bluuebunny/crossref_metadata_2025 huggingface dataset:
Gene Transfer to Intact Mesenteric Arteries by Electroporation
Authors: Martin Jason B. , Young Jennifer L. , Benoit Joseph N. , Dean David A.
Published: April 2003

The purpose of the present study was to develop a rapid, reproducible method of nonviral gene transfer to the intact vasculature. Male Sprague-Dawley rats were anesthetized, a midline abdominal incision was made and segmental branches of the superior mesenteric artery were dissected free of surrounding mesentery. A specially designed electroporation probe was placed around the neurovascular bundle and the electroporation chamber filled with a solution containing the firefly luciferase expressing plasmid (pCMV-Lux-DTS) or the green fluorescent protein expressing plasmid (pEGFP-N1). Vessels were electroporated with eight 10-ms pulses of 200 V/cm. Sixty seconds after electroporation, the DNA solution was removed, the intestine returned to the abdomen and the abdominal wall closed with suture and metal wound clips. Six hours to 5 days later, rats were sacrificed and electroporated vessels were recovered. Luciferase activity of the blood vessels was monitored. Gene expression was detected as early as 6 h postelectroporation, peaked at 1–3 days with levels up to 1 ng of reporter gene product per vessel segment and returned towards baseline by day 5. Histological analysis of blood vessel segments revealed green fluorescent protein-positive cells throughout the thickness of the vessel wall (endothelial cells to adventitia). Responses of electroporated vessels to vasoconstricting stimuli were indistinguishable from those of control vessels at either 2 or 40 days posttreatment. The results of this study provide evidence that electroporation is an effective means for introducing naked DNA into the blood vessel wall and form the basis for future studies on targeted gene therapy to the intact vasculature.
Expression Profile of Hyaluronidase mRNA Transcripts in the Kidney and in Renal Cells
Authors: Sun Li-kang , Feusi Ernst , Sibalic Anita , Beck-Schimmer Beatrice , Wüthrich Rudolf P.
Published: April 2003

The accumulation of hyaluronan (HA) in the renal cortex is a characteristic feature of inflammatory renal diseases. Fragments of HA derived from high molecular weight precursors are known to display inflammatory effects in vitro and could, therefore, participate in immune renal injury. To understand the mechanisms of HA fragmentation in vivo we examined the expression of recently characterized mammalian hyaluronidases in normal and autoimmune kidneys and in cell lines. We found that transcripts for the lysosomal–type hyaluronidases Hyal1 and Hyal2 were constitutively expressed in normal and autoimmune kidneys as well as in tubular epithelial cells and in a macrophage cell line. The expression of hyaluronidase genes in the cell lines did not increase in response to treatment with tumor necrosis factor alpha or gamma interferon. Interestingly, transcripts for the testicular–type hyaluronidase PH–20 (Spam1, Hyal3) were also detected in normal and autoimmune kidneys as well as in tubular cells and macrophages. Transcript levels were higher in kidneys from male mice as compared with age–matched females. Again, transcript levels did not change in vitro in response to cytokines. We conclude that mRNA for three different hyaluronidases is found in murine kidneys. The functional role played by these hyaluronidases in the degradation and metabolism of HA remains to be investigated further.
Effect of Epidermal Growth Factor on Sodium–Dependent L–Alanine Transport in LLC–PK1 Cells
Authors: Nishida Masashi , Kawakatsu Hidekazu , Matsumura Takafumi , Ishiwari Kohhei , Tamai Megumi , Sawada Tadashi
Published: April 2003

We evaluated the role of epidermal growth factor (EGF) in the regulation of L–alanine transport in LLC–PK1 renal epithelia. After 2 h of incubation, EGF had no significant effect on L–alanine uptake by LLC–PK1 cells. However, prolonged (16 h) incubation with 2 and 20 ng/ml of EGF resulted in significant increases in sodium–dependent L–alanine uptake as compared with controls. Treatment with 12–O–tetradecanoylphorbol–13–acetate (TPA; 20 ng/ ml) caused a marked increase in sodium–dependent L–alanine uptake after both 2 and 16 h of incubation, and the treatment with TPA (20 ng/ml) EGF (20 ng/ml) for 16 h resulted in significant acceleration of the TPA–stimulated increase in L–alanine uptake by LLC–PK1 cells. Coincubation with H–7 (20 μ M) inhibited both EGF– and TPA–stimulated increases in L–alanine uptake, and genistein (20 μg/ml) blocked the stimulatory effect of EGF in L–alanine transport to the control level. Furthermore, coincubation with cycloheximide (20 μg/ml) for 16 h inhibited both EGF– and TPA–stimulated increases in L–alanine transport to a great extent. The sodium– independent L–alanine uptake was not affected by treatment with either EGF or TPA. These results suggest that the activation of protein kinase C through tyrosine kinase activation plays a role in the EGF effect of stimulating L–alanine transport in LLC–PK1 cells and that the effect is mainly due to increased protein de novo synthesis which occurs after protein kinase C activation.
Combined Therapy with Estrogen and Testosterone Eliminates the Aggravating Effect of Estrogen Replacement Therapy on Glomerular Injury in Hypercholesterolemic Female Imai Rats
Authors: Ikeda Yuji , Sakemi Takanobu , Tomiyoshi Yoshiyuki , Miyazono Motoaki
Published: April 2003

