Components and mechanisms of thermal hyperpnea.

The pattern of breathing during a hyperthermia-induced hyperventilation varies across different species. Thermal tachypnea is a first phase panting response adopted during hyperthermia when tidal volume is minimized and the frequency of breathing is maximized. Blood-gas tensions and pH are maintained during this hyperventilation, and the associated heat loss helps the animal regulate its body temperature. A second pattern of breathing adopted in hyperthermia is thermal hyperpnea; this response is the focus of this review. This form of hyperventilation is evident after an increase in core temperature and it is apparent in humans. Increases of tidal volume as well as frequency of breathing are evident during this response that results in a respiratory alkalosis. The cause of thermal hyperpnea is not resolved; evidence of the potential mechanisms underlying this response support that modulators of the response act in either a multiplicative or additive manner with body temperatures. The details of the designs and methodologies of the studies supporting or refuting these two views are discussed. A physiological rationale for thermal hyperpnea is presented in which it is suggested this response serves a heat-loss role and contributes to selective brain cooling in hyperthermic humans. Ongoing research in this area is focused on resolving the mechanisms underlying thermal hyperpnea and its contribution to cranial thermoregulation. The direct application of this research is for the care of febrile and hyperthermic patients.     

The ΔT thermal dose concept 1: in vivo teratogenesis

This project was an initial test of the hypothesis that there would be a ΔT thermal dose relationship for birth defects in rats (Rattus norvegicus) during neural tube closure (NTC). Additionally, the same thermal dose as applied during NTC in utero in vivo, was also applied to exteriorized (i.e., ex vivo) in utero pregnant uterine horns at a comparable stage of organogenesis. Since the yields of the two regimens were comparable, the hyperthermia-induced teratogenic effects appear to result from the thermal dosing of the in utero embryos and not the elevated temperature of the mother. The hypothesis was supported.     

Fetal thermal dose considerations during the obstetrician's watch: Implications for the pediatrician's observations

There are a number of seemingly "usual" thermal episodes during pregnancy for which it is relatively easy to determine a rudimentary aspect of thermal dose; these episodes include fever, labor, labor plus epidural, and the normally-occurring 0.5 degrees C temperature elevation above maternal core temperature of the fetus during the entirety of the third trimester. Complications can involve, for instance, fever during the third trimester. We consider the thermal doses of five different but "usual" or "normal" hyperthermic episodes during human pregnancy and compare those doses with the thermal doses involved with both single and cohort exposures of pregnant guinea pigs throughout their gestational period. The end-point studied in the guinea pigs was microencephaly. In nine of the 10 comparisons (human fetal thermal dose vs. guinea pig fetal thermal dose) the human dose is substantially larger than that of the guinea pig thermal dose, which was substantially teratogenic. This situation is essentially the inverse of the type of information contained in the Physician's Desk Reference (PDR) on drugs, in which it is not unusual to discern that at high drug levels there may be teratogenic effects in laboratory animals, but such effects were not observed at "clinical" drug levels in animals or subsequent clinical trials. With hyperthermic events, however, it appears that the teratogenically-effective thermal dose levels associated with animal testing are quite low relative to those thermal doses associated with relatively "normal" obstetric observations during a pregnancy.     

Marshall J. Edwards: discoverer of maternal hyperthermia as a human teratogen

In a series of animal studies performed over a career spanning 40 years at the University of Sydney, Professor Marshall J. Edwards investigated the hypothesis that maternal hyperthermia during gestation can be teratogenic to the developing fetus. He is one of few investigators to have discovered a known human teratogen primarily through animal studies. In 1970 he earned his Ph.D. from the University of Sydney, writing a doctoral thesis entitled "A Study of Some Factors Affecting Fertility of Animals with Particular Reference to the Effects of Hyperthermia on Gestation and Prenatal Development of the Guinea-Pig." He went on to prove that hyperthermia-induced malformations in animals involve many organs and structures, particularly the central nervous system. Other defects include craniofacial anomalies, heart defects and hypodactyly, cataracts and coloboma, kyphoscoliosis, renal anomalies, dental agenesis, and abdominal wall defects. In a series of carefully planned and executed experiments, he demonstrated that the type of defect is related to the timing of the hyperthermic insult, and analyzed the underlying mechanisms. Cell death, membrane disruption, vascular disruption, and placental infarction were all implicated in causing embryonic damage. This special article reviews the scientific discoveries and personal philosophy of Marshall J. Edwards, the discoverer of maternal hyperthermia as a human teratogen.     

