Prospective association between maternal allostatic load during pregnancy and child mitochondrial content and bioenergetic capacity.

BACKGROUND: Mitochondria are multifunctional energy-producing and signaling organelles that support life and contribute to stress adaptation. There is a growing understanding of the dynamic relationship between stress exposure and mitochondrial biology; however, the influence of stress on key domains of mitochondrial biology during early-life, particularly the earliest phases of intra-uterine/prenatal period remains largely unknown. Thus, the goal of this study was to examine the impact of fetal exposure to stress (modeled as the biological construct allostatic load) upon mitochondrial biology in early childhood. METHODS: In n = 30 children (range: 3.5-6 years, 53% male), we quantified mitochondrial content via citrate synthase (CS) activity and mtDNA copy number (mtDNAcn), and measured mitochondrial bioenergetic capacity via respiratory chain enzyme activities (complexes I (CI), II (CII), and IV (CIV)) in platelet-depleted peripheral blood mononuclear cells (PBMCs). In a cohort of healthy pregnant women, maternal allostatic load was operationalized as a latent variable (sum of z-scores) representing an aggregation of early-, mid- and late-gestation measures of neuroendocrine (cortisol), immune (interleukin-6, C-reactive protein), metabolic (homeostasis model assessment of insulin resistance, free fatty acids), and cardiovascular (aggregate systolic and diastolic blood pressure) systems, as well as an anthropometric indicator (pre-pregnancy body mass index [BMI]). RESULTS: An interquartile increase in maternal allostatic load during pregnancy was associated with higher mitochondrial content (24% and 15% higher CS and mtDNAcn), and a higher mitochondrial bioenergetic capacity (16%, 23%, and 25% higher CI, CII and CIV enzymatic activities) in child leukocytes. The positive association between maternal allostatic load during pregnancy and child mitochondrial content and bioenergetic capacity remained significant after accounting for the effects of key pre- and post-natal maternal and child covariates (p's < 0.05, except CI p = 0.073). CONCLUSION: We report evidence that prenatal biological stress exposure, modeled as allostatic load, was associated with elevated child mitochondrial content and bioenergetic capacity in early childhood. This higher mitochondrial content and bioenergetic capacity (per leukocyte) may reflect increased energetic demands at the immune or organism level, and thus contribute to wear-and-tear and pathophysiology, and/or programmed pro-inflammatory phenotypes. These findings provide potential mechanistic insight into the cellular processes underlying developmental programming, and support the potential role that changes in mitochondrial content and bioenergetic functional capacity may play in altering life-long susceptibility for health and disease.

Mitochondrial lipid oxidation is impaired in cultured myotubes from obese humans.

OBJECTIVE: The skeletal muscle of obese humans is characterized by an inability to appropriately respond to alterations in substrate availability. The purpose of this study was to determine if this metabolic inflexibility with obesity is retained in mitochondria of human skeletal muscle cells raised in culture (HSkMC) and to identify potential mechanisms involved. DESIGN: Mitochondrial respiration was measured in permeabilized myotubes cultured from lean and obese individuals before and after a 24-h lipid incubation. RESULTS: Mitochondrial respiration (state 3) in the presence of lipid substrate (palmitoyl carnitine) increased by almost twofold after lipid incubation in HSkMC from lean, but not obese subjects, indicative of metabolic inflexibility with obesity. The 24-h lipid incubation increased mitochondrial DNA (mtDNA) copy number in HSkMC from lean subjects by +16% (P<0.05); conversely, mtDNA copy number decreased in myotubes cultured from obese individuals (-13%, P=0.06). When respiration data were normalized to mtDNA copy number and other indices of mitochondrial content (COX-IV protein content and CS activity), the significant treatment effects of lipid incubation persisted in the lean subjects, suggesting concomitant alterations in mitochondrial function; no similar adjustment was evident in HSkMC from obese individuals. CONCLUSION: These data indicate that the skeletal muscle of obese individuals inherently lacks metabolic flexibility in response to lipid exposure, which consists of an inability to increase mitochondrial respiration in the presence of lipid substrate and perhaps by an inability to induce mitochondrial proliferation.

