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.

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.

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.

The scalp flap only onlay: a method for managing large dural defects.

The standard approach to loss of substantial amounts of calvarium and dura is replacement of the dura with pathches, usually of biologic material such as fascia. We question the need for such patches and offer experimental and clinical evidence to support a different approach. Treatment of large calvarium and dural defects in 20 rats divided in two groups showed no difference in dural regeneration between animals repaired with patches and those repaired with the scalp flap only onlay on the brain. An illustrative clinical case confirms the observations. The scalp flap only onlay repair of cranial defects involving the dura provides a reasonable means for reconstruction. (1) In experimental animals there appeared to be no histologic difference between dura repaired by autogenous patch and that repaired by the scalp flap only onlay. (2) Clinically, well-nourished galea effects an ideal onlay repair of the dura. Secondary reconstruction of the bony calvarium can be performed utilizing a modified crane technique. (3) The procedure is simple in design, requires no donor sites, and certainly has application in cases other than trauma.

The posterior calf fasciocutaneous free flap.

Four clinical cases are presented that represent our initial experience with a new fasciocutaneous free-flap unit. The territory of this flap incorporates the skin, fat, and fascia of the posterior calf region. Its design is based on the principle of the fasciocutaneous flap. Anatomic studies confirm that the blood supply to this flap is derived from a descending subfascial branch of the popliteal artery. The flap is well endowed with cutaneous sensory nerves, making it a potential neurosensory free flap. Our technique of flap design and elevation is presented, and potential advantages and disadvantages of this flap are discussed.

Aspergillus colonization associated with bilateral silicone mammary implants.

A case of Aspergillus niger fungal colonization associated with bilateral inflatable silicone mammary implants is reported. Painful fibrous capsular contractures without clinical evidence of infection or inflammation characterized the presenting symptoms. Operative findings included a cheesy-white exudate that surrounded the implants and turbid fluid within the implants. All specimens yielded a heavy growth of Aspergillus niger. Special stains of the fibrous capsules were negative for fungal invasion. The etiology and pathogenesis of Aspergillus colonization in this patient are postulated.

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.

The posterior calf fascial free flap.

Six posterior calf fascial free flaps were employed to reconstruct defects of the upper and lower extremities. One flap failed due to a constricting dressing. Two flaps sustained partial loss secondary to bleeding and hematoma formation. One flap dehisced at the distal suture line due to mobility of an underlying fracture. All surviving flaps eventually healed and resulted in stable, thin coverage. Donor-site morbidity has been minimal. Shortcomings of this flap model have been defined in the peculiarities of its thinness, diffuse vascular oozing, the extent of the vascular territory, and in postoperative monitoring. These problems are analyzed and recommendations for their resolution are presented. Fascia represents a unique tissue which offers an exciting new dimension in the reconstruction of certain defects--particularly those in which thinness is a desirable option. In the posterior calf model, the inclusion of fat represents an alternative modification that allows the surgeon to tailor the design to a variety of problems where fascia alone is too thin and a cutaneous flap is too thick. This concept may find its greatest application in wounds involving the hand or foot. We believe that this and other fascial flap prototypes may offer an ideal solution for reconstruction of major wounds of the extremities.

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.

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.

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.

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.

Surface quantification of injected fluorescein as a predictor of flap viability.

In a laboratory model, quantitative skin-surface fluorescence has been used to reliably measure skin perfusion in ischemic random flaps and to predict viability. The method is reproducible and allows investigators to sequentially monitor soft-tissue perfusion using a fluorescent indicator. It is superior to the conventional fluorescein test (Wood's lamp method), which allows only a single subjective assessment within a 24-hour period.

Experience with the transverse lower rectus abdominis operation for breast reconstruction.

Our initial experience with the lower rectus abdominis procedure for breast reconstruction in 19 patients is presented. Anatomic considerations, surgical technique, and results are reviewed. Errors in flap design and execution resulted in a disproportionately high complication rate, which improved following certain technical refinements. The lower rectus flap has proved to be an alternative to conventional techniques of breast reconstruction. As more experience is gained with this flap, its particular role in the reconstructive armamentarium will be more clearly defined.

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.

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.

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.

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.