bluuebunny/crossref_metadata_2025 huggingface dataset:
The cGAS/STING Pathway Detects Streptococcus pneumoniae but Appears Dispensable for Antipneumococcal Defense in Mice and Humans
Authors: Ruiz-Moreno Juan Sebastian , Hamann Lutz , Jin Lei , Sander Leif E. , Puzianowska-Kuznicka Monika , Cambier John , Witzenrath Martin , Schumann Ralf R. , Suttorp Norbert , Opitz Bastian
Published: December 2017

Streptococcus pneumoniae
is a frequent colonizer of the upper respiratory tract and a leading cause of bacterial pneumonia. The innate immune system senses pneumococcal cell wall components, toxin, and nucleic acids, which leads to production of inflammatory mediators to initiate and control antibacterial defense. Here, we show that the cGAS (cyclic GMP-AMP [cGAMP] synthase)-STING pathway mediates detection of pneumococcal DNA in mouse macrophages to primarily stimulate type I interferon (IFN) responses. Cells of human individuals carrying
HAQ TMEM173
, which encodes a common hypomorphic variant of STING, were largely or partly defective in inducing type I IFNs and proinflammatory cytokines upon infection. Subsequent analyses, however, revealed that STING was dispensable for restricting
S. pneumoniae
during acute pneumonia in mice. Moreover, explorative analyses did not find differences in the allele frequency of
HAQ TMEM173
in nonvaccinated pneumococcal pneumonia patients and healthy controls or an association of
HAQ TMEM173
carriage with disease severity. Together, our results indicate that the cGAS/STING pathway senses
S. pneumoniae
but plays no major role in antipneumococcal immunity in mice and humans.
Cost-effectiveness of sacubitril/valsartan in the treatment of heart failure with reduced ejection fraction
Authors: McMurray John J V , Trueman David , Hancock Elizabeth , Cowie Martin R , Briggs Andrew , Taylor Matthew , Mumby-Croft Juliet , Woodcock Fionn , Lacey Michael , Haroun Rola , Deschaseaux Celine
Published: December 2017

Objective

Chronic heart failure with reduced ejection fraction (HF-REF) represents a major public health issue and is associated with considerable morbidity and mortality. We evaluated the cost-effectiveness of sacubitril/valsartan (formerly LCZ696) compared with an ACE inhibitor (ACEI) (enalapril) in the treatment of HF-REF from the perspective of healthcare providers in the UK, Denmark and Colombia.

Methods

A cost-utility analysis was performed based on data from a multinational, Phase III randomised controlled trial. A decision-analytic model was developed based on a series of regression models, which extrapolated health-related quality of life, hospitalisation rates and survival over a lifetime horizon. The primary outcome was the incremental cost-effectiveness ratio (ICER).

Results

In the UK, the cost per quality-adjusted life-year (QALY) gained for sacubitril/valsartan (using cardiovascular mortality) was £17 100 (€20 400) versus enalapril. In Denmark, the ICER for sacubitril/valsartan was Kr 174 000 (€22 600). In Colombia, the ICER was COP$39.5 million (€11 200) per QALY gained. Deterministic sensitivity analysis showed that results were most sensitive to the extrapolation of mortality, duration of treatment effect and time horizon, but were robust to other structural changes, with most scenarios associated with ICERs below the willingness-to-pay threshold for all three country settings. Probabilistic sensitivity analysis suggested the probability that sacubitril/valsartan was cost-effective at conventional willingness-to-pay thresholds was 68%–94% in the UK, 84% in Denmark and 95% in Colombia.

Conclusions

Our analysis suggests that, in all three countries, sacubitril/valsartan is likely to be cost-effective compared with an ACEI (the current standard of care) in patients with HF-REF.
What is the level of household gun ownership in urban Mexico? An estimate from the first Mexican survey on gun ownership 2017
Authors: Perez Esparza David , Hemenway David
Published: December 2017

Gun violence has increased in Mexico since the mid-2000s, but little is known about patterns of gun ownership. We examine the size and composition of the privately held urban firearm stock in Mexico, motivations for ownership, and attitudes about gun laws. To this end, a household telephone survey of 1361 adults living in nine Mexican cities was conducted in the summer of 2017. We find that few urban Mexican households contain guns. Most of those who report ownership possess one gun, having purchased it recently for self-defense. Few urban Mexican citizens plan to purchase a gun in the future. Respondents are more likely to believe that crime in Mexico would increase if guns were allowed in more places (ie, workplaces and motor vehicles). Evidence suggests urban Mexico has relative low rates of firearm ownership. Few city dwellers plan on obtaining a firearm in the near future.
Patterns of plasma free fatty acid concentrations in fasted, resting dogs.
Authors: Smith S W , Odell R H , Marsh D J , Yates F E
Published: December 2017

Free fatty acid (FFA) concentrations were determined in arterial plasma samples obtained during short or prolonged fasts from resting, conscious adult male mongrel dogs. Arterial blood was continuously collected during experiments ranging from 2.25 to 15 h, from dogs fasted 1 or 5 days. Each continuous collection stream was divided at 45 equal intervals into separate sequential samples. In 18 experiments, no consistent pattern was found in plasma FFA concentrations: the concentrations were never constant, and fluctuations were only rarely periodic. Large, spontaneous, seemingly random level changes with amplitudes of 200-600 mueq/liter were observed in 14 experiments, that took from 1 to 8 h to complete. There was no apparent relation between these fluctuations and time of day or rectal temperature, and glucose concentrations remained unchanged during the FFA fluctuations. The inconstancy of plasma FFA levels and the irregularity of their fluctuations suggests that FFA production rates may be unregulated or only loosely regulated within a wide regulation band during the first few days of starvation. No current model of FFA metabolism preducts the observed patterns of FFA levels.
Effect of histamine on canine gastric mucosal adenylate cyclase.
Authors: Dozois R R , Wollin A , Rettmann R D , Dousa T P
Published: December 2017

