Table of Contents
1
UI - 11898515
AU - Gropman AL
TI -
Diagnosis and treatment of childhood mitochondrial diseases.
SO - Curr Neurol Neurosci Rep 2001 Mar;1(2):185-94
AD - National Human Genome Research Institute, Neurogenetics Branch, National
Institutes of Neurologic Disorders and Stroke, National Institutes of
Health, 10 Center Drive, Building 10, Room 3B04, Bethesda, MD 20892,
USA. gropman@ninds.nih.gov
Mitochondrial cytopathies are caused by genetic alterations of nuclear-
or mitochondrial-encoded genes involved in the synthesis of subunits of
the electron transport chain. Mutations of mitochondrial DNA are
associated with a wide range of clinical presentations [1-4]. The
ubiquitous nature of mitochondria and the role of the mitochondria in
cellular metabolism result in the potential for any tissue in the body
to be affected [5-7,8..,9]. Although some children with mitochondrial
disease present with life-threatening lactic acidosis in the newborn
period, the majority of children come to clinical attention for
nonspecific problems, including failure to thrive, developmental delay,
seizures, hypotonia, and loss of developmental milestones. The diagnosis
of these disorders is made through careful clinical evaluation, coupled
with biochemical, morphologic, and molecular biologic techniques.
Genetic counseling is difficult due to unique aspects of mitochondrial
genetics. Despite advances in our understanding of mitochondrial
biochemistry and genetics, treatment options remain limited.
2
UI - 11530711
AU - Feith GW
TI -
[From gene to disease; from polycystines to polycystic kidney disease]
SO - Ned Tijdschr Geneeskd 2001 Apr 7;145(14):708
3
UI - 11778984
AU - Burke W; Pinsky LE; Press NA
TI -
Categorizing genetic tests to identify their ethical, legal, and social
implications.
SO - Am J Med Genet 2001 Fall;106(3):233-40
AD - Department of Medical History and Ethics, University of Washington,
Seattle 98195, USA. wburke@u.washington.edu
Practice standards in medical genetics provide an implicit guide to the
ethical, legal, and social implications (ELSI) of genetic tests. The
common use of nondirective counseling reflects the principle that many
testing decisions should be determined by personal values. Yet
geneticists make test recommendations in some circumstances, e.g., RET
mutation testing for MEN2 and newborn screening for phenylketonuria
(PKU). Conversely, many geneticists recommend against testing for
Apolipoprotein E (ApoE) alleles to predict Alzheimer disease (AD) risk.
Taken together, these examples suggest that genetic tests can be
categorized by a joint consideration of clinical validity and
availability of effective treatment for persons who test positive. For
genetic tests with high clinical validity/no treatment (e.g.,
presymptomatic testing for Huntington disease), the predominant concern
is adequate nondirective counseling to ensure an informed, autonomous
decision. By contrast, the predominant concern for tests with high
clinical validity/effective treatment (e.g., PKU) is assuring access to
care for eligible persons. For tests with limited clinical validity/no
treatment (e.g., ApoE), recommending against test use can be justified
on the principle of avoiding harm. For a fourth category, tests with
limited clinical validity/effective treatment (e.g., HFE mutation
testing for hereditary hemochromatosis), net benefit is the issue: the
balance between potential benefits of treatment and potential harms of
genetic labeling must be weighed. Where uncertainty exists concerning
both clinical validity and effectiveness of treatment, as in the case of
BRCA 1/2 mutation testing, the value of testing may vary according to
different testing contexts. This approach to test categorization allows
a rapid determination of the predominant ELSI concerns for different
kinds of genetic tests and identifies the data most urgently needed for
test evaluation.
4
UI - 11955446
AU - Kramps T; Peter O; Brunner E; Nellen D; Froesch B; Chatterjee S; Murone
TI -
M; Zullig S; Basler K
Wnt/wingless signaling requires BCL9/legless-mediated recruitment of
pygopus to the nuclear beta-catenin-TCF complex.
SO - Cell 2002 Apr 5;109(1):47-60
AD - Institut fur Molekularbiologie, Universitat Zurich, Winterthurerstrasse
190, CH-8057, Zurich, Switzerland.
Wnt/Wingless signaling controls many fundamental processes during animal
development. Wnt transduction is mediated by the association of
beta-catenin with nuclear TCF DNA binding factors. Here we report the
identification of two segment polarity genes in Drosophila, legless
(lgs), and pygopus (pygo), and we show that their products are required
for Wnt signal transduction at the level of nuclear beta-catenin. Lgs
encodes the homolog of human BCL9, and we provide genetic and molecular
evidence that these proteins exert their function by physically linking
Pygo to beta-catenin. Our results suggest that the recruitment of Pygo
permits beta-catenin to transcriptionally activate Wnt target genes and
raise the possibility that a deregulation of these events may play a
causal role in the development of B cell malignancies.
5
UI - 11760823
AU - Struse HM; Montoya ID
TI -
Health services implications of DNA testing.
SO - Clin Lab Sci 2001 Fall;14(4):247-51
AD - Affiliated Systems Corporation, Houston TX 77027-6022, USA.
