Postnatal morphological lung development of wild type and CD26/DPP4 deficient rat pups in dependency of LPS exposure.

BACKGROUND: Rodents are born with morphological immature lungs and an intact surfactant system. CD26/DPP4 is a multifactorial transmembrane integral type II protein, which is involved in physiological and pathophysiological processes and is already expressed during development. CD26/DPP4, called CD26 in the following, is able to enhance or dampen differently triggered inflammation. LPS exposure often used to simulate perinatal infection delays lung development. OBJECTIVE: A perinatal LPS rat model was used to test the hypothesis that CD26 deficiency modulates LPS-induced retardation in morphological lung development. METHODS: New born Fischer CD26 positive (CD26+) and deficient (CD26-) rats were exposed to LPS on postnatal day (day post partum, dpp) 3 and 5. Morphological parameters of lung development were determined stereologically. Lung development was analysed in 7, 10 14 and 21day old rats. RESULTS: Compared to controls LPS application resulted (1) in a mild inflammation independent of the strain, (2) in significantly lower total surface and volume of alveolar septa combined with significantly higher total volume of airspaces and alveolar size on dpp 7 in both substrains. However, compared to controls in LPS treated CD26- rats significant lower values of total septal surface and volume combined with higher values of total parenchymal airspaces and alveolar size were found until the end of classical alveolarization (dpp14). In LPS treated CD26+ rat pups the retardation was abolished already on dpp 10. CONCLUSION: In absence of CD26, LPS enhances the delay of morphological lung development. Morphological recovery was slower after the end of LPS exposure in CD26 deficient lungs.

A rat RNA-Seq transcriptomic BodyMap across 11 organs and 4 developmental stages.

The rat has been used extensively as a model for evaluating chemical toxicities and for understanding drug mechanisms. However, its transcriptome across multiple organs, or developmental stages, has not yet been reported. Here we show, as part of the SEQC consortium efforts, a comprehensive rat transcriptomic BodyMap created by performing RNA-Seq on 320 samples from 11 organs of both sexes of juvenile, adolescent, adult and aged Fischer 344 rats. We catalogue the expression profiles of 40,064 genes, 65,167 transcripts, 31,909 alternatively spliced transcript variants and 2,367 non-coding genes/non-coding RNAs (ncRNAs) annotated in AceView. We find that organ-enriched, differentially expressed genes reflect the known organ-specific biological activities. A large number of transcripts show organ-specific, age-dependent or sex-specific differential expression patterns. We create a web-based, open-access rat BodyMap database of expression profiles with crosslinks to other widely used databases, anticipating that it will serve as a primary resource for biomedical research using the rat model.

Age-specific absolute and relative organ weight distributions for Fischer 344 rats.

The Fischer 344 (F344) rat has been the standard rat strain used in toxicology studies conducted by the National Cancer Institute (NCI) and the National Toxicology Program (NTP). However, the numerous reports published to date on growth, survival, and tumor incidence have not included an overall compilation of organ weight data. Notably, dose-related organ weight effects are endpoints used by regulatory agencies to develop toxicity reference values (TRVs) for use in human health risk assessments. In addition, physiologically-based pharmacokinetic (PBPK) models, which utilize relative organ weights, are increasingly being used to develop TRVs. Because a compilation of organ weights for F344 rats could prove beneficial for TRV development and PBPK modeling, all available absolute and relative organ weight data for untreated control F344 rats were collected from NCI/NTP feed, drinking-water, and inhalation studies in order to develop age-specific distributions. Results showed that organ weights were collected more frequently at 2-wk (59 studies), 3-mo (148 studies), and 15-mo (38 studies) intervals than at other intervals and more frequently from feeding and inhalation than from drinking-water studies. Liver, right kidney, lung, heart, thymus, and brain weights were most frequently collected. From the collected data, the mean and standard deviation for absolute and relative organ weights were calculated. Findings showed age-related increases in absolute weights and decreases in relative weights for brain, liver, right kidney, lung, heart, thyroid, and right testis. The results suggest a general variability trend in absolute organ weights of brain < right testis < heart < right kidney < liver < lung < thymus < thyroid.

Aging cochleas in the F344 rat: morphological and functional changes.

