Hereditary neuropathy with liability to pressure palsies is not a major cause of idiopathic carpal tunnel syndrome.

BACKGROUND: Carpal tunnel syndrome is a debilitating neuropathy affecting millions of individuals. Although there are published reports of familial associations of carpal tunnel syndrome, the molecular mechanisms are unknown. OBJECTIVE: To determine the prevalence and potential role of the chromosome 17 microdeletion associated with hereditary neuropathy with liability to pressure palsies in patients diagnosed as having carpal tunnel syndrome. DESIGN: Prospective study. PATIENTS AND METHODS: Since hereditary neuropathy with liability to pressure palsies may present as carpal tunnel syndrome, we evaluated 50 patients with idiopathic carpal tunnel syndrome for hereditary neuropathy with liability to pressure palsies. RESULTS: No hereditary neuropathy with liability to pressure palsies deletions were detected. CONCLUSION: Molecular genetic testing for hereditary neuropathy with liability to pressure palsies in patients with idiopathic carpal tunnel syndrome is of limited value.

Enhancement of neointima formation with tissue-type plasminogen activator.

PURPOSE: Indirect evidence suggests that tissue plasminogen activator (tPA) either limits or does not alter restenosis. However, tPA enhances tumor invasiveness through matrix remodeling, and several elements of degraded matrix enhance smooth muscle cell mitogenesis. We use either local adenoviral-mediated overexpression of tPA or systemic infusion of recombinant tPA combined with mechanical overdilation of rabbit common femoral arteries to evaluate the impact of tPA on neointima formation. METHODS: Left common femoral arteries of New Zealand white rabbits were transfected in situ either with an adenoviral-construct-expressing tPA or a viral control (adenoviral-construct-expressing beta-galactosidase) or nonviral (buffer) control after balloon angioplasty injury. At 7 and 28 days, left common femoral artery segments were harvested (n = 4 for each group and time point). Vessel segments were examined for intimato-media ratio, smooth muscle cell proliferation, extracellular matrix, and inflammatory response. Thrombus formation was evaluated after 3 days (n = 3 for each group). In a second experiment, New Zealand white rabbits (n = 3 per group, per time point) underwent mechanical dilation followed by buffer treatment or systemic tPA infusion according to a widely clinically used accelerated infusion protocol. Treated artery segments were harvested after 7 or 28 days and processed for intima-to-media ratio determination and class-wide histochemical determination of collagenous extracellular matrix and collagen content. RESULTS: Both rate and degree of neointima formation increase dramatically with overexpression (250%-461% relative to controls at 7 and 28 days). Substantial early matrix degradation is observed in vessels treated with local overexpression of tPA, although no increases in local inflammation or in smooth muscle proliferation occur. Late enhancement of smooth muscle proliferation emerges, consistent with secondary impact of perturbed matrix components. Systemic infusion of tPA according to clinical protocols also results in early and late enhancement of neointima formation in this model (34%-52% relative to controls at at 7 and 28 days), with significant early collagenous matrix degradation. Systemic infusion, although significant, did not attain the degree of neointima formation present with overexpression. CONCLUSION: With some evidence of dose-dependence, tissue plasminogen activator enhances neointima formation after angioplasty in a rabbit model. Early matrix degradation precedes change in rates of proliferation and underlies this effect in spite of several antirestenotic actions including decreased thrombus and decreased macrophage recruitment in this model.

Thrombomodulin overexpression to limit neointima formation.

