LITERATURE.1992

[Dr.S.Baranidharan]

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\section*{1 }
  Applications of chaos theory to the molecular biology of aging.

  Kyriazis M
  Age Concern Institute of Gerontology, King's College, London, United Kingdom.

  Exp Gerontol  1991  26 (6) p569-72.
  
  New developments in the field of chaos theory can help us describe in detail 
many hitherto unexplained natural phenomena.  Some of the developments of this 
theory can be applied to molecular gerontology to complement existing 
techniques used in this field.  Thus, there is the potential of better 
description, quantification, and manipulation of some aging mechanisms.

\section*{2}
  Genetic linkage of Werner's syndrome to five markers on chromosome 8.

  Goto M, Rubenstein M, Weber J, Woods K, Drayna D
  Department of Rheumatology, Tokyo Metropolitan Otsuka Hospital, Japan.

  Nature  Feb 20 1992  355 (6362) p735-8
  
  Werner's syndrome (WS) is a rare autosomal recessive disease in which the 
affected individuals display symptoms of premature ageing.  The substantial 
phenotypic overlap between WS and normal ageing indicates that these two 
conditions may have pathogenetic mechanisms in common.  The WS mutation has 
pleiotropic effects, and patients and their cells show many differences 
compared with normals.  Despite extensive study of the clinical and biochemical 
features of this disorder, the primary genetic defect remains unknown.  We have 
undertaken a genetic linkage study in an effort to identify the locus of the 
primary defect.  Here we report close genetic linkage of the WS mutation to a 
group of markers on chromosome 8.

\section*{3}
  Cockayne syndrome a case report, and a review of the premature aging 
syndromes in paediatrics.

  Loke KY
  National University of Singapore.

  J Singapore Paediatr Soc  1991  33 (1-2) p49-54
  
  The premature aging syndromes are a rare eccentric group of syndromes in 
which predominantly senile features develop prematurely.  Cockayne Syndrome is 
one of several premature aging syndromes, it has been recognised, but hitherto 
unreported in the local literature.  This is a case report of a child with the 
classical features of Cockayne Syndrome.  

\section*{4}
  Developmental aspects of experimental pulmonary oxygen toxicity.

  Frank L
  Pulmonary Research (R-120), University of Miami School of Medicine, FL 33101.

  Free Radic Biol Med  1991  11 (5) p463-94
  
  One of the more fascinating aspects of in vivo research on pulmonary O2 
toxicity is the striking difference in the response of the neonatal versus the 
adult animal to hyperoxia.  In general, neonatal animals are much more 
resistant to the characteristic O2-induced lung pathology seen in adult animals 
in hyperoxia.  Neonatal animals are also able to rapidly mount a protective 
lung biochemical response to high O2 exposure [increased pulmonary antioxidant 
enzyme (AOE) activities], an adaptive response which adult animals have lost 
the ability to manifest in greater than 95% O2.  This review focuses on the 
disparate AOE responses of the neonatal versus adult animal in hyperoxia.  It 
also explores other possible explanations for the striking O2 tolerance of 
young versus adult animals, including comparative O2 free radical production 
rates, inflammatory cell responses, lung lipid composition, repair 
capabilities, etc. Discussion also centers on a less well studied toxic 
complication associated with hyperoxic exposure in the neonatal animal, i.e., 
the marked inhibitory effect of O2 exposure on normal lung growth and 
development of an alveolarized lung with an expanded respiratory exchange 
surface area.  Finally, effective experimental means of protecting adult (and 
neonatal) animals from pulmonary O2 toxicity are reviewed.  A closing section 
considers the enlightening new information that molecular biology has revealed 
about the regulation of AOE gene expression during normal development and under 
conditions of hyperoxidant challenge.  


\section*{5} 
  Exposure to low-frequency pulsed electromagnetic fields increases mitogen-
induced lymphocyte proliferation in Down's syndrome.

  Cossarizza A, Monti D, Bersani F, Scarfi MR, Zanotti M, Cadossi R, Franceschi 
C
  Institute of General Pathology, University of Modena School of Medicine, 
Italy.

  Aging (Milano)  Sep 1991  3 (3) p241-6
  
  We previously reported that exposure of human mitogen-stimulated peripheral 
blood lymphocytes (PBL) to extremely low frequency pulsed electromagnetic 
fields (PEMFs) could restore the defective proliferative capability of PBL from 
aged subjects.  The effects of exposure to PEMFs were studied in PBL from 25 
patients with Down's syndrome (DS), a syndrome of premature aging characterized 
by precocious immune system derangement, including age-related defective PBL 
proliferative capability.  PBL were stimulated with different doses of 
phytohemagglutinin, and cell proliferation was assessed by measuring the 
incorporation of tritiated thymidine.  After PEMF-exposure, a significant 
increase in cell proliferation was observed in cells from DS children and young 
adults, but it was much more evident in PBL from relatively aged DS patients.  
The age-related effect of PEMFs on DS lymphocytes demonstrates that age must be 
considered a major variable when studies on DS are performed, and confirms that 
DS must be regarded as a syndrome of accelerated aging.


\section*{6}
  Oxidants and antioxidants in proliferative senescence.

  Poot M
  Department of Human Genetics, University of Wurzburg, Germany.

  Mutat Res  Mar-Nov 1991  256 (2-6) p177-89
  
  In terms of the amount of experimental research it has generated the free 
radical theory of ageing is one of the most popular hypotheses to explain this 
ubiquitous phenomenon.  From the theory two postulates were derived: either 
cellular defence mechanisms against free radical-dependent oxidants deteriorate 
during ageing of cells, or essential, unrepairable damages are imparted to the 
cell by oxidants regardless of the activity of antioxidant defence systems.  
The many reports dealing with a putative breakdown in antioxidant defence 
systems failed to positively support this postulate.  However, a minor 
depletion in cellular glutathione by exposure to a model lipophilic peroxide 
led to a significant decrement in DNA and protein synthesis.  In other words, 
the glutathione redox cycle is intrinsically fallible with respect to defending 
the cellular DNA replication system against this model lipophilic peroxide.  
Interestingly, after ageing in culture cells a partial uncoupling of the NADPH-
producing and -consuming systems tends to take place.  Experiments involving 
the addition of antioxidants to the culture medium have failed to significantly 
extend the lifespan of cultured diploid somatic cells.  The level of 
antioxidants appears to be a modulator rather than a primary determinant of 
cellular ageing in culture.  Several lines of evidence suggest that DNA damages 
accumulate during ageing of the organism, but no oxidant-related DNA damage has 
been pinpointed in the cultured cell system.  Human mutants with defects in 
antioxidant enzymes have not shown conclusive signs of accelerated ageing.  
Cells from patients with Werner's syndrome (progeria of the adult), on the 
other hand, do not suffer from a defect in their antioxidant defence system, 
nor do they accumulate more than normal amounts of autofluorescent products 
resulting from lipid peroxidation.  The recent finding that Werner's syndrome 
constitutes a mutator phenotype may prompt the comparison of oxidant- and 
ageing-related mutation spectra in order to investigate a mutational theory of 
ageing as a new derivative from the free radical hypothesis.  


