Blood pressure levels in the acute phase after intracerebral hemorrhage are associated with mortality in young adults.

BACKGROUND AND PURPOSE: Blood pressure (BP) levels in acute intracerebral hemorrhage (ICH) and mortality have not been thoroughly studied in the young. METHODS: The relationship between BP and mortality was assessed in consecutive patients with first-ever, non-traumatic acute ICH at ≤50 years of age, enrolled in the Helsinki ICH Young Study. BP parameters included systolic BP (SBP), diastolic BP (DBP), mean arterial pressure and pulse pressure (SBP - DBP) at admission and 24 h, and delta (admission-24 h) BP parameters. Outcome measures were 3-month and long-term mortalities, adjusted for demographics and ICH score parameters for short-term and cardiovascular risk factors for long-term prognostics. Cox regression models were used to assess independent BP parameters associated with mortality. RESULTS: Of our 334 patients (61% male), 92 (27%) had pre-stroke hypertension and 54 (16%) used antihypertensive treatment. The follow-up extended to 17 years with a median of 12 (interquartile range, 9.65-14.7) years. Both 3-month (n = 56; 16%) and long-term (n = 97; 29%) mortalities were associated with significantly higher admission SBP and mean arterial pressure levels, but not with 24-h BP levels, compared with survivors. Patients with SBP ≥ 160 mmHg (n = 156; 46%) had a significantly higher mortality rate (n = 59, 17% vs. n = 38, 11%; P = 0.001) and died earlier (9.6; 95% confidence interval, 2.9-12.9 years vs. 11.3; 95% confidence interval, 8.1-13.9 years; P = 0.001) within the follow-up period. In multivariable analyses, admission SBP ≥160 mmHg was independently associated with both 3-month (hazard ratio, 2.50; 95% confidence interval, 1.19-5.24; P < 0.05) and long-term (hazard ratio, 2.02; 95% confidence interval, 1.18-3.43; P < 0.01) mortalities. CONCLUSIONS: In young patients with ICH, acute-phase SBP levels ≥160 mmHg are independently associated with increased mortality.

Symptomatic post-thrombolytic intracerebral hemorrhage is not related to the cause of stroke.

BACKGROUND AND PURPOSE: The development of intracerebral hemorrhage following intravenous thrombolysis (IVT) can be influenced by various confounders related to the underlying vessel and tissue conditions. There are some data on association of cause of the stroke and the hemorrhage transformation. We tested the hypothesis that the cause of stroke is associated with the development of symptomatic intracerebral hemorrhage (sICH) following IVT. METHODS: A consecutive cohort of 2485 IVT-treated patients at the Helsinki University Central Hospital was classified according to the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria. An sICH was classified according to the European Cooperative Acute Stroke Study II criteria. The associations of sICH with nominal, ordinal and continuous variables were analyzed in a univariate binary regression model and adjusted in multivariate binary regression models. RESULTS: In univariate analyses, cardioembolism [odds ratio (OR), 1.14; 95% confidence interval (CI), 0.79-1.64] and large-artery atherosclerosis (OR, 1.30; 95% CI, 0.85-2.00) were not associated with sICH, and small-vessel occlusion was associated with lower odds for sICH (OR, 0.18; 95% CI, 0.06-0.57). When adjusted for previously identified factors associated with sICH, none of the TOAST categories was associated with a higher or lower frequency of sICH. CONCLUSIONS: The development of sICH in IVT-treated patients is not related to the cause of stroke.

