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PubMed2005

Resting potential-dependent regulation of the voltage sensitivity of sodium channel gating in rat skeletal muscle in vivo.

Normal muscle has a resting potential of -85 mV, but in a number of situations there is depolarization of the resting potential that alters excitability. To better understand the effect of resting potential on muscle excitability we attempted to accurately simulate excitability at both normal and depolarized resting potentials. To accurately simulate excitability we found that it was necessary to include a resting potential-dependent shift in the voltage dependence of sodium channel activation and fast inactivation. We recorded sodium currents from muscle fibers in vivo and found that prolonged changes in holding potential cause shifts in the voltage dependence of both activation and fast inactivation of sodium currents. We also found that altering the amplitude of the prepulse or test pulse produced differences in the voltage dependence of activation and inactivation respectively. Since only the Nav1.4 sodium channel isoform is present in significant quantity in adult skeletal muscle, this suggests that either there are multiple states of Nav1.4 that differ in their voltage dependence of gating or there is a distribution in the voltage dependence of gating of Nav1.4. Taken together, our data suggest that changes in resting potential toward more positive potentials favor states of Nav1.4 with depolarized voltage dependence of gating and thus shift voltage dependence of the sodium current. We propose that resting potential-induced shifts in the voltage dependence of sodium channel gating are essential to properly regulate muscle excitability in vivo.

Action Potentials↗

PubMed2003

Productive HIV infection of resting CD4+ T cells: role of lymphoid tissue microenvironment and effect of immunomodulating agents.

The ability of resting CD4+ T cells to support HIV replication is relevant to understanding how the reservoir of HIV-1-infected resting CD4+ T cells is generated, maintained and, hopefully, how it might be reduced or eliminated. We have utilized a tonsillar histoculture system to demonstrate that HIV, particularly X4 strains, can productively infect phenotypically resting CD4+ T cells in vitro and that this event is largely dependent on the lymphoid tissue microenvironment. Highly purified CD4+ tonsillar T cells that lack expression of both cell surface and nuclear antigens characteristic of classic T cell activation produce X4 HIV-1 mRNA, p24, and infectious virus while maintaining a resting phenotype when cultured in a tonsillar tissue microenvironment; in contrast, comparable purified resting CD4+ tonsillar T cells that have been exposed to X4 HIV do not support HIV replication when cultured in the absence of a lymphoid tissue microenvironment. HIV production from phenotypically resting CD4+ T cells is dramatically inhibited by anti-proinflammatory cytokine agents or immunosuppressive cytokines, but is only modestly suppressed by an inhibitor of the cell cycle. The ability of resting CD4+ T cells to support HIV replication in the microenvironment of the lymphoid tissue has implications in the pathogenesis of HIV disease and may provide an additional avenue for therapeutic intervention.

Adult↗

PubMed1984

The Harris Benedict equation reevaluated: resting energy requirements and the body cell mass.

The Harris Benedict equations (HBE) were derived from indirect calorimetric data obtained in 239 normal subjects. Using these data and additional data published by Benedict, which were obtained from subjects spanning a wider age range (n = 98), the present study evaluated the relationship between measured resting energy expenditure and age, sex, and predicted body cell mass (BCM). When the additional subjects from the subsequently published series are included, the regression equations, standard error of the estimate, and 95% confidence limits are similar to the original equations. The HBE estimate resting energy expenditure of a normal subject with a precision of 14%. Resting energy expenditure is directly related to the size of the BCM and is independent of age and sex. The variables of height, weight, age, and sex in the HBE reflect the relationship between body weight and the BCM. Indirect calorimetry and body composition measurements were performed in both normally nourished and malnourished patients (n = 74) to assess the accuracy of the HBE in malnourished patients. Malnutrition is associated with an increase in resting oxygen consumption (VO2) which becomes apparent only when VO2 is expressed as a function of the BCM. There is no difference in resting VO2 between the sexes when expressed as a function of BCM. A regression equation was derived from the Harris Benedict data to predict resting VO2 from age, height, weight, and sex. Predicted VO2 was not significantly different from measured VO2 for the normally nourished patients (n = 33) whereas in the malnourished (n = 41) predicted VO2 underestimated the measured value. The HBE accurately predict resting energy expenditure in normally nourished individuals with a precision of +/- 14%, but are unreliable in the malnourished patient.

