Care for Adolescents With Polycystic Ovary Syndrome: Development and Prescribing Patterns of a Multidisciplinary Clinic.

STUDY OBJECTIVE: Based on updated guidelines and expressed patient needs, we created a multidisciplinary clinic including endocrinology, gynecology/adolescent medicine, dermatology, psychology, and nutrition to provide comprehensive care to adolescent girls with polycystic ovary syndrome (PCOS). We describe the patient population presenting to this clinic, and prescribing patterns when a multidisciplinary approach is used. DESIGN: Retrospective chart review. SETTING: Tertiary care hospital. PARTICIPANTS: Female patients, aged 11-24 years, presenting for initial assessment in a multidisciplinary PCOS clinic. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Medical history, physical examination findings, laboratory measurements and prescribed therapies. RESULTS: A total of 92 patients seen from 2014 to 2018 are described (age 15.9 years, range 11-24 years, body mass index 35.6 kg/m2, range 19.9-53.5). Metabolic syndrome features were common: 26% had a prediabetes hemoglobin A1c (>5.6%), 83% had a high-density lipoprotein (HDL) <50 mg/dL, 40% had a systolic blood pressure >120 mm Hg, and 43% had an alanine aminotransferase level of >30 U/L. Dermatologic findings included acne 93%, hirsutism 38%, acanthosis nigricans 85%, hidradenitis suppurativa 16%, and androgenic alopecia 2%. Of the patients, 33% had a diagnosis of depression or anxiety, 16% of patients had a diagnosis of obstructive sleep apnea, and an additional 59% had symptoms warranting a sleep study The most commonly prescribed medications were topical acne preparations (62%), followed by estrogen-containing hormonal therapy (56%) and metformin (40%). CONCLUSION: In adolescents with PCOS and obesity, metabolic, dermatologic, and psychologic co-morbidities are common. The use of a multidisciplinary clinic model including dermatology in addition to endocrinology, gynecology, psychology, and lifestyle experts provides care for most aspects of PCOS.

Slow mortality rate accelerations during aging in some animals approximate that of humans.

A general measure of the rate of senescence is the acceleration of mortality rate, represented here by the time required for the mortality rate to double (MRD). Rhesus monkeys have an MRD close to that of humans, about 8 years; their shorter life-span results mainly from higher mortality at all ages. In contrast, some groups with short life-spans (rodents and galliform birds) have shorter MRDs and faster senescence. On the basis of the Gompertz mortality rate model, one may estimate the MRD from the maximum life-span (tmax) and the overall population mortality rate. Such calculations show that certain birds have MRDs that are as long as that of humans. These results show that high overall mortality rates or small body sizes do not preclude slow rates of senescence.

The role of dietary carbohydrates in muscle glycogen resynthesis after strenuous running.

This study examined the effect of the type, amount, and the frequency of feeding of carbohydrates on muscle glycogen resynthesis after running. Trained male runners performed a 16.1 km run at 80% VO2 max to decrease gastrocnemius glycogen levels. A complex or simple carbohydrate diet (approximately 3000 kcal) resulted in similar muscle glycogen levels 24 h after exercise. Forty-eight hours after exercise the complex carbohydrate diet resulted in significantly higher (p less than 0.05) muscle glycogen levels. Consuming increasing amounts of carbohydrate, between 88 to 648 g carbohydrate/day, resulted in increasingly larger amounts of muscle glycogen resynthesis (24 h) after exercise. Frequent feedings of a high carbohydrate diet did not enhance muscle glycogen synthesis when compared to equal amounts of carbohydrates in two meals. It appears that muscle glycogen can be normalized between daily strenuous running activity.

A return to time, cells, systems, and aging: V. Further thoughts on Gompertzian survival dynamics--the geriatric years.

In this paper, I attempt to address the problem of how to model the survival curve in the later lifespan years; the geriatric years. I present a new general model for a three group population in which the first group represents early life failure (neonatal failure), the second group represents the classical "Gompertzian failure", and the third group represents the later life failure or geriatric failure. Theoretical results are compared to the known biological data. It is demonstrated that this three group model embeds, within itself, a greater variety of the known biological survival dynamics. In particular, this new model resolves some of these issues concerning the failure of the pure Gompertzian to model the later life (geriatric) survival distribution.

