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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.

1. Pulmonary ventilation was found to be similar in high-altitude and low-altitude newborn infants, but the breathing pattern was deeper and slower at high altitude (Mortola, J. P., Frappell, P. B., Frappell, D. E., Villena-Cabrera, N., Villena-Cabrera, M., Peña, F., Am Rev Respir Dis 1992, 46: 1206–9). We questioned the contribution of vagal reflexes to these differences in breathing pattern. 2. Measurements were performed on high-altitude (La Paz, Bolivia, 3600–4050 m, inspired O2 pressure ∼92 mmHg, n = 34) and low-altitude infants (Santa Cruz, Bolivia, 400 m, Pio2 ∼141 mmHg, n = 26). The strength of the Hering—Breüer inspiratory inhibitory reflex was estimated from the inspiratory time during a respiratory effort against airways closed at end-expiration (TIoccl). The strength of the Hering—Breüer expiratory facilitatory reflex was estimated from the expiratory duration when airways were occluded during expiration (TEoccl). 3. TIoccl was significantly longer than the open-airways TI at both low and high altitude, but significantly more so (∼14%) at high altitude. TEoccl was longer than open-airways TE in both groups of infants, but significantly less so at high altitude, whether TEoccl was compared between occlusions of similar tidal volume (on average, TEoccl at high altitude was 79% of that at low altitude) or similar airway pressure (87%). 4. The results suggest that at high altitude the contribution of the phasic volume-dependent vagal input to the inspiratory off-switch threshold is higher, and that the tonic vagal expiratory facilitation is lower, than at low altitude, presumably because of hypoxia. The larger VT and longer TE of the HA infant cannot be explained by these differences in vagal pulmonary reflexes.

1. The trachea is constructed by a series of U‐shaped cartilaginous rings supporting a membranous posterior wall. We have studied separately the pressure‐volume relationships of the two components. 2. The motion of the membranous posterior wall contributes most to the tracheal volume change caused by any given transmural pressure change; the cartilaginous rings provide a semi‐rigid support to the posterior wall and have a far greater compliance with negative than positive transmural pressure. 3. The response of tracheal stretch receptors to transmural pressure can be explained by the mechanical coupling between cartilages and posterior wall. They respond both to positive and negative transmural pressure, they are active at zero transmural pressure and have a point of least activity with small negative transmural pressures. 4. The stress‐strain relationship of the posterior wall has been studied in static and dynamic conditions in control situations and after removal of either the tunica fibrosa or the trachealis muscle. Each of these two components contributes to the stiffness of the posterior wall, with the trachealis muscle providing most of its viscosity. 5. The response of tracheal stretch receptors to transverse traction of the posterior membranous wall has been studied in both static and dynamic conditions before and after removal of the tunica fibrosa. The behaviour of these receptors reflects the visco‐elastic properties of the trachealis muscle in which they have been localized.

To establish a quantitative method for the diagnosis of premenstrual syndrome (PMS), a simple prospective inventory, the calendar of premenstrual experiences, was constructed. The validity and reliability of this instrument were assessed by administering it throughout two consecutive ovulatory cycles to 36 rigidly screened women with PMS and to 18 controls. To establish concurrent validity, scores on behavioral items were correlated with simultaneously obtained scores on lengthier, well-validated psychiatric inventories designed to measure depression rather than PMS, the Beck Depression Inventory and the Profile of Mood States. The results showed that the calendar of premenstrual experiences luteal phase score distinguished PMS women from controls correctly in 104 of 108 cycles, with a 2.8 falsenegative rate and no false positives when used for two consecutive cycles. An upper limit follicular phase score was observed beneath which all PMS and normal control subjects fell, suggesting that a higher score is not consistent with PMS. Correlation coefficients of calendar item scores with Profile of Mood States scale scores were 0.58 for tension, 0.51 for depression, 0.46 for anger, 0.61 for fatigue, and 0.57 for confusion (P<.0001 for all correlations). The correlation of the- calendar depression item with the Beck Depression Inventory score was 0.56 (P<.0001). The test-retest reliability of the calendar given in the same phase of two consecutive menstrual cycles was high (r0.78, P<.0001). We conclude that this instrument is a valid, reliable, and practical PMS inventory, applicable to clinical and some research settings.

