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1.
J Trauma Acute Care Surg ; 95(2S Suppl 1): S113-S119, 2023 08 01.
Article in English | MEDLINE | ID: mdl-37199525

ABSTRACT

BACKGROUND: Shock index (SI) equals the ratio of heart rate (HR) to systolic blood pressure (SBP) with clinical evidence that it is more sensitive for trauma patient status assessment and prediction of outcome compared with either HR or SBP alone. We used lower body negative pressure (LBNP) as a human model of central hypovolemia and compensatory reserve measurement (CRM) validated for accurate tracking of reduced central blood volume to test the hypotheses that SI: (1) presents a late signal of central blood volume status; (2) displays poor sensitivity and specificity for predicting the onset of hemodynamic decompensation; and (3) cannot identify individuals at greatest risk for the onset of circulatory shock. METHODS: We measured HR, SBP, and CRM in 172 human subjects (19-55 years) during progressive LBNP designed to determine tolerance to central hypovolemia as a model of hemorrhage. Subjects were subsequently divided into those with high tolerance (HT) (n = 118) and low tolerance (LT) (n = 54) based on completion of 60 mm Hg LBNP. The time course relationship between SI and CRM was determined and receiver operating characteristic (ROC) area under the curve (AUC) was calculated for sensitivity and specificity of CRM and SI to predict hemodynamic decompensation using clinically defined thresholds of 40% for CRM and 0.9 for SI. RESULTS: The time and level of LBNP required to reach a SI = 0.9 (~60 mm Hg LBNP) was significantly greater ( p < 0.001) compared with CRM that reached 40% at ~40 mm Hg LBNP. Shock index did not differ between HT and LT subjects at 45 mm Hg LBNP levels. ROC AUC for CRM was 0.95 (95% CI = 0.94-0.97) compared with 0.91 (0.89-0.94) for SI ( p = 0.0002). CONCLUSION: Despite high sensitivity and specificity, SI delays time to detect reductions in central blood volume with failure to distinguish individuals with varying tolerances to central hypovolemia. LEVEL OF EVIDENCE: Diagnostic Test or Criteria; Level III.


Subject(s)
Hemodynamics , Hypovolemia , Humans , Hypovolemia/diagnosis , Hemodynamics/physiology , Blood Volume/physiology , Blood Pressure/physiology , Heart Rate/physiology , Lower Body Negative Pressure
2.
J Dairy Sci ; 104(3): 3082-3097, 2021 Mar.
Article in English | MEDLINE | ID: mdl-33358790

ABSTRACT

Our objectives were to determine the effect of starter crude protein (CP) content on body composition of male Holstein calves from birth to 10 wk of age in an enhanced early nutrition program, and to compare the enhanced program to a conventional milk replacer program. Calves (n = 45) were purchased on the day of birth and assigned to a randomized block design. Eight calves were harvested at baseline and remaining calves were divided among the following 3 dietary treatments: (1) low rate of milk replacer [LMR; 20.6% CP, 21.7% fat; 1.25% of body weight (BW) as dry matter (DM)] plus conventional starter (CCS; 21.5% CP, DM basis); n = 11 calves; (2) high rate of milk replacer (HMR; 29.1% CP, 17.3% fat; 1.5% of BW as DM for wk 1, 2% of BW as DM wk 2-5, 1% of BW as DM wk 6) plus conventional starter; n = 12 calves; and (3) enhanced milk replacer (HMR) plus high-CP starter (HCS; 26% CP, DM basis); n = 14 calves. A subset of calves (n = 8) was harvested on d 2 to provide baseline data. Calves began treatments on d 2 or 3 of age. Calves were weaned at d 42. Starter was available ad libitum. Calves from each treatment were harvested at 5 (n = 18) and 10 (n = 19) wk of age and divided into 4 fractions: carcass; viscera; blood; and head, hide, feet, and tail. Fractions were analyzed for energy, CP, lipid, and ash. Average weekly starter intake did not differ between enhanced treatments. Gain of BW was greater for calves fed HMR than for LMR, but was unaffected by starter CP. Carcass weights at 5 wk were greater for HMR but did not differ between starter CP content. At 10 wk, carcass weights were heavier for HMR and had a greater percentage of empty BW for HMR + CCS than for HMR + HCS. At 10 wk, the weights of reticulorumen and liver were greater for calves fed HMR + HCS than for those fed HMR + CCS. At 5 wk, empty BW gain for HMR contained more water and less fat and ash than in calves fed LMR. At 10 wk, empty BW gain for calves fed HMR + HCS contained a greater percentage of water and less fat than for calves fed HMR + CCS. Plasma ß-hydroxybutyrate was greater after weaning for calves fed HMR + HCS than for those fed HMR + CCS. After weaning, calves fed HMR had greater plasma total protein concentration than those fed LMR, and total protein was greater for calves fed HMR + HCS than those fed HMR + CCS. Plasma urea N was greater for calves fed HMR treatments, and postweaning was greater for calves fed HMR + HCS. A high-CP starter had minimal effect on empty BW gain before weaning, but after weaning it tended to increase mass of reticulorumen and liver.


