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The objective of this study was to investigate the effect of manual lymphatic drainage (MLD) on the insulin resistance parameter (HOMA-IR), glycated hemoglobin (HbA1c), C-peptide, insulin, fasting plasma glucose (FPG), 2h-post-loadglucose (2h-PG) and the concentration of high-sensitivity C-reactive protein (hsCRP) in patients with abnormal body mass index. The study involved 30 patients, including patients with normal body weight (as a control group; group I; n = 14), overweight patients (group II; n = 9) and obese patients (group III; n = 7). Each patient underwent 10 sessions of MLD therapy, 3 times a week for 30 min. In addition, we measured body mass index (BMI) and waist-to-hip ratio (WHR) and performed body composition analysis as well as biochemical tests before MLD therapy (stage 0') and after MLD therapy (stage 1'). A statistically significant correlation was demonstrated between the concentration of C-peptide, BMI, the amount of visceral adipose tissue (r = 0.87, p = 0.003; r = 0.76, p = 0.003, respectively), and the HOMA-IR index, BMI and the amount of visceral adipose tissue (r = 0.86, p = 0.005; r = 0.84, p = 0.042, respectively), before and after MLD therapy. In overweight patients (group II), a statistically significant (p = 0.041) decrease in the hsCRP level by 2.9 mg/L and a significant (p = 0.050) decrease in the 2h-PG level by 12 mg/dL after the MLD therapy was detected. Moreover, in the group of obese patients (group III), a statistically significant (p = 0.013) decrease in HbA1c level by 0.2% after MLD therapy was demonstrated. Our results indicate that MLD may have a positive effect on selected biochemical parameters, with the most favorable changes in overweight patients. Further studies in a larger number of patients are warranted to confirm our findings, to test in-depth their mechanism, and to investigate clinical benefits of this alternative therapy in patients with abnormal body mass index.

Background: Lipedema of lower limbs is characterized by bilateral accumulations of excess adipose tissue starting from the ankle to the hips and buttocks. The studies with lymphoscintigraphy (LSC) and magnetic resonance (MR) lymphography show altered transport index and enlarged lymphatic vessels (LVs). Our studies aimed to investigate the superficial lymph flow, water accumulation, skin and subcutaneous tissue elasticity, and the possibility of using this information to diagnose lipedema. Methods and Results: Fifty patients with lipedema and 50 control subjects (women) were included. The Indocyanine Green (ICG) lymphography, LSC, skin water measurement, skin durometry, and deep tissue tonometry were done in all participants. ICG lymphography revealed: (1) Slower lymph flow in lipedema patients; after 3 minutes of feet movement in a horizontal position, the ICG-dyed lymph reached the upper calf level in 8% of lipedema patients compared with 56% in the control group (p ˂ 0.0001). (2) More than three LVs were noticed more often in lipedema patients. (3) The higher number of abnormal LV images at all limb levels and during each observation stage with a statistically significant number of foggy and dilated. (4) Statistically significant higher fluorescent intensity in all limb levels. Skin water concentration was higher in the feet in lipedema (p = 0.000189). Conclusion: Our studies have shown the differences in superficial lymph flow and water concentration between lipedema and normal limbs. Data proove the usefulness of ICG lymphography, skin water concentration and skin and subcutaneous tissue elasticity measurements in diagnosing lipedema.

Lipedema is a chronic disease that mostly manifests in females as the abnormal distribution of subcutaneous adipose connective tissue, usually coupled with bruising, pain, and edema. Lipedema molecular pathophysiology is currently not clear, but several studies suggest that genetics and hormonal imbalance participate in lipedema pathogenesis. Women with lipedema present in some cases with elevated body mass index, and the appearance of obesity in addition to lipedema, where the obesity can cause serious health issues as in lipedema-free individuals with obesity, such as diabetes and cardiovascular disorders. Unlike obesity, lipedema tissue does not respond well to diet or physical exercise alone. Therefore, in this review we discuss the effect of various dietary supplements that, along with diet and physical exercise, cause fat burning and weight loss, and which could potentially be important in the treatment of lipedema. Indeed, an effective fat burner should convert stored fats into energy, mobilize and break down triglycerides in adipocytes, boost metabolism and inhibit lipogenesis. Common ingredients of fat burning supplements are green tea, caffeine, chromium, carnitine, and conjugated linoleic acid. The use of fat burners could act synergistically with a healthy diet and physical exercise for decreasing adipose tissue deposition in patients with lipedema and resolve related health issues. The effects of fat burners in human studies are sometimes contradictory, and further studies should test their effectiveness in treating lipedema.

