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Dercum's disease (DD), also described as adiposis dolorosa, is a poorly understood and rare adipose tissue disorder involving obesity and painful adipose tissue masses. Patients may have associated bruising and constitutional symptoms such as fatigue, difficulty concentrating, and sleep disturbance. DD was initially described in 1888 by Francis Xavier Dercum, and was classified into four subtypes, including generalized diffuse, generalized nodular, localized nodular, and juxta-articular subtypes. While this disease has been described for more than 130 years, its etiology and treatment remain elusive. We describe a case of a patient with DD who presented to Ochsner Medical Center, New Orleans, LA, for evaluation of treatment options. We review current knowledge on this rare disease and data on modern treatment methods.

Lipedema, a poorly understood chronic disease of adipose hyper-deposition, is often mistaken for obesity and causes significant impairment to mobility and quality-of-life. To identify molecular mechanisms underpinning lipedema, we employed comprehensive omics-based comparative analyses of whole tissue, adipocyte precursors (adipose-derived stem cells (ADSCs)), and adipocytes from patients with or without lipedema.

Lipedema adalah penyakit kronis dan progresif yang dapat menyebabkan kecacatan yang cukup besar, gangguan fungsi sehari-hari, dan gangguan psikososial. Ciri khasnya adalah distribusi lemak tubuh yang tidak proporsional pada ekstremitas Lipedema seringkali tidak dikenali atau salah didiagnosis; Meskipun prevalensi diperkirakan 10% pada keseluruhan populasi wanita, penyebabnya masih belum diketahui. Penelitian bertujuan untuk mengetahui lebih lanjut mengenai penyakit Lipedema secara komprehensif. Literature  review tipe  naratif dari berbagai jurnal internasional. Penulisan ini berdasarkan hasil pencarian sumber literature Google Cendekia dan NCBI Pubmed dengan criteria inklusi penelitian yang dilakukan dengan batas waktu 10 tahun kebelakang dengan rentang waktu 2010 - 2020. Kata kunci yang digunakan untuk mencari literature review adalah “lipedema”, “obesity”, “oedema” dan “lipid”. Literature searching ini menghasilkan 2.509 artikel kemudian dipilih 21 artikel yang kemudian digunakan untuk dianalisis menggunakan systemic literature review. Evaluasi diagnostik dasar lipedema terdiri dari anamnesis, inspeksi, dan palpasi, dengan perhatian khusus pada manifestasi yang tercantum sebagai kriteria klinis. Metode diagnostik lainnya adalah, dual-energy X-ray absorptiometri (DEXA), yang mengukur komposisi tubuh regional, memberikan informasi penghitungan dan distribusi tentang lemak total dan regional, dan massa tulang. Terkait terapi yang dapat diberikan terdiri dari perawatan konservatif dan bedah. Pendekatan terapi secara multidisplin ilmu merupakan pilihan terbaik pada kondisi lipedema saat ini, serta terdapat banyak hal yang tidak diketahui mengenai Lipedema.

Breast cancer treatment-related lymphedema (BCRL) is a common co-morbidity of breast cancer therapies, yet factors that contribute to BCRL progression remain incompletely characterized. We investigated whether magnetic resonance imaging (MRI) measures of subcutaneous adipose tissue were uniquely elevated in women with BCRL.

Diffuse Lipomatosis is a dermatological lesion consisting of a poorly circumscribed, infiltrative overgrowth of mature adipose tissue that usually affects the trunk and the extremities. The lesions in the Tuberous Sclerosis Complex (TSC) are usually hamartomatous in nature, but lesions arising from adipocytes are rare. There are only three previous reports of association of TSC with diffuse lipomatosis. Herein we present a case series of diffuse lipomatosis in three subjects with TSC and proceed to review the literature for any other reported cases. On the basis of the three index cases and identification of three more cases in the literature, we believe that there is an association of diffuse lipomatosis with TSC that has not been appreciated until now. We believe that this association in some selected cases will serve to improve diagnosis, surveillance, and management..

Lymphatic vessels have crucial roles in the regulation of interstitial fluids, immune surveillance, and the absorption of dietary fat in the intestine. Lymphatic function is also closely related to the pathogenesis of various disease states such as inflammation, lymphedema, endometriosis, liver dysfunction, and tumor metastasis. Lymphangiogenesis, the formation of new lymphatic vessels from pre-existing lymphatic vessels, is a critical determinant in the above conditions. Although the effect of growth factors on lymphangiogenesis is well-characterized, and biologically active lipids are known to affect smooth muscle contractility and vasoaction, there is accumulating evidence that biologically active lipids are also important inducers of growth factors and cytokines that regulate lymphangiogenesis. This review discusses recent advances in our understanding of biologically active lipids, including arachidonic acid metabolites, sphingosine 1-phosphate, and lysophosphatidic acid, as regulators of lymphangiogenesis, and the emerging importance of the lymphangiogenesis as a therapeutic target.

