TDP-43 pathology in multiple system atrophy: colocalization of TDP-43 and α-synuclein in glial cytoplasmic inclusions.

AIMS: This study aimed to assess clinicopathologic features of transactive response DNA-binding protein of 43 kDa (TDP-43) pathology and its risk factors in multiple system atrophy (MSA). METHODS: Paraffin-embedded sections of the amygdala and basal forebrain from 186 autopsy-confirmed MSA cases were screened with immunohistochemistry for phospho-TDP-43. In cases having TDP-43 pathology, additional brain regions were assessed. Immunohistochemical and immunofluorescence double-staining and immunogold electron microscopy (IEM) were performed to evaluate colocalization of TDP-43 and α-synuclein. Genetic risk factors for TDP-43 pathology were also analysed. RESULTS: Immunohistochemistry showed various morphologies of TDP-43 pathology in 13 cases (7%), such as subpial astrocytic inclusions, neuronal inclusions, dystrophic neurites, perivascular inclusions and glial cytoplasmic inclusions (GCIs). Multivariable logistic regression models revealed that only advanced age, but not concurrent Alzheimer's disease, argyrophilic grain disease or hippocampal sclerosis, was an independent risk factor for TDP-43 pathology in MSA (OR: 1.11, 95% CI: 1.04-1.19, P = 0.002). TDP-43 pathology was restricted to the amygdala in eight cases and extended to the hippocampus in two cases. The remaining three cases had widespread TDP-43 pathology. Immunohistochemical and immunofluorescence double-staining and IEM revealed colocalization of α-synuclein and TDP-43 in GCIs with granule-coated filaments. Pilot genetic studies failed to show associations between risk variants of TMEM106B or GRN and TDP-43 pathology. CONCLUSIONS: TDP-43 pathology is rare in MSA and occurs mainly in the medial temporal lobe. Advanced age is a risk factor for TDP-43 pathology in MSA. Colocalization of TDP-43 and α-synuclein in GCIs suggests possible direct interaction between the two molecules.

DNAJC13 p.Asn855Ser mutation screening in Parkinson's disease and pathologically confirmed Lewy body disease patients.

BACKGROUND: Recently, a novel mutation in exon 24 of DNAJC13 gene (p.Asn855Ser, rs387907571) has been reported to cause autosomal dominant Parkinson's disease (PD) in a multi-incident Mennonite family. METHODS: In the present study the mutation containing exon of the DNAJC13 gene has been sequenced in a Caucasian series consisting of 1938 patients with clinical PD and 838 with pathologically diagnosed Lewy body disease (LBD). RESULTS: Our sequence analysis did not identify any coding variants in exon 24 of DNAJC13. Two previously described variants in intron 23 (rs200204728 and rs2369796) were observed. CONCLUSION: Our results indicate that the region surrounding the DNAJC13 p.Asn855Ser substitution is highly conserved and mutations in this exon are not a common cause of PD or LBD among Caucasian populations.

[Complete aesthetic reconstruction of nose and adjacent facial units with optimized use of free flaps, cartilaginous grafts and forehead flap combinations]. / Reconstruction esthétique totale du nez et des unités faciales adjacentes par combinaison optimisée lambeaux libres, greffes cartilagineuses et lambeau pédiculé frontal paramédian.