Strain differences in heat-induced neural tube defects in mice

Neural tube defects are common congenital anomalies affecting approximately 0.1% of liveborn infants. It is widely accepted that these disorders are of a multifactorial origin, having both a genetic and an environmental component to their development. In a study designed to elucidate the genetic factors involved in a mouse model of hyperthermia-induced neural tube defects, it is apparent that a hierarchy of susceptibility exists among various inbred mouse strains. Female SWV mice were extremely sensitive to a 10-minute hyperthermic treatment on day 8.5 of gestation, with 44.3% of their offspring having exencephaly. The other strains used in these studies (LM/Bc, SWR/J, C57BL/6J, and DBA/2J) all had less than 14% affected offspring. In experimental situations where the environment is held constant and the only difference between the strains is their genotype, it is assumed that the difference in response to a teratogen is genetically mediated. To test the hypothesis that several genes are involved, reciprocal crosses were made between strains of high, moderate, and low sensitivity. When this was done, the high sensitivity of the SWV strain was lost in the F1 hybrid, implying not only that multiple genes are involved, but that it is the embryo's genotype and not the maternal genotype that is the major factor in determining susceptibility to heat-induced neural tube defects.     

Teratogenic interaction of ethanol and hyperthermia in mice

Alcohol and maternal hyperthermia have been implicated in human birth defects. Both ethanol and heat can induce neural tube defects (NTDs) and other developmental abnormalities in mice when large doses are given during pregnancy. To explore the teratogenic interaction of both agents, pregnant ICR mice were injected with a single dose of 25% ethanol and/or were heat-stressed in a water bath at 42 degrees C on the morning of Day 8 of gestation. Combined treatment with ethanol (0.01-0.02 ml/g) and heat (10 min), when they were given concurrently or 1 hr apart, resulted in a significant increase of resorptions and externally malformed fetuses. Skeletal malformations and visceral variations also increased significantly following a concurrent exposure to both agents. These results indicate that ethanol and heat can be synergistically teratogenic in mice when the doses of each agent are below the teratogenic threshold. It was also suggested that pretreatment with a small dose of ethanol may not enhance the teratogenicity of heat when the hyperthermic stress is strong enough and teratogenic by itself.     

Pharmacological evidence for adrenergic activation of hyperthermic responses associated with psychosocial stimulation

1. Brief social encounters between strange voles living adjacent compartments of a population cage lead to rapid increases of more than 1 degrees C in their core temperatures. 2. Socially induced core temperature responses remain elevated for more than 1 hr following social contact, and are of greater amplitude and duration than can be elicited by handling, noise or exercise. 3. Pretreatment of opponents with adrenergic blockers reduces the amplitude and duration of hyperthermic response proportional to drug intake; both alpha and beta blocking effects are completely reversed within 24 hr. 4. The dynamics of the hyperthermic response and effects of the drugs suggest that the rapid rise in core temperature is due to both vasoconstrictor (alpha) heat conservation and metabolic (beta) heat generating mechanisms, and that the protracted elevation of core temperature is primarily due to (beta) metabolic activation.     

Effects of hyperthermia on cerebral blood flow and metabolism during prolonged exercise in humans.

The development of hyperthermia during prolonged exercise in humans is associated with various changes in the brain, but it is not known whether the cerebral metabolism or the global cerebral blood flow (gCBF) is affected. Eight endurance-trained subjects completed two exercise bouts on a cycle ergometer. The gCBF and cerebral metabolic rates of oxygen, glucose, and lactate were determined with the Kety-Schmidt technique after 15 min of exercise when core temperature was similar across trials, and at the end of exercise, either when subjects remained normothermic (core temperature = 37.9 degrees C; control) or when severe hyperthermia had developed (core temperature = 39.5 degrees C; hyperthermia). The gCBF was similar after 15 min in the two trials, and it remained stable throughout control. In contrast, during hyperthermia gCBF decreased by 18% and was therefore lower in hyperthermia compared with control at the end of exercise (43 +/- 4 vs. 51 +/- 4 ml. 100 g(-1). min(-1); P < 0.05). Concomitant with the reduction in gCBF, there was a proportionally larger increase in the arteriovenous differences for oxygen and glucose, and the cerebral metabolic rate was therefore higher at the end of the hyperthermic trial compared with control. The hyperthermia-induced lowering of gCBF did not alter cerebral lactate release. The hyperthermia-induced reduction in exercise cerebral blood flow seems to relate to a concomitant 18% lowering of arterial carbon dioxide tension, whereas the higher cerebral metabolic rate of oxygen may be ascribed to a Q(10) (temperature) effect and/or the level of cerebral neuronal activity associated with increased exertion.     

