bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phosphatidylinositol transfer protein α‐dependent survival factor protects cultured primary neurons against serum deprivation‐induced cell death
Authors: Bunte Hanneke , Schenning Martijn , Sodaar Peter , Bär Dop P. R. , Wirtz Karel W. A. , van Muiswinkel Freek L. , Snoek Gerry T. 
Published: March 2006

AbstractSelective neuronal loss is a prominent feature in both acute and chronic neurological disorders. Recently, a link between neurodegeneration and a deficiency in the lipid transport protein phosphatidylinositol transfer protein α (PI‐TPα) has been demonstrated. In this context it may be of importance that fibroblasts overexpressing PI‐TPα are known to produce and secrete bioactive survival factors that protect fibroblasts against UV‐induced apoptosis. In the present study it was investigated whether the conditioned medium of cells overexpressing PI‐TPα (CMα) has neuroprotective effects on primary neurons in culture. We show that CMα is capable of protecting primary, spinal cord‐derived motor neurons from serum deprivation‐induced cell death. Since the conditioned medium of wild‐type cells was much less effective, we infer that the neuroprotective effect of CMα is linked (in part) to the PI‐TPα‐dependent production of arachidonic acid metabolites. The neuroprotective activity of CMα is partly inhibited by suramin, a broad‐spectrum antagonist of G‐protein coupled receptors. Western blot analysis shows that brain cortex and spinal cord express relatively high levels of PI‐TPα, suggesting that the survival factor may be produced in neuronal tissue. We propose that the bioactive survival factor is implicated in neuronal survival. If so, PI‐TPα could be a promising target to be evaluated in studies on the prevention and treatment of neurological disorders.
The 3‐hydroxy‐3‐methylglutaryl co‐enzyme A reductase inhibitor pravastatin enhances neurite outgrowth in hippocampal neurons
Authors: Pooler Amy M. , Xi Shijun C. , Wurtman Richard J. 
Published: March 2006

AbstractEpidemiological studies demonstrate a relationship between statin [3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase inhibitor] usage and reduced risk of developing Alzheimer's disease. To determine whether statins affect neuronal development, we treated cultured rat hippocampal neurons with pravastatin. After 4–48 h of treatment, pravastatin significantly increased the number of neurites produced by each cell and caused a corresponding increase in levels of the membrane phospholipid phosphatidylcholine. Pravastatin treatment also significantly increased neurite length and branching but did not affect cellular cholesterol levels. Co‐incubation with mevalonate, but not cholesterol, abolished the stimulatory effect of pravastatin on neurite outgrowth. Treatment of neurons with isoprenoids also abolished the effect of pravastatin on neurite growth, suggesting that pravastatin may stimulate neuritogenesis by preventing isoprenylation of signaling molecules such as the Rho family of small GTPases. A specific inhibitor of geranylgeranylation, but not farnesylation, mimicked the stimulatory effect of pravastatin on neuritogenesis. Pravastatin treatment significantly decreased levels of membrane‐associated RhoA. These data suggest that pravastatin treatment increases neurite outgrowth and may do so via inhibiting the activity of geranylgeranylated proteins such as RhoA.
Susceptibility to rotenone is increased in neurons from parkin null mice and is reduced by minocycline
Authors: Casarejos M. J. , Menéndez J. , Solano R. M. , Rodríguez‐Navarro J. A. , García de Yébenes J. , Mena M. A. 
Published: March 2006

