Association of ischemic stroke onset time with presenting severity,acute progression,and long-term outcome: A cohort study

BackgroundPreclinical data suggest circadian variation in ischemic stroke progression, with more active cell death and infarct growth in rodent models with inactive phase (daytime) than active phase (nighttime) stroke onset. We aimed to examine the association of stroke onset time with presenting severity, early neurological deterioration (END), and long-term functional outcome in human ischemic stroke.Methods and findingsIn a Korean nationwide multicenter observational cohort study from May 2011 to July 2020, we assessed circadian effects on initial stroke severity (National Institutes of Health Stroke Scale [NIHSS] score at admission), END, and favorable functional outcome (3-month modified Rankin Scale [mRS] score 0 to 2 versus 3 to 6). We included 17,461 consecutive patients with witnessed ischemic stroke within 6 hours of onset. Stroke onset time was divided into 2 groups (day-onset [06:00 to 18:00] versus night-onset [18:00 to 06:00]) and into 6 groups by 4-hour intervals. We used mixed-effects ordered or logistic regression models while accounting for clustering by hospitals. Mean age was 66.9 (SD 13.4) years, and 6,900 (39.5%) were women. END occurred in 2,219 (12.7%) patients. After adjusting for covariates including age, sex, previous stroke, prestroke mRS score, admission NIHSS score, hypertension, diabetes, hyperlipidemia, smoking, atrial fibrillation, prestroke antiplatelet use, prestroke statin use, revascularization, season of stroke onset, and time from onset to hospital arrival, night-onset stroke was more prone to END (adjusted incidence 14.4% versus 12.8%, p = 0.006) and had a lower likelihood of favorable outcome (adjusted odds ratio, 0.88 [95% CI, 0.79 to 0.98]; p = 0.03) compared with day-onset stroke. When stroke onset times were grouped by 4-hour intervals, a monotonic gradient in presenting NIHSS score was noted, rising from a nadir in 06:00 to 10:00 to a peak in 02:00 to 06:00. The 18:00 to 22:00 and 22:00 to 02:00 onset stroke patients were more likely to experience END than the 06:00 to 10:00 onset stroke patients. At 3 months, there was a monotonic gradient in the rate of favorable functional outcome, falling from a peak at 06:00 to 10:00 to a nadir at 22:00 to 02:00. Study limitations include the lack of information on sleep disorders and patient work/activity schedules.ConclusionsNight-onset strokes, compared with day-onset strokes, are associated with higher presenting neurologic severity, more frequent END, and worse 3-month functional outcome. These findings suggest that circadian time of onset is an important additional variable for inclusion in epidemiologic natural history studies and in treatment trials of neuroprotective and reperfusion agents for acute ischemic stroke.

Wi-Sun Ryu and colleagues investigate the association of stroke onset time with presenting severity, early neurological deterioration (END), and long-term functional outcome in ischemic stroke.     

Time of symptom onset and value of myocardial blush and infarct size on prognosis in patients with ST-elevation myocardial infarction

In patients with ST-segment elevation myocardial infarction (STEMI), the time of onset of ischemia has been associated with myocardial infarction (MI) size. Myocardial blush grade (MBG) reflects myocardial response to ischemia/reperfusion injury, which may differ according to time of the day. The aim of our study was to explore the 24-hour variation in MBG and MI size in relation to outcomes in STEMI patients. A retrospective multicenter analysis of 6970 STEMI patients was performed. Time of onset of STEMI was divided into four 6-hour periods. STEMI patients have a significant 24-hour pattern in onset of symptoms, with peak onset around 09:00 hour. Ischemic time was longest and MI size, estimated by peak creatine kinase concentration, was largest in patients with STEMI onset between 00:00 and 06:00 hours. Both MBG and MI size were independently associated with mortality. Time of onset of STEMI was not independently associated with mortality when corrected for baseline and procedural factors. Interestingly, patients presenting with low MBG between 00:00 and 06:00 hours had a better prognosis compared to other groups. In conclusion, patients with symptom onset between 00:00 and 06:00 hours have longer ischemic time and consequently larger MI size. However, this does not translate into a higher mortality in this group. In addition, patients with failed reperfusion presenting in the early morning hours have better prognosis, suggesting a 24-hour pattern in myocardial protection.     

