Daily and Seasonal Rhythms in Immune Responses of Splenocytes in the Freshwater Snake,Natrix piscator

Present study was designed to examine daily and seasonal variability in the innate immune responses of splenocytes in the fresh water snake, Natrix piscator. Animals were mildly anesthetized and spleen was aseptically isolated and processed for macrophage phagocytosis, NBT reduction, nitrite production, splenocyte proliferation and serum lysozyme activity. Samples were collected at seven time points, viz., 0000, 0400, 0800, 1200, 1600, 2000 and 0000 h during three different seasons, namely summer, winter and spring. Cosinor analysis revealed that percent phagocytosis had a significant 24-h rhythm during summer and spring seasons. The peaks of rhythms in NBT reduction and nitrite release occurred in the morning hours at 10.88 h and 8.31 h, respectively, in winter. A significant 24-h rhythm was also observed in lysozyme concentration and splenocyte proliferation (both Basal and Concanavalin A stimulated) in all three seasons. A significant phase shift in splenocyte proliferation was obtained with a trend of delayed phase shift from winter to spring and from spring to summer. Of the nine variables, significant annual (seasonal) rhythms were detected in almost all variables, excluding phagocytic and splenosomatic indices. All rhythmic variables, except spleen cellularity, exhibited tightly synchronized peaks coinciding with the progressive and recrudescence phases of annual reproductive cycle. It is concluded that the snake synchronizes its daily and seasonal immune activity with the corresponding external time cues. The enhancement of immune function coinciding with one of its crucial reproductive phases might be helping it to cope with the seasonal stressors, including abundance of pathogens, which would otherwise jeopardize the successful reproduction and eventual survival of the species.     

The nutritional status and eating habits of shift workers: a chronobiological approach

The eating habits of workers may vary according to the season of the year and corresponding work schedule. A study aiming at verifying the changes in their diet in summer and winter, as well as the nutritional status of those who work fixed shifts, was conducted. The distribution during the 24h in the quantity of calories and macronutrients ingested and the circadian rhythm of calories consumed were also analyzed. The study was conducted on 28 workers subject to three fixed work (morning, afternoon, and night) shifts at a transport company in the city of S?o Paulo, Brazil. The mean age of the workers was 32.8 (SD+/-5.3) yrs. Their food intake was ascertained by the use of a 3-day dietary record, and their nutritional status was evaluated by their body mass index (BMI), both in winter and summer. Two-way ANOVA (shift and season) showed food consumption--measured in calories/24 h--was significantly higher in winter than summer (F(1.25)=11.7; p<0.001). No statistically significant differences were found among shifts (F(2.25)=0.85; p<0.44), and the interaction effect between shift and season was also not significant (F(2.25) = 0.15; p < 0.86). No seasonal difference in BMI was detected (Kruskal-Wallis test). Cosinor analyses showed circadian rhythmicity in calories consumed by morning (p < 0.01) as well as afternoon shift workers (p < 0.001), both in the winter and summer. Circadian rhythmicity in calories consumed by night workers was found only in summer (p < 0.01). The changes observed in the workers' eating habits from one season to another and during the 24h period show the need for further studies to help develop educational programs to improve the nutrition of shift employees taking into consideration shift schedule and season of the year when work is performed.     

Seasonal characteristics of the circadian rhythm of peripheral blood leukocyte content in Wistar rats]

In Wistar rats, the seasonal variability of acrophase position, mesor value and circadian rhythm amplitudes of total leukocyte count, as well as of percentage and absolute lymphocyte count was revealed. The leukocyte count and absolute lymphocyte content were found highest in spring, while eosinophils--in autumn, neutrophils and monocytes--in winter.     

