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PubMed2000

Cell mechanics: mechanical response, cell adhesion, and molecular deformation.

As the basic unit of life, the cell is a biologically complex system, the understanding of which requires a combination of various approaches including biomechanics. With recent progress in cell and molecular biology, the field of cell mechanics has grown rapidly over the last few years. This review synthesizes some of these recent developments to foster new concepts and approaches, and it emphasizes molecular-level understanding. The focuses are on the common themes and interconnections in three related areas: (a) the responses of cells to mechanical forces, (b) the mechanics and kinetics of cell adhesion, and (c) the deformation of biomolecules. Specific examples are also given to illustrate the quantitative modeling used in analyzing biological processes and physiological functions.

Animals↗
PubMed2006

Analysis of inflammation.

In the past, inflammation has been associated with infections and with the immune system. But more recent evidence suggests that a much broader range of diseases have telltale markers for inflammation. Inflammation is the basic mechanism available for repair of tissue after an injury and consists of a cascade of cellular and microvascular reactions that serve to remove damaged and generate new tissue. The cascade includes elevated permeability in microvessels, attachment of circulating cells to the vessels in the vicinity of the injury site, migration of several cell types, cell apoptosis, and growth of new tissue and blood vessels. This review provides a summary of the major microvascular, cellular, and molecular mechanisms that regulate elements of the inflammatory cascade. The analysis is largely focused on the identification of the major participants, notably signaling and adhesion molecules, and their mode of action in the inflammatory cascade. We present a new hypothesis for the generation of inflammatory mediators in plasma that are derived from the digestive pancreatic enzymes responsible for digestion. The inflammatory cascade offers a large number of opportunities for development of quantitative models that describe various aspects of human diseases.

Animals↗
PubMed2004

Technology assessment for radiologists.

Health technology assessment is the systematic and quantitative evaluation of the safety, efficacy, and cost of health care interventions. This article outlines aspects of technology assessment of diagnostic imaging. First, it presents a conceptual framework of a hierarchy of levels of efficacy that should guide thinking about imaging test evaluation. In particular, the framework shows how the question answered by most evaluations of imaging tests, "How well does this test distinguish disease from the nondiseased state?" relates to the fundamental questions for all health technology assessment, "How much does this intervention improve the health of people?" and "What is the cost of that improvement?" Second, it describes decision analysis and cost-effectiveness analysis, which are quantitative modeling techniques usually used to answer the two core questions for imaging. Third, it outlines design and operational considerations that are vital if researchers who are conducting an experimental study are to make a quality contribution to technology assessment, either directly through their findings or as an input into decision analyses. Finally, it includes a separate discussion of screening--that is, the application of diagnostic tests to nonsymptomatic populations--because the requirements for good screening tests are different from those for diagnostic tests of symptomatic patients and because the appropriate evaluation methods also differ.

Cost-Benefit Analysis↗
PubMed2006

Placental perfusion and permeability: simultaneous assessment with dual-echo contrast-enhanced MR imaging in mice.

PURPOSE: To assess placental perfusion and permeability in mice with magnetic resonance (MR) imaging. MATERIALS AND METHODS: This study was conducted according to French law and National Institutes of Health recommendations for animal care. Twenty-two pregnant BALB/c mice were examined at 1.5 T with a single-section dual-echo fast spoiled gradient-echo sequence. Two injection protocols were used: monophasic injection (double the clinical dose of contrast agent) and biphasic injection (quadruple the clinical dose). Signal intensities (SIs) were measured in the maternal left ventricle, placenta, and fetus (n = 16). At these high gadolinium doses, a T2* effect correction was used. SIs were converted to gadolinium concentrations and were analyzed by using a three-compartment model. Quantitative microcirculation parameters were calculated. Results with the monophasic and biphasic protocols were compared, and final arterial concentrations determined with MR imaging were compared with those determined with atomic emission spectrophotometry by using the unpaired Student t test. RESULTS: Perfusion and permeability parameters for monophasic and biphasic injections were similar: Mean placental blood flow was 180 mL/min/100 g, mean permeability surface coefficient from maternal placental to fetal placental compartment was 10.3 x 10(-4) sec(-1) +/- 6.81 (standard deviation), mean permeability surface coefficient from fetal placental to maternal placental compartment was 4.65 x 10(-4) sec(-1) +/- 4.37, and mean fractional volume of the maternal vascular placental compartment was 36.5% +/- 0.9. Placental (146 vs 105 micromol/L, P < .004) and fetal (33.3 vs 19.1 micromol/L, P < .001) gadolinium concentrations were higher with the biphasic than with the monophasic protocol. Arterial gadolinium concentrations at MR imaging did not differ significantly from those at spectrophotometry for the monophasic (P = .254) or biphasic (P = .776) injection protocol. CONCLUSION: Placental perfusion and permeability can be measured in vivo by using high gadolinium doses and a dual-echo MR imaging sequence.

