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ABSTRACTIntroduction: Cardiovascular disease remains the major contributor to morbidity and mortality in diabetes. From the need to reduce cardiovascular risk in diabetes and to ensure that such risk is not exacerbated by drug treatments, governmental regulators and drug manufacturers have focused on clinical trials evaluating cardiovascular outcomes.Areas covered: Findings from mechanistic and clinical trials of biguanides, sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and sodium-glucose co-transporter 2 (SGLT-2) inhibitors will be reviewed. These drug classes will be compared within the context of available cardiovascular outcomes data. Clinical implications of new study regulations will be examined.Expert opinion: Recent cardiovascular studies provide a more comprehensive evaluation of specific anti-diabetes therapy in individuals with high cardiovascular risk. Long-term effects of anti-hyperglycemic agents in patients with lower cardiovascular risk are still speculative. Historical data supports continued use of metformin as a first-line agent. DPP-4 inhibitors and GLP-1 receptor agonists appear to have neutral effects on cardiovascular outcomes. The significantly decreased cardiovascular risk associated with empagliflozin SGLT-2 inhibitor therapy is impressive and may change how practitioners prescribe add-on therapy to metformin.

Introduction:Cardiovascular disease remains one of the leading causes of morbidity and mortality in diabetes mellitus. A causal link between insulin, atherosclerosis and cardiovascular risk has been investigated at the basic science level and studied in large clinical trials.Areas covered:The cardiovascular actions of insulin and its role at the level of the endothelium will be reviewed. Cardiovascular outcomes in several large diabetes trials where insulin management was prominent will be summarized.Expert opinion:The vascular actions of insulin are complex and mediated primarily via nitric oxide and endothelin-1. It appears that insulin resistance, rather than hyperinsulinemia itself, increases cardiovascular risk. In fact, hyperinsulinemia in the setting of normal beta cell function protects obese and insulin-resistant individuals from type 2 diabetes. Large clinical trials have supported that insulin management is not associated with increased adverse outcomes. A multifactorial approach targeting modifiable risk factors, including smoking cessation, blood pressure and lipid management, reduces cardiovascular risk. Therapy goals should be individualized and hypoglycemia, especially in individuals receiving insulin management, should be strictly avoided.

Introduction:Available anti-hyperglycemic therapy in type 1 diabetes (T1DM) is currently restricted to insulin, pramlintide, and pancreas or islet cell transplantation. The imperfect replication of normal insulin secretion and glucose control has been a driver for development of other anti-hyperglycemic agents for this population. Empagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, is currently under investigation as an add-on therapy to insulin in T1DM.Areas covered:Within the drug evaluation, the authors describe the mechanism of action of SGLT2 inhibitors and preliminary results from studies investigating treatment in rodent models and in individuals with T1DM.Expert opinion:Studies on adjunct therapeutic effects of empagliflozin in individuals with T1DM are limited, but initial reports show favorable effects on reducing HbA1c, body weight, total daily insulin dose and hypoglycemic events. Intriguingly, this drug may confer a degree of renal protection by reducing glomerular hyperfiltration that can arise in the diabetic state. Currently, the primary concern seems to be the presence of ketone levels indicating an under-insulinized state. Long-term effects can only be inferred from studies in type 2 diabetes mellitus at this time. Empagliflozin represents a novel non-insulin-mediated therapy that warrants further investigation.