In recent years, more attention is being paid to the hormonal aspect of lipoedema. There are suggestions that lipoedema patients may have particular imbalances or sensitivities with regard to oestrogens and/ or progesterone. This article examines the specifics of gluteofemoral fat storage during pregnancy: increased gluteofemoral storage with strong resistance to lipolysis. It then asks if hormonal dysregulation in lipoedema patients could result in a hormonal profile that mimics pregnancy. Such a profile may include high levels of oestrogens, progesterone, prolactin and relaxin, or any combination of the above. This pseudopregnancy hormonal profile would instruct the body to store gluteofemoral fat and strongly resist all attempts to mobilise it.

2 Abstract 2.1 Participating professional associations and organisations These guidelines for the diagnosis and treatment of varicose veins were prepared under the guidance of the Deutsche Gesellschaft für Phlebologie e. V. (DGP) in cooperation with the Deutsche Gesellschaft für Gefäßchirurgie und Gefäßmedizin—Gesellschaft für operative, endovaskuläre und präventive Gefäßmedizin e. V. (DGG), the Deutschen Gesellschaft für Angiologie, Gesellschaft für Gefäßmedizin e. V. (DGA), the Deutsche Dermatologischen Gesellschaft (DDG), the Deutsche Gesellschaft für Dermatochirurgie e. V. (DGDC), the Berufsverband der Phlebologen e. V. (BVP), and the Arbeitsgemeinschaft der niedergelassenen Gefäßchirurgen Deutschlands e. V. (ANG). This updated 2018/2019 version is based on the guidelines agreed and drafted by the same associations in 2004 and 2009, and it was adopted by the Boards of the participating professional associations on 30 April 2019. 2.2 Development stage of the guidelines These guidelines are based on a structured consensus process, drawing on published data to create consensus-based guidelines at development stage S2k. 2.3 Delegates of the professional associations See: https://www.awmf.org/uploads/tx_szleitlinien/037-018l_S2k_Varikose_Diagnostik-Therapie_2019-07.pdf. 2.4 Selected literature The recommendations are based on the same publications used in previous versions and a systematic literature review carried out on 21 July 2016 in the German Institute for Vascular Public Health Research (DIGG). The review included randomised studies, meta-analyses, and controlled studies. The literature search was carried out in the Medline and PubMed databases with the following search fields in German and/or English: sclerotherapy, endovenous thermal ablation, mechanochemical ablation, cyanoacrylate glue, surgical procedures (stripping), and diagnosis, prognosis, and postoperative care of varicose veins. A manual search was carried out for later publications up to December 2018.

High-quality three-dimensional (3D) microscopy allows detailed, unrestricted and non-destructive imaging of entire volumetric tissue specimens and can therefore increase the diagnostic accuracy of histopathological tissue analysis. However, commonly used IgG antibodies are oftentimes not applicable to 3D imaging, due to their relatively large size and consequently inadequate tissue penetration and penetration speed. The lack of suitable reagents for 3D histopathology can be overcome by an emerging class of single-domain antibodies, referred to as nanobodies (Nbs), which can facilitate rapid and superior 2D and 3D histological stainings. Here, we report the generation and experimental validation of Nbs directed against the human endothelial cell-selective adhesion molecule (hESAM), which enables spatial visualization of blood vascular networks in whole-mount 3D imaging. After analysis of Nb binding properties and quality, selected Nb clones were validated in 2D and 3D imaging approaches, demonstrating comparable staining qualities to commercially available hESAM antibodies in 2D, as well as rapid and complete staining of entire specimens in 3D. We propose that the presented hESAM-Nbs can serve as novel blood vessel markers in academic research and can potentially improve 3D histopathological diagnostics of entire human tissue specimens, leading to improved treatment and superior patient outcomes.

Lower extremity edema is a common complaint of patients across all medical specialties. This is a wide group of conditions, ranging from relatively minor conditions such as false swelling in lipedema to life-threatening conditions such as heart failure and nephrotic syndrome. The most common cause of chronic edema is chronic venous disease. High-quality differential diagnosis aims to determine the etiology of edema and initiate targeted treatment.