The effects of histamine, Nalpha-dimethylhistamine, 4,5-methylhistamine, Ntau-methylhistamine, pentagastrin, carbachol, and NaF on the adenylate cyclase activity from canine gastric mucosa were investigated in cell-free preparations. In gastric fundic mucosa, histamine (10(-4) M), Nalpha-dimethylhistamine (10(-4) M), 4,5-methylhistamine (10(-4 M), and NaF (10)-2) M) significantly (P less than 0.001) increased adenylate cyclase activity (means+/-SE) by 44.7+/-6.6, 49.4+/-6.7, 34.0+/-6.4, and 572.0+/-100%, respectively, above basal activity. The effect of histamine and Na-dimethyl histamine was dose-dependent. In contrast, other tested agents failed to stimulate the formation of cyclic AMP in gastric fundic mucosa. Metiamide (10(-4) M) blocked the stimulation of fundic mucosa adenylate cyclase by histamine and Nalpha-dimethylhistamine, without significantly altering basal and NaF-induced adenylate cyclase activity. Histamine, however, did not stimulate the adenylate cyclase activity from the gastric antral mucosa. The findings support the proposal that the canine gastric acid response to histamine may be mediated by cyclic AMP formed in response to stimulation of histamine H2-receptors.
Secretory surface area and phosphatase activity of frog gastric mucosa.
Authors: Helander H F , Durbin R P
Published: December 2017

Gastric mucosae were isolated from the European frog, R. temporaria, and after 5-7 h, stimulated with histamine (10(-4) M) and theophylline (5 mM). Acid secretion increased about fourfold, and this was accompanied by a threefold increase in secretory surface of the oxyntic cells, as determined in electron micrographs with conventional morphometric techniques. At the same time phosphatase activity of the secretory surface increased. Other experiments showed that the latter was due to an acid phosphatase, with pH optimum near 3. It appears that the increase in surface phosphatase with stimulation can be attributed to a diminished local pH and not to the increase in surface area demonstrated in this study.
Lack of adaptation of pancreatic colipase in rats and mice.
Authors: Vandermeers-Piret M C , Vandermeers A , Wijns W , Rathé J , Christophe J
Published: December 2017

A new automated potentiometric method for the determination of colipase was developed, taking advantage of the reactivation of purified lipase, in the presence of bile salt and at pH 6.5. High-fat and high-starch diets induced an opposite regulation of lipase and amylase in the rat pancreas. At the same time, the level of colipase was not influenced by nutrition. During fasting and in alloxan diabetes, the specific activity of lipase almost doubled, that of amylase decreased sharply, and colipase was not affected in the rat pancreas. In obese-hyperglycemic mice, suffering from obesity, hyperinsulinism, and moderate diabetes, there was also no regulation of pancreatic colipase. Thus, at variance with a number of hydrolases, there was no dietary or hormonal adaptation of colipase. However, this was probably without any bearing on intraluminal lipolysis. Indeed, comparison of lipase and colipase activities in pancreas and in small intestine suggests that colipase concentration is not a limiting factor of intraluminal lipolysis. The molecular mechanism of this assumption is discussed on the basis of in vitro studies.
Tracer kinetic analysis of Cori cycle activity in the rat: effect of feeding.
Authors: Kusaka M , Ui M
Published: December 2017

Turnover rates of blood glucose and lactate, along with the rates of their interconversion, were calculated from changes of their specific activities in rats infused with [U-14C] glucose and [U-14C] lactate based on a simple flux model of the Cori cycle. In the fasted state, most (75%) of the glucose metabolized was converted to lactate, whereas only a small fraction (35%) of the lactate metabolized was converted to glucose. Of the glucose metabolized, 27% returned from the lactate pool to the glucose pool. Feeding stimulated the outflow of glucose carbon from the Cori cycle via the action of secreted insulin. Insulin-induced stimulation of blood glucose removal was associated with increased glucose production, whereas anti-insulin serum-induced stimulation of glucose production was associated with increased glucose removal. It is argued that a "compensatory" mechanism independent of insulin and epinephrine might be in operation to minimize the glycemic changes that would otherwise occur in response to drastic metabolic changes.
Daily rhythms of lipogenesis in fat and lean white-throated sparrows Zonotrichia albicollis.
Authors: Meier A H
Published: December 2017