Hypercholesterolemic Imai rats spontaneously develop proteinuria and glomerulosclerosis, especially male animals. Ovariectomy aggravates glomerular injury in femal Imai rats. However, estrogen replacement therapy did not abolish this aggravating effect of ovariectomy and rather aggravated glomerular injury with an increase in serum levels of lipids and growth hormone (GH). Whereas we have already reported that treatment with testosterone in addition to estrogen reduces GH levels and attenuates glomerular injury as compared with estrogen alone in male Imai rats, in the present study, to investigate whether increased GH levels may contribute to an enhancing effect of estrogen on glomerular injury, we treated ovariectomized female Imai rats with estrogen puls testosterone. Group 1 was sham operated and group 2 was ovariectomized at 6 weeks of age. Groups 3, 4, and 5 were ovariectomized and received estrogen, testosterone, or estrogen plus testosterone, respectively. Body weight, urinary protein, and serum constituents were investigated every 4 weeks from 12 to 24 weeks of age. At 24 weeks of age, the rats were studied morphologically. Each treatment with estrogen or testosterone equally aggravated glomerular injury with an increase in both proteinuria and serum lipids with increased serum GH levels in estrogen–treated rats but without influencing GH levels in testosterone–treated rats; combined treatment with estrogen plus testosterone resulted in a reduction of both proteinuria and serum lipids to levels of the controls and attenuated glomerular injury to levels close to those of controls with a reduction of the elevated serum GH levels. These results suggest that increased GH levels may contribute to an enhancing effect of estrogen replacement therapy on glomerular injury and that testosterone, when administered to the estrogen–treated rats, seems to exert an attenuating effect on glomerular injury by suppressing GH levels.
Spinal Muscular Atrophy
Authors: Ludvigsson Petur , Olafsson Elias , Hauser W. Allen
Published: April 2003

Spinal muscular atrophy (SMA) is among the commonest degenerative disorders of the nervous system in childhood. This is an inherited autosomal recessive disease which results in premature death of anterior horn cells of the spinal cord and is manifested by progressive weakness and atrophy of skeletal muscles. Few studies have looked at the frequency of the disease in a defined population. We identified all patients diagnosed with SMA in Iceland during a 15-year period. The diagnosis is based on typical symptoms and supported by results of electromyography/nerve conduction studies and muscle biopsy. The average annual incidence was 13.7 per 100,000 live births for all types of SMA, which is similar to that reported in other population-based studies.
Creutzfeldt-Jakob Disease in a Recipient of a Dura mater Graft Processed in the US: Cause or Coincidence?
Authors: Dobbins James G. , Belay Ermias D. , Malecki Jean , Buck Bill E. , Bell Michael , Cobb Judy , Schonberger Lawrence B.
Published: April 2003

Iatrogenic Creutzfeldt-Jakob disease (CJD) has never been reported among recipients of dura mater grafts processed in the US. We recently investigated a report of such a case in a 72-year-old man with a typical clinical presentation of CJD. We found no evidence of CJD in either the 34-year-old donor or in other, proximal patients undergoing craniotomies. Although the graft may have caused the illness, sporadic CJD is a more likely explanation, with the graft being coincidental.
Are Prior Head Injuries or Diagnostic X-Rays Associated with Glioma in Adults? The Effects of Control Selection Bias
Authors: Wrensch Margaret , Miike Rei , Lee Marion , Neuhaus John
Published: April 2003

The causes of glioma, the most common type of primary malignant brain tumors, are poorly understood. This study compares personal histories of head injury and diagnostic radiation procedures of the head and neck among 476 adults newly diagnosed with glioma in the San Francisco Bay Area between August of 1991 and April of 1994 (82% of all those diagnosed during that time period) with 462 age-, gender-, and ethnicity-frequency-matched controls (63% of those eligible from random digit dialing). In addition, limited information was obtained from 101 controls during a brief telephone interview conducted with controls who declined participation in the lengthy in-person interview. Controls who participated in the full interview were much more likely than controls who only completed the telephone interview to report head injury [odds ratios (OR) and 95% confidence intervals (CI) were 2.3 (1.0–4.9) and 3.0 (1.6–5.8) for women and men, respectively]. The OR for any head injury in cases versus controls who completed the full interview was 0.9. However, OR for any head injury in cases versus both control groups was 1.3, 95% CI (1.0–1.7), and the OR for head injury for which the subject sought medical attention was 1.1, 95% CI (0.8–1.4). Among subjects completing the full interview, cases who responded by self-report were less likely than controls to report prior non-dental head and neck X-rays (OR = 0.7; 95% CI: 0.5–1.0). However, stratification by respondents’ history of head injury indicated no difference in history of head and neck X-ray among those without prior head injury; OR 0.9; 95% CI (0.6–1.2). Cases and controls shared a very similar history of dental procedures and frequency of dental visits. These results suggest that head injury requiring medical attention, dental visits, or non-dental diagnostic X-rays to the head and neck are not important contributors to the risk of adult glioma and reveal some of the methodological obstacles encountered in forming convincing conclusions about these risk factors for brain tumors.
Simultaneous Measurement of Brain and Core Temperature in the Rat during Fever, Hyperthermia, Hypothermia and Sleep
Authors: Sundgren-Andersson Anna K. , Östlund Pernilla , Bartfai Tamas
Published: April 2003

