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PubMed1991

Ventromedial hypothalamic stimulation enhances peripheral glucose uptake in anesthetized rats.

Effects of electrical and chemical stimulation of the ventromedial (VMH) and lateral hypothalamic (LH) nuclei on glucose uptake in peripheral tissues were studied by the 2-deoxy-D-[3H]glucose (2-[3H]DG) method in anesthetized rats. Electrical stimulation of the VMH increased the rate constant of glucose uptake in brown adipose tissue (BAT; 8 times), heart (3 times), and skeletal muscles (1.5 times) but not in white adipose tissue, diaphragm, and brain, without detectable changes in plasma insulin levels. Chemical stimulation of the VMH by microinjection of L-glutamate also enhanced the rate constant of glucose uptake in BAT, heart, and skeletal muscles preferentially, which indicates that the enhancement of glucose uptake in these tissues is derived from activation of VMH neurons. The increased rate of glucose uptake in BAT in response to VMH stimulation was effectively suppressed by surgical sympathetic denervation, suggesting a mediation of the sympathetic nerve in this effect. On the other hand, electrical stimulation of the LH had no appreciable effect on 2-[3H]DG uptake in any tissues. It is concluded that glucose uptake in certain peripheral tissues is accelerated selectively by activation of VMH neurons, the action of which is independent of plasma insulin but which is probably via the sympathetic nervous system.

Adipose Tissue, Brown↗
PubMedDate not supplied

2-[125I]iodomelatonin binding sites in the lung and heart: a link between the photoperiodic signal, melatonin, and the cardiopulmonary system.

The pineal gland plays an important role in seasonal adaptation including variation in energy requirement. Animals exhibiting seasonal changes in their energy expenditure would be benefited if their cardiac and pulmonary systems respond to the pineal photoperiodic signal, melatonin, appropriately. Thus, we would like to hypothesize that melatonin receptors are present in the heart and lung. Using a specific labeled melatonin agonist, 2-[125I]iodomelatonin, binding sites were demonstrated in the lung and heart of birds and other animals. In the chicken lung, there were high affinity (equilibrium dissociation constant, Kd = 9.11 +/- 0.73 pmol/l) and low density (maximum number of binding sites, Bmax = 1.29 +/- 0.16 fmol/mg protein) 2-[125I]iodomelatonin binding sites that were highly specific to melatonin. Similar binding with lower density was demonstrated in the quail and frog lungs. In the duck heart, specific 2-[125I]iodomelatonin binding sites with a Kd of 30.5 +/- 3.5 pmol/l and a Bmax of 0.46 +/- 0.1 fmol/mg protein (n = 4) were demonstrated. Competitive studies suggested that these binding sites were specific to melatonin. Thus, saturable and reversible 2-[125I]iodomelatonin binding was present in the lung and heart membrane preparations of birds and possibly other animals. The picomolar affinity, femtomolar density and highly specific pharmacological profile of these binding sites suggest that they can be classified as ML-1 melatonin receptors. The 2-[125I]iodomelatonin binding sites described in the lung and heart as well as those binding sites demonstrated in other peripheral tissues suggest the ubiquitous direct action of melatonin on peripheral tissues.

Animals↗
PubMed1995

Severe insulin-resistant diabetes mellitus in patients with congenital muscle fiber type disproportion myopathy.

Congenital muscle fiber type disproportion myopathy (CFTDM) is a chronic, nonprogressive muscle disorder characterized by universal muscle hypotrophy and growth retardation. Histomorphometric examination of muscle shows a preponderance of smaller than normal type 1 fibers and overall fiber size heterogeneity. Concomitant endocrine dysfunctions have not been described. We report the findings of altered insulin secretion and insulin action in two brothers affected with CFTDM and glucose intolerance as well as in their nonconsanguineous glucose-tolerant parents. Results are compared with those of six normoglycemic control subjects. All study participants underwent an oral glucose tolerance test to estimate insulin secretion. The oldest boy and his parents volunteered for studies of whole-body insulin sensitivity consisting of a 4-h euglycemic hyperinsulinemic clamp in combination with indirect calorimetry. Insulin receptor function and glycogen synthase (GS) activity and expression were examined in biopsies of vastus lateralis muscle. Despite a 45-90-fold increase in both fasting and postprandial serum insulin levels, both CFTDM patients had diabetes mellitus. Clamp studies revealed that the oldest boy had severe insulin resistance of both liver and peripheral tissues. The impaired insulin-stimulated glucose disposal to peripheral tissues was primarily due to reduced nonoxidative glucose metabolism. These changes were paralleled by reduced basal values of muscle GS total activity, allosterical activation of GS by glucose-6-phosphate, GS protein, and GS mRNA. The father expressed a lesser degree of insulin resistance, and studies of muscle insulin receptor function showed a severe impairment of receptor kinase activity. In conclusion, CFTDM is a novel form of severe hyperinsulinemia and insulin resistance. Whether insulin resistance is causally related to the muscle disorder awaits to be clarified.