This review article summarizes the state of the art in genetic testing
and discusses the many issues that new technologies have raised. A
health services perspective is offered to aid in providing laboratorians
with an understanding of the dilemma that society faces with the
exponential advances in knowledge. Unmistakably, these new technologies
are a mixed blessing: on the one hand, diagnoses can be made with
greater accuracy and preventive measures implemented more fruitfully and
individuals may be more conclusively identified and/or exonerated for
forensic purposes. On the other hand, however, are the very real
concerns that discrimination under a medical guise will be encouraged
and that privacy rights may be compromised. Another important issue is
how the laboratory profession will serve in moving these new
technologies from research to practice. We examine the role of the CLS
in moving forward to a role of patient counselor and advocate in the
emerging complex world of DNA-related biotechnology.
6
UI - 11873549
AU - Fries MH; Holt C; Carpenter I; Carter CL; Daniels J; Flanagan J; Murphy
TI -
K; Hailey BJ; Martin L; Hume R; Hudson G; Cadman M; Weatherly R; Nunes
ME
Guidelines for evaluation of patients at risk for inherited breast and
ovarian cancer: recommendations of the Department of Defense Familial
Breast/Ovarian Cancer Research Project.
SO - Mil Med 2002 Feb;167(2):93-8
AD - Air Force Medical Genetics Center, Keesler Air Force Base, MS 39534,
USA.
Patients at high risk for inherited breast and/or ovarian cancer are
frequently encountered in all medical specialties. Department of
Defense, Health Affairs funding as part of the Breast Cancer Education
and Awareness Program was used to develop a comprehensive program for
the identification, counseling, genetic testing, and long-term follow-up
of such high-risk patients. This article reports the recommendations for
high-risk patient management based on 4 years of evaluation and care,
including discussions of the approach to counseling, indications for
genetic testing, post-testing counseling, patient surveillance with
examination, imagining, and laboratory testing, and suggested options
for surgical and chemoprophylaxis as well as lifestyle modifications.
7
UI - 11873550
AU - Fries MH; Holt C; Carpenter I; Carter CL; Daniels J; Flanagan J; Murphy
TI -
K; Hailey BJ; Martin L; Hume R; Hudson G; Cadman M; Weatherly R; Nunes
ME
Diagnostic criteria for testing for BRCA1 and BRCA2: the experience of
the Department of Defense Familial Breast/Ovarian Cancer Research
Project.
SO - Mil Med 2002 Feb;167(2):99-103
AD - Air Force Medical Genetics Center, Keesler Air Force Base, MS 39534,
USA.
The Department of Defense Familial Breast/Ovarian Cancer Research
Project has offered genetic counseling and testing for BRCA1 and BRCA2
on a research basis to patients meeting specific diagnostic criteria,
with risk for BRCA1 and BRCA2 mutations calculated based on the Couch
model. In 2.5 years, 250 patients were evaluated and 101 patients met
criteria requirements, including 33 who met criteria in more than one
category. Ninety patients elected to undergo DNA testing. In this group
of 90 patients, 14 mutations (15.5%) and 16 unclassified variants
(17.7%) were identified. The most common inclusion criteria were onset
of breast/ovarian cancer before age 45 years (n = 32) and onset of
breast/ovarian cancer before age 45 years with strong family history (n
= 21). However, when number of mutations and unclassified variants found
were compared separately across all diagnostic criteria (including those
of more than one capacity) using the chi 2 statistic, no significant
differences were seen among the categories to suggest that one criterion
was more predictive of mutations or variants than another. Couch risk
values for patients with mutations showed a mean of 14% and ranged from
3.2 to 43.5% (range for all patients, 1.2-69.7%). These findings
emphasize the importance of using multiple diagnostic criteria and
suggest that a Couch risk value of > 3% may be useful in selecting
patients for testing. The data also underscore the necessity of genetic
counseling in the testing process, particularly given the large number
of unclassified variants diagnosed and their uncertain status for
disease predisposition.
8
UI - 11894280
AU - Steele R
TI -
The human genome project--what will we do with it?
SO - Can Oncol Nurs J 2000 Summer;10(3):91
9
UI - 11954395
AU - Benjamin C; Gibson J
TI -
Will the human genome project have any impact on nursing?
SO - Nurs Times 2001 Mar 22-28;97(12):17
10
UI - 11912108
AU - Pickering-Brown SM; Richardson AM; Snowden JS; McDonagh AM; Burns A;
TI -
Braude W; Baker M; Liu WK; Yen SH; Hardy J; Hutton M; Davies Y; Allsop
D; Craufurd D; Neary D; Mann DM
Inherited frontotemporal dementia in nine British families associated
with intronic mutations in the tau gene.
SO - Brain 2002 Apr;125(Pt 4):732-51
AD - The School of Biological Sciences, Division of Neuroscience, University
of Manchester, UK.
Genetic screening of 171 patients with frontotemporal lobar degeneration
disclosed 14 patients, across nine pedigrees, with mutations in the
intron to exon 10 in the tau gene, a region regulating the splicing of
exon 10 via a stem loop mechanism. Thirteen of these patients had the
+16 splice site mutation and one had the +13 splice site mutation.
Affected members of all nine families presented with changes in
behaviour and social conduct that were prototypical of frontotemporal
dementia (FTD). In all patients with the +16 splice site mutation, the
behavioural profile was characterized by disinhibition, restless
overactivity, a fatuous affect, puerile behaviour and verbal and motor
stereotypies. The single patient with the +13 mutation presented a
contrasting picture of apathy and inertia. In addition, all patients had
evidence of semantic loss. Pathologically, five of the six patients so
far autopsied shared frontotemporal atrophy with involvement of the
substantia nigra. The underlying histology was that of
microvacuolar-type cortical degeneration with a few swollen cells. Tau
pathology was widespread throughout the brain and present in neurones
and glial cells, mostly in the frontal and temporal cortical regions.