The neuropathological outcome of metabolic, vascular or mechanical insults to the CNS depends on brain temperature; mild hypothermia is neuroprotective, whereas elevated brain temperature can cause additional neural damage. Studies in both animals and humans have shown that the core and the brain temperature do not always concur with one another. It is therefore important to develop methods for monitoring brain temperature. This paper describes an animal model (the rat) in which we have developed a method to measure, at thermoneutral ambient temperature, the brain and core temperature concomitantly, during different drug treatments. We have used this animal model to study body temperature during fever (induced by human recombinant IL-1β, 5 µg/kg, i.p.), stress-induced hyperthermia (handling of the animal), hypothermia (induced by (±)-8-hydroxy-2-dipropylaminotetralin hydrobromide, 0.5 mg/kg, i.p.) and sleep (non-induced, other than by light and diurnal variation). We show that the thermal curves are similar in the brain and the peritoneum, independent of the thermal state.
Hypothalamic-Pituitary-Adrenal Axis Suppression and Inhaled Corticosteroid Therapy
Authors: Chrousos George P. , Harris Alan G.
Published: April 2003

In the first part of this two-part review it was noted that inhaled corticosteroids had become the mainstay of treatment for chronic asthma and yet the effects of long-term use of these compounds on the hypothalamic-adrenal-pituitary (HPA) axis were largely being determined by testing methods of limited reliability, especially by morning plasma cortisol measurements. It was established in our examination of the published literature and in our presentation of current knowledge of the structure and function of the HPA axis that safe, accurate and discriminating techniques to assess the functional status of the HPA axis were available. It was concluded that two state-of-the-art tests that have been insufficiently used were the ACTH stimulation test and measurement of the 24-hour integrated serial plasma cortisol concentrations. These two tests can detect adrenal suppression before the appearance of clinical effects. For part 2 of this review we conducted an exhaustive search of the English language clinical and pharmacological literature on the use of inhaled corticosteroids from 1988 until the present time to identify studies in which one or both of these testing methods have been used. We present our analysis of this limited number of studies to determine what accurately can be known of the HPA axis safety profile of three of the most commonly used and investigated inhaled corticosteroids – beclomethasone dipropionate, budesonide and fluticasone propionate. The first finding of significance was that only 50 reports were identified in which information on the HPA axis safety effects of orally inhaled steroids in asthma patients or in clinical pharmacological studies met our inclusion requirements. By analysis of the data presented in these reports we were able to reach the following conclusions: (1) inhaled corticosteroids administered chronically, and prudently, within recommended dose ranges do not endanger the functioning of the HPA axis, (2) the increasing tendency to use higher doses of inhaled corticosteroids on the assumption that there are clear dose-response benefits and no adverse HPA axis effects from long-term high-dose regimens is misguided and not supported by reliable published information, (3) the corollary – that higher corticosteroid potencies (as measured, for example, by skin-blanching activity) can have greater therapeutic effect in lung tissue without greater concomitant systemic activity – is a flawed concept, and (4) the limited clinical and pharmacological data support our part 1 conclusions that discriminating techniques to assess the functional HPA axis status should be an integral part of the drug development process and that further HPA axis function studies are required on existing inhaled corticosteroids – if they lack a rigorous testing history or long-term record of clinical safety.
The Thymus-Pituitary Axis and Its Changes during Aging
Authors: Goya Rodolfo G. , Brown Oscar A. , Bolognani Federico
Published: April 2003

The pituitary-thymic axis constitutes a bidirectional circuit where the ascending feedback loop is effected by thymic factors of epithelial origin. The aim of the present article is to review the evidence demonstrating that aging brings about a progressive disruption in the integration of this network. In doing so, we briefly review the experimental evidence supporting the view that immune and neuroendocrine aging are interdependent processes. The advantages and limits of the nude mouse as a model of thymus-dependent accelerated aging is also discussed. Next, we review a number of studies which show that the endocrine thymus produces several bioactive molecules, generally called thymic hormones, which in addition to possessing immunoregulatory properties are also active on nervous and endocrine circuits. In particular, the reported activities of thymosin fraction 5 (TF5), thymosin α-1 and thymosin β-4 on β-endorphin, ACTH, glucocorticoids, LHRH and LH secretion in different animal and cell models are reviewed. The known hypophysiotropic actions of other thymic hormones like thymulin, homeostatic thymus hormone (HTH) and thymus factor are summarized. Aging has a significant impact on pituitary responsiveness to thymic hormones. Thus, it has been reported that TF5 and HTH have thyrotropin-inhibiting activity in young but not in old rats. Furthermore, intravenous administration of HTH was also able to reduce plasma GH and increase corticosterone levels in both young and old rats, although these responses were much weaker in the old animals. Further evidence on this topic is discussed. It is proposed that in addition to its central role in the regulation of the immune function, the thymus gland may extend its influence to nonimmunologic components of the body, including the neuroendocrine system. The early onset of thymus involution might therefore act as a triggering event which would initiate the gradual decline in homeostatic potential that characterizes the aging process.
Autonomic Innervation of Human Airways: Structure, Function, and Pathophysiology in Asthma
Authors: van der Velden Vincent H.J. , Hulsmann Anthon R.
Published: April 2003