Role of patient chronotype on circadian pattern of myocardial infarction: a pilot study

Population-based studies indicate the risk of acute myocardial infarction (AMI) is greatest in the morning, during the initial hours of diurnal activity. The aim of this pilot study was to determine whether chronotype, i.e., morningness and eveningness, impacts AMI onset time. The sample comprised 63 morning- and 40 evening-type patients who were classified by the Horne-?stberg Morningness-Eveningness Questionnaire (MEQ) in the hospital after experiencing the AMI. The average wake-up and bed times of morning types were ~2?h earlier than evening types. Although the lag in time between waking up from nighttime sleep and AMI onset during the day did not differ between the two chronotypes, the actual clock-hour time of the peak in the 24-h AMI pattern did. The peak in AMI of morning types occurred between 06:01 and 12:00?h and that of the evening types between 12:01 and 18:00?h. Although the results of this small sample pilot study suggest one's chronotype influences the clock time of AMI onset, larger scale studies, which also include assessment of 24-h patterning of events in neither types, must be conducted before concluding the potential influence of chronotype on the timing of AMI onset.     

Role of Patient Chronotype on Circadian Pattern of Myocardial Infarction: A Pilot Study

Population-based studies indicate the risk of acute myocardial infarction (AMI) is greatest in the morning, during the initial hours of diurnal activity. The aim of this pilot study was to determine whether chronotype, i.e., morningness and eveningness, impacts AMI onset time. The sample comprised 63 morning- and 40 evening-type patients who were classified by the Horne-Östberg Morningness-Eveningness Questionnaire (MEQ) in the hospital after experiencing the AMI. The average wake-up and bed times of morning types were ～2?h earlier than evening types. Although the lag in time between waking up from nighttime sleep and AMI onset during the day did not differ between the two chronotypes, the actual clock-hour time of the peak in the 24-h AMI pattern did. The peak in AMI of morning types occurred between 06:01 and 12:00?h and that of the evening types between 12:01 and 18:00?h. Although the results of this small sample pilot study suggest one's chronotype influences the clock time of AMI onset, larger scale studies, which also include assessment of 24-h patterning of events in neither types, must be conducted before concluding the potential influence of chronotype on the timing of AMI onset. (Author correspondence: dryavuzselvi@yahoo.com).     

大绒鼠及高山姬鼠体温调节和蒸发失水的日节律

为比较横断山区同域分布物种大绒鼠(Eothenomys miletus)和高山姬鼠(Apodemus chevrieri)的日节律特征,对两种鼠在24 h中4个时间段(04:00～06:00时、10:00～12:00时、16:00～18:00时和22:00～24:00时)的体温和蒸发失水进行了测定.结果显示,大绒鼠、高...     

Sleepiness and Sleep in a Simulated “Six Hours On/Six Hours Off” Sea Watch System

