Is Oncotype DX Recurrence Score (RS) of Prognostic Value Once HER2‐Positive and. Low‐ER Expression Patients are Removed?

Oncotype DX has been criticized for not providing significantly more prognostic information than histopathologic analysis. Oncotype DX was validated in cohorts that included poor prognostic factors (HER2‐positive, low‐estrogen receptor [ER] expression), raising the question: if patients with known high recurrence rates are excluded, is the Recurrence Score (RS) still valid? Our purpose was to determine if RS can be predicted with readily available measures. One hundred and twenty samples from August 2006 to November 2010 that underwent Oncotype DX testing were analyzed. Data included RS, ER, progesterone receptor (PR), HER2, and Ki67 status by immunohistochemistry (IHC). IHC data were used to create two linear regression models to predict RS. SAS's JMP‐7 was used for statistical analysis. When comparing Oncotype DX‐ and IHC‐derived ER and PR values, there were 21 discordant samples. The linear regression model PRS‐F created with IHC data (ER, PR, HER2, Ki67) from all samples (n = 120) had an adjusted R² = 0.60 indicating a good model for predicting RS. The PRS‐R model was built without low‐ER and HER2‐positive samples (n = 110). It had an adjusted R² = 0.38 indicating poor prediction of RS. Oncotype DX data showed good concordance with IHC for ER‐ and PR‐expression in this cohort. Low‐ER samples had high RS. After removing low‐ER and HER2‐positives, calculating RS with PRS‐R from remaining data showed poor predictive power for RS (adjusted R² = 0.38). This result questions whether RS is prognostic in this subgroup (who would most benefit from further clarification of recurrence risk) and independent of pathology, or is simply producing random RS values. Data bases available to Genomic Health can resolve this issue.     

Genomic Assays and the Great Unknown: The Oncotype DX™ May Miss the Mark in Certain Populations

Annals of Surgical Oncology -     

Is Age Trumping Genetic Profiling in Clinical Practice? Relationship of Chemotherapy Recommendation and Oncotype DX Recurrence Score in Patients Aged < 50 Years versus ≥ 50 Years,and Trends Over Time

Background

Oncotype DX (oDX) is used to predict recurrence and indicate response to chemotherapy in patients with early-stage breast cancer (BC). We evaluated the relationship between age (<?50 vs.?≥?50 years), recurrence score (RS), chemotherapy use, and trends of oDX testing over time.

Methods

Using the National Cancer Database, we identified women with T1/T2, N0, estrogen receptor-positive BC from 2009 to 2014. We stratified patients by age (<?50 and?≥?50 years) and RS (low: <?18; intermediate: 18–30; and high: >?30), and compared demographics, tumor characteristics, and chemotherapy recommendations. Management trends were also assessed.

Results

From 2009 to 2014, a total of 377,725 cases met the eligibility criteria for oDX testing; 115,052 (30.5%) patients had oDX, and 60,804 (16.1%) were <?50 years of age. The majority had low RS and T1N0 disease. Patients <?50 years of age were more likely to be recommended chemotherapy than those ≥?50 years of age, regardless of RS (p?≤?0.001), and were more likely to ultimately undergo chemotherapy (p?<?0.001). When stratified by year, oDX utilization increased. There was a decreasing trend in chemotherapy recommendations in both the low- and intermediate-RS groups for both age groups (all p?=?0.001), with no change in the high-RS group (<?50 years: p?=?0.52;?≥?50 years: p?=?0.67). Univariate and multivariate analyses demonstrated that patients?<?50 years of age and those with a higher RS were more likely to be recommended chemotherapy (p?<?0.001).

Conclusions

The testing of oDX in BC has significantly increased since first implemented. Results from additional studies such as TAILORx will clarify the current discordant practice patterns between low oDX RSs and adjuvant chemotherapy recommendations.

