Faunal record identifies Bering isthmus conditions as constraint to end-Pleistocene migration to the New World.

Human colonization of the New World is generally believed to have entailed migrations from Siberia across the Bering isthmus. However, the limited archaeological record of these migrations means that details of the timing, cause and rate remain cryptic. Here, we have used a combination of ancient DNA, 14C dating, hydrogen and oxygen isotopes, and collagen sequencing to explore the colonization history of one of the few other large mammals to have successfully migrated into the Americas at this time: the North American elk (Cervus elaphus canadensis), also known as wapiti. We identify a long-term occupation of northeast Siberia, far beyond the species's current Old World distribution. Migration into North America occurred at the end of the last glaciation, while the northeast Siberian source population became extinct only within the last 500 years. This finding is congruent with a similar proposed delay in human colonization, inferred from modern human mitochondrial DNA, and suggestions that the Bering isthmus was not traversable during parts of the Late Pleistocene. Our data imply a fundamental constraint in crossing Beringia, placing limits on the age and mode of human settlement in the Americas, and further establish the utility of ancient DNA in palaeontological investigations of species histories.

Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes on background metformin and pioglitazone.

AIM: The efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, was evaluated in patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin and pioglitazone. METHODS: In this randomized, double-blind, phase 3 study, patients (N = 342) received canagliflozin 100 or 300 mg during a 26-week, placebo-controlled, core period and a 26-week, active-controlled extension in which placebo-treated patients were switched to sitagliptin 100 mg. Efficacy comparisons for canagliflozin versus placebo at week 26 are reported, with no comparisons versus sitagliptin at week 52 (sitagliptin used to maintain double-blind and control for safety). Safety data are reported for canagliflozin and placebo/sitagliptin. RESULTS: Canagliflozin 100 and 300 mg significantly lowered haemoglobin A1c (HbA1c) compared with placebo at week 26 (-0.89%, -1.03% and -0.26%; p < 0.001); reductions with canagliflozin 100 and 300 mg were maintained at week 52 (-0.92% and -1.03%). Relative to placebo, both canagliflozin doses significantly reduced body weight (-2.5 and -3.5 kg), fasting plasma glucose and systolic blood pressure (BP) at week 26 (p < 0.05 for all), with reductions maintained at week 52. Overall adverse event (AE) incidence over 52 weeks was 69.9, 76.3 and 76.5% with canagliflozin 100 and 300 mg and placebo/sitagliptin; AE-related discontinuation and serious AE rates were low. Incidences of genital mycotic infections and AEs related to osmotic diuresis and volume depletion were higher with canagliflozin than placebo/sitagliptin. CONCLUSION: Canagliflozin improved glycaemic control, reduced body weight and systolic BP, and was generally well tolerated in patients with T2DM on metformin and pioglitazone over 52 weeks.

New carbon dates link climatic change with human colonization and Pleistocene extinctions.

Drastic ecological restructuring, species redistribution and extinctions mark the Pleistocene-Holocene transition, but an insufficiency of numbers of well-dated large mammal fossils from this transition have impeded progress in understanding the various causative links. Here I add many new radiocarbon dates to those already published on late Pleistocene fossils from Alaska and the Yukon Territory (AK-YT) and show previously unrecognized patterns. Species that survived the Pleistocene, for example, bison (Bison priscus, which evolved into Bison bison), wapiti (Cervus canadensis) and, to a smaller degree, moose (Alces alces), began to increase in numbers and continued to do so before and during human colonization and before the regional extinction of horse (Equus ferus) and mammoth (Mammuthus primigenius). These patterns allow us to reject, at least in AK-YT, some hypotheses of late Pleistocene extinction: 'Blitzkrieg' version of simultaneous human overkill, 'keystone' removal, and 'palaeo-disease'. Hypotheses of a subtler human impact and/or ecological replacement or displacement are more consistent with the data. The new patterns of dates indicate a radical ecological sorting during a uniquely forage-rich transitional period, affecting all large mammals, including humans.

Rapid body size decline in Alaskan Pleistocene horses before extinction.

