bluuebunny/crossref_metadata_2025 huggingface dataset:
KLRL1, a novel killer cell lectinlike receptor, inhibits natural killer cell cytotoxicity
Authors: Han Yanmei , Zhang Minghui , Li Nan , Chen Taoyong , Zhang Yi , Wan Tao , Cao Xuetao
Published: July 2004

Natural killer (NK) cell inhibitory receptors play important roles in the regulation of target susceptibility to natural killing. Here, we report the molecular cloning and functional characterization of a novel NK cell receptor, KLRL1, from human and mouse dendritic cells. KLRL1 is a type II transmembrane protein with an immunoreceptor tyrosine-based inhibitory motif and a C-type lectinlike domain. The KLRL1 gene is located in the central region of the NK gene complex in both humans and mice, on human chromosome 12p13 and mouse chromosome 6F3, adjacent to the other KLR genes. KLRL1 is preferentially expressed in lymphoid tissues and immune cells, including NK cells, T cells, dendritic cells, and monocytes or macrophages. Western blot and fluorescence confocal microscopy analyses indicated that KLRL1 is a membrane-associated glycoprotein, which forms a heterodimer with an as yet unidentified partner. Human and mouse KLRL1 are both predicted to contain putative immunoreceptor tyrosine-based inhibitory motifs (ITIMs), and immunoprecipitation experiments demonstrated that KLRL1 associates with the tyrosine phosphatases SHP-1 (SH2-domain-containing protein tyrosine phosphatase 1) and SHP-2. Consistent with its potential inhibitory function, pretreatment of target cells with human KLRL1-Fc fusion protein enhances NK-mediated cytotoxicity. Taken together, our results demonstrate that KLRL1 belongs to the KLR family and is a novel inhibitory NK cell receptor.
Protease inhibitors potentiate chemotherapy-induced neutropenia
Authors: Bower Mark , McCall-Peat Neil , Ryan Natalie , Davies Liz , Young Anne Marie , Gupta Srirupa , Nelson Mark , Gazzard Brian , Stebbing Justin
Published: July 2004

Pharmacokinetic interactions between chemotherapy and highly active antiretroviral therapy (HAART) are described, but there are few data on their clinical relevance. Patients with systemic AIDS-related non-Hodgkin lymphoma (ARL) were treated with concomitant HAART and infusional cyclophosphamide-doxorubicin-etoposide (CDE) chemotherapy. We compared neutropenia according to whether patients received protease inhibitor (PI)-based HAART or non-PI regimens. Differences in survival, response rates, immunologic parameters, and virologic parameters were also investigated. The day-10 (Mann-Whitney U test; P = .012) and day-14 (P = .025) neutrophil counts were significantly lower in patients receiving PIs, though there were no differences in the number of days of granulocyte colony-stimulating factor (G-CSF) administered between groups (P = .16). Grade 3 or 4 infections requiring hospitalization were recorded for a total of 58 (31%) of 190 cycles of CDE: 23 (48%) of 48 when prescribed PIs and 35 (25%) of 142 with concomitant PI-sparing HAART (χ2 test; P = .0025). There were no statistically significant differences in the response rates, relapse-free survival, or disease-free survival between patients receiving PIs and those not receiving PIs. PI-based HAART appears to significantly potentiate the myelotoxicity of CDE chemotherapy. This potentiation may be a consequence of microsomal enzyme inhibition reducing the metabolism of cytotoxics in this regimen.
Relationship between emotional distress in caregivers and health status in persons with multiple sclerosis
Authors: Pozzilli C , Palmisano L , Mainero C , Tomassini V , Marinelli F , Ristori G , Gasperini C , Fabiani M , Battaglia M A
Published: July 2004

Caregivers of persons with multiple sclerosis (MS) exhibit less satisfaction with quality of life with respect to the general population. To assess the relationship between depression in caregivers and health status profiles of MS patients, we examined data from 133 patients and their respective caregivers, as a part of a prospective randomized trial aimed to investigate the effectiveness of home-based care. Patients were evaluated at baseline and one year later with measures of physical and psychological impairment and health status (SF-36 Health Survey). Caregivers’ psychological morbidity was assessed by the Profile of Mood State (POMS) at the same time points. An improvement of patients’ health status as measured in four out of eight SF-36 dimensions was observed over the study period, while psychological morbidity of their caregivers did not change significantly. Depression in caregivers was related to physical, emotional and health status of the patients at baseline and/or at 12-month follow-up. Changes in the degree of depression of caregivers were also associated with changes in disability and health status of the patients. This study confirms and extends in a home-care setting previous findings on relationships between patients’ status and depression in caregivers. It suggests that the caregiver is an appropriate and independent target for more focused therapeutic strategies.
Mitoxantrone therapy in multiple sclerosis and acute leukaemia: a case report out of 644 treated patients
Authors: Voltz Raymond , Starck Michaela , Zingler Vera , Strupp Michael , Kolb Hans-Jochem
Published: July 2004

