Natural history and clinical characteristics of inhibitors in previously treated haemophilia A patients: a case series.

BACKGROUND: Development of inhibitors is the most serious complication in haemophilia A treatment. The assessment of risk for inhibitor formation in new or modified factor concentrates is traditionally performed in previously treated patients (PTPs). However, evidence on risk factors for and natural history of inhibitors has been generated mostly in previously untreated patients (PUPs). The purpose of this study was to examine cases of de novo inhibitors in PTPs reported in the scientific literature and to the EUropean HAemophilia Safety Surveillance (EUHASS) programme, and explore determinants and course of inhibitor development. METHODS: We used a case series study design and developed a case report form to collect patient level data; including detection, inhibitor course, treatment, factor VIII products used and events that may trigger inhibitor development (surgery, vaccination, immune disorders, malignancy, product switch). RESULTS: We identified 19 publications that reported 38 inhibitor cases and 45 cases from 31 EUHASS centres. Individual patient data were collected for 55/83 (66%) inhibitor cases out of 12 330 patients. The median (range) peak inhibitor titre was 4.4 (0.5-135.0), the proportion of transient inhibitors was 33% and only two cases of 12 undergoing immune tolerance induction failed this treatment. In the two months before inhibitor development, surgery was reported in nine (22%) cases, and high intensity treatment periods reported in seven (17%) cases. CONCLUSIONS: By studying the largest cohort of inhibitor development in PTPs assembled to date, we showed that inhibitor development in PTPs, is on average, a milder event than in PUPs.

Mitochondrial function, grip strength, and activity are related to recovery of mobility after a total knee arthroplasty.

Low muscle quality and a sedentary lifestyle are indicators for a slow recovery after a total knee arthroplasty (TKA). Mitochondrial function is an important part of muscle quality and a key driver of sarcopenia. However, it is not known whether it relates to recovery. In this pilot study, we monitored activity after TKA using a wrist mounted activity tracker and assessed the relation of mitochondrial function on the rate of recovery after TKA. Additionally, we compared the increase in activity as a way to measure recovery to traditional outcome measures. Patients were studied 2 weeks before TKA and up to 6 months after. Activity was monitored continuously. Baseline mitochondrial function (citrate synthase and complex [CP] 1-5 abundance of the electron transport chain) was determined on muscle tissue taken during TKA. Traditional outcome measures (Knee Injury and Osteoarthritis Outcome Score [KOOS], timed up-and-go [TUG] completion time, grip, and quadriceps strength) were performed 2 weeks before, 6 weeks after, and 6 months after TKA. Using a multivariate regression model with various clinical baseline parameters, the following were significantly related to recovery: CP5 abundance, grip strength, and activity (regression weights 0.13, 0.02, and 2.89, respectively). During recovery, activity correlated to the KOOS-activities of daily living (ADL) score (r = 0.55, p = 0.009) and TUG completion time (r = -0.61, p = 0.001). Mitochondrial function seems to be related to recovery, but so are activity and grip strength, all indicators of sarcopenia. Using activity trackers before and after TKA might give the surgeon valuable information on the expected recovery and the opportunity to intervene if recovery is low.

Postoperative pain reduction by pre-emptive N-acetylcysteine: an exploratory randomized controlled clinical trial.

BACKGROUND: A new potential target for multimodal pain management is the group-II metabotropic glutamate receptor subtypes, which can be activated by N-acetylcysteine. We investigated whether pre-emptive administration of N-acetylcysteine leads to a reduction in postoperative pain after laparoscopic inguinal hernia repair. METHODS: Sixty American Society of Anesthesiologists I-II patients scheduled for elective inguinal hernia repair were randomized to receive either N-acetylcysteine (150 mg/kg) or placebo intravenously 1 hour before surgery. The primary outcome was the visual analogue score during movement in the morning (approximately 24 hours) after surgery. Among secondary outcomes were postoperative opioid consumption and safety of intravenous N-acetylcysteine. RESULTS: In total, 23 patients were analyzed per group. Pain scores were similar at all timepoints with a 24 hours median score of 34 (IQR of 19.0 to 42.5) in the N-acetylcysteine group and a median score of 26 (16.0 to 50.0) in the placebo group. The percentage of patients using opioids after surgery was 22% versus 39% day 1 (p=0.63); 9% versus 26% day 2 (p=0.14); 9% versus 17% day 3 (p=0.35) in the N-acetylcysteine group compared with placebo group. Side effects resembling anaphylactoid reactions in response to the administration of N-acetylcysteine were present in more than half of the patients. CONCLUSIONS: Without finding important differences between N-acetylcysteine and placebo group in pain scores postoperatively, but with a high percentage of bothersome side effects for the N-acetylcysteine group, we would not recommend the use of pre-emptive intravenous N-acetylcysteine to reduce postoperative pain in laparoscopic inguinal hernia repair patients based on this study. TRIAL REGISTRATION NUMBER: NCT03354572.