Lipogenesis was assayed at 6 times a day in the migratory white-throated sparrow Zonotrichia albicollis by measuring the incorporation of label in liver and body lipid 4 h after injection of [3H] acetate. There were daily rhythms of 3H incorporation by liver lipid both in fat birds in the vernal migratory condition and in lean birds in the summer photorefractory condition. Most of the liver lipid incorporation of 3H was restricted to the late afternoon and early evening in both the fat and lean birds. In addition, the total liver incorporation was similar for both groups. On the other hand, nearly twice as much 3H was incorporated in the body lipid of fat birds as in that of lean birds, and a daily rhythm was present only in fat sparrows. Injections of prolactin given simultaneously with [3H] acetate early during the day (at a time when daily injections of the hormone can cause severe losses in body fat stores) drastically reduces liver and body lipid incorporation of 3H. However, injections of prolactin during the afternoon (when daily injections of the hormone produce large increases in body fat stores) have no apparent influence on the incorporation of label. Our results indicate that a principal difference between lean and fat birds resides in a greater capacity in fat birds to transport triglycerides from the liver, in which they are produced, to the body storage depots. The daily rhythm of prolactin in some temporal relations may cause fattening by increasing the transport capacity or cause loss in fat stores in other temporal relations by directly inhibiting hepatic lipogenesis.
Effect of isoproterenol on amino acid levels and protein turnover in skeletal muscle.
Authors: Li J B , Jefferson L S
Published: December 2017

The effect of isoproterenol on amino acid concentrations in perfusate and skeletal muscle was studied during a 3-h perfusion of the isolated rat hemicorpus. The beta-adrenergic agonist inhibited the accumulation of alanine, threonine, phenylalanine, tyrosine, lysine, arginine, leucine, and valine and increased the loss of glutamate, aspartate, serine, and isoleucine from the pool of free amino acids in perfusate and muscle. The loss of glutamate was accompanied by a greater accumulation of glutamine. Changes in alanine levels showed the greatest response with a net accumulation of 98 mumol in the controls becoming a net loss of 54 mumol in the experimentals. These changes in amino acid levels were accounted for in part by a 20% decrease in protein degradation. Protein synthesis was not affected by isoproterenol. In addition to an effect on degradation, it appeared that isoproterenol affected amino acid levels by increasing alanine utilization and causing formation of glutamine instead of alanine. Other effects of the drug included increased rates of lactate production, muscle glycogen breakdown, and oxygen consumption, whereas no effects were observed on ATP and creatine phosphate levels. Pyruvate content of muscle was maintained at a higher level in the presence of the drug than in control perfusions.
Immunofluorescent localization of renin in mouse submaxillary gland and kidney.
Authors: Menzie J W , Hoffman L H , Michelakis A M
Published: December 2017

An antibody prepared against purified submaxillary renin was used to determine the site of renin concentration in male mice using immunofluorescent localization. The results provide direct evidence that the granular tubules of the submaxillary glands are the source of submaxillary renin. The antibody against submaxillary renin cross-reacts with kidney renin as evidenced by immunofluorescent localization in the juxtaglomerular apparatus of mouse kidney.
Studies of glucose transport system of fat cells: effects of insulin and insulin mimickers.
Authors: Livingston J N , Amatruda J M , Lockwood D H
Published: December 2017

The rate of uptake of [U-14C]glucose or 3-O-[14C]methylglucose by isolated fat cells was rapidly measured (within 30 s) by an oil-centrifugation method. Insulin and the chemical agents, H2O2 (0.3 mM), vitamin K5 (48 micron), and spermine (0.3 mM), enhanced the uptake of both sugars. Each agent required a characteristic time period of incubation with the cells to produce maximum activation of transport. Insulin and the chemical agents increased the equilibrium exchange rate of methylglucose by the cells. The increase in rate elicited by the hormone and the reagents resulted primarily from increasing the Vmax of the exchange process. The Kt ranged from 7.5 to 10 mM after treatment of cells with insulin or the other agents. Basal Kt values were more difficult to measure, but in a sugar concentration range of 5-15 mM the values were similar to those found under conditions of stimulated exchange. Overall, these findings suggest that the chemical agents may be useful as probes to study certain aspects of insulin-mediated activation of glucose transport. However, because of the differences in time courses needed for activation, the actual steps that lead to stimulation may differ for the chemical agents and insulin.
Uptake of labeled palmitate by the intact liver: role of intracellular binding sites.
Authors: Goresky C A , Daly D S , Mishkin S , Arias I M
Published: December 2017

The multiple-indicator dilution technique was utilized to examine the hepatic uptake of albumin-bound labeled palmitate from the portal vein blood of the pentobarbital-anesthetized dog, in a fasted state and after infusion of a variety of compounds that were expected to bind to Z protein, the cellular cytosolic protein binding free fatty acids, and their acyl-CoA derivatives. Analysis of the data indicates that after infusion of alpha-bromopalmitate, 16-bromo-9-hexadecenoate, and sulfobromophthalein sodium (which also bind to albumin), the palmitate label influx, efflux, and metabolic sequestration (removal of label from the pool of free fatty acids able to leave the cell) all increase and that, after infusion of flavaspidic acid, label efflux and metabolic sequestration increase. In vitro competitive binding studies carried out on the cellular cytosol indicat that the basis for the increase in efflux and metabolic sequestration is displacement of labeled palmitate from high affinity sites on the intracellular Z protein (which are presumably in equilibrium with and may be taken to be representative of other intracellular binding sites). These studies also suggest that increased uptake is due to similar displacement from high affinity sites on serum albumin.
Glucose lactate interrelations in sheep.
Authors: Reilly P E , Chandrasena L G
Published: December 2017