A high-fat diet elicits differential responses in genes coordinating oxidative metabolism in skeletal muscle of lean and obese individuals.

CONTEXT: In lean individuals, increasing dietary lipid can elicit an increase in whole body lipid oxidation; however, with obesity the capacity to respond to changes in substrate availability appears to be compromised. OBJECTIVE: To determine whether the responses of genes regulating lipid oxidation in skeletal muscle differed between lean and insulin resistant obese humans upon exposure to a high-fat diet (HFD). DESIGN AND SETTING: A 5-d prospective study conducted in the research unit of an academic center. PARTICIPANTS: Healthy, lean (n = 12; body mass index = 22.1 ± 0.6 kg/m(2)), and obese (n=10; body mass index = 39.6 ± 1.7 kg/m(2)) males and females, between ages 18 and 30. INTERVENTION: Participants were studied before and after a 5-d HFD (65% fat). MAIN OUTCOME MEASURES: Skeletal muscle biopsies (vastus lateralis) were obtained in the fasted and fed states before and after the HFD and mRNA content for genes involved with lipid oxidation determined. Skeletal muscle acylcarnitine content was determined in the fed states before and after the HFD. RESULTS: Peroxisome proliferator activated receptor (PPAR) α mRNA content increased in lean, but not obese, subjects after a single high-fat meal. From Pre- to Post-HFD, mRNA content exhibited a body size × HFD interaction, where the lean individuals increased while the obese individuals decreased mRNA content for pyruvate dehydrogenase kinase 4, uncoupling protein 3, PPARα, and PPARγ coactivator-1α (P ≤ 0.05). In the obese subjects medium-chain acylcarnitine species tended to accumulate, whereas no change or a reduction was evident in the lean individuals. CONCLUSIONS: These findings indicate a differential response to a lipid stimulus in the skeletal muscle of lean and insulin resistant obese humans.

Laparoscopic ablation of symptomatic parenchymal and peripelvic renal cysts.

OBJECTIVES: To assess the safety and efficacy of laparoscopic ablation of symptomatic renal cysts as minimally invasive therapeutic techniques have largely supplanted open surgical intervention for the treatment of symptomatic renal cysts. METHODS: The records of 32 consecutive adult patients who underwent laparoscopic ablation of renal cysts (11 peripelvic, 21 parenchymal) were retrospectively reviewed. All patients were symptomatic at presentation; 26 had a single cyst, 5 had two cysts, and 1 had four cysts. RESULTS: Twenty patients underwent a transperitoneal laparoscopic approach, and 12 patients underwent a retroperitoneal laparoscopic approach. An average of 3.2 ports were used for each procedure, and no open conversions or transfusions were necessary. When comparing patients with parenchymal and peripelvic cysts, statistically significant differences were noted in the mean operative time (164 versus 233 minutes, respectively; P = 0.003) and mean operative blood loss (98 versus 182 mL, respectively; P = 0.04). Four patients (13%) had complications (one major and three minor), including a persistent ureteral stricture. One patient with negative preoperative aspiration cytology and negative intraoperative frozen section analysis was later found to have malignancy within the cyst wall, necessitating radical nephrectomy and trocar site excision. One patient (3%) developed a recurrence. CONCLUSIONS: Laparoscopic ablation of symptomatic renal cysts is a safe and efficacious procedure. We report an overall complication rate of 13% and a recurrence rate of 3% with a mean follow-up of 18.1 months (median 10.0).

Laparoscopic management of urachal cysts in adulthood.

