1: Bioelectromagnetics. 2005 Nov 10; [Epub ahead of print] Influence of strong static magnetic fields on primary cortical neurons. Prina-Mello A, Farrell E, Prendergast PJ, Campbell V, Coey JM. SFI Trinity Nanoscience Laboratory, Trinity College, Dublin, Ireland. Intense uniform magnetic fields, such as those used in magnetic resonance imaging (MRI), are thought to exert little influence at the cellular level. Here we report modifications of the signaling cascades in rat cortical neurons cultured for 1 h in magnetic fields of up to 5 Tesla. The activation of c-Jun N-terminal kinase (JNK) increases monotonically with field strength, with a maximal activation of approximately 10% at 5 T, whereas the activation of extra cellular-regulated kinase (ERK) shows a maximum at 0.75 T ( approximately 10%). Since ERK is involved in cellular differentiation, these results indicate a magnetic induction of the signaling events associated with differentiation. However, the cells respond to further increases in field strength by evoking a stress response, since JNK is a stress-activated protein kinase. Three possible mechanisms are discussed and of these, the most plausible is magnetic field induced change in the membrane rest potential, a microscale magnetohydrodynamic effect. This mechanism most likely involves the activation of voltage dependent Ca(2+) channel opening; since intracellular Ca(2+) concentration was also found to be modified by the static magnetic field. Bioelectromagnetics (c) 2005 Wiley-Liss, Inc. PMID: 16283651 [PubMed - as supplied by publisher] --------------------------------------------------------------- 2: Cell Signal. 2005 Aug;17(8):929-39. Epub 2005 Mar 3. IB1/JIP-1 controls JNK activation and increased during prostatic LNCaP cells neuroendocrine differentiation. Tawadros T, Martin D, Abderrahmani A, Leisinger HJ, Waeber G, Haefliger JA. Service of Urology, University Hospital, Lausanne, Switzerland. The scaffold protein Islet-Brain1/c-Jun amino-terminal kinase Interacting Protein-1 (IB1/JIP-1) is a modulator of the c-Jun N-terminal kinase (JNK) activity, which has been implicated in pleiotrophic cellular functions including cell differentiation, division, and death. In this study, we described the presence of IB1/JIP-1 in epithelium of the rat prostate as well as in the human prostatic LNCaP cells. We investigated the functional role of IB1/JIP-1 in LNCaP cells exposed to the proapoptotic agent N-(4-hydroxyphenyl)retinamide (4-HPR) which induced a reduction of IB1/JIP-1 content and a concomittant increase in JNK activity. Conversely, IB1/JIP-1 overexpression using a viral gene transfer prevented the JNK activation and the 4-HPR-induced apoptosis was blunted. In prostatic adenocarcinoma cells, the neuroendocrine (NE) phenotype acquisition is associated with tumor progression and androgen independence. During NE transdifferentiation of LNCaP cells, IB1/JIP-1 levels were increased. This regulated expression of IB1/JIP-1 is secondary to a loss of the neuronal transcriptional repressor neuron restrictive silencing factor (NRSF/REST) function which is known to repress IB1/JIP-1. Together, these results indicated that IB1/JIP-1 participates to the neuronal phenotype of the human LNCaP cells and is a regulator of JNK signaling pathway. PMID: 15894166 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 3: Ai Zheng. 2005 May;24(5):587-90. [Treating renal carcinoma with ablation or ablation combined with 125I seed implantation: a report of eleven cases] [Article in Chinese] Qi DF, Wu KJ, Li X, Zeng GH, Chen WZ. Microsurgery Center, The First Affiliated Hospital, Guangzhou Medical College, Guangzhou, Guangdong, 510230, P.R.China. qdf70818@tom.com BACKGROUND & OBJECTIVE: Recently, multi-needles radiofrequency ablation and brachyradiotherapy have been used to treat some solid tumors, such as liver cancer and prostate cancer. This study was to explore the feasibility and efficacy of radiofrequency ablation or ablation combined with 125I seed implantation on treating renal carcinoma. METHODS: From Jun. 2000 to Feb. 2004, 11 patients with a total of 13 renal carcinoma lesions were treated with ablation or ablation combined with (125)I seed implantation, including 6 cases of renal carcinoma of solitary kidney, 2 cases of renal carcinoma combined with contralateral renal atrophy resulted from ureteric stone, 1 case of bilateral tumor, and 2 cases with general conditions contraindicated to surgery. Of the 13 lesions, 1 was resected by open operation, 6 were treated with multi-needles radiofrequency ablation, and 6 were treated with ablation and simultaneous (125)I seed implantation around tumor margin. RESULTS: The patients were followed-up for 6-46 months (mean 27 months). One patient died of cardiac muscle infarction 4 months after operation. Of the 10 alive patients, 2 with recurrent tumors 7 months and 13 months after operation were treated with ablation again, 1 with postoperative uremia was treated with intermittent peritoneal dialysis, the rest 7 had normal renal function. CONCLUSION: Multi-needles radiofrequency ablation or ablation combined with (125)I seed implantation would be an option in the treatment for patients with renal carcinoma of solitary kidney or bilateral kidney lesions, or for patients can't suffer from surgery. PMID: 15890103 [PubMed - in process] --------------------------------------------------------------- 4: J Hum Hypertens. 2005 May;19(5):401-6. Brachial-ankle pulse wave velocity: an index of central arterial stiffness? Sugawara J, Hayashi K, Yokoi T, Cortez-Cooper MY, DeVan AE, Anton MA, Tanaka H. Institute for Human Science and Bioengineering, National Institute of Advanced Industrial Science and Technology, Tsukuba, Japan. jun.sugawara@aist.go.jp Brachial-ankle pulse wave velocity (baPWV) is a promising technique to assess arterial stiffness conveniently. However, it is not known whether baPWV is associated with well-established indices of central arterial stiffness. We determined the relation of baPWV with aortic (carotid-femoral) PWV, leg (femoral-ankle) PWV, and carotid augmentation index (AI) by using both cross-sectional and interventional approaches. First, we studied 409 healthy adults aged 18-76 years. baPWV correlated significantly with aortic PWV (r = 0.76), leg PWV (r = 0.76), and carotid AI (r = 0.52). A stepwise regression analysis revealed that aortic PWV was the primary independent correlate of baPWV, explaining 58% of the total variance in baPWV. Additional 23% of the variance was explained by leg PWV. Second, 13 sedentary healthy men were studied before and after a 16-week moderate aerobic exercise intervention (brisk walking to jogging; 30-45 min/day; 4-5 days/week). Reductions in aortic PWV observed with the exercise intervention were significantly and positively associated with the corresponding changes in baPWV (r = 0.74). A stepwise regression analysis revealed that changes in aortic PWV were the only independent correlate of changes in baPWV (beta = 0.74), explaining 55% of the total variance. These results suggest that baPWV may provide qualitatively similar information to those derived from central arterial stiffness although some portions of baPWV may be determined by peripheral arterial stiffness. Publication Types: Multicenter Study PMID: 15729378 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 