The Nutritional Status and Eating Habits of Shift Workers: A Chronobiological Approach

The eating habits of workers may vary according to the season of the year and corresponding work schedule. A study aiming at verifying the changes in their diet in summer and winter, as well as the nutritional status of those who work fixed shifts, was conducted. The distribution during the 24 h in the quantity of calories and macronutrients ingested and the circadian rhythm of calories consumed were also analyzed. The study was conducted on 28 workers subject to three fixed work (morning, afternoon, and night) shifts at a transport company in the city of São Paulo, Brazil. The mean age of the workers was 32.8 (SD ± 5.3) yrs. Their food intake was ascertained by the use of a 3-day dietary record, and their nutritional status was evaluated by their body mass index (BMI), both in winter and summer. Two-way ANOVA (shift and season) showed food consumption—measured in calories/24 h—was significantly higher in winter than summer (F_(1.25) = 11.7; p < 0.001). No statistically significant differences were found among shifts (F_(2.25) = 0.85; p < 0.44), and the interaction effect between shift and season was also not significant (F_(2.25) = 0.15; p < 0.86). No seasonal difference in BMI was detected (Kruskal-Wallis test). Cosinor analyses showed circadian rhythmicity in calories consumed by morning (p < 0.01) as well as afternoon shift workers (p < 0.001), both in the winter and summer. Circadian rhythmicity in calories consumed by night workers was found only in summer (p < 0.01). The changes observed in the workers’ eating habits from one season to another and during the 24 h period show the need for further studies to help develop educational programs to improve the nutrition of shift employees taking into consideration shift schedule and season of the year when work is performed.     

Seasonal variation in in vitro immune activity of milk leukocytes in elite and non-elite crossbred cows of Indian sub-tropical semi-arid climate

Immunity of mammary gland in terms of in vitro activity of milk leukocytes has been evaluated during hot-humid, summer, and winter season in elite (n = 10) and non-elite (n = 10) crossbred cows. Milk samples were collected from all the cows throughout the year at 15-day interval. Milk somatic cell counts (SCC) and differential leukocyte counts (DLC) were evaluated microscopically. Milk neutrophils, macrophages, and lymphocytes were isolated and cultured in vitro. In vitro PI of milk neutrophils and macrophages was evaluated by colorimetric NBT (nitro-blue tetrazolium) reductive assay. Mitogen-induced milk lymphocyte blastogenic response was measured by colorimetric MTT (thiazolyl blue tetrazolium bromide) assay. Milk SCC was found to be significantly (p < 0.01) higher in elite cows compared to non-elite cows irrespective of season. There was significant (p < 0.05) increase in milk SCC during hot-humid season compared to winter season in both the group of the cows. There was no significant difference between group and season in terms of DLC. In vitro phagocytic index of elite cows was significantly (p < 0.01) higher than non-elite cows. The phagocytic index was significantly (p < 0.01) decreased in summer and hot-humid season compared to winter season in both the group of animals. Macrophages isolated from elite cows having significantly (p < 0.01) lower phagocytic index than non-elite cows which significantly (p < 0.01) decreased during summer and hot-humid season compared to winter. In vitro milk lymphocyte proliferative response was significantly (p < 0.01) lower in elite cows. Activity of B-lymphocytes decreased significantly (p < 0.01) during summer and hot-humid season than winter, but activity of T-lymphocytes remains unaltered during different seasons. In conclusion, the mammary immunity in terms of in vitro activity of milk leukocytes is compromised during summer and hot-humid season in elite crossbred cows; therefore, better care and management should be taken in high-yielding cows during summer and hot-humid season to minimize intramammary infections.     

Circadian Hematologic Time Structure in the Elderly

Twenty-three clinically healthy, diurnally active elderly subjects, 71 ± 5 years of age were studied over a 24-hr span (six samples). Complete blood counts and differential counts were done (Ortho ELT-8, Wright stained smears). The circadian rhythm parameters of the hematologic variables in the elderly subjects were compared with reference values obtained from a larger group of clinically healthy young adult and adult subjects studied independently. The data were analyzed by cosinor and the Bingham test. Circadian rhythms in the number of circulating formed elements in the peripheral blood persist in the aged. In comparison with the young adult, the elderly subjects show differences in the timing (phase advance) of the circadian rhythms in circulating neutrophil leukocytes and lymphocytes, a decrease in the circadian amplitude of circulating platelets, a decrease in circadian rhythm adjusted mean (mesor) in the red cell count, and in the neutrophil band forms.     