BACKGROUND-These studies were initiated to confirm that high-level thrombomodulin overexpression is sufficient to limit neointima formation after mechanical overdilation injury. METHODS AND RESULTS-An adenoviral construct expressing thrombomodulin (Adv/RSV-THM) was created and functionally characterized in vitro and in vivo. The impact of local overexpression of thrombomodulin on neointima formation 28 days after mechanical overdilation injury was evaluated. New Zealand White rabbit common femoral arteries were treated with buffer, viral control, or Adv/RSV-THM and subjected to mechanical overdilation injury. The treated vessels (n=4 per treatment) were harvested after 28 days and evaluated to determine intima-to-media (I/M) ratios. Additional experiments were performed to determine early (7-day) changes in extracellular elastin and collagen content; local macrophage, T-cell, and neutrophil infiltration; and local thrombus formation as potential contributors to the observed impact on 28-day neointima formation. The construct significantly decreased neointima formation after mechanical dilation injury in this model. By histological analysis, buffer controls exhibited mean I/M ratios of 0.76+/-0.06%, whereas viral controls reached 0.77+/-0.08%; in contrast, Adv/RSV-THM reduced I/M ratios to 0.47+/-0.06%. Local inflammatory infiltrate decreased in the Adv/RSV-THM group relative to controls, whereas matrix remained relatively preserved. Rates of early thrombus formation also decreased in Adv/RSV-THM animals. CONCLUSIONS-This construct thus offers a viable technique for promoting a locally neointima-resistant small-caliber artery via decreased thrombus bulk, normal matrix preservation, and decreased local inflammation without the inflammatory damage that has limited many other adenoviral applications.

Increased free fat-graft survival with the long-term, local delivery of insulin, insulin-like growth factor-I, and basic fibroblast growth factor by PLGA/PEG microspheres.

The present investigation evaluates the effects of long-term, local delivery of insulin, insulin-like growth factor-1 (IGF-1), and basic fibroblast growth factor (bFGF) on fat-graft survival using a poly (lactic-co-glycolic-acid)-polyethylene glycol (PLGA/PEG) microsphere delivery system. Twelve-micrometer PLGA/PEG microspheres incorporated separately with insulin, IGF-1, and bFGF were manufactured using a double-emulsion solvent-extraction technique. Inguinal fat from Sprague Dawley rats was harvested, diced, washed, and mixed with (1) insulin microspheres, (2) insulin-like growth factor-1 microspheres, (3) basic fibroblast growth factor microspheres, (4) a combination of the insulin and IGF-1 microspheres, and (5) a combination of insulin, IGF-1, and bFGF microspheres. The treated fat grafts were implanted autologously into subdermal pockets in six animals for each group. Animals receiving untreated fat grafts and fat grafts treated with blank microspheres constituted two external control groups (six animals per external control group). At 12 weeks, all fat-graft groups were compared on the basis of weight maintenance and a histomorphometric analysis of adipocyte area percentage, indices of volume retention and cell composition, respectively. Weight maintenance was defined as the final graft weight as a percent of the implanted graft weight. All growth factor treatments significantly increased fat-graft weight maintenance objectively, and volume maintenance grossly, in comparison with the untreated and blank microsphere-treated controls. Treatment with insulin and IGF-1, alone or in combination, was found to increase the adipocyte area percentage in comparison with fat grafts treated with bFGF alone or in combination with other growth factors. In conclusion, the findings of this study indicate that long-term, local delivery of growth factors with PLGA/PEG microspheres has the potential to increase fat-graft survival rates. Further, the type of growth factor delivered may influence the cellular/stromal composition of the grafted tissue.

De novo adipose tissue generation through long-term, local delivery of insulin and insulin-like growth factor-1 by PLGA/PEG microspheres in an in vivo rat model: a novel concept and capability.

This study was undertaken to characterize the duration of long-term growth factor delivery by poly(lactic-co-glycolic-acid)-polyethylene glycol (PLGA/PEG) microspheres and to evaluate the potential of long-term delivery of insulin and insulin-like growth factor-1 (IGF-1) for the de novo generation of adipose tissue in vivo. PLGA/PEG microspheres containing insulin and IGF-1, separately, were produced by a double-emulsion solvent-extraction technique. In the first phase of the experiment, the in vitro release kinetics of the microspheres were evaluated for the optical density and polyacrylamide gel electrophoresis of solutions incubated with insulin-containing microspheres for four different periods of time (n = 1). The finding of increased concentrations of soluble insulin with increased incubation time confirmed continual protein release. In the second stage of the experiment, 16 rats were divided equally into four study groups (insulin, IGF-1, insulin + IGF-1, and blank microspheres) (n = 4). Insulin and IGF-1 containing microspheres were administered directly to the deep muscular fascia of the rat abdominal wall to evaluate the potential for de novo adipose tissue generation via adipogenic differentiation from native nonadipocyte cell pools in vivo. Animals treated with blank microspheres served as an external control group. At the 4-week harvest period, multiple ectopic islands of adipose tissue were observed on the abdominal wall of the animals treated with insulin, IGF-1, and insulin + IGF-1 microspheres. Such islands were not seen in the blank microsphere group. Hematoxylin and eosin-stained sections of the growth factor groups demonstrated mature adipocytes interspersed with fibrous tissue superficial to the abdominal wall musculature and continuous with the fascia. Oil-Red-O stained sections demonstrated that these cells contained lipid. Computer-aided image analysis of histologic sections confirmed that there were statistically significant increases in the amount of "ectopic" adipose neotissue developed on the abdominal wall of animals treated with growth factor microspheres. In conclusion, this study confirms the long-term release of proteins from PLGA/PEG microspheres up to 4 weeks and demonstrates the potential of long-term local insulin and IGF-1 to induce adipogenic differentiation to mature lipid-containing adipocytes from nonadipocyte cell pools in vivo at 4 weeks.

