bluuebunny/crossref_metadata_2025 huggingface dataset:
Lymph Node Metastases in the Neck from Unknown Primary Sites
Authors: Al-Saleh K. , Ali A. , Jaffer A.M. , Farghaley T. , Abdulla M.A.
Published: April 2003

Objective: To evaluate the experience of the Kuwait Cancer Control Center in the diagnosis and management of patients with cervical lymph node metastasis from an unknown primary site. Methods: We have undertaken a retrospective study of 24 patients for the years 1979–1994. All cases were pathologically confirmed; a primary tumor was not detected in any of these cases despite extensive diagnostic procedures. There were 24 patients, 9 Kuwaitis and 15 non-Kuwaitis, 20 males and 4 females (5:1). Their ages ranged from 10 to 83 years with a median of 55.5 years. Results: Twenty patients presented with a neck mass. The supraclavicular lymph node was the site in 9 cases; 9 had multinodal metastases, 3 in the upper third of the neck, 2 at the submental-submaxillary level and 1 in the middle third. The local stage of nodal involvement was 6 N1, 8 N2 and 9 N3. The pathological diagnosis was squamous cell carcinoma in 14 cases, adenocarcinoma in 6 cases, 1 undifferentiated case and unknown in 2 cases. Sixteen cases were graded as poorly differentiated. Radiotherapy was used for 9 patients, 4 were treated with chemotherapy, 2 were treated with surgery, 2 were treated with surgery followed by radiotherapy and 2 with chemotherapy and radiotherapy. The median survival was 6 months for the whole group. Conclusion: We concluded that, in patients with metastatic carcinoma to the cervical lymph nodes from an unknown primary, supraclavicular localization and male gender were high risk factors. The prognosis in these cases was disastrous because of late diagnosis, and therapy was only palliative.
Helicobacter pylori Gastritis: A Histopathological and Bacteriological Study
Authors: Anim J.T. , Rotimi V.O. , Al-Sobkie N. , Prasad A. , Pazhoor A.A. , John B. , Chugh T.D. , Gaber A.H. , Mashali A.
Published: April 2003

Objective: The primary objective of this study was to investigate five readily available methods for the diagnosis of Helicobacter pylori infection (both invasive and non-invasive) in order to establish the local definition of the disease in our hospital because of the regional variations in the prevalence, strains of organism and antibiotic susceptibility. Methods: Two histological methods (HE and immunohistochemistry, IHC) and microbiological methods (culture, urease test and Gram stain of tissue smears) for processing gastric antral biopsies were compared in a prospective study in 115 consecutive patients. H. pylori positivity by these methods was correlated with histopathological changes in the antral biopsies. Susceptibility of the H. pylori isolates to various antibiotics was performed by the modified disc diffusion test. Results: There was no significant difference between HE and IHC in the demonstration of H. pylori. Using culture as the ‘gold standard’ for specificity, both had specificity of 91 and 86%, respectively. However, when HE was used as a standard for sensitivity, the other methods had the following sensitivities: culture 69%, Gram stain 86%, biopsy urease 85%, and IHC 91%. Higher density of H. pylori infection correlated with higher culture positivity and more with the presence of active chronic gastritis than with chronic inactive gastritis. Of the antibiotics tested, only metronidazole showed appreciable resistance against the H. pylori isolates. Conclusion: We recommended the use of HE and culture in the definition of H. pylori infection at the local level, together with drug sensitivity testing to ensure an appropriate eradication strategy.
Attitudes of General Practitioners and Pediatricians to Management of Acute Pyelonephritis in Children
Authors: Al-Eisa A. , Al-Mosawi M. , Gupta R. , D’Souza T.M. , Sharma P.N.
Published: April 2003

Objective: To study the attitudes of different groups of physicians toward management of acute pyelonephritis in children and the impact of such attitudes on the long-term sequelae of this problem. Materials and Methods: A questionnaire, describing a case history of a child with acute pyelonephritis, was distributed to general practitioners working in 12 primary health care centers and pediatricians working in the pediatric departments of the 6 main hospitals in Kuwait. The responses of the two groups were analyzed regarding their views toward hospitalization of the child, investigations requested, the choice of antibiotics, its route of administration, duration of treatment and the need for long-term follow-up. Results: A total of 83 general practitioners (group A) and 65 hospital pediatricians (group B) responded to the questionnaire. Hospitalization of the child was thought to be essential by 19% of group A compared to 89% of group B (p < 0.0001). Only 25% of group A decided to fully investigate the child compared to 58% of group B (p < 0.0001). Treatment with a single antibiotic was preferred by 72% of group A compared to 80% of group B. Only 6% of group A, compared to 74% of group B favored parenteral antibiotics (p < 0.0001). A 7-day course of treatment was considered by 70% of group A and 52% of group B (p < 0.02). Long-term follow-up was thought to be necessary by 63% of group A and 75% of group B. Conclusion: A marked discrepancy existed in the management of acute pyelonephritis between the two groups, indicating the need of a unified policy. Children presenting with such a problem can be managed by general practitioners on an outpatient basis provided that proper antibiotics are used, compliance is ensured and appropriate investigations and follow-up are provided.
Sample Size Justification in Phase III/IV Clinical Trials
Authors: Richardson DeJuran , Leurgans Sue
Published: April 2003

A sample size justification is often a key component in securing funding to conduct a clinical trial. Sample size computations typically require supplying values of parameters that are unknown and subject to misspecification. As an alternative, we advocate a power analysis approach based on a range of reasonable values for such parameters. We illustrate this approach in the context of a secondary stroke prevention trial.
Null Hypothesis of Husband-Wife Concordance of Parkinson’s Disease in 1,000 Married Couples Over Age 50 in Spain
Authors: Ubeda J.V.
Published: April 2003