\section*{7}
  Altered p53 gene structure and expression in human epithelial cells after 
exposure to nickel.

  Maehle L, Metcalf RA, Ryberg D, Bennett WP, Harris CC, Haugen A
  Department of Toxicology, National Institute of Occupational Health, Oslo, 
Norway.

  Cancer Res  Jan 1 1992  52 (1) p218-21
  
  The carcinogenicity of certain nickel compounds is well known.  We have 
previously shown that human kidney epithelial cells were immortalized by 
treatment with Ni(II) and in cooperation with the v-Ha-ras oncogene transformed 
the cells to acquire tumorigenicity in athymic nude mice.  Immunocytochemistry 
and sequence analysis of DNA from the nickel-immortalized cells revealed 
abnormal p53 expression and a T  C transition mutation in codon 238.  These 
data are consistent with the hypothesis that Ni(II)-induced mutation in the p53 
gene can be involved in the escape from senescence of kidney epithelial cells.

\section*{8} 
  Lethal progeroid syndrome with osteolysis. Case report.

  Le Merrer M, Guillot M, Briard ML, Maroteaux P
  U12, Unite de Recherches INSERM sur les Handicaps Genetiques de l'Enfant, 
Hopital des Enfants-Malades, Paris, France.

  Ann Genet  1991  34 (2) p82-4
  
  A particular progeroid syndrome with severe acro-osteolysis, cutaneous 
changes, failure to thrive, and early death is described in a young boy.  
Progeria and mandibulo-acral dysplasia are discussed, but early death is 
unusual in these two syndromes.  This observation raises the question of a 
large spectrum including all of these syndromes.

\section*{9} 
  Progressive early dermatologic changes in Hutchinson-Gilford progeria 
syndrome.

  Gillar PJ, Kaye CI, McCourt JW
  University of Texas Health Science Center, Department of Pediatrics, San 
Antonio 78284-7802.

  Pediatr Dermatol  Sep 1991  8 (3) p199-206
  
  We describe evolving dermatologic findings in a male with progeria from age 1 
month to 21.5 months.  At 18 months of age, irregular pigmentary changes of the 
abdomen, early occipital alopecia, superficial scalp veins, glyphic nasal tip, 
absent ear lobules, coarse hair that stands on end, crowded dentition with 
delayed tooth development, and dystrophic nails permitted the diagnosis of 
progeria.  Radiographs showed evidence of resorption of the distal ends of the 
clavicles, attenuation of the terminal phalanges, diffuse osteopenia, and 
fishmouth vertebral bodies, which are typical of this syndrome.  Appreciation 
of the evolution of early dermatologic findings may permit earlier diagnosis of 
this condition in infants with skin changes.


\section*{10}
  Peripheral dopamine in pathophysiology of hypertension. Interaction with 
aging and lifestyle.

  Kuchel OG, Kuchel GA
  Clinical Research Institute of Montreal, Quebec, Canada.

  Hypertension  Dec 1991  18 (6) p709-21
  
  Dopamine, an ancestral catecholamine, is physiologically natriuretic and 
vasodilating, thus essentially protecting against hypertension.  Its actions 
are overshadowed by the opposite effects of its main biological partner, 
norepinephrine, and this is accentuated with aging.  Clinical observations 
combined with molecular biology approaches to catecholamine-synthesizing and 
catecholamine-metabolizing enzymes and receptors permit the identification of 
some inborn defects.  Subtle changes in the dopamine-norepinephrine balance may 
account for the enhanced peripheral noradrenergic activity seen in the setting 
of decreased dopaminergic activity in advanced age.  These changes may 
contribute to the diminished ability of the aged kidney to excrete a salt load, 
as well as to the finding that systolic blood pressure increases with age in 
populations with a high, but not in those with a low, intake of salt.  The 
attainment of advanced age in Western societies with adverse lifestyle changes 
(mental rather than physical stress, excess salt intake, overeating, 
sedentarism) appears to facilitate the development of hypertension.  The 
adaptation to all the preceding lifestyle changes necessitates an increased 
dopamine generation, which may initially compensate to maintain appropriate 
natriuresis and vasodilation since many patients with initial borderline 
essential hypertension express their sympathetic hyperfunction, in addition to 
increased norepinephrine release, by excessive dopamine release.  However, the 
progression of hypertension is accompanied by a peripheral dopaminergic 
deficiency and diminished ability to excrete salt.  This may represent an 
eventual inadequacy of a phylogenetically redundant system resulting in 
decreased natriuresis and vasodilation and may account for the responsiveness 
of established chronic hypertension to salt restriction, diuretics, and 
dopaminomimetic medication.  

\section*{11} 
  Insulin-like growth factor binding protein 3 accumulates to high levels in 
culture medium of senescent and quiescent human fibroblasts.

  Goldstein S, Moerman EJ, Jones RA, Baxter RC
  Department of Medicine, University of Arkansas for Medical Sciences, Little 
Rock.

  Proc Natl Acad Sci U S A  Nov 1 1991  88 (21) p9680-4
  
  Insulin-like growth factor binding protein 3 (IGFBP-3) mRNA levels were 
consistently higher in both senescent normal human diploid fibroblasts (HDFs) 
at late passage (old cells) and prematurely senescent HDFs from a subject with 
Werner syndrome (WS) during serum depletion and repletion of growth medium and 
during proliferation from sparse to high-density inhibited cultures, compared 
to normal early-passage (young) HDFs.  However, IGFBP-3 protein accumulated to 
higher levels in conditioned medium of old cells than in medium of WS and young 
cells, in that order, under the same conditions.  Insulin-like growth factor I 
(IGF-I) was not detected in naive medium or in any of the media conditioned by 
these three cell types, whereas IGF-II was detectable in serum-repleted medium 
and remained relatively constant.  Thus, molar ratios of IGFBP-3/IGF-II were 
consistently higher in old and WS cells and increased substantially as all 
three cell types became quiescent, due to either serum depletion or high cell 
density.  These data are consistent with either an adaptive or a causal role 
for IGFBP-3 protein in the senescent and quiescent growth arrest of HDFs.