Static and dynamic rotational eye tracking during LASIK treatment of myopic astigmatism with the Zyoptix laser platform and Advanced Control Eye Tracker.

PURPOSE: To evaluate the amount of cyclotorsion and the effect of static and dynamic rotational eye tracking with the Advanced Control Eye Tracker (Bausch & Lomb) based on iris recognition in the treatment of myopic astigmatism with LASIK. METHODS: All patients with myopic LASIK and attempted cylinder correction >0.75 diopters (D) on the Zyoptix 217z100 excimer laser platform between May 2005 and May 2007 were identified retrospectively through the existing databank. Pre- and postoperative refraction and the amount of cyclotorsion during treatment were extracted and analyzed in 828 eyes with >3-month follow-up. RESULTS: Preoperative mean manifest refraction spherical equivalent (MRSE) was -4.31+/-1.84 D (range: -0.37 to -9.50 D), and mean cylinder was -1.27+/-0.87 D (range: -0.75 to -6.75 D). Mean static rotation was 3.96+/-2.96 degrees (maximum 14.8 degrees ). Median dynamic rotation was 1.32+/-1.85 degrees (maximum 24 degrees). At 3 months postoperatively, MRSE was -0.10+/-0.36 D (range: -2.25 to +1.25 D), and mean cylinder was -0.33+/-0.35 D (range: -2.00 to 0 D). Predictability was 90.2% within +/-0.50 D and 98.2% within +/-1.00 D (MRSE), and 82.5% within +/-0.50 D and 96.9% within +/-1.00 D (cylinder). The efficacy ratio was 0.99. Safety was 99.4% (5 dry eyes), reaching 100% at 12 months. Stability from 3 to 12 months (n=275) was 98.2% for sphere, 95.3% for cylinder, and 96.0% for MRSE. CONCLUSIONS: Our study demonstrates that significant cyclotorsion occurs before and during treatment. By using the dynamic rotational eye tracker presented, the efficacy of cylinder correction can be improved compared to those studies not performing cyclotorsional correction.

TRANSPARENT TESTA GLABRA 1 participates in flowering time regulation in Arabidopsis thaliana.

Pleiotropic regulatory factors mediate concerted responses of the plant's trait network to endogenous and exogenous cues. TRANSPARENT TESTA GLABRA 1 (TTG1) is such a factor that has been predominantly described as a regulator of early developmental traits. Although its closest homologs LIGHT-REGULATED WD1 (LWD1) and LWD2 affect photoperiodic flowering, a role of TTG1 in flowering time regulation has not been reported. Here we reveal that TTG1 is a regulator of flowering time in Arabidopsis thaliana and changes transcript levels of different targets within the flowering time regulatory pathway. TTG1 mutants flower early and TTG1 overexpression lines flower late at long-day conditions. Consistently, TTG1 can suppress the transcript levels of the floral integrators FLOWERING LOCUS T and SUPPRESSOR OF OVEREXPRESSION OF CO1 and can act as an activator of circadian clock components. Moreover, TTG1 might form feedback loops at the protein level. The TTG1 protein interacts with PSEUDO RESPONSE REGULATOR (PRR)s and basic HELIX-LOOP-HELIX 92 (bHLH92) in yeast. In planta, the respective pairs exhibit interesting patterns of localization including a recruitment of TTG1 by PRR5 to subnuclear foci. This mechanism proposes additional layers of regulation by TTG1 and might aid to specify the function of bHLH92. Within another branch of the pathway, TTG1 can elevate FLOWERING LOCUS C (FLC) transcript levels. FLC mediates signals from the vernalization, ambient temperature and autonomous pathway and the circadian clock is pivotal for the plant to synchronize with diurnal cycles of environmental stimuli like light and temperature. Our results suggest an unexpected positioning of TTG1 upstream of FLC and upstream of the circadian clock. In this light, this points to an adaptive value of the role of TTG1 in respect to flowering time regulation.

