Case Report: Plasticity in Central Sensory Finger Representation and Touch Perception After Microsurgical Reconstruction of Infraclavicular Brachial Plexus Injury

After brachial plexus injury (BPI), early microsurgery aims at facilitating reconnection of the severed peripheral nerves with their orphan muscles and sensory receptors and thereby reestablishing communication with the brain. In order to investigate this sensory recovery, here we combined functional magnetic resonance imaging (fMRI) and tactile psychophysics in a patient who suffered a sharp, incomplete amputation of the dominant hand at the axilla level. To determine somatosensory detection and discomfort thresholds as well as sensory accuracy for fingers of both the intact and affected hand, we used electrotactile stimulation in the framework of a mislocalization test. Additionally, tactile stimulation was performed in the MRI scanner in order to determine the cortical organization of the possibly affected primary somatosensory cortex. The patient was able to detect electrotactile stimulation in 4 of the 5 fingertips (D1, D2, D4, D5), and in the middle phalanx in D3 indicating some innervation. The detection and discomfort threshold were considerably higher at the affected side than at the intact side, with higher detection and discomfort thresholds for the affected side. The discrimination accuracy was rather low at the affected side, with stimulation of D1/D2/D3/D4/D5 eliciting most commonly a sensation at D4/D1/D3/D2/D5, respectively. The neuroimaging data showed a mediolateral succession from D2 to D5 to D1 to D4 (no activation was observed for D3). These results indicate a successful regrowth of the peripheral nerve fibers from the axilla to four fingertips. The data suggest that some of the fibers have switched location in the process and there is a beginning of cortical reorganization in the primary somatosensory cortex, possibly resulting from a re-education of the brain due to conflicting information (touch vs. vision)

A distinct M2 macrophage infiltrate and transcriptomic profile decisively influence adipocyte differentiation in lipedema

Lipedema is a chronic and progressive adipose tissue disorder, characterized by the painful and disproportionate increase of the subcutaneous fat in the lower and/or upper extremities. While distinct immune cell infiltration is a known hallmark of the disease, its role in the onset and development of lipedema remains unclear. To analyze the macrophage composition and involved signaling pathways, anatomically matched lipedema and control tissue samples were collected intra-operatively from gender- and BMI-matched patients, and the Stromal Vascular Fraction (SVF) was used for Cytometry by Time-of-Flight (CyTOF) and RNA sequencing. The phenotypic characterization of the immune component of lipedema versus control SVF using CyTOF revealed significantly increased numbers of CD163 macrophages. To gain further insight into this macrophage composition and molecular pathways, RNA sequencing of isolated CD11b+ cells was performed. The analysis suggested a significant modification of distinct gene ontology clusters in lipedema, including cytokine-mediated signaling activity, interleukin-1 receptor activity, extracellular matrix organization, and regulation of androgen receptor signaling. As distinct macrophage populations are known to affect adipose tissue differentiation and metabolism, we evaluated the effect of M2 to M1 macrophage polarization in lipedema using the selective PI3Kγ inhibitor IPI-549. Surprisingly, the differentiation of adipose tissue-derived stem cells with conditioned medium from IPI-549 treated SVF resulted in a significant decreased accumulation of lipids in lipedema versus control SVF. In conclusion, our results indicate that CD163+ macrophages are a critical component in lipedema and re-polarization of lipedema macrophages can normalize the differentiation of adipose-derived stem cells in vitro evaluated by the cellular lipid accumulation. These data open a new chapter in understanding lipedema pathophysiology and may indicate potential treatment options

A Distinct Cytokine Profile and Stromal Vascular Fraction Metabolic Status without Significant Changes in the Lipid Composition Characterizes Lipedema.

