Whitney L. Quong

Ldlr−/− Mice Display Decreased Susceptibility to Western-Type Diet-Induced Obesity Due to Increased Thermogenesis

The low-density lipoprotein receptor (Ldlr) is a key molecule involved with lipid clearance. The Ldlr(-/-) mouse has been used extensively as a model for studying atherosclerosis. This study sought to characterize the energy balance phenotype of Ldlr(-/-) mice with respect to weight gain, body composition, energy expenditure (EE), glucose homeostasis, and leptin sensitivity. Adult Ldlr(-/-) mice and Ldlr(+/+) controls on a C57Bl/6J background were fed either a chow or a high-fat, high-sucrose Western-type diet (WTD) for eight wk. Physiological studies of food intake, EE, activity, insulin sensitivity, and leptin responsiveness were performed. The effect of these diet interventions on circulating leptin and on leptin gene expression was also examined. On the chow diet, Ldlr(-/-) mice had lower EE and higher activity levels relative to controls. On the WTD, Ldlr(-/-) mice gained less weight relative to Ldlr(+/+) mice, specifically gaining less fat mass. Increased thermogenesis in Ldlr(-/-) mice fed the WTD was detected. Additionally, leptin responsiveness was blunted in chow-fed Ldlr(-/-) mice, suggesting a novel role for the Ldlr pathway that extends to leptins regulation of energy balance. In addition to its known role in lipid transport, these results demonstrate the importance of the Ldlr in energy homeostasis and suggest a direct physiological link between altered lipid transport and energy balance.

Leptin Administration Enhances Islet Transplant Performance in Diabetic Mice

Islet transplantation is an effective method to obtain long-term glycemic control for patients with type 1 diabetes, yet its widespread use is limited by an inadequate supply of donor islets. The hormone leptin has profound glucose-lowering and insulin-sensitizing action in type 1 diabetic rodent models. We hypothesized that leptin administration could reduce the dose of transplanted islets required to achieve metabolic control in a mouse model of type 1 diabetes. We first performed a leptin dose-response study in C57Bl/6 mice with streptozotocin (STZ)-induced diabetes to determine a leptin dose insufficient to reverse hyperglycemia. Subsequently, we compared the ability of suboptimal islet transplants of 50 or 125 syngeneic islets to achieve glycemic control in STZ-induced diabetic C57Bl/6 mice treated with or without this dose of leptin. The dose-response study revealed that leptin reverses STZ-induced diabetes in a dose-dependent manner. Supraphysiological leptin levels were necessary to restore euglycemia but simultaneously increased risk of hypoglycemia, and also lost efficacy after 12 days of administration. In contrast, 1 µg/day leptin only modestly reduced blood glucose but maintained efficacy throughout the study duration. We then administered 1 µg/day leptin to diabetic mice that underwent transplantation of 50 or 125 islets. Although these islet doses were insufficient to ameliorate hyperglycemia alone, coadministration of leptin with islet transplantation robustly improved control of glucose and lipid metabolism, without increasing circulating insulin levels. This study reveals that low-dose leptin administration can reduce the number of transplanted islets required to achieve metabolic control in STZ-induced diabetic mice.

Reassessing the normal toe-brachial index in young healthy adults

OBJECTIVE The purpose of this study was to measure the toe-brachial index (TBI) in healthy young adults and to compare it with the accepted reference range. METHODS Medical students from the undergraduate classes at the University of British Columbia were prospectively recruited. Participants were surveyed on physical parameters (height, weight), lifestyle factors (physical activity and type, smoking status, alcohol consumption), and medical history (current medications, medical conditions, family history). Bilateral brachial, ankle (using both dorsalis pedis and posterior tibial arteries), and toe blood pressures were measured by stethoscope, Doppler device, and photoplethysmograph, respectively. Ankle-brachial index (ABI) and TBI were calculated and assessed against published reference ranges. TBI was calculated as the mean great toe blood pressure divided by the average of the higher arm systolic blood pressures. RESULTS Seventy-three medical students with a mean age of 24.3 ± 2.0 years without any comorbidity were studied. Participants maintained relatively healthy lifestyles (hours of activity per week, 4.6 ± 2.7; body mass index, 21.9 ± 2.4). Caffeine and alcohol consumption was modest (8.2 ± 8.0 and 1.7 ± 2.6 servings/week, respectively). There were no current or past smokers. No significant differences in lifestyle factors were observed between men and women. Mean brachial blood pressure was 116 ± 10 mm Hg (left) and 120 ± 11 mm Hg (right). Mean TBI was 0.98 ± 0.12 (left) and 0.97 ± 0.12 (right) for men and 0.95 ± 0.21 (left) and 0.94 ± 0.21 (right) for women. The overall ABI was 1.10 ± 0.07 when averaged by gender and side. Whereas men had significantly higher blood pressures in the arm, toe, and ankle compared with women, these differences disappeared when the indices were determined. There were no significant differences in TBI or ABI between men and women. CONCLUSIONS In comparison to published reference values, the TBI in young, healthy individuals is significantly higher. Whereas no gender difference existed, greater variability of the TBI was observed in women. Further studies are recommended to determine if the threshold for diagnosis of peripheral arterial disease based on TBI should be raised.