Animals↗
PubMed1998

Age-dependent reductions in A1 adenosine receptor expression in rat testes.

The rat testis expresses high levels of A1 adenosine receptors (A1 AR) that couple to the inhibition of adenylyl cyclase activity. However, the physiological role of these receptors in the testis is not clear. Previous studies have documented a number of changes in the testis associated with the aging process. The goal of this study was to assess whether alteration in the expression and function of the testicular A1 AR occurs in aging, using the Fischer 344 rats as an aging model. Quantitation of A1 AR expression by radioligand binding of [3H]1,3-dipropyl-8-cyclopentylxanthine, an antagonist radioligand, indicates reductions in receptor number by 35 +/- 13.3 and 53 +/- 18.2% in 18- and 25-mo-old rats, respectively, compared with 3-mo-old rats. Similar reductions in A1 AR expression were determined using Western blotting and receptor autoradiography. Quantitation of the Gi proteins using selective antibodies indicate age-dependent reductions in the levels of alpha i-1,2-, alpha i-3- and beta-subunits. Furthermore, the modulatory influences of guanosine 5'-O-(3-thiotriphosphate) on the binding of agonist and antagonist radioligands to the A1 AR were substantially reduced. Northern blotting analysis of rat testicular poly(A)+ RNA indicates both a 3.4-kb transcript and a 5.6-kb transcript that hybridized to the canine A1 AR cDNA probe. The levels of the 5.6-kb transcript were decreased by 24 +/- 18 and 52 +/- 3% in the 18- and 25-mo-old rats, respectively, compared with the 3-mo-old rats. These results indicate age-dependent deficits in the A1 AR signal transduction pathway in the testes and predict concomitant reductions in the action of adenosine.

Aging↗
PubMed1985

Effect of cell turnover and leaky junctions on arterial macromolecular transport.

A new quantitative model is presented to explore the changes in vascular permeability that would result if the intercellular clefts around widely scattered endothelial cells were to become leaky to macromolecules in the range of roughly 4-10 nm during normal cell turnover. Although these open junctions occupy less than 10(-5) of the en face area of the endothelial surface, it is shown that the endothelial permeability can increase by 50-100% due to the experimentally observed regional variations in turnover in the larger arteries, whereas in the thinner walled veins and smaller arteries the subendothelial concentration is not significantly elevated. These results provide a very plausible explanation for the observed focal differences in the uptake of 125I-albumin and 131I-fibrinogen in blue and white areas and the nonselectivity of the local enhancement in uptake for these two molecules as a function of molecular size. The model has important implications for the localization of atherogenesis and the importance of endothelial cell turnover on the transport of proteins in vessels of all sizes.

Arteries↗
PubMed1987

Atrioventricular interactions: a theoretical simulation study.

A quantitative model that describes the complex atrioventricular interactions, based on the structure and myocardial properties of the left atrium (LA) and left ventricle (LV), is presented. The description of the LV follows our earlier study that assumes a nested-shell spheroidal structure with fanlike fiber angle distribution, transmural electrical activation velocity, and the muscle fiber dynamics with the classical passive and active features of the sarcomeres. The LV model is extended here to include an exponential load-dependent relaxation and viscous (strain rate-dependent) features of the LV passive myocardium. The proposed LA model is based on a thin-wall spherical geometry with a random fibrous structure. The atrial muscle features differ from the ventricular muscle by being much stiffer in the passive state and weaker but faster in the active state. The LV and LA compartments are connected to a preload and afterload scheme and interconnected by the mitral flow with its inertial properties. The complex interactions between the LA and the LV are thoroughly studied here, and the calculated results are consistent with well-established experimental data.