BACKGROUND: Facial reconstruction with only free microvascular flaps has rarely produced an aesthetic result. Menick : "Distant skin always appears as a mismatched patch within residual normal facial skin." In addition, earlier techniques using a single large nasal lining flap or bilateral nasal lining vaults incurred a high incidence of airway obstruction. METHODS: The authors describe 10 consecutive patients requiring reconstruction of the nasal vestibule and columella lining from October of 1997 through May of 2005. Most of them also required reconstruction of the floor of the nose, the platform on which the alar bases and columella rest, and of the facial units adjacent to the nose. Aesthetic nasal reconstruction used two separate skin paddles to reconstruct the lining for the nasal vestibule and columella, an artistically constructed nasal framework made of cartilage, a forehead flap for cover, and other flaps and grafts to reconstruct adjacent facial unit defects. RESULTS: The average patient age was 41.8 years (range, 10.4 to 65.3 years). Follow-up (from the time of the first operative stage) averaged 26.4 months (range, 4 to 49 months). Nine patients had functional airways and one required nasal airway support with internal silicone tubes. At the time of publication, eight patients had normal-appearing noses and two were awaiting secondary surgery to correct persistent deformity. CONCLUSIONS: Microvascular free flaps have proved to be highly reliable and efficacious for restoration of missing elements of the nasal lining and adjacent facial soft-tissue defects in total and subtotal nasal reconstruction. Combined with a forehead flap, this aesthetic approach allows for reconstruction of the center of the face layer-by-layer and facial unit by facial unit. Specific attention is paid to the artistic creation of normal nasal dimensions, proportion, and form using carved and assembled cartilage grafts and by secondary subcutaneous contouring. In addition, this technique produces a patent airway.

Single-stage sacral coccygectomy and repair using human acellular dermal matrix (AlloDerm) with bilateral gluteus maximus flaps for hernia prophylaxis.

Sacrococcygectomy is often necessary for the ablation of malignancies involving the sacrum and coccyx, and can result in deep posterior peritoneal defects with disruption of the pelvic floor. Such a radical procedure is frequently associated with significant morbidity, including sacral herniation. Numerous techniques for the closure of the surgical defect have been described, with varying degrees of success in avoiding future herniation. We report the first single-stage coccygectomy and partial sacrectomy with closure utilizing human acellular dermal matrix (HADM) (AlloDerm; LifeCell Corporation, Branchburg, NJ) and bilateral gluteus maximus transposition flaps.

Microsurgical replantation of the lip: a multi-institutional experience.

Traumatic amputation of the lip is a rare yet devastating event affecting both form and function. Considering the available methods for reconstruction, replantation may offer a reasonable solution. We sought to characterize the variables associated with lip replantation and to assess the outcome in a retrospective review of 13 lip replantations performed in 12 institutions utilizing a form database and clinical and photographic analysis. Lip replantation was successful in all 13 patients; partial flap loss occurred in one patient owing to iatrogenic injury. Follow-up averaged 3.1 years. Average patient age at the time of injury was 21.1 years. There were six male and seven female patients. Injuries in two patients were the result of a human bite, the remaining injuries resulted from dog bites. One patient had significant associated injuries. Average length of hospital stay was 11.9 days. Ten patients suffered amputations of the upper lip, and three suffered amputations of the lower lip. Average defect size was 10.6 cm2. Operative time averaged 5.7 hours (range 2.5 to 12 hours). Warm ischemia time averaged 2.9 hours, and cold ischemia time averaged 2.7 hours. Donor and recipient veins were often scarce; all patients had at least one arterial anastomosis, whereas no vein was available in 7 of 13 patients; vein grafts were required in one patient. Leech therapy was employed in 11 of 13 patients. Anticoagulant therapy was administered in the majority of patients. Systemic heparin was utilized in 10 of 13 patients, low molecular weight dextran was used in 7 of 13 patients, and aspirin was given to 7 of 13 patients. One bleeding complication was incurred. An average of 6.2 units of packed red blood cells was administered to 12 of 13 patients (adjusted to 250 cc/unit). Antispasmodic therapy was employed in six of eight patients intraoperatively and in two of eight patients postoperatively. Intraoperative complications included difficulty identifying veins in 7 of 13 patients, arterial spasm in 1 of 13 patients, and vessel diameter < 0.5 mm in 4 patients. Postoperatively, one patient suffered vein thrombosis requiring anastomotic revision. Broad spectrum antibiotics were administered to all patients, and there were no infections. Nearly one-third (4 of 13) patients suffered prolonged edema lasting > 4 months. Color match of the replanted lip segment was rated excellent in all cases. Hypertrophic scarring occurred in 6 of 13 patients. A total of 12 revision procedures was performed in six patients. Interestingly, leech therapy resulted in permanent visible scarring as a result of the leech bite in 6 of 11 patients treated. Ten patients demonstrated active orbicularis muscle contraction in the replanted lip segment. Stomal continence was present in all lips. Sensibility return in the replanted lip segment was quite good with 12 of 13 patients demonstrating at least protective moving two-point sensibility (> or = 10 mm). Partial replant necrosis in one patient resulted in significant scar and contraction that compromised the aesthetic appearance. Overall, however, all patients were uniformly pleased with their final results. This clinical study is one of the largest of its kind on lip replantation. Although this represents a multi-institutional experience, the data are remarkably consistent. Re-establishment of venous outflow seems to be the most problematic technical challenge. By incorporating the adjuncts of anticoagulation, leech therapy, and antispasmodics, a successful outcome can be expected despite the paucity of vessels and small vessel size. The risks of blood transfusion, lengthy operative time, and hospital stay must be weighed against the functional benefits.