5: J Biol Chem. 2005 Mar 11;280(10):9043-8. Epub 2005 Jan 6. PRAM-1 potentiates arsenic trioxide-induced JNK activation. Denis FM, Benecke A, Di Gioia Y, Touw IP, Cayre YE, Lutz PG. Hopital Robert Debre, INSERM U417, 48 Boulevard Serurier, F-75935 Paris, Cedex 19, France. The promyelocytic leukemia RARalpha target gene encoding an adaptor molecule-1 (PRAM-1) is involved in a signaling pathway induced by retinoic acid in acute promyelocytic leukemia (APL) cells. To better understand the function of PRAM-1, we have undertaken the identification of its partners through a yeast two-hybrid screen. Here, we show that the proline-rich domain of PRAM-1 interacted with the Src homology 3 (SH3) domain of hematopoietic progenitor kinase 1 (HPK-1)-interacting protein of 55 kDa (HIP-55, also called SH3P7 and Abp1) known to stimulate the activity of HPK-1 and c-Jun N-terminal kinase (JNK). Overexpression of PRAM-1 in the NB4 APL cell line increased arsenic trioxide-induced JNK activation through a caspase 3-like-dependent activity. Dissociation of the SH3 domain from the rest of the HIP-55 protein was observed in the NB4 APL cell line treated with arsenic trioxide due to specific cleavage by caspase 3-like enzymes. The cleavage of HIP-55 correlated with the induction of PRAM-1 mRNA and protein expression. Taken together, our results suggest that the caspase 3-cleaved SH3 domain of HIP-55 is likely involved in PRAM-1-mediated JNK activation upon arsenic trioxide-induced differentiation of NB4 cells. PMID: 15637062 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 6: Free Radic Biol Med. 2005 Jan 1;38(1):2-11. Kinase signaling cascades in the mitochondrion: a matter of life or death. Horbinski C, Chu CT. Division of Neuropathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. In addition to powering energy needs of the cell, mitochondria function as pivotal integrators of cell survival/death signals. In recent years, numerous studies indicate that each of the major kinase signaling pathways can be stimulated to target the mitochondrion. These include protein kinase A, protein kinase B/Akt, protein kinase C, extracellular signal-regulated protein kinase, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase. Although most studies focus on phosphorylation of pro- and antiapoptotic proteins (BAD, Bax, Bcl-2, Bcl-xL), kinase-mediated regulation of complex I activity, anion and cation channels, metabolic enzymes, and Mn-SOD mRNA has also been reported. Recent identification of a number of scaffold proteins (AKAP, PICK, Sab) that bring specific kinases to the cytoplasmic surface of mitochondria further emphasizes the importance of mitochondrial kinase signaling. Immunogold electron microscopy, subcellular fractionation and immunofluorescence studies demonstrate the presence of kinases within subcompartments of the mitochondrion, following diverse stimuli and in neurodegenerative diseases. Given the sensitivity of these signaling pathways to reactive oxygen and nitrogen species, in situ activation of mitochondrial kinases may represent a potent reverse-signaling mechanism for communication of mitochondrial status to the rest of the cell. Publication Types: Review PMID: 15589366 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 7: Int J Clin Oncol. 2004 Oct;9(5):383-7. The efficacy of long-term oral chemotherapy with 5'-deoxy-5-fluorouridine and cyclophosphamide for recurrent breast cancer. Iba T, Kidokoro A, Fukunaga M, Sugiyama K, Aihara N, Suda M. Department of Surgery, Juntendo University Urayasu Hospital, 2-1-1 Tomioka, Urayasu, Chiba 279-0021, Japan. iba-jun@umin.ac.jp BACKGROUND: 5'-Deoxy-5-fluorouridine (5'-DFUR) is a prodrug of 5-fluorouracil (5-FU), which is known to be converted by thymidine phosphorylase (dThdPase). A recent preclinical study revealed that cyclophosphamide (CPA) upregulated dThdPase activity, specifically in tumor cells. The purpose of the present study was to examine the efficacy of long-term administration of 5'-DFUR/CPA for patients with recurrent breast cancer. METHODS: Fifteen breast cancer patients with recurrent tumors entered this study. Ten patients had bone metastasis, five had lung metastasis, and two had liver metastasis. Three patients had multiorgan metastases. All patients had had previous exposure to standard chemotherapy such as CAF (CPA, doxorubicin, and 5-FU) and CMF (CPA, methotrexate, and 5-FU). The patients were orally administered with daily doses of 5'-DFUR at 800-1200 mg and CPA at 200 mg for 2 weeks as induction therapy, followed by 2 weeks' rest (one to two cycles). Daily doses of 800 mg of 5'-DFUR and 100 mg of CPA (as maintenance therapy) were continuously administered thereafter. Ten of the 15 patients received the maintenance therapy alone. The treatment was continued for at least 24 months (average, 35.2 months). RESULTS: The main findings included a significant decrease in pain in nine patients with bone metastasis, and this effect continued for more than 2 years. As the pain decreased, the patients' quality of life (QOL) was improved. Liver metastasis was diminished in two out of two patients. Hematological toxicity of more than grade 3 was recognized in three patients, but only during the induction therapy. CONCLUSION: Oral administration of 5'-DFUR/CPA is well tolerated and useful for patients with recurrent breast cancer. Publication Types: Clinical Trial PMID: 15549589 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 8: J Mol Cell Cardiol. 2004 Sep;37(3):705-15. Transgenic mice with cardiac-specific over-expression of MLK7 have increased mortality when exposed to chronic beta-adrenergic stimulation. Christe M, Jin N, Wang X, Gould KE, Iversen PW, Yu X, Lorenz JN, Kadambi V, Zuckerman SH, Bloem LJ. Cardiovascular Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Mixed lineage kinase 7 (MLK7) is a recently identified mitogen-activated protein kinase kinase kinase with enriched expression in skeletal muscle and heart. When over-expressed in cardiac myocytes, MLK7 activates both the p38 and c-Jun N-terminal kinase (JNK) stress-activated pathways and induces a cellular phenotype characteristic of cardiac hypertrophy, including a fetal gene expression pattern and increased protein synthesis. We sought to determine the effect of MLK7 on cardiac function in vivo by generating transgenic (Tg) mice with cardiac restricted over-expression of the enzyme. The mice were viable and demonstrated no visible signs of distress at rest. Microscopic examination of the hearts showed myocardial fibrosis and hypertrophy. Hemodynamic analysis of the Tg mice revealed impaired systolic function and significant diastolic dysfunction. Furthermore, significant mortality was observed in MLK7 Tg mice following 24-48 h of isoproterenol administration. Isoproterenol activation of JNK and p38, but not extracellular signal-regulated kinase, was significantly greater in the MLK7 Tg mice compared to littermate controls. These data indicate that MLK7 is an important signal transducer in cardiac compensation. Simultaneous activation of JNK and p38 by MLK7 may contribute to cardiac decompensation during the periods of acute cardiac stress. PMID: 15350844 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 9: Mol Cell Biol. 2004 Sep;24(18):8026-36. A targeting mutation of tyrosine 1062 in Ret causes a marked decrease of enteric neurons