As a rare complication of mitoxantrone (MITOX) therapy in multiple sclerosis (MS), a therapy-related acute leukaemia (TRAL) may develop. The incidence is difficult to estimate, as frequently single cases are reported, up to now a total of eight MS patients. Here we report a new case out of 644 patients. This is a 45-year-old female patient with secondary progressive MS who developed TRAL after a total dose of 48 mg/m2 MITOX. The TRAL was classified as acute myeloblastic leukaemia (AML) M4eo and showed an inversion of chromosome 16 and a partial trisomy 11. Her TRAL was treated with chemotherapy followed by allogeneic bone marrow transplantation. It responded well to the transplantation, whereas the MS symptoms initially worsened but have nearly returned to the pretransplantation level. This report brings the currently published frequency of MITOX-associated TRAL in MS therapy to five in a total of 2336 treated MS patients, representing an incidence of 0.21%.
Efficacy, safety and tolerability of an orally administered cannabis extract in the treatment of spasticity in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled, crossover study
Authors: Vaney C , Heinzel-Gutenbrunner M , Jobin P , Tschopp F , Gattlen B , Hagen U , Schnelle M , Reif M
Published: July 2004

Objective: Cannabis may alleviate some symptoms associated with multiple sclerosis (MS). This study investigated the effect of an orally administered standardized Cannabis sativa plant extract in MS patients with poorly controlled spasticity.

Methods: During their inpatient rehabilitation programme, 57 patients were enrolled in a prospective, randomized, double-blind, placebo-controlled crossover study of cannabis-extract capsules standardized to 2.5 mg tetrahydrocannabinol (THC) and 0.9 mg cannabidiol (CBD) each. Patients in group A started with a drug escalation phase from 15 to maximally 30 mg THC by 5 mg per day if well tolerated, being on active medication for 14 days before starting placebo. Patients in group B started with placebo for seven days, crossed to the active period (14 days) and closed with a three-day placebo period (active drug dose escalation and placebo sham escalation as in group A). Measures used included daily self-report of spasm frequency and symptoms, Ashworth Scale, Rivermead Mobility Index, 10-m timed walk, nine-hole peg test, paced auditory serial addition test (PASAT), and the digit span test.

Results: In the 50 patients included into the intention-to-treat analysis set, there were no statistically significant differences associated with active treatment compared to placebo, but trends in favour of active treatment were seen for spasm frequency, mobility and getting to sleep. In the 37 patients (per-protocol set) who received at least 90% of their prescribed dose, improvements in spasm frequency (P- 0.013) and mobility after excluding a patient who fell and stopped walking were seen (P- 0.01). Minor adverse events were slightly more frequent and severe during active treatment, and toxicity symptoms, which were generally mild, were more pronounced in the active phase.

Conclusion: A standardized Cannabis sativa plant extract might lower spasm frequency and increase mobility with tolerable side effects in MS patients with persistent spasticity not responding to other drugs.
Cerebrospinal fluid molecular demonstration of Chlamydia pneumoniae DNA is associated to clinical and brain magnetic resonance imaging activity in a subset of patients with relapsing-remitting multiple sclerosis
Authors: Contini C , Cultrera R , Seraceni S , Castellazzi M , Granieri E , Fainardi E
Published: July 2004

To further explore the link between Chlamydia pneumoniae and multiple sclerosis (MS), we examined cerebrospinal fluid (CSF) samples from 71 patients with MS and from 72 patients suffering from other inflammatory neurological disorders (OIND) or noninflammatory neurological disorders (NIND). All samples were analysed by a touchdown nested polymerase chain reaction (n-PCR) forC. pneumoniae with primer sets which amplify target sequence genes encoding the major outer membrane protein (MOMP), the16S rRNA and the Hsp- 70 protein. A molecular study was also performed to evaluate genetic diversity among isolates of C. pneumoniae and to compare chlamydial sequences. PCR was found positive in 36.6% of total MS, in 28.1% of OIND and in 37.5% of NIND patients, without any statistical differences among the various groups examined. CSF PCR evidence of C. pneumoniae was significantly more frequent in relapsing-remitting (RR) than in secondary progressive (SP) (PB-0.001) and in primary progressive (PP)MS (PB-0.05), in clinically active than in clinically stable MS (PB-0.05) and in MRI active than in MRI inactive MS(PB-0.001). The analysis of CSF expression of each single C. pneumoniae-specific gene revealed that detectable levels of MOMP were significantly more frequent in MS patients with relapse (PB-0.05), whereas PCR positivity for MOMP and 16S rRNA genes were more represented in MS patients with clinical and MRI evidence of disease activity (PB-0.05). Similar rates for MOMP and 16S rRNA genes were detected in CSF of both MS patients and controls, whereas CSF PCR positivity for Hsp-70 gene was observed in only three active RR MS patients. Sequence analysis revealed significant homologies withC. pneumoniae compared to otherChlamydial spp. These findings confirm that theC. pneumoniae detection within the central nervous system (CNS) is not selectively restricted to MS, but accounts in a variety of neurological diseases. In addition, our results suggest that CSF C. pneumoniae-specific DNA detection can occur in a subset of MS patients with clinical and MRI active RR form in whom a C. pneumoniae brain chronic persistent infection may play a significant role in the development of disease.
Prognostic value of cerebrospinal fluid IgA and IgG in multiple sclerosis
Authors: Vrethem Magnus , Fernlund Ingrid , Ernerudh Jan , Öhman Sten
Published: July 2004

IgA antibodies do not activate complement and may compete with and protect against myelin degradation caused by IgM and IgG in multiple sclerosis (MS). We retrospectively evaluated cerebrospinal fluid (CSF) IgA and IgG (as indices and extended indices) from 1980 to 1988 in 68 patients with definitive MS. Sixty-one of them had survived since the time of sampling (11- 19 years). IgA Extended Index was significantly higher for surviving patients (median 0.65) than for the dead patients (median 0.33). CSF IgA or IgG indices did not correlate with disability, walking distance, or time from onset of symptoms to the need of walking aid. The retrospective experimental design allowed an unusually long follow-up time, but it also had the disadvantages of such a study. Thus the results warrant a prospective study to verify the prognostic vale of CSF IgA in MS.
Multiple sclerosis pathology in the normal and abnormal appearing white matter of the corpus callosum by diffusion tensor imaging
Authors: Coombs Bernard D , Best Alan , Brown Mark S , Miller David E , Corboy John , Baier Monika , Simon Jack H
Published: July 2004

