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PubMed1996

The six-minute walking test in children with cystic fibrosis: reliability and validity.

There is a need to judge general exercise tolerance in children with cystic fibrosis (CF) under normal daily activity conditions and -when more extensive testing is required-in an exercise laboratory in a specialized center. We investigated the reproducibility, validity, and criterion for a 6-minute walking test, which simulates normal childhood activities. In Part A, we evaluated the reproducibility of a 6-minute walking test in 23 children (12 girls and 11 boys; ages 11.1 +/- 2.2 years; range, 8.2 15.6 years) with mild symptoms of CF [forced expiratory volume in 1 second (FEV1) 94.4 +/- 16.5% of predicted values (range, 60.6-129.7); body weight Z-score -0.71 +/- 0.81 (range, -1.73-0.93)]. The subjects performed two standardized 6-minute walking tests with 1 week between tests. There was no significant difference between the two walking distances reached (737 +/- 85 versus 742 +/- 90 meters; P = 0.56), and there was a strong correlation between the two walking distances reached by the individuals (r = 0.90, P < 0.0001). In Part B, the validity of the walking test was evaluated in 15 children (6 girls and 9 boys; ages 14.5 +/- 2.0 years; range, 10.2-16.9 years) with moderate symptoms of CF [FEV1 = 58 +/- 16.0% of predicted values, (range, 41.1-89.4); RV/TLC ratio = 46.3 +/- 6.5% (range, 31.6-57.2); body weight Z-score: -1.29 +/- 0.60 (range, -2.20-0.14)]. They underwent standardized maximum incremental exercise testing on a cycle ergometer and a 6-minute walking test. Postexertional lactate values exceeded threshold values (as described in the literature) in all patients but one. Correlation analysis (Pearson) showed a significant correlation between the walking distance reached (WD = 697 +/- 104 meters), and the maximum workload (Wmax = 118 +/- 44 watt; r = 0.76, P < 0.001) or the maximum oxygen uptake (1,688 +/- 495 ml; r = 0.76, P < 0.001), the latter two being determined on a cycle ergometer, RV/TLC% showed a significant negative correlation (r = -0.72, P < 0.01) with WD. Stepwise multiple regression analysis showed a multiple regression coefficient of R = 0.84 (P < 0.001) for Wmax and RV/TLC % as the independent variables vs. WD as the dependent variable. We conclude that the 6-minute walking test is a valid and useful test in children with mild to moderate symptoms of CF to assess their exercise tolerance and endurance. Exercise test results correlated negatively with pulmonary hyperinflation expressed by the RV/TLC ratio.

Adolescent↗
PubMed1997

Pinacidil's Effects on Defibrillation Outcomes: Role of Increased Potassium Conductance Via the K(ATP) Channel.

BACKGROUND: It has been shown that the inhibition of potassium ion conductance decreases defibrillation threshold. We postulated that if potassium conductance is a primary mechanism affecting defibrillation threshold values, then increasing potassium ion conductance will increase defibrillation values. The primary objective of this study was to determine if the ATP-dependent potassium (K(ATP)) channel opener pinacidil would increase defibrillation threshold values. The second objective was to prove that the observed changes were due to potassium conductance by using the K(ATP) inhibitor, glyburide, to reverse the electrophysiologic actions of pinacidil. The third objective was to determine if the electrophysiology action sof pinacidil correlate with changes in defibrillation threshold value. METHODS AND RESULTS: Domestic farm swine (n = 14) were anesthetized and intubated. Subsequently, they were instrumented with monophasic action potential catheters and epicardial defibrillation patches. Defibrillation threshold values, action potential duration, effective refractory period, and ventricular fibrillation cycle length were determined at baseline and during treatment phase 1 and treatment phase 2. Pigs were randomized into 2 groups: group 1 (n = 6) received D(5)W in treatment phase one followed by D(5)W in treatment phase 2 and group 2 (n = 8) received pinacidil in treatment phase one followed by the addition of glyburide in treatment phase two. DFT(ED50) did not change at baseline, treatment phase one or treatment phase two for group 1 (10.5 +/- 2, 11.1 +/- 1.7, 10.5 +/- 1.0 J) or for group 2 (10.1 +/- 2.2, 11.4 +/- 4.2, 11.4 +/- 3.0 J). Electrophysiologic parameters )QRS, effective refractory period, action potential duration(90), and ventricular fibrillation cycle length) were not significantly changed from baseline in group 1. In contrast, effective refractory period, action potential duration(90), and ventricular fibrillation cycle length significantly decreased at all recorded sites after the administration of pinacidil in group 2 (range of 7-13%, 6-9%, and 12-17%, respectively). However, pinacidil did not change the basal level of dispersion in effective refractory period, action potential duration, and ventricular fibrillation cycle length during paced rhythm or ventricular fibrillation. Glyburide reversed pinacidil's electrophysiologic actions. CONCLUSIONS: Pinacidil does not alter defibrillation threshold, but it reduces effective refractory period, action potential duration, and ventricular fibrillation cycle length and does not increase electrical heterogeneity. Therefore, changes in potassium channel conductance as well as shortening repolarization are unlikely primary mechanisms for elevating defibrillation threshold.