PURPOSE: Managing persistent and symptomatic urachal anomalies requires wide surgical excision. Such intervention is recommended to prevent symptom recurrence and complications, most notably malignant degeneration. However, traditional open excision is associated with significant morbidity and prolonged convalescence. We report our experience with the laparoscopic excision of urachal remnants as a less morbid, minimally invasive surgical alternative. MATERIALS AND METHODS: Between October 1993 and December 1999, 4 patients with a mean age of 43.3 years who had a symptomatic urachal cyst underwent laparoscopic radical excision of the urachal remnant. Using 2, 10 mm. and 1 or 2, 5 mm. ports the urachus and medial umbilical ligaments were divided at the umbilicus cephalad to the cyst. The specimen, which included the urachus, cyst and medial umbilical ligaments, was then separated from the bladder dome with or without the bladder cuff and removed intact. We reviewed the perioperative records to assess morbidity, recovery and outcome. RESULTS: All 4 procedures were completed successfully. No intraoperative or postoperative complications were reported at a mean followup of 15 months (range 2 to 24). Mean operative time was 180 minutes (range 150 to 210) and average hospital stay was 2.75 days (range 1 to 4). Pathological evaluation confirmed a benign urachal remnant in each case. All patients resumed normal activity within 2 weeks. CONCLUSIONS: To minimize the morbidity of radical excision the laparoscopic management of benign urachal remnants in adulthood is efficacious and our preferred method of management.

Parental attitudes regarding interviews about injuries to their children.

BACKGROUND: Questions about the circumstances of injuries, especially to infants and young children, might be perceived by parents as threatening or intrusive. Some institutional research review committees express concerns that interviews about childhood injuries may be offensive to parents. The perceived value and potential risk of questions about a young child's injury could affect the quality of responses. OBJECTIVES: To assess parents' perceptions of threat and value of interviews about injury to their young children. SETTING: District of Columbia, 1 October 1995 to 30 September 1996. METHODS: Trained research assistants telephoned the parents of children seen in an emergency department or admitted to the hospital after an injury. To be eligible for inclusion the child must have been <3 years of age and a resident of the District of Columbia at the time of the event. After collection of sociodemographic information and circumstances of injury, the respondents were asked if the interview caused them to feel angry, offended or threatened, and if participation in the study was considered worthwhile. RESULTS: Seventy eight per cent of eligible families were contacted. Among those contacted, 93% completed the interview. Eighty two per cent of respondents were mothers and 11% fathers. Ninety per cent (95% confidence interval (CI) 88.4 to 91.6) of the respondents reported that the interview did not make them feel angry, offended, or threatened. Only 13 (1%; 95% CI 0.5 to 1.5) reported being very angry and 7.1% (95% CI 5.8 to 8.5) reported being a little angry. The majority of participants (61.2%, 95% CI 58.6 to 63.8) felt that participation in the study was definitely worthwhile and only 5.5% (95% CI 4.3 to 6.7) felt that it was not at all worthwhile. Parents of children with intentional injuries were more likely to report feelings of anger than parents of children with unintentional injuries (24% v 8%; p=0.02). The per cent of respondents reporting any anger was greater when the interview was conducted within 14 days of the hospital visit compared with later interviews (11% v 7%; p=0.02). CONCLUSIONS: In similar populations most parents of young, injured children are neither upset nor threatened by interviews that probe for details about how their children become injured. In general, collecting data aimed to prevent injuries is perceived as worthwhile, and parents readily cooperate with providing this information. Investigators and review committees should consider that interviews about infant and young child injuries are of no or minimal risk.

Kinetics and mechanism of exchange of apolipoprotein C-III molecules from very low density lipoprotein particles.