Parturition in gilts: duration of farrowing, birth intervals and placenta expulsion in relation to maternal, piglet and placental traits

Large White x Meishan F2 crossbred gilts (n = 57) were observed continuously during farrowing while the placentae of their offspring were labeled in order to examine the duration of farrowing and placenta expulsion in relation to maternal-, piglet- and placental traits and the duration of birth interval in relation to birth weight, birth order and placental traits. Independently from each other, litter size, gestation length and offspring directed aggression significantly (P 0.05) affected duration of farrowing. An increase in litter size was associated with an increase of duration of farrowing and an increase in gestation length was associated with a decrease of duration of farrowing. Aggressive gilts took longer to farrow, compared to non-aggressive ones. After taking into account litter size, gestation length and offspring directed aggression, placental thickness (i.e., placental weight corrected for placental surface area) was significantly (P < 0.05) related to duration of farrowing, i.e., litters with on average thicker placentae took longer to farrow. The latter effect is the result of the fact that individual placental thickness significantly (P < 0.01) affected individual birth interval, independent of birth weight. The piglet has to break its own membranes to be able to start its journey through the uterus towards the birth channel. Apparently, a thicker placenta offers more resistance and thus prolongs the process of birth. Independent of placental thickness, birth interval significantly (P < 0.01) decreased with an increase in birth order (first born to last born). The high variation of birth intervals for the last born piglets, caused a slight increase in average birth interval for the latter piglets. Litters with on average more areolae per placenta took significantly (P < 0.001) less time to be born than litters with on average less areolae per placenta (independent of total number of piglets born and other placental traits), while birth intervals within litters were not affected by this trait. Thus, these results are probably due to a gilt trait rather than a piglet trait. Since the number of areolae represent the number of uterine glands present, the gilt trait might be uterine development. Duration of placenta expulsion significantly (P < 0.01) increased with an increase of duration of farrowing. Furthermore, the first placenta was expelled significantly (P < 0.01) earlier relative to last piglet when duration of farrowing was protracted, while there was no relation of the time interval between first placenta and last piglet and the duration of placenta expulsion. In conclusion, the most important finding of this study is that placental thickness rather than birth weight appears to play an important role in the duration of birth intervals and as a result, of duration of parturition in gilts.     

Effects of Maternal Basking and Food Quantity during Gestation Provide Evidence for the Selective Advantage of Matrotrophy in a Viviparous Lizard

The evolution of matrotrophy (i.e., direct supply of nutrients by the mother during gestation) may be associated with high maternal energy availability during gestation. However, we lack knowledge about the selective advantages of matrotrophic viviparity (live-bearing) in reptiles. In reptiles, the interaction between body temperature and food intake affect maternal net energy gain. In the present study, we examined the effects of basking and food availability (2 by 2 factorial design) during gestation on offspring phenotype in a matrotrophic viviparous lizard (Pseudemoia entrecasteauxii). Subsequently, we investigated if the maternal effects were context-dependent using offspring growth rate as an indicator of the adaptive significance of matrotrophy. Offspring were exposed either to the same thermal conditions as their mothers experienced or to thermal conditions different from those experienced by their mothers. We provide the first evidence that an interaction between maternal thermal and maternal food conditions during gestation strongly affects offspring phenotype, including date of birth, body size and performance ability, which affect offspring fitness. Offspring growth rate was dependent on offspring thermal conditions, but was not influenced by maternal effects or offspring sex. Matrotrophic viviparity provided gravid females with the means to enhance offspring fitness through greater energetic input to offspring when conditions allowed it (i.e., extended basking opportunity with high food availability). Therefore, we suggest that selective advantages of matrotrophic viviparity in P. entrecasteauxii may be associated with high maternal energy availability during gestation.     

