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Biomedical subjects

R S Harris

Publications and source records attributed to R S Harris.

At least 19 recordsLinked to original sources
PubMed2006

Locally generated particulate pollution and respiratory symptoms in young children.

BACKGROUND: Particulate matter <10 mum (PM(10)) from fossil fuel combustion is associated with an increased prevalence of respiratory symptoms in children and adolescents. However, the effect of PM(10) on respiratory symptoms in young children is unclear. METHODS: The association between primary PM(10) (particles directly emitted from local sources) and the prevalence and incidence of respiratory symptoms was studied in a random sample cohort of 4400 Leicestershire children aged 1-5 years surveyed in 1998 and again in 2001. Annual exposure to primary PM(10) was calculated for the home address using the Airviro dispersion model and adjusted odds ratios (ORS) and 95% confidence intervals were calculated for each microg/m(3) increase. RESULTS: Exposure to primary PM(10) was associated with the prevalence of cough without a cold in both 1998 and 2001, with adjusted ORs of 1.21 (1.07 to 1.38) and 1.56 (1.32 to 1.84) respectively. For night time cough the ORs were 1.06 (0.94 to 1.19) and 1.25 (1.06 to 1.47), and for current wheeze 0.99 (0.88 to 1.12) and 1.28 (1.04 to 1.58), respectively. There was also an association between primary PM(10) and new onset symptoms. The ORs for incident symptoms were 1.62 (1.31 to 2.00) for cough without a cold and 1.42 (1.02 to 1.97) for wheeze. CONCLUSION: In young children there was a consistent association between locally generated primary PM(10) and the prevalence and incidence of cough without a cold and the incidence of wheeze which was independent of potential confounders.

Air Pollution↗
PubMed2003

Modeling kinetics of infused 13NN-saline in acute lung injury.

A mathematical model was developed to estimate right-to-left shunt (Fs) and the volume of distribution of 13NN in alveolar gas (VA) and shunt tissue (Vs). The data obtained from this model are complementary to, and obtained simultaneously with, pulmonary functional positron emission tomography (PET). The model describes 13NN kinetics in four compartments: central mixing volume, gas-exchanging lung, shunting compartment, and systemic recirculation. To validate the model, five normal prone (NP) and six surfactant-depleted sheep in the supine (LS) and prone (LP) positions were studied under general anesthesia. A central venous bolus of 13NN-labeled saline was injected at the onset of apnea as PET imaging and arterial 13NN sampling were initiated. The model fit the tracer kinetics well (mean r2 = 0.93). Monte Carlo simulations showed that parameters could be accurately identified in the presence of expected experimental noise. Fs derived from the model correlated well with shunt estimates derived from O2 blood concentrations and from PET images. Fs was higher for LS (54 +/- 18%) than for LP (5 +/- 4%) and NP (1 +/- 1%, P < 0.01). VA, as a fraction of PET-measured lung gas volume, was lower for LS (0.18 +/- 0.09) than for LP (0.96 +/- 0.28, P < 0.01), whereas Vs, as a fraction of PET-measured lung tissue volume, was higher for LS (0.46 +/- 0.26) than for LP (0.05 +/- 0.08, P < 0.01). The main conclusions are as follows: 1) the model accurately describes measured arterial 13NN kinetics and provides estimates of Fs, and 2) in this animal model of acute lung injury, the fraction of available gas volume participating in gas exchange is reduced in the supine position.

Algorithms↗
PubMed2001

Appendiceal disease in women with endometriosis and right lower quadrant pain.

