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PubMed1998

Does postmenopausal estrogen administration increase the risk of breast cancer? Contributions of animal, biochemical, and clinical investigative studies to a resolution of the controversy.

Despite nearly six decades of epidemiological studies, meta-analyses, and reviews, there is still considerable controversy in the literature about the question, does postmenopausal estrogen administration increase the risk of breast cancer? In an effort to resolve the controversy, a number of animal, biochemical, and clinical investigative studies in this field have been reviewed. The following summary formulation is proposed: 1. Administration of estrogen is inherently capable of promoting the growth of breast cancer, and therefore of increasing the incidence of clinical breast cancer. 2. Human response to estrogen is like that of the low-cancer-incidence strains of mice studied by Lacassagne, in that large doses and prolonged administration are required to induce clinical breast cancer. 3. The blood levels of estradiol produced by the usual doses of postmenopausal estrogen are relatively low, equivalent to those of the follicular phase of the menstrual cycle. These levels may be near the threshold for producing breast-cancer-promoting effects; therefore, the tumor response will vary greatly in different populations, depending on genetic susceptibility factors: a. The prevalence of a family history of premenopausal breast cancer in a first-degree relative. b. The prevalence of abnormal BRCA1, BRCA2, and p53 genes. c. The prevalence of increased 16 alpha-hydroxylation of estradiol. d. The prevalence of smokers who are slow acetylators. 4. Consumption of alcohol (5 grams or more daily) along with the postmenopausal estrogen administration results in elevation of blood estradiol levels to values equivalent to those of the periovulatory peak of the menstrual cycle, which may be well above the threshold for producing breast-cancer-promoting effects in all women. The risk for cancer will therefore be uniformly increased in women who use alcohol and take estrogen. 5. Increased risk of breast cancer from postmenopausal estrogen administration can be eliminated by taking two synergistic steps: a. Eliminating alcohol consumption, or at least keeping it well below an average of 5 grams daily (equivalent to 2/3 ounce of whiskey or 3 ounces of wine). b. Diminishing the capacity to 16 alpha-hydroxylate estradiol, either through pharmacological agents such as indole-3-carbinol or through increased consumption of cruciferous vegetables. It is concluded that despite the inherent ability of postmenopausal estrogen therapy to increase the risk of breast cancer in theory, the increased risk can be eliminated in practice by minimizing or eliminating consumption of alcohol and ingesting pharmacological or dietary agents that reduce the 16 alpha-hydroxylation of estradiol.

Alcohol Drinking↗
PubMed1996

Interlaboratory reproducibility of semiautomated cell cycle analysis of flow cytometry DNA-histograms obtained from fresh material of 1,295 breast cancer cases.

Conflicting prognostic results have been published as to the DNA variables, such as DNA ploidy, DNA index, and % S-phase cells for breast cancer patients. These variables can be obtained by interpreting DNA histograms by cell cycle analysis. Explanations for these conflicting results might be found on the level of the interpretation of the DNA histograms. In a previous study, the semi automated cell cycle analysis computer program MultiCycle (Phoenix Flow Systems, San Diego, CA) showed high intralaboratory reproducibility. However, what types of DNA histograms may cause disagreements was still unclear. The aim of this study was to determine the interlaboratory reproducibility of MultiCycle-based cell cycle analysis of 1,295 flow cytometric DNA histograms derived from fresh frozen breast cancer material and to clarify potential sources of interobserver variation when analyzing DNA histograms. DNA ploidy classification into diploid, hyperdiploid, tetraploid, hypertetraploid, and multiploid showed an interlaboratory agreement of 94% (kappa value = 0.92). The 6% discrepancies (n = 74) were caused by tetraploid peaks, as established in one laboratory, which shifted outside the tetraploid region on reanalysis by the other laboratory (37%), shoulders sometimes interpreted as peaks (24%), small peaks not always recognized as such (24%), fitting failures (10%), and overlooking of tetraploid peaks (5%). Furthermore, the cell cycle analysis variables showed variable reproducibility. The % S-phase cells of the first, second, and third cell cycle showed overall a moderate reproducibility (0.62 < or = R < or = 0.79), but the average % S-phase cells and the average aneuploid % S-phase cells were more reproducible with correlation coefficients of 0.89 and 0.81, respectively. The coefficient of variation of the G0/G1 peak of the first cell cycle, the DNA indices and the % diploid cells were highly reproducible (R > or = 0.94), and the % G2/M-phase cells of the first, second, and third cell cycle were poorly reproducible (0.22 < or = R < or = 0.68). When a cut-point was used at the mean value of 7% for the average % S-phase cells, the number of "threshold discrepancy cases" was 6%. Sources of variation for cell cycle analysis were variations in the debris correction procedures, disagreement about the modes of the aneuploid peaks, disagreement about small peaks, shoulders sometimes interpreted as peaks, and overlooking of tetraploid peaks.