Lesions in the corpus callosum in multiple sclerosis (MS) include those that are hyperintense on T2-weighted images, which can be either focal (isolated) or connected, but there is evidence that the corpus callosum, similar to other white matter regions, contains normal appearing white matter (NAWM) which is abnormal based on quantitative MR methodologies. In this pilot study, diffusion tensor based measures were determined in corpus callosum from 10 patients with MS and 12 age and gender matched controls. T2-hyperintense lesions were carefully segmented out from normal appearing corpus callosum to minimize contamination of the NAWM fraction with these lesions. The orientationally averaged diffusion coefficient was increased and the fractional anisotropy reduced in the NAWM fraction of the MS patients. These results confirm prior studies which suggest that pathology in the NAWM occurs independent of focal MS lesions, and are not likely the result of sample contamination through or across slices. This injury to the NAWM may be the result of focal, microscopic T2-invisible lesions and/or secondary degeneration related to distant lesions whose related fibres cross the corpus callosum.
Distribution and quantification of human herpesvirus 6 in multiple sclerosis and control brains
Authors: Tuke P W , Hawke S , Griffiths P D , Clark D A
Published: July 2004

Multiple sclerosis (MS) is thought to be precipitated by environmental factors, potentially including viruses, in genetically susceptible individuals and recently human herpesvirus 6 (HHV-6) has been associated with the disease. We have analysed post mortem brain for the presence, variant type and quantity of HHV-6 by PCR. A total of 124 samples from seven anatomically defined regions of brain were tested from MS cases and controls. HHV-6 DNA was detected in 41% and 44% of MS case and control samples. The median viral loads were 11 and 9 genome copies/mg DNA in cases and controls respectively and the viral load was not increased in lesions. Except in one instance, the HHV-6 DNA detected was variant B. There was no apparent difference in the distribution of HHV-6 DNA in the brains of MS cases versus controls, nor between normal appearing and lesional tissue in MS cases. Periventricular regions of the brain were more frequently positive for HHV-6 DNA in both MS cases and controls, although this difference was not statistically significant. These studies confirm the neurotropism of HHV-6 but do not demonstrate differences in the distribution, variant type or quantity of HHV-6 in brains from patients with MS versus controls.
Decreased MMP-9 production in primary progressive multiple sclerosis patients
Authors: Sastre-Garriga J , Comabella M , Brieva L , Rovira A , Tintoré M , Montalban X
Published: July 2004

Background: An increase in MMP-9 levels has been found in relapsing-remitting (RR) multiple sclerosis (MS) showing correlation with magnetic resonance (MR) parameters mainly during relapses. However, data regarding primary progressive (PP) MS is scarce. Objectives: To determine both the pro and active forms of MMP-9 in PPMS and transitional progressive (TP) MS, RRMS and healthy controls (HC), and to assess the relationship between MMP-9 levels and clinical and radiological variables in PP/TPMS. Methods: 73 patients with PP/TPMS, 50 RRMS and 43 HC were studied. Levels of pro and active forms of MMP-9 in serum were measured with ELISA. EDSS and MSFC scores were recorded and T2- and T1-weighted MR scans were obtained at the time of blood sampling and one and two years later for PP/TP MS cases. Results: MMP-9 levels were 202.27 ng/ml for PP/TPMS, 242.20 ng/ml for RRMS and 274.49 ng/ml for HC. MMP-9 levels were significantly lower in PP/TPMS compared to RRMS(P-0.026) and HC (P- 0.001). No significant correlations were found between MMP-9 levels and clinical scores or radiological parameters. Conclusions: These results point to different regulatory mechanisms of MMP-9 production and/or activity between PP/TPMS and RRMS.
Clinical characteristics of progressive relapsing multiple sclerosis
Authors: Tullman M J , Oshinsky R J , Lublin F D , Cutter G R
Published: July 2004

Objective: Patients with progressive relapsing (PR) multiple sclerosis (MS) may accrue disability by incomplete recovery from acute exacerbations and by ongoing deterioration. In primary progressive (PP) MS, disability accumulates solely by continuous decline. Because it is the least common form of MS, there is scant information regarding the clinical characteristics of PRMS, but relapses are reportedly uncommon. The purpose of this study is to describe the clinical features of a cohort of patients with PRMS. Methods: A retrospective chart review of 16 patients diagnosed with PRMS at two academic MS centres over a four-year period. Results: Nine men and seven women had PRMS. The mean age at onset was 35.19/11.2 years. The most common presenting symptom was a progressive myelopathy. The mean disease duration was 10.19/8.5 years and the average time to first exacerbation was 4.19/3.7 years. Patients had an average of 2.89/2.3 relapses with an annualized relapse rate of 0.69/0.8. Time to Expanded Disability Status Scale (EDSS) 6.0 was strongly associated with time to first exacerbation. Although there was no correlation between the number of relapses and time to EDSS 6.0, there was a modest inverse relation between time to EDSS 6.0 and annualized relapse rate. Conclusions: Relapses in PRMS may occur more often than previously described and disability may accumulate more rapidly in PRMS than in PPMS. We suggest differentiating between these two forms of MS.
HLA determinants of susceptibility to multiple sclerosis in an Arabian Gulf population
Authors: Al-Shammri S , Nelson R F , Al-Muzairi I , Akanji A O
Published: July 2004

