Child, parent, and family mental health and functioning in Australia during COVID-19: comparison to pre-pandemic data.

The COVID-19 pandemic presents significant risks to population mental health. Despite evidence of detrimental effects for adults, there has been limited examination of the impact of COVID-19 on parents and children specifically. We aim to examine patterns of parent and child (0-18 years) mental health, parent substance use, couple conflict, parenting practices, and family functioning during COVID-19, compared to pre-pandemic data, and to identify families most at risk of poor outcomes according to pre-existing demographic and individual factors, and COVID-19 stressors. Participants were Australian mothers (81%) and fathers aged 18 years and over who were parents of a child 0-18 years (N = 2365). Parents completed an online self-report survey during 'stage three' COVID-19 restrictions in April 2020. Data were compared to pre-pandemic data from four Australian population-based cohorts. Compared to pre-pandemic estimates, during the pandemic period parents reported higher rates of parent depression, anxiety, and stress (Cohen's d = 0.26-0.81, all p < 0.001), higher parenting irritability (d = 0.17-0.46, all p < 0.001), lower family positive expressiveness (d = - 0.18, p < 0.001), and higher alcohol consumption (22% vs 12% drinking four or more days per week, p < 0.001). In multivariable analyses, we consistently found that younger parent age, increased financial deprivation, pre-existing parent and child physical and mental health conditions, COVID-19 psychological and environmental stressors, and housing dissatisfaction were associated with worse parent and child functioning and more strained family relationships. Our data suggest wide-ranging, detrimental family impacts associated with the COVID-19 pandemic; and support policy actions to assist families with financial supports, leave entitlements, and social housing.

Thoroughbred stallion fertility is significantly associated with FKBP6 genotype but not with inbreeding or the contribution of a leading sire.

This is a follow-up study to validate the previously detected association of the FKBP6 gene with stallion subfertility. Using a select cohort of 150 Thoroughbred stallions with detailed breeding records, we confirm significant association (P < 0.0001) between low per-cycle pregnancy rates (≤50%) and a combined A/A-A/A genotype of SNPs chr13:11 353 372G>A and chr13:11 353 436A>C in FKBP6 exon 5. We also show that stallion subfertility and the combined genotype A/A-A/A are not associated with the level of genetic diversity based on 12 autosomal microsatellite markers, or with pedigree-based inbreeding rate, or the extent of contribution of a leading Thoroughbred sire, Northern Dancer, in a stallion's pedigree. We develop a TaqMan allelic discrimination assay for the two SNPs to facilitate accurate and high-throughput genotyping. We determine allele, genotype and combined genotype frequencies of FKBP6 exon 5 SNPs in a global cohort of 518 Thoroughbreds (76% stallions or geldings and 24% mares) and show that the frequency of the A/A-A/A genotype is 4%. Because there is no similar association between the FKBP6 exon 5 genotype and stallion subfertility in Hanoverians, we suggest that the two SNPs are not causative but rather tagging a breed-specific haplotype with genetic variants unique to Thoroughbreds. Further WGS-based research is needed to identify the molecular causes underlying the observed genotype-phenotype association in Thoroughbred stallions.

Effect of artificial vagina lubricants on stallion sperm quality.