Autoanalysis↗
PubMed1986

The capsaicin-sensitive innervation of the rat urinary bladder: further studies on mechanisms regulating micturition threshold.

The functional role of the capsaicin-sensitive innervation of the rat urinary bladder in regulating micturition has been investigated by means of the transvesical cystometrogram which allows study of the effects of drugs on the various phases of the bladder voiding cycle in urethane-anesthetized rats. Capsaicin desensitization (50-125 mg./kg., 4 to 60 days before) significantly increased both the volume and pressure threshold for micturition, indicating functional impairment of the mechanisms which transmit volume information from the bladder to the central nervous system. On the other hand the parameters related to the expulsive phase of the voiding cycle of the rat bladder are unaffected by capsaicin pretreatment. In capsaicin-desensitized rats the bladder weight remained within the limits of controls up to 60 days from the treatment although at this time the volume threshold was still elevated. In capsaicin-desensitized rats an increase of infusion rate above the physiological range produced micturition cycles having a normal volume and pressure threshold. These findings suggest that at high values of volume/pressure threshold micturition could be initiated through capsaicin-resistant sensory mechanism(s); in effect, multiple sensory systems, having different thresholds, relay volume/pressure information from the detrusor to the CNS.

Animals↗
PubMed2003

Direct quantification of fungal DNA from soil substrate using real-time PCR.

Detection and quantification of genomic DNA from two ecologically different fungi, the plant pathogen Fusarium solani f. sp. phaseoli and the arbuscular mycorrhizal fungus Glomus intraradices, was achieved from soil substrate. Specific primers targeting a 362-bp fragment from the SSU rRNA gene region of G. intraradices and a 562-bp fragment from the F. solani f. sp. phaseoli translation elongation factor 1 alpha gene were used in real-time polymerase chain reaction (PCR) assays conjugated with the fluorescent SYBR(R) Green I dye. Standard curves showed a linear relation (r(2)=0.999) between log values of fungal genomic DNA of each species and real-time PCR threshold cycles and were quantitative over 4-5 orders of magnitude. Real-time PCR assays were applied to in vitro-produced fungal structures and sterile and non-sterile soil substrate seeded with known propagule numbers of either fungi. Detection and genomic DNA quantification was obtained from the different treatments, while no amplicon was detected from non-seeded non-sterile soil samples, confirming the absence of cross-reactivity with the soil microflora DNA. A significant correlation (P<0.0001) was obtained between the amount of genomic DNA of F. solani f. sp. phaseoli or G. intraradices detected and the number of fungal propagules present in seeded soil substrate. The DNA extraction protocol and real-time PCR quantification assay can be performed in less than 2 h and is adaptable to detect and quantify genomic DNA from other soilborne fungi.

DNA, Fungal↗
PubMed2002

Quantification of newly developed T cells in mice by real-time quantitative PCR of T-cell receptor rearrangement excision circles.