Subject(s)
Animal Feed , Diet , Animal Feed/analysis , Animals , Body Composition , Body Weight , Diet/veterinary , Male , Nutritional Status , Weaning
3.
J Dairy Sci ; 103(10): 8864-8879, 2020 Oct.
Article in English | MEDLINE | ID: mdl-32747108

ABSTRACT

The effects of source of corn silage and trace mineral on rumen fermentation, turnover, and particle passage rates were evaluated with 8 ruminally cannulated Holstein cows averaging 83 (standard error = 5) days in milk in a replicated 4 × 4 Latin square design with a 2 × 2 factorial arrangement of treatments and 28-d periods. The diets consisted (dry basis) of 55% conventional (CON) or brown midrib-3 (BM3) corn silage, 2% chopped wheat straw, and 43% grain mix with either sulfate (STM) or hydroxy (HTM) source of Cu, Zn, and Mn trace minerals. The targeted supplemental amount of Cu, Zn, and Mn was 194, 1,657, and 687 mg/d, respectively. The dietary treatments were (1) CON-STM, (2) CON-HTM, (3) BM3-STM, and (4) BM3-HTM. Dietary nutrient composition of BM3 diets averaged 32.1% amylase neutral detergent fiber on an organic matter basis (aNDFom) and 6.9% undigested neutral detergent fiber at 240 h of in vitro fermentation (uNDF240om; % of dry matter), and CON diets averaged 36.2% aNDFom and 8.6% uNDF240om (% of dry matter). Data were summarized by period and analyzed as a replicated Latin square design with fixed model effects for corn silage, trace mineral, corn silage and trace mineral interaction, period within replicated square, and replicated square using the MIXED procedure of SAS (version 9.4, SAS Institute Inc., Cary, NC). Cow within replicate was a random effect. Daily mean, standard deviation, minimum, and maximum for rumen pH were unaffected by corn silage or trace mineral source. Cows fed the CON diets had greater rumen acetate percentage than cows fed the BM3 diets (65.7 vs. 64.7 molar %). In contrast, cows fed the BM3 diets had greater rumen propionate percentage than cows fed the CON diets (21.4 vs. 20.4 molar %). Total volatile fatty acid concentration was lower for cows fed STM versus HTM in BM3 diets, but not for the cows fed the CON diets. Cows fed the BM3 diets had faster turnover rate and shorter turnover time for uNDF240om than cows fed the CON diets (3.12 vs. 2.86%/h and 33.3 vs. 36.5 h, respectively). Cows fed the BM3 diets had a faster passage rate of small and medium corn silage neutral detergent fiber particles than cows fed the CON diets (5.73 vs. 5.37%/h and 4.74 vs. 4.31%/h, respectively). We observed a corn silage by source of trace mineral interaction on organic matter and uNDF240om rumen pool size and organic matter turnover. Overall, source of corn silage had a pronounced influence on rumen dynamics presumably related to greater in vitro neutral detergent fiber digestibility and lower uNDF240om content of BM3 corn silage that allowed for faster turnover of indigestible neutral detergent fiber and greater passage rate of corn silage particles. In contrast, the source of trace mineral had much less significant effects on rumen fermentation, turnover, and particle passage rates. Corn silage-based diets intended to enhance rumen fiber fermentation, turnover, and passage are more affected by source and digestibility of neutral detergent fiber than source of dietary trace minerals.


