LITERATURE.1990

Dr.S.Baranidharan barani at mace.cc.purdue.edu
Thu Jan 19 19:07:19 EST 1995


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\section*{1}
  Increase of deleted mitochondrial DNA in the striatum in 
  Parkinson's disease and senescence.

  Ikebe S, Tanaka M, Ohno K, Sato W, Hattori K, Kondo T, Mizuno Y, Ozawa T
  Department of Biomedical Chemistry, Faculty of Medicine, University of 
Nagoya, Japan.

  Biochem. Biophys. Res. Commun.  Aug 16 1990  170 (3) p1044-8.
  
  A mutant mitochondrial DNA (mtDNA) with a 4,977-bp deletion was detected in 
the parkinsonian brain by using the polymerase chain reaction.  Although the 
deleted mtDNA was detectable even in the brain of aged controls, the proportion 
of deleted mtDNA to normal mtDNA in the striatum was higher in the parkinsonian 
patients than in the controls.  In both the parkinsonian patients and the aged 
controls, the proportion was higher in the striatum than in the cerebral 
cortex. These results indicate that age-related accumulation of deleted 
mtDNA is accelerated in the parkinsonian striatum and suggest that the 
deletion contributes to pathophysiological processes underlying 
Parkinson's disease.

\section*{2}  
  Hutchinson-Gilford progeria: familial occurrence.

  Parkash H, Sidhu SS, Raghavan R, Deshmukh RN
  Department of Dental Surgery, All-India Institute of Medical Sciences, New 
Delhi.

  Am J Med Genet  Aug 1990  36 (4) p431-3
  
  We report on 2 brothers with Hutchinson-Gilford progeria.  These patients 
have 2 unusual findings, i.e., marked resorption of the mandible along with 
loss of teeth in the elder sib and prolonged survival.  Both sibs are still 
alive and active at the age of 32 and 24 years.


\section*{3}
  Altered regulation of platelet-derived growth factor A-chain and c-fos gene 
expression in senescent progeria fibroblasts.

  Winkles JA, O'Connor ML, Friesel R
  Laboratory of Molecular Biology, Jerome H. Holland Laboratory for the 
Biomedical Sciences, American Red Cross, Rockville, Maryland 20855.

  J Cell Physiol  Aug 1990  144 (2) p313-25
  
  The study of human genetic disorders known as premature aging syndromes may 
provide insight into the mechanisms of cellular senescence.  These diseases are 
clinically characterized by the premature onset and accelerated progression of 
numerous features normally associated with human aging.  Previous studies have 
indicated that fibroblasts derived from premature aging syndrome patients have 
in vitro growth properties similar to senescent fibroblasts from normal 
individuals.  As an initial approach to determine whether gene expression is 
altered in premature aging syndrome fibroblasts, RNA was prepared from various 
cell strains and used for gel blot hybridization experiments.  Although normal 
fibroblasts only express platelet-derived growth factor (PDGF) A-chain mRNA for 
a brief period following mitogenic stimulation, one strain of Hutchinson-
Gilford (progeria) syndrome fibroblasts, AG3513, constitutively expresses PDGF 
A-chain mRNA and PDGF-AA homodimers.  The PDGF A-chain gene does not appear to 
be amplified or rearranged in these fibroblasts.  AG3513 progeria fibroblasts 
have properties characteristic of senescent cells, including an altered 
morphology and a diminished mitogenic response to growth promoters.  The 
diminished response of AG3513 progeria fibroblasts to PDGF stimulation was 
examined in some detail.  Studies using 125I-PDGF-BB, which binds with high 
affinity to both A- and B-type PDGF receptors, indicate that normal and AG3513 
progeria fibroblasts have a similar number of PDGF receptors.  Although 
receptor autophosphorylation occurs normally in PDGF-stimulated AG3513 
progeria fibroblasts, c-fos mRNA induction does not.  The senescent phenotype 
of AG3513 fibroblasts is probably unrelated to their constitutive PDGF A-chain 
gene expression, further studies are necessary in order to directly address 
this issue.  Also, additional analysis of this progeria fibroblast strain may 
provide information on the control of mitogen-inducible gene expression in 
normal cells.

\section*{4}
  Does progeria provide the best model of accelerated ageing in humans?

  Mills RG, Weiss AS
  Department of Biochemistry, University of Sydney, Australia.