While the search for environmental neurotoxins as causal factors of Parkinson’s disease (PD) continues, we have found no concordance in 1,000 married couples over age 50 in Spain. In addition, it has been possible to identify a structural grouping of similar chemical characteristics that is repeated in the majority of organic compounds that can induce parkinsonism. These compounds have a structural relationship with the dopamine molecule. The principal epidemiological aspects of PD have a preliminary rational explanation.
Incidence and Prevalence of Myasthenia gravis in the County of the Coast and Gorski kotar, Croatia, 1976 through 19961
Authors: Zivadinov R. , Jurjevic A. , Willheim K. , Cazzato G. , Zorzon M.
Published: April 2003

For the period 1976 through 1996, we carried out an incidence and prevalence study of myasthenia gravis in the County of the Coast and Gorski kotar, Croatia. This was the first epidemiological study of myasthenia gravis in Croatia. A total of 43 incident cases were identified. Overall the average crude annual incidence rate was 6.52 per 1,000,000 person-years; 5.59 per 1,000,000 person-years for men and 7.41 per 1,000,000 person-years for women. The incidence rate was 6.30 (95% confidence intervals 4.56–8.51), age-adjusted to the European population and 5.17 (95% confidence intervals 3.74–6.98), age-adjusted to the world population. On 31 December 1996, there were 32 prevalent cases. The crude prevalence was 99 per 1,000,000 population (95% confidence intervals 67.7–139.6). The prevalence adjusted to the European and world populations was 101.9 (95% confidence intervals 69.7–143.7) and 75.9 (95% confidence intervals 51.9–107) per 1,000,000 population, respectively. Our incidence findings are similar to those reported in North-East Italy but lower than those in the United States. Our prevalence findings were generally higher than those in Northern European Countries but lower than those in the United States. Standardization of rates to the European or world population could facilitate comparison between different populations.
Alcohol and Stroke: Pathophysiologic Mechanisms
Authors: Hillbom Matti , Numminen Heikki
Published: April 2003

Epidemiological evidence indicates that recent heavy alcohol consumption increases the risk for all major types of stroke, whereas light-to-moderate alcohol intake is associated with a decreased risk of ischemic stroke. Although heavy drinking elevates blood pressure, there is no firm evidence to indicate that alcohol consumption causes the formation of aneurysms, microaneurysms or other lesions in human arteries. Alcohol has been reported to precipitate vasoconstriction and rupture of small cerebral arteries in experimental animals. Alcohol-induced neck trauma has been shown to precipitate traumatic strokes, and alcohol-induced cardiac arrhythmias have been observed in patients with embolic brain infarction. The effects of alcohol on hemostasis, fibrinolysis and blood clotting are variable and could either prevent or promote the occurrence of strokes. The antiatherogenic effects of regular light-to-moderate alcohol consumption could be mediated by inhibition of low-density lipoprotein oxidation, and by elevated estrogen levels.
Diabetes mellitus and Cerebrovascular Disease
Authors: Lukovits Timothy G. , Mazzone Theodore , Gorelick Philip B.
Published: April 2003

In the past several years, a substantial amount of new information on the epidemiology and pathophysiology of diabetes and vascular disease has become available. Autopsy studies suggest that diabetic patients are susceptible to cerebral small-artery disease and lacunar infarction and may be at risk for large-artery atherosclerotic occlusive disease. Epidemiological studies show that diabetes is a risk factor for ischemic stroke. The pathogenesis of diabetes-associated stroke appears to be linked to excessive glycation and oxidation, endothelial dysfunction, increased platelet aggregation, impaired fibrinolysis and insulin resistance. Macrovascular complications may be prevented by simple primary prevention measures including exercise, weight loss and treatment of dyslipidemia. The role of tight glycemic control in reducing the risk of stroke is still uncertain. Many new insights and treatment strategies are expected in the future.
Prevalence of Dementia in the Rural Village of Hanazono-mura, Japan
Authors: Shiba Mitsuru , Shimogaito Jun , Kose Asami , Fujiuchi Shinichi , Nishiyama Hitoshi , Yoshimasu Fumio , Asai Tadashi , Rocca Walter A.
Published: April 2003

We studied the prevalence of dementing disorders in a rural municipality of Japan (Hanazono-mura), using a door-to-door two-phase design. In phase 1, the Hasegawa’s Dementia Scale-Revised was applied as a screening test to all subjects aged 65 years and older (n = 201). Among subjects screened positive, 17 were diagnosed with dementia in phase 2. The prevalence (cases/100 aged 65 years and older) was 8.5 for all types of dementia, 3.5 for Alzheimer’s disease, 3.0 for vascular dementia, and 2.0 for other dementia (including mixed dementia). The prevalence of dementia was slightly but consistently higher in men than women at all ages. The overall prevalence was higher in women for Alzheimer’s disease and in men for vascular dementia.
HTLV-II Risk Factors in Native Americans in Florida
Authors: Lowis George W. , Sheremata William A. , Wickman Patricia R. , Dube Symalima , Dube Dipak K. , Poiesz Bernard J.
Published: April 2003