Commercially available vaginal lubricants, typically labeled as non-spermicidal, are used to lubricate equine artificial vaginas prior to semen collection. Improper type or amount of lubricant might affect stallion sperm quality, either after short-time exposure or following cooled storage of extended semen previously exposed to lubricant. The aim of this study was to evaluate stallion sperm quality following exposure to lubricant-containing extender for 1 h (T1h) or 24 h (T24h). Three ejaculates were collected from each of four stallions using a small volume of petrolatum to lubricate artificial vaginas, and gel-free semen was diluted to 30 × 106 sperm/mL in extender containing: no lubricant (control), or 1 or 5% (v/v) HR® Lubricating Jelly (HR1 or HR5); K-Y® Jelly (KY1 or KY5); Therio-gel® (TG1 or TG5); Priority Care® Sterile Lubricating Jelly (PC1 or PC5); or Clarity® A.I. Lubricating Jelly (CL1 or CL5). Sperm were evaluated at T1h and T24h for percentages of: total and progressive sperm motility (TMOT and PMOT); curvilinear velocity (VCL; µm/s); and straightness (STR; %); viable acrosome intact sperm (VAI); sperm with abnormal DNA (COMP-αt); viable lipid peroxidation negative sperm (VLPN); and sperm with no detectable DNA oxidative injury [8OHdG(-)]. Following short-term exposure of sperm to lubricants, KY5 reduced TMOT, PMOT, VCL, VAI, VLPN, and COMP-αt in comparison with controls (i.e., P < 0.05). PC5 reduced TMOT, PMOT, VCL, VAI, and 8OHdG(-), and KY1 reduced TMOT, VAI, VLPN in comparison to controls (P < 0.05). Lubricant CL1, HR1 and HR5 yielded similar values to controls for all 8 endpoints, and CL5 yielded similar values to controls for all 8 endpoints (P > 0.05), except for VCL. Following long-term exposure, KY5 decreased TMOT, PMOT, VCL, VAI, VLPN, and COMP-αt as compared to controls (i.e., P < 0.05), PC5 decreased TMOT, VCL, VAI, and 8OHdG(-)as compared to controls in PC5, and KY1 decreased TMOT, VAI, VLPN, and COMP-αt (P < 0.05). TG5 decreased TMOT, PMOT, and VCL as compared to controls (P < 0.05). Lubricant CL5 decreased VCL (P < 0.05), and CL1, HR5, HR1, PC1, and TG1 were similar to controls for all 8 endpoints (P > 0.05). Overall, lubricant KY was the most detrimental to sperm quality, with most profound changes detected at a 5% concentration. Lubricants CL and HR were generally similar to controls and were less affected by lubricant concentration.

Factors impacting equine sperm recovery rate and quality following cushioned centrifugation.

Two experiments were conducted to investigate modifications in cushioned centrifugation of stallion semen. Specifically, the effects of tube type, centrifugation medium, cushion type, and centrifugation force on post-centrifugation sperm recovery rate and quality were evaluated. In Experiment 1, sperm recovery rate was higher (P<0.05) in conventional plastic conical-bottom tubes (103%) than in newly developed glass nipple-bottom tubes (96%) following cushioned centrifugation; however, several measures of semen quality (i.e., % total motility [MOT], % progressive motility [PMOT], curvilinear velocity, and average-path velocity) yielded higher values following centrifugation in nipple-bottom tubes (P<0.05). Sperm recovery rate following cushioned centrifugation was similar between semen previously diluted in optically clear centrifugation extender (100%) and semen diluted in opaque centrifugation extender (100%); however, MOT and PMOT were higher in semen subjected to cushioned centrifugation in opaque extender (P<0.05). An extender by tube-type interaction was not detected for recovery rate or post-centrifugation semen quality. In Experiment 2, sperm recovery rate following cushioned centrifugation in nipple-bottom tubes was similar when forces of 400xg or 600xg were applied (90 and 90%, respectively; P>0.05), and no resulting differences in semen quality were detected between these treatment groups (P>0.05). The type of iodixanol cushion medium used (i.e., OptiPrep, Eqcellsire Component B, or Cushion Fluid did not impact post-centrifugation semen quality, based on the laboratory values measured (P>0.05). In conclusion, cushioned centrifugation of stallion semen in either conical-bottom or nipple-bottom tubes yielded a high sperm harvest, while maintaining sperm function. An optically opaque extender, commonly used in the equine breeding industry, can be used to achieve this goal.

Effects of seminal plasma and flash-freezing on DNA structure of stallion epididymal sperm exposed to different potentiators of DNA damage.

