OBJECTIVE AND BACKGROUND:Local and distant disease recurrence are frequently observed following pancreatic cancer resection, but an improved understanding of resection margin assessment is required ...to aid tailored therapies.
METHODS:Analyses were carried out to assess the association between clinical characteristics and margin involvement as well as the effects of individual margin involvement on site of recurrence and overall and recurrence-free survival using individual patient data from the European Study Group for Pancreatic Cancer (ESPAC)-3 randomized controlled trial.
RESULTS:There were 1151 patients, of whom 505 (43.9%) had an R1 resection. The median and 95% confidence interval (CI) overall survival was 24.9 (22.9–27.2) months for 646 (56.1%) patients with resection margin negative (R0 >1 mm) tumors, 25.4 (21.6–30.4) months for 146 (12.7%) patients with R1<1 mm positive resection margins, and 18.7 (17.2–21.1) months for 359 (31.2%) patients with R1-direct positive margins (P < 0.001). In multivariable analysis, overall R1-direct tumor margins, poor tumor differentiation, positive lymph node status, WHO performance status ≥1, maximum tumor size, and R1-direct posterior resection margin were all independently significantly associated with reduced overall and recurrence-free survival. Competing risks analysis showed that overall R1-direct positive resection margin status, positive lymph node status, WHO performance status 1, and R1-direct positive superior mesenteric/medial margin resection status were all significantly associated with local recurrence.
CONCLUSIONS:R1-direct resections were associated with significantly reduced overall and recurrence-free survival following pancreatic cancer resection. Resection margin involvement was also associated with an increased risk for local recurrence.
In this paper, a nanostructured biosensor is developed to detect glucose in tear by using fluorescence resonance energy transfer (FRET) quenching mechanism. The designed FRET pair, including the ...donor, CdSe/ZnS quantum dots (QDs), and the acceptor, dextran-binding malachite green (MG-dextran), was conjugated to concanavalin A (Con A), an enzyme with specific affinity to glucose. In the presence of glucose, the quenched emission of QDs through the FRET mechanism is restored by displacing the dextran from Con A. To have a dual-modulation sensor for convenient and accurate detection, the nanostructured FRET sensors were assembled onto a patterned ZnO nanorod array deposited on the synthetic silicone hydrogel. Consequently, the concentration of glucose detected by the patterned sensor can be converted to fluorescence spectra with high signal-to-noise ratio and calibrated image pixel value. The photoluminescence intensity of the patterned FRET sensor increases linearly with increasing concentration of glucose from 0.03mmol/L to 3mmol/L, which covers the range of tear glucose levels for both diabetics and healthy subjects. Meanwhile, the calibrated values of pixel intensities of the fluorescence images captured by a handhold fluorescence microscope increases with increasing glucose. Four male Sprague-Dawley rats with different blood glucose concentrations were utilized to demonstrate the quick response of the patterned FRET sensor to 2µL of tear samples.
•The nanostructured biosensor is designed for dual detection of tear glucose.•Fluorescence intensity increases linearly with glucose level from 0.03 to 3mM.•Image pixel intensity value of the sensor is corresponding to the glucose level.•Animal test indicates the sensor can measure 2µL tear glucose in 30s.