Earlier virologic studies established that human T-cell lymphotropic virus type II (HTLV-II) is the predominant retrovirus type found among Seminole Indians in southern Florida. We studied 46 members of the Seminole tribe living on 3 reservations to determine the risk factors for HTLV-II and to investigate disease association with the virus. The donors’ plasma samples were evaluated with the enzyme-linked immunosorbent and Western blot assays. DNA extracted from their peripheral blood mononuclear cells were analyzed by type-specific polymerase chain reaction amplification and detection of the HTLV pol gene using the primer pair SK110/SK111, and the probes SK112 or SK188. One of 46 (2%) subjects was identified as HTLV-I positive and 11 (24%) were identified as HTLV-II positive. Restriction fragment length polymorphism and sequence analyses indicated that all of the HTLV-II strains were subtype b. Mitochondrial DNA analyses indicated that all of the HTLV-II-positive subjects had an Amerindian haplotype. HTLV-II was more prevalent in Indians who were >45 years of age or female, had multiple sex partners or had received a blood transfusion. However, only the latter risk factor was statistically significant. Three of the HTLV-II-positive Indians demonstrated signs and symptoms of an ataxic neuropathy. The data support that HTLV-IIb is endemic among the Seminoles and that they will be a key population for further virologic studies.
Apolipoprotein E Polymorphism in Elderly Chilean People with Alzheimer’s Disease
Authors: Quiroga Pilar , Calvo Carlos , Albala Cecilia , Urquidi Julio , Santos JoséL. , Pérez Heberto , Klaassen Gonzalo
Published: April 2003

As a part of the WHO Age-Associated Dementia Project, Chile has been participating in a cross-national survey on dementia frequency and determinants since 1989. In the present study, apolipoprotein E (ApoE) polymorphism genotypes have been compared in 95 patients with Alzheimer’s disease (AD) (mean age 80.7; 95% CI 79.2–82.2, range 66–97) and 187 healthy people (mean age 78.2; 95% CI 77.2–79.2, range 65–93). Isoelectric focusing and immunoblotting with anti-human ApoE polyclonal antibody were used to determine the distribution of ApoE genotypes. Dementia was diagnosed according to DSM-III-R and ICD-10 clinical criteria. The diagnosis of probable or possible AD was made according to the NINCDS-ADRDA criteria. The ApoE allele frequencies in healthy people were calculated to be σ2 = 0.07, σ3 = 0.74 and σ4 = 0.19. In the probable AD disease group, the frequencies were σ2 = 0.08, σ3 = 0.52 and σ4 = 0.40. The odds ratio (OR) for σ4 carriers compared with non-σ4 carriers was estimated to be 2.9 (95% CI 1.7–5.1). Taking the genotype σ3/σ3 as the reference group, the OR for the σ4/σ4 genotype was estimated to be 12.8 (95% CI 3.9–47.6) and for σ3/σ4 subjects it was 2.4 (1.3–4.5). These results support the association between ApoE σ4 allele with late-onset AD in a Chilean population.
Prevalence and Incidence of Clinically Diagnosed Memory Impairments in a Geographically Defined General Population in Sweden
Authors: Andreasen Niels , Blennow Kaj , Sjödin Christina , Winblad Bengt , Svärdsudd Kurt
Published: April 2003

In the Piteå River Valley all persons with memory impairment that interferes with normal life are referred to one hospital department for clinical workup and diagnosis. 619 patients were assessed in the department during the years 1990–1995. Of these, 36.9% had Alzheimer’s disease (AD), 30.4% had vascular dementia (VaD), 3.0% had a mixed AD/VaD, 3.2% had frontotemporal dementia and 5.3% had other forms of dementia. Another 7% had memory impairment but no dementia. The overall mean annual incidence rate of clinically relevant dementia was 295/100,000 persons at risk and the mean prevalence rate was 755/100,000 persons. For persons 65 years and older the incidence and prevalence rates were 840 and 2,150/100,000 persons, respectively. This means that annually, approximately 300 persons/100,000 population over the age of 40 need medical attention or social services.
Association of Cigarette Smoking with Amyotrophic Lateral Sclerosis
Authors: Kamel Freja , Umbach David M. , Munsat Theodore L. , Shefner Jeremy M. , Sandler Dale P.
Published: April 2003

We explored the relationship between amyotrophic lateral sclerosis (ALS) and cigarette smoking in a case-control study conducted in New England from 1993 to 1996. Recently diagnosed ALS cases (n = 109) were recruited from two major referral centers. Population controls (n = 256) were identified by random telephone screening. Data were analyzed by logistic regression. After adjusting for age, sex, region and education, ever having smoked cigarettes was associated with an increase in risk for ALS (odds ratio 1.7; 95% confidence interval 1.0–2.8). Average cigarettes smoked per day, years smoked and pack-years were all greater in cases than controls, but dose-response trends were not observed. Similar numbers of cases and controls had ever used alcohol, and only a small, nonsignificant association of drinks per month with ALS was observed. The association of cigarette smoking with ALS was not affected by adjusting for alcohol use. In contrast, the weak relationship of ALS with alcohol use was apparently due to confounding by smoking.
Prevalence of Multiple Sclerosis in Gypsies and Bulgarians
Authors: Milanov I. , Topalov N. , Kmetski Ts.
Published: April 2003

There are occasional reports about the low prevalence of multiple sclerosis among Gypsies. To verify these reports of low prevalence of multiple sclerosis among Gypsies compared to the white population in Bulgaria, an epidemiological study was conducted in two small regions of Bulgaria. All patients with clinically or laboratory-supported, definite multiple sclerosis according to Poser’s criteria were personally interviewed and examined. The study was begun on January 1, 1997 and March 31, 1998 was selected as prevalence day. For the white population, the prevalence ratio of multiple sclerosis per 100,000 population was 44.9 in the first region and 44.4 in the second. The prevalence of multiple sclerosis in Gypsies was found to be 19.1/100,000 in the first region and 18.4 in the second. It is concluded that multiple sclerosis is less common in Gypsies than in whites living in the same areas.
Evolution of Neuronetworks
Authors: Terry John B.
Published: April 2003

