SuperAging functional connectomics from resting-state functional MRI.

Understanding the relationship between functional connectivity (FC) of higher-order neurocognitive networks and age-related cognitive decline is a complex and evolving field of research. Decreases in FC have been associated with cognitive decline in persons with Alzheimer's disease and related dementias (ADRD). However, the contributions of FC have been less straightforward in typical cognitive aging. Some investigations suggest relatively robust FC within neurocognitive networks differentiates unusually successful cognitive aging from average aging, while others do not. Methodologic limitations in data processing and varying definitions of 'successful aging' may have contributed to the inconsistent results to date. The current study seeks to address previous limitations by optimized MRI methods to examine FC in the well-established SuperAging phenotype, defined by age and cognitive performance as individuals 80 and older with episodic memory performance equal to or better than 50-to-60-year-olds. Within- and between-network FC of large-scale neurocognitive networks were compared between 24 SuperAgers and 16 cognitively average older-aged control (OACs) with stable cognitive profiles using resting-state functional MRI (rs-fMRI) from a single visit. Group classification was determined based on measures of episodic memory, executive functioning, verbal fluency and picture naming. Inclusion criteria required stable cognitive status across two visits. First, we investigated the FC within and between seven resting-state networks from a common atlas parcellation. A separate index of network segregation was also compared between groups. Second, we investigated the FC between six subcomponents of the default mode network (DMN), the neurocognitive network commonly associated with memory performance and disrupted in persons with ADRD. For each analysis, FCs were compared across groups using two-sample independent t-tests and corrected for multiple comparisons. There were no significant between-group differences in demographic characteristics including age, sex and education. At the group-level, within-network FC, between-network FC, and segregation measurements of seven large-scale networks, including subcomponents of the DMN, were not a primary differentiator between cognitively average aging and SuperAging phenotypes. Thus, FC within or between large-scale networks does not appear to be a primary driver of the exceptional memory performance observed in SuperAgers. These results have relevance for differentiating the role of FC changes associated with cognitive aging from those associated with ADRD.

Multimodal MRI reveals brainstem connections that sustain wakefulness in human consciousness.

Consciousness is composed of arousal (i.e., wakefulness) and awareness. Substantial progress has been made in mapping the cortical networks that underlie awareness in the human brain, but knowledge about the subcortical networks that sustain arousal in humans is incomplete. Here, we aimed to map the connectivity of a proposed subcortical arousal network that sustains wakefulness in the human brain, analogous to the cortical default mode network (DMN) that has been shown to contribute to awareness. We integrated data from ex vivo diffusion magnetic resonance imaging (MRI) of three human brains, obtained at autopsy from neurologically normal individuals, with immunohistochemical staining of subcortical brain sections. We identified nodes of the proposed default ascending arousal network (dAAN) in the brainstem, hypothalamus, thalamus, and basal forebrain. Deterministic and probabilistic tractography analyses of the ex vivo diffusion MRI data revealed projection, association, and commissural pathways linking dAAN nodes with one another and with DMN nodes. Complementary analyses of in vivo 7-tesla resting-state functional MRI data from the Human Connectome Project identified the dopaminergic ventral tegmental area in the midbrain as a widely connected hub node at the nexus of the subcortical arousal and cortical awareness networks. Our network-based autopsy methods and connectivity data provide a putative neuroanatomic architecture for the integration of arousal and awareness in human consciousness.

Sustaining wakefulness: Brainstem connectivity in human consciousness.

Consciousness is comprised of arousal (i.e., wakefulness) and awareness. Substantial progress has been made in mapping the cortical networks that modulate awareness in the human brain, but knowledge about the subcortical networks that sustain arousal is lacking. We integrated data from ex vivo diffusion MRI, immunohistochemistry, and in vivo 7 Tesla functional MRI to map the connectivity of a subcortical arousal network that we postulate sustains wakefulness in the resting, conscious human brain, analogous to the cortical default mode network (DMN) that is believed to sustain self-awareness. We identified nodes of the proposed default ascending arousal network (dAAN) in the brainstem, hypothalamus, thalamus, and basal forebrain by correlating ex vivo diffusion MRI with immunohistochemistry in three human brain specimens from neurologically normal individuals scanned at 600-750 µm resolution. We performed deterministic and probabilistic tractography analyses of the diffusion MRI data to map dAAN intra-network connections and dAAN-DMN internetwork connections. Using a newly developed network-based autopsy of the human brain that integrates ex vivo MRI and histopathology, we identified projection, association, and commissural pathways linking dAAN nodes with one another and with cortical DMN nodes, providing a structural architecture for the integration of arousal and awareness in human consciousness. We release the ex vivo diffusion MRI data, corresponding immunohistochemistry data, network-based autopsy methods, and a new brainstem dAAN atlas to support efforts to map the connectivity of human consciousness.