About 70% of North American large mammal species were lost at the end of the Pleistocene epoch. The causes of this extinction--the role of humans versus that of climate--have been the focus of much controversy. Horses have figured centrally in that debate, because equid species dominated North American late Pleistocene faunas in terms of abundance, geographical distribution, and species variety, yet none survived into the Holocene epoch. The timing of these equid regional extinctions and accompanying evolutionary changes are poorly known. In an attempt to document better the decline and demise of two Alaskan Pleistocene equids, I selected a large number of fossils from the latest Pleistocene for radiocarbon dating. Here I show that horses underwent a rapid decline in body size before extinction, and I propose that the size decline and subsequent regional extinction at 12,500 radiocarbon years before present are best attributed to a coincident climatic/vegetational shift. The present data do not support human overkill and several other proposed extinction causes, and also show that large mammal species responded somewhat individualistically to climate changes at the end of the Pleistocene.

Radiocarbon evidence of mid-Holocene mammoths stranded on an Alaskan Bering Sea island.

Island colonization and subsequent dwarfing of Pleistocene proboscideans is one of the more dramatic evolutionary and ecological occurrences, especially in situations where island populations survived end-Pleistocene extinctions whereas those on the nearby mainland did not. For example, Holocene mammoths have been dated from Wrangel Island in northern Russia. In most of these cases, few details are available about the dynamics of how island colonization and extinction occurred. As part of a large radiocarbon dating project of Alaskan mammoth fossils, I addressed this question by including mammoth specimens from Bering Sea islands known to have formed during the end-Pleistocene sea transgression. One date of 7,908 +/- 100 yr bp (radiocarbon years before present) established the presence of Holocene mammoths on St Paul Island, a first Holocene island record for the Americas. Four lines of evidence--265 accelerator mass spectrometer (AMS) radiocarbon dates from Alaskan mainland mammoths, 13 new dates from Alaskan island mammoths, recent reconstructions of bathymetric plots and sea transgression rates from the Bering Sea--made it possible to reconstruct how mammoths became stranded in the Pribilofs and why this apparently did not happen on other Alaskan Bering Sea islands.

Phenylalanine depletion for the management of phenylketonuria: use of enzyme reactors with immobilized enzymes.

Multitubular enzyme reactors with immobilized phenylalanine ammonia lyase were tested in vitro and in vivo for depletion of phenylalanine in circulating blood. Sustained reduction of phenylalanine was achieved in less than 30 minutes. A 50% decrease of phenylalanine was obtained with a 2-hour application of enzyme reactors and was maintained for more than 2 days. Similar enzyme reactors have therapeutic potential for temporary management of phenylketonuric patients when their circulating phenylalanine becomes exceedingly high because of infection, fever, or pregnancy.

Long-term analysis of a full-scale activated sludge wastewater treatment system exhibiting seasonal biological foaming.

The seasonal accumulation of biological foam on the activated sludge system of the Urbana-Champaign Sanitary District Northeast (UCSD-NE) wastewater treatment plant was investigated over an 8-year period by statistical analyses including path analysis, multivariate regression, and principal component analysis. Results of these analyses suggested that variation in the activated sludge reactor temperature and the use of a stream bypassing the primary clarifier were the two main factors determining the observed temporal foam profile. Characterization of the primary clarifier influent and effluent suggested the involvement of high lipid loading rates from the bypass stream in foam accumulation. In light of these results, it is hypothesized that increasing temperatures and lipid loading rates are responsible for foam formation through the same mechanism: the foam-forming microbial population is specialized in consuming lipids, substrates classified as slowly degradable. When the temperature increases, the rate of lipid hydrolysis becomes sufficiently high for this population to become abundant, accumulate on the surfaces of the aeration basins, and cause biological foaming.

Electrophoretic separation and immunological identification of type 2X myosin heavy chain in rat skeletal muscle.

One slow and three fast myosin heavy chains have been described in typical skeletal muscles of the adult rat using immunocytochemical analysis. Electrophoretic isolation and immunochemical identification of these four isoforms has not been achieved. An electrophoretic procedure is described which, by altering the cross-linkage and polymerization kinetics of 5% polyacrylamide gels, allows resolution of these four distinct myosin heavy chains. Using specific monoclonal antibodies and double immunoblotting analysis, the identity and electrophoretic migration order of the myosin heavy chains was established to be: 2A less than 2X less than 2B less than beta/slow.