Ships are operated around the clock using rapidly rotating shift schedules called sea watch systems. Sea watch systems may cause fatigue, in the same way as other irregular working time arrangements. The present study investigated subjective sleepiness and sleep duration in connection with a 6 h on/6 h off duty system. The study was performed in a bridge simulator, very similar to those found on ships. Twelve officers divided into two groups participated in the study that lasted 66 h. Half of the subjects started with the 06:00–12:00 h watch and the other half with the 12:00–18:00 h watch. The subjects alternated between off‐duty and on‐duty for the remainder of the experimental period. Approximately halfway through the experiment, the 12:00–18:00 h watch was divided into two 3 h watches/off‐duty periods. The effect of this was to reverse the on‐duty/off‐duty pattern between the two groups. This enabled all subjects to work the four possible watches (00:00–06:00 h, 06:00–12:00 h, 12:00–18:00 h, and 18:00–24:00 h) in an order that was essentially counterbalanced between groups. Ratings of sleepiness (Karolinska Sleepiness Scale; KSS) were obtained every 30 min during on‐duty periods and if subjects were awake during off‐duty periods. The subjectively rated duration of sleep was recorded after each off‐duty period that preceded watch periods when KSS was rated. The results showed that the average level of sleepiness was significantly higher during the 00:00–06:00 h watch compared to the 12:00–18:00 h and 18:00–24:00 h watches, but not to the 06:00–12:00 h watch. Sleepiness also progressed significantly from the start toward the end of each watch, with the exception of the 06:00‐12:00 h watch, when levels remained approximately stable. There were no differences between groups (i.e., the order between watches). Sleep duration during the 06:00–12:00 h off‐duty period (3 h 29 min) was significantly longer than during the 12:00–18:00 h period (1 h 47 min) and the 18:00–24:00 h period (2 h 7 min). Sleep during the 00:00–06:00 h period (4 h 23 min) was longer than all sleep periods except the 06:00–12:00 h period. There were no differences between groups. In spite of sufficient opportunities for sleep, sleep was on the average around 1–1 h 30 min shorter than the 7–7 h 30 min that is considered “normal” during a 24 h period. This is probably a consequence of the difficulty to sleep during daytime due to the alerting effects of the circadian rhythm. Also, sleepiness during the night and early mornings reached high levels, which may be explained by a combination of working close to or during the circadian trough of alertness and the relatively short sleep periods obtained. An initial suppression of sleepiness was observed during all watches, except for the 06:00–12:00 h watch. This suppression may be explained by the “masking effect” exerted by the relative high levels of activity required when taking over the responsibility of the ship. Toward the end of watches, the levels of sleepiness progressively increased to relatively high levels, at least during the 00:00–06:00 h watch. Presumably, initially high levels of activity are replaced by routine and even boredom.     

The effects of sleep deprivation and time of day on cognitive performance

The extent to which the diurnal fluctuations of different cognitive processes could be affected by sleep loss may be explored to predict performance decrements observed in the real world. Twenty healthy male subjects voluntarily took part in 8 test sessions at 06:00, 10:00, 14:00, and 18:00 h, following either a night with or without sleep in random order. Measurements included oral temperature, simple reaction time, sign cancelation, Go/NoGo, and the Purdue pegboard test. The results indicate that simple reaction time and motor coordination had morning–afternoon variations closely following the rhythms of temperature and vigilance. Inhibitory attention (Go/NoGo) presented no morning–afternoon variations. Sleep deprivation may affect the profiles of cognitive performance depending on the processes solicited. Sustained and inhibitory attention are particularly affected in the morning (after 24 and 28 waking hours), while a complex task (visuo-motor coordination) would be affected after 32 waking hours only.     

Circadian and seasonal cortico-medullary variations in pinealocyte nuclear size. A comparative statistical analysis.

Circadian and seasonal variations were observed in the karyometric index of pinealocytes in the cortical and medullary regions of the distal pineal body. The study involved 70 Wistar rats over a 24-hour interval (0:6, 10:00, 14:00, 18:00, 22:00, 02:00, 06:00 h) during two natural photoluminous periods, i.e. late summer (Long photoperiod) and Winter (Short photoperiod). The results show a difference between the high and low points of both photoperiods. Cortico-medullary differences are found at different times of day during long photoperiod (0:6; 10:00; 14:00 and 18:00 h.) and short photoperiod (14:00; 22:00 and 02:00 h.). The variance analyses between nuclear volume and point-time and between nuclear volume, point-time and location are significative. A high correlation between circadian rhythms and volumetric variations in both layers and photoperiod are found. The results also show significant differences in cortico-medullary karyometric indices between both seasons as well as between the diurnal and nocturnal hours of both photoperiods. It is suggested that the pineal body of the rat is influenced by circadian and seasonal photoperiod and may have groups of cells with different functional characteristics, depending on their location within the gland.     