Higher baseline international normalized ratio value correlates with higher mortality in intracerebral hemorrhage during warfarin use.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) is the most feared complication of oral anticoagulation (OAC). Our aim was to investigate the impact of the international normalized ratio (INR) level on mortality in OAC-associated ICH compared with non-OAC-associated ICH. METHODS: A retrospective chart review of consecutive ICH patients treated at the Helsinki University Central Hospital from January 2005 to March 2010 (n = 1013) was performed. An ICH was considered to be OAC-associated if the patient was on warfarin at ICH onset. The association of INR with 3-month mortality was adjusted in a multivariable logistic regression model for factors influencing the crude odds ratios (ORs) in bivariable logistic regression by more than 5%. RESULTS: One in eight ICHs was OAC-associated (n = 132). Of these, 50% had therapeutic INR (2.0-3.0), 7% had INR <2.0 and 43% had high INR (>3.0) on admission. Patients on OAC were older (median 76 vs. 66 years; P < 0.001) with more severe symptoms (median National Institutes of Health Stroke Scale 14 vs. 10; P < 0.001) and larger hematomas (median 11.4 vs. 9.7 ml; P < 0.001) on admission than patients not on OAC. After adjustment for confounders, 3-month mortality in the whole cohort was associated with higher baseline INR (OR 1.06; CI 1.03-1.09 per 0.1 increment). Mortality was higher with both therapeutic (51% at 3 months; OR 3.59; CI 1.50-8.60) and high (61%; OR 5.26; CI 1.94-14.27) INR values compared with non-OAC-associated ICH (29%). CONCLUSIONS: Patients with OAC-associated ICH had more severe strokes and higher mortality compared with patients with ICH not related to OAC. Higher baseline INR was associated with increased 3-month mortality.

Lost potential of kidney and liver donors amongst deceased intracerebral hemorrhage patients.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) has high acute mortality. The number of potential kidney and liver donors amongst deceased ICH patients was estimated to improve our institutional guidelines on acute care of neurocritical patients to increase organ donation. METHODS: A chart review was carried out by a multi-professional team for consecutive ICH patients admitted to the emergency department at Helsinki University Central Hospital and dying within 14 days between 2005 and 2010. RESULTS: In all, 955 patients had follow-up data, of whom 254 (27%) died within 14 days and eight ended up as organ donors. An additional 51 potentially suitable donors not different from actual donors were identified: nine suitable for kidney donation, 11 for liver and 31 for both. In 49/51 (96%) cases prognosis seemed non-existent and do-not-resuscitate orders were issued early, which led to refrainment from intensive care in 76.5%. These potential donors differed from those ICH patients surviving a whole year (n = 529) by male preponderance, more severe symptoms (median National Institutes of Health Stroke Scale 25 vs. 6 and Glasgow Coma Scale 7 vs. 15), larger hematoma volumes of 24.8 cm(3) (vs. 6.7), and frequent finding of midline shift and intraventricular rupture of the hemorrhage in admission brain CT. Based on the results, our guidelines were revised towards more active treatment including mechanical ventilation for neurocritical patients at the emergency department for at least 48 h, resulting in an increase in organ donations in 2012. CONCLUSIONS: A considerable number of ICH patients are potential organ donors if the evaluation takes place on arrival and organ donation is considered as part of usual end-of-life care.

Functional outcome in young adult ischemic stroke: impact of lipoproteins.

AIM: To determine the functional outcome in a cohort of young adults with ischemic stroke patients, focusing on components of lipid profile. METHODS: In our registry including consecutive patients with first-ever ischemic stroke aged 15-49 from 1994 to 2007, we analyzed predictors of 3-month functional outcome (modified Rankin Scale, mRS). Infarct size fell into small, medium, large posterior, or large anterior. Stroke severity was assessed with NIH Stroke Scale (NIHSS). Serum lipids were measured within 72 h after admission. Binary, multinomial ordinal, and Poisson regressions allowed revealing factors associated with size of infarct, stroke severity, and unfavorable outcome or death (mRS, 2-6) or mRS as an ordinal measure. RESULTS: In the 968 patients included (mean age, 41.3 ± 7.6; 62.6% men; 49.5% with mRS 0-1), factors associated with unfavorable outcome after multivariable analysis were increasing age (odds ratio, 1.03 per year; 95% confidence interval, 1.01-1.05), higher NIHSS score (1.23 per point, 1.17-1.29), large anterior (4.37, 2.26-8.42) or posterior (1.73, 1.05-2.85) infarcts, bilateral lesions (2.28, 1.30-3.98), internal carotid artery dissection (ICAD) (3.65, 1.41-9.47), and inversely high-density lipoprotein (HDL) levels (0.58 per unit increase, 0.38-0.86). Increasing HDL associated with smaller infarct size (0.71, 0.51-0.98). Both higher total and HDL cholesterol associated with lower NIHSS score (0.96, 0.93-0.98 for total cholesterol and 0.82, 0.75-0.88 for HDL) and lower 3-month mRS (0.87, 0.78-0.97 for total cholesterol and 0.65, 0.47-0.90 for HDL). CONCLUSION: In addition to known prognosticators, ICAD and lower HDL levels were independently associated with adverse clinical outcomes in our young adult stroke cohort.