     

Adaptation of β-Cell and Endothelial Function to Carbohydrate Loading: Influence of Insulin Resistance

High-carbohydrate diets have been associated with β-cell strain, dyslipidemia, and endothelial dysfunction. We examined how β-cell and endothelial function adapt to carbohydrate overloading and the influence of insulin resistance. On sequential days in randomized order, nondiabetic subjects (classified as insulin-sensitive [IS] [n = 64] or insulin-resistant [IR] [n = 79] by euglycemic clamp) received four mixed meals over 14 h with either standard (300 kcal) or double carbohydrate content. β-Cell function was reconstructed by mathematical modeling; brachial artery flow-mediated dilation (FMD) was measured before and after each meal. Compared with IS, IR subjects showed higher glycemia and insulin hypersecretion due to greater β-cell glucose and rate sensitivity; potentiation of insulin secretion, however, was impaired. Circulating free fatty acids (FFAs) were less suppressed in IR than IS subjects. Baseline FMD was reduced in IR, and postprandial FMD attenuation occurred after each meal, particularly with high carbohydrate, similarly in IR and IS. Throughout the two study days, higher FFA levels were significantly associated with lower (incretin-induced) potentiation and impaired FMD. In nondiabetic individuals, enhanced glucose sensitivity and potentiation upregulate the insulin secretory response to carbohydrate overloading. With insulin resistance, this adaptation is impaired. Defective suppression of endogenous FFA is one common link between impaired potentiation and vascular endothelial dysfunction.     

AMP-Activated Protein Kinase α1 Protects Against Diet-Induced Insulin Resistance and Obesity

AMP-activated protein kinase (AMPK) is an essential sensor of cellular energy status. Defects in the α2 catalytic subunit of AMPK (AMPKα1) are associated with metabolic syndrome. The current study investigated the role AMPKα1 in the pathogenesis of obesity and inflammation using male AMPKα1-deficent (AMPKα1^−/−) mice and their wild-type (WT) littermates. After being fed a high-fat diet (HFD), global AMPKα1^−/− mice gained more body weight and greater adiposity and exhibited systemic insulin resistance and metabolic dysfunction with increased severity in their adipose tissues compared with their WT littermates. Interestingly, upon HFD feeding, irradiated WT mice that received the bone marrow of AMPKα1^−/− mice showed increased insulin resistance but not obesity, whereas irradiated AMPKα1^−/− mice with WT bone marrow had a phenotype of metabolic dysregulation that was similar to that of global AMPKα1^−/− mice. AMPKα1 deficiency in macrophages markedly increased the macrophage proinflammatory status. In addition, AMPKα1 knockdown enhanced adipocyte lipid accumulation and exacerbated the inflammatory response and insulin resistance. Together, these data show that AMPKα1 protects mice from diet-induced obesity and insulin resistance, demonstrating that AMPKα1 is a promising therapeutic target in the treatment of the metabolic syndrome.AMP-activated protein kinase (AMPK) is a major cellular energy sensor and plays a major role in regulating metabolic homeostasis (1,2). In mammals, AMPK is a heterotrimeric complex with a catalytic subunit (α1 or α2) and two regulatory subunits (β1 or β1 and γ1, γ2, or γ3) (1,2). AMPKα2 is the predominant catalytic form of AMPK in the liver, muscle, and hypothalamus. There is evidence that AMPKα2 is important for the regulation of systemic insulin sensitivity and metabolic homeostasis. In the hypothalamus, AMPKα2 signals regulate food intake and body weight gain (3). Mice globally deficient in AMPKα2 display different metabolic phenotypes when fed different diets (4,5). A lack of AMPKα2 activity in skeletal muscle exacerbates glucose intolerance and the insulin resistance that is caused by high-fat diets (HFDs) (6). In addition, AMPKα2 is required for the effects of many physiologic regulators or pharmaceutical modalities that maintain insulin sensitivity and metabolic homeostasis (7–10).Mice deficient in AMPKα1 had an increased inflammatory response in an experimental autoimmune encephalomyelitis model (11). AMPKα1 deficiency elevated the levels of reactive oxygen species and oxidized proteins, thereafter shortening the erythrocyte life span in mice (12). Macrophage AMPKα1 has been characterized as a key regulator of inflammatory function (13,14). Its role in protecting against diet-induced metabolic disorders has been hypothesized but not demonstrated (14). The activation of AMPK in adipocytes with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) suppresses adipocyte differentiation and diet-induced obesity (15). However, the activation of AMPK is able to reduce isoproterenol-induced lipolysis; this result is supported by a decrease in adipocyte size and adipose mass in globally deficient in AMPKα1 (AMPKα1^−/−) mice (16). To define the physiologic role of AMPKα1 in energy homeostasis, we administered an HFD to AMPKα1^−/− mice and then evaluated diet-induced obesity and insulin resistance. We also used bone marrow (BM) transplantation (BMT) to characterize the specific roles of AMPKα1 in macrophages and adipocytes in the regulation of the diet-induced inflammatory response, adiposity, and systemic insulin resistance.     