Background: An association between HLA antigens and susceptibility to multiple sclerosis (MS) has been established, especially in Caucasian populations. Such associations have not been as clearly defined in many Arab populations, where even the frequencies of specific HLA antigens remain unclear. Objective: The study was designed to (i) investigate the frequencies of HLA Class I and II antigens in Kuwaiti Arabs with MS, and; (ii) assess possible inter-relationships between HLA Class II antigens and such clinical phenotypic variables in MS as age at onset, gender, disease subtype and scale of disability. Subjects and methods: HLA Class I (A, B, C) and Class II (DR, DQ) antigens’ tissue-typing was performed by the standard complement-dependent microlymphocytotoxicity technique in two groups of ageand sex-matched Kuwaiti subjects: (i) 67 patients with definite MS (48 relapsing-remitting, 19 relapsing-progressive) and (ii) 145 unrelated healthy controls. The frequencies of specific HLA types were then compared between patients with controls, and in the former, related to specified clinical parameters. Results: The frequencies for the Class I antigens: A9, A10, A19, A33, B5 and CW4 appeared higher with the presence of MS, although the numbers of positive subjects were rather low. For the Class II antigens, frequencies of DR4, DQ5, DQ6, DQ7 and DQ8 were increased while those for DR6 and DR1 were decreased in the patients with MS. HLA types DR15 and DR4 were present at higher frequencies in patients with a younger age at disease onset; DR15 also appeared more frequent in the female patients. Conclusion: There is a trend towards an association between HLA Class II antigens (DR4, DQ6, DQ7 and DQ8) and MS in Kuwaiti subjects. Additionally, it appeared that DR4 and DR15 were more frequent in females and those with an early onset of the disease. These patterns of HLA Class II determinants of susceptibility to MS differ from reports in some other populations, and may reflect the recognized variability in genetic influence on HLA and disease expression.
The use of magnetic resonance imaging in multiple sclerosis: lessons learned from clinical trials
Authors: Boneschi Filippo Martinelli , Rovaris Marco , Comi Giancarlo , Filippi Massimo
Published: July 2004

Magnetic resonance imaging (MRI) is an important paraclinical tool for the diagnosis of multiple sclerosis (MS) and for monitoring its disease course. The efficacy of most of the available MS disease-modifying treatments has been tested in clinical trials where MRI-derived quantities served as primary or secondary outcome measures. However, conventional MRI measures (i.e., the number and volume of contrast-enhancing, the volumes of T2-hyperintense and T1-hypointense lesions and the assessment of brain volume changes) are limited in terms of pathological specificity and, as a consequence, are modestly correlated with clinical measures of disease activity and have a modest prognostic value as predictors of MS evolution. In the present review, we discuss the main factors potentially responsible for the so-called ‘clinicaluMRI paradox’ and how modern quantitative MR-based techniques might contribute to, at least partially, overcome it. The lessons learned from MS trials suggest that future applications of MRI to assess MS evolution should rely upon the use of composite measures thought to reflect the various components of the disease, as well as on study protocols specifically designed on the individual trial characteristics.
Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients
Authors: Wade Derick T , Makela Petra , Robson Philip , House Heather , Bateman Cynthia
Published: July 2004

The objective was to determine whether a cannabis-based medicinal extract (CBME) benefits a range of symptoms due to multiple sclerosis (MS). A parallel group, double-blind, randomized, placebo-controlled study was undertaken in three centres, recruiting 160 outpatients with MS experiencing significant problems from at least one of the following: spasticity, spasms, bladder problems, tremor or pain. The interventions were oromucosal sprays of matched placebo, or whole plant CBME containing equal amounts of delta-9- tetrahydrocannabinol (THC) and cannabidiol (CBD) at a dose of 2.5- 120 mg of each daily, in divided doses. The primary outcome measure was a Visual Analogue Scale (VAS) score for each patient’s most troublesome symptom. Additional measures included VAS scores of other symptoms, and measures of disability, cognition, mood, sleep and fatigue. Following CBME the primary symptom score reduced from mean (SE) 74.36 (11.1) to 48.89 (22.0) following CBME and from 74.31 (12.5) to 54.79 (26.3) following placebo [ns]. Spasticity VAS scores were significantly reduced by CBME (Sativex) in comparison with placebo (P- 0.001). There were no significant adverse effects on cognition or mood and intoxication was generally mild.
Hormones and the Stressed Brain
Authors: DE KLOET E RONALD
Published: July 2004