The tolerance of sperm DNA structure to seminal plasma and freezing conditions has both clinical and basic biologic relevance. In this study, fresh (FS) or flash-frozen (FZ) stallion epididymal sperm were exposed (SP+) or unexposed (SP-) to seminal plasma. Sperm were then evaluated to monitor the degree of change in DNA structure following challenge with chemical (dithiothreitol-DTT), oxidative (iron sulfate; FeSO4) or enzymatic (DNase I) potentiators of DNA damage. For sperm not treated with potentiators (controls), there was no effect of SP treatment (SP- vs. SP+) or freezing treatment (FS vs. FZ; non-significant) on measures of any DNA assays (i.e., 8-hydroxy, 2'deoxyguanosine [8OHdG], TUNEL, or sperm chromatin structure [SCSA] assays). Group FZ was more susceptible than Group FS to potentiators of DNA damage. Percent 8OHdG-positive sperm was higher in Group FZ/SP- treated with FeSO4 than all other groups (P < 0.05). Percent TUNEL-positive sperm was similar among FZ/SP- groups treated with DTT, FeSO4, or DNase (non-significant) and was higher in these groups than all other treatments (P < 0.05). Percent COMP-αt was higher following treatment with DNase or DTT, as compared to their respective controls, regardless of prior exposure to SP (P < 0.05). Overall, sperm DNA structure was unaffected by seminal plasma or freezing treatment when samples were not exposed to potentiators of sperm DNA damage; however, marked differences were identified in DNA structure when sperm were challenged with chemical, oxidative or enzymatic treatments. These results highlight the importance of challenging DNA structure prior to analysis. The use of potentiators of DNA damage provided a model to evaluate sperm DNA structure following exposure of sperm to various experimental treatments.

The effects of antibiotic type and extender storage method on sperm quality and antibacterial effectiveness in fresh and cooled-stored stallion semen.

Two experiments were conducted to evaluate the effects of antibiotic-containing extender of on sperm quality and control of bacterial growth. In Experiment 1, ejaculates were diluted in extender containing no antibiotics, potassium penicillin G-amikacin disulfate (PEN-AMIK), ticarcillin disodium-potassium clavulanate (TICAR-CLAV), piperacillin sodium/tazobactam sodium (PIP-TAZ), or meropenem (MERO). In freshly extended semen, only slight differences were detected among some antibiotic treatments for total sperm motility, curvilinear velocity, and viable acrosome-intact sperm (P < 0.05). In cool-stored semen, slight differences were also detected among certain antibiotic treatments for curvilinear velocity and chromatin integrity (P < 0.05). In Experiment 2, ejaculates were diluted in extender and subjected to no bacterial spiking, or inoculated with lower or higher doses of K. pneumoniae or P. aeruginosa. Following cooled storage of semen, colony forming units/ml (CFU/mL) were less in PEN-AMIK (706 ±â€¯244) and MERO (1576 ±â€¯1076) treatment groups than in TICAR-CLAV (4678 ±â€¯1388) or PIP-TAZ (8108 ±â€¯3198) treatment groups (P < 0.05). The CFU/mL were lower in all antibiotic-containing treatment groups than the control group (18478 ±â€¯4374; P < 0.05). The percentage of culture plates containing no bacterial growth in unspiked semen was greater in PEN-AMIK (75%) than PIP-TAZ (15%) or TICAR-CLAV (20%; P < 0.05). The percentages of culture plates containing no bacterial growth in semen spiked with a lower doses of K. pneumoniae or P. aeruginosa were higher in PEN-AMIK (70% and 50%, respectively) then in all other treatment groups (0-40% and 0-15% for K. pneumonia and P. aeruginosa, respectively; P < 0.05); however, complete control of bacterial load was only modest even with PEN-AMIK. In both experiments, freezing and thawing extender prior to use did not have any appreciable detrimental effect on sperm quality or antibiotic efficacy. In summary, all antibiotics tested had minimal effects on measures of sperm quality in fresh or cool-stored semen extenders; however, PEN-AMIK, followed by MERO, yielded the best results in terms of antimicrobial efficacy. None of the antibiotic types controlled bacterial growth, in comparison with the antibiotic-free control group, when extended semen was spiked with a high concentration of Pseudomonas aeruginosa. Cooled storage of extended semen reduced bacterial growth in comparison with freshly extended semen.