Multiple brain infarcts in young adults: clues for etiologic diagnosis and prognostic impact.

BACKGROUND AND PURPOSE: There are little data on the etiology of multiple brain infarcts (MBI) and their impact on clinical outcome in young patients. METHODS: We studied 548 MRI-imaged patients (15-49 years) with a first-ever ischaemic stroke. Ischaemic lesions were categorized into three groups: single lesions, MBI in one or >1 circulation territories. Outcomes were unfavorable 3-month modified Rankin Scale (mRS) score of ≥ 2 and, during long-term follow-up (mean 8.20 ± 4.01 years), recurrent ischaemic stroke or death from any cause. RESULTS: Multiple brain infarcts occurred in 185 patients (33.8%; mean age 39.2 ± 8.2), of which 144 patients (26.3%) had lesions located in a single territory and 41 patients (7.5%) in multiple territories. Patients with MBI in a single territory were more likely than patients with single lesions to have a high-risk source of cardioembolism (CE) (9.0% vs. 3.0%; P = 0.001), large-artery atherosclerosis (8.3% vs. 4.9%; P = 0.012), vertebral (22% vs. 10%; P < 0.001) or carotid artery dissections (8.3% vs. 6.3%; P = 0.036), and MBI in multiple territories a high-risk source of CE (34% vs. 3.0%, P < 0.001). Adjusted for age, gender, baseline stroke severity, size of the largest lesion, and stroke subtype, MBI remained independently associated with an unfavorable 3-month outcome (odds ratio 2.84, 95% confidence interval 1.22-6.61). In multivariate Cox proportional hazards analysis, MBI had independent influence on the risk for death (hazard ratio 3.75, 1.58-8.86), but not on recurrent ischaemic stroke. CONCLUSIONS: Compared with the elderly, young stroke patients have a distinct stroke etiology underlying MBI, being an independent indicator of poor short-term outcome and long-term risk of death.

Cognitive deficits after subcortical infarction are comparable with deficits after cortical infarction.

BACKGROUND AND PURPOSE: Cerebral cortical infarctions are often considered to be associated with more severe cognitive deficits than subcortical infarctions, but the evidence is conflicting. We compared early and late cognitive deficits between cortical and subcortical lesions. METHODS: Consecutive patients with first-ever cortical (n = 61) or subcortical (n = 71) cerebral infarctions were assessed neuropsychologically after a mean of 8 days and again at 6 months after infarction. Examinations included evaluation of verbal memory, executive functions, psychomotor speed and visuospatial function as well as orientation, insight and mood state. At 6 months, verbal and non-verbal reasoning were also evaluated. Neurological examinations included National Institutes of Health Stroke Scale and Barthel Index at both time-points and the modified Rankin Scale at 6 months. RESULTS: In the acute phase, memory (P = 0.007), especially delayed verbal recall (P = 0.005), was more severely affected in patients with subcortical infarctions than in those with cortical infarctions, and this trend persisted at 6 months post-infarction. Psychomotor speed (P = 0.040) was lower in the subcortical group in the acute phase than in the cortical group. Neurological scores did not differ between the two groups either in the acute phase or at 6 months. CONCLUSIONS: Patients with subcortical cerebral infarctions may have even worse cognitive profiles than patients with cortical infarctions.

Two years of Finnish Telestroke: thrombolysis at spokes equal to that at the hub.