Reconstruction of the lower extremity after ablative resection for cancer.

Limb-sparing surgery for cancer of the lower extremity has ushered the development of composite, one-stage reconstructions that employ a combination of autologous tissues, bone allografts, and endoprosthetic devices. The success of these efforts in preserving limb function has been generally good, yet the ultimate level of function is less than normal. Microsurgery has assumed a progressively greater role in the reconstruction of composite defects and allows much latitude in the surgical planning and in the management of delayed complications. Although patients who opt for limb salvage reconstructions frequently require more operative procedures and have longer hospitalizations than patients undergoing primary amputation, their functional outcome surpasses that of the amputation group and thus justifies the surgical effort.

The effects of radiation on neovascularization in a rat model.

It is thought that radiation treatment inhibits neovascularization of recipient and/or graft tissues, and this may account in part for abnormalities in wound healing associated with radiation therapy. We have examined this hypothesis using a model that measures the neovascularization of an implanted foreign material. Expanded polytetrafluoroethylene (PTFE) sheets were implanted adjacent to both superficial epigastric vascular pedicles of 63 rats distributed into 7 groups (n = 7) that differed with respect to dose and timing of irradiation. Zero to 10 daily fractions of electron-beam radiation (300 cGy each) were delivered to the implant in the right groin, while the implant in the left groin served as a nonirradiated internal control. Unirradiated animals showed equal neovascularization of both implants. Rats that were irradiated twice (single fractions at 0 and 24 hours after implantation) did not show a significant decrease in the neovascularization of the irradiated implant compared with the contralateral control implant. In contrast, the implants that were irradiated three times (single fractions at 0, 24, and 48 hours after implantation) demonstrated significantly diminished ( > 25 percent, p < 0.05) neovascularization beyond day 7, whereas implants irradiated only at 48 hours after implantation did not. Interestingly, neovascularization of the implants irradiated with 10 fractions (3000 cGy) was not significantly decreased compared with irradiation with three fractions (900 cGy). Irradiation delivered before implantation (900 cGy) inhibited neovascularization significantly less than the same dose administered after implantation. The results of this study suggest that a subclinical cumulative dose of 900 cGy is the threshold for impaired tissue revascularization provided that treatment is delivered immediately after implantation over a 48-hour interval.

Free flap valvular transplantation for refractory venous ulceration.