Atrial Function↗
PubMed1996

Simulations of light effects on the human circadian pacemaker: implications for assessment of intrinsic period.

The sensitivity of the human circadian system to light has been the subject of considerable debate. Using computer simulations of a recent quantitative model for the effects of light on the human circadian system, we investigated these effects of light during different experimental protocols. The results of the simulations indicate that the nonuniform distribution over the circadian cycle of exposure to ordinary room light seen in classical free-run studies, in which subjects select their exposure to light and darkness, can result in an observed period of approximately 25 h, even when the intrinsic period of the subject's endogenous circadian pacemaker is much closer to 24 h. Other simulation results suggest that accurate assessment of the true intrinsic period of the human circadian pacemaker requires low ambient light intensities (approximately 10-15 lx) during scheduled wake episodes, desynchrony of the imposed light-dark cycle from the endogenous circadian oscillator, and a study length of at least 20 days. Although these simulations await further experimental substantiation, they highlight the sensitivity to light of the human circadian system and the potential confounding influence of light on the assessment of the intrinsic period of the circadian pacemaker.

Biological Clocks↗
PubMed1995

Airway edema potentiates airway reactivity.

Thickening of the airway wall has been hypothesized to be one of the mechanisms contributing to airway hyperresponsiveness in asthma. If such thickening of the wall is internal to the airway smooth muscle or otherwise causes a decrease in baseline airway caliber, it should also cause exaggerated airway responsiveness. In the present study, we used high-resolution computed tomography to directly measure the changes in the caliber and wall thickness of conducting airways after aerosol histamine challenge before and after normal saline volume loading. On separate days, five anesthetized dogs received either a baseline aerosol challenge of 3 mg/ml of histamine for five breaths or the same aerosol challenge immediately after a 100 ml/kg bolus of normal saline infused over a 10-min period. Baseline aerosol histamine challenge decreased airway area to 71 +/- 2% (SE) of the control value (P < 0.05). Intravenous administration of 100 ml/kg of normal saline increased wall area by decreasing airway luminal area to 78 +/- 3% of the control value (P < 0.01), with no change in outer airway area. Aerosol histamine challenge superimposed on this engorgement with normal saline challenge further decreased airway luminal area to 54 +/- 3% of the control value (P < 0.01). Quantitative modeling indicated that the edema in the airway wall was mostly outside the smooth muscle and that the smooth muscle shortening with histamine was similar with and without edema. We conclude that a moderate degree of acute airway wall thickening can lead to a potentiated constrictor response to histamine.

Aerosols↗
PubMed2002

Developmental changes in short-term synaptic depression in the neonatal mouse spinal cord.

We examined age-dependent changes in short-term synaptic depression of monosynaptic excitatory postsynaptic potentials (EPSPs) recorded in lumbar motoneurons in hemisected spinal cords of neonatal Swiss-Webster mice between postnatal day 2 (P2) and 12 (P12). We used four paradigms that sample the input-output dependence on stimulation history in different but complementary ways: 1) paired-pulse depression; 2) steady-state depression during constant frequency trains; 3) modulation during irregular stimulation sequences; and 4) recovery after high-frequency conditioning trains. Paired-pulse synaptic depression declined more than steady-state depression during 10-pulse trains at frequencies from 0.125 to 8 Hz in this age range. Depression during sequences of irregular stimulations that more closely mimic physiological activation also declined with postnatal age. On the other hand, the overall rate of synaptic recovery after a 4-Hz conditioning train exhibited surprisingly little change between P2 and P12. Control experiments indicated that these observations depend primarily, if not exclusively, on changes in presynaptic transmitter release. The data were examined using quantitative models that incorporate factors that have been suggested to exist at more specialized central synapses. The model that best predicted the observations included two presynaptic compartments that are depleted during activation, plus two superimposed processes that enhance transmitter release by different mechanisms. One of the latter produced rapidly-decaying enhancement of transmitter release fraction. The other mechanism indirectly enhanced the rate of renewal of one of the depleted presynaptic compartments. This model successfully predicted the constant frequency and irregular sequence data from all age groups, as well as the recovery curves following short, high-frequency tetani. The results suggest that a reduction in release fraction accounts for much of the decline in synaptic depression during early postnatal development, although changes in both enhancement processes also contribute. The time constants of resource renewal showed surprisingly little change through the first 12 days of postnatal life.