This was in the form of neurofibrillary tangles and amorphous tau
deposits (pre-tangles); Pick bodies were not observed.
Ultrastructurally, the tau filaments had a twisted, ribbon-like
morphology distinct from the paired helical filaments of Alzheimer's
disease. One patient died from an unrelated illness whilst in the early
clinical stages of FTD. In this patient, cortical microvacuolar and
astrocytic changes were absent, though there were scattered neurones and
glial cells, immunoreactive to tau, throughout the cortical and
subcortical regions. The disease process underlying the
neurodegeneration within these inherited forms of FTD may therefore stem
directly from early, primary alterations in the function of tau. All
eight families with the +16 mutation seem to be part of a common
extended pedigree, possibly originating from a founder member residing
within the North Wales region of Great Britain.
11
UI - 11912113
AU - Caparros-Lefebvre D; Sergeant N; Lees A; Camuzat A; Daniel S; Lannuzel
TI -
A; Brice A; Tolosa E; Delacourte A; Duyckaerts C
Guadeloupean parkinsonism: a cluster of progressive supranuclear
palsy-like tauopathy.
SO - Brain 2002 Apr;125(Pt 4):801-11
AD - Neurologie, Centre Hospitalier Universitaire de la Guadeloupe, Pointe a
Pitre, French West Indies. caparros.lefebvre@chu-guadeloupe.fr
An unusually high frequency of atypical Parkinson syndrome has been
delineated over the last 5 years in the French West Indies. Postural
instability with early falls, prominent frontal lobe dysfunction and
pseudo-bulbar palsy were common and three-quarters of the patients were
L-dopa unresponsive. One-third of all patients seen had probable
progressive supranuclear palsy (PSP). This new focus of atypical
parkinsonism is reminiscent of the one described in Guam and may be
linked to exposure to tropical plants containing mitochondrial complex I
inhibitors (quinolines, acetogenins, rotenoids). Two hundred and twenty
consecutive patients with Parkinson's syndrome seen by the neurology
service at Pointe a Pitre, Guadeloupe University Hospital were studied.
Currently accepted operational clinical criteria for Parkinson's
syndromes were applied. The pathological findings of three patients who
came to autopsy are reported. Fifty-eight patients had probable PSP, 96
had undetermined parkinsonism and 50 had Parkinson's disease, 15 had
amyotrophic lateral sclerosis with parkinsonism and one had probable
multiple system atrophy. All three PSP patients in whom post-mortem
study was performed had early postural instability, gaze palsy and
parkinsonian symptoms, followed by a frontolimbic dementia and
corticobulbar signs. Neuropathological examination showed an
accumulation of tau proteins, predominating in the midbrain. There was
an exceptionally large accumulation of neuropil threads in Case 1.
Biochemical studies detected a major doublet of pathological tau at 64
and 69 kDa in brain tissue homogenates. All cases were homozygous for
the H1 tau haplotype, but no mutation of the tau gene was observed.
Clinical, neuropathological and biochemical features were compatible
with the diagnosis of PSP, although some unusual pathological features
were noted in Case 1. A cluster of cases presenting with atypical
parkinsonism is reported. Guadeloupean parkinsonism may prove to be a
tauopathy identical or closely related to PSP.
12
UI - 11927624
AU - Hogeveen KN; Cousin P; Pugeat M; Dewailly D; Soudan B; Hammond GL
TI -
Human sex hormone-binding globulin variants associated with
hyperandrogenism and ovarian dysfunction.
SO - J Clin Invest 2002 Apr;109(7):973-81
AD - Department of Obstetrics and Gynecology, University of Western Ontario,
London, Ontario, Canada.
The access of testosterone and estradiol to target tissues is regulated
by sex hormone-binding globulin (SHBG) in human blood. Serum SHBG levels
are low in patients with hyperandrogenism, especially in association
with polycystic ovarian syndrome (PCOS) and in individuals at risk for
diabetes and heart disease. Here, we identify SHBG coding region
variations from a compound heterozygous patient who presented with
severe hyperandrogenism during pregnancy. Serum SHBG levels in this
patient measured 2 years after her pregnancy were exceptionally low, and
her non-protein-bound testosterone concentrations greatly exceeded the
normal reference range. A single-nucleotide polymorphism within the
proband's maternally derived SHBG allele encodes a missense mutation,
P156L, which allows for normal steroid ligand binding but causes
abnormal glycosylation and inefficient secretion of SHBG. This
polymorphism was identified in four other patients with either PCOS,
ioiopathic hirsutism, or ovarian failure. The proband's paternal SHBG
allele carries a single-nucleotide deletion within exon 8, producing a
reading-frame shift within the codon for E326 and a premature
termination codon. CHO cells transfected with a SHBG cDNA carrying this
mutation fail to secrete the predicted truncated form of SHBG. To our
knowledge, these are the first examples of human SHBG variants linked to
hyperandrogenism and ovarian dysfunction.
13
UI - 11988625
AU - Rundek T; Elkind MS; Pittman J; Boden-Albala B; Martin S; Humphries SE;
TI -
Juo SH; Sacco RL
Carotid intima-media thickness is associated with allelic variants of
stromelysin-1, interleukin-6, and hepatic lipase genes: the Northern
Manhattan Prospective Cohort Study.
