Daniel F. Fisher

Leukocyte Common Antigen-Related Phosphatase Is a Functional Receptor for Chondroitin Sulfate Proteoglycan Axon Growth Inhibitors

Chondroitin sulfate proteoglycans (CSPGs) are a family of extracellular matrix molecules with various functions in regulating tissue morphogenesis, cell division, and axon guidance. A number of CSPGs are highly upregulated by reactive glial scar tissues after injuries and form a strong barrier for axonal regeneration in the adult vertebrate CNS. Although CSPGs may negatively regulate axonal growth via binding and altering activity of other growth-regulating factors, the molecular mechanisms by which CSPGs restrict axonal elongation are not well understood. Here, we identified a novel receptor mechanism whereby CSPGs inhibit axonal growth via interactions with neuronal transmembrane leukocyte common antigen-related phosphatase (LAR). CSPGs bind LAR with high affinity in transfected COS-7 cells and coimmunoprecipitate with LAR expressed in various tissues including the brain and spinal cord. CSPG stimulation enhances activity of LAR phosphatase in vitro. Deletion of LAR in knock-out mice or blockade of LAR with sequence-selective peptides significantly overcomes neurite growth restrictions of CSPGs in neuronal cultures. Intracellularly, CSPG–LAR interaction mediates axonal growth inhibition of neurons partially via inactivating Akt and activating RhoA signals. Systemic treatments with LAR-targeting peptides in mice with thoracic spinal cord transection injuries induce significant axon growth of descending serotonergic fibers in the vicinity of the lesion and beyond in the caudal spinal cord and promote locomotor functional recovery. Identification of LAR as a novel CSPG functional receptor provides a therapeutic basis for enhancing axonal regeneration and functional recovery after CNS injuries in adult mammals.

Vein patch versus primary closure for carotid endarterectomy: A randomized prospective study in a selected group of patients

During a 4-year period, 136 patients undergoing 152 carotid endarterectomies consented to be randomized to primary or saphenous vein patch closure of the arteriotomy. At operation, before randomization, careful assessment of arterial dimensions and anatomy was made. Patients who had an internal carotid artery (ICA) diameter less than 5 mm, arteriotomy extending more than 3 cm beyond the origin of the ICA, or tortuous or kinked ICAs were not randomized; they received obligatory vein patch closure (necessary in 20% cases). All patients were followed up every 3 months for 1 year and every 6 months thereafter with duplex scanning, ocular pneumoplethysmography, and neurologic assessment. The incidence of atherosclerotic risk factors was equal in the groups and all except one of the patients were male. Perioperative morbidity was not significantly different among those having primary closure (n = 60), saphenous vein patch closure (n = 62), and obligatory vein patch closure (n = 30). Operative time among patients having primary closure (122 +/- 4 minutes) was significantly less (p less than 0.001) than among those having saphenous vein patch closure (150 +/- 3 minutes). Three perioperative strokes were evenly distributed among the groups (2% for all procedures); no deaths and no acute postoperative occlusions occurred. Recurrent disease occurred in 12.9% of patients having saphenous vein patch closure compared with its occurrence in 1.7% of those having primary closure (p less than 0.05). However, most recurrences were moderate stenoses (25% to 50% diameter reduction), all were smooth-surfaced, and none required a second operation. All except one of the recurrences among those patients with saphenous vein patch closure were in the bulb and the origin of the ICA; two had evidence of regression. This finding suggested that thrombus layering in the dilated part of the saphenous vein patch reconstruction was the cause. This study demonstrates that in men with carotid arteries of predetermined minimal dimensions undergoing carotid endarterectomy routine saphenous vein patch closure does not produce superior results, is associated with a higher incidence of early recurrence, and increases operative time. In selected patients with anatomic risk factors for recurrent disease or acute postoperative occlusion, saphenous vein patch closure is appropriate.

Mandibular subluxation for high carotid exposure

Twenty-four patients with internal carotid artery lesions extending above the second cervical vertebra underwent mandibular subluxation for additional exposure. The original technique of bilateral arch bar wiring requiring 90 minutes for application has evolved into a circummandibular/transnasal wiring technique requiring approximately 10 minutes. Subluxation of the mandibular condyle 10 to 15 mm anteriorly results in displacement of the mandibular ramus 20 to 30 mm anteriorly. This technique provides a marked increase in exposure of the internal carotid artery up to the base of the skull by transforming a triangular operating field into a rectangular field. The technique is quick, easy to perform, and not associated with objective or subjective temporomandibular joint dysfunction.