Abstract: The stress system orchestrates brain and body responses to the environment. Cortisol (in humans) or corticosterone (in rodents) are important mediators of the stress system. Their action—in concert—is crucial for individual differences in coping with other individuals, which in turn depend on genetic‐ and experience‐related factors. The actions exerted by cortisol and corticosterone have an enormous diversity. They include the regulation of rapid molecular aggregations, membrane processes, and gene transcription. In the latter transcriptional regulation, the corticosteroid hormones have two modes of operation. One mode is mediated by high‐affinity mineralocorticoid receptors (MRs), which control gene networks underlying stabilization of neuronal activity as determinant for the sensitivity to trigger immediate responses to stress organized by corticotrophin‐releasing hormone (CRH)‐1 receptor. Whereas disturbance of homeostasis is prevented by MR‐mediated processes, its recovery is facilitated via the low‐affinity glucocorticoid receptors (GRs) that require stress levels of cortisol. GRs promote in coordination with CRH‐2 receptors and the parasympathetic system behavioral adaptation and enhances storage of energy and information in preparation for future events. The balance in the two stress system modes is thought to be essential for cell homeostasis, mental performance, and health. Imbalance induced by genetic modification or stressors changes specific neural signaling pathways underlying cognition and emotion. This yin‐yang concept in stress regulation is fundamental for genomic strategies to understand the mechanistic underpinning of corticosteroid‐induced stress‐related disorders such as severe forms of depression.
Brain Circuits Involved in Corticotropin‐Releasing Factor‐Norepinephrine Interactions during Stress
Authors: DUNN A J. , SWIERGIEL A H , PALAMARCHOUK V
Published: July 2004

Abstract: Corticotropin‐releasing factor (CRF)‐ and norepinephrine (NE)‐containing neurons in the brain are activated during stress, and both have been implicated in the behavioral responses. NE neurons in the brain stem can stimulate CRF neurons in the hypothalamic paraventricular nucleus (PVN) to activate the hypothalamic‐pituitary‐adrenocortical axis and may affect other CRF neurons. CRF‐containing neurons in the PVN, the amygdala, and other brain areas project to the area of the locus coeruleus (LC), and CRF injected into the LC alters the electrophysiologic activity of LC‐NE neurons. Neurochemical studies have indicated that CRF applied intracerebroventricularly or locally activates the LC‐NE system, and microdialysis and chronoamperometric measurements indicate increased NE release in LC‐NE terminal fields. However, chronoamperometric studies indicated a significant delay in the increase in NE release, suggesting that the CRF input to LC‐NE neurons is indirect. The reciprocal interactions between cerebral NE and CRF systems have been proposed to create a “feed‐forward” loop. It has been postulated that a sensitization of such a feed‐forward loop may underlie clinical depression. However, in the majority of studies, repeated or chronic stress has been shown to decrease the behavioral and the neurochemical responsivity to acute stressors. Repeated stress also seems to decrease the responsivity of LC neurons to CRF. These results do not provide support for a feed‐forward hypothesis. However, a few studies using certain tasks have indicated sensitization, and some other studies have suggested that the effect of CRF may be dose dependent. Further investigations are necessary to establish the validity or otherwise of the feed‐forward hypothesis.
Anatomic and Functional Topography of the Dorsal Raphe Nucleus
Authors: ABRAMS JOLANE K. , JOHNSON PHILIP L. , HOLLIS JACOB H. , LOWRY CHRISTOPHER A.
Published: July 2004

Abstract: Serotonergic systems play an important and generalized role in regulation of sleep‐wake states and behavioral arousal. Recent in vivo electrophysiologic recording studies in animals suggest that several different subtypes of serotonergic neurons with unique behavioral correlates exist within the brainstem raphe nuclei, raising the possibility that topographically organized subpopulations of serotonergic neurons may have unique behavioral or physiologic correlates and unique functional properties. We have shown that the stress‐related and anxiogenic neuropeptide corticotropin‐releasing factor can stimulate the in vitro neuronal firing rates of topographically organized subpopulations of serotonergic neurons within the dorsal raphe nucleus (DR). These findings are consistent with a wealth of behavioral studies suggesting that serotonergic systems within the DR are involved in the modulation of ongoing anxiety‐related behavior and in behavioral sensitization, a process whereby anxiety‐ and fear‐related behavioral responses are sensitized for a period of up to 24 to 48 h. The dorsomedial subdivision of the DR, particularly its middle and caudal aspects, has attracted considerable attention as a region that may play a critical role in the regulation of acute and chronic anxiety states. Future studies aimed at characterization of the molecular and cellular properties of topographically organized subpopulations of serotonergic neurons are likely to lead to major advances in our understanding of the role of serotonergic systems in stress‐related physiology and behavior.
A Functional Subset of Serotonergic Neurons in the Rat Ventrolateral Periaqueductal Gray Implicated in the Inhibition of Sympathoexcitation and Panic
Authors: JOHNSON PHILIP L. , LIGHTMAN STAFFORD L. , LOWRY CHRISTOPHER A.
Published: July 2004

Abstract: The ability of serotonin (5‐HT) to facilitate or attenuate autonomic, endocrine, and behavioral responses to stressful stimuli has received much attention. The effects of 5‐HT on physiologic and behavioral responses to stressful stimuli seem to depend on the brain region where it is released and the effector system it acts upon. This and the distinct morphology and topographic organization of subpopulations of serotonergic neurons have led to the hypothesis that subpopulations of serotonergic neurons are functionally distinct. Serotonin's role as a modulator of the “fight‐or‐flight” response is mediated in part by 5‐HT release in the dorsolateral periaqueductal gray (DLPAG) and in the rostral ventrolateral medulla (RVLM), an area that contains sympathoexcitatory C1 adrenergic (A) neurons. The release of 5‐HT in either region inhibits stress‐induced sympathetic activity in part via actions on 5‐HT1A receptors. In addition, 5‐HT release in the DLPAG inhibits fight‐or‐flight or “Go” behaviors. The origin of endogenous 5‐HT in the DLPAG and RVLM seems to be a subpopulation of serotonergic neurons within the ventrolateral PAG, a region implicated in “freezing” or “No Go” behaviors. These serotonergic neurons are located in the lateral “wings” of the dorsal raphe nucleus (DRN) a region also referred to as the ventrolateral DRN. The existence of a functional subpopulation of serotonergic neurons capable of inhibiting sympathoexcitation and fight‐or‐flight behavioral responses may be clinically relevant for explaining in part the efficacy of serotonergic drugs in the treatment of hypertension and panic attacks in panic disorder patients.
Inhibitory Effect of Formalin Administration on Immobilization‐Induced Epinephrine Release
Authors: MRAVEC B. , BODNAR I. , KUBOVCAKOVA L. , NAGY G M. , PALKOVITS M. , KVETNANSKY R.
Published: July 2004

