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Part One of a MEDLINE on PD and childhood diseases, influenza, and possible environmental exposures: ------------------------------------------------------------ 2/L/6 DIALOG(R)File 154:MEDLINE(R) (c) format only 1995 Knight-Ridder Info. All rts. reserv. 07594964 91113964 Similarities of guamanian ALS/PD to post-encephalitic parkinsonism/ALS: possible viral cause. Hudson AJ; Rice GP Department of Clinical Neurological Sciences, University Hospital, London, Ontario. Can J Neurol Sci (CANADA) Nov 1990, 17 (4) p427-33, ISSN 0317-1671 Journal Code: CJ9 Languages: ENGLISH Document type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL JOURNAL ANNOUNCEMENT: 9105 Subfile: INDEX MEDICUS Guamanian amyotrophic lateral sclerosis with parkinsonism-dementia (ALS/PD) has been the subject of intensive study since its discovery in 1947 because of its extraordinarily high incidence in a small ethnic group (Chamorros) whose dietary lack and customs have suggested possible causes. As yet, these and other suspected causes have eluded proof. Because of marked similarities between Guamanian ALS/PD and late onset post-encephalitic (encephalitis lethargica) parkinsonism and ALS it is suggested that they have a common cause. The parkinsonism and ALS in the two disorders are clinically very similar and neuropathological studies have shown a very similar distribution of neurofibrillary tangles in neurons. Some clinical differences, such as ocular features in the post-encephalitic cases and dementia in Guamanian ALS/PD, can be explained by differences in the severity of infection and the interval between the encephalitis and onset of sequelae. Although unproven, influenza A (HswilN1 strain) has long been suspected as the cause of encephalitis lethargica because of simultaneous pandemics of the two diseases in the 1920s. Because influenza A can persistently infect cells and has a marked propensity to mutate it is an optimal candidate among other RNA viruses for delayed nervous system infection as a possible cause of ALS/PD. (55 Refs.) Tags: Human Descriptors: *Amyotrophic Lateral Sclerosis--Microbiology--MI; *Parkinson Disease, Postencephalitic--Microbiology--MI; Dementia--Complications--CO; Guam 2/L/8 DIALOG(R)File 154:MEDLINE(R) (c) format only 1995 Knight-Ridder Info. All rts. reserv. 07059495 89361495 Could Parkinson's disease follow intra-uterine influenza? A speculative hypothesis [letter; comment] Singer C; Weiner WJ J Neurol Neurosurg Psychiatry (ENGLAND) Jul 1989, 52 (7) p931, ISSN 0022-3050 Journal Code: JBB Comment on J Neurol Neurosurg Psychiatry 1988 Jun;51(6):753-6 Languages: ENGLISH Document type: COMMENT; LETTER JOURNAL ANNOUNCEMENT: 8912 Subfile: INDEX MEDICUS Tags: Female; Human Descriptors: *Parkinson Disease, Postencephalitic--Etiology--ET; *Prenatal Exposure Delayed Effects; Diseases in Twins; Pregnancy; Risk Factors 2/L/9 DIALOG(R)File 154:MEDLINE(R) (c) format only 1995 Knight-Ridder Info. All rts. reserv. 07059484 89361484 Does idiopathic parkinsonism in Aberdeen follow intrauterine influenza? Ebmeier KP; Mutch WJ; Calder SA; Crawford JR; Stewart L; Besson JO Department of Mental Health, University of Aberdeen, UK. J Neurol Neurosurg Psychiatry (ENGLAND) Jul 1989, 52 (7) p911-3, ISSN 0022-3050 Journal Code: JBB Languages: ENGLISH Document type: JOURNAL ARTICLE JOURNAL ANNOUNCEMENT: 8912 Subfile: INDEX MEDICUS A study is presented which fails to replicate a recent report that peak years of birth of patients later developing Parkinson's disease are related to the influenza pandemics of the period 1890-1930. The years of birth of a whole population cohort of 243 patients suffering from Parkinson's disease examined in Aberdeen in 1983 and reexamined in 1986/7 were compared with deaths due to influenza in the City of Aberdeen in the years 1900-1930. Although a significant peak of Parkinson births (compared with the age profile of the Aberdeen population in 1983) occurred in 