Subject(s)
Cattle/physiology , Dietary Fiber/administration & dosage , Rumen/drug effects , Silage/analysis , Trace Elements/administration & dosage , Zea mays/chemistry , Animals , Copper/administration & dosage , Diet/veterinary , Digestion/drug effects , Female , Fermentation , Lactation , Manganese/administration & dosage , Milk/chemistry , Nutrients , Rumen/physiology , Zinc/administration & dosage
4.
J Dairy Sci ; 103(4): 3147-3160, 2020 Apr.
Article in English | MEDLINE | ID: mdl-32037164

ABSTRACT

We evaluated the effects of source of corn silage and trace minerals on lactational performance and total-tract digestibility (TTD) of nutrients in 16 Holstein cows averaging 82 (standard error = 3) days in milk in a replicated 4 × 4 Latin square design with a 2 × 2 factorial arrangement of treatments with 28-d periods. The diets consisted [dry matter (DM) basis] of 55% conventional (CON) or brown midrib-3 (BM3) corn silage, 2% chopped wheat straw, and 43% grain mix with either sulfate (STM) or hydroxy (HTM) sources of copper, manganese, and zinc trace minerals. The targeted supplemental concentrations of copper, zinc, and manganese were 194, 1,657, and 687 mg/d, respectively. The dietary treatments were CON-STM, CON-HTM, BM3-STM, and BM3-HTM. The dietary nutrient composition of the BM3 diets averaged 32.1% amylase neutral detergent fiber on an organic matter basis (aNDFom) and 6.9% undigested neutral detergent fiber at 240 h (uNDF240om; % of DM), and CON diets averaged 36.2% aNDFom and 8.6% uNDF240om (% of DM). The average supplemental concentrations of copper, zinc, and manganese for the STM diets were 10, 41, and 64 mg/kg, respectively, and the average supplemental concentrations of copper, zinc, and manganese for the HTM diets were 10, 40, and 62 mg/kg, respectively. The average total dietary concentrations of copper, zinc, and manganese for the STM diets were 17, 104, and 60 mg/kg, respectively, and the average total dietary concentrations of copper, zinc, and manganese for the HTM diets were 17, 91, and 66 mg/kg, respectively. Data were summarized by period and analyzed as a replicated Latin square design with fixed model effects for corn silage, trace minerals, corn silage × trace mineral interaction, period within replicated square, and replicated square using the MIXED procedure of SAS. Cow within replicated square was a random effect. Cows fed the BM3 diets had greater dry matter intake (DMI) and milk yield (28.1 and 47.0 kg/d) than cows fed the CON diets (27.5 and 44.7 kg/d). We found no significant interaction between corn silage and trace minerals for DMI and milk yield. Cows fed the HTM diets (28.1 kg/d) had a greater DMI than cows fed the STM diets (27.5 kg/d). Cows fed the BM3 diets had greater TTD of DM and OM (72.8 and 74.1% of DM) than cows fed the CON diets (71.1 and 72.3% of DM). Cows fed the HTM diets had a tendency for greater TTD of aNDFom than cows fed the STM diets (56.8 vs. 54.9% of DM). Cows fed the CON diets ruminated longer during the day than cows fed the BM3 diets (524 vs. 496 min/d). Corn silage with greater NDF digestibility and lower uNDF240om enhanced DMI, milk yield, and TTD of DM and OM, and hydroxy trace minerals improved DMI and tended to improve TTD of aNDFom. The source of corn silage and trace minerals should be taken into consideration when formulating diets for high-producing dairy cows.


Subject(s)
Cattle/physiology , Dietary Fiber/analysis , Milk/metabolism , Silage/analysis , Trace Elements/analysis , Animals , Copper/metabolism , Diet/veterinary , Digestion , Female , Gastrointestinal Tract/metabolism , Lactation , Manganese/metabolism , Nutrients , Zea mays , Zinc/metabolism
5.
Am Fam Physician ; 98(7): 437-442, 2018 10 01.
Article in English | MEDLINE | ID: mdl-30252420