AbstractParkinson's disease is a neurodegenerative disorder which is in most cases of unknown etiology. Mutations of the Park‐2 gene are the most frequent cause of familial parkinsonism and parkin knockout (PK‐KO) mice have abnormalities that resemble the clinical syndrome. We investigated the interaction of genetic and environmental factors, treating midbrain neuronal cultures from PK‐KO and wild‐type (WT) mice with rotenone (ROT). ROT (0.025–0.1 µm) produced a dose‐dependent selective reduction of tyrosine hydroxylase‐immunoreactive cells and of other neurons, as shown by the immunoreactivity to microtubule‐associated protein 2 in PK‐KO cultures, suggesting that the toxic effect of ROT involved dopamine and other types of neurons. Neuronal death was mainly apoptotic and suppressible by the caspase inhibitor t‐butoxycarbonyl‐Asp(OMe)‐fluoromethyl ketone (Boc‐D‐FMK). PK‐KO cultures were more susceptible to apoptosis induced by low doses of ROT than those from WT. ROT increased the proportion of astroglia and microglia more in PK‐KO than in WT cultures. Indomethacin, a cyclo‐oxygenase inhibitor, worsened the effects of ROT on tyrosine hydroxylase cells, apoptosis and astroglial (glial fibrillary acidic protein) cells. N‐nitro‐l‐arginine methyl ester, an inhibitor of nitric oxide synthase, increased ROT‐induced apoptosis but did not change tyrosine hydroxylase‐immunoreactive or glial fibrillary acidic protein area. Neither indomethacin nor N‐nitro‐l‐arginine methyl ester had any effect on the reduction by ROT of the mitochondrial potential as measured by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide. Microglial NADPH oxidase inhibition, however, protected against ROT. The roles of p38 MAPK and extracellular signal‐regulated kinase signaling pathways were tested by treatment with SB20358 and PD98059, respectively. These compounds were inactive in ROT‐naive cultures but PD98059 slightly increased cellular necrosis, as measured by lactate dehydrogenase levels, caused by ROT, without changing mitochondrial activity. SB20358 increased the mitochondrial failure and lactate dehydrogenase elevation induced by ROT. Minocycline, an inhibitor of microglia, prevented the dropout of tyrosine hydroxylase and apoptosis by ROT; the addition of microglia from PK‐KO to WT neuronal cultures increased the sensitivity of dopaminergic neurons to ROT. PK‐KO mice were more susceptible than WT to ROT and the combined effects of Park‐2 suppression and ROT reproduced the cellular events observed in Parkinson's disease. These events were prevented by minocycline.
The protein tyrosine phosphatase, Shp2, is required for the complete activation of the RAS/MAPK pathway by brain‐derived neurotrophic factor
Authors: Easton John B. , Royer Amanda R. , Middlemas David S. 
Published: March 2006

AbstractBrain‐derived neurotrophic factor (BDNF) and other neurotrophins induce a unique prolonged activation of mitogen‐activated protein kinase (MAPK) compared with growth factors. Characterization and kinetic and spatial modeling of the signaling pathways underlying this prolonged MAPK activation by BDNF will be important in understanding the physiological role of BDNF in many complex systems in the nervous system. In addition to Shc, fibroblast growth factor receptor substrate 2 (FRS2) is required for the BDNF‐induced activation of MAPK. BDNF induces phosphorylation of FRS2. However, BDNF does not induce phosphorylation of FRS2 in cells expressing a deletion mutant of TrkB (TrkBΔPTB) missing the juxtamembrane NPXY motif. This motif is the binding site for SHC. NPXY is the consensus sequence for phosphotyrosine binding (PTB) domains, and notably, FRS2 and SHC contain PTB domains. This NPXY motif, which contains tyrosine 484 of TrkB, is therefore the binding site for both FRS2 and SHC. Moreover, the proline containing region (VIENP) of the NPXY motif is also required for FRS2 and SHC phosphorylation, which indicates this region is an important component of FRS2 and SHC recognition by TrkB. Previously, we had found that the phosphorylation of FRS2 induces association of FRS2 and growth factor receptor binding protein 2 (Grb2). Now, we have intriguing data that indicates BDNF induces association of the SH2 domain containing protein tyrosine phosphatase, Shp2, with FRS2. Moreover, the PTB association motif of TrkB containing tyrosine 484 is required for the BDNF‐induced association of Shp2 with FRS2 and the phosphorylation of Shp2. These results imply that FRS2 and Shp2 are in a BDNF signaling pathway. Shp2 is required for complete MAPK activation by BDNF, as expression of a dominant negative Shp2 in cells attenuates BDNF‐induced activation of MAPK. Moreover, expression of a dominant negative Shp2 attenuates Ras activation showing that the protein tyrosine phosphatase is required for complete activation of MAPKs by BDNF. In conclusion, Shp2 regulates BDNF signaling through the MAPK pathway by regulating either Ras directly or alternatively, by signaling components upstream of Ras. Characterization of MAPK signaling controlled by BDNF is likely to be required to understand the complex physiological role of BDNF in neuronal systems ranging from the regulation of neuronal growth and survival to the regulation of synapses.
Blood 5‐hydroxytryptamine, 5‐hydroxyindoleacetic acid and melatonin levels in patients with either Huntington's disease or chronic brain injury
Authors: Christofides J. , Bridel M. , Egerton M. , Mackay G. M. , Forrest C. M. , Stoy N. , Darlington L. G. , Stone T. W. 
Published: March 2006

