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Within the subcutaneous adipose tissue diseases, multiple symmetric lipomatosis (MSL) (syn.: Launois Bensaude Syndrome, Morbus Madelung, benign symmetric lipomatosis) is rare. The pathogenesis of MSL remains unclear. We investigated the largest German cohort of MSL patients to obtain anamnestic data and quality of life with a standard questionnaire. Twenty-nine patients with confirmed MSL were included and filled in a questionnaire designed for this study. The questionnaire assessed common anamnestic factors, such as quality of life (EQ-5D-3L) and subjective treatment goals and success (“Patient-Benefit-Index-Lymphedema”, PBI-L). The gender distribution of the patients involved in the study was m/f: 1/4 (male: n = 6 (21%); female n = 23 (79%)). While the exact pathophysiology of MSL remains unclear, a subset of patients’ positive family history suggests a strong genetic factor, sometimes compatible with autosomal dominant inheritance. Patients with MSL showed lower health states (EQ VAS Score: m = 51, sd = 24, range = 0–90) than the German norm population (m = 77). Around two thirds (68%) of patients reported relevant benefits of therapy (liposuction/lipectomy). In our cohort about one third of the patients reported a positive family history for MSL-like features. Additionally, at least in some patients, a strong genetic factor, compatible with autosomal dominant inheritance, seems a possible major driver of MSL development. Alcohol consumption and MSL development has to be regarded as a controversial issue. Patients suffering from MSL have a clear decrease in quality of life and a marked wish for treatment.

(1) Background: Lipoedema is a disease characterized by excessive bilateral and symmetrical accumulation of subcutaneous tissue in the lower extremities. It is a poorly understood condition, and low awareness of its existence often leads to incorrect diagnosis Initially, lipoedema was considered to be completely independent of lifestyle Currently, however, more and more cases of the coexistence of lipoedema and obesity are described in the literature as additionally affecting the severity of the disease The aim of the review is to present lipoedema as a social problem. (2) Methods: Materials on lipoedema in the social context were selected from 2018-2021. The PRISMA-Scr checklist was used in the review. (3) Results: Research has shown that more than 3/4 of patients with lipoedema are also overweight or obese. Patients with lipoedema have many comorbidities, and their presence negatively affects the quality of life. The quality of life in patients with lipoedema is lower than in healthy patients. (4) Conclusions: The number of studies available on lipoedema is low. Obesity is common in patients with lipoedema. Mental disorders increase the level of experienced pain. Lipoedema significantly reduces quality of life. A healthy lifestyle in patients with lipoedema could be helpful for prevention of complications and disability.

Whole-body three-dimensional surface imaging (3DSI) offers the ability to monitor morphologic changes in multiple areas without the need to individually scan every anatomical region of interest. One area of application is the digital quantification of leg volume. Certain types of morphology do not permit complete circumferential scan of the leg surface. A workflow capable of precisely estimating the missing data is therefore required. We thus aimed to describe and apply a novel workflow to collect bilateral leg volume measurements from whole-body 3D surface scans regardless of leg morphology and to assess workflow precision. For each study participant, whole-body 3DSI was conducted twice successively in a single session with subject repositioning between scans. Paired samples of bilateral leg volume were calculated from the 3D surface data, with workflow variations for complete and limited leg surface visibility. Workflow precision was assessed by calculating the relative percent differences between repeated leg volumes. A total of 82 subjects were included in this study. The mean relative differences between paired left and right leg volumes were 0.73 ± 0.62% and 0.82 ± 0.65%. The workflow variations for completely and partially visible leg surfaces yielded similarly low values. The workflow examined in this study provides a precise method to digitally monitor leg volume regardless of leg morphology. It could aid in objectively comparing medical treatment options of the leg in a clinical setting. Whole-body scans acquired using the described 3DSI routine may allow simultaneous assessment of other changes in body morphology after further validation.

