Avoiding the operated on look in multiple face lifts

SUMMARY AIM: Reviewing 43 patients of ours who have had three or more face lifts, we wanted to demonstrate that it is possible to avoid the multi-operated on look. MATERIAL AND METHODS: Forty-three patients have been operated on three times or more: 42 females and one male. Thirty-six patients had three face lifts, six had four face lifts, one patient had five face lifts. The mean age at time of surgery was 50.3 years for the first face lift, 56.7 for the second, and 64.2 for the third face lift. These patients were operated on by the same surgeon using a technique which has evolved over the years but with the same basic goal of hiding the scars and of minimising hairline displacement. General appearance, scars and hairline displacement were evaluated in patients who had had three or more face lifts. RESULTS: The results of the evaluation of our 43 multi-operated on face lift patients were as follows: 35 patients did not appear to have had face lifts, eight patients did appear to have had face lifts, but with satisfactory appearance, 30 patients had no visible scars at a conversational distance, 10 patients had slightly visible scars when their hair was lifted, five had obvious scars when the hair was lifted, 34 patients had a normal hairline, six patients had a slightly receding hairline at the temporal level and three had hair loss at the level of the temporal scar. CONCLUSIONS: New technical improvements allow the preservation of a natural appearance, with well-hidden scars and a well-placed hairline. The common opinion that several repeated face lifts should be avoided because they give an unnatural appearance and severe sequelae in terms of scars and hairline displacement has not been confirmed by our clinical experience with 43 patients having undergone at least three face lifts.     

Consequences of lipid droplet coat protein downregulation in liver cells: abnormal lipid droplet metabolism and induction of insulin resistance

OBJECTIVE—Accumulation of intracellular lipid droplets (LDs) in non-adipose tissues is recognized as a strong prognostic factor for the development of insulin resistance in obesity. LDs are coated with perilipin, adipose differentiation–related protein, tail interacting protein of 47 kd (PAT) proteins that are thought to regulate LD turnover by modulating lipolysis. Our hypothesis is that PAT proteins modulate LD metabolism and therefore insulin resistance.RESEARCH DESIGN AND METHODS—We used a cell culture model (murine AML12 loaded with oleic acid) and small interfering RNA to directly assess the impact of PAT proteins on LD accumulation, lipid metabolism, and insulin action. PAT proteins associated with excess fat deposited in livers of diet-induced obese (DIO) mice were also measured.RESULTS—Cells lacking PAT proteins exhibited a dramatic increase in LD size and a decrease in LD number. Further, the lipolytic rate increased by ∼2- to 2.5-fold in association with increased adipose triglyceride lipase (ATGL) at the LD surface. Downregulation of PAT proteins also produced insulin resistance, as indicated by decreased insulin stimulation of Akt phosphorylation (P < 0.001). Phosphoinositide-dependent kinase-1 and phosphoinositide 3-kinase decreased, and insulin receptor substrate-1 307 phosphorylation increased. Increased lipids in DIO mice livers were accompanied by changes in PAT composition but also increased ATGL, suggesting a relative PAT deficiency.CONCLUSIONS—These data establish an important role for PAT proteins as surfactant at the LD surface, packaging lipids in smaller units and restricting access of lipases and thus preventing insulin resistance. We suggest that a deficiency of PAT proteins relative to the quantity of ectopic fat could contribute to cellular dysfunction in obesity and type 2 diabetes.The surge in obesity predicts a further increase in associated complications, insulin resistance, diabetes, and heart disease (1,2). Increased fatty acid availability in obesity is associated with accumulation of ectopic fat, mainly in the form of triacylglyerol (TAG) (3). Although ectopic fat correlates with systemic and tissue insulin resistance (4–6), a number of circumstances are known in which high tissue lipid stores are not associated with insulin resistance. Endurance-trained athletes have high intramyocellular lipids yet are highly insulin sensitive. Importantly, the size and intracellular distribution of lipid droplets (LDs) differs in muscle from insulin-sensitive athletes compared with insulin-resistant patients (7). Thus, the negative consequences of high cellular lipids may be related to the ability of the cell to regulate lipid storage and utilization.LDs are energy-storage organelles but have a surprisingly complex function in lipid homeostasis. LD biogenesis is a fundamental cellular function; when exposed to nonesterified fatty acids (NEFAs), cells store them as TAG in LDs (8). Such LD accumulation maintains low intracellular NEFAs, avoiding their toxic effects on cellular physiology while supporting cellular needs by releasing NEFAs for use in β-oxidation and membrane synthesis. LDs’ function to sequester and release NEFAs is thus critical for proper cellular function. Nonadipogenic tissues in patients with metabolic syndrome are exposed to chronically elevated serum levels of NEFAs, and these tissues respond by LD accumulation. Such ectopic fat deposition protects from NEFA-mediated lipotoxicity (9), but in patients with metabolic syndrome the LD is inadequate to prevent pathological consequences. An important question arises: what molecular mechanisms regulate lipid storage in nonadipogenic tissues?To date, we have only limited information on nonadipose LDs. Recent studies (10,11) identified a proteomic “signature,” consistently including at least one member of the PAT protein family: perilipin, adipose differentiation–related protein (ADFP), tail interacting protein of 47 kDa (Tip47), S3–12, and lipid dosage droplet protein-5 (LSDP-5). Despite tissue dependence, the ubiquitous nature of the family suggests an important role in LD machinery. ADFP, Tip47, and LSDP-5 are broadly distributed, notably in nonadipogenic liver and muscle tissues that do not express perilipin (13,24). Our hypothesis is that saturation of nonadipogenic tissue''s capacity to appropriately regulate storage and release of NEFAs via LDs results from variations in the expression and/or activity of PAT proteins. To study functional consequences of downregulating two major PAT proteins, ADFP and Tip47, on insulin resistance and lipid metabolism, we used small interfering RNA (siRNA) in a cell culture model. To assess the in vivo relevance of this finding, we measured the expression of PAT proteins associated with excess lipids accumulated in the livers of high-fat–fed obese mice.     