\section*{12}
  Reduced DNA repair in progeria cells and effects of gamma-ray irradiation on 
UV-induced unscheduled DNA synthesis in normal and progeria cells.
  Wang SM, Nishigori C, Yagi T, Takebe H
  Department of Experimental Radiology, Faculty of Medicine, Kyoto University, 
Japan.
  Mutat Res  Jan 1991  256 (1) p59-66
  
  A reduction in the amount of UV-induced unscheduled DNA synthesis (UDS), and 
reduced cell survival and host-cell reactivation against UV exposure in 
Hutchinson-Gilford progeria syndrome cell strains were shown.  UV-induced UDS 
in 4 progeria cell strains was 33-50% of the normal level.  A similar reduction 
in the UV-induced UDS in normal cells was caused by gamma-ray irradiation to 
the cells before UV irradiation.  The dose of gamma-rays required to cause a 
reduction in UDS of normal cells to the level of progeria cells was 40 Gy and 
the reduction was reversible after 2 days.  In progeria cells, gamma-ray 
irradiation further reduced UDS with a lower gamma-ray dose required than in 
normal cells, and the reduction was also reversible but with less relative 
recovery than in normal cells.  The presence of a 'built-in' defect in 
progeria cells responsible for the reduced DNA-repair capacity was suggested, 
and such defect may share a common mechanism with the reduction of UV-induced 
UDS in normal cells caused by gamma-ray irradiation.

\section*{13} 
  Receptor function of low-density lipoproteins in Werner's syndrome.

  Saito Y
  Second Department of Internal Medicine, School of Medicine, Chiba University, 
Japan.

  Gerontology  1991  37 Suppl 1 p48-55
  
  Abnormal lipoprotein metabolism and its cause were studied in 10 patients 
with Werner's syndrome.  Seven of the 10 patients had hypercholesterolemia 
(greater than 250 mg dl-1).  A significant positive correlation (p less than 
0.01) was found between serum total cholesterol levels and LDL receptor 
activity.  In monocyte-derived macrophages of patients with this syndrome, the 
uptake, lysosomal hydrolysis and re-esterification of free cholesterol are 
enhanced.  This abnormal accumulation of cholesterol ester may cause 
accelerated conversion of macrophages to foam cells in Werner's syndrome.

\section*{14}
  
Possible Werner syndrome. A unique association with spontaneous digital 
gangrene in infancy and decreased life span of cultured skin fibroblasts.

  Iijima S, Arinami T, Otsuka F
  Department of Dermatology, Mito Red Cross Hospital, Japan.

  Arch Dermatol  Sep 1992  128 (9) p1238-42  

  Background-Werner syndrome is a hereditary disease characterized by several 
features generally associated with aging.  However, the differences between 
Werner syndrome and the normal aging process are clear.  Werner syndrome is 
usually diagnosed through the clinical signs and symptoms it presents.  In 
recent years, however, the cultured skin fibroblasts of patients have grown 
slowly and patients have a short life span, these characteristics provide a 
useful diagnostic aid.  OBSERVATIONS We recently examined a 42-year-old single 
man who had short fingers, marked facial scars resulting from chilblain-like 
eruption in infancy, glaucoma caused by uveitis developed in his middle age, 
callosities on the soles, and immaturation of sexual glands.  Repeated 
peripheral blood examinations showed a positive result for antinuclear factor, 
slight elevation of immunoglobulin levels, and a low leukocyte count.  His 
family had repeated consanguineous marriages and his parents were cousins.  We 
cultured skin fibroblasts from the patient's forearm and compared them with 
those of four normal control male subjects.  The patient's skin fibroblasts 
showed a remarkably low population growth rate and a total replicative life 
span.  CONCLUSION The patients presented unique clinical features for Werner 
syndrome such as chilblain-like eruption in infancy and glaucoma caused by 
uveitis.  Cell culture studies revealed cellular abnormalities compatible with 
Werner syndrome.  We thus diagnosed the patients as possibly having Werner 
syndrome.

\section*{15}
  Protein oxidation and aging.

  Stadtman ER
  Laboratory of Biochemistry, National Heart, Lung, and Blood Institute, 
National Institutes of Health, Bethesda, MD 20892.

  Science  Aug 28 1992  257 (5074) p1220-4  
  
  A number of systems that generate oxygen free radicals catalyze the oxidative 
modification of proteins.  Such modifications mark enzymes for degradation by 
cytosolic neutral alkaline proteases.  Protein oxidation contributes to the 
pool of damaged enzymes, which increases in size during aging and in various 
pathological states.  The age-related increase in amounts of oxidized protein 
may reflect the age-dependent accumulation of unrepaired DNA damage that, in a 
random manner, affects the concentrations or activities of numerous factors 
that govern the rates of protein oxidation and the degradation of oxidized 
protein.  

\section*{16}
             
  Difficulties with studying accelerated aging [editorial]

  Harrison DE

  Growth Dev Aging  Summer 1992  56 (2) p67  
  
\section*{17}
  DNA extraction from bloodstains in respect to age and stained substrate.

  Prinz M, Staak M, Berghaus G

  Acta Med Leg Soc (Liege)  1989  39 (2) p213-20  
  
  The amount and the quality of DNA that could be extracted from bloodstains 
equivalent to 200 microliters blood were examined after 3, 6, 9, 12, 15, 18 and 
21 days of storage under dry or humid conditions at room temperature.  DNA was 
also extracted from two days old 200 microliters bloodstains on different stain 
carriers.  The amount of DNA that could be extracted showed a dependency on all 
the parameters that were examined.  On carriers with a rough surface structure, 
where the blood can soak in, the resolving of leukocytes was impaired and the 
DNA recovery rate was low, e.g. carpeting and suede.  The DNA yield was higher 
for substrates with a smooth surface, e.g. paper, glass and smooth leather.  
The aging experiments revealed that for the stains stored under dry conditions, 
there was no decrease in the DNA yield for stains on glass, while the amount of 
DNA that could be extracted became less for older stains on cotton.  Under 
humid conditions the DNA yield was high and did not decrease for both glass and 
cotton fabric.  The quality of the DNA was not impaired by aging or storage 
conditions, but for several stain carriers the DNA was contaminated by chemical 
substances which inhibited restriction enzyme digestion and successful DNA-
typing.


\section*{18}
  A pattern of accumulation of a somatic deletion of mitochondrial DNA in aging 
human tissues.

  Cortopassi GA, Shibata D, Soong NW, Arnheim N
  Molecular Biology Section and Medical Center, University of Southern 
California, Los Angeles 90089-1340.