and renal hypoplasia. Jijiwa M, Fukuda T, Kawai K, Nakamura A, Kurokawa K, Murakumo Y, Ichihara M, Takahashi M. Department of Pathology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. The Ret receptor tyrosine kinase plays a crucial role in the development of the enteric nervous system and the kidney. Tyrosine 1062 in Ret represents a binding site for the phosphotyrosine-binding domains of several adaptor and effector proteins that are important for the activation of intracellular signaling pathways, such as the RAS/ERK, phosphatidylinositol 3-kinase/AKT, and Jun-associated N-terminal kinase pathways. To investigate the importance of tyrosine 1062 for organogenesis in vivo, knock-in mice in which tyrosine 1062 in Ret was replaced with phenylalanine were generated. Although homozygous knock-in mice were born normally, they died by day 27 after birth and showed growth retardation. The development of the enteric nervous system was severely impaired in homozygous mutant mice, about 40% of which lacked enteric neurons in the whole intestinal tract, as observed in Ret-deficient mice. The rest of the mutant mice developed enteric neurons in the intestine to various extents, although the size and number of ganglion cells were significantly reduced. Unlike Ret-deficient mice, a small kidney developed in all knock-in mice, accompanying a slight histological change. The reduction of kidney size was due to a decrease of ureteric bud branching during embryogenesis. Thus, these findings demonstrated that the signal via tyrosine 1062 plays an important role in histogenesis of the enteric nervous system and nephrogenesis. PMID: 15340065 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 10: Seishin Shinkeigaku Zasshi. 2003;105(5):589-92. [Morita therapy over history] [Article in Japanese] Usa S. Sansei Hospital. At Sansei Hospital in Kyoto we performed Morita Therapy not only for Japanese clients but also foreign clients from several countries, like Germany, Switzerland, U.S.A., China, Korea, India and Indonesia. We could treat those foreign clients using Morita Therapy with good success although they came from various cultural backgrounds. One of the characteristic Approaches of Morita Therapy was that it avoided the conceptualization of self-consciousness and self image as a subjective fiction established by abstract and logical thinking. Secondary Morita Therapy moves clients to deal with activities in real life. These 2 approaches help clients not to be involved in symptom development or fixation mechanisms and break through self-centeredness. At the first stage of Morita Therapy, namely in the bed rest period clients can experience his psychic state as if he were a just born baby. The founder of Gestalt Therapy, Frederick S. Perls experienced by himself Morita Therapy. During bed rest therapy he behaved as if he were a baby. This behavior came out not from conscious abstract and logical thinking but from spontaneous "pre-conscious" state of mind. Morita called this "Jun-na-kokoro" (Pure mind). Morita knew that neurotic symptoms come out from those abstract and logical thinking which could lead to fixation of symptoms so that therapy principle might be the de-centralization of self and the pure mind experience which is found in our daily life and also in daily life of foreign people from various cultural backgrounds. Publication Types: Review Review, Tutorial PMID: 12875225 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 11: Mol Cell Biol. 2001 Nov;21(21):7256-67. The transcriptional repressor REST determines the cell-specific expression of the human MAPK8IP1 gene encoding IB1 (JIP-1). Abderrahmani A, Steinmann M, Plaisance V, Niederhauser G, Haefliger JA, Mooser V, Bonny C, Nicod P, Waeber G. Department of Internal Medicine, CHUV-University Hospital, Lausanne, Switzerland. Islet-brain 1 (IB1) is the human and rat homologue of JIP-1, a scaffold protein interacting with the c-Jun amino-terminal kinase (JNK). IB1 expression is mostly restricted to the endocrine pancreas and to the central nervous system. Herein, we explored the transcriptional mechanism responsible for this preferential islet and neuronal expression of IB1. A 731-bp fragment of the 5' regulatory region of the human MAPK8IP1 gene was isolated from a human BAC library and cloned upstream of a luciferase reporter gene. This construct drove high transcriptional activity in both insulin-secreting and neuron-like cells but not in unrelated cell lines. Sequence analysis of this promoter region revealed the presence of a neuron-restrictive silencer element (NRSE) known to bind repressor zinc finger protein REST. This factor is not expressed in insulin-secreting and neuron-like cells. By mobility shift assay, we confirmed that REST binds to the NRSE present in the IB1 promoter. Once transiently transfected in beta-cell lines, the expression vector encoding REST repressed IB1 transcriptional activity. The introduction of a mutated NRSE in the 5' regulating region of the IB1 gene abolished the repression activity driven by REST in insulin-secreting beta cells and relieved the low transcriptional activity of IB1 observed in unrelated cells. Moreover, transfection in non-beta and nonneuronal cell lines of an expression vector encoding REST lacking its transcriptional repression domain relieved IB1 promoter activity. Last, the REST-mediated repression of IB1 could be abolished by trichostatin A, indicating that deacetylase activity is required to allow REST repression. Taken together, these data establish a critical role for REST in the control of the tissue-specific expression of the human IB1 gene. PMID: 11585908 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 12: Ginecol Obstet Mex. 2001 Mar;69:108-17. [Most of the complaints in gynecology and obstetrics care are generated by perceptions stemming from unavoidable results] [Article in Spanish] Morales Ramirez JJ, Sauceda Gonzalez LF. The annual rises in the cost of claims suffered by some countries had led to increases in: costs of the attention; malpractice premiums; health personnel stress level; risks for the patients with difficult problems, and lack of opportune attention. The intricate interaction between clinical state, responses variability and medical procedures flaws makes impossible stop unavoidable outcomes (UO). Though UO are not derived from negligence or inability, patients and relatives can see it as a malpractice result. OBJECTIVE: To determine the proportion of complaints generated by UO related perceptions (UORP) and their distribution in obstetric and gynecologic stages of care. MATERIAL AND METHODS: A search for claims derived from gynecologic or obstetric care was undertaken in the Medical Arbitrition National Commission (CONAMED) database, those presented between Jun. 1, 1996, and Nov. 30, 1998, were chosen. Some claims were derived directly from UORP (D-UORP claims), others were derived indirectly (UORP clamis); claims were grouped for stage of the attention in which they were originated; non D-UORP claims were grouped also by motives. RESULTS: In 625 claims (98.6% of total) was possible obtain precise information as required for the study. 79% of complaints were derived from UORP; 17% from perceptions generated for medical activities unrelated to UO (MAU-UO claims) and 4% by perception originated from care system (CS claims). 