Acute tryptophan depletion decreases intensity dependence of auditory evoked magnetic N1/P2 dipole source activity

Abstract Rationale. Intensity dependence of the N1/P2 components may be regulated by serotonergic neurons in the primary auditory cortex, where low activity leads to a high intensity dependence and vice versa. Depletion of tryptophan (TRP), a precursor for serotonin has been described to reduce serotonin content in brain of animals and humans. Objective. We investigated the intensity dependence of magnetic and electric N1/P2 components in ten subjects in a double-blind, controlled, cross-over design study after oral mixture of amino-acids leading to acute tryptophan depletion (ATD) and control. Methods. Auditory evoked magnetic fields (AEF) and potentials (AEP) were recorded with 122-channel magnetoencephalography simultaneously with 64-channel EEG 5 h after ingestion of mixtures. The AEF sources and strength were estimated by a least-squares fit of a single equivalent current dipole. The amplitudes and latencies of N1 and P2 recorded with EEG were analyzed at frontal electrode site. Results. TRP depletion decreased the total and free TRP levels by 76 and 45% and control mixture increased it by 48 and 28%. ANOVA showed that ATD had a significant main effect on the N1m/P2m dipole moments at the contralateral (P=0.02), but failed significantly to influence the ipsilateral responses. A significant mixture ingestion-by-stimulus intensity interaction was observed on the N1m/P2m dipole moments at the contralateral hemisphere (P=0.01). The N1/P2 slope for intensity dependence function was decreased following ATD compared with the control experiment (P=0.01) at the contralateral hemisphere. For EEG, a significant mixture ingestion-by-stimulus intensity interaction on the N1 latencies at the Fz electrode position was observed (P=0.01). Conclusion. ATD decreased the intensity dependence of N1m/P2m source dipole moments in the primary auditory cortex at the hemisphere contralateral to the ear stimulated. These results suggest that serotonin participates in the regulation of intensity of auditory stimulation. Electronic Publication     

Maleimide is a potent inhibitor of topoisomerase II in vitro and in vivo: a new mode of catalytic inhibition

Maleimide, N-ethyl-maleimide (NEM), and N-methyl-maleimide (NMM) were identified as potent catalytic inhibitors of purified human topoisomerase IIalpha, whereas the ring-saturated analog succinimide was completely inactive. Catalytic inhibition was not abrogated by topoisomerase II mutations that totally abolish the effect of bisdioxopiperazine compounds on catalytic inhibition, suggesting a different mode of action by these maleimides. Furthermore, in DNA cleavage assay maleimide and NEM could antagonize etoposide-induced DNA double-strand breaks. Consistently, maleimide could antagonize the effect of topoisomerase II poisons in three different in vivo assays: 1) In an alkaline elution assay maleimide protected against etoposide-induced DNA damage. 2) In a band depletion assay maleimide reduced etoposide-induced trapping of topoisomerase IIalpha and beta on DNA. 3) In a clonogenic assay maleimide antagonized the cytotoxicity of etoposide and daunorubicin on four different cell lines of human and murine origin. at-MDR cell lines with reduced nuclear topoisomerase IIalpha content are fully sensitive to maleimide, indicating that it is not a topoisomerase II poison in vivo. Our finding that topoisomerase II is sensitive to maleimide, NMM, and NEM but insensitive to succinimide demonstrates a strict requirement for the unsaturated ring bond for activity. We suggest that the observed antagonism in vitro and in vivo is caused by covalent modification of topoisomerase II cysteine residues reducing the amount of catalytically active enzyme sensitive to the action of topoisomerase II poisons.     

Salivary carbonic anhydrase VI and its relation to salivary flow rate and buffer capacity in pregnant and non-pregnant women

OBJECTIVE: Previous studies have shown that pregnancy may have unfavourable effects on oral health. The pH and buffer capacity (BC) of paraffin-stimulated saliva, for example, have been found to decrease towards late pregnancy. Salivary carbonic anhydrase VI (CA VI) probably protects the teeth by accelerating the neutralization of hydrogen ions in the enamel pellicle on dental surfaces. Since estrogens and androgens are known to regulate CA expression in some tissues, we studied here whether salivary CA VI concentration shows pregnancy-related changes. DESIGN: Paraffin-stimulated salivary samples were collected from nine pregnant women 1 month before delivery and about 2 months afterwards and assayed for salivary CA VI concentration, BC and flow rate. The enzyme concentration was determined using a specific time-resolved immunofluorometric assay. The control group consisted of 17 healthy non-pregnant women. RESULTS: The results indicated that salivary CA VI levels varied markedly among individuals, but no significant differences in mean concentrations were seen between the samples collected during late pregnancy and postpartum. BC values were lower during pregnancy, however. CONCLUSIONS: Our findings suggest that CA VI secretion is not significantly affected by the hormonal alterations associated with pregnancy, and confirm the earlier reports that CA VI is not involved in the regulation of actual salivary BC.     