Transfer of apolipoprotein (apo) molecules between lipoprotein particles is an important factor in modulating the metabolism of the particles. Although the phenomenon is well established, the kinetics and molecular mechanism of passive apo exchange/transfer have not been defined in detail. In this study, the kinetic parameters governing the movement of radiolabeled apoC molecules from human very low density lipoprotein (VLDL) to high density lipoprotein (HDL3) particles were measured using a manganese phosphate precipitation assay to rapidly separate the two types of lipoprotein particles. In the case of VLDL labeled with human [14C]apoCIII1, a large fraction of the apoCIII1 transfers to HDL3 within 1 minute of mixing the two lipoproteins at either 4 degrees or 37 degrees C. As the diameter of the VLDL donor particles is decreased from 42-59 to 23-25 nm, the size of this rapidly transferring apoCIII1 pool increases from about 50% to 85%. There is also a pool of apoCIII1 existing on the donor VLDL particles that transfers more slowly. This slow transfer follows a monoexponential rate equation; for 35-40 nm donor VLDL particles the pool size is approximately 20% and the t1/2 is approximately 3 h. The flux of apoCIII molecules between VLDL and HDL3 is bidirectional and all of the apoCIII seems to be available for exchange so that equilibrium is attained. It is likely that the two kinetic pools of apoCIII are related to conformational variations of individual apo molecules on the surface of VLDL particles. The rate of slow transfer of apoCIII1 from donor VLDL (35-40 nm) to acceptor HDL3 is unaffected by an increase in the acceptor to donor ratio, indicating that the transfer is not dependent on collisions between donor and acceptor particles. Consistent with this, apoCIII1 molecules can transfer from donor VLDL to acceptor HDL3 particles across a 50 kDa molecular mass cutoff semipermeable membrane separating the lipoprotein particles. These results indicate that apoC molecules transfer between VLDL and HDL3 particles by an aqueous diffusion mechanism.

New visualization techniques for in utero surgery: amnioscopy with a three-dimensional head-mounted display and a computer-controlled endoscope.

Endoscopic fetal surgery may reduce preterm labor associated with open hysterotomy but is partially limited by current visualization technology. We investigated a three-dimensional (3D) imaging system coupled to a head-mounted display (3D-HMD) and also employed a computer-controlled zoom endoscope for noninsufflated amnioscopy. Pregnant sheep were prepared in aseptic fashion for general anesthesia. Uterine access was obtained following maternal laparoscopy. A 10-mm zoom endoscope (Vista Medical Technologies, Carlsbad, CA) was used to examine the fetus and uterine contents. Fetal limbs were exteriorized for microsurgery. A new system (Vista Medical Technologies) was attached to an operative microscope, permitting projection of a 3D image via an HMD. The fetus and umbilical cord were inspected using the zoom endoscope, which changes the depth of focus under computer control. Basic manipulations of the fetus and cord were easily completed. Real-time 3D fetal imaging was accomplished. The added depth perception enabled detailed fetal and placental examination, fostering manipulation of the fetus and cord. The HMD was adjusted to fit several surgeons, permitting a natural operative posture. This unit has the capacity to display any video, CT, MR, or ultrasound image as a picture-in-picture. The success of minimally invasive fetal surgery is in part dependent on the development of video technologies capable of providing both magnification and optimal resolution. The zoom endoscope affords excellent visibility of multiple surgical targets without instrument repositioning. A 3D HMD system such as this provides greater anatomic detail and an appreciation of fetal movements that may make intrauterine procedures more feasible.

Endoscopic subcutaneous neurovascular lower-extremity myofascial flap harvesting for genitourinary reconstruction.