The human airways are innervated via efferent and afferent autonomic nerves, which regulate many aspects of airway function. It has been suggested that neural control of the airways may be abnormal in asthmatic patients, and that neurogenic mechanisms may contribute to the pathogenesis and pathophysiology of asthma. In this review, the autonomic innervation of the human airways and possible abnormalities in asthma are discussed. The parasympathetic nervous system is the dominant neuronal pathway in the control of airway smooth muscle tone. Stimulation of cholinergic nerves causes bronchoconstriction, mucus secretion, and bronchial vasodilation. Although abnormalities of the cholinergic innervation have been suggested in asthma, thus far the evidence for cholinergic dysfunction in asthmatic subjects is not convincing. Sympathetic nerves may control tracheobronchial blood vessels, but no innervation of human airway smooth muscle has been demonstrated. β-Adrenergic receptors, however, are abundantly expressed on human airway smooth muscle and activation of these receptors causes bronchodilation. The physiological role of β-adrenergic receptors is unclear and their function seems normal in asthmatic patients. Inhibitory nonadrenergic noncholinergic (NANC) nerves, containing vasoactive intestinal peptide and nitric oxide, may be the only neural bronchodilator pathways in human airways. Although a dysfunction of inhibitory NANC nerves has been proposed in asthma, thus far no differences in inhibitory NANC responses have been found between asthmatics and healthy subjects. Excitatory NANC nerves, extensively studied in animal airways, have also been detected in human airways. In animal studies, stimulation of excitatory NANC nerves causes bronchoconstriction, mucus secretion, vascular hyperpermeability, cough, and vasodilation, a process called ‘neurogenic inflammation’. Recent studies have demonstrated an interaction between the excitatory NANC nervous system and inflammatory cells. Neuropeptides may influence the recruitment, proliferation, and activation of leukocytes. On the other hand, inflammatory cells may modulate the neuronal phenotype and function. The functional relevance of the excitatory NANC nervous system and its interaction with the immune system in asthma still remains to be elucidated.
Salivary Cortisol Profiles in Chronic Fatigue Syndrome
Authors: Wood Barbara , Wessely Simon , Papadopoulos Andrew , Poon Lucia , Checkley Stuart
Published: April 2003

Salivary cortisol profiles (hourly sampling over a 16-hour period) of 10 patients with chronic fatigue syndrome (CFS) but without concurrent depressive disorder were compared with those of 10 healthy volunteers matched for age, sex and menstrual cycle. The mean saliva cortisol concentration over the 16-hour period was slightly but significantly greater in the patients than the controls (p < 0.05). These findings are at variance with earlier reports that CFS is a hypocortisolaemic state and suggest that in CFS the symptom of fatigue is not caused by hypocortisolaemia.
Greater Metabolic Rate Decreases in Hippocampal Formation and Proisocortex than in Neocortex in Alzheimer’s Disease
Authors: Stein Dan J. , Buchsbaum Monte S. , Hof Patrick R. , Siegel Jr. Benjamin V. , Shihabuddin Lina
Published: April 2003

Neuropathological studies of Alzheimer’s disease (AD) have found pathological changes in some cytoarchitectural regions and relative sparing in others. Positron emission tomography (PET) studies have also shown selective decreases in glucose metabolic rates but have generally focused on whole brain lobes or geometrically derived regions of interest. In this report, a template of Brodmann areas, derived from a whole brain histological section atlas, was used to analyze PET findings from 34 AD patients and 16 control subjects matched for age, sex, and educational level. AD patients had lowest glucose metabolic rates in limbic areas of the temporal lobe and other proisocortical areas higher rates in frontal lobe and unimodal association areas, and relative sparing of parietal/occipital lobes and motor/sensory cortices. Analysis of variance revealed larger effect sizes when AD and control subjects were compared on metabolic rate for cortical type than for lobe. These findings, which parallel neuropathological studies of regional distribution of neurofibrillary tangles in AD, suggest that vulnerability is greatest in cortical areas that are in closer synaptic contact with limbic areas.
The Effects of Tetrahydrocannabinol on the Recognition of Emotionally Charged Words: An Analysis Using Event-Related Brain Potentials
Authors: Leweke Markus , Kampmann Christina , Radwan Maren , Dietrich Detlef E. , Johannes Sönke , Emrich Hinderk M. , Münte Thomas F.
Published: April 2003

The effects of synthetic tetrahydrocannabinol (THC) on event-related brain potentials (ERPs) were assessed in 19 healthy male volunteers while they performed a visual continuous word recognition task. The study used a double-blind cross-over design. Specifically, word lists were manipulated to contain an equal number of emotionally neutral, negative, and positive words. Most words were repeated after several intervening items with the subject’s task to classify each word as old (previously seen) or new. Behaviorally, a decrease in recognition rate was observed under THC but no influence of the emotional charge of a word on recognition rate was seen. The ERPs showed a typical difference between old and new words taking the form of an enhanced positivity for old words beginning 250 ms poststimulus. The effects of THC were confined to the positive words, for which an enhancement of the positivity to the old words was seen. This effect was interpreted in terms of a congruity of the drug-induced mood state and the material to be recognized. The dissociation between ERPs and behavioral indices suggested that the former primarily reflect implicit memory processes.
Acetazolamide in the Treatment of Acute Mania
Authors: Brandt C. , Grunze H. , Normann C. , Walden J.
Published: April 2003

Several antiepileptic drugs are also being used in affective disorders. There are some hints that also the carbonic anhydrase inhibitor acetazolamide might be useful in the treatment of bipolar affective disorder. We report a 39-year-old male patient with a history of bipolar affective disorder who presented with his second manic episode. Acetazolamide was added to a low dose of valproic acid and to perazine. A marked decrease of the BRMAS score was achieved. The implications of this case are discussed.
CYP2D6 HhaI Genotype and the Neuroleptic Malignant Syndrome
Authors: Iwahashi Kazuhiko , Yoshihara Eiji , Nakamura Kazuhiko , Ameno Kiyoshi , Watanabe Masao , Tsuneoka Yutaka , Ichikawa Yoshiyuki , Igarashi Kazuo
Published: April 2003

