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Biomedical subjects

P J McNamara

Publications and source records attributed to P J McNamara.

At least 19 recordsLinked to original sources
PubMed2005

Dedicated neonatal retrieval teams improve delivery room resuscitation of outborn premature infants.

BACKGROUND: Morbidity related to ineffective resuscitation and stabilization of premature infants is increased when delivery occurs outside tertiary perinatal centers. The regional neonatal transport team received extensive training to expand their scope of practice to include delivery room resuscitation allowing them to attend high-risk deliveries in community hospitals when maternal transfer was not possible. OBJECTIVE: Compare the resuscitation and stabilization of premature infants when a specialized neonatal retrieval team (SNRT) is in attendance at delivery with immediate resuscitation and stabilization performed by the referral hospital team (RHT). STUDY DESIGN: We assessed the impact of a specially trained neonatal transport team by comparing the initial resuscitation process, airway and vascular access skills, illness severity and patient stabilization in both groups. RESULTS: Neonates resuscitated by the RHT were more likely to receive oxygen, mask CPAP, bag and mask ventilation and cardiac compressions for a significantly longer time period. Neonates resuscitated by the SNRT were intubated more promptly (8.5 minutes {1 to 22} vs 16 minutes {1 to 90}, p=0.035) following a fewer number of attempts. The endotracheal tube was correctly positioned on radiological assessment in 72% of cases in the SNRT group vs 38.1% in the RHT group (p<0.001). Many neonates had no vascular access (31%) and were profoundly hypothermic (38.5%) on arrival of the SNRT. Although there was no significant difference in maximum FiO(2) or oxygenation index, babies with respiratory distress syndrome resuscitated by the RHT were less likely to receive surfactant therapy (76.6 vs 34.4%, p=0.001). There was no difference in transport-related mortality between the groups CONCLUSIONS: The presence of a highly skilled transport team at a high-risk preterm delivery improves the quality of neonatal resuscitation by increasing intubation success rates and achieving earlier vascular access. Neonates resuscitated by dedicated neonatal retrieval teams were less likely to become significantly hypothermic. Although the severity of RDS was similar neonates in the RHT were less likely to receive surfactant.

Analysis of Variance↗
PubMed2003

Global regulation of Staphylococcus aureus genes by Rot.

Staphylococcus aureus produces a wide array of cell surface and extracellular proteins involved in virulence. Expression of these virulence factors is tightly controlled by numerous regulatory loci, including agr, sar, sigB, sae, and arl, as well as by a number of proteins with homology to SarA. Rot (repressor of toxins), a SarA homologue, was previously identified in a library of transposon-induced mutants created in an agr-negative strain by screening for restored protease and alpha-toxin. To date, all of the SarA homologues have been shown to act as global regulators of virulence genes. Therefore, we investigated the extent of transcriptional regulation of staphylococcal genes by Rot. We compared the transcriptional profile of a rot agr double mutant to that of its agr parental strain by using custom-made Affymetrix GeneChips. Our findings indicate that Rot is not only a repressor but a global regulator with both positive and negative effects on the expression of S. aureus genes. Our data also indicate that Rot and agr have opposing effects on select target genes. These results provide further insight into the role of Rot in the regulatory cascade of S. aureus virulence gene expression.

Bacterial Proteins↗
PubMed2002

Transporter gene expression in lactating and nonlactating human mammary epithelial cells using real-time reverse transcription-polymerase chain reaction.

Transporter-mediated processes in the lactating mammary gland may explain the significant accumulation of certain drugs in breast milk. The purpose of this study was to identify potential candidate drug transport proteins involved in drug accumulation in milk. Quantitative reverse transcription-polymerase chain reaction methods were developed to determine the relative RNA levels of 30 different drug transporter genes. Transporter gene RNA levels in lactating mammary epithelial cells (MEC) purified from pooled fresh breast milk samples were compared with levels in nonlactating MEC, liver, and kidney tissue. Transcripts were detected in lactating MEC for OCT1, OCT3, OCTN1, OCTN2, OATP-A, OATP-B, OATP-D, OATP-E, MRP1, MRP2, MRP5, MDR1, CNT1, CNT3, ENT1, ENT3, NCBT1, PEPT1, and PEPT2. No transcripts were detected for OCT2, OAT1, OAT2, OAT3, OAT4, OATP-C, MRP3, MRP4, CNT2, ENT2, and NCBT2. Lactating MEC demonstrated more than 4-fold higher RNA levels of OCT1, OCTN1, PEPT2, CNT1, CNT3, and ENT3, and more than 4-fold lower RNA levels of MDR1 and OCTN2 relative to nonlactating MEC. Lactating MEC showed significantly higher RNA levels of CNT3 relative to liver and kidney, increased PEPT2 RNA levels relative to liver, and increased OATP-A RNA levels relative to kidney. These data imply CNT3 may play a specialized role in nucleoside accumulation in milk and may identify an important role for PEPT2 and OATP-A transporters at the lactating mammary epithelium. Furthermore, transporters expressed in lactating MEC identify a potential role for these transporters in drug disposition at the mammary gland.

