Neuronal activity and stress differentially regulate hippocampal and hypothalamic corticotropin-releasing hormone expression in the immature rat.
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Corticotropin-releasing hormone, a major neuromodulator of the neuroendocrine stress response, is expressed in the immature hippocampus, where it enhances glutamate receptor-mediated excitation of principal cells. Since the peptide influences hippocampal synaptic efficacy, its secretion from peptidergic interneuronal terminals may augment hippocampal-mediated functions such as learning and memory. However, whereas information regarding the regulation of corticotropin-releasing hormone's abundance in CNS regions involved with the neuroendocrine responses to stress has been forthcoming, the mechanisms regulating the peptide's levels in the hippocampus have not yet been determined. Here we tested the hypothesis that, in the immature rat hippocampus, neuronal stimulation, rather than neuroendocrine challenge, influences the peptide's expression. Messenger RNA levels of corticotropin-releasing hormone in hippocampal CA1, CA3 and the dentate gyrus, as well as in the hypothalamic paraventricular nucleus, were determined after cold, a physiological challenge that activates the hypothalamic pituitary adrenal system in immature rats, and after activation of hippocampal neurons by hyperthermia. These studies demonstrated that, while cold challenge enhanced corticotropin-releasing hormone messenger RNA levels in the hypothalamus, hippocampal expression of this neuropeptide was unchanged. Secondly, hyperthermia stimulated expression of hippocampal immediate-early genes, as well as of corticotropin-releasing hormone. Finally, the mechanism of hippocampal corticotropin-releasing hormone induction required neuronal stimulation and was abolished by barbiturate administration. Taken together, these results indicate that neuronal stimulation may regulate hippocampal corticotropin-releasing hormone expression in the immature rat, whereas the peptide's expression in the hypothalamus is influenced by neuroendocrine challenges. (+info)
Characterization of heat shock protein 110 and glucose-regulated protein 170 as cancer vaccines and the effect of fever-range hyperthermia on vaccine activity.
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Several studies have confirmed that certain stress proteins can function as potent vaccines against a specific cancer when purified from the same tumor. Recent studies of two long-recognized but unstudied stress proteins, heat shock protein (hsp) 110 and glucose-regulated protein (grp) 170, have shown them to be efficient peptide chain-binding proteins. The present investigation examines the vaccine potential of hsp110 and grp170. First, it is shown that prior vaccination with hsp110 or grp170 purified from methylcholanthrene-induced fibrosarcoma caused complete regression of the tumor. In a second tumor model, hsp110 or grp170 purified from Colon 26 tumors led to a significant growth inhibition of this tumor. In addition, hsp110 or grp170 immunization significantly extended the life span of Colon 26 tumor-bearing mice when applied after tumor transplantation. A tumor-specific cytotoxic T lymphocyte response developed in the mice immunized with tumor-derived hsp110 or grp170. Furthermore, treatments of the mice with bone marrow-derived dendritic cells pulsed with these two proteins from tumor also elicited a strong antitumor response. Last, we showed that mild, fever-like hyperthermic conditions enhance the vaccine efficiency of hsp110 as well as heat shock cognate 70, but not grp170. These studies indicate that hsp110 and grp170 can be used in hsp-based cancer immunotherapy, that Ag-presenting dendritic cells can be used to mediate this therapeutic approach, and that fever-level hyperthermia can significantly enhance the vaccine efficiency of hsps. (+info)
Regulatory effects of fever-range whole-body hyperthermia on the LPS-induced acute inflammatory response.