Adult↗

PubMed2001

Aerobic exercise and resting blood pressure in older adults: a meta-analytic review of randomized controlled trials.

BACKGROUND: It is well established that resting systolic and diastolic blood pressure (SBP and DBP, respectively) increases as one ages. This study used the meta-analytic approach to examine the effects of aerobic exercise for reducing resting SBP and DBP in older adults. METHODS: Study data were compiled through use of the following: (i) computer searches (MEDLINE, Current Contents, and Sport Discus), (ii) cross-referencing from bibliographies of retrieved studies and review articles, and (iii) an expert who reviewed our reference list. Inclusion criteria and sources for this study were (i) randomized trials, (ii) aerobic activity as the only exercise intervention, (iii) a nonexercise control group, (iv) an assessment of changes in resting SBP and/or DBP, (v) within-study ages of subjects > or = 50 years, (vi) English-language studies published in journals, and (vii) studies published between January 1966 and January 1998. Net changes in resting BP were calculated as the exercise minus control group difference. RESULTS: Fourteen primary outcomes were derived from seven studies. Decreases of approximately 2% and 1% were found for resting SBP and DBP, with only changes in SBP as statistically significant (SBP, mean +/- SD = -2 +/- 3 mm Hg, 95% confidence interval [CI] = -4 to -1 mm Hg; DBP, mean +/- SD = -1 +/- 2 mm Hg, 95% CI = -2 to 0 mm Hg). CONCLUSIONS: This study supports the efficacy of aerobic exercise for reducing resting SBP in older adults. However, a need exists for studies that address the effectiveness of this intervention for reducing resting BP in older adults.

Aged↗

PubMed1991

Resting energy expenditure in patients with pancreatitis.

OBJECTIVE: To assess the resting energy expenditure of hospitalized patients with pancreatitis. DESIGN: Prospective, case-referent study. SETTING: Nutrition support service in a university tertiary care hospital. PATIENTS: Patients referred to the Nutrition Support Service with the diagnosis of pancreatitis. Excluded from study entry included those with cancer, obesity (greater than 150% ideal body weight), those measured within 3 postoperative days, or patients requiring ventilator support with an FIO2 of greater than 0.5. Forty-eight patients with either acute pancreatitis (n = 13), chronic pancreatitis (n = 24), acute pancreatitis with sepsis (n = 7), or chronic pancreatitis with sepsis (n = 7) were studied. The two septic groups were combined into a single pancreatitis-with-sepsis group, since no significant differences among measured variables were observed between individual septic groups. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Resting energy expenditure was measured by indirect calorimetry and compared with the predicted energy expenditure, as determined by the Harris-Benedict equations. Resting energy expenditure (percent of predicted energy expenditure) was significantly (p less than .02) greater for patients with pancreatitis complicated by sepsis (120 +/- 11%) compared with the nonseptic chronic pancreatitis group (105 +/- 14%). Resting energy expenditure for the nonseptic acute pancreatitis patients (112 +/- 17%) was not significantly different from the other groups. The septic pancreatitis group had the largest percentage (82%) of hypermetabolic (resting energy expenditure greater than 110% of predicted energy expenditure) patients, whereas 61% and 33% of the acute and chronic pancreatitis groups were hypermetabolic, respectively (p less than .02). CONCLUSIONS: Resting energy expenditure is variable in patients with pancreatitis (77% to 139% of predicted energy expenditure). The Harris-Benedict equations are an unreliable estimate of caloric expenditure. Septic complications are associated with hypermetabolism and may be the most important factor influencing resting energy expenditure in pancreatitis patients.