The effect of flash-freezing temperature on stallion sperm DNA structure.

The effect of flash-freezing storage temperature on stallion sperm DNA has not been evaluated. Commonly, sperm are flash-frozen at various temperatures to preserve sperm DNA prior to analysis. It is unclear whether the temperature at which sperm are frozen and stored may affect the results of DNA assays. In this study, the neutral comet assay was used to evaluate the effect of flash-freezing storage temperature (freezer [-60 °C], dry ice [-78.5 °C], liquid nitrogen [-196 °C]) compared to fresh sperm DNA structure. In addition, intra- and inter-assay and intra- and inter-stallion variabilities were determined. All comet tail measures were higher following any flash-freezing method, as compared to fresh sperm DNA (P < 0.05), with no difference among flash-frozen treatments (P > 0.05). For most comet variables, intra- and inter-assay variabilities were <10%. Intra- and inter-stallion variabilities revealed that comet head length (HL) and width (CW) were less variable as compared to comet tail values, i.e., % comet tail DNA (T-DNA), tail length (TL), tail moment (OTM), and tail migration (TM). Certain comet tail values in fresh (% T-DNA, and OTM) and flash-frozen sperm (OTM, % T-DNA, TL, and TM) were correlated to the Sperm Chromatin Structure Assay (SCSA) variable, COMP-αt. The comet tail measures were negatively correlated to % morphologically normal sperm (P < 0.05) and positively correlated to % abnormal heads and premature germ cells (P < 0.05). Variables COMP-αt and % total sperm motility were not correlated to any morphologic sperm feature in this group of stallions (P > 0.05). While significant differences in the structure of the sperm DNA were identified in the flash-frozen as compared to the fresh sperm DNA with the neutral comet assay, it cannot be assumed that these changes are fertility limiting.

The effect of two levels of hemospermia on stallion fertility.

Hemospermia can occur consistently or intermittently in stallion ejaculates and may cause a reduction in the fertility of the affected ejaculate. It is unknown what amount of blood in an ejaculate leads to subfertility. This study investigated the effect of higher and lower levels of hemospermia (50% and 5%, respectively) on fertility using 24 reproductively normal mares inseminated over three consecutive estrous cycles with fresh extended semen. Mares inseminated with a 5% blood-contaminated ejaculate became pregnant at the same rate (75% per cycle; 18 of 24) as the mares inseminated with blood-free (control) semen (75% per cycle; 18 of 24). The ejaculates containing 50% blood were sterile (0% per cycle, 0 of 24). We concluded that it is the amount of blood, not the mere presence of blood, in an ejaculate that impacts fertility.

Doppler echocardiographic profiles in obstructive right and left atrial myxomas.

Previous reports have suggested that atrioventricular (AV) flow disturbances accompanying atrial myxomas mimic mitral stenosis. Two patients complaining of orthostatic syncope and positional intolerance had a large right and left atrial myxoma, respectively. Doppler flow records showed abrupt early diastolic flow cessation and normal velocity half-times, unlike AV valve stenosis. Large, obstructing atrial myxomas may behave as ball valves.

Determination of aortic valve area by two-dimensional and Doppler echocardiography in patients with normal and stenotic bioprosthetic valves.