Superficial ulnar artery: embryology, case report, and clinical significance in reconstructive microsurgery.

In this paper the authors describe and illustrate a rare anatomic variation of the ulnar artery, a superficial ulnar artery. The possible embryologic events responsible for this variation are discussed. In addition, they describe the surgical considerations that should be kept in mind when this abnormality is encountered in the clinical setting of free-tissue transfer and vascularized nerve grafting.

Gene therapy to promote thromboresistance: local overexpression of tissue plasminogen activator to prevent arterial thrombosis in an in vivo rabbit model.

Tissue-type plasminogen activator (tPA) catalyzes the rate-limiting initial step in the fibrinolytic cascade. Systemic infusion of tPA has become the standard of care for acute myocardial infarction. However, even the relatively short-duration protocols currently employed have encountered significant hemorrhagic complications, as well as complications from rebound thrombosis. Gene therapy offers a method of local high-level tPA expression over a prolonged time period to avoid both systemic hemorrhage and local rebound thrombosis. To examine the impact of local tPA overexpression, an adenoviral vector expressing tPA was created. The construct was characterized functionally in vitro, and the function of the vector was confirmed in vivo by delivery to the rabbit common femoral artery. Systemic coagulation parameters were not perturbed at any of the doses examined. The impact of local overexpression of tPA on in vivo thrombus formation was examined subsequently in a stasis/injury model of arterial thrombosis. The construct effectively prevented arterial thrombosis in treated animals, whereas viral and nonviral controls typically developed occluding thrombi. This construct thus offers a viable technique for promoting a locally thromboresistant small-caliber artery.

Perioperative dilation for vessel-size discrepancy using a percutaneous transluminal angioplasty catheter.

The problem of vessel-size discrepancy is still unsolved in microvascular-free tissue transfers. In an effort to develop a technique perioperatively to dilate smaller vessel diameters, the authors utilized a catheter customarily used in coronary angioplasties, the percutaneous transluminal coronary angioplasty (PTCA) catheter. Twenty New Zealand rabbits were divided into two groups: Group 1 consisted of 14 experimental animals; Group 2 of six control animals. In both groups, a segmental defect of 2 cm was created in the proximal portion of the femoral artery just below the inguinal ligament, where the vessel diameter is 2.0+/-0.1 mm. In Group 1 animals, an arterial graft was harvested from the superficial femoral artery in the contralateral lower extremity, where the vessel diameter is 1.0+/-0.1 mm. The arterial graft along its entire length was dilated, using a PTCA catheter up to 2 mm in diameter. The duration of dilation was 3 min with pressure applied at 2.5 atm. Before and following dilation, sections were obtained from both ends of the graft for histologic comparison. The grafts were then interposed within the defect and microvascular anastomoses were performed. In the control group, an arterial graft of the same length as in the experimental group was harvested from the contralateral upper femoral region, where the vessel diameter is 2.0+/-0.1 mm. These grafts were then interposed within the defect and microsurgically anastomosed. Seven days later, the patency of the anastomoses was evaluated in both groups. In 13 of 14 rabbits in the experimental group, the anastomoses were patent and the arterial grafts maintained their dilated diameters (2 mm). In all six control animals, the anastomoses were patent. A statistical comparison of vessel patency using Fischer's exact chi-square test showed no significant differences between the experimental and control groups (p = 0.7). Histologically, the dilated arteries demonstrated intact endothelial layers.