Lipedema is an adipose tissue disorder characterized by the disproportionate increase of subcutaneous fat tissue in the lower and/or upper extremities. The underlying pathomechanism remains unclear and no molecular biomarkers to distinguish the disease exist, leading to a large number of undiagnosed and misdiagnosed patients. To unravel the distinct molecular characteristic of lipedema we performed lipidomic analysis of the adipose tissue and serum of lipedema versus anatomically- and body mass index (BMI)-matched control patients. Both tissue groups showed no significant changes regarding lipid composition. As hyperplastic adipose tissue represents low-grade inflammation, the potential systemic effects on circulating cytokines were evaluated in lipedema and control patients using the Multiplex immunoassay system. Interestingly, increased systemic levels of interleukin 11 (p = 0.03), interleukin 28A (p = 0.04) and interleukin 29 (p = 0.04) were observed. As cytokines can influence metabolic activity, the metabolic phenotype of the stromal vascular fraction was examined, revealing significantly increased mitochondrial respiration in lipedema. In conclusion, despite sharing a comparable lipid profile with healthy adipose tissue, lipedema is characterized by a distinct systemic cytokine profile and metabolic activity of the stromal vascular fraction

Surgical defect reconstructions in knee, lower leg, and foot with flaps: a retrospective analysis

<jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>The first description of local fascio-cutaneous flaps used for the coverage of soft tissue defects of the limbs originates from the 1980s. Over the years, this technique has advanced, and in the meantime, a sub-group of flaps named <jats:italic>perforator-based propeller flaps</jats:italic> has gained increased attention. In our study, we aimed to demonstrate our experience of operating surgeries with <jats:italic>perforator-based propeller flaps</jats:italic> and to compare this technique with other flap techniques, which are to reconstruct tissue defects of the knee, lower leg, and foot.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p> A systematic retrospective search for flap procedures for defect reconstructions in the knee, lower leg, and foot from our database was performed. All data between January 2010 and August 2018 were considered. We identified 56 procedures performed on 14 female and 42 male patients with the mean age of 54.13 years. Reconstruction procedures consisted of 34 <jats:italic>free flaps</jats:italic>, 14 <jats:italic>perforator-based propeller flaps</jats:italic>, and eight <jats:italic>other perforator-based flaps</jats:italic>. Compared to <jats:italic>free flaps</jats:italic>, the <jats:italic>perforator-based propeller flaps</jats:italic> had shorter surgery duration by 46.6% (<jats:italic>p</jats:italic> < 0.0001) and the complication rate in the cases of <jats:italic>perforator-based propeller flaps</jats:italic> was reduced by 31.14% (<jats:italic>p</jats:italic> = 0.0315). Furthermore, the operations carried out with <jats:italic>perforator-based propeller flaps</jats:italic> resulted in a significantly lower rate of revisions by 36.03% (<jats:italic>p</jats:italic> = 0.0204), compared to those with <jats:italic>free flaps</jats:italic>. The majority of the donor sites of <jats:italic>free flaps</jats:italic> were self-closing with the direct suture (<jats:italic>p</jats:italic> = 0.004).</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p> Based on our findings, we can propose the applicability of <jats:italic>perforator-based flaps</jats:italic> in treating defects of the knee, lower leg, and foot. With a correct indication, <jats:italic>perforator-based propeller flap</jats:italic> represents a promising alternative to <jats:italic>free flaps</jats:italic>, with its significantly shorter surgery duration, lower complications rate, and lower revision rate. However, both techniques of the free flap transfer and the transfer of local pedicle-based flap possess their advantages and disadvantages. Therefore, it is hard to define which microsurgical technique is exclusive in treating lower leg defects.</jats:p> <jats:p>Level of evidence: Level IV, therapeutic study.</jats:p> </jats:sec&gt

Adipose tissue hypertrophy, an aberrant biochemical profile and distinct gene expression in lipedema.

BACKGROUND: Lipedema is a common adipose tissue disorder affecting women, characterized by a symmetric subcutaneous adipose tissue deposition, particularly of the lower extremities. Lipedema is usually underdiagnosed, thus remaining an undertreated disease. Importantly, no histopathologic or molecular hallmarks exist to clearly diagnose the disease, which is often misinterpreted as obesity or lymphedema. MATERIALS AND METHODS: The aim of the present study is to characterize in detail morphologic and molecular alterations in the adipose tissue composition of lipedema patients compared with healthy controls. Detailed histopathologic and molecular characterization was performed using lipid and cytokine quantification as well as gene expression arrays. The analysis was conducted on anatomically matched skin and fat tissue biopsies as well as fasting serum probes obtained from 10 lipedema and 11 gender and body mass index-matched control patients. RESULTS: Histologic evaluation of the adipose tissue showed increased intercellular fibrosis and adipocyte hypertrophy. Serum analysis showed an aberrant lipid metabolism without changes in the circulating adipokines. In an adipogenesis gene array, a distinct gene expression profile associated with macrophages was observed. Histologic assessment of the immune cell infiltrate confirmed the increased presence of macrophages, without changes in the T-cell compartment. CONCLUSIONS: Lipedema presents a distinguishable disease with typical tissue architecture and aberrant lipid metabolism, different to obesity or lymphedema. The differentially expressed genes and immune cell infiltration profile in lipedema patients further support these findings