STUDY OBJECTIVE: To evaluate the frequency and range of appendiceal disease in women with endometriosis and right lower quadrant (RLQ) pain, and to estimate the value of preoperative gastrograffin enema (GGE) as a screen for the disease. DESIGN: Nonrandomized clinical trial (Canadian Task Force classification II-2). SETTING: University-affiliated hospital with a private practice setting. PATIENTS: A subpopulation of 65 women from a group of 337 patients undergoing laparoscopy for symptomatic endometriosis. INTERVENTION: Preoperative GGE was performed whenever possible in these women. At laparoscopy, the appendix was removed if it appeared abnormal or if the preoperative GGE was positive. MEASUREMENTS AND MAIN RESULTS: Of 65 women (19%) with symptomatic endometriosis and preoperative RLQ pain, 52 (80%) underwent appendectomy as part of surgery. Of these 52 excised appendixes, 39 (75%) had histologically confirmed pathology including appendicitis or periappendicitis, endometriosis, fibrous obliteration, lymphoid hyperplasia, and carcinoid tumor. Preoperative GGE had sensitivity of 74% and specificity of 83% for appendiceal disease. Its positive predictive value was 95% and negative predictive value was 42%. No complications from laparoscopic appendectomy occurred. CONCLUSION: Disease of the appendix is common in women with endometriosis and RLQ pain. Appendectomy is particularly likely if preoperative GGE is positive.

Abdominal Pain↗
PubMed2001

Epstein-Barr virus and the somatic hypermutation of immunoglobulin genes in Burkitt's lymphoma cells.

It has been suggested that Epstein-Barr virus (EBV) might suppress antibody maturation either by facilitating bypass of the germinal center reaction or by inhibiting hypermutation directly. However, by infecting the Burkitt's lymphoma (BL) cell line Ramos, which hypermutates constitutively and can be considered a transformed analogue of a germinal center B cell, with EBV as well as by transfecting it with selected EBV latency genes, we demonstrate that expression of EBV gene products does not lead to an inhibition of hypermutation. Moreover, we have identified two natural EBV-positive BL cell lines (ELI-BL and BL16) that hypermutate constitutively. Thus, contrary to expectations, EBV gene products do not appear to affect somatic hypermutation.

Amino Acid Sequence↗
PubMed2000

The SOS response regulates adaptive mutation.

Upon starvation some Escherichia coli cells undergo a transient, genome-wide hypermutation (called adaptive mutation) that is recombination-dependent and appears to be a response to a stressful environment. Adaptive mutation may reflect an inducible mechanism that generates genetic variability in times of stress. Previously, however, the regulatory components and signal transduction pathways controlling adaptive mutation were unknown. Here we show that adaptive mutation is regulated by the SOS response, a complex, graded response to DNA damage that includes induction of gene products blocking cell division and promoting mutation, recombination, and DNA repair. We find that SOS-induced levels of proteins other than RecA are needed for adaptive mutation. We report a requirement of RecF for efficient adaptive mutation and provide evidence that the role of RecF in mutation is to allow SOS induction. We also report the discovery of an SOS-controlled inhibitor of adaptive mutation, PsiB. These results indicate that adaptive mutation is a tightly regulated response, controlled both positively and negatively by the SOS system.

Adaptation, Physiological↗
PubMed2000

Use of recruitment maneuvers and high-positive end-expiratory pressure in a patient with acute respiratory distress syndrome.

OBJECTIVE: To present the use of a novel high-pressure recruitment maneuver followed by high levels of positive end-expiratory pressure in a patient with the acute respiratory distress syndrome (ARDS). DESIGN: Observations in one patient. SETTING: The medical intensive care unit at a tertiary care university teaching hospital. PATIENT: A 32-yr-old woman with severe ARDS secondary to streptococcal sepsis. INTERVENTIONS: The patient had severe gas exchange abnormalities because of acute lung injury and marked lung collapse. Attempts to optimize recruitment based on the inflation pressure-volume (PV) curve were not sufficient to avoid dependent lung collapse. We used a recruitment maneuver using 40 cm H2O of positive end-expiratory pressure (PEEP) and 20 cm H2O of pressure controlled ventilation above PEEP for 2 mins to successfully recruit the lung. The recruitment was maintained with 25 cm H2O of PEEP, which was much higher than the PEEP predicted by the lower inflection point (P(Flex)) of the PV curve. MEASUREMENTS AND MAIN RESULTS: Recruitment was assessed by improvements in oxygenation and by computed tomography of the chest. With the recruitment maneuvers, the patient had a dramatic improvement in gas exchange and we were able to demonstrate nearly complete recruitment of the lung by computed tomography. A PV curve was measured that demonstrated a P(Flex) of 16-18 cm H2O. CONCLUSION: Accumulating data suggest that the maximization and maintenance of lung recruitment may reduce lung parenchymal injury from positive pressure ventilation in ARDS. We demonstrate that in this case PEEP alone was not adequate to recruit the injured lung and that a high-pressure recruitment maneuver was required. After recruitment, high-level PEEP was needed to prevent derecruitment and this level of PEEP was not adequately predicted by the P(Flex) of the PV curve.