OBJECTIVE: Thymic output of newly developed ab T cells in humans can be measured via signal joint T-cell receptor rearrangement excision circles (sjTRECs). Deletion of the TCRD locus via dRec to psiJa recombination during TCRA rearrangement results in the production of such sjTRECs. The deleting elements dRec and psiJa are highly conserved between humans and mice and used in a comparable manner. We developed and evaluated a real-time quantitative PCR (RQ-PCR) to detect and quantify dRec-psiJa sjTRECs in murine peripheral blood leukocytes for estimation of thymic output of newly developed ab T cells in mice. METHODS: The threshold cycle (Ct) of the sjTREC RQ-PCR was related to the Ct value of an endogenous reference gene. The difference in Ct value (DCt) was correlated to the absolute numbers of CD45+ and CD3+ cells per mL of blood, as obtained by a single platform flow cytometric assay, resulting in the frequency of sjTRECs in CD45+ and CD3+ cells. RESULTS: The RQ-PCR proved to be sensitive with a detection level of approximately one sjTREC copy in 100 ng of DNA. SjTRECs could not be detected in peripheral blood leukocytes of RAG-1(-/-) mice, demonstrating the specificity of the assay. As in humans and primates, sjTREC levels declined in aging and thymectomized mice. Remarkably, significant mouse strain-dependent differences in sjTREC levels were observed. 129Sv and C57BL/6 mice had significantly lower sjTREC levels in blood than Balb/c and DBA2 mice. CONCLUSION: Quantification of murine sjTRECs by RQ-PCR may allow for accurate assessment of thymic output in mice.

Aging↗
PubMed1983

A comparison of incremental exercise tests during cycle and treadmill ergometry.

We evaluated a short-duration maximum exercise test by comparing a 15-s incremental exercise protocol with a 1-min incremental method. Twenty normal men and women were studied using cycle and/or treadmill ergometry. In subjects tested on both exercise devices, anaerobic threshold and maximal oxygen uptake (VO2max) were higher for both protocols on the treadmill than on the cycle ergometer (P less than 0.001). However, when the 15-s and 1-min tests were compared using the same device (treadmill or cycle), there were no significant differences between protocols in anaerobic threshold or maximum exercise values of minute ventilation, respiratory rate, tidal volume, VO2max, oxygen pulse, and peak expiratory flow rate. Linear regression analyses indicated differences between the 15-s and 1-min protocols when cardiopulmonary measurements were related to power; however, the two protocols were comparable when cardiopulmonary data were related to oxygen uptake. Comparisons between protocols or between exercise devices were not systematically different in large vs small individuals, or in men vs women. Short-duration incremental exercise tests appear to be reliable, practical methods for assessing exercise performance in normal individuals.

Exercise Test↗
PubMed2004

Menstrual cycle dependent changes in blue-on-yellow visual field analysis of young diabetic women with severe non-proliferative diabetic retinopathy.

PURPOSE: To evaluate menstrual cycle dependent changes on blue-on-yellow visual fields of diabetic women, and to compare the results with those of healthy women. METHODS: Left eyes of 93 normally menstruating women were included in the study, comprising 45 with type-1 diabetes mellitus and severe non-proliferative diabetic retinopathy and 48 healthy controls. All subjects underwent baseline complete ocular examination and achromatic visual field analysis. Blue-on-yellow visual field tests (short-wavelength automated perimetry) were performed in both follicular (days 7-10 of the cycle) and luteal phases (days 3-6 before the bleeding) of two consecutive menstrual cycles. Visual field analyses were performed using Humphrey Field Analyser II with full threshold, central 30-2 program. Visual fields were divided into four regions: superior temporal, inferior temporal, superior nasal and inferior nasal. Visual field mean sensitivity (MS) was calculated for all regions separately. RESULTS: The mean ages of diabetic and control subjects were not significantly different (P > 0.05). Mean MS values of the diabetic group were significantly lower than that of the control group (P < 0.05). Control subjects did not demonstrate any menstrual cycle dependent changes in MS values (P > 0.05). However, diabetic women demonstrated a significant decrease in MS values in the luteal phase (P < 0.05). The decrease in MS was most marked in the nasal visual field (P < 0.05). CONCLUSION: Young diabetic women demonstrated a significant depression in visual field threshold sensitivity in the luteal phase of the menstrual cycle. Nasal visual fields are more prone to have menstrual cycle dependent threshold sensitivity depression. This should be taken into consideration in the clinical assessment of women with advanced diabetes who are at risk of glaucomatous optic neuropathy.