Journal Article↗
PubMed1992

The cell division cycle: a physiologically plausible dynamic model can exhibit chaotic solutions.

A mitotic oscillator with one slowly increasing variable (tau L of the order of hours) and one rapidly increasing variable (tau R of the order of minutes) modulated by a timer (ultradian clock) gives an auto-oscillating solution: cells divide when this relaxation oscillator reaches a critical threshold to initiate a rapid phase of the limit cycle. Increasing values of the velocity constant in the slow equation give quasi-periodic, chaotic and periodic solutions. Thus dispersed and quantized cell cycle times are consequences of a chaotic trajectory and have a purely deterministic basis. This model of the dispersion of cell cycle times contrasts with many previous ones in which cell cycle variability is a consequence of stochastic properties inherent in a sequence of many thousands of reactions or the random nature of a key transition step.

Activity Cycles↗
PubMed1999

Modulation frequency and orientation tuning of second-order texture mechanisms.

Modulation frequency and orientation tuning of second-order mechanisms underlying the detection of modulation in local spatial-frequency information are assessed by using an oblique-masking paradigm. Stimuli were Gabor-filtered noise patterns in which the local carrier spatial frequency was modulated about an average value of 4.7 cycles per degree (cpd) according to sinusoidal function. Thresholds were determined for spatial-frequency modulated test patterns (0.2 and 0.8 cpd) with fixed vertical carrier and modulation orientations presented alone and in the presence of spatiotemporally superimposed masks. Mask modulation frequency (0.1, 0.2, 0.4, 0.8, or 1.6 cpd), modulation orientation (0 degree, 45 degrees, or 90 degrees relative to vertical), and carrier orientation (18.5 degrees or 90 degrees relative to vertical) were manipulated independently while the mask modulation amplitude remained fixed at 0.25. Manipulating the modulation frequency of the mask revealed some modulation frequency specificity, particularly at lower test modulation frequencies. Spatial-frequency modulated masks produced threshold elevations regardless of the local carrier orientation. However, there was no evidence of threshold elevation when the mask modulation orientation was orthogonal to that of the test pattern. These results suggest a second-order texture mechanism that is tuned to both modulation frequency and modulation orientation but is not selective in terms of the orientation of first-order inputs.

Contrast Sensitivity↗
PubMed1998

Progesterone determination in equine plasma using different immunoassays.