[Lay version of the 2018 EULAR recommendations for physical activity in people with inflammatory arthritis and osteoarthritis : Translation into German and linguistic validation in German-speaking countries with people affected]. / Die laienverständliche Version der 2018 EULAR Empfehlungen zu körperlicher Aktivität von Menschen mit entzündlich-rheumatischen und degenerativen Erkrankungen : Übersetzung ins Deutsche und sprachliche Validierung im deutschsprachigen Raum mit Betroffenen.

BACKGROUND: Physical activity and exercise are beneficial for people with rheumatic diseases; however, recommendations for the management of rheumatoid arthritis (RA), spondyloarthritis (SpA) and hip- and knee osteoarthritis (HOA/KOA) are usually unspecific with respect to mode and dose of exercise. This is why the 2018 EULAR recommendations for physical activity in people with inflammatory arthritis and osteoarthritis were formulated. The recommendations consist of 4 overarching principles and 10 recommendations. These were also published as a lay version in the English language. AIM: Translation of the lay version into German and its linguistic validation in Austria, Germany and Switzerland. METHODS: A professional translation was reviewed by the authors, including people with, RA, SpA, HOA/KOA from the three German-speaking countries, which provided a prefinal lay version. Subsequently, eight interviews with people with RA, SpA, HOA/KOA were conducted in each country to evaluate understandability, wording, completeness and feasibility of the prefinal lay version. Finally, the authors, i.e. those with RA, SpA, and osteoarthritis, anonymously rated their agreement to the final lay version on a 0-10 scale. RESULTS: The professional translation was substantially revised by the authors and based on the interviews. Formulations were adapted to increase readability and understandability and specify statements. Comments that would have changed content or structure were not considered. Average agreement with the particular recommendations was between 10 (SD 0) and 7.6 (SD 1.67). DISCUSSION: For people with RA/SpA/HOA/KOA the EULAR physical activity recommendations should be available in their mother language. The final German lay version is valid and accepted across all three German-speaking countries. Thus, the physical activity recommendations can be provided to people with rheumatic diseases in an understandable and feasible way.

The Effect of Preoperative Gender-Affirming Hormone Therapy Use on Perioperative Adverse Events in Transmasculine Individuals Undergoing Masculinizing Chest Surgery for Gender Affirmation.

BACKGROUND: Many providers require cessation of gender-affirming hormone therapy (GAHT) for transgender patients prior to undergoing masculinizing chest surgery (MCS) due to concerns about increased adverse events in the presence of exogenous hormones. Evidence has suggested that continuation of GAHT for certain patients may be safe for gender-affirming procedures. OBJECTIVES: The aim of this study was to compare adverse event rates for GAHT cessation vs GAHT continuation in patients undergoing MCS. METHODS: This multicenter, retrospective study included patients at the Cleveland Clinic and MetroHealth System who underwent MCS between 2016 and 2020. RESULTS: There were 236 patients who met the inclusion criteria. Of these, 172 (72.9%) discontinued testosterone GAHT prior to surgery and 64 (27.1%) continued the therapy. Mean [standard deviation] age at surgery was 25 [8] years, and mean BMI was 29.5 [6.6] kg/m.2 The median duration of testosterone therapy was 18 months (range, 0-300 months). There was no significant difference in tobacco use (P = 0.73), diabetes (P = 0.54), thrombophilia (P = 0.97), or history of thromboembolism (P = 0.39). Most patients underwent the double-incision free nipple graft technique (77.9%). There was no significant difference in surgical time (P = 0.12), intraoperative complications (P = 0.54), or postoperative complications (P = 0.34). The most common complication was postoperative bleeding/hematoma (7.2%). Other complications included seroma (2.1%), infection (1.3%), and nipple graft failure (0.4%). There were no thromboembolic complications. CONCLUSIONS: There is no significant difference in the incidence of perioperative adverse events for patients who continue GAHT preoperatively vs patients who stop GAHT prior to MCS.