The Fischer 344 rat strain has been frequently used as an animal model of rapid aging. The present study was aimed at evaluating the incidence of apoptotic cells in the inner ear of 20-24-month-old F344 rats and to correlate it with cochlear function using otoacoustic emissions. Staining with cresyl violet and the enzymatic labeling (terminal deoxynucleotidyl transferase, TdT) of fragmented DNA revealed large numbers of apoptotic cells in the marginal and basal layers of the stria vascularis and in adjacent cells of the spiral ligament. The amplitudes of distortion products otoacoustic emissions (DPOAEs), which reflect functional state of the outer hair cells, were significantly reduced or totally absent in these animals. In contrast to old F344 rats, no marked DPOAE amplitude reduction and smaller numbers of apoptotic cells were found in young 4-month-old F344 rats or in aged 24-28-month-old Long Evans rats. The accumulation of apoptotic cells, mainly in the basal layer of the stria vascularis and in adjacent cells of the spiral ligament, leads to a detachment of the stria vascularis from the spiral ligament and results in the impairment of outer hair cell function. This specific type of strial deterioration suggests that aged F344 rats can serve as an animal model of strial presbycusis.

Lectin-like oxidized low-density lipoprotein (LDL) receptor (LOX-1)-mediated pathway and vascular oxidative injury in older-age rat renal transplants.

BACKGROUND: Older-age renal allografts are associated with inferior survival; however, the mechanisms are unclear. Reactive oxygen species participate in aging and in chronic vascular disease. We investigated how mediators of oxidative stress may increase allograft susceptibility to vascular injury. METHODS: We employed the low-responder allogeneic F344-to-Lew rat renal transplantation model. We used nonimmunosuppressed young (donors and recipients aged 12 weeks), old (donors and recipients aged 52 weeks), and old-to-young animal (donors aged 52 weeks and recipients aged 12 weeks) combinations. Grafts were transplanted after 2 hours cold preservation in University of Wisconsin solution and harvested 1, 2, 7 and 10 days later. Additionally, old animals receiving continuous 1.5 mg/kg cyclosporine (CyA) immunosuppression were included. Renal allograft pathology was scored according to Banff criteria. We studied intragraft vascular adhesion molecule-1 (VCAM-1), lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1), and hypochlorite-modified LDL expression as well as ED-1+ monocytes/macrophages and CD8+ lymphocyte infiltration. Intragraft in situ superoxide anion radical production was determined with dihydroethidium assay on cryosections. RESULTS: During the first 2 posttransplant days, old transplants demonstrated higher functional impairment and increased oxidative stress, while young transplant had higher ED-1+ monocytes/macrophage infiltration and VCAM-1 expression. The degree of VCAM-1 expression and ED-1+ monocytes/macrophage and CD8+ lymphocyte infiltration correlated at later time points directly with the transplant age. VCAM-1 and LOX-1 staining were localized predominantly on the endothelium of arterial vessels, shifting the distribution to vascular smooth muscle layer strongly dependent on donor age and the grade of vascular injury. LOX-1 staining colocalized with hypochlorite-modified epitopes in the media of injured arteries. We measured increased in situ superoxide anion radical production in corresponding areas. Immunosuppression with CyA had no protective effect on vascular injury and LOX-1 expression. CONCLUSION: Induction of LOX-1-related oxidation pathways and increased susceptibility to oxidative stress could play an important role in promoting vascular injury in old renal transplants independent of the recipient age.

Energy metabolism and thyroid hormone levels of growing rats in response to different dietary proteins--soy protein or casein.

Energy balances were measured by indirect calorimetry in four experiments on male growing rats, fed restrictively on isoenergetic and isonitrogenous (10% CP) diets based on either casein supplemented with methionine, or soy protein isolate (experiments 1, 2 and 3) and soy protein isolate supplemented with methionine (experiment 0), respectively. At the end of experiments the rats were killed for body analysis and determination of thyroid hormones and lipids in blood as well as mitochondrial respiration in liver and heart. Feeding of non-supplemented soy protein resulted in a lower efficiency of energy utilisation as well as a lower protein utilisation compared to casein-fed and supplemented soy protein-fed rats. Chemical body composition was not markedly different between the dietary groups. After long-term feeding of soy protein (experiment 3) mass and mitochondrial protein content of the interscapular brown adipose tissue were increased compared to casein-fed rats. Serum thyroid hormone levels were not changed (T3 and free T3) or were significantly lowered (T4 and free T4) following soy protein feeding in comparison with casein feeding (except for experiment 2). Cholesterol and triglycerides were decreased on an average in response to soy protein or supplemented soy protein feeding. In two of three experiments a significant lower efficiency of hepatic mitochondrial respiration with succinate as substrate, expressed by the ratio of added ADP to oxygen consumed, was observed in soy protein-fed rats compared to casein-fed rats.