Several assay systems (3H radioimmunoassay (RIA) with and without extraction; microplate enzyme-linked immunoassay (ELISA); qualitative ELISA (tube test)] were used to measure plasma progesterone concentration in mare plasma. The direct RIA showed a close correlation (R = 0.94) with the extraction RIA. The direct RIA and the microplate ELISA were compared in two different studies. In the first study 1155 samples of postpartum mares were used for progesterone determination with both assays. The ELISA resulted in more elevated values both in oestrus and dioestrus (0.19+/-0.3 and 2.44+/-3.62 nmol/l for oestrus, n = 436, and 8.94+/-4.29 and 27.88+/-18.34 nmol/l for dioestrus, N = 719, for the RIA and ELISA, respectively, R = 0.71). The evaluation of individual progesterone profiles has revealed that the microplate ELISA detects the time of ovulation at the same time as it is determined by the RIA and clinical examination. The sensitivity and specificity were calculated for different progesterone threshold values. In the second study including 7 non-pregnant, cycling mares the progesterone concentration of 240 samples was determined by both assays. Basal values (Day 0) obtained with the ELISA were higher (1.57 nmol/l) than those of the RIA (0.2 nmol/l). Both curves reached the same maximum concentration (12.11 and 12.45 nmol/l) 5 days after ovulation. The correlation between the RIA and ELISA values was high (R = 0.90). The tube test was compared to the microplate ELISA as reference using 576 plasma samples of 34 non-pregnant, non-cycling mares included in an ovulation induction study. Of these samples 118 had higher and 458 had lower values than 3.18 nmol/l. In most cases the tube test was in complete agreement with the microplate ELISA. The sensitivity, specificity, + predictive and - predictive values for the tube test were 79.7%, 95.4%, 81.7% and 94.8%, respectively.

Animals↗
PubMed1984

Direct assay of urinary steroid glucuronides for monitoring the approach of ovulation.

The concentrations of estrone-3-glucuronide (E(1)3G) and pregnanediol-3-glucuronide (P(2)3G) in daily samples of early morning urine (EMU) were correlated with the levels of estradiol (E2), progesterone (P) and LH in respective plasma samples. Forty-six menstrual cycles were studied, in order to determine the practical usefulness of the urine assays for detecting: a) an individualized estrogen concentration threshold value, announcing the approach of ovulation. b) an individualized signal provided by P(2)3G in urine from which it can be assumed that ovulation has already occurred. The results showed that the concentration of E2 in plasma, in any day of the cycle, can be precisely inferred from the respective concentration of E(1)3G in EMU. The estimation of the plasmatic P values from those of P(2)3G in EMU had to be based on different factors according to the phase of the cycle, fact that suggests the presence of a phase-related variation in the glucuronization of P metabolites. Considering three consecutive E(1)3G urinary assay results, it was possible to identify a threshold value termed Estrogen-Peak Initiating Rise (E-PIR), which anticipated in 3.02 +/- 0.18 days the occurrence of an LH peak. The attempts to detect the occurrence of ovulation by an individualized urinary P(2)3G signal proved disappointing. The signal was detected, either before, simultaneously or after the LH peak.

Adult↗
PubMed1996

Olfactory information processing during the course of the menstrual cycle.

In the present study we examined whether olfactory information processing depends on the phase of the menstrual cycle. Five female subjects were investigated during three phases (follicular, ovulatory, luteal) of their menstrual cycle. In each session chemosensory (olfactory) event-related potentials (CSERP) were recorded and olfactory thresholds and the hedonic tone of the test stimulus (citral) were determined. Threshold values were correlated with the salivary cortisol level. The results show that olfactory perception changes during the menstrual cycle. After the first stimulus presentations in a recording session, odors were perceived as more complex or novel during the ovulatory period (enhanced amplitude of P3-1). With continued stimulation, odor processing became faster (reduced latency of NI, P2 and P3-2) around ovulation and slower during the follicular phase. Moreover, odors were described more differentially during the ovulatory period. Olfactory sensitivity was correlated positively with the peripheral cortisol level.

Adult↗
PubMed2006

Stable low-level expression of p21WAF1/CIP1 in A549 human bronchogenic carcinoma cell line-derived clones down-regulates E2F1 mRNA and restores cell proliferation control.

