Intermittent hypoxia causes REM sleep deficits and decreases EEG delta power in NREM sleep in the C57BL/6J mouse.

BACKGROUND AND PURPOSE: Obstructive sleep apnea (OSA) severely impairs sleep architecture. We hypothesized that both intermittent hypoxia (IH) and non-hypoxic arousals of OSA result in significant disruption of non-rapid eye movement sleep (NREMS) and rapid eye movement sleep (REMS). PATIENTS AND METHODS: Polysomnography was performed in C57BL/6J mice (n=5) exposed to IH (cycling of FIO2 from 20.9 to 5.0%) or sleep fragmentation (SF: high flow air blasts) throughout the 12-h light phase over 5 consecutive days. RESULTS: Both IH and SF induced arousals from sleep. On Day 1 of exposure, total NREMS during the light phase decreased comparably during IH (44.1+/-7.8%/12h, P<0.05) and SF (43.7+/-3.3%/12h, P<0.05) but returned to baseline levels of 62.0+/-7.8%/12h by Day 5 of exposure under both conditions. During IH, however, the electroencephalographic (EEG) delta power of NREMS remained impaired throughout the 5-day period of IH with a nadir of 65.4+/-5.6% relative to baseline (P=0.01), and REMS was effectively abolished during the light phase. In contrast, SF did not cause a significant reduction in either EEG delta power or REMS during the light phase. CONCLUSIONS: Thus, hypoxic exposure, but not arousals, caused overall deficits in the EEG delta power of NREMS and marked deficits in the total amount of REMS. We propose that hypoxic arousals may have a more severe impact on sleep architecture in patients with OSA than non-hypoxic arousals.

Cynicism about organizational change: an attribution process perspective.

The underlying attribution process for cynicism about organizational change is examined with six samples from four different organizations. The samples include hourly (n=777) and salaried employees (n= 155) from a manufacturing plant, faculty (n=293) and staff (n=302) from a large university, managers from a utility company (n=97), and young managers (n=65) from various organizations who were attending an evening MBA program. This form of cynicism is defined as the combination of Pessimism (about future change efforts) and a Dispositional attribution (why past efforts to change failed). Three analyses support this definition. First, an exploratory factor analysis (from the largest sample) produced two factors, one composed of Pessimism and the Dispositional attribution items and the second of the Situational attribution items. Second, the average correlation (across several samples) between Pessimism and Dispositional attribution is much higher (.59) than the average correlation between Pessimism and Situational attribution (.17). Third, scores on two different trait-based measures of cynicism correlate highest with the Dispositional attribution component of cynicism. A practical implication is that organizational leaders may minimize cynicism by managing both employees' pessimism about organizational change and employees' attributions about it. Specific suggestions for how this might be done are offered.

Effect of hypothalamic electrolytic lesions in White Leghorn and broiler male cockerels.

1. This study compared the effect of bilateral electrolytic lesions of the basomedial hypothalamus (HL) in broiler and White Leghorn (WL) males. 2. Hypothalamic lesions were placed in WL at 10 weeks of age (body weight 1.1 kg) and in broilers, either at 6 weeks (body weight 1.5kg) or at 10 weeks of age (body weight 3.4kg). They were fed ad libitum until autopsy at 16 and 17 weeks of age for broilers and WL, respectively. 3. Hypothalamic lesions caused obesity (high percentage weight of abdominal adipose tissue) in both strains. Obese fowls with unimpaired reproductive systems were classified as OB and those with functional castration as FC (functionally castrated) or FCLC (functionally castrated with large comb). 4. All post-HL syndromes-OB, FC and FCLC-were present in WL, whereas all obese broilers (which are immature at this age) were classified as OB. 5. The percentage weight of abdominal adipose tissue in OB broilers was lower than in OB WL (3% vs 5%, respectively). 6. Daily food intake of OB broilers was higher than control at 12 to 15 weeks of age, regardless of time of placement of HL, whereas daily food intake of OB WL was significantly higher than that of control WL only during the first 2 weeks following HL. 7. Body weight of OB broilers at autopsy was 20% higher than control broilers, whereas body weight of OB WL was not significantly affected. 8. An additional group of broilers was reared to sexual maturity under food restriction until 28 weeks of age. HL were placed at 10 weeks of age (body weight 1.7 kg). Autopsy was performed after a 4-week period of ad libitum feeding. 9. There were OB as well as FC and FCLC among the HL, food-restricted broilers. Percentage weight of testes and spleen were reduced in OB fowls of both strains, but more so in OB WL. 10. Hyperphagia and weight gain were not observed during the ad libitum feeding period of those obese broilers after HL, indicating that hyperphagia and weight gain are secondary to obesity.