Abstract: Injection of formalin is used as a classical painful stressor that produces a biphasic nociceptive response consisting of a 1‐ to 10‐min early phase and a later phase 30 to 240 min after injection. The period between these two phases, called “interphase,” is characterized by attenuated nociception. We evaluated the response of catecholamine plasma levels to formalin‐induced pain stress with special attention to these three time periods. Subcutaneous injection of 4% formalin (0.2 mL/100 g bw) into the hind limb produced a slight reduction of plasma epinephrine levels in the first 15 min, which was followed by a significant increase that remained high up to 120 min after injection. Norepinephrine levels increased immediately after injections and remained high from 30 until 120 min. To test the effect of formalin injection in a stressful condition, we exposed animals to 2 h immobilization stress. In the first experiment, formalin was injected before the start of immobilization. A significant decrease of plasma epinephrine levels was measured up to 25 min post‐injection, whereas plasma norepinephrine levels remained high. A second formalin injection during immobilization was as effective as the first one: It depleted plasma epinephrine levels from 5 to 15 min post‐injection without significant changes in norepinephrine levels. In the second experiment, formalin given after the beginning of immobilization produced a significant decrease of epinephrine levels 15 min after the injection and produced a significant increase 60 min after injection. The plasma norepinephrine levels were significantly increased by 40 min post‐injection. The data show that the inhibitory process during the interphase of formalin test is able to significantly decrease epinephrine release not only during basal conditions but also during exposure to a severe stressor, such as immobilization without suppression of plasma norepinephrine levels.
Immobilization Stress‐Induced Increase in Plasma Catecholamine Levels Is Inhibited by a Prolactoliberin (Salsolinol) Administration
Authors: BODNAR IBOLYA , MRAVEC BORIS , KUBOVCAKOVA LUCIA , FEKETE MARTON I.K. , NAGY GYORGY M. , KVETNANSKY RICHARD
Published: July 2004

Abstract: Catecholamines (CAs) are significantly involved in the regulation of homeostasis of the organism at rest and especially during stressful situations. Stress induces increases in plasma CA (epinephrine and norepinephrine) levels and prolactin (PRL) release from the adenopituitary. We have recently observed that salsolinol, which is produced by the neuro‐intermediate lobe of the pituitary gland and by the hypothalamus, can selectively release PRL. Salsolinol is therefore considered to be a putative endogenous PRL‐releasing factor. Based on the similarity of CA and PRL responses to stressors, we investigated whether salsolinol plays a role in the regulation of plasma CA levels at rest and of CA release induced by immobilization stress (IMO). Salsolinol did not affect CA baseline levels; however, it did inhibit IMO‐induced CA release. Thus, the present study shows for the first time that salsolinol is not only a PRL‐releasing factor but is also a potent inhibitor of stress‐induced release of epinephrine and norepinephrine.
The Role of Vasopressin in Hypothalamo‐Pituitary‐Adrenal Axis Activation during Stress: An Assessment of the Evidence
Authors: MAKARA GÁBOR B. , MERGL ZSUZSA , ZELENA DÓRA
Published: July 2004

Abstract: The hypothalamo‐pituitary‐adrenal (HPA) axis is a key component of the stress reaction. Most contemporary reviews mention the corticotropin‐releasing hormone and arginine vasopressin (AVP)‐containing parvocellular neurons of the hypothalamic paraventricular nucleus as the endocrinomotor component of the system. Although there are many studies about the role of AVP in the stress activation, there is evidence consistent and inconsistent with the general view on the importance of AVP. We propose a list of experiments that may provide critical evidence for or against the widely held opinion. The naturally AVP‐deficient Brattleboro rat seems to be a good tool for studying the role of AVP. Our experiments on Brattleboro rats with restraint and ip hypertonic saline injection did not support the prominent role of AVP in acute stress, although in forced swim the lack of AVP influenced the HPA axis activation. Among different chronic stress situations (14 days' restraint, chronic morphine or ip hypertonic saline treatment, streptozotocin‐induced diabetes mellitus), the role of AVP was not confirmed by changes in somatic parameter (i.e., body, thymus, and adrenal weight changes).
Long‐Term Effects of a Single Exposure to Immobilization on the Hypothalamic‐Pituitary‐Adrenal Axis: Neurobiologic Mechanisms
Authors: ARMARIO A , MARTÍ O , VALLÈS A , DAL‐ZOTTO S , ONS S
Published: July 2004