“Deficiency” of Mitochondria in Muscle Does Not Cause Insulin Resistance

Based on evidence that patients with type 2 diabetes (T2DM), obese insulin-resistant individuals, and lean insulin-resistant offspring of parents with T2DM have ∼30% less mitochondria in their muscles than lean control subjects, it appears to be widely accepted that mitochondrial “deficiency” is responsible for insulin resistance. The proposed mechanism for this effect is an impaired ability to oxidize fat, resulting in lipid accumulation in muscle. The purpose of this counterpoint article is to review the evidence against the mitochondrial deficiency concept. This evidence includes the findings that 1) development of insulin resistance in laboratory rodents fed high-fat diets occurs despite a concomitant increase in muscle mitochondria; 2) mitochondrial deficiency severe enough to impair fat oxidation in resting muscle causes an increase, not a decrease, in insulin action; and 3) most of the studies comparing fat oxidation in insulin-sensitive and insulin-resistant individuals have shown that fat oxidation is higher in T2DM patients and obese insulin-resistant individuals than in insulin-sensitive control subjects. In conclusion, it seems clear, based on this evidence, that the 30% reduction in muscle content of mitochondria in patients with T2DM is not responsible for insulin resistance.In a series of studies, Kelley and colleagues (1–4) measured the levels of activity of mitochondrial marker enzymes in skeletal muscles from patients with T2DM or obese insulin-resistant individuals and found that they were lower than in normal, healthy individuals of the same age. In these studies, the enzymes that were measured were citrate synthase (1,3), cytochrome oxidase (2,3), NADH₂ oxidoreductase (1,3), carnitine palmitoyl transferase (2), and succinate dehydrogenase (4). The activities of these enzymes were 20–40% lower in the diabetic patients than in normal control subjects. The mitochondria in diabetic muscle were also smaller than normal (1). They referred to these findings as “mitochondrial dysfunction,” although no measurements of function were made; and although this phenomenon is sometimes referred to as mitochondrial dysfunction, studies in which mitochondrial function was evaluated found that the remaining mitochondria in diabetic muscle have normal function (5–7). There is evidence suggesting that accumulation of lipids in muscle plays a role in mediating insulin resistance, and Kelley and colleagues hypothesized that the reduction in muscle mitochondria in T2DM impairs the ability of muscle to oxidize fatty acids, resulting in muscle lipid accumulation and, as a result, insulin resistance.These articles were followed by publication of a number of studies showing that patients with T2DM, obese insulin-resistant individuals, and lean insulin-resistant offspring of diabetic parents have a ∼30% reduction in muscle mitochondrial content (8–11), suggesting that the only abnormality is a ∼30% decrease in size or number of mitochondria. The mechanism responsible for the reduction in mitochondrial content of diabetic skeletal muscle is not known. One possibility that has been suggested is that the decrease in mitochondria is due to impaired insulin action (12). A second is that it is mediated by oxidative stress (13). A third is that it is due to low physical activity. Another possibility is that it is genetically determined, i.e., that it is a genetic trait that is linked to the genetic predisposition to develop insulin resistance and T2DM. This third possibility is suggested by the findings that reversal of T2DM by weight loss does not result in normalization of muscle mitochondrial content (14), and that some lean offspring of diabetic parents are insulin resistant and have a reduced muscle content of mitochondria (10).As a result of the many studies showing that T2DM patients, insulin-resistant obese people, and insulin resistant offspring of diabetic parents generally have a ∼30% reduction in muscle mitochondria, the hypothesis that insulin resistance is mediated by a deficiency of muscle mitochondria appears to have gained considerable acceptance (15,16). Assuming that mitochondrial deficiency causes insulin resistance because these two phenomena occur together, i.e., with this, therefore, because of this, is a logical fallacy. Correlation provides no information regarding causality. This raises the question, is there any scientific evidence in support of the hypothesis? As reviewed in the three following sections, the answer is no, the available experimental evidence shows that a decrease in muscle mitochondria does not cause insulin resistance.     