BACKGROUND: Deregulated cell cycle progression and loss of proliferation control are key properties of malignant cells. In previous studies, an interactive transcript abundance index (ITAI) comprising three cell cycle control genes, [MYC x E2F1]/p21 accurately distinguished normal from malignant bronchial epithelial cells (BEC), using a cut-off threshold of 7,000. This cut-off is represented by a line with a slope of 7,000 on a bivariate plot of p21 versus [MYC x E2F1], with malignant BEC above the line and normal BEC below the line. This study was an effort to better quantify, at the transcript abundance level, the difference between normal and malignant BEC. The hypothesis was tested that experimental elevation of p21 in a malignant BEC line would decrease the value of the [MYC x E2F1]/p21 ITAI to a level below this line, resulting in loss of immortality and limited cell population doubling capacity. In order to test the hypothesis, a p21 expression vector was transfected into the A549 human bronchogenic carcinoma cell line, which has low constitutive p21 TA expression relative to normal BEC. RESULTS: Following transfection of p21, four A549/p21 clones with stable two-fold up-regulated p21 expression were isolated and expanded. For each clone, the increase in p21 transcript abundance (TA) was associated with increased total p21 protein level, more than 5-fold reduction in E2F1 TA, and 10-fold reduction in the [MYC x E2F1]/p21 ITAI to a value below the cut-off threshold. These changes in regulation of cell cycle control genes were associated with restoration of cell proliferation control. Specifically, each transfectant was capable of only 15 population doublings compared with unlimited population doublings for parental A549. This change was associated with an approximate 2-fold increase in population doubling time to 38.4 hours (from 22.3 hrs), resumption of contact-inhibition, and reduced dividing cell fraction as measured by flow cytometric DNA analysis. CONCLUSION: These results, likely due to increased p21-mediated down-regulation of E2F1 TA at the G1/S phase transition, are consistent with our hypothesis. Specifically, they provide experimental confirmation that a line with slope of 7,000 on the p21 versus [MYC x E2F1] bivariate plot quantifies the difference between normal and malignant BEC at the level of transcript abundance.

Biomarkers, Tumor↗
PubMed2005

Development of a SYBR green real-time polymerase chain reaction assay for quantitative detection of Babesia gibsoni (Asian genotype) DNA.

A real-time fluorogenic polymerase chain reaction (PCR) assay based on SYBR green that allows for sensitive, reproducible, and accurate quantification of Babesia gibsoni (Asian genotype). DNA from peripheral blood of infected dogs was developed. Standard curves were created by plotting the input amount of a standard template, constructed with plasmid DNA containing 182 base pairs (bp) of the p18 gene, against threshold cycle numbers. The curves showed a wide dynamic range (1,000,000-fold input) and high correlation values (>0.99). The PCR amplification efficacy of the standard template was similar to that of intact genomic DNA obtained from peripheral blood with B. gibsoni infection. The detection limit of the assay was 9 parasites/microl of blood with B. gibsoni infection. The intra-assay and interassay coefficients of variation of the threshold cycles ranged from 0.70% to 1.89% and from 1.18% to 1.92%, respectively. This assay system was found to be reproducible and accurate for the quantification of parasite DNA in experimentally infected dogs and far more sensitive than traditional microscopic examination.

Animals↗
PubMed1982

The measurement of urinary steroid glucuronides as indices of the fertile period in women. World Health Organization, Task Force on Methods for the Determination of the Fertile Period, special programme of research, development and research training in human reproduction.

The concentrations of various estrogen glucuronides and pregnanediol-3 alpha-glucuronide have been measured in daily samples of early morning urine (EMU) and 24 h pooled collections throughout a total of 70 menstrual cycles (58 subjects). The immediate objective was to identify and assess the potential value of measuring hormone metabolites to locate the fertile period in women, with the ultimate aim of developing a non-invasive immunochemical test. The project was undertaken in five centres and the results showed that: (i) there was good agreement in the patterns and mean concentrations of metabolites between the centres; (ii) estrone-3-glucuronide should be the estrogen glucuronide selected for further study; (iii) the analysis of EMU provided information that was as useful as the corresponding measurements on pooled collections for 24 h; (iv) a rise in the concentration of estrone-3-glucuronide (50% over the mean of three preceding values) could be used to locate the start of the fertile period in greater than 90% of the ovarian cycles (from day LHmax -- 3 to day LHmax -- 7); attempts to locate the end of the fertile period by a threshold value or a defined rise in the level of pregnanediol-3 alpha-glucuronide were disappointing. A 50% rise over the mean of three preceding values in the derived concentration ratio of estrone-3-glucuronide/pregnanediol-3 alpha-glucuronide could be used to indicate the start of the fertile period, and a 50% decrease plus two days the start of the infertile period in greater than 80% of the ovarian cycles. The limitations, implications and future developments are discussed.