AbstractFollowing a study of oxidative tryptophan metabolism to kynurenines, we have now analysed the blood of patients with either Huntington's disease or traumatic brain injury for levels of 5‐hydroxytryptamine (5‐HT), 5‐hydroxyindoleacetic acid (5‐HIAA) and melatonin. There were no differences in the baseline levels of these compounds between patients and healthy controls. Tryptophan depletion did not reduce 5‐HT levels in either the controls or in the patients with Huntington's disease, but it increased 5‐HT levels in patients with brain injury and lowered 5‐HIAA in the control and Huntington's disease groups. An oral tryptophan load did not modify 5‐HT levels in the patients but increased 5‐HT in control subjects. The tryptophan load restored 5‐HIAA to baseline levels in controls and patients with brain injury, but not in those with Huntington's disease, in whom 5‐HIAA remained significantly depressed. Melatonin levels increased on tryptophan loading in all subjects, with levels in patients with brain injury increasing significantly more than in controls. Baseline levels of neopterin and lipid peroxidation products were higher in patients than in controls. It is concluded that both groups of patients exhibit abnormalities in tryptophan metabolism, which may be related to increased inflammatory status and oxidative stress. Interactions between the kynurenine, 5‐HT and melatonin pathways should be considered when interpreting changes of tryptophan metabolism.
Dementia with Lewy Bodies (DLB) presenting with catatonic symptoms
Authors: LAKSHMANA Raju , SUNDRAM Suresh , CAIRNS Fiona 
Published: March 2006

AbstractIn this report, we demonstrate through a putative case that Dementia with Lewy Bodies (DLB) can present with a catatonic syndrome which can pose diagnostic and management challenges. The patient was an 88‐year‐old gentleman presenting with acute psychotic and catatonic symptoms on a background of 5 months of functional decline. He showed good response of catatonic symptoms to Clonazepam and psychotic symptoms to Olanzapine. This led to resolution of behavioral problems and the establishment of a putative diagnosis of DLB.Patients with DLB may present with catatonic states; benzodiazepines help resolve catatonic symptoms and facilitate assessment in such patients; and Olanzapine effectively treats psychotic symptoms in DLB.
Predictors of mortality in an aging community‐based cohort in Korea
Authors: SUH Guk‐Hee 
Published: March 2006

AbstractBackground:  Multiple factors related to specific dimensions of health – general, physical and mental – contribute to mortality in the elderly, but their relative contributions to mortality risk is not well‐known. The objectives of this prospective population‐based cohort study were to measure mortality rates and to identify predictors of mortality in community‐dwelling men and women aged 65 years or older in Korea by examining self assessments of general health, objective medical burden, and measurement of cognition, mood and function.Methods:  A total of 1245 elderly (529 men; 716 women) were followed up longitudinally for 3.5 years. Fixed predictor variables observed at baseline examined in Cox proportional hazards models were age, sex, education, chronic medical illnesses, self‐rated health, basic activities of daily living, depression measured by the Geriatric Depression Scale, and cognition measured by the Mini‐Mental State Examination.Results:  Mortality rates were similar to those of the 2001 Korean population. Older age, male sex, poor self‐rated health and presence of cerebrovascular disease were significant predictors of mortality. Presence of ischemic heart disease and cerebrovascular disease at baseline predicted mortality in men, but not in women. Depression predicted mortality only when chronic medical illnesses were excluded from the model.Conclusions:  Subjective self‐rated health and objective medical burden are strong independent predictors of mortality in this elderly community population, in addition to age and sex.
Testosterone Replacement Therapy for Treatment Refractory Cluster Headache
Authors: Stillman Mark J. 
Published: March 2006

