Biomedical subjects

R LaFrance

Publications and source records attributed to R LaFrance.

18 recordsLinked to original sources

PubMed2005

Age-dependent changes in the calcium sensitivity of striatal mitochondria in mouse models of Huntington's Disease.

Striatal and cortical mitochondria from knock-in and transgenic mutant huntingtin mice were examined for their sensitivity to calcium induction of the permeability transition, a cause of mitochondrial depolarization and ATP loss. The permeability transition has been suggested to contribute to cell death in Huntington's Disease. Mitochondria were examined from slowly progressing knock-in mouse models with different length polyglutarnine expansions (Q20, Q50, Q92, Q111) and from the rapidly progressing transgenic R6/2 mice overexpressing exon I of human huntingtin with more than 110 polyglutamines. As previously observed in rats, striatal mitochondria from background strain CD1 and C57BL/6 control mice were more sensitive to calcium than cortical mitochondria. Between 5 and 12 months in knock-in Q92 mice and between 8 and 12 weeks in knock-in Q111 mice, striatal mitochondria developed resistance, becoming equally sensitive to calcium as cortical mitochondria, while those from Q50 mice were unchanged. Cortical mitochondrial calcium sensitivity did not change. In R6/2 mice striatal and cortical mitochondria were equally resistant to Ca2+ while striatal mitochondria from littermate controls were more susceptible. No increases in calcium sensitivity were observed in the mitochondria from Huntington's Disease (HD) mice compared to controls. Neither motor abnormalities, nor expression of cyclophilin D corresponded to the changes in mitochondrial sensitivity. Polyglutamine expansions in huntingtin produced an early increased resistance to calcium in striatal mitochondria suggesting mitochondria undergo compensatory changes in calcium sensitivity in response to the many cellular changes wrought by polyglutamine expansion.

Aging↗

PubMed2005

Age-related changes in regional brain mitochondria from Fischer 344 rats.

Brain mitochondrial function has been posited to decline with aging. In order to test this hypothesis, cortical and striatal mitochondria were isolated from Fischer 344 rats at 2, 5, 11, 24 and 33 months of age. Mitochondrial membrane potential remained stable through 24 months, declining slightly in mitochondria from both brain regions at 33 months. The ability of calcium to induce mitochondrial swelling and depolarization, characteristics of the permeability transition, was remarkably stable through 24 months of age and increased at advanced ages only for cortical, but not striatal, mitochondria. Striatal mitochondria were more sensitive to calcium than were cortical mitochondria throughout the first 2 years of life. A two-fold increased resistance to calcium was observed in striatal mitochondria between 5 and 11 months. Although these measurements do demonstrate changes in mitochondrial function with aging, the changes in polarization are relatively small and the increased cortical susceptibility to the permeability transition only occurred at very advanced ages. Thus mitochondrial decline with advanced age depends upon brain region.

Aging↗

PubMed1998

Reciprocal subtraction differential RNA display: an efficient and rapid procedure for isolating differentially expressed gene sequences.

A reciprocal subtraction differential RNA display (RSDD) approach has been developed that permits the rapid and efficient identification and cloning of both abundant and rare differentially expressed genes. RSDD comprises reciprocal subtraction of cDNA libraries followed by differential RNA display. The RSDD strategy was applied to analyze the gene expression alterations resulting during cancer progression as adenovirus-transformed rodent cells developed an aggressive transformed state, as documented by elevated anchorage-independence and enhanced in vivo oncogenesis in nude mice. This approach resulted in the identification and cloning of both known and a high proportion (>65%) of unknown sequences, including cDNAs displaying elevated expression as a function of progression (progression-elevated gene) and cDNAs displaying suppressed expression as a function of progression (progression-suppressed gene). Sixteen differentially expressed genes, including five unknown progression-elevated genes and six unknown progression-suppressed genes, have been characterized. The RSDD scheme should find wide application for the effective detection and isolation of differentially expressed genes.

Animals↗

PubMed1989

Protein synthesis in liver following infusion of the catabolic hormones corticosterone, epinephrine, and glucagon in rats.