Transgenic Restoration of Long-Chain n-3 Fatty Acids in Insulin Target Tissues Improves Resolution Capacity and Alleviates Obesity-Linked Inflammation and Insulin Resistance in High-Fat�CFed Mice

OBJECTIVE

The catabasis of inflammation is an active process directed by n-3 derived pro-resolving lipid mediators. We aimed to determine whether high-fat (HF) diet-induced n-3 deficiency compromises the resolution capacity of obese mice and thereby contributes to obesity-linked inflammation and insulin resistance.

RESEARCH DESIGN AND METHODS

We used transgenic expression of the fat-1 n-3 fatty acid desaturase from C. elegans to endogenously restore n-3 fatty acids in HF-fed mice. After 8 weeks on HF or chow diets, wild-type and fat-1 transgenic mice were subjected to insulin and glucose tolerance tests and a resolution assay was performed. Metabolic tissues were then harvested for biochemical analyses.

RESULTS

We report that the n-3 docosanoid resolution mediator protectin D1 is lacking in muscle and adipose tissue of HF-fed wild-type mice. Accordingly, HF-fed wild-type mice have an impaired capacity to resolve an acute inflammatory response and display elevated adipose macrophage accrual and chemokine/cytokine expression. This is associated with insulin resistance and higher activation of iNOS and JNK in muscle and liver. These defects are reversed in HF-fed fat-1 mice, in which the biosynthesis of this important n-3 docosanoid resolution mediator is improved. Importantly, transgenic restoration of n-3 fatty acids prevented obesity-linked inflammation and insulin resistance in HF-fed mice without altering food intake, weight gain, or adiposity.