ABSTRACT

Anemia is associated with increased morbidity and mortality in older adults. Diagnostic cutoff values for defining anemia vary with age, sex, and possibly race. Anemia is often asymptomatic and discovered incidentally on laboratory testing. Patients may present with symptoms related to associated conditions, such as blood loss, or related to decreased oxygen-carrying capacity, such as weakness, fatigue, and shortness of breath. Causes of anemia in older adults include nutritional deficiency, chronic kidney disease, chronic inflammation, and occult blood loss from gastrointestinal malignancy, although in many patients the etiology is unknown. The evaluation includes a detailed history and physical examination, assessment of risk factors for underlying conditions, and assessment of mean corpuscular volume. A serum ferritin level should be obtained for patients with normocytic or microcytic anemia. A low serum ferritin level in a patient with normocytic or microcytic anemia is associated with iron deficiency anemia. In older patients with suspected iron deficiency anemia, endoscopy is warranted to evaluate for gastrointestinal malignancy. Patients with an elevated serum ferritin level or macrocytic anemia should be evaluated for underlying conditions, including vitamin B12 or folate deficiency, myelodysplastic syndrome, and malignancy. Treatment is directed at the underlying cause. Symptomatic patients with serum hemoglobin levels of 8 g per dL or less may require blood transfusion. Patients with suspected iron deficiency anemia should be given a trial of oral iron replacement. Lower-dose formulations may be as effective and have a lower risk of adverse effects. Normalization of hemoglobin typically occurs by eight weeks after treatment in most patients. Parenteral iron infusion is reserved for patients who have not responded to or cannot tolerate oral iron therapy.


Subject(s)
Anemia/diagnosis , Physical Examination/methods , Aged , Aged, 80 and over , Anemia/blood , Anemia/etiology , Anemia/therapy , Female , Ferrous Compounds/administration & dosage , Ferrous Compounds/adverse effects , Humans , Male , Middle Aged
6.
Int J Numer Method Biomed Eng ; 34(12): e3144, 2018 12.
Article in English | MEDLINE | ID: mdl-30133165

ABSTRACT

Computational fluid dynamics (CFD) simulations of airflow in the human airways have the potential to provide a great deal of information that can aid clinicians in case management and surgical decision making, such as airway resistance, energy expenditure, airflow distribution, heat and moisture transfer, and particle deposition, as well as the change in each of these due to surgical interventions. However, the clinical relevance of CFD simulations has been limited to date, as previous models either did not incorporate neuromuscular motion or any motion at all. Many common airway pathologies, such as obstructive sleep apnea (OSA) and tracheomalacia, involve large movements of the structures surrounding the airway, such as the tongue and soft palate. Airway wall motion may be due to many factors including neuromuscular motion, internal aerodynamic forces, and external forces such as gravity. Therefore, to realistically model these airway diseases, a method is required to derive the airway wall motion, whatever the cause, and apply it as a boundary condition to CFD simulations. This paper presents and validates a novel method of capturing in vivo motion of airway walls from magnetic resonance images with high spatiotemporal resolution, through a novel combination of non-rigid image, surface, and surface-normal-vector registration. Coupled with image-synchronous pneumotachography, this technique provides the necessary boundary conditions for dynamic CFD simulations of breathing, allowing the effect of the airway's complex motion to be calculated for the first time, in both normal subjects and those with conditions such as OSA.


Subject(s)
Computer Simulation , Magnetic Resonance Imaging , Models, Biological , Movement , Respiratory System , Sleep Apnea, Obstructive , Adult , Child , Humans , Male , Respiratory Mechanics , Respiratory System/diagnostic imaging , Respiratory System/physiopathology , Sleep Apnea, Obstructive/diagnostic imaging , Sleep Apnea, Obstructive/physiopathology
7.
J Dairy Sci ; 97(1): 383-91, 2014.
Article in English | MEDLINE | ID: mdl-24210480

ABSTRACT

The molecular mechanisms by which level of nutrient intake enhances skeletal muscle growth in young ruminants are not fully understood. We examined mammalian target of rapamycin (mTOR), insulin, and insulin-like growth factor-1 (IGF-1) gene network expression in semitendinosus muscle tissue of young male Holstein calves fed a conventional milk replacer plus conventional starter (CON) or an enhanced milk replacer plus high-protein starter (ENH) for 5 wk followed by a conventional starter or a high-protein starter until 10 wk of age. Feeding ENH led to greater concentration of plasma IGF-1 and leptin and greater carcass protein and fat mass throughout the study. Despite the greater plasma IGF-1 and protein mass at wk 5, calves fed ENH had lower expression of IGF1R, INSR, and RPS6KB1 but greater expression of IRS1 and PDPK1 in muscle tissue. Except for IGF1R expression, which did not differ at wk 10, these differences persisted at wk 10, suggesting a long-term effect of greater nutrient intake on physiological and molecular mechanisms. Components of mTOR complex (mTORC)1 and mTORC2 (RICTOR and RPTOR) and FOXO1 expression decreased by wk 10 regardless of diet. Overall, the present data revealed that greater nutrient intake throughout the milk-fed and early postweaning phase alters body mass composition partly by altering hormonal and molecular profiles of genes associated with glucose and amino acid signaling. Those networks may play a crucial role in coordinating neonatal muscle growth and metabolism in response to level of nutrient intake.