The constant-infusion, isotope-dilution method was used to investigate the interrelationships between the glucose and lactate pools of six trained sheep deprived of food overnight. Arterial plasma lactate concentration was a linear function of the net lactate entry rate as was the net production of glucose from lactate, which suggests that the net rate of formation of glucose from lactate is dependent on the availability of lactate. Similarly the arterial plasma glucose concentration was correlated with the net entry rate of glucose as was the net production rate of lactate from glucose, suggesting that the net rate of lactate production from glucose is a function of arterial plasma glucose concentration. The demonstration of these two interrelations between glucose and lactate in normal sheep suggests that, in the absence of external factors producing hormonal or other changes that could cause perturbations of carbohydrate homeostasis, the net rates of conversion of glucose to lactate and of lactate to glucose may be largely determined by the arterial concentrations of glucose and lactate, respectively.
Insulin release, cGMP, cAMP, and membrane potential in acetylcholine-stimulated islets.
Authors: Gagerman E , Idahl L A , Meissner H P , T�ljedal I B
Published: December 2017

Acetylcholine potentiated the glucose-induced insulin release from microdissected mouse islets of Langerhans but had no effect on basal insulin release. Significant potentiation was obtained with 0.1 micron acetylcholine in the presence of 10 micron eserine and with 1 micron or more acetylcholine in the absence of a choline esterase inhibitor. Carbamylcholine, too, potentiated insulin release. Potentiation was blocked by methylatropine, whereas methylatropine alone had no effect on insulin release. Acetylcholine or carbamylcholine (5-500 micron) had no obvious effect on cyclic GMP or cyclic AMP in the islets. In the presence of 11.1 mM D-glucose, the membrane potential of beta-cells oscillated slowly between a polarized silent state of -50 to -55 mV and a depolarized active state of -33 to -39 mV, at which a fast spike activity occurred. Acetylcholine made the potential stay at the plateau and induced a continuous spike activity pattern. Atropine inhibited the electrical effects of acetylcholine but not those of glucose alone. It is suggested that cholinergic potentiation of insulin release is mediated by changes of transmembrane ionic fluxes, probably without the intervention of cyclic GMP or cyclic AMP.
Electrical responses in cat adrenal cortex: possible relation to aldosterone secretion.
Authors: Natke E , Kabela E
Published: December 2017

The effects of secretagogues for aldosterone release were studied on the membrane potential of cells in the adrenal cortex of the cat. Adrenal glands were excised, sliced, and continuously superfused. Membrane potentials were recorded from both zona glomerulosa and zona fasciculata-reticularis. Secretagogues, angiotensin II (1 microgram/ml) and 20 mM KCl, were found to depolarize cells rapidly. Ouabain (10(-5) M) also depolarized the membrane potential although the response was sluggish. Samples of the superfusate were collected and analyzed by radioimmunoassay for their aldosterone and cortisol content. Depolarizing concentrations of angiotensin II, KCl, and ouabain seemed to increase aldosterone release. Cortisol output was more variable. Saralasin blocked the effects of angiotensin II on the membrane potential. These experiments suggest that membrane depolarization plays a role in the stimulus-secretion coupling of mineral corticoids.
Hyperglucagonemia and alpha-adrenergic receptor in acute hypoxia.
Authors: Baum D , Porte D , Ensinck J
Published: December 2017

The plasma immunoreactive glucagon (IRG) response to hypoxia was studied in puppies. Three groups of paired experiments were performed. In group I, 8% O2:92% N2 ventilation (PaO2 20--30 torr) produced a rise in plasma IRG and glucose as well as hypotension and bradycardia. However, when group I was air ventilated (PaO2 greater than 70 torr) and given glucose infusions producing hyperglycemia of similar degree, plasma IRG was unchanged. Group II received alpha-adrenergic blockade (phenoxybenzamine). When made hypoxic, group II developed no significant IRG rise and less hyperglycemia than with hypoxia alone. Hypotension was more severe with hypoxia plus alpha-blockade. Phenoxybenzamine itself did not change plasma IRG or glucose during air breathing. Group III receivi developed hyperglucagonemia and hyperglycemia not significantly different from that with hypoxia alone. However, hypoxia-caused hypotension and bradycardia was more pronounced with beta-blockade. No change in plasma IRG or glucose occurred in group III animals breathing air. These data suggest that a) glucagon release is caused by acute oxygen deficiency, and b) the hypoxic response is largely adrenergically mediated with the major role played by the alpha-receptor.
Motor events in equine large colon.
Authors: Sellers A F , Lowe J E , Brondum J
Published: December 2017

The equine large colon is the major cellulose-fermentation locus of these species. The area of juncture of the ventral and dorsal divisions of the equine large colon was characterized, in 13 chronic unanesthetized animals and in 25 in vitro preparations, as an area of resistance to aboral flow. This is a probable pacemaker area. The reservoir function of this part of the colon is apparently facilitated by the presence of a pacemaker at this level. There was a general rise in recorded intraluminal pressure peaks during the first hour of feeding. This characteristic was not altered after resection of the extrinsic nerve supply. Electrical stimulation of the extrinsic nerve net in conscious animals at times mimicked the groups of intraluminal pressure peaks seen at the beginning of feeding.
Mammary gland function and development: effect of zinc deficiency in rat
Authors: Mutch P. B. , Hurley L. S.
Published: December 2017