Breast↗
PubMed2001

Aluminum bioavailability from drinking water is very low and is not appreciably influenced by stomach contents or water hardness.

The objectives were to estimate aluminum (Al) oral bioavailability under conditions that model its consumption in drinking water, and to test the hypotheses that stomach contents and co-administration of the major components of hard water affect Al absorption. Rats received intragastric 26Al in the absence and presence of food in the stomach and with or without concomitant calcium (Ca) and magnesium (Mg) at concentrations found in hard drinking water. The use of 26Al enables the study of Al pharmacokinetics at physiological Al concentrations without interference from 27Al in the environment or the subject. 27Al was intravenously administered throughout the study. Repeated blood withdrawal enabled determination of oral 26Al bioavailability from the area under its serum concentrationxtime curve compared to serum 27Al concentration in relation to its infusion rate. Oral Al bioavailability averaged 0.28%. The presence of food in the stomach and Ca and Mg in the water that contained the orally dosed 26Al appeared to delay but not significantly alter the extent of 26Al absorption. The present and published results suggest oral bioavailability of Al from drinking water is very low, about 0.3%. The present results suggest it is independent of stomach contents and water hardness.

Administration, Oral↗
PubMed2001

Active transport of nitrofurantoin into rat milk.

Most xenobiotics are transferred into milk by passive diffusion; however, some drugs have been reported to accumulate in milk as a result of active transport. In the present study, lactating Sprague Dawley rats were used to characterize the transfer of nitrofurantoin into milk. The observed milk to serum concentration ratio (M/S) of 31.1+/-4.0 was 100 times higher than the M/S predicted by diffusion (0.3+/-0.1), indicative of an active transfer into milk. Randomized crossover infusions of nitrofurantoin (0.5mg/h) in the absence and presence of a cimetidine infusion regimen (15mg/h) resulted in the corresponding mean M/S of 29.5+/-5.4 vs. 30.7+/-5.0 and systemic clearance (Cls) of 2.7+/-0.7 vs. 2.2+/-0.4 L/h/kg, respectively. Nitrofurantoin infusions (0.5mg/h) in the absence and presence of a higher cimetidine infusion regimen (30mg/h) resulted in the corresponding mean values for M/S of 23.0+/-7.7 vs. 19.8+/-5.9 and Cls of 2.8+/-0.4 vs. 1.4+/-0.4L/h/kg, respectively. Only the decrease in Cls at the higher cimetidine infusion was statistically significant. These observations provide evidence that nitrofurantoin is actively transported into rat milk by a transporter that is not inhibited by cimetidine. These data suggest the presence of at least two distinct mammary epithelial transporter systems, one that transports organic cations (e.g., cimetidine) and another for anions (e.g., nitrofurantoin).

Animals↗
PubMed2001

Influence of lysine on cimetidine uptake and on excretion of cimetidine by the rat mammary gland.