SO - Stroke 2002 May;33(5):1420-3
AD - Neurological Institute, New York Presbyterian Hospital, Columbia
University, New York, NY 10032, USA. tr89@columbia.edu
BACKGROUND AND PURPOSE: Atherosclerosis is a complex disorder with
hereditary and environmental causes. Carotid artery intima-media wall
thickness (IMT) is a useful measure of atherosclerosis. The objective of
this study was to determine the association between carotid IMT and
functional promoter variants of stromelysin-1 (MMP3: -1612 5A>6A),
interleukin-6 (IL6: -174G>C), and hepatic lipase (HL: -480C>T) genes.
METHODS: B-mode carotid ultrasound was performed among 87 subjects (mean
age, 70+/-12 years; 55% women; 60% Caribbean-Hispanic, 25% black, and
13% white) from the Northern Manhattan Prospective Cohort Study. Carotid
IMT was calculated as a composite measure (mean of the maximum IMT in
the bifurcation, the common carotid artery, and the internal carotid
artery). RESULTS: For all polymorphisms, genotype distribution was not
significantly different from Hardy-Weinberg equilibrium. The frequencies
of the rare alleles were as follows: MMP3 -1612 5A>6A, 0.31 (95% CI,
0.25 to 0.39); IL6 -174 G>C, 0.20 (95% CI, 0.13 to 0.25); and HL -480
C>T, 0.45 (95% CI, 0.35 to 0.50). Carotid IMT in the sample was
0.78+/-0.18 mm. Subjects with the MMP3 genotype 6A6A had 8% greater mean
carotid IMT than the other MMP3 genotypes combined (0.95+/-0.17 versus
0.87+/-0.15 mm; P=0.04). Subjects with the IL6 genotype GG had 11%
greater IMT (0.85+/-0.17 versus 0.76+/-0.16 mm; P=0.03), and those with
the HL genotype CC had 13% greater IMT (0.87+/-20 versus 0.76+/-0.18 mm;
P=0.02) than the other genotypes combined. Adjustment for other risk
factors did not change these associations. CONCLUSIONS: Carotid IMT is
higher among subjects homozygous for functional variants in genes
related to matrix deposition (MMP3 -16126A), inflammation (IL6 -174G),
and lipid metabolism (HL -480C). These associations were independent of
race-ethnicity and some environmental exposures. Further studies are
needed to confirm these genotype-phenotype associations.
14
UI - 11973868
AU - Nevanlinna H; Kallioniemi OP
TI -
[Susceptibility genes of familiar breast cancer in Finland]
SO - Duodecim 1999;115(21):2365-74
AD - HYKS:n naistenklinikka, tutkimuslaboratorio PL 140, 00029 HYKS.
heli.nevanlinna@huch.fi
15
UI - 11960582
AU - Pallares-Ruiz N; Blanchet P; Mondain M; Low-Hong S; Demaille J;
TI -
Claustres M; Roux AF
Evaluation of dHPLC for CX26 mutation screening in patients from
southern France with sensorineural deafness.
SO - Genet Test 2001 Winter;5(4):339-43
AD - Laboratoire de Genetique Moleculaire, CHU Montpellier, France.
The GJB2 gene (or CX26 for connexin 26) is one of the major genes
causing nonsyndromic sensorineural hearing loss (NSSNHL). More than 50
sequence variations have been identified as polymorphisms or associated
with autosomal or recessive forms of deafness. Though a major mutation,
35delG, is easily detectable by PCR digest; it is often present in the
compound heterozygous state in our population in trans with recurrent,
but less frequent, mutations. The CX26 gene is composed of a single
coding exon that facilitates sequencing strategies. However, for
mutation screening purposes, it is necessary to use high-throughput and
cost-effective genotyping methods. Therefore, we have assessed
denaturing high-performance liquid chromatography (dHPLC) in patients
with known mutations in the CX26 gene. We conclude that dHPLC analysis
is suitable for rapid and reliable scanning of the gene in deaf
patients.
16
UI - 12000821
AU - Dluhy RG
TI -
Pheochromocytoma--death of an axiom.
SO - N Engl J Med 2002 May 9;346(19):1486-8
17
UI - 11861307
AU - Hofmann WK; Jones LC; Lemp NA; de Vos S; Gschaidmeier H; Hoelzer D;
TI -
Ottmann OG; Koeffler HP
Ph(+) acute lymphoblastic leukemia resistant to the tyrosine kinase
inhibitor STI571 has a unique BCR-ABL gene mutation.
SO - Blood 2002 Mar 1;99(5):1860-2
AD - Division of Hematology/Oncology, Cedars Sinai Research Institute, UCLA
School of Medicine, Los Angeles, California 90048, USA.
w.k.hofmann@em.uni-frankfurt.de
The tyrosine kinase inhibitor STI571 is a promising agent for the
treatment of advanced Philadelphia chromosome positive (Ph(+)) acute
lymphoblastic leukemia (ALL), but resistance develops rapidly in most
patients after an initial response. To identify mechanisms of resistance
to STI571, 30 complementary DNAs (including 9 matched samples) obtained
from the bone marrow of individuals with Ph(+) ALL were analyzed by
direct sequencing of a 714-base pair region of ABL encoding for the
adenosine triphosphate (ATP)-binding site and the kinase activation
loop. A single point mutation was found at nucleotide 1127 (GI6382056)
resulting in Glu255Lys. This mutation occurred in 6 of 9 patients (67%)
following their treatment with STI571 but not in the samples from
patients before beginning treatment with STI571. Glu255Lys is within the
motif important for forming the pocket of the ATP-binding site in ABL
and it is highly conserved across species. In conclusion, Ph(+) ALL
samples resistant to STI571 have a unique mutation Glu255Lys of BCR-ABL.