The effect of dietary zinc deficiency during late pregnancy and lactation on the rat mammary gland was investigated by feeding female rats either a zinc-deficient diet (0.4 ppm Zn) or a zinc-sufficient diet (100 ppm Zn) ad libitum or restricted in amount. Zinc deficiency from day 0 of lactation specifically reduced the total RNA content of lactating mammary glands on day 14, but had no effect beyond that of food restriction on their total DNA content, Both RNA and DNA content of the mammary gland were decreased by reduced food intake. Zinc deficiency from day 14 of pregnancy to day 2 of lactation severely impaired parturition and prevented the normal rise in mammary gland RNA seen during lactogenesis in control animals. A shorter deficiency period, from day 18 of gestation, had no effect on mammary gland nucleic acids other than that due to inanition.
Kinetic analysis of calcium distribution in rat anterior pituitary slices
Authors: Moriarty C. M.
Published: December 2017

A kinetic analysis of exchangeable calcium associated with rat anterior pituitary slices was carried out. Slices were permitted to accumulate 45Ca for 1 h, and then a desaturation experiment was initiated. The resulting data was represented as a polyexponential function and analyzed with a weighted nonlinear least-squares method. The resulting coefficients and exponents were used to determine, at the steady state, the size of each calcium compartment, the unidirectional fluxes into and out of each compartment, and the corresponding rat constants. Three kinetically distinguishable compartments were defined. The first compartment exchanges with a half-time slower than calcium free in the extracellular space and can be removed by a 1.5-min exposure to Ca-free EGTA media suggesting that this calcium is bound in the extracellular matrix perhaps to the cell surfaces. The second compartment is intracellular and does not contain calcium accumulating structures such as mitochondria or microsomes. The third compartment has many of the characteristics associated with these organelles. Experiments were performed with two pituitary secretagogues, elevated K+ and ouabain, to assess changes in the study-state calcium distribution associated with enhanced secretion.
Intracellular glucose concentration in small and large rat adipose cells
Authors: Foley J. E. , Cushman S. W. , Salans L. B.
Published: December 2017

Intracellular free glucose concentrations have been estimated in small and large isolated epididymal adipose cells prepared from young lean and older obese rats using glucose-induced steady-state tracer 3-O-methylglucose countertransport. Steady-state 3-O-methylglucose uptake was measured in the presence of 2--50 mM glucose or sucrose in the absence or presence of 100 microU insulin/ml. The ratio of the uptake of 3-O-methylglucose in the presence of glucose to that in the presence of sucrose at each sugar concentration was then utilized to estimate the corresponding intracellular glucose concentration. At all three extracellular glucose concentrations tested in the absence of insulin, intracellular concentrations of glucose are greater in the large cells than in the small cells. In the presence of 2 mM glucose and insulin, on the other hand, intracellular glucose concentrations of 2 mM are attained, regardless of cell size. These results suggest that transport may not be the rate-limiting step for glucose metabolism at physiologic glucose concentrations either in the enlarged adipose cell in the absence or presence of insulin or in the small adipose cell in the presence of maximally stimulating concentrations of insulin.
Effects of wheat germ agglutinin on insulin binding and insulin sensitivity of fat cells
Authors: Livingston J. N. , Purvis B. J.
Published: December 2017

The plant lectin (wheat germ agglutinin, WGA) produces several alterations in the ability of fat cells to bind and respond to insulin. Although WGA markedly stimulated glucose oxidation, it caused only a modest stimulation of glucose transport. WGA (0.25-20 micrograms/ml) increased the binding of insulin by adipocytes, apparently by increasing the binding affinity of the insulin receptor. With low WGA concentrations (0.25-2.5 micrograms/ml), the elevation in binding was accompanied by an increase in the sensitivity of the adipocytes to insulin stimulation of glucose transport. However, the sensitivity of these cells to vitamin K5 and H2O2 was not altered. With higher WGA concentrations (5-20 micrograms/ml), stimulation of the glucose transport system by insulin, vitamin K5, or H2O2 was markedly inhibited, an effect that is reversed by the addition of ovomucoid. These findings suggest that low WGA concentrations increase the affinity of the insulin receptor and the insulin sensitivity of the cells. At higher concentrations, the lectin appears to act at another site(s) to inhibit the activation of the transport system by insulin or other agents.
Evidence that body size does not determine voluntary food intake in the rat
Authors: Oscai L. B.
Published: December 2017

Rats, 5.5 wk of age, were food restricted for a period of 30 days duration. On termination of caloric deprivation, the food-restricted rats were 142 g lighter than comparable freely eating control rats (177 +/- 3 g vs. 319 +/- 4 g; P less than 0.001). Because of the smaller body size, adipocyte diameter in epididymal pads of the calorie-deprived rats was 52 +/- 1 micron compared to a value of 72 +/- 3 micron for the control rats (P less than 0.001). After restoration of ad libitum feeding, the food-restricted rats experienced an accelerated rate of weight gain until body weight and adipocyte diameter approached those of the control animals. The greater rate of weight gain occurred despite the fact that voluntary food intake remained essentially the same for both groups of animals. Food intake over the 18-wk-long restoration period totaled 3,078 +/- 40 g for the food-restricted rats compared to a value of 3,108 +/- 53 g for the control rats. These results demonstrate that neither body size nor the size of the adipocyte determines voluntary food intake in the rat.
Effect of insulin on in vitro intestinal fatty acid esterification in the rat
Authors: Shiau Y. F. , Holtzapple P. G.
Published: December 2017

