Peripheral artery disease and all-cause and cardiovascular mortality in patients with NAFLD.

PURPOSE: Cardiovascular disease (CVD) is the first cause of death in patients with non-alcoholic fatty liver disease (NAFLD) and risk stratification is recommended by current guidelines. The aim of this study is to assess the prevalence of peripheral arterial disease (PAD) in patients with NAFLD and its association with all-cause and cardiovascular disease (CVD) mortality. METHODS: 9145 participants 40 years or older attended a mobile examination center visit in the 1999-2004 cycles of the National Health and Nutrition Examination Survey. PAD was defined as an ankle-brachial index (ABI) < 0.90 in either of the legs and mortality data through December 2015 were obtained from the National Death Index. NAFLD was defined by a fatty liver index ≥ 60 in the absence of other liver conditions, leading to a final sample of 3094 subjects. RESULTS: The overall prevalence of PAD was 5.9% (95% CI 5.0-6.9). Over a median follow-up of 13 years, 876 participants died, 208 of cardiovascular causes. Incidence rates of all-cause mortality (for 1000 person-years) were 20.2 (95% CI 18.7-21.7) and 70.0 (95% CI 60.1-81.6) for participants without and with PAD, respectively. Multivariable-adjusted Cox proportional hazard models showed that PAD was associated with a higher risk of all-cause (1.8, 95% CI 1.4-2.4) and cardiovascular mortality (HR 2.5, 95% CI 1.5-4.3) after adjustment for potential confounders including prevalent CVD. CONCLUSION: Current guidelines strongly encourage the screening of CVD in patients with NAFLD and the use of the simple and inexpensive measurement of ABI in routine clinical practice may find indication.

[Laparoscopic treatment of UPJ obstruction in ectopic pelvic kidneys in children]. / Trattamento laparoscopico dell'Ostruzione del Giunto Pielo-Ureterale nei reni ectopici in età pediatrica.

AIMS: To assess the feasibility and safety of a laparoscopic approach to UPJ obstruction (UPJO) in ectopic pelvic kidneys. MATERIAL AND METHODS: In a retrospective analysis we selected 14 children, aged 6 months to 17 years, 12 males, 2 females, who had been treated in our Department between January 2004 and June 2011. 9 patients presented ureteropelvic junction obstruction (in 3 cases pelvic stones coexisted) with normal/moderately reduced (> or = 25%) relative function at radionuclide scan (MAG3), 3 nonfunctioning kidneys associated or not to hypertension, 2 congenital hypo-dysplastic kidneys. The evaluation of each patient involved the medical history, ultrasound examination, VCUG, MAG3 diuresis renogram and MRI in some cases. Of the patients presenting UPJO, 5 underwent dismembered pyeloplasty with pyelolithotomy, if required, and 4 pelvic derotation with straightening of the uretero-pelvic junction. A previous cystoscopic placement of a Double J stent was utilized. This facilitated the identification and dissection around the pelvis. With the patient in Trendelenburg position we utilized an umbilical trocar and two trocar in the right and left iliac fossae; an additional trocar, when required, was inserted more cephalad on the midclavear line contralaterally to the lesion. The derotation of ureteropelvic junction was obtained by freeing the kidney's lower pole and by placing intraperitoneally the junction protected with a Double J stent. This was obtained by suturing the peritoneum behind the ureteropelvic junction resulting in a forward rotation of the major axis of the kidney and a straightening of the junction. The 5 patients presenting nonfunctioning ectopic kidneys underwent laparoscopic nephrectomy. While the removal of congenital hypoplasic kidneys resulted easy, the removal of nonfunctioning kidneys was more difficult due to their complex vascular situation and for the embryonic disposition. RESULTS: The operating time varied between 40 to 200 minutes. No patient required conversion to open surgery. The hypertension resolved after nephrectomy in all cases. 2 cases of dismembered pyeloplasty required a placement of Double J stent due the recurrence of symptoms and ! patient is waiting for redo operation. The pelvic derotation showed an improvement of diuretic MAG3 renogram and the function remained stable and patiens are symptoms-free. CONCLUSION: The UPJO in ectopic pelvic kidneys presents a large spectrum of presentation. The laparoscopic approach provides good surgical exposure, and operative times are acceptable compared to those of laparoscopic procedure in anatomically normal kidneys. It has also proved a very useful tool in the non-functioning kidney nephrectomy thank to the help of magnification in the identification of numerous aberrant vessels that are quite often found in the pelvic kidneys. The derotation of the pelvis seems a useful procedure in moderate obstruction even if a longer followup is needed.