18
UI - 11963951
AU - Marchant GE
TI -
Genetics and toxic torts.
SO - Seton Hall Law Rev 2001;31(4):949-82
AD - Center for the Study of Law, Science & Technology, Arizona State
University College of Law, USA.
19
UI - 11977532
AU - Katai M; Sakurai A; Fukushima Y
TI -
[Genetic testing and counseling for familial tumor syndromes]
SO - Gan To Kagaku Ryoho 2002 Apr;29(4):502-7
AD - Division of Molecular and Clinical Genetics, Shinshu University
Hospital.
Recent developments in molecular biology have increased our
understanding of the genetics of familial tumor syndromes. Isolation of
the responsible genes has made it possible to identify gene carriers
before they manifest clinical symptoms, which enables early detection of
disease and at times prophylactic surgery. Indications for genetic
testing of susceptible family members, however, should be carefully
considered. Genetic counseling must be provided to clients before
genetic tests. Patients should be provided with the latest knowledge on
the disease and appropriately informed of the benefits and possible
problems associated with genetic test, as such information is essential
for clients to decide whether they will undergo such tests. Genetic
medicine is not sufficiently available at present in Japan.
Establishment of genetic services that deal with genetic counseling,
family support and ethical, social and legal issues is strongly desired.
20
UI - 11977534
AU - Miyoshi Y; Noguchi S
TI -
[Genetic test and prophylactic treatment in breast cancer families]
SO - Gan To Kagaku Ryoho 2002 Apr;29(4):512-22
AD - Dept. of Surgical Oncology, Osaka University Graduate School of
Medicine.
Fifteen (13.3%) and 21 (18.6%) deleterious germline mutations were
identified in BRCA1, and BRCA2 genes among 113 Japanese breast cancer
families. We found a BRCA1 codon 63 (nucleotide 307) nonsense mutation
and a 4-bp deletion at codon 1858 (nucleotide 5802) of BRCA2 in 4 and 7
independent families, respectively. Haplotype analysis has revealed that
these two mutations were founder mutations. Lifetime risk of breast
cancer in BRCA1 or BRCA2 mutation carriers was estimated at nearly 80%,
and that of ovarian cancer in BRCA1 mutation carriers was about 40%. A
questionnaire survey as to the genetic testing (BRCA1 and BRCA2) and
prevention was carried out with 146 healthy women (hospital workers or
medical students) and 84 breast cancer patients. About 80% of healthy
women as well as breast cancer patients responded positively to the
genetic testing, based on the assumption their's was a breast cancer
family, and about 20% of each group answered that they would opt for
prophylactic mastectomy and oophorectomy if they were found to be
germline mutation carriers. These results indicate that genetic testing
and prophylactic surgery would be acceptable among a considerable number
of Japanese women, and seem to support the establishment an
infrastructure for genetic testing in Japan.
21
UI - 11804383
AU - Pignata S; Ballatori E; Favalli G; Scambia G
TI -
Quality of life: gynaecological cancers.
SO - Ann Oncol 2001;12 Suppl 3():S37-42
AD - Oncologia Medica B. Istituto Nazionale Tumori, Naples, Italy.
pignata@sirio-oncology.it
The clinical management of gynaecological cancer patients has been
mainly focused on prolonging the survival of the patients. Thus,
research on MEDLINE using as keywords 'Quality of Life' (QoL) allowed us
to identify few papers which reported data on QoL in gynecological
oncology. However, the assessment of QoL is becoming one of the most
important issues in gynecological oncology, and there is a growing
interest in including quality of life measurements in clinical trials.
In fact, in several randomised trials on ovarian cancer now ongoing in
Europe, the evaluation of QoL has been planned. The one underlying this
article focuses on the symptoms and problems particular to gynecologic
cancer and the treatments of them that could affect quality of life
evaluations. These include limitations of sexual activity and fertility,
early menopause, chemotherapy induced toxicity, and loss of body image.
In this report, we will discuss the aspects affecting the QoL in
gynaecological cancer in relation to surgical treatment, medical
therapy, and follow-up.
22
UI - 11891502
AU - Neumann HP; Hoegerle S; Manz T; Brenner K; Iliopoulos O
TI -
How many pathways to pheochromocytoma?
SO - Semin Nephrol 2002 Mar;22(2):89-99
AD - Nephrology Section, Department of Medicine, Albert-Ludwigs University,
Freiburg, Germany. neumann@mm41.ukl.uni-freiburg.de
Pheochromocytomas, like several other tumors, may be either sporadic or
the manifestation of a familial cancer syndrome. Recently, major
advances have occurred in both the understanding of diverse molecular
mechanisms leading to pheochromocytoma and the diagnostic modalities
available for detection of the disease. Familial pheochromocytoma may be
a manifestation of multiple endocrine neoplasia type 2 (MEN-2), von
Hippel-Lindau (VHL), or neurofibromatosis-1 (NF 1) disease.
Tumor-suppressor genes responsible for the familial occurrence of
extra-adrenal pheochromocytoma, called paraganglioma, have been
identified. This wealth of genetic information, coupled with the
availability of sensitive and specific biochemical tests as well as
imaging studies, allows for genetic screening and early diagnosis of
pheochromocytoma. In addition, genetic screening of relatives at risk is
now feasible. In this article, we review recent clinical and molecular
advances in our understanding of pheochromocytoma. Copyright 2002,
Elsevier Science (USA). All rights reserved.