Melatonin and circadian rhythms in autism: Case report

Among the most co-occurring conditions in autism spectrum disorders (ASD), there are sleep disorders which may exacerbate associated behavioral disorders and lead to intensification of existing autistic symptoms. Several studies investigating the use of melatonin in the treatment of sleep disorders in ASD have shown comparative efficiency in sleep with little or no side effects. Here we report a case of ASD with non-24-hour rhythm and the effect of melatonin in circadian parameters by actigraphy. Visual analysis of the first 10 days recorded and the periodogram suggest that this patient showed a non-24-hour rhythm. This ASD subject showed before melatonin administration an activity/rest rhythm lower than 24 hours. The results show that melatonin increased approximately 4.7 times the regularity of circadian activity rhythm and resting staying on average between 00:00 and 06:00 and showed positive effects in improving the quality of sleep and behavior. So, the actigraphy showed an ASD subject with a non-24-hour activity/rest rhythm which changed this rhythm to a 24-hour rhythm after melatonin administration. This result reinforces the prospect of therapy with melatonin for synchronization (increased regularity) of endogenous rhythms and improve sleep quality and hence behavior and indicates the actigraphy as a choice tool to characterize several parameters of the activity/rest rhythm of ASD individuals.     

Diel cycle size‐dependent trophic structure of neotropical fishes: a three year case analysis from 35 floodplain lakes in Colombia

Investigated were whether fish assemblages in 35 neotropical floodplain lakes along the Magdalena River, Colombia (ranging from 4 to 2333 ha) have a trophic structure that is dependent on fish body size within the diel cycle (24 h), and whether any changes to the trophic structure of fish assemblages occur during the diel cycle. Sampling was done during diel cycles in the rainy seasons between 2008 and 2011 (ten lakes in 2008, 20 in 2010, and five in 2011). Small fish (27–87 mm) were most active from 06:01 to 18:00, while larger predatory fish (>87 mm) were inactive during this time. In addition to fish body size, trophic group composition also varied throughout the diel cycle: insectivores, piscivores, and omnivore‐insectivores were the dominant groups from 06:01 to 18:00; carnivores, carnivore‐insectivores, and detritivores dominated from 18:01 to 06:00. This study highlights the importance of fish size in predicting predator‐prey interactions during different periods of the diel cycle.     

Locomotor activity rhythm in two wrasses,Halichoeres tenuispinnis andPteragogus flagellifera,under various light conditions

The locomotor activity rhythms were examined by using an actograph with infra-red photo-electric switches for two species of wrasses, (Halichoeres tenuispinnis andPteragogus flagellifera) under various light conditions. InH. tenuispinnis, the locomotor activity of almost all fish under light-dark cycle regimen (LD12:12; 06:00–18:00 light, 18:00–06:00 dark) commenced somewhat earlier than the beginning of light period and continued till somewhat earlier than the beginning of the dark period. This species clearly showed free-running activity rhythms under both constant illumination (LL) and constant darkness (DD). Therefore,H. tenuispinnis appeared to have a circadian rhythm. The length of the circadian period ranged from 23 hr. 30 min. to 23 hr. 44 min. under LL, and was from 23 hr. 39 min. to 24 hr. 18 min. under DD. On the other hand, the locomotor activity ofP. flagellifera occurred mostly in the light period under LD 12:12. The activity of this species continued through LL, but was greatly suppressed in DD, so that none of the fish had any activity rhythm in both constant conditions. It was known from field observations thatH. tenuispinnis burrowed and lay in sandy bottoms, whileP. flagellifera hid and rested in bases of seagrasses and shallow crevices of rocks during the night. In the present two wrasses, it seemed that the above-mentioned difference of noctural behavior was closely related to the intensity of the endogenous factor in the activity rhythm.     