A cost-effectiveness analysis after implementation of a fast-track protocol for total knee arthroplasty.

BACKGROUND: Since the introduction of arthroplasty fast-track protocols, many studies have investigated their effect on complications and length of hospital stay. However, few fast-track studies have examined the long-term effects on cost and health-related quality of life after total knee arthroplasty (TKA). This study aimed to specifically analyze, after implementation of fast-track TKA, cost-effectiveness with functional outcome, length of stay, thromboembolic complications, medical costs, and quality of life after 12 months. METHODS: A retrospective cohort of 403 TKA patients treated by a fast-track pathway were compared with 283 patients in a non-fast-track pathway. Length of stay and thromboembolic complications were registered postoperatively. Healthcare costs were based on hospital production costs and calculated on average. Costs were compared with EQ-5D questionnaires to derived quality-adjusted life year (QALY) scores. RESULTS: No between-protocol differences were found in functional outcome and quality of life after TKA. The fast-track protocol reduced the length of stay from a median five days to median three days, and did not influence the thromboembolic complication rate (2.6%). After one-year follow-up for fast-track pathway patients, QALY was 0.85 vs. 0.84 for non-fast-track. A reduction of 268,- euro per patient was calculated in favor of the fast-track protocol. CONCLUSION: Fast-track protocol implementation is a cost-effective strategy for patients undergoing TKA, with high QALY and reduced costs. Fast-track TKA treatment is safe, with low thromboembolic complications. This is the first study to measure fast-track implementation effects on functional outcome and quality of life up to 12 months postoperatively, and calculate equivalent QALYs for both groups. LEVEL OF EVIDENCE: Level III.

Gastro-intestinal function and quality of life are favorable in adolescent and adult gastroschisis patients.

BACKGROUND AND AIMS: Studies on long-term sequelae of gastroschisis are scarce. The limited data suggest increased abdominal complaints in young children. To provide proper counseling for both parents and patients, more information on long-term outcome is needed. This study aims to evaluate long-term outcome regarding GI function, gastroesophageal reflux (GER), health-related quality of life (HRQoL) and cosmetic satisfaction. METHODS: An observational longitudinal cohort study was performed. All patients (N = 43) born between 1982 and 2008 with gastroschisis that were admitted to the University Medical Centre Utrecht, Wilhelmina Children's Hospital were invited to fill in a survey. Data of included patients were compared to validated Dutch reference standards. RESULTS: Fourteen patients responded to the survey. The median follow-up was 18 years. Abdominal pain on weekly basis was present in two patients (14%) and feeding difficulties were present in one patient. Presence of a complication during gastroschisis treatment led to more GI symptoms (80% versus 22%). One patient experienced moderate complaints of regurgitation or dyspepsia. Although the overall HRQoL was lower in teenage gastroschisis patients as compared to healthy controls (73/100 versus 83/100, respectively), we found no relevant difference in overall HRQoL in the other age groups. Seven patients (50%) were satisfied with the cosmetic result of the scar. CONCLUSIONS: GI function and HRQoL in gastroschisis patients seem similar to healthy controls at adolescent and adult age. Complications during gastroschisis treatment led to an increase of abdominal complaints later in life. The surgical technique had no significant effect on the cosmetic results.

Online optical coherence pachymetry as a safety measure for laser in situ keratomileusis treatment in 1859 cases.

PURPOSE: To evaluate the reliability and applicability of online optical coherence pachymetry (OCP) (OCPonline, Heidelberg Engineering GmbH) integrated into the Zyoptix 217z100 excimer laser platform (Bausch & Lomb) under routine clinical conditions. SETTING: Private laser clinic, Munich, Germany. METHODS: Between July 2004 and June 2006, 1859 consecutive eyes having laser in situ keratomileusis (LASIK) using the Zyoptix 217z100 excimer laser platform had preoperative pachymetry with the Orbscan II (Bausch & Lomb) and DGH II (Pachette 2, DGH Technology, Inc.) and continuous intraoperative online OCP with the OCPonline. Preoperative pachymetry values and actual flap thicknesses with the Hansatome and Zyoptix XP microkeratomes (both Bausch & Lomb) and the IntraLase FS30 femtosecond laser keratome (IntraLase Corp.) were evaluated. RESULTS: Preoperative pachymetry values showed a high correlation between the OCPonline device and the Orbscan II (R(2) = 0.78, difference = 0.37%) and DGH II (R(2) = 0.77, difference = 0.69%). The OCPonline measurements resulted in a mean flap thickness of 121.4 microm +/- 19.1 (SD) with the Hansatome (160 microm head), 126.5 +/- 15.5 microm with the Zyoptix XP (120 microm head), and 121.7 +/- 14.7 microm with the IntraLase FS30 (110 microm flap thickness). A correlation between the calculated laser ablation depth and the measured stromal thinning was established. CONCLUSION: OCPonline technology provided reliable intraoperative noncontact pachymetry measurements integrated into a clinical flow, indicating the technology has the potential to improve the safety of corneal ablation procedures.