Neurovascular myofascial flaps have been widely utilized when healthy tissues outside the anatomic confines of the pelvis are necessary for complex genitourinary reconstructions. Myofascial flaps have great potential in providing support and tone to the bladder neck in a model of total urinary incontinence. Two muscles were evaluated for minimally invasive harvesting utilizing an adult rabbit and human cadaveric model: the gracilis, because of its neurovascular supply and length, and the sartorius, because of its location. Three adult New Zealand White rabbits were prepared and draped in sterile fashion after general anesthesia. Bilateral 2-cm incisions were made over the origins of the gracilis and sartorius muscles. Dissection times were entered in a database on a personal computer for paired Student t-tests. Special techniques for dissection included utilization of a 5-mm subcutaneous dissector/retractor and reticulated scissors and dissector. Once the tissues were harvested, rotational angles of the functional arcs around the origins of the gracilis and sartorius flaps were measured, as were the lengths of the muscular flaps from the proximal pedicle to the free distal end. Initial positioning of the myofascial flap at the bladder neck was investigated in this nonsurvival study. Blood loss was estimated before the animals were humanely sacrificed. The possibilities of minimally invasive genitourinary reconstruction are numerous. Both flaps can be dissected endoscopically and have rotational angles allowing transfer to more cephalad positions in the groin or intra-abdominally. Further studies are needed to establish the efficacy of the myofascial graft for minimally invasive genitourinary reconstructions.

Initial studies of holmium:YAG laser creation of spinal defects in fetal rabbits: model for urologic effects of myelomeningocele.

Myelomeningocele (MMC) is characterized by paraplegia and incontinence, often necessitating surgery. Current models of MMC in sheep and primates create a spinal defect long after anomalous neural tube closure ordinarily occurs. An ideal model of MMC would allow creation of the defect at the earliest age in a low-cost species with a short gestation. We present a method utilizing the holmium laser to create spinal defects in rabbits in utero for the study of the pathophysiology and repair of MMC. Pregnant rabbits of 22 to 23 days' gestational age were prepared and draped in sterile fashion for laparotomy under general anesthesia. The abdomen was opened, and both uterine horns were inspected. Double opposing pursestring sutures were placed to secure the chorioamniotic membranes over the fetal lumbar spine. Amniotic fluid was removed with a needle and saved. Electrocautery was used to open the uterus within the pursestring suture, exposing the fetal dorsum. The spine was exposed by laser dissection of the fetal dorsal musculature. Posterior laminectomy was accomplished with laser incisions of each side of the spinous process, leaving the underlying dura and cord exposed. The pursestring was then cinched, amniotic fluid was returned, and the uterus and trocar sites were closed. Cesarian section was performed at 30 to 31 gestational days, and the pups were examined and then humanely sacrificed for histologic evaluation of the lesion. The rabbit is an inexpensive species with a short gestation (33-35 days), and four or more fetuses may be operated on per litter, with the remainder serving as controls. Utilization of minimally invasive techniques including holmium:YAG laser dissection facilitates creation of spinal defects at an early age in this small-animal model.

Disposition of metabolically labeled recombinant soluble CD4 (sT4) in male Sprague-Dawley rats following intravenous and subcutaneous administration.

Soluble CD4 (sT4) has been metabolically labeled with [3H]leucine in Chinese hamster ovary cells and purified by S Sepharose chromatography. Over 250 microCi of high specific radioactivity [3H]sT4 (42 Ci/mmol) was prepared. The radiolabeled molecule was chemically and biologically representative of the unlabeled molecule and thus appropriate for in vivo metabolic investigations. To explore the biotransformation and disposition of a recombinant protein, this uniformly labeled [3H]sT4 was administered intravenously and subcutaneously to male Sprague-Dawley rats. Following a single dose of 0.3 mg/kg, blood samples were collected for 9 days and analyzed for total radioactivity, total plasma radioactivity, trichloroacetic acid-precipitable plasma radioactivity, sT4-related plasma radioactivity (by extraction with a Sepharose-bound polyclonal anti-sT4 antibody), and plasma sT4 concentration (by an N and C terminal-specific Leu3A/OKT4 ELISA). Excreta were analyzed for total radioactivity. The pharmacokinetic profiles of intact sT4 were as expected from the results of previous studies. sT4 was cleared rapidly from plasma with an elimination t1/2 of 7 min (intravenous), and low sT4 levels were observed following subcutaneous administration. Comparison of the kinetic profiles of total radiolabel, trichloroacetic acid-precipitable radiolabel, sT4-related radiolabel, and the isolation of plasma proteins containing tritium have led to the following conclusions. One of the major metabolic pathways for [3H]sT4 was the degradation of the polypeptide to its constituent amino acids, which were subsequently incorporated into endogenous proteins. Incorporation of tritium into blood cell proteins resulted in a prolonged radiolabel blood profile (t1/2 greater than 250 hr). Following subcutaneous administration, [3H] sT4 was significantly degraded before reaching the vascular circulation.