The mediator(s) and mechanism(s) of acute-phase protein synthesis in the liver following injury and sepsis are not fully known. Elevated plasma levels of the catabolic hormones cortisol, glucagon, and epinephrine have been reported in trauma and sepsis. In previous reports, when these hormones were infused simultaneously (triple hormone infusion), several, but not all, of the metabolic alterations characteristic of sepsis occurred. In the current investigation, the effect of triple hormone infusion on hepatic protein synthesis was studied. Rats were infused intravenously during 16 hours with a solution containing corticosterone (4.2 mg/kg/h), glucagon (2.5 micrograms/kg/h), and epinephrine (6 micrograms/kg/h). Control animals were infused with a corresponding volume of vehicle. Total hepatic protein synthesis in vivo was measured with a flooding dose technique using [14C]-leucine. The synthesis of total secretory proteins and of the individual proteins albumin, complement component C3, and alpha 1-acid glycoprotein was measured in isolated, perfused liver using [3H]-leucine and a recirculating technique. Urinary excretion of nitrogen and plasma concentration of glucose were higher and plasma total amino acid concentration was lower in hormone-infused than in control rats. Total hepatic protein synthesis in vivo, expressed as the proportion of the protein pool that was replaced each day, was increased from 39% +/- 2% per day to 48% +/- 3% per day (P less than .05) by hormone infusion, but synthesis of secretory proteins in perfused liver was not significantly altered. The results suggest that although total hepatic protein synthesis may be increased by catabolic hormones, other mediator(s) are probably responsible for the stimulation of acute-phase protein synthesis in sepsis.

Acute-Phase Proteins↗

PubMed1988

Renal prostaglandin production is increased during abdominal sepsis in the rat and unaffected by the infusion of different amino acid formulations.

Renal prostaglandin (PG) production was studied in 32 laparotomized (control) and 33 septic rats (cecal ligation and puncture). Control and septic rats were infused for 18 hr with 5% glucose or 5% glucose and one of three amino acid formulations containing 22, 35, or 45% branched chain amino acids. When comparing renal PG production from endogenous precursors in septic versus control rats, significant increases (P less than 0.01) could be detected for PGE2, 6-keto-PGF1 alpha, and TxB2. The infusion of either 5% glucose alone or 5% glucose with 4.25% of any of the three amino acid formulations tested did not change renal PG production in either control or septic rats.

6-Ketoprostaglandin F1 alpha↗

PubMed1988

Administration of balanced or BCAA-enriched amino acid solution in septic rats. Effects on protein synthesis in the liver.

Total hepatic protein synthesis was measured in vivo with a flooding-dose technique, and the production of total secreted proteins, albumin, complement component C3, and seromucoid fraction was measured in perfused livers of septic rats that received one of three different solutions infused intravenously; Group 1 received 16.4% dextrose; Group 2 received Aminosyn (25% BCAA) in 10.6% dextrose, and Group 3 received Freamine HBC (45% BCAA) in 10.6% dextrose. All solutions were isocaloric, and the amino acid solutions were isonitrogenous. The solutions were administered for 18 or 48 hours after the induction of sepsis. There were no significant differences in mortality rates in the three treatment groups. The negative nitrogen balance seen in the dextrose-infused animals was reversed to the same degree by the two different amino acid solutions. There were no significant differences in hepatic protein synthesis rates in vivo between the three groups of rats. Synthesis rates of secreted proteins in perfused liver were similar in the different treatment groups in the 18-hour experiments, whereas in the 48-hour experiments, synthesis rates of total secreted proteins, C3, and the serumucoid fraction were higher in Group 1 than in Groups 2 and 3. The results suggest that administration of an amino acid solution improves nitrogen balance in sepsis, but that this effect is not caused by stimulated hepatic protein synthesis. The nitrogen-sparing effect during sepsis of a branched chain amino acid (BCAA)-enriched solution does not seem to be superior to that of a balanced amino acid solution.

Amino Acids↗

PubMed1988

A circuit modification that improves mammographic phototimer performance.

The typical mammographic phototimer does not track with breast thickness. For four common, relatively new mammographic units, phototimed density decreases markedly as breast thickness increases. This trend is attributed to three factors: beam hardening, film reciprocity law failure (RFL), and photosensor dark or leakage current. The contributions of these three factors were experimentally quantitated for the phototimer of a Senographé 500T mammography unit. For a phototimed 28-kVp nongrid technique, the density varied from 2.0 for a 2.5-cm-thick phantom to 0.3 for one 7.6 cm thick. Of the 1.7 difference in film density, 1.1 was attributed to beam hardening, 0.2 to RFL, and 0.4 to photomultiplier tube dark current. A circuit modification was installed in the phototimer that offsets the photomultiplier dark current and has a nonlinear response to compensate for beam hardening and RFL effects. The modified phototimer tracked to within +/- 0.06 density for a 28-kVp grid technique as phantom thickness was varied from 2.0 to 6.0 cm. Similar results were obtained for nongrid techniques.