Treating patients with documented atherosclerosis to National Cholesterol Education Program-recommended low-density-lipoprotein cholesterol goals with atorvastatin, fluvastatin, lovastatin and simvastatin.

OBJECTIVES: This study compared the efficacy and safety of atorvastatin, fluvastatin, lovastatin, and simvastatin in patients with documented atherosclerosis treated to U.S. National Cholesterol Education Program (NCEP) recommended low-density-lipoprotein (LDL) cholesterol concentration (< or = 100 mg/dl [2.59 mmol/liter]). BACKGROUND: For patients with advanced atherosclerosis, NCEP recommends lipid-lowering drug therapy if LDL cholesterol remains > or = 130 mg/dl (3.36 mmol/liter). METHODS: A total of 318 men or women with documented atherosclerosis and LDL cholesterol > or = 130 mg/dl (3.36 mmol/liter) and < or = 250 mg/dl (6.5 mmol/liter), and triglycerides < or = 400 mg/dl (4.5 mmol/liter) participated in this 54-week, multicenter, open-label, randomized, parallel-group, active-controlled, treat-to-target study. Patients were titrated at 12-week intervals until the LDL cholesterol goal was reached. Number of patients reaching target LDL cholesterol levels and dose to reach target were evaluated. RESULTS: At the starting doses, atorvastatin 10 mg produced significantly greater decreases (p < 0.05) in plasma LDL cholesterol than the other treatments. Subsequently, the percentage of patients reaching goal at the starting dose was 32% for atorvastatin, 1% for fluvastatin, 10% for lovastatin and 22% for simvastatin. Atorvastatin-treated patients required a lower median dose than other treatments. Median doses at week 54 with the last available visit carried forward were atorvastatin 20 mg/day, fluvastatin 40 mg/day + colestipol 20 g/day, lovastatin 80 mg/day, simvastatin 40 mg/day. CONCLUSIONS: A significantly greater number (p < 0.05) of patients with confirmed atherosclerosis treated with atorvastatin reached the target LDL cholesterol concentration at the starting dose than patients treated with fluvastatin or lovastatin, and significantly fewer (p < 0.05) patients treated with atorvastatin required combination therapy with colestipol to achieve target LDL cholesterol concentrations than all other statins tested.

Use of insulin aspart, a fast-acting insulin analog, as the mealtime insulin in the management of patients with type 1 diabetes.

OBJECTIVE: To compare long-term glycemic control and safety of using insulin aspart (IAsp) with that of regular human insulin (HI). RESEARCH DESIGN AND METHODS: This was a multicenter randomized open-label 6-month study (882 subjects) with a 6-month extension period (714 subjects) that enrolled subjects with type 1 diabetes. Subjects administered IAsp immediately before meals or regular HI 30 min before meals; basal NPH insulin was taken as a single bedtime dose in the majority of subjects. Glycemic control was assessed with HbA1c values and 8-point blood glucose profiles at 3-month intervals. RESULTS: Mean postprandial blood glucose levels (mg/dl +/- SEM) were significantly lower for subjects in the IAsp group compared with subjects in the HI group after breakfast (156 +/- 3.4 vs. 185 +/- 4.7), lunch (137 +/- 3.1 vs. 162 +/- 4.1), and dinner (153 +/- 3.1 vs. 168 +/- 4.1), when assessed after 6 months of treatment. Mean HbA1c values (% +/- SEM) were slightly, but significantly, lower for the IAsp group (7.78% +/- 0.03) than for the regular HI group (7.93% +/- 0.05, P = 0.005) at 6 months. Similar postprandial blood glucose and HbA1c values were observed at 12 months. Adverse events and overall hypoglycemic episodes were similar for both treatment groups. CONCLUSIONS: Postprandial glycemic control was significantly better with IAsp compared with HI after 6 and 12 months of treatment. The improvement was not obtained at an increased risk of hypoglycemia. HbA1c was slightly, but significantly, lower for IAsp compared with HI at 6 and 12 months.

Changes in cortical functioning with acute hypoglycemia and hyperglycemia in type I diabetes.