To investigate the relationship between CYP2D6 genotypes (reported to be associated with the susceptibilities to Parkinson’s disease and multisystem atrophy) and the possible susceptibility to neuroleptic malignant syndrome (NMS) and subacute myelo-optico-neuropathy (SMON), we analyzed the CYP2D6 gene by polymerase chain reaction and restriction fragment length polymorphism in Japanese schizophrenia patients with a history of NMS. There was no significant difference in the frequency of the poor metabolizer genotype of CYP2D6 between the cases with a history of NMS and controls (p > 0.05). The frequency of the mutation located at the HhaI site in exon 6 of CYP2D6 in the cases was higher, but not significantly (p > 0.05; the mutated allele frequency was 0.25), than that in the controls, schizophrenia patients without NMS (0.11) and healthy controls (0.09). The frequency (0.10) of the HhaI mutation type in patients with a diagnosis of SMON was also not significantly higher than in healthy controls. These results suggest that the poor metabolizer and HhaI polymorphism of CYP2D6 may not be a useful molecular marker for predicting the onset of NMS and SMON.
High Serum and Cerebrospinal Fluid Ca/Mg Ratio in Recently Hospitalized Acutely Depressed Patients
Authors: Levine Joseph , Stein Daniel , Rapoport Avraham , Kurtzman Larisa
Published: April 2003

Calcium (Ca) and magnesium (Mg) are involved in many processes related to depression. Evaluations of serum and plasma Ca and Mg levels in depressive disorders do not show consistent results. The few studies that examined their cerebrospinal fluid (CSF) levels tended to find no differences between depressed patients and controls. Because both hypercalcemia and hypomagnesemia are associated with depression, and as Mg may function as a Ca antagonist, it is suggested that the relationship between these cations could be different in depressed patients and controls. We examined CSF and serum Ca and Mg in acutely depressed patients diagnosed as having major depressive disorder or being in a depressive episode of bipolar disorder. Controls were subjects undergoing lumbar puncture as part of an evaluation for headache or suspected meningitis and found to demonstrate no physical or mental disorder. Serum and CSF Ca/Mg ratios were found to be elevated in the depressed patients compared with the controls. A retrospective analysis of previous trials assessing serum/plasma or CSF Ca and Mg does not seem to refute the findings of this study. We further discuss our findings in their relation to the acuteness of the depressive disorders.
Sensation Seeking and Affective Disorders: Characteristics in the Intensity Dependence of Acoustic Evoked Potentials
Authors: Brocke Burkhard , Beauducel André , John Regina , Debener Stefan , Heilemann Hubert
Published: April 2003

Augmenting/reducing of the evoked potential has been shown to be related to sensation seeking (SS) and specific clinical disorders. Buchsbaum demonstrated that patients with bipolar affective disorders (BAD) tend to be augmenters, as is the case with sensation seekers, and patients with unipolar affective disorders (UPD) tend to be reducers. In addition, he reported that prophylactic medication reduced the tendency to augment in bipolar patients. However, evidence for these relations is restricted to a few studies. This study explores whether Buchsbaum’s initial findings can be found in a naturalistic clinical setting. Acoustic evoked potentials were recorded for six levels of intensity (59, 71, 79, 88, 92, 96 dB SPL) from 24 healthy adults, 21 unipolar depressed patients, and 21 patients with BAD. Participants also completed personality questionnaires, especially the Sensation Seeking Scales Form V. Results revealed a positive correlation between SS and augmenting/reducing in healthy controls, thereby replicating earlier findings. Bipolar depressed patients showed larger P1/N1 slopes than healthy controls, when medication was statistically controlled. Unipolar depressed patients showed smaller P2 slopes, but only when medication was not controlled. Implications of these results for further research on augmenting/reducing and affective disorders and their relationship to SS are discussed.
(±)3,4-Methylenedioxymethamphetamine (‘Ecstasy’)-Induced Serotonin Neurotoxicity: Clinical Studies
Authors: McCann Una D. , Eligulashvili Victoria , Ricaurte George A.
Published: April 2003

(±)3,4-Methylenedioxymethamphetamine (MDMA, ‘Ecstasy’) is a brain serotonergic neurotoxin in experimental animals, including nonhuman primates. It is also an increasingly popular recreational drug of abuse, and doses of MDMA that are used recreationally overlap with those that produce serotonin (5-HT) neurotoxicity in animals. Studies in human MDMA users probing for evidence of brain serotonergic neurotoxicity indicate that some MDMA users may incur MDMA-related 5-HT neural injury and, possibly, functional sequelae. In particular, MDMA users have selective decrements in cerebrospinal fluid 5-hydroxyindoleacetic acid and brain 5-HT transporters, similar to nonhuman primates with documented MDMA-induced neurotoxicity. Functional abnormalities seen in MDMA users that may be related to 5- HT injury include cognitive deficits, altered sleep architecture, altered neuroendocrine function, altered behavioral responses to 5-HT selective drugs, and increased impulsivity. Additional studies in animals, as well as longitudinal and epidemiological studies in MDMA users, are required to confirm and extend the present data, and to determine whether MDMA users are at increased risk for developing neuropsychiatric illness as they age.
Hippocampal Perfusion and Pituitary-Adrenal Axis in Alzheimer’s Disease
Authors: Murialdo Giovanni , Nobili Fl avio , Rollero Alessandro , Gianelli Maria Vittoria , Copello Francesco , Rodriguez Guido , Polleri Alessandro
Published: April 2003