23
UI - 11708319
AU - Park WY
TI -
[Application of DNA chip technology to biomedical research]
SO - Exp Mol Med 2001 Apr 21;33(1 Suppl):113-24
AD - Department of Biochemistry and Molecular Biology, Seoul National
University College of Medicine, Korea.
The completion of Human Genome Project enabled us to access to the
information on nucleotide sequences of whole human genome. One of the
most valuable information on human genome would be the list of
approximately 35,000 genes. Although 35% of them are still needed to
annotate their functions, we can genome-widely approach to various
conditions including disease states. To analyze bunch of information at
once, we need high-throughput technology containing most of genes. DNA
chip successfully provide a stable platform technology for the massive
screening of genomes. Microarrays can be used to obtain genome-wide
fingerprint on transcriptional changes in various physiological and
pathological conditions, leading to the mining novel genes related to
those specific states. We can check the multiple molecular markers for
diagnosis, prediction or prognosis of specific diseases. Data from
microarray will provide huge amounts of experssion profile, which might
induce the transformation of biomedical research.
24
UI - 11708324
AU - Suh Y
TI -
[CSNP discovery by two-dimensional gene scanning (TDGS)]
SO - Exp Mol Med 2001 Apr 21;33(1 Suppl):21-47
AD - Metagentech, Co., Ltd., Seoul, Korea.
Challenges in the post-genomic era are to use genetic information in
correlating individual gene variations (SNPs; single nucleotide
polymorphisms, the most common form of genetic variation) with medically
important parameters, such as disease susceptibility, individual
responses to drugs and prognostic variables. What is missing is a
high-throughput technology to identify all possible SNPs in essentially
all human genes in population-based studies with high accuracy and speed
in a cost-effective manner. Most tests advocated for their high
throughput at low cost are actually SNP screening tests. That is, they
screen samples for the presence of one or multiple previously identified
SNPs. Such screening methods are only useful when all relevant SNPs in
the genes of interest are known, which is presently not the case.
Moreover, the usefulness of any one SNP varies enormously from
population to population. Indeed, for the Korean population, where no
information on possible sequence variation is available, a mutational
scanning method, capable to detect all possible gene variations will be
most useful. Two-Dimensional Gene Scanning (TDGS) is a high-throughput
platform that enables to detect all possible SNPs in an entire gene in
one gel under one set of conditions, with high sensitivity and
specificity. TDGS is based on automated two-dimensional (2-D) DNA
electrophoresis according to size and base pair sequence to detect DNA
fragments containing all possible variations. Because the 2-D format
permits the analysis of as many as 40 fragments of 250 bp on average in
parallel, TDGS allows extensive multiplex PCR (megaplex PCR), i.e. up to
26 fragments in one single reaction, resulting in a significant cost
reduction. TDGS tests are designed using a computer program to optimally
position PCR primers around the relevant target sequences (exons). A
simple automated 2-D instrument allows scanning all exons of a large
gene in 8 different samples well within 3 hours. Using three different
fluorophores this provides a throughput.
25
UI - 11708326
AU - Shin HD
TI -
[Host genetic epidemiology by single nucleotide polymorphism(SNP)
analysis]
SO - Exp Mol Med 2001 Apr 21;33(1 Suppl):51-69
AD - SNP Genetics, Seoul, Korea.
The completion of the whole human genome sequences is now a reality.
Emphasis on the analysis of genetic variations on both an individual
level and a population level is more important than ever. The
identification and characterization of single nucleotide polymorphisms
(SNPs) in target genes or candidate genes plays a crucial role in
identification of disease genes and in expediting drug
discovery/development. Identification of known SNPs can be easily
accomplished by searching the ever-expanding public domain databases.
However, discovery of new SNPs is best accomplished by sequencing a
reasonable subset of the applicable population groups. Particular SNPs
of interest will be the ones that affect coding changes and regulatory
functions of genes. Once SNPs have been identified, the next step is to
examine their frequency in disease models by accurate, cost-effective
and high-throughput SNP genotyping methods. This presentation will cover
the overview of principal techniques of SNP genotyping which have been
developed so far. And also will be discussed the importance of
well-defined disease model and error-free high-throughput SNP genotyping
in candidate genes and genome-wide SNP screening in the near future.
26
UI - 11708327
AU - Kang DH
TI -
[Molecular and genetic epidemiology]
SO - Exp Mol Med 2001 Apr 21;33(1 Suppl):73-82
AD - Department of Prerentive Medicine, Seoul National Univarsity College of
Medicine, Korea.