BACKGROUND: Official guidelines on stroke promote the use of telemedicine via bidirectional videoconferencing equipment, which provides a valid and reliable means of facilitating thrombolysis delivery to patients in distant or rural hospitals. METHODS: The present prospective cohort study describes the characteristics and 3-month outcome of the thrombolysis patients treated in 5 community hospitals served by the Helsinki University Central Hospital (HUCH) in a telestroke network during 2007 to 2009. The characteristics and outcome of telestroke thrombolysis patients are compared with consecutive thrombolysis patients (n = 985) treated at HUCH. RESULTS: A total of 106 consecutive telestroke consultations in 2 years led to IV thrombolysis in 61 patients (57.5%). The median NIH Stroke Scale score was 10 (range 3-26), onset to treatment time 120 minutes (interquartile range [IQR] 49), length of consultation 25 minutes (IQR 18) if the consultation led to thrombolysis and 15 minutes (IQR 10) if not (p = 0.032). The rate of symptomatic intracranial bleedings was 6.7% (4/60) according to the National Institute of Neurological Disorders and Stroke definition. Half (28/57) of the thrombolysis patients with complete follow-up data had a favorable outcome (modified Rankin Scale [mRS] 0-2) and a third (17/57) had an excellent recovery (mRS 0-1). Thus the patients treated with thrombolysis based on teleconsultation had similar outcome with those treated at HUCH (mRS 0-2: 49.1% vs 58.1%, p = 0.214 and mRS 0-1: 17/57 [29.4%] vs 352/957 [36.8%], p = 0.289). CONCLUSIONS: A special feature of the Finnish pilot is the high percentage of consultations leading to thrombolytic treatment with features and results very similar to on-site thrombolysis at the neurologic emergency room of HUCH.

Non-cholesterol sterols in serum and endarterectomized carotid arteries after a short-term plant stanol and sterol ester challenge.

BACKGROUND AND AIMS: It is not known whether dietary intake of plant stanols or sterols changes the composition of arterial sterols. Therefore, we compared serum and carotid artery cholesterol and non-cholesterol sterols after plant stanol (staest) or sterol (steest) ester feeding in endarterectomized patients. METHODS AND RESULTS: Elderly statin-treated asymptomatic patients undergoing carotid endarterectomy were randomized double-blind to consume staest (n=11) or steest (n=11) spread (2 g of stanol or sterol/day) for four weeks preoperatively. Non-cholesterol sterols from serum and carotid artery tissue were analysed with gas-liquid chromatography. Staest spread lowered serum total (17.2%), VLDL, and LDL cholesterol and serum triglycerides, while steest spread lowered serum total (13.8%) and LDL cholesterol levels from baseline (p<0.05 for all). Serum cholestanol and avenasterol were decreased in both groups, but campesterol and sitosterol were decreased by staest and increased by steest from baseline (p<0.05 from baseline and between the groups). Serum sitostanol to cholesterol ratio was increased by staest, but in arterial tissue this ratio was similar in both groups. On staest, lathosterol, campesterol, and sitosterol, and on steest sitosterol and avenasterol correlated significantly between serum and arterial tissue. Cholesterol metabolism, eg. lathosterol/campesterol, suggested that plant sterols were reduced in serum and in arterial tissue during staest. CONCLUSION: The novel observations were that plant stanol ester consumption, in contrast to plant sterols, tended to reduce carotid artery plant sterols in statin-treated patients. Furthermore, despite increased serum sitostanol contents during plant stanol ester consumption, their arterial levels were unchanged suggesting that sitostanol is not taken up into the arterial wall.

No evidence for extraocular light induced phase shifting of human melatonin, cortisol and thyrotropin rhythms.

The view that light affects the mammalian circadian clock only through the eyes was recently challenged by a study in which the phases of human circadian rhythms were shifted by extraocular light exposure. This finding has not been confirmed, however. We studied the effects of light exposure (3 h, broad spectrum fluorescent white light, 13000 lux) on abdomen and chest on the circadian rhythms of serum melatonin, cortisol and thyrotropin in six subjects. The protocol consisted of two 3-day sessions in a dimly lit (< 10 lux) experimental unit. In both sessions hourly serum samples were collected for hormone analysis on days 1 and 3. The skin light exposure was delivered on day 2 from 22.00 to 01.00h in one of the two sessions in a randomized order. In both sessions all three rhythms tended to delay, presumably due to the endogenous circadian cycle length being slightly longer than 24 h. However, the phase shifts did not differ significantly between the sessions. Thus, the present study does not support the existence of extraocular photic regulation of the circadian rhythms in humans.

Evidence for central alpha(2)-adrenergic modulation of rat pineal melatonin synthesis.

This study was performed to distinguish central and peripheral alpha(2)-adrenoceptors in the inhibition of rat pineal melatonin synthesis. The rats received lipo- or hydrophilic alpha(2)-adrenoceptor ligand injections at middark; after 1 or 2 h the pineal melatonin contents were measured. The lipophilic agonist medetomidine (100 microg/kg s.c.) suppressed the melatonin contents significantly, while the hydrophilic agonists ST-91 and p-aminoclonidine (10 or 100 microg/kg i.v.) did not. The suppression by medetomidine was counteracted by the lipophilic antagonist yohimbine (0.3-3.0 mg/kg i.p.) but not by the hydrophilic antagonist L-659,066 (1-10 mg/kg i.v.). In conclusion, the suppression of nocturnal melatonin synthesis by alpha(2)-adrenoceptor agonists is mainly of central origin.