Introduction:Canagliflozinis an orally administered sodium glucose cotransporter 2 inhibitor proposed for the treatment of type 2 diabetes. Canagliflozin improves glycemic control in an insulin-independent fashion through inhibition of glucose reuptake in the kidney.Areas covered:This article reviews the available data on the pharmacodynamics, the pharmacokinetics and metabolism, and the efficacy and safety of canagliflozin. Relevant articles were identified via PubMed using the search term canagliflozin with no date restriction. The authors also discuss the abstracts from canagliflozin studies presented at large diabetes conferences.Expert opinion:Canagliflozin offers a relatively modest reduction in HbA1c, FPG, and PPG. It has a low incidence of hypoglycemia and a reduction in body weight. Dose adjustment may be recommended in the elderly, those on loop diuretics, and those with an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2if there are concerns or symptoms of volume-related side effects. Issues remain with observed increases in low-density lipoprotein cholesterol (LDL-C) and the odds of heart attack and stroke. Canagliflozin offers a novel mechanism of action, a modest glycemic control, and a favorable side-effect profile. It was approved by the US Food and Drug Administration in April 2013 and is undergoing evaluation by the European Medicines Agency.

Fish stocking, often from multiple source populations, is a common management practice frequently conducted without the means or effort to determine the reproductive contributions of stocked fish. Historically, the Minnesota Department of Natural Resources (MNDNR) has stocked four strains of muskellunge Esox masquinongy, but the contribution of these strains to current populations was unknown. Two strains came from Minnesota lakes, Shoepack Lake and Leech Lake, and the other strains came from Wisconsin and Iowa hatcheries and were of uncertain origin. The MNDNR discontinued stocking the Shoepack strain in the 1980s when that strain displayed poor growth in stocked waters. Managers were concerned that ancestry from this strain might be limiting the genetic potential for muskellunge to attain trophy size in stocked populations. Using 13 microsatellite DNA markers, we determined the ancestry of muskellunge in 10 supplemented native populations and 10 introduced populations. The ancestry from each of the four stocked strains of muskellunge was detected in some populations, but the level of ancestry was unrelated to the amount of stocking of a strain. Ancestry from native populations persisted in six of the supplemented populations despite years of stocking. The potential effects of Shoepack strain ancestry on fish size were limited in most lakes because of its low persistence. All stocked strains reproduced in at least some of the lakes, but some lakes had no evidence of reproduction by any stocked strain. Our results will help MNDNR manage genetic diversity among muskellunge populations and direct efforts toward appropriate actions to improve size structure. This study reinforces how genetic data are often useful for evaluating ancestry in stocked fish populations, whereas stocking histories may be poor indicators of current genetic composition.

AbstractFish stocking, often from multiple source populations, is a common management practice frequently conducted without the means or effort to determine the reproductive contributions of stocked fish. Historically, the Minnesota Department of Natural Resources (MNDNR) has stocked four strains of muskellunge Esox masquinongy, but the contribution of these strains to current populations was unknown. Two strains came from Minnesota lakes, Shoepack Lake and Leech Lake, and the other strains came from Wisconsin and Iowa hatcheries and were of uncertain origin. The MNDNR discontinued stocking the Shoepack strain in the 1980s when that strain displayed poor growth in stocked waters. Managers were concerned that ancestry from this strain might be limiting the genetic potential for muskellunge to attain trophy size in stocked populations. Using 13 microsatellite DNA markers, we determined the ancestry of muskellunge in 10 supplemented native populations and 10 introduced populations. The ancestry from each of the four stocked strains of muskellunge was detected in some populations, but the level of ancestry was unrelated to the amount of stocking of a strain. Ancestry from native populations persisted in six of the supplemented populations despite years of stocking. The potential effects of Shoepack strain ancestry on fish size were limited in most lakes because of its low persistence. All stocked strains reproduced in at least some of the lakes, but some lakes had no evidence of reproduction by any stocked strain. Our results will help MNDNR manage genetic diversity among muskellunge populations and direct efforts toward appropriate actions to improve size structure. This study reinforces how genetic data are often useful for evaluating ancestry in stocked fish populations, whereas stocking histories may be poor indicators of current genetic composition.Received April 6, 2011; accepted May 19, 2012

