A Family-Based Study of Inherited Genetic Risk in Lipedema.

Background: Lipedema is a progressive condition involving excessive deposition of subcutaneous adipose tissue, predominantly in the lower limbs, which severely compromises quality of life. Despite the impact of lipedema, its molecular and genetic bases are poorly understood, making diagnosis and treatment difficult. Historical evaluation of individuals with lipedema indicates a positive family history in 60%-80% of cases; however, genetic investigation of larger family cohorts is required. Here, we report the largest family-based sequencing study to date, aimed at identifying genetic changes that contribute to lipedema. Methods and Results: DNA samples from 31 individuals from 9 lipedema families were analyzed to reveal genetic variants predicted to alter protein function, yielding candidate variants in 469 genes. We did not identify any individual genes that contained likely disease-causing variants across all participating families. However, gene ontology analysis highlighted vasopressin receptor activity, microfibril binding, and patched binding as statistically significantly overrepresented categories for the set of candidate variants. Conclusions: Our study suggests that lipedema is not caused by a single exomic genetic factor, providing support for the hypothesis of genetic heterogeneity in the etiology of lipedema. As the largest study of its kind in the lipedema field, the results advance our understanding of the disease and provide a roadmap for future research aimed at improving the lives of those affected by lipedema.

Radiation therapy attenuates lymphatic vessel repair by reducing VEGFR-3 signalling.

Introduction: Surgery and radiotherapy are key cancer treatments and the leading causes of damage to the lymphatics, a vascular network critical to fluid homeostasis and immunity. The clinical manifestation of this damage constitutes a devastating side-effect of cancer treatment, known as lymphoedema. Lymphoedema is a chronic condition evolving from the accumulation of interstitial fluid due to impaired drainage via the lymphatics and is recognised to contribute significant morbidity to patients who survive their cancer. Nevertheless, the molecular mechanisms underlying the damage inflicted on lymphatic vessels, and particularly the lymphatic endothelial cells (LEC) that constitute them, by these treatment modalities, remain poorly understood. Methods: We used a combination of cell based assays, biochemistry and animal models of lymphatic injury to examine the molecular mechanisms behind LEC injury and the subsequent effects on lymphatic vessels, particularly the role of the VEGF-C/VEGF-D/VEGFR-3 lymphangiogenic signalling pathway, in lymphatic injury underpinning the development of lymphoedema. Results: We demonstrate that radiotherapy selectively impairs key LEC functions needed for new lymphatic vessel growth (lymphangiogenesis). This effect is mediated by attenuation of VEGFR-3 signalling and downstream signalling cascades. VEGFR-3 protein levels were downregulated in LEC that were exposed to radiation, and LEC were therefore selectively less responsive to VEGF-C and VEGF-D. These findings were validated in our animal models of radiation and surgical injury. Discussion: Our data provide mechanistic insight into injury sustained by LEC and lymphatics during surgical and radiotherapy cancer treatments and underscore the need for alternative non-VEGF-C/VEGFR-3-based therapies to treat lymphoedema.

Environmental enrichment for stroke and other non-progressive brain injury.