  Proc Natl Acad Sci U S A  Aug 15 1992  89 (16) p7370-4  
  
  An assay that selectively amplifies a specific deletion of the mitochondrial 
genome has been used to study the extent of the deletion's accumulation in a 
variety of human tissues.  The deletion occurs at much higher levels in nervous 
and muscle tissues than in all other tissues studied.  The variation in 
deletion level between the same tissues in different persons of similar age 
appears to be less than the variation among tissues within an individual.  
Tests for artifactual explanations of the level differences were each 
negative.  Three cellular parameters that are correlated with the level of 
the deletion are identified.  The preferential accumulation of deleterious 
mitochondrial mutations in a restricted subset of aging human 
tissues may compound deficiencies of function in those tissues that 
accrue with age.

\section*{19}
           
  Contractile proteins and sarcoplasmic reticulum calcium-ATPase gene 
expression in the hypertrophied and failing heart.

  Schwartz K, Carrier L, Lompre AM, Mercadier JJ, Boheler KR
  I.N.S.E.R.M. Unite 127, Hopital Lariboisiere, Paris, France.

  Basic Res Cardiol  1992  87 Suppl 1 p285-90  
  
  The physiology of myocardial contractility has been studied for over a 
century, but only recently has molecular biology provided new insights into the 
mechanisms responsible for the alterations of contraction and relaxation 
observed during cardiac hypertrophy and heart failure.  Pressure and volume 
overload produce in the myocyte both qualitative changes characterized by 
protein isoform switches and quantitative changes characterized by modulation 
of single genes through a mechanogenic transduction the pathways of which are 
largely unknown.  The qualitative changes involve differential expression of 
multigene families of contractile proteins, especially myosin heavy chain (MHC) 
and actin.  All situations of pressure overload, or of combined pressure and 
volume overload activate the beta-MHC gene and deactivate the alpha-MHC one, 
which leads to a slower, more efficient contraction.  In rat, pressure overload 
transitorily activates the alpha-skeletal actin gene, and both the timing and 
the distribution of the newly formed beta-MHC and alpha-skeletal actin mRNAs 
differ.  We recently found that the isoactin pattern is the same in patients 
with end-stage heart failure as that of control human hearts.  Moreover, both 
in rat and human, expression of isomyosins and isoactins are not coordinated, 
neither during ontogeny nor senescence.  All this suggests the existence of 
several regulatory mechanisms activated during normal cardiac growth or by a 
mechanical trigger, and preliminary results indicate that it is possible to 
perform nuclear run-on assays in order to analyze the transcriptional step of 
these isogenes.(ABSTRACT TRUNCATED AT 250 WORDS) 

\section*{20}
  Reduced 5-hydroxymethyluracil-DNA glycosylase activity in Werner's syndrome 
cells.

  Ganguly T, Duker NJ
  Department of Pathology, Temple University School of Medicine, Philadelphia, 
PA 19140.

  Mutat Res  Mar 1992  275 (2) p87-96  
  
  Werner's syndrome (WS) is an autosomal recessive disease marked by early 
symptoms of accelerated aging.  There is evidence indicating accumulation of 
oxidized DNA bases to be a major factor in cellular aging.  The first step of 
excision repair of such bases in human cells is their removal from DNA by 
glycosylases.  5-Hydroxymethyluracil (HMU)-DNA glycosylase excises HMU from 
DNA, another glycosylase removes many non-aromatic pyrimidine derivatives.  
Levels of glycosylases that excise oxidized pyrimidines from DNA were compared 
between confluent and proliferating populations of WS cells, age-matched 
controls, and young control cells.  They were assayed by measurements of direct 
release of free bases from their respective DNA substrates.  Specific 
activities of the glycosylase that releases various modified pyrimidines and of 
uracil-DNA glycosylase (which removes uracil from DNA) were essentially the 
same in all cell lines.  Cell cycle variations of these enzymes also did not 
differ between WS and control cells.  HMU-DNA glycosylase specific activity was 
reduced in WS cells.  Reduction of HMU-DNA glycosylase has been described in 
senescent human WI-38 cells.  Therefore, while neither WS nor senescent cells 
have overall deficiencies of DNA glycosylase activities, they both might have 
reduced excision of HMU from DNA.  This indicates a possible role of HMU 
accumulation in the aging process.

\section*{21}
           
  Flow cytometric analysis of deoxyribonucleic acid in human granulosa cells as 
a function of chronological age and ovulation induction regimen.

  Seifer DB, Honig J, Penzias AS, Lavy G, Nadkarni PM, Jones EE, DeCherney AH, 
Flynn SD
  Department of Obstetrics and Gynecology, Yale University School of Medicine, 
New Haven, Connecticut 06510.

  J Clin Endocrinol Metab  Aug 1992  75 (2) p636-40  
  
  We examined whether the proliferative index of granulosa cells as determined 
by flow cytometry varied with a women's age or ovulation induction regimen that 
included leuprolide acetate (LA).  This prospective cohort study included three 
groups of patients undergoing assisted reproductive technologies.  Group I 
consisted of 9 women age less than or equal to 30 yr, who received LA plus 
human menopausal gonadotropin (hMG).  Group II included 9 women age more than 
or equal to 40 yr, who received LA plus hMG.  Group III consisted of 6 women 
age less than or equal to 30 yr who received hMG alone.  A total of 79 
preovulatory follicles containing greater than 10(4) granulosa cells were 
obtained from these 24 women and examined by flow cytometry.  Group I was 
compared to group II to match for ovulation induction regimen and to examine 
proliferative index as a function of age.  Group I was compared to group III to 
match for age and to examine proliferative index as a function of ovulation 
induction regimen.  Outcome measures included proliferative index of granulosa 
cells as a function of age, ovulation induction regimen, ampules of hMG, 
estradiol on day of hCG, and serum FSH.  Group I demonstrated a greater 
proliferative index than group II: 23.4% +/- 1.4 vs.  18.4% +/- 0.96 (P less 
than 0.01).  Group I had a greater proliferative index than group III: 23.4% +/-
 1.4 vs.  11.9 +/- 0.61 (P less than 0.001).  Although both age and the 
presence of LA appeared to affect the PI, multiple linear regression 
demonstrated that only the addition of LA and not age, per se, had an 
independent effect upon granulosa cells undergoing proliferation (P less than 
0.0005).  We conclude that LA followed by hMG leads to an increase in the 
percentage of granulosa cells undergoing proliferation when compared to 
ovulation induction regimens that include hMG alone.  Chronological age does 
not appear to have a significant independent influence upon the proliferative 
index.

\section*{22}
  Differential expression of metalloproteinase and tissue inhibitor of 
metalloproteinase genes in aged human fibroblasts.

  Millis AJ, Hoyle M, McCue HM, Martini H
  Department of Biological Sciences, State University of New York, Albany 
12222.