Female↗

PubMed1987

Effect of catabolic hormone infusion on organ amino acid uptake.

Elevated plasma levels of the so-called catabolic hormones (glucocorticoid, epinephrine, glucagon) have been observed in severely injured patients, and infusion of these hormones to normal subjects has reportedly simulated several metabolic aberrations characteristic of severe trauma and sepsis. We recently reported that amino acid uptake was reduced in soleus muscle, heart, and diaphragm, and increased in the liver, of septic rats. The purpose of the present study was to investigate organ amino acid uptake in nonseptic rats infused with catabolic hormones. Central venous catheters were placed in male Sprague-Dawley rats (100-150 g) and after 24 hr hormones (glucagon 5 micrograms/kg/hr, epinephrine 6 micrograms/kg/hr, corticosterone 4.2 mg/kg/hr) or vehicle (saline, ascorbic acid 1 mg/ml, albumin 3 mg/ml) was infused for 72 hr. Animals were housed in metabolic cages and allowed food and water ad lib. One hour prior to sacrifice, alpha-[3H]aminoisobutyric acid (AIB) (2.5 microCi), a nonmetabolized amino acid analog mainly transported by system-A, was injected intravenously. Animals were killed and organs were removed, weighed, and dissolved in tissue solubilizer for measurement of radioactivity. AIB uptake was significantly elevated in all organs of catabolic hormone-infused animals studied. The results suggest that catabolic hormones may be involved in the pathogenesis of increased amino acid uptake in the liver during sepsis. Inhibited amino acid uptake in skeletal muscle during sepsis, however, is probably not primarily mediated by catabolic hormones.

Aminoisobutyric Acids↗

PubMed1986

Regional brain amino acid and neurotransmitter derangements during abdominal sepsis and septic encephalopathy in the rat. The effect of amino acid infusions.

Regional amino acids and brain neurotransmitters were studied in 33 normal and 32 rats with sepsis (induced by cecal ligation and puncture) infused with different amino acid formulations. The brain amino acid pattern during sepsis showed increased concentrations of most essential and six of the nonessential amino acids. The most consistent finding was the accumulation of indoleamines in all six brain regions studied during sepsis; increased brain tryptophan levels presumably resulted in enhanced metabolism of serotonin (5HT), increased production of 5-hydroxyindoleacetic acid (5HIAA), and a high 5HT/5HIAA ratio. Infusion of branched-chain amino acid-enriched formulas restored brain amino acid and neurotransmitter profiles, decreasing levels of tryptophan, tyrosine, 5HIAA, and 5HT/5HIAA ratios while increasing norepinephrine levels in some regions. These alterations in brain neurotransmitter metabolism may be at least partially responsible for the development of septic encephalopathy.

Amino Acids↗

PubMed1986

The effect of indomethacin on muscle and liver protein synthesis and on whole-body protein degradation during abdominal sepsis in the rat.

It has been recently suggested that increased muscle protein degradation during injury or infection is at least partially mediated by the increased production of prostaglandin E2 in muscle, and some have suggested that cyclooxygenase inhibitors might decrease protein loss in injured or septic patients. In these experiments, fractional synthesis rates of mixed muscle and liver protein and whole-body tyrosine flux were measured by constant intravenous infusion of tyrosine labeled with carbon 14 in 17 rats with sham operations and 15 severely septic rats with or without indomethacin treatment (20 mg/kg/d). Fractional synthesis rates in muscle and liver were decreased in late sepsis and were lowest in the septic group receiving indomethacin. Unlike the fractional synthesis rate, which was affected by indomethacin in septic rats only, tyrosine flux was significantly lower in indomethacin-treated rats with sham operations and those with sepsis. Although indomethacin reduced total-body protein breakdown during sepsis, it was also associated with lower plasma albumin levels and with decreased protein synthesis in muscle and liver at a time when the survival of the septic host may be dependent on its ability to produce new protein for a variety of vital functions. These results do not support the use of indomethacin in sepsis.

Abdomen↗

PubMed1986

Branched chain amino acid-enriched solutions in the septic patient. A randomized, prospective trial.