The quantitative assessment of lymphatic dermal clearance using NIR fluorescent tracers is particularly important for the early diagnosis of several potential disabling diseases. Currently, half-life values are computed using a mono-exponential mathematical model, neglecting diffusion of the tracer within the dermis after injection. The size and position of the region of interest are subjectively manually selected around the point of injection on the skin surface where the fluorescence signal intensity is averaged, neglecting any spatial information contained in the image. In this study we present and test a novel mathematical model allowing the objective quantification of dermal clearance, taking into consideration potential dermal diffusion. With only two parameters, this "clearance-diffusion" model is simple enough to be applied in a variety of settings and requires almost no prior information about the system. We demonstrate that if dermal diffusion is low, the mono-exponential approach is suitable but still lacking objectivity. However, if dermal diffusion is substantial, the clearance-diffusion model is superior and allows the accurate calculation of half-life values.

OBJECTIVE: Upper extremity lymphedema (UEL) is a burdensome disease with significant impact on quality of life underscoring the importance of quality of life measurements in this patient population. Only recently, the LYMPH Q Upper Extremity Module, a new patient-reported outcome measurement (PROM), has been developed. The aim of the study was to translate the LYMPH Q Upper Extremity Module from English to German and perform a comprehensive validation. METHODS: Translation was performed in accordance with the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) best-practice guidelines. To validate the German LYMPH Q, a multicenter study was conducted. Internal consistency was determined by Cronbach's alpha. Reliability was assessed by the intra-class correlation coefficient (ICC). To analyse construct validity, a Pearson correlation coefficient between the LYMPH Q, quickDASH and SF-36 was calculated. Responsiveness was assessed by comparing the pre- and postoperative LYMPH Q scores in five patients receiving lymphatic reconstructive surgery. RESULTS: Validation was performed in a cohort of 65 patients. Internal consistency of the different domains was good to excellent (α: 0.87-0.97). ICC ranged from 0.74 to 0.92. The domains of the LYMPH Q correlated significantly with the corresponding domains of the SF-36 and quick DASH. Construct validity was good with eight of ten hypotheses confirmed. Significant improvements of function (46.4 ± 13.3 vs. 77.8 ± 11.5; p= 0.03), symptoms (42.0 ± 10.7 vs. 70.6 ± 11.6; p= 0.02) and psychological well-being (40.4 ± 14.6 vs. 78.0 ± 17.3; p= 0.03) were observed after lymphatic reconstructive surgery. CONCLUSION: The German version of The LYMPH Q Upper Extremity Module is conceptually equivalent to the original English version. It is a reliable and valid PROM to assess physical and psychological impairments in patients with UEL.

BACKGROUND: Despite an increasing demand for surgical treatment of lipedema, the evidence for liposuction is still limited to five peer-reviewed publications. Little is known about the influence of disease stage, patient age, body mass index, or existing comorbidities on clinical outcomes. Considering the chronically progressive nature of lipedema, it was hypothesized that younger patients with lower body mass index and stage would report better results. METHODS: This retrospective, single-center, noncomparative study included lipedema patients who underwent liposuction between July of 2009 and July of 2019. After a minimum of 6 months since the last surgery, all patients completed a disease-related questionnaire. The primary endpoint was the need for complex decongestive therapy based on a composite score. Secondary endpoints were the severity of complaints (i.e., spontaneous pain, sensitivity to pressure, feeling of tension, bruising, impairment of body image) measured on a visual analogue scale. RESULTS: One hundred six patients underwent a total of 298 large-volume liposuctions (mean lipoaspirate, 6355 ± 2797 ml). After a median follow-up of 20 months (interquartile range, 10 to 42 months), a median complex decongestive therapy score reduction of 37.5 percent (interquartile range, 0 to 88.8 percent; p < 0.0001) was observed. An improvement in lipedema-associated symptoms was also observed (p < 0.0001). The percentage reduction in complex decongestive therapy scores was greater in patients with a body mass index less than or equal to 35 kg/m2; (compared to higher body mass index; p < 0.0001) and in stage I and II patients (compared to stage III patients; p = 0.0019). CONCLUSION: Liposuction reduces the severity of symptoms and the need for conservative treatment in lipedema patients, especially if it is performed in patients with a body mass index below 35 kg/m2; at an early stage of the disease. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

In daily practice, medical history and physical examination are commonly coupled with anthropometric measurements for the diagnosis and management of patients with lymphatic diseases. Herein, considering the current progress of ultrasound imaging in accurately assessing the superficial soft tissues of the human body; it is noteworthy that ultrasound examination has the potential to augment the diagnostic process. In this sense/report, briefly revisiting the most common clinical maneuvers described in the pertinent literature, the authors try to match them with possible (static and dynamic) sonographic assessment techniques to exemplify/propose an 'ultrasound-guided' physical examination for different tissues in the evaluation of lymphedema.