Tractography-Pathology Correlations in Traumatic Brain Injury: A TRACK-TBI Study.

Diffusion tractography magnetic resonance imaging (MRI) can infer changes in network connectivity in patients with traumatic brain injury (TBI), but the pathological substrates of disconnected tracts have not been well defined because of a lack of high-resolution imaging with histopathological validation. We developed an ex vivo MRI protocol to analyze tract terminations at 750-µm isotropic resolution, followed by histopathological evaluation of white matter pathology, and applied these methods to a 60-year-old man who died 26 days after TBI. Analysis of 74 cerebral hemispheric white matter regions revealed a heterogeneous distribution of tract disruptions. Associated histopathology identified variable white matter injury with patchy deposition of amyloid precursor protein (APP), loss of neurofilament-positive axonal processes, myelin dissolution, astrogliosis, microgliosis, and perivascular hemosiderin-laden macrophages. Multiple linear regression revealed that tract disruption strongly correlated with the density of APP-positive axonal swellings and neurofilament loss. Ex vivo diffusion MRI can detect tract disruptions in the human brain that reflect axonal injury.

Optimizing the accuracy of cortical volumetric analysis in traumatic brain injury.

Cortical volumetric analysis is widely used to study the anatomic basis of neurological deficits in patients with traumatic brain injury (TBI). However, patients with TBI-related lesions are often excluded from MRI analyses because cortical lesions may compromise the accuracy of reconstructed surfaces upon which volumetric measurements are based. We developed a FreeSurfer-based lesion correction method and tested its impact on cortical volume measures in 87 patients with chronic moderate-to-severe TBI. We reconstructed cortical surfaces from T1-weighted MRI scans, then manually labeled and removed vertices on the cortical surfaces where lesions caused inaccuracies. Next, we measured the surface area of lesion overlap with seven canonical brain networks and the percent volume of each network affected by lesions.•The lesion correction method revealed that cortical lesions in patients with TBI are preferentially located in the limbic and default mode networks (95.7% each), with the limbic network also having the largest average surface area (4.4+/-3.7%) and percent volume affected by lesions (12.7+/-9.7%).•The method has the potential to improve the accuracy of cortical volumetric measurements and permit inclusion of patients with lesioned brains in MRI analyses.•The method also provides new opportunities to elucidate network-based mechanisms of neurological deficits in patients with TBI.

Gut T cell-independent IgA responses to commensal bacteria require engagement of the TACI receptor on B cells.

The gut mounts secretory immunoglobulin A (SIgA) responses to commensal bacteria through nonredundant T cell-dependent (TD) and T cell-independent (TI) pathways that promote the establishment of mutualistic host-microbiota interactions. SIgAs from the TD pathway target penetrant bacteria, and their induction requires engagement of CD40 on B cells by CD40 ligand on T follicular helper cells. In contrast, SIgAs from the TI pathway bind a larger spectrum of bacteria, but the mechanism underpinning their production remains elusive. Here, we show that the intestinal TI pathway required CD40-independent B cell-activating signals from TACI, a receptor for the innate CD40 ligand-like factors BAFF and APRIL. TACI-induced SIgA responses targeted a fraction of the gut microbiota without shaping its overall composition. Of note, TACI was dispensable for TD induction of IgA in gut-associated lymphoid organs. Thus, BAFF/APRIL signals acting on TACI orchestrate commensal bacteria-specific SIgA responses through an intestinal TI program.

The Muscle-Sparing Descending Branch Latissimus Dorsi Free Flap for Lower Extremity Reconstruction.