Abstract: In apparent contrast to previous results from other labs, we have found that a single exposure to a severe stressor such as immobilization (IMO) caused a long‐term desensitization of the hypothalamic‐pituitary‐adrenal (HPA) response to the homotypic stressor. Because such HPA desensitization was not found in response to heterotypic stressors, it seemed at first that we were describing a habituation process already observed after a single experience with the stressor. However, a more detailed analysis revealed two main properties incompatible with the interpretation of the results in terms of habituation: (1) The intensity of desensitization increases over the course of days to weeks with no additional exposures to the stressor, and (2) the degree of desensitization was greater with more severe stressors. The long‐term effects were also observed after a single exposure to a high dose of a systemic stressor such as endotoxin but not after insulin‐induced hypoglycemia, suggesting that not all severe systemic stressors can induce such long‐term desensitization. Because systemic stressors are known to be processed in specific brain areas and because we have found changes in c‐fos mRNA response to the homotypic stressor in some brain areas as a consequence of previous experience with IMO, we hypothesize that some severe stressors do not induce long‐term desensitization because they are not processed in brain areas sensitive to previous experience with the stressor. The neurochemical mechanisms involved in the induction of long‐term effects on the HPA axis are in process, but our results suggest only a partial role of glucocorticoids and NMDA receptors.
Glucocorticoids and Vulnerability to Psychostimulant Drugs: Toward Substrate and Mechanism
Authors: DE JONG INGE E.M. , DE KLOET E RONALD
Published: July 2004

Abstract: Glucocorticoid hormones can modulate the propensity of individuals to develop addictive behavior and, by doing so, contribute to the existence of individual differences in vulnerability to drugs. This article summarizes recent findings that increase our knowledge about drug‐induced neuronal adaptations in the brain reward system and the role glucocorticoids may play in this process. Evidence exists that drugs and stress can induce similar changes in excitatory synaptic strength within the mesolimbic dopamine system, suggesting a coordinate mechanism for drugs of abuse and glucocorticoids. The glucocorticoid receptor (GR) plays an essential role in the stress‐induced synaptic alterations, and studies using transgenic mice suggest that the GR is a key modulator of the motivation to take drugs and of the behavioral effects of repeated drug intake. The current state of research into the interplay between glucocorticoid hormones and addiction has reached a new phase in which detailed cellular and molecular analyses of the actual mechanisms will become possible. An important role is assigned to the GR, although many issues remain to be addressed, such as the actual site of glucocorticoid action in the brain, the mole‐cular mechanisms and targets of GR‐mediated glucocorticoid effects, and their interaction with genetic background.
Effect of Cold Exposure on Serum DBH and Interscapular Brown Adipose Tissue MAO Activity in Hypothyroid T3‐ and T4‐Treated Rats
Authors: CVIJIĆ G , PETROVIĆ N , DJORDJEVIĆ J , DAVIDOVIĆ V , PETROVIĆ V M
Published: July 2004

Abstract: As the indicators of sympathetic nervous system (SNS) function, the activity of serum dopamine‐β‐hydroxylase (DBH) and interscapular brown adipose tissue (IBAT) monoamine oxidase (MAO) were examined in rats that were chemically thyroidectomized (TX), treated with thyroid hormones, and exposed to cold (4°C). In TX animals, body temperature (bt) significantly decreased, and relative IBAT mass increased as compared with control, euthyroid animals, independent of the ambient temperature. The bt fall in TX cold‐exposed animals was more severe, provoking hypothermia after 4 h. Under the same experimental conditions, the SNS function was enhanced as judged by the increased serum DBH and IBAT MAO activities. The treatment of TX animals with T4 and T3 re‐established the temperature (bt was at the level of controls) and sympathetic homeostasis (DBH activity was at the level of controls) in animals maintained at room temperature but not in those kept under cold conditions. T4 and T3 did not affect IBAT MAO activity of TX rats: It remained significantly above the control values whether the animals were maintained at room temperature or exposed to cold. In conclusion, the IBAT of TX cold‐exposed rats is incapable of responding to the enhanced thermogenic needs despite the increased SNS activity and thyroid hormone substitution.
Subcellular Compartmentation of Neuronal Protein Synthesis: New Insights into the Biology of the Neuron
Authors: KAPLAN BARRY B. , LAVINA ZENO SCOTTO , GIOIO ANTHONY E.
Published: July 2004

Abstract: During the past few years, it has become well established that the distal structural/functional domains of the neuron contain numerous mRNAs. However, there is a paucity of information on the composition and function of these unique mRNA populations. In this article, we review recent evidence to support the hypothesis that protein synthesis occurs in multiple subcellular compartments in the neuron, to include the axon and presynaptic nerve terminal. The studies we describe use the squid giant axon and photoreceptor neuron as model invertebrate motor and sensory systems, respectively. Initial cell‐free translation studies and molecular hybridization analysis established that the giant axon contained a heterogeneous population of polyadenylated mRNAs. The application of differential mRNA display methodology greatly facilitated the isolation and identification of 29 of these mRNAs, which encode cytoskeletal proteins, molecular motors, translation factors, various nuclear‐encoded mitochondrial mRNAs, and several novel mRNA species. RT‐PCR analysis of RNA from squid brain synaptosomes confirmed the presence of these mRNAs in the presynaptic nerve terminal. The presence of these mRNAs in polysomes purified from the synaptosomal fraction establish that these messengers are actively translated in the terminal. Results of in vitro labeling studies demonstrate that a significant fraction of the nuclear‐encoded mitochondrial protein derives from the local synthesis in the terminal. This finding calls attention to the intimacy of the relationship that has evolved between the nerve terminal and its energy‐generating system. The role that local protein synthesis might play in the mammalian nervous system and in the neuronal response to stress is discussed.
Mechanisms Underlying the Gastroprotective Action of Glucocorticoids Released in Response to Ulcerogenic Stress Factors
Authors: FILARETOVA L P , PODVIGINA T T , BAGAEVA T R , TANAKA A , TAKEUCHI K
Published: July 2004