AbstractThe popularity of sportfishing for muskellunge Esox masquinongyin Minnesota has increased substantially during the last 20 years and has resulted in a call for creating more fishing opportunities. As new waters are considered for muskellunge management, some anglers have expressed concern over the effects on other popular game fish species of adding a top-level predator. We evaluated the responses of seven fish species to muskellunge by comparing gill-net and/or trap-net catch per unit effort (CPUE) before and after muskellunge were stocked in 41 Minnesota lakes composed of 12 lake-classes. The species examined were northern pike Esox lucius, walleye Sander vitreus, yellow perch Perca flavescens, bluegill Lepomis macrochirus, black crappie Pomoxis nigromaculatus, white sucker Catostomus commersonii, and cisco Coregonus artedi. We found no significant decreases among the lakes in the mean CPUE of any species after muskellunge stocking, either for the stocked lakes as a whole or within lake-classes. There was a significant increase in the mean CPUE for bluegills over the entire group of lakes and within lake-class 24 in addition to an increase in the mean CPUE for black crappies sampled by gill nets in lake-class 25. Nevertheless, there was large variability in the changes in CPUE among lakes, and several individual lakes had significant changes in mean CPUE for some species following muskellunge stocking. The trend in CPUE increased for yellow perch and declined for white suckers over the entire group of lakes after muskellunge stocking. Because Minnesota follows established, biologically based guidelines for selecting new muskellunge lakes, the study lakes were not chosen at random and therefore the study conclusions most appropriately apply to lakes chosen in this manner. The lack of consistent negative changes in CPUE after stocking suggests that these fish species have generally coexisted well with muskellunge in these lakes at the densities that have resulted from stocking.Received June 21, 2010; accepted October 28, 2011

The popularity of sportfishing for muskellunge Esox masquinongyin Minnesota has increased substantially during the last 20 years and has resulted in a call for creating more fishing opportunities. As new waters are considered for muskellunge management, some anglers have expressed concern over the effects on other popular game fish species of adding a top-level predator. We evaluated the responses of seven fish species to muskellunge by comparing gill-net and/or trap-net catch per unit effort (CPUE) before and after muskellunge were stocked in 41 Minnesota lakes composed of 12 lake-classes. The species examined were northern pike Esox lucius, walleye Sander vitreus, yellow perch Perca flavescens, bluegill Lepomis macrochirus, black crappie Pomoxis nigromaculatus, white sucker Catostomus commersonii, and cisco Coregonus artedi. We found no significant decreases among the lakes in the mean CPUE of any species after muskellunge stocking, either for the stocked lakes as a whole or within lake-classes. There was a significant increase in the mean CPUE for bluegills over the entire group of lakes and within lake-class 24 in addition to an increase in the mean CPUE for black crappies sampled by gill nets in lake-class 25. Nevertheless, there was large variability in the changes in CPUE among lakes, and several individual lakes had significant changes in mean CPUE for some species following muskellunge stocking. The trend in CPUE increased for yellow perch and declined for white suckers over the entire group of lakes after muskellunge stocking. Because Minnesota follows established, biologically based guidelines for selecting new muskellunge lakes, the study lakes were not chosen at random and therefore the study conclusions most appropriately apply to lakes chosen in this manner. The lack of consistent negative changes in CPUE after stocking suggests that these fish species have generally coexisted well with muskellunge in these lakes at the densities that have resulted from stocking. Received June 21, 2010; accepted October 28, 2011

Introduction:Type 2 diabetes often involves derangements in lipid levels in addition to insulin resistance and diminishing insulin secretion. Colesevelam hydrochloride, a bile acid sequestrant (BAS), is approved for adjunctive therapy to diet and exercise for glycemic control in type 2 diabetes. In clinical studies in patients with type 2 diabetes, colesevelam, added to existing metformin, sulfonylurea or insulin therapy, reduced hemoglobin A1c(HbA1c) by a mean of 0.5% and low-density lipoprotein-cholesterol (LDL-C) by 13 – 17%.Areas covered:Information pertaining to colesevelam and other BAS was collected using a PubMed literature search of journal articles dating from 1960 to present. Additional articles were identified from bibliographies and from abstracts from American Diabetes Association conferences. The authors review the pharmacology of colesevelam as well as clinical efficacy, safety and tolerability data generated from clinical trials.Expert opinion:Colesevelam induces moderate but significant improvements in HbA1cand LDL-C. Outcomes data are needed to determine whether or not colesevelam confers long-term protection against micro- and macrovascular complications. Although colesevelam does not induce weight gain, triglyceride levels tend to increase ∼ 15%, the implications of which are unknown at this time. The mechanism(s) by which colesevelam improves glycemia are not yet understood but might involve enhanced meal-induced incretin secretion and altered farnesoid X receptor signaling.