  Exp Cell Res  Aug 1992  201 (2) p373-9  
  
  The basal levels of mRNAs encoding two metalloproteinases, collagenase and 
stromelysin, were increased as a function of in vitro serial subcultivation 
(cellular aging) of human fibroblasts.  Procollagenase and prostromelysin 
synthesis and secretion were also greater in the old cultures (late passage).  
In contrast, the steady-state expression of mRNA for an inhibitor of 
metalloproteinases, tissue inhibitor of metalloproteinase-1 (TIMP-1), in late-
passage cultures was lower than that in young cell cultures (early passage).  
Each mRNA was analyzed using total RNA preparations isolated from normal 
fibroblast cultures at different phases of the in vitro life span and from 
cultures derived from donors with the premature senescence syndromes 
characterized as Werner syndrome, progeria (Hutchinson-Gilford) syndrome, or 
Cockayne syndrome.  In normal cell cultures expression of metalloproteinase 
mRNAs was increased after the culture had completed greater than 90% of the in 
vitro life span, and the reduction in TIMP-1 mRNA expression occurred after the 
culture had completed greater than 74% of the in vitro lifespan.  In Werner 
syndrome cultures expression of metalloproteinase and TIMP-1 mRNAs was similar 
to the level of expression observed in late-passage cell cultures.  Levels of 
metalloproteinase and TIMP-1 mRNA expression in progeria and Cockayne syndromes 
were similar to those of early-passage cell cultures.  To determine if young 
and old cells were each responsive to mediators of metalloproteinase synthesis, 
cultures were treated with phorbol ester or cytokines.  12-O-
tetradecanoylphorbol-13-acetate treatment increased the steady-state levels of 
all three mRNAs in young, old, and Werner syndrome cultures and increased 
procollagenase levels in all cultures.  Early- and late-passage cell cultures 
also responded to cytokines.  Interleukin-1 alpha treatment increased 
collagenase and stromelysin mRNA levels while transforming growth factor-beta 
reduced the steady-state levels of both transcripts.  Neither cytokine affected 
the steady-state level of TIMP-1 mRNA.  The results indicate that in vitro 
cellular aging is associated with changes in expression of mRNAs encoding 
proteins that mediate inflammatory responses and connective tissue remodeling.


\section*{23}
  Human erythrocyte aging: cellular and molecular biology.

  Kay MM, Marchalonis JJ, Schluter SF, Bosman G
  Department of Microbiology and Immunology, University of Arizona, Tucson 
85724.

  Transfus Med Rev  Jul 1991  5 (3) p173-95  

\section*{24}
  Age-dependent 6kb deletion in human liver mitochondrial DNA.

  Yen TC, Pang CY, Hsieh RH, Su CH, King KL, Wei YH
  Department of Biochemistry and General Surgery, National Yang-Ming Medical 
College, Taipei, Taiwan, Republic of China.

  Biochem Int  Mar 1992  26 (3) p457-68  
  
  Using PCR technique, restriction mapping and DNA sequencing, we analyzed 
liver mitochondrial DNA (mtDNA) of 2 stillborn babies and 62 Chinese subjects 
with non-liver disease from 27 to 86 years old.  The results showed an age-
dependent 6,063 bp deletion in the liver mtDNA of older subjects.  We found a 
TAACAGAC sequence flanking the 5'-end breakpoint at 7,842 nucleotide position 
and an imperfect repeat sequence CAACATAC flanking the 3'-end breakpoint at 
13,905 nucleotide position.  The incidence of the deleted mtDNA was found to 
increase with age.  The deleted mtDNA was not detected in the liver of the 
stillbirth or blood cells of all the subjects.  This is the first account that 
an age-related 6,063 bp deletion occurs in the liver mtDNA of old humans.  The 
occurrence of this and previously reported 4,977 bp deletions is consistent 
with our recent finding that liver mitochondrial respiratory functions decline 
with age and support the hypothesis that continuous accumulation of mtDNA 
mutations is an important contributor to ageing process in the human.

\section*{25}
  Hyaluronic acid in progeria and the aged phenotype?

  Sweeney KJ, Weiss AS
  Department of Biochemistry, University of Sydney, NSW, Australia.

  Gerontology  1992  38 (3) p139-52  
  
  Hyaluronic acid (HA) is implicated in functions such as vascularity, 
morphogenesis, repair, and the general integrity of the extracellular matrix.  
Hence, it is considered possible that HA is involved in the most conspicuous 
features of the progeroid phenotype.  However, it is not known whether the 
increase in HA excretion seen in progeria patients is due to a primary genetic 
defect or is a secondary effect due to some deeper problem.  The phenomenon of 
'normal' aging is suggested to have a more complex etiology and phenotype than 
progeria and the role of HA levels is less well-defined.  

\section*{26}
  Ataxia telangiectasia in the British Isles: the clinical and laboratory 
features of 70 affected individuals.

  Woods CG, Taylor AM
  Department of Clinical Genetics, Churchill Hospital, Headington, Oxford.

  Q J Med  Feb 1992  82 (298) p169-79  
  
  Seventy individuals with ataxia telangiectasia were studied: 29 females and 
41 males with an age range of 2 to 42 years.  The majority (43/68) presented by 
3 years of age with truncal ataxia.  All had progressive, handicapping 
neurological symptoms exhibiting ataxia (70/70), ocular motor apraxia (70/70), 
an impassive face (70/70), dysarthria (70/70), chorea (68/70), dystonia (55/70) 
and peripheral neuropathy (50/70).  Clinical immune deficiency was present in 
43 of 70 patients.  Ocular telangiectasia were seen in all but one case and 
excessive thinness in 54 of 70.  The mean age of loss of walking was 10 years 
and of writing 8 years.  All 60 tested showed increased sensitivity to ionizing 
irradiation, 43 of 48 had an elevated alpha-fetoprotein level and 14 of 21 had 
an immunoglobulin deficiency.  Although there was a marked variation in disease 
findings sibs were always similar.  The heterogeneity seen seems at odds with 
the unilocus linkage of ataxia telangiectasia to 11q23.

\section*{27}
  Two sibs with Wiedemann-Rautenstrauch syndrome: possibilities of prenatal 
diagnosis by ultrasound.

  Castineyra G, Panal M, Lopez Presas H, Goldschmidt E, Sanchez JM
  Fundacion de Genetica Humana, Buenos Aires, Argentina.