1902, there appeared to be no systematic relationship between Parkinson births and influenza deaths. In addition, no season of birth effect could be detected in a comparison with 232 matched controls. The presence of peaks of birth years, for whatever aetiological reason, is of significance to epidemiological studies in that prevalence estimates may be influenced by the year of study relative to these mini-cohorts. Tags: Female; Human; Support, Non-U.S. Gov't Descriptors: *Parkinson Disease, Postencephalitic--Etiology--ET; *Prenatal Exposure Delayed Effects; Aged; Aged, 80 and over; Cohort Studies ; Follow-Up Studies; Middle Age; Pregnancy; Risk Factors; Scotland 2/L/10 DIALOG(R)File 154:MEDLINE(R) (c) format only 1995 Knight-Ridder Info. All rts. reserv. 06655091 88300091 Could Parkinson's disease follow intra-uterine influenza?: a speculative hypothesis [see comments] Mattock C; Marmot M; Stern G Department of Community Medicine, University College and Middlesex School of Medicine, London, UK. J Neurol Neurosurg Psychiatry (ENGLAND) Jun 1988, 51 (6) p753-6, ISSN 0022-3050 Journal Code: JBB Comment in J Neurol Neurosurg Psychiatry 1989 Jul;52(7):931 Languages: ENGLISH Document type: JOURNAL ARTICLE JOURNAL ANNOUNCEMENT: 8811 Subfile: INDEX MEDICUS Patients with idiopathic Parkinson's disease do not appear to be distributed smoothly with respect to year of birth. Individuals born within the years 1892, 1904, 1909, 1918, 1919 and 1929 appear to have had an increased risk of developing idiopathic Parkinson's disease in later life. These years are close to those of the influenza pandemics of the period 1890-1930. The estimated risk of an individual developing idiopathic Parkinson's disease shows a significant correlation with the crude influenza mortality for the year of his birth, within the range 1900 to 1930. It is suggested that intra-uterine influenza may be cytotoxic to the developing foetal substantia nigra, and that an affected individual may be born without evident disability but with limited striatal neurochemical reserves and a reduced nigral cell count. In later life normal cellular involution with ageing or exposure to environmental neurotoxic factors may further erode these reserves to a level where the substantia nigra fails and idiopathic Parkinson's disease becomes clinically apparent. Tags: Female; Human; Male Descriptors: *Disease Outbreaks--Epidemiology--EP; *Influenza--Mortality --MO; *Parkinson Disease--Mortality--MO; *Pregnancy Complications, Infectious--Mortality--MO; *Prenatal Exposure Delayed Effects; Aged; Aged, 80 and over; England; Middle Age; Pregnancy; Risk Factors; Wales 2/L/12 DIALOG(R)File 154:MEDLINE(R) (c) format only 1995 Knight-Ridder Info. All rts. reserv. 06312535 87286535 Was a neurovirulent influenza virus the cause of amyotrophic lateral sclerosis and parkinsonism-dementia on Guam? Maurizi CP Med Hypotheses (ENGLAND) Jul 1987, 23 (3) p325-6, ISSN 0306-9877 Journal Code: M0M Languages: ENGLISH Document type: JOURNAL ARTICLE JOURNAL ANNOUNCEMENT: 8711 Subfile: INDEX MEDICUS Tags: Human Descriptors: *Amyotrophic Lateral Sclerosis--Microbiology--MI; *Dementia --Microbiology--MI; *Orthomyxoviridae--Pathogenicity--PY; *Parkinson Disease--Microbiology--MI; Adolescence; Adult; Amyotrophic Lateral Sclerosis--Epidemiology--EP; Child; Child, Preschool; Dementia --Epidemiology--EP; Dementia--Etiology--ET; Guam; Middle Age; Parkinson Disease--Complications--CO; Parkinson Disease--Epidemiology--EP 2/L/14 DIALOG(R)File 154:MEDLINE(R) (c) format only 1995 Knight-Ridder Info. All rts. reserv. 