Rhythmic patterns in phagocytosis and the production of reactive oxygen species by zebrafish leukocytes

Multiple components of vertebrate immune systems have been shown to exhibit circadian fluctuations. While the zebrafish is currently generating a wealth of information on the molecular pacemakers that may control circadian rhythms, there have been no reports of rhythmic activity in zebrafish leukocytes. In this study, we found that phagocytosis and the production of reactive oxygen species by zebrafish leukocytes varied significantly throughout twenty-four hour periods. A distinct peak in cellular ROS levels occurred before dawn, while the kinetics of respiratory burst responses were least rapid at this time of day. Phagocytosis of E. coli peaked late in the day, whereas there was no daily variation in phagocytosis of S. aureus. As seen in other species, the number of bacteria ingested per cell peaked during the night. These data provide direct evidence of rhythmic immune system activity, and demonstrate that zebrafish can be a valuable model in which to study the relationships between circadian gene expression, systemic pacemakers, and the activity of vertebrate immune system cells.     

Circadian rhythms in surface molecules of rat blood lymphocytes

The present article examines whether the expression of certain surface molecules that trigger immune responses shows a circadian rhythm. We also analyzed the rhythms in the number and percentage of lymphocyte subpopulations, in the leukocyte differential counts, and in the total red and white blood cell counts. Blood samples obtained from rats at 2-h intervals for 24 h were stained with several mouse monoclonal antibodies directed against lymphocyte surface molecules and processed by flow cytometry. The number of B, total T, Tgammadelta, Th, and Ts/c cells followed a 24-h rhythm with a peak in the first half of the resting period. The expression of CD45, CD5, CD3, and CD4 followed a circadian rhythm. Their acrophases suggested temporal association between CD45 and CD5 at the end of the active phase and between CD4 and CD3 at the beginning of this phase. This temporal organization could have an important role for immune cell function.     

Circadian activity rhythms in the crayfish Paranephrops zealandicus (Crustacea)

The diel activity rhythm shown by Paranephrops is usually unimodal with most activity occurring at night. In constant darkness, locomotor activity is expressed for up to 60 days as a free-running circadian rhythm. The period varies from 18 to 38 hours following a seasonal cycle (summer mean period 24 hours, winter mean 30 hours). No adaptive significance can be attached to either seasonal or individual variations in period and it is suggested that such variations are a consequence of the way in which the clock mechanism operates, the period being linked to the overall activity level following Aschoff's ( 1960 ) "Circadian Rule". Activity levels will inevitably vary individually and seasonally.     

When the sun never sets: diverse activity rhythms under continuous daylight in free-living arctic-breeding birds

Circadian clocks are centrally involved in the regulation of daily behavioural and physiological processes. These clocks are synchronized to the 24 h day by external cues (Zeitgeber), the most important of which is the light–dark cycle. In polar environments, however, the strength of the Zeitgeber is greatly reduced around the summer and winter solstices (continuous daylight or continuous darkness). How animals time their behaviour under such conditions has rarely been studied in the wild. Using a radio-telemetry-based system, we investigated daily activity rhythms under continuous daylight in Barrow, Alaska, throughout the breeding season in four bird species that differ in mating system and parental behaviour. We found substantial diversity in daily activity rhythms depending on species, sex and breeding stage. Individuals exhibited either robust, entrained 24 h activity cycles, were continuously active (arrhythmic) or showed ‘free-running’ activity cycles. In semipalmated sandpipers, a shorebird with biparental incubation, we show that the free-running rhythm is synchronized between pair mates. The diversity of diel time-keeping under continuous daylight emphasizes the plasticity of the circadian system, and the importance of the social and life-history context. Our results support the idea that circadian behaviour can be adaptively modified to enable species-specific time-keeping under polar conditions.     

Do night and around-the-clock firefighters’ shift schedules induce deviation in tau from 24 hours of systolic and diastolic blood pressure circadian rhythms?