Aging↗
PubMed2004

Encoding of amplitude and rate of tooth loads by human periodontal afferents from premolar and molar teeth.

Microneurographic recordings were obtained from 20 periodontal mechanoreceptive afferents in the inferior alveolar nerve while force profiles of different amplitudes and rates were applied to a premolar or the first molar in the most sensitive direction. The majority of afferents (17/20) showed a hyperbolic relationship between the steady-state discharge rate and the amplitude of the stimulating force, featuring a pronounced saturation tendency. These afferents were also characterized by a similar decline in dynamic sensitivity with increasing amplitude of background force. However, a few afferents (3/20) showed nearly linear stimulus-response relationships and a small decline in dynamic sensitivity with increasing tooth load. Quantitative models developed for all afferents successfully predicted the afferent discharge rates for novel force stimulations. Application of the transfer function to chewing forces predicted that the discharge rates of periodontal afferents rapidly increased at initial tooth contact and continued to discharge as long as the tooth was loaded. However, due to the marked saturation tendencies at higher forces, most periodontal afferents poorly encoded the magnitude of the strong chewing forces. In addition, the discharge rates of a minority of afferents continued to reflect the force profile during high chewing forces. The results revealed that periodontal afferents of posterior teeth were less sensitive at low tooth loads compared with afferents of anterior teeth. During each chewing cycle, periodontal afferents may provide information about the mechanical properties of food shortly after tooth contact that can be used to scale the muscle commands of the upcoming power phase.

Action Potentials↗
PubMed1987

Linear mechanism of orientation tuning in the retina and lateral geniculate nucleus of the cat.

1. The orientation tuning of lateral geniculate nucleus (LGN) neurons and retinal ganglion cells (recorded as S potentials in the LGN) was investigated with drifting grating stimuli. 2. Results were compared with a quantitative model, in which receptive fields were constructed from linear, elliptical Gaussian center and surround subunits, and responses could be predicted to gratings of any spatial frequency at any orientation. 3. The orientation tuning of X and Y retinal ganglion cells and LGN neurons was shown to result from the linear mechanism of receptive-field elongation, as data from these cells could be well fit with this model. 4. The responses of LGN neurons and their input retinal ganglion cells were compared. The orientation tuning of LGN neurons was found to be a reflection of the tuning of their retinal inputs, showing that neither intrageniculate neural interactions nor the corticogeniculate projection play any role in LGN orientation selectivity.

Action Potentials↗
PubMed1988

Influence of anomalous rectifier activation on afterhyperpolarizations of neurons from cat sensorimotor cortex in vitro.

1. Large neurons from layer V of cat sensorimotor cortex (Betz cells) were studied to determine the influence of the anomalous rectifier current (IAR) on slow afterhyperpolarizations (AHPs). The neurons were examined using intracellular recording and single-microelectrode voltage clamp in an in vitro brain slice preparation. 2. A faster medium-duration AHP (mAHP) and slower AHP (sAHP) followed repetitive firing (22, 23). The amplitude of the mAHP often increased or remained constant during membrane potential hyperpolarization. The membrane potential trajectory resulting solely from IAR activation was similar to the mAHP. 3. Postrepetitive firing voltage clamp was used to measure directly slowly decaying K+ currents (IK) and IAR at different membrane potentials. IK exhibited both a fast and slow decay. The time constants of the fast decay of IK and IAR activation were similar. IAR increased with hyperpolarization or raised extracellular K+ concentration [( K+]o), whereas both the fast and slow components of IK reversed or nulled near -100 mV and behaved as pure K+ currents in response to raised [K+]o. 4. To determine the precise contribution of IK and IAR to the AHP waveform, theoretical AHPs were computed using a quantitative model based on voltage-clamp measurements. The calculated AHPs were qualitatively similar to measured AHPs. The amplitude of the mAHP showed little change with hyperpolarization because of the increasing dominance of IAR at more negative membrane potentials. The sAHP was little affected by IAR activation. 5. Several model parameters subject to biological variation among Betz cells were varied in the calculations to determine their importance in the AHP waveform. With IK parameters held constant, the amplitude and time course of the mAHP depended on resting potential, membrane time constant, the kinetics of the anomalous rectifier conductance (GAR), and the maximum value of GAR. IAR activation could result in a biphasic AHP even when the fast decay of IK was omitted from the calculations. 6. A wider variation of model parameters revealed behavior that may be relevant to other neurons. Certain values of membrane or IAR activation time constants resulted in a monophasic AHP even when the fast decay of IK was present. The decay of a biphasic AHP could reflect either the onset of IAR or the fast decay of IK, depending on the relative value of their time constants. Procedures are outlined to discriminate between these possibilities using current clamp methods.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Mechanics of stretch in activated crustacean slow muscle. II. Dynamic changes in force in response to stretch.

1. The mechanical dynamics of the ventral superficial muscles (VSM) of the abdomen of the hermit crab, Pagurus pollicarus, have been analyzed to develop a quantitative model of gradedly excitable arthropod muscle. Such a model is important for understanding the role of proprioceptive reflexes in posture and movement. 2. The decay in force produced after ramp stretch of both passive and active muscle was approximated by the use of regression equations involving a direct term and one to three exponential terms. A second-order equation produced an acceptable description of this decay over short (0.5 s) sampling durations. 3. The rate constants of the regression equation did not vary with stretch length, velocity, or activation level of the muscle. For the two-exponential-term model, the rate constants were approximately 90 and 9 s-1 for a sample duration of 0.3 s. An additional rate constant of approximately 1 s-1 was needed to adapt the model to longer sample times. 4. The direct term and the middle-order (9 s-1) residual were both functions of stretch length and activation level. The high-order (90 s-1) residual was primarily a function of stretch length and velocity. Transfer functions omitting the velocity dependence adequately described the mechanical dynamics of the muscle for physiological ranges of stretch velocity. 5. White-noise length perturbations were used to calculate spectral density functions of muscle force and length. These measurements confirmed the principal observations of the ramp stretch analysis: the frequency response of the muscle was independent of the level of activation; the magnitude of the stiffness increased over the stretch frequency range of 4-40 Hz and was then almost constant; and the phase response of the muscle became slightly positive over the same range of stretch frequency. 6. The speed of activation of the muscle to different stimulus frequencies was estimated by fitting a single exponential equation to the rise in isometric tension at the onset of stimulation of the motor nerve. The rate constant increased with stimulus frequency, but its maximum value was only 1.8 s-1, about one-fourth of the middle mechanical rate constant. 7. Because muscle activation is slower than the mechanical dynamics, it is unlikely that the nervous system can regulate muscle dynamics. However, it is possible that mechanical impedance could be regulated to maintain a desired time-averaged value.

Animals↗
PubMed1997

Study of the inhibitor of the crayfish neuromuscular junction by presynaptic voltage control.

The inhibitor of the crayfish opener muscle was investigated by a presynaptic voltage control method. Two microelectrodes were inserted into the inhibitor and the amplitude and duration of presynaptic depolarization were controlled by a voltage-clamp amplifier. The inhibitory postsynaptic potential (IPSP) was measured from a muscle fiber located near the presynaptic voltage electrode. Nonlinear summation of IPSP amplitudes was corrected after chloride equilibrium potential was measured. With the use of 5-ms presynaptic pulses, the depolarization-release coupling (D-R) curve constructed from IPSP peak amplitudes (IPSPcor) had a threshold of about -35 mV and reached its maximal level at -5 to -10 mV. Depolarization beyond the maximum led to a suppression of neurotransmitter release. When transmitter release during a presynaptic pulse was completely suppressed, IPSPs activated by tail current could be identified with an average synaptic delay of 2.5 ms. Transmitter secretion triggered by a calcium current activated during the 5-ms pulses (IPSPon) was also measured on the rising phase of an IPSP, at 2.5 ms after the end of the 5-ms pulses. D-R coupling plots measured from IPSPon exhibited a more pronounced suppression than that obtained from IPSPcor. The effect of presynaptic pulse duration on the level of transmitter release was analyzed. Transmitter release increased with increasing duration and was nearly saturated by 20-ms pulses depolarized to 0 mV. The following conditions were identified as necessary to obtain a consistent D-R curve with a clear suppression: 1) small animals, 3.8 cm head to tail, 2) 15 degrees C, 3) 40 mM tetraethylammonium and 1 mM 4-aminopyridine, 4) an extracellular calcium concentration of < or = 10 mM. In addition, a consistent correlation was found among the branching pattern of the inhibitor, the placement of the presynaptic electrode, and the characteristics of the D-R curves. An ideal presynaptic electrode configuration involved placing the voltage electrode in a secondary branch, approximately 100 microns from the main branch point, and placing the current electrode at the branch point. Postsynaptically, optimal recordings were obtained from muscle fibers innervated by a single branch of the inhibitor that originated from a point near the presynaptic voltage electrode. A cable-release model was constructed to evaluate the relationship between the shape of the D-R coupling curves and the space constants of the presynaptic terminals. A comparison between the model and the D-R coupling curves suggested that the space constant of an inhibitor branch on a muscle fiber is > or = 8 times longer than its actual length. Therefore the upper limit estimate of the space constant of a typical preparation is approximately 3 mm. Results reported here outline morphological and physiological conditions needed to achieve optimal control of the presynaptic branch of the crayfish inhibitor. The cable-release model quantitatively defines the extent of presynaptic voltage control.

Animals↗
PubMed1998

Dynamics of excitatory transmitter release: analysis of synaptic responses in CA3 hippocampal neurons after repetitive stimulation of afferent fibers.

The patch-clamp technique (whole cell configuration) was used to record excitatory postsynaptic currents (EPSCs) evoked by repetitive stimulation (4 pulses at 50-ms intervals) of afferent fibers in the stratum lucidum-radiatum. Different synaptic behaviors (EPSC patterns) were classified in terms of facilitation or depression of the mean amplitude of the second, third, and fourth EPSC with respect to the previous one. A large variety of EPSC patterns was observed by stimulating different afferent fibers. Experiments with the mGluR2/mGluR3 agonist 2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV) (1 microM), a compound that reduces release at mossy but not at associative commissural fibers and therefore allows to identify the origin of synaptic responses, showed that particular EPSC patterns could not be associated to the activation of a specific type of synaptic input. To investigate the role of the probability of release in the dynamics of synaptic activity, the extracellular calcium concentration was varied from 0.8 to 4 mM in several experiments. EPSC patterns dominated by depression, characteristics of high release probability conditions, could be observed in the majority of the cases in the presence of higher calcium concentrations. A quantitative model for dynamics of transmitter release has been developed. Experimental results were compared with data computed with the model taking into account the probability of release and the time course of reavailability. This work indicates that short-term changes of presynaptic conditions occurring during a train of action potentials can account for the high variability of EPSC responses. The model that is proposed also suggests a general method of experimental data analysis to investigate the possible presynaptic mechanisms underlying long-lasting changes in synaptic efficacy.

Action Potentials↗
PubMed2005

A strategy for integrative computational physiology.

Organ function (the heart beat for example) can only be understood through knowledge of molecular and cellular processes within the constraints of structure-function relations at the tissue level. A quantitative modeling framework that can deal with these multiscale issues is described here under the banner of the International Union of Physiological Sciences Physiome Project.

Cell Physiological Phenomena↗
PubMed2002

Where have all the young girls gone or where do all the men come from? Change and lack of change in demographic characteristics of the norwegian heroin user population.

A rough estimate indicates that women amount to one third of the heroin user population in Norway. However, among the youngest users females account and have accounted for a larger proportion. Given this greater representation of females in the younger age groups one would expect that the gender difference in the general population of users would be reduced over time due to a cohort effect. However, the ratio of male to female users has remained stable. The prevailing explanation for this stability is based on the claim that women are more likely to overcome their abuse. This paper addresses both the basis for the assumption of a missing cohort effect and examines an alternative explanation linked to the way into abuse rather than the way out. The study primarily draws upon two distinct data sources. The first body of material consists of interviews carried out in the period 1993-1997 with people attending the only needle exchange service in Oslo. The second data source consists of police records, which provide the number of persons arrested each year in the period 1984-1997 for using, possessing or selling heroin distributed by age and gender. We find that the age of injection debut has increased and that this is especially true for male users. Applying a simple quantitative model, the effect a change in recruitment may have on the male-to-female ratio is analysed. The results indicate that a higher debut age may have contributed to stabilizing the gender gap. The finding suggests that more research is needed on the conditions of recruitment in order to better predict the future population demographics and to avoid hasty and incorrect conclusions.

Adult↗