Introduction:Postprandial glucose excursions negatively affect glycemic control and markers of cardiovascular health. Pramlintide, an amylinomimetic, is approved for treatment of elevated postprandial glucose levels in type 1 and type 2 diabetes mellitus.Areas covered:A literature search of PubMed was conducted to locate articles (up to January 2011) pertaining to original preclinical and clinical research and reviews of amylin and pramlintide. Additional sources were selected from reference lists within articles obtained through the original literature search and from the internet. This article describes the known effects of endogenous amylin and the pharmacodynamics, pharmacokinetics and clinical efficacy of pramlintide. Drug––drug interactions and safety and tolerability are also reviewed.Expert opinion:Pramlintide significantly reduces hemoglobin A1cand body weight in patients with type 1 and type 2 diabetes mellitus. Newer research is focusing on weight loss effects of pramlintide and pramlintide plus metreleptin in nondiabetic obese individuals. Preliminary results of these studies are discussed.

Introduction:In preliminary clinical studies, aleglitazar, a new dual PPAR-αα––γγ agonist, has been demonstrated to improve hyperglycemia and dyslipidemia in patients with type 2 diabetes mellitus. This review will provide up-to-date information on the clinical safety and efficacy of aleglitazar, which is currently under Phase III clinical investigation for reduction of cardiovascular events in patients with type 2 diabetes and recent acute coronary syndrome.Areas covered:A PubMed literature search (January 1950 to February 2011) was conducted using the following search terms: aleglitazar, PPAR, PPAR αα agonist, PPAR γγ agonist and PPAR αα/γγ agonist. Additional articles were gathered using reference lists from sources obtained from the original literature search. This review summarizes available information pertaining to pharmacodynamics, pharmacokinetics, clinical studies and safety/tolerability of aleglitazar. The effects of this new drug are compared and contrasted with those of fibrates (PPAR-αα agonists), thiazolidinediones (PPAR-γγ agonists) and other dual PPAR-αα––γγ agonists.Expert opinion:Preliminary evidence from clinical studies with aleglitazar is promising, with reported improvements in glycemia, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, triglycerides, apolipoprotein B and blood pressure. However, PPAR-αα- and -γγ-associated side effects have been observed and additional large-scale, long-term clinical studies are necessary to better understand the clinical implications of these effects.

Fisheries professionals charged with managing muskellunge Esox masquinongyfrequently seek population information that requires the ability to identify cohorts as well as individuals; hence, reliable tagging methods are needed. Our approach was to simultaneously assess multiple marking techniques on different life stages of muskellunge over short and long time scales. We evaluated the short-term detection of visible implant elastomer (VIE) and passive integrated transponder (PIT) tags in muskellunge fingerlings in experimental ponds. We compared survival (relative to that of control fish) and tag retention for two PIT tagging locations (the cheek and dorsal musculature) and one VIE location (the jaw). Overwinter survival did not differ between tagged and untagged fish (84–98%), but overwinter PIT tag retention was lower for the cheek (92%) than the dorsal musculature (100%). We also fin-clipped and VIE-tagged (jaw) 1,651 muskellunge fingerlings from 1997 to 2002 to evaluate long-term tag retention in a broodstock lake. In addition, 125 adult muskellunge were captured and PIT-tagged from 2003 to 2006. Muskellunge were sampled annually with trap nets and electrofishing during spring and fall. Only 2 VIE tags were detected in adults marked as fingerlings. The proportion of PIT-tagged adults recaptured ranged from 52% to 84% during the sampling period. Our results indicate that both VIE and PIT tags are viable short-term marks for muskellunge fingerlings, while PIT tags appear to be reliable long-term tags when implanted in the dorsal musculature of adults.