Local gene delivery: arterial thrombosis model for endothelial cell-targeted thrombolytic gene therapy research.

The authors describe a rabbit arterial thrombosis model that employs vessel division followed by microsurgical anastomosis and transluminal sutures, to reliably induce thrombus formation in the common femoral artery (CFA). Using two objective measures, "evacuation/refill" evaluation of patency and computer-aided histomorphometric analysis of the thrombus area, thrombus formation was confirmed and characterized in the model at both short- and long-term observation time-points. In addition, a gene delivery method was developed in the CFA that employs an adenoviral vector solution injected through the inferior epigastric artery (IEA). Using this method, a marker transgene (beta-galactosidase) was delivered to endothelial cells locally and without trauma. By subsequently performing beta-galactosidase staining, effective endothelial transfection was demonstrated simultaneously with endothelial viability, with preserved endothelial synthetic function in the immediate environment of the occluding thrombus. The results suggest that these two techniques can be used together in one model, to effectively introduce a foreign therapeutic transgene into endothelial cells and to evaluate the effect of the expressed protein product in a consistent in vivo thrombosis system. This combined model may be used as one of several assays of efficacy in future endothelial cell-targeted thrombolytic/antithrombotic vascular gene therapy research.

Local overexpression of thrombomodulin for in vivo prevention of arterial thrombosis in a rabbit model.

-Endothelial thrombomodulin plays a critical role in hemostasis by binding thrombin and subsequently converting protein C to its active form, a powerful anticoagulant. Thrombomodulin thus represents a central mechanism by which patency is maintained in normal vessels. However, thrombomodulin expression decreases in perturbed endothelial cells, predisposing to thrombotic occlusion. An adenoviral construct expressing thrombomodulin (Adv/RSV-THM) was created and functionally characterized in vitro and in vivo. The impact of local overexpression of thrombomodulin on in vivo thrombus formation was subsequently examined in a stasis/injury model of arterial thrombosis. The construct prevented arterial thrombosis formation in all animals, while viral and nonviral controls typically developed occluding thrombi. By histological analysis, nonviral controls exhibited intravascular thrombus occluding a mean of 70.52+/-3.72% of available lumen, while viral controls reached 86. 85+/-2.82% thrombotic occlusion; in contrast, Adv/RSV-THM reduced thrombosis to 28.61+/-3.31% of lumen in cross section. No significant intima-to-media ratio was observed in the thrombomodulin group relative to controls. Local infiltration of granulocytes and macrophages significantly decreased in the Adv/RSV-THM group relative to controls, while neutrophilic infiltration increased in viral controls relative to nonviral controls. This construct thus offers a viable technique for promoting a locally thromboresistant small-caliber artery, without the inflammatory damage that has limited many other adenoviral applications.

Vascular gene therapy.

Gene therapy is an exciting frontier in medicine today. Radiologists will be involved in tracking the effects of these new therapies through imaging. Vascular and interventional radiology techniques also are ideally suited for minimally invasive, readily monitored gene delivery. Gene therapy is accomplished through gene augmentation or gene blocking. The latter is accomplished through antisense oligonucleotides or transcription factor decoys. Vectors are agents that facilitate gene delivery and expression and can be viral or nonviral. The vascular wall is an ideal target for gene therapy because of its central role in many biologic processes and its ready accessibility. Recombinant genes can be delivered ex vivo and in vivo, with the latter approaches involving open surgical, percutaneous injection, and endovascular catheter-based methods. Perforated, hydrogel-coated, and double balloon catheters have been used with varying success. Optimal catheter systems for gene transfer will enable delivery of the vector to the precise anatomic location with transfection limited to the cells of interest and will minimize shedding of the vector to distal sites, systemic effects of the therapeutic agent, and morbidity from the delivery method. Radiologists must become familiar with the basic rationale, strategies, and mechanisms of gene therapy and involved in its clinical trials to ensure an active role in this field.

Endoscopic exploration of the orbital floor: a technique for transantral grafting of floor blowout fractures.