Objective: Lipedema is a relatively common yet debilitating and often misdiagnosed lipodystrophy that mainly affects females. Very little is known about the etiology and pathophysiology of the disease. However, due to its high preference for female patients, hormonal factors may contribute to the pathogenesis., Case: A 62-year-old male patient presented to the authors with painful swelling of the thighs. The patient had been treated elsewhere for lymphedema with subsequent disease progression. Lipedema stage IV was confirmed by clinical examination and ultrasound. The patient underwent three sessions of tumescence liposuction which was well tolerated. Later on, the patient reported great improvement in terms of complaints as well as disfigurement., Conclusion: The etiology and pathophysiology of lipedema remain unclear. However, the case at hand shows that lipedema may, albeit rare, also present in male patients. Moreover, we show that liposuction is efficient and safe in treating lipedema even in atypical cases.

Lymphedema is a chronic disease with a high incidence in our society. In this paper, we present a review with the latest advances in imaging techniques and surgical reconstructive treatment of lymphedema (lymphovenous anastomosis, vascularized lymph node transfer, and prophylactic lymphedema surgery). In addition, a protocol is established based on a multidisciplinary team (composed of physiatrists, plastic surgeons, radiologists and nuclear medicine radiologists) to optimize the treatment of these patients.

Introduction, Breast cancer-related lymphedema (BCRL) is a complication of treatment for breast cancer. The aim of the present study is to report a form of intensive treatment for BCRL., Method, A crossover study was conducted involving the evaluation of the change in the volume of the upper limbs of 45 women with BCRL who underwent the intensive Godoy Method® (eight hours/day for five days). Volumetric analyses were performed before and after treatment and differences were analyzed using the paired t-test. Reductions in volume were found in all patients., Results, The average reduction was 45.38%. The reduction was between 15% and 20% in 6.67% of the women (n = 3); 20% to 30% in 13.33% (n = 6); 30% to 40% in 20% (n = 9); 40% to 50% in 40% (n = 18); and more than 50% in 20% of the women (n = 9)., Conclusion, The intensive form of treatment for lymphedema is highly effective in a short period of time, with a 40% to 50% reduction in volume in five days, but requires specialized centers adapted to this form of therapy. This is an option for reference centers in the treatment of lymphedema and the formation of human resources.

The World Health Organization (WHO) has recognised obesity as one of the top ten threats to human health. Obesity is not only a state of abnormally increased adipose tissue in the body, but also of an increased release of biologically active metabolites. Moreover, obesity predisposes the development of metabolic syndrome and increases the incidence of type 2 diabetes (T2DM), increases the risk of developing insulin resistance, atherosclerosis, ischemic heart disease, polycystic ovary syndrome, hypertension and cancer. The lymphatic system is a one-directional network of thin-walled capillaries and larger vessels covered by a continuous layer of endothelial cells that provides a unidirectional conduit to return filtered arterial and tissue metabolites towards the venous circulation. Recent studies have shown that obesity can markedly impair lymphatic function. Conversely, dysfunction in the lymphatic system may also be involved in the pathogenesis of obesity. This review highlights the important findings regarding obesity related to lymphatic system dysfunction, including clinical implications and experimental studies. Moreover, we present the role of biological factors in the pathophysiology of the lymphatic system and we propose the possibility of a therapy supporting the function of the lymphatic system in the course of obesity.

T helper cell responses are tailored to their respective antigens and adapted to their specific tissue microenvironment. While a great proportion of T cells acquire a resident identity, a significant proportion of T cells continue circulating, thus encountering changing microenvironmental signals during immune surveillance. One signal, which has previously been largely overlooked, is sodium chloride. It has been proposed to have potent effects on T cell responses in the context of autoimmune, allergic and infectious tissue inflammation in mouse models and humans. Sodium chloride is stringently regulated in the blood by the kidneys but displays differential deposition patterns in peripheral tissues. Sodium chloride accumulation might furthermore be regulated by dietary intake and thus by intentional behavior. Together, these results make sodium chloride an interesting but still controversial signal for immune modulation. Its downstream cellular activities represent a potential therapeutic target given its effects on T cell cytokine production. In this review article, we provide an overview and critical evaluation of the impact of this ionic signal on T helper cell polarization and T helper cell effector functions. In addition, the impact of sodium chloride from the tissue microenvironment is assessed for human health and disease and for its therapeutic potential.