To assess the feasibility and accuracy of determining bioprosthetic aortic valve area from two-dimensional and Doppler echocardiographic measurements, three partially overlapping groups were selected from 55 patients with such bioprosthetic valves and adequate Doppler studies. These were Group 1, 37 patients with recent aortic valve replacement surgery and no clinical or echocardiographic evidence of valve dysfunction; Group 2, 12 patients with prosthetic valve stenosis documented by cardiac catheterization; and Group 3, 22 patients with both Doppler and catheterization studies in whom noninvasive and invasive determinations of aortic valve area could be directly compared. Left ventricular outflow tract diameter was measured from two-dimensional still frame images. Flow velocity proximal to the aortic valve, transvalvular velocity and acceleration time were determined from pulsed and continuous wave Doppler spectra. Aortic valve gradient was calculated with the modified Bernoulli equation and valve area by the continuity equation. In the 37 patients with a normally functioning valve, the calculated mean gradient ranged from 5 to 25 mm Hg (average 13.6 +/- 5.2) and valve area from 1.0 to 2.3 cm2 (mean 1.6 +/- 0.31). Linear regression analysis of prosthetic aortic valve area determined by Doppler imaging and cardiac catheterization demonstrated a high correlation (r = 0.93) between the two techniques. Comparison of the patients with and without prosthetic valve stenosis revealed statistically significant differences in mean gradient (42.8 +/- 12.3 versus 13.6 +/- 5.2 mm Hg; p = 0.0001), acceleration time (116 +/- 15 versus 80 +/- 13 ms; p = 0.0001) and valve area by the continuity equation (0.80 +/- 0.16 versus 1.6 +/- 0.31 cm2; p = 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Noninvasive evaluation of aortic stenosis severity utilizing Doppler ultrasound and electrical bioimpedance.

Aortic valve area was calculated noninvasively in 30 patients with aortic stenosis undergoing cardiac catheterization. Continuous wave Doppler ultrasound was employed to estimate the mean transvalvular pressure gradient. The mean left ventricular outflow tract flow velocity and cross-sectional area were determined from pulsed Doppler and two-dimensional ultrasound recordings. Electrical transthoracic bioimpedance cardiography performed simultaneously with the ultrasonic study and repeated at the time of catheterization measured heart rate, systolic ejection period and cardiac output. These noninvasive data permitted calculation of aortic valve area using the Gorlin equation (range 0.21 to 1.75 cm2) and the continuity equation (range 0.25 to 1.9 cm2). Subsequent cardiac catheterization showed valve area to range from 0.21 to 1.75 cm2. The mean Doppler pressure gradient estimate was highly predictive of the gradient measured at catheterization (r = +0.92, SEE = 10). Bioimpedance cardiac output measurements agreed with the average of Fick and indicator dye estimates (r = +0.90, SEE = 0.52). Valve area estimates utilizing continuous wave Doppler ultrasound and electrical bioimpedance were superior (r = +0.91, SEE = 0.12) to estimates obtained utilizing the continuity equation (r = +0.76, SEE = 0.29) and were more reliable in the detection of patients with severe aortic stenosis (9 of 11 versus 6 of 11). These data show that 1) electrical bioimpedance methods accurately estimate cardiac output in the presence of aortic stenosis; 2) the hybridized bioimpedance-Doppler ultrasound method yields accurate estimates of aortic stenosis area; and 3) the speed, accuracy and cost-effectiveness of aortic stenosis evaluation may be improved by this hybridized approach.

Quantification of aortic regurgitation utilizing continuous wave Doppler ultrasound.

Aortic regurgitation and mitral stenosis are hemodynamically similar, insofar as both result in passive ventricular filling across a narrow orifice driven by a declining pressure gradient. Because mitral stenosis is successfully characterized by Doppler ultrasound determination of the velocity half-time, or time constant, aortic regurgitation might be quantified in an analogous fashion. Eighty-six patients with diverse causes of aortic regurgitation underwent continuous wave Doppler examination before cardiac catheterization or urgent aortic valve replacement. The Doppler velocity half-time was defined as the time required for the diastolic aortic regurgitation velocity profile to decay by 29%, whereas catheterization pressure half-time was calculated as the time required for transvalvular pressure to decay by 50%. Doppler velocity and catheterization pressure half-times were linearly related (r = 0.91). Doppler velocity half-times were inversely related to regurgitant fraction (r = -0.88). Angiographic severity (1+ = mild to 4+ = severe) was also inversely related to pressure and velocity half-time; a Doppler half-time threshold of 400 ms separated mild (1+, 2+) from significant (3+, 4+) aortic regurgitation with high specificity (0.92) and predictive value (0.90). The Doppler velocity half-time was independent of pulse pressure, mean arterial pressure, ejection fraction and left ventricular end-diastolic pressure. Estimation of transvalvular aortic pressure half-time utilizing continuous wave Doppler ultrasound is a reliable and accurate method for the noninvasive evaluation of the severity of aortic regurgitation.