Combined intravenous, topical and oral tranexamic acid administration in total knee replacement: Evaluation of safety in patients with previous thromboembolism and effect on hemoglobin level and transfusion rate.

BACKGROUND: The aims of this study were to investigate the safety of combined intravenous, oral and topical tranexamic acid (TXA) in primary total knee replacement. We assessed dose-related efficacy on hemoglobin level, transfusion, length of stay and thromboembolic complications. In addition, TXA safety in patients with previous history of thromboembolism >12months ago was monitored specifically. METHODS: From January 2013 until January 2016, 922 patients were included who received TXA after primary total knee replacement. Patients without TXA administration or with thromboembolic events <12months ago were excluded. TXA dosage groups were divided into ≤10mg/kg, >10-25mg/kg and >25-50mg/kg. RESULTS: Between the three TXA groups no significant difference was found in thromboembolic complications (deep venous thrombosis (DVT) and pulmonary embolism (PE)), wound leakage and transfusion rate. For patients with DVT or PE in their history >12months ago specifically, no more complications were noted in higher-TXA-dosage groups compared to the low-dosage group. Length of stay was shorter in the highest-TXA-dosage group compared with lower-dosage groups (median two vs three days). With high TXA dose a smaller difference between pre- and postoperative Hb was found: the >25-50mg/kg TXA group had a 0.419mmol/l smaller decrease in postoperative hemoglobin compared to the lowest-dosage group (P<0.05). CONCLUSION: Combined intravenous, oral and topical TXA is effective in knee replacement and can safely be given to patients with a thromboembolic history >12months ago. High dosage (>25-50mg/kg) TXA resulted in the smallest decrease in postoperative hemoglobin.

Age-related behavior of posterior chamber lenses in myopic phakic eyes during accommodation measured by anterior segment partial coherence interferometry.

PURPOSE: To evaluate age-related position shifts of the crystalline lens and the implantable contact lens (ICL, Staar Surgical) by a new, commercially available, anterior segment partial coherence interferometer, the ACMaster (Carl Zeiss Meditec), during accommodation in myopic eyes. SETTING: ALZ Augenklinik, Munich, Germany. METHODS: Fifty-three eyes of 29 consecutive patients were measured after myopic ICL implantation before and during subjective accommodation to a stimulus of 3 diopters (D) by anterior segment partial coherence interferometry (PCI). Nine eyes were also measured with a 5.00 diopters (D) stimulus; 14 eyes were measured repeatedly at different visits. The mean patient age was 33 years +/- 9 (SD) (range 21 to 59 years). The preoperative mean sphere was -7.6 +/- 1.9 D (range -5.0 to -11.5 D) and the cylinder, -1.4 +/- 1.1 D (range 0 to -4.25 D). RESULTS: Older patients had a tendency toward smaller vaults on desaccommodation between the ICL and the crystalline lens compared to younger individuals. In younger patients, there was a decrease of the vault on accommodation, whereas it increased in older persons (P = .005). During accommodation, the more the anterior lens surface shifted forward, the more the ICL bulged (P = .005). The change in vaulting was significantly larger at 5.00 D than at 3.00 D accommodation stimulus (P = .012). CONCLUSIONS: The behavior of ICLs in relation to the crystalline lens during accommodation varied with age and could be shown by PCI. The position shift of the ICL depended on the initial vault at desaccommodation and the ability of the anterior lens surface to bulge forward. Even though the crystalline lens stiffened, and therefore accommodation deteriorated with age, there was still a movement of the ICL, pointing to the role of the ciliary muscle movement in accommodation.

Recommendations for authors of manuscripts reporting inhibitor cases developed in previously treated patients with hemophilia: communication from the SSC of the ISTH.