Adolescent↗
PubMed1999

Peripheral oxygenation in hypotensive preterm babies.

Monitoring oxygenation in peripheral tissues of preterm babies may be useful in understanding the redistribution of blood flow during hypotension. Hemoglobin flow and venous saturation were measured in the forearm using near infrared spectroscopy with venous occlusion and were used to calculate fractional oxygen extraction, oxygen delivery, and oxygen consumption. Thirty ventilated preterm babies (median birth weight 976 g) were studied; 15 were hypotensive and 15 normotensive. Treatment for hypotension was dopamine alone (median dose 5 microg/kg/min) in eight cases, 4.5% human albumin solution (20 mL/kg) with dopamine in five cases, and only a blood transfusion (20 mL packed cells/kg) in two cases. There was a weak correlation between hemoglobin flow and mean arterial blood pressure (r = 0.40, p = 0.03). In hypotensive compared with normotensive babies, there was a significantly lower median hemoglobin flow (10.2 versus 20.2 micromol/100 mL/min, p = 0.0006), forearm oxygen delivery (37.8 versus 75.2 micromol/100 mL/min, p = 0.0008), and oxygen consumption (11.0 versus 23.9 micromol/100 mL/min, p = 0.006), but the fractional oxygen extraction (0.327 versus 0.306, p = 0.48) and the blood lactate concentration (1.22 versus 1.20 mmol/L, p = 0.44) were similar. Following treatment of hypotension, oxygen delivery (p = 0.02) and oxygen consumption (p = 0.04) increased to 64.2 and 21.7 micromol/100 mL/min, respectively, but fractional oxygen extraction (p = 0.81) and blood lactate concentration (p = 0.94) after treatment were unchanged. VO2 was variable in the forearm of human infants. It reduced when DO2 was low, and there was no evidence of tissue injury or switch to anaerobic metabolism. Measurements of peripheral tissue oxygenation seem to be of some value in understanding the pathophysiologic changes that occur with hypotension.

Humans↗
PubMed1985

The synthesis and metabolism of gonadal steroids in pouch young of the opossum, Didelphis virginiana.

We have measured steroid hormone biosynthesis from pregnenolone in ovaries and testes, aromatization of testosterone in gonads and peripheral tissues, and 5 alpha-reduction of testosterone in peripheral tissues of developing opossum pouch young. Sex of the newborn opossums is discernible grossly with development of the pouch in females and the scrotum in males approximately 10 days after birth. Differentiated endocrine function of ovaries and testes was demonstrable as soon as development of the pouch or scrotum was apparent. The testes synthesized testosterone, and ovaries aromatized androgens to estrogens as assessed by the conversion of [1 beta-3H] testosterone to 3H2O. This endocrine differentiation of the gonads occurs days or weeks before differentiation of the male and female urogenital tracts. As in other species, 5 alpha-reduction of [1 beta-3H] testosterone was high in urogenital sinus and urogenital tubercle. However, 5 alpha-reductase activity was highest in mesonephros and structures derived from the mesonephros. In wolffian and mullerian ducts of pouch young less than 10 days old, 5 alpha-reductase activity was greater than 50 pmol/h . mg protein and decreased by 19 days of age to approximately 3 pmol/h . mg protein, a pattern different than in eutherian mammals in which testosterone itself appears to mediate virilization of the wolffian ducts. These studies provide the framework for studies of the endocrine control of phenotypic sexual differentiation in the opossum.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1995

Regulation of CD4 T cell reactivity to self and non-self.