BACKGROUND: The muscle-sparing descending branch latissimus dorsi muscle (MSLD) flap is a versatile flap with numerous benefits. It is an often overlooked but useful option when considering free flap donors. In this article, the authors present the largest experience with the MSLD flap, with focus on its use in lower extremity reconstruction. METHODS: Patients undergoing lower extremity reconstruction with the MSLD flap at a single institution from 2012 to 2017 were identified. Patient and wound characteristics, surgical details, complications, and outcomes were examined. Outcomes were compared to a cohort who underwent lower extremity reconstruction with other free muscle flaps during the same period. RESULTS: Thirty-six consecutive patients who underwent MSLD flap surgery were identified. Mean follow-up was 18.8 months. Mean body mass index was 29.2 kg/m and 56 percent were smokers. The most common wound causes were motor vehicle collision (46 percent) and fall (22 percent). The most common anatomical location was the distal third of the tibia (33 percent). Mean operative time was 380 minutes. Complications included three total losses (8 percent) and one partial loss (3 percent). No donor-site seromas were reported. Four patients required subsequent amputation for orthopedic issues (nonunion/pain). Patients receiving MSLD and other flaps had similar rates of amputation, donor- and recipient-site complications, and ambulation status (p > 0.05). CONCLUSIONS: The MSLD flap is a useful and reliable option for free flap reconstruction of the lower extremity. Advantages include an easily contourable flap, low revision rate, low complication rate, and the ability to harvest in supine position. In addition, the MSLD flap preserves donor function useful for rehabilitation and minimizes seroma risk. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

7 Tesla MRI of the ex vivo human brain at 100 micron resolution.

We present an ultra-high resolution MRI dataset of an ex vivo human brain specimen. The brain specimen was donated by a 58-year-old woman who had no history of neurological disease and died of non-neurological causes. After fixation in 10% formalin, the specimen was imaged on a 7 Tesla MRI scanner at 100 µm isotropic resolution using a custom-built 31-channel receive array coil. Single-echo multi-flip Fast Low-Angle SHot (FLASH) data were acquired over 100 hours of scan time (25 hours per flip angle), allowing derivation of synthesized FLASH volumes. This dataset provides an unprecedented view of the three-dimensional neuroanatomy of the human brain. To optimize the utility of this resource, we warped the dataset into standard stereotactic space. We now distribute the dataset in both native space and stereotactic space to the academic community via multiple platforms. We envision that this dataset will have a broad range of investigational, educational, and clinical applications that will advance understanding of human brain anatomy in health and disease.

Precision of aiming with a portable X-ray device (Nomad Pro 2) compared to a wall-mounted device in intraoral radiography.

METHODS AND MATERIALS: 20 operators obtained intraoral radiographs of four regions (bitewing, upper molar, lower molar and upper anterior) in five mannequins, using HH and WM devices. Beam-aiming devices were fitted with metal cross-wires to project on image sensors. Deviation from ideal perpendicular incidence of beam was calculated, based on positions of cross-wires relative to gold-standard positions (i.e. average of 10-fold precise aiming by authors via WM system). Analytic models relied on Wilcoxon signed-rank test and mixed model analyses. RESULTS: Mean deviations from perfect aim were 2.88˚ (± 1.80˚) for WM and 3.06˚ (± 1.90˚) for HH methods. The difference among all operators (HH vs WM) was 0.17˚ (± 2.48˚), which was not significant. Seven operators showed better aim by HH device (13 by WM system); and in one instance, this difference was significant. CONCLUSIONS: Aiming precision proved similar for HH and WM methods of intraoral radiography, although individual operators may perform better using one of these modalities. Aim is not an expected limiting factor for image quality in HH (vs WM) diagnostics.

Hexapod Stacked Transport for Tibial Infected Nonunions With Bone Loss: Long-Term Functional Outcomes.

OBJECTIVES: To analyze long-term functional outcomes in patients with posttraumatic infected tibial nonunions having undergone bone transport with hexapod external fixator. DESIGN: Retrospective cohort study. SETTING: Level 1 trauma center. PATIENTS/PARTICIPANTS: Thirty-eight patients with infected nonunions of the tibia. INTERVENTION: Resection of nonunion with application of stacked hexapod external fixator for bone transport. MAIN OUTCOME MEASUREMENTS: Functional outcome was measured using the short Musculoskeletal Functional Assessment (sMFA). Parameters measured included age, sex, presence of diabetes, smoking, use of a free flap, bone defect size, length in frame, external fixation index, and direction of lengthening. RESULTS: The mean sMFA score for the entire group was 27.1. Average patient age was 46.8 ± 12.7 years, 74% patients were male, 8% were diabetic, and 29% were smokers. Seventeen patients had soft-tissue defects that required a free flap. Smokers had higher degrees of disability compared with nonsmokers (39 ± 16 vs. 22 ± 14, P = 0.011). Patients requiring adjunctive stabilization had worse functional scores compared with those who did not receive adjunctive stabilization (33 ± 17 vs. 22 ± 15, P = 0.049). Sixteen patients returned 2 sMFA surveys at different time points after completion of bone transport. Initial average sMFA score was 26.5 at a mean of 25.3 months; subsequent sMFA scores averaged 19.4 at a mean of 98.8 months. CONCLUSIONS: Stacked hexapod external fixator bone transport is a reliable technique for infected nonunion of the tibia with bone loss. Improved sMFA scores can be expected from 2 to 8 years, suggesting full recovery takes longer than previously anticipated. Limb salvage with hexapod bone transport is justified over time. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Bipedicle Flaps for Posterior Elbow Reconstruction.

