denervation-induced increase in the globular G4 isoform, which is predominantly associated with the plasmalemma. This enzymatic increase was (a) transient (occurring between 24 and 60 h) and accompanied by declines in all other identifiable AChE isoforms; (b) observed after concurrent denervation and inactivation of the enzyme with diisopropylfluorophosphate, but not following treatment with cycloheximide; and (c) more prominent in the extracellular compartment of muscle endplate regions. Aside from this transient change, G4 activity did not fall below control levels, indicating that at least the short-term maintenance of G4 AChE (i.e., at both normal and temporarily elevated levels) does not critically depend on the presence of the motor nerve. In addition, this isoform's activity increases in response to perturbations of the neuromuscular system that are known to produce elevated levels of acetylcholine (ACh), such as short-term denervation and exercise-induced enhancement of motor activity. The present study is consistent with the hypothesis that individual AChE isoforms in gracilis muscle are subject to distinct modes of neural regulation and suggests a role for ACh in modulating the activity of G4 AChE at the motor endplate.

Coated vesicles from developing and adult rat skeletal muscles contain multiple molecular forms of acetylcholinesterase.

The main purpose of this work was to determine which of the multiple isoforms of acetylcholinesterase (AChE) are associated with clathrin-coated vesicles (CVs) from developing and adult rat skeletal muscles. CV-enriched preparations were obtained by subcellular fractionation/equilibrium sedimentation and further purified by immunoadsorption to anti-clathrin IgG-coated Staphylococcus aureus cells. Analysis of individual AChE isoforms by velocity sedimentation ultracentrifugation showed that a) while both globular (G-forms) and asymmetric (A-forms) AChE were detected in all subcellular fractions evaluated, the CV-enriched fraction contained a higher proportion of A-forms (mainly the A12 species); b) most of the AChE activity contained in such a CV fraction was recovered following immunoadsorption; c) alkaline extraction conditions (pH 8.5) which depolymerize clathrin were necessary to detect a large proportion of A-forms in both the CV-enriched and immunoprecipitated preparations, while most of the G-forms (especially G1 + G2 AChE) were detected following extraction at pH 6.8; and d) comparison of AChE isoform profiles from neonate and adult muscle CV-enriched fractions showed a greater concentration of A-forms in the former. These data suggest that considerable amounts of A12 and, to a lesser extent, G4 AChE are sequestered within muscle CVs which may be destined for the plasmalemma. Our findings also indicate that the relative proportions of AChE isoenzymes in rat muscle CVs vary according to the extent of muscle development and lend support to the contention that CVs participate in the externalization of functionally important AChE isoenzymes.

Megestrol acetate therapy for advanced breast cancer.

One hundred twenty-four patients with metastatic breast cancer were treated with 40 mg of megestrol acetate four times daily. Complete responses (CR) or partial responses (PR) were seen in 29 patients (23%). CR, PR, or stable disease (S) was seen in 80 patients (65%). The median duration of response was 22 months for CR and PR and ten months for S. A significantly higher response rate (CR + PR) was seen in estrogen-receptor-positive (ER-positive) patients (26%) and in patients who had not received prior therapy (39%). A significant relationship to response could not be established for menopausal status, progesterone-receptor (PrR) status, dominant site of disease, or prior administration of chemotherapy. Median survival was 66+ months for responders, 35 months for patients with stable disease, and 9 months for nonresponders. These differences are all statistically significant (P less than .001). Toxicity was minimal, and side effects consisted primarily of weight gain, which was seen in 18 patients (14.5%). Megestrol acetate can provide effective palliation in patients with advanced breast cancer.

Correlation of primary breast cancer histopathology and estrogen receptor content.

We studied the association of estrogen receptor (ER) with several histologic variables that correlate with breast tumor differentiation and with patient prognosis. Contingency table analysis revealed highly statistically significant correlations between ER content and histologic and nuclear grades, tumor necrosis, and the degree of elastosis and lymphoid cell infiltration. ER positive tumors were more likely than ER negative tumors to demonstrate histological evidence of tumor differentiation. All tumors with histologic grade 1 or nuclear grade 1 (best differentiated) were ER positive or borderline positive. Eighty-nine percent of ER negative tumors were histologic grade 3 and 78.4% were nuclear grade 3 (poor differentiation). ER positive tumors were also correlated with absent tumor necrosis, higher elastic content, and absent lymphoid cell infiltration, all features of good differentiation. Medullary carcinomas were frequently (73%) ER negative, but no relationship between ER and other morphologic types of breast cancer or 9 other morphologic variables was found. ER appears to be a biochemical marker for the degree of differentiation of human breast cancer providing a rationale for the observed differences in biological behavior between receptor positive and negative tumors.

Estrogen receptor as an independent prognostic factor for early recurrence in breast cancer.

The usefulness of estrogen receptor measurements in primary breast tumors in the prediction of early recurrence was examined in a series of 145 patients. The absence of estrogen receptor in such tumors was associated with early recurrence independent of other known prognostic factors such as axillary lymph node status and tumor size.