While the thymus may be effective in inducing tolerance to lymphoid associated antigens, it is not as efficient in deleting T cells reactive to peripheral tissue specific antigens. Therefore, to maintain self tolerance to peripheral tissues, post-thymic mechanisms must be invoked. One important way to prevent autoimmune pathology mediated by autoreactive CD4 T cells is the diversion of clones to regulatory Th2 effector cells. However, many different factors contribute in vivo to the decision of stimulated CD4 T cells to develop into Th1 versus Th2 cells. For example, T cell signaling pathways may influence the types of cytokines produced by naive T cells, and studies have provided evidence for a genetic polymorphism among common mouse strains that can significantly influence the early cytokine production in stimulated naive CD4 T cells. The allele carried by the BALB/c strain promotes IL-4 production, and consequently provides resistance to autoimmune diabetes in our transgenic mouse model. In addition, antigen presenting cells can influence the development of stimulated CD4 T cells in part through the production of cytokines such as IL-12. The absorption of IL-12 in vivo can permit the expansion of Th2 type effector cells, and this phenomenon will also protect mice from autoimmunity. Finally, the relative potency of various class II positive antigen presenting cell types can influence the development of autoreactive T cells, with dendritic cells apparently being the strongest stimulator of Th1 responses. Consistent with this notion, a relB knockout mouse, which is missing dendritic cells, appears to drive Th2 development even in response to viral infection. In sum, these various influences over the Th1/Th2 decision in vivo may provide new targets for immunotherapy of autoimmune diseases.

Animals↗
PubMed1983

[Radiologic diagnosis of malignant peripheral soft tissue tumors].

In malignant soft-tissue tumors of the extremities the radiologist is asked to define size and extent of the lesion and it's relationship to adjacent structures. The assessment of the nature of the lesion is of utmost importance, however, the contribution of the different imaging modalities varies considerably. In a review article the current roles of conventional radiography, xeroradiography, real-time ultrasonography, computed tomography and arteriography in the diagnostic workup of malignant soft-tissue tumors of the extremities are discussed. The statements made are based upon own comparative studies as well as on a review of the literature. In the assessment of the nature of a soft-tissue mass the contribution of all radiologic imaging methods is rather limited, although arteriography may add valuable information if performed complementary to CT. Real-time ultrasonography is well suited to define size, location and extent of peripheral soft-tissue masses. It is therefore recommended as the first imaging method and for follow-up studies. Equivocal findings by real-time sonography and new cases for treatment planning must be confirmed by computed tomography which proved to be the most reliable and the best reproducible imaging method for soft-tissue tumors of the extremities.

Adult↗
PubMed1996

Density correction of peripheral breast tissue on digital mammograms.

When digital mammograms are viewed on video displays, evaluation of the skin and subcutaneous tissue is often difficult and may require special window settings. An algorithm has been developed for selective enhancement (ie, density correction) of the dark peripheral portions of the breast on mammograms. After an automated segmentation of the digital mammogram and identification of the skin line, a fitted enhancement curve is generated to selectively enhance all pixels within a certain distance from the skin to match the density of the center part of the breast. After enhancement, skin and breast parenchyma can be evaluated simultaneously without the need for different window settings. When tested on a set of 400 digitized mammograms, the density correction algorithm significantly (P < .0001) increased the maximum area of breast tissue visualized simultaneously at window width settings of 0.5-2.0 delta OD (optical density). Artifacts interfering with interpretation were observed in less than 1%. The algorithm for correcting the density of peripheral breast tissue substantially facilitates and improves the display of digital mammograms and thus will be a valuable component of an integrated workstation for computer-aided diagnosis in mammography.

Algorithms↗
PubMed2003

Approaches to tissue engineered peripheral nerve.

The late 1980s and early 1990s brought excitement to the idea that we would be able to replace body tissues and organs through the field of tissue engineering. This enthusiasm was soon replaced by the realization of the limitations in our knowledge for specific tissue types and replication efforts. Such is the case with nerve tissue. We have progressed in this field of knowledge; however, full elucidation to the complex interactions of nerve repair falls short.