BACKGROUND: Rehabilitation is effective for recovery after stroke and other non-progressive brain injuries but it is unclear if the rehabilitation environment itself, outside of limited therapy hours, is maximally conducive to recovery. Environmental enrichment is a relatively new concept within rehabilitation for humans. In this review, this is defined as an intervention designed to facilitate physical (motor and sensory), cognitive and social activity by the provision of equipment and organisation of a structured, stimulating environment. The environment should be designed to encourage (but not force) activities without additional specialised rehabilitation input. OBJECTIVES: To assess the effects of environmental enrichment on well-being, functional recovery, activity levels and quality of life in people who have stroke or non-progressive brain injury. SEARCH METHODS: We conducted the search on 26 October 2020. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library; MEDLINE (from 1950); Embase (from 1980); the Cumulative Index to Nursing and Allied Health Literature (CINAHL; from 1982); the Allied and Complementary Medicine Database (AMED; from 1985); PsycINFO (from 1806); the Physiotherapy Evidence Database (PEDro; from 1999); and 10 additional bibliographic databases and ongoing trial registers. SELECTION CRITERIA: We planned to include randomised controlled trials (RCTs) that compared environmental enrichment with standard services. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligible studies, extracted data, and assessed study quality. Any disagreements were resolved through discussion with a third review author. We determined the risk of bias for the included study and performed a 'best evidence' synthesis using the GRADE approach. MAIN RESULTS: We identified one RCT, involving 53 participants with stroke, comparing environmental enrichment (which included physical, cognitive and social activities such as reading material, board and card games, gaming technology, music, artwork, and computer with Internet) with standard services in an inpatient rehabilitation setting. We excluded five studies, found two studies awaiting classification and one ongoing study which described environmental enrichment in their interventions. Of the excluded studies, three were non-RCTs and two described co-interventions with a significant component of rehabilitation. Based on the single small included RCT at high risk of bias, data are insufficient to provide any reliable indication of benefit or risk to guide clinical practice in terms of the provision of environmental enrichment. AUTHORS' CONCLUSIONS: The gap in current research should not, however, be interpreted as proof that environmental enrichment is ineffective. Further research is needed with robust study designs, such as cluster RCTs, and consistent outcome measurement evaluating the effectiveness of environmental enrichment in different settings (inpatient versus outpatient), the relative effectiveness of various components of environmental enrichment, cost-effectiveness, and safety of the intervention in people following stroke or other non-progressive brain injuries. It should be noted, however, that it is challenging to randomise or double-blind trials of environmental enrichment given the nature of the intervention.

Extensive abdominal surgery and scar does not absolutely contraindicate bilateral flap harvest from the abdomen: A case report.

INTRODUCTION: This case reports a female patient with a history of multiple laparotomies including stoma formations and reversals, who underwent successful bilateral abdominal flap based breast reconstruction. It highlights that even complex and repeated abdominal surgery is not an absolute contraindication to this procedure. PRESENTATION OF CASE: A 52-year-old female with a history of bilateral mastectomy and implant-based breast reconstruction presented with bilateral capsular contracture, wanting removal and alternative breast reconstruction. Her history of ulcerative colitis and multiple complex and extensive abdominal surgeries initially seemed to preclude bilateral abdominal flap harvest and the patient was referred on for another opinion. CT-angiography after the subsequent opinion identified adequate deep inferior epigastric artery perforators and successful bilateral abdomen-based flap reconstruction was performed. DISCUSSION: This is the first case report of successful bilateral abdomen-based flap harvest in a patient with 6 previous laparotomies including stoma formations and reversals. CONCLUSION: Complex and extensive abdominal surgery is not an absolute contraindication to bilateral flap harvest from the abdomen. With accurate CT-angiography to guide pre-operative planning and meticulous surgery, safe flap harvest is possible.

An enriched environmental programme during inpatient neuro-rehabilitation: A randomized controlled trial.

OBJECTIVE: To assess the effectiveness of an enriched environmental activities programme in an inpatient tertiary neuro-rehabilitation unit. METHODS: A total of 103 participants were randomized to an intervention group (n = 52) undertaking an enriched environmental activities programme or a control group (n = 51) receiving usual ward activity. PRIMARY OUTCOME MEASURE: Depression, Anxiety Stress Scale (DASS). Other measures included: Neurological Impairment Scale; Multidimensional Health Locus of Control, Rosenberg Self-Esteem Scale, Montreal Cognitive Assessment (MoCA); Functional Independence Measure (FIM), and Euro-Quality of Life-5D. Questionnaire assessments were performed at admission, discharge and 3-months post-discharge. RESULTS: Mean age of subjects was 62.5 years (standard deviation 18.5), 63% were male; 53 had stroke and the remainder had other neurological conditions. Compared with controls, the intervention group showed significant improvement at discharge in: DASS: "total", "depression", and "stress" subscales (p < 0.05 for all, with small effect sizes (η2) = 0.04-0.05); MoCA (p = 0.048, η2 = 0.04) and FIM motor (total and "self-care", "mobility" subscales (p < 0.05 for all, with moderate effect sizes, η2 = 0.0-0.08). At 3-month follow-up, significant differences were maintained in most secondary outcomes in the intervention group. Cognitive function and activities improved most in participants with stroke. CONCLUSION: An enriched environmental programme can produce significant improvements in functional and cognitive ability in inpatient neurological cohorts compared with routine ward activity programmes.