A prospective, randomized trial was undertaken to compare the nutritional efficacy in surgical stress of a standard amino acid solution and two branched chain-enriched amino acid solutions: one enriched primarily with valine, the other with leucine. The study comprised 37 patients in the surgical intensive care unit who received isocaloric, isonitrogenous parenteral nutrition started within 24 hours of the onset of major operation, injury, or sepsis. Nitrogen retention was marginally but statistically significantly better on days 5, 7, and 10 in both groups of patients receiving the branched chain-enriched solutions, but differences in cumulative nitrogen balance were not statistically significant. Amino acid composition appeared to be important in that the group receiving the leucine-enriched solution appeared to maintain hepatic protein synthesis better (as manifest by higher short-turnover plasma protein concentrations) and required less exogenous insulin to maintain euglycemia. Improved outcome was not seen in the groups receiving the branched chain-enriched solutions.

Adolescent↗

PubMed1985

Muscle prostaglandin production in the rat. Effect of abdominal sepsis and different amino acid formulations.

Recent in vitro studies attribute regulatory functions to prostaglandins (PGs) in muscle protein metabolism, particularly enhancing proteolysis. In the present study, the amount of muscle PG production from endogenous precursors was determined in control and septic animals (cecal ligation and puncture) that were infused with 5% dextrose or dextrose with three amino acid formulations differing in their branched-chain amino acid (BCAA) content. We could not detect any differences in prostaglandin E, 6-keto-prostaglandin F1 alpha, and thromboxane B2 production between control and septic animals. Furthermore, the infusion of BCAAs, which have previously been shown to be nitrogen sparing following injury, did not influence the production of any of the PGs studied in either control or septic muscle. It is likely that the effects of the BCAAs on muscle synthesis and degradation are independent of the PGs.

Abdomen↗

PubMed1985

A possible beneficial effect of metronidazole in reducing TPN-associated liver function derangements.

Cholestasis and fatty infiltration of the liver are common complications of total parenteral nutrition (TPN). Following a recent suggestion that TPN-associated liver function derangements may be related to intestinal overgrowth of anaerobic bacteria, the effect of metronidazole on hepatic dysfunction during TPN in rats was investigated. After 5 days of TPN with either amino acids and glucose or amino acids with glucose and fat, all groups exhibited a mild weight gain, positive nitrogen balance, increased liver weight, increased liver:body weight ratio, increased levels of liver enzymes, and increased hepatic lipid content. The administration of metronidazole at 15 mg/kg/day significantly decreased the hepatic lipid content from 0.077 g fat/g liver for controls to 0.053 g fat/g liver. The efficacy of metronidazole in reducing hepatic fat accumulation during nutritionally effective and adequate TPN in rats suggests the possible involvement of anaerobic bacterial flora of the intestinal tract, at least in part, in the pathogenesis of TPN-associated liver function derangements. However, the various biochemical and morphological expressions of these changes and the discrepancy between unchanged liver weight, liver:body weight ratio, liver enzymes, and the improved hepatic fat content suggest multifactorial mechanisms for TPN-related liver damage.

Amino Acids↗

PubMed1985

Power spectral analysis of hippocampal and cortical EEG activity following severe prenatal protein malnutrition in the rat.

We have studied the effects of prenatal protein malnutrition on development of the hippocampal and frontal cortical electroencephalographic (EEG) activity. Using power spectral analyses in rats of several age groups we found that protein malnutrition, instituted prenatally and continued postnatally, produces marked alterations in power spectral measures, i.e., alterations in peak theta frequency in the hippocampus during rapid eye movement (REM) sleep. Peak theta frequency was found to be significantly retarded in malnourished animals, especially during the preweaning period of development. Protein malnutrition, therefore, appears to affect mechanisms responsible for generating the tonic component of theta activity.

Age Factors↗

PubMed1985

Effect of indomethacin on proteolysis in septic muscle.

The effect of indomethacin on protein degradation in skeletal muscle from septic rats was investigated. Sepsis was induced by cecal ligation and puncture (CLP). Control rats were sham-operated. Protein degradation rate was estimated by measuring release of tyrosine from incubated soleus (SOL) and extensor digitorum longus (EDL) muscles. Three experiments were performed. In the first experiment, indomethacin was administered subcutaneously (3 mg/kg) at the time of CLP and again after 3 hours. Control rats received corresponding volumes of solvent. Groups of rats were studied after 8 hours (early sepsis) or 16 hours (late sepsis). In the second experiment, the animals were pretreated 45 minutes before induction of sepsis with indomethacin (3 mg/kg) and again 3 hours after CLP and were studied during early sepsis. In the third experiment, indomethacin was added in vitro (3 microM) to incubated normal or septic muscle or to normal muscle incubated in the presence of plasma from septic animals, and release of prostaglandin E2 (PGE2) by incubated muscle was measured in addition to protein degradation. There was no mortality in early sepsis. Survival rate 16 hours after CLP was 8/16 (50%) in rats receiving control injections and 7/15 (47%) in indomethacin-treated rats (NS). Proteolytic rate in incubated EDL and SOL was increased by 20-25% during early sepsis and by 30-50% during late sepsis. The increased proteolytic rate was not affected by administration of indomethacin, neither in the first nor in the second experiment. When indomethacin was added in vitro, release of PGE2 by septic muscles and by normal muscles incubated in the presence of septic plasma was reduced by about 50%, but the increased proteolytic rate in these muscles was not affected. In normal muscle, neither release of PGE2 nor protein degradation was affected by indomethacin in vitro. The present results do not support a role for prostaglandins in the enhancement of muscle proteolysis during sepsis. Since neither survival rate nor protein breakdown was affected by indomethacin, recent suggestions to use this substance in the treatment of septic patients might be questioned.

