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Multiple linear regression with some correlated errors: classical and robust methods.

In this paper we consider classical and robust methods of estimation and diagnostics for the multiple linear regression model when some of the errors are correlated. This work was motivated by the analysis of a medical data set, from an observational study aimed at identifying factors affecting the outcome of a surgical method for the correction of scoliosis (abnormal lateral spinal curvature). There are 392 observations but some of them are on the same patient (double curves). It seems adequate to consider a multiple linear regression model but, since it is not desirable to discard the double curves, the assumption of non-correlated errors is clearly violated, and this is indeed confirmed by related diagnostics on the residuals (Durbin-Watson test). A more appropriate model retains the linear structure but allows for non-null correlation between the errors on the same patient. We propose two different procedures for the estimation of the parameters of the linear model and the correlation parameters: maximum likelihood assuming normal errors and a robustified version obtained by plugging-in results from robust linear regression. The latter procedure is designed to be resistant to outlying observations or error distributions with heavy tails and has produced the most satisfactory results for the analysed data set.

Data Interpretation, Statistical↗

Comparison of cognitive performances during a placebo period and an atypical antipsychotic treatment period in schizophrenia: critical examination of confounds.

Although previous studies report cognitive improvement following atypical antipsychotic administration in schizophrenia (SC), few placebo-controlled within-subject studies with examination of confounds (symptom reduction, cooperation, learning, and outliers) have been reported. The present study examines the effects of atypicals and confounds upon cognition in SC. The hypothesis tested was that relative to placebo, atypicals as a general class of medication would elicit cognitive improvement in SC. In all, 19 patients with SC (15 males) completed the double-blind, counterbalanced, randomized within-subject study of the effects of atypical antipsychotics (risperidone, clozapine, olanzapine, or quetiapine) vs placebo administration upon cognitive performance in the domains of executive function, attention, memory, language, visual perception, and general intellect. Significant cognitive improvement during atypical antipsychotic administration relative to placebo withdrawal occurred in most cognitive domains with robust improvements in intelligence (p=0.001), memory (p=0.0009), and fluency (p <0.002) even after outliers and unmotivated performances were excluded. These findings suggest that relative to placebo withdrawal, atypicals improve cognitive performance in SC. However, this finding may not be specific to atypicals, since analogous studies of typicals have not been performed.

Adult↗

Proximal versus distal cue utilization in spatial navigation: the role of visual acuity?

Proximal versus distal cue use in the Morris water maze is a widely accepted strategy for the dissociation of various problems affecting spatial navigation in rats such as aging, head trauma, lesions, and pharmacological or hormonal agents. Of the limited number of ontogenetic rat studies conducted, the majority have approached the problem of preweanling spatial navigation through a similar proximal-distal dissociation. An implicit assumption among all of these studies has been that the animal's visual system is sufficient to permit robust spatial navigation. We challenged this assumption and have addressed the role of visual acuity in spatial navigation in the preweanling Fischer 344-N rat by training animals to locate a visible (proximal) or hidden (distal) platform using double or null extramaze cues within the testing environment. All pups demonstrated improved performance across training, but animals presented with a visible platform, regardless of extramaze cues, simultaneously reached asymptotic performance levels; animals presented with a hidden platform, dependent upon location of extramaze cues, differentially reached asymptotic performance levels. Probe trial performance, defined by quadrant time and platform crossings, revealed that distal-double-cue pups demonstrated spatial navigational ability superior to that of the remaining groups. These results suggest that a pup's ability to spatially navigate a hidden platform is dependent on not only its response repertoire and task parameters, but also its visual acuity, as determined by the extramaze cue location within the testing environment. The standard hidden versus visible platform dissociation may not be a satisfactory strategy for the control of potential sensory deficits.

Aging↗

Altered auditory-evoked potentials in mice carrying mutated human amyloid precursor protein and presenilin-1 transgenes.