Sperm DNA quality evaluated by comet assay and sperm chromatin structure assay in stallions after unilateral orchiectomy.

Unilateral orchiectomy (UO) may interfere with thermoregulation of the remaining testis caused by inflammation surrounding the incision site, thus altering normal spermatogenesis and consequently sperm quality. Two measures of sperm DNA quality (neutral comet assay and the sperm chromatin structure assay [SCSA]) were compared before UO (0 days) and at 14, 30, and 60 days after UO to determine whether sperm DNA changed after a mild testis stress (i.e., UO). The percent DNA in the comet tail was higher at 14 and 60 days compared to 0 days (P < 0.05) after UO. All other comet tail measures (i.e., length, moment, migration) were higher at all time periods after UO compared to 0 days (P < 0.05). Two SCSA measures (mean-αt, mode-αt) increased at 14 days after UO (P < 0.05), whereas two measures (SD-αt and COMP-αt) did not change. This study identified a decrease in sperm DNA quality using both the neutral comet assay and the SCSA, which was not identified using traditional measures of sperm quality.

Isosorbide-5-mononitrate in angina pectoris: plasma concentrations and duration of effects after acute therapy.

In a double-blind, randomized, crossover study, the duration of effects of single oral doses of 20 and 40 mg isosorbide-5-mononitrate (IS-5MN) and matching placebo were studied in 12 male patients with angina pectoris. Plasma IS-5MN concentrations (mean +/- SD) 2 and 6 hours after administration were 300 +/- 60 and 144 +/- 43 ng/ml after 20 mg IS-5MN and 551 +/- 191 and 376 +/- 129 ng/ml after 40 mg IS-5MN. Exercise time to the onset of angina 2 and 6 hours after administration increased after 20 mg IS-5MN (5.88 +/- 1.85; P less than 0.001 and 5.08 +/- 1.97 minutes; P less than 0.002) and 40 mg IS-5MN (6.17 +/- 1.88; P less than 0.001 and 5.78 +/- 1.72 minutes; P less than 0.001) in comparison to placebo (4.57 +/- 1.22 and 4.15 +/- 1.22 minutes). Similarly, total exercise duration increased at 2 (P less than 0.001) and 6 hours (P less than 0.002) after both doses of IS-5MN. Compared with placebo, ECG ST segment depression during exercise was less (P less than 0.05) 2 hours after both doses of IS-5MN. Thus single oral doses of 20 and 40 mg IS-5MN exert antianginal and anti-ischemic effects for at least up to 6 hours.

Clinical evaluation of an interstitial remote afterloading device for multichannel intracavitary irradiation.

PURPOSE: The purpose of this report is to describe the clinical implementation and evaluation of an interstitial remote afterloading device for multichannel intracavitary brachytherapy. METHODS AND MATERIALS: Two 15-channel low dose rate devices were adapted for use with Fletcher-Suit tandem and ovoids and Simon-Heyman capsules. The technical records for 103 intracavitary brachytherapy procedures performed from February 1989 through February 1991 were reviewed. RESULTS: Isodose distributions from fixed source trains for Microselectron low dose rate gynecologic applicators closely approximate standard manual afterloading sources and applicators. Device malfunctions occurred in 51% (53 out of 103) of the procedures. Malfunctions by applicator type were 70% (51 out of 73) for tandem, ovoids, and capsules, 12% (2 out of 17) for tandem and ovoids, and none (0 out of 13) for ovoids only. The most common malfunction occurred during source transfer. Total implant time was prolonged 0 to 4% by malfunction and 10% by patient care interruptions, depending on applicator type. CONCLUSION: The adaptation of the Microselectron device for multichannel gynecologic intracavitary brachytherapy results in similar dose distributions as standard manual after loading sources and a decreased radiation exposure to nursing personnel. The system has a high rate of malfunctions but a low overall prolongation of implant time due to malfunction.