Since the 1970s, the care of critically ill neurologic and neurosurgical patients has emerged as a developing subspecialty. Management of these patients involves an enormous amount of data generation and analysis. Review of the history of neuroepidemiology and neurocritical care demonstrates the inevitability of their present unwieldy burden of information. Compelling advantages of computerization in direct patient care include aid in data acquisition, analysis and remote access. Infrastructure and resources used to collect data on individual patients may be augmented to archive data in clinical databases. Several investigators have initiated information management projects including automation of bedside clinical documentation, development of systems for remote access to information and patient registries to study the natural history and outcome of specific neurological conditions. These are steps toward the development of integrated systems to aid in patient monitoring, data management, continuous quality improvement and the generation of hypotheses for further clinical investigation. Improvements in information management technology will allow increased efficiency in an era where information generation continues to increase exponentially.
Clinical Correlates of Ventricular and Sulcal Size on Cranial Magnetic Resonance Imaging of 3,301 Elderly People
Authors: Longstreth Jr. W.T. , Arnold Alice M. , Manolio Teri A. , Burke Gregory L. , Bryan Nick , Jungreis Charles A. , O’Leary Daniel , Enright Paul L. , Fried Linda
Published: April 2003

To identify potential risk factors for and clinical manifestations of ventricular and sulcal enlargement on cranial magnetic resonance imaging (MRI), 3,301 community-dwelling people 65 years or older without a history of stroke or transient ischemic attack underwent extensive standardized evaluations and MRI. In the multivariate model, increased age and white matter grade on MRI were the dominant risk factors for ventricular and sulcal grade. For ventricular grade, other than race, for which non-Blacks had higher grades, models for men and women shared no other factors. For sulcal grades, models for men and women shared variables reflecting cigarette smoking and diabetes. Clinical features were correlated more strongly with ventricular than sulcal grade and more strongly for women than men. Significant age-adjusted correlations between ventricular grade and the Digit-Symbol Substitution Test were found for men and women. Prospective studies will be needed to extend findings of this cross-sectional analysis.
Recruitment Procedures and Their Impact on the Prevalence of Dementia
Authors: Riedel-Heller Steffi G. , Schork Astrid , Matschinger Herbert , Angermeyer Matthias C.
Published: April 2003

Recruitment procedures may exert a considerable influence on the outcome of health surveys in the elderly. Their impact on the prevalence of dementia will be measured in an epidemiological field study in a sample of 1,692 randomly selected individuals (75+). Face-to-face interviews were conducted using SIDAM (structured interview for the diagnosis of dementia of Alzheimer type, multi-infarct dementia and dementias of other etiology according to ICD-10 and DSM-III-R). Furthermore, proxy interviews were performed with relatives of fragile and functionally dependent individuals. Considering face- to-face interviews of community-dwelling individuals, a prevalence of moderate and severe dementia of 5.3% was found. When including information on respondents by proxy and institutionalized individuals, the prevalence rate increased to 6.3 and 10.5%, respectively. It will be argued that covering the whole population in question and ensuring high response rates are central issues to minimize selection bias.
Incidence of Stroke on Kinmen, Taiwan
Authors: Fuh Jong-Ling , Wang Shuu-Jiun , Liu Hsiu-Chih , Shyu Hann-Yeh
Published: April 2003

This study aims to assess the incidence, case-fatality rate and risk factors of stroke on Kinmen Island, Taiwan, from 1993 to 1996. A population-based stroke survey was carried out in 1993 and 1996 to collect data on all subjects in the population aged 50 years and older residing on Kinmen. There were 63 stroke events (53 first ever and 10 recurrent) identified in this period. The average annual incidence rate of first-ever stroke for people aged 50 years or older was 527 per 100,000 population (95% confidence interval, CI, 297–757). The 28-day case-fatality rate was 24.5% (95% CI 12.9–36.1%) for first-ever stroke and 60% (95% CI 29.6–90.4%) for recurrent stroke. Multivariate analyses performed with the Cox proportional hazard model revealed the following risk factors to be independent predictors of stroke: hypertension, diabetes and alcohol use. The incidence and case- fatality rate of stroke on Kinmen is similar to that of several other countries. Hypertension is the most common risk factor in this population. Due to a relatively small number of outcome events, these findings require confirmation.
Apolipoprotein E Phenotype Alone Does Not Influence Survival in Alzheimer’s Disease: A Population-Based Longitudinal Study
Authors: Koivisto Anne M. , Lempiäinen Päivi , Koivisto Keijo , Helkala Eeva-Liisa , Mykkänen Leena , Kuusisto Johanna , Kervinen Kari , Kesäniemi Y. Antero , Laakso Markku , Soininen Hilkka
Published: April 2003

Apolipoprotein E4 (ApoE4) phenotype is a known risk factor for development of Alzheimer’s disease (AD). Contradictory results exist concerning the role of ApoE4 in the rate of decline and mortality in AD. Conflicting findings have also been reported about ApoE and gender interactions with respect to survival. We examined the survival of subjects with AD and non-AD controls with respect to ApoE phenotype and gender in a population-based longitudinal study. Cognitive evaluation was performed for a total of 980 subjects (then aged 69–78 years), and 48 cases with AD were identified. ApoE4 phenotype was more frequently present among subjects with AD. In the whole study population, survival was not related to the presence of AD or ApoE4 phenotype. Risk of death was increased for men compared to women, independently of the ApoE4 phenotype (HR 0.5, 95% confidence interval 0.44–0.69). In subjects with AD, the presence of ApoE4 alone did not influence survival. However, in the AD group, ApoE4-negative men had significantly increased risk of mortality compared to the risk in ApoE4-negative women (p < 0.01). We conclude that the presence of ApoE4 phenotype or AD did not influence mortality in the aged population. Once AD had become manifest, ApoE4 alone did not relate to survival. However, in subjects with AD not carrying ApoE4, men had reduced survival compared to women.
Transgenic Models to Study the Actions of Cytokines in the Central Nervous System
Authors: Campbell Iain L. , Stalder Anna K. , Akwa Yvette , Pagenstecher Axel , Asensio Valérie C.
Published: April 2003