Angiogenesis, the growth of blood vessels from pre-existing vasculature, is primarily regulated by vascular endothelial growth factor receptors (VEGFRs). Dysregulated angiogenesis is associated with cancers, obesity, and over 70 vascular diseases. Upregulated VEGFR protein expressions in diseased vasculature are promising biomarkers for predicting clinical outcomes, as indicated by non-quantitative immunohistochemical studies in patients with impaired vascularization or tumor angiogenesis. While the quantitative characterization of VEGFRs is critical in identifying biomarkers for anti-angiogenic therapies, VEGFR biomarker development presents two particular challenges: (1) The invasive tissue biopsy needed limits the amount of VEGFR data that can be collected from both normal and diseased vasculatures, and (2) we poorly understand the significance of endothelial and various non-endothelial VEGFR-expressing cells in angiogenic therapies. To address these challenges, here I pioneer a blood biopsy-based proteomic approach that allows non-invasive VEGFR quantification. More significantly, I identify and establish age- and sex-specific basal levels of VEGFRs on endothelial cells and bone marrow-derived progenitor cells (Chapter 2). In recent years, blood biopsies have expanded our knowledge of vascular pathology. In particular, circulating angiogenic cells, such as circulating endothelial cells (cECs) and circulating progenitor cells (cPCs), are isolated and counted, and their elevated abundances are often correlated with vascular disease progression and cancer prognosis. However, cECs and cPCs have been overlooked as accessible proxies for profiling vascular biomarker expressions by activated or damaged vasculatures. For the first time, I show that cPCs and cECs exhibit heterogeneous plasma membrane expression of VEGFRs, which are correlated with donor sexes and ages, particularly pre- vs. post-menopausal status. Menopause is known to reduce regenerative and angiogenic capacities, as manifested by decreased capillary growth in skeletal muscle and increased risks for cardiovascular diseases. Here I provide baseline VEGFR expression ranges for these cells, showing that ~50% of cECs in premenopausal females exhibit intermediate-to-high plasma membrane expression (138,000 VEGFR1 and 39,000-236,000 VEGFR2/cell) and ~25% of cECs in males exhibit high VEGFR plasma membrane expression (206,000 VEGFR1 and 155,000 VEGFR2/cell). In marked contrast, nearly all cECs in postmenopausal females are VEGFR-low (2,900 VEGFR1 and 3,400 VEGFR2/cell), agreeing with the reduced angiogenic capacities after menopause. Additionally, VEGFR1 signaling is critical for cPC localization to activated or damged blood vessels. My data show that VEGFR1 plasma membrane localization in cPCs occurs only in postmenopausal females, suggesting menopause activates VEGFR1 signaling pathways in cPCs. Therefore, my data offer quantitative insights into how VEGFR-regulated regenerative and angiogenic capacities are altered due to menopause. Overall, these findings provide the first insights into how sex and age interactions, particularly menopause, influence VEGFR plasma membrane localization in circulating angiogenic cells. More importantly, the findings help establish age- and sex-specific VEGFR baselines for predicting vascular disease progression and therapeutic outcomes. The second challenge is quantitatively characterize how endothelial and non-endothelial VEGFR-expressing cells contribute to angiogenic regulation. Here, I quantitatively elucidate the changes in VEGFR expressions by endothelial cells and non-enodthelial cells in adipose tissues, and identify biomarkable adipose tissue cells that show altered VEGFR membrane expressions in normal versus high-adiposity states (Chapter 3). Obesity is a major risk factor for vascular disorders, including peripheral artery disease, critical limb ischemia, and several cancers. I hypothesize that VEGFR membrane expression by adipose tissue cells is altered as body fat accumulates (increased adiposity). The VEGFR quantification data presented here indicate that ~ 20% of activated lymphocytes upregulate their membrane expressions of VEGFR1 and VEGFR3 by tenfold in response to increased subcutaneous adiposity induced by lipedema, which is very commonly accompanied by impaired vascularization and chronic inflammation. On the other hand, in murine visceral adipose tissue, myeloid progenitor cells exhibit the highest VEGFR membrane expressions (16,000 ± 4,700 VEGFR1, 50,000 ± 6,200 VEGFR2, and 2,100 ± 460 VEGFR3/cell). Compared to myeloid progenitor cells, visceral endothelial cells exhibit an order of magnitude lower VEGFR1 and VEGFR2 levels (2,400 ± 710 VEGFR1/cell, 1,100 ± 190 VEGFR2/cell, and 1,200 ± 220 VEGFR3/cell, respectively). My approach and findings are foundational to a systematic understanding of how VEGFR-expressing adipose cells regulate adipose angiogenesis and adipogenesis. Future studies are warranted to compare how VEGFR membrane expressions differ in chow-fed and high fat-fed mice, and the quantitative proteomic findings will guide therapies for visceral obesity-associated vascular disorders. Last but not least, unlike VEGFRs, many receptors of clinical interest, particularly the oxytocin receptor (OXTR) and its genetic variants, do not have specific antibodies that enable quantitative characterization. To overcome this issue, I have designed a transfected cell model that is engineered to express HA-OXTR-GFP protein complexes, in which an N-terminal HA acts as a proxy for membrane OXTR detection and a C-terminal GFP acts as an indicator in selecting transfected cells from untransfected cells (Chapter 4). This transfected cell model is applied to characterize the varied dose-response profiles of OXTR wild-type and variant cells to oxytocin, a common labor induction drug. My OXTR quantification data show clear correlations to oxytocin-induced functional outcomes, including calcium release and cell desensitization, suggesting that the quantities of different OXTR variants are predictive of cell responses to administered oxytocin and should be considered when making personalized oxytocin dosing decisions. Overall, my results demonstrate that membrane expression of VEGFRs is significantly associated with physiological factors such as sex, age, and menopause, and with pathological adipose tissue expansion. Although VEGFR protein expression is a promising biomarker for many vascular diseases and cancers, quantitative and baseline VEGFR data are still needed for VEGFR-driven pathology. My work on both VEGFRs and other biomarkable receptors, such as OXTR, provides much-needed standardized approaches and quantitative data, a first step towards proteomic biomarker-driven precision medicine.