The purpose of this study was to examine sex-specific differences in the blood glucose (BG) response to recurrent aerobic exercise in type 1 diabetes rats. Specifically, we examined the role of peak ...estrogen (E2) concentrations during proestrus on BG response to prolonged repetitive aerobic exercise. To do so, nineteen Sprague-Dawley rats were assigned to four exercised groups: control female (CXF; n = 5), control male (CXM; n = 5), diabetic female (DXF, n = 5) and diabetic male (DXM, n = 4). Diabetes was induced in DX groups via subcutaneous multiple injections of low dose streptozotocin (20mg/day for 7 days). After four days of exercise, muscle and liver glycogen content, liver gluconeogenic enzyme content, muscle Beta oxidation activity and BG responses to exercise were compared. The final bout of exercise took place during proestrus when E2 concentrations were at their highest in the female rats. During days 1–3 DXM had significantly lower BG concentrations during exercise than DXF. While both T1DM and non-T1DM females demonstrated higher hepatic G6Pase expression and muscle beta oxidation activity levels on day 4 exercise, no differences in BG response between the male and female T1DM rats were evident. Further, no differences in liver and muscle glycogen content following day 4 of exercise were seen between the sexes. These results would suggest that heightened E2 levels during proestrus may not be an important factor governing glucose counter regulatory response to exercise in female T1DM rats. Rather, the pre-exercise blood glucose levels are likely to be a large determinant of the blood glucose response to exercise in both male and female rats.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Previous studies have suggested that the loss of microvessel density in the peripheral circulation with evolving metabolic disease severity represents a significant contributor to impaired skeletal ...muscle oxygenation and fatigue-resistance. Based on this and our recent work, we hypothesized that cerebral microvascular rarefaction was initiated from the increased prooxidant and proinflammatory environment with metabolic disease and is predictive of the severity of the emergence of depressive symptoms in obese Zucker rats (OZRs). In male OZR, cerebrovascular rarefaction followed the emergence of elevated oxidant and inflammatory environments characterized by increased vascular production of thromboxane A
(TxA
). The subsequent emergence of depressive symptoms in OZR was associated with the timing and severity of the rarefaction. Chronic intervention with antioxidant (TEMPOL) or anti-inflammation (pentoxifylline) therapy blunted the severity of rarefaction and depressive symptoms, although the effectiveness was limited. Blockade of TxA
production (dazmegrel) or action (SQ-29548) resulted in a stronger therapeutic effect, suggesting that vascular production and action represent a significant contributor to rarefaction and the emergence of depressive symptoms with chronic metabolic disease (although other pathways clearly contribute as well). A de novo biosimulation of cerebrovascular oxygenation in the face of progressive rarefaction demonstrates the increased probability of generating hypoxic regions within the microvascular networks, which could contribute to impaired neuronal metabolism and the emergence of depressive symptoms. The results of the present study also implicate the potential importance of aggressive prodromic intervention in reducing the severity of chronic complications arising from metabolic disease.
With clinical studies linking vascular disease risk to depressive symptom emergence, we used obese Zucker rats, a model of chronic metabolic disease, to identify potential mechanistic links between these two negative outcomes. Depressive symptom severity correlated with the extent of cerebrovascular rarefaction, after increased vascular oxidant stress/inflammation and TxA
production. Anti-TxA
interventions prevasculopathy blunted rarefaction and depressive symptoms, while biosimulation indicated that cerebrovascular rarefaction increased hypoxia within capillary networks as a potential contributing mechanism.
The etiology of insulin resistance (IR) in Type 1 Diabetes (T1D) is unclear; however, intramyocellular lipids (IMCL) are likely contributors. While exercise lessens IR and IMCL content; T1D patients ...elevate glycemia to offset exercise-induced hypoglycemic risk. The preferred treatment for T1D patients is tight glucose management through intensive insulin therapy (IIT); however, IIT is accompanied with a sedentary lifestyle. The purpose of this study was to examine IR development and IMCL in combined exercise (DARE; aerobic/resistance) and IIT-treated T1D animals. 76 rats were divided into control sedentary (C), diabetic sedentary (CD), diabetes sedentary intensive insulin therapy (DIT) and DARE groups. Following streptozotocin (STZ), glycemia was maintained at either 9-15 mM (CD, DARE) or 5-9 mM (DIT) using insulin. DARE alternated between running and weighted climbing for 12 weeks. Results demonstrate that DARE exhibited reduced onset of IR compared with C, DIT and CD, indicated by increased glucose infusion rate (hyperinsulinemic-euglycemic-clamp). A shift in lipid metabolism was evident whereby diacylglycerol was elevated in DIT compared to DARE, while triacylglycerol was elevated in DARE. These findings indicate enhanced IMCL metabolism and the sequestration of fat as neutral triacylglycerol leads to reduced IR in DARE. In contrast, IIT and sedentary behavior leads to diacylglycerol accumulation and IR.
•Despite moderate hyperglycemia, combined exercise leads to greater increases in insulin sensitivity in comparison to intensive insulin therapy alone.•Combined exercise leads to a reduction in harmful DAG accumulation in skeletal muscle that was evident in intensively insulin treated Type 1 diabetic rats.•Exercise may mitigate insulin resistance development in Type 1 Diabetes through the increased ability to oxidize glucose and harmful fat intermediates in skeletal muscle rather than via improvements to the insulin signaling pathway.