A return to time, cells, systems and aging: II. Relational and reliability theoretic approaches to the study of senescence in living systems.

In this paper, we approach the problem of attempting to understand senescence by understanding the complexity and hierarchical structure of mammalian organisms. To do this, we make use of some concepts from abstract relational biology; in particular, graph theory. We subsequently utilize these concepts to develop the idea of an irreplaceable element in a mammalian system. We then make use of these elements, and some concepts from reliability theory, to show how senescence processes in mammalian systems may be related to the failure of a critical number of irreplaceable elements. Finally, we show how we may derive formulas for the expected number of elements which fail by a given time, and how this time is related to actual lifespan and expected lifespan of the organism. In particular, we relate this to some recent work by Cutler on the evolution of longevity.

Some mathematics of recombination: evolution of complexity and genotypic modification in somatic cells - a possible model for aging and cancer effects.

A plausible discrete time model is proposed, in an effort to explain genotypic modificaton via genetic recombination. The model is used in an effort to explain the evolution of macromolecular complexity. By macromolecular complexity we mean the evolution of a more complex form of a given protein or enzyme from its less-complex ancestors. The model is also used to draw some conclusions concerning the utility of recombination events in aging and carcinogenesis.

Modeling cellular systems and aging processes: I. Mathematics of cell system models-a review.

A review of the literature on mathematical models of populations of cellular systems is presented. Continuous, discrete, and stochastic models are presented in a semihistorical manner as a prelude to answering the question of how to model an asynchronously dividing cellular system. This analysis is then broadened, in an attempt to broach the more general question of modeling the distribution of a set or collection of cell properties through an asynchronously dividing cellular system. Such properties might be cell motility, cell cycle length, time to mitosis, or number of epigenetic particles. It is shown that one fruitful approach to this modeling question is a coupled continuous-probabilistic model. The ramifications of this type of formalism are discussed.

Might stochasticity and sampling variation be a possible explanation for variation in clonal population survival curves.

Biogerontological survival analysis attempts to understand, through the use of mathematical and computer models, how biological and environmental processes affect the dynamics of survival. The survival model parameters are assumed to reflect an average or mean response to some intervention. Further, these parameters are usually assumed to be constant over the time course of the experiment and across the elements of the experimental cohort. In this paper, we introduce stochastic (random) features to the survival curve parameters and we observe how this might affect our interpretation of the biology; as reflected in the estimates of the model parameters. In particular, we provide a possible explanation for variation in parameter estimates within sample populations drawn from a population of genetic clones.

A return to time, cells, systems, and aging: III. Gompertzian models of biological aging and some possible roles for critical elements.

In this paper, I continue my investigation into the modeling of senescence in biological hierarchies. Making use of my previous discussion on non-reestablishable biological components, I derive a mathematical model which has Gompertzian-like dynamics. I show how this model may be approximated, in certain instances, by a Gompertzian equation. I then demonstrate how our approach yields a biological interpretation for the parameters in the Gompertzian equation. I then demonstrate how changes in the parameter values may be interpreted in light of the biology. Subsequently, I review the literature on the allometry of aging, and I demonstrate how my reliability model may be used to obtain--in a qualitative manner--some of the lifespan curves found in the literature. I close my discussion by constructing a more complex reliability model which incorporates the deterministic failure of biological components with stochastic aspects of senescence.

A return to time, cells, systems, and aging: IV. Further thoughts on Gompertzian survival dynamics--the neonatal years.

In this paper, I attempt to address the problem of how to model the survival curve in the early lifespan years; the neonatal years. I present a general model for a two group population in which the first group represents early stage failure and the second group represents the classical Gompertzian failure. After calculating the instantaneous failure rate for this population, I compare it to the single group Gompertzian with log-linear instantaneous failure rate. The theoretical results are then compared to the known biological data. It is demonstrated that this new model embeds, within itself, a variety of the known biological survival dynamics.