  Gerontology  1990  36 (2) p84-98
  
  Studies of the causes of ageing are often obscured by the complexity of this 
phenomenon, hindering investigations in this area.  In particular, the variable 
characteristics of ageing complicate analysis at a molecular level.  It is 
proposed that to gain insight into ageing, the problem must first be simplified 
by restricting studies to an aspect of the ageing processes.  It is suggested 
that progeria, which presents a less complicated etiology and phenotype than 
other accelerated ageing diseases, allows research to focus on a regulation 
site involved in development and ageing.


\section*{5}
  Ophthalmological aspects in patients with Werner's syndrome.

  Ruprecht KW
  Department of Ophthalmology, University of Erlangen-Nurnberg, F.R.G.

  Arch Gerontol Geriatr  Nov-Dec 1989  9 (3) p263-70
  
  In ten of 18 eyes from nine patients with Werner's syndrome, cataract surgery 
was complicated by wound dehiscence and its consequences: peripheral anterior 
synechiae (4), secondary epiretinal gliosis (4), cystoid macular edema (3) in 
the framework of Hruby-Irvine-Gass syndrome, unplanned filtering bleb (2), and 
post-operative anterior ischemic optic neuropathy (1).  Additionally, corneal 
endothelial decompensation occurred in eight eyes.  In view of the fibroblasts' 
reduced growth potential, we suggest small surgical incisions, extracapsular 
cataract surgery using phacoemulsification, intraocular irrigation solutions 
protecting corneal endothelium, nonabsorbable single knot sutures not removed 
before 1 year after surgery, and no local or systemic use of cortisone.


\section*{6}
  Bilateral spontaneous dislocated lenses, retinal vasculitis and progeria-like 
changes.

  Sharir M, Ragenbogen L
  Goldschlager Eye Institute, Sheba Medical Center, Tel Hashomer, Israel.

  Metab Pediatr Syst Ophthalmol  1990  13 (1) p5-9
  
  Findings are reported for a 70-year-old man with a progeria-like syndrome 
consisting of premature aging (per history), diffuse wasting, skin atrophy, 
disseminated skeletal osteoporosis (documented for at least 25 years), 
especially in the vertebral column and metacarpal joints with short stature, 
beaked nose and high-pitched voice, The ocular findings include: spontaneous 
bilateral dislocation of spherophakic mature cataracts into the vitreous 
together with bilateral retinal vasculitis, characterized by venous congestion, 
tortuosity and occlusion, To the best of our knowledge, there is no case report 
with all the above features in one person, Hence, the differential diagnosis 
will also be discussed.


\section*{7}
  Clonal structural chromosomal rearrangements in lymphocytes of four patients 
with Werner's syndrome.

  Scappaticci S, Forabosco A, Borroni G, Orecchia G, Fraccaro M
  Biologia Generale e Genetica Medica, Universita di Pavia, Italia.

  Ann Genet  1990  33 (1) p5-8
  
  Multiple numerical and structural chromosome abnormalities were found in 
cultured lymphocytes of four patients with Werner's syndrome.  The proportion 
of metaphases with structural and/or numerical aberrations varied from 30 to 
44% and several of them were clonal.  These results confirm definitively that 
Werner's syndrome is a chromosome rearrangement syndrome and that these non-
constitutional chromosome changes are not exclusive of cultured fibroblasts but 
present also in lymphocytes.


\section*{8}
  Ultraviolet light-induced DNA damage in transcribed sequences: no change in 
repair with age.

  Kunisada T, Miller CD, Schneider EL
  Laboratory of Molecular Genetics, National Institute on Aging, Baltimore, MD 
21224.

  Mutat Res  Mar 1990  237 (2) p75-81
  
  We studied the repair of a plasmid vector containing the chloramphenicol 
acetyltransferase (CAT) gene by treating the plasmid with UV light and then 
transfecting this plasmid into fibroblasts from human fetal lung (in vitro 
aging) and into primary cultured fibroblasts from rat lung and skin.  This 
methodology allows us to examine the repair of specific transcribed DNA 
sequences.  There was no age-related change in the repair of UV damage in these 
cells.  Rat embryo fibroblasts at different passages transfected with the 
plasmid also revealed no significant alteration in UV repair as a function of 
passage number.

\section*{9}
  Are transposons a cause of ageing?

  Murray V
  Molecular Sciences Group, Peter MacCallum Cancer Institute, Melbourne, Vic., 
Australia.

  Mutat Res  Mar 1990  237 (2) p59-63
  
  A hypothesis for ageing is proposed based on the properties of transposons.  
During the process of transposition, one copy of the DNA sequence generally 
remains at the same position while the other copy moves to another location in 
the genome.  In this manner the DNA sequence of the transposon is effectively 
duplicated.  With time the number of transposons increases exponentially and 
since in their new location they can inactivate an essential gene, they will 
eventually kill a cell line or organism.  Thus transposons could be a cause of 
ageing.  This hypothesis is attractive because it can explain many of the 
properties of senescent cells.  Other processes capable of DNA self-duplication 
(e.g., reverse transcription) could also contribute to the increase in 
transposable DNA sequences.  