Interaction between theory and experiment in the study of sleep physiology: a historical survey of early sleep research.

The interaction between theory and experiment in sleep research was considered on the grounds of a selective historical survey of early sleep studies up to the first half of the twentieth century. The dialectic pair of experimental reductionism and theoretical holism was the motor of progress in sleep research as soon as it was supported by the electroencephalographic technique, a by-product of applied physics. The identification of sleep stages was a turning point in the development of the experimental methodology of sleep research. Also, other scientific disciplines, particularly anatomy and chemistry, provided technical support increasingly suitable for the experimental study of the physiology and pathology of sleep. In general, cognitive advances depended on a research methodology (theoretical and experimental) free from the influence of cultural prejudices and supposedly indisputable scientific paradigms.

REM sleep related increase in brain temperature: a physiologic problem.

The roles of metabolic heat production, arterial blood flow and temperature in the genesis of the brain temperature increase related to REM sleep occurrence in several mammalian species are discussed on the basis of available experimental evidence. The experimental data show that only changes in arterial blood flow and temperature consistently underlie the rise in brain temperature in presence (cat) or absence (rabbit) of the carotid rete. The alteration of cardiovascular regulation in REM sleep is the remote cause of such rise. The proximate causes are decrease in carotid blood supply and increase in vertebral blood supply to the brain and related depression of systemic and selective brain cooling.

Brain cooling across wake-sleep behavioral states in homeothermic species: an analysis of the underlying physiological mechanisms.

The behavioral state-dependent changes in the hypothalamic temperature of homeotherms reflect extracerebral adjustments in circulatory variables to influence the temperature and flow of the arterial blood cooling the brain. There are different mechanisms for brain cooling, i.e. systemic and selective brain cooling, which are affected by the changes in body posture and vasoconstrictor sympathetic outflow related to wake-sleep behavioral states.

Interaction between sleep and thermoregulation: an aspect of the control of behavioral states.

Studies on the interaction between sleep and thermoregulation are reviewed with regard to the processes underlying the ultradian evolution of behavioral states. The experimental evidence shows that thermoregulatory mechanisms influence the waking-sleeping cycle in both the absence or the presence of a thermal load. Such a control appears to be a functional necessity to maintain physiological homeostasis.

Respiratory effects of preoptic-anterior hypothalamic electrical stimulation during sleep in cats.

The respiratory effects of preoptic-anterior hypothalamic (PO-AH) and vagal repetitive electrical stimulation (RES) were studied in unrestrained cats during sleep. PO-AH RES influenced breathing consistently during synchronized sleep but only occasionally during desynchronized sleep. Induction of desynchronized sleep by PO-AH RES was also observed. The respiratory effects of PO-AH RES on one side were enhanced by concomitant PO-AH warming on the other side during synchronized sleep but not during desynchronized sleep. Breathing was affected by vagal RES during both sleep stages, although an increase in threshold and in variability of respiratory responses was apparent during the latter sleep stage. The results show that PO-AH unresponsiveness during desynchronized sleep is nonspecific.

Kinetic parameters of tyrosine hydroxylase in the rat's preoptic region during sleep deprivation and recovery induced by ambient temperature.

The role of catecholaminergic mechanisms in determining the changes in the rat's preoptic cyclic adenosine monophosphate (cAMP) concentration during sleep deprivation and recovery induced by ambient temperature was investigated in the present study. To this end, the activity of tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis, was measured in the preoptic region of rats maintained in: (a) control (22 degrees C for 52 h), (b) deprivation (-10 degrees C for 52 h), and (c) recovery (22 degrees C for 4 h after 48 h at -10 degrees C) conditions. The enzyme followed a Michaelis-Menten kinetic. The analysis of substrate-related kinetic parameters (Km and Vmax) did not show any clear-cut difference between experimental conditions, which, as already known, induce both sleep deprivation and recovery in relation to significant cAMP changes.

Pattern of REM sleep occurrence in continuous darkness following the exposure to low ambient temperature in the rat.