Differences in sleep-induced hypoxia between A/J and DBA/2J mouse strains.

In obstructive sleep apnea, hypoxic ventilatory sensitivity may affect the degree of hypoxic stress and sleep disruption that occurs in response to upper airway obstruction. We induced (1) sleep-induced hypoxia (SIH) or (2) sleep fragmentation (SF) without hypoxia for 5 days (12-hour light/dark cycle) in two inbred mouse strains with low (A/J) and high (DBA/2J) hypoxic ventilatory sensitivities. During SIH, the time to arousal (26.4 +/- 1.1 vs. 21.3 +/- 1.5 seconds, p<0.025) and the severity of hypoxic exposure (nadir FIO2: 11.5 +/- 0.4 vs. 13.6 +/- 0.1%, p<0.002) was greater in A/J than DBA/2J mice. Furthermore, A/J mice had a greater frequency of hypoxic events (640 +/- 29 vs. 368 +/- 33 events per 24 hours, p<0.001) and total sleep time (47.5 +/- 2.8% vs. 26.5 +/- 2.4% per 24 hours, p<0.0001) during SIH than DBA/2J mice. In contrast, the event characteristics and total sleep time during SF were the same in both strains. Furthermore, in the light phase, both strains showed a longer (p<0.01) time to arousal during SIH and SF compared with the dark phase. We conclude that genetic background can influence respiratory events and sleep architecture during SIH and that the arousal threshold is subject to circadian variation. Our data imply that individuals with low hypoxic sensitivity may be at a greater risk for hypoxia-related complications of obstructive sleep apnea.

Intermittent hypoxia increases insulin resistance in genetically obese mice.

Obstructive sleep apnoea, a syndrome that leads to recurrent intermittent hypoxia, is associated with insulin resistance in obese individuals, but the mechanisms underlying this association remain unknown. We utilized a mouse model to examine the effects of intermittent hypoxia on insulin resistance in lean C57BL/6J mice and leptin-deficient obese (C57BL/6J-Lepob) mice. In lean mice, exposure to intermittent hypoxia for 5 days (short term) resulted in a decrease in fasting blood glucose levels (from 173 +/- 11 mg dl-1 on day 0 to 138 +/- 10 mg dl-1 on day 5, P < 0.01), improvement in glucose tolerance without a change in serum insulin levels and an increase in serum leptin levels in comparison with control (2.6 +/- 0.3 vs. 1.7 +/- 0.2 ng ml-1, P < 0.05). Microarray mRNA analysis of adipose tissue revealed that leptin was the only upregulated gene affecting glucose uptake. In obese mice, short-term intermittent hypoxia led to a decrease in blood glucose levels accompanied by a 607 +/- 136 % (P < 0.01) increase in serum insulin levels. This increase in insulin secretion after 5 days of intermittent hypoxia was completely abolished by prior leptin infusion. Obese mice exposed to intermittent hypoxia for 12 weeks (long term) developed a time-dependent increase in fasting serum insulin levels (from 3.6 +/- 1.1 ng ml-1 at baseline to 9.8 +/- 1.8 ng ml-1 at week 12, P < 0.001) and worsening glucose tolerance, consistent with an increase in insulin resistance. We conclude that the increase in insulin resistance in response to intermittent hypoxia is dependent on the disruption of leptin pathways.

Tracheobronchial stenosis from acid aspiration presenting as asthma.

We report a case of a 42-year-old man who fell in a vat of hydrochloric acid, resulting in ingestion and aspiration of acid. Initially, he suffered from a chemical pneumonitis and GI burns. He was released from the hospital without complications, only to return with signs and symptoms consistent with asthma. Evaluation revealed multiple areas of large airway stenosis, resulting from the chemical burns. The stenoses were treated with multiple stents.

Glucocorticoid administration during incubation: embryo mortality and posthatch growth in chickens.