Adult↗
PubMed2006

Determination of urinary norandrosterone excretion in females during one menstrual cycle by gas chromatography/mass spectrometry.

Conjugated norandrosterone is the main urinary metabolite of anabolic steroids like nandrolone, norandrostenedione and norandrostenediol. Nandrolone traces of endogenous origin have been identified in human follicular fluid, and further investigations revealed urinary excretion of norandrosterone in pregnant and non-pregnant females and even males. A threshold level for the norandrosterone concentration in urine has been established when controlling the administration of prohibited nandrolone or its precursors in human doping control. This level has been set to 2 ng/mL for males and females. To investigate the excretion of conjugated norandrosterone in females more systematically, we collected daily urine samples from 12 female volunteers during a whole menstrual cycle. These samples were analysed for norandrosterone down to a limit of quantification and identification of 0.05 ng/mL (180 pmol/L). The results clearly show that all the volunteers excreted norandrosterone glucuronide in a characteristic pattern during one menstrual cycle. Concentrations in urine were considerably lower at the beginning of the follicular and the end of the luteal phases than midcyclic. Peak concentrations up to 0.8 ng/mL (2.9 nmol/L) were recorded and they were three to four times higher than the values at the beginning and end of the cycle. The time of the peak concentration was clearly related to the increased excretion of luteinizing hormone. These results strongly support the possibility of endogenous nandrolone production as a side reaction to enzymatic aromatisation. However, a threshold value of 2 ng/mL for reporting adversed findings in doping control of females was never reached in any of the samples.

Adult↗
PubMed1991

Ventilatory threshold and maximal oxygen uptake during cycling and running in female triathletes.

Maximal oxygen uptake (VO2max) and the ventilatory threshold (Tvent) were measured during cycle ergometry (CE) and treadmill running (TR) in a group of 10 highly trained female triathletes. Tvent was defined as the VO2 at which the ventilatory equivalent for oxygen increased without a marked rise in the ventilatory equivalent for carbon dioxide. Female triathletes achieved a significantly higher mean (+/- SE) relative VO2max for running (63.6 +/- 1.2 ml.kg-1.min-1) than for cycling (59.9 +/- 1.3 ml.kg-1.min-1). When oxygen uptake measured at the ventilatory threshold was expressed as a percent of VO2max, the mean value obtained for TR (74.0 +/- 2.0% of VO2max) was significantly greater than the value obtained for CE (62.7 +/- 2.1% of VO2max). This occurred even though the total training time and intensity were similar for the two modes of exercise. Female triathletes had average running and cycling VO2max values that compared favorably with maximal oxygen uptake values previously reported for elite female runners and cyclists, respectively. However, mean running and cycling Tvent values (VO2 Tvent as%VO2max) were lower than recently reported values for single-sport athletes. The physiological variability between the triathletes studied and single-sport athletes may be attributed in part to differences in training distance or intensity, and/or to variations in the number of years of intense training in a specific mode of exercise. It was concluded that these triathletes were well-trained in both running and cycling, but not to the same extent as female athletes who only train and compete in running or cycling.

Adult↗
PubMed2000

First ovulation and ketone body status in the early postpartum period of dairy cows.

The effect of ketone body status on occurrence of first ovulation during early lactation was assessed in 84 multiparous dairy cows under field conditions. Animals were equally distributed across 8 farms and were controlled by the same herd fertility monitoring program. Cows were visited twice antepartum and 6 times postpartum at weekly intervals between 5:30 and 8:30 AM. On these occasions, body condition scores and milk yields were measured, blood and milk samples were taken, cows were gynecologically examined, and parameters of reproduction were determined. The onset of first ovulation was specified by milk progesterone determination and rectal palpation. Cows starting postpartum ovarian cyclicity within or after 30 d were classified as early and late responders (ER and LR, respectively). Resumption of the estrous cycle within 30 d postpartum is considered optimal under practical conditions, and classification based on this threshold value resulted in groups of equal size and equal distribution of ER + LR cows within farms. Ketone bodies measured were beta-hydroxybutyrate in serum and acetoacetate and acetone in serum and milk. Blood serum and milk ketone body concentrations during the first 6 wk of lactation were higher in LR than in ER, whereas plasma glucose and nonesterified fatty acid and milk fat, protein and urea concentrations did not differ between groups. Maximal concentrations of ketone bodies from parturition to first ovulation were better predictors of the onset of the estrous cycle than mean or minimal concentrations over the same period. Milk acetone and serum beta-hydroxybutyrate concentrations provided the most reliable information with regard to resumption of ovarian activity of all ketone bodies.