In this study, 18 type I (insulin-dependent) diabetic subjects aged 22-35 yr (mean age 29.3) and within 10 yr of diagnosis (mean 7.7) performed a battery of cognitive and psychomotor tasks under conditions of hypoglycemia (50 mg/dl), normoglycemia (100 mg/dl), and hyperglycemia (300 mg/dl). Blood glucose levels during testing were precisely maintained at the preselected level via a Biostator insulin/glucose-infusion system. The order of glycemic level was counterbalanced across subjects in a single-blinded design. Performance on tasks requiring visual tracking, visuomotor speed, concentration, and planning ability (pursuit rotor and trails B) were significantly impaired under conditions of hypoglycemia compared with normoglycemic levels. Visual reaction time was not significantly impaired under conditions of hypoglycemia or hyperglycemia.

A multisite physician's office laboratory evaluation of an immunological method for the measurement of HbA1c.

OBJECTIVE: To evaluate the clinical performance of a new immunological HbA1c method in physicians' office laboratories. RESEARCH DESIGN AND METHODS: Three physicians' offices participated in the evaluations. The clinicians routinely use HbA1c test results to monitor their patients' long-term blood glucose control. Precision and interlaboratory variability were assessed using three levels of lyophilized controls. Correlation of the method's results to currently available laboratory methods was made. Comparison of finger-stick (capillary) results to venous EDTA whole blood results was made on 134 patients. Physician and laboratory personnel input was evaluated with regard to the clinical utility of the system. RESULTS: The CVW and CVB were a maximum of 4.5 and 4.4% for the immunoassay system on three levels of control materials at the three sites. Interlaboratory variability among the control means was found to be 4.9-5.4, 8.0-8.3, and 11.7-12.0% HbA1c. Correlation coefficients (r) ranged from 0.95 to 0.99. There was a positive bias by the DCA 2000 compared with the in-house method at site 1. Minimal negative biases were seen by the DCA 2000 with comparative methods used at sites 2 and 3. Median percentage differences with the comparative methods were 12, -1.4, and -5.6%. Comparison of capillary to venous sample results, from the DCA 2000, showed no clinically significant differences. Operator and physician feedback were positive with respect to technical ease in performance of the test and accuracy of results. CONCLUSIONS: Precision was acceptable and interlaboratory variability was low. The immunological method correlated well with manual ion-exchange and automated HPLC methods. The small sample size and good comparison between capillary and venous sample results make fingerstick sampling acceptable. The method provided immediate test results (within 9 min) to the clinicians.

Randomized prospective trial of pure porcine and conventional bovine/porcine insulin.

Use of pure porcine insulin versus partially purified insulin of bovine/porcine origin might be expected to have certain clinical benefits, e.g., a lower incidence of skin reactions, a lower insulin dosage, better diabetes regulation, and greater preservation of endogenous insulin secretion. To test this hypothesis, we randomly assigned 112 newly diagnosed, untreated, insulin-dependent diabetic children to therapy with either pure porcine or partially purified bovine/porcine insulin. They were followed for 1 yr, data being available on at least 90 subjects at each visit. More skin reactions were found in the group treated with the bovine/porcine insulin. This insulin was of higher antigenicity, and binding of radiolabeled insulin (mean +/- SE) by serum from bovine/porcine insulin treatment was 35.5 +/- 2.6 versus 16.8 +/- 1.4% (P less than .001) for pure porcine insulin treatment 12 mo after initiation of insulin therapy. However, throughout the 12 mo of observation the levels of glycosylated hemoglobin, insulin dosage, fasting plasma glucose, and C-peptide concentration were similar for the groups. Reported incidences of hypoglycemia and nocturia were also similar. Thus, insulin-antibody formation and skin reactions were minimized by the use of pure porcine versus partially purified bovine/porcine insulin, but no other clinical advantages were apparent.

Hypnotizability in acute stress disorder.

OBJECTIVE: This study investigated the relationship between acute dissociative reactions to trauma and hypnotizability. METHOD: Acutely traumatized patients (N=61) with acute stress disorder, subclinical acute stress disorder (no dissociative symptoms), and no acute stress disorder were administered the Stanford Hypnotic Clinical Scale within 4 weeks of their trauma. RESULTS: Although patients with acute stress disorder and patients with subclinical acute stress disorder displayed comparable levels of nondissociative psychopathology, acute stress disorder patients had higher levels of hypnotizability and were more likely to display reversible posthypnotic amnesia than both patients with subclinical acute stress disorder and patients with no acute stress disorder. CONCLUSIONS: The findings may be interpreted in light of a diathesis-stress process mediating trauma-related dissociation. People who develop acute stress disorder in response to traumatic experience may have a stronger ability to experience dissociative phenomena than people who develop subclinical acute stress disorder or no acute stress disorder.