The hippocampus is involved in Alzheimer’s disease (AD) and regulates the hypothalamus-pituitary-adrenal axis (HPAA). Enhanced cortisol secretion has been reported in AD. Increased cortisol levels affect hippocampal neuron survival and potentiate β-amyloid toxicity. Conversely, dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) are believed to antagonize noxious glucocorticoid effects and exert a neuroprotective activity. The present study was aimed at investigating possible correlations between hippocampus perfusion – evaluated by SPECT – and HPAA function in AD. Fourteen patients with AD and 12 healthy age-matched controls were studied by 99mTc-HMPAO high-resolution brain SPECT. Plasma adrenocorticotropin, cortisol, and DHEAS levels were determined at 2.00, 8.00, 14.00, 20.00 h in all subjects and their mean values were computed. Cortisol/DHEAS ratios (C/Dr) were also calculated. Bilateral impairment of SPECT hippocampal perfusion was observed in AD patients as compared to controls. Mean cortisol levels were significantly increased and DHEAS titers were lowered in patients with AD, as compared with controls. C/Dr was also significantly higher in patients. Using a stepwise procedure for dependent SPECT variables, the variance of hippocampal perfusional data was accounted for by mean basal DHEAS levels. Moreover, hippocampal SPECT data correlated directly with mean DHEAS levels, and inversely with C/Dr. These data show a relationship between hippocampal perfusion and HPAA function in AD. Decreased DHEAS, rather than enhanced cortisol levels, appears to be correlated with changes of hippocampal perfusion in dementia.
Relationship of N-Acetyl-β- Glucosaminidase Levels to Seriousness of Suicide Attempts
Authors: Garvey Michael J. , Underwood Kara
Published: April 2003

We hypothesized that levels of N-acetyl-β-glucosaminidase (NAG) would differ between patients making serious versus nonserious suicide attempts. The levels of NAG from 11 patients hospitalized for serious suicide attempts were compared to 5 patients whose suicide attempts were not rated serious. There was a significant difference in the mean NAG levels of the serious suicide attempters and the nonserious attempters (23 versus 52; p = 0.01). NAG may be a marker for a biological variable that is associated with the seriousness of a suicide attempt.
Choroidal Schwannoma: Immunohistochemical and Electron-Microscopic Study
Authors: Matsuo Toshihiko , Notohara Kenji
Published: April 2003

Schwannoma (neurilemoma) arising from the ciliary body and choroid is a rare form of intraocular tumor and usually misdiagnosed clinically as amelanotic melanoma. This case report describes a 73-year-old woman who developed a large nonpigmented intraocular tumor of the choroid in the left eye and underwent enucleation with a clinical diagnosis of malignant melanoma. The tumor consisted of spindle-shaped cells with an indefinite cytoplasm and twisted nuclei, which had positive immunoreactivity for S-100 protein, vimentin, glial fibrillary acidic protein and neural cell adhesion molecule. A continuous basal lamina encompassing the tumor cells was demonstrated by immunostaining for laminin and type IV collagen. Ultrastructurally, tumor cells with scant organelles had delicate cytoplasmic processes apposing each other, all indicative of Schwann cell origin. In reexamination of fluorescein angiograms, ultrasonograms and magnetic resonance images, no findings were incompatible with a diagnosis of choroidal melanoma. Histopathological studies showed that the tumor was a schwannoma. At present, we do not have a benchmark for the clinical diagnosis of intraocular schwannoma.
Staphylococcus aureus Exotoxin Has Limited and Transient Effects on Cochlear Electrophysiology
Authors: Hsu Wey-Jim , Anniko Matti , Kubo Takeshi , Lundholm Monica , Huang Tsun-Sheng
Published: April 2003

Seven ears of Sprague-Dawley rats were exposed to 20 µl Staphylococcus aureus exotoxin suspension by injection via the tympanic membrane into the round window niche. Another 6 ears were exposed to 20 µl broth as controls. ABR was performed in the interval 2–31.5 kHz immediately before and 1, 2, 5, 7 and 10 days after the exposure. Although threshold changes could be found in the toxin-exposed group but not the control group in the frequency range 10–20 kHz, there were only statistically significant threshold changes – at 31.5 kHz – on the 1st, 2nd, 5th, and 7th days after the exotoxin injection. S. aureus exotoxin has minor transient but reversible effects on the inner ear, causing chiefly high-frequency threshold and latency changes.
Optic Neuropathy Caused by an Isolated Mucocele in an Onodi Cell
Authors: Ogata Yoichi , Okinaka Yoshihiko , Takahashi Masahiro
Published: April 2003

A rare case of retrobulbar optic neuropathy caused by an isolated mucocele in an Onodi cell is presented. A 63-year-old man suffering from left recurrent optic neuropathy had shown improved visual acuity with steroid treatment at the age of 48 and 56 years. Impaired visual acuity and blurred vision in the left eye appeared again, and a marked inferior decrease in the left visual field was noted. Although axial computed tomography (CT) showed no abnormal findings, magnetic resonance imaging (MRI) revealed a small squamous-shaped lesion (17 × 17 × 7.3 mm) in the left posterior ethmoidal air cell (Onodi cell) hanging over the left optic nerve. Endoscopic sinus surgery was performed. The optic canal was extruding into the Onodi cell cavity, and the superior bony wall of the canal was eroded by the mucocele. The isolated mucocele in the Onodi cell seemed to be compressing the optic nerve downward and causing retrobulbar optic neuropathy. An Onodi cell lesion, even if it was isolated and small, would cause optic neuropathy. MRI and coronal CT scanning should be performed for the diagnosis and preoperative planning in a case of retrobulbar optic neuropathy.
Nasal Mucosal Swelling and Reactivity during a Menstrual Cycle
Authors: Haeggström A. , Östberg B. , Stjerna P. , Graf P. , Hallén H.
Published: April 2003