Acute Disease↗

PubMed1993

Oxygen consumption and resting metabolic rate in sepsis, sepsis syndrome, and septic shock.

OBJECTIVE: To test the hypothesis that variations in oxygen consumption (VO2) and resting metabolic rate reflect the severity of bacterial infections and reflect the development of sepsis syndrome and septic shock. DESIGN: Observational study with sequential measurements of VO2 and resting metabolic rate by expiratory gas analysis. SETTING: Medical intensive care unit. PATIENTS: Thirty patients, treated primarily for presumed bacterial infection, were examined on 118 treatment days. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: VO2 and resting metabolic rate were measured by expiratory gas analysis. For mechanically ventilated patients, a measurement system was developed, based on a paramagnetic oxygen sensor, an infrared CO2 sensor, and digital signal averaging. Measurements in spontaneously breathing patients were performed with a metabolic monitor. Patients were assigned by clinical criteria to the following groups: sepsis, sepsis syndrome, and septic shock. The lowest VO2 value of each patient in each stage was evaluated. Mean VO2 in 15 patients with sepsis was 180 +/- 19 (SD) mL/min/m2, in 11 patients with sepsis syndrome 156 +/- 22 mL/min/m2, and in eight patients with septic shock 120 +/- 27 mL/min/m2 (p < .001). Mean resting metabolic rate in sepsis was +55 +/- 14%, in sepsis syndrome +24 +/- 12%, and in septic shock +2 +/- 24% (p < .001). Mean oxygen delivery (DO2) was 501 +/- 116 mL/min/m2 in sepsis, 515 +/- 186 mL/min/m2 in sepsis syndrome, and 404 +/- 96 mL/min/m2 in septic shock. Oxygen extraction (VO2/DO2) was highest in sepsis (0.39 vs. 0.33 in sepsis syndrome and 0.29 in septic shock). During recovery from sepsis syndrome or septic shock, a significant increase in resting metabolic rate to +61 +/- 22% was measured in nine patients. CONCLUSIONS: In sepsis syndrome, VO2 and resting metabolic rate are enhanced by 30% compared with normal basal metabolism, but they are markedly reduced compared with uncomplicated sepsis. The higher VO2 in uncomplicated sepsis is flow independent. The noninvasive measurement of VO2 and resting metabolic rate by expiratory gas analysis therefore can be used as a quantitative staging and monitoring parameter for the development of sepsis syndrome and septic shock.

Adult↗

PubMed1998

Sodium sensitivity in young adults with high resting end-tidal CO2.

BACKGROUND: Previous research with normotensive adults aged over 40 years ('older') found that sensitivity of blood pressure of subjects with high resting end-tidal partial pressures of CO2 to high sodium intake was greater than normal. OBJECTIVE: To test the hypothesis that the lesser sensitivity of blood pressure of young normotensive adults to high sodium intake is also a function of resting end-tidal partial pressure of CO2. DESIGN: Forty-eight Caucasian men and women (age 28.5 +/- 1.4 years) had a lower than normal dietary intake of sodium chloride for 4 days, and then ingested sodium chloride capsules for 7 days (an additional 190 mmol/day sodium chloride). Resting end-tidal partial pressure of CO2 and blood pressure, and 24 h ambulatory blood pressure, were measured before and after the high-sodium diet. Overnight urine samples were collected before and after the high-sodium diet to determine dietary compliance, and to assess changes in urinary excretion of endogenous digitalis-like factors (a ouabain-like factor, and a marinobufagenin-like factor) that covary with plasma volume. RESULTS: Subjects with high end-tidal partial pressures of CO2 had lower resting heart rates and lower urinary excretion of ouabain-like factor before sodium loading. Sodium loading decreased mean partial pressure of CO2 (by 0.8 +/- 0.2 mmHg) and increased only ambulatory systolic blood pressure (by 2.1 +/- 0.8 mmHg) for the whole group. However, the changes in resting systolic (r = 0.32, P < 0.025) and diastolic (r = 0.36, P < 0.01) blood pressures and in 24 h systolic (r = 0.28, P < 0.05) blood pressure after sodium loading were all positive functions of individual resting end-tidal partial pressures of CO2. Sodium loading increased urinary excretion of marinobufagenin-like factor (by 1.78 +/- 0.88 nmol) and the magnitude of the individual increase was a function of end-tidal partial pressure of CO2. CONCLUSIONS: The results indicate that a high resting partial pressure of CO2 augments the effects of high sodium intake on plasma volume, levels of endogenous digitalis-like factors, and blood pressure in young normotensive humans.