\section*{10}
  Sister chromatid exchange and proliferation pattern in lymphocytes from 
newborns, elderly subjects and in premature aging syndromes.

  Melaragno MI, Smith M de A
  Disciplina de Genetica, Escola Paulista de Medicina, Sao Paulo SP, Brazil.

  Mech Ageing Dev  May 15 1990  54 (1) p43-53
  
  Sister chromatid exchange (SCE) frequency and cell proliferation were 
examined in lymphocyte cultures from a group of newborns, a group of elderly 
subjects and from patients with syndromes who exhibit progeriform 
characteristics (progeria, Cockayne syndrome, Rothmund-Thomson syndrome and 
Christ-Siemens-Touraine syndrome) by using the bromodeoxyuridine incorporation 
differential staining technique.  We observed a significantly increase in basal 
SCE frequency and a less intensive cell proliferation in cultures from elderly 
subjects than from newborns, as shown by the significant increase in percentage 
of cells in first generation simultaneous with a reduction of cells in more 
advanced generations.  Lymphocyte cultures from each one of the patients 
studied also showed a decreased cell proliferation in relation to their 
respective control and to newborn cultures.  Each of these syndromes showed 
higher baseline SCE levels than the control and than the newborn and elderly 
groups.  Only the patient with progeria showed values similar to those for the 
elderly group.  Thus, in addition to showing clinical characteristics similar 
to those observed during the normal aging process, these progeriform syndromes 
also show cytogenetic characteristics similar to those of older individuals.


\section*{12}
  Mitochondrial mutations may increase oxidative stress: implications for 
carcinogenesis and aging?

  Bandy B, Davison AJ
  Bioenergetics Research Laboratory, School of Kinesiology, Simon Fraser 
University, Burnaby, B.C., Canada.

  Free Radic Biol Med  1990  8 (6) p523-39
  
  The sensitivity of mitochondrial DNA to damage by mutagens predisposes 
mitochondria to injury on exposure of cells to genotoxins or oxidative stress.  
Damage to the mitochondrial genome causing mutations or loss of mitochondrial 
gene products, or to some nuclear genes encoding mitochondrial membrane 
proteins, may accelerate release of reactive species of oxygen.  Such aberrant 
mitochondria may contribute to cellular aging and promotion of cancer.

\section*{13}
  Inheritable abnormal lipoprotein metabolism in Werner's syndrome similar to 
familial hypercholesterolaemia.

  Mori S, Yokote K, Morisaki N, Saito Y, Yoshida S
  Second Department of Internal Medicine, School of Medicine, Chiba University, 
Japan.

  Eur J Clin Invest  Apr 1990  20 (2) p137-42
  
  Studies were made on the abnormality of lipoprotein metabolism and its cause 
in 10 patients with Werner's syndrome.  Seven of the 10 patients had 
hypercholesterolaemia (above 250 mg dl-1).  Six of the seven patients with 
hypercholesterolaemia had thickened Achilles' tendons (greater than 9 mm).  A 
significant positive correlation (P less than 0.01) was found between the serum 
total cholesterol levels and the thickness of Achilles' tendons in these 10 
patients, suggesting that the substance precipitated in the thickened tendons 
is derived from serum cholesterol.  Some first-degree relatives of three 
patients with both hypercholesterolaemia and xanthoma-like thickening of 
Achilles' tendons also suffered from hypercholesterolaemia.  Moreover, the low 
density lipoprotein (LDL) receptor activities in peripheral lymphocytes of five 
patients with both hypercholesterolaemia and xanthoma-like tendons were 
significantly (P less than 0.001) lower than those of controls, whereas the LDL 
receptor activities of two patients without hypercholesterolaemia were almost 
the same as those of controls.  These findings suggest that, at least these 
five patients with lower lymphocyte LDL receptor activities, and probably 
another patient with both hypercholesterolaemia and xanthoma-like thickening of 
Achilles' tendons suffered from familial hypercholesterolaemia (FH).  If this 
is the case, this high frequency of association of Werner's syndrome with FH 
(in six of 10 patients) suggests some relationship between these two diseases.


\section*{14}
  Recessively inherited deficiencies predisposing to cancer.

  Muller H
  Department of Research, University Clinics, Kantonsspital, Basel, 
Switzerland.