A dose-response analysis of skin cancer from inorganic arsenic in drinking water.

A study of the prevalence of skin cancer among 40,421 persons consuming arsenic-contaminated drinking water in Taiwan was used for a cancer dose-response assessment of ingested arsenic. The numbers of persons at risk over three dose intervals and four exposure durations were estimated from the data in order to apply the method of maximum likelihood to a multistage-Weibull time/dose-response model. A constant exposure level since birth for each of the exposure categories was assumed. It was found that the cumulative hazard increases as a power of three in age, and is linear or quadratic (with a linear coefficient) in dose. Observations from a smaller epidemiologic survey in Mexico were similar to what would be predicted from the model of the Taiwan data. Assuming that the skin cancer risk from ingested arsenic in the American population would also be similar to the Taiwan population, an American male would have a lifetime risk of developing skin cancer of 1.3 x 10(-3) (3.0 x 10(-3] if exposed to 1 microgram/kg/day for a 76-year lifespan (median lifespan in the U.S.).

Cervical intraepithelial neoplasia among women with papillomavirus infection compared to women with Trichomonas infection.

This study was undertaken to determine if women with papillomavirus infection were more likely to develop cervical intraepithelial neoplasia (CIN) than women with other sexually transmitted infections. Women with cytologic evidence of papillomavirus infection and a comparison group of women with cytologic evidence of Trichomonas infection were identified from a reexamination of cervicovaginal smears initially evaluated between 1973 and 1981 in a private pathology laboratory. To identify subsequent CIN among these women the authors reviewed records of private obstetric and gynecology practices and public clinics through 1983. After accounting for possible confounding variables, including age, marital status, frequency of cervical cytologic examination, and selected characteristics of pregnancy history, a 2.7-fold increase in the rate of CIN was found among the 613 women with prior papillomavirus infection compared to the 410 women with previous Trichomomas infection. The rate ratio was higher among women with more severe cervical neoplasia than for those with less severe neoplasia and for those followed for greater than 12 months than for those followed 7 to 12 months. The results of this study provide further evidence of the role of papillomavirus in the etiology of cervical cancer.

Dose-dependent pharmacokinetics of recombinant tissue-type plasminogen activator in anesthetized dogs following intravenous infusion.

The pharmacokinetics of SK&F recombinant two-chain tissue-type plasminogen activator (tPA) following intravenous (iv) infusion were characterized in anesthetized, open chested mongrel dogs in which artificial intracoronary thrombi were formed. SK&F tPA was infused at rates of 0.5, 1, 2, 4, and 8 micrograms/kg/min (N = 3 to 5 per dose) for 90 min, and arterial blood samples were withdrawn during and after infusion for determination of functionally active tPA concentrations using a modified and validated S-2251 chromogenic assay. At all doses studied, steady state active tPA plasma concentrations were achieved 10-20 min after the onset of infusion. Upon cessation of infusion, active tPA plasma concentrations declined rapidly with a t1/2 of 2-3 min. The active tPA plasma concentration at steady state (Css) and the area under the tPA plasma concentration-time curve (AUC) increased linearly with the dose in the range of 0.5-4 micrograms/kg/min. However, as the dose was increased 2-fold from 4 to 8 micrograms/kg/min, the AUC and the Css increased 2.5-fold. The systemic clearance ranged from 15-16 ml/min/kg at doses of 0.5-4 micrograms/kg/min, but decreased to 11.7 ml/min/kg at the 8 micrograms/kg/min dose. With exceptions in three dogs, the volume of distribution at steady state approached or slightly exceeded the blood volume. Plasma tPA antigen concentrations were also determined in the dogs receiving the 2 micrograms/kg/min dose. At steady state, active tPA accounted for 40-60% of the total tPA antigen. The postinfusion t1/2 of the tPA antigen was considerably longer (13.46 +/- 5.94 min) than that of active tPA.(ABSTRACT TRUNCATED AT 250 WORDS)