Asynchrony in the Diurnal Rhythms of Dopaminergic D2 Receptors in Different Brain Regions of the Rat

Diurnal variations of dopaminergic D₂ receptors have been described in the striatum of rats, while other dopaminergic regions remain unstudied. Diurnal variations of dopamine D₂ receptors in the striatum, frontal cortex, and amygdala of the rat, were characterized by the stereospecific binding of [³H]-spiperone. Clear rhythms were found in all these areas, but asynchronous to each other. Striatal receptors had diurnal variations with a single peak at 00:00 hours. Frontal cortex receptors showed two peaks at 00:00 and 12:00 hours. Amygdaline complex receptors had two peaks at 18:00 and 06:00 hours. Saturation binding curves and their Scatchard analysis indicated that the diurnal variations in [³H]-spiperone binding are related to changes in receptor density rather than its affinity. The diurnal variations asynchrony in [³H]-spiperone binding to dopaminergic D₂ receptors from different neural regions, suggest different regulation in each area. Other functional implications of these rhythms remains to be established.     

Sleepiness and sleep in a simulated "six hours on/six hours off" sea watch system

Ships are operated around the clock using rapidly rotating shift schedules called sea watch systems. Sea watch systems may cause fatigue, in the same way as other irregular working time arrangements. The present study investigated subjective sleepiness and sleep duration in connection with a 6 h on/6 h off duty system. The study was performed in a bridge simulator, very similar to those found on ships. Twelve officers divided into two groups participated in the study that lasted 66 h. Half of the subjects started with the 06:00-12:00 h watch and the other half with the 12:00-18:00 h watch. The subjects alternated between off-duty and on-duty for the remainder of the experimental period. Approximately halfway through the experiment, the 12:00-18:00 h watch was divided into two 3 h watches/off-duty periods. The effect of this was to reverse the on-duty/off-duty pattern between the two groups. This enabled all subjects to work the four possible watches (00:00-06:00 h, 06:00-12:00 h, 12:00-18:00 h, and 18:00-24:00 h) in an order that was essentially counterbalanced between groups. Ratings of sleepiness (Karolinska Sleepiness Scale; KSS) were obtained every 30 min during on-duty periods and if subjects were awake during off-duty periods. The subjectively rated duration of sleep was recorded after each off-duty period that preceded watch periods when KSS was rated. The results showed that the average level of sleepiness was significantly higher during the 00:00-06:00 h watch compared to the 12:00-18:00 h and 18:00-24:00 h watches, but not to the 06:00-12:00 h watch. Sleepiness also progressed significantly from the start toward the end of each watch, with the exception of the 06:00-12:00 h watch, when levels remained approximately stable. There were no differences between groups (i.e., the order between watches). Sleep duration during the 06:00-12:00 h off-duty period (3 h 29 min) was significantly longer than during the 12:00-18:00 h period (1 h 47 min) and the 18:00-24:00 h period (2 h 7 min). Sleep during the 00:00-06:00 h period (4 h 23 min) was longer than all sleep periods except the 06:00-12:00 h period. There were no differences between groups. In spite of sufficient opportunities for sleep, sleep was on the average around 1-1 h 30 min shorter than the 7-7 h 30 min that is considered “normal” during a 24 h period. This is probably a consequence of the difficulty to sleep during daytime due to the alerting effects of the circadian rhythm. Also, sleepiness during the night and early mornings reached high levels, which may be explained by a combination of working close to or during the circadian trough of alertness and the relatively short sleep periods obtained. An initial suppression of sleepiness was observed during all watches, except for the 06:00-12:00 h watch. This suppression may be explained by the “masking effect” exerted by the relative high levels of activity required when taking over the responsibility of the ship. Toward the end of watches, the levels of sleepiness progressively increased to relatively high levels, at least during the 00:00-06:00 h watch. Presumably, initially high levels of activity are replaced by routine and even boredom.     