CONCLUSIONS

We conclude that inefficient biosynthesis of n-3 resolution mediators in muscle and adipose tissue contributes to the maintenance of chronic inflammation in obesity and that these novel lipids offer exciting potential for the treatment of insulin resistance and diabetes.Obesity is linked to chronic inflammation that plays a key role in the pathogenesis of insulin resistance, leading the way to type 2 diabetes and cardiovascular disease (1,2). Efforts to understand this process have focused on identifying the many factors that may initiate and promote inflammation. We took an alternate approach with the view that pathological inflammation in obesity likely represents an impaired endogenous capacity to “switch off” or more precisely counterregulate the natural immune response to adipose tissue expansion and lipid excess.The newly identified genus of n-3 derived lipid mediators termed resolvins and protectins have been shown to play an important role in the endogenous regulation of inflammation (3,4). Interestingly, dietary long-chain n-3 polyunsaturated fatty acid (PUFA) insufficiency has been linked to the incidence of chronic metabolic disorders, including type 2 diabetes and cardiovascular disease (5–7). It is thus conceivable that inefficient biosynthesis of n-3 resolution mediators due to low substrate availability might inherently contribute to the development of obesity-linked inflammation.González-Périz et al. recently showed that acute administration of n-3 derived Resolvin E1 (RvE1) prevents hepatic steatosis in genetically obese mice (8). However, the other main resolution mediator Protectin D1 (PD1) remains to be investigated, and it is unknown whether high-fat (HF) feeding per se actually restricts resolution mediator biosynthesis and whether this might alter the endogenous resolution capacity of obese mice. Furthermore, it is critical to determine whether n-3 lipid mediators regulate key obesity-related inflammatory reactions such as macrophage accrual in adipose tissue or activation of inflammatory signaling molecules such as JNK and iNOS that play a role in the etiology of insulin resistance (1,2).Unfortunately, studying the effects of dietary n-3 content in the context of HF feeding has proven to be rather complicated because incorporation of n-3 fatty acids in rodent diets often prevents weight gain (9). As a result, it is not clear whether it is the lack of weight gain or the n-3 fatty acids themselves that offer the protection from insulin resistance and type 2 diabetes and what mechanism underlies this protection. Therefore, innovative models that overcome the requirement for dietary manipulation are needed to help clarify whether or not n-3 fatty acids act directly to prevent obesity-linked insulin resistance and which mechanisms are involved.The fat-1 transgenic mouse has been genetically engineered to ubiquitously express the fat-1 n-3 fatty acid desaturase from C. elegans (10). This enzyme, not found in mammals, efficiently converts endogenous n-6 to n-3 fatty acids such that, in fat-1 mice fed a diet extremely rich in n-6 and deficient in n-3, the tissue n-6:n-3 ratio is ∼1:1 compared with ∼50:1 in wild-type animals. The fat-1 transgenic mouse therefore represents the ideal model to study the effects of n-3 fatty acids in an environment that is not confronted by dietary issues.Herein we show that HF feeding wild-type mice results in diminished n-3 docosanoid resolution mediator synthesis in muscle and adipose tissue and impaired resolution. Transgenic restoration of n-3 fatty acids in HF-fed fat-1 mice improved resolution capacity and prevented the development of obesity-linked inflammation and insulin resistance. These data uncover a new role for pro-resolving lipid mediators in the counterregulation of obesity-linked inflammation and its associated metabolic complications.     

Comparison of Permacol™ and Strattice™ for the repair of abdominal wall defects

Background  

Incisional hernias repaired with mesh can be expected have a lower recurrence rate than with primary repair. Biologic implants have replaced synthetic meshes in certain complex settings. We compared two porcine-dermis derived implants—cross-linked Permacol™ biologic implant and non-cross linked Strattice-firm™ tissue matrix—in a ventral hernia animal model. Our hypothesis is that cross-linked biologic implants are remodeled differently and thus behave differently than non-cross-linked biologic implants.     

Disruption of the Cereblon Gene Enhances Hepatic AMPK Activity and Prevents High-Fat Diet–Induced Obesity and Insulin Resistance in Mice