The DNA/RNA-dependent RNA polymerase QDE-1 generates aberrant RNA and dsRNA for RNAi in a process requiring replication protein A and a DNA helicase.

The Neurospora RNA-dependent RNA polymerase QDE-1 is an RNA polymerase that can use both RNA and DNA as templates, suggesting a new mechanism for small RNA production.

One-stage versus two-stage amputation for wet gangrene of the lower extremity: A randomized study *

Although the two-stage amputation technique entails an additional operation, several authors have advocated this approach to deal with wet gangrene because it allows primary wound closure with a reduced chance of wound infection. To examine this issue, 47 patients with necrotizing wet gangrene of the foot were randomized prospectively to receive either a one-stage amputation (definitive below- or above-knee amputation with delayed secondary skin closure in 3 to 5 days) or a two-stage amputation (open ankle guillotine amputation followed by definitive, closed below- or above-knee amputation). Antibiotic coverage was standardized with clindamycin and gentamicin used in all patients. Preoperative blood cultures and intraoperative foot cultures were obtained, as well as cultures from the deep muscle and lymphatic area along the saphenous vein to determine the presence of bacteria at the level of initial amputation. Twenty-four patients (11 diabetic and 13 nondiabetic) were randomized to the one-stage procedure. Twenty-three patients (14 diabetic and nine nondiabetic) were randomized to the two-stage procedure. Five of 24 patients in the one-stage group (21%) had positive muscle cultures vs 10 of 23 patients in the two-stage group (43%). Two of 24 patients in the one-stage group (8%) had positive lymphatic cultures vs 7 of 23 patients in the two-stage group (30%). Five of 24 patients in the one-stage group (21%) had wound complications attributable to the amputation technique vs none of 23 patients in the two-stage group (p = 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

RhoA-inhibiting NSAIDs promote axonal myelination after spinal cord injury

Nonsteroidal anti-inflammatory drugs (NSAIDs) are extensively used to relieve pain and inflammation in humans via cyclooxygenase inhibition. Our recent research suggests that certain NSAIDs including ibuprofen suppress intracellular RhoA signal and improve significant axonal growth and functional recovery following axonal injury in the CNS. Several NSAIDs have been shown to reduce generation of amyloid-beta42 peptide via inactivation of RhoA signal, supporting potent RhoA-repressing function of selected NSAIDs. In this report, we demonstrate that RhoA-inhibiting NSAIDs ibuprofen and indomethacin dramatically reduce cell death of oligodendrocytes in cultures or along the white matter tracts in rats with a spinal cord injury. More importantly, we demonstrate that treatments with the RhoA-inhibiting NSAIDs significantly increase axonal myelination along the white matter tracts following a traumatic contusion spinal cord injury. In contrast, non-RhoA-inhibiting NSAID naproxen does not have such an effect. Thus, our results suggest that RhoA inactivation with certain NSAIDs benefits recovery of injured CNS axons not only by promoting axonal elongation, but by enhancing glial survival and axonal myelination along the disrupted axonal tracts. This study, together with previous reports, supports that RhoA signal is an important therapeutic target for promoting recovery of injured CNS and that RhoA-inhibiting NSAIDs provide great therapeutic potential for CNS axonal injuries in adult mammals.