Transgenic mice carrying human APPswe and PS1-A264E transgenes (A/P mice) have elevated levels of the highly fibrillogenic amyloid Abeta(1-42) (Abeta) and develop amyloid plaques around the age of 9 months. Our aim was to find whether the gradual accumulation of Abeta in these mice can be detected with long-term recording of auditory-evoked potentials. The A/P double-mutant mice had impaired auditory gating and a tendency toward increased latency of the cortical N35 response, but these changes were not age-dependent between 7 and 11 months of age. In a control experiment that included also APP and PS1 single-mutant mice, the A/P double-mutant mice had weaker auditory gating than either APP or PS1 mice. In contrast, increased N35 latency was found in both A/P and APP mice compared with nontransgenic or PS1 mice. The Abeta40 and Abeta42 levels were robustly increased in A/P mice and Abeta40 moderately increased also in APP mice. Plaques were deposited only in A/P mice. We conclude that the impaired auditory gating is associated with the overproduction Abeta42 but does not reflect its amount. In contrast, increased N35 latency is related to the APP genotype independent of Abeta42 production.

Alzheimer Disease↗

Typification of cider brandy on the basis of cider used in its manufacture.

A study of typification of cider brandies on the basis of the origin of the raw material used in their manufacture was conducted using chemometric techniques (principal component analysis, linear discriminant analysis, and Bayesian analysis) together with their composition in volatile compounds, as analyzed by gas chromatography with flame ionization to detect the major volatiles and by mass spectrometric to detect the minor ones. Significant principal components computed by a double cross-validation procedure allowed the structure of the database to be visualized as a function of the raw material, that is, cider made from fresh apple juice versus cider made from apple juice concentrate. Feasible and robust discriminant rules were computed and validated by a cross-validation procedure that allowed the authors to classify fresh and concentrate cider brandies, obtaining classification hits of >92%. The most discriminating variables for typifying cider brandies according to their raw material were 1-butanol and ethyl hexanoate.

Alcoholic Beverages↗

A hypoxia-inducible vigilant vector system for activating therapeutic genes in ischemia.

Hypoxia represents an endogenous pathophysiological signal underlying cell growth, adaptation and death in a variety of diseases, including ischemic heart diseases, stroke and solid tumors. A vigilant vector system depends on a gene switch which can sense the hypoxia signal occurring in ischemic events and turn on/off protective gene expressions when necessary. This system uses the oxygen-dependent degradation domain derived from hypoxia-inducible factor 1alpha as the hypoxia sensor and a double-vector system as signal amplifier. For treating ischemic heart diseases, a cardiac-specific MLC-2v promoter is used to deliver transgenes specifically to the heart. When tested in cardiomyocyte cultures, it produced a rapid and robust gene induction upon exposure to low oxygen. In a mouse model for myocardial infarction, the vigilant vectors turned on therapeutic genes such as heme oxygenase-1 in response to ischemia, significantly reduced apoptosis in the infarct area and improved cardiac functions. The hypoxia-regulated gene transfer afforded by the vigilant vectors may provide a powerful tool for delivering therapeutic proteins specifically to ischemic tissues with optimal physiological control.

Animals↗

Rapid antidepressant response after nocturnal TRH administration in patients with bipolar type I and bipolar type II major depression.

BACKGROUND: Thyrotropin-releasing hormone (TRH) is a tripeptide that produces endocrine and behavioral effects in animals and humans. Some studies have shown transient antidepressant activity after morning administration of TRH. We hypothesized that nocturnal administration of TRH, when the circadian sensitivity of the TRH receptor is at its peak, may result in a more robust antidepressant effect. METHODS: Twenty patients with bipolar (BP) type I or BP type II major depressive episode (MDE) were given nocturnal intravenous TRH 500 microg (n = 10) or saline (n = 10) at midnight in a randomized, double-blind fashion. Antidepressant activity was assessed using the Hamilton Depression Rating (HAM-D), Young Mania Rating (YMR), and Profile of Mood (POMS) scales over a 48-hour period. Thyrotropin (TSH), total T4, and free T3 concentrations were measured before and after TRH administration. Data were analyzed using chi test, Fisher exact test, and repeated-measures ANOVA. RESULTS: Sixty percent of the TRH group and 10% of the saline group showed a > or =50% reduction in baseline total HAM-D score within 24 hours (P = 0.03). HAM-D ratings fell by an average of 52% after TRH administration versus 12% after saline administration (P = 0.038). There was a modest increase in YMR scores after TRH compared with saline (P < 0.032). No manic or hypomanic episodes were observed. Antidepressant effects of TRH lasted up to 48 hours. There was no correlation between DeltaTSH, DeltaT4, or DeltaT3 measures after TRH (or saline) administration and the change in HAM-D scores. CONCLUSIONS: Nocturnal TRH administration may produce a rapid antidepressant effect in some patients with BP I and BP II MDE.