Chronic posterior elbow soft tissue defects often require soft tissue reconstruction because of exposure of the underlying triceps tendon and proximal ulna. Current options for soft tissue coverage require sacrifice of a local muscle or microsurgery. The purpose of this study is to evaluate patient and surgical outcomes after reconstruction of small-sized to medium-sized (<50 cm) posterior elbow defects with bipedicle advancement flaps. A retrospective chart review was performed for 3 patients who underwent posterior elbow reconstruction with bipedicle flaps. The etiology of the soft tissue elbow defect was chronic infected olecranon bursitis (n=2) and exposed olecranon plate after open fracture (n=1). Patient comorbidities included: diabetes, CREST (Calcinosis, Raynaud phenomenon, Esophageal dysmotility, Sclerodactyly, Telangiectasia) syndrome, and rheumatoid arthritis. The mean patient age at time of reconstruction was 44 years (39 to 51 y), and the mean area of soft tissue defect was 39.3 cm (24 to 54 cm) after debridement of involved tissue. All patients had positive intraoperative cultures and were treated with culture-directed long-term intravenous antibiotics. There were no surgical complications or flap loss. All patients had reepithelialization of the donor site by postoperative week 8 and stable soft tissue coverage of the elbow after surgery at final follow-up with full preoperative elbow range of motion. This technique offers a simple, reliable solution for soft tissue coverage of the posterior elbow using excess local tissue for primary closure of posterior elbow wounds with minimal donor-site morbidity.

Hexapod Frame Stacked Transport for Tibial Infected Nonunions With Bone Loss: Analysis of Use of Adjunctive Stability.

OBJECTIVES: The stacked hexapod bone transport technique is an effective treatment for infected tibial nonunions with bone loss. The purpose of this study was to evaluate the patients' risk factors and timing for requiring adjunctive stabilization. DESIGN: Retrospective cohort study. SETTING: Level 1 trauma center. PATIENTS/PARTICIPANTS: Seventy-five patients with infected posttraumatic nonunions of the tibia. INTERVENTION: Resection of nonunion with application of stacked hexapod frame for bone transport. MAIN OUTCOME MEASUREMENTS: Parameters measured included age, sex, diabetes, smoking, use of a free flap, bone defect size, length in frame, external fixation index, and direction of lengthening. Outcomes recorded: removal of frame, below knee amputation, or adjunctive stability. Further analysis evaluated location of nonunion, timing of adjunctive stabilization, and type of fixation. RESULTS: The average patient age was 45.7 ± 12.5 years, 76% patients were men, 11% were diabetic, and 44% were smokers. Forty two percent had soft tissue defects that required a free flap. Thirty-eight patients had removal of frame, whereas 36 patients required adjunctive stability of the hexapod frame. Patient receiving adjunctive stabilization had a longer length of time in the hexapod frame (P = 0.026) and were more likely to require a free flap (P = 0.053). Ninety-three percent docking site nonunions occurred after the removal of the frame (P = 0.032); whereas 79% regenerate nonunions occurred before the hexapod frame was removed (P = 0.029). CONCLUSIONS: The use of a hexapod frame for the infected tibial nonunions with bone loss is an effective method for achieving union and eradicating infection in a difficult orthopaedic patient population. Use of adjunctive stabilization is a reasonable technique to address delayed regenerate and docking site nonunions. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Prime-boost using separate oncolytic viruses in combination with checkpoint blockade improves anti-tumour therapy.