Adult↗

PubMed2001

Gender and the relationship between resting heart rate and left ventricular geometry.

OBJECTIVES: Heightened mortality is common to both an elevated resting heart rate and left ventricular hypertrophy (LVH). We examined the relationship between resting heart rate and left ventricular geometry. METHODS: We analysed resting heart rate and echocardiographic data on 1,685 individuals aged 25-93 years, 756 males and 929 females, without heart failure. The study population, 719 normotensives and 966 untreated hypertensives, was derived from the Egyptian National Hypertension Project (1991-94); a cross-sectional study of the prevalence of hypertension and cardiovascular risk factors in Egyptians. The mean of the last two of three heart rate readings was used to represent the resting heart rate. RESULTS: Left ventricular mass index (LVMI) was weakly inversely related to heart rate in total males (r= -0.14, P< 0.0005) and total females (r= -0.1, P= 0.007) after controlling for age and blood pressure. The relative wall thickness (RWT) of the left ventricle was positively associated with heart rate in females. Resting heart rate increased linearly from 83.8 to 89 b.p.m. (P= 0.03) from the lowest (< or = 0.33) to highest (> or = 0.47) RWT quintiles in hypertensive females after adjusting for age and blood pressure. In both those with and without LVH (defined as LVMI > 125 g/m2), hypertensive females with RWT > 0.45 compared to those with RWT < or = 0.45 had consistently higher resting heart rate (93.8 b.p.m. versus 84.2 b.p.m., P = 0.047 and 88.9 b.p.m. versus 85 b.p.m., P = 0.005, respectively) after adjusting for age and blood pressure. No such relationship was found in males. CONCLUSIONS: Among hypertensive females, an elevated resting heart rate is associated with abnormal left ventricular geometry, namely, concentric left ventricular remodelling and hypertrophy.

Adult↗

PubMed1996

Endurance exercise training has a minimal effect on resting heart rate: the HERITAGE Study.

This study determined the effects of a 20-wk endurance training program (The HERITAGE Family Study) on resting heart rate (HRrest). HRrest was obtained on a sample of 26 men and 21 women during sleep; during resting metabolic rate and resting blood pressure measurement periods in the early morning following a 12-h fast and 24-h post-exercise; and at rest prior to a maximal bout of exercise. Following training, the subjects exhibited a 16.0 +/- 9.4% (mean +/- SD) increase in VO2max (P < 0.05), but the HRrest for each of the resting conditions was decreased by only 1.9 to 3.4 bpm (P < 0.05), or an average across the three conditions of 2.7 bpm. In a larger sample of 253 HERITAGE subjects, HRrest obtained only at the time of the resting blood pressure measurement decreased by only 2.6 bpm, while VO2max increased 17.7 +/- 10.0%. It is concluded that there is a significant, but small, decrease in resting heart rate as a result of 20 wk of moderate- to high-intensity endurance training; which suggests a minimal alteration in either, or both, intrinsic heart rate and autonomic control of HRrest.

Adolescent↗

PubMed1998

99Tcm-sestamibi tomoscintigraphy at rest and after nitrate administration in predicting wall motion recovery after revascularization.