To better understand the actions of cytokines in the mammalian central nervous system (CNS), we have developed transgenic mice in which the expression of various cytokines including interleukin (IL)-3, IL-6, IL-12, interferon-α or tumor necrosis factor-α was targeted to astrocytes under the transcriptional control of the glial fibrillary acidic protein (GFAP) promoter. Transgenic lines displaying low astrocyte expression of the respective cytokine were developed and characterized. The findings indicate that expression of these different cytokines in the intact CNS produces divergent inflammatory responses which are associated with the development of wide-ranging and progressive molecular, cellular and functional CNS impairments. These transgenic mice provide a powerful tool which we are now exploiting further to define novel mechanisms that might underlie the individual cytokine-driven neuroinflammatory responses. To date the results clearly show there are distinct model-associated patterns of cerebral expression of key molecules involved in the inflammatory response including the cellular adhesion molecules, chemokines, major histocompatibility complex molecules and the matrix metalloproteinases. In conclusion, these GFAP-cytokine transgenic mice highlight the potent and diverse array of actions mediated by cytokines when expressed in the CNS and provide a valuable resource to further our knowledge of the mechanisms by which cytokines exert their effects.
Cytokines and Cognitive Behavior
Authors: Gibertini Michael
Published: April 2003

Proinflammatory cytokines help orchestrate host responses to infection and are a major communication link between peripheral immunity and the CNS. These cytokines initiate a number of CNS events that culminate in both physiological and behavioral changes. Peripheral IL-1β also affects information processing. A series of experiments examining the effect of learning intensity, motivation, and cytokine dose are reported. Using a well-established Morris water maze (MWM) system with female C57BL/6 mice, we report that (1) IL-1 (100 ng/mouse, i.p.) has no effect on MWM learning when mice are subjected to a spaced as opposed to a massed learning protocol; (2) water temperature is critical to the IL-1 effect on learning insofar as IL-1 interferes with learning in a warm-water but not a cold-water maze, and (3) higher doses (1,000 ng/mouse, i.p.) of IL-1 in experimental systems known to produce the IL-1-induced learning deficit with lower doses (100 ng/mouse, i.p.) show consistent facilitation, not impairment, of learning.
Neuroimmunomodulatory Actions of Hypothalamic Interferon-α
Authors: Hori Tetsuro , Katafuchi Toshihiko , Take Sachiko , Shimizu Nobuaki
Published: April 2003

Recent studies have revealed that the brain produces interferon-α (IFN-α) in response to noninflammatory as well as inflammatory stress and that it might have a role in normal physiology. When administered intracerebrally, IFN-α causes diverse effects including fever, anorexia, analgesia and changes in the central neuronal activities. These responses are inhibited by the opioid receptor antagonist naloxone. This is consistent with the reports suggesting that recombinant human (rh) IFN-α binds to opioid receptors in rodent brain membrane. We revealed that rhIFN-α altered the activity of thermosensitive neurons in the medial preoptic area (MPO) and glucose-responsive neurons in the ventromedial hypothalamus in an opioid-receptor-dependent way. As a stress which produces opioid-dependent analgesia is known to suppress the cytotoxicity of splenic natural killer cells, we investigated whether the administration of β-endorphin and rhIFN-α may induce a similar immunosuppression. We found that central, but not peripheral, injection of both compounds inhibited natural killer (NK) cytotoxicity. Further studies revealed that rhIFN-α decreased the activity of MPO neurons via opioid receptors and the altered activity of MPO neurons in turn resulted in the activation of corticotropin-releasing factor neurons, thereby suppressing NK cytotoxicity predominantly through activation of the splenic sympathetic nerve and β-receptor mechanisms in splenocytes. Thus, IFN-α may alter the brain activity to exert a feedback effect on the immune system. Further detailed whole-cell clamping analyses on neuronal mechanisms in rat brain tissue slices showed that the inhibitory effect of rhIFN-α on N-methyl-D-aspartate-induced membrane current responses of MPO neurons was mediated not only by opioid receptors but also by the local production of reactive oxygen intermediates, nitric oxide and prostanoids, possibly due to neuron-glial cell interaction.
Repeated in vivo Hydrocortisone Treatment Promotes a Dual Modulation of Cytokeratin Expression by Mouse Thymic Epithelial Cells
Authors: Obino Cirne-Lima Elizabeth , Savino Wilson
Published: April 2003

Previous studies showed that a single dose of hydrocortisone in mice was able to transiently upregulate the expression of cytokeratins (CKs) 3 and 10 by medullary epithelial cells of the mouse thymus. Herein we studied these cells (specifically recognized by immunocytochemistry with the anti-CK monoclonal antibody KL1) following a series of repeated injections of the glucocorticoid hormone. A progressive dual (up and down) modulation of KL1+ medullary epithelial cells was observed with a late appearance of KL1 immunoreactivity in the thymic cortex. The data indicate that a single versus repeated exposure to high doses of glucocorticoid hormone may trigger different circuits regulating intrathymic CK expression. Lastly, the model described herein may be regarded as promising in studies concerning the effect of repeated stress conditions upon the thymus.
Cytokine-Mediated or Direct Effects of Thymulin on the Nervous System as Assessed by Pain-Related Behavior
Authors: Safieh-Garabedian Bared , Kanaan Salim A. , Jabbur Suhayl J. , Saadé NayefE.
Published: April 2003