Populations and methods for assessing dyslipoproteinemia and its correlates. The Lipid Research Clinics Program Prevalence Study.

This article presents the basic methods and populations of the Lipid Research Clinics (LRC) Program Prevalence Study. The purpose is to provide a frame of reference for the other articles in this monograph; hence, the populations and major data collected are described briefly, as are procedures for enhancement of data quality and approaches to statistical analysis. More detailed descriptions for some procedures are included in the pertinent articles. The two sequential screening examinations of the Prevalence Study provided 60,502 participants from centers in the United States and Canada for the first phase and 13,852 for the second. The monograph is based on data from 11,657 white and 644 black participants aged 6 years or older screened at both visits.

Dyslipoproteinemias and manifestations of coronary heart disease. The Lipid Research Clinics Program Prevalence Study.

The Lipid Research Clinics Prevalence Study population underwent a noninvasive evaluation to assess the odds of coronary heart disease (CHD) among individuals with various types of dyslipoproteinemia (DLP) relative to the odds for individuals free of DLP in a nonselected population. The noninvasive evaluation included the Rose questionnaire for angina, a resting electrocardiogram, and a graded treadmill exercise test. The presence of manifestations of CHD was assessed by a combination of these findings. Multiple linear regression and multiple logistic regression analyses were used to evaluate associations between CHD and DLP, with adjustments for the following covariates: age, body mass, systolic blood pressure, alcohol consumption, and cigarette use. There were no consistent associations in women or in men 30 to 49 years old. In men 50 to 69 years old, the mean high-density lipoprotein cholesterol (HDL-C) values and HDL-C/cholesterol ratio were significantly lower in the definite CHD and angina categories, compared with the negative (no evidence of CHD) group. Higher odds ratios for CHD were present in those classified as having type IIa, type IV, and hypoHDL DLPs, relative to those classified as normal by the phenotyping algorithm. These associations were consistent across the several categories of CHD manifestations, but did not reach statistical significance after adjustment for multiple testing. A statistically significant lower odds ratio for CHD was observed in men 50 to 69 classified as having hyperHDL when compared with those without DLPs. The associations between CHD and the various forms of DLP were consistent with those observed between CHD and the plasma lipid and lipoprotein-cholesterol concentrations. The Lipid Research Clinics Prevalence Study confirmed the relationship between elevated low-density lipoprotein cholesterol, decreased HDL-C, and noninvasively determined CHD in a free-living asymptomatic population of older men.

Survival models for fertility evaluation.

"Two proportional hazards models for cohort fertility evaluation are constructed. Time-dependent covariates describe sources of heterogeneity between and within women regarding fertility characteristics. In the first model, U.S. birth rates specific to maternal age, race, parity, and birth cohort are used as underlying hazard rates. Covariate effects are estimated by maximizing the full likelihood. In the second model, covariate effects are estimated via Cox regression with stratified underlying hazard rates regarded as unknown nuisance parameters." The authors illustrate the models "with an evaluation of the fertility histories of the wives of workers at a manufacturing plant with potential for hazardous exposure. Adjustments to the U.S. birth rates for maternal age and parity zero experience are required with the first approach. Then, despite differences in the model-specific estimation procedures, the point estimates of the exposure effect and the estimated standard errors from the two models are practically equivalent."