We have previously shown that glucose metabolism plays an important role in modifying intestinal fatty acid esterification. Because it is well known that glucose metabolism is under insulin regulation, we examined the effect of insulin on intestinal fatty acid esterification. Insulin pretreatment led to a marked decrease in in vitro intestinal fatty acid esterification, but this decrease was abolished by maintaining blood glucose above 80 mg/dl. Addition of insulin to the incubation medium failed to produce any effect on intestinal fatty acid esterification. The decreased fatty acid esterification on hypoglycemic rats was not associated with changes in fatty acid uptake or lipid esterifying enzyme activities. However, there was a significant increase in the production of volatile metabolites of fatty acid. We conclude that 1) insulin itself has no effect on intestinal fatty acid esterification, 2) the effects observed in this study are due to insulin-induced hypoglycemia, 3) hypoglycemia does not alter intestinal fatty acid uptake or intrinsic esterification activity, but leads to preferential oxidation rather than esterification of fatty acid by the small intestine, and 4) the critical blood glucose concentration needed to maintain normal esterification in the rat was approximately at 80 mg/dl.
Carnitine metabolism in normal-weight and obese human subjects during fasting
Authors: Hoppel C. L. , Genuth S. M.
Published: December 2017

Carnitine metabolism was studied in normal-weight and obese subjects by measurement of carnitine and its acyl derivatives in plasma and urine. When first fed an isocaloric, low-carnitine diet, both groups showed a decrease in plasma total carnitine, primarily due to a decrease in the free carnitine fraction. Urinary free carnitine excretion also fell significantly. When fasting was instituted, plasma total carnitine concentration increased. This was the net result of a rapid increase in short-chain and long-chain acylcarnitine and a delayed decrease in free carnitine. Urinary excretion of short-chain acylcarnitines increased parallel to rising plasma concentrations, whereas free carnitine excretion first decreased and then tended to increase slightly. Both plasma and urinary short-chain acylcarnitine correlated with beta-hydroxybutyrate. All of these changes were reversed by refeeding, in the obese even with a low-carnitine hypocaloric intake. Obese subjects also developed hyperketonemia significantly more slowly than did normal-weight subjects, yet demonstrated substantially the same changes in magnitude and direction in carnitine and its metabolites.
Thyroidal response to peroral TSH in suckling and weaned rats
Authors: Tenore A. , Parks J. S. , Gasparo M. , Koldovsky O.
Published: December 2017

The biological activity of perorally administered bovine thyroid-stimulating hormone (bTSH) was investigated in suckling (14-day-old) and weaned (30-day-old) rats. Animals were treated with water or bTSH given either by subcutaneous injection or by the oral route. Both suckling and weaned animals responded to subcutaneous administration of bTSH by an increase in serum thyroxine (T4) and triiodothyronine (T3) concentrations. Bovine TSH administered orally to weaned animals had no effect on thyroid hormone levels. In contrast, suckling pups responded to perorally administered bTSH with increases of T4 and T3 levels comparable to those achieved in animals that received bTSH subcutaneously. The characteristics of the gastric secretion and intestinal epithelium of the weaned animal, therefore, appear to play a role in preventing absorption of a polypeptide hormone. However, protein hormones contained in maternal milk can be transferred to the suckling in which their full biological functions can be expressed.
Importance of muscle lipoprotein lipase in rats during suckling
Authors: Planche E. , Boulange A. , de Gasquet P. , Tonnu N. T.
Published: December 2017

In order to evaluate the relative importance of groups of tissues containing lipoprotein lipase (LPL) in the removal of serum triacylglycerols during development, LPL activity was determined in cardiac and skeletal muscle, brown (BAT) and white adipose tissue (WAT), lung and kidney of rats aged 0–60 days, either fed or fasted for 6 h. On fasting, LPL activity did not change in lung and kidney, decreased in WAT except at 14 days and to a lesser extent in BAT, whereas muscle LPL decreased at 0, 3, and 7 days and increased from 14 days onward. The fasting-induced changes in serum triacylglycerol concentrations in suckling pups could be attributed to corresponding changes in muscle LPL. In the adult, the main contributor to total LPL activity was WAT in fed rats and muscle in fasted rats, as expected. In suckling pups, however, muscle LPL contributed 63-85% of the total and WAT less than 25%, whatever the nutritional state. The results strongly suggest that clearing of circulating chylomicrons during suckling largely depends on muscle LPL.
Effects of glucocorticoids on muscle protein turnover in perfused rat hemicorpus
Authors: Rannels S. R. , Jefferson L. S.
Published: December 2017

Normal and adrenalectomized rats treated with cortisone lost 2% of their initial body weight per day, whereas controls gained weight at a rate of 2%/day. Five days of treatment resulted in a 25% reduction in the weights of a number of mixed fiber type muscles, but did not affect the weights of heart or soleus, a muscle consisting of slow-twitch red fibers. Reductions in muscle weights were accompanied by a loss of protein and RNA. Perfused hemicorpus preparations from rats receiving 5 days of treatment released several amino acids in greater amounts than the controls. Protein synthesis in perfused gastrocnemius was reduced 50–60% after 3 or 5 days of steroid treatment. This reduction was due to a loss of RNA and to an inhibition of translation resulting from an impairment in peptide-chain initiation. In contrast, RNA content and initiation were not altered in heart and soleus. Protein degradation in perfused hemicorpus and cathepsin D activity in gastrocnemius were unaffected by cortisone treatment, suggesting that loss of muscle weight and protein content as well as increased amino acid release resulted from the reduction in protein synthesis.
25-hydroxyvitamin D3 metabolism by isolated perfused rat kidney
Authors: Rosenthal A. M. , Jones G. , Kooh S. W. , Fraser D.
Published: December 2017