The effects of glucocorticoids (GC) on embryonic mortality and posthatch BW were studied. Cortisol hemisuccinate or corticosterone in 0.1-mL vehicles were injected into the albumen of 7-d-old White Leghorn chicken embryos. Embryonic mortality rates and the age after injection at which death occurred were determined. When 0.02 to 20 microg cortisol per egg were injected in saline, total embryonic mortality rate increased in a doseresponse manner, with a median lethal dose (LD50) at 10 microg. Saline injection alone caused a similar mortality rate to that caused by injection of 2 microg cortisol (around 35%). However, whereas mortality among the cortisol-treated embryos was greatest on Days 16 to 18, most of the saline-treated embryos died around the time of injection. The lethal effect of corticosterone, which is endogenous GC in adult chickens, was compared to that of cortisol by injecting both in the same vehicle (a saline:ethanol mixture) and was found to be similar. However, when 2, 10, or 20 microg of corticosterone was injected in oil, mortality rates were lower than those caused by the matching doses of cortisol in saline, probably due to the lower diffusion rate of the steroid out of the oil carrier. Hatch weight was significantly lower in chicks treated with 10 and 20 microg cortisol, and BW of the latter was lower compared with control throughout the 3-mo observation. In conclusion, cortisol and corticosterone are equally active in causing embryonic mortality. Posthatch BW is affected only by GC doses that are equal to or greater than the LD50.

Short-term stress increases testosterone secretion from testes in male domestic fowl.

Prolonged stress inhibits the hypothalamus-pituitary-gonadal (HPG) axis and reduces plasma testosterone (T). However, enhanced secretion of luteinizing hormone (LH) and T has been documented during the initial stages of acute stress in mammals. This study assayed the effect of short-term stress on plasma T and corticosterone (B) in juvenile, pubertal, and adult White Leghorn cockerels. Stress was induced by brief physical restraint of caged juvenile (7 weeks), pubertal (17 weeks), and adult (40 weeks) cockerels, as well as 40-week-old adults reared together in a room lined with wood shavings (group reared). Blood was sampled immediately before restraint (0 time), at the end of a 10-min restraint period, and at 30, 60, and 180 min after 0 time. Restraint resulted in an initial increase in plasma T in all groups, along with a rise in B. Whereas B generally reached its peak level at the end of the restraining period, T peaked 20 min later. The maximum increase of T and B relative to prestress levels (T and B ratios) was similar in all groups, with median T ratio reaching 1.25-1. 5-about half that of the B ratio. Thus, the extent of T and B response to short-term stress was not influenced by basal levels of T, which were highest in adults, and basal levels of B, which were higher in caged adults than in group-reared adults. Injection of ACTH did not induce a greater increase in plasma T than in sham-injected controls. Further, the elevation of T in response to stress was extinguished in castrated adults, indicating that T is secreted from the testes rather than the adrenals in response to stress. When the same regime of blood sampling was applied to adults not subjected to restraint, the T ratio rose by up to 11 times. It can therefore be stipulated that T response depends on the type of stress applied, a factor that should be considered when investigating androgen levels in plasma.

The cytoskeleton and related proteins in the human failing heart.

In addition to functional alterations, heart failure has a structural basis as well. This concerns all components of the cardiac myocytes as well as the extracellular space. Proteins of the cardiomyocyte can be subdivided in 5 different categories: 1) Contractile proteins including myosin, actin, tropomyosin and the troponins. 2) Sarcomeric skeleton: titin, myosin binding protein C, alpha-actinin, myomesin, and M-protein. 3) True 'cytoskeletal' proteins: tubulin, desmin and actin. 4) Membrane-associated proteins: dystrophin, spectrin, talin, vinculin, ankyrin and others. 5) Proteins of the intercalated disc: desmosomes consisting of desmoplakin, desmocollin, desmoglein and desmin; adherens junctions with N-cadherin, the catenins and vinculin, and gap junctions with connexin. Failing myocardium obtained from patients undergoing cardiac transplantation exhibits ultrastuctural degeneration and an altered nucleus/cytoplasm relationship. The contractile proteins and those of the sarcomeric skeleton, especially titin, are downregulated, the cytoskeletal proteins desmin and tubulin and membrane-associated proteins such as vinculin and dystrophin are upregulated and those of the intercalated disc are irregularly arranged. Elevation of cytoskeletal proteins correlates well with diastolic and contractile dysfunction in these patients. The enlarged interstitial space contains fibrosis, i.e. accumulations of fibroblasts and extracellular matrix components, in addition to macrophages and microvascular elements. Loss of the contractile machinery and related proteins such as titin and alpha-actinin may be the first and decisive event initiating an adaptive increase in cytoskeleton and membrane associated components. Fibrosis may be stimulated by subcellular degeneration. The hypothesis is put forward that all proteins of the different myocardial compartments contribute to the deterioration of cardiac function in heart failure.