Treating acute stress disorder: an evaluation of cognitive behavior therapy and supportive counseling techniques.

OBJECTIVE: Acute stress disorder permits an early identification of trauma survivors who are at risk of developing chronic posttraumatic stress disorder (PTSD). This study aimed to prevent PTSD by an early provision of cognitive behavior therapy. Specifically, this study indexed the relative efficacy of prolonged exposure and anxiety management in the treatment of acute stress disorder. METHOD: Forty-five civilian trauma survivors with acute stress disorder were given five sessions of 1) prolonged exposure (N = 14), 2) a combination of prolonged exposure and anxiety management (N = 15), or 3) supportive counseling (N = 16) within 2 weeks of their trauma. Forty-one trauma survivors were assessed at the 6-month follow-up. RESULTS: Fewer patients with prolonged exposure (14%, N = 2 of 14) and prolonged exposure plus anxiety management (20%, N = 3 of 15) than supportive counseling (56%, N = 9 of 16) met the criteria for PTSD after treatment. There were also fewer cases of PTSD in the prolonged exposure group (15%, N = 2 of 13) and the prolonged exposure plus anxiety management group (23%, N = 3 of 13) than in the supportive counseling group (67%, N = 10 of 15) 6 months after the trauma. Chronic PTSD in the supportive counseling condition was characterized by greater avoidance behaviors than in the prolonged exposure condition or the prolonged exposure plus anxiety management condition. CONCLUSIONS: These findings suggest that PTSD can be effectively prevented with an early provision of cognitive behavior therapy and that prolonged exposure may be the most critical component in the treatment of acute stress disorder.

Morphometric analysis of phrenic motoneurons in the cat during postnatal development.

The dendritic geometry of 20 phrenic motoneurons from four postnatal ages (2 weeks, 1 and 2 months, and adult) was examined by using intracellular injection of horseradish peroxidase. The number of primary dendrites (approximately 11-12) remained constant throughout postnatal development. In general, postnatal growth of the dendrites resulted from an increase in the branching and in the length and diameter of segments at all orders of the dendritic tree. There was one exception. Between 2 weeks and 1 month, the maximum extent of the dendrites increased in parallel with the growth of the spinal cord; however, there was no increase in either combined dendritic length or total membrane surface area. In addition, there was a significant decrease in the number of dendritic terminals per cell (59.8 +/- 9.3 vs. 46.4 +/- 7.4 for 2 weeks and 1 month, respectively). The distance from the soma, where the peak number of dendritic terminals per cell occurred, ranged from 700-900 microns at 2 weeks and 2 months to 1,300-1,700 microns in the adult. The diameter of dendrites as a function of distance from the soma along the dendritic path increased with age. The process of maturation tended to increase the distance from the soma over which the surface area and dendritic trunk parameter (sigma d1.5/D1.5) remained constant. The three-dimensional distribution of dendrites was analyzed by dividing space into six equal volumes or hexants. This analysis revealed that the postnatal growth in surface area in the rostral and caudal hexants was proportionately larger than that in either the medial, lateral, dorsal, or ventral hexants. Strong linear correlations were found between the diameter of the primary dendrite and the combined length, surface area, volume, and number of terminals of the dendrite at all ages studied.

Ellipticine derivatives.

Several acyloxy and alkyl derivatives of ellipticine have been prepared. In addition, a modified synthesis leading to the hitherto unobtainable 8,9-dimethoxy- and 8,9-methylenedioxyellipticines is described. Some of the derivatives described herein exhibit antitumor activity. However, none of the compounds showed activity superior to that of the naturally occurring pyridocarbazoles, ellipticine and 9-methoxyellipticine.

Propenyl carboxamide derivatives as antagonists of platelet activating factor.