Melatonin release from rat pineals in vitro is stimulated by both the alpha(2)-adrenoceptor agonist medetomidine and the antagonist atipamezole.

This study was done to clarify the role of alpha(2)-adrenoceptors in the regulation of pineal melatonin synthesis. Rat pineal glands were incubated in oxygenated Krebs-Ringer solution in perifusion chambers, and perifused for 30 min with alpha(2)-adrenoceptor ligands. The melatonin concentrations were measured from the perifusate by radioimmunoassay. Both medetomidine and atipamezole (>/=10(-5) M) increased melatonin release. Yohimbine blocked the increase caused by medetomidine but not by atipamezole. The effects of medetomidine and atipamezole were also additive: the maximum response to atipamezole could be significantly increased by medetomidine. These results suggest that the two drugs stimulate the melatonin synthesis through different mechanisms: medetomidine through alpha(2)-adrenoceptors and atipamezole possibly through nonadrenergic mechanisms. The results differ from previous in vivo experiments suggesting that alpha(2)-adrenoceptor ligands affect melatonin synthesis both centrally and locally in the pineal gland. The local effects are most likely masked under the central regulatory systems in vivo.

Suppression of melatonin by 2000-lux light in humans with closed eyelids.

BACKGROUND: In order to clarify the role of light in regulating body functions in sleeping humans, we studied whether the light-sensitive pineal hormone melatonin can be suppressed by facial light exposure in subjects with closed eyelids. METHODS: Eight healthy volunteers participated in 3 nightly sessions: a dim-light control session (< 10 lux) and two light-exposure sessions (2000 lux, 60 min between 2400 and 0200 h). One light exposure occurred with eyes open and the other with eyes closed. Saliva samples were collected at least every hour from 1900 to 0300 h. Melatonin concentrations were measured by radioimmunoassay. RESULTS: Salivary melatonin concentrations decreased only in 2 of the 8 volunteers during light-exposure sessions with eyes closed. On average, light exposure did not decrease the salivary melatonin concentration. CONCLUSIONS: Because indoor illuminance is usually much lower than 2000 lux, light is probably ineffective in regulating the neuroendocrine hypothalamic functions in people during their sleep. Nevertheless, the possibility remains that higher illuminances, often used for therapeutic purposes, can inhibit the secretion of melatonin even in sleeping patients.

Evidence against alpha2-adrenoceptor involvement in the regulation of rat melatonin synthesis by ambient lighting.

This study was carried out to clarify the role of alpha2-adrenoceptors in the regulation of pineal melatonin synthesis. Medetomidine, a selective alpha2-adrenoceptor agonist, was previously found to be a potent suppressor of nocturnal melatonin levels in rats. Medetomidine and alpha2-adrenoceptor antagonists atipamezole and yohimbine were injected into rats in different conditions, and their pineal melatonin contents were measured by radioimmunoassay. Experiment 1: Blocking the alpha2-adrenoceptors and possible non-adrenergic binding sites with atipamezole did not counteract the light-induced suppression of nocturnal melatonin. These receptors are, thus, not essential for the suppression of melatonin by light. Experiment 2: Blocking the alpha2-adrenoceptors with atipamezole or yohimbine did not sensitize the pineal melatonin synthesis to daytime darkness in the light/dark-entrained rats. The binding sites are not involved in keeping the daytime melatonin levels low, even in darkness. Experiment 3: The rats were sensitized to daytime darkness by keeping them for seven days in constant light. The dark-elicited melatonin rise was suppressed by a lower dose of medetomidine than the normal nocturnal rise in light/dark-entrained rats, while atipamezole had no effect. The results showed that alpha2-adrenoceptor insufficiency is not involved in the constant light-induced pineal supersensitivity. In summary, the experiments indicated that the physiological regulation of melatonin synthesis by ambient lighting in rats does not depend on alpha2-adrenergic mechanisms.