Introduction: Nasal stuffness is a great problem for many women in the later part of pregnancy. Objective: This study was performed to evaluate whether oestrogen causes nasal congestion and/or a hyperreactive reaction of the nasal mucosa. Material and Methods: Ten healthy fertile women were examined during menstruation. Nasal mucosal congestion was studied with rhinostereometry and acoustic rhinometry. The nasal mucosa was challenged with 3 doses of histamine solution to study nasal reactivity. Measurements were made 3 times during menstruation. To find the exact time of ovulation, when oestrogen reaches its peak value, intravaginal ultrasound tests were done and blood samples taken, to determine the oestrogen and progesterone levels. Results: The nasal mucosa became hyperreactive to histamine in connection with ovulation, when the blood level of oestrogen reached its peak. This does not occur during the menstrual or the luteal phase. No significant alteration was found in the baseline position during the menstruation. Conclusion: There is a connection between high oestrogen level and nasal mucosal reactivity.
Histiocytosis X or Langerhans’ Cell Histiocytosis – Evaluation, Treatment and Prognosis
Authors: Haas I. , Donner A.
Published: April 2003

Objectives: The pathology and the extreme clinical varieties of this disease with emphasis on head and neck manifestations are discussed. Material: A case of Langerhans’ cell histiocytosis (LCH) with extensive destruction of temporal bones is presented. Results and Conclusions: LCH or histiocytosis X embraces a group of rare, mainly pediatric disorders of disputable nature. Granulomatous lesions can be detected in one (unifocal) or multiple organs or tissues (multifocal) with extreme clinical variety from self-healing monostotic lesions to multisystemic life-threatening disease. Lesions typically consist of dendritic antigen-presenting Langerhans’ cells, eosinophilic granulocytes, lymphocytes, ordinary histiocytes, foam cells and multinucleated giant cells. No histopathologic criteria exist in regard to prognosis. Unpredictable behavior of LCH also defies a convenient clinical classification, but number of lesions, vital organ involvement and dysfunction seem to be prognostically and thus therapeutically relevant. Although proof of monoclonality indicates a true neoplastic process, no prognostic use results so far since clonality has been detected in all forms of LCH.
Contact Tolerance
Authors: Steinbrink K. , Pior J. , Vogl T. , Sorg C. , Macher E.
Published: April 2003

Contact tolerance describes an immunological state which is caused by ordinary contact allergens painted in doses too low to sensitize, either once or repeatedly, onto healthy intact skin. The tolerance state accomplished by this means in BALB/c and C57BI/6 mice was found to be mediated by hapten-specific T cells that adoptively transferred tolerance to naive recipients. Furthermore, these cells were shown to be sensitive to cyclophosphamide, to express the Lyt2+ (CD8) phenotype, and to produce, upon restimulation in vitro, predominantly anti-inflammatory cytokines such as IL-4, IL-5 and IL-10. These data indicate that contact tolerance of the low zone type is actively mediated by Th2-like CD8 T cells rather than arising as a consequence of clonal anergy. The induction of contact tolerance appeared to be strictly dose-dependent. As opposed to sensitizing doses of allergen, subsensitizing doses did not involve epidermal Langerhans cells discernibly. This was suggested by their normal ultrastructure, their unaffected adenosine triphosphatase system, the inefficacy of functional blocking and excision experiments. Both radiolabeled and fluorescent contact sensitizers were observed to readily enter the bloodstream, thereby being dispersed throughout the body. Presumably, contact tolerance is induced systemically rather than locally. The presence of hapten-specific tolerance can only be uncovered through a subsequent attempt to sensitize. If the attained sensitization turns out to be significantly lower than that of immunologically naive controls, and if sensitization to chemically unrelated sensitizers is not impaired, hapten-specific tolerance does exist. Thus, contact tolerance is a result obtained from experimental sensitization in animals. Nonetheless, it is assumed to occur also in humans, although it is not demonstrable unless different proofs of existence become available.
The Scavenger Receptor CD163: Regulation, Promoter Structure and Genomic Organization
Authors: Ritter M. , Buechler C. , Langmann T. , Orso E. , Klucken J. , Schmitz G.
Published: April 2003

CD163 is a recently identified member of the scavenger receptor cysteine-rich superfamily expressed on peripheral blood monocytes and most tissue macrophages. We demonstrate that in vitro culture of human blood monocytes with recombinant M-CSF induces CD163 transcription. In contrast, dendritic differentiation in the presence of GM-CSF and IL-4 suppresses CD163 mRNA and protein levels. Because an important function of CD163 in inflammation has been suggested, we investigated the influence of pro- and anti-inflammatory stimuli on CD163 expression and found a significant suppression by lipoposaccharide and IFN-γ, whereas IL-10 or dexamethasone strongly induced the expression of CD163. The induction of CD163 mRNA by dexamethasone is suggested to be mediated by several glucocorticoid receptor binding sites located in the proximal promoter region. In addition, this sequence contains potential binding sites for the transcription factors Sp1, C/EBPα, Ets-2, PU.1 and AP-1, which have been shown to play an important role in myeloid-specific gene expression. We also identified an L1-transposable element 1.4 kb upstream of the transcription start site that might influence the promoter activity. The function of CD163 may also depend on the use of different isoforms. Several variants of CD163 mRNA have been described that encode proteins with altered cytoplasmic or extracellular domains and thus may differ in their functional properties. We analyzed the genomic organization of the CD163 gene and could demonstrate that these isoforms result from alternative splicing. Further characterization of the isoforms may help to understand the complete function of CD163.
The Regulatory Role of the Antigen-Presenting Cell in the Development of Hepatic Immunopathology during Infection with Schistosoma mansoni
Authors: Stadecker Miguel J.
Published: April 2003