Thymulin is a thymic hormone with known immunomodulatory activities. Recent evidence has indicated a signaling role for this peptide in the interaction between the immune, endocrine and the nervous system. In this report, we review recent experimental findings on the analgesic actions of thymulin (high doses) in rats with endotoxin-induced localized inflammation and the hyperalgesic actions (low doses) of this peptide in intact animals. These actions involve both proinflammatory cytokines and PGE2. The possibility of a dual role played by thymulin as a hormone that might also involve a direct effect on the nervous system is discussed.
Antiorthostatic Suspension Stimulates Profiles of Macrophage Activation in Mice
Authors: Miller Edwin S. , Bates Roge A. , Koebel D. Anne , Sonnenfeld Gerald
Published: April 2003

The antiorthostatic suspension model simulates certain physiological effects of spaceflight. We have previously reported BDF1 mice suspended by the tail in the antiorthostatic orientation for 4 days express high levels of resistance to virulent Listeria monocytogenesinfection. In the present study, we examined whether the increased resistance to this organism correlates with profiles of macrophage activation, given the role of the macrophage in killing this pathogen in vivo. We infected BDF1 mice with a lethal dose of virulent L. monocytogenes on day 4 of antiorthostatic suspension and 24 h later constructed profiles of macrophage activation. Viable listeria could not be detected in mice suspended in the antiorthostatic orientation 24 h after infection. Flow cytometric analysis revealed the numbers of granulocytes and mononuclear phagocytes in the spleen of infected mice were not significantly altered as a result of antiorthostatic suspension. Splenocytes from antiorthostatically suspended infected mice produced increased titers of IL-1. Serum levels of neopterin, a nucleotide metabolite secreted by activated macrophages, were enhanced in mice infected during antiorthostatic suspension, but not in antiorthostatically suspended naive mice. Splenic macrophages from mice infected on day 4 of suspension produced enhanced levels of lysozyme. In contrast to the results from antiorthostatically suspended infected mice, macrophages from antiorthostatically suspended uninfected mice did not express enhanced bactericidal activities. The collective results indicate that antiorthostatic suspension can stimulate profiles of macrophage activation which correlate with increased resistance to infection by certain classes of pathogenic bacteria.
Urocortin and Inflammation: Confounding Effects of Hypotension on Measures of Inflammation
Authors: Torpy David J. , Webster Elizabeth L. , Zachman E. Keith , Aguilera Greti , Chrousos George P.
Published: April 2003

Urocortin, a newly isolated 40-amino-acid mammalian peptide homologous to corticotropin-releasing hormone (CRH), activates both CRH type 1 and 2 receptors, but may be an endogenous ligand for CRH receptor type 2. Urocortin given systemically inhibited heat-induced paw edema in the rat, and was therefore ascribed anti-inflammatory properties. We examined the effects of urocortin in the carrageenin-induced subcutaneous inflammation model. Rats were treated with urocortin 200 (n = 6) or 20 nmol/kg (n = 6); inflammatory exudates were reduced by approximately 30% compared to controls (n = 7) at both doses. However, since subcutaneous urocortin has been shown to reduce arterial blood pressure, we tested the hypothesis that its antiedema and antiextravasatory effects were secondary to arterial hypotension. Therefore, we examined the parallel effects of urocortin- and hydralazine-induced hypotension on acute inflammation induced by carrageenin in the rat. Rats were treated with subcutaneous carrageenin and control injections (n = 8), carrageenin and urocortin (20 nmol/kg, n = 9), or carrageenin and intraperitoneal hydralazine (10 mg/kg, n = 8). Mean arterial blood pressure was measured hourly for 7 h in 12 animals, and after 2 h, the nadir of treatment, in a further 13 animals. Rats were then sacrificed, and the inflammatory exudate volume and leukocyte count were measured. Mean exudate volumes were reduced from 4.8 ± 0.5 ml (controls) to 2.4 ± 0.3 ml (p = 0.004) and 2.9 ± 0.6 ml (p = 0.007) in urocortin- and hydralazine-treated animals, respectively. Urocortin and hydralazine both produced a significant fall in blood pressure compared to controls, with mean arterial pressure 2 h after carrageenin injection falling to 51.0 ± 4.1 (p < 0.001) and 34.6 ± 4.6 (p < 0.001) vs. 92.9 ± 3.7 mm Hg in controls, respectively. A significant positive correlation was noted between blood pressure and inflammatory exudate volume (r = 0.52, p = 0.007). As both hydralazine and urocortin lowered blood pressure and inflammatory exudate volume, we suggest that the anti-inflammatory effects of urocortin and related neuropeptides may be nonspecific, acting through hypotension rather than through direct anti-inflammatory mechanisms. The use of inflammatory models which rely on extravasation may be inappropriate for the study of substances that produce hypotension.
Peripheral Effects of Centrally Administered Interleukin-1β in Mice in Relation to Its Clearance from the Brain into the Blood and Tissue Distribution
Authors: Di Santo Elena , Benigni Fabio , Agnello Davide , Sipe Jean D. , Ghezzi Pietro
Published: April 2003

Administration of interleukin IL-1 induces acute-phase response and inhibition of gastric secretion more efficiently when administered intracerebroventricularly (i.c.v.) than when the same dose of IL-1 is administered systemically. In this study we describe the pharmacokinetics of IL-1β, administered centrally or systemically, in the serum or in peripheral tissues. IL-1β administered i.c.v. resulted in higher peak IL-1β concentrations, and lasted longer, than intravenous (i.v.) or intraperitoneal (i.p.) administration. Higher IL-1β levels in the liver and heart were observed after i.c.v. administration (compared to the i.p. or i.v. route). Our data suggest that centrally injected IL-1 induces higher circulating and hepatic IL-1 levels and contributes to the fact that the i.c.v. route of administration is particularly effective in inducing a liver acute-phase response.
β-Adrenergic Receptor Subtype Effects on Stress Fever and Thermoregulation
Authors: Mayfield Kimberly P. , Soszynski Dariusz , Kozak Wieslaw , Kozak Anna , Rudolph Karin , Kluger Matthew J.
Published: April 2003