A nonsense mutation in cereblon (CRBN) causes a mild type of mental retardation in humans. An earlier study showed that CRBN negatively regulates the functional activity of AMP-activated protein kinase (AMPK) in vitro by binding directly to the α₁-subunit of the AMPK complex. However, the in vivo role of CRBN was not studied. For elucidation of the physiological functions of Crbn, a mouse strain was generated in which the Crbn gene was deleted throughout the whole body. In Crbn-deficient mice fed a normal diet, AMPK in the liver showed hyperphosphorylation, which indicated the constitutive activation of AMPK. Since Crbn-deficient mice showed significantly less weight gain when fed a high-fat diet and their insulin sensitivity was considerably improved, the functions of Crbn in the liver were primarily investigated. These results provide the first in vivo evidence that Crbn is a negative modulator of AMPK, which suggests that Crbn may be a potential target for metabolic disorders of the liver.Initially, cereblon (CRBN) was identified as a target gene for a mild type of mental retardation in humans (1) and was subsequently characterized in several different functional contexts. CRBN interacts directly with large-conductance calcium-activated potassium channels and regulates their surface expression (2). Later, CRBN was identified as a primary target for thalidomide-induced teratogenicity and as a substrate receptor for the E3 ligase complex (3). More recently, we reported that CRBN interacts directly with the α₁-subunit of AMP-activated protein kinase (AMPK) and inhibits activation of the enzyme in vitro (4).AMPK is a metabolic master switch in response to variations in cellular energy homeostasis (5). The activity of AMPK can be modulated by the phosphorylation of a threonine at position 172 (Thr172) in the α-subunit by upstream kinases such as LKB1 (6). AMPK inactivates acetyl-CoA carboxylase (ACC) via direct protein phosphorylation and suppresses expression of lipogenic genes, including fatty acid synthase (FAS), thereby inhibiting fatty acid synthesis (7,8). AMPK is implicated in the regulation of hepatic glucose and lipid metabolism, thereby affecting the energy status of the whole body (7,9). Moreover, AMPK was identified as a major pharmacological target protein for the treatment of metabolic diseases. For example, experimental animal models of type 2 diabetes and obesity show that activation of AMPK by metformin or 5-aminoimidazole-4-carboxamide ribonucleoside reduces blood glucose levels and improves lipid metabolism (10–12).Our recent study found that CRBN interacted directly with the AMPK α₁-subunit both in cultured cell lines and in vitro, and the binding sites within the two proteins were localized (4). The levels of the AMPK γ-subunit and CRBN in the AMPK complex varied in a reciprocal manner; i.e., a higher CRBN content corresponded to lower γ-subunit content. AMPK activation was reduced as its γ-subunit content was decreased by CRBN. Thus, it was proposed that CRBN may act as a negative regulator of AMPK in vivo (4). The aims of the current study were to test this hypothesis and to understand the physiological role(s) of CRBN by generating Crbn knockout (KO) mice. The results showed that AMPK activity was activated constitutively in Crbn KO mice under normal conditions and that Crbn KO mice fed a long-term high-fat diet (HFD) showed a marked improvement in their metabolic status.     

Overexpression of Sphingosine Kinase 1 Prevents Ceramide Accumulation and Ameliorates Muscle Insulin Resistance in High-Fat Diet–Fed Mice