Adult↗

Membrane proteinase 3 expression and ANCA-induced neutrophil activation.

BACKGROUND: Proteinase 3 is the major autoantigen in Wegener's granulomatosis (WG). Membrane PR3 expression is bimodal; low expressing cells (mPR3(low)) can be distinguished from cells with high expression (mPR3(high)) within a given individual. High mPR3 expression is a WG risk factor and is associated with relapse. However, no mechanisms for this important clinical observation have been provided. We tested the hypothesis that mPR3 expression, rather than the expression of other membrane molecules implicated in anti-neutrophil cytoplasmic autoantibodies (ANCA) activation, determines the robustness of the PR3-ANCA-mediated response. METHODS: mPR3(low) and mPR3(high) neutrophils from a given individual were separated by magnetic cell sorting. Superoxide was measured by the ferricytochrome assay, and Akt phosphorylation by Western blotting. Double staining and flow cytometry were used to assay Fc gamma-receptor and beta 2-integrin expression with respect to the mPR3 phenotype. Degranulation was measured via beta-glucuronidase activity, migration with fibronectin-coated transwells, and cell quantification by the myeloperoxidase (MPO) assay. RESULTS: PR3-ANCA-treated mPR3(high) versus mPR3(low) neutrophils showed more superoxide generation (33.7 +/- 15.2 nmol O(2) (-) to 14.6 +/- 8.4, P < 0.01), more degranulation (29%+/- 5 to 22%+/- 3, P < 0.05), and more PI3-K/Akt activation. In contrast, all responses in both mPR3 subsets were similar after other stimuli. We observed no differences in the beta 2-integrin, Fc gamma R IIa, and III expression with respect to the mPR3 subtype. Furthermore, we found no differences in the mobilization of PR3-containing granules and no differences in migration through fibronectin. CONCLUSION: The degree of neutrophil mPR3 expression has definitive functional consequences.

Antibodies, Antineutrophil Cytoplasmic↗

A reevaluation of the cultural eutrophication of Lake Okeechobee using multiproxy sediment records.

Lake Okeechobee, the hydrological lynchpin of the Everglades ecosystem, is the subject of an ambitious, multiagency restoration effort aimed at reducing phosphorus inputs and resulting algal blooms and impaired water clarity. This restoration is predicated on returning the lake to something closer to its predisturbance condition, but that goal has been challenged on the premise that the lake has always been eutrophic. The resolution of this debate and the appropriateness of the nutrient reduction goals thus depend on obtaining a reliable sediment record of past limnological conditions--the aim of this study. Because of the potential for severe sediment mixing from tropical storms, this investigation used multiple dating tools to examine the integrity of the sediment record and then analyzed proxies for nutrient enrichment, phytoplankton composition, and paleoproductivity. Sediment profiles for atmospheric pollutants, fertilizer contaminants, and radiocesium from three widely spaced cores showed good preservation of stratigraphic detail and coherence with the 210Pb chronologies. These results demonstrated that sediment stratigraphy is largely intact and retains a reliable record of limnological change. Geochemical proxies provide strong evidence of increased nutrient loading beginning ca. 1950. Concentrations of sediment P double, and N:P and C:N ratios drop, while those for N isotopes (delta15N) increase. At the same time, tracers of phosphate fertilizers (uranium, vanadium, and arsenic) rise. These changes are synchronous among cores and constitute a robust, internally consistent record of increasing water-column P. Biotic responses are manifested in higher concentrations and in changing composition of fossil algal pigments, including (1) large increases in the concentrations of chemically robust carotenoids, (2) corresponding decreases in the ratios of pigments from diatoms to chlorophyte and cyanobacterial algae, and (3) increases in UVR-photo-protective compounds indicating greater prevalence of surface algal blooms. This study provides strong evidence that Lake Okeechobee has experienced accelerated eutrophication linked with post-1950s land use changes in its watershed, a conclusion consistent with the nutrient reduction goals of the Lake Okeechobee Protection Program. The results contradict recent claims that the lake's trophic state has not changed over time, as well as the assertion that sediments of large shallow lakes cannot support a reliable chronology of past events.

Carbon↗

Small interfering RNA for experimental cancer therapy.