Left ventricular (LV) twist is defined as the wringing motion of the LV around its long-axis during systole generated by rotation of the LV apex in a counterclockwise direction, as viewed from the apex, while the LV base moves in a clockwise direction. In several cases, the LV apex and base move in the same direction during ejection demonstrating a special condition called as LV 'rigid body rotation'. The present review aimed to summarize our knowledge about this rare but not fully understood entity demonstrating its theoretic pathophysiologic background, clinical significance, associated diseases, and reversibility based on available literature.

BACKGROUND: Lipedema often remains undiagnosed in patients with obesity, leading to mismanagement of treatment. Because of this, despite remarkable weight loss after bariatric surgery and decreases in hip and abdomen circumference, some patients show only small decreases in circumference of the extremities and report persistent limb pain. OBJECTIVE: The goal of this work is to raise awareness of lipedema coincident with obesity, mistakenly diagnosed as obesity alone, in order to ensure the correct diagnosis of the condition and to achieve better treatment outcomes for people with lipedema and coincident obesity. SETTING: CG Lympha Clinic, Cologne, and Ernst von Bergmann Clinic, Potsdam. METHODS: From clinical records, we identified 13 patients who were diagnosed with lipedema only after undergoing bariatric surgery. We describe the course of their pain before and after bariatric surgery, focusing on the long-term progression of symptoms accompanying the disease. RESULTS: Lipedema cannot be cured by bariatric surgery, and although the patients in this study lost an average of more than 50 kg of weight, they displayed no improvement in the pain symptoms typical of lipedema. CONCLUSIONS: Because of the different etiologies of lipedema and obesity, lipedema requires its own specific treatment. Patients suffering from obesity should always be assessed for pain and lipedema. If coincident lipedema is diagnosed, we suggest that bariatric surgery only be performed first if diet and exercise have failed, the patient's body mass index is >40 kg/m2, and the patient has been informed of the possible persistence of pain. Lipedema, like a coincident disease, must be additionally treated conservatively or preferably surgically. This optimized treatment may help to better manage patient expectations after weight loss.

Lipohyperplasia dolorosa (LiDo) - commonly referred to as lipedema - is a painful disproportionate but symmetrical fat distribution disorder of the extremities. An accompanying proportional symmetrical adipose tissue proliferation in the sense of coincident obesity can complicate the diagnosis and therapy of LiDo. Surprisingly, no valid anthropometric parameters are used to determine this obesity percentage. The often used parameter body mass index (BMI) lacks construct validity. An alternative is the waist-toheight ratio (WHtR).

Background: A detailed quantitative evaluation would be beneficial for management of patients with limb lymphedema. Methods and Results: In 47 patients with lower limb lymphedema at International Society of Lymphology clinical stage 2A (18 limbs), 2B (41 limbs), and 3 (13 limbs), we measured the limb circumference and thickness of epidermis, dermis, and subcutis layers with B-mode ultrasonography and subcutis elastic modulus with ultrafast shear wave velocity (ultrasound elastography) at 5 anatomical levels (M1 to M5) before and after a 3- to 5-day intensive decongestive therapy (IDT) session. Limb circumference and thickness of the epidermis, dermis, and subcutis were greater in the 72 limbs with lymphedema than in the 22 unaffected limbs before and after IDT. The affected limb volume was 10,980 [8458-13,960] mL before and 9607 [7720-11,830] mL after IDT (p < 0.0001). The IDT-induced change in subcutis thickness was -9 [-25 to 13]% (NS), -11 [-26 to 3]% (p = 0.001), -18 [-40 to -1]% (p < 0.0001), -15 [-35 to 3]% (p = 0.0003), and -25 [-45 to -4]% (p < 0.0001) and significantly correlated with the change in elastic modulus, which was 13 [-21 to 90]% (p = 0.004), 33 [-27 to 115]% (p = 0.0002), 40[-13 to 169]% (p < 0.0001), 9 [-36 to 157]% (p = 0.024), and -13 [-40 to 97]% (NS), respectively, at the M1, M2, M3, M4, and M5 levels. Intraobserver reproducibility was satisfactory for skin thickness and fairly good for elastography, but interobserver reproducibility was poor or unacceptable. Conclusions: IDT reduced the circumference and subcutis thickness of lower limbs with lymphedema and increased their elastic modulus, implying greater tissue stiffness probably due to fluid evacuation. Although subcutis thickness measurement proved to be reliable, technological and methodological improvements are required before ultrasonographic elastography can be used in clinical practice.