Cimetidine is actively transported into human and rat milk. However, the transporters involved have not been characterized. It is possible that xenobiotics may be actively transported into milk by an amino acid transport system. The objective of these studies was to determine the influence of lysine on the uptake of cimetidine into rat mammary explants (study 1), and on the excretion of cimetidine into rat milk (study 2). In study 1, excised lactating rat mammary epithelial tissue fragments were exposed to 3H-cimetidine and 14C-lysine in the presence of 10 microM, 1 mM, or 1 M cold lysine, and the uptake of 3H-cimetidine and 14C-lysine were measured by liquid scintillation counting after 5 or 20 minutes of incubation. After 5 minutes of incubation, 1 M lysine inhibited 3H-cimetidine uptake by 47.7% (SD +/- 6.5%), compared with 10 microM lysine (P < 0.05), and 14C-lysine uptake was also inhibited by 54.1% (SD +/- 6.4%) (P < 0.05). Similar results were seen after 20 minutes of incubation. In a randomized crossover study (study 2), 6 lactating female rats were infused to steady state with cimetidine (0.5mg/h) in the presence or absence of lysine (360mg/h). Cimetidine concentrations in serum and milk were determined by high-performance liquid chromatography. Cimetidine systemic clearance (28.6+/-15.0mL/kg/min vs. 38.9+/-3.9 mL/kg/min, mean +/- SD) and milk to serum cimetidine ratio (M/S) (28.0+/-16.1 vs. 28.9+/-6.7), respectively, were not significantly altered by the presence or absence of lysine. Although 1 M lysine inhibited uptake of cimetidine in rat mammary explants, the concentrations of lysine used in this study, which approached toxicity in vivo, produced no significant effects on cimetidine transport into milk or the systemic clearance of cimetidine.

Animals↗
PubMed2001

Aluminium toxicokinetics: an updated minireview.

This MiniReview updates and expands the MiniReview of aluminium toxicokinetics by Wilhelm et al. published by this journal in 1990. The use of 26Al, analyzed by accelerator mass spectrometry, now enables determination of Al toxicokinetics under physiological conditions. There is concern about aluminium in drinking water. The common sources of aluminium for man are reviewed. Oral Al bioavailability from water appears to be about 0.3%. Food is the primary common source. Al bioavailability from food has not been adequately determined. Industrial and medicinal exposure, and perhaps antiperspirant use, can significantly increase absorbed aluminium. Inhalation bioavailability of airborne soluble Al appears to be about 1.5% in the industrial environment. Al may distribute to the brain from the nasal cavity, but the significance of this exposure route is unknown. Systemic Al bioavailability after single underarm antiperspirant application may be up to 0.012%. All intramuscularly injected Al, e.g. from vaccines, may eventually be absorbed. Al distributes unequally to all tissues. Distribution and renal excretion appear to be enhanced by citrate. Brain uptake of Al may be mediated by Al transferrin and Al citrate complexes. There appears to be carrier-mediated efflux of Al citrate from the brain. Elimination half-lives of years have been reported in man, probably reflecting release from bone. Al elimination is primarily renal with < or = 2% excreted in bile. The contribution of food to absorbed Al needs to be determined to advance our understanding of the major components of Al toxicokinetics.

Aluminum↗
PubMed2001

Comparison of EML 105 and advantage analysers measuring capillary versus venous whole blood glucose in neonates.

AIM: Near-patient blood glucose monitoring is an essential component of neonatal intensive care but the analysers currently used are unreliable and inaccurate. The aim of this study was to compare a new glucose electrode-based analyser (EML 105) and a non-wipe reflectance photometry method (Advantage) as opposed to a recognized laboratory reference method (Hexokinase). We also investigated the effect of sample route and haematocrit on the accuracy of the glucose readings obtained by each method of analysis. METHODS: Whole blood glucose concentrations ranging from 0 to 3.5 mmol/l were carefully prepared in a laboratory setting and blood samples from each respective solution were then measured by EML 105 and Advantage analysers. The results obtained were then compared with the corresponding plasma glucose reading obtained by the Hexokinase method, using linear regression analysis. An in vivo study was subsequently performed on 103 neonates, over a 1-y period, using capillary and venous whole blood samples. Whole blood glucose concentration was estimated from each sample using both analysers and compared with the corresponding plasma glucose concentration estimated by the Hexokinase method. Venous blood was centrifuged and haematocrit was estimated using standardized curves. The effect of haematocrit on the agreement between whole blood and plasma glucose was investigated, estimating the degree of correlation on a scatterplot of the results and linear regression analysis. RESULTS: Both the EML 105 and Hexokinase methods were highly accurate, in vitro, with small proportional biases of 2% and 5%, respectively. However, in vivo, both study analysers overestimated neonatal plasma glucose, ranging from at best 0.45 mmol/l (EML 105 venous) to 0.69 mmol/l (EML capillary). There was no significant difference in the agreement of capillary (GD = 0.12, 95% CI, [-0.32,0.08], p = 0.2) or venous samples (GD = 0.05, 95% CI. [0.09, 0.19], p = 0.49) with plasma glucose when analysed by either study method (GD = glucose difference between study analyser and reference method) However, the venous samples analysed by EML 105 estimated plasma glucose significantly better than capillary samples using the same method of analysis (GD = 0.24, 95% CI. [0.09,0.38], p < 0.01). The relationship between haematocrit and the resultant glucose differences was non-linear with correlation coefficients of r = -0.057 (EML 105 capillary), r = 0.145 (EML 105 venous), r = -0.127 (Advantage capillary) and r = -0.275 (Advantage venous). There was no significant difference in the effect of haematocrit on the performance of EML 105 versus Advantage, regardless of the sample route. CONCLUSION: Both EML 105 and Advantage overestimated plasma glucose, with no significant difference in the performance of either analyser, regardless of the route of analysis. Agreement with plasma glucose was better for venous samples but this was only statistically significant when EML 105 capillary and venous results were compared. Haematocrit is not a significant confounding factor towards the performance of either EML 105 or Advantage in neonates, regardless of the route of sampling. The margin of overestimation of blood glucose prohibits the recommendation of both EML 105 and Advantage for routine neonatal glucose screening. The consequences include failure accurately to diagnose hypoglycaemia and delays in the instigation of therapeutic measures, both of which may potentially result in an adverse, long-term, neurodevelopmental outcome.