Brain glucagon-like peptide-1 regulates arterial blood flow, heart rate, and insulin sensitivity

OBJECTIVE— To ascertain the importance and mechanisms underlying the role of brain glucagon-like peptide (GLP)-1 in the control of metabolic and cardiovascular function. GLP-1 is a gut hormone secreted in response to oral glucose absorption that regulates glucose metabolism and cardiovascular function. GLP-1 is also produced in the brain, where its contribution to central regulation of metabolic and cardiovascular homeostasis remains incompletely understood.RESEARCH DESIGN AND METHODS— Awake free-moving mice were infused with the GLP-1 receptor agonist exendin-4 (Ex4) into the lateral ventricle of the brain in the basal state or during hyperinsulinemic eu-/hyperglycemic clamps. Arterial femoral blood flow, whole-body insulin-stimulated glucose utilization, and heart rates were continuously recorded.RESULTS— A continuous 3-h brain infusion of Ex4 decreased femoral arterial blood flow and whole-body glucose utilization in the awake free-moving mouse clamped in a hyperinsulinemic-hyperglycemic condition, only demonstrating that this effect was strictly glucose dependent. However, the heart rate remained unchanged. The metabolic and vascular effects of Ex4 were markedly attenuated by central infusion of the GLP-1 receptor (GLP-1R) antagonist exendin-9 (Ex9) and totally abolished in GLP-1 receptor knockout mice. A correlation was observed between the metabolic rate and the vascular flow in control and Ex4-infused mice, which disappeared in Ex9 and GLP-1R knockout mice. Moreover, hypothalamic nitric oxide synthase activity and the concentration of reactive oxygen species (ROS) were also reduced in a GLP-1R–dependent manner, whereas the glutathione antioxidant capacity was increased. Central GLP-1 activated vagus nerve activity, and complementation with ROS donor dose-dependently reversed the effect of brain GLP-1 signaling on peripheral blood flow.CONCLUSIONS— Our data demonstrate that central GLP-1 signaling is an essential component of circuits integrating cardiovascular and metabolic responses to hyperglycemia.There is now compelling evidence supporting the interplay between metabolic and vascular diseases (1,2) in which neuronal circuits in the central nervous system seem to play a critical role in orchestrating the control of glucose homeostasis (3). We recently demonstrated that the central infusion of insulin decreased blood pressure and increased arterial blood flow and heart rate through a molecular mechanism depending on the synthesis of nitric oxide in the hypothalamus (4). Importantly, the central regulation of nitric oxide (NO) metabolism affected whole-body glucose utilization (5). This mechanism was impaired during high-fat diet–induced insulin resistance and diabetes and reverted upon central NO supplementation (4). These findings raise the possibility that signals from peripheral tissues, which act on the brain to control glucose metabolism, could also regulate vascular function.Enteroendocrine cells have important roles in regulating energy intake and glucose homeostasis through their actions on peripheral target organs, including the endocrine pancreas. Enteroendocrine cells secrete multiple hormones, including glucagon-like peptide (GLP)-1, which controls pancreatic endocrine secretion (6). GLP-1 is also a neuropeptide synthesized by neurons in the caudal regions of the nucleus of the solitary tract (NTS) (7,8). GLP-1 is released into the hypothalamus and controls food intake, blood pressure, and heart rate (9,10). Whereas most of the glucose-lowering actions of GLP-1 have been attributed to the direct effect of the hormone on the endocrine pancreas, i.e., to stimulation of insulin and inhibition of glucagon secretion, we demonstrated the importance of extra-pancreatic GLP-1 receptor–dependent control of insulin secretion (11) and whole-body glucose distribution (12). The infusion into the brain of the GLP-1 receptor antagonist exendin-9 (Ex9) inhibited insulin secretion induced by gut glucose (11). Conversely, central administration of the GLP-1 receptor agonist exendin-4 (Ex4) augmented intravenous glucose-stimulated insulin secretion to a level similar to that obtained during an intragastric glucose infusion (11). Our data suggested that the absorptive state was associated with the stimulation of the gut-to-brain axis leading to the activation of brain GLP-1 signaling and, consequently, to hyperinsulinemia. During the absorptive state, blood flow redistribution toward mesenteric organs is also observed, which has been proposed to favor nutrient redistribution into the liver (13). Importantly, stimulation of the central GLP-1 receptor increases blood pressure and heart rate and activates autonomic regulatory neurons (8,14,15). However, recently it has been shown that GLP-1 reduced islet blood flow after glucose administration (16). Therefore, the role of brain GLP-1 signaling also in the control of cardiovascular homeostasis remains incompletely understood.We have now pursued the importance of GLP-1 action in the central nervous system for control of cardiovascular function using studies in conscious free-moving mice. After central GLP-1 infusion, we simultaneously recorded femoral arterial blood flow, heart rate, and insulin and glucose sensitivity during hyperinsulinemic-euglycemic or hyperglycemic clamps. We now demonstrate that hypothalamic reactive oxygen and nitrogen species are controlled by brain GLP-1 and are essential for the coordinated regulation of metabolic and cardiovascular function.     