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The thermal component of fever is one of the most poorly understood aspects of inflammation. To evaluate the role of fever-range hyperthermia on acute inflammation, BALB/c and C57BL/6 mice were exposed to mild, long-duration whole-body hyperthermia (WBH), and serum concentrations of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), IL-1beta, and the acute phase proteins (APPs) alpha1-acid glycoprotein and haptoglobin were analyzed. WBH alone did not affect serum concentrations of these cytokines or APPs when compared with controls. In contrast, when WBH was applied just after intraperitoneal administration of lipopolysaccharide (LPS), serum concentrations of TNF-alpha and IL-6 were greater than or equal to threefold higher in BALB/c mice compared with LPS-treated controls. LPS-induced IL-6 levels were also enhanced in WBH-treated C57BL/6 mice. However, APP levels were prolonged only in WBH-treated BALB/c mice. It is interesting that in vitro hyperthermia treatment of LPS-stimulated peritoneal cells resulted in decreased cytokine production compared with controls. These results suggest that fever-range hyperthermia regulates acute inflammation in a mouse strain-specific manner that is more complex than that observed in vitro. (+info)
Laparoscopic myolysis.
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This review will focus on the different techniques and the long-term effects of the technique called myolysis on myoma growth. Indications for myolysis are essentially pelvic pain, compression symptoms and global uterine volume in order to avoid hysterectomy. In the late 1980s, myolysis was performed laparoscopically with the help of the neodynium: yttrium aluminium garnet (Nd:YAG) laser. Later, bipolar needles were developed as an alternative to the Nd:YAG laser. Diathermy and cryomyolysis were also proposed but series are small in the literature. Very recently, myoma interstitial thermo-therapy (MITT) was performed using the diode laser and a specific optical light diffuser that is designed to transmit laser light in all directions. Laparoscopic myolysis was proved to be effective in provoking myoma shrinkage, with a dramatic decrease in size and a marked devascularization of the myoma and this technique can be proposed as an alternative to myomectomy in selected patients: only those aged >40 years or those not desiring to bear any more children. (+info)
Pharmacokinetics of tissue plasminogen activator in an isolated extracorporeal circuit.
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PURPOSE: The aim of this study was to investigate the pharmacokinetics of tissue plasminogen activator (tPA) under the conditions of an isolated extracorporeal circuit. METHODS: Plasma levels of tPA were measured in the perfusion solution and in central venous blood before, during, and after the perfusion in seven patients undergoing regional hyperthermic fibrinolytic perfusion with tPA in addition to surgical thrombectomy for extended deep venous thrombosis. RESULTS: After 15 minutes of fibrinolytic perfusion, the level of tPA in the perfusion solution was 10,427 +/- 4432 ng/mL, and after 30 minutes the maximum level of 19,726 +/- 5630 ng/mL was reached. After 60 minutes when the perfusion was discontinued, tPA concentrations dropped to 15,931 +/- 4818 ng/mL. In central venous blood, tPA levels increased to a maximum of 230.7 +/- 89.6 ng/mL after 60 minutes of perfusion, which represented 1.4% of the concentration measured in the perfusion solution at the same time. With disconnection of the extracorporeal circuit, the tPA levels in central venous blood decreased rapidly and reached a level of 24.1 +/- 8.7 ng/mL after 120 minutes. CONCLUSION: The use of regional hyperthermic fibrinolytic perfusion in the treatment of extended deep venous thrombosis makes it possible to achieve extremely high concentrations of tPA in the perfusion solution. At the same time, the entry of the fibrinolytic agent into the systemic circulation is minimized. (+info)
Transpupillary thermotherapy (TTT) for the treatment of choroidal neovascularisation.