Blood Chemical Analysis↗
PubMed2001

Entry, half-life, and desferrioxamine-accelerated clearance of brain aluminum after a single (26)Al exposure.

The objectives of our study were to estimate the percentage of aluminum (Al) that enters the brain, the half-life of brain Al, and the ability of an Al chelator to reduce brain Al. Rats received an iv infusion of Al transferrin, the primary Al species in plasma, or Al citrate, the predominant small molecular weight Al species in plasma. The infusion contained approximately 0.2-0.3 nCi (0.4-0.6 nmol) (26)Al, enabling the study of Al distribution into and retention by the brain at physiological Al concentrations. Some Al transferrin-infused rats received ip injections of the Al chelator desferrioxamine (DFO), 0.15 mmol/kg, three times weekly. The others received saline injections. The rats were euthanized from 4 hr to 4 days (Al citrate) or 256 days (Al transferrin) later. Brain (26)Al was determined by accelerator mass spectrometry. Peak brain (26)Al concentration was approximately 0.005% of the (26)Al dose in each gram of brain, irrespective of Al species administered. In the absence of DFO treatments, brain (26)Al concentration decreased with a half-life of approximately 150 days. The brain Al half-life in the DFO-treated rats was approximately 55 days. The results show a small fraction of Al in blood enters the brain, where it persists for a long time. The ability of repeated DFO treatments to modestly accelerate the reduction of brain Al is consistent with the necessity of prolonged DFO therapy to significantly reduce Al-induced dialysis encephalopathy.

Aluminum↗
PubMed2001

Active transport of nitrofurantoin into human milk.

STUDY OBJECTIVE: To determine the extent to which nitrofurantoin is transferred into human milk. DESIGN: Prospective, single-dose pharmacokinetic study. SETTING: University-affiliated clinical research center. PATIENTS: Four healthy lactating women 8-26 weeks postpartum. INTERVENTION: All subjects received a single, oral, 100-mg dose of nitrofurantoin macrocrystals with food. Serial serum and milk samples were obtained and analyzed by high-performance liquid chromatography. MEASUREMENTS AND MAIN RESULTS: Milk pH, milk fat partitioning, and protein binding in serum and milk were determined. Predicted milk:serum ratio (M:S) was compared with the observed M:S. Nitrofurantoin M:S predicted was 0.28+/-0.05, whereas M:S observed was 6.21+/-2.71. Average milk concentration was 1.3 mg/L, and estimated suckling infant dosage was 0.2 mg/kg/day or 6% of maternal dose (mg/kg). CONCLUSIONS: Nitrofurantoin is actively transported into human milk, achieving concentrations in milk greatly exceeding those in serum. Concern is warranted for suckling infants younger than 1 month old, or for infants with a high frequency of glucose-6-phosphate dehydrogenase deficiency or sensitivity to nitrofurantoin.