PURPOSE: Nonoperative therapeutic approaches to chronic venous ulceration, although effective, often require prolonged dressing care and immobilization with leg elevation. Results of skin grafting, perforator ligation, and valve interpositions and reconstructions improve results of ulcer healing but have not uniformly prevented ulcer recurrence. Our hypothesis is that reconstruction of chronic venous ulcers by excision of the diseased tissue bed and replacement with a free flap containing multiple competent microvenous valves and a normal tissue microcirculation will result in long-term cure of these debilitated patients. METHODS: Six patients with chronic venous insufficiency and recurrent ulceration (class 3) underwent excision of ulcers and surrounding liposclerotic tissue beds and reconstruction with fasciocutaneous free flaps (two bilateral). Preoperative and postoperative photoplethysmography was used to assess venous refilling times. Duplex scanning was performed to assess deep venous reflux. RESULTS: There were no flap failures. Photoplethysmographic venous refilling times measured on flaps demonstrated significant immediate and long-term increases from preoperative values (all results +3 by Society of Vascular Surgery outcome grading). Long-term maintenance of tissue integrity is shown by absence of recurrent ulceration and no evidence of recurrent tissue lipodermatosclerosis in all flaps at follow-up (8 months to 7.5 years; mean 24 months). No recurrent lipodermatosclerosis was seen on flap biopsy at 2 and 7 years. Separate cadaveric injection studies, including scanning electron microscopy, revealed numerous microvenous valves directed toward the draining pedicle in the flaps used for reconstruction. CONCLUSIONS: This is the first comprehensive report providing combined laboratory and clinical evaluation, anatomic rationale, and long-term outcome of surgical rehabilitation of patients with chronic venous ulceration who have undergone microsurgical flap reconstruction.

The versatile superficial inferior epigastric flap for breast reconstruction.

The superficial inferior epigastric flap is a versatile free flap that has added to the techniques available for autogenous breast reconstruction. It is especially advantageous when previous thoracic radiation and/or abdominal surgery preclude the use of conventional transverse rectus abdominis musculocutaneous flaps. Eight superficial inferior epigastric flaps were used to reconstruct 7 breasts in 6 patients. In 4 patients the superficial inferior epigastric flap was used as part of a composite free flap. In 1 patient, a lower abdominal wall flap was transferred on bilateral pedicles. In another, bilateral flaps were raised to reconstruct both breasts. The superficial inferior epigastric flap offers several advantages. It uses relatively abundant lower abdominal wall skin and subcutaneous tissue while preserving the underlying fascia and rectus muscles. A cadaver study illustrates the clinical territory of this flap. The superficial inferior epigastric flap provides an excellent option for autogenous free flap reconstruction of the breast, alone or in combination with other flaps.

Preoperative and postoperative nipple-areola sensibility in patients undergoing reduction mammaplasty.

Objective data on nipple and areola sensibility are scarce. For women with macromastia, there is little published information available indicating the incidence and intensity of postoperative nipple and areola sensibility. This prospective study was undertaken to evaluate nipple and areola sensibility in "small-breasted" control subjects as well as in patients with macromastia before and after reduction mammaplasty. Preoperative and postoperative Semmes-Weinstein pressure threshold testing was performed on 84 breasts in 43 patients and on 12 breasts of A or B cup size in the control group. The patients underwent reduction mammaplasty by the central parenchymal pedicle technique or the laterally based inferior pedicle technique. Nipple-areola sensibility was retained in 96 percent of breasts when the excision of breast tissue was less than 550 gm and 85 percent of breasts when the excision was greater than 550 gm. Overall, nipple-areola sensibility was retained in 90.5 percent of the 84 breasts tested. In those breasts in which nipple-areola sensibility was retained after surgery, there was no statistical difference in the preoperative and postoperative Semmes-Weinstein pressure threshold values. When pressure threshold values were compared in patients who had less than 550 gm of tissue resected, patients who had greater than 550 gm of tissue resected, and controls who had not undergone surgery, the trend of decreasing nipple-areola sensibility with increasing breast size was clearly seen.

Reduction mammaplasty improves symptoms of macromastia.