Systolic (S) and diastolic (D) blood pressures (BP) [SBP and DBP] are circadian rhythmic with period (τ) in healthy persons assumed to be maintained at 24.0h. We tested this assumption in a sample of 30 healthy career (mean >12 yrs) 30-to-46 yr-old male Caucasian French firefighters (FFs) categorized into three groups according to work schedule and duties: Group A – 12 FFs working 12h day, 12h night, and occasionally 24h shifts and whose primary duties are firefighting plus paramedical and road rescue services; Group B – 9 FFs working mostly 12h day and 12h night shifts and whose duties are answering incoming emergency calls and coordinating service vehicle dispatch from fire stations with Group A personnel; Group C – 9 day shift (09:00–17:00h) FFs charged with administrative tasks. SBP and DBP, both in winter and in summer studies of the same FFs, were sampled by ambulatory BP monitoring every 1h between 06:00–23:00h and every 2h between 23:01–05:59h, respectively, their approximate off-duty wake and sleep spans, for 7 consecutive days. Activity (wrist actigraphy) was also sampled at 1-min intervals. Prominent τ of each variable was derived by a power spectrum program written for unequal-interval time series data, and between-group differences in incidence of τ≠24h of FFs were assessed by chi square test. Circadian rhythm disruption (τ≠24h) of either the SBP or DBP rhythm occurred almost exclusively in night and 24h shift FFs of Group A and B, but almost never in day shift FFs of Group C, and it was not associated with altered τ from 24.0h of the circadian activity rhythm. In summer, occurrence of τ≠24 for FFs of Group A and B differed from that for FFs of Group C in SBP (p=0.042) and DBP (p=0.015); no such differences were found in winter (p>0.10). Overall, manifestation of prominent τ≠24h of SBP or DBP time series was greater in summer than winter, 27.6% versus 16.7%, when workload of Group B FFs, i.e. number of incoming emergency telephone calls, and of Group A FFs, i.e. number of dispatches for provision of emergency services, was, respectively, two and fourfold greater and number of 12h night shifts worked by Group B FFs and number of 24h shifts worked by Group A FFs was, respectively, 92% and 25% greater. FFs of the three groups exhibited no winter-summer difference in τ≠24h of SBP or SDP; however, τ≠24h of DBP in Group B FFs was more frequent in summer than winter (p=0.046). Sleep/wake cycle disruption, sleep deprivation, emotional and physical stress, artificial light-at-night, and altered nutrient timings are hypothesized causes of τ≠24h for BP rhythms of affected Groups A and B FFs, but with unknown future health effects.     

A forced desynchrony study of circadian pacemaker characteristics in seasonal affective disorder

The circadian pacemaker is an endogenous clock that regulates oscillations in most physiological and psychological processes with a near 24-h period. In many species, this pacemaker triggers seasonal changes in behavior. The seasonality of symptoms and the efficacy of light therapy suggest involvement of the circadian pacemaker in seasonal affective disorder (SAD), winter type. In this study, circadian pacemaker characteristics of SAD patients were compared with those of controls. Seven SAD patients and matched controls were subjected to a 120-h forced desynchrony protocol, in which core body temperature and melatonin secretion profiles were measured for the characterization of circadian pacemaker parameters. During this protocol, which enables the study of unmasked circadian pacemaker characteristics, subjects were exposed to six 20-h days in time isolation. Patients participated twice in winter (while depressed and while remitted after light therapy) and once in summer. Controls participated once in winter and once in summer. Between the SAD patients and controls, no significant differences were observed in the melatonin-derived period or in the phase of the endogenous circadian temperature rhythm. The amplitude of this rhythm was significantly smaller in depressed and remitted SAD patients than in controls. No abnormalities of the circadian pacemaker were observed in SAD patients. A disturbance in thermoregulatory processes might explain the smaller circadian temperature amplitude in SAD patients during winter.     

Interseasonal variation in the circadian rhythms of locomotor activity and temperature selection in sleepy lizards, <Emphasis Type="Italic">Tiliqua rugosa</Emphasis>

Few studies in non-mammalian vertebrates have examined how various effectors of the circadian system interact. To determine if the daily locomotor and behavioural thermoregulatory rhythms of Tiliqua rugosa are both controlled by the circadian system in different seasons, lizards were tested in laboratory thermal gradients in four seasons and in constant darkness. Circadian rhythmicity for both rhythms was present in each season, being most pronounced in spring and summer and least evident in autumn. Most lizards displayed a unimodal locomotor activity pattern across all seasons. However, some individuals presented a bimodal locomotor activity pattern in spring and summer. Seasonal variations in the phase relationships of both rhythms to the light:dark (LD) cycle were demonstrated. No seasonal differences in the free-running period lengths of either rhythm were detected, raising the possibility that a single circadian pacemaker drives both rhythms in this species. Our present results demonstrate that both rhythms are similarly controlled by the circadian system in each season. Although seasonal variations in the thermal preferences of reptiles both in the field and laboratory have previously been well documented, this study is the first to demonstrate circadian rhythms of temperature selection in a reptile species in each season.     