  J Med Genet  Jun 1992  29 (6) p434-6  
  
  A girl with Wiedemann-Rautenstrauch syndrome was born to a non-consanguineous 
couple.  During the pregnancy, growth retardation particularly in the 
biparietal and abdominal diameters but not the femoral length was detected 
through serial ultrasound scans.  When the woman became pregnant again, in 
spite of having been assessed as having a 25% risk of recurrence, the prenatal 
findings seen in her previous pregnancy led us to suggest sequential echography 
and a similar pattern of growth retardation was shown.  After termination, the 
male fetus was found to be affected by Wiedemann-Rautenstrauch syndrome.  This 
case shows that ultrasound examination can be a useful tool in the prenatal 
diagnosis of this rare, autosomal recessive syndrome.  

\section*{28}
  Telomere end-replication problem and cell aging.

  Levy MZ, Allsopp RC, Futcher AB, Greider CW, Harley CB
  Department of Biochemistry, McMaster University Hamilton, Ontario, Canada.

  J Mol Biol  Jun 20 1992  225 (4) p951-60  
  
  Since DNA polymerase requires a labile primer to initiate unidirectional 5'-
3' synthesis, some bases at the 3' end of each template strand are not copied 
unless special mechanisms bypass this "end-replication" problem.  Immortal 
eukaryotic cells, including transformed human cells, apparently use telomerase, 
an enzyme that elongates telomeres, to overcome incomplete end-replication.  
However, telomerase has not been detected in normal somatic cells, and these 
cells lose telomeres with age.  Therefore, to better understand the 
consequences of incomplete replication, we modeled this process for a 
population of dividing cells.  The analysis suggests four things.  First, if 
single-stranded overhangs generated by incomplete replication are not degraded, 
then mean telomere length decreases by 0.25 of a deletion event per generation.  
If overhangs are degraded, the rate doubles.  Data showing a decrease of about 
50 base-pairs per generation in fibroblasts suggest that a full deletion event 
is 100 to 200 base-pairs.  Second, if cells senesce after 80 doublings in 
vitro, mean telomere length decreases about 4000 base-pairs, but one or more 
telomeres in each cell will lose significantly more telomeric DNA.  A 
checkpoint for regulation of cell growth may be signalled at that point.  
Third, variation in telomere length predicted by the model is consistent with 
the abrupt decline in dividing cells at senescence.  Finally, variation in 
length of terminal restriction fragments is not fully explained by incomplete 
replication, suggesting significant interchromosomal variation in the length of 
telomeric or subtelomeric repeats.  This analysis, together with assumptions 
allowing dominance of telomerase inactivation, suggests that telomere loss 
could explain cell cycle exit in human fibroblasts.

\section*{29}

  A patient with Werner's syndrome and osteosarcoma presenting as scleroderma.

  Khraishi M, Howard B, Little H
  Department of Medicine, Sunnybrook Health Science Centre, University of 
Toronto, ON, Canada.

  J Rheumatol  May 1992  19 (5) p810-3  
  
  Werner's syndrome (WS) is often mistaken for scleroderma.  We describe a 
patient with WS who presented with an enlarging, painful mass of the right knee 
that proved to be a juxtaarticular osteosarcoma of the distal femur.  
Recognition of WS and prompt investigation of any painful, enlarging masses to 
exclude sarcomatous degeneration will benefit these patients.

\section*{30}
  Hyaluronate synthesized by cultured skin fibroblasts derived from patients 
with Werner's syndrome.

  Nakamura T, Takagaki K, Kubo K, Saito T, Endo M, Mori S, Morisaki N, Saito Y, 
Yoshida S
  Department of Biochemistry, Hirosaki University School of Medicine, Japan.

  Biochim Biophys Acta  Jun 9 1992  1139 (1-2) p84-90  
  
  Hyaluronate in cultured skin fibroblasts derived from patients with Werner's 
syndrome, who excrete large amounts of urinary hyaluronate, was investigated.  
The amount of hyaluronate secreted into the medium by Werner's fibroblasts was 
2-3-times that of normal fibroblasts, whereas no difference in enzyme 
activities related to the degradation of hyaluronate was found.  Werner's 
fibroblasts were then cultured in the presence of [3H]glucosamine, and the 
amount of [3H]hyaluronate and its chain lengths in the medium and matrix 
(trypsinate) fractions were compared with those of normal cells.  No 
significant difference in the chain length of hyaluronate was observed between 
normal and Werner's fibroblasts.  On the other hand, a significant increase of 
hyaluronate was found in the matrix fraction of Werner's fibroblasts when the 
cells reached confluency.  In addition, a hyaluronate of small chain length was 
found in the matrix fraction of Werner's fibroblasts, although this was absent 
from that of normal cells.  It was concluded that the constituents of the 
extracellular matrix of Werner's fibroblasts differed from those of normal 
cells, characterized by the presence of a large amount of hyaluronate and a 
relatively small hyaluronate chain.

\section*{31}
  Insulin resistance in Werner's syndrome.

  Okamoto M, Okamoto M, Yamada K, Yoshimasa Y, Kosaki A, Kono S, Inoue G, Maeda 
I, Kubota M, Hayashi T, et al
  Department of Medicine, Kyoto University School of Medicine, Japan.

  Mech Ageing Dev  Mar 15 1992  63 (1) p11-25  
  
  Insulin resistance in Werner's syndrome (WS) was studied using the glucose 
clamp technique, and compared with physiologically aged and young subjects.  
Fasting immuno-reactive insulin (IRI) was increased in patients with Werner's 
syndrome compared with aged and young subjects.  Metabolic clearance rate (MCR) 
of glucose was decreased in the aged and WS.  A rightward shift of the dose-
response curves of insulin and MCR of glucose was observed in the aged and WS 
with a more pronounced shift in the latter.  MCR of insulin was also decreased 
in WS. [125I]insulin binding to erythrocytes was similar in the three groups.  
These results suggest that insulin resistance associated with WS is due to a 
post-binding defect manifested by a rightward shift of the dose-response curve 
of insulin-induced glucose disposal and a decrease in insulin clearance rate.

\section*{32}
  A new look at the management of the oculo-mandibulo-facial syndrome.

  Bitoun P, Timsit JC, Trang H, Benady R
  Service du Pr. Gaudelus, Hopital Jean Verdier, Bondy, France.

  Ophthalmic Paediatr Genet  Mar 1992  13 (1) p19-26  
  
  The authors review the literature on the oculo-mandibulo-facial syndrome and 
present the case of a six-year-old boy with congenital cataracts, 
microphthalmos, nystagmus, failure to thrive, dysmorphic features with a tiny 
pinched nose, mandibular hypoplasia, microstomia, double chin, chronic snoring, 
recurrent respiratory infections and dental problems.  Chronic obstructive 
sleep apnoea with decreased oxygen saturation was present.  Optimal medical 
management of OMFS-patients is described.

\section*{33}
  Progeria: a human-disease model of accelerated aging.

  Brown WT
  Department of Human Genetics, New York State Institute for Basic Research, 
Staten Island 10314.