RNA interference describes the recently discovered process of sequence-specific, post-transcriptional gene silencing that is initiated by double-stranded RNA molecules known as small interfering RNAs (siRNAs). siRNAs have an acceptable half-life in vitro, a predictable biodistribution profile similar to that of single-stranded antisense oligonucleotides (ASOs), and have repeatedly been more robust than ASO techniques in terms of consistency of transcript knockdown and threshold concentration. Following validation in mammalian cells by Tuschl and co-workers in 2001, synthetic siRNAs have gained wide acceptance as a laboratory tool for target validation. Currently, there is considerable interest in the therapeutic use of siRNA, particularly in areas of infectious disease and cancer. In vitro and in vivo findings demonstrate the efficacy of siRNA knockdown of gene messages that are pivotal for tumor cell growth, metastasis, angiogenesis and chemoresistance, leading to tumor growth suppression. However, siRNA-based cancer therapy faces similar pharmacokinetic limitations to ASO therapy with respect to the extent that siRNA accesses primary and metastatic target cells. The recently identified 'off-target activity' of siRNAs is also of concern. The concept of carrier-restricted delivery of siRNA by conditionally replicative, oncolytic adenoviruses is discussed. Oncolytic adenoviral delivery offers the potential benefits of restricted and renewable siRNA expression within the tumor microenvironment, an additive antitumor outcome through viral oncolysis and siRNA-mediated oncogene silencing, and a proven clinical platform with respect to infectivity and safety.

Adenoviridae↗

Prolactin levels in schizophrenia and schizoaffective disorder patients treated with clozapine, olanzapine, risperidone, or haloperidol.

BACKGROUND: Prolactin levels are elevated to varying degrees by antipsychotics. Prolactin elevations may result in sexual and other adverse effects, and they may be related to antipsychotic effects. We used the data collected in a trial of antipsychotics to study the differential effect of these drugs on prolactin level, to explore the relation between clinical effects and prolactin level, and to determine the relationship between plasma levels of antipsychotics and prolactin level. METHOD: Treatment-resistant patients (133 men, 24 women) diagnosed with DSM-IV schizophrenia or schizoaffective disorder participated in a double-blind, randomized, 14-week trial comparing clozapine (N = 40), olanzapine (N = 39), risperidone (N = 41), and haloperidol (N = 37). Plasma levels of prolactin and antipsychotics were determined at baseline and at weeks 5, 8, 10, 12, and 14 during the trial. Clinical effects were measured with the Positive and Negative Syndrome Scale and the Extrapyramidal Symptom Rating Scale. Statistical analyses were limited to the 75 men for whom repeated prolactin levels were available. Data were gathered from June 1996 to December 1999. RESULTS: Risperidone caused significant elevation of prolactin levels (p <.05) that appeared to be dose-dependent. Clozapine and olanzapine were associated with decreases of prolactin, whereas haloperidol led to a minor, nonsignificant increase. Plasma olanzapine and prolactin levels were correlated. Prolactin levels were not related to clinical improvement or extrapyramidal side effects. CONCLUSION: Antipsychotics show major differences in their effects on prolactin, and risperidone has clearly the most robust effect.

Adult↗

Cost effectiveness of fluticasone propionate and flunisolide in the treatment of corticosteroid-naive patients with moderate asthma.

OBJECTIVE: The aim of this study was to determine the cost effectiveness of 2 inhaled corticosteroids, fluticasone propionate and flunisolide, in the management of asthma from a third-party payer perspective in Germany (German Sickness Fund). DESIGN AND SETTING: Direct treatment costs were retrospectively applied to 2 prospective randomised parallel group clinical trials conducted in Germany comparing fluticasone propionate and flunisolide: one 6-week open-label study (n = 332) and one 8-week double-blind study (n = 308) in corticosteroid-naive patients with asthma of moderate severity aged between 18 and 70 years. All costs were adjusted to 1997 Deutschmarks. Efficacy parameters included changes in morning and evening peak expiratory flow rate (PEFR) measurements, the number of successfully treated patients (defined as those with a PEFR improvement of > or = 10%) and proportion of symptom-free days. MAIN OUTCOME MEASURES AND RESULTS: The fluticasone propionate groups had higher respective proportions of successfully treated patients and symptom-free days than the flunisolide groups in both the open-label (56.8 vs 39.6% and 36.4 vs 28.5%) and double-blind (55.3 vs 44.5% and 35.1 vs 31.1%) studies. Improvements in both morning and evening PEFR measurements were also significantly (p < 0.01) greater with fluticasone propionate than with flunisolide. Although average daily treatment costs were slightly higher in the fluticasone propionate groups than in the flunisolide groups, all cost-effectiveness ratios (daily cost per successfully treated patient and daily cost per symptom-free day) favoured fluticasone propionate. Sensitivity analysis showed that these results were robust over a wide range of assumptions. CONCLUSION: In these patients, management with fluticasone propionate was more cost effective than with flunisolide in the German healthcare setting.