46% of complaints concerned surgical treatment, 27% medical treatment, 14% initial study, 2.1% delivery, in 10% a specific stage of the attention was not mentioned. The motives of the non D-UORP complaints were: 1) I-UORP claims; a) opportunity of the action, when the patient referred delay or inopportuneness as cause of the complaint (17%, overall); b) Professional quality, when questioned de outcomes or medical criteria (23%); 2) MAU-UO claims: a) Professional capacity when patient questions ability, or complaint of error in diagnosis (failure to diagnose or incorrect diagnosis), wrong removal, unnecessary treatment or other actions outside of the norm (13%); b) Improper information (3%); c) Inappropriate manner (0.8%); 3) CS claims: a) Resources (1%); b) Accessibility (2.9%). COMMENTS: The damage risk attributable to medical negligence is very low among patients who had received obstetrical or gynecological care, most of the complaints are UORP generated. In obstetrical care--from 1997 national statistics and described results--a benefit was procured to 1,705,161 persons and were produced 17 possible wrong attentions by professional capacity, five by improper information and one by inappropriate manner; the rest, 123 complaints, were derived from perceptions induced by UO. Undoubtedly there is low complaint registration, however, even at worst the wrong attention effect is lower than the impact attained if the possibility of economic benefit search through medical demands is not totally canceled. The damage risk derived from cost of claims is greater, as suffered on many countries. Medical associations in countries without professional liability problems must accomplish negotiations so that the legislation does not establish compensations by medical care results, the request may be based in: a) the deleterious consequences derived from cost of claims; and, b) the low probability of affecting the patients interests, in Mexico complaints derived from perceptions about the professional capacity are one in 103,022 obstetrical care attentions, the improper information derived one in 316,989 and the inappropriate manner generated one in 1,373,620. These organizations and other health related could assume the commitment to abate the foreseeable complaints and to do research on feasible forms to forecast UO, technically this must be long-range and though international collaboration. PMID: 11387879 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 13: J Theor Biol. 2001 Mar 7;209(1):3-8. Control of 92 kDa collagenase secretion in mammalian cells by modulation of AP-1 activity: an experimentally based theoretical study. Marique T, Werenne J. Biotechnologie des cellules animales CP 160 17, Universite Libre de Bruxelles, Avenue F. D. Roosevelt 50, Brussels, 1050, Belgium. Collagenolytic enzymes control cell migration through connective tissues. They appear to be of crucial importance for angiogenesis, tumor metastasis or wound repair. A well-documented stimulation pathway of collagenase secretion, either by natural (cytokines) or synthetic (phorbol esters) molecules, acts through activation of the proto-oncogene activating protein 1 (AP-1). Interestingly, this nuclear factor enhances its own synthesis. It also modulates the activity of different genes, including the one coding for 92 kDa gelatinase. We developed a mathematical model to describe this pathway. It led us to conjecture the existence of an hysteresis cycle for PMA-stimulated collagenase secretion, which was experimentally demonstrated later in MDBK cells in culture. We also modified our model to simulate the behavior of tumoral cells expressing AP-1. In this case, the system becomes highly unstable and, once stimulated, cannot be brought back to rest. This approach paved the way for the understanding and the control of mammalian cell processes, connective tissue maintenance or metastasis dissemination. Copyright 2001 Academic Press. PMID: 11237566 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 14: An Med Interna. 2000 Aug;17(8):410-5. [Evaluation of the functional component underlying the frequent attendance to a hospital emergency service and its economic consequences] [Article in Spanish] Santos Martin MD, Bascunana Morejon de Giron J, Lumbreras Garcia G, Alvarez Martin E, Martinez Pascual B, Sanz Correcher P, Hernando de Larramendi C, Mancebo Aragoneses L. Medicina Familiar y Comunitaria, Hospital Severo Ochoa, Leganes, Madrid. OBJECTIVE: To analyse the psychosocial characteristics of frequent emergency department (ER) users with a relevant non-organic component and estimate the generated costs. METHODS: Retrospective-descriptive study (Jan 1996-Jun 1997) about overusers (OU) defined as > = 3 visits/6 months during at least two 6 months periods, coming to our hospital's emergency department. Reviewing their medical records and making a psychiatric interview we identified Non-organic OU (NOU). Subsequently we estimated the cost generated by discharge visits during the first six months of 1997. RESULTS: Sixty six out of 220 OU were identified as NOU. The mean consultation rate was 11.3 +/- 9.4. Clinician-psychiatrist agreement on non-organicity was 72.7%. The most frequent diagnoses were: personality disorders (37.5%) and depression-anxiety (35%). Psychiatric OU were significantly younger (51.7 vs 62.5 years) and attended more often (17.6 vs. 9.9 times). In six months only one of 240 ER consultation cause admission. The mean cost of each discharge episode was 8682.9 +/- 6633.8 pta (25.06% due to variable costs). The cost per minute of emergency room stay was 19.26 ptas. Overall NOU attention cost during the six month period studied was 1,903,775 ptas (0.36% of overall ER costs). CONCLUSIONS: Compared with the rest of users, NOU entail a higher burden for the ER. Mentally-ill patients are younger and consult more frequently than the rest of OU. Only 25% of the cost per consultation is due to treatments, tests or diets. PMID: 11218987 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 15: J Burn Care Rehabil. 2000 Mar-Apr;21(2):135-41. Gene expression and cytokine and enzyme activation in the liver after a burn injury. Nishiura T, Nishimura T, deSerres S, Godfrey V, Bradham CA, Nakagawa T, Brenner DA, Meyer AA. Department of Surgery and the Jaycee Burn Center, University of North Carolina School of Medicine, USA. The liver plays a critical role in the inflammatory response to injury; however, the mechanisms by which the liver is affected and how it influences the rest of the immune system are not well understood. Partial hepatectomy is a direct injury to the liver, whereas a burn is an indirect injury to liver, but both injuries appear to produce damage to the liver. In this study, we used a mouse model of 25% total body surface area and 40% total body surface area full-thickness burns to investigate the mechanism of liver damage and response to burn injury by measuring levels of c-Jun messenger (m)RNA, NFkappaB nuclear protein, interleukin-6, transaminases, and liver tissue histology over time. c-Jun and NFkappaB are 2 transcription factors that are induced by partial hepatectomy and related to hepatocyte injury and growth. In both groups of mice with burns, expression of c-Jun mRNA and NFkappaB nuclear protein was activated within 30 minutes after the burn injury, followed by increased