Abstract: Our previous results demonstrate the gastroprotective but not ulcerogenic action of glucocorticoids released in response to ulcerogenic stress factors. The present study was undertaken to investigate the possible mechanisms underlying the gastroprotective action of glucocorticoids in rat stomachs. The effects of deficiency of glucocorticoid production, with or without corticosterone supplementation, on blood flow velocity in gastric microvessels, microvascular permeability, mucus production, motility as well as gastric lesions were studied 3 to 4 h after the onset of ulcerogenic stimuli: water‐restraint stress or indomethacin administration. The contribution of glucocorticoids in the healing process of gastric injury was also evaluated. The deficiency in glucocorticoid production significantly potentiated the functional disorders induced by ulcerogenic stimuli, such as a decrease in blood flow velocity and mucus production and an increase in gastric motility and in microvascular permeability, which resulted in aggravation of the formation of gastric lesions as well as impairment of their healing. The changes observed were prevented by supplementation of corticosterone at a dose mimicking a stress‐induced corticosterone rise. We conclude that a gastroprotective action of glucocorticoids may be provided by multiple actions, including maintenance of the gastric mucosal blood flow and mucus production, attenuation of the enhanced gastric motility and microvascular permeability as well as beneficial influences on healing processes.
Inositol 1,4,5‐Trisphosphate Receptors in the Heart Compared to Other Tissues Are Differently Modulated by Stress
Authors: KRIZANOVA OLGA , KREPSOVA KATARINA , MICUTKOVA LUCIA , KVETNANSKY RICHARD
Published: July 2004

Abstract: IP3 receptors are intracellular calcium channels, releasing calcium from the sarcoplasmic reticulum. In the heart, IP3 receptors of type 1 and 2 were found. These receptors predominate in atria, although they occur also in ventricles, as determined by real‐time PCR and Western blot analysis. Single‐immobilization stress was found to increase mRNA and/or protein levels of types 1 and 2 IP3 receptors in cardiac atria. However, in stellate ganglia, which innervate the heart, no changes in the mRNA of the type 1 IP3 receptors were observed after single‐immobilization stress. In adrenal medulla, a moderate decrease in both mRNA and protein levels of IP3 receptors was observed after single‐immobilization exposure. After repeated immobilization, mRNA and protein levels of types 1 and 2 IP3 receptors decreased significantly in all tested tissues. Our results point to different processing of the single stress in different tissues, while repeated stress results in rapid and significant decrease of the IP3 receptors.
5‐HT1A Receptor Activation before Acute Stress Counteracted the Induced Long‐Term Behavioral Effects
Authors: RIOJA J , SANTÍN L J. , GARCÍA M , DOÑA A , DE PABLOS L , CUADRADO M I , ALCALDE F J , GONZÁLEZ‐BARÓN S , AGUIRRE J A
Published: July 2004

Abstract: The long‐term behavioral consequences of acute immobilization (IMMO) in rats and the effects of 5‐HT1A receptor activation (8‐OH‐DPAT: 0.3 mg/kg, sc) were studied. Corticosterone levels after IMMO with previous 8‐OH‐DPAT treatment were also studied. Twenty‐four hours after IMMO (3 h), rats performed conditioned (passive avoidance) and unconditioned (escape behavior) anxiety tests in the elevated T maze. Pre‐exposure to IMMO induces long‐term behavioral changes in contrast with control rats. These behavioral alterations include an increase of anxiogenic responses, such as exploratory behavior and passive avoidance response. This effect was counteracted by 8‐OH‐DPAT pretreatment and reversed by WAY‐100635 when administered before 8‐OH‐DPAT. Serum corticosterone levels increased during the first hour of stress and after 8‐OH‐DPAT administration. Our results support the hypothesis that involvement of acute stress is crucial in the anxiety‐like behaviors and in the potentiation of fear. The activation of 5‐HT1A receptors counteracted the long‐term effects induced by IMMO.
Repeated Immobilization Stress Decreases mRNA and Protein Levels of the Type 1 IP3 Receptor in Rat Heart
Authors: KREPSOVA KATARINA , MICUTKOVA LUCIA , NOVOTOVA MARTA , KUBOVCAKOVA LUCIA , KVETNANSKY RICHARD , KRIZANOVA OLGA
Published: July 2004

Abstract: Stress is one of the major contributors to the development of cardiovascular disorders and psychiatric illnesses. Immobilization stress belongs to severe stressors and is known to activate several calcium transport systems. The aim of this work was to determine whether repeated immobilization stress changes mRNA and protein levels of the type 1 and 2 inositol‐1,4,5‐trisphosphate (IP3) receptors in cardiac tissue. Rats were immobilized for 7 days, 2 h daily. After repeated immobilization, increased numbers of collagen fibers were accumulated in the heart atria compared to hearts of the control group of rats. Gene expression was determined after reverse transcription and subsequent real‐time polymerase chain reaction, using SYBR Green fluorescent dye. Protein levels were determined by Western blot and hybridization with the primary antibody against IP3 receptors. Contrary to single immobilization, repeated immobilization decreased a gene expression of the type 1 and 2 IP3 receptors, and also protein levels of the IP3 receptors. Although the physiologic relevance of our observations remains to be elucidated, we propose that the decrease in IP3 receptors may have an impact on the development of the pathophysiologic changes in the heart.