The occurrence of REM sleep episodes, separated by intervals >3 min (single episodes) and < or =3 min (sequential episodes), was determined in the rat during the recovery (ambient temperature (Ta) 23 degrees C, L period of the LD [12 h:12 h]-cycle), which followed the exposure to low Ta (0 and -10 degrees C) during the D period of the previous LD-cycle, either in normal light (DL) or in continuous darkness (DD). Both exposures were characterized by an almost complete disappearance of REM sleep, whilst the recoveries showed an increase in the amount of REM sleep in the form of sequential episodes, which in DD was particularly prominent and concomitant with a decrease in the amount of REM sleep in the form of single episodes. The initial 2 h-rate of REM sleep occurrence was lower following the exposure to Ta -10 degrees C, than to Ta 0 degrees C. In DD, such an effect was due to the large reduction in the occurrence of sequential REM sleep episodes. A functional correlate of this finding is that the accumulation capacity of a second messenger (cAMP) was found to be lower at the end of the exposure to Ta -10 degrees C, with respect to both the control (Ta 23 degrees C) and the end of exposure to Ta 0 degrees C, in the preoptic-anterior hypothalamus, but not in the cerebral cortex.

REM sleep enhancement due to rhythmical auditory stimulation in the rat.

From a physiological viewpoint, REM sleep (REMS) is a period during which homeostatic physiological regulations are impaired. In the rat, REMS occurs in two forms respectively characterized by episodes separated by long intervals (single REMS episodes) and by episodes which have short intervals and occur in sequences (REMS clusters). Since the partition of REMS in the form of either single or clustered episodes may reveal how the REMS drive and body homeostatic processes interact in the control of REMS occurrence, we have used this approach to clarify the effects of the rhythmical delivery of an auditory stimulus (1000 Hz, 63 or 88 dB, 50 ms, every 20 s), which has been previously observed by different authors to enhance REMS in the absence of a previous sleep deprivation. Stimuli were delivered to pairs of animals and triggered by the occurrence of REMS in one rat (REMS-selective stimulation), whilst the other animal received the same stimulus irrespectively of the stage of the wake-sleep cycle (REMS-unselective stimulation). The results showed that the REMS-selective stimulation did not change the overall amount of REMS, since an increase in the occurrence of REMS clusters was concomitant with a decrease in the occurrence of single REMS episodes. In contrast, under the REMS-unselective stimulation, the total amount of REMS was increased during the second day of stimulation through an increase in the duration of both types of REMS episodes. Since during the REMS-unselective stimulation 87% of the stimuli fell outside REMS (i.e., during the REMS interval), the results show that the occurrence of REMS is more consistently affected when the stimuli are delivered in a period during which homeostatic physiological regulations are fully operant.

Mechanisms underlying hypothalamic temperature changes during sleep in mammals.

The mechanisms underlying hypothalamic temperature (Thy) changes across the ultradian wake-sleep cycle were analyzed in cats chronically implanted with EEG and EMG electrodes, and transducers that measured Thy and pontine temperature (Tp). The influence of artificially induced changes in (i) systemic blood temperature, (ii) heat loss from the specific heat exchangers of the head, and (iii) carotid artery occlusion, on Thy, Tp and ear pinna temperature (Ts) during waking (W), synchronized sleep (SS) and desynchronized sleep (DS) were assessed in animals maintained in a thermoneutral environment. The results show that the decrease in Thy during SS is dependent on increased heat loss from heat exchangers (ear pinna), whereas the increase in Thy during DS is due to an alteration in the arterial blood perfusion of the circle of Willis receiving an increased supply of warm vertebral blood that replaces a decrease in supply of cool carotid blood.

Postural and sympathetic influences on brain cooling during the ultradian wake-sleep cycle.

The influence of posture and tonic vasoconstrictor sympathetic outflow on systemic (ear pinna-environment) and selective (carotid rete-venous plexus) heat exchange underlying brain cooling was studied in cats chronically implanted with EEG and EMG electrodes, and transducers that measured hypothalamic, pontine and ear pinna temperatures across the ultradian wake-sleep cycle in a thermoneutral environment. Transmural pressure on heat exchanger vasculature was varied by keeping the animal's head above or at heart level. The vasoconstrictor sympathetic outflow to heat exchanger vasculature was varied both by keeping the animal's abdomen cool or warm and by means of bilateral common carotid ligature. The results show that a rise in transmural pressure enhances selective brain cooling and weakens systemic brain cooling. An increase in tonic vasoconstrictor sympathetic outflow decreases both systemic and selective brain cooling.