Acute hypoxia in newborns of various species including humans is associated with decreased thermogenesis and a fall in body temperature. We have investigated the cardiorespiratory consequences of correcting the fall in colonic temperature (Tc) during acute hypoxia in newborn cats. Experiments were conducted on 21 unanesthetized kittens (12 ± 1 d SEM, 244 ± 8 g) instrumented with catheters in the left common carotid artery and superior vena cava for measurements of systemic arterial pressure, central venous pressure, heart rate, arterial blood gases, arterial O2saturation (Sao2) and mixed venous O2saturation. Oxygen consumption (?Vo2) and CO2production (?Vco2) were also measured. Alveolar ventilation (?Va), cardiac index (CI), and systemic vascular resistance index (SVRI) were calculated. These determinations were made in 21% O2at an ambient temperature (Tamb) of 25 °C, and after 80 min of exposure to Fio2= 0.10. In one group Tamb was maintained at 25 °C (n = 8) during hypoxia and Tc fell by 2.7 ± 0.4 °C whereas in a second group Tamb was increased to 35°C for the second 40 min of hypoxia to raise Tc to the prehypoxic level(n = 13). ?Vo2, ?Vco2, ?Va, Sao2, and systemic arterial pressure during hypoxia did not differ between the animals which were warmed and those which were not. However, CI and heart rate were greater (452 ± 23 versus 346 ± 30 mL·min-1·kg-1p < 0.05, 279 ± 8versus 228 ± 12 beats·min-1p < 0.05) and SVRI lower (0.115 ± 0.022 versus 0.153 ± 0.014 mm Hg·mL-1·min·kg, p < 0.05) during hypoxia in the warmed animals compared with the unwarmed group. Thus, artificially raising Tc during hypoxia resulted in peripheral vasodilatation, whereas systemic arterial pressure was maintained by the increase in cardiac output. We conclude that, in the hypoxic kitten, raising Tc to normoxic values elicits a response that may reflect a condition of relative hyperthermia.

Abstract:  Brown adipose tissue (BAT) non-shivering thermogenesis is stimulated by cold temperature and depressed by hypoxia. We investigated the extent to which changes in metabolic rate during cold and hypoxia, singly or combined, were accompanied by changes in BAT perfusion. One-month-old rabbits were instrumented for measurements of regional blood flow by the coloured microsphere technique. One group of rabbits was tested in warm (24 C, n=17), and the other in cold (13 C, n=9) conditions, first in normoxia (inspired oxygen concentration FIO2 about 21%, arterial oxygen saturation S aO2 approximately 88%) followed by hypoxia (FIO2 approximately 10%, S aO2 approximately 54%). In warm conditions, oxygen consumption (VO2, measured by an open-flow method) averaged 22 mlkg–1min–1 (STPD), and BAT blood flow 98 ml100g–1min–1. In hypoxia, VO2 dropped on average to 87%, whereas BAT flow dropped to 43% of the normoxic values. In the cold during normoxia, VO2 averaged 31 mlkg–1min–1 (STPD), and BAT blood flow was 155 ml100g–1min–1. In cold and hypoxia VO2 dropped to 19 mlkg–1min–1 (STPD) (i.e. 60% of the normoxic value), whereas BAT blood flow was not altered significantly (148 ml100g–1min–1). Hence, BAT blood flow decreased in hypoxia in absence of cold stimuli, whereas it remained high when hypoxia occurred during cold, despite the major drop in VO2. We conclude that cold is more important than hypoxia in determining BAT perfusion, and that changes in BAT blood flow are not a mechanism for the hypoxic control of VO2.

We questioned whether the decrease in O2consumption (V˙o2) during hypoxia in newborns is a regulated response or reflects a limitation in O2availability. Experiments were conducted on previously instrumented conscious newborn dogs.V˙o2was measured at a warm ambient temperature (30°C, n= 7) or in the cold (20°C, n= 6), while the animals breathed air or were sequentially exposed to 15 min of fractional inspired O2(FIO2): 21, 18, 15, 12, 10, 8, and 6%. In normoxia,V˙o2averaged 15 ± 1 (SE) and 25 ± 1 ml ⋅ kg−1⋅ min−1in warm and cold conditions, respectively. In the warm condition, hypometabolism (i.e., hypoxicV˙o2< normoxicV˙o2) occurred atFIO2≤10%, whereas in the cold condition, hypometabolism occurred atFIO2≤12%. The same results were obtained in a separate group (n= 14) of noninstrumented puppies. For all levels of FIO2with hypometabolism, the relationships between measures of O2availability (arterial O2saturation or content, venousPO2or saturation,x-axis) vs.V˙o2(y-axis) had lower slopes in warm than in cold conditions. Hence, V˙o2during hypometabolism in the warm condition was not the maximal attainable for the level of oxygenation. The results do not support the possibility that the hypoxic drop inV˙o2in the newborn reflects a limitation in O2availability. The results are compatible with the idea that the phenomenon is one of “regulated conformism” to hypoxia.