Kidneys of adult rats were removed and perfused with semisynthetic media with the object of elucidating the separate actions of factors implicated as modulators of renal metabolism of 25-hydroxyvitamin D3 (25(OH)D3). During a 3-h perfusion with 3[H]25(OH)D3, the kidney produced high yields of 24,25-dihydroxyvitamin D3 (24,25(OH)2D3) or 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) depending on whether the rat had previously been, respectively, normocalcemic, normophosphatemic, vitamin D-replete or hypocalcemic, hypophosphatemic, vitamin D-deplete. With longer perfusion (up to 12 h), kidneys from normocalcemic, normophosphatemic, vitamin D-replete rats mainly produced 24,25(OH)2D3 but also amounts of 1,25(OH)2D3. This pattern was unaltered by reducing Ca or Pi concentrations of perfusate or by adding parathyroid hormone. Kidneys of hypocalcemic, hypophosphatemic, vitamin D-deplete rats perfused with low Ca, low Pi medium for 12 h at first produced 1,25(OH)2D3 exclusively. However, 24,25(OH)2D3 appeared after 4 h and accumulated thereafter, whereas 1,25(OH)2D3 synthesis ceased after 7 h, a metabolic pattern unaffected by the concentration of substrate or end products in the perfusate or by addition of cyclic AMP. The model shows promise for studying regulation of 25(OH)D3 metabolism by the kidney.
Nitrogen retention during late gestation in the rat in response to marginal zinc intake
Authors: Greeley S. , Fosmire G. J. , Sandstead H. H.
Published: December 2017

This study was conducted to characterize nitrogen retention in response to marginal dietary zinc during gestation. Long-Evans rats were randomly assigned to one of two dietary groups on day 1 of gestation. The dams were fed a basal diet supplemented with either restricted or control levels of zinc. Feces and urine were collected for 24 h on day 20 of pregnancy, and their nitrogen and zinc contents were determined. Urinary and fecal nitrogen excretions were similar for zinc-restricted and control dams, whereas fecal zinc excretions were depressed by feeding the zinc-restricted diet. Mean zinc and nitrogen retentions were negative for the zinc-restricted and positive for the control groups. Multiple stepwise regression analysis showed that nitrogen retention on day 20 depended on both dietary nitrogen and zinc intakes. Zinc-restricted offspring weighed 12% less and the maternal plasma zinc concentrations were reduced by 66% when compared with the control group values on day 22. Marginal dietary zinc and the associated anorexia limited fetal growth without causing excessive nitrogen excretion or severe weight loss.
Protein synthesis and degradation in skeletal muscle of normal and dystrophic hamsters
Authors: Li J. B.
Published: December 2017

Dystrophic hamsters (BIO 53.58) had lower body weights and gastrocnemius muscle weights than normal hamsters (BIO RB). Dystrophic muscle contained less protein than normal muscle. The proportion of collagenous to noncollagenous protein remained unchanged. Loss of protein in the dystrophic muscle was the result of an increase in the rate of protein degradation. This was accompanied by higher activities of two lysosomal proteases, cathepsins B and D. The net effect of the increase in protein degradation was blunted by an increase in the rate of synthesis of total protein and myosin. The faster rate of synthesis in dystrophic muscle was partially due to an increase in the concentration of cellular RNA. Rates of peptide-chain initiation and protein synthesis decreased in muscles of normal hamsters perfused in the absence of insulin. In the presence of insulin, these processes were maintained at higher rates. However, the rate of protein synthesis in dystrophic muscle appeared less insulin-dependent than normal muscle. Protein degradation was inhibited by insulin in both types of muscle.
Vascular responsiveness and serum biochemical parameters in alloxan diabetes mellitus
Authors: Turlapaty P. D. , Lum G. , Altura B. M.
Published: December 2017

Responses of isolated aorta and portal vein (PV) to norepinephrine (NE), angiotensin II (AII), KCl, and CaCl2 were investigated in alloxan diabetic rats. Based on serum biochemical parameters (i.e., glucose, cholesterol, triglycerides, and creatinine) (alloxan, 150 mg/kg), diabetic rates were divided into three groups: 1) mildly diabetic at 1 week (only elevated glucose levels), 2) moderately diabetic at 4 wk (elevated glucose, triglycerides, and creatinine), and 3) severely diabetic at 8 wk (all serum biochemical parameters elevated). The sensitivity (i.e., ED50) of aortic smooth muscle from diabetic rats when compared to saline controls was 1) unchanged in mild diabetes; 2) decreased to KCl, AII, and CaCl2 in moderate diabetes; and 3) decreased to KCl, NE, and CaCl2 in severe diabetes. Ability of aortic smooth muscle to develop maximal contractions (i.e., contractility) to all these agonists was markedly diminished in severe diabetes. Spontaneous phasic contractions of PV from diabetic rats exhibited progressively greater tension as the disease advanced. Unlike aortas, contractility of PV to vasoactive agents was not affected at any stage of diabetes. PV sensitivity to AII in moderate diabetes and to Ca in severe diabetes was decreased when compared to saline controls. These differences in reactivity and contractility of aorta and PV in progressive stages of experimental diabetes could be due to alterations in calcium handling and its metabolism in arterial and venous smooth muscle cells in the diabetic state.
Stimulation of angiotensinogen production: a dose-related effect of angiotensin II in the conscious dog
Authors: Sernia C. , Reid I. A.
Published: December 2017