Subject(s)
Energy Intake , Insulin/blood , Muscle, Skeletal/metabolism , Sirolimus/pharmacology , Age Factors , Animal Feed/analysis , Animals , Cattle , Diet/veterinary , Dietary Proteins/administration & dosage , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Gene Expression , Gene Regulatory Networks , Genetic Markers , Growth Hormone/blood , Insulin-Like Growth Factor I/genetics , Insulin-Like Growth Factor I/metabolism , Male , Muscle, Skeletal/drug effects , Receptor, Insulin/genetics , Receptor, Insulin/metabolism , Ribosomal Protein S6 Kinases, 70-kDa/antagonists & inhibitors , Ribosomal Protein S6 Kinases, 70-kDa/genetics , Ribosomal Protein S6 Kinases, 70-kDa/metabolism , Somatomedins , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolism , Tuberous Sclerosis Complex 1 Protein , Tuberous Sclerosis Complex 2 Protein , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolism , Up-Regulation
9.
Lipids ; 48(5): 469-79, 2013 May.
Article in English | MEDLINE | ID: mdl-23504269

ABSTRACT

Supplementing dairy cows with n-3 fatty acid-rich feeds does not easily increase quantities in milk fat. Previous results demonstrated very long-chain n-3 fatty acids are primarily transported in the PL fraction of blood, making them largely unavailable to the mammary gland for enrichment of milk fat. Our objective was to compare mammary uptake of fatty acids of increasing chain length and unsaturation delivered intravenously as TAG emulsions. Late lactation dairy cows were assigned to a completely randomized block design. Treatments were intravenous TAG emulsions enriched with oleic acid (OLA), linoleic acid (LNA), alpha-linolenic acid (ALA), or docosahexaenoic acid (DHA) and were delivered continuously at 16 mL/h for 72 h. Each treatment supplied 30 g/day of the target fatty acid. Treatment did not affect feed intake, milk yield, or milk composition, but all treatments reduced intake and yield. The proportion of DHA increased in plasma FFA, TAG, and PL with infusion. Increases of n-3 fatty acids, ALA, EPA, and DHA, were evident in the plasma PL fraction, suggesting re-esterification in the liver. Transfer efficiencies were 37.8 ± 4.1, 27.6 ± 5.4, and 10.9 ± 4.1 %, and day 3 total milk fatty acyl yields were 37.0 ± 3.4, 10.8 ± 0.4, and 3.3 ± 0.3 g for LNA, ALA, and DHA. Variation in oleic acyl yield prevented calculation of OLA transfer efficiency. Mammary uptake of fatty acids was reduced with increased chain length and unsaturation. Both liver and mammary mechanisms may regulate transfer of long-chain polyunsaturates.


Subject(s)
Docosahexaenoic Acids/administration & dosage , Lactation , Linoleic Acid/administration & dosage , Mammary Glands, Animal/metabolism , Oleic Acid/administration & dosage , alpha-Linolenic Acid/administration & dosage , Animals , Cattle , Dietary Supplements/analysis , Docosahexaenoic Acids/blood , Docosahexaenoic Acids/metabolism , Fatty Acids, Omega-3/blood , Fatty Acids, Omega-3/metabolism , Female , Infusions, Intravenous , Linoleic Acid/blood , Linoleic Acid/metabolism , Milk/chemistry , Milk/metabolism , Oleic Acid/blood , Oleic Acid/metabolism , Triglycerides/administration & dosage , Triglycerides/blood , alpha-Linolenic Acid/blood , alpha-Linolenic Acid/metabolism
11.
Am Fam Physician ; 75(9): 1365-71, 2007 May 01.
Article in English | MEDLINE | ID: mdl-17508532