A series of N-[4-(3-pyridinyl)butyl] 3-substituted propenyl carboxamide derivatives bearing an unsaturated bicyclic moiety in the 3-position was prepared and evaluated for PAF (platelet activating factor) antagonist activity. These compounds represent conformationally constrained direct analogues of the corresponding potent 5-aryl-pentadienecarboxamides (5). Most of the new compounds were active in a PAF-binding assay employing whole, washed dog platelets as the receptor source and inhibited PAF-induced bronchoconstriction in guinea pigs after intravenous administration. However, oral activity in the PAF-induced bronchoconstriction model was highly sensitive to the nature and substitution of the bicyclic ring system. The most interesting compounds included [R-(E)]-(1-butyl-6-methoxy-2-naphthyl)-N-[1-methyl-4-(3- pyridinyl)butyl]-2-propenamide (4b), [R-(E)]-(3-butyl-6-methoxy-2- benzo[b]thiophene-yl)-N-[1-methyl-4-(3-pyridinyl)butyl]-2-propenamide (4k), and [R-(E)]-(3-butyl-6-methoxy-1-methyl-2-indoly)-N-[1-ethyl-4- (3-pyridinyl)butyl]-2-propenamide (4l) which inhibited PAF-induced broncho-constriction in guinea pigs with IC50s of 3.0-5.4 mg/kg, when the animals were challenged 2 h after drug treatment. They were also highly effective 6 h after a 50 mg/kg oral dose. This study supports the notion that the key remote aromatic ring present in the 5-arylpentadienecarboxamides (5) is preferentially coplanar with the diene system for good PAF antagonist activity.

beta 1-selective adrenoceptor antagonists. 1. Synthesis and beta-adrenergic blocking activity of a series of binary (aryloxy)propanolamines.

A series of binary (aryloxy)propanolamines has been prepared and examined in vitro and in vivo for beta-adrenoreceptor blocking activity. These symmetrical compounds consist of two (S)-(phenyloxy)propanolamine pharmacophores coupled through alkylenedioxy or poly(oxyethylenedioxy) linking units of varying lengths. Examples of such binary compounds linked through the 2,2', 3,3', and 4,4' positions in the aromatic rings of the pharmacophores have been prepared. In vitro and in vivo test data indicate that the 2,2' compounds tend to be selective beta 2-adrenergic blocking agents, the 4,4' binaries tend to be selective beta 1-blocking agents, and those compounds with 3,3' linkages exhibit intermediate selectivities. One of the 4,4'-linked binary compounds, 4s, exhibited potent, cardioselective beta-blockade in vivo, which was of short duration and was accompanied by a prolonged tachycardia.

Pentadienyl carboxamide derivatives as antagonists of platelet-activating factor.

A series of N-[4-(3-pyridinyl)butyl]-5,5-disubstituted-pentadienamides was prepared and evaluated for PAF-antagonist activity. Compounds were assayed in vitro in a PAF-binding assay employing washed, whole dog platelets as the receptor source and in vivo after intravenous or oral administration for their ability to prevent PAF-induced bronchoconstriction in guinea pigs. Criteria required for good oral activity in the latter model include an (E,-E)-5-phenyl-2,4-pentadienamide, a second phenyl or a four- or five-carbon alkyl moiety in the 5-position of the diene, and an (R)-[1-alkyl-4-(3-pyridinyl)butyl] substituent on the carboxamide nitrogen atom. The alkyl substituent on this side chain can be methyl, ethyl, or cyclopropyl. Two members of this series, [R-(E)]-5,5-bis(4-methoxy-phenyl)-N- [1-methyl-4-(3-pyridinyl)butyl]- 2,4-pentadienamide (31) and [R-(E,E)]-5-(4-methoxyphenyl)-N-[1-methyl-4- (3-pyridinyl)butyl]-2,4-decadienamide (58), were selected for further pharmacological evaluation. Both were found to be substantially longer acting after oral administration than the corresponding S enantiomers in the guinea pig bronchoconstriction assay. A second in vivo model used to evaluate PAF antagonists determines the ability of test compounds to decrease the area of skin wheals induced by an intradermal injection of PAF. In this model, using both rats and guinea pigs, compounds 31 and 58 were found to be as active as the reference PAF antagonist 3-[4-(2-chlorophenyl)-9-methyl-6H- 1-(4-morpholinyl)-1-propanone (45).