The condition macromastia has not been defined and characterized precisely by the medical community. Whether the patient with hypertrophic breasts is a candidate for or can be helped by reduction mammaplasty is unclear to both the medical and the lay community. A prospective study of 39 women undergoing reduction mammaplasty surgery was initiated to answer these questions. Patients rated the severity of their somatic pain symptoms and discomfort before reduction mammaplasty and again after complete recovery. The severity of their symptoms and complaints was numerically graded and analyzed. These data were compared with similar data obtained from 40 "small-breasted" women of similar age. Headache, neck pain, back pain, shoulder pain, and bra strap groove pain were present in 60 to 92 percent of patients, and 97 percent of patients had at least three of these pain symptoms preoperatively. All the patients had reduction of their pain symptomatology postoperative, and 25 percent of the study patients had total elimination of pain symptoms by reduction mammaplasty. The postoperative incidence and severity of pain symptoms and discomfort complaints were statistically equivalent to or less than the levels in the control group.

Efficacy of epidural anesthesia in free flaps to the lower extremity.

Epidural anesthesia is an effective means of providing pain control and chemical sympathectomy at the spinal nerve root level. The purpose of this study is to compare the efficacy of the combination of epidural and general anesthesia to general anesthesia alone in patients undergoing free flaps to the lower extremity. A retrospective review of 35 consecutive patients (36 operations) from November of 1988 to November of 1990 undergoing free tissue transfer to the lower extremity was undertaken. Sixteen patients had epidural and general anesthesia, and 19 (20 operations) had general anesthesia alone. There were no significant differences in the age or sex of the patients, the distribution between acute and chronic wounds, or the number of cigarette smokers in the two groups. There were no flap losses in the epidural group (100 percent success) and one major, but nonmicrovascular complication (6 percent). In the nonepidural group, there were one flap loss (95 percent success) and five major complications (25 percent). These included three microvascular complications (15 percent). There were significantly fewer patients with postoperative atelectatic fevers in the epidural group versus the nonepidural group. In this consecutive series of patients, epidural supplementation of general anesthesia for free flaps to the lower extremity was associated with uniformly successful flap survival and a lower rate of microvascular complications compared to general anesthesia alone.

Tissue engineering of biomaterials for composite reconstruction: an experimental model.

The fibrovascular integration of a biomaterial scaffold was examined in a rabbit model. Eight disks of expanded polytetrafluoroethylene measuring 2 x 2 x 0.2 cm were placed adjacent to dissected vascular pedicles in the ears of four rabbits and sealed between leaves of silicone sheeting. Fibrovascular outgrowth from the vascular pedicles completely integrated the biomaterial scaffolds by 6 weeks and was sufficient to sustain split-thickness skin grafts. Division of the distal vascular pedicle allowed isolation of the blood flow circuit to the construct. Successful microsurgical transfer was achieved in one construct. This model has proved useful in the study of tissue engineering of biomaterials for reconstruction and may well have use in the study of neovascularization as an isolated event.

Treatment of hand injuries by external fixation.

Thirty-five consecutive applications of external fixation to the hand, including 27 acute cases and 8 reconstructive procedures, were studied. In both settings, external fixation was used not only for skeletal stabilization but also for management of the soft tissues. Twenty of the 22 acute fractures healed, and six arthrodeses with interposition bone grafts resulted in fusion. Three septic nonunions resolved, and two united successfully. There were no complications. We recommend external fixation systems in the hand, and several case reports are included in the study to illustrate the various applications.

Free flaps in the elderly.

Microsurgical transfer of tissue has become a primary tool of the reconstructive surgeon. The elderly, as a growing segment of our society, are requiring free-tissue transfers in proportion to their numbers. To investigate the potential morbidity of free-tissue transfers in the elderly, we studied consecutive populations of 31 patients above the age of 65 years and 90 patients below the age of 65 years. Complication rates were 65 and 49 percent, respectively. Premorbid medical conditions were present in 87 percent of patients 65 years and older and in 72 percent of those under 65 years. Medically related complications in free-tissue transfers, previously unreported in the literature, were 35 percent in the elderly group and 10 percent in the younger group. Wound-healing complications were seen in equal proportions between groups. The rates of wound and medically related complications observed in the elderly group were nearly double those observed in the younger group; however, after correction for the presence of preexisting medical conditions, no significant differences were seen between the two groups. These observations suggest that age alone is not a variable in risk for free-tissue transfers. Elective microsurgery can be performed in the elderly patient with a high expectation of success.