To evaluate whether nitroglycerin administered before the injection of sestamibi improves the detection of viable but hypoperfused myocardium, 41 post-infarction patients with left ventricular dysfunction underwent echocardiography and SPET at rest and after nitrate administration. In 25 revascularized patients, perfusion at rest and contractility were assessed 3-4 months after coronary artery bypass grafting. Perfusion (PI) and wall motion indices (WMI) were calculated for each revascularized area. There was a strong correlation between contractility and perfusion defect (r = 0.58, P < 0.0001). Nitrates significantly reduced the number of perfusion defects in hypokinetic (delta PI = 0.25 +/- 0.66) and akinetic (delta PI = 0.32 +/- 0.62), but not in dyskinetic (delta PI = 0.08 +/- 0.62), segments. Twenty-five revascularized patients had 110 asynergic segments and 136 segments with a resting perfusion defect. Function improved in 42% and perfusion in 64% of segments after surgery. Viable segments had a lower PI at rest (2.78 +/- 1.38 vs 3.86 +/- 1.29, P < 0.001) and a lower WMI (2.46 +/- 0.50 vs 2.79 +/- 0.59, P = 0.002). Nitrates reduced the number of perfusion defects slightly more in viable than non-viable segments (delta PI = 0.58 +/- 0.89 vs 0.30 +/- 0.46, P = 0.06). Contractility and perfusion at rest were the most important predictors of functional recovery. The sensitivity and specificity in predicting contractile improvement were 74% and 64% for resting SPET respectively, and 80% and 50% for nitrate SPET respectively. Nitrate administration significantly reduces perfusion defects in asynergic regions; however, its usefulness in predicting contractile recovery may be limited owing to its low specificity. Contractility and sestamibi uptake at rest were the strongest predictors of post-operative wall motion improvement.

Cardiac Catheterization↗

PubMed1992

Protein synthesis inhibitors, like growth factors, may render resting 3T3 cells competent for DNA synthesis: a radioautographic and cell fusion study.

Serum-deprived (0.1-0.2%) resting NIH 3T3 mouse fibroblasts pre-incubated with cycloheximide (7.5 micrograms/ml), or puromycin (10 micrograms/ml), were fused with stimulated cells taken 10 h after changing the medium to one containing 10% serum, and DNA synthesis was investigated in the nuclei of monokaryons, homodikaryons and heterodikaryons using radioautography with the double-labelling technique. Pre-incubation of resting cells with inhibitors of protein synthesis for 1-4 h abolished their ability to suppress DNA synthesis in stimulated nuclei in heterokaryons. Three hours after the removal of cycloheximide from the medium, the resting cells acquired once again the inhibitory capacity for entry of stimulated nuclei into the S period. This inhibitory influence disappeared also in the case of post-fusion cycloheximide application as well as following an 8-12 h pre-treatment of resting cells with actinomycin D (1 microgram/ml) prior to fusion. Pre-incubation of resting cells for 12 h with PDGF (1 u/ml-1) followed by an 8-48 h incubation in serum-free medium stimulated the onset of DNA synthesis. A brief exposure (45 min) of resting cells to cycloheximide (7.5 micrograms/ml), or puromycin (7.5 micrograms/ml), exerted a similar effect, inducing by itself the entry of cells into the S period. The results support the assumption that acquirement, by resting cells, of competence for DNA replication includes as a necessary step the down-regulation of intracellular growth inhibitors whose formation depends on protein synthesis.

3T3 Cells↗

PubMed2005

What is the optimum methodology for the clinical measurement of resting anal sphincter pressure?

UNLABELLED: There are conflicting recommendations from consensus groups with regard to the assessment of resting anal sphincter pressure. Our aims were to evaluate and compare the performance of three recognized techniques for the clinical measurement of resting anal sphincter pressure. METHODS: In each of 54 patients presenting for anorectal manometry, and suffering from constipation or fecal incontinence, three different techniques for assessment of resting anal pressure were undertaken, namely stationary, stationary pull-through and slow pull-through techniques. Resting anal sphincter pressures were compared between groups and between techniques. RESULTS: Mean resting anal sphincter pressure was lower with stationary, compared with stationary pull-through and slow pull-through, techniques (P < or = 0.002). Resting pressure was higher for constipation than incontinence regardless of technique used (P < 0.00001). The techniques were highly correlated with each other (P < 0.0001). The stationary pull-through technique conferred a minor advantage in the discrimination between constipation and incontinence. The stationary technique required significantly less time for completion (P < 0.0001). CONCLUSION: Resting anal sphincter pressure varies according to the specific technique employed, yet each technique is valid. The stationary pull-through technique confers a minor advantage in clinical discrimination of patients, but the stationary technique is more time-efficient. Standardized anal sphincter testing should be established to enable inter-laboratory comparisons.