Lipedema is a painful fat disorder that affects ~11% of the female population. It is characterized by bilateral, disproportionate accumulation of subcutaneous adipose tissue predominantly in the lower body. The onset of lipedema pathophysiology is thought to occur during periods of hormonal fluctuation, such as puberty, pregnancy, or menopause. Although the identification and characterization of lipedema have improved, the underlying disease etiology remains to be elucidated. Estrogen, a key regulator of adipocyte lipid and glucose metabolism, and female-associated body fat distribution are postulated to play a contributory role in the pathophysiology of lipedema. Dysregulation of adipose tissue accumulation via estrogen signaling likely occurs by two mechanisms: (1). altered adipocyte estrogen receptor distribution (ERα/ERß ratio) and subsequent metabolic signaling and/or (2). increased release of adipocyte-produced steroidogenic enzymes leading to increased paracrine estrogen release. These alterations could result in increased activation of peroxisome proliferator-activated receptor γ (PPARγ), free fatty acid entry into adipocytes, glucose uptake, and angiogenesis while decreasing lipolysis, mitochondriogenesis, and mitochondrial function. Together, these metabolic alterations would lead to increased adipogenesis and adipocyte lipid deposition, resulting in increased adipose depot mass. This review summarizes research characterizing estrogen-mediated adipose tissue metabolism and its possible relation to excessive adipose tissue accumulation associated with lipedema.

Dr. Allen and Dr. Hines pioneered and first described lipedema in the 1940s, a common subcutaneous adipose tissue disorder characterized as enlargement of both lower extremities. Lipedema is not edema; it is a genetically determined disturbance in adipose tissue mass and adipose tissue distribution.[1][2][3][4] In 1951 a second seminal paper provided more description of lipedema. Fat distribution involves lower extremities, upper arms, hips, buttocks, thighs sparing trunks, and feet.[2] Lower extremities are characterized by pain, easy bruisability, firm subcutaneous nodules of adipose tissue, and resistance of fat to traditional diet and exercise.[5][6]

Lipoedema UK welcomed our involvement with NICE and the opportunity to comment on noncosmetic liposuction (NCL) as a proposed interventional procedure for chronic lipoedema. In response, we have been proactive in capturing the views and experiences of individuals in the UK living with lipoedema and from those who have undergone non-cosmetic liposuction.

Bone is one of the preferential target organs of cancer metastasis. Bone metastasis is associated with various complications, of which bone pain is most common and debilitating. The cancer-associated bone pain (CABP) is induced as a consequence of increased neurogenesis, reprogramming and axonogenesis of sensory nerves (SNs) in harmony with sensitization and excitation of SNs in response to the tumor microenvironment created in bone. Importantly, CABP is associated with increased mortality, of which precise cellular and molecular mechanism remains poorly understood. Bone is densely innervated by autonomic nerves (ANs) (sympathetic and parasympathetic nerves) and SNs. Recent studies have shown that the nerves innervating the tumor microenvironment establish intimate communications with tumors, producing various stimuli for tumors to progress and disseminate. In this review, our current understanding of the role of SNs innervating bone in the pathophysiology of CABP will be overviewed. Then the hypothesis that SNs facilitate cancer progression in bone will be discussed in conjunction with our recent findings that SNs play an important role not only in the induction of CABP but also the progression of bone metastasis using a preclinical model of CABP. It is suggested that SNs are a critical component of the bone microenvironment that drives the vicious cycle between bone and cancer to progress bone metastasis. Suppression of the activity of bone-innervating SNs may have potential therapeutic effects on the progression of bone metastasis and induction of CABP.

The article presents a case of a 17-year-old female who was presented to a clinic due to a 2-year history of unilateral swelling of her left lower extremity. She also reported a poorly healed ankle sprain on her affected extremity. Also cited are her differential diagnosis like lipidema and lymphatic and venous etiologies of edema, and her clinical diagnosis of lymphedema praecox.

<p>Bei 640 Patientinnen einer Fachklinik für operative Lymphologie erfolgte mittels Fragebogen der Deutschen Schmerzgesellschaft e. V. eine Befragung. Neben Fragen zum Schmerz und zur Schmerzcharakteristik wurden gleichzeitig noch demografische Daten miterhoben. Es ergab sich, dass nur bei etwas über 50 % eine echte Adipositas nachgewiesen werden konnte. Lipödem und Adipositas müssen als unabhängige Krankheitsbilder gewertet werden. Der Schmerz wurde überwiegend als drückend und ziehend empfunden. Attribute wie klopfend oder pochend, passend zu einer akuten Entzündung, erfuhren die Wertung „nicht zutreffend“. Die Beschwerdesymptomatik war unabhängig vom BMI, der bei der Lipohyperplasie dolorosa nur bedingt verwertbar ist. Insgesamt ist das Leitsymptom „Schmerz“ sehr facettenreich, das angeborene, nicht erworbene Lipödemfett der Extremitäten führt zu einer deutlichen Beeinträchtigung der Aktivitäten sowohl allgemein als auch im Freizeitbereich. Die durch den G-BA initiierte Studie muss daher kritisch gesehen werden. Da bislang keine objektivierbaren Befunde beim Lipödem erhoben werden können, ist eine subtile Befragung betroffener Patientinnen zur Diagnosestellung notwendig.</p>

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.

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.