Adolescent↗
PubMed2002

Modeling of 5' nuclease real-time responses for optimization of a high-throughput enrichment PCR procedure for Salmonella enterica.

The performance of a 5' nuclease real-time PCR assay was studied to optimize an automated method of detection of preenriched Salmonella enterica cells in buffered peptone water (BPW). The concentrations and interactions of the PCR reagents were evaluated on the basis of two detection responses, the threshold cycle (C(T)) and the fluorescence intensity by a normalized reporter value (DeltaR(n)). The C(T) response was identified as the most suitable for detection modeling to describe the PCR performances of different samples. DNA extracted from S. enterica serovar Enteritidis was studied in double-distilled H2O (ddH2O) and in two different enrichment media (brain heart infusion and BPW) with two PCR mixtures based on AmpliTaq Gold or rTTH: A descriptive model was proposed and fitted to the available experimental data. Equivalent PCR performances for the two PCR mixtures were obtained when DNA was diluted in ddH2O. However, the level of detection of DNA was affected when BPW was present during amplification. Use of the rTth mixture generated a 1-log-unit wider linear range of amplification, and the DNA detection levels were 2 x 10(-13) g/microwell for the rTth mixture and 2 x 10(-12) g/microwell for the AmpliTaq Gold mixture. To verify the improved amplification capacity of the rTth mixture, BPW was inoculated with 1 CFU of S. enterica serovar Enteritidis per ml and the mixture was incubated at 30 degrees C. Samples for PCR were withdrawn every 4 h during a 36-h enrichment. Use of the rTth mixture resulted in an earlier PCR detection during enrichment than use of the AmpliTaq Gold mixture. For accurate detection (C(T) < or = 30) of S. enterica serovar Enteritidis inoculated in BPW, the rTth mixture required 8.4 h of enrichment, while the AmpliTaq Gold mixture needed 11.6 h. In conclusion, the principle applied can improve the methodology of 5' nuclease real-time PCR for numerical optimization of sample pretreatment strategies to provide automated diagnostic PCR procedures.

Animals↗
PubMed2006

A kinetic study of a ternary cycle between adenine nucleotides.

In the present paper, a kinetic study is made of the behavior of a moiety-conserved ternary cycle between the adenine nucleotides. The system contains the enzymes S-acetyl coenzyme A synthetase, adenylate kinase and pyruvate kinase, and converts ATP into AMP, then into ADP and finally back to ATP. L-Lactate dehydrogenase is added to the system to enable continuous monitoring of the progress of the reaction. The cycle cannot work when the only recycling substrate in the reaction medium is AMP. A mathematical model is proposed whose kinetic behavior has been analyzed both numerically by integration of the nonlinear differential equations describing the kinetics of the reactions involved, and analytically under steady-state conditions, with good agreement with the experimental results being obtained. The data obtained showed that there is a threshold value of the S-acetyl coenzyme A synthetase/adenylate kinase ratio, above which the cycle stops because all the recycling substrate has been accumulated as AMP, never reaching the steady state. In addition, the concept of adenylate energy charge has been applied to the system, obtaining the enabled values of the rate constants for a fixed adenylate energy charge value and vice versa.

Adenine Nucleotides↗
PubMed2003

Automated semen analysis: 'zona pellucida preferred' sperm morphometry and straight-line velocity are related to pregnancy rate in subfertile couples.

BACKGROUND: Standard semen analysis has low objectivity and reproducibility and is not closely related to fertility. We assess the prognostic value of automated measurements of sperm motility and morphology. METHODS: During 1997-1999, 1191 infertile couples with no known absolute barrier to conception were assessed by conventional semen analysis, and automated measurements of average straight-line velocity (VSL) and the percentage of sperm with characteristics that conform to those of sperm which bind to the zona pellucida of the human oocyte (%Z). During follow-up to 2001, there were 336 natural pregnancies. RESULTS: Only %Z, VSL and female age were independently significantly related to pregnancy rate by Cox regression analysis. Pregnancy rate was higher with above average %Z and VSL, indicating a continuous rather than a threshold relationship. The likelihood of pregnancy within 12 cycles can be evaluated for specific values of %Z, VSL and female age using the Cox regression model. CONCLUSIONS: The automated semen measures of sperm morphometry (%Z) and velocity (VSL) are related to pregnancy rates in subfertile couples and should assist clinicians in counselling subfertile patients about their prognosis for a natural pregnancy. Objective automated methods should replace the traditional manual assessments of semen quality.