Reproduction in female copperhead snakes (Agkistrodon contortrix): plasma steroid profiles during gestation and post-birth periods

We investigated levels of plasma progesterone (P4), 17β-estradiol (E2), testosterone (T), and corticosterone (CORT) during gestation and post-birth periods in wild-collected female copperhead snakes (Viperidae; Agkistrodon contortrix). We also sought to determine whether CORT levels at (or near) birth dramatically increase and were correlated with duration of labor and litter size. Specifically, pregnant subjects (N = 14) were collected during early- to mid-gestation, held in the laboratory, and repeatedly bled to obtain plasma for steroid analyses. Progesterone showed significant changes during gestation, with the highest levels at the onset of sampling (circa 50 days prior to birth); P4 progressively declined up to parturition, and basal levels were observed thereafter. At the onset of sampling, E2 was at peak levels and fell sharply at circa 30 days prior to birth, a trend observed throughout the post-birth sampling period. Throughout the entire sampling period, T was undetectable. Although CORT showed no significant changes during gestation and several days following parturition, there was a highly significant peak at the time of birth. Our findings mirror the results of previous studies on pregnancy and steroid hormones of other live-bearing snakes, lizards, and mammals. As expected, there was a significant relationship between duration of labor and litter size; however, although levels of CORT did not achieve significance, there was a positive trend with litter size. We suggest that elevation of CORT at birth is involved in the mobilization and regulation of energy stores necessary for the physiological process of parturition and as a possible mechanism to trigger birth.     

Timing of birth in Syrian hamsters.

The effects of mating time and of LD cycles on the timing of birth and length of gestation were examined in Syrian hamsters (Mesocricetus auratus). Hamsters maintained on 14L:10D cycles were mated for 2 h either in the evening or in the morning, and groups of hamsters mated in the morning were subjected to either a 6-h advance shift or a 6-h delay shift of the LD cycle on Days 5-14 of gestation. For the last 2 days of gestation the hamsters were kept in constant dim light and observed every hour to determine the time of birth. Hamsters mated in the evening gave birth an average of 4.8 h before those mated in the morning, and the hamsters subjected to an advance shift gave birth an average of 8.1 h before those subjected to delay shift. The results show that 80-100% of births occur during the subjective day on Day 16 of gestation and that the minimum duration of gestation is 15 days and 2 h. The regulation of birth appears to involve two processes, an interval timer related to the time of conception and a circadian rhythm that is governed by the LD cycle.     

Acute undernutrition is not associated with excess of females at birth in humans: the Dutch hunger winter

It has been suggested that maternal undernutrition results in adjustment of the sex ratio at birth, favouring females. We tested this hypothesis using births during the Dutch Hunger Winter of 1944-1945, an acute severe famine of seven months' duration. There was no evidence of an excess of female births among deliveries of human infants exposed to famine in any period in gestation. Indeed, among deliveries to women maximally exposed to famine prior to conception, there was an excess (odds ratio = 1.31, 95% CI 1.09-1.58; p = 0.004) of male offspring. Our data do not provide any support for acute and severe maternal undernutrition as a trigger for an increase in female conceptions or in male foetal deaths in human populations.     

Thermal environment and human birth weight

Human birth weight is known to be influenced by several factors, including maternal energy supply, maternal stature, disease status, smoking status and gestation length. This article proposes that the thermal environment may be a further factor influencing birth weight. Experimental animal studies demonstrate clear effects of thermal stress on placental function and birth weight, but may have limited relevance for humans due to between-species differences in pregnancy physiology. Observational studies suggest an inverse relationship between environmental temperature and birth weight within and between human populations. Variation in maternal size, body fatness, pregnancy weight gain and heat production is predicted to influence maternal thermoregulatory capacity, as are the size and composition of the foetus. These associations generate the hypothesis that low birth weight in hot environments may in part represent an adaptation to environmental heat stress.     

中国出生缺陷遗传学研究的回顾与展望

减少出生缺陷是我国“健康中国2030”规划中的重要组成部分。遗传因素单独或协同作用导致了超过80%的出生缺陷疾病。与出生缺陷相关的遗传学研究可为临床筛查、诊断和治疗提供精准的分子靶标。我国的出生缺陷遗传学研究自20世纪60年代以来取得了长足的发展。同时,随着相关研究成果的不断涌现,以遗传咨询和检测为核心的临床转化工作也在不断深化和完善。基础研究与临床应用的紧密结合,将为我国孕育“健康孩”提供可靠的技术保障。本文首先回顾了我国出生缺陷遗传学研究的历史,继而介绍当前国内外出生缺陷遗传学研究的现状和热点,最后对未来的研究方向及相关的临床应用趋势进行展望和讨论,旨在为读者提供了一个全局性的视角来认知我国的出生缺陷遗传学研究发展之路。     