A phase II study of high-dose calcitriol combined with mitoxantrone and prednisone for androgen-independent prostate cancer

OBJECTIVE

To evaluate the preliminary efficacy, safety, and impact on quality of life (QoL) of high‐dose calcitriol (DN‐101) combined with mitoxantrone and glucocorticoids in androgen‐independent prostate cancer (AIPC).

PATIENTS AND METHODS

Nineteen patients with metastatic AIPC and no previous chemotherapy received DN‐101 180 µg orally on day 1 and mitoxantrone 12 mg/m² intravenously on day 2 every 21 days with continuous daily prednisone 10 mg orally for a maximum of 12 cycles. A confirmed decline in prostate‐specific antigen (PSA) levels by half was the primary endpoint. QoL was evaluated using the European Organization for Research and Treatment of Cancer QLQ‐C30 questionnaire, and pain and analgesic use were evaluated.

RESULTS

Five of 19 patients (26%; 95% confidence interval, CI, 9–51) achieved a ≥50% decline in PSA level. The median (95% CI) time to PSA progression was 16 (6–26) weeks. The overall median (95% CI) survival was 16 (6–26) months; 47 (21–73)% of patients achieved an analgesic response. Toxicity was similar to that expected with mitoxantrone and prednisone alone. The QoL analysis suggested a decrease in physical functioning and increase in fatigue, insomnia, and diarrhoea.

CONCLUSIONS

DN‐101 given every 3 weeks does not add significant activity to mitoxantrone and prednisone in AIPC, as measured by the PSA decline. The high rate of analgesic response is encouraging. The addition of DN‐101 does not appear to increase the toxicity of mitoxantrone.     

A PAI-1 mutant, PAI-1R, slows progression of diabetic nephropathy

Plasminogen activator inhibitor-1 (PAI-1) has been implicated in renal fibrosis. In vitro, PAI-1 inhibits plasmin generation, and this decreases mesangial extracellular matrix turnover. PAI-1R, a mutant PAI-1, increases glomerular plasmin generation, reverses PAI-1 inhibition of matrix degradation, and reduces disease in experimental glomerulonephritis. This study sought to determine whether short-term administration of PAI-1R could slow the progression of glomerulosclerosis in the db/db mouse, a model of type 2 diabetes in which mesangial matrix accumulation is evident by 20 wk of age. Untreated uninephrectomized db/db mice developed progressive albuminuria and mesangial matrix expansion between weeks 20 and 22, associated with increased renal mRNA encoding alpha1(I) and (IV) collagens and fibronectin. Treatment with PAI-1R prevented these changes without affecting body weight, blood glucose, glycosylated hemoglobin, creatinine, or creatinine clearance; therefore, PAI-1R may prevent progression of glomerulosclerosis in type 2 diabetes.