ABSTRACT

Hypertriglyceridemia is associated with an increased risk of cardiovascular events and acute pancreatitis. Along with lowering low-density lipoprotein cholesterol levels and raising high-density lipoprotein cholesterol levels, lowering triglyceride levels in high-risk patients (e.g., those with cardiovascular disease or diabetes) has been associated with decreased cardiovascular morbidity and mortality. Although the management of mixed dyslipidemia is controversial, treatment should focus primarily on lowering low-density lipoprotein cholesterol levels. Secondary goals should include lowering non-high-density lipoprotein cholesterol levels (calculated by subtracting high-density lipoprotein cholesterol from total cholesterol). If serum triglyceride levels are high, lowering these levels can be effective at reaching non-high-density lipoprotein cholesterol goals. Initially, patients with hypertriglyceridemia should be counseled about therapeutic lifestyle changes (e.g., healthy diet, regular exercise, tobacco-use cessation). Patients also should be screened for metabolic syndrome and other acquired or secondary causes. Patients with borderline-high serum triglyceride levels (i.e., 150 to 199 mg per dL [1.70 to 2.25 mmol per L]) and high serum triglyceride levels (i.e., 200 to 499 mg per dL [2.26 to 5.64 mmol per L]) require an overall cardiac risk assessment. Treatment of very high triglyceride levels (i.e., 500 mg per dL [5.65 mmol per L] or higher) is aimed at reducing the risk of acute pancreatitis. Statins, fibrates, niacin, and fish oil (alone or in various combinations) are effective when pharmacotherapy is indicated.


Subject(s)
Hypertriglyceridemia/therapy , Clofibric Acid/therapeutic use , Diet , Fish Oils/therapeutic use , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hypertriglyceridemia/classification , Hypertriglyceridemia/diagnosis , Hypolipidemic Agents/therapeutic use , Life Style , Niacin/therapeutic use
12.
Virology ; 315(1): 93-102, 2003 Oct 10.
Article in English | MEDLINE | ID: mdl-14592762

ABSTRACT

The H-2(b)-restricted CD8 T-cell response against lymphocytic choriomeningitis virus is directed against at least 10 dominant and subdominant epitopes, including two newly identified epitopes in the nucleoprotein. We have used this set of epitopes to characterize the plasticity of the hierarchy under different experimental circumstances, i.e., loss of MHC class I molecules, loss of specific epitopes (CTL escape), and prolonged antigenic stimulation (chronic infection). We found that loss of epitope-specific responses was almost inevitably associated with compensatory responses against other, subdominant, epitopes. Multiple epitope loss was required to change the hierarchy. Persistent viral infection was associated with a loss of not only the dominant response against the NP396 epitope, but also a loss of subdominant responses against nucleoprotein epitopes. In contrast, responses against glycoprotein epitopes, dominant and subdominant, survived under chronic infection conditions, and even dominated the response (GP118). Our results suggest that the fate of each specific T-cell response during chronic infection is in part determined by the origin of the cognate epitopes, i.e, the proteins from which they are processed, or, more specifically, nucleoprotein versus glycoprotein. A model in which recruitment time plays a role in the longevity of antiviral T-cell responses during persistent infection is discussed.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Epitopes, T-Lymphocyte/immunology , Immunodominant Epitopes/immunology , Lymphocytic choriomeningitis virus/immunology , Acute Disease , Amino Acid Sequence , Animals , Antigen Presentation , Chronic Disease , Disease Models, Animal , Glycoproteins/immunology , Immunologic Memory , Lymphocytic Choriomeningitis/immunology , Mice , Mice, Inbred C57BL , Molecular Sequence Data , Nucleoproteins/immunology
13.
J Clin Invest ; 111(12): 1887-95, 2003 Jun.
Article in English | MEDLINE | ID: mdl-12813024

ABSTRACT

Many strategies have been proposed to induce tolerance to transplanted tissue in rodents; however, few if any have shown equal efficacy when tested in nonhuman primate transplant models. We hypothesized that a critical distinction between specific pathogen-free mice and nonhuman primates or human patients is their acquired immune history. Here, we show that a heterologous immune response--specifically, virally induced alloreactive memory--is a potent barrier to tolerance induction. A critical threshold of memory T cells is needed to promote rejection, and CD8(+) "central" memory T cells are primarily responsible. Finally, treatment with deoxyspergualin, an inhibitor of NF-kappa B translocation, together with costimulation blockade, synergistically impairs memory T cell activation and promotes antigen-specific tolerance of memory. These data offer a potential explanation for the difficulty encountered when inducing tolerance in nonhuman primates and human patients and provide insight into the signaling pathways essential for memory T cell activation and function.