Histological evidence for the role of mechanical stress in modulating thermal denaturation of collagen

The hyperthermia and thermal denaturation literatures reveal a time-temperature equivalency when heating cells or connective tissues: thermal damage increases with increasing temperature (for the same duration) and increases with increasing duration (for the same temperature). Recent findings conversely suggest that increasing the mechanical loading on a tissue during heating decreases the thermal damage (for a given temperature and duration of heating). Surprisingly, however, there are few histological correlates of such damage. In this paper, we show that progressive light microscopic changes – swelling of collagen bands, thickening of collagen-rich layers, hyalinization, and loss of birefringence~– correlate very well with both increased heating times and decreased mechanical loading. Increased mechanical stress is thus thermally protective and should be considered in the design of clinical procedures that use heating to treat diseases or injuries. P. B. Wells and S. Thomsen contributed equally to this work.     

Integrin and cytoskeleton behaviour in human neuroblastoma cells during hyperthermia-related apoptosis

Hyperthermia induces several cellular responses leading to morphological changes, cell detachment and death. Loss of integrins from the cell surface after acute heat-treatment may block several physiological signalling pathways, but whether the assembly network between integrin and cytoskeletal actin is perturbed during hyperthermic treatment is unknown. In this study we tested this hypothesis by evaluating cell morphology, protein cytoskeletal profile and integrin CD11a content in both adherent and floating SK-N-MC human neuroblastoma cells. Morphological and cytometric analyses confirmed that hyperthermia is an effective apoptotic trigger, revealing the typical chromatin margination, cell shape changes and 7-AAD incorporation. After hyperthermia, cytoskeletal proteins showed an increase of high-molecular-weight aggregates and a significant decrease of both actin and CD11a content with respect to control cells. The integrin CD11a and membrane-bound actin alterations found in detached floating neuroblastoma cells recovered after heat-shock may cause the cytoskeletal abnormalities related to the observed surface cell rounding/blebbing and anoikis, early events of hyperthermia-induced programmed cell death.     

Factors Affecting Date of Implantation,Parturition, and Den Entry Estimated from Activity and Body Temperature in Free-Ranging Brown Bears

Knowledge of factors influencing the timing of reproduction is important for animal conservation and management. Brown bears (Ursus arctos) are able to vary the birth date of their cubs in response to their fat stores, but little information is available about the timing of implantation and parturition in free-ranging brown bears. Body temperature and activity of pregnant brown bears is higher during the gestation period than during the rest of hibernation and drops at parturition. We compared mean daily body temperature and activity levels of pregnant and nonpregnant females during preimplantation, gestation, and lactation. Additionally we tested whether age, litter size, primiparity, environmental conditions, and the start of hibernation influence the timing of parturition. The mean date of implantation was 1 December (SD = 12), the mean date of parturition was 26 January (SD = 12), and the mean duration of the gestation period was 56 days (SD = 2). The body temperature of pregnant females was higher during the gestation and lactation periods than that of nonpregnant bears. The body temperature of pregnant females decreased during the gestation period. Activity recordings were also used to determine the date of parturition. The parturition dates calculated with activity and body temperature data did not differ significantly and were the same in 50% of the females. Older females started hibernation earlier. The start of hibernation was earlier during years with favorable environmental conditions. Dates of parturition were later during years with good environmental conditions which was unexpected. We suggest that free-ranging pregnant brown bears in areas with high levels of human activities at the beginning of the denning period, as in our study area, might prioritize investing energy in early denning than in early parturition during years with favorable environmental conditions, as a strategy to prevent disturbances caused by human.     

Maternal factors in congenital limb-reduction defects

Various maternal characteristics were examined in case-control studies of limb-reduction defects among live births in Upstate New York (i.e., New York State exclusive of New York City). In a study using birth records of 305 cases and 915 controls born in 1970-81, mean birth weight and gestation length were significantly lower in cases than in controls, and certain pregnancy complications (i.e., abnormal vaginal bleeding and diabetes mellitus) were reported more often in cases than in controls. Several subgroups of defects (i.e., isolated defects vs. multiple, long-bone defects vs. other) were also compared with their respective controls. The subgroup with multiple (including nonskeletal) defects had the lowest mean birth weight and length of gestation. In an interview study of 108 cases and 108 controls born in 1968-74, a history of maternal use of thyroid medication was a significant risk factor; possible explanations for this association are discussed.