Amino Acids↗

PubMedDate not supplied

The effect of different intravenous nutritional regimens on renal function during acute renal failure in the rat.

Acute renal failure in the surgical patient is accompanied by a state of hypermetabolism and increased catabolism. Nutritional therapy is therefore directed at the preservation of body cell mass and protein synthesis for repair of wounds and damaged renal tubuli and for maintenance of host defense mechanisms. We examined the effect of two levels of protein intake (18.4 +/- 1.4 and 30.8 +/- 2.4 mg N/100 g BW/day) and three different amino acid formulations (Freamine III, Nephramine, and a made-up mixture of Nephramine + Freamine HBC) on renal function following mercury chloride-induced acute renal failure in the rat. All animals suffered severe renal failure manifested by increased plasma urea and creatinine levels, decreased creatinine clearance, and increased fractional excretion of sodium. On day 4 of acute renal failure, rats receiving low dose amino acids had better-preserved renal function than those receiving high dose amino acids. However, the type of solution infused did not affect recovery of renal function.

Acute Kidney Injury↗

PubMedDate not supplied

Infusion of a branched-chain amino acid-enriched solution and alpha-ketoisocaproic acid in septic rats: effects on nitrogen balance and skeletal muscle protein turnover.

Sepsis was induced by cecal ligation and puncture in male Sprague-Dawley rats weighing approximately 70 g and the animals were intravenously infused with one of four isocaloric solutions: group I (N = 16), 8.5% dextrose solution; group II (N = 16), alpha-ketoisocaproic acid (KIA, 5.1 mg/ml) in 8.5% dextrose; group III (N = 16), FreAmine HBC (containing 45% branched-chain amino acids) in 2.5% dextrose; and group IV (N = 17), FreAmine HBC in 2.5% dextrose + KIA (5.1 mg/ml). Eighteen hr after induction of sepsis, extensor digitorum longus (EDL) and soleus (SOL) muscles were dissected with intact tendons and incubated for the study of protein synthesis and degradation, which were measured as incorporation of 14C-phenylalanine into protein and release of tyrosine into incubation medium, respectively. Urine was collected for determination of nitrogen balance. Nitrogen balance, which was equally negative in groups I and II, was significantly improved in groups III and IV and became equally positive in these groups. Protein synthesis and degradation rates in incubated EDL and SOL muscles were similar to those which we have reported previously in septic rats. Except for a higher synthetic rate in SOL in group II, no other differences in protein synthesis or degradation rates between the four experimental groups were found. Thus, the present study showed that infusion of a branched-chain amino acid-enriched solution improved nitrogen balance in septic rats. KIA alone or administered with the amino acid solution did not affect nitrogen balance.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗

PubMedDate not supplied

Treatment of an infected silicone right atrial catheter with combined fibrinolytic and antibiotic therapy: case report and review of the literature.

Tunnelled silicone rubber right atrial catheters are commonly used to administer long-term total parenteral nutrition (TPN), cancer chemotherapeutic agents, and antimicrobial agents. The indwelling devices potentiate platelet-fibrin thrombi formation, providing a nidus for infection. Although many episodes of sepsis associated with thrombotic tunnelled catheters respond to antimicrobial therapy alone, a significant number require catheter removal. Evidence from case studies and small clinical trials suggests that fibrinolytic agents may increase the response rate and prevent removal of the device when combined with antimicrobial therapy. We present the first case reported of bacterial sepsis secondary to a thrombotic indwelling Hickman catheter for long-term TPN successfully treated with a combination of streptokinase and antibiotic therapies.

Anti-Bacterial Agents↗