Organ weights and fat volume in rats as a function of strain and age.

The Fischer 344 (F344) rat and the Sprague-Dawley (SD) rat are used commonly to evaluate potential adverse health effects resulting from environmental exposure to chemicals. They are also the most common rat strain/stock used in physiologically based pharmacokinetic (PBPK) modeling. Accurate characterization of model input parameters will improve the usefulness of PBPK model predictions. Thus, organ (i.e., liver, kidneys, spleen, stomach, small intestine, large intestine, heart, lungs, brain) weights and body fat were measured in male SD rats of different ages (4 to 40 wk) and in young (9 to 10 wk) and old (22 to 23 mo) male F344 rats. Comparison of age-matched (9 to 10 wk) F344 and SD rats revealed that the SD rats weighed significantly more and had significantly higher absolute organ weights. These significant differences usually disappeared when organ weights were expressed as a percentage of body weight (relative organ weight). Percent body fat was significantly lower in the age-matched SD rats (6.48%) than in their F344 counterparts (8.67%). As expected, both body weight and absolute organ weights were significantly higher in old than in young F344 rats. However, these differences were largely reversed when relative organ weights were considered, with most relative organ weights significantly lower in the old F344 rats. Body fat as a percentage of body weight was 14.02% in the old F344 rats. When SD rats of various ages were examined, relative organ weights declined between the ages of 4 and 14 wk. In contrast, significant differences in percent body fat were not detected among the SD rats of different ages and weights examined in this study (4 to 40 wk, approximately 75 to approximately 450 g). In summary, values for physiological input parameters are provided that should prove useful in development and implementation of more accurate PBPK models.

Whole body protein turnover of growing rats in response to different dietary proteins--soy protein or casein.

Whole body protein turnover was studied in growing rats fed restrictively on isoenergetic (GE 17.6 MJ/kg DM) and isonitrogenous (104 g CP/kg DM) diets based on soy protein isolate or casein supplemented with D,L-methionine. During each of the three separate experiments six male Fischer rats per group were housed individually in metabolic cages at 24 degrees C. Prefeeding of both dietary groups up to similar body weights at the start of the main experimental periods (105-134 g) lasted up to 16 d for casein-fed rats and up to 30 d for the soy protein-fed rats. Following the energy and nitrogen balance periods whole-body protein synthesis was estimated by the end-product method using a single tracer dose of a mixture of 15N-labelled amino acids. Fractional protein accretion rate [% of the protein pool accreted per day] was significantly lower in soy protein-rats than in casein-fed rats in all three experiments whereas fractional synthesis rate was not significantly lower. Therefore, protein breakdown subsequently calculated as the difference between synthesis and accretion showed a tendency towards higher values in this group. In soy protein-fed rats also a tendency towards higher excretion of 3-methylhistidine as a marker of myofibrillar protein breakdown was observed. It is concluded that increase in lean tissue growth resulting from improved protein quality is brought about by changes of both rates, by small increase of protein synthesis and by reduced rate of body protein breakdown.

Decreased synaptic density in aged brains and its prevention by rearing under enriched environment as revealed by synaptophysin contents.

Changes in synaptic density in various brain regions were assessed among different age groups of rats maintained in ordinary small cages, as determined by synaptophysin assay. The synaptophysin content in hippocampus decreases as early as in the adult stage. The most remarkable decrement occurs in occipital cortex. In other regions, synaptophysin contents decrease in senescence to 60-77% of the respective peak values during young and adult stages. The other rat group reared under enriched environment in a large cage until 30 months of age was examined for synaptic density, and was revealed to maintain the similar levels as in young, or even higher levels in frontal, temporal, entorhinal cortices and hippocampus. These results indicate that the synaptic density in cerebrum decreases in senescence and this decrease can be prevented by rearing under enriched environment.

Hippocampal plasticity induced by primed burst, but not long-term potentiation, stimulation is impaired in area CA1 of aged Fischer 344 rats.