Exposure to psychological stress increases body temperature (Tb). This stress fever may be immunologically beneficial in some patient populations but detrimental in others (e.g., HIV-infected individuals). For this reason, it is desirable to determine pharmacological methods of preventing stress fever. In rats, stress fever is modeled by exposure to a novel environment or ‘open field.’ The β-adrenergic antagonists, nadolol and propranolol, block this stress fever. Neither of these β-antagonists discriminates between subtypes of β-receptors. The purpose of this study was to determine the relative contribution of the different β-receptor types to stress fever using β1-, β2-, and β3-receptor subtype selective antagonists (atenolol [β1], ICI-118551 [β2], and SR 59230A [β3]) and agonists (dobutamine [β1], salbutamol [β2], and BRL 37344 [β3]) on the Tb of rats. Tb was measured with a biotelemetry system. Our data suggest that central nervous system β-receptor blockade with subtype-selective antagonists prevents the stress-induced rise in Tb; however, the β3-antagonist was effective only at doses that produced hypothermia in a non-stressed control group. The stress-induced fever was mimicked by central nervous system administration of the selective β2-agonist, salbutamol, and the β3-agonist, BRL 37344. We hypothesize that the blockade of stress-induced fever by β-blockers may be due to the sedative actions of these drugs.
Acute Stress May Facilitate Recovery from a Subcutaneous Bacterial Challenge
Authors: Deak Terrence , Nguyen Kien T. , Fleshner Monika , Watkins Linda R. , Maier Steven F.
Published: April 2003

The effects of stress on the immune system vary with both the duration and type of stressor. Many studies suggest that stress may compromise an organism’s ability to recover from immune challenge. However, recent findings suggest that stress may actually enhance some aspects of immune function. For example, exposure to a single session (∼2 h) of intermittent inescapable tailshocks (IS) has been shown to activate the acute phase response and increase some aspects of macrophage function. Thus, the following experiments assessed whether IS exposure would alter local inflammation produced by peripheral injection of streptomycin-killed bacteria. Rats (Harlan Sprague Dawley) were exposed to IS (100 1.6-mA, 60 s variable intertrial interval) and injected with Escherichia coli (∼2.5 × 108 CFU s.c. posterior to the shoulder blades). The area of inflammation was measured until the inflammation had completely resolved (typically 7–8 days). When bacteria were administered immediately after IS, rats resolved inflammation significantly faster than did nonstressed rats. Since adrenalectomy did not reduce the effect of IS, it is unlikely that this effect is a result of elevated corticosterone levels. Furthermore, IS does not appear to alter the rat’s ability to sequester bacteria in the subcutaneous space since no swelling of lymph nodes or chronic activation of the hypothalamic-pituitary-adrenal axis was observed.
δ-Opioid Receptor Antagonist Inhibits Immunomodulation by Met-Enkephalin Analogs
Authors: Singh Vijay K. , Bajpai Kirti , Narayan Prem , Yadav Virendra S. , Dhawan Vikas C. , Haq Wahajul , Mathur Krishna B. , Agarwal Shyam S.
Published: April 2003

The methionine-enkephalin (Met-enkephalin, Tyr-Gly- Gly-Phe-Met) analogs Tyr-D-Ala-Gly-MePhe-Met NHC3H7- iso (1) and Tyr-D-Ala-Gly-MePhe-Gly-NHC3H7-iso (2) have been shown to enhance human T cell proliferation in in vitro treatment. Their immunomodulatory activities were completely blocked by naloxone, an opioid antagonist. Now we demonstrate that a selective δ-opioid receptor antagonist, ICI-174,864, completely blocks enhancement of T cell proliferation by analogs (1) and (2). The T cell-stimulatory effect was only partially inhibited by the µ-receptor-selective antagonist, β-funaltrexamine hydrochloride. The κ-opioid receptor antagonist, nor-binaltorphimine dihydrochloride, showed no effect on T cell-proliferation stimulated by analogs (1) and (2). These observations suggest that analogs (1) and (2) of Met-enkephalin stimulate T cell proliferation predominantly via δ-opioid receptor present on T cells.
Recombinant Forms of the Neurotrophic Factor Pigment Epithelium-Derived Factor Activate Cellular Metabolism and Inhibit Proliferation of the RAW Macrophage Cell Line
Authors: Cohen Joseph , Sugita Yukihiro , Chader Gerald J. , Schwartz Joan P.
Published: April 2003

Recombinant forms of the neurotrophic factor pigment epithelium-derived factor (PEDF) activate metabolism of RAW macrophage cells while simultaneously inhibiting their proliferation. The recombinant forms (rPEDF) acted with EC50s of 0.1–1 nM while full-length native bovine PEDF was inactive. Urea, which is the buffer used to extract recombinant PEDF, stimulated RAW cell proliferation, the first report of an effect of urea on non-kidney cells. PEDF acted within 12 h and its effects persisted up to 72 h with continuous exposure. Although rPEDF had no direct action on glioma cell lines, it increased the amount of a soluble factor released by RAW cells which was capable of blocking glioma cell division. Thus PEDF may function as a neuroimmune modulator, affecting both neural and immune system cells.
Suppression of Lymphocyte Mitogenesis by Tamoxifen: Studies on Protein Kinase C, Calmodulin and Calcium
Authors: Baral Edward , Nagy Eva , Kwok Siuchan , McNicol Archibald , Gerrard Jon , Berczi Istvan
Published: April 2003