A cadaveric study was conducted with a twofold purpose--to perform diagnostic transantral endoscopy in pure blowout fractures of the orbital floor and to attempt restoration of bony defects in the orbital floor using the endoscope. Endoscopic visual access of the orbital floor allows precise determination of the fracture size and the presence and extent of entrapped periorbital fasciae. A bony defect was created surgically in the orbital floor of 6 fresh cadaver heads, and a split-thickness calvarial bone graft and an alloplast were used to repair the orbital floor. Grafting of the orbital floor with endoscopic visual access was successful, and the potential risks associated with the traditional eyelid incisions were minimized. The anatomic course of the infraorbital nerve was observed and protected. The study confirmed that endoscopy could be used successfully in obtaining visual access to the orbital floor.

Brachial plexus birth injuries and current management.

OBPP is a condition that, for the majority of patients, resolves spontaneously with appropriate nonoperative treatment. However, those patients who do not improve spontaneously now have a better chance for recovery owing to recent advances in microsurgery and nerve-transfer techniques. The most important aspect of therapy is timely recognition and referral.

A new design of the iliac crest microsurgical free flap without including the "obligatory" muscle cuff.

The iliac crest free flap has undergone a gradual evolution to provide more functional and cosmetic oromandibular reconstructions. The soft-tissue cutaneous component has largely resisted refinement and currently constitutes the flap's principal drawback. Conventionally, the cutaneous vessel's soft-tissue encasement and a protective cuff of abdominal muscle are harvested to ensure skin perfusion. These protective measures, however, produce a bulky flap that is tethered to the bone and difficult to inset into complex three-dimensional defects. A series of anatomic and clinical investigations has confirmed that in 30 percent of individuals, the skin island can be elevated on a dominant cutaneous branch from the deep circumflex iliac artery. Harvesting the skin as an axial pattern flap greatly increases its independence from the bone, improving maneuverability. A small collar of abdominal muscle is incised around the pedicle, obviating the need for the customary 2.5-cm protective muscle cuff. Exclusion of the abdominal muscular component reduces the flap's volume, decreases the need for secondary debulking, and reduces the donor site morbidity.

Closure of upper extremity soft-tissue defects using the new "supra-crest" fasciocutaneous free flap.

A fasciocutaneous island (15 x 10 cm) can be elevated from the inferolateral abdominal wall in a region encompassing the iliac crest and extending to the lower costal margin. This new fasciocutaneous flap was named the "supra-crest flap," in accordance with its anatomic location and vascular pattern. The blood supply stems from the direct cutaneous branches of the lumbar arteries (L2-3), which pierce the abdominal musculature approximately 2.0 cm above the iliac crest in the midaxillary line. The arteries and two vena comitantes have an average external diameter of 2.0 mm, and their dissection can be extended deep into the iliac fosa to provide a pedicle 8 or more cm in length. Two cutaneous nerves accompany the lumbar arteries, furnishing the possibility of a sensate flap. These structures have been transferred as a free flap with the donor site concealed by conventional underwear and bathing suits. Additionally, this region could be harvested as an island flap wherein the arc of rotation may be sufficient to cover defects of the thoracic wall and lumbosacral regions.

A comparative study of gut suture, human amnion collagen, bovine skin collagen and Vicryl suture implants in rats.

This study compares the persistence and histological characteristics of gut suture with those of human amnion collagen, bovine collagen, and Vicryl suture implants in rats. Gut suture and human amnion collagen more resembled living tissue than did bovine collagen and were characterized by their cellularity and the presence of numerous capillaries. The Vicryl suture implants were quickly absorbed. Picrosirius polarization revealed the synthesis of host collagen by rat fibroblasts which immigrated into the gut suture and human amnion collagen implants. The authors suggest the potential of gut suture as a soft tissue substitute to improve linear skin contour deficits.

Soft-tissue reconstruction following extravasation of chemotherapeutic agents.

The incidence of chemotherapeutic extravasation injuries ranges from 0.5% to 6%. Chronicity and an indolent course are prominent characteristics of such wounds, as are severe pain and ulceration with no tendency to spontaneous healing. Prevention is the best treatment. Aggressive surgical debridement is recommended for patients with persistent pain or ulceration. Whirlpool therapy, wet-to-dry dressing changes, and a vigorous physical therapy program are all helpful. Soft-tissue coverage can be obtained by skin grafting, delayed flaps, various local muscle or fasciocutaneous flaps, or by free tissue transfer.