Adolescent↗

Fast low-angle dual spin-echo (FLADE): a new robust pulse sequence for structural imaging of trabecular bone.

Mechanical strength and fracture resistance of trabecular bone (TB) are largely determined by the structural arrangement of individual trabeculae. Fast 3D spin-echo approaches are preferable to gradient echoes in that they are less sensitive to local induced gradients at the bone/marrow interface caused by magnetic susceptibility difference between the two tissues. FLASE is a 3D pulse sequence that serves this purpose. Here, we present a new pulse sequence dubbed FLADE (fast low-angle dual spin-echo) that overcomes some of the limitations inherent to FLASE, such as sensitivity to artifactual stimulated echoes. The double-echo sequence features a flip angle <90 degrees allowing for TR << T(1). The second phase-reversal pulse has the dual function of creating a second echo and restoring inverted longitudinal magnetization. The prolonged TR, made possible by sampling only half of k(z)-space, is used to collect navigator echoes in adjacent slabs for sensing subpixel translational displacements. FLADE is shown to provide SNR comparable to FLASE while having narrower point-spread function and being more robust to imperfections in the nonselective 180 degree pulses. Structural parameters derived from the in vivo images with the two pulse sequences are highly correlated, therefore suggesting that clinical data obtained with either pulse sequence can be merged.

Bone and Bones↗

Low-density DNA microarrays are versatile tools to screen for known mutations in hypertrophic cardiomyopathy.

Familial hypertrophic cardiomyopathy (HCM or CMH) is a myocardial disorder caused by mutations that affect the contractile machinery of heart muscle cells. Genetic testing of HCM patients is hampered by the fact that mutations in at least eight different genes contribute to the disease. An affordable high-throughput mutation detection method is as yet not available. Since a significant number of mutations have been repeatedly found in unrelated families, we consider it feasible to pre-screen patients for known mutations, before more laborious techniques capable of detecting new mutations are applied. Here we demonstrate that the principle of hybridization of DNA to oligonucleotide probes immobilized on chips (glass slides) can be applied for this purpose. We have developed a low-density oligonucleotide probe array capable of detecting 12 different heterozygous mutations (in four different genes), among them single- and double-base exchanges, a single nucleotide insertion, and a trinucleotide deletion. The assay is simple and may be amenable to automation. Detection is achieved with a CCD camera-based fluorescence biochip reader. The technique turned out to be robust: Variations in either the relative position of a mutation, or the amount and size of target-DNA were compatible with mutation detection. Mutations could even be detected in amplicons as long as 800 bp, allowing the screening of more than one exon in one amplicon. Our data suggest that the development of a chip that covers all or most of known HCM-associated mutations is feasible and useful.

Cardiomyopathy, Hypertrophic, Familial↗

Accelerated infarct development, cytogenesis and apoptosis following transient cerebral ischemia in aged rats.

Old age is associated with a deficient recovery from stroke, but the cellular mechanisms underlying such phenomena are poorly understood. To address this issue, focal cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery in 3- and 20-month-old male Sprague-Dawley rats. Aged rats showed a delayed and suboptimal functional recovery in the post-stroke period. Using BrdU-labeling, quantitative immunohistochemistry and 3-D reconstruction of confocal images, we found that aged rats are predisposed to rapidly develop an infarct within the first few days after ischemia. The emergence of the necrotic zone is associated with a high rate of cellular degeneration, premature accumulation of proliferating BrdU-positive cells that appear to emanate from capillaries in the infarcted area, and a large number of apoptotic cells. With double labeling techniques, we were able to identify, for the first time, over 60% of BrdU-positive cells either as reactive microglia (45%), oligodendrocyte progenitors (17%), astrocytes (23%), CD8+ lymphocytes (4%), or apoptotic cells (<1%). Paradoxically, despite a robust reactive phenotype of microglia and astrocytes in aged rats, at 1-week post-stroke, the number of proliferating microglia and astrocytes was lower in aged rats than in young rats. Our data indicate that aging is associated with rapid infarct development and a poor prognosis for full recovery from stroke that is correlated with premature cellular proliferation and increased cellular degeneration and apoptosis in the infarcted area.