3-Hydroxybutyric Acid↗
PubMed2001

The stochastic evolution of catalysts in spatially resolved molecular systems.

A fully stochastic chemical modelling technique is derived which describes the influence of spatial separation and discrete population size on the evolutionary stability of coupled amplification in biopolymers. The model is analytically tractable for an infinite-dimensional space (simplex geometry), which also provides insight into evolution in normal Euclidean space. The results are compared with stochastic simulations describing the co-evolution of combinatorial families of molecular sequences both in the simplex geometry and in lower (one, two and three) space dimensions. They demonstrate analytically the generic limits which exploitation place on co-evolving multi-component amplification systems. In particular, there is an optimal diffusion (or migration) coefficient for cooperative amplification and minimal and maximal threshold values for stable cooperation. Over a bounded range of diffusion rates, the model also exhibits stable limit cycles. Furthermore, the co-operatively coupled system has a maximum tolerable error rate at intermediate rates of diffusion. A tractable model is thereby established which demonstrates that spatial effects can stabilize catalytic biological information. The analytic behaviour in infinite-dimensional simplex space is seen to provide a reasonable guide to the spatial dependence of the error threshold in physical space. Nanoscale possibilities for the evolution of catalysis on the basis of the model are outlined. We denote the modelling technique by PRESS, Probability Reduced Evolution of Spatially-discrete Species.

Catalysis↗
PubMed1997

Dorzolamide hydrochloride and visual function in normal eyes.

PURPOSE: To determine by a pilot study whether standard treatment with the topical carbonic anhydrase inhibitor dorzolamide hydrochloride influences visual function under normal breathing conditions, during carbon dioxide inhalation, or during hyperventilation, and to establish criteria for future larger-scale studies. METHODS: We enrolled 12 normal subjects into this randomized double-masked placebo-controlled crossover study. Each subject was treated with either dorzolamide 2% or placebo, three times daily, for 4 days. After a 2-week washout period, the alternative topical agent was used under identical testing conditions. On day 2 of each treatment phase, contrast sensitivities to sinusoidal gratings of 1 and 4 cycles per degree (cpd) were assessed. On day 4, mean deviation values from full-threshold 10-2 visual fields were obtained. Three sets of each visual function test were obtained before each treatment phase, and in sequence on each testing day, during normal breathing (baseline), inhalation of carbon dioxide-enriched air, and hyperventilation while intraocular pressure was monitored. RESULTS: Contrast sensitivity at 4 cpd decreased significantly (P < .01) during carbon dioxide supplementation with placebo but showed no significant change with dorzolamide. The decrease in contrast sensitivity accompanying hyperventilation was attenuated (by nearly 50% at 1 cpd) during dorzolamide treatment. Dorzolamide treatment was associated with higher perimetry mean deviation values under each treatment condition and was statistically significant (P < .05) at baseline. CONCLUSIONS: Dorzolamide appears to enhance contrast sensitivity in normal subjects during physiologic hypercapnia and hypocapnia at 4 and 1 cpd, respectively. Also, under normal breathing conditions, dorzolamide therapy increases perimetric light sensitivity.

Adult↗
PubMedDate not supplied

Non-invasive fetal RHD exon 7 and exon 10 genotyping using real-time PCR testing of fetal DNA in maternal plasma.