Reduced speed of sound in tibial bone of haemodialysed patients: association with serum PTH level.

BACKGROUND: In end-stage renal disease, average bone mineral density has been reported to be normal or only modestly reduced, more so in the cortical bone. The purpose of the present study was to explore the potential use of quantitative ultrasound, a method reflecting both quantitative and qualitative properties of bone, in assessing bone status in patients on maintenance haemodialysis. METHODS: We studied 71 patients (age 17-81 years, time on dialysis 0-18 years). The speed of sound waves (tSOS; m/s) propagating along the cortical bone has been determined at the tibial shaft. tSOS results were expressed as Z scores, i.e. units of standard deviations from age- and sex-matched normal mean values, and correlated with relevant clinical and biochemical variables. RESULTS: SOS Z score averaged -2. 0 (range -6.8 to 0.6; P<0.001) and was negative in 93% of the patients. Significant inverse correlations were found between SOS Z score and both time on dialysis (r=-0.52; P<0.0001) and serum PTH (r=-0.39; P=0.0002). Markedly reduced SOS Z score, below -2, was found in 80% of the patients whose PTH levels exceeded 34 pmol/l (five times the upper normal limit), compared with 43% of the patients whose PTH levels were below 34 pmol/l(P=0.04). Compared to patients without bone pain (n=51), subjects with bone pain (n=20) had somewhat lower SOS Z scores -2.5+/-2.0 versus -1.8+/-1.4; P=0. 08), but this could be accounted for by longer time on dialysis. CONCLUSIONS: tSOS is substantially reduced in the majority of haemodialysed patients and is related to time on dialysis and serum PTH level. The clinical value of this novel method needs further exploration.

Effects of estradiol and tamoxifen on feeding, fattiness, and some endocrine criteria in hypothalamic obese hens.

In White Leghorn hens, basomedial hypothalamic (BMH) lesions result in two syndromes: a) obese, functionally castrated (OFC) hens, in which both the ventromedial hypothalamic nucleus (VMH) and the mammillary nuclei are damaged and plasma estrogen is very low; and b) obese laying (OL) hens, which have normal levels of plasma estrogen and are less obese than the former, and whose lesion is limited to the VMH. In the present study, the involvement of estrogen in regulation of fattiness and energy metabolism was assayed in OFC, OL, and control (CONT) hens. BMH lesions were made at 13 weeks of age. When the typical syndromes reached the static phase, 20 weeks later, CONT, OFC, and OL hens were divided into three subgroups and were injected for 10 weeks on each alternate day, with either 10 mg tamoxifen (TAM)/kg, 2 mg estradiol benzoate (E2)/kg, or the vehicle, corn oil (0.5 ml). E2 raised plasma total lipids and reduced plasma glucose, insulin, and hematocrit in all treated hens, and increased liver weight in OL and OFC, but not in CONT hens. In OFC hens only, E2 reduced food intake (FI) and fattiness. In OL and CONT hens, E2 increased plasma T3, but raised the resting metabolic rate (RMR) only in CONT ones. In OFC hens, E2 reduce plasma T3 and T4 without affecting RMR. E2 reduced comb weight and egg production in CONT and more severely in OL hens. In the latter, E2 diminished ovarian and oviduct weights, whereas in OFC hens it increased the size of the atrophied oviduct. TAM had no visible effect on OFC hens.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of bilateral basomedial hypothalamic lesions on feeding, fattiness, and reproductive functions in the White Leghorn hen.