05746779 86047779 Measles infection and Parkinson's disease. Sasco AJ; Paffenbarger RS Jr Am J Epidemiol (UNITED STATES) Dec 1985, 122 (6) p1017-31, ISSN 0002-9262 Journal Code: 3H3 Contract/Grant No.: CA 25264 Languages: ENGLISH Document type: JOURNAL ARTICLE JOURNAL ANNOUNCEMENT: 8602 Subfile: INDEX MEDICUS A case-control analysis of Parkinson's disease and infections in childhood was conducted in a cohort of 50,002 men who attended Harvard College (Cambridge, MA) or the University of Pennsylvania (Philadelphia, PA) between 1916 and 1950 and who were followed in adulthood for morbidity and mortality data. Cases of Parkinson's disease were identified from responses to mailed questionnaires and death certificates through 1978. Four controls from the same population were selected for each case. A reduced risk of Parkinson's disease was associated with most childhood viral infections. The negative association was statistically significant for a history of measles prior to college entrance (exposure odds ratio = 0.53; 95% confidence limits: 0.31, 0.93). The reduced risk of Parkinson's disease among subjects with a positive history of measles in childhood may reflect an adverse effect of measles in adulthood or of subclinical or atypical measles. Furthermore, a negative history of measles, especially if associated with a lack of other common diseases, could be a marker for negative influenza history before 1918 and thus a higher risk of infection during the 1918 influenza epidemic, because of the lack of partial influenza immunity. These data may also suggest a truly protective effect of measles, compatible with some complex interaction between measles virus and the virus of the 1918 influenza epidemic. Tags: Human; Male; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S. Descriptors: *Measles--Complications--CO; *Parkinson Disease--Etiology --ET; Adolescence; Adult; Aged; Child; Child, Preschool; Death Certificates ; Epidemiologic Methods; Infant; Influenza--Complications--CO; Longitudinal Studies; Massachusetts; Measles--Epidemiology--EP; Middle Age; Parkinson Disease--Epidemiology--EP; Parkinson Disease--Mortality--MO; Pennsylvania; Questionnaires; Regression Analysis; Risk 2/L/16 DIALOG(R)File 154:MEDLINE(R) (c) format only 1995 Knight-Ridder Info. All rts. reserv. 05597157 85213157 Why was the 1918 influenza pandemic so lethal? The possible role of a neurovirulent neuraminidase. Maurizi CP Med Hypotheses (ENGLAND) Jan 1985, 16 (1) p1-5, ISSN 0306-9877 Journal Code: M0M Languages: ENGLISH Document type: JOURNAL ARTICLE JOURNAL ANNOUNCEMENT: 8509 Subfile: INDEX MEDICUS Epidemiological, viral, behavioral and neuropathological evidence suggests that some influenza epidemics were neurovirulent. Re-examination of the data from the lethal 1918 pandemic armed with recent observations about the influenza virus implicates a neurovirulent influenza virus in manic-depressive disease, schizophrenia and Parkinson's disease. The neurovirulence seems to have been related to the species of neuraminidase. Tags: Human Descriptors: *Encephalitis--Etiology--ET; *Neuraminidase--Toxicity--TO; *Orthomyxoviridae--Enzymology--EN; Antigens, Viral--Analysis--AN; Brain --Pathology--PA; Disease Outbreaks; Encephalitis--Immunology--IM; Encephalitis--Mortality--MO; Influenza--Mortality--MO; Orthomyxoviridae --Pathogenicity--PY; Time Factors; Virulence CAS Registry No.: 0 (Antigens, Viral) Enzyme No.: EC 3.2.1.18 (Neuraminidase) 2/L/17 DIALOG(R)File 154:MEDLINE(R) (c) format only 1995 Knight-Ridder Info. All rts. reserv. 05526368 85142368 Influenza and mania: a possible connection with the locus ceruleus. Maurizi CP South Med J (UNITED STATES) Feb 1985, 78 (2) p207-9, ISSN 0038-4348 Journal Code: UVH Languages: ENGLISH Document type: JOURNAL ARTICLE JOURNAL ANNOUNCEMENT: 8506 Subfile: AIM; INDEX MEDICUS I have presented a possible case of mania induced by influenza B. Some epidemic influenza viruses may be neurovirulent. These epidemics seem to be associated with postencephalitic Parkinson's disease, mania, and depression. Viral, neuroanatomic, neurophysiologic, neurochemical, pharmacologic, clinical, and epidemiologic evidence can be found to suggest a connection between the locus ceruleus, the influenza virus, and the induction of a manic psychosis. Tags: Case Report; Human; Male Descriptors: *Influenza--Complications--CO; *Locus Coeruleus; *Manic Disorder--Etiology--ET; Adult; Locus Coeruleus--Microbiology--MI; Orthomyxoviruses Type B 3/L/4 DIALOG(R)File 154:MEDLINE(R) (c) format only 1995 Knight-Ridder Info. All rts. reserv. 