Changes in selective brain cooling across the behavioral states of the ultradian wake-sleep cycle.

In cats, the behavioral state-dependent negative correlation of the pontine-hypothalamic temperature difference, an indicator of selective brain cooling, with the hypothalamic-ear pinna temperature difference, which is an indicator of heat loss from the heat exchangers of the head, is suppressed after bilateral common carotid ligature. Behavioral state-dependent selective brain cooling may underlie a thermal feedback mechanism differentiating the relative influences of hypothalamic and extra-hypothalamic thermoreceptors on the thermoregulatory system during quiet wakefulness and NREM sleep.

Respiratory frequency as a function of preoptic temperature during sleep.

The effects on respiratory frequency of preoptic heating during slow-and fast-wave sleep were studied in freely moving cats. During slow-wave sleep, at neutral ambient temperature, the subliminal range of preoptic temperature for thermal polypnea extends to 0.2-0.4 degrees C above control preoptic temperature. During fast-wave sleep, at neutral ambient temperature, the subliminal range of preoptic temperature for thermal polypnea increases beyond 0.9-1.0 degrees C above control preoptic temperature. Moreover, the polypneic response is weak and unstable. The results show the suspension of a precise thermoregulatory control during fast-wave sleep in a homoiothermic species.

Thermosensitivity of anterior hypothalamic-preoptic neurons during the waking-sleeping cycle: a study in brain functional states.

The thermosensitivity of anterior hypothalamic-preoptic neurons was studied in cats during the waking-sleeping cycle. Direct cooling and warming of the anterior hypothalamic-preoptic region was accomplished with water-perfused thermodes. Neuronal thermosensitivity was determined by means of the linear regression analysis of firing rate changes vs anterior hypothalamic-preoptic temperature changes. A total of 117 neurons were classified as thermosensitive during wakefulness and synchronized sleep (20.1% of the studied neurons). Cold-sensitive neurons outnumbered warm-sensitive neurons by 3.7:1. The homeothermic states, wakefulness and synchronized sleep, are characterized by similar frequency distributions of neuronal thermosensitivity, although variable changes in single neuron thermosensitivity are state-dependent. Such changes underlie the quantitative differences in homeothermic regulation between these states. The impairment of thermoregulation during desynchronized sleep is characterized by a different frequency distribution of neuronal thermosensitivity resulting from both a drop in the responsiveness to thermal stimulation of a majority of neurons and a reversal in the sensitivity to cooling and warming of a minority of neurons. In conclusion, only the frequency distribution of thermosensitivity in the neuronal population is indicative of changes in the thermoregulation paradigm across behavioral states.

Ultradian and circadian changes in the cAMP concentration in the preoptic region of the rat.

The concentration of adenosine 3',5'-cyclic monophosphate was measured, during the wake-sleep cycle, in the preoptic region and the cerebral cortex of rats kept in normal laboratory conditions (ambient temperature 22 +/- 0.5 degrees C, 12 h:12 h light-dark cycle) and, during wakefulness, in the preoptic region of rats exposed to extended light and dark periods (i.e. dark in the light hours of the normal photoperiod, and light in the dark hours of the normal photoperiod). The results show that the concentration of cAMP in the preoptic region changes according to the ultradian wake-sleep cyclic, decreasing from wakefulness, through synchronized sleep and to desynchronized sleep. This pattern of change was found to occur both in light and dark hours, however, in the dark hours the levels of preoptic cAMP are higher than those observed in the light hours. In contrast, no significant modification in cAMP concentration was found in the cerebral cortex. In the extended light and dark periods preoptic cAMP concentration increases above the levels found during wakefulness in normal photoperiods. These results show that preoptic cAMP concentration is influenced by ultradian and circadian factors which also appear to be related to sleep processes.

Responses of anterior hypothalamic-preoptic neurons to direct thermal stimulation during wakefulness and sleep.