AbstractFisheries professionals charged with managing muskellunge Esox masquinongyfrequently seek population information that requires the ability to identify cohorts as well as individuals; hence, reliable tagging methods are needed. Our approach was to simultaneously assess multiple marking techniques on different life stages of muskellunge over short and long time scales. We evaluated the short-term detection of visible implant elastomer (VIE) and passive integrated transponder (PIT) tags in muskellunge fingerlings in experimental ponds. We compared survival (relative to that of control fish) and tag retention for two PIT tagging locations (the cheek and dorsal musculature) and one VIE location (the jaw). Overwinter survival did not differ between tagged and untagged fish (84–98%), but overwinter PIT tag retention was lower for the cheek (92%) than the dorsal musculature (100%). We also fin-clipped and VIE-tagged (jaw) 1,651 muskellunge fingerlings from 1997 to 2002 to evaluate long-term tag retention in a broodstock lake. In addition, 125 adult muskellunge were captured and PIT-tagged from 2003 to 2006. Muskellunge were sampled annually with trap nets and electrofishing during spring and fall. Only 2 VIE tags were detected in adults marked as fingerlings. The proportion of PIT-tagged adults recaptured ranged from 52% to 84% during the sampling period. Our results indicate that both VIE and PIT tags are viable short-term marks for muskellunge fingerlings, while PIT tags appear to be reliable long-term tags when implanted in the dorsal musculature of adults.

The effects of stocked fish on native populations of the same species are poorly understood. During the 1960s-1980s, the Minnesota Department of Natural Resources (MNDNR) stocked muskellunge Esox masquinongyderived from Shoepack Lake in the Hudson Bay drainage of northern Minnesota into Moose Lake in the Upper Mississippi River drainage. In the mid-1980s, the MNDNR recognized that stocked Shoepack Lake-strain fish (hereafter, Shoepack strain) were not attaining large sizes, and sources were switched statewide; subsequently, muskellunge from a Wisconsin hatchery were stocked once into Moose Lake. We used 14 microsatellite DNA markers to estimate the genetic contribution by each source population to muskellunge sampled in four different years from 1981 to 2004, and we evaluated the effects of Shoepack-strain ancestry on fish size. Two samples in the 1980s had mostly fish with a single ancestry; thus, these fish were probably Shoepack-strain fish stocked a few years earlier or native fish. By 2004, when most fish would have been naturally produced in the lake, contributions from all three source populations were detected, including admixed individuals from crosses among all ancestral sources. The estimated ancestry by source was 52% native Moose Lake ancestry, 29% Wisconsin strain, and 19% Shoepack strain, with 24% of the individuals having pure Moose Lake ancestry. Fish without Shoepack-strain ancestry had a greater median length than did those with Shoepack-strain ancestry and had a greater proportion of legal-sized individuals (total length = 1,016 mm) in the population. In contrast, Moose Lake and Wisconsin-strain descendents were common among all sizes of fish. Management options include doing nothing, accepting that extensive introgression has already occurred, or manipulating the population by either stocking to dilute Shoepack-strain ancestry or genetic screening to purge the population of Shoepack-strain ancestry.

Recent research has indicated that creel limits are largely ineffective in regulating recreational fish harvest in Minnesota. Current creel limits give an unrealistic picture of the biological capabilities of Minnesota's fisheries and less than 5% of angler-trips culminate with the harvesting of a creel limit. We present evidence that high creel limits may cause anglers to have unrealistic expectations of their potential harvest. When fishing success expectations are not met, the result is often dissatisfied anglers. We propose reducing creel limits to more appropriate levels by using a probability angling management strategy. These new limits would be based on past recreational harvest data from completed angler-trips. Our goal is to select creel limits that more anglers could attain, or come closer to attaining. Over time, we anticipate reduced creel limits would function more as an educational tool and may help anglers develop more realistic expectations of Minnesota's fisheries.