Adult↗
PubMed2000

An objective analysis of the pressure-volume curve in the acute respiratory distress syndrome.

To assess the interobserver and intraobserver variability in the clinical evaluation of the quasi-static pressure-volume (P-V) curve, we analyzed 24 sets of inflation and deflation P-V curves obtained from patients with ARDS. We used a recently described sigmoidal equation to curve-fit the P-V data sets and objectively define the point of maximum compliance increase of the inflation limb (P(mci, i)) and the true inflection point of the deflation limb (P(inf,d)). These points were compared with graphic determinations of lower Pflex by seven clinicians. The graphic and curve-fitting methods were also compared for their ability to reproduce the same parameter value in data sets with reduced number of data points. The sigmoidal equation fit the P-V data with great accuracy (R(2) = 0.9992). The average of Pflex determinations was found to be correlated with P(mci,i) (R = 0.89) and P(inf,d) (R = 0.76). Individual determinations of Pflex were less correlated with the corresponding objective parameters (R = 0.67 and 0.62, respectively). Pflex + 2 cm H(2)O was a more accurate estimator of P(inf,d) (2 SD = +/-6.05 cm H(2)O) than Pflex was of P(mci,i) (2 SD = +/-8.02 cm H(2)O). There was significant interobserver variability in Pflex, with a maximum difference of 11 cm H(2)O for the same patient (SD = 1.9 cm H(2)O). Clinicians had difficulty reproducing Pflex in smaller data sets with differences as great as 17 cm H(2)O (SD = 2.8 cm H(2)O). In contrast, the curve-fitting method reproduced P(mci,i) with great accuracy in reduced data sets (maximum difference of 1.5 cm H(2)O and SD = 0.3 cm H(2)O). We conclude that Pflex rarely coincided with the point of maximum compliance increase defined by a sigmoid curve-fit with large differences in Pflex seen both among and within observers. Calculating objective parameters such as P(mci,i) or P(inf,d) from curve-fitted P-V data can minimize this large variability.

Adult↗
PubMed1999

Somatic hypermutation and the three R's: repair, replication and recombination.

Somatic hypermutation introduces single base changes into the rearranged variable (V) regions of antigen activated B cells at a rate of approximately 1 mutation per kilobase per generation. This is nearly a million-fold higher than the typical mutation rate in a mammalian somatic cell. Rampant mutation at this level could have a devastating effect, but somatic hypermutation is accurately targeted and tightly regulated. Here, we provide an overview of immunoglobulin gene somatic hypermutation; discuss mechanisms of mutation in model organisms that may be relevant to the hypermutation mechanism; and review recent advances toward understanding the possible role(s) of DNA repair, replication, and recombination in this fascinating process.

Animals↗
PubMed1999

Mismatch repair is diminished during stationary-phase mutation.

This paper is an invited Response to a recent Commentary [P.L. Foster, Rev. Mut. Res. 436 (1999) 179-184] entitled "Are adaptive mutations due to a decline in mismatch repair? The evidence is lacking". The Commentary argues that no evidence exists supporting the idea that mismatch repair is limiting specifically during stationary-phase mutation. A primary concern of the author is to question the method that we used previously to measure growth-dependent mutation. In this method, mutation rates are calculated using counts of mutant colonies taken at times when those colonies arise, rather than at a predetermined, fixed time. Here we show further data that illustrate why this must be done to ensure accurate mutation measurements. Such accuracy was necessary for our published determination that mismatch repair proteins are not limiting during growth-dependent mutation, but become so during stationary-phase mutation. We review the evidence supporting the idea that stationary-phase reversion of a lac frameshift mutation occurs in an environment of decreased mismatch repair capacity. Those data are substantial. The data presented in the Commentary, in apparent contradiction to this idea, do not justify the conclusion presented there.