The responses of anterior hypothalamic-preoptic units to direct thermal stimulation were studied during wakefulness and sleep in cats. Seventy-nine percent of the selected units showed changes in firing rate in relation to wakefulness and sleep stages. Forty-nine percent of the units characterized by activity related to EEG patterns were found to be responsive to thermal stimulation in wakefulness and synchronized sleep. Unit responses to thermal stimulation were either absent or inconsistent in desynchronized sleep.

The influence of a heavy thermal load on REM sleep in the rat.

This study was carried out in order to further test the hypothesis that the occurrence of REM sleep in the rat in the form of episodes separated by long intervals (single REM sleep episodes) and by short intervals (sequential REM sleep episodes) is differently influenced by changes in both sleep and ambient related processes. Rats were studied during the exposure to Ta -10 degrees C for 24 or 48 h and during a 12 h recovery period at laboratory Ta (23 degrees C) following either the first or the second 24 h of cold exposure. The exposure to such a low Ta induced an almost complete abolition of REM sleep which was followed, during recovery, by a marked REM sleep rebound. However, in spite of the larger REM sleep deprivation, the REM sleep rebound was weaker following the 48 h-exposure than that following the exposure for 24 h. The increase in the amount of REM sleep during the recovery period was due to an increase in the amount of that occurring in the form of sequential episodes, whilst that in the form of single episodes did not change with respect to control levels. However, the occurrence of REM sleep in the form of sequential episodes was partially impaired during the REM sleep rebound observed in the recovery period following the 48 h-exposure. These results would suggest that the homeostatic regulation of physiological variables may conflict with that of REM sleep occurrence and that the degree of such a contrast is indicated, at low Ta, by the amount of REM sleep in the form of single episodes and, during the following recovery, by the amount of REM sleep in the form of sequential episodes.

cAMP accumulation in the hypothalamus, cerebral cortex, pineal gland and brown fat across the wake-sleep cycle of the rat exposed to different ambient temperatures.

The concentration of adenosine 3':5' cyclic monophosphate (cAMP) was determined in the anteroventro-medial hypothalamus, the cerebral cortex, the pineal gland and the interscapular brown adipose tissue, during the different stages of the wake-sleep cycle of rats kept, under a 12-12-h light-dark cycle, in different environmental conditions, i.e., control (47-52 h at ambient temperature (Ta) 23 +/- 0.5 degrees C), exposure (47-52 h at Ta 0 +/- 1 degree C) and recovery (1-4 h at Ta 23 degrees C after 48 h at Ta 0 degree C). The results show that cAMP concentration consistently changed: (1) during the wake-sleep cycle in the anteroventro-medial hypothalamus, decreasing from wakefulness to sleep; (2) during the dark-light transition in the pineal gland, increasing with the onset of the light phase; and (3) with the environmental condition in the interscapular brown adipose tissue increasing, with respect to the control condition, in exposure and recovery. No significant changes in cAMP concentration were observed in the cerebral cortex.

Changes in REM sleep occurrence due to rhythmical auditory stimulation in the rat.

The effects of the rhythmical delivery of an auditory stimulus (1000 Hz, from 50 to 100 dB, 20 ms, every 20 s) on the pattern of rapid eye movement (REM) sleep occurrence was studied in the rat. The stimulation was simultaneously carried out on pairs of rats over 5 consecutive days (10-h recording sessions), during which a tone of increasing intensity (50, 63, 75, 88, 100 dB) was used. In each experimental session, auditory stimulation was triggered by the REM sleep occurrence of one rat (REMS-selective stimulation) whilst the other rat simultaneously received the same stimuli, but during any stage of the wake-sleep cycle (REMS-unselective stimulation). The results showed that the total amount of REM sleep in the 10-h recording session was increased over the 5 days of stimulation in the REMS-unselective group. This effect was due to an increase in the mean duration of REM sleep episodes. However, no significant changes were observed in animals under REMS-selective stimulation, nor in a third group of animals in which the spontaneous evolution of REM sleep occurrence (REMS-spontaneous) was studied. Since 86% of the stimuli under the REMS-unselective auditory stimulation fell outside REM sleep, the result would suggest that REM sleep occurrence is affected when the stimuli are delivered during a time period (i.e. during wakefulness or non-REM sleep) in which it is well known that physiological regulations are fully operant.