The effect of two types of electrical stimulation designed to induce long-lasting plasticity of the Schaffer/commissural inputs to CA1 pyramidal neurons was investigated using in vitro hippocampal slices made from young (3-6 month) and old (24-27 month) Fischer 344 rats. The first stimulation paradigm, primed burst (PB) stimulation, consisted of a total of five physiologically patterned stimuli: a single priming pulse followed 170 ms later by a burst of four pulses at 200 Hz. The second stimulation paradigm, long-term potentiation (LTP) stimulation, consisted of a 200 Hz/1 second train (a total of 200 stimuli). Primed burst and LTP stimulation were equally effective at inducing a lasting increase in the population spike recorded from slices made from young rats. However, the enhancement of population spike amplitude produced by PB, but not LTP, stimulation was significantly less in slices made from old rats. These results suggest that the capacity of the hippocampus to demonstrate long-lasting synaptic plasticity is not altered with age, but that engaging plasticity-inducing mechanisms becomes more difficult. Furthermore, these data suggest that physiologically patterned paradigms for inducing long-lasting synaptic plasticity may more accurately assess the functional status of hippocampal memory encoding mechanisms than does conventional LTP stimulation.

An extended developmental study of gamma-glutamyltranspeptidase in rat liver plasma membranes: identification of specific patterns of changes in activity in the adult as well as the neonatal state.

Homogenates and plasma membranes were isolated from the livers of male Fischer 344 rats ranging in age from 19 hr to 92 days postnatal. These plasma membranes exhibited comparable levels of purity: protein yields were 2-2.5%; relative specific activities of 5'-nucleotidase and ouabain-sensitive Na+/K(+)-ATPase were from 8-11 and from 12-19, respectively. 5'-nucleotidase and ouabain-sensitive Na+ K(+)-ATPase displayed distinct and different developmental patterns. The activity of gamma-glutamyltranspeptidase was found to be at exceptionally high levels in isolated plasma membranes immediately after birth and to decline precipitously thereafter achieving and maintaining low levels from days 3-21 postnatal. Liver plasma membrane gamma-glutamyltranspeptidase activity was observed to increase 9.2 fold from this low point, first rising on day 21, peaking on day 40 and returning to low levels by day 56. From day 56 day to 92 postnatal, gamma-glutamyltranspeptidase activity was expressed at a uniformly low level but a level 2 fold higher than that preceding the rise at day 40. The hormone determinants of these developmental changes in gamma-glutamyltranspeptidase activity are discussed.

Kinetics of 1,25-dihydroxyvitamin D metabolism in the aging rat.

To determine whether postmaturational aging influences the kinetics of 1,25-dihydroxyvitamin D [1,25(OH)2D] metabolism in the rat, we measured the metabolic clearance (MCR) and production (PR) rates of 1,25(OH)2D in 6-, 12-, 18-, and 24-mo-old Fischer 344 rats using the constant infusion method. Plasma calcium, phosphorus, and parathyroid hormone (PTH), urinary calcium and phosphorus, and glomerular filtration rate (GFR) were also measured. MCR and PR increased 57 and 91%, respectively (when expressed per rat), and 32 and 39%, respectively (when expressed per kg body wt), between 6 and 24 mo of age, with the greatest increase occurring between 18 and 24 mo. The plasma concentration of 1,25(OH)2D remained unchanged. Plasma PTH, when compared with 6-mo-old animals, was significantly elevated at 18 mo (147%) and even higher at 24 mo (240%). GFR (51Cr-labeled EDTA clearance) remained unchanged through 18 mo but tended to be reduced at 24 mo. Plasma phosphorus tended to decrease with age, whereas plasma calcium, urinary calcium, and urinary phosphorus did not differ among the age groups. These data indicate that both clearance and production of 1,25(OH)2D increase with postmaturational aging in the rat. They also suggest that the early age-related rise in plasma PTH is neither a consequence of low plasma calcium nor of renal insufficiency.

Neonatal sympathetic denervation alters the development of in vitro spleen cell proliferation and differentiation.

The ontogeny of spleen cell proliferation to T and B cell mitogens and immunoglobulin secretion, measured in vitro, was examined in neonatally sympathectomized Fischer 344 (F344) rats, administered the neurotoxic drug 6-hydroxydopamine (6-OHDA) from 1 to 3 days of age. Compared to cells from age-matched controls, spleen cells from neonatally sympathectomized animals, aged 7-14 days, exhibited a shift in the proliferative response to the T cell mitogen, concanavalin A (Con A), with reduced proliferation in the presence of low doses of Con A, but increased proliferation with higher doses. During the same period, from 7 to 14 days, the B cell mitogen STM/DxS inhibited proliferation by spleen cells from all rats, and no effect of sympathectomy was observed. As adult-like patterns of mitogen responsiveness emerged from 21 to 42 days of age, neonatally sympathectomized rats showed reduced proliferative responses of both T and B cells. This effect dissipated by 56 days of age. Polyclonal immunoglobulin (Ig) production by B cells was assessed in vitro in the presence or absence of STM/DxS. Neonatal sympathectomy resulted in reduced spontaneous IgM production throughout development. From 28 to 42 days of age, when mitogen-triggered IgM secretion first developed, neonatal sympathectomy decreased the magnitude of the response. By 56 days of age, mitogen-induced IgM secretion was no longer affected by sympathectomy, similar to the proliferative response. Gender influenced the time course of sympathectomy-induced changes in spleen cell proliferation and differentiation; however, the magnitude and direction of these changes were similar in both males and females. Desipramine, administered prior to 6-OHDA, prevented both sympathetic denervation and the 6-OHDA-induced changes in spleen cell responsiveness. This indicates that the alterations in immune function were dependent on NA nerve fiber destruction and were not simply the result of direct 6-OHDA action on other cells. The results of this study suggest that sympathetic innervation may play an important potentiating role in the development of the lymphoid system, through effects on lymphocyte proliferation and differentiation.