A recent meeting held in Berlin (2nd Teupitz Colloquium) focused on the striking ability of mononuclear phagocytes to either stimulate or inhibit a variety of immune and immunopathological responses, and ascribed a distinctive phenotype to the antigen-presenting cells (APC) when exercising these opposite functions. Thus, the phenotype and secretory profile of APC associated with ‘classical activation’ is achieved following stimulation with pro-inflammatory cytokines such as interferon-γ, and leads to full T cell activation. On the other hand, it has long been known that T cells may also be downregulated after interacting with certain APC. Many of such APC, originally simply thought to lack or have lost their stimulatory potential, are now thought to be in a state of ‘alternative activation’, which is associated with a different phenotype and secretory profile that can typically be induced with anti-inflammatory reagents, including the cytokines IL-4, IL-10 and IL-13. The purpose of this article is to analyze the immunopathological events that characterize the infection with Schistosoma mansoni in context with these distinct APC activation pathways. Available evidence from human and experimental data suggests that a desirable outcome of the APC during this parasitic disease is to attain ‘alternative activation’, which serves to promote and sustain a Th-2-polarized immune response associated with a more favorable anti-inflammatory and host-protective environment.
Tumor Necrosis Factor Receptor 2 Plays a Minor Role for Mycobacterial Immunity
Authors: Jacobs Muazzam , Brown Najimeeah , Allie Nasiema , Chetty Kamsellin , Ryffel Bernhard
Published: April 2003

Tumor necrosis factor (TNF) signalling via the TNF receptor 1 (TNF-R1) is required for host resistance to mycobacterial infection. The role of TNF-R2 in anti-mycobacterial immunity is not known. Therefore, we compared TNF-R1 and TNF-R2 knockout (KO) mice infected with Mycobacterium bovis BCG (107 CFU, i.v.). While the bacterial burden of TNF-R1-deficient mice was significantly increased and the mice succumbed to infection between 4 and 5 weeks, TNF-R2 KO mice were less sensitive, and only 3 of 10 mice died within 12 weeks. Wild-type (WT) mice were resistant to BCG infection. The inability to clear the infection of TNF-R1 KO mice was associated with a reduced delayed-type hypersensitivity (DTH) response to purified protein derivative and severe impairment in forming granulomas with reduced macrophage recruitment and activation, and diminished expression of adhesion molecules. By contrast, TNF-R2 KO mice developed normal DTH response and mature mycobactericidal granulomas as the WT mice. Therefore, anti-mycobacterial immunity is largely dependent on TNF signalling via the TNF-R1, while activation of TNF-R2 plays a minor role.
An Antigen Reacting with Das-1 Monoclonal Antibody Is Ontogenically Regulated in Diverse Organs Including Liver and Indicates Sharing of Developmental Mechanisms Among Cell Lineages
Authors: Badve Sunil , Lôgdberg Lennart , Sokhi Rana , Sigal Samuel H. , Botros Nashed , Chae Scott , Das Kiron M. , Gupta Sanjeev
Published: April 2003

The monoclonal antibody designated mAb Das-1, which was generated against a colon epithelial protein, reacts with the normal biliary epithelium and keratinocytes, which are among targets of tissue injury in ulcerative colitis. Moreover, mAb Das-1 reacts with abnormal cells in Barrett’s esophagus and chronic cystitis profunda, as well as so-called ‘oval cells’ in the adult liver, which are considered oncogenic progenitor cells. To establish ontogenic regulation of mAb Das-1 reactivity, we studied 7- to 24-week-old human fetuses by immunohistochemistry. In liver, mAb Das-1 reactivity was further correlated with glycogen, dipeptidyl peptidase IV, glucose-6-phosphatase and γ-glutamyl transpeptidase expression. mAb Das-1 reacted with cells in organs arising from the pharyngeal cleft (thymus), primitive gut (oral cavity, pharynx, lung, esophagus, stomach, biliary tree, pancreas, liver, colon), ureteric bud (renal tubules, collecting duct), mesonephros (kidney, testis), mesoderm (muscle) and elsewhere (skin, adrenal cortex). In distinction from the adult liver, mAb Das-1 staining was more pronounced in hepatoblasts compared with biliary cells. In adult tissues, however, mAb Das-1 reactivity was restricted to the colon, biliary epithelium, keratinocytes, and ciliary body. These data indicated that the mAb Das-1 recognized epitopes in fetal cells of diverse ectodermal, mesodermal and endodermal origin, compatible with sharing of lineage mechanisms in tissues. Reactivation of mAb Das-1 staining in epithelial precancerous conditions, including carcinomas arising in these organs, is compatible with oncofetal regulation of the antigen, which will facilitate analysis of cell subpopulations during organ development, regeneration and oncogenesis.