  Anticancer Res  Mar-Apr 1990  10 (2B) p513-8
  
  The genetic factors involved in the multistep process of carcinogenesis can 
be divided at least into two major categories: 1. Mutated or lost genes, which 
may directly represent one step in the sequential process (tumour suppressor 
genes), inheritance of one tumour suppressor gene causes dominant expression of 
the carcinogenic phenotype (the dominant inheritance is described in the 
accompanying paper), 2. Other genes, which lead to conditions that favour the 
development of cancer and generally are inherited in a recessive fashion, they 
are the subject of this paper.  Autosomal recessively inherited diseases, such 
as xeroderma pigmentosum, ataxia-telangiectasia, Bloom's syndrome and Fanconi's 
anaemia display increased genome instability (chromosomal fragility and/or DNA-
repair deficiencies) and are associated in the homozygote and probably also in 
the heterozygote state with defined malignancies.  Neoplasms particularly of 
the lymphoreticular system frequently occur in patients with genetically 
determined immunodeficiencies (e.g. severe combined immune deficiency or 
Wiskott-Aldrich syndrome).  People differ due to their individual genetic 
constitution in their responses to various classes of carcinogens such as 
physical and chemical agents, to dietary habits, as well as to viruses.  
Furthermore, tumours are often found in patients displaying premature aging 
(e.g.  Werner's syndrome).  In addition, several metabolic abnormalities such 
as genetic syndromes featuring chronic liver disease, but also many other 
inherited metabolic conditions have cancer as a regular or frequent 
complication.  

\section*{16}
  Growth properties and in vitro life span of Alzheimer disease and Down 
syndrome fibroblasts. A blind study.

  Carmeliet G, Hauman R, Dom R, David G, Fryns JP, Van den Berghe H, Cassiman 
JJ,   
  Center for Human Genetics, University of Leuven, Belgium.

  Mech Ageing Dev  Mar 31 1990  53 (1) p17-33
  
  A blind study was set up to examine the in vitro growth characteristics of 
skin fibroblasts from 2 individuals with and 9 at risk for familial Alzheimer 
disease, 4 individuals with sporadic Alzheimer disease, 18 with Down syndrome 
as well as 5 younger and 6 older controls.  Several variables (biopsy size, 
number of explants, medium, passage procedure) were standardized.  Two growth 
characteristics were examined quantitatively: (i) the actual in vitro 
replicating life span was determined by counting the number of cells plated the 
previous week at 500,000 cells/flask (cumulative population doublings), and 
(ii) the growth potential was examined by a colony size distribution assay.  A 
difference from the age-matched controls in the growth characteristics of skin 
fibroblasts was only observed for two patients with and one older individual at 
risk for familial Alzheimer disease.  The growth properties of skin fibroblast 
cultures from patients with sporadic Alzheimer disease or Down syndrome were 
not at variance with their age-matched controls.  The decrease in the growth 
potential observed in the familial Alzheimer disease fibroblasts is however 
modest and needs confirmation.  It is clear that the growth properties of skin 
fibroblasts, as examined in this study, do not provide a good marker for any 
form of Alzheimer disease, nor do they provide an appropriate in vitro system 
to study factors which may contribute to the etiopathogenesis of Alzheimer 
disease or Down syndrome.


\section*{17}
  Establishment of immortalized primate epithelial cells with sub-genomic EBV 
DNA.

  Karran L, Teo CG, King D, Hitt MM, Gao YN, Wedderburn N, Griffin BE
  Department of Virology, Royal Postgraduate Medical School, Hammersmith 
Hospital, London, UK.

  Int J Cancer  Apr 15 1990  45 (4) p763-72
  
  The genetic information in a sub-fragment of EBV DNA, designated p31 
(containing less than a quarter of the viral genome and derived from a 
recombinant DNA cosmid library) allows epithelial cells from primary monkey and 
human kidney cultures to escape senescence under standard tissue culture 
conditions.  A number of epithelial cell lines, designated M1/31, 483/31, 
199/31 and HK/31, have been established and characterized following 
transfection of primary cells with p31 DNA.  They share many properties, 
although morphologically they are not all identical.  The cultures are 
immortalized but not fully transformed or tumorigenic.  They appear to be 
phenotypically stable, although DNA hybridization studies indicate that 
genotypic alterations, including amplification, occur subsequent to 
transfection with p31 DNA and the establishment of a continuously proliferating 
epithelium.  All cell lines consistently express high levels of cytokeratin 18 
and varying amounts of cytokeratin 7, demonstrating their epithelial origin.  



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