08981498 94296498 Clinical spectrum of secondary parkinsonism in childhood: a reversible disorder. Pranzatelli MR; Mott SH; Pavlakis SG; Conry JA; Tate ED Department of Neurology, George Washington University, Washington, D.C. 20010. Pediatr Neurol (UNITED STATES) Mar 1994, 10 (2) p131-40, ISSN 0887-8994 Journal Code: AA5 Contract/Grant No.: FD-U-000746-01/2, FD, FDA; FD-U-000955-01, FD, FDA Languages: ENGLISH Document type: JOURNAL ARTICLE; REVIEW; REVIEW OF REPORTED CASES JOURNAL ANNOUNCEMENT: 9410 Subfile: INDEX MEDICUS Parkinsonism is an uncommon movement disorder in childhood. Six unusual cases of acquired parkinsonism in hospitalized children are described. Clinical manifestations included an akinetic-rigid syndrome with and without tremor, the combination of parkinsonism and dystonia, and a parkinsonism-plus syndrome. Altered mental status, mutism, dysphagia, and sialorrhea were frequent associations. Etiologies included hypoxic-ischemic encephalopathy; haloperidol treatment with and without neuroleptic malignant syndrome; toxicity of cytosine arabinoside, cyclophosphamide, amphotericin B, and methotrexate; St. Louis encephalitis and other encephalitides; and a pineal tumor with hydrocephalus. Cranial magnetic resonance imaging results ranged from normal to profound cerebral and cerebellar atrophy with chemotherapeutic toxicity. The illnesses usually were severe enough to require pharmacotherapy. Incorrect diagnoses of depression or catatonia delayed treatment or aggravated the problem. Acute treatment included amantadine, levodopa/carbidopa with or without selegiline, diphenhydramine, or benztropine. The concentration of CSF homovanillic acid was normal in a neuroleptic-associated patient, but the level was low in an encephalitic patient. All patients demonstrated dramatic improvement, including two who were not treated; some had complete resolution of symptoms and none required continued antiparkinsonian drugs despite poor scores on the Unified Parkinson's Disease Rating Scale and the Modified Hoehn and Yahr Rating Scales. The causes of parkinsonism described are more common in a general pediatric hospital than the parkinsonism associated with the popularized Segawa syndrome. (52 Refs.) Tags: Case Report; Female; Human; Male; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S. Descriptors: *Parkinson Disease, Symptomatic--Etiology--ET; Adolescence; Antiparkinson Agents--Adverse Effects--AE; Antiparkinson Agents --Therapeutic Use--TU; Atrophy; Brain--Drug Effects--DE; Brain--Pathology --PA; Child; Diagnosis, Differential; Follow-Up Studies; Magnetic Resonance Imaging; Neurologic Examination--Drug Effects--DE; Parkinson Disease, Symptomatic--Chemically Induced--CI; Parkinson Disease, Symptomatic --Diagnosis--DI; Parkinson Disease, Symptomatic--Drug Therapy--DT; Psychoses, Substance-Induced--Diagnosis--DI; Psychoses, Substance-Induced --Etiology--ET; Tomography, X-Ray Computed CAS Registry No.: 0 (Antiparkinson Agents) 3/L/5 DIALOG(R)File 154:MEDLINE(R) (c) format only 1995 Knight-Ridder Info. All rts. reserv. 08794985 94109985 Birthplace as a risk factor in motor neurone disease and Parkinson's disease. Betemps EJ; Buncher CR University of Cincinnati College of Nursing and Health, OH 45221. Int J Epidemiol (ENGLAND) Oct 1993, 22 (5) p898-904, ISSN 0300-5771 Journal Code: GR6 Languages: ENGLISH Document type: JOURNAL ARTICLE JOURNAL ANNOUNCEMENT: 9404 Subfile: INDEX MEDICUS A proportional mortality study was conducted to determine if state of birth is a risk factor associated with motor neurone disease (MND) and Parkinson's disease (PD) using US death certificate information for 1981. State of birth was used as a surrogate variable for location of early childhood environment. A gradient of risk by geographical area in the US was found for