Subject(s)
Immune Tolerance , Transplantation Immunology , Animals , Antigens , Bone Marrow Transplantation/immunology , CD8-Positive T-Lymphocytes/immunology , Cross Reactions , Graft Rejection , Guanidines/pharmacology , Humans , Immune Tolerance/drug effects , Immunologic Memory , Immunosuppressive Agents/pharmacology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Models, Immunological , Primates , Species Specificity , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , Transplantation, Homologous , Virus Diseases/immunology
14.
J Immunol ; 170(9): 4745-51, 2003 May 01.
Article in English | MEDLINE | ID: mdl-12707355

ABSTRACT

Following many viral infections, there are large expansions of Ag-specific CD8(+) T cells. After viral clearance, mechanisms exist to ensure that the vast majority of effector cells undergo apoptosis. In studies of thymocyte apoptosis, loss of mitochondrial potential (deltapsi(m)) and excess production of reactive oxygen intermediates have been implicated as key events in cellular apoptosis. The purpose of the experiments presented in this work was to determine these parameters in Ag-specific CD8(+) T cells during a physiological response such as viral infection. Using lymphocytic choriomeningitis virus infection of mice, we found that Ag-specific CD8(+) effector T cells that had undergone recent TCR stimulation had an increased deltapsi(m). These cells also had increased levels of superoxide. As these cells progressed through the contraction of the immune response, their potential decreased, but superoxide levels remained similar to naive cells. One of the consequences of reduced mitochondrial potential is membrane permeability and subsequent caspase activation. We examined both the enzymatic activity and levels of cleaved caspase 3, an effector caspase, and could only detect increased levels in Ag-specific CD8(+) T cells on day 5 postinfection, a time point in which virus was still present. This contrasts with Ag-specific effector cells examined during the contraction phase that had no detectable caspase activity directly ex vivo. These data suggest that the apoptotic program begins earlier than previously expected on day 5, during the expansion phase.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Epitopes, T-Lymphocyte/immunology , Intracellular Membranes/immunology , Lymphocytic Choriomeningitis/immunology , Lymphocytic Choriomeningitis/metabolism , Mitochondria/immunology , Reactive Oxygen Species/metabolism , Animals , Apoptosis/genetics , Apoptosis/immunology , CD8-Positive T-Lymphocytes/enzymology , CD8-Positive T-Lymphocytes/virology , Caspases/metabolism , Down-Regulation/genetics , Down-Regulation/immunology , Enzyme Activation/genetics , Enzyme Activation/immunology , Female , Immunologic Memory/genetics , Intracellular Membranes/metabolism , Intracellular Membranes/virology , Lymphocytic Choriomeningitis/genetics , Lymphocytic Choriomeningitis/pathology , Membrane Potentials/genetics , Membrane Potentials/immunology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Mitochondria/genetics , Mitochondria/metabolism , Mitochondria/virology , Up-Regulation/genetics , Up-Regulation/immunology
15.
J Immunol ; 169(7): 3760-70, 2002 Oct 01.
Article in English | MEDLINE | ID: mdl-12244170

ABSTRACT

Apoptosis is a critical regulator of homeostasis in the immune system. In this study we demonstrate that memory CD8(+) T cells are more resistant to apoptosis than naive cells. After whole body irradiation of mice, both naive and memory CD8(+) T cells decreased in number, but the reduction in the number of naive cells was 8-fold greater than that in memory CD8(+) T cells. In addition to examining radiation-induced apoptosis, we analyzed the expansion and contraction of naive and memory CD8(+) T cells in vivo following exposure to Ag. We found that memory CD8(+) T cells not only responded more quickly than naive cells after viral infection, but that secondary effector cells generated from memory cells underwent much less contraction compared with primary effectors generated from naive cells (3- to 5-fold vs 10- to 20-fold decrease). Increased numbers of secondary memory cells were observed in both lymphoid and non-lymphoid tissues. When naive and memory cells were transferred into the same animal, secondary effectors underwent less contraction than primary effector cells. These experiments analyzing apoptosis of primary and secondary effectors in the same animal show unequivocally that decreased downsizing of the secondary response reflects an intrinsic property of the memory T cells and is not simply due to environmental effects. These findings have implications for designing prime/boost vaccine strategies and also for optimizing immunotherapeutic regimens for treatment of chronic infections.