Extracellular Matrix↗
PubMed2000

Cloning and characterization of human NTT5 and v7-3: two orphan transporters of the Na+/Cl- -dependent neurotransmitter transporter gene family.

Orphan transporters form a growing subfamily of genes related by sequence similarity to the Na+/Cl- -dependent neurotransmitter superfamily. Using a combination of database similarity searching and cloning methods, we have identified and characterized two novel human orphan transporter genes, v7-3 and NTT5. Similar to other known orphan transporters, v7-3 and NTT5 contain 12 predicted transmembrane domains, intracellular N- and C-terminal domains, and large extracellular loops between transmembrane (TM) domains 3 and 4 and between TM domains 7 and 8. Residues within the extracellular loops are also predicted to contain sites for N-linked glycosylation. Human v7-3, the species orthologue of rat v7-3, contains an open reading frame (ORF) of 730 amino acids. Human NTT5 is a new member of the orphan transporter family and has an ORF of 736 amino acids. The amino acid sequences of human v7-3 and NTT5 are greater than 50% similar to other known orphan neurotransmitter transporters and also show sequence similarity to the human serotonin and dopamine transporters. Radiation hybrid mapping located the human v7-3 and NTT5 genes on chromosomes 12q21.3-q21.4 and 19q13.1-q13.4, respectively. Human mRNA distribution analysis by TaqMan reverse transcription-polymerase chain reaction showed that v7-3 mRNA is predominantly expressed in neuronal tissues, particularly amygdala, putamen, and corpus callosum, with low-level expression in peripheral tissues. In contrast, NTT5 mRNA was highly expressed in peripheral tissues, particularly in testis, pancreas, and prostate. Transient transfection with epitope-tagged transporter constructs demonstrated v7-3 to be expressed at the cell surface, whereas NTT5 was predominantly intracellular, suggestive of a vesicular location. Although the substrates transported by these transporters remain unknown, their specific but widespread distribution suggests that they may mediate distinct and important functions within the brain and the periphery.

AMP-Activated Protein Kinases↗
PubMed2000

Response of nitrogen metabolism in preparturient dairy cows to methionine supplementation.

Three multiparous Holstein cows (607 kg of BW) were surgically prepared with an elevated carotid artery and indwelling catheters in the hepatic, portal, and two mesenteric veins to study the effects of methionine supplementation on amino acid metabolism during the last 2 wk of pregnancy. The study began 15 d before the expected calving date. Dietary treatments were Control (1.53 Mcal NE(l)/kg, 15.6% CP, and 40% ruminally undegradable protein) and Control supplemented with 60 g/d of ruminally protected methionine (MET, supplying 39 g/d of DL-methionine and approximately 18 g/d of methionine available for intestinal absorption). Each cow received both dietary treatments in a crossover design. Cows were fed once daily. After 5 d on treatment, a blood flow marker (para-aminohippurate) was infused into a mesenteric vein, and arterial, portal, and hepatic blood samples were obtained at 0, 2, 6, 12, and 18 h after feeding. Net flux of methionine was calculated as the plasma arteriovenous difference multiplied by plasma flow. Dry matter intake (10.8 kg/d) and portal (824 L/h) and hepatic (995 L/h) plasma flows were not affected (P > .10) by treatment. Arterial plasma concentration of methionine was greater (P = .10) with MET (27.67 microM) than with Control (16.42 microM). Net portal absorption of methionine increased (P = .10) with MET (26.2 g/d) compared with Control (9.5 g/d). The net portal methionine flux was negatively correlated (r = -.59; P < .001) with arterial urea concentrations. Net flux of methionine across splanchnic tissues shifted (P = .06) from a net uptake with Control (4 g/d) to a net output with MET (11 g/d). Therefore, MET increased by 15 g/d the methionine supply to the rest of the body. The net uptake of methionine by splanchnic tissues observed with Control indicated a net mobilization of methionine by peripheral tissues. Results indicate that methionine was the limiting amino acid with Control and that MET was beneficial because it increased methionine supply to peripheral tissues and reduced arterial urea concentrations.

Animal Feed↗
PubMedDate not supplied

Basic study on hepatic resection under partial perfusion cooling.