The hypothesis that angiotensin II (AII) provides a positive feedback stimulus for production of angiotensinogen was examined in conscious dogs. AII was infused intravenously for 24 h at 5, 20, and 50 ng x kg-1 x min-1 and blood pressure, plasma renin activity (PRA), and the concentrations of AII, angiotensinogen, corticosteroids, and total protein in plasma were measured 0, 2, 4, and 24 h after the start of infusion. In addition, the liver content of angiotensinogen and the release of angiotensinogen by liver slices in vitro were measured after the 24-h sampling period. AII infusion increased blood pressure in a dose-related manner. PRA was markedly decreased by all doses of AII. Plasma corticosteroids were increased only at the highest dose of AII and did not bear any relationship to changes in the concentration of angiotensinogen. Plasma protein concentration and hematocrit were unchanged. Plasma angiotensinogen concentration was unchanged at 2 and 4 h but was increased significantly at 24 h by the two highest doses of AII. A linear relationship was found between the dose of AII and plasma angiotensinogen concentration, the liver content of angiotensinogen, and the release from liver slices during a 2-h incubation. These results provide further evidence that AII has a role in angiotensinogen production but suggest that it is of minor importance in physiological conditions.
Time and dose dependencies for priming effect of glucose on insulin secretion
Authors: Grill V.
Published: December 2017

Short-term exposure to glucose increases insulin secretion during subsequent stimulation. This priming effect of glucose was further investigated in the perfused rat pancreas. A 5-min pulse of 27.7 mM glucose enhanced the response to a second pulse of the sugar after a 5- or 30-min period of 3.9 mM glucose. With a 10-min pulse of 27.7 mM glucose, the priming effect tended to persist also after a 60-min but not after a 90-min rest period. The priming effects of glucose were also evaluated from enhancement of stimulation 15 min later with 3-isobutyl-l-methylxanthine (IBMX). A 10-min pulse of 8.3 and 27.7, but not 5.6 mM glucose enhanced IBMX-induced insulin secretion. Cycloheximide did not abolish the priming effect of glucose on IBMX-induced insulin secretion. Conclusions are 1) priming is rapidly induced; 2) it persists longer than the time of induction; 3) threshold concentrations of glucose that induce priming are similar to those that initiate insulin secretions; and 4) mechanisms causing priming may not involve protein synthesis.
Autoregulation of thyroid iodide transport: possible mediation by modification in sodium cotransport
Authors: Berkowitz M. , Daughtridge D. , Sherwin J. R.
Published: December 2017

Cat thyroid slices were employed to determine whether preincubation with excess iodide, a procedure previously reported to depress subsequently measured iodide transport activity, is associated with any alteration in the relationship between sodium and iodide transport. Kinetic analysis revealed that the inhibition of iodide-concentrating activity by iodide pretreatment was accompanied by a reduction in the apparent affinity of the iodide transport for iodide as reflected by increase in the value of KA, the concentration of iodide required to achieve half-maximal transport activity. A reduction in extracellular sodium concentration was also accompanied by an increase in the value of KA for iodide transport. Thus, the KA of iodide transport in control thyroid tissue was increased from a value of 8.6 +/- 1.2 to 16.5 +/- 2.4 microM, by a reduction in extracellular sodium from 144 to 52 mM. In contrast, in thyroid tissue subjected to a 2-h preincubation with 30 microM NaI, a similar reduction in extracellular sodium concentration was associated with only a 20% increase in KA from a value of 17.7 +/- 2.4 to 21.7 +/- 2.2 microM. Analysis of the kinetic data suggests that the autoregulatory effect of excess iodide results in a decline in the sodium dependency of iodide transport. This loss of sodium dependency is accompanied by an increase in the affinity of the process for sodium, as well as a reduction in the affinity of the transport system for iodide.
Increased enzymatic activity of renin and hyperlipidemia
Authors: Kotchen T. A. , Talwalkar R. T.
Published: December 2017

We have previously reported that the in vitro enzymatic activity of exogenous renin, plasma renin reactivity (PRR), is increased in plasma of patients with chronic renal failure, possibly due to the deficiency of a renin inhibitor. To determine whether increases PRR is related to renal failure per se or to hyperlipidemia, PRR was measured in 10 control subjects, 10 patients with renal failure, and 10 hyperlipidemic patients with normal renal function. Compared to that in control subjects (52.6 ng angiotensin I generated per ml/h +/- 3.8 SE) PRR was increased (P < 0.05) in plasma of uremic patients (65.1 +/- 4.3) and hyperlipidemic patients (71.4 +/- 10.7). Renin substrate concentration did not differ among groups, and after denaturation of endogenous substrate by acidification of plasma, PRR was still increased. A "protein-free" extract of plasma from normal subjects inhibited renin, whereas little or no inhibition occurred with a comparable extract from uremic patients and hyperlipidemic patients. Thus, alterations in lipid metabolism may account for the increased enzymatic activity of renin in uremic plasma. Increased PRR may be related to the deficiency of a normally occurring renin inhibitor.