  Am J Clin Nutr  Jun 1992  55 (6 Suppl) p1222S-1224S  
  
  Progeria is a rare genetic disease with striking features that resemble 
accelerated aging.  The inheritance pattern, paternal age effect, and lack of 
consanguinity argue that it is due to a sporadic dominant mutation.  We have 
observed elevated levels of hyaluronic acid (HA) excretion in progeria patients.  
In several progeria patients we observed normal levels of growth hormone (GH) 
but very low levels of insulin-like growth factor I along with very high basal 
metabolic rates (BMRs).  A trial of GH treatment was begun, which resulted in a 
marked increase in linear growth and a paradoxical drop in BMRs in these two 
patients.  We hypothesize that the failure of patients with progeria to thrive 
may be due to a bioinactive form of GH and a lack of vasculogenesis caused by 
excess HA.  An understanding of the progeria genetic mutation may define a key 
gene with a major effect on normal aging.  

\section*{34}
  Werner's syndrome: no difference in in vitro life span of dermal fibroblasts 
from proximal and distal parts of the body.

  Kondo S, Hozumi Y, Aso K
  Department of Dermatology, Yamagata University School of Medicine, Japan.

  Acta Derm Venereol (Stockh)  1992  72 (1) p11-4  
  
  Recently it has been reported that fibroblasts from distal parts of the body 
of a patient with Werner's syndrome grew poorly in vitro as compared with those 
from the proximal part of the same patient.  To confirm this observation, 
cultures of fibroblasts from different parts of the body were set up in 2 cases 
of Werner's syndrome, but no significant difference in life span was observed.  
Fetal calf serum (FCS) and fibroblast growth factor (FGF) stimulated growth of 
fibroblasts from different body parts equally well.  These data indicate that 
there is no difference in growth activity of fibroblasts from proximal and 
distal body parts in patients with Werner's syndrome.  Moreover, the growth 
rate of epidermal outgrowths did not differ significantly between proximal and 
distal parts of these patients.

\section*{35}
  Mitochondrial genetics: a paradigm for aging and degenerative diseases?

  Wallace DC
  Department of Genetics and Molecular Medicine, Emory University School of 
Medicine, Atlanta, GA 30322.

  Science  May 1 1992  256 (5057) p628-32  
  
  Studies of diseases caused by mitochondrial DNA mutations suggest that a 
variety of degenerative processes may be associated with defects in oxidative 
phosphorylation (OXPHOS).  Application of this hypothesis has provided new 
insights into such diverse clinical problems as ischemic heart disease, late-
onset diabetes, Parkinson's disease, Alzheimer's disease, and aging.

\section*{36}
  Increased plasma fibronectin in Werner syndrome [letter]

  Kanzaki T, Murano S, Morisaki N, Saito Y, Yoshida S, Wada M

  Lancet  May 16 1992  339 (8803) p1244  
  

\section*{37}
  Methylated cytosine level in human liver DNA does not decline in aging 
process.
 
  Tawa R, Ueno S, Yamamoto K, Yamamoto Y, Sagisaka K, Katakura R, Kayama T, 
Yoshimoto T, Sakurai H, Ono T
  Department of Analytical Chemistry, Kyoto Pharmaceutical University, Japan.
 
  Mech Ageing Dev  Mar 1 1992  62 (3) p255-61  
  
  In order to ascertain a generality of the age-dependent decrease in DNA 
methylation level among different mammalian species, methylated cytosine 
contents in human liver and spleen DNA at different ages have been determined 
using high performance liquid chromatography (HPLC).  Unexpectedly, the liver 
DNA revealed no appreciable decline with age while the spleen DNA showed a 
slight reduction.  It indicates that a decrease of methylation level in genomic 
DNA is not a common denominator of age-related changes in mammals.

\section*{38}
  Aging-associated deletions of human diaphragmatic mitochondrial DNA.

  Torii K, Sugiyama S, Tanaka M, Takagi K, Hanaki Y, Iida K, Matsuyama M, 
Hirabayashi N, Uno Y, Ozawa T
  Department of Internal Medicine, Faculty of Medicine, University of Nagoya, 
Japan.

  Am J Respir Cell Mol Biol  May 1992  6 (5) p543-9  
  
  It is known that respiratory function deteriorates with age.  Endogenous 
damage to DNA is thought to contribute to the aging process.  The mitochondrial 
oxidative phosphorylation system, a bio-engine, consists of five complexes, and 
13 subunits of those complexes are biosynthesized from information encoded in 
mitochondrial DNA.  Mitochondrial DNA is shown to have a much higher mutation 
rate than nuclear DNA.  We examined the diaphragms obtained at autopsy from 34 
humans, 23 men and 11 women, ranging in age from 25 to 85 yr, for mitochondrial 
DNA deletions using the polymerase chain reaction method.  Multiple 
mitochondrial DNA deletions were detected particularly among the elderly, the 
number of deletions in those over age 70 was significantly higher than in those 
under age 40.  The occurrence of a 3.4-kbp deletion of mitochondrial DNA 
increased with age, i.e., 0% of those under age 30, 20.0% of those in their 
forties, 25.0% of those in their fifties, 28.6% of those in their sixties, 
72.7% of those in their seventies, and in all of those over age 80.  The 
mutation was based on the directly repeated sequence, 5'-TCACCCC-3', which 
exists in both the CO3 gene and the ND5 gene.  Replication impairment occurred 
at that directly repeated sequence, which caused the elimination of a genome 
between the CO3 gene and the ND5 gene, and information for biosynthesis of four 
subunits in complex I (ND3, ND4L, ND4, and ND5), one in complex IV (CO3), and 
five transfer RNA genes was missing.(ABSTRACT TRUNCATED AT 250 WORDS)

\section*{39}
 
  Accelerated aging of the brain in Werner's syndrome.

  Kakigi R, Endo C, Neshige R, Kohno H, Kuroda Y
  Department of Internal Medicine, Saga Medical School, Nabeshima, Japan.

  Neurology  Apr 1992  42 (4) p922-4  
  
  We report the electrophysiologic examination of a 55-year-old woman with 
Werner's syndrome.  Needle EMG and peripheral conduction studies were normal.  
In contrast, EEG was moderately abnormal, the N20 and P25 potentials of SEPs 
were delayed and enlarged, and the event-related potential, P300, was delayed.  
These characteristic findings indicated accelerated aging of the brain, as in 
the other organs, in Werner's syndrome.

\section*{40}
 
  Homozygosity mapping and Werner's syndrome [letter]

  Schellenberg GD, Martin GM, Wijsman EM, Nakura J, Miki T, Ogihara T

  Lancet  Apr 18 1992  339 (8799) p1002  
  
\section*{41}
  Altered response of progeria fibroblasts to epidermal growth factor.