Aim The scope of this recommendation is to provide guidance for reporting of inhibitor cases in previously treated patients (PTPs) with hemophilia A. This guidance is intended to improve transparency and completeness of reporting of observed events; it does not cover planning, executing or analyzing original studies aimed at the assessment of inhibitor rates. Recommendation We recommend that for each case of inhibitor development reported in a published paper, a paragraph or a table is included in the main publication reporting as a minimum the underlined data fields in Table . We recommend transparent reporting when any of the suggested information is not available. We recommend that particular care is used in reporting the timeline of events by clearly identifying a reference time-point. We suggest that journals in the field adopt this guidance as instructions for the authors and as a guide for reviewers. Conclusion Development of inhibitors in PTPs is a very rare event. Standardized reporting of inhibitor characteristics will contribute to generating a body of evidence otherwise not available. Case by case reporting of the recommended data elements may shed light on the natural history and risk factors of inhibitor development in PTPs and be useful for tailoring care in similar future cases.

Detecting Meniscal Tears in Primary Care: Reproducibility and Accuracy of 2 Weight-Bearing Tests and 1 Non-Weight-Bearing Test.

STUDY DESIGN: Diagnostic accuracy study using a cross-sectional design. OBJECTIVES: To determine the interexaminer reliability and the diagnostic accuracy in primary care of 1 existing weight-bearing meniscal test, the Thessaly test, 1 new weight-bearing test, the deep squat test, and 1 non-weight-bearing test, the joint-line tenderness test. BACKGROUND: Meniscal tears are difficult to detect in primary care. Although valuable in secondary care, weight-bearing physical examination tests require validation in primary care in unselected patients. METHODS: Between October 2009 and December 2013, 121 patients (age range, 18-65 years) seen in primary care and suspected of having internal derangement of the knee of less than 6 months in duration were included in the study. Diagnostic accuracy of the 3 meniscal tests was determined based on assessment with magnetic resonance imaging. The meniscal tests were performed by 3 trained physical therapists, who were not informed about the patient history and magnetic resonance imaging results. Each test was performed independently by 2 of the 3 trained physical therapists in alternating pairs. RESULTS: The Thessaly test and the deep squat test had a moderate level of interexaminer reliability, with kappas of 0.54 and 0.46, respectively. The joint-line tenderness test had poor interexaminer reliability and was therefore not assessed for diagnostic accuracy. The following results are reported separately for both examiners. The Thessaly test had a sensitivity of 66.7% (95% confidence interval [CI]: 53.0%, 78.0%) and 51.2% (95% CI: 36.8%, 65.4%), a specificity of 37.9% (95% CI: 27.2%, 50.0%) and 43.5% (95% CI: 30.2%, 57.8%), a positive likelihood ratio of 1.07 (95% CI: 0.82, 1.41) and 0.91 (95% CI: 0.62, 1.33), and a negative likelihood ratio of 0.88 (95% CI: 0.54, 1.45) and 1.12 (95% CI: 0.72, 1.76). Similarly, the deep squat test had a sensitivity of 74.5% (95% CI: 61.1%, 84.5%) and 76.7% (95% CI: 62.3%, 86.9%), a specificity of 42.4% (95% CI: 31.2%, 54.4%) and 36.2% (95% CI: 24.0%, 50.5%), a positive likelihood ratio of 1.29 (95% CI: 0.97, 1.68) and 1.20 (95% CI: 0.92, 1.58), and a negative likelihood ratio of 0.60 (95% CI: 0.35, 1.04) and 0.64 (95% CI: 0.33, 1.25). CONCLUSION: Although the Thessaly and deep squat tests have a moderate level of reliability, neither test is sufficiently accurate to help in the diagnosis of meniscal tears in primary care. Future research should focus on other relevant patient variables instead of on physical examination tests in the detection of meniscal tears. LEVEL OF EVIDENCE: Diagnosis, level 3b.

Increase in somatostatin immunoreactivity in the suprachiasmatic nucleus of aged Wistar rats.

Decreased immunoreactivity has been reported for several neuropeptides in the aged suprachiasmatic nucleus (SCN). We compared somatostatin (SS) and substance P (SP) immunoreactivity (ir) in aged (20-26 months) and young (6 months) Wistar rats. The old rat SCN revealed a significant increase in SSir (2.6-fold) and SPir. The results show that not all SCN-neuropeptidergic systems decline with age, and suggest a specific age-related role for SS in the SCN.