Adenosine Triphosphatases↗
PubMed1998

Transient and heritable mutators in adaptive evolution in the lab and in nature.

Major advances in understanding the molecular mechanism of recombination-dependent stationary-phase mutation in Escherichia coli occurred this past year. These advances are reviewed here, and we also present new evidence that the mutagenic state responsible is transient. We find that most stationary-phase mutants do not possess a heritable stationary-phase mutator phenotype, although a small proportion of heritable mutators was found previously. We outline similarities between this well-studied system and several recent examples of adaptive evolution associated with heritable mutator phenotype in a similarly small proportion of survivors of selection in nature and in the lab. We suggest the following: (1) Transient mutator states may also be a predominant source of adaptive mutations in these latter systems, the heritable mutators being a minority (Rosenberg 1997); (2) heritable mutators may sometimes be a product of, rather than the cause of, hypermutation that gives rise to adaptive mutations.

Adaptation, Biological↗
PubMed1998

Recombination-based mechanisms for somatic hypermutation.

We review some experiments designed to test recombination-based mechanisms for somatic hypermutation in mice, particularly mechanisms involving templated mutation or gene conversion. As recombination and repair functions are highly conserved among prokaryotes and eukaryotes, pathways of mutation in microorganisms may prove relevant to the mechanism of somatic hypermutation. Escherichia coli initiates a recombination-based pathway of mutation in response to environmental stimuli, and this "adaptive" pathway of mutation has striking similarities with somatic hypermutation, as does a process of mutagenic repair that occurs at double-strand breaks in Saccharomyces cerevisiae. We present a model for recombination-based hypermutation of the immunoglobulin loci which could result in either templated or non-templated mutation.

Animals↗
PubMed1998

Mismatch repair in Escherichia coli cells lacking single-strand exonucleases ExoI, ExoVII, and RecJ.

In vitro, the methyl-directed mismatch repair system of Escherichia coli requires the single-strand exonuclease activity of either ExoI, ExoVII, or RecJ and possibly a fourth, unknown single-strand exonuclease. We have created the first precise null mutations in genes encoding ExoI and ExoVII and find that cells lacking these nucleases and RecJ perform mismatch repair in vivo normally such that triple-null mutants display normal mutation rates. ExoI, ExoVII, and RecJ are either redundant with another function(s) or are unnecessary for mismatch repair in vivo.

Bacterial Proteins↗
PubMed1998

A comprehensive equation for the pulmonary pressure-volume curve.

Quantification of pulmonary pressure-volume (P-V) curves is often limited to calculation of specific compliance at a given pressure or the recoil pressure (P) at a given volume (V). These parameters can be substantially different depending on the arbitrary pressure or volume used in the comparison and may lead to erroneous conclusions. We evaluated a sigmoidal equation of the form, V = a + b[1 - e-(P-c)/d]-1, for its ability to characterize lung and respiratory system P-V curves obtained under a variety of conditions including normal and hypocapnic pneumoconstricted dog lungs (n = 9), oleic acid-induced acute respiratory distress syndrome (n = 2), and mechanically ventilated patients with acute respiratory distress syndrome (n = 10). In this equation, a corresponds to the V of a lower asymptote, b to the V difference between upper and lower asymptotes, c to the P at the true inflection point of the curve, and d to a width parameter proportional to the P range within which most of the V change occurs. The equation fitted equally well inflation and deflation limbs of P-V curves with a mean goodness-of-fit coefficient (R2) of 0.997 +/- 0.02 (SD). When the data from all analyzed P-V curves were normalized by the best-fit parameters and plotted as (V-a)/b vs. (P-c)/d, they collapsed into a single and tight relationship (R2 = 0.997). These results demonstrate that this sigmoidal equation can fit with excellent precision inflation and deflation P-V curves of normal lungs and of lungs with alveolar derecruitment and/or a region of gas trapping while yielding robust and physiologically useful parameters.