Molecular epidemiology is defined as "the use of biological markers in
epidemiologic research" and genetic epidemiology is defined as "the
study of the interaction between genetic and environmental factors in
epidemiologic research". Traditional epidemiologic approaches defined as
"the study of the distribution and determinants of disease frequency in
human population" could not address the importance of genetic
susceptibility of humans in disease occurrence. However, the use of
biological or genetic markers identified and characterized by the help
of advance in molecular biology and human genetics now can provide us
better understanding of multi-factorial or multistep disease occurrence
in humans. Biological markers used in molecular epidemiology are
classified into three groups: biomarkers of exposure (i.e., carcinogen
metabolites in human urine, DNA-adducts, etc.), biomarkers of effects
(i.e., oncoproteins, tumor markers, etc.), and biomarkers of
susceptibility (i.e., genetic polymorphisms of carcinogen metabolism
enzymes, DNA repair, etc.). Susceptibility genes involved in disease
pathogenesis are categorized into two groups: high penetrance genes
(i.e., BRAC1, RB, etc.) and low penetrance genes (i.e., GSTs, XRCC1,
etc.). This paper will address the usefulnesses of bomarkers in
edpidemiologic research and will show the examples of the use of
selected low penetrance genes involved in human carcinogenesis. The
importance of multidisciplinary approaches among epidemiologists,
molecular biologists, and human geneticists will also be discussed.
27
UI - 11914928
AU - Dralle H
TI -
The MEN 1 syndrome: the actual role of genetic testing on the timing and
extent of surgery.
SO - Langenbecks Arch Surg 2002 Mar;386(8):545-6
28
UI - 11914929
AU - Karges W; Schaaf L; Dralle H; Boehm BO
TI -
Clinical and molecular diagnosis of multiple endocrine neoplasia type 1.
SO - Langenbecks Arch Surg 2002 Mar;386(8):547-52
AD - Division of Endocrinology, Department of Internal Medicine, University
of Ulm, Robert Koch Strasse, 89081 Ulm, Germany.
wolfram.karges@medizin.uni-ulm.de
Multiple endocrine neoplasia type 1 (MEN1) is a classic hereditary tumor
syndrome characterized by a genetic predisposition to develop a variety
of neuroendocrine neoplasias and hormone excess syndromes. The disease
is caused by inactivating mutations of the MEN1 tumor suppressor gene,
detectable in >95% of MEN1 families. The distinction of MEN1-associated
tumors from sporadic neuroendocrine neoplasias is clinically important
for providing optimal surgical and medical therapy, appropriate clinical
follow-up, and counsel for affected patients and their families. Since
MEN1 gene analysis became available in 1997, new diagnostic approaches
have evolved in clinical management, to be reviewed in this article.
Genetic screening of MEN1 families will allow definition of individual
disease risk at a preclinical stage, thus helping to allocate medical
resources and treatment as individually needed. These new diagnostic
approaches are expected to reduce MEN1-associated morbidity and
mortality, health care expenses, and psychological disease burden.
29
UI - 11987443
AU - Chikhaoui Y; Gelinas H; Joseph L; Lance JM
TI -
Cost-minimization analysis of genetic testing versus clinical screening
of at-risk relatives for familial adenomatous polyposis.
SO - Int J Technol Assess Health Care 2002 Winter;18(1):67-80
AD - Quebec Agency for Health Services and Technology Assessment.
OBJECTIVE: Familial adenomatous polyposis (FAP) is a well-known
hereditary colorectal cancer-predisposing syndrome. Genetic testing for
colorectal cancer risk is now part of standard medical practice, but
very little is known about the economic impact of this technology. The
aim of this study was to assess, from a healthcare system perspective,
the direct costs of two strategies for screening at-risk relatives of
FAP patients: clinical screening versus genetic testing for FAP.
METHODS: A systematic review of the literature was carried out.
Additional information was gathered from experts in research and
clinical laboratories and in hospital departments. A decision tree was
constructed to compare per-person and per-family costs of the two
strategies for screening at-risk relatives of FAP patients. Sensitivity
analysis was performed to assess the stability of the model across the
full range of plausible values for all key parameters. RESULTS:
According to the decision analysis, with FAP screening starting at
puberty, the average screening costs are $3,181 and $2,259 (Canadian
dollars), respectively, for the clinical screening and the genetic
testing strategies. Genetic screening is cost saving up to a first
screening age of 36. Sensitivity analysis shows that the results of the
baseline analysis hold across a variety of assumptions concerning the
parameter values. CONCLUSIONS: The genetic testing strategy is cost
saving relative to the clinical screening alternative. Apart from its
lower costs, it is associated with many other benefits. Accordingly,
under predefined conditions, predictive genetic testing seems to be the
optimal screening strategy for FAP.
30
UI - 11761722
AU - Rickert CH; Dockhorn-Dworniczak B; Busch G; Moskopp D; Albert FK; Rama
TI -
B; Paulus W
Increased chromosomal imbalances in recurrent pituitary adenomas.
SO - Acta Neuropathol (Berl) 2001 Dec;102(6):615-20
AD - Institute of Neuropathology, University Clinics Munster, Domagkstr. 19,
48129 Munster, Germany. rickchr@uni-muenster.de
Eight pituitary adenomas (four gonadotroph cell adenomas, three
prolactin cell adenomas, one null cell adenoma) and their respective
recurrences in the same patients were studied by comparative genomic
hybridization. Chromosomal imbalances were found in seven of eight
patients affecting two of eight primary and seven of eight recurrent
tumors. Overall, pituitary adenomas showed an average of 1.6 chromosomal
imbalances per primary and 3.4 per recurrent tumor (P < 0.01). Prolactin
cell adenomas showed an average of 4.3 chromosomal changes per primary
and 6.3 per recurrent tumor, which were significantly more common than
in gonadotroph cell adenomas (0 vs 1.7 changes; P < 0.05) and the null
cell adenoma (0 vs 1.0 changes; P < 0.05). The most common changes were
gains of 4q (in three of eight recurrences), 5q, and 13q (in two of
eight recurrences each) as well as losses of chromosome 2 (in both
primary and recurring tumors of two patients), 1p, 8q, 10, and 12q (in
two of eight recurrences). Minimal common regions associated with
recurrent adenomas were gains of 4q31.2-34 (three recurrences), 5q14-23
and 13q21-31 and losses of 12q24.3-qter (two recurrences each). The
average MIB-1 proliferation indices were 1.2% for primary and 1.9% for
recurrent adenomas (P < 0.005). Our findings suggest that acquisition of
certain chromosomal imbalances is related to and may underlie adenoma
recurrence.