Photoperiod affects growth, behaviour and stress variables in Clarias gariepinus

Short periods of light or no light (18D : 06L and 24D : 00L) resulted in an increased growth compared to extended periods of light (06D : 18L and 12D : 12L) in African catfish Clarias gariepinus . Fish under longer periods of light (12D : 12L and 18D : 06L) showed higher swimming activity, more aggression (injuries on the body) and higher lactate, free fatty acids and cortisol levels compared to those who were reared at shorter periods of light (24D : 00L and 18D : 06L). Feeding activity during light and dark periods in this experiment showed that C. gariepinus had both night and day feeding activities, with a preference to diurnal feeding in the 12D : 12L photoperiod. The results showed that light plays an important role in the African catfish behaviour and its well‐being. As the hours of light increased during the 24 h cycle, data suggests that the fish were more stressed and aggressive, compared to those under a reduced number of light hours.     

Neuroproteome Changes after Ischemia/Reperfusion Injury and Tissue Plasminogen Activator Administration in Rats: A Quantitative iTRAQ Proteomics Study

The thrombolytic, recombinant tissue plasminogen activator (rt-PA) is the only approved therapy for acute ischemic stroke (AIS). When administered after AIS, rt-PA has many adverse pleiotropic actions, which are currently poorly understood. The identification of proteins showing differential expression after rt-PA administration may provide insight into these pleiotropic actions. In this study we used a 2D-LC MS/MS iTRAQ proteomic analysis, western blotting, and pathway analysis to analyze changes in protein expression 24-hours after rt-PA administration in the cortical brain tissue of 36 rats that underwent a sham or transient middle cerebral artery occlusion surgery. After rt-PA administration we reported alterations in the expressions of 18 proteins, many of which were involved in excitatory neurotransmitter function or cytoskeletal structure. The expression changes of GAD2 and EAAT1 were validated with western blot. The interactions between the identified proteins were analyzed with the IPA pathway analysis tool and three proteins: DPYSL2, RTN4, and the NF-kB complex, were found to have characteristics of being key proteins in the network. The differential protein expressions we observed may reflect pleiotropic actions of rt-PA after experimental stroke, and shine light on the mechanisms of rt-PA''s adverse effects. This may have important implications in clinical settings where thrombolytic therapy is used to treat AIS.     

Chronotype,gender, and time for sex

The study aimed at testing chronotype and gender differences in the time of day when humans feel the greatest need for sex and the time of day they actually undertake sexual activity. A Polish sample of 565 participants aged between 18 and 57 was tested. In females, regardless of chronotype, the greatest need for sex occurred between 18:00 and 24:00, but a secondary peak appeared only in morning types at 6:00–9:00. In males, the greatest need for sex occurred either in the morning or evening hours: in evening types at 9:00–12:00 and 18:00–3:00; in neither types at 6:00–9:00 and 18:00–24:00; in morning types at 6:00–12:00 and 18:00–24:00. Considering time of day when subjects were undertaking sexual activity most frequently, this appeared between 18:00 and 24:00 for all the participants, and prolonged until 3:00 at night in evening type males. Morningness preference was more strongly related to the timing of need for sex than to the timing of actual sexual activity (r?=??0.275 vs. r?=??0.174), while the timing of desire and the timing of sexual activity were positively, but moderately related (r?=?0.320).     

Omitting Late-Night Eating May Cause Hypoglycemia in “Well Controlled” Basal Insulin-Treated Type 2 Diabetes

ObjectiveTo assess hypoglycemia caused by eating the last meal of the day earlier or its omission in “well controlled” type 2 diabetes mellitus patients treated with once-nightly basal insulin.MethodsPreviously basal insulin-titrated subjects (n = 20) (fasting plasma glucose, FPG, < 110 mg/dL and no self-reported hypoglycemia) underwent continuous glucose monitoring (CGM) during 3 consecutive eating conditions of 3 days each; (1) usual eating, (2) the last meal restricted to 18:00, and (3) 1 sequential meal omitted/day thereby creating a fasting day after transposing the 4-hour period after a meal with that when the meal was omitted. One 24-hour (00:00 to 00:00) period within each eating condition was selected for comparison.ResultsThe mean duration in all hypoglycemic ranges doubled (P = .0584 or greater) when the last meal was omitted or eaten at 18:09 ± 0:39 instead of 19:43 ± 1:01, the usual time for the subjects’ undisturbed eating. The mean duration of hypoglycemia was greatest between 00:00 to 06:00 compared to the 3 other 6-hour periods of the day.ConclusionsIncreased hypoglycemia occurs when the subject’s last meal is eaten earlier or omitted and may not be recognized because it occurs predominately during sleep. When titrating basal insulin from the morning FPG, considerations should be given to the effect of the last meal of the day and possible hypoglycemia between 00:00 and 06:00 to avoid excessive basal insulin treatment. (Endocr Pract. 2015;21:280-285)     