Algorithms↗
PubMed1998

The integration of a tuberculosis control plan into a standard of care for tuberculosis.

Tuberculosis is a significant public health problem. Health care agencies and hospitals are mandated to have in place protocols to manage patients with suspected or confirmed cases and to implement infection control measures to prevent the spread of the disease. A facility with a high percentage of infected patients developed and integrated a standard of care to improve the management and outcomes of infected patients.

Humans↗
PubMed1997

Mismatch repair protein MutL becomes limiting during stationary-phase mutation.

Postsynthesis mismatch repair is an important contributor to mutation avoidance and genomic stability in bacteria, yeast, and humans. Regulation of its activity would allow organisms to regulate their ability to evolve. That mismatch repair might be down-regulated in stationary-phase Escherichia coli was suggested by the sequence spectrum of some stationary-phase ("adaptive") mutations and by the observations that MutS and MutH levels decline during stationary phase. We report that overproduction of MutL inhibits mutation in stationary phase but not during growth. MutS overproduction has no such effect, and MutL overproduction does not prevent stationary-phase decline of either MutS or MutH. These results imply that MutS and MutH decline to levels appropriate for the decreased DNA synthesis in stationary phase, whereas functional MutL is limiting for mismatch repair specifically during stationary phase. Modulation of mutation rate and genetic stability in response to environmental or developmental cues, such as stationary phase and stress, could be important in evolution, development, microbial pathogenicity, and the origins of cancer.

Adenosine Triphosphatases↗
PubMed1997

Genome-wide hypermutation in a subpopulation of stationary-phase cells underlies recombination-dependent adaptive mutation.

Stationary-phase mutation in microbes can produce selected ('adaptive') mutants preferentially. In one system, this occurs via a distinct, recombination-dependent mechanism. Two points of controversy have surrounded these adaptive reversions of an Escherichia coli lac mutation. First, are the mutations directed preferentially to the selected gene in a Lamarckian manner? Second, is the adaptive mutation mechanism specific to the F plasmid replicon carrying lac? We report that lac adaptive mutations are associated with hypermutation in unselected genes, in all replicons in the cell. The associated mutations have a similar sequence spectrum to the adaptive reversions. Thus, the adaptive mutagenesis mechanism is not directed to the lac genes, in a Lamarckian manner, nor to the F' replicon carrying lac. Hypermutation was not found in non-revertants exposed to selection. Therefore, the genome-wide hypermutation underlying adaptive mutation occurs in a differentiated subpopulation. The existence of mutable subpopulations in non-growing cells is important in bacterial evolution and could be relevant to the somatic mutations that give rise to cancers in multicellular organisms.

Adaptation, Biological↗
PubMed1997

A direct role for DNA polymerase III in adaptive reversion of a frameshift mutation in Escherichia coli.

The sequences of adaptive reversions of a lac frameshift mutation in Escherichia coli resemble DNA polymerase errors, and the adaptive reversions decrease in strains with an antimutator DNA polymerase III (PolIII) allele. The latter finding could imply that DNA PolIII itself makes adaptive mutations. Alternatively, normal DNA PolIII errors could saturate post-synthesis mismatch repair during adaptive mutation. If so, the antimutator strain would produce fewer adaptive mutations because it possesses greater capacity for mismatch repair which could correct errors made by a polymerase other than DNA PolIII. Mismatch repair capacity is limited specifically during adaptive mutation, necessitating a test of this indirect model. This indirect model is ruled out here by the observation that the antimutator PolIII allele decreases adaptive mutation even in mismatch repair-defective cells. This supports a direct role for DNA PolIII in recombination-dependent adaptive mutation.

Adaptation, Physiological↗