31
UI - 11877310
AU - Tobin G; Thunberg U; Johnson A; Thorn I; Soderberg O; Hultdin M; Botling
TI -
J; Enblad G; Sallstrom J; Sundstrom C; Roos G; Rosenquist R
Somatically mutated Ig V(H)3-21 genes characterize a new subset of
chronic lymphocytic leukemia.
SO - Blood 2002 Mar 15;99(6):2262-4
AD - Department of Genetics and Pathology, Uppsala University, SE-751 85
Uppsala, Sweden.
Recent studies on the immunoglobulin variable heavy chain (IgV(H)) genes
have revealed that B-cell chronic lymphocytic leukemia (B-CLL) consists
of at least 2 clinical entities with either somatically mutated or
unmutated V(H) genes. We have analyzed the V(H) gene mutation status and
V(H) gene usage in 119 B-CLL cases and correlated them to overall
survival. A novel finding was the preferential use of the V(H)3-21 gene
in mutated cases, whereas biased V(H)1-69 gene usage was found in
unmutated cases as previously reported. Interestingly, the subset of
mutated cases using the V(H)3-21 gene displayed distinctive
genotypic/phenotypic characteristics with shorter average length of the
complementarity determining region 3 and clonal expression of lambda
light chains. In addition, this mutated subset showed significantly
shorter survival than other mutated cases and a similar clinical course
to unmutated cases. We therefore suggest that B-CLL cases with mutated
V(H)3-21 genes may constitute an additional entity of B-CLL.
32
UI - 11902139
AU - Reid AG; Huntly BJ; Hennig E; Niederwieser D; Campbell LJ; Bown N;
TI -
Telford N; Walker H; Grace CD; Deininger MW; Green AR; Nacheva EP
Deletions of the derivative chromosome 9 do not account for the poor
prognosis associated with Philadelphia-positive acute lymphoblastic
leukemia.
SO - Blood 2002 Mar 15;99(6):2274-5
33
UI - 11885637
AU - Warren V
TI -
Rest assured.
SO - New Sci 2000 Feb 12;165(2225):48-9
AD - BUPA.
34
UI - 11897368
AU - Teupser D; Heino N; Wilfert W; Thiery J
TI -
Rapid detection of the prion protein M129V polymorphism with the
LightCycler.
SO - J Neurosci Methods 2002 Mar 30;115(1):93-6
AD - Institute of Laboratory Medicine, Clinical Chemistry and Molecular
Diagnostics, University Hospital Leipzig, Liebigstr. 27, 04103 Leipzig,
Germany. daniel@teupser.de
The common single nucleotide polymorphism at codon 129 of the prion
protein gene is a key determinant of the genetic susceptibility to
Creutzfeldt-Jakob disease (CJD). Recently, a molecular classification of
sporadic CJD based on the M129V genotype in conjunction with other
determinants was proposed. In the present study, we describe the
development and evaluation of a rapid fluorescent-based assay to detect
this polymorphism using the LightCycler system. The two polymorphic
alleles could be clearly distinguished by their melting points at 52.1
and 60.4 degrees C, representing the 129V and 129M alleles,
respectively. These results were confirmed by DNA sequencing. We
evaluated our test in 400 patient samples and found no deviations from
the expected melting patterns. The calculated allele frequency for the
M-allele was 0.66. Thus, we have established a rapid, reliable
fluorescent assay for high-throughput detection of the prion protein
M129V polymorphism.
35
UI - 11906302
AU - Huoponen K; Puomila A; Savontaus ML; Mustonen E; Kronqvist E;
TI -
Nikoskelainen E
Genetic counseling in Leber hereditary optic neuropathy (LHON).
SO - Acta Ophthalmol Scand 2002 Feb;80(1):38-43
AD - Department of Medical Genetics, University of Turku, Finland.
kirsi.huoponen@utu.fi
PURPOSE: To demonstrate the importance of mitochondrial DNA (mtDNA)
analysis in the diagnosis of Leber hereditary optic neuropathy (LHON)
and illustrate the difficulties in genetic counseling of the disease.
PARTICIPANTS AND METHODS: Ophthalmological and molecular genetic study
of one affected and three unaffected members from a family with
heteroplasmic ND1/3460 mtDNA mutation associated with LHON. RESULTS: The
proband had variable amounts of mutant mtDNA in all his tissues studied,
ranging from 58% in blood to 92% in subcutis. The mother had an
extremely low amount of mutant mtDNA in her tissues, except for hair
roots, which contained only normal mtDNA. No mutant mtDNA could be
detected in the proband's unaffected sister and maternal aunt.
CONCLUSIONS: Despite her minimal mutation load, the mother of the
proband has still transmitted a considerable amount of mutant mtDNA to
her son, who is severely affected. Although proband's unaffected sister
and maternal aunt had no mutant mtDNA, a theoretical risk that they may
transmit the disease to their offspring cannot be excluded.
36
UI - 11961686
AU