A Distinct Cytokine Profile and Stromal Vascular Fraction Metabolic Status without Significant Changes in the Lipid Composition Characterizes Lipedema

Lipedema is an adipose tissue disorder characterized by the disproportionate increase of subcutaneous fat tissue in the lower and/or upper extremities. The underlying pathomechanism remains unclear and no molecular biomarkers to distinguish the disease exist, leading to a large number of undiagnosed and misdiagnosed patients. To unravel the distinct molecular characteristic of lipedema we performed lipidomic analysis of the adipose tissue and serum of lipedema versus anatomically- and body mass index (BMI)-matched control patients. Both tissue groups showed no significant changes regarding lipid composition. As hyperplastic adipose tissue represents low-grade inflammation, the potential systemic effects on circulating cytokines were evaluated in lipedema and control patients using the Multiplex immunoassay system. Interestingly, increased systemic levels of interleukin 11 (p = 0.03), interleukin 28A (p = 0.04) and interleukin 29 (p = 0.04) were observed. As cytokines can influence metabolic activity, the metabolic phenotype of the stromal vascular fraction was examined, revealing significantly increased mitochondrial respiration in lipedema. In conclusion, despite sharing a comparable lipid profile with healthy adipose tissue, lipedema is characterized by a distinct systemic cytokine profile and metabolic activity of the stromal vascular fraction

Increased levels of VEGF-C and macrophage infiltration in lipedema patients without changes in lymphatic vascular morphology

Lipedema is a chronic adipose tissue disorder characterized by the disproportional subcutaneous deposition of fat and is commonly misdiagnosed as lymphedema or obesity. The molecular determinants of the lipedema remain largely unknown and only speculations exist regarding the lymphatic system involvement. The aim of the present study is to characterize the lymphatic vascular involvement in established lipedema. The histological and molecular characterization was conducted on anatomically-matched skin and fat biopsies as well as serum samples from eleven lipedema and ten BMI-matched healthy patients. Increased systemic levels of vascular endothelial growth factor (VEGF)-C (P = 0.02) were identified in the serum of lipedema patients. Surprisingly, despite the increased VEGF-C levels no morphological changes of the lymphatic vessels were observed. Importantly, expression analysis of lymphatic and blood vessel-related genes revealed a marked downregulation of Tie2 (P < 0.0001) and FLT4 (VEGFR-3) (P = 0.02) consistent with an increased macrophage infiltration (P = 0.009), without changes in the expression of other lymphatic markers. Interestingly, a distinct local cytokine milieu, with decreased VEGF-A (P = 0.04) and VEGF-D (P = 0.02) expression was identified. No apparent lymphatic anomaly underlies lipedema, providing evidence for the different disease nature in comparison to lymphedema. The changes in the lymphatic-related cytokine milieu might be related to a modified vascular permeability developed secondarily to lipedema progression

Case report: plasticity in central sensory finger representation and touch perception after microsurgical reconstruction of infraclavicular brachial plexus injury

After brachial plexus injury (BPI), early microsurgery aims at facilitating reconnection of the severed peripheral nerves with their orphan muscles and sensory receptors and thereby reestablishing communication with the brain. In order to investigate this sensory recovery, here we combined functional magnetic resonance imaging (fMRI) and tactile psychophysics in a patient who suffered a sharp, incomplete amputation of the dominant hand at the axilla level. To determine somatosensory detection and discomfort thresholds as well as sensory accuracy for fingers of both the intact and affected hand, we used electrotactile stimulation in the framework of a mislocalization test. Additionally, tactile stimulation was performed in the MRI scanner in order to determine the cortical organization of the possibly affected primary somatosensory cortex. The patient was able to detect electrotactile stimulation in 4 of the 5 fingertips (D1, D2, D4, D5), and in the middle phalanx in D3 indicating some innervation. The detection and discomfort threshold were considerably higher at the affected side than at the intact side, with higher detection and discomfort thresholds for the affected side. The discrimination accuracy was rather low at the affected side, with stimulation of D1/D2/D3/D4/D5 eliciting most commonly a sensation at D4/D1/D3/D2/D5, respectively. The neuroimaging data showed a mediolateral succession from D2 to D5 to D1 to D4 (no activation was observed for D3). These results indicate a successful regrowth of the peripheral nerve fibers from the axilla to four fingertips. The data suggest that some of the fibers have switched location in the process and there is a beginning of cortical reorganization in the primary somatosensory cortex, possibly resulting from a re-education of the brain due to conflicting information (touch vs. vision).PeerReviewe