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AIM: To assess the effectiveness of transpupillary thermotherapy (TTT) for the treatment of classic and occult choroidal neovascularisation (CNV). METHOD: In a retrospective, case selected, open label trial 44 eyes of 42 patients with CNV secondary to age related macular degeneration (ARMD) were studied. 44 eyes with angiographically defined CNV were treated with diode laser (810 nm) TTT. Laser beam sizes ranged between 0.8 and 3.0 mm and power settings between 250-750 mW. Treatment was given in one area for 1 minute, the end point being no visible change, or a slight greying of the retina. Outcome was assessed with Snellen visual acuity and clinical examination; in 24/44 patients angiographic follow up was available. RESULTS: 12 predominantly classic CNV and 32 predominantly occult membranes were followed up for a mean of 6.1 months (range 2-19). Mean change in vision for classic membranes was -0.75 (SD 1.75) Snellen lines and occult membranes was -0.66 Snellen lines (2.1) (p>0.05). Predominantly classic membranes were closed in 75% (95% CI: 62.5-87.5) of eyes, remained persistent in 25% (95% CI: 12.5-37.5); no recurrences occurred. Predominantly occult membranes were closed in 78% (95% CI: 70.1-85.3) of eyes, remained persistent in 12.5% (95% CI: 6.6-18.5), and were recurrent in 5.1% (95% CI: 4.2-14.3). CONCLUSIONS: Transpupillary thermotherapy is a potential treatment for CNV. It is able to close choroidal neovascularisation while maintaining visual function in patients with classic and occult disease. Further trials of TTT are needed to compare this intervention with the natural history and other treatment modalities. (+info)
Protoporphyrin IX occurs naturally in colorectal cancers and their metastases.
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Colorectal cancers exhibit a red fluorescence. The nature of the responsible fluorophore and its eventual diagnostic potential were investigated. Thirty-three consecutive colorectal resection specimen, 32 of which with histologically confirmed cancer, and a total of 1053 palpable mesenteric nodes were fluorimetrically characterized ex vivo. Furthermore, frozen material from 28 patients was analyzed, selected for the availability of primary tumor material and metastatic tissue, e.g., lymphatic and liver metastases from the same patient. Biochemical characterization was carried out through chemical extraction and reversed phase high-performance liquid chromatography. The fluorescence spectra of tissues, tissue extracts, and standard solutions of porphyrins were determined using a pulsed solid-state laser system for excitation and an imaging polychromator, together with an intensified CCD camera for time-delayed observation. Protoporphyrin IX (PpIX) was identified as the predominant fluorophore in primary tumors and their metastases. The fluorophore occurred in the absence of necrosis and in sterile locations. In untreated cases (n = 24), PpIX fluorescence discriminates metastatically involved lymph nodes from all other palpable nodes with a sensitivity of 62% at a specificity of 78% (P < 0.0001). After neoadjuvant treatment of rectal cancer, the PpIX fluorescence level of the primary tumors was reduced and a discrimination of lymph nodes based on PpIX-fluorescence was impossible. We conclude that colorectal cancer metastases accumulate diagnostic levels of endogenous PpIX as a result of a tumor-specific metabolic alteration. (+info)
Heat-directed gene targeting of adenoviral vectors to tumor cells.
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Targeting therapeutic gene expression to tumor cells represents a major challenge for cancer gene therapy. The strong transcriptional response exhibited by heat shock genes, along with the beneficial therapeutic effects of hyperthermia have led us to develop a heat-directed gene-targeting strategy for cancer treatment. Heat shock gene expression is mediated in large part by the interaction of heat shock factor 1 with specific binding sites (heat shock elements; HSE) found in the promoters of heat-inducible genes. Here we present a quantitative analysis of heat-inducible gene expression mediated by the wild-type hsp70b gene promoter, as well as a modified hsp70b promoter containing additional HSE sequences. Beta-galactosidase (beta-gal) expression was induced between 50- and 800-fold in a panel of human breast cancer cell lines infected with an adenoviral vector containing the wild-type hsp70b promoter (Ad.70b.betag) following treatment at 43 degrees C for 30 minutes. Infection with an adenoviral vector containing the modified hsp70b promoter (Ad.HSE.70b.betag) resulted in a 200- to 950-fold increase in beta-gal expression under the same conditions, and also provided a 1-2 degrees C decrease in the threshold of activation. Significant increases in the heat responsiveness of the Ad.HSE.70b.betag construct were observed in five of six tumor cell lines tested, as well as under thermotolerant conditions. Finally, we demonstrate that localized heating of a HeLa cell xenograft can effectively target beta-gal gene expression following intratumoral injection of Ad.70b.betag. Adenoviral vectors incorporating heat-inducible therapeutic genes may provide useful adjuncts for clinical hyperthermia. (+info)