The anti-tumour effects associated with oncolytic virus therapy are mediated significantly through immune-mediated mechanisms, which depend both on the type of virus and the route of delivery. Here, we show that intra-tumoral oncolysis by Reovirus induced the priming of a CD8+, Th1-type anti-tumour response. By contrast, systemically delivered Vesicular Stomatitis Virus expressing a cDNA library of melanoma antigens (VSV-ASMEL) promoted a potent anti-tumour CD4+ Th17 response. Therefore, we hypothesised that combining the Reovirus-induced CD8+ T cell response, with the VSV-ASMEL CD4+ Th17 helper response, would produce enhanced anti-tumour activity. Consistent with this, priming with intra-tumoral Reovirus, followed by an intra-venous VSV-ASMEL Th17 boost, significantly improved survival of mice bearing established subcutaneous B16 melanoma tumours. We also show that combination of either therapy alone with anti-PD-1 immune checkpoint blockade augmented both the Th1 response induced by systemically delivered Reovirus in combination with GM-CSF, and also the Th17 response induced by VSV-ASMEL. Significantly, anti-PD-1 also uncovered an anti-tumour Th1 response following VSV-ASMEL treatment that was not seen in the absence of checkpoint blockade. Finally, the combination of all three treatments (priming with systemically delivered Reovirus, followed by double boosting with systemic VSV-ASMEL and anti-PD-1) significantly enhanced survival, with long-term cures, compared to any individual, or double, combination therapies, associated with strong Th1 and Th17 responses to tumour antigens. Our data show that it is possible to generate fully systemic, highly effective anti-tumour immunovirotherapy by combining oncolytic viruses, along with immune checkpoint blockade, to induce complementary mechanisms of anti-tumour immune responses.

Effect of Clostridium botulinum toxin type A injections into the deep digital flexor muscle on the range of motion of the metacarpus and carpus, and the force distribution underneath the hooves, of sound horses at the walk.

In the treatment of laminitis, reducing deep digital flexor muscle (DDFM) activity might diminish its pull on the distal phalanx, thereby preventing displacement and providing pain relief. Injection of Clostridium botulinum toxin type A into the DDFM of horses is potentially therapeutic. However, the effects of C. botulinum toxin type A on the gait characteristics of sound horses at the walk are not known. The aim of this study was to test if a reduced DDFM activity would lead to (1) alterations of the sagittal range of motion of the metacarpus (SROM) and range of motion of the carpal joint (CROM); (2) changes in the force distribution underneath the hoof (toe vs. heel region: balance index); and (3) changes in the force distribution between the treated and untreated limb (symmetry index). The DDFMs of the left forelimbs of seven sound Royal Dutch Sport Horses were injected with 200 IU C. botulinum toxin type A using electromyography and ultrasound guidance. Measurements using an inertial sensor system and dynamically calibrated pressure plate were performed before and after injections. The SROM and CROM of the treated limb were significantly increased after C. botulinum toxin type A injections. No significant changes were detected in the balance index or in the symmetry index, indicating that no lameness was induced. C. botulinum toxin type A injections into the DDFM of sound horses do not appear to result in substantial gait alterations at the walk.

The effect of Clostridium botulinum toxin type A injections on motor unit activity of the deep digital flexor muscle in healthy sound Royal Dutch sport horses.

Therapeutic reduction of the activity of the deep digital flexor (DDF) muscle may play a role in treatment of laminitic horses. Clostridium botulinum toxin type A induces reduced muscle activity and has a spasmolytic effect in horses. In this study, the effectiveness of 200 IU C. botulinum toxin type A on reduction of DDF muscle activity was measured in seven healthy, sound, adult Royal Dutch sport horses. C. botulinum toxin type A was injected using ultrasound and electromyographic (EMG) guidance. The effectiveness was assessed by interference pattern analysis (IPA) and motor unit action potential (MUAP) analysis. All needle EMG MUAP variables, along with IPA amplitude/turn and turns/s, were significantly reduced after C. botulinum toxin type A injections. The strongest effect occurred within the first 3 days after injection. The reduced muscle induced by C. botulinum toxin type A may have benefits in the treatment of horses with laminitis.

Free tissue transfer with distraction osteogenesis is effective for limb salvage of the infected traumatized lower extremity.