Risk factors for meniscal tears: a systematic review including meta-analysis.

STUDY DESIGN: Systematic review with meta-analysis. OBJECTIVES: To review and critically appraise the literature for factors that increase the risk for meniscal tears. BACKGROUND: Meniscal tears are an important cause of disability and time lost from work, and are associated with a 4-fold increase in the long-term risk of knee osteoarthritis. Knowledge of the risk factors that lead to meniscal tears can help to correctly diagnose knee injuries and is important to the development of prevention strategies for knee osteoarthritis. METHODS: A search of the Cochrane Database of Systematic Reviews, MEDLINE, and Embase, from 1950 to January 2012, and a hand search of reference lists of all initially selected studies, without restriction on language or date of publication, were conducted. Prospective, retrospective, and case-control studies that included individuals over 16 years of age, who had no previous meniscal injuries or surgeries, were selected. A meta-analysis for 17 risk factors was performed. Where considerable heterogeneity among studies was present or the data did not provide sufficient information to perform a meta-analysis, a qualitative synthesis was conducted. RESULTS: Eleven studies, with a total of 7358 participants, were selected for systematic review. Data were available for meta-analysis for 10 of the 11 studies. Qualitative analysis was conducted using data from 3 of the 11 studies. Results showed strong evidence that age (older than 60 years), gender (male), work-related kneeling and squatting, and climbing stairs (greater than 30 flights) were risk factors for degenerative meniscal tears. We also found strong evidence that playing soccer and playing rugby were strong risk factors for acute meniscal tears. Waiting longer than 12 months between the anterior cruciate ligament injury and reconstructive surgery was a strong risk factor for a medial meniscal tear but not for a lateral meniscal tear. CONCLUSION: The literature indicates a number of risk factors leading to either degenerative or acute meniscal tears, with some of these factors being potentially modifiable. LEVEL OF EVIDENCE: Prognosis, level 2a.

A qualitative analysis of women's satisfaction with primary care from a panel of focus groups in the National Centers of Excellence in Women's Health.

Health issues unique to women and differences in healthcare experiences have recently gained attention as health plans and systems seek to extend and improve health promotion and disease prevention in the population. Successful efforts focused on enhancing quality of care will require information from the patient's perspective on how to improve such services to best support women's attempts to lead healthy and productive lives. The National Centers of Excellence in Women's Health program (CoE), sponsored by the Office on Women's Health within the Department of Health and Human Services, is based on an integrated model uniting research, training, healthcare, and community education and outreach. To examine women's concept and definitions of healthcare quality, 18 focus groups comprising 137 women were conducted nationwide on experiences and attributes of healthcare that women value in primary care. Following the focus groups, a woman-focused healthcare satisfaction instrument was developed for the purpose of assessing and improving healthcare delivery. We describe the qualitative results of the focus group study.

Habituation to a test apparatus during associative learning is sufficient to enhance muscarinic acetylcholine receptor-immunoreactivity in rat suprachiasmatic nucleus.

The suprachiasmatic nucleus (SCN) is engaged in modulation of memory retention after (fear) conditioning, but it is unknown which pathways and neurotransmitter system(s) play a role in this action. Here we examine immunocytochemically whether muscarinic acetylcholine receptors (mAChRs), mediating cholinergic signal transduction in the SCN, are involved. For this purpose, mAChR immunoreactivity (mAChR-ir) was studied in the SCN after various stages of passive shock avoidance (PSA) and active shock avoidance (ASA) training and, for ASA, at various posttraining time points. mAChR-ir was significantly enhanced in SCN neurons as a result of the training procedure, and the number of mAChR-positive glial cells in the SCN increased significantly. The increase in mAChR-ir as a result of PSA and ASA training was not due to fear conditioning or the number of correct avoidances (in case of ASA training) but rather to behavioral arousal as a consequence of (brief) exposure to a novel environment (the test apparatus). This finding was confirmed by a cage-change experiment in which the rats were allowed to stay in a novel cage for 15 min or 24 hr. Only the brief exposure to the fresh cage triggered alterations for SCN mAChRs 24 hr later. These results shed new light on a possible function of the cholinergic system in the SCN mediated by mAChRs in relation to modulation of memory processes and demonstrate that behavioral arousal during (the habituation stage of) a learning task is sufficient to alter the mAChR system in the SCN.