The sphingolipids sphingosine-1-phosphate (S1P) and ceramide are important bioactive lipids with many cellular effects. Intracellular ceramide accumulation causes insulin resistance, but sphingosine kinase 1 (SphK1) prevents ceramide accumulation, in part, by promoting its metabolism into S1P. Despite this, the role of SphK1 in regulating insulin action has been largely overlooked. Transgenic (Tg) mice that overexpress SphK1 were fed a standard chow or high-fat diet (HFD) for 6 weeks before undergoing several metabolic analyses. SphK1 Tg mice fed an HFD displayed increased SphK activity in skeletal muscle, which was associated with an attenuated intramuscular ceramide accumulation compared with wild-type (WT) littermates. This was associated with a concomitant reduction in the phosphorylation of c-jun amino-terminal kinase, a serine threonine kinase associated with insulin resistance. Accordingly, skeletal muscle and whole-body insulin sensitivity were improved in SphK1 Tg, compared with WT mice, when fed an HFD. We have identified that the enzyme SphK1 is an important regulator of lipid partitioning and insulin action in skeletal muscle under conditions of increased lipid supply.Obesity is associated with the development of insulin resistance and type 2 diabetes. The pathogenesis of insulin resistance is a well-investigated area, yet the precise interplay between the molecular pathways that leads to this disorder is not fully understood (1). Extensive evidence, however, suggests that defects in fatty acid (FA) metabolism and subsequent lipid accumulation in liver and skeletal muscle play a major role (2,3). Although the increase in lipid manifests as an increase in triacylglycerol (TAG), it is likely that this is a marker of dysfunctional FA metabolism and that accumulation of bioactive lipids, such as ceramide and diacylglycerol (DAG), impair insulin action. DAG accumulation in muscle is associated with insulin resistance in humans (4), whereas mice with DAG kinase delta haploinsufficiency display increased DAG content and reduced peripheral insulin sensitivity (5).Ceramide is a potent lipid-signaling molecule that can cause insulin resistance by inhibiting the ability of insulin to activate Akt (6) and/or via the activation of c-jun amino terminal kinase (JNK) (7,8). Importantly, preventing ceramide accumulation by inhibiting de novo ceramide synthesis protects against the development of insulin resistance (9,10). These observations support the hypothesis that increases in ceramide are an important mechanism underlying the development of muscle insulin resistance, and therefore, targeting pathways to prevent ceramide accumulation may be a viable therapeutic approach.One such approach is to increase ceramide degradation and clearance. Two important enzymes in this pathway are ceramidase and sphingosine kinase (SphK). Ceramidase is responsible for converting ceramide to sphingosine, and SphK phosphorylates sphingosine to sphingosine 1 phosphate (S1P). Because breakdown of S1P is the only way for cellular lipids to exit the sphingolipid pathway, SphK is important in regulating sphingolipid metabolism (11). SphK exists in two isoforms, SphK1 and SphK2. Despite clear evidence that SphK1 activation reduces ceramide (12,13), the role of SphK1 in regulating insulin action has been largely overlooked. Activation of SphK1 prevents ceramide accumulation by promoting its metabolism into S1P. SIP is a molecule with many complex functions: it not only activates five specific G-coupled protein receptors that subsequently activate many downstream signaling pathways but also has important second messenger actions (14). SIP is generally thought to promote activation of inhibitor of κ kinase-β (IKK-β) and JNK via upstream activation of transforming growth factor-β–activated kinase 1 (14), however, SphK1 can block JNK activation (13,15) and prevent tissue inflammation (15), which is linked to insulin resistance (16). In contrast, inhibiting SphK1 leads to JNK activation (17). Interestingly, S1P itself opposes the effects of ceramide. For example, S1P has been shown to counteract ceramide-induced activation of JNK (18). Thus, it has been proposed that the ceramide-to-S1P ratio may function as an intracellular rheostat (19,20).Although not well studied in the context of metabolic disease, evidence is emerging to suggest that the sphingolipid rheostat is important in regulating insulin action. Adiponectin has been thought to exert insulin-sensitizing effects via activation of AMP-activated protein kinase (AMPK) (21). However, Scherer and colleagues (22) recently provided compelling evidence that adiponectin, by stimulating ceramidase activity, decreases intracellular ceramide and concomitantly increases S1P. Hence, the dynamic balance between the levels of ceramide and S1P may have implications for the development of obesity-induced insulin resistance. The aim of the current study was, therefore, to examine the role of SphK in regulating skeletal muscle ceramide content and insulin sensitivity in conditions of lipid oversupply. We hypothesized that SphK1 overexpression would promote flux through the sphingolipid degradative pathway, which would prevent high-fat diet (HFD)–induced ceramide accumulation and, therefore, enhance muscle insulin action.     

Recurrence of chronic subdural hematoma after trepanation and drainage

Objective: To sum up the causes of recurrence of chronic subdural hematoma (CSDH) from failure of trepanation and drainage and explore its prevention and treatment. Methods- From October 1988 to June 2002 a total of 358 patients with CSDH were treated with trepanation and drainage in our hospital. Among them 15 patients had recurrence of CSDH after operation. The data of the 15 patients were reviewed retrospectively. Results: Of the 15 patients, 13 were cured by retrepanation and redrainage, one cured by removal of hematoma by craniotomy with bone flap, and one, a 1-year old child, gave up reoperation due to severe encephalatrophy. Conclusions: Most CSDHs which recur after trepanation and drainage can be cured by retrepanation and redrainage. For the patients with repeated recurrence of CSDH removal of hematoma capsule can be considered.The causes of recurrence of CSDH are related to disease course, the thickness of hematoma capsule, the severity of encephalatraphy and whether the hematoma cavity is drained or irrigated completely, and operation methods.     

What is the Effect of Laparoscopic Colectomy on Pattern of Colon Cancer Recurrence? A Propensity Score and Competing Risk Analysis Compared with Open Colectomy

Background

Variability in colon cancer recurrence after laparoscopic colectomy (LAC) remains poorly understood. The aim of our study was to quantify the influence of LAC on colon cancer recurrence patterns.