Objectives.—To describe the clinical characteristics and laboratory findings of cluster headache patients whose headaches responded to testosterone replacement therapy.Background.—Current evidence points to hypothalamic dysfunction, with increased metabolic hyperactivity in the region of the suprachiasmatic nucleus, as being important in the genesis of cluster headaches. This is clinically borne out in the circadian and diurnal behavior of these headaches. For years it has been recognized that male cluster headache patients appear overmasculinized. Recent neuroendocrine and sleep studies now point to an association between gonadotropin and corticotropin levels and hypothalamically entrained pineal secretion of melatonin.Results.—Seven male and 2 female patients, seen between July 2004 and February 2005, and between the ages of 32 and 56, are reported with histories of treatment resistant cluster headaches accompanied by borderline low or low serum testosterone levels. The patients failed to respond to individually tailored medical regimens, including melatonin doses of 12 mg a day or higher, high flow oxygen, maximally tolerated verapamil, antiepileptic agents, and parenteral serotonin agonists. Seven of the 9 patients met 2004 International Classification for the Diagnosis of Headache criteria for chronic cluster headaches; the other 2 patients had episodic cluster headaches of several months duration. After neurological and physical examination all patients had laboratory investigations including fasting lipid panel, PSA (where indicated), LH, FSH, and testosterone levels (both free and total). All 9 patients demonstrated either abnormally low or low, normal testosterone levels. After supplementation with either pure testosterone in 5 of 7 male patients or combination testosterone/estrogen therapy in both female patients, the patients achieved cluster headache freedom for the first 24 hours. Four male chronic cluster patients, all with abnormally low testosterone levels, achieved remission.Conclusions.—Abnormal testosterone levels in patients with episodic or chronic cluster headaches refractory to maximal medical management may predict a therapeutic response to testosterone replacement therapy. In the described cases, diurnal variation of attacks, a seasonal cluster pattern, and previous, transient responsiveness to melatonin therapy pointed to the hypothalamus as the site of neurological dysfunction. Prospective studies pairing hormone levels and polysomnographic data are needed.
A Novel Method of Eliciting Pain‐Related Potentials by Transcutaneous Electrical Stimulation
Authors: Katsarava Zaza , Ayzenberg Ilya , Sack Florian , Limmroth Volker , Diener Hans‐Christoph , Kaube Holger 
Published: March 2006

Background.—Electrophysiological techniques such as laser and contact heat evoked pain‐related potentials are very useful for studying trigeminal and somatic pain transmission in humans. These methods are, however, partly invasive, expensive, and therefore not available for broad clinical use. We recently proposed a novel technique of noninvasive transcutaneous electrical stimulation.Objective.—To elicit pain‐related evoked potentials (PREP) by using a concentric planar electrode and demonstrate their nociceptive specificity.Methods.—We registered PREP following stimulation of the forehead and hand in 14 healthy volunteers. Latencies, peak‐to‐peak amplitudes, and conduction velocities of nociceptive fibers have been estimated. Effects of temporal and spatial summation and of cutaneous anesthesia were evaluated.Results.—Stimulation with the concentric planar electrode produced pinprick‐like painful sensation. Cutaneous anesthesia led to abolishment of PREP responses. Estimated mean conduction velocity was 11.61 ± 5.12 m/s, which corresponded well with conduction via A‐delta fibers. Spatial as well as temporal summation resulted in a parallel increase of perceived pain intensity and PREP amplitudes.Conclusion.—The technique is noninvasive, affordable, and easy to perform and allows quantitative assessment of human nociceptive pathways.
Epigenetic DNA Hypermethylation of the HERP Gene Promoter Induces Down‐regulation of Its mRNA Expression in Patients With Alcohol Dependence
Authors: Bleich Stefan , Lenz Bernd , Ziegenbein Marc , Beutler Sonja , Frieling Helge , Kornhuber Johannes , Bönsch Dominikus 
Published: March 2006