Intensive insulin therapy (IIT; 4–7 mmol/L) is the preferred treatment for type 1 diabetes mellitus (T1DM) patients to reduce the risk of cardiovascular disease (CVD). However, this treatment ...strategy has been questioned as it is accompanied with a sedentary lifestyle leading to weight gain and insulin resistance. T1DM patients who partake in high-intensity aerobic training (AThigh) to reduce CVD often utilize conventional insulin therapy (CIT; 9–15 mmol/L) to offset the risk of hypoglycemia. Moreover, exercise modalities incorporating resistance training (RT) have been shown to further reduce this risk. The purpose of this investigation was twofold: (1) to determine if CIT paired with AThigh results in larger cardioprotection from an ischemia-reperfusion (I-R) injury than IIT and (2) to establish if the integration of RT with AThigh (ART) results in similar cardioprotection as AThigh. Diabetic (D) male Sprague-Dawley rats were divided into D-IIT (n=12), D-CIT (n=12), D-AThigh (n=8), D-RT (n=8), and D-ART (n=8). T1DM was induced with streptozotocin, and blood glucose was adjusted with insulin. D-AThigh occurred on a treadmill (27 m/min; 1 hr), D-RT performed weighted ladder climbs, and D-ART alternated daily between AThigh and RT. Exercise occurred 5 days/wk for 12 wks. This investigation demonstrates that cardioprotection following an I-R injury was similar between D-AThigh and D-IIT. This cardioprotection is not exercise-specific, and each provides unique advantages. D-AThigh leads to improved glycemia while insulin sensitivity was enhanced following resistance exercises. Thus, exercise is an effective means to elicit cardioprotection in T1DM. However, in addition to glycemia, other factors should be considered when tailoring an exercise program for T1DM patients.
OBJECTIVETo compare the risk of 1-year ischemic stroke recurrence between atrial fibrillation (AF) diagnosed after stroke (AFDAS) and sinus rhythm (SR) and investigate whether underlying heart ...disease is as frequent in AFDAS as it is in AF known before stroke (KAF).
METHODSIn this retrospective cohort study, we included all ischemic stroke patients admitted to institutions participating in the Ontario Stroke Registry from July 1, 2003, to March 31, 2013. Based on heart rhythm assessed during admission, we classified patients as AFDAS, KAF, or SR. We modeled the relationship between heart rhythm groups and 1-year ischemic stroke recurrence by using Cox regression adjusted for multiple covariates (e.g., oral anticoagulants). We compared the prevalence of coronary artery disease, myocardial infarction, and heart failure among the 3 groups.
RESULTSAmong 23,376 ischemic stroke patients, 15,885 had SR, 587 AFDAS, and 6,904 KAF. At 1 year, 39 (6.6%) patients with AFDAS, 661 (9.6%) with KAF, and 1,269 (8.0%) with SR had recurrent ischemic strokes (p = 0.0001). AFDAS-related ischemic stroke recurrence adjusted risk was not different from that of SR (hazard ratio 0.90 95% confidence interval 0.63, 1.30; p = 0.57). Prevalence of coronary artery disease (18.2% vs 34.7%; p < 0.0001), myocardial infarction (11.6% vs 20.5%; p < 0.0001), and heart failure (5.5% vs 16.8%; p < 0.0001) were lower in AFDAS relative to KAF.
CONCLUSIONSThe lack of difference in 1-year ischemic stroke recurrence between AFDAS and SR and the lower prevalence of heart disease in AFDAS compared to KAF suggest that the underlying pathophysiology of AFDAS may differ from that of KAF.
The etiology of insulin resistance in Type 1 Diabetes (T1D) is unknown, however it affects approximately 20% of T1D patients. Intramyocellular lipids (IMCL) have been identified as a mechanism of ...insulin resistance. We examined skeletal muscle of T1D rats to determine if alterations in lipid metabolism were evident and whether aerobic exercise training improves IMCL and insulin resistance. To do so, 48 male Sprague-Dawley rats were divided into control (C), sedentary diabetes (D) and diabetes exercise (DX) groups. Following multiple low-dose Streptozotocin (STZ) injections (20 mg/kg), glycemia (9-15 mM) was maintained using insulin treatment. DX were treadmill trained at high intensity (~75% V02max; 5days/week) for 10 weeks. The results demonstrate that D exhibited insulin resistance compared with C and DX, indicated by decreased glucose infusion rate during a hyperinsulinemic-euglycemic clamp (p < 0.05). There were no differences between C and DX, suggesting that exercise improved insulin resistance (p < 0.05). Metabolomics analysis revealed a significant shift in lipid metabolism whereby notable fatty acid metabolites (arachidonic acid, palmitic acid and several polyunsaturated fatty acids) were significantly elevated in D compared to C and DX. Based on the intermediates observed, insulin resistance in T1D is characterized by an insulin-desensitizing intramyocellular fatty acid metabolite profile that is ameliorated with exercise training.