A gerontological distance metric for analysis of survival dynamics.

A metric for quantifying a gerontological mapping 'distance' or displacement consistent with the historical concept of velocity of aging and with the more recent concept of acceleration of aging, is introduced using the paradigm of a simple linear dynamics system of elementary physics. This analysis is extended to recent analytical methods utilizing intrinsic or internal time scaling so that biological or gerontological similarity can be distinguished from chronological age similarity, not only among various intraspecies populations but also among interspecies populations which may not even have the same underlying mechanisms of senescence or survival distributions. Illustrative examples are provided and discussed. Also, applications involving the comparison of an individual from one population to an individual from another population, when both can be assessed with respect to their respective group properties, are considered.

How square is the survival curve of a given species?

An investigator-independent parameter, the prolate rectangularity index kappa for describing the so-called rectangularity of biological population survival curves, is introduced, developed, and applied to realworld survival datasets. This new rectangularity parameter is constructed using an intrinsic time scaling that places the intrinsic inflection point time at a value of unity so that species populations may be compared independently of their extrinsic life span distributions. The analytical expressions for the prolate rectangularity index of the theoretical Gompertz and Weibull continuous models are obtained, as are numerical values of this index for discrete experimental population survival data sets from two dissimilar species with orders of magnitude difference in extrinsic life span range. The values of the parameter are also compared for populations of a single species having differing dietary regimens, and for human demographic populations at decade intervals in extrinsic chronological time during the current century. It is found that scaling time, using the survival inflection point, appreciably collapses extrinsic survival profile dispersion among similar populations and allows a more meaningful comparison of profiles among dissimilar populations. Using this method of scaling, demographic populations within the United States are seen to have rectangularity parameter values that have been slowly drifting during this century toward values indicating a higher degree of rectangularity. In recent decades, however, the trend appears to be stabilizing with kappa values indicating no approach towards the theoretical maximum rectangularity. This apparent submaximal stabilization of kappa supports a hypothesis of no genetically pre-determined maximum life span in human populations. Or, if such a maximum exists, we are not currently near it.

The waste-product theory of aging: simulation of metabolic waste production.

A mathematical model of cellular metabolism is used to relate the rates of cell division and waste production to the concentrations of oxygen and glucose in the medium in which a normal diploid cell culture is grown. The metabolic model in tandem with an earlier waste-content model based on the waste-product theory of aging provides a unified cell-culture model with which population size and intracellular waste content can be calculated. Population size is measured by the number of population doublings which have been achieved. After suitable adjustment of parameters in the metabolic model, maximum values of population size are calculated numerically with the use of the unified model. Results show that the population maxima are related in a plausible way to the oxygen and glucose concentrations. The effects of temperature changes and contact inhibition of growth are also simulated. Small changes in the cell-division and waste-production rates can cause transformation to unlimited growth in the waste-content model, but the unified model is not correspondingly sensitive to changes in the oxygen and glucose concentrations or to changes in temperature.

The waste-product theory of aging: transformation to unlimited growth in cell cultures.

A differential equation governing intracellular waste content is solved numerically to determine the circumstances under which the growth of an in vitro cell population is limited. Parameter values derived from data on human glial cell cultures are employed. It is assumed that a) waste accumulation depresses the rate of cellular reproduction and b) intracellular waste is diluted by cell division, but is not otherwise eliminated. Population size depends upon two parameters: the rate of waste production and the rate of cell division in the absence of waste. If the rate of waste production is sufficient, the population size approaches an asymptote as in phase III growth in vitro. If a lower rate of waste production allows the cells to outmultiply the waste, growth is unlimited as in a transformed cell population. The asymptotic population size and the threshold for unlimited growth are remarkably sensitive to small changes in the values of the two rate parameters unless the ratio of their values is constant. This suggests that there may be a cellular mechanism that relates the waste production and cell division rates.

Survival estimates and sample size: what can we conclude?