Methods

We included 986 patients undergoing curative colectomy at our institution between 1992 and 2008. Kaplan–Meier, multivariable Cox regression, propensity score adjustment, and competing risks modeling were used to evaluate the influence of laparoscopic surgery on the site of colon cancer recurrence, including the following: liver metastasis, lung metastasis, local recurrence, peritoneal dissemination, other, and multiple sites. We estimated the risk factors for each recurrence site.

Results

Laparoscopic surgery was used in 419 (42.5 %) of 986 patients, with an overall median follow-up time of 5.0 years (interquartile range 3.5). The overall 5-year disease-free survival rate was 86.1 % (open surgery 81.8 % vs. laparoscopic surgery 92.0 %; p < 0.001). However, after covariates and propensity score adjustment, laparoscopic surgery was not a significant risk factor for each type of recurrence: liver hazard ratio (HR) 0.93 (95 % CI 0.45–1.89), p = 0.84; lung HR 0.67 (95 % CI 0.26–1.70), p = 0.39; local HR 0.56 (95 % CI 0.12–2.63), p = 0.46; peritoneal HR 2.49 (95 % CI 0.75–8.27), p = 0.14; others HR 0.47 (95 % CI 0.04–5.13), p = 0.53; multiple HR 0.88 (95 % CI 0.25–3.14), p = 0.84. The risk factors for each type of recurrence were variable and characterized by specific clinicopathological features.

Conclusion

Our study reveals that LAC and open colectomy demonstrate comparable overall colon cancer recurrence rates and recurrence sites. Specific clinicopathological characteristics may have a stronger influence on colon cancer recurrence site compared with the surgical technique.     

Insulin Resistance,Leptin and TNF-α System in Morbidly Obese Women after Gastric Bypass

Obesity is a complex disease associated with insulin resistance. Leptin and the TNF-α system could be involved in the pathogenesis of obesity and insulin resistance. Gastric bypass (GBP) is a surgical treatment for morbidly obese patients. We conducted a study after GBP to analyze the pattern of variation of anthropometric and body composition variables, leptin and sTNFR1 and 2. Methods: 29 morbidly obese women were studied, at baseline and throughout 6 months after gastric bypass. Results: At baseline, the BMI was 49 ± 6 kg/m² and patients showed a higher fasting insulin resistance index (FIRI), leptin, leptin/fat mass and sTNFR1 and 2 than did controls. 6 months after GBP, BMI was 35±4, and FIRI, leptin and leptin/fat mass decreased significantly in the first months and throughout the follow-up. sTNFR1 and 2 showed an initial increase, but at 6 months their concentrations were similar to baseline (2.6±0.8 vs 3.1±0.95 ng/ml, P < 0.05; 4.6±1.4 vs 7±2.5 ng/ml, P < 0.05). At baseline, there was no correlation between leptin and BMI and body composition variables but there was a correlation with fat mass (r=0.42, P=0.004) and sTNFR1 (r=0.58, P=0.001). At 6 months, there was a correlation between leptin and BMI (r=0.53, P=0.004) and sTNFR1 (r=0.46, P=0.013). Conclusions: Morbidly obese women after GBP became less insulin resistant with lower leptin concentrations, but showed an initial increase of sTNFR1 and 2. This pattern of variation of the leptin TNF-α axis suggests a disregulation of the system after dramatic weight loss and also that insulin and leptin up-regulate TNF-α production irrespective of insulin resistance status.     

Correlation Between Post Over Preoperative Surrogate Insulin Resistance Indexes’ Ratios and Reversal of Metabolic Syndrome After Roux-en-Y Gastric Bypass

Metabolic syndrome (MetS) is strongly linked to insulin resistance and has a high resolution rate after bariatric surgery. This study aims to determine whether post over preoperative ratios of surrogate insulin resistance markers (HOMA, TyG, and TG/HDL-c) are associated to postsurgical MetS reversal. This is a retrospective cohort study which involved 96 subjects with MetS who underwent Roux-en-Y gastric bypass (RYGB). Post over preoperative ratios of TyG and TG/HDL-c indexes were statistically associated to MetS resolution. The use of these ratios as a way to assess postsurgical insulin sensitivity response appears to be a simple and useful tool in clinical practice.