Heat shock proteins and exercise: a primer Noble, Earl G; Milne, Kevin J; Melling, C.W. James
Applied physiology, nutrition, and metabolism,
10/2008, Letnik:
33, Številka:
5
Journal Article
Recenzirano
Heat shock proteins (HSPs) are, in general, prosurvival molecules within the cellular environment, and the overexpression of even just 1 family of HSPs can lead to protection against and improvements ...after a variety of stressors. Not surprisingly, a fertile area of study has grown out of effors to exploit the innate biologic behaviour of HSPs. Exercise, because of the inherent physiologic stresses associated with it, is but 1 stimulus that can result in a robust increase in various HSPs in several tissues, not the least of which happen to be the heart and skeletal muscle. The purpose of this review is to introduce the reader to the major HSP families, the control of their expression, and some of their biologic functions, specifically with respect to the influence of exercise. Moreover, as the first in a series of reviews from a common symposium, we will briefly introduce the concepts presented by the other authors, which include the effects of different exercise paradigms on skeletal muscle HSPs in the adult and aged systems, HSPs as regulators of inflammation, and the ion channel stabilizing effects of HSPs.
Celotno besedilo
Dostopno za:
DOBA, FSPLJ, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Imaging Islets Labeled With Magnetic Nanoparticles at 1.5 Tesla
Joo Ho Tai 1 ,
Paula Foster 2 ,
Alma Rosales 1 ,
Biao Feng 1 ,
Craig Hasilo 3 ,
Violetta Martinez 4 ,
Soha Ramadan 2 ,
Jonatan Snir 2 ,
...C.W. James Melling 3 ,
Savita Dhanvantari 5 ,
Brian Rutt 2 and
David J.G. White 1 3
1 Department of Transplantation, Robarts Research Institute, London, Ontario, Canada
2 Imaging Research Laboratories, Robarts Research Institute, London, Ontario, Canada
3 Human Islet Transplantation Program, London Health Sciences Centre, London, Ontario, Canada
4 Department of Pathology, London Health Sciences Centre, London, Ontario, Canada
5 Department of Medical Biophysics and Medicine, University of Western Ontario, Lawson Health Research Institute, London, Ontario,
Canada
Address correspondence and reprint requests to Dr. David J.G. White, FRCPath, PhD, Novartis/Stiller Professor of Xenotransplantation,
Robarts Research Institute, Room 200, SDRI Building, University of Western Ontario, 1400 Western Rd., London, Ontario, Canada
N6G 2V4. E-mail: david.white{at}robarts.ca
Abstract
We have developed a magnetic resonance imaging (MRI) technique for imaging Feridex (superparamagnetic iron oxide SPIO)-labeled
islets of Langerhans using a standard clinical 1.5-Tesla (T) scanner and employing steady-state acquisition imaging sequence
(3DFIESTA). Both porcine and rat islets were labeled with SPIO by a transfection technique using a combination of poly- l -lysine and electroporation. Electron microscopy demonstrated presence of SPIO particles within the individual islet cells,
including β-cells and particles trapped between cell membranes. Our labeling method produced a transfection rate of 860 pg
to 3.4 ng iron per islet, dependent on the size of the islet. The labeling procedure did not disrupt either the function or
viability of the islets. In vitro 3DFIESTA magnetic resonance images of single-labeled islets corresponded with their optical
images. In vivo T2*-weighted scan using 1.5 T detected as few as 200 SPIO-labeled islets transplanted under rat kidney capsule,
which correlated with immunohistochemistry of the transplant for insulin and iron. Ex vivo 3DFIESTA images of kidneys containing
200, 800 or 2,000 SPIO-labeled islet isografts showed good correlation between signal loss and increasing numbers of islets.
These data provide evidence that islets can be labeled with SPIO and imaged using clinically available 1.5- T MRI.
HBSS, Hanks’ balanced salt solution
ICP-MS, inductively coupled plasma mass spectrometry
ISG, insulin secretory granule
MRI, magnetic resonance imaging
PGFL, Phen Green FL
PLL, poly-l-lysine
SPIO, superparamagnetic iron oxide
Footnotes
J.H.T. and P.F. contributed equally to this work.
J.H.T. is currently affiliated with the Metabolism and Diabetes Imaging Program, Lawson Health Research Institute, St. Joseph’s
Hospital, London, Ontario, Canada.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted July 25, 2006.
Received March 23, 2006.
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