During the last three decades, syndromes caused by bilateral destruction of the basomedial hypothalamus (BMH) were extensively studied in cockerels but not in hens. In the present study bilateral electrolytic lesions in the BMH of White Leghorn (WL) hens produced two main sets of symptoms: (a) Obese, functionally castrated hen (OFC); and (b) Obese, laying hen (OL). Following the placement of the hypothalamic lesion, the OFC hens developed transient hyperphagia, that was followed by hypophagia. Weight gain was accelerated in both periods, and marked obesity developed. These hens had high hematocrit values, and atrophied ovary, oviduct, comb, and adenohypophysis. Plasma estrogen, and total lipids and liver weight were reduced in the OFC hens. In these hens, the lesioned area included the ventromedial hypothalamic nucleus (VMH), the mammillary nuclei, and in some birds also the arcuate nuclei, and the tuberal nucleus. The OL hens manifested transient hyperphagia that subsided into normophagia with the development of obesity. These hens were less obese than the OFC ones and showed normal reproductive traits. The lesioned area in the OL hens was limited to the VMH. Unlike functionally castrated cockerels, where the induced fattiness is accompanied with higher rate of lipogenesis, the OFC hen manifested a unique syndrome: increased fattiness with arrest in estrogen-dependent lipogenesis.

Precocious puberty in tamoxifen-treated cockerels: hypothalamic gonadotrophin-releasing hormone-I and plasma luteinising hormone, prolactin, growth hormone and testosterone.

1. The administration of the anti-oestrogen, tamoxifen (TAM) to juvenile chicks results in precocious puberty. In the present study the effects of TAM administration (1 mg/kg body weight on alternate days from 12 d of age) on testicular function, hypothalamic chicken gonadotropin-releasing hormone (cGn-RH-I), plasma luteinising hormone (LH), growth hormone (GH), prolactin (PRL) and testosterone were studied in juvenile White Leghorn cockerels. 2. The increase in hypothalamic GnRH-I content which occurs during sexual development was advanced in TAM-treated birds, in association with precocious testicular development, an early rise of plasma testosterone content and enhanced comb growth. 3. Plasma LH concentrations behaved similarly and were higher in the TAM-treated than in control birds, during most of the experimental period. Plasma PRL concentration, which is high at hatching, decreased more quickly in TAM-treated than in control birds; plasma GH values were not consistently affected by TAM treatment. 4. Both the growth and the involution of the bursa of Fabricius in the TAM-treated cockerels preceded that in the control chicks. 5. It is concluded that TAM treatment induces precocious puberty in the cockerel by blocking the negative feedback action of aromatised testicular androgens on the hypothalamus.

Tamoxifen advances puberty in the White Leghorn hen.

1. Tamoxifen (TAM) administration advances puberty in cockerels. In the present study the effect of TAM administration on the sexual development of White Leghorn hens was studied. 2. Two-week-old White Leghorn females were injected intramuscularly with TAM on alternate days at doses of 0.1 mg (0.1 TM), 1 mg (1TM), 5 mg (5TM) and 10 mg/kg body weight (10TM) respectively, while the controls were injected with maize oil (vehicle). The experiment was terminated at 23 weeks of age, when all the control hens laid eggs. Sample autopsies were made on chicks of 6, 14 and 23 weeks of age. 3. Body growth was not affected by any of the treatments. 4. Comb growth was accelerated by all doses of TAM, while hematocrit increased in the 1TM, 5TM and 10TM hens. 5. Egg laying advanced in the 0.1TM and 1TM birds, was delayed in 5TM hens and did not occur at all in the 10TM females. 6. TAM caused a precocious increase in plasma oestrogen and androgen, suppressed adiposity in a dose-related manner and, at low doses, advanced the development of the gonadal system. 7. At 23 weeks of age, when the gonadal system of the controls was fully active, TAM caused a dose-related depression in abdominal fat, liver, ovary, and oviduct weights, plasma total lipids and calcium concentrations and a dose-related increase in plasma oestrogen and androgen titres, and comb weight. 8. It seems that TAM increased gonadotropic activity and its androgen stimulating action, but suppressed peripheral signs of the elevated plasma oestrogen titres. Low doses of TAM enhanced gonadotropic activity and egg laying but the antioestrogenic effect depressed development of the gonadal system, suppressing egg production when high doses were administered. It therefore seems that oestrogens are necessary for normal ovarian development in hens.