1. In newborn and adult rats, hypoxia decreases metabolic rate, especially at low ambient temperatures (Ta). We examined whether a similar effect can occur during hypercapnia. 2. We measured metabolism (oxygen consumption, Vo2, open flow‐through method), and expiratory ventilation (VE; barometric method (adults), airflow plethysmograph (newborns)) in air and 2% or 5% CO2 in normoxia. 3. In adults, Vo2 was higher at Ta = 10 degrees C than 25 degrees C. At each Ta, CO2 breathing did not change Vo2, but increased VE, less at 10 degrees C (up to +100%) than at 25 degrees C (+161%). Blood pressure was maintained at both values of Ta and CO2, while pulse rate and body temperature were decreased in 5% CO2 at 10 degrees C. 4. In newborns, the metabolic response to lowering Ta (from 40 to 20 degrees C) much depended on behavioural responses, being larger in groups of two or four pups than in individual animals. In no case did CO2 influence the response. VE increased during 5% CO2 exposure, more so at Ta = 33 percent C (+69%) than at 25 degrees C (+49%). 5. In both adults and newborns, hypoxia (10% O2) always decreased metabolic rate. 6. We conclude that hypercapnia has no appreciable effects on metabolic rate in rats (both newborns and adults) even at low Ta, a result quite different from the hypometabolic response to hypoxia.

1. We have studied the motion of the abdomen and the rib cage in patients with a transection of the lower cervical spinal cord during normal breathing both in the supine and sitting posture, and compared it with that of normal subjects. 2. In the supine posture the rib cage of a patient moves paradoxically inward, therefore his chest wall is deformed, which explains the high work of breathing. 3. During expiration, beside the recoil of the respiratory system, there is also the recoil of the deformed chest wall, toward its passive configuration, with an expansion of the rib cage above its resting position during the first part of expiration and an alteration of the expiratory flow profile. 4. In a sitting ‘relaxed’ posture the paradoxical inward motion disappears in the lower rib cage, and it is reduced but still present in the higher rib cage. 5. We conclude that contraction of the diaphragm constricts the ‘passive rib cage’, either directly through its insertions or indirectly through the reduction of intrathoracic pressure. In seated subjects the diaphragm causes some expansion of the rib cage at its lower level. Therefore the motion of the rib cage is not only related to the balance between the forces developed by the diaphragm and the intercostal muscles, but also to the diaphragm dome configuration, the geometry of the rib cage and the lung volume.

1. During respiratory efforts against a closed airway, the afferent activity of vagal fibres from pulmonary stretch receptors does not appreciably increase during the inspiratory phase because the lung is prevented from expanding.

The lung's only vital function is to provide sufficient gas-exchange surface area (Sa) to meet the organism's needs for oxygen uptake (VO2) and carbon dioxide elimination. A direct linear relation between Sa and VO2 and an inverse linear relation between the size of the lung's gas-exchange units and the species mass-specific VO2 are strongly conserved across species. Within species, Sa increases in response to prolonged (weeks) elevation of VO2. We now report sex-dependent deviations from these relationships that seem to anticipate the need for increased gas-exchange capacity engendered in females by the metabolic demands of pregnancy and lactation. We found that although VO2 almost doubled in rats during pregnancy and lactation, Sa was the same in age-matched virgin, pregnant, and lactating females. However, at the onset of sexual maturity, virgin female rats and mice had higher mass-specific Sa than males of the same species although mass-specific VO2 was identical, within species, in both sexes. In addition, even though mass-specific VO2 was identical in males and females, alveoli were 30% and 50% smaller in female rats and mice, respectively, than males of the same species. We suggest the greater mass-specific Sa and smaller alveoli in females in spite of identical mass-specific VO2 as males were selected for evolutionarily; they help females meet the metabolic demands of reproduction without adding to the energy demands of these periods a requirement to form additional lung.

In utero diethylstilbestrol (DES) exposure results in long term reproductive consequences. Preliminary evidence suggests a link between prenatal DES exposure and long term alterations in the immune system. To further test this hypothesis, we compared the phytohemaglutinin (PHA) and concavlin A (con A) induced blastogenic response of mononuclear cell in prenatally exposed women (n=13) to age matched non DES exposed women (n=9). 15 ml. of whole blood obtained during the early follicular phase of cycling women were heparinized, diluted 1:2, layered over ficoll-paqun density gradient. The mononuclear cells were washed X 3 (10%, R.P.M.I. 1640). Aliquots (final cone, of 5 × 105ml). Either PHA (7.5ug-1ug/ml) or Con-A were added to each well. After 48 hours of incubation at 37° C the cells were pulsed with 1 Cµ-thymidine(H-Td), reincubated for 18 hours, harvested, counted, and a geometric mean of 3 determinations obtained.Results: Decreasing H-Td proliferation responses paralleled declining mitogen concentrations both with PHA and Con-A. Con-A showed no significantly different response in cells from DES subjects compared to controls. In contrast, PHA responses were greater in DES subjects (p<.005 2 way ANOVA).These data indicate long lasting effects on the immune system in DES exposed women. Such lasting effects on the immune system may be accounted for by a genomic mechanism altering the cellular responses in daughter cells throughout the reproductive years.

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