OBJECTIVE: Lipedema is a chronic and progressive disease associated with lymphatic impairment at later stages. The aim of our study was to describe the functional status and anatomy of lower limb superficial lymphatic system using indocyanine green (ICG) lymphography in patients with lipedema. METHODS: Following ICG injection at the dorsum of the foot, distance (cm) covered by the dye at 10 (T10') and 25 min (T25') was measured and normalized for limb length. If the dye did not reach the groin within 25 min, patients were classified as "drainage-needing" group (DNG). Values of fat and lean distribution assessed by dual-energy X-ray absorptiometry were extracted, and correlation analysis was performed. Furthermore, anatomical patterns of superficial lymphatics were assessed. RESULTS: Overall, 45 women were included, 25 (56%) of whom were classified as DNG. Symptoms duration was significantly associated with DNG status at multivariate analysis (odds ratio 1.07; 95% CI 1.01-1.14; p = 0.047). Moreover, Spearman's analysis showed a negative correlation between symptoms duration and T25' dye migration (r = -0.469; p = 0.037). Overall, no major anatomical lymphatic changes were found. CONCLUSIONS: Present study suggests that lymphatic functioning in patients with lipedema correlates with symptoms duration. Further research on larger cohorts should verify our findings and clarify their potential therapeutic implications. Overall, ICG lymphography may be promising technique to assess both lymphatic anatomy and functioning in patients with lipedema.

Background: Expressed by endothelial cells, CDH5 is a cadherin involved in vascular morphogenesis and in the maintenance of vascular integrity and lymphatic function. The main purpose of our study was to identify distinct variants of the CDH5 gene that could be associated with lymphatic malformations and predisposition for lymphedema. Methods and Results: We performed Next Generation Sequencing of the CDH5 gene in 235 Italian patients diagnosed with lymphedema but who tested negative for variants in known lymphedema genes. We detected six different variants in CDH5 five missense and one nonsense. We also tested available family members of the probands. For family members who carried the same variant as the proband, we performed lymphoscintigraphy to detect any lymphatic system abnormalities. Variants were modeled in silico. The results showed that CDH5 variants may contribute to the onset of lymphedema, although further in vitro studies are needed to confirm this hypothesis. Conclusions: Based on our findings, we propose CDH5 as a new gene that could be screened in patients with lymphedema to gather additional evidence.

Human aldo-keto reductase family 1C1 (AKR1C1) is an important enzyme involved in human hormone metabolism, which is mainly responsible for the metabolism of progesterone in the human body. AKR1C1 is highly expressed and has an important relationship with the occurrence and development of various diseases, especially some cancers related to hormone metabolism. Nowadays, many inhibitors against AKR1C1 have been discovered, including some synthetic compounds and natural products, which have certain inhibitory activity against AKR1C1 at the target level. Here we briefly reviewed the physiological and pathological functions of AKR1C1 and the relationship with the disease, and then summarized the development of AKR1C1 inhibitors, elucidated the interaction between inhibitors and AKR1C1 through molecular docking results and existing co-crystal structures. Finally, we discussed the design ideals of selective AKR1C1 inhibitors from the perspective of AKR1C1 structure, discussed the prospects of AKR1C1 in the treatment of human diseases in terms of biomarkers, pre-receptor regulation and single nucleotide polymorphisms, aiming to provide new ideas for drug research targeting AKR1C1.

Lipomas are the most common soft tissue tumors and are malignant in only 1% of cases. Lipomatosis is defined as the presence of multiple benign lipomas on the body, without lipoatrophy. Their impact on quality of life is significant. Different entities have been described such as symmetrical multiple lipomatosis (MSL), also called Madelung's disease and familial multiple lipomatosis (FML). MSL occurs preferentially in men (but also women) who are alcohol abuser. There are different subtypes of the disease, the most classic of which affects the upper body and the nuchal region with a buffalo hump appearance. A metabolic component with obesity is frequent. In contrast to Dercum's disease, there is no pain. SAOS, complications of the metabolic syndrome and of alcohol abuse including cancers, may be associated and should be screened. FML has been little described in the literature since Brodie's first report in 1846. FML occurs preferentially in the third decade but equally in women and men. Its autosomal dominant component is classically accepted with variable penetrance within the same family. Association with naevi, angiomas, polyneuropathies and with gastrointestinal comorbidities has been reported. Interestingly, and in contrast with most lipodystrophy disorders, the patients show an insulin sensitivity profile. A better understanding of the underlying pathophysiological mechanisms would open up avenues on therapeutic research, since treatments are only symptomatic to date.