Adult↗

PubMed2006

Reevaluation of the resting time period when preparing whole blood-derived platelet concentrates with the platelet-rich plasma method.

BACKGROUND: The resting of platelet (PLT) pellets during the preparation of whole blood-derived PLT concentrates (PCs) is considered an essential step. A reevaluation of the rest period was conducted because preparation and storage conditions have been modified during the past 20 years. STUDY DESIGN AND METHODS: A two-site in vitro study (Study 1) was conducted with rest times of 0 to 5 minutes, 1 hour, and 4 hours (n = 31-33 per rest period). Leukoreduced PCs were stored for 5 days. A second study (Study 2) measuring in vivo viability was conducted at a third site (14 paired studies). PCs were prepared from 2 units of whole blood on the same day to simultaneously compare viability following storage and radioisotopic labeling. RESULTS: In Study 1, comparable in vitro parameters and swirling were observed with the three rest periods. The mean (+/-1 SD) values after storage for the extent of shape change and hypotonic stress parameters were 0 to 5 minutes, 16.7 +/- 7.2 and 66.0 +/- 15.7%; 1 hour, 19.1 +/- 6.9 and 69.3 +/- 17.9%; and 4 hours, 17.6 +/- 5.5 and 64.1 +/- 11.3%. In Study 2, the in vivo recovery was 49.9 +/- 15.3 and 50.9 +/- 20.2% with 0- to 5-minute and 1-hour rest periods, respectively. The corresponding survival time was 111.2 +/- 50.7 and 114.9 +/- 43.8 hours. CONCLUSION: These studies indicate comparable in vitro and in vivo viability properties with 0- to 5-minute and 1-hour rest periods and at 4 hours (in vitro only).

Anticoagulants↗

PubMed2003

Analysis of human immunodeficiency virus type 1 gene expression in latently infected resting CD4+ T lymphocytes in vivo.

In individuals with human immunodeficiency virus type 1 (HIV-1) infection, a small reservoir of resting memory CD4(+) T lymphocytes carrying latent, integrated provirus persists even in patients treated for prolonged periods with highly active antiretroviral therapy (HAART). This reservoir greatly complicates the prospects for eradicating HIV-1 infection with antiretroviral drugs. Therefore, it is critical to understand how HIV-1 latency is established and maintained. In particular, it is important to determine whether transcriptional or posttranscriptional mechanisms are involved. Therefore, HIV-1 DNA and mRNAs were measured in highly purified populations of resting CD4(+) T lymphocytes from the peripheral blood of patients on long-term HAART. In such patients, the predominant form of persistent HIV-1 is latent integrated provirus. Typically, 100 HIV-1 DNA molecules were detected per 10(6) resting CD4(+) T cells. Only very low levels of unspliced HIV-1 RNA ( approximately 50 copies/10(6) resting CD4(+) T cells) were detected using a reverse transcriptase PCR assay capable of detecting a single molecule of RNA standard. Levels of multiply spliced HIV-1 RNA were below the limit of detection (<50 copies/10(6) cells). Only 1% of the HIV-1 DNA-positive lymphocytes in this compartment could be induced to up-regulate HIV-1 mRNAs after cellular activation, indicating that most of the proviral DNA in resting CD4(+) T cells either carries intrinsic defects precluding transcription or is subjected to transcriptional control mechanisms that preclude high-level production of multiply spliced mRNAs. Nevertheless, by inducing T-cell activation, it is possible to isolate replication-competent virus from resting CD4(+) T lymphocytes of all infected individuals, including those on prolonged HAART. Thus, a subset of integrated proviruses (1%) remains competent for high-level mRNA production after cellular activation, and a subset of these can produce infectious virus. Measurements of steady-state levels of multiply spliced and unspliced HIV-1 RNA prior to cellular activation suggest that infected resting CD4(+) T lymphocytes in blood synthesize very little viral RNA and are unlikely to be capable of producing virus. In these cells, latency appears to reflect regulation at the level of mRNA production rather than at the level of splicing or nuclear export of viral mRNAs.