To improve liver quality after reperfusion following partial hepatectomy under total or partial cooling of the liver (HPC), a new perfusion solution containing 100 mM L-histidine (KM solution) was developed. The livers of Lewis rats were removed and perfused for 2 hours at 20 degrees C with lactated Ringer's (LR) solution (group A) or the KM solution (group B). They were reperfused with rat blood at 37 degrees C at a perfusion pressure of 5 cmH2O while monitoring the portal and peripheral tissue blood flows. At the end of reperfusion, bile production, lactate dehydrogenase (LDH) secretion, and tissue adenosine triphosphate (ATP) was measured. Recovery of portal and peripheral tissue blood flows of the group B livers after reperfusion were significantly better than those of group A. Viability of the group B livers, assessed by bile production, tissue ATP value, and LDH release, was preserved better than that of group A livers. In situ total liver perfusion with LR (group C) and KM (group D) solutions for 1 hour at 20 degrees C followed by partial hepatectomy of the left lateral lobe was performed. The 1-week survivals of the group C and D rats were 25% and 100%, respectively (p < 0.05). It was concluded that KM solution is suitable for HPC.

Animals↗
PubMed1991

Dietary regulation of maternal and fetal cholesterol metabolism in the guinea pig.

Studies to determine the effects of pre-natal interventions on maternal and fetal cholesterol homeostasis were carried out in the guinea pig. Guinea pig dams were fed either non-purified guinea pig diet or diet supplemented with either 1.1% of the bile acid binding resin cholestyramine or 0.25% cholesterol. Whole body rates of endogenous cholesterol synthesis were determined by quantitation of [3H]water incorporation into digitonin precipitable sterols in non-pregnant animals and at 40 and 60 days of gestation in the dam and fetus. Maternal hepatic cholesterol synthesis was reduced 87% by dietary cholesterol and was increased 3.5-fold with cholestyramine feeding. Fetal hepatic and peripheral tissue cholesterol synthesis rates peaked at 40 days gestation when peripheral tissue cholesterol synthesis was 5.7-fold higher and hepatic synthesis 6.2-fold greater than the near adult levels observed at 60 days. Cholesterol synthesis in the fetus was relatively insensitive to dietary manipulations; however, maternal cholestyramine treatment did result in a 1.4-fold increase in fetal carcass cholesterol synthesis at 60 days gestation. These data demonstrate that maternal cholesterogenic systems maintain responsiveness to dietary regulation during pregnancy; whereas fetal cholesterol homeostasis is relatively insensitive to dietary cholesterol throughout gestation yet may respond to induction by maternal cholestyramine treatment during the late gestation period.

Animals↗
PubMed2002

Decompensation characterized by decreased perfusion of the heart and brain during hemorrhagic shock: role of endothelin-1.