The role of autonomic efferents and uncoupling protein 1 in the glucose-lowering effect of leptin therapy

Objective Leptin reverses hyperglycemia in rodent models of type 1 diabetes (T1D). Direct application of leptin to the brain can lower blood glucose in diabetic rodents, and can activate autonomic efferents and non-shivering thermogenesis in brown adipose tissue (BAT). We investigated whether leptin reverses hyperglycemia through a mechanism that requires autonomic innervation, or uncoupling protein 1 (UCP1)-mediated thermogenesis. Methods To examine the role of parasympathetic and sympathetic efferents in the glucose-lowering action of leptin, mice with a subdiaphragmatic vagotomy or 6-hydroxydopamine induced chemical sympathectomy were injected with streptozotocin (STZ) to induce hyperglycemia, and subsequently leptin treated. To test whether the glucose-lowering action of leptin requires activation of UCP1-mediated thermogenesis in BAT, we administered leptin in STZ-diabetic Ucp1 knockout (Ucp1−/−) mice and wildtype controls. Results Leptin ameliorated STZ-induced hyperglycemia in both intact and vagotomised mice. Similarly, mice with a partial chemical sympathectomy did not have an attenuated response to leptin-mediated glucose lowering relative to sham controls, and showed intact leptin-induced Ucp1 expression in BAT. Although leptin activated BAT thermogenesis in STZ-diabetic mice, the anti-diabetic effect of leptin was not blunted in Ucp1−/− mice. Conclusions These results suggest that leptin lowers blood glucose in insulin-deficient diabetes through a manner that does not require parasympathetic or sympathetic innervation, and thus imply that leptin lowers blood glucose through an alternative CNS-mediated mechanism or redundant target tissues. Furthermore, we conclude that the glucose lowering action of leptin is independent of UCP1-dependent thermogenesis.

Disrupted Leptin Signaling in the Lateral Hypothalamus and Ventral Premammillary Nucleus Alters Insulin and Glucagon Secretion and Protects Against Diet-Induced Obesity

Leptin signaling in the central nervous system, and particularly the arcuate hypothalamic nucleus, is important for regulating energy and glucose homeostasis. However, the roles of extra-arcuate leptin responsive neurons are less defined. In the current study, we generated mice with widespread inactivation of the long leptin receptor isoform in the central nervous system via Synapsin promoter-driven Cre (Lepr(flox/flox) Syn-cre mice). Within the hypothalamus, leptin signaling was disrupted in the lateral hypothalamic area (LHA) and ventral premammillary nucleus (PMV) but remained intact in the arcuate hypothalamic nucleus and ventromedial hypothalamic nucleus, dorsomedial hypothalamic nucleus, and nucleus of the tractus solitarius. To investigate the role of LHA/PMV neuronal leptin signaling, we examined glucose and energy homeostasis in Lepr(flox/flox) Syn-cre mice and Lepr(flox/flox) littermates under basal and diet-induced obese conditions and tested the role of LHA/PMV neurons in leptin-mediated glucose lowering in streptozotocin-induced diabetes. Lepr(flox/flox) Syn-cre mice did not have altered body weight or blood glucose levels but were hyperinsulinemic and had enhanced glucagon secretion in response to experimental hypoglycemia. Surprisingly, when placed on a high-fat diet, Lepr(flox/flox) Syn-cre mice were protected from weight gain, glucose intolerance, and diet-induced hyperinsulinemia. Peripheral leptin administration lowered blood glucose in streptozotocin-induced diabetic Lepr(flox/flox) Syn-cre mice as effectively as in Lepr(flox/flox) littermate controls. Collectively these findings suggest that leptin signaling in LHA/PMV neurons is not critical for regulating glucose levels but has an indispensable role in the regulation of insulin and glucagon levels and, may promote the development of diet-induced hyperinsulinemia and weight gain.

The use of de-epithelialized skin flap in the surgical repair of terminal myelocystoceles.