Sexual differentiation of copulatory behaviour in the male chick requires gonadal steroids.

1. Embryonic injections of 0.3 mg/egg of tamoxifen (TAM), 0.2 mg/egg CI-628 (both antioestrogens), 0.5 mg/egg (ATD (aromatisation inhibitor), or antibodies to oestradiol (E), all suppressed male copulatory activity (MCA) in young male chicks. 2. Embryonic injections with either flutamide (F, androgen antagonist) or high dose of antibodies to testosterone (T) only slightly suppressed MCA. 3. TAM had no effect on embryonic plasma LH levels, 24 and 48 h after injection. 4. It seems that at the embryonic stage oestradiol is required for the normal differentiation of MCA.

The effects of embryonic treatments with gonadal hormones on sexually dimorphic behavior of chicks.

In order to study the role of sex steroids in the differentiation of chick behavior, two groups of experiments were carried out. The first part of the study documented sexual dimorphisms in three behavioral measures in chicks: open-field activity, flocking response, and masculine sexual behavior activated by testosterone (crowing, waltzing, and mating attempts). In the second part, possible organizing influences on these sexually dimorphic behaviors were examined. Male and female embryos were injected with estradiol benzoate (EB) or testosterone propionate (TP). Treatment of males with EB or TP demasculinized all three behaviors. None of the steroid treatments had any effect on the behavior of the females. Plasma testosterone levels of the chicks were not affected by any of these treatments, either before or after testosterone activation. Comb weight was reduced by treatment of male embryos with EB and increased by TP in female embryos, which suggests different mechanism for the development of somatic and behavioral characteristics. The results suggest that exogenous T or E given embryonically can exert similar effects on both sexual behavior and nonreproductive activity of chicks.

The response of broilers' adiposity to testosterone after embryonic exposure to androgen and tamoxifen.

1. The effects of early exposure of heavy breed (HB) chicks to an anti-oestrogen (tamoxifen--TAM) and to an androgen which cannot be aromatised (5 alpha-dihydrotestosterone--DHT) on subsequent adiposity and its response to testosterone were studied. 2. Embryonic TAM administration reduced adiposity in females but not in males at 8 weeks of age. Embryonic DHT produced similar responses but to a lesser extent. 3. Testosterone propionate (TP) administration during growth had no effect on adiposity in any of the treated groups but TP reduced adiposity in males which had been exposed to DHT at the embryonic stage.

The effect of tamoxifen on semen fertilization capacity in White Leghorn male chicks.

Tamoxifen (TAM) is an antiestrogen that advances sexual puberty in cockerels, turkey toms, and Muscovy drakes. The effect of TAM on semen-fertilization capacity in White Leghorn (WL) male chicks was assayed in the present study. Sixty, 2-wk-old, male chicks were divided into two equal groups. The chicks from one group were injected im with 1 mg of TAM per kg of BW every other day; those from the second group were vehicle-treated (with corn oil) and served as controls. Each chick was paired with a virgin, WL laying hen. When semen was produced, the paired female was inseminated twice a week. The results revealed that TAM administration caused the early production of fertile semen, which resulted in the first normal descendants as early as 8 wk of age and brought about 100% of parenthood by the age of 88 days.

The effect of tamoxifen on sexual puberty of turkey toms and Muscovy drakes.

The effects of Tamoxifen (TAM) on reproductive traits in young turkey toms and Muscovy drakes were studied. At 6 wk of age, five toms were injected every other day with 1 mg TAM/kg BW, while six others were treated with corn oil (controls). In the toms, using TAM advanced semen production by 4 wk (13.5 versus 17.5 wk of age) and increased the size of the snood and testes. Similarly, in the Muscovy drake, using TAM enhanced penis growth and advanced semen production by 5 wk.

Effect of embryonic and neonatal administration of tamoxifen on adiposity in the broiler chicken.

1. The effect of early exposure of heavy breed (HB) chicks to an anti-oestrogen (tamoxifen--TAM) on later adiposity was studied. 2. TAM administration at the embryonic stage, but not at the day of hatching, reduced adiposity in females but not in males, at 8 to 9 weeks of age. This reduction in adiposity in females minimised or even alleviated the excess of fat in females compared to males.