Chloropentafluorobenzene: short-term inhalation toxicity, genotoxicity and physiologically-based pharmacokinetic model development.

Ten Fischer 344 rats and six B6C3F1 mice of each sex were exposed to air, 0.25, 0.80, or 2.50 mg chloropentafluorobenzene (CPFB)/liter of air for three weeks, excluding weekends. Exposure to 2.50 mg/liter caused a reduction in the growth rate of rats but did not affect the growth rate of mice. Following the exposure there was reduced SGOT activity in the blood serum of exposed rats and a dose related increase in liver weights. Increased liver weights were observed in mice as well; the response in the female groups was clearly dose dependent. Histologically the livers of both rats and mice presented single cell necrosis. In exposed mice hepatocytes exhibited mild hepatocytomegaly with increased granular eosinophilic cytoplasm. In evaluations for its potential to induce chromosomal damage following this exposure regimen, CPFB did not alter the rate of bone marrow cellular proliferation. Assessment of the micronucleated polychromatic erythrocytes and normochromatic erythrocyte populations during the inhalation exposures indicated a general absence of genotoxic activity.

Growth, body weight, survival, and tumor trends in F344/N rats during an eleven-year period.

Time trends for growth, body weight, survival and tumor prevalences in 144 diet control groups with a total of 5,184 male F344/N rats and 146 diet control groups with a total of 5,289 female rats of NCI-NTP 2-yr chemical carcinogenicity studies started during an 11-yr period (1971 to 1981) in 11 toxicology testing laboratories were evaluated. Male and female rats in more recent studies grew faster and attained a higher body weight than rats from earlier studies. Survival of males showed a significantly decreasing trend over time, which may have been related to diseases associated with increasing body weight, prevalence of leukemia and changes in criteria for euthanasia of moribund animals. The time trend for survival of females was not significant. There were highly significant (p less than 0.001) positive time trends for prevalences of leukemia, anterior pituitary tumors and thyroid C-cell tumors in both sexes, adrenal pheochromocytomas in males and mammary tumors and endometrial stromal polyps in females. The prevalence of mammary tumors in females and pituitary tumors in males had a highly significant (p less than 0.01) positive association with body weight. Histological reevaluation of tumor prevalences in approximately 250 rats of each sex at each of 4 different time periods indicated that changes in diagnostic criteria may have contributed to but could not totally explain the increased prevalence of leukemia. Changes in diagnostic criteria and the amount of tissue examined may have contributed to the increased prevalence of anterior pituitary tumors in both sexes and adrenal pheochromocytomas in males. Interlaboratory variability and changes in diet may also have contributed to the time-related trends.

On the role of the 200-kDa neurofilament protein at the developing neuromuscular junction.

To examine whether the 200-kDa neurofilament protein (200K NFP) is involved in mechanically stabilizing axons, we studied the developmental appearance of immunoreactivity to nonphosphorylated and phosphorylated 200K NFP at the neuromuscular junction. Polyinnervated rat muscle fibers become singly innervated during the first 3 weeks of postnatal life through the process of synapse elimination. If production or post-translational modification of the 200K NFP is actively involved in imparting mechanical stability on neuromuscular synapses, then the selective presence of this protein in only one of several axons at each developing end plate region might make that one axon selectively resistant to elimination. The remaining axons would then be eliminated. Immunoreactivity to the 200K NFP is present on Gestational Day 14 and can be seen in more than one preterminal axon in the end plate region of a muscle fiber during the period of synapse elimination. These results suggest that the 200K NFP is present and phosphorylated early in development and, although the 200K NFP may increase the mechanical stability of axons, this increased stability does not determine the final outcome of synapse elimination.