OBJECTIVE: In this prospective study, we assessed the feasibility of foetal RHD genotyping by analysis of DNA extracted from plasma samples of Rhesus (Rh) D-negative pregnant women using real-time PCR and primers and probes targeted toward exon 7 and 10 of RHD gene. METHODS: We analysed 24 RhD-negative pregnant woman and 4 patients with weak D phenotypes at a gestational age ranging from 11th to 38th week of gestation and correlated the results with serological analysis of cord blood after the delivery. RESULTS: Non-invasive prenatal foetal RHD exon 7 genotyping analyses of maternal plasma samples was in complete concordance with the serological analysis of cord blood in all 24 RhD-negative pregnant women delivering 12 RhD-positive and 12 RhD-negative newborns. RHD exon-10-specific PCR amplicons were not detected in 2 out of 12 studied plasma samples from women bearing RhD-positive foetus, despite the positive amplification in RHD exon 7 region observed in all cases. In 1 case red cell serology of cord blood revealed that the mother had D-C-E-c+e+ C(w)- and the infant D+C-E-c+e+ C(w)+ phenotypes. RhD exon 10 real-time PCR analysis of cord blood was also negative. These findings may reflect that DC(w)- paternally inherited haplotype probably possesses no RHD exon 10. In another case no cord blood sample has been available for additional studies. The specificity of both RHD exon 7 and 10 systems approached 100% since no RhD-positive signals were detected in women currently pregnant with RhD-negative foetus (n = 8). Using real-time PCR and DNA isolated from maternal plasma, we easily differentiated pregnant woman whose RBCs had a weak D phenotype (n = 4) from truly RhD-negative patients since the threshold cycle (C(T)) for RHD exon 10 or 7 amplicons reached nearly the same value like C(T) for control beta-globin gene amplicons detecting the total DNA present in maternal plasma. However in these cases foetal RhD status cannot be determined. CONCLUSION: Prediction offoetal RhD status from maternal plasma is highly accurate and enables implementation into clinical routine. We suggest that safe non-invasive prenatal foetal RHD genotyping using maternal plasma should involve the amplification of at least two RHD-specific products.

Exons↗
PubMed2004

Sodium and potassium currents of larval zebrafish muscle fibres.

The steady-state and kinetic properties of Na(+) and K(+) currents of inner (white) and outer (red) muscles of zebrafish larvae 4-6 days post-fertilization (d.p.f.) are described. In inner muscle, the outward currents were half-activated at -1.0 mV and half-inactivated at -30.4 mV, and completely inactivated within 100 ms of depolarization. The inward currents of inner fibres were half-activated at -7.3 mV and half-inactivated at -74.5 mV and completely inactivated within 5 ms of depolarization. Inner muscle fibres were found to support action potentials, while no action potentials could be evoked in outer muscles. In inner muscle fibres, all tested levels of depolarizing current above a threshold value evoked only one action potential. However, spiking at frequencies of up to 200 cycles s(-1) was evoked by the injection of depolarizing pulses separated by short hyperpolarizing currents. We suggest that the properties of the inward sodium and outward potassium currents permit high frequency firing in response to a pulsatile depolarizing input of the kind expected in fast swimming, whilst safeguarding against tetany during a strong depolarization.

Action Potentials↗
PubMed2000

Determination of threshold energy dose for ultrasound-induced transdermal drug transport.

Low-frequency (20 kHz) ultrasound has been shown to enhance transdermal transport of drugs, a phenomenon referred to as sonophoresis. In this paper, we report the threshold energy dose for ultrasound-induced transdermal drug transport. The threshold was determined by in vitro measurements of the dependence of sonophoretic enhancement on ultrasound parameters, including intensity, duty cycle, and exposure time. While the enhancement varies linearly with ultrasound intensity and exposure times, it is independent of the duty cycle in the range of parameters studied. The enhancement is also directly proportional to the ultrasound energy density once the threshold value is crossed. For full thickness pig skin, the threshold value is about 222 J/cm(2). The overall dependence of transport enhancement on ultrasound parameters is similar to that of cavitation measured in a model system, pitting of aluminum foil. Specifically, the extent of pitting is proportional to ultrasound intensity and exposure time and is independent of duty cycle. Furthermore, the extent of pitting is also proportional to the ultrasound energy density. The similarity between the parametric dependence of transport enhancement and cavitation is consistent with previous findings that cavitation plays the dominant role in sonophoresis.