Base Sequence↗

PubMed2004

Analysis of human immunodeficiency virus type 1 transcriptional elongation in resting CD4+ T cells in vivo.

A stable latent reservoir for human immunodeficiency virus type 1 (HIV-1) in resting memory CD4+ T cells presents a barrier to eradication of the infection even in patients on highly active antiretroviral therapy. Potential mechanisms for latency include inaccessibility of the integrated viral genome, absence of key host transcription factors, premature termination of HIV-1 RNAs, and abnormal splicing patterns. To differentiate among these mechanisms, we isolated extremely pure populations of resting CD4+ T cells from patients on highly active antiretroviral therapy. These cells did not produce virus but retained the capacity to do so if appropriately stimulated. Products of HIV-1 transcription were examined in purified resting CD4+ T cells. Although short, prematurely terminated HIV-1 transcripts have been suggested as a marker for latently infected cells, the production of short transcripts had not been previously demonstrated in purified populations of resting CD4+ T cells. By separating RNA into polyadenylated and nonpolyadenylated fractions, we showed that resting CD4+ T cells from patients on highly active antiretroviral therapy produce abortive transcripts that lack a poly(A) tail and that terminate prior to nucleotide 181. Short transcripts dominated the pool of total HIV-1 transcripts in resting CD4+ T cells. Processive, polyadenylated HIV-1 mRNAs were also present at a low level. Both unspliced and multiply spliced forms were found. Taken together, these results show that the nonproductive nature of the infection in resting CD4+ T cells from patients on highly active antiretroviral therapy is not due to absolute blocks at the level of either transcriptional initiation or elongation but rather relative inefficiencies at multiple steps.

Anti-HIV Agents↗

PubMed2005

A novel assay allows genotyping of the latent reservoir for human immunodeficiency virus type 1 in the resting CD4+ T cells of viremic patients.

A latent reservoir for human immunodeficiency virus type 1 (HIV-1) consisting of integrated provirus in resting memory CD4+ T cells prevents viral eradication in patients on highly active antiretroviral therapy (HAART). It is difficult to analyze the nature and dynamics of this reservoir in untreated patients and in patients failing therapy, because it is obscured by an excess of unintegrated viral DNA that constitutes the majority of viral species in resting CD4+ T cells from viremic patients. Therefore, we developed a novel culture assay that stimulates virus production from latent, integrated HIV-1 in resting CD4+ T cells in the presence of antiretroviral drugs that prevent the replication of unintegrated virus. Following activation, resting CD4+ T cells with integrated HIV-1 DNA produced virus particles for several days, with peak production at day 5. Using this assay, HIV-1 pol sequences from the resting CD4+ T cells of viremic patients were found to be genetically distinct from contemporaneous plasma virus. Despite the predominance of a relatively homogeneous population of drug-resistant viruses in the plasma of patients failing HAART, resting CD4+ T cells harbored a diverse array of wild-type and archival drug-resistant viruses that were less fit than plasma virus in the context of current therapy. These results provide the first direct evidence that resting CD4+ T cells serve as a stable reservoir for HIV-1 even in the setting of high levels of viremia. The ability to analyze archival species in viremic patients may have clinical utility in detecting drug-resistant variants not present in the plasma.

Anti-HIV Agents↗

PubMed1995

Arm-ankle systolic blood pressure difference at rest and after exercise in the assessment of aortic coarctation.