Circadian rhythms in rat brain alpha- and beta-adrenergic receptors are modified by chronic imipramine

Circadian rhythms of α- and ß-adrenergic receptor number, with different wave forms, as well as differences in timing of maximal binding, are present in rat brain. Chronic treatment with the tricyclic antidepressant drug imipramine modifies these rhythms: peak binding of both receptors occurs 4–12 hours later than in controls, the 24-hour mean is decreased by 15–30%, and the amplitude is increased by 20–30%. Delaying of the phase position of neurotransmitter receptor rhythms by a tricyclic antidepressant may be relevant to its clinical mode of action, since depressive patients appear to have abnormally phase-advanced circadian rhythms.     

Diurnal rhythms in cyclic nucleotide metabolism in Helix nervous system

Concentrations of cAMP (cyclic adenosine 3′,5′-monophosphate) and cGMP (cyclic guanosine 3′,5′-monophosphate), in ganglia from the garden snail Helix pomatia, vary considerably over the course of the day. There is a maximum in the concentration of both cyclic nucleotides between 08:00 and 12:00 (lights on 06:00 to 18:00), with the cAMP maximum occurring slightly later than that in cGMP. In addition there can be several smaller maxima in cAMP and cGMP levels; the timing of these can be markedly different from experiment to experiment, with cAMP and cGMP sometimes in and sometimes out of phase with each other. This pattern is observed in Helix which had been activated from the dormant state 4–6 days earlier, but is not present in dormant or in long-active animals. The cyclic nucleotide rhythm can be seen in ganglia maintained in organ culture, and persists for at least 24 hours after removal of the tissue from the animal. There appears to be little change in the level of basal or Na Fstimulated adenylate cyclase activity in Helix ganglia over the course of the day. On the other hand, both cAMP and cGMP phosphodiesterase activities exhibit rhythms which are consistent with the rhythms in cAMP and cGMP concentrations.     

Protocol for the combined immunosuppression & radiotherapy in thyroid eye disease (CIRTED) trial: A multi-centre, double-masked, factorial randomised controlled trial

Background

Intravenous recombinant tissue plasminogen activator (rt-PA) is approved for use in selected patients with ischaemic stroke within 3 hours of symptom onset. IST-3 seeks to determine whether a wider range of patients may benefit.

Design

International, multi-centre, prospective, randomized, open, blinded endpoint (PROBE) trial of intravenous rt-PA in acute ischaemic stroke. Suitable patients must be assessed and able to start treatment within 6 hours of developing symptoms, and brain imaging must have excluded intracerebral haemorrhage. With 1000 patients, the trial can detect a 7% absolute difference in the primary outcome. With3500 patients, it can detect a 4.0% absolute benefit & with 6000, (mostly treated between 3 & 6 hours), it can detect a 3% benefit.

Trial procedures

Patients are entered into the trial by telephoning a fast, secure computerised central randomisation system or via a secure web interface. Repeat brain imaging must be performed at 24–48 hours. The scans are reviewed 'blind' by expert readers. The primary measure of outcome is the proportion of patients alive and independent (Modified Rankin 0–2) at six months (assessed via a postal questionnaire mailed directly to the patient). Secondary outcomes include: events within 7 days (death, recurrent stroke, symptomatic intracranial haemorrhage), outcome at six months (death, functional status, EuroQol).

Trial registration

ISRCTN25765518