Adult↗
PubMed1997

[The 40 Hertz auditory event-related potential in chick: optimized recording conditions and threshold value].

In order to seek optimized recording parameters for 40 Hz AERP in chick, the present study was carried out with a statistical model of orthogonal test. The following measuring parameters to be selected includ the rise/decay time of tone pip (1, 2 and 3 cycle), platform time (1, 2 and 3 cycle), high-pass filters (5, 20 and 30 Hz), low-pass filter (70, 100 and 250 Hz). The results showed that 1. the filter setting is a high significant factor, the most optimum basswidth is 20-70 Hz; 2. the ideal time of rise/decay and platform of tone pip are 2-1-2 cycle. The adult animals showed the greatest sensitivity nearby 1.5-2 kHz frequency. In sixday-old chicks, the threshold at every frequency has reached the same values as adult, indicating that their auditory function is essentially mature.

Animals↗
PubMed1977

Objective identification of cell cycle phases and subphases by automated image analysis.

Frequency distributions of integrated optical density, perimeter, projection, area, form factor, average optical density, and mean dispersion path of nuclear images of Feulgen-stained HeLa S3 cells were obtained by automated image analysis at the base threshold of 0.04 OD. The mean values and standard deviations of these geometric parameters were then computed versus increasing values of threshold (0.08--0.32 OD). There is clear evidence of differential chromatin dispersion and convolution during the cycle of synchronized HeLa S3 cells at different times after selective mitotic detachment. The combination of average OD, form factor, and mean dispersion path at base threshold with the threshold dependence of nuclear morphometric parameters permits objective identification of cell cycle phases and their subphases, by characterizing variations in chromatin geometry within and between phases, regardless of whether DNA content remains constant (early G1, middle G1, late G1), varies only slightly (late G1-early S or late S-G2 transitions), or varies significantly (early S-middle S).

Autoanalysis↗
PubMed1976

Sustained oscillations and threshold phenomena in an operon control circuit.

A genetic regulatory model involving a positive feedback (via induction) and a negative feedback (via catabolite repression) is analyzed and applied to the problem of the lac operon regulation in E. coli. Damped and sustained oscillations of the limit cycle type are found along with threshold phenomena corresponding to multiple limit cycles or to multiple steady states, for values of the parameters compatible with experimental data. A comparison with the observations of Knorre and Goodwin is outlined.

Escherichia coli↗
PubMed1989

[Accuracy of the measurements of left ventricular volume and ejection fraction determined by multigated blood pool tomography].

Accuracy of the measurements of LV volumes and ejection fraction determined from multigated blood pool tomography (MGBPT) was tested in 23 patients with various heart diseases who underwent cineventriculography (CV). Preliminary phantom studies showed that a 42% threshold value was found to provide the best relationship between measured and actual volumes (r = 0.99, standard error of the estimate (SEE) = 4.7 ml). The patients studies were performed at 16 frames/cardiac cycle at 18 angles over a 180 degrees rotation for one minute per angle. Long-axis horizontal views were reconstructed. The numbers of LV voxel with counts above the threshold value were summed and multiplied by the known volume of a voxel. Measurements of LV volume (r = 0.82, SEE = 29 ml), end-systolic LV volume (r = 0.83, SEE = 25 ml), end-diastolic LV volume (r = 0.68, SEE = 33 ml), and ejection fraction (r = 0.73, SEE = 10%) determined from MGBPT correlated well with those determined by CV. However, the ratios (Y) of the difference of the MGBPT-volume from the CV-volume to the CV-volume were decreased progressively and negatively as the CV-volumes (X) were smaller (Y = 38-3,996/X). Thus, we conclude that the determinations of volume by MGBPT would lead to more errors with the smaller volumes.

Aged↗
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↗