Attempts to understand aging processes often involve life-span measurements from which a survival curve is constructed and model parameters estimated. The parameter estimates are then compared, and conclusions concerning the underlying biological processes are subsequently deduced, based upon the magnitude of the parameter differences. In this article we discuss the role of sample size and sample fluctuation on the parameter estimates and the profound effect that these factors may play in our arrival at meaningful biological conclusions. We then extend this discussion to examine one methodology that can help select sample sizes for specific parametric survival models.

Estimating parametric survival model parameters in gerontological aging studies: methodological problems and insights.

Studies of the biology of aging (both experimental and evolutionary) frequently involve the estimation of parameters arising in various multi-parameter survival models such as the Gompertz or Weibull distribution. Standard parameter estimation methodologies, such as maximum likelihood estimation (MLE) or nonlinear regression (NLR), require knowledge of the actual life spans or their explicit algebraic equivalents in order to provide reliable parameter estimates. Many fundamental biological discussions and conclusions are highly dependent upon accurate estimates of these survival parameters (this has historically been the case in the study of genetic and environmental effects on longevity and the evolutionary biology of aging). In this article, we examine some of the issues arising in the estimation of gerontologic survival model parameters. We not only address issues of accuracy when the original life-span data are unknown, we consider the accuracy of the estimates even when the exact life spans are known. We examine these issues as applied to known experimental data on diet restriction and we fit the frequently used, two-parameter Gompertzian survival distribution to these experimental data. Consequences of methodological misuse are demonstrated and subsequently related to the values of the final parameter estimates and their associated errors. These results generalize to other multiparametric distributions such as the Weibull, Makeham, and logistic survival distributions.

Smoke aldehyde component influences pulmonary edema.

The pulmonary edema of smoke inhalation is caused by the toxins of smoke and not the heat. We investigated the potential of smoke consisting of carbon in combination with either acrolein or formaldehyde (both common components of smoke) to cause pulmonary edema in anesthetized sheep. Seven animals received acrolein smoke, seven animals received a low-dose formaldehyde smoke, and five animals received a high-dose formaldehyde smoke. Pulmonary arterial pressure, pulmonary capillary wedge pressure, and cardiac output were not affected by smoke in any group. Peak airway pressure increased after acrolein (14 +/- 1 to 21 +/- 2 mmHg; P less than 0.05) and after low- and high-dose formaldehyde (14 +/- 1 to 21 +/- 1 and 20 +/- 1 mmHg, respectively; both P less than 0.05). The partial pressure of O2 in arterial blood fell sharply after acrolein [219 +/- 29 to 86 +/- 9 (SE) Torr; P less than 0.05] but not after formaldehyde. Only acrolein resulted in a rise in lung lymph flow (6.5 +/- 2.2 to 17.9 +/- 2.6 ml/h; P less than 0.05). Lung lymph-to-plasma protein ratio was unchanged for all three groups, but clearance of lymph protein was increased after acrolein. After acrolein, the blood-free extravascular lung water-to-lung dry weight ratio was elevated (P less than 0.05) compared with both low- and high-dose formaldehyde groups (4.8 +/- 0.4 to 3.3 +/- 0.2 and 3.6 +/- 0.2, respectively). Lymph clearance (ng/h) of thromboxane B2, leukotriene B4, and the sulfidopeptide leukotrienes was elevated after acrolein but not formaldehyde.(ABSTRACT TRUNCATED AT 250 WORDS)

Cyclooxygenase and lipoxygenase inhibition by BW-755C reduces acrolein smoke-induced acute lung injury.