Seasonal Modulation of the 8‐and 24‐Hour Rhythms of Ondansetron Tolerance in Mice

Ondansetron (Zophren®) is a serotonin 5HT₃-receptor antagonist used primarily to control nausea and vomiting caused by cytotoxic chemo‐and radio‐therapy. Tolerance to this drug shows both 24 and 8 h periodicities. In this framework, this study aimed to determine whether these ondansetron tolerance rhythms are modulated by season. The chronotoxic effect of a fixed dose (3.5 mg/kg, i.p.) of the drug was investigated with reference to both time of the day and year dependencies. Season‐related studies were performed on 560 male Swiss mice, 10 to 12 wks old, synchronized with L:D=12:12 for three weeks. During a 1 yr span (2005), four 24 h studies were performed with a single dosing time at 1, 7, 13, and 19 hours after light onset (HALO), respectively. Tolerance was assessed daily during a 40‐day span after acute ondansetron treatment. Both χ² test and cosinor methods were used to analyze the time series data. Statistically significant dosing time‐dependent changes were validated in both yearly and daily time scales. The 24 h mean survival rate peaked in spring (92%) compared to fall (72%), the 20% difference being statistically significant (χ² test with p<0.05 and cosinor with p<0.0001 for seasonal rhythm detection and with a peak time, Ø,=April 3±6.6 days). A 24 h rhythm was also detected in each of the seasonal time points. However, the curve pattern was monophasic in fall as well as spring. In fall, a large amplitude (A) circadian rhythm was detected that peaked at 19 HALO, while in the spring, a small circadian rhythm was detected that peaked at 1 HALO. The curve pattern was biphasic in summer (with large A) and in winter (with a small A). The existence of two peaks of equal magnitude in winter (100% survival rate) and in summer (100% and 90%) suggests the presence of both circadian and ultradian rhythms rather than an ultradian component of the 24 h period. The seasonal modulation of ondansetron circadian chronotolerance seems to involve several rhythm parameters: season‐related changes in the 24 h mean (M), amplitude (A), acrophase location (Ø), as well as bimodal curve patterns including the coexistence of rhythms with respectively 24 and 8 h periods in winter and summer. In conclusion, tolerance to ondansetron varies not only according to the 24 and 8 h periods but also according to seasons, which suggests the complexity of ondansetron toxicity rhythms. Seasonal modulation of ondansetron tolerance may also influence the strategies of chemo‐and chrono‐therapy, and it is therefore necessary to take it into account in clinical drug‐delivery protocols to minimize side effects of cytotoxic anticancer and antiemetic agents.     

Circadian Rhythms of Circulating NK Cells in Healthy and Human Immunodeficiency Virus-Infected Men

Antiviral immunity involves NK cells, which circulate rhythmically every 24 hours. We have investigated circadian and 12-hour rhythms in the peripheral count of circulating NK cells in 15 men infected with human immunodeficiency virus (HIV) and 13 healthy controls. We analyzed three phenotypes using double-labeling with monoclonal antibodies and flow cytometry assessment: CD3^? CD16⁺, CD3^?CD57⁺, and CD2⁺CD3^?. A statistical validation of time-dependent differences was achieved if significance (p < 0.05) was validated both with analysis of variance and cosinor. The circadian rhythm had a similar asymmetric waveform for the three phenotypes and is homogeneous on an individual basis. The circulating NK cell count peaked in the early morning and was low at night. A circadian rhythm and a circahemidian harmonic characterized all phenotypes in healthy subjects. We considered two groups of HIV-infected men: those who were asymptomatic (eight) and those with acquired immune deficiency syndrome (AIDS) (seven). Circadian changes in NK cell count were similar in both subgroups and in healthy controls. The circadian pattern was also consistent among individual patients. Asymptomatic HIV-infected men (early-stage disease) exhibited more pronounced 12-hour rhythmicity than did patients with AIDS or controls. The circulation of NK cells does not appear to share the same synchro-nizer(s) as other circulating T- or B-lymphocyte subsets. Thus, HIV infection gradually abolished circadian rhythmicity in circulating T and B cells, whereas it did not disturb that in NK cells.     

