New options for the treatment of obesity and type 2 diabetes mellitus (narrative review)

AbstractModerate weight loss (>5%), which has been associated with improvements in glycemic parameters in patients with dysglycemia, also reduces the presence of other comorbidities, including dyslipidemia and hypertension, culminating in a reduced risk of cardiovascular disease. Lifestyle changes are the recommended preliminary approach to weight loss, with an initial weight-loss goal of 10% of body weight achieved over 6 months at a rate of 1–2 pounds per week selected as an appropriate target to decrease the severity of obesity-related risk factors. Implementing and maintaining the lifestyle changes associated with weight loss can, however, be challenging for many patients. Therefore, additional interventions sometimes may be necessary. Bariatric surgery can also be a highly effective option for weight loss and comorbidity reduction, but surgery carries considerable risks and is still applicable only to selected patients with type 2 diabetes. Thus, attention is turning to the use of weight-loss medications, including 2 recently approved compounds: twice-daily lorcaserin and a once-daily combination of phentermine and topiramate extended-release, both shown to be safe and effective therapies in the management of obesity in patients with type 2 diabetes

The Expression of TNFα by Human Muscle: Relationship to Insulin Resistance

TNFα is overexpressed in the adipose tissue of obese rodents and humans, and is associated with insulin resistance. To more closely link TNF expression with whole body insulin action, we examined the expression of TNF by muscle, which is responsible for the majority of glucose uptake in vivo. Using RT-PCR, TNF was detected in human heart, in skeletal muscle from humans and rats, and in cultured human myocytes. Using competitive RT-PCR, TNF was quantitated in the muscle biopsy specimens from 15 subjects whose insulin sensitivity had been characterized using the glucose clamp technique. TNF expression in the insulin resistant subjects and the diabetic patients was fourfold higher than in the insulin sensitive subjects, and there was a significant inverse linear relationship between maximal glucose disposal rate and muscle TNF (r = -0.60, P \u3c 0.02). In nine subjects, muscle cells from vastus lateralis muscle biopsies were placed into tissue culture for 4 wk, and induced to differentiate into myotubes. TNF was secreted into the medium from these cells, and cells from diabetic patients expressed threefold more TNF than cells from nondiabetic subjects. Thus, TNF is expressed in human muscle, and is expressed at a higher level in the muscle tissue and in the cultured muscle cells from insulin resistant and diabetic subjects. These data suggest another mechanism by which TNF may play an important role in human insulin resistance

Design, Synthesis, and Characterization of a Fluoroprobe for Live Human Islet Cell Imaging of Serotonin 5-HT1A Receptor

Mounting evidence suggests that the serotonin system serves in signal transmission to regulate insulin secretion in pancreatic islets of Langerhans. Among the 5-HT receptor subtype found in pancreatic islets, serotonin receptor 1 A (5-HT1A) demonstrates a unique ability to inhibit β-cell insulin secretion. We report the design, synthesis, and characterization of two novel fluorescent probes for the 5-HT1A receptor. The compounds were prepared by conjugating the scaffold of the 5-HT1A receptor agonist 8-OH-DPAT with two fluorophores suitable for live-cell imaging. Compound 5a {5-(dimethylamino)-N-[5-[(8-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino]pentyl]naphtalen-1-sulfonammide} showed high affinity for the 5-HT1A receptor (Ki=1.8 nM). Fluoroprobe 5a was able to label the 5-HT1A receptor in pancreatic islet cell cultures in a selective manner, as the fluorescence emission was significantly attenuated by co-administration of the 5-HT1A receptor antagonist WAY-100635. Thus, fluoroprobe 5a showed useful properties to further characterize this unique receptor‘s role

The Investigational Drug VT-1129 Is a Highly Potent Inhibitor of Cryptococcus Species CYP51 but Only Weakly Inhibits the Human Enzyme

Cryptococcosis is a life-threatening disease often associated with HIV infection. Three Cryptococcus species CYP51 enzymes were purified and catalyzed the 14α-demethylation of lanosterol, eburicol, and obtusifoliol. The investigational agent VT-1129 bound tightly to all three CYP51 proteins (dissociation constant [K(d)] range, 14 to 25 nM) with affinities similar to those of fluconazole, voriconazole, itraconazole, clotrimazole, and ketoconazole (K(d) range, 4 to 52 nM), whereas VT-1129 bound weakly to human CYP51 (K(d), 4.53 μM). VT-1129 was as effective as conventional triazole antifungal drugs at inhibiting cryptococcal CYP51 activity (50% inhibitory concentration [IC(50)] range, 0.14 to 0.20 μM), while it only weakly inhibited human CYP51 activity (IC(50), ∼600 μM). Furthermore, VT-1129 weakly inhibited human CYP2C9, CYP2C19, and CYP3A4, suggesting a low drug-drug interaction potential. Finally, the cellular mode of action for VT-1129 was confirmed to be CYP51 inhibition, resulting in the depletion of ergosterol and ergosta-7-enol and the accumulation of eburicol, obtusifolione, and lanosterol/obtusifoliol in the cell membranes