Can Early Post-Operative Scoring of Non-Traumatic Amputees Decrease Rates of Revision Surgery?

Background and Objectives: Medical registries evolved from a basic epidemiological data set to further applications allowing deriving decision making. Revision rates after non-traumatic amputation are high and dramatically impact the following rehabilitation of the amputee. Risk scores for revision surgery after non-traumatic lower limb amputation are still missing. The main objective was to create an amputation registry allowing us to determine risk factors for revision surgery after non-traumatic lower-limb amputation and to develop a score for an early detection and decision-making tool for the therapeutic course of patients at risk for non-traumatic lower limb amputation and/or revision surgery. Materials and Methods: Retrospective data analysis was of patients with major amputations lower limbs in a four-year interval at a University Hospital of maximum care. Medical records of 164 patients analysed demographics, comorbidities, and amputation-related factors. Descriptive statistics analysed demographics, prevalence of amputation level and comorbidities of non-traumatic lower limb amputees with and without revision surgery. Correlation analysis identified parameters determining revision surgery. Results: In 4 years, 199 major amputations were performed; 88% were amputated for non-traumatic reasons. A total of 27% of the non-traumatic cohort needed revision surgery. Peripheral vascular disease (PVD) (72%), atherosclerosis (69%), diabetes (42%), arterial hypertension (38%), overweight (BMI > 25), initial gangrene (47%), sepsis (19%), age > 68.2 years and nicotine abuse (17%) were set as relevant within this study and given a non-traumatic amputation score. Correlation analysis revealed delayed wound healing (confidence interval: 64.1% (47.18%; 78.8%)), a hospital length of stay before amputation of longer than 32 days (confidence interval: 32.3 (23.2; 41.3)), and a BKA amputation level (confidence interval: 74.4% (58%; 87%)) as risk factors for revision surgery after non-traumatic amputation. A combined score including all parameters was drafted to identify non-traumatic amputees at risk for revision surgery. Conclusions: Our results describe novel scoring systems for risk assessment for non-traumatic amputations and for revision surgery at non-traumatic amputations. It may be used after further prospective evaluation as an early-warning system for amputated limbs at risk of revision

A Comparative Analysis to Dissect the Histological and Molecular Differences among Lipedema, Lipohypertrophy and Secondary Lymphedema

Lipedema, lipohypertrophy and secondary lymphedema are three conditions characterized by disproportionate subcutaneous fat accumulation affecting the extremities. Despite the apparent similarities and differences among their phenotypes, a comprehensive histological and molecular comparison does not yet exist, supporting the idea that there is an insufficient understanding of the conditions and particularly of lipohypertrophy. In our study, we performed histological and molecular analysis in anatomically-, BMI- and gender-matched samples of lipedema, lipohypertrophy and secondary lymphedema versus healthy control patients. Hereby, we found a significantly increased epidermal thickness only in patients with lipedema and secondary lymphedema, while significant adipocyte hypertrophy was identified in both lipedema and lipohypertrophy. Interestingly, the assessment of lymphatic vessel morphology showed significantly decreased total area coverage in lipohypertrophy versus the other conditions, while VEGF-D expression was significantly decreased across all conditions. The analysis of junctional genes often associated with permeability indicated a distinct and higher expression only in secondary lymphedema. Finally, the evaluation of the immune cell infiltrate verified the increased CD4+ cell and macrophage infiltration in lymphedema and lipedema respectively, without depicting a distinct immune cell profile in lipohypertrophy. Our study describes the distinct histological and molecular characteristics of lipohypertrophy, clearly distinguishing it from its two most important differential diagnoses