Dendritic arborization is critical for the establishment and maintenance of precise neural circuits. Vascular endothelial growth factor D (VEGF-D), well-characterized as a “lymphangiogenic” growth factor, reportedly maintains dendritic arborization and synaptic strength in the hippocampus of adult mice through VEGF receptor (VEGFR-3) signaling. Here, we investigated the effect of chronic VEGFR-3-specific activation on adipose arbor morphometry using the Adipo-VD mouse, a model of inducible, adipose-specific VEGF-D overexpression. We examined whether adipose tissue innervation was preserved or functionally different in Adipo-VD mice during stress in vivo and if VEGFR-3 signaling afforded neuroprotection to challenged neurons in vitro. Chronic VEGFR-3 signaling in Adipo-VD subcutaneous adipose tissue resulted in a reduction in the dendrite length, dendritic terminal branches (filament length), dendritic terminal branch volume (filament volume), but increased dendrite branching. We also identified reduced stimulus-evoked excitatory sympathetic nerve activity in Adipo-VD mice. Following 6-hydroxydopamine (6-OHDA) denervation, Adipo-VD dendritic arbors were preserved, including improved dendritic branch volume, length, and dendritic branches than in wildtype tissues. In vitro, we found that chronic elevation of VEGFR-3 signaling in developing mVC neurons changes the dendritic arbor complexity and improves stress-induced structure remodeling. Developing neurons are conferred neuroprotection against stress, potentially by upregulation of proteolytic conversion of pro-BDNF to mature BDNF. Mature neurons, however, display improved dendritic arbor complexity, and unaltered dendritic structural remodeling and improved resistance to stress with VEGFR-3 signaling. Overall, chronically increasing VEGFR-3 signaling in neurons has a synergistic impact on neurosensitization and neuroprotection during stress.

Introduction: Cellulite is associated with variations in the skin appearance with cottage cheese, mattress-like, or orange peel. The most common areas for these lesions are the posterior or upper thighs and buttocks and mainly affect females after puberty. The objective of the study was to determine whether extracorporeal shock wave therapy (ESWT) or manual lymphatic drainage (MLD) is more effective for the reduction of the grade of cellulite after liposuction. Methods: This study is a single-blinded randomized controlled clinical trial. Thirty females with grade 3 cellulite were randomly distributed into two groups equal in number (n = 15), group A was equipped to ESWT and group B was equipped to MLD. The cellulite grading scale was used to assess cellulite grade, and the skinfold caliper was used to assess the thickness of subcutaneous fat. The assessment was carried out before and four weeks after starting the treatment. Both groups received topical retinol twice daily for four weeks; in addition, group A received ESWT, while group B received MLD, two times/week for 4 weeks. Results: The mean values of the skinfold caliper in group A decreased by 24.4% and in group B by 15.38% with a significant difference between the two groups (p < 0.001). Also, the mean values of the cellulite grading scale decreased significantly after treatment in group A compared with the mean values of group B (p < 0.001). Conclusions: There was more reduction in the grade of cellulite and thickness of subcutaneous fat in the ESWT group than the MLD group after liposuction.