levels of interleukin-6 and, finally, elevated enzyme levels. Liver injuries were similar in both groups despite the magnitude of the burns. We believe that these gene products are initiated in the hepatocyte injury after a burn and that they precede other inflammatory responses such as cytokine release, plasma transaminase levels, and histologic changes. PMID: 10752746 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 16: J Orthop Res. 2000 Jul;18(4):524-31. Compressive compared with tensile loading of medial collateral ligament scar in vitro uniquely influences mRNA levels for aggrecan, collagen type II, and collagenase. Majima T, Marchuk LL, Sciore P, Shrive NG, Frank CB, Hart DA. McCaig Center for Joint Injury and Arthritis Research, University of Calgary, Alberta, Canada. To test the hypothesis that loading conditions can be used to engineer early ligament scar behaviors, we used an in vitro system to examine the effect that cyclic hydrostatic compression and cyclic tension applied to 6-week rabbit medial collateral ligament scars had on mRNA levels for matrix molecules, collagenase, and the proto-oncogenes c-fos and c-jun. Our specific hypothesis was that tensile stress would promote more normal mRNA expression in ligament whereas compression would lead to higher levels of mRNA for cartilage-like molecules. Femur (injured medial collateral ligament)-tibia complexes were subjected to a hydrostatic pressure of 1 MPa or a tensile stress of 1 MPa of 0.5 Hz for 1 minute followed by 14 minutes of rest. On the basis of a preliminary optimization experiment, this 15-minute testing cycle was repeated for 4 hours. Semiquantitative reverse transcription-polymerase chain reaction analysis was performed for mechanically treated medial collateral ligament scars with use of rabbit specific primer sets for types I, II, and III collagen, decorin, biglycan, fibromodulin, versican, aggrecan, collagenase, c-fos, c-jun, and a housekeeping gene, glyceraldehyde-3-phosphate dehydrogenase. Cyclic hydrostatic compression resulted in a statistically significant increase in mRNA levels of type-II collagen (171% of nonloaded values) and aggrecan (313% of nonloaded values) but statistically significant decreases in collagenase mRNA levels (35% of nonloaded values). Cyclic tension also resulted in a statistically significant decrease in collagenase mRNA levels (66% of nonloaded values) and an increase in aggrecan mRNA levels (458% of nonloaded values) but no significant change in the mRNA levels for the other molecules. The results show that it is possible to alter mRNA levels for a subset of genes in scar tissue by supplying unique mechanical stimuli in vitro and thus that further investigation of scar engineering for potential reimplantation appears feasible. PMID: 11052487 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 17: Neuroscience. 1999;94(3):917-27. Prevention of neuronal apoptosis by phorbol ester-induced activation of protein kinase C: blockade of p38 mitogen-activated protein kinase. Behrens MM, Strasser U, Koh JY, Gwag BJ, Choi DW. Department of Neurology and Center for the Study of the Nervous System Injury, Washington University School of Medicine, St Louis, MO 63110, USA. behrensm@neuro.wustl.edu Consistent with previous studies on cell lines and non-neuronal cells, specific inhibitors of protein kinase C induced mouse primary cultured neocortical neurons to undergo apoptosis. To examine the complementary hypothesis that activating protein kinase C would attenuate neuronal apoptosis, the cultures were exposed for 1 h to phorbol-12-myristate-13-acetate, which activated protein kinase C as evidenced by downstream enhancement of the mitogen-activated protein kinase pathway. Exposure to phorbol-12-myristate-13-acetate, or another active phorbol ester, phorbol-12,13-didecanoate, but not to the inactive ester, 4alpha-phorbol-12,13-didecanoate, markedly attenuated neuronal apoptosis induced by serum deprivation. Phorbol-12-myristate-13-acetate also attenuated neuronal apoptosis induced by exposure to beta-amyloid peptide 1-42, or oxygen-glucose deprivation in the presence of glutamate receptor antagonists. The neuroprotective effects of phorbol-12-myristate-13-acetate were blocked by brief (non-toxic) concurrent exposure to the specific protein kinase C inhibitors, but not by a specific mitogen-activated protein kinase 1 inhibitor. Phorbol-12-myristate-13-acetate blocked the induction of p38 mitogen-activated protein kinase activity and specific inhibition of this kinase by SB 203580 attenuated serum deprivation-induced apoptosis. c-Jun N-terminal kinase 1 activity was high at rest and not modified by phorbol-12-myristate-13-acetate treatment. These data strengthen the idea that protein kinase C is a key modulator of several forms of central neuronal apoptosis, in part acting through inhibition of p38 mitogen-activated protein kinase regulated pathways. PMID: 10579584 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 18: Biochem Biophys Res Commun. 1998 Oct 9;251(1):106-10. Exercise stimulates c-Jun NH2 kinase activity and c-Jun transcriptional activity in human skeletal muscle. Aronson D, Boppart MD, Dufresne SD, Fielding RA, Goodyear LJ. Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, One Joslin Place, Boston, Massachusetts, 02215, USA. Exercise causes selective changes in gene expression leading to alterations in the structure and function of human skeletal muscle. However, little is known about the specific signaling pathways that enable exercise to modulate gene regulatory events. We determined the effects of exercise on c-Jun NH2-terminal kinase (JNK) activity, a signaling molecule involved in the regulation of transcription. Biopsies of vastus lateralis muscle were taken from eight subjects at rest and after 60 min of cycle ergometer exercise. Exercise increased JNK activity in all subjects (5.9 +/- 1.8 fold above basal). JNK activation was associated with an increased expression of its downstream nuclear target c-Jun mRNA. When two additional subjects were studied using a one-legged exercise protocol, JNK activity increased only in the exercising leg, indicating that exercise-induced JNK signaling represents an intrinsic response of the contracting muscle, rather than a systemic response to exercise. These studies demonstrate that the JNK pathway may serve as a link between contractile activity and transcriptional responses in human skeletal muscle. Copyright 1998 Academic Press. PMID: 9790915 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 19: J Biol Chem. 1998 Jun 5;273(23):14435-41. Domain mapping of human apurinic/apyrimidinic endonuclease. Structural and functional evidence for a disordered amino terminus and a tight globular carboxyl domain. Strauss PR, Holt CM. Department of Biology, Northeastern University, Boston, Massachusetts 02115, USA. We recently described the pre-steady state enzymatic binding kinetics of apurinic/apyrimidinic endonuclease (AP endo). In this report we describe the domain structure of the enzyme in solution determined by mild protease digestion in the presence and absence of substrate, product, and an efficient competitive inhibitor (HDP). AP endo is a 35.5-kDa protein with a high degree of homology to its prokaryotic counterpart, exonuclease III (Exo III), except for the amino terminus, which is lacking