MND and PD. Cerebral vascular accident (CVA) deaths served as a comparison group. Multiple sclerosis (MS) deaths were analysed to validate the methods used. A geographical relationship between latitude proportional mortality ratios for MND, PD and MS by state of birth, and a geographical relationship between latitude and proportional mortality ratios for MND and MS by state of birth were found. Statistical modelling was used to compare the deaths from MND, PD, MS, CVA to all other deaths in the US by state of birth. The resulting models were evaluated to determine if any individual states were not well represented by the model for each disease. As predicted, no pattern was evident for CVA. The geographical gradient observed for MS was as predicted by other studies. The geographical pattern found for MND has a northwest to southeast gradient and the pattern found for PD has a west to east gradient. Tags: Comparative Study; Female; Human; Male; Support, Non-U.S. Gov't Descriptors: *Motor Neuron Disease--Epidemiology--EP; *Parkinson Disease --Epidemiology--EP; Cause of Death; Cerebrovascular Disorders--Mortality --MO; Death Certificates; Models, Statistical; Motor Neuron Disease --Mortality--MO; Multiple Sclerosis--Mortality--MO; Parkinson Disease --Mortality--MO; Risk Factors; United States--Epidemiology--EP 3/L/9 DIALOG(R)File 154:MEDLINE(R) (c) format only 1995 Knight-Ridder Info. All rts. reserv. 08721869 94036869 Parkinsonian syndrome in childhood after sodium valproate administration. Alvarez-Gomez MJ; Vaamonde J; Narbona J; Barao M; Barona P; Brannan T; Gudin M; Ibanez R Pediatric Neurology Unit, University of Navarra, Pamplona, Spain. Clin Neuropharmacol (UNITED STATES) Oct 1993, 16 (5) p451-5, ISSN 0362-5664 Journal Code: CNK Languages: ENGLISH Document type: JOURNAL ARTICLE JOURNAL ANNOUNCEMENT: 9402 Subfile: INDEX MEDICUS Among the side effects attributed to sodium valproate administration, the production of a parkinsonian syndrome is very uncommon, particularly in children. We report a 12-year-old girl with secondary epilepsy; 7 days after the initiation of valproate therapy she developed parkinsonism that disappeared completely when valproate was replaced by carbamazepine. We discuss the possible role of alterations in GABAergic neurotransmission in the extrapyramidal syndrome that developed. Tags: Case Report; Female; Human Descriptors: *Parkinson Disease, Symptomatic--Chemically Induced--CI; *Valproic Acid--Adverse Effects--AE; Child CAS Registry No.: 99-66-1 (Valproic Acid) 3/L/17 DIALOG(R)File 154:MEDLINE(R) (c) format only 1995 Knight-Ridder Info. All rts. reserv. 08185442 92323442 Life-style and dietary factors early and late in Parkinson's disease. Vieregge P; von Maravic C; Friedrich HJ Klinik fur Neurologie, Medizinische Universitat zu Lubeck, Federal Republic of Germany. Can J Neurol Sci (CANADA) May 1992, 19 (2) p170-3, ISSN 0317-1671 Journal Code: CJ9 Languages: ENGLISH Document type: JOURNAL ARTICLE JOURNAL ANNOUNCEMENT: 9210 Subfile: INDEX MEDICUS The study investigated features of life-style and dietary habits early and late in life of patients with idiopathic Parkinson's disease (IPD). Seventy-one patients and 103 controls were interviewed personally with a structured questionnaire. Living in villages during primary school time was significantly more frequent among patients, and in the urban environment patients had lived less frequently in larger-sized towns. Mushroom harvesting during childhood was more frequent among patients. No difference between patients and controls was found in childhood water supply, habits of fishing in the countryside or at the seaside, and eating such fish. Actual food preference in patients was greater for almonds and plums, while no difference was found in the actual intake of mushrooms, peanuts, oil-dressed salad, fish and animal offals. The study did not indicate a higher consumption of foods known to harbour heavy metals and pesticides in IPD patients either long before or during the disease. Reduced consumption of foodstuffs rich in vitamin E, as reported previously for premorbid patients, is no longer observed in patients with overt disease. Tags: Animal; Female; Human; Male Descriptors: *Food Habits; *Life Style; *Parkinson Disease--Psychology --PX; Adolescence; Adult; Aged; Basidiomycetes; Cookery; Fishes; Meat; Metals--Analysis--AN; Middle Age; Questionnaires; Rural Population; Urban Population; Water Supply--Analysis--AN CAS Registry No.: 0 (Metals) 3/L/18 DIALOG(R)File 154:MEDLINE(R) (c) format only 1995 Knight-Ridder Info. All rts. reserv. 