Aging↗

Efficacy and safety of mometasone furoate nasal spray in nasal polyposis.

BACKGROUND: Studies have suggested that topical corticosteroids are effective in the treatment of nasal polyps; however, this has yet to be confirmed in a large, robust clinical trial. OBJECTIVE: To evaluate the efficacy and safety of mometasone furoate nasal spray (MFNS) for nasal polyposis. METHODS: A total of 354 subjects with bilateral nasal polyps and clinically significant congestion/obstruction participated in this multinational, randomized, double-blind, placebo-controlled study. Subjects received MFNS 200 microg once or twice daily or placebo for 4 months. Coprimary endpoints were (1) change from baseline to last assessment in physician-evaluated bilateral polyp grade score and (2) change from baseline averaged over month 1 in subject-assessed nasal congestion/obstruction. ANOVA was used for all efficacy endpoints, except for change in bilateral polyp grade score, for which baseline polyp grade was added as a covariate. RESULTS: Compared with placebo, MFNS 200 microg administered once or twice daily produced significantly greater reductions in bilateral polyp grade score (P < .001, P = .010, respectively) and congestion/obstruction (P = .001, P < .001), as well as improvement in loss of smell (P < .001, P = .036), anterior rhinorrhea (P < .001 for both), and postnasal drip (P < .001, P = .001) over month 1. MFNS 200 microg twice daily was superior to MFNS 200 microg once daily in reducing congestion/obstruction (P = .039), and there were more improvers in the MFNS 200 microg twice daily group (P = .035). MFNS was well tolerated in both groups. CONCLUSION: MFNS 200 mug, once or twice daily, was safe and significantly superior to placebo in reducing polyp grade (size and extent) and improving congestion/obstruction and return of sense of smell. MFNS is an effective medical treatment for nasal polyposis and may reduce or delay the need for surgery.

Administration, Intranasal↗

DNA molecules and configurations in a solid-state nanopore microscope.

A nanometre-scale pore in a solid-state membrane provides a new way of electronically probing the structure of single linear polymers, including those of biological interest in their native environments. Previous work with biological protein pores wide enough to let through and sense single-stranded DNA molecules demonstrates the power of using nanopores, but many future tasks and applications call for a robust solid-state pore whose nanometre-scale dimensions and properties may be selected, as one selects the lenses of a microscope. Here we demonstrate a solid-state nanopore microscope capable of observing individual molecules of double-stranded DNA and their folding behaviour. We discuss extensions of the nanopore microscope concept to alternative probing mechanisms and applications, including the study of molecular structure and sequencing.

DNA↗

Distinct localization of prokineticin 2 and prokineticin receptor 2 mRNAs in the rat suprachiasmatic nucleus.

The suprachiasmatic nucleus (SCN) is the master circadian clock that regulates physiological and behavioral circadian rhythms in mammals. Prokineticin 2 (PK2) is highly expressed in the SCN, and its involvement in the generation of circadian locomotor activity has been reported previously. In the present study, using in situ hybridization methods, we investigated the localization of PK2 and prokineticin receptor 2 (PKR2), a specific receptor for PK2, in the rat SCN. In steady light : dark (L : D = 12 : 12 h) and constant dark conditions, rPK2 mRNA displayed a robust circadian oscillation with a peak occurring during the day. Moreover, during peak expression, the rPK2 mRNA-positive neurons were scattered in both the dorsomedial and ventrolateral SCN, which are two functionally and morphologically distinct subregions. Furthermore, double-labeling in situ hybridization experiments revealed that greater than 50% of the rPK2 mRNA-containing neurons co-expressed either vasoactive intestinal peptide (VIP), gastrin-releasing peptide (GRP) or arginine vasopressin (AVP) in the SCN. In contrast, the rPKR2 mRNA levels did not show significant diurnal alterations. rPKR2 mRNA-containing neurons were also clustered in the dorsolateral part of the SCN, which shows negligible labeling of either rAVP, rVIP, rGRP or rPK2 transcripts. In addition, this region exhibited a delayed cycling of the rPer1 gene. These results suggest an intrinsic PK2 neurotransmission and functionally distinct roles for PKR2-expressing neurons in the SCN.

Animals↗