Design and dosimetric characteristics of a high dose rate remotely afterloaded endocavitary applicator system.

PURPOSE: An applicator is described for endocavitary treatment of rectal cancers using a high dose rate (HDR) remote afterloading system with a single high-intensity 192Ir source as an alternative to the 50 kVp x-ray therapy contact unit most frequently used in this application. METHODS AND MATERIALS: The applicator consists of a tungsten-alloy collimator with a 45 degree beveled end, placed in a protoscope with an elliptical cross-section. The resultant 3 cm diameter circular treatment aperture, located in the beveled face of the proctoscope, is irradiated by circular array of dwell positions located about 6.5 mm from the applicator surface. This beveled end allows patients with posterior wall tumors to be treated in the dorsal lithotomy position. The dose-rate distributions about the applicator were determined using a combination of thermoluminescent dosimetry (TLD-100 detectors) and radiochromic film dose measurement techniques along with Monte Carlo dosimetry calculations. TLD-100 (3 x 3 x 0.9 mm3 chips) measurements were used to measure the distribution of dose over the proctoscope surface as well as the central axis dose-rate distribution. Relative radiochromic film measurements were used to measure off-axis ratios (flatness and penumbra width) within the treatment aperture. These data were combined with Monte Carlo simulation results to obtain the final dose distribution. RESULTS: The tungsten collimator successfully limits the dose to the tissue in contact with the proctoscope walls to less than 12% of the prescribed dose. These results indicate that the HDR applicator system has slightly more penetrating depth-dose characteristics than the most widely used contact therapy x-ray machine. Flatness characteristics of the two treatment delivery systems are comparable, although the HDR endocavitary applicator has a significantly wider penumbra. Finally, the HDR applicator has a lower surface dose rate (1.5-4 Gy/min of dwell time) compared to 9-10 Gy/min for the x-ray unit. CONCLUSIONS: An applicator system has been developed for endocavitary treatment of early stage rectal carcinoma that uses a single-stepping source HDR remote afterloading system as a radiation source. The advantages of the HDR-based system over x-ray therapy contact units currently used in this clinical application are (a) enhanced flexibility in applicator design and (b) widespread availability of single-stepping source HDR remote afterloading systems.

Discovery and synthesis of methyl 2,5-dimethyl-4-[2- (phenylmethyl)benzoyl]-1H-pyrrole-3-carboxylate (FPL 64176) and analogues: the first examples of a new class of calcium channel activator.

Methyl 2,5-dimethyl-4-[2-(phenylmethyl)benzoyl]-1H-pyrrole-3-carboxylate, FPL 64176 (1), is the first example of a new class of calcium channel activator (CCA) that does not act on any of the well-defined calcium channel modulator receptor sites, as typified by verapamil, diltiazem, and the dihydropyridines. The potent activity of 1, having the 2-(phenylmethyl)benzoyl substituent, was predicted using QSAR on an initial set of less potent benzoylpyrroles. When compared to the CCA Bay K 8644, 1 has similar potency on calcium uptake into GH3 cells (both have EC50 approximately 0.015 microM) but is appreciably more potent functionally at increasing contractility in a guinea pig atria preparation (1 has EC50 = 0.049 microM vs Bay K 8644 EC50 = 1.95 microM). 1 is an achiral, pharmacologically clean agonist with no demonstrable partial agonist properties and possesses appreciably higher efficacy than Bay K 8644. It should therefore become a useful biochemical and pharmacological tool for the study of calcium channels in many cell types.

Long-term bepridil monotherapy for angina pectoris.