生物钟基因研究进展

昼夜节律是以大约24 h为周期波动的生物现象.这些节律包括血压、体温、激素水平、血中免疫细胞的数量、睡眠觉醒周期循环等.基因水平上的昼夜节律研究还只是刚起步,介绍不同物种控制昼夜行为的共同基因(如period 、timless 、clock基因等)的研究进展,特别是一些有关调控昼夜节律基因的转录因子的研究.同时讨论果蝇和人类生物钟调节的共同分子机制.     

The circadian rhythms of valve movements in the mussel <Emphasis Type="Italic">Mytilus galloprovincialis</Emphasis>

The long-term (10–30 day) continuous recording of valve movements in the mussel Mytilus galloprovincialis was carried out in the laboratory under nearly natural conditions. Fourier analysis revealed the circadian (close to the diurnal) rhythm of the valve activity, the phase of which is readily shifted by a shift in the beginning of the daytime, since the light regime is one of the main factors determining the circadian rhythm. The circadian rhythm was manifested in the daily dynamics of mussel valve activity: in the daytime, mussels hold their valves closed more often than at night. This behavior may be a protective response, namely the “shadow reflex”: mussels close their valves upon a sudden decrease in illumination, thus protecting themselves from possible predators. Circadian activity can mask a mussel’s response to environmental pollution; therefore, regular valve closure should be taken into account in early warning systems such as “MusselMonitor®” with a correction for the season of the year, time of day, and other factors.     

Interindividual differences in a set of biological rhythms documented during the high arctic summer (79 degrees N) in three healthy subjects

The High Arctic summer with its permanent sunlight provides a situation in which one of the natural synchronizers, the light-dark alternation, is minimal. During the summers of 1981 and 1982 three healthy right-handed geographers who were performing field studies in Svalbard as part of their own research volunteered to document, 4-6 times per 24 hr for respectively 63,141 and 147 days, a set of circadian rhythms: self-rated fatigue, oral temperature, grip strength of both hands, heart rate and times of awakening and retiring. Tests were performed before departure from France, in Svalbard (79°IN latitude) where their daily activities were often strenuous, and after returning to France. Time series were treated individually according to three methods: display of data as a function of time, cosinor analyses to quantify rhythm parameters, and spectral analyses to estimate component periods of rhythms. Circadian parameters such as period and acrophase of activity-rest, oral temperature and fatigue rhythms were not altered. On the other hand, the circadian rhythm in grip strength was altered: the period differed from 24 hr in one subject, while grip strength acrophase of the left, but not the right, hand of the other two subjects was phase shifted during the sojourn in Svalbard. A prominent circahemidian (about 12 hr) rhythm was observed in two subjects for their heart rate in Svalbard, while a prominent circadian rhythm (differing from exactly 24 hr) was observed in France associated with a small circahemidian component.     

Daily and circadian rhythms in the activity of mixed function oxidases system in rats of different age

Abstract

An age‐associated alterations in daily and circadian changes of cytochrome P‐450‐linked monooxygenases system activity were studied using 1‐, 6‐ and 12‐months old male Wistar rats, in winter and in spring season. Cytochrome P‐450 and NADPH‐cytochrome P‐450 reductase showed 12h rhythm in all investigated age groups of animals. Cytochrome b₅ and NADH‐cytochrome b₅ reductase were characterized by a 12h daily rhythm in 1‐month old rats, but in older ones 24h circadian rhythm was found. There was not significant changes of the rhythm pattern in the activity of investigated MFO system ingredients in rats of different age, between spring and winter.     

Human circadian rhythms in temperature, trace metals, and blood variables

The literature supports the concept that circadian changes in body temperature reflect changes in the thermoregulatory set point. We were interested in studying the relationship between the circadian rhythm in body temperature and 24-h variations in plasma concentrations of iron, zinc, circulating leukocyte counts, and plasma interleukin 1 (IL-1) activity. Eight healthy men were studied for two separate 48-h sessions. Rectal temperature, plasma iron and zinc concentrations, plasma IL-1 activity, circulating leukocyte counts, and several other blood variables were monitored. Circadian rhythms in temperature, trace metals, and various leukocyte populations were demonstrated. The 24-h pattern of changes in plasma concentrations of iron and zinc approximate an inverse relationship with rectal temperature. Although we were unable to detect any IL-1 activity in human plasma collected at 4-h intervals, the daily changes in plasma trace metal concentrations and the variations in leukocyte populations may provide indirect evidence for a daily variation in local (e.g., in liver) or central nervous system release of IL-1.