Individually fitted sports shoes for overuse injuries among newspaper carriers

OBJECTIVES: The aim of the study was to determine the effectiveness of new, individually fitted sports shoes against overuse injuries to the lower limb among newspaper carriers. METHODS: Patients (N = 176) with lower-limb overuse injuries were randomly assigned to use new, individually adjusted footwear with good shock absorbing properties (test group = 86) or the subjects' own, used footwear (control group = 90). The main outcome measurements were lower-limb pain intensity during walking, as rated on a visual analogue scale (0-100), number of painful days, subjective assessment of global improvement, foot fatigue, number of hyperkeratotic skin lesions and diagnosed overuse injuries, and costs of foot care as compared between the treatment groups. RESULTS: At the 6-month follow-up there was a difference in favor of the test group with respect to lower-limb pain intensity and number of painful days, when compared with the control group. At 1 year, 53% and 33% of the test and control groups, respectively, thought they were better than at the time of the baseline examination (number needed to treat being 5 between the test and control groups). The test subjects had less foot fatigue and fewer hyperkeratotic skin lesions. There was no difference in the number of diagnosed overuse injuries between the groups. During the year of follow-up, the all-inclusive mean costs of foot care were USD 70 and USD 158 in the test and control groups, respectively. CONCLUSIONS: Individually adjusted shock-absorbing shoes offer slight health benefits for lower-limb overuse injuries. Proper shoes may decrease the need to use health care resources.     

The combination of HSV-tk and endostatin gene therapy eradicates orthotopic human renal cell carcinomas in nude mice

BACKGROUND AND METHODS: Gene therapy may offer a new tool for the treatment of renal cell carcinoma (RCC). We have tested a combination of cytotoxic and antiangiogenic gene therapy for wild-type orthotopic human RCC xenografts in nude mice using intratumoral adenovirus-mediated herpes simplex virus thymidine kinase (HSV-tk) and endostatin (ES) gene therapy. In vivo magnetic resonance imaging, morphometry, immunocytochemistry, and survival were used to evaluate the treatment effect. Adenovirus-mediated marker gene transfers (GFP) were used as controls. Results: In vivo transduction efficiency, measured using GFP gene transfer, was 27+/-7%. The combination gene therapy with HSV-tk and ES adenoviruses resulted in a significant antitumor effect (P<.01) compared to single HSV-tk (n.s.) or ES (n.s.). In the survival study, all tumors with single gene therapy using HSV-tk, ES, and marker gene adenoviruses showed progression in magnetic resonance imaging. In contrast, the majority of the tumors in the combination treatment group remained dormant or were eradicated (57%). Survival of these mice equaled healthy nude mice, and was significantly prolonged (P<.0001) compared to HSV-tk (P<.028) and ES (n.s.) groups. Conclusions: It is concluded that the inhibition of angiogenesis using ES gene transfer together with the cytotoxic HSV-tk gene therapy results in a significantly improved treatment effect in RCC compared to the single gene treatments.     

Dense innervation in pseudocapsular tissue compared to aneural interface tissue in loose totally replaced hips

BACKGROUND: The function of many inflammatory cells is in part regulated by neuronal cells, which may lead to so-called neurogenic inflammation. Sensory nerves also mediate the pain sensation. METHODS: This immunohistochemical study focused on visualization of C-sensory and sympathetic innervation in the synovial membrane-like interface and pseudocapsular tissue around loosened total hip replacement. RESULTS: The synovial membrane-like interface did not contain C-sensory peptidergic or sympathetic neural structures. Only limited attempts to neural regeneration were detected. In contrast, pseudocapsule expressed dense innervation with strong CPON-ir sympathetic innervation and osteoarthritis also had C-sensory fibers. Intense neural regeneration was seen in these synovial membranes. Surprisingly, stellate and/or highly dendritic fibroblast-like cells in the fibrotic areas in the interface tissue expressed strong immunoreactivity to the neural marker PGP 9.5, ubiquitin carboxyterminal hydrolase. CONCLUSION: Pain related to aseptic loosening cannot arise in the aneural interface membrane. Inflammation in interface/aseptic loosening seems to be driven by non-neurogenic factors, such as foreign bodies and micromovement. Insufficient lysosomal degradation of denatured proteins causes accumulation of ubiquitinated conjugates and enzymes involved in the process. This leads to insufficient degradation of platelet derived growth factor (PDGF)-receptor complex and can contribute to the accumulation of connective tissue in the interface. Failure in ubiquitin mediated proteolysis might support overgrowth of interface tissue and aseptic loosening.     

Genes involved in atherosclerosis

Atherosclerosis is a multifactorial disease that involves several genes and proteins. The purpose of this article is to focus on the arterial wall and to review lipoprotein receptors, growth factors, cytokines, chemokines, matrix metalloproteinases, adhesion molecules, and apoptosis genes and their involvement in atherogenesis.     

Radioimmunodetection and Radioimmunotherapy of Malignant Melanoma: A Review

Radioimmunodetection utilizing monoclonal antibodies to various melanoma-associated surface antigens has been studied by several investigators during the past ten years. In the early trials, antibodies were labeled with ¹³¹I or ¹¹¹In, but now ^99mTc is almost exclusively used because of its more favorable energy for gamma camera imaging. Excellent specificity has been achieved in most studies, whereas sensitivity has been less good. In a recent European multicenter study on 493 patients sensitivity was 79% and specificity 96%. In this largest study on melanoma so far performed many previously unknown metastatic deposits were identified indicating that radioimmunodetection has a role in the management of metastatic disease. The clinical utility of immunoscintigraphy in localization of regional lymph node metastases has been documented in several investigations in recent years, indicating that this method can be used in the preoperative evaluation of patients. Radioimmunodetection has also been successfully used in the differential diagnosis of ocular lesions. However, conclusive evidence of improved patient outcome resulting from the earlier detection of melanoma lesions by immunoscintigraphy is still lacking. Anti-melanoma antibodies labeled with alpha- and beta-emitting isotopes are potential therapeutic agents, but so far there is little clinical experience with radio-immunotherapy of metastatic melanoma.