Administration, Oral↗
PubMed2001

Interactions between cimetidine, nitrofurantoin, and probenecid active transport into rat milk.

The purpose of these studies was to further elucidate the active mammary epithelial transport processes for the organic cation cimetidine and the organic anion nitrofurantoin and to determine which of the identified rat organic anion (rOATs) and organic cation (rOCTs) transporters may be responsible for transport of these drugs into milk. Milk-to-serum ratios (M/S) were predicted in vitro for nitrofurantoin, p-aminohippurate (PAH), and probenecid, and were compared with the observed M/S values. Groups of six lactating female rats received intravenous infusions of cimetidine, nitrofurantoin, PAH, or probenecid alone and with another agent. Steady-state milk and serum concentrations were measured by high performance liquid chromatography. Reverse transcriptase-polymerase chain reaction was performed to detect rOATs and rOCTs in livers, kidneys, and mammary glands of lactating rats. Nitrofurantoin and probenecid were actively transported into rat milk with an M/S 100- and 4.7-fold greater than predicted, respectively, but predicted and observed M/S values for PAH were similar. The cimetidine infusion did not alter nitrofurantoin M/S. Nitrofurantoin significantly decreased M/S of cimetidine (26.6 +/- 4.9 versus 17.7 +/- 5.6). Probenecid did not alter the M/S of nitrofurantoin, or PAH, but increased the M/S of cimetidine from 15.5 +/- 3.6 to 21.5 +/- 7.7. Of the six transporter genes, evidence of expression in lactating rat mammary tissue was found for only rOCT1 and rOCT3. The results suggest different secretory transport systems for cimetidine, nitrofurantoin, and probenecid, but that passive diffusion governs PAH passage into milk. The products of rOCT1 and rOCT3 might transport these drugs into milk.

Actins↗
PubMed2000

FnrP interactions with the Pasteurella haemolytica leukotoxin promoter.

Pasteurella haemolytica FnrP is homologous to Fnr, the global transcriptional regulator of anaerobic respiration in Escherichia coli. To investigate the role of O(2) in the expression of P. haemolytica leukotoxin, we tested a lktC::lacZ fusion constructed in E. coli for a FnrP-mediated regulatory effect under aerobic and anaerobic growth conditions. Both E. coli Fnr and FnrP suppressed leukotoxin transcription under aerobic conditions. Under anaerobic conditions, Fnr suppressed transcription, while FnrP increased transcription. These results were confirmed using FnrP*, a mutant form of FnrP that activates anaerobically inducible genes under aerobic conditions. In mobility shift assays, partially purified FnrP bound to a potential regulatory site in a P. haemolytica lktC promoter fragment.

Aerobiosis↗
PubMed2000

Staphylococcus aureus small colony variants, electron transport and persistent infections.

Staphylococcus aureus can mutate to form a sub-population of bacteria known as small colony variants (SCVs). These bacteria have a characteristic phenotype defined by slow growth, the lack of pigment, an altered pattern of carbohydrate utilization, and a reduction in toxin production. This complex phenotype can be explained by deficiencies in electron transport. In clinical isolates, the most common mutations that affect electron transport are in the operons encoding menaquinone or heme biosynthesis. These isolates are responsible for persistent antibiotic resistant infections. The clinical presentation of these infections is readily explained by a reduction electron transport. SCVs survive within host cells, increasing the instances of recurrent infections and have a novel mechanism of resistance based upon their altered trans-membrane potential. Additionally, SCVs provide a connection between energy metabolism and toxin production. This link may operate through the bacteria responding to altered levels of NADH and ATP. A more complete understanding of these signaling pathways may provide new targets for the development of drugs to ameliorate staphylococcal virulence and disease.

Adenosine Triphosphate↗
PubMed2000

Identification, cloning, and initial characterization of rot, a locus encoding a regulator of virulence factor expression in Staphylococcus aureus.