07867018 92005018 Parkinson's disease and exposure to rural environmental factors: a population based case-control study. Semchuk KM; Love EJ; Lee RG Department of Community Health Sciences, University of Calgary, Canada. Can J Neurol Sci (CANADA) Aug 1991, 18 (3) p279-86, ISSN 0317-1671 Journal Code: CJ9 Languages: ENGLISH Document type: JOURNAL ARTICLE JOURNAL ANNOUNCEMENT: 9201 Subfile: INDEX MEDICUS To determine whether a history of exposure to rural environmental factors leads to an increased likelihood of developing idiopathic Parkinson's disease, we conducted a case-control study of 130 cases and 260 randomly selected community controls (matched with the cases by sex and age +/- 2.5 years at a ratio of 2 controls: 1 case) in the city of Calgary. The data were collected by personal interviews and were analyzed using conditional logistic regression for matched sets. The ages of the cases ranged from 36.5 to 90.7 years (mean = 68.5 +/- 11.3 years). The mean age at diagnosis was 61.1 +/- 12.4 years. The mean duration of disease was 7.8 +/- 0.6 years. Eleven (9.1%) cases were diagnosed before age 40. In this sample from the Province of Alberta, Canada, no significant increase in risk for Parkinson's disease was associated with a history of rural living, farm living, or well water drinking in early childhood or at any time during the first 45 years of life. Tags: Female; Human; Male; Support, Non-U.S. Gov't Descriptors: *Environmental Exposure; *Parkinson Disease--Epidemiology --EP; *Rural Health; Adult; Aged; Aged, 80 and over; Alberta--Epidemiology --EP; Case-Control Studies; Middle Age; Regression Analysis; Risk Factors 3/L/21 DIALOG(R)File 154:MEDLINE(R) (c) format only 1995 Knight-Ridder Info. All rts. reserv. 07681441 91200441 Encephalitis lethargica-like illness in a five-year-old. Mellon AF; Appleton RE; Gardner-Medwin D; Aynsley-Green A Newcastle General Hospital. Dev Med Child Neurol (ENGLAND) Feb 1991, 33 (2) p158-61, ISSN 0012-1622 Journal Code: E83 Languages: ENGLISH Document type: JOURNAL ARTICLE JOURNAL ANNOUNCEMENT: 9107 Subfile: INDEX MEDICUS A five-year-old boy presented with an encephalitis lethargica-like illness, characterised by somnolence, mutism and Parkinsonian rigidity two weeks after an acute exanthem. Investigation revealed increased serum measles antibody titre. He made a complete recovery. Encephalitis lethargica associated with Parkinsonism in childhood is rare and usually carries a poor prognosis. Tags: Case Report; Human; Male Descriptors: *Arousal--Physiology--PH; *Encephalomyelitis--Diagnosis--DI; *Neurologic Examination--Methods--MT; *Parkinson Disease, Postencephalitic --Diagnosis--DI; Akinetic Mutism--Diagnosis--DI; Akinetic Mutism --Physiopathology--PP; Brain--Physiopathology--PP; Child, Preschool; Encephalomyelitis--Physiopathology--PP; Follow-Up Studies; Parkinson Disease, Postencephalitic--Physiopathology--PP; Spinal Cord--Physiopatholog y--PP ============================================================== Part Two to Follow Best, Bob -- ******************************************************** Robert A. Fink, M. D., F.A.C.S. Phone: 510-849-2555 Neurological Surgery FAX: 510-849-2557 2500 Milvia Street Suite 222 Berkeley, California 94704-2636 USA E-Mail: [log in to unmask] CompuServe: 72303,3442 America Online: BobFink "Ex Tristitia Virtus" ********************************************************