BACKGROUND: Salvage of acute and chronic tibial osseocutaneous defects in the lower extremity poses a formidable problem. Although local, distant, and free tissue transfer or bone grafting alone may be adequate for repair of small wounds or osseous defects, large or complicated defects necessitate a different approach. The authors describe their experience with free tissue transfer in combination with distraction osteogenesis for complex composite osteocutaneous defects. METHODS: The authors reviewed a consecutive series of 28 patients who underwent treatment over an 8-year period, with follow-up ranging from 1 to 8.5 years. Mean time to flap after injury was 1082 days (range, 6 days to 30 years). Indications for treatment included infected nonunion of the tibia (n = 18), acute traumatic bone loss (n = 5), skin and soft-tissue breakdown that occurred during distraction osteogenesis (n = 4), and exposed bone following previous failed free flap (n = 1). RESULTS: Free flaps used included the rectus abdominis (n = 17), latissimus dorsi (n = 5), gracilis (n = 5), and radial forearm (n = 1). Mean length of bone gap was 63 mm (range, 30 to 140 mm), and mean area of wound requiring flap coverage was 219 cm (range, 35 to 400 cm). Twenty-five patients (89.3 percent) had successful flap coverage and went on to ambulate independently and return to work. The minor complication rate was 42.9 percent. CONCLUSIONS: Distraction osteogenesis in combination with free tissue transfer is a powerful technique that allows limb salvage, particularly when local and regional flaps are unavailable or inadequate. For infected nonunion of the tibia, it permits a staged approach that allows underlying osteomyelitis to declare itself and provides vascularized healthy soft-tissue coverage that facilitates repeated operations for the purpose of distraction.

[Clinical and urodynamic repercussions after treatment of female stress incontinence with transobturator suburethral tape]. / Répercussions cliniques et urodynamiques du traitement de l'incontinence urinaire d'effort par bandelettes sous-urétrales transobturatrice.

AIMS: Analyse changes in voiding patterns after the treatment of female urodynamic stress incontinence (USI) with suburethral transobturator tape (TOT). PATIENTS AND METHODS: Prospective study of 50 women with pure stress urinary incontinence treated between March 2004 and February 2006; mean age was 53+/-13 (34-87); parity was 2+/-0.75; mean follow-up was of 15 months (7-43). Each patient did a complete urodynamic examination and filled in two questionnaires (MHU and Contilife), before and three months after surgery. RESULTS: Cure rate was 94% (47/50). Three of 50 patients remained incontinent after surgery (6%). No peroperative complications occurred. Analysis of questionnaires showed that two clinical symptoms predominated postoperatively: dysuria (14%; n=7) and urgency (6%; n=3). Urodynamic profiles showed the following: a decrease in maximum flow rate from 23.6 to 18.9 ml/s (p<0.01), and an increase in urethral resistance from 0.12 to 0.23 (p<0.01). The number of patients with at least two Massey Abrams criteria defining obstruction rose from six to 19, while only seven patients had symptomatic dysuria. Quality of life improved significantly, from 2.32 to 4.63 (p<0.05). CONCLUSIONS: TOT is a safe, effective procedure with few complications. While urodynamic data show some obstruction, this has little impact upon clinical results or mid-term complications; it only mildly affects voiding and does not compromise patient satisfaction.

CAML regulates Bim-dependent thymocyte death.

Appropriate control of apoptosis during T lymphocyte differentiation is critical for destruction of T cells bearing potentially autoreactive or useless immuno-receptors and for survival of those T cells bearing antigen receptors that may recognize foreign proteins. Despite the well-established importance of thymocyte survival, the exact signals regulating thymocyte apoptosis have not been fully elucidated. Here, we show that thymocytes lacking the endoplasmic reticulum protein calcium-modulating cyclophilin ligand (CAML) failed to undergo normal T-cell development and exhibited dramatically increased rates of apoptosis. In vitro, CAML-deficient thymocytes accumulated high levels of reactive oxygen species (ROS) and underwent abnormally accelerated death in response to several cytotoxic stimuli, including treatment with etoposide, cytokine deprivation, or Fas ligation. Although neither p53 deletion nor loss of Fas rescued the survival and continued development of CAML-deficient thymocytes, removal of the pro-apoptotic BH3-only Bcl-2 family member Bim significantly restored their survival. This work reveals CAML to be a critically important regulator of ROS- and Bim-dependent thymocyte death.