Subject(s)
Apoptosis/immunology , CD8-Positive T-Lymphocytes/immunology , Immunologic Memory , Interphase/immunology , T-Lymphocyte Subsets/immunology , Adoptive Transfer , Animals , Apoptosis/radiation effects , CD8-Positive T-Lymphocytes/radiation effects , CD8-Positive T-Lymphocytes/transplantation , CD8-Positive T-Lymphocytes/virology , Cell Division/immunology , Cell Division/radiation effects , Epitopes, T-Lymphocyte/administration & dosage , Epitopes, T-Lymphocyte/immunology , Epitopes, T-Lymphocyte/radiation effects , Gamma Rays , Immunization, Secondary , Immunologic Memory/radiation effects , Injections, Intravenous , Interphase/radiation effects , Lymphocyte Activation/radiation effects , Lymphocytic Choriomeningitis/immunology , Lymphocytic Choriomeningitis/pathology , Lymphocytic choriomeningitis virus/immunology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Transgenic , T-Lymphocyte Subsets/radiation effects , T-Lymphocyte Subsets/transplantation , T-Lymphocyte Subsets/virology , Whole-Body Irradiation
16.
J Immunol ; 167(3): 1333-7, 2001 Aug 01.
Article in English | MEDLINE | ID: mdl-11466350

ABSTRACT

It is now well established that viral infections can induce large expansions of Ag-specific CD8(+) T cells. These cells divide very rapidly with an estimated doubling time of approximately 6 h. When virus is cleared, the vast majority of these effector CD8 T cells undergo apoptosis. The remaining memory cells persist at constant levels and provide the basis for the accelerated recall response upon rechallenge. The molecular mechanisms that control the rapid proliferation and death of Ag-specific T cells are poorly understood. Because of its important role in controlling cell proliferation and death, we examined antiviral immune responses in p53(-/-) mice using lymphocytic choriomeningitis virus. We found that effector CD8 and CD4 responses were comparable but that memory levels were slightly higher in -/- mice compared with +/+ mice. The lack of a major difference in virus-specific T cell responses between +/+ and -/- mice suggests that p53 only plays a minor role in regulating the proliferation, apoptosis, and maintenance of Ag-specific T cells. Thus, it appears that the primary function of p53 is in controlling "illegitimate" proliferation and tumor development and not in regulating Ag-specific T cell responses.


Subject(s)
Lymphocyte Activation , Lymphocytic choriomeningitis virus/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/virology , Tumor Suppressor Protein p53/physiology , Animals , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/virology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/virology , Cytotoxicity, Immunologic/genetics , Epitopes, T-Lymphocyte/immunology , Female , Immunologic Memory/genetics , Longitudinal Studies , Lymphocyte Activation/genetics , Lymphocyte Count , Lymphocytic Choriomeningitis/genetics , Lymphocytic Choriomeningitis/immunology , Lymphocytic Choriomeningitis/virology , Mice , Mice, Inbred C57BL , Mice, Knockout , Tumor Suppressor Protein p53/deficiency , Tumor Suppressor Protein p53/genetics
17.
Appl Anim Behav Sci ; 73(2): 93-101, 2001 Jul 28.
Article in English | MEDLINE | ID: mdl-11358607

ABSTRACT

The objective of this study was to further describe the relationships between facial hair whorls and temperament in cattle. Cattle (n=1636) from six commercial cattle auctions in Colorado and Texas were observed. Whorl location was classified according to lateral position (left, right, or middle) and height (high: above the top of the eye, middle: at eye level, low: below the bottom of the eye). A 4-point temperament score was used to rate each animal while it was in the auction ring. Cattle with a score of 1 remained calm and stood still or walked around, and those with a score of 4 were highly agitated and hit the ring fence, walls, partitions, or people with its head. The cattle observed were 75% Bos taurus beef breeds, 21% Holstein dairy cattle, 3% Bos indicus beef breeds, and 1% non-Holstein dairy breeds. Ten percent of cattle surveyed had no facial hair whorl, while 86% had a single spiral hair whorl, of which 47% had middle-middle whorl placement. Animals with a high whorl position or no hair whorl had higher temperament scores (P=0.01). Cattle with low whorls were more likely to have greater lateral displacement of whorls off of the centerline than cattle with high or middle whorls (P<0.01). Abnormally shaped whorls were more common on cattle with low whorls (P<0.01) and on cattle with lateral whorls located off of the centerline (P<0.01). Cattle with hair whorls on the centerline had more variable temperament scores (P=0.04). Beef cattle had more abnormal whorls than Holsteins (P<0.01). Temperament scores showed that Holsteins were calmer than beef cattle (P<0.01). Facial hair whorls in cattle may be a useful management tool in assessing which animals may become disturbed in novel environments.

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