Administration, Cutaneous↗
PubMed1988

Dose versus pharmacokinetics for predicting tolerance to 5-day continuous infusion of 5-FU.

This non-randomized study reports pharmaco-clinical data on 5-FU administered by the widely used 5-day continuous infusion schedule to 42 patients with metastatic colorectal cancer; 5-FU was given by hepatic intra-arterial route (h.i.a.) at doses ranging from 800 to 1,450 mg/m2, and by a systemic intravenous route (i.v.) at doses ranging from 650 to 1,300 mg/m2. 5-FU blood levels were available for a total of 179 cycles. Toxicity was dose-dependent during h.i.a. cycles but not during i.v. cycles. For h.i.a. cycles, 1,000 mg/m2/day represented the threshold dose for tolerance. The individual total cycle drug concentration-time product might predict toxicity for both i.v. and h.i.a. cycle when the threshold is set at 30,000 ng/ml.hr. These data may be of practical value for improving the therapeutic index of 5-day continuous treatment by 5-FU given by i.v. or h.i.a. routes.

Adult↗
PubMed2003

Semiquantitative detection by real-time PCR of Aspergillus fumigatus in bronchoalveolar lavage fluids and tissue biopsy specimens from patients with invasive aspergillosis.

A real-time PCR method was developed and used to detect Aspergillus fumigatus mitochondrial DNA (mtDNA) in bronchoalveolar lavage (BAL) fluids and tissue biopsy specimens. The analytical sensitivity of the assay was one A. fumigatus conidium per reaction, and the assay was linear at least over 4 orders of magnitude above the detection limit. BAL fluids from 66 immunocompromised patients at risk of invasive pulmonary aspergillosis (IPA) and 33 immunocompetent controls and tissue biopsy specimens from 10 immunocompromised patients were analyzed. The results were related to the clinical diagnosis established according to recently published consensus criteria. A. fumigatus mtDNA positivity was encountered in 16 of 81 (20%) BAL fluid specimens from patients at risk and 1 of 33 (3%) specimens from immunocompetent controls. PCRs were positive in six of seven, two of four, and four of five of the patients with proven, probable, and possible IPA, respectively, as well as in four patients at risk but without any other evidence of IPA. With qualitative detection, the diagnostic sensitivity of PCR was 73%, specificity was 93%, and predictive values of positive (PPV) and negative (NPV) results were 73 and 95%, respectively. Using a threshold cycle of <35 as a limit for positive PCR, the specificity and PPV of PCR in the diagnosis of invasive aspergillosis were 100%, but its sensitivity was only 45% and NPV was 92%. PCR was positive in tissue biopsy specimens from all patients with invasive aspergillosis caused by A. fumigatus. Semiquantitative detection of A. fumigatus mtDNA in BAL fluid may be helpful in the diagnosis of IPA. PCR is well suited for the verification of the presence of A. fumigatus in tissue biopsy specimens.

Adolescent↗
PubMed1999

A 0.5-million-year record of millennial-scale climate variability in the north atlantic

Long, continuous, marine sediment records from the subpolar North Atlantic document the glacial modulation of regional climate instability throughout the past 0.5 million years. Whenever ice sheet size surpasses a critical threshold indicated by the benthic oxygen isotope (delta18O) value of 3.5 per mil during each of the past five glaciation cycles, indicators of iceberg discharge and sea-surface temperature display dramatically larger amplitudes of millennial-scale variability than when ice sheets are small. Sea-surface temperature oscillations of 1 degrees to 2 degreesC increase in size to approximately 4 degrees to 6 degreesC, and catastrophic iceberg discharges begin alternating repeatedly with brief quiescent intervals. The glacial growth associated with this amplification threshold represents a relatively small departure from the modern ice sheet configuration and sea level. Instability characterizes nearly all observed climate states, with the exception of a limited range of baseline conditions that includes the current Holocene interglacial.

Journal Article↗