The effect of tamoxifen (TX; 1.0 μM) on the mitogenic response of rat lymphocytes was compared with the effect of drugs that are known to act on protein kinase C (PKC), calmodulin (CM), and calcium (Ca2+). The calcium ionophore A23187 (0.2 μM) was mitogenic on its own which was not influenced by TX. The agents modulating PKC or CM (phorbol-myristate-13-acetate; R24571, chlorpromazine) influenced mitogenesis differently than did TX. General inhibition of lymphocyte proliferation was seen with the Ca2+ antagonist agents (EGTA, TMB-8) as with TX. The antiproliferative effect of TX was partially reversed by the increase of Ca2+ in the culture medium when T cell mitogens were used, but not in the case of lipid A, a B lymphocyte mitogen. However, the concanavalin A-induced Ca2+ influx was further elevated by TX which differed from the effect of the Ca2+ channel-blocking agent verapamil. The results suggest that TX resets the threshold stimulus necessary for mitogenesis and is completely reversible.
Time of Day-Dependent Effects of Thyroliberin and Thyrotropin on Thymocyte Proliferation in Rats
Authors: Winczyk Katarzyna , Pawlikowski Marek
Published: April 2003

Our earlier studies have shown that thyroliberin (TRH) as well as thyrotropin (TSH) enhanced thymus cell proliferation. The aim of the present study was to investigate whether the effects of TRH and TSH on thymocyte proliferation depend on time of day. A single subcutaneous injection of TRH (25 μg/animal) or TSH (3 IU/animal) was made at 9:00 h (1 h after light onset) or at 18:00 h (10 h after light onset) in 3-month-old male Wistar rats. The animals were killed 24 h later. The proliferation of thymocytes was assessed by incorporation of bromodeoxyuridine into cell nuclei. Thymocyte proliferation was significantly increased by TSH administration at 9:00 h, whereas treatment given at 18:00 h was ineffective. TRH enhanced the proliferation when injected at 9:00 h, but had an inhibitory effect when administered at 18:00 h. These data indicate that the effects of TRH and TSH on thymocyte proliferation are dependent on time of day.
Human Amylin Stimulates Inflammatory Cytokine Secretion from Human Glioma Cells
Authors: Gitter Bruce D. , Cox Laura M. , Carlson Christopher D. , May Patrick C.
Published: April 2003

Chronic neurodegeneration in the brains of Alzheimer’s disease (AD) patients may be mediated, at least in part, by the ability of amyloid beta (Aβ) to exacerbate inflammatory pathways in a conformation-dependent manner. In this regard, we previously reported that the Aβ-peptide-mediated potentiation of inflammatory cytokine secretion from interleukin-1β (IL-1β)-stimulated human astrocytoma cells was conformation dependent. Other amyloidogenic peptides, such as human amylin, which display similar conformation-dependent neurotoxic effects, may also elicit inflammatory cytokine secretion from glial cells. To test this hypothesis, we compared human and rat amylin for the effects on cytokine production in U-373 MG human astrocytoma cells. Human amylin alone stimulated U-373 MG cells to secrete IL-6 and IL-8 in a concentration-dependent manner with maximum effects seen at 10–25 μM peptide. In addition, human amylin markedly potentiated IL-1β-stimulated cytokine production with a similar concentration dependence. In contrast, nonamyloidogenic rat amylin modestly stimulated cytokine secretion, either alone or combined with IL-1β. Aging human amylin resulted in diminished cytokine secretion, probably due to the formation of large, less active aggregates. In agreement with our previous studies using Aβ, extracellular Ca2+ was necessary for human amylin stimulation of cytokine secretion. Our data suggest that amyloidogenic peptides promote cytokine secretion through similar β-sheeted secondary-structure- and extracellular-Ca2+-dependent mechanisms.
Activation of the Hypothalamic- Pituitary-Adrenal Axis in IL-1β-Converting Enzyme-Deficient Mice
Authors: Liège Stéphane , Moze Elisabeth , Kelley Keith W. , Parnet Patricia , Neveu Pierre J.
Published: April 2003

Interleukin-1β (IL-1β) plays a key role in immune, behavioral and neuroendocrine responses to inflammation or infection. IL-1β could also be involved in the response of the hypothalamic-pituitary-adrenal (HPA) axis during stress. Mature IL-1β derives from a 31-kD precursor (pro-IL-1β) that is processed by IL-1β-converting enzyme (ICE). Mice in which the ICE gene has been nullated by homologous recombination were used to investigate the role of IL-1β in the HPA axis response. Plasma levels of corticosterone and adrenocorticotropic hormone (ACTH) in response to an intraperitoneal injection of 5 μg lipopolysaccharide (LPS) were similar in ICE-deficient mice and wild-type (WT) controls. In contrast, plasma ACTH response to restraint or to 200 ng of rat recombinant IL-1β (rrIL-1β) was higher in ICE-deficient mice as compared to WT animals. This hyperreactivity of the HPA axis in ICE knockout mice appears not to be related to the production of plasma IL-1β or IL-6, which was similar to that of WT mice after rrIL-1β injection. After lypopolysaccharide, ICE-deficient mice exhibited a smaller increase in plasma-immunoreactive IL-1β and IL-6 as compared to WT controls. After restraint stress neither increase in plasma IL-1β nor IL-6 was observed. The mechanisms responsible for the increased reactivity of the HPA axis in ICE-deficient mice may result from a higher sensitivity of the HPA axis to inflammatory cytokines or to cleavage products of pro-IL-1β processed by non-ICE proteases.