Background: Elevated plasma homocysteine concentrations can influence genomic and gene‐specific DNA methylation in peripheral blood cells. The aim of this study was to investigate in patients with alcohol dependence, who show chronically elevated homocysteine levels, whether DNA methylation pattern within the HERP (homocysteine‐induced endoplasmic reticulum protein) promoter region and expression of HERP mRNA is altered.Methods: The HERP mRNA expression level was measured by quantitative PCR in the blood of 66 male alcoholic patients and 55 nondrinking healthy controls. Epigenetic genomic DNA methylation status and HERP promoter methylation were measured with a nonradioactive elongation assay.Results: We observed a significant increase (7.6%) in the HERP promoter DNA methylation in patients with alcohol dependence (t test, t=−2.45, p<0.02) when compared with healthy controls (80.4%, SD 14.5), which was significantly associated with their elevated homocysteine levels (multiple linear regression, p<0.007). Furthermore, we found a significantly lower HERP mRNA expression in patients with alcohol dependence (t test, −7.61 ΔCT; SD 1.87, p<0.001) when compared with healthy controls (−6.04 ΔCT; SD 2.41). The lowered HERP mRNA expression in alcoholic patients was best explained by the hypermethylation of the regulatory HERP gene promoter (regression analysis, p=0.004).Conclusions: To our knowledge, this is the first study evaluating HERP mRNA expression and its specific gene promoter methylation in alcoholic patients. As hypermethylation of DNA is an important epigenetic factor in the down‐regulation of gene expression, and as HERP has been considered to play an essential role within the intracellular defense system, these findings may be useful in the understanding and treatment of different disease conditions associated with alcohol dependence.
Use of Record Linkage to Examine Alcohol Use in Pregnancy
Authors: Burns Lucy , Mattick Richard P. , Cooke Margaret 
Published: March 2006

Background: To date, no population‐level data have been published examining the obstetric and neonatal outcomes for women with an alcohol‐related hospital admission during pregnancy compared with the general obstetric population. This information is critical to planning and implementing appropriate services.Methods: Antenatal and delivery admissions to New South Wales (NSW) hospitals from the NSW Inpatient Statistics Collection were linked to birth information from the NSW Midwives Data Collection over a 5‐year period (1998–2002). Birth admissions were flagged as positive for maternal alcohol use where a birth admission or any pregnancy admission for that birth involved an alcohol‐related International Statistical Classification of Diseases and Related Health Problems, 10th Revision, Australian Modification (ICD‐10‐AM) code. Key demographic, obstetric, and neonatal variables were compared for births to mothers in the alcohol group with births where no alcohol‐related ICD10‐AM was recorded.Results: A total of 416,834 birth records were analyzed over a 5‐year period (1998–2002). In this time, 342 of these were coded as positive for at least 1 alcohol‐related ICD‐10‐AM diagnosis. Mothers in the alcohol group had a higher number of previous pregnancies, smoked more heavily, were not privately insured, and were more often indigenous. They also presented later on in their pregnancy to antenatal services and were more likely to arrive at hospital unbooked for delivery. Deliveries involved less epidural and local and more general anesthesia. Cesarean sections were more common to women in the alcohol group and were performed more often for intrauterine growth retardation. Neonates born to women in the alcohol group were smaller for gestational age, had lower Apgar scores at 5 minutes, and were admitted to special care nursery more often.Conclusions: This study shows that linked population‐level administrative data provide a powerful new source of information for examining the maternal and neonatal outcomes associated with alcohol use in pregnancy.
Comorbidity of Alcohol Abuse and Dependence with Medical Conditions in 2 American Indian Reservation Communities
Authors: Shore Jay H. , Beals Janette , Orton Heather , Buchwald Dedra ,   the AI‐SUPERPFP Team
Published: March 2006

Background: The objective was to examine the association of self‐reported Diagnostic and Statistical Manual–IV edition alcohol abuse and dependence with medical conditions among American Indians (AIs).Methods: We analyzed data previously collected in a large epidemiological study of members of 2 culturally distinct AI tribes from the Southwest (SW; n=1,446) and the Northern Plains (NP; n=1,638) living on or near their reservations. Associations of combined self‐reported alcohol abuse and alcohol dependence with 19 medical conditions were examined through multinomial logistic regression.Results: Medical conditions that had significant relationships with alcohol abuse/dependence were sprains and strains [odds ratio (OR) 2.04, p<0.001], hearing and vision problems (OR 2.05, p<0.001), kidney and bladder problems (OR 1.55, p<0.01), head injuries (OR 2.20, p<0.001), pneumonia/tuberculosis (OR 1.49, p<0.01), dental problems (OR 1.89, p<0.001), and liver problems/pancreatitis (OR 2.18, p<0.001). The total count of medical conditions was also significantly related to alcohol abuse/dependence, with a higher count being associated with the outcome (OR 1.17, p<0.001).Conclusions: In this community‐based study of rural AIs, diverse medical conditions were associated with alcohol abuse and dependence. Further research should examine, and confirm, the nature, extent, and tribal variation of the medical consequences of alcohol abuse and dependence in these unique populations.