INTRODUCTION: Radiation-induced cavernomas (RIC) after cranial radiotherapy have an unknown risk of hemorrhage. Zabramski magnetic resonance imaging (MRI) classification is touted as being able to indicate non-radiation-induced cavernomas hemorrhage risk. The aim of our study was to assess the hemorrhage risk of RIC during long-term follow-up of childhood cancer survivors based on brain MRI examinations. PATIENTS AND METHODS: We analyzed retrospectively long-term follow-up data of 36 childhood cancer survivors after initial diagnosis with acute leukemia (n = 18) or brain tumor (n = 18), all treated with cranial radiotherapy. Detected RIC in long-term follow-up brain MRI (1.5 or 3 Tesla) were classified following the Zabramski MRI classification and were categorized into "high" (Zabramski type I, II or V) or "low" (type III or IV) risk of hemorrhage. RESULTS: 18 patients (50%) showed RIC with a significant relation to the original tumor entity (p = 0.023) and the cumulative radiation dose to the brain (p = 0.016): all 9 childhood cancer survivors diagnosed with medulloblastoma developed RIC. We classified RIC in only 3/36 childhood cancer survivors (8%) (1 patient with acute lymphoblastic leukemia [Zabramski type II] and 2 patients with medulloblastoma [type I and type II]) as high risk for hemorrhage, the remaining RIC were classified as Zabramski type IV with low risk for hemorrhage. None of the childhood cancer survivors with RIC showed symptomatic hemorrhages. CONCLUSIONS: RIC are common late effects in childhood cancer survivors treated with cranial radiotherapy affecting half of these patients. However, only a few RIC (occurring in 8% of all reviewed childhood cancer survivors) were classified as high risk for hemorrhage and none of the childhood cancer survivors with RIC developed symptomatic hemorrhages. Thus, we conclude that RIC are low-risk findings in brain MRI and the course is mainly benign.

Introduction: Lipedema is an abnormal deposit of subcutaneous fat most often involving the lower limbs symmetrically. The physiopathology is poorly understood, but its peak of the almost exclusively female involvement and its peak of appearance at puberty, during pregnancy or at menopause orient toward a hormonal involvement, whereas other elements are in favor of a strong genetic predisposition. Klinefelter syndrome (KS) is a genetic disease linked to aneuploidy resulting in a karyotype 47 XXY most of the time. There is a substantial variation in clinical presentation, but it often features infertility, firm testicular hypotrophy, hypergonadotropic hypogonadism, gynecomastia, and learning difficulties. Many other pathologies are associated with KS, but lipedema is never mentioned and there are no data in the literature linking these two pathologies.

Both lipedema and juxta-articular adiposis dolorsa are painful disorders of subcutaneous adipose tissue. We investigated 297 female patients with lipedema treated at our department for the presence of juxta-articular adiposis dolorsa. Occurrence of both disorders was identified in 4.4% of lipedema patients. The common presence of both disorders was observed only in more advanced lipedema (grade II and III). Juxta-articular adiposis dolorosa of the knees is seen exclusively on the inner knees, and it presents neither bruising nor creases or hypothermia. Choices of surgical treatment are either microcannula liposuction or dermolipectomy. Recurrences have not been observed.