OBJECTIVE: To evaluate the difference in systolic blood pressure at the arm and ankle at rest and after various exercise tests for the assessment of aortic coarctation. METHODS: 22 patients (mean age 33 years, range 17-66) were investigated on the suspicion of having haemodynamically significant aortic coarctation. Eight had undergone previous coarctation surgery, of whom five had received vascular grafts and three end to end anastomoses. The patients exercised submaximally while supine, seated on a bicycle, and walking on a treadmill, as well as exercising maximally on a treadmill. Arm and ankle blood pressure were measured with a cuff at rest and 1-10 minutes after exercise. Invasive pressures and cardiac output by thermodilution were recorded during catheterisation while patients were at rest and during and after supine bicycle exercise. The degree of constriction was assessed by angiography. Twelve healthy volunteers (mean age 32 years, range 17-56) provided reference values for cuff pressures after exercise. RESULTS: All patients with a difference in cuff pressure at rest of 35 mm Hg or more had a difference in invasive pressure of 35 mm Hg or more. Increasing severity of constriction on angiography correlated with larger pressure gradients at rest and during exercise (P < 0.0001). When cuff measurements after exercise were considered singly or combined to form a predictor they did not improve the prediction of the invasive pressure gradients at rest or after maximal exercise. A pressure gradient between arm and ankle also developed in normal subjects after maximal but not after submaximal exercise. CONCLUSION: In most patients with suspected haemodynamically significant coarctation the difference in cuff pressure between arm and ankle at rest is sufficient to select patients in need of further evaluation. If exercise is performed submaximal exercise is preferable.

Adolescent↗

PubMed2002

Volume effect and exertional dyspnoea after bronchodilator in patients with COPD with and without expiratory flow limitation at rest.

BACKGROUND: A study was undertaken to investigate whether bronchodilators are associated with less breathlessness at rest and during light exercise in patients with moderate to severe chronic obstructive pulmonary disease (COPD) with resting tidal expiratory flow limitation (EFL; flow limited (FL)) compared with those without EFL (non-flow limited (NFL)). METHODS: Twenty subjects (13 men) of mean (SD) age 65 (8) years (range 43-77) suffering from COPD with forced expiratory volume in 1 second (FEV(1)) 47 (18)% predicted were studied before and after inhalation of salbutamol (400 microg). Routine pulmonary function tests were performed in the seated position at rest. EFL was assessed by the negative expiratory pressure (NEP) method and changes in end expiratory lung volume (EELV) were inferred from variations in inspiratory capacity (IC). Dyspnoea was measured using the Borg scale at rest and at the end of a 6 minute steady state exercise test at 33% of the maximal predicted workload. RESULTS: EFL occurred in 11 patients. Following salbutamol IC did not change in NFL patients but increased by 24% (95% CI 15 to 33) in FL patients (p<0.001). Maximal inspiratory pressure (PImax) improved at EELV from 45 (95% CI 26 to 63) to 55 (95% CI 31 to 79) cm H(2)O (p<0.05) in FL patients after salbutamol but remained unchanged in NFL patients. The workload performed during exercise amounted to 34 (95% CI 27 to 41) and 31 (95% CI 21 to 40) watts (NS) for patients without and with EFL, respectively. After salbutamol, dyspnoea did not change either at rest or during exercise in the NFL patients, but decreased from 0.3 (95% CI -0.1 to 0.8) to 0.1 (95% CI -0.1 to 0.4) at rest (NS) and from 3.7 (95% CI 1.7 to 5.7) to 2.6 (95% CI 1.1 to 4.0) at the end of exercise (p<0.01) in FL patients. CONCLUSIONS: Patients with COPD with EFL may experience less breathlessness after a bronchodilator, at least during light exercise, than those without EFL. This beneficial effect, which is closely related to an increase in IC at rest, occurs even in the absence of a significant improvement in FEV(1) and is associated with a greater PImax.

Administration, Inhalation↗