Luminescence of lead azide Pb(N3)2crystals in the range of 400–1000nm is studied experimentally. As the detonation of lead azide is initiated by an electron accelerator pulse, the onset of the mechanical destruction is preceded by intensive luminescence and a rapid growth of the conductivity. Theoretical investigation of the electronic structure of a lead azide crystal was done by means of the Hartree–Fock method for a periodic system. Detailed comparative analysis of the calculated density of states and experimental luminescence spectrum of lead azide suggests that decomposition proceeds by a chain reaction mechanism. A model of the pre-explosive luminescence based on the hypothesis of the quasi-local state formation in the valence band is proposed. The position of a possible energy level of the state in the valence band is predicted.

Pre-explosive luminescence of lead azidePb(N3)2in the range from 400 to 1000 nm was investigated both experimentally and theoretically. A theoretical investigation of the electron structure for a lead azide crystal was made using the Hartree-Fock method. The rated density of states and experimental pre-explosive luminescence spectrum of lead azide were analyzed in detail. The probable location of the hole quasi-local state in the valence band was determined.

Abstract: A study of the benthic communities in Corpus Christi Bay was carried out between 1974 and 1979 to identify both natural and human-induced variations in community dynamics of the benthos over a long time period of monthly samples collection. General results of the investigation were comparable to previous shorter-term studies of this estuary in respect to species list of dominant fauna, total densities and species diversity measures. The present study emphasized two habitats: a channel 15 m deep and a shoal less than 3.5 m deep. Channel stations exhibited lower species numbers, densities, and species diversity than shoal sites but in contrast showed more even distributions of population numbers between species (equitability) than shoal sites. Hierarchical classification procedures identified community structure patterns that were associated with a major disturbance to the area, dredging, as well as minor, more frequent disturbances associated with large ship traffic and shrimp trawling activities in the channel. The community variable of species number and total density were also related to changes in salinity patterns in the study area. The results of this long-term study illustrated the resilience of benthic communities to disturbance. They also provided supportive evidence to hypotheses concerning the high resistence of communities to disturbance in inconstant environments and the source of colonists in these environments after a major disturbance to the bottom.

Solid energetic substances have long played an important technological role as explosives, as well as for fuels. In this article, the authors concentrate on a type of explosive considered a primary explosive, lead azide, and its related compounds, lithium azide and sodium azide. Recent interest in more fundamental questions relating to the basic properties of these systems as materials, coupled with a desire to probe fundamental questions relating to the initiation and sustaining of the chemical reactions leading to combustion/detonation, is generating significant interest in the basic solid-state properties of such energetic systems. In particular, recent analysis of detonation by Gilman emphasizes the need to include excitation of the electronic system in obtaining an understanding. In this article, the band structures of the three solid metal azides are studied. This is done for both the normal lattice geometry and also in isotropically compressed geometries. These studies found that the alkali azide band gaps are far wider than is the lead azide gap and the lead azide gap is far more sensitive to narrowing with lattice compression than are the gaps for the alkali azides. In fact, the gap for sodium azide is found to widen with compression rather than narrow. The authors found that there is much seen in the band structures of these azides to lend some support to the Gilman model and also to demonstrate the importance of solid-state effects on the electronic structure and possible behavior of such energetic systems. © 1997 John Wiley & Sons, Inc.

Several letters to the editor are presented in response to various issues about bicycle motocross, including third series of BMX drawings, praises for the magazine's coverage and available extra parts for a Mongoose bike.

Reports on the increase in the number of buyers seeking waterfront recreational properties in Wisconsin. Home prices; Factors behind the change; Buyers' willingness to invest in property that provides fun for their families and which appreciates in value.