OBJECTIVES: The association between serum Vitamin D (Vit. D) and mood disorders in lipedema patients has not been investigated. Therefore, the main aim of this study is to investigate the correlation between serum Vit. D, depression and anxiety risk. METHODS: A cross-sectional cohort of lipedema patients were investigated by collecting the clinical and demographic data. The Hamilton Depression Scale (HAM-D) and the Hamilton of Anxiety Scale (HAM-A) were used to evaluating the risk of depression and anxiety. Serum concentrations of Vit. D were measured. The association between Vit. D levels and both HAM-A and HAM-D scores were statistically examined by bivariate and partial correlations. RESULTS: Forty lipedema patients were enrolled in this study. Around two-thirds of them had a higher depression or anxiety risk, and 77.5% were under the normal serum Vit. D levels. A significant and inverse correlation was observed between serum Vit. D levels and both HAM-D (r=-0.661, p<0.001), and HAM-A (r=-0.496, p=0.001) scores. This strong association was sustained after the statistical model adjusted for the main potential confounding factors (age, body mass index (BMI), disease duration, and lipedema stages). Additionally, serum Vit. D correlated significantly and inversely with BMI (r=-0.647, p<0.001). Moreover, BMI significantly correlated with HAM-D: r=0.560, p<0.001, and HAM-A: r=0.511, p=0.00. CONCLUSIONS: This study suggests a strong correlation between Vit. D levels, depression scores, and anxiety scores in lipedema patients. Our results also demonstrate a strong and direct relationship between BMI, Vit. D levels, depression, and anxiety.

Lipedema is a chronic, progressive disease marked by abnormal fat distribution in the limbs, resulting in disproportionately sized and painful limbs. It primarily affects women and causes significant disability, functional impairment, and psychological distress. Despite its clinical significance in women’s health, lipedema is largely unknown, underdiagnosed, and misdiagnosed with other diseases with similar symptoms including obesity. It is difficult to distinguish between obesity and lipedema since these two conditions often coexist. Since the precise etiology of lipedema is yet to be determined, there is no treatment that targets the underlying cause. The most basic conservative treatment is decongestive physical therapy, which is normally needed life-long. In some cases, surgical procedures such as liposuction and excisional lipectomy are the therapeutic alternatives. Lipedematous scalp is a rare, dermatological condition with no known cause, characterized by increased subcutaneous tissue thickness and a smooth and boggy scalp. When it occurs in conjunction with alopecia, it is known as lipedematous alopecia, often mistaken as androgenetic alopecia. The goals of this article are to explain the etiology, clinical features, and treatment options for lipedema and lipedematous scalp (two relatively less known conditions), as well as to highlight their diagnostic features.

Introduction Lipoedema is a chronic and progressive fat distribution disorder characterised by a symmetrical disproportional increase of adipose tissue on the extremities. The disorder is most commonly associated with pain, oedemas, increased tendency of bruising, as well as sensory dysfunctions on the affected limbs, resulting in severely reduced quality of life (QoL) for exclusively female patients. According to current clinical guidelines, conservative treatment of lipoedema consists of manual lymphatic drainage, compression garments, or both combined as complex decongestive therapy (CDT). If conservative therapy does not result in sufficient improvement of symptoms, a surgical intervention, in the form of liposuction under tumescence anaesthesia, may be indicated. This systematic review aims to assess the clinical effectiveness and safety of liposuction in patients with lipoedema (stage I-III) in comparison to any conservative treatment, concerning patient-relevant outcomes, as reduction of pain, reduction in the size of extremities, improvement of QoL, and procedure-related adverse events. Methods A systematic literature search was conducted in December 2020 in five databases to answer customised research questions on clinical effectiveness and safety-related outcomes, yielding in overall 294 potentially relevant hits. One additional hit was identified by hand search. The study selection, data extraction, and assessment of the methodological quality of the studies were performed by two independent researchers. Results A total of six prospective and one retrospective single-arm before/after studies were eligible for inclusion in the current report. Overall, data on safety and clinical effectiveness were evaluated in 492 and 467 female patients of all three lipoedema stages, respectively. The post-operative follow-up ranged from six months to twelve years. Clinical effectiveness Due to the lack of controlled trials, no conclusions on the comparative clinical effectiveness of liposuction for lipoedema could be made. Therefore, data from the prospective single-arm studies comparing patient-reported complaints before and after the liposuction were analysed. All six prospective studies reported statistically significant improvements in pain outcomes pre- vs post-liposuction. These effects were reported beginning at a six-month follow-up but also up to twelve years after the intervention. Reduced sizes of patients’ extremities before-and-after liposuction were reported in three of the included studies, in terms of reduced leg volume and circumference of lower extremities. Statistically significant changes in lipoedema-related QoL outcomes were reported by four studies. Further, reduction in complaints about oedema/swelling, bruising and sensory dysfunctions were reported in some of the included studies.