in the prokaryotic enzyme. The entire conserved region plus an additional 20 residues unique to the eukaryotic enzyme was inaccessible to trypsin and V8 protease, indicating that it forms a tight globular structure. In contrast, the amino-terminal 35 residues were readily accessible to all the proteases investigated, leading us to conclude that they associate poorly with the rest of the structure and constitute a highly fluid region. When AP endo was boiled with SDS and cooled prior to the addition of V8 protease, several acidic residues within the globular domain became protease-accessible, indicating rapid renaturation except along the nuclease fold with restoration of globular conformation for the carboxyl two-thirds of the molecule. Of all the proteases tested, only chymotrypsin was able to cleave internal to the globular portion without prior denaturation. Although AP endo cleaved with chymotrypsin retained full enzymatic activity, the activity was lost when the digested peptides were recovered after denaturation by heat and/or boiling in SDS, precipitation, and renaturation or when fragments were recovered from an SDS gel and renatured. Thus, the protein is probably held together strongly by noncovalent interactions that maintain enzymatic function after protease nicking. The three major chymotrypsin cleavage sites, Tyr-144, Leu-179, and Leu-205, became strikingly less accessible to protease digestion in the presence of abasic site-containing DNA. Since the three residues form a spherical triangle on the surface of the molecule on one side of the nuclease fold, there must be multiple means by which DNA containing an abasic site associates with the enzyme. The most likely explanation is that substrate and product, both of which were present during proteolysis, bind differently to the enzyme. Finally, the two cysteine residues thought to be involved in the redox reaction of AP endo with Jun protein were entirely inaccessible to proteolysis even after prolonged exposure of AP endo to reducing agents. Consequently, if AP endo plays a role in the physiological function of Jun, it must undergo major conformational changes in the process. Alternatively, the two cysteines could maintain an appropriate conformation such that other residues participate directly in the redox activity. PMID: 9603956 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 20: Anaesthesist. 1997 Sep;46 Suppl 3:S147-53. [Neurophysiological aspects of pain and its consequences for the anesthetist] [Article in German] Wiebalck A, Zenz M. Universitatsklinik fur Anaesthesiologie, Intensiv- und Schmerztherapie, Berufsgenossenschaftliche Kliniken Bergmannsheil, Bochum. Nociception is a protective system of the body which prevents it from injury and tissue damage. Human beings respond to noxious stimuli by moving away. They learn by pain to avoid these situations in future. Shortly after major injury, there is a limited analgesic period allowing the body to flee the area of danger, later on, emerging pain compels the body to rest and supports recuperation. While acute pain has a certain meaning, chronic pain does not. It induces a comprehensive suffering including loss of initiative, appetite and vigilance. It reduces life-quality, often accompanied by depressive moods. Acute pain causes changes in the central nervous system leading to an increased sensitivity of nociception (hyperalgesia). During healing, the central processing of noxious stimuli is normalised taking minutes to weeks. Sometimes, unknown factors initiate chronification of pain. Changes on a molecular level in peripheral tissue as well as in the central nervous system induce "cellular early genes", a synthesis of c-fos, c-jun and other proteins favouring the chronification of pain. All efforts have to be made to depress or interrupt such a development. One of the first steps to pain prophylaxis in a hospital is an optimal surgical technique: incision, extension, limited tissue damage and minimal invasive surgery should guarantee the smallest impairment of the nociceptive system possible. However, nociceptive input is intense and of long duration and leads to central sensibilisation. Postoperative pain has lost its function as surgery anticipates healing. Pain induces a reduction of ventilation, circulation, digestion and increases the risk of other disorders. There is need of aggressive pain treatment for humanitarian reasons and for reasons of late sequelae like permanent pain and increased reduction of function. This is of pivotal importance in patients with amputations or sympathetic reflex dystrophy (SRD). Antinociception is best provided by regional anaesthesia technique with a combination of local anaesthetics and opioids which results in better outcome. Hence, regional anaesthesia techniques are strongly indicated in those patients. Good antinociception may be even more important than it is assumed today. Anand demonstrated a lower morbidity and mortality in 45 newborns undergoing cardiothoracic surgery, when general anaesthesia was performed with high-dose sufentanil versus halothane supplementary doses of morphine. Anaesthesiologists have to reconsider the quality of general anaesthesia: the antinociception of their regimen. Publication Types: Review Review, Tutorial PMID: 9412270 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 21: Brain Res Mol Brain Res. 1997 Aug;48(1):73-86. Daily variation of CNS gene expression in nocturnal vs. diurnal rodents and in the developing rat brain. O'Hara BF, Watson FL, Andretic R, Wiler SW, Young KA, Bitting L, Heller HC, Kilduff TS. Center for Sleep and Circadian Neurobiology, Department of Biological Sciences, Stanford University, CA 94305, USA. Expression of c-fos has been shown to vary throughout the brain over the course of the 24-h day. The magnitude of these changes appear to be similar in a light:dark (LD) cycle or in constant dark (DD). To further examine whether the diurnal and circadian changes in c-fos and other immediate-early gene (IEG) expression in brain are related to waking behaviors such as locomotor activity, we conducted three experiments using Northern analysis. First, we compared IEG expression in nocturnal vs. diurnally active species. Second, we investigated IEG expression in a hibernating species during its active and inactive phases. Third, we examined the development of IEG expression in the young post-natal rat. As a comparison to results obtained in extra-SCN brain regions, we also examined IEG and vasopressin expression in the SCN itself across the circadian cycle. Animals maintained under a 12:12-h LD cycle were sacrificed in the morning (10:00-11:00 h, ZT2-ZT3) or night (22:00-23:00 h, ZT14-ZT15) or at the corresponding circadian times (CT) when kept in DD. Rats sacrificed in the morning always showed lower c-fos expression than at night in all brain areas examined while the reverse pattern was seen in squirrels under both LD and DD conditions, suggesting a direct correlation between c-fos message and activity. The cerebellum displayed the greatest magnitude change between morning and night (often reaching 10-fold). Among other IEGs examined, the expression of NGFI-A and junB are similar to c-fos, but of lesser magnitude, whereas c-jun appears to be invariant in the rat but is increased during the active phase in squirrels. During the hibernation season, squirrels have lower levels of c-fos consistent with their low levels of activity even during their euthermic interbout periods. c-fos expression in the cerebellum and rest of brain of 1-week-old rats sacrificed at ZT3 and ZT15 showed low levels at both timepoints whereas 2- and 3-week-old animals had higher levels at night as do adults. Among other IEGs, junB and NGFI-A again were similar to c-fos while c-jun and junD were more constant. Our observations support the idea of a diurnal rhythm of IEG expression in the CNS that is related to waking behaviors. Among IEGs, c-fos exhibits the greatest daily variation in expression. PMID: 9379853 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 22: Invest Ophthalmol Vis Sci. 1996 Sep;37(10):2068-80. Differential regulation of cytokine and receptor transcript expression in human corneal and limbal fibroblasts by epidermal growth factor, transforming growth factor-alpha, platelet-derived growth factor B, and interleukin-1 beta. Li DQ, Tseng SC. Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami School of Medicine, Florida 33101, USA. PURPOSE: To explore further the significance of three patterns of cytokine dialogues that have been characterized between human corneal and limbal epithelial cells and fibroblasts. METHODS: Northern hybridization of the transcript expression of type I cytokine receptors (EGFR, IL-1R, and PDGFR-beta), type II cytokines (bFGF, LIF, and TGF-beta 1), and type III cytokines (HGF and KGF) by human corneal and limbal fibroblasts was conducted under the modulation of TGF-alpha, PDGF-BB, IL-1 beta, and EGF (type I cytokines). The mechanism of upregulation by IL-1 beta was studied further with respect to proto-oncogene expression and under the treatment of cycloheximide and actinomycin D. RESULTS: Results showed that EGF upregulated LIF and HGF but downregulated KGF and M-CSF. Unlike EGF, TGF-alpha upregulated additional EGFR, PDGFR-beta, bFGF, and TGF-beta 1, suggesting that although they share the same EGFR, TGF-alpha, which is produced by epithelium, is more effective in activating fibroblasts than EGF, which is present in tears. The upregulation of PDGF-BB was similar to that of TGF-alpha, except that it further stimulated IL-8, supporting their synergistic roles in promoting wound healing. Uniquely, IL-1 beta upregulated KGF expression by limbal fibroblasts more than corneal fibroblasts and IL-8 and M-CSF expression, but it downregulated PDGFR-beta. In IL-1 beta, the upregulation of cytokines and receptors was preceded by the upregulation of c-fos, c-jun, and c-myc, and it was inhibited by actinomycin D. Its upregulation of LIF was superinduced, but the upregulation of bFGF and KGF was inhibited, and that of the rest was not affected by cycloheximide. CONCLUSIONS: These findings suggest that epithelial cells under stress or injury (producing IL-1) might preferentially activate limbal epithelial stem cells indirectly by fibroblasts and simultaneously might promote inflammation during wound healing. PMID: 8814146 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 23: J Invest Dermatol. 1995 Jan;104(1):78-82. Changes in expression of apoptosis-associated genes in skin mark early catagen. Seiberg M, Marthinuss J, Stenn KS. Skin Biology Research Center, R.W. Johnson Pharmaceutical Research Institute, Raritan, NJ 08869-0602. Programmed cell death is central to hair biology, as the hair follicle undergoes cycles of growth (anagen), regression (catagen), and rest (telogen). During catagen, the hair follicle shortens via a pathway of programmed cell death and apoptosis. The molecular mechanisms involved in this process have not been elucidated yet. Using reverse transcriptase-polymerase chain reaction, we examined in this study the expression in total skin, throughout one hair cycle, of a series of regulatory genes associated with apoptosis. We show that gene expression within skin is hair-cycle-dependent. Transforming growth factor-beta was expressed immediately before catagen; therefore, it might be involved in the early signaling of this process. Tumor necrosis factor-beta was expressed during catagen and might be involved in follicular apoptosis. Several proto-oncogenes and transcription factors have been described in the regulation of apoptosis in other systems. Here we show that the transcript levels of c-myc, c-myb, and c-jun changed immediately before or during early catagen and thus could be involved in the signaling or regulation of catagen. Levels of p53 remained constant throughout anagen and catagen, suggesting that p53 is not involved in the developmentally induced apoptosis of the hair follicle. The variable expression throughout the hair cycle of the genes described demonstrates the dynamic changes of the skin and underscores the importance of studying the complete hair cycle when characterizing any molecule in skin. PMID: 7798646 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 24: Chronobiologia. 1994 Jan-Jun;21(1-2):93-7. Different programs of gene expression are associated with different phases of the 24h and sleep-wake cycles. Grassi Zucconi G, Menegazzi M, Carcereri De Prati A, Vescia S, Ranucci G, Bentivoglio M. Istituto di Biologia Cellulare, Universita di Perugia, Italy. The Fos and Jun proteins are encoded by proto-oncogenes acting as immediate early genes in that they are rapidly induced by different kinds of stimuli in the nervous system. These two proteins bind to DNA regulating gene transcription, and thus determining the specificity of the neuronal response to the applied stimulation. We investigated whether the expression of these genes undergoes a variation during 24h in the absence of exogenous stimulation. Male Wistar adult (200 gr. body weight) rats, kept under a 12h/12h light-dark cycle, were sacrificed every 4h starting at 0700. The expression of c-fos, c-jun and jun B mRNAs was studied in six different brain areas by means of Northern blot hybridization, c-fos expression was also studied with in situ hybridization and immunohistochemistry. In basal conditions c-fos expression displayed a highly significant spontaneous oscillation, with the highest level during the darkness hours and the lowest during the light hours. Parallel levels of jun B expression were found in the cortex and striatum, whereas c-jun mRNA remained constantly high throughout 24 h. The periodicity of c-fos and jun B oscillation persisted also when the animals were exposed for 6 days to constant (24h/24h) light or darkness. Such oscillation could instead be inverted by manipulating the rest-activity cycle, i.e. keeping the animals awake during the light hours and allowing them to sleep during the dark hours. We then verified whether the expression of fos and jun could be correlated with states of wakefulness (W) and sleep (S), monitored with EEG recording under behavioral control.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 7924645 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 25: Crit Rev Oncog. 1994;5(4):359-71. Retrodifferentiation and cell death. Hass R. Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115. The reversibility of a differentiation program termed dedifferentiation, redifferentiation, or retrodifferentiation opens a spectrum of new possibilities for cellular development. During differentiation and retrodifferentiation, the expression of gene products associated with a differentiated phenotype and cell cycle regulation demonstrate inverse patterns. This effect requires a coordinated network that simultaneously controls cell growth and differentiation. In particular, crosstalk between induction of differentiation and G0/G1 cell cycle exit can be initiated and sustained by activated serine/threonine kinases and tyrosine kinases. Phosphorylation signals are relayed to certain genes or transcription factors such as Fos/Jun, EGR-1, NF-kappa B, MyoD, or the Myc/Max gene family. However, the precise regulation of these transcription factors to confer signals to differentiation-associated and cell cycle-regulatory genes remains unclear. Cell cycle exit into a transient G0'-arrest cycle or a terminal G0 phase is determined by a network of phosphorylation signals involving the retinoblastoma protein and a variety of factors such as the E2F family, cyclins, and cyclin-dependent kinases. In this context, a variety of differentiation-induced cell lines, including monocytic, neuronal, or muscle cells, can progress through the G0'-arrest cycle, whereby a certain population retains the capacity to retrodifferentiate and reenter the cell cycle. In contrast, the rest of the differentiated population enters the irreversible G0 phase (terminal commitment) that finally results in programmed cell death. The expression of growth arrest-specific (gas and gadd) genes is associated with the G0'-arrest cycle, and other factors, including c-myc, p53, mdm2, and bcl2/bclx, contribute to the regulation of the cell death program. Although the precise signaling cascade determining retrodifferentiation or cell death remains unclear, a coordinated inter- and intracellular regulation could establish a certain biological balance between these exclusive pathways. Consequently, a retrodifferentiation process may provide a potential for cell type conversion or transdifferentiation, whereby retrodifferentiated cells can be induced to develop via a different pathway according to tissue-specific requirements. Publication Types: Review Review, Tutorial PMID: 7711113 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 26: Korean J Intern Med. 1993 Jul;8(2):78-85. Changes in spectral indices of heart rate variability during exercise in acute myocardial infarction. Chae SC, Kang SW, Lee BY, Jun JE, Park WH, Park HM. Department of Internal Medicine, Kyungpook National University School of Medicine, Taegu, Korea. Physical exertions are related to sudden cardiac death following acute myocardial infarction (AMI). Abnormalities in the autonomic modulation during exercise were noted in animals with AMI that were susceptible to potentially lethal arrhythmias. This study was done to evaluate the changes in the autonomic activity during exercise and recovery in AMI patients with good exercise capacity, using spectral analysis of R-R intervals of electrocardiogram (ECG). Symptom-limited treadmill exercise test was done on 17 patients of AMI with mild heart failure (in 7-10 days after the attack) and 21 healthy controls. The exercise was divided into 7 stages; rest, early exercise, mid-exercise, peak exercise, early recovery, mid-recovery, and late recovery. Power spectral analysis of R-R intervals of ECG was performed for each stage. Low frequency (0.04-0.15 Hz) and high frequency (0.15-0.40 Hz) powers, and their ratio were obtained. These parameters were observed throughout the stages in both groups. The trend of their changes during exercise and recovery was essentially the same for both groups; high and low frequency powers progressively decreased during exercise and abruptly increased during early recovery, but did not return to the values at those of rest until 9 minutes into the recovery. When the parameters were compared between the groups, there was a significantly greater decrease of high frequency power during the early exercise (p < 0.05), and a higher ratio of low to high frequency power during the early recovery (p < 0.05) in the patients.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 8031727 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 27: J Natl Cancer Inst. 1992 Apr 15;84(8):592-601. Comment in: J Natl Cancer Inst. 1992 Apr 15;84(8):556-8. Spontaneous transformation of rat ovarian surface epithelial cells: association with cytogenetic changes and implications of repeated ovulation in the etiology of ovarian cancer. Godwin AK, Testa JR, Handel LM, Liu Z, Vanderveer LA, Tracey PA, Hamilton TC. Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pa 19111. BACKGROUND: Ovarian surface epithelial cells undergo several rounds of division to repair the wound created by follicular rupture at the time of ovulation. This cyclical requirement for cell division, when not interrupted by the long anovulatory rest periods that occur during pregnancy and lactation, may contribute to the development of ovarian cancer. PURPOSE AND METHODS: To test this hypothesis, we isolated rat ovarian surface epithelial cells from 10 adult female Fisher rats, initiated two mixed-population and seven clonal cell lines, and repeatedly subcultured these cells in vitro for more than 20 passages. We then tested them for the acquisition of the following four features associated with transformation: 1) the loss of contact inhibition, 2) the capacity for substrate-independent growth, 3) the ability to form tumors when injected subcutaneously and/or intraperitoneally into athymic mice, and 4) cytogenetic abnormalities. RESULTS: Loss of contact inhibition was observed in all nine late-passage cell lines. Six of the nine late-passage, but none of the early-passage, cell lines tested exhibited a capacity for substrate-independent growth that was augmented in a dose-dependent manner by epidermal growth factor. Two late-passage cell lines (clone 2 and mixed-population 2) generated tumors in athymic BALB/c mice within 3 weeks following subcutaneous injection of 5 x 10(6) cells, whereas similar numbers of early-passage cells from the same cell lines failed to generate palpable tumors. Late-passage clone 7 cells were tumorigenic when 5 x 10(7) cells were injected intraperitoneally. Two of the cell lines analyzed exhibited alterations involving losses of part or all of one member of the chromosome 5 pair. Clone 2 possessed an interstitial deletion, del(5)(q21.3q24), consistent with the loss of an uncloned putative tumor suppressor gene at 5q22q23 previously reported to reside near the loci for the interferon alpha, interferon beta, and c-jun genes. Early-passage clone 7 cells exhibited chromosome 5 monosomy, while late-passage cells contained one normal chromosome 5 and a derivative (5q12q). Southern analysis of the three cell lines revealed no consistent loss of loci for the interferon and c-jun genes, although early-passage clone 7 cells had one half the gene copy number for the interferon beta and c-jun genes and both early- and late-passage clone 7 cells lacked DNA sequences hybridizing with the probe for interferon alpha. CONCLUSION: This pattern of passage-dependent spontaneous transformation of rat ovarian surface epithelial cells in vitro supports the hypothesis that repetitious ovulation contributes to the etiology of human ovarian cancer. PMID: 1556770 [PubMed - indexed for MEDLINE] ---------------------------------------------------------------