Inhalation of smoke containing acrolein, the most common toxin in urban fires after carbon monoxide, causes vascular injury with non-cardiogenic pulmonary edema containing potentially edematogenic eicosanoids such as thromboxane (Tx) B2, leukotriene (LT) B4, and the sulfidopeptide LTs (LTC4, LTD4, and LTE4). To determine which eicosanoids are important in the acute lung injury, we pretreated sheep with BW-755C (a combined cyclooxygenase and lipoxygenase inhibitor), U-63557A (a specific Tx synthetase inhibitor), or indomethacin (a cyclooxygenase inhibitor) before a 10-min exposure to a synthetic smoke containing carbon particles (4 microns) with acrolein and compared the results with those from control sheep that received only carbon smoke. Acrolein smoke induced a fall in arterial PO2 and rises in peak inspiratory pressure, main pulmonary arterial pressure, pulmonary vascular resistance, lung lymph flow, and the blood-free wet-to-dry weight ratio. BW-755C delayed the rise in peak inspiratory pressure and prevented the fall in arterial PO2, the rise in lymph flow, and the rise in wet-to-dry weight ratio. Neither indomethacin nor U-63557A prevented the increase in lymph flow or wet-to-dry weight ratio, although they did blunt and delay the rise in airway pressure and did prevent the rises in pulmonary arterial pressure and pulmonary vascular resistance. Thus, cyclooxygenase products, probably Tx, are responsible for the pulmonary hypertension after acrolein smoke and to some extent for the increased airway resistance but not the pulmonary edema. Prevention of high-permeability pulmonary edema after smoke with BW-755C suggests that LTB4, may be etiologic, as previous work has eliminated LTC4, LTD4, and LTE4.

Changes in lung mechanics and reactivity with age after viral bronchiolitis in beagle puppies.

We measured changes with growth in lung function and airway reactivity after acute canine parainfluenza virus type 2 (CPI2, n = 5), canine adenovirus type 2 (CAV2, n = 7), and sequential CAV2-CPI2 (n = 6) infections or no infection (controls, n = 6) in beagle puppies (age approximately 79 days). In the CPI2 and CAV2 groups, a lower respiratory illness developed by day 3 postinfection with clinical recovery by day 14. In the CAV2-CPI2 group, puppies were inoculated initially with CAV2 and 12 days later with CPI2. In this group, illness persisted until day 14 after infection with CPI2. Lung resistance (RL), dynamic (Cdyn) and static (Cst) lung compliance, functional residual capacity (FRC), and responsiveness to aerosolized histamine were measured before infection and at periodic intervals until 239 +/- 43 days of age. Lung function data were analyzed using a longitudinal random effects model. In all groups, FRC, Cst, and Cdyn increased with age. In all infected groups, the regression slopes for Cdyn were steeper than in controls. RL decreased linearly with age without group slope differences. Histamine reactivity increased with age, but there were no differences in slope among groups. Lung pathological studies showed areas of obliterative bronchiolitis and chronic small airways inflammation particularly in the CAV2 and CAV2-CPI2 groups. Thus, viral bronchiolitis produces chronic small airways inflammation in beagle puppies and alters the changes in lung function occurring with growth. Histamine reactivity increases with age and is not modified by viral infection.

Differential effects of intracerebroventricular glucagon-like peptide-1 on feeding and energy expenditure regulation.

Intracerebroventricular (i.c.v.) administration of glucagon-like peptide-1-(7-37) amide (GLP-1) has been shown to modulate food and water intake. The present studies further characterize the effects of i.c.v. GLP-1 in the regulation of energy balance in lean and obese animals. In both obese and lean Zucker rats, a single i.c.v. infusion of GLP-1 (1-30 microg) resulted in a dose-dependent reduction of food intake and decrease in respiratory quotient relative to the saline control during the first 2 h of the nocturnal cycle. In obese Zucker rats, the food intake was reduced by 73 +/- 11% of the control at the 30 microg dose, whereas a modest 45 +/- 18% reduction was observed in lean rats. Despite the large reduction in food intake seen with GLP-1, there was no compensatory decrease in nocturnal oxygen consumption in the obese Zucker rats. Interestingly, low doses of GLP-1 (1 microg) in lean Zucker rats, which had minimal effects on food intake, caused a 19 +/- 7% increase in O2 consumption during the first 2 h of the nocturnal cycle. These data suggest that central GLP-1 may be an important factor controlling negative energy balance in both the lean and obese Zucker rats.