Studies of sequence heterogeneity of mitochondrial DNA from rat and mouse tissues: evidence for an increased frequency of deletions/additions with aging.

To obtain information on the extent of random nucleotide changes in mitochondrial DNA (mtDNA) from different organs of young adult and senescent Fischer 344 rats, the temperature of thermal denaturation (tm) was measured in (1) the native mtDNA cut at a single SstI site and (2) the reannealed duplexes formed after the initial melting of the mtDNA sample. No change was found between the two tm values in either young or senescent mtDNA, suggesting that the overall mismatch in nucleotide sequence in these samples was below the resolution of the method estimated at about 0.2%. In another experiment, mtDNA samples from young adult or senescent BALB/c mouse liver were digested with EcoRI, denatured and allowed to reanneal. The duplexes formed by the 14-kb EcoRI fragment were analyzed in randomly taken electron micrographs for the occurrence of mismatched segments. About 1.8% of reconstituted duplexes in adult mtDNA and 11% of those in senescent mtDNA contained small loops or knobs suggestive of deletions/additions of about 400 +/- 150 nucleotides. These data correspond to about 1% of the native mtDNA population in adult liver and about 5% in senescent liver having deleted/inserted segments. Although deletions/insertions may occur at variable sites, their distribution appears to be non-random. These findings suggest that small sequence rearrangements, which have been observed previously in unicircular dimers of mouse and human mtDNA, occur also in monomeric mtDNA from normal tissues and accumulate with aging.

Vascular tissue (Na,K)ATPase activity and aging in the F344 rat.

Vascular tissue (heart, thoracic aorta and tail artery) was removed from Fischer 344 rats, 12, 18 and 27 months of age. The intact tissue was then used to determine total, ouabain-sensitive and ouabain-insensitive 86Rubidium (86Rb) uptakes, to provide a reflection of (Na,K)ATPase activity. These studies indicate no change in total, ouabain-sensitive nor ouabain-insensitive 86Rb uptakes into cardiac tissue isolated from these rats. However, tail artery total and ouabain-sensitive 86Rb uptake decreased with age (a 61% decrease in ouabain-sensitive 86Rb uptake in 12 vs. 27-month-old rats) without significant changes in the ouabain-insensitive 86Rb uptake. This pattern was repeated in aortic tissue with a 56% decrease in ouabain-sensitive 86Rb uptake in 12 vs. 27-month-old rats. The results of these studies support an age-related decline in (Na,K)ATPase activity in aortic and tail artery tissue without a significant change in cardiac (Na,K)ATPase activity between 12, 18 and 27-month-old Fischer 344 rats.

Periodic cessation of respiratory effort during sleep in adult rats.

Using a noninvasive technique which measures respiration as a function of chest and abdominal movement, it was found that adults rats have periodic cessations of respiratory effort during the daytime. In a preliminary study, male Fischer-344 rats had respiratory pauses of 2.4-2.6 seconds duration, which tended to be more frequent in older (22-month) compared to young adult (3-month) rats. Respiratory rate was lower and respiratory volume greater in the 22-month-old animals. In a more detailed study of 3-month-old male Sprague-Dawley rats, respiratory pauses were divided into two types: those preceded by a large inspiration ("sighs") and those which were not. The latter, which appear to be most analogous to human apneas of clinical interest, occurred in all animals studied, with a frequency of 13 to 26 events during six hour recordings. These pauses varied in duration from 2.0 to 6.1 seconds and were most frequent and longest in REM sleep.

A comparison of the response of woodchucks and rats to variations in dietary lipotrope and protein content.

Juvenile woodchucks and weanling Fisher F344 rats were fed purified diets with or without supplemental lipotropic factors (choline, methionine, folic acid and vitamin B-12). The diets contained 10 or 20% protein. Lower weight gain due to low protein was observed in both species, while lipotrope depletion resulted in lower gain in male rats only. Urinary excretion of formimino-glutamic acid was higher due to low lipotrope in both species, as was relative liver weight. In rats, lipotrope depletion resulted in hepatic fatty metamorphosis at both levels of dietary protein with the low protein diet resulting in more severe lesions. No liver lesions were observed in woodchucks fed low lipotropes at the higher level of dietary protein, but fatty metamorphosis was observed in those fed the lower protein diets. The lesion was more severe in the low lipotrope group. The woodchuck appears to be less sensitive than the rat to induction of fatty liver by lipotrope deficiency, although the lesion was induced by lowering dietary protein.