A chromosomal insertion of transposon Tn917 partially restores the expression of protease and alpha-toxin activities to PM466, a genetically defined agr-null derivative of the wild-type Staphylococcus aureus strain RN6390. In co-transduction experiments, transposon-encoded erythromycin resistance and a protease- and alpha-toxin-positive phenotype are transferred at high frequency from mutant strains to agr-null strains of S. aureus. Southern analysis of chromosomal DNA and sequence analysis of DNA flanking the Tn917 insertion site in mutant strains revealed that the transposon interrupted a 498-bp open reading frame (ORF). Similarity searches using a conceptual translation of the ORF identified a region of homology to the known staphylococcal global regulators AgrA and SarA. To verify that the mutant allele conferred the observed phenotype, a wild-type allele of the mutant gene was introduced into the genome of a mutant strain by homologous recombination. The resulting isolates had a restored agr-null phenotype. Virulence factor gene expression in mutant, restored mutant, and wild-type strains was quantified by measuring alpha-toxin activity in culture supernatant fluids and by Northern analysis of the alpha-toxin transcript. We named this ORF rot (for repressor of toxins) (GenBank accession no. AF189239) because of the activity associated with rot::Tn917 mutant strains.

Amino Acid Sequence↗
PubMed1999

Cloning and characterization of the gene encoding Pasteurella haemolytica FnrP, a regulator of the Escherichia coli silent hemolysin sheA.

A Pasteurella haemolytica A1 gene was identified from a recombinant library clone that expressed hemolysis in host Escherichia coli cells. The gene, designated fnrP, had sequence identity to E. coli fnr, a global transcriptional regulator of genes required for conversion to anaerobic growth. FnrP complemented anaerobic deficiencies of a fnr-null mutant strain of E. coli and increased expression of the Fnr-dependent, anaerobic terminal reductase gene, frdA. FnrP was purified, identified by immunoblotting, and shown to be nonhemolytic. When FnrP was expressed in E. coli DeltasheA, a null mutant of the cryptic hemolysin SheA, the transformants were nonhemolytic, indicating that FnrP activates this silent hemolysin.

Anaerobiosis↗
PubMed1999

The effect of pregnenolone 16alpha-carbonitrile on the pharmacokinetics and metabolism of dapsone in rats.

The purpose of this study was to evaluate the effect of pregnenolone 16 alpha-carbonitrile (PCN) on the interconversion pharmacokinetics and metabolism of dapsone. To determine microsomal CYP3A activity and protein, eight rats (4 PCN, 4 corn oil) received a 1 mg kg(-1) intravenous bolus dose of dapsone, followed by blood and urine sampling. The formation clearance of dapsone hydroxylamine (CLf DDS-NOH) was calculated from the obtained samples. Interconversion pharmacokinetics estimates were obtained after 10 rats (5 PCN, 5 control) received 1 mg kg(-1) dapsone or 1.17 mg kg(-1) monoacetyldapsone, with a 24-h wash-out. Results from the interconversion analysis demonstrated that PCN significantly increased systemic clearance (CLs) of dapsone, but not its interconversion. The in-vivo/in-vitro correlation study demonstrated that PCN significantly increased CLs of dapsone (8.55 to 16.39mLmin(-1); P<0.01) and CLf DDS-NOH (0.13 to 0.18mLmin(-1); P<0.01). PCN treatment produced a 69% increase in CYP3A protein, and increased 6beta- and 2beta-hydroxytestosterone formation rates. Significant correlations were found between CLf DDS-NOH and either 6beta- (r2 = 0.925), 2beta-hydroxytestosterone (r2 = 0.92), or CYP3A1/2 protein (r2= 0.60). We conclude that PCN treatment produces significant increases in CLs (dapsone) and CLf (DDS-NOH) in rats. These changes were not due to changes in the reversible metabolism of dapsone. These results suggest that the formation clearance of dapsone hydroxylamine reflects alterations in CYP3A activity, despite the fact that it accounted for a small part of the systemic clearance of dapsone.

Animals↗
PubMed1998

Survival of a preterm neonate with late onset hydrops fetalis due to parvovirus B19 infection.

This paper presents a case of non-immune hydrops (NIH) which presented late at 28 weeks' gestation during an otherwise asymptomatic pregnancy. A severely hydropic female infant was born with significant cardiorespiratory compromise; however, aggressive resuscitation and postnatal treatment resulted in a favourable outcome. Parvovirus B19 DNA was subsequently detected in postnatal blood samples by nested polymerase chain reaction. This case emphasizes that survival is achievable even in those cases where intrauterine transfusion is not performed. It highlights the importance of prompt delivery and intensive neonatal support in such situations.

Adult↗