Impact of race on renal transplant outcome

The influence of race on the outcome of cadaver renal transplantation (CRT) continues to be controversial even in the cyclosporine era. The present study examines the effect of race in 343 adult CRT performed from 1/1/82 through 10/1/88 with regard to the incidence of delayed function (DF), graft survival (GS), and patient survival (PS). Blacks constituted 38% of the patients. A history of nephrosclerosis secondary to hypertension was more common in blacks, with 51% (67/130) vs. 8% (17/213) in whites, while glomerulonephritis and Type 1 diabetes mellitus were more common in whites. There was no significant difference in the number of HLA (A,B,DR) matches or DR mismatches between whites and blacks. With azathioprine immunosuppression DF was more common in blacks than in whites, 54% (14/26) vs. 20% (11/55) respectively (P less than 0.01). The higher incidence of DF in blacks than in whites on Aza was associated with a significantly lower dose of intraoperative albumin, 0.25 g/kg vs. 0.44 g/kg, respectively (P less than 0.01). Of the Aza treated black recipients who had DF, 79% (11/14) had graft loss within three months, significantly worse than 25% (3/12) with graft loss when immediate function was present (P less than 0.005). Currently, all patients receive at least 0.80 g/kg of albumin intraoperatively and CsA quadruple induction therapy. With the current regimen, black and white recipients of primary CRT recipients have a comparable low incidence of DF of 18% and 22%, respectively. However, DF remains high among repeat black or white recipients: 33% (10/30) and 57% (8/14), respectively. The incidence of rejection within 30 days was similar for black and white recipients during the Aza and CsA eras, 62% vs. 75% and 34% vs. 42% respectively. GS and PS at three months for blacks on Aza were 54% and 89%, respectively, reflecting the corresponding high incidence of DF. This compares with 71% and 97% GS and PS for whites on Aza. Blacks and whites receiving CsA had equivalent 1-year GS and PS: 76% and 92%, respectively. We conclude that, in our center during the Aza era, blacks had a higher incidence of DF and lower GS than whites. With our current intraoperative fluid replacement and CsA immunosuppression, the incidence of DF and GS and PS are equivalent in black and white recipients.

Postoperative follow-up of renal artery reconstruction with duplex ultrasound

We evaluated the accuracy of duplex ultrasound in the postoperative follow-up of patients after renal revascularization. Between May 1976 and December 1987, 125 adult patients underwent 153 renal reconstructive procedures for renovascular occlusive disease. Technically satisfactory duplex scans were obtained in 49 of 59 patients (84%) at an average follow-up of 32 months (maximum 11 years). Arteriograms were available for correlation in 51 arteries or bypasses in 36 patients. Duplex scans accurately classified 8 of 10 stenotic (greater than 60% diameter reduction) or occluded vessels and 36 of 41 patent vessels. The overall diagnostic accuracy was 86%, sensitivity was 80%, and specificity was 87%. We confirmed previous reports that decreased diastolic flow correlated with advanced renal parenchymal dysfunction. We conclude that a normal duplex scan makes it highly unlikely that arteriography will reveal significant recurrent disease. An abnormal duplex scan, particularly in the presence of hypertension or deteriorating renal function, warrants arteriography.

Tuberculous aortitis with associated necrosis and perforation: Treatment and options

Tuberculous aortitis is a rare entity and its association with necrosis and perforation is even more unusual. Our pulmonary medicine service originally evaluated an elderly woman with a right pleural effusion and upper lobe infiltrate thought to be tuberculosis. An abdominal CT scan performed at that time showed extensive periaortic adenopathy. Isoniazid and rifampin were started, but both were stopped by the patient after less than 6 months of therapy. The patient later had night sweats, a left pleural effusion, and a tender abdominal mass thought to be a symptomatic aneurysm. At operation, the aorta was necrotic and had an inflammatory mass and perforation on the left side. Infrarenal aortic ligation and resection were performed to control infection. A previously placed axillofemoral graft obviated the need for concomitant revascularization. The patient was treated postoperatively with isoniazid and rifampin until hyperbilirubinemia developed, which necessitated alternate therapy with ethambutol and streptomycin. The patient died one month after operation of a presumed pulmonary embolus.

Emergency operation in patients with symptomatic abdominal aortic aneurysms

To assess the need for routine preoperative computerized tomography scanning to discern patients with rupture among those presenting with acutely symptomatic abdominal aortic aneurysms, a retrospective review was performed. During a 5-year period, all patients presenting with symptomatic aneurysm underwent emergency operation without preoperative computerized tomography. The mortality rate was not significantly different among patients with symptomatic, intact aneurysms undergoing emergency operation (3 percent) and those without symptoms having elective operation (5 percent). The mortality rate of patients with ruptured aneurysms was 68 percent. We concluded that the addition of preoperative computerized tomography to the clinical evaluation would not have improved these results. Furthermore, since it is expensive and delays emergency operation in patients with ruptured aneurysms, computerized tomography seems rarely indicated in symptomatic patients with obvious aneurysms.