Movement and Habitat Selection by Invasive Asian Carps in a Large River

We evaluated the habitat use and movements of 50 adult bighead carp Hypophthalmichthys nobilis and 50 silver carp H. molitrix by means of ultrasonic telemetry during spring–summer 2004 and 2005 to gain insight into the conditions that facilitate their establishment, persistence, and dispersal in the lower Illinois River (river kilometer 0–130). Movement and habitat use were monitored with stationary receivers and boat-mounted tracking. The relative availability of four macrohabitat categories (main channel, island side channel, channel border, and connected backwater) was quantified to determine selection; discriminant function analysis was used to evaluate changes in physical characteristics within each category. A flood pulse occurred in spring through early summer of 2004 but not 2005. Movement rates (km/week) of both species were positively correlated with flow but not with temperature. Including data from stationary receivers greatly increased estimates of daily movement. During low summer flow, both species typically selected channel borders and avoided the main channel and backwaters. Both species rarely occupied depths over 4 m, regardless of abiotic conditions. Flood pulses appear to trigger dispersal, while habitat use is only specific during low summer flow. Thus, movement prevention efforts (e.g., dispersal barriers) will require particular vigilance during late-winter or spring flooding, and controlled removal (e.g., harvest) should be directed toward selected habitats during summer

Gear-Specific Population Demographics of Channel Catfish in a Large Midwestern River

Various gear types have been used to sample populations of channel catfish Ictalurus punctatus in lotic systems. However, these gears produce different population characteristics (i.e., recruitment, growth, and mortality). We compared the population demographics of channel catfish in the Wabash River, Indiana, sampled with baited 25- and 32-mm-bar mesh hoop nets and three-phase alternating current (AC) electrofishing. Based on catch per unit effort, the relative abundance of channel catfish sampled with 32-mm hoop nets was lower than that of fish sampled with 25-mm hoop nets and AC electrofishing. Each gear type also resulted in a different length frequency, mean length increasing progressively in sampling with 25-mm hoop nets, 32-mm hoop nets, and AC electrofishing. Similarly, age-frequency distributions differed among gears. The 25-mm hoop nets biased the age structure toward younger individuals (mean age = 2.5), whereas both 32-mm hoop nets (mean age = 4.0) and AC electrofishing (mean age = 5.8) included older fish. Catch-curve analysis generated different mortality rates for the three gear types, the mortality rate being highest (50%) in fish sampled with 25-mm hoop nets. Gear-specific size and age structures led to differences in von Bertalanffy statistics among the 25-mm hoop nets and AC electrofishing, while the results for 32-mm hoop nets were uninterpretable. Because the different gears led to conflicting parameter estimates, management practices based on sampling with single gears may be contradictory. Given the differences in gear selectivity, biologists need to approach management cautiously until calibration to the true size and age structure is conducted

Intramyocellular Lipid and Insulin Resistance: Differential Relationships in European and African Americans

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/93716/1/oby.2011.45.pd

Measurement of electron-neutrino electron elastic scattering

The cross section for the elastic scattering reaction nu_e+e- -> nu_e+e- was measured by the Liquid Scintillator Neutrino Detector using a mu+ decay-at-rest nu_e beam at the Los Alamos Neutron Science Center. The standard model of electroweak physics predicts a large destructive interference between the charge current and neutral current channels for this reaction. The measured cross section, sigma_{nu_e e-}=[10.1 +- 1.1(stat.) +- 1.0(syst.)]x E_{nu_e} (MeV) x 10^{-45} cm^2, agrees well with standard model expectations. The measured value of the interference parameter, I=-1.01 +- 0.13(stat.) +- 0.12(syst.), is in good agreement with the standard model expectation of I^{SM}=-1.09. Limits are placed on neutrino flavor-changing neutral currents. An upper limit on the muon-neutrino magnetic moment of 6.8 x 10^{-10} mu_{Bohr} is obtained using the nu_mu and \bar{nu}_mu fluxes from pi+ and mu+ decay.Comment: 22 pages, 11 figure

Regional Systems of Care Demonstration Project: American Heart Association Mission: Lifeline STEMI Systems Accelerator.

BACKGROUND: Up to 50% of patients fail to meet ST-segment-elevation myocardial infarction (STEMI) guideline goals recommending a first medical contact-to-device time of <90 minutes for patients directly presenting to percutaneous coronary intervention-capable hospitals and <120 minutes for transferred patients. We sought to increase the proportion of patients treated within guideline goals by organizing coordinated regional reperfusion plans. METHODS: We established leadership teams, coordinated protocols, and provided regular feedback for 484 hospitals and 1253 emergency medical services (EMS) agencies in 16 regions across the United States. RESULTS: Between July 2012 and December 2013, 23 809 patients presented with acute STEMI (direct to percutaneous coronary intervention hospital: 11 765 EMS transported and 6502 self-transported; 5542 transferred). EMS-transported patients differed from self-transported patients in symptom onset to first medical contact time (median, 47 versus 114 minutes), incidence of cardiac arrest (10% versus 3%), shock on admission (11% versus 3%), and in-hospital mortality (8% versus 3%; P<0.001 for all comparisons). There was a significant increase in the proportion of patients meeting guideline goals of first medical contact-to-device time, including those directly presenting via EMS (50% to 55%; P<0.001) and transferred patients (44%-48%; P=0.002). Despite regional variability, the greatest gains occurred among patients in the 5 most improved regions, increasing from 45% to 57% (direct EMS; P<0.001) and 38% to 50% (transfers; P<0.001). CONCLUSIONS: This Mission: Lifeline STEMI Systems Accelerator demonstration project represents the largest national effort to organize regional STEMI care. By focusing on first medical contact-to-device time, coordinated treatment protocols, and regional data collection and reporting, we were able to increase significantly the proportion of patients treated within guideline goals

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure