Mechanics of the respiratory system in the newborn tammar wallaby.

We investigated whether the mechanical properties of the respiratory system represent a major constraint to spontaneous breathing in the newborn tammar wallaby Macropus eugenii, which is born after a very short gestation (approximately 28 days, birth mass approximately 380 mg). The rate of oxygen consumption (V(O(2))) through the skin was approximately 33 % of the total V(O(2)) at day 1 and approximately 14 % at day 6. The mass-specific resting minute ventilation (E) and the ventilatory equivalent (VE/(O(2))) were approximately the same at the two ages, with a breathing pattern significantly deeper and slower at day 1. The mass-specific compliance of the respiratory system (C(rs)) did not differ significantly between the two age groups and was close to the values predicted from measurements in eutherian newborns. Mass-specific respiratory system resistance (R(rs)) at day 1 was higher than at day 6, and also higher than in eutherian newborns. Chest distortion, quantified as the degree of abdominal motion during spontaneous breathing compared with that required to inflate the lungs passively, at day 1 was very large, whereas it was modest at day 6. We conclude that, in the tammar wallaby at birth, the high resistance of the respiratory system and the distortion of the chest wall greatly reduce the mechanical efficiency of breathing. At this age, gas exchange through the skin is therefore an important complement to pulmonary ventilation.

Altered immune response in adult women exposed to diethylstilbestrol in utero.

OBJECTIVE: Between 1940 and 1970, 1.5 million female fetuses were exposed to diethylstilbestrol in utero. Numerous deleterious effects on reproductive anatomic and physiologic characteristics have been documented in these women. However, the effects of this exposure on nonreproductive systems, which may have lifelong consequences as this cohort of women progresses beyond the childbearing years, have received little attention. On the basis of an earlier preliminary observation of altered immune reponse, we hypothesized that diethylstilbestrol-exposed women may show abnormalities in T-cell-mediated immune response. STUDY DESIGN: Thirteen women exposed to diethylstilbestrol in utero were compared with 13 age- and menstrual cycle phase-matched control subjects with respect to the in vitro T-cell response to the mitogens phytohemagglutinin, concanavalin A, and interleukin 2. RESULTS: As compared with controls, tritiated thymidine incorporation by T cells harvested from diethylstilbestrol-exposed women was increased 3-fold over a range of concentrations in response to concanavalin A (P <.001), increased by 50% over a range of concentrations in response to phytohemagglutinin (P <.001), and increased 2-fold in response to the endogenous mitogen interleukin 2 (P <.05). CONCLUSIONS: In vitro evidence suggests that women exposed to diethylstilbestrol have alterations in T-cell-mediated immunity. These changes require further attention with regard to their characterization, their role in the pathogenesis of cancer and autoimmunity, and their presence in normal women exposed to diethylstilbestrol in utero.

Circadian patterns in men acclimatized to intermittent hypoxia.

Six men, normally working shifts of 7 days at high altitude (HA, 3800 m, approximately 480 mm Hg barometric pressure) followed by 7 days of rest at sea level (SL), were studied during the last days of their HA and SL shifts with a 24-h constant routine protocol of sustained wakefulness and minimal activity. The amplitude of the circadian oscillations of oxygen consumption, breathing rate, thoracic skin temperature and diastolic pressure did not differ between HA and SL. At HA, the amplitude of the tympanic and calf temperature oscillations, were, respectively, lower and higher than at SL. End-tidal P(CO2) and systolic pressure had larger amplitude oscillations at HA than at SL. Hence, also in humans, as previously shown in animals, hypoxia can affect some circadian patterns, including those involved in thermoregulation. These effects of hypoxia could contribute to sleep disturbances at HA and in patients with cardiorespiratory diseases.

Vascular repair after menstruation involves regulation of vascular endothelial growth factor-receptor phosphorylation by sFLT-1.

Regeneration of the endometrium after menstruation requires a rapid and highly organized vascular response. Potential regulators of this process include members of the vascular endothelial growth factor (VEGF) family of proteins and their receptors. Although VEGF expression has been detected in the endometrium, the relationship between VEGF production, receptor activation, and endothelial cell proliferation during the endometrial cycle is poorly understood. To better ascertain the relevance of VEGF family members during postmenstrual repair, we have evaluated ligands, receptors, and activity by receptor phosphorylation in human endometrium throughout the menstrual cycle. We found that VEGF is significantly increased at the onset of menstruation, a result of the additive effects of hypoxia, transforming growth factor-alpha, and interleukin-1beta. Both VEGF receptors, FLT-1 and KDR, followed a similar pattern. However, functional activity of KDR, as determined by phosphorylation studies, revealed activation in the late menstrual and early proliferative phases. The degree of KDR phosphorylation was inversely correlated with the presence of sFLT-1. Endothelial cell proliferation analysis in endometrium showed a peak during the late menstrual and early proliferative phases in concert with the presence of VEGF, VEGF receptor phosphorylation, and decrease of sFLT-1. Together, these results suggest that VEGF receptor activation and the subsequent modulation of sFLT-1 in the late menstrual phase likely contributes to the onset of angiogenesis and endothelial repair in the human endometrium.

Hypoxic depression of circadian oscillations in sino-aortic denervated rats.

We hypothesized that hypoxia depresses the circadian oscillations of body temperature (T(b)) and oxygen consumption (V(O(2))) even in the absence of inputs from the peripheral chemoreceptors. Adult rats were sino-aortic denervated bilaterally (SAX, N=17) or sham-operated (Sham, N=17). Ten rats of each group were instrumented for measurements of T(b) and activity by telemetry. Animals were exposed to normoxia (21% O(2)), hypoxia (10.5% O(2)), and again normoxia, each for a 5-day duration, in constant light ('free-running') conditions. Hypoxia almost eliminated the T(b) circadian oscillations, mostly by abolishing the daily rise in T(b). Upon return to normoxia T(b) rapidly increased and the normal oscillation was reestablished at the expected phase of the cycle. The hypoxic effects did not differ between Sham and SAX. During hypoxia the amplitude of the circadian oscillation of activity was reduced by approximately 25%, and that of V(O(2)), measured by an open flow method in the remaining Sham and SAX rats (N=7 each), was reduced by almost 50%. In all cases there was no difference between the two groups. We conclude that activation of the peripheral chemoreceptors is not required for the manifestation of the hypoxic depression of the metabolic and temperature circadian oscillations. The results are compatible with the view that hypoxia depresses thermogenesis acting on the thermoregulatory centers of the hypothalamus.

Variability of the breathing pattern in newborn rats: effects of ambient temperature in normoxia or hypoxia.

We hypothesized that the inter-breath variability of the breathing pattern in newborn rats varied with temperature and oxygenation. Breathing pattern was recorded in 4-day-old rats by airflow plethysmography, during normoxia in warm (control) and cold conditions, or during hypoxia (inspired O2 = 10%) in warm or cold conditions, each lasting 15 min. The warm phase (36 degrees C) either preceded or followed the cold (24 degrees C). Time-domain analysis was applied to 500 continuous breaths recorded toward the end of each phase. All parameters describing the breathing pattern (instantaneous ventilation, tidal volume, and inspiratory and expiratory time) had lower variability when the condition differed from control i.e. in cold or hypoxia, with no correlation with the absolute level of ventilation. The difference in variability between warm-normoxia and the other conditions was reduced when cold preceded the warm phase. Gaseous metabolism was increased in cold because of thermogenesis. When the cold preceded the warm phase the increased thermogenesis partly persisted into the warm phase, raising the metabolic level. We conclude that the variability of the breathing pattern in newborn rats 1) does not depend on the absolute level of ventilation, and 2) is reduced by the increased chemical stimuli occurring during cold-hypermetabolism or hypoxia. In normoxia in warm condition metabolic and chemical stimuli are low, and the variability is the highest. The results are in agreement with the clinical observations of a higher incidence of apneic episodes in infants during warm conditions.

Ventilatory responses to changes in temperature in mammals and other vertebrates.

This article reviews the relationship between pulmonary ventilation (VE) and metabolic rate (oxygen consumption) during changes in ambient temperature. The main focus is on mammals, although for comparative purposes the VE responses of ectothermic vertebrates are also discussed. First, the effects of temperature on pulmonary mechanics, chemoreceptors, and airway receptors are summarized. Then we review the main VE responses to cold and warm stimuli and their interaction with exercise, hypoxia, or hypercapnia. In these cases, mammals attempt to maintain both oxygenation and body temperature, although conflicts can arise because of the respiratory heat loss associated with the increase in ventilation. Finally, we consider the VE responses of mammals when body temperature changes, as during torpor, fever, sleep, and hypothermia. In ectotherms, during changes in temperature, VE control becomes part of a general strategy to maintain constant relative alkalinity and ensure a constancy of pH-dependent protein functions (alphastat regulation). In mammals on the other hand, VE control is aimed to balance metabolic needs with homeothermy. Therefore, alphastat regulation in mammals seems to have a low priority, and it may be adopted only in exceptional cases.

Compliance of the respiratory system in newborn and adult rats after gestation in hypoxia.

We hypothesized that hypoxia during gestation modifies the compliance of the respiratory system of newborn and adult rats. Pregnant rats were placed in a hypobaric chamber at an inspired oxygen pressure of 86 mmHg (equivalent to 12% O2 in normobaria) from day 4 of gestation until day 2 post-partum. Three-day-old rat pups were smaller than controls, with higher hematocrit; the lungs were also small, with less protein and DNA content. The pressure (x-axis)-volume (y-axis) curve of the respiratory system was displaced to the right of the control curve, and the compliance of the respiratory system, measured on the inflation or deflation limb of the pressure-volume curve, was decreased by approximately 20-25%, depending upon the normalization procedure (per body mass or per dry lung weight). In 50-day-old rats exposed to hypoxia during gestation, body weight, hematocrit, lung mass and DNA content were normal; the compliance of the respiratory system, measured at ventilation frequencies between 20 cpm and 100 cpm, was higher than in controls by approximately 20%. It is concluded that the effects of prenatal hypoxia on the compliance of the respiratory system can vary with age. In the rat the process of alveolar formation initiates postnatally. Hence, in the newborn the effects of the prenatal hypoxia on the compliance of the respiratory system are likely to be dominated by the hypoxic pulmonary hypoplasia and hypertension, which decrease the compliance of the respiratory system. In the adult, the effects of the decreased alveolar formation are the prevailing ones, increasing the compliance of the respiratory system.

Light-dark differences in the effects of ambient temperature on gaseous metabolism in newborn rats.

Body temperature (T(b)) of rat pups (7-9 days old) raised under a 12:12-h light-dark (L-D) regimen (L: 0700-1900, D: 1900-0700) was consistently higher in D than in L by approximately 1.1 degrees C. We tested the hypothesis that the L-D differences in T(b) were accompanied by differences in the set point of thermoregulation. Measurements were performed on rat pups at 7-9 days after birth. O(2) consumption (VO(2)) and CO(2) production (VCO(2)) were measured with an open-flow method during air breathing, as ambient temperature (T(a)) was decreased from 40 to 15 degrees C at the constant rate of 0.5 degrees C/min. At T(a) >/=33 degrees C, VO(2) was not significantly different between L and D, whereas VCO(2) was higher in L, suggesting a greater ventilation. Over the 33 to 15 degrees C range the VO(2) values in D exceeded those in L by approximately 30%. Specifically, the difference was contributed by differences in thermogenesis at T(a) = 30 to 20 degrees C. As T(a) was decreased, the critical temperature at which VO(2) began to rise was lower in L. We conclude that the higher T(b) of rat pups in D is accompanied by a higher set point for thermoregulation and a greater thermogenesis. These results are consistent with the idea that, in newborns, endogenous changes in the set point of thermoregulation contribute to the circadian oscillations of T(b).

Respiratory function in a newborn marsupial with skin gas exchange.

The Julia Creek dunnart (Sminthopsis douglasi) is a marsupial born after approximately 12 days of gestation. At birth, the newborn is approximately 4 mm long and weighs approximately 15 mg. Gaseous metabolism (oxygen consumption rate, V(O2), rate of carbon dioxide production, V(CO2) was measured separately across the airways (lungs) and the rest of the body (skin). At pouch temperature (36 degrees C) total V(O2) (i.e. skin + lungs) averaged 15 +/- 2 S.E.M. ml x kg(-1) x min(-1). At birth the skin contributed almost the total gaseous metabolism, and at 3 weeks approximately 1/3 of the total. The compliance of the respiratory system, per unit of body weight, was similar to that of other newborn mammals. During the first postnatal days breathing was an occasional event determined by gross body movements. Artificial expansion of the lungs temporarily stopped breathing, presumably a manifestation of the Hering-Breuer reflex. By the 2nd-3rd week breathing was regular, pulmonary ventilation (V(E)) averaged 263 ml x kg(-1) x min(-1), tidal volume (V(T)) 3.4 ml x kg(-1), breathing frequency (f) 87 breaths x min(-1). Lowering ambient temperature in steps from 36 to 20 degrees C reduced both lung and skin gaseous metabolism. V(E) and f, at first, were little affected but eventually they dropped in approximate proportion to metabolism, whereas V(T) remained unchanged. In conclusion, for the newborn dunnart gas exchange through the skin is a requirement because of the inefficient V(E). To what extent the V(E) adjustments to changes in metabolic rate reflect mechanisms of regulation remains unresolved.

Continuous circadian measurements of ventilation in behaving adult rats.

Body temperature (Tb) and oxygen consumption (V(O(2))) are important determinants of ventilation (VE). While the circadian rhythms in Tb and V(O(2)) have been well described, the daily pattern of VE has not due to limitations in the available methods for measuring VE. Here we describe an adaptation of the barometric method using a chamber in which a large flow through very small restrictions was generated by the combined action of a positive pressure pump on the entrance and a negative pressure pump at the outlet. In this way the chamber effectively behaved as a closed system, despite having a high enough flow for long-term recording in freely moving, undisturbed small animals. This system was then used to test the hypothesis that VE oscillates with a circadian pattern similar to that of Tb(.) Measurements of tidal volume (VT) and breathing rate (f), in combination with Tb and activity by telemetry, were made in eight adult rats over 4-6 days under 12:12 light:dark conditions. Both VT, f, and thus VE, showed a circadian pattern similar to that of Tb and activity; that is, values were higher during the dark compared to the light phase. The differences in VE levels according to the time of the day suggest that mechanisms involved in the control of breathing may also have circadian patterns.

Birth weight and altitude: a study in Peruvian communities.

We tested the hypothesis that at high altitude birth weight decreases once a critical barometric pressure (Pb) is reached. Birth weight data covering the 1-year period from November 1997 to October 1998 were collected in Peru from the data files of 15 community and mining centers between sea level and 4575 m altitude. These centers are scattered along the main road that joins Lima (on the Pacific shore) to Cerro de Pasco (4330 m) and surroundings. Above approximately 2000 m (ie, at Pb below approximately 590 mm Hg, inspired O(2) partial pressure of approximately 114 mm Hg) and up to approximately 4500 m altitude birth weight declined at an average of 65 g for every additional 500 m altitude (or 105 g for every additional 50 mm Hg drop in Pb). This pattern did not differ between sexes. Averages and modal distributions of the birth weight from 2 hospitals in Cerro de Pasco (4330 m) serving different social groups were similar. Body length at birth was similar at various altitudes, with the exception of the 2 highest locations above 4500 m, where it was slightly reduced. From these data, together with additional data collected in the North of Peru (Chacas, 3360 m) and with results from other ethnic groups previously published, we conclude that the drop in birth weight at altitude is (1) apparent once the critical Pb of approximately 590 mm Hg is reached, corresponding to an altitude of approximately 2000 m, (2) proportional to the increase in altitude between approximately 2000 m and 4500 m, and (3) independent from socioeconomic factors.

Hypoxic depression of circadian rhythms in adult rats.

Because the circadian rhythms of oxygen consumption (VO(2)) and body temperature (T(b)) could be contributed to by differences in thermogenesis and because hypoxia depresses thermogenesis in its various forms, we tested the hypothesis that hypoxia blunts the normal daily oscillations in VO(2) and T(b). Adult rats were instrumented for measurements of T(b) and activity by telemetry; VO(2) was measured by an open-flow method. Animals were exposed to normoxia (21% O(2)), hypoxia (10.5% O(2)), and normoxia again, each 1 wk in duration, in either a 12:12-h light-dark cycle ("synchronized") or constant light ("free running"). In this latter case, the period of the cycle was approximately 25 h. In synchronized conditions, hypoxia almost eliminated the T(b) circadian oscillation, because of the blunting of the T(b) rise during the dark phase. On return to normoxia, T(b) rapidly increased toward the maximum normoxic values, and the normal cycle was then reestablished. In hypoxia, the amplitude of the activity and VO(2) oscillations averaged, respectively, 37 and 56% of normoxia. In free-running conditions, on return to normoxia the rhythm was reestablished at the expected phase of the cycle. Hence, the action of hypoxia was not on the clock itself but probably at the hypothalamic centers of thermoregulation. Hyperoxia (40% O(2)) or hypercapnia (3% CO(2)) had no significant effects on circadian oscillations, indicating that the effects of hypoxia did not reflect an undifferentiated response to changes in environmental gases. Modifications of the metabolism and T(b) rhythms during hypoxia could be at the origin of sleep disturbances in cardiorespiratory patients and at high altitude.

Low-dose esterified estrogens (0.3 mg/day): long-term and short-term effects on menopausal symptoms and quality of life in postmenopausal women.

OBJECTIVE: To study the impact of low-dose unopposed esterified estrogens on menopausal symptoms and quality of life. METHODS: In a long-term, 2-year, randomized, double-blind, placebo-controlled study, 204 postmenopausal women were treated with esterified estrogens 0.3 mg daily or placebo. Menopausal symptoms were assessed with a modified Kupperman index at baseline, 3, 6 and thereafter every 6 months. In a second 12-week, open-label, short-term pilot study, 25 postmenopausal women with moderate to severe vasomotor symptoms were treated with esterified estrogens 0.3 mg daily for 12 weeks. Vasomotor symptoms and quality of life were assessed using the Greene scale and Quality of Life Menopause Scale (QUALMS). RESULTS: In the long-term study, significant (p < 0.05) reductions in total symptom scores were observed at each time point with esterified estrogens compared with placebo. Somatic symptom scores (hot flushes, night sweats, vaginal dryness) decreased significantly (p < 0.01) in patients treated with esterified estrogens 0.3 mg compared to baseline and placebo. In the short-term, open-label pilot study, the incidence of vasomotor symptoms was significantly (p < 0.01) reduced with esterified estrogens 0.3 mg from week 4 until the study end. Significant (p < 0.05) improvements versus baseline were seen in the somatic and vasomotor/sleep domains and in the total quality-of-life score. CONCLUSIONS: Esterified estrogens 0.3 mg given daily provide adequate menopausal symptom relief and improved quality of life in postmenopausal women.

Hering-Breuer reflex in conscious newborn rats: effects of changes in ambient temperature during hypoxia.

In a previous study in conscious normoxic newborn rats, we found that the strength of the Hering-Breuer reflex (HB reflex) was greater (188%) at high (36 degrees C) than at low (24 degrees C) ambient temperature (T(a); D. Merazzi and J. P. Mortola. Pediatr. Res. 45: 370-376, 1999). We now asked what the effect would be of changes in T(a) during hypoxia. Rat pups at 3-4 days of age were studied in a double-chamber airflow plethysmograph. The HB reflex was induced by negative body surface pressures of 5 or 10 cmH(2)O and quantified from the inhibition of breathing during maintained lung inflation. Rats were first studied at T(a) = 32 degrees C in normoxia, followed by hypoxia (10% O(2) breathing). During hypoxia, oxygen consumption (VO(2)) averaged 47%, and HB reflex 115%, of the corresponding normoxic values, confirming that in the newborn, differently from the adult, hypoxia does not decrease the strength of the HB reflex. As hypoxia was maintained, lowering T(a) to 24 degrees C or increasing it to 36 degrees C, on average, had no significant effects on VO(2) and the HB reflex. However, with 5-cmH(2)O inflations, the HB reflex during the combined hypoxia and hyperthermia was significantly stronger than in normoxia. We conclude that in conscious newborn rats during normoxia the T(a) sensitivity of the HB reflex is largely mediated by the effects of T(a) on thermogenesis and VO(2); in hypoxia, because thermogenesis is depressed and VO(2) varies little with T(a), the HB reflex is T(a) independent. The observation that the reflex response to lung inflations during hypoxic hyperthermia can be greater than in normoxia may be of importance in the pathophysiology of apneas during the neonatal period.

How newborn mammals cope with hypoxia.

The most immediate response to acute hypoxia in newborn mammals is hyperventilation, like in the adult. However. hyperventilation is often achieved by a reduction in metabolic rate (hypometabolism), rather than by an increase in ventilation (hyperpnea). This response is a regulated phenomenon largely based on inhibition of thermogenesis in all its forms, shivering, non-shivering and behavioural, with a resetting of the thermocontrol at a lower value of body temperature (Tb). Forcing Tb to the normoxic value in an hypoxic newborn can therefore provoke responses that are disadvantageous to the general strategy against hypoxia. The small or absent hyperpnea in the hypoxic newborn is the expected response to the decrease in metabolic rate; therefore, it should not be necessarily regarded as an expression of inadequate ventilatory control. However, during hypoxia the low metabolic rate can enhance the relative efficacy of inputs inhibitory on breathing, and this could be a mechanism contributing to ventilatory irregularities and apneas. The advantages of the hypometabolic strategy are numerous, and are at the basis of the extraordinary ability of newborn mammals to survive periods of severe hypoxia. The disadvantages become apparent with chronic hypoxia, because the reduced growth of tissues and organs may be incompatible with survival, or could lead to long-lasting structural and functional alterations.

Effects of changes in ambient temperature on the Hering-Breüer reflex of the conscious newborn rat.

We questioned to what extent changes in temperature could affect the newborn's ventilatory inhibition provoked by lung inflation, or Hering-Breüer (HB) inflation reflex. Conscious newborn rats (3-4 d old) were studied in a double chamber airflow plethysmograph at ambient temperatures of 32 degrees C (slightly below their thermoneutrality), 24 degrees C (cold), and 36 degrees C (warm). At these ambient temperatures, the corresponding body temperatures averaged 35.4, 31.0, and 37 degrees C. The HB reflex was triggered by negative body surface pressures of 5 or 10 cm H2O, and quantified as the duration of the expiratory time during the maintained inflation, either in absolute values or in relation to the control expiratory time. In cold the HB reflex decreased to 80%, and in warm it increased to 150%, of the values measured at 32 degrees C. Oxygen consumption, measured by an open flow system, averaged 59, 47, and 29 mL x kg(-1) x min(-1) at, respectively, 24, 32, and 36 degrees C. In cold, the ventilatory response to hypoxia (10% O2) was almost absent, that to hypercapnia (5% CO2) was greater, and that to hypoxia and hypercapnia combined was less than in warm. We conclude that in newborn rats the strength of the vagal inhibition on breathing, evaluated in the form of the HB reflex, is sensitive to temperature, becoming stronger as temperature increases. One contributing factor is the temperature-induced change in metabolic rate, whereas the role of temperature-induced changes in ventilatory chemosensitivity is variable. The strong temperature-dependency of the neonatal HB reflex implies that in newborns exposed to a warm environment breathing is more susceptible to inhibitory inputs.