BACKGROUND: Endothelin-1 (ET-1), a 21-amino-acid peptide produced by vascular endothelium, is a potent vasoconstrictor and a component of local regulation of vascular tone through its effect on underlying vascular smooth muscle. Hemorrhagic shock (HS) is characterized by compensatory regional vasoconstriction to decrease peripheral tissue perfusion and to maintain core organ perfusion. Decompensation occurs with prolonged duration of HS. In the present study, we hypothesized that systemic and vital organ tissue ET-1 concentrations would correlate with changes in systemic and vital organ perfusion associated with compensatory and decompensatory states of HS. METHODS: After surgical instrumentation, HS was induced in male Sprague-Dawley rats by withdrawing blood via femoral artery to a mean arterial pressure of 35 to 40 mm Hg that was maintained for either 30 minutes or 90 minutes in separate groups of male Sprague-Dawley rats. Systemic hemodynamics and regional blood flow were measured using a radioactive microsphere technique. In separate groups of animals, sham, 30 minutes of HS, or 90 minutes of HS, plasma and tissue concentrations of ET-1 were determined using a radioimmunoassay technique. RESULTS: HS maintained for 90 minutes was associated with increased arterial base deficit from 3.6 +/- 0.53 mEq/L to 13 +/- 0.37 mEq/L, decreased cardiac output from 79 +/- 18 mL/min to 18 +/- 5 mL/min, and increased systemic vascular resistance from 1,004 +/- 102 mm Hg/L. min to 2,392 +/- 447 mm. Hg/L min as compared with baseline values. With 90 minutes of HS as compared with 30 minutes of HS, perfusion was significantly decreased in brain (72 +/- 11 vs. 29 +/- 6 mL/min. 100 g tissue) and heart (483 +/- 30 vs. 173 +/- 38 mL/min. 100 g tissue) and kidney perfusion was decreased (from 114 +/- 28 mL/min/100 g tissue to 29 +/- 2 mL/min. 100 g tissue), and ET-1 concentration was increased significantly in brain (cerebral cortex, 89 +/- 14 pg/100 g tissue to 144 +/- 19 pg/100 g tissue; midbrain, 172 +/- 15 pg/100 g tissue to 211 +/- 10 pg/100 g tissue), heart (left ventricle, 312 +/- 11 pg/100 g tissue to 360 +/- 14 pg/100 g tissue), kidney (medulla, 857 +/- 61 pg/100 g tissue to 1,277 +/- 41 pg/100 g tissue), and plasma (5.31 +/- 0.6 pg/100 g tissue to 21.26 +/- 2.9 pg/mL). CONCLUSION: Decreased vital organ and peripheral tissue perfusion, a primary decompensation effect of HS, was apparent with 90 minutes of HS but not with 30 minutes, and was associated with increased vital organ tissue and plasma ET-1 concentrations. These data suggest a role for ET-1 in control mechanisms of progressive vasoconstriction that occurs with prolonged duration of HS.

Animals↗
PubMed1982

Syndromes of thyroid hormone resistance.

Resistance to the action of thyroid hormone can involve both peripheral tissues and the pituitary (global resistance), the pituitary only or peripheral tissues alone. Global resistance is of variable severity and has been observed in more than 60 individuals, the majority occurring in 17 families. Affected subjects are commonly eumetabolic and have goiters, elevated plasma levels of total and free thyroxine and triiodothyronine, normal thyroid hormone metabolism, and normal serum TSH levels (albeit high for the corresponding levels of thyroid hormone). A variable degree of delayed bone maturation, mental retardation, learning disabilities, and hearing defects have been reported; and a variety of treatment regimens, most of which are aimed at reducing the level of plasma hormones and/or goiter, have been attempted before the correct diagnosis has been reached. The clinical disorder is equally common in males and females and appears to be due to one or more autosomal gene mutations. The causes for the hormone resistance may be heterogeneous, either influencing the receptor for thyroid hormones or some unidentified steps in hormone action. At present, the diagnosis is one of exclusion; no effective therapy is available, and all measures designed to lower serum thyroid hormone levels should be avoided.

Adolescent↗
PubMed1987

Cold exposure potentiates the effect of insulin on in vivo glucose uptake.

The effects of cold exposure (48 h at 4 degrees C) and insulin injection (0.5 U/kg iv) on the rates of net 2-[3H]deoxyglucose uptake (Ki) in peripheral tissues were investigated in warm-acclimated rats (25 degrees C). Cold exposure and insulin treatment independently increased Ki values in skeletal muscles (soleus, extensor digitorum longus, and vastus lateralis), heart, white adipose tissue (subcutaneous, gonadal, and retroperitoneal), and brown adipose tissue (P less than 0.01). The effects of cold exposure were particularly evident in brown adipose tissue where the Ki increased greater than 100 times. When the two treatments were combined (insulin injection in cold-exposed rats), it was found that cold exposure synergistically enhanced the maximal insulin responses for glucose uptake in brown adipose tissue, all white adipose tissue depots, and skeletal muscles investigated. The results indicate that cold exposure induces an "insulin-like" effect on Ki that does not appear to be specifically associated with shivering thermogenesis in skeletal muscles, because that effect was observed in all insulin-sensitive tissues. The data also demonstrate that cold exposure significantly potentiates the maximal insulin responses for glucose uptake in the same tissues. This potentialization may result from an enhanced responsiveness of peripheral tissues to insulin, possibly occurring at metabolic steps lying beyond the insulin receptor and an increased tissue blood flow augmenting glucose and insulin availability and thereby amplifying glucose uptake.

Animals↗