Supersensitivity with reduced capacity for pineal melatonin synthesis in constant light-treated rats.

Melatonin is synthetized from serotonin in two steps driven by the enzymes N-acetyltransferase and hydroxyindole-O-methyltransferase. Constant light treatment reduces rat pineal hydroxyindole-O-methyltransferase activity while the activation of N-acetyltransferase becomes supersensitive to adrenergic stimulation. We studied the effect of this discrepancy on the production of melatonin. Male rats were kept under 12/ 12-h light/dark (LD) conditions or for 7 days under constant light (LL). They received subcutaneous injections of isoproterenol or methoxamine in the middle of the light period (LD-rats) or the estimated rest phase (LL-rats). A low dose of isoproterenol (0.1 mg/kg) increased pineal melatonin only marginally in LD-rats, while a maximum effect was found in LL-rats. A medium dose (0.2mg/kg) produced similar levels in both groups. A high dose (0.4 mg/kg) elevated pineal melatonin contents significantly more in normal than light-treated rats. Methoxamine (0.8 mg/kg) had no effects alone nor combined with isoproterenol. The results suggest supersensitivity with reduced capacity for melatonin formation in constant light-treated rats.

Pineal melatonin in rats: suppression by the selective alpha2-adrenoceptor agonist medetomidine.

This study was done to clarify the role of alpha2-adrenoceptors in the regulation of pineal melatonin synthesis. A selective alpha2-adrenoceptor agonist, medetomidine, and antagonist, atipamezole, were injected subcutaneously into rats and their pineal melatonin contents were measured by radioimmunoassay. Medetomidine (120 microg/kg) suppressed melatonin at night to a similar extent during the rising and descending phase of melatonin synthesis, but it did not affect the daytime level. A dose of 12 microg/kg was ineffective; doses of 30-180 microg/kg suppressed nocturnal melatonin levels close to the daytime levels. Significant suppression was reached within 15 min and the effect started to fade 3 h after the injection (120 microg/kg). At midday, medetomidine did not inhibit isoproterenol-stimulated synthesis of melatonin. Atipamezole (0.4 or 1.2 mg/kg) had no effect alone, but it counteracted the medetomidine-induced suppression. The effects of alpha2-adrenoceptor ligands on melatonin synthesis depend on the time of day and/or on the activity of the pineal sympathetic nerves.

Alpha2-adrenoceptor agonist medetomidine affects the melatonin rhythm in rats.

We investigated whether alpha2-adrenergic mechanisms participate in the regulation of the daily melatonin rhythm. Female Wistar rats, living under 12:12 h light-dark conditions, received a subcutaneous injection of saline or medetomidine (alpha2-adrenoceptor agonist; 100 microg/kg) 1 h after lights off. Thereafter they were kept in continuous darkness. Pineal glands were collected for melatonin measurements at 2-h intervals during the first and second subjective nights. During both nights, a significant elevation of melatonin levels in medetomidine-injected rats was found 2 h later than in control rats. We interpret the first-night delay to be a sign of medetomidine's suppressive effect on melatonin synthesis, and the second-night delay a medetomidine-induced resetting of the circadian clock controlling the melatonin onset.

Ontogeny of pineal melatonin rhythm in rats under 12:12-hr and 14:14-hr light:dark conditions.

The aim of the study was to determine whether a discrepancy between the genetically determined endogenous circadian period and an abnormally long Zeitgeber period disturbs the development of melatonin synthesis. Breeding pairs of rats were kept under 12:12- or 14:14-hr light:dark (LD) conditions. Pineal melatonin contents in the offspring were measured by radioimmunoassay. At 2 weeks of age high melatonin contents were found from lights-off to lights-on in both conditions suggesting dominance of the photic regulation. At 3 weeks of age the signs of the circadian regulation in the melatonin profiles were evident: a lag period after the light offset in control conditions and a significant decline before the light onset in both conditions. However, in 14:14-hr LD conditions the melatonin content did not decrease to daytime levels until the lights were on. This could suggest incomplete maturation of the circadian system. The phase relationships between the melatonin peak and LD cycle were different in the two conditions. A statistically significant LD difference was first found at the age of 8-10 days in male pups and at 14 days in female pups under both lighting. The results suggest that the abnormally long LD cycle did not cause any major disorders in the development of photic or circadian regulation of the melatonin synthesis.