  Colige A, Nusgens B, Lapiere CM
  Laboratory of Experimental Dermatology, Tour de Pathologie, University of 
Liege, Belgium.

  J Cell Sci  Nov 1991  100 ( Pt 3) p649-55  
  
  The Hutchinson-Gilford syndrome (progeria) is a rare disorder in childhood 
characterized by premature and accelerated aging.  This study reports the 
effect of a potent growth factor, EGF, on the proliferative capacities and 
extracellular matrix macromolecules and collagenase expression of two strains 
of progeria skin-derived cells.  At low population doubling levels (PDL less 
than 10), confluent cultures of progeria fibroblasts made quiescent by lowering 
the concentration of serum in the medium did not respond to EGF while the 
mitotic activity of normal PDL-matched fibroblasts was almost maximally 
restored upon addition of EGF.  No obvious difference between normal and low 
PDL progeria fibroblasts was observed in the number and in the affinity of the 
receptors measured by [125I]EGF binding.  The synthesis of collagen and non-
collagen proteins was similar in normal and affected cells at low and high 
serum concentration and both types of cells responded to EGF by a specific 
inhibition of collagen synthesis.  Besides a normal level of mRNA coding for 
type I and type III collagens, collagenase and laminin, progeria fibroblasts 
expressed a high level of elastin and type IV collagen mRNA.  Like normal 
fibroblasts, progeria cells responded to EGF by a decrease in the level of mRNA 
for fibrillar collagens and elastin.  In contrast, a complete lack of response 
to EGF was observed for collagenase mRNA whereas the expression of this enzyme 
was strikingly induced by EGF in normal PDL-matched cells.  The abnormal 
expression of type IV collagen was not significantly modified by EGF.  At PDL 
greater than 10, progeria cells exhibited features of senescence.  A 
significant reduction of collagen synthesis was observed and no further 
inhibition by EGF was recorded.

\section*{42}
  Regional differences in insulin receptor function in Werner's syndrome.

  Yamasaki H, Akazawa S, Okuno S, Ikari N, Yamaguchi Y, Chikuba N, Yamamoto H, 
Maeda Y, Tahara D, Nagataki S
  First Department of Internal Medicine, Nagasaki University, School of 
Medicine, Japan.

  Diabetes Res Clin Pract  Feb 1992  15 (2) p105-11  
  
  Werner's syndrome is a genetic disease characterized by premature aging and 
is often associated with glucose intolerance due to insulin resistance.  The 
clinical manifestations in this syndrome are preferentially expressed in the 
face and acral regions without apparent involvement of the trunk.  We compared 
insulin receptor binding and amino acid uptake of fibroblasts derived from the 
forearm that had sclerodermoid features, and from the abdomen that was 
apparently normal in a patient with Werner's syndrome.  In normal controls, 
specific insulin binding was not different in forearm and abdomen-derived 
fibroblasts (10.72 +/- 2.11%, 10.40 +/- 1.27%, respectively).  In the patient, 
however, specific insulin binding was reduced in the fibroblasts derived from 
the forearm compared with those derived from the abdomen (3.55%, 8.16%, 
respectively).  Scatchard analysis revealed that the reduction in insulin 
binding of the forearm fibroblasts from the patient was due to a reduction in 
receptor number with no change in receptor affinity.  The dose-response curve 
for insulin of alpha-aminoisobutyric acid (AIB) uptake is shifted to the right 
in the fibroblasts derived from the acral area.  The results show that in a 
patient with Werner's syndrome, regional differences occur in fibroblast 
insulin receptor binding and function.  This suggests early phenotypic 
expression of the genetic abnormality of insulin receptor function in these 
patients.

\section*{43}
  Renewed DNA synthesis in senescent WI-38 cells by expression of an inducible 
chimeric c-fos construct.

  Phillips PD, Pignolo RJ, Nishikura K, Cristofalo VJ
  Center for Gerontological Research, Medical College of Pennsylvania, 
Philadelphia 19129.

  J Cell Physiol  Apr 1992  151 (1) p206-12  
  
  As normal human cells approach the end of their proliferative lifespan in 
vitro they lose responsiveness to a variety of growth factors, to which they 
respond with DNA replication when they are young.  Recently it has been 
reported that the protooncogene c-fos is not expressed in senescent cells 
(Seshadri and Campisi, 1990).  In this study we have found that both c-jun and 
jun B, partners of c-fos in heterodimeric transactivating complexes, are 
equivalently expressed in young and senescent cells at both early (1-6 hr) and 
late (12 or 16 hr) time points following serum stimulation of quiescent cells.  
We have also investigated the effect of the enforced expression of c-fos in 
senescent WI-38 cells using an inducible construct carrying the murine c-fos 
gene under the control of the sheep metallothionein promoter.  We have found 
that the transient transfection and subsequent activation of the conditional 
promoter with Zn++ stimulated DNA synthesis in a significant fraction of 
senescent cells which had completed 90%-95% of their proliferative lifespan.  
However, populations which had completed 100% of their proliferative life span 
and nondividing cultures which had been selected with BrdU did not respond to 
the expression of the c-fos gene.  These results demonstrate that one of the 
primary events associated with senescence in human cells is the suppression of 
c-fos gene expression, but additional phenotypic changes must also occur in 
order to explain the ultimate loss of proliferative responsiveness of these 
cells.

\section*{44}
  Frequent deletions in nine newly immortal human cell lines.

  Ray FA, Kraemer PM
  Cellular and Molecular Biology Group, Los Alamos National Laboratory, New 
Mexico.

  Cancer Genet Cytogenet  Mar 1992  59 (1) p39-44  
  
  Nine newly immortal lines of human fibroblasts transfected with SV40 T 
antigen were examined for recurrent chromosome losses.  In order of decreasing 
frequency, all nine lines had three or more of the following minimal deletions 
specifically associated with the immortalization event: del(6)(q21), 
del(3)(p24), del(1)(p34), del(4)(p25), del(5)(p14), del(11)(p11), del(11)(q14), 
del(12)(p12), and del(14)(p?).  Many other chromosome changes were not clearly 
associated with immortalization, but were acquired during other stages of this 
multistep model of neoplastic transformation.  We propose that these chromosome 
loci associated with immortalization are candidates for the location of genes 
involved in cellular senescence.

\section*{45}
  Newly recognized congenital progeroid disorder [letter, comment]

  Wiedemann HR
  Am J Med Genet  Apr 1 1992  42 (6) p857  

  NOTE: Comment on:  Am J Med Genet 1990 Mar;35(3):383-7

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