Judgment and approach for management of severe lower extremity injuries.

Severe lower extremity injuries are devastating in their impact on the patient, his or her family, and the future. A critical evaluation of the results of previous salvage efforts provides the basis for the formulation of a treatment strategy. Success can be measured only in terms of functional outcome. The type of therapy is perhaps less important than the effectiveness of establishing a coordinated multidisciplinary approach to these injuries.

Aesthetic results following partial mastectomy and radiation therapy.

This study was undertaken to determine the aesthetic changes inherent in partial mastectomy followed by radiation therapy in the treatment of stage I and stage II breast cancer. A retrospective analysis of breast cancer patients treated according to the National Surgical Adjuvant Breast Project Protocol B-06 was undertaken in 57 patients from 1984 to the present. The size of mastectomy varied between 2 x 1 cm and 15 x 8 cm. Objective aesthetic outcome, as determined by physical and photographic examination, was influenced primarily by surgical technique as opposed to the effects of radiation. These technical factors included orientation of resections, breast size relative to size of resection, location of tumor, and extent and orientation of axillary dissection. Regarding cosmesis, 80 percent of patients treated in this study judged their result to be excellent or good, in comparison to 50 percent excellent or good as judged by the plastic surgeon. Only 10 percent would consider mastectomy with reconstruction for contralateral disease. Asymmetry and contour abnormalities are far more common than noted in the radiation therapy literature. Patients satisfaction with lumpectomy and radiation, however, is very high. This satisfaction is not necessarily based on objective criteria defining aesthetic parameters, but is strongly influenced by retainment of the breast as an original body part.

Optimum management of hand blast injuries.

A series of 27 blast and gunshot injuries of the hand is presented. These wounds exhibit a spectrum of complexity and may include extensive soft tissue trauma complicated by burns, foreign bodies, fractures and amputations. A systematic management sequence is outlined to evaluate, treat, reconstruct and rehabilitate these hands, with the primary goal of obtaining early maximal function. Since these injuries vary in nature and complexity, this management sequence is specifically adapted to deal with the individual injury. A "reconstructive ladder" of techniques is utilized, ranging from "simple" (e.g., direct closure, skin grafts, local flaps) to "complex" (free flaps, toe-to-thumb transfer). The individual procedure selected is the most straightforward, consistent with expediency and early return of a functional hand. The return of these hands to function has been facilitated by recent advances in tissue assessment, free tissue transfer, and skilled hand therapy.

Autogenous vein graft repair of digital nerve defects in the finger: a retrospective clinical study.

Twenty-two digital nerve repairs were performed in the finger using autogenous vein grafts. Eighty-two percent of the repairs were available for follow-up. Results of sensibility return were assessed using moving two-point discrimination, Semmes-Weinstein monofilaments, and vibratory testing. Two-point discrimination averaged 4.6 mm for 11 acute digital nerve repairs using vein conduits 1 to 3 cm in length. Delayed digital nerve repair with vein conduits yielded poor results. Semmes-Weinstein values demonstrated comparable levels of return of slowly adapting fiber/receptors to the quickly adapting fiber/receptors, as evidenced by moving two-point discrimination tests. Vibratory sensibility was present in all. A review of previous experiences with end-to-end digital neurorrhaphies and digital nerve grafting suggests that repair of 1- to 3-cm gaps in digital nerves with segments of autologous vein grafts appears to give comparable results to nerve grafting. Further laboratory and clinical research is necessary to better define the role of interpositional vein conduits for repair of peripheral nerves.