BackgroundTerminal myelocystocele is a severe form of spinal dysraphism characterized by cystic expansion of the terminal spinal cord that herniates through a deficiency of the posterior sacral spinal elements to fuse with the subcutaneous fat. Postnatal enlargement of the subcutaneous fluid-filled sac may result in progressive neurological deficit and threaten the viability of the overlying skin. Surgical repair entails spinal cord untethering, resection of nonfunctional neural elements and watertight reconstruction of the terminal thecal sac. Young age at the time of surgery, large dural defect, attenuated tissues and locally altered CSF dynamics frequently mean that wound complications including CSF leakage and pseudomeningocele formation are common.TechniqueWith consideration of these requirements, we describe our surgical technique in terminal myelocystocele repair, which combines a novel surgical incision and for the first time in a neurosurgical setting, the use of a de-epithelialized skin flap to augment the closure. We report successful operative outcomes in three infant patients with terminal myelocystocele.

Aorto-Tracheopexy in the Treatment of Hunter Syndrome

Hunter syndrome is a multisystem genetic disease in which a significant proportion of morbidity and mortality arise from respiratory dysfunction. Notably, tracheal abnormalities in Hunter syndrome can compromise clinical stability, and management is primarily supportive. We describe here the first successful implementation of aorto-tracheopexy in a 19-year-old patient as a surgical strategy to resolve progressive respiratory deterioration.

Mirror ear—surgical correction of this rare external ear anomaly: A case series

BackgroundMirror ear, also known as polyotia, is an infrequently reported form of external ear malformation characterized by morphologic and dimensional similarity to a normal pinna. The condition has been described in association with various syndromes, and in isolation. However, as the data with specific relevance to polyotia is sparse, not only are the precise causative processes of mirror ear unknown, but the paucity of documented cases also lends the operative approach to be daunting.MethodsSix patients with eight mirror ears underwent surgical reconstruction at Great Ormond Street Hospital for Children. All children were followed from infancy and reviewed in a multidisciplinary setting to coordinate aspects of their care—including plastic surgery, maxillofacial surgery, dentistry, audiology, speech and language pathology, and psychiatry where relevant. Concurrent surgical procedures in addition to mirror ear correction occurred in four patients.Results Pleasing results were achieved in all cases, as reconstruction employed a bespoke approach. Nonetheless, there were unifying principles adhered to, which began in the planning stages by assessing the morphology of the anomalous ear and evaluating the accessory cartilage available for utilization. Deliberate positioning of the incisions, exploiting cartilage remnants to fill the depression of the mirrored ear, and manipulation of excess tissue to reconstruct an anatomically sound tragus were crucial to achieving agreeable aesthetic results.Conclusions Given that it is rarely encountered, the successful reconstruction of a mirrored ear requires a thoughtful surgical approach. With this report, we provide a comprehensive review of this unique type of ear deformity, significantly add to the documented cases of polyotia, and describe our operative technique to recreate a tragus that throws a natural shadow in the conchal bowl and shields the external auditory meatus.Level of evidence: level V, therapeutic study.

Determining the Toe-Brachial Index in Young Healthy Adults

Results: Between 2005 and 2013, nine patients (3%) with malignant lower extremity STS underwent surgical resection with vascular reconstruction. Of these, 6 (67%) underwent resection of femoral and popliteal vessels with subsequent femoropopliteal bypass, 1 (11%) underwent resection of femoral vessels with iliac-SFA bypass, 1 (11%) underwent transection of the femoral and popliteal vessels with reanastomosis, and 1 (11%) underwent resection of the superficial femoral vessels with superficial femoral artery-distal superficial femoral artery bypass. All bypasses were performed using saphenous vein from the contralateral leg. Four patients (44%) returned to the operating room for wound complications requiring incision and drainage. Three (33%) required plastic surgery each for one of the following: VRAM flap, split-thickness skin graft, and pedicle gracilis flap. Functional activity was assessed using the criterion 1 of the Musculoskeletal Tumor Society (MSTS) functional assessment forms preoperatively and at follow-up at 6 months and 1 year. A score of 5 indicates no functional restrictions, whereas a score of 0 indicates total disability. The mean MSTS scores preoperatively and at 6 months and 1 year were 4.1, 3.6, and 3.8, respectively, for the vascular reconstruction group, and 4.2, 4.3, and 4.3, respectively, for the limb-sparing surgery without vascular reconstruction group. Conclusions: The need for vascular reconstruction during limbsparing surgery for lower extremity malignant STS is rare in a high-volume sarcoma center. Wound morbidity is high, and these patients frequently require plastic surgery to achieve wound healing. Postoperative functional status as assessed by the MSTS is acceptable but may be lower than in patients not requiring vascular reconstruction.