The long-term efficacy of bepridil as once-a-day monotherapy was studied in 19 men with stable angina pectoris. After 2 weeks of single-blind placebo therapy and a 12-week parallel placebo-controlled, dose-response study, each patient received open-label bepridil. After a dose-titration period of 3 months, patients received bepridil (100 to 400 mg once a day, mean 290 mg) for 24 months. The response to treatment was assessed by patient diaries and serial treadmill exercise testing 24 hours after dose administration, every 3 months. Only 2 patients were released from the study due to therapeutic failure. Compared with placebo, 3 months of bepridil therapy resulted in a significant reduction in the weekly frequency of angina from 10.3 +/- 9.1 to 1.8 +/- 3.5 (p less than 0.002) and nitroglycerin consumption from 5.0 +/- 5.4 to 1.4 +/- 2.3 (p less than 0.01). In addition, there was a simultaneous significant increase in the walking time to angina from 5.2 +/- 2.3 to 7.9 +/- 2.6 minutes (p less than 0.001) and total exercise time from 7.1 +/- 2.2 to 8.8 +/- 1.9 minutes (p less than 0.001). These favorable effects were sustained throughout the 24 months of the study. Although resting QTc interval was prolonged by 36 to 42 ms (p less than 0.001) during bepridil therapy, ventricular dysrhythmias were not observed immediately before or during exercise testing and were not manifested by symptoms. Neurologic and gastrointestinal side effects of mild to moderate severity were observed, but none required discontinuation of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac adaptation to increased systemic blood pressure in borderline hypertensive men.

The present study examined cardiac characteristics of borderline hypertensive men with a positive parental history of hypertension. Hemodynamics in relation to left ventricular function and structure were evaluated in 15 borderline hypertensive men with a parental history of hypertension and in 20 normotensive control subjects with a negative parental history. Groups were matched in age, height, weight and percent body fat. Left ventricular mass and dimensions were measured by M-mode echocardiography, and left ventricular function was assessed by radionuclide ventriculography. Both groups had similar left ventricular mass, dimensions and wall thicknesses. In relation to control subjects, borderline hypertensive men had a significantly higher heart rate and blood pressure (BP) (p < 0.001), but a similar cardiac index. Borderline hypertensive men had a higher peripheral resistance index (p < 0.02), longer time to peak filling rate, and reduced cardiac efficiency, whereas they had higher contractility, minute and stroke work indexes than did control subjects (all p < 0.05); they also had higher diastolic BP (p < 0.03) during exercise, and sustained higher BP during recovery than did controls. Although this group of borderline hypertensive men did not have an altered cardiac anatomy, they had an increased vascular resistance, an altered diastolic function and a reduced cardiac efficiency while undergoing a greater work load. These cardiodynamic profiles are consistent with functional vascular changes and a parallel compensation by the heart.(ABSTRACT TRUNCATED AT 250 WORDS)

Prognostic value of dobutamine stress echocardiography in patients referred because of suspected coronary artery disease.

To determine whether dobutamine stress echocardiography (DSE) provides prognostic information beyond that available from routine clinical data, we reviewed the outcome of 210 consecutive patients referred for DSE to evaluate chest pain, perioperative risk, and myocardial viability. Dobutamine was infused in increments of 10 micrograms/kg/min in 5-minute stages to a maximum of 40 micrograms/kg/min. The dobutamine stress echocardiogram was considered abnormal only if dobutamine induced a new wall motion abnormality as determined by review of the digitized echocardiographic images in a quad screen format and on videotape. Thirty percent of tests were abnormal. An abnormal test was more common (p < or = 0.02) in men and patients with angina pectoris, in patients taking nitrate therapy, or those with prior myocardial infarction or abnormal left ventricular wall motion at rest. Twenty-two deaths, 17 of which were cardiac, occurred over a median follow-up of 240 days (range 30 to 760). Sixteen cardiac deaths occurred in the 63 patients with versus 1 cardiac death among the 147 without a new wall motion abnormality (p < or = 0.0001). Other variables associated with cardiac death (p < or = 0.05) were age > 65 years, nitrate therapy, ventricular ectopy during DSE, suspected angina pectoris, and hospitalization at the time of DSE. When cardiac death, myocardial infarction, and revascularization procedures were all considered as adverse outcomes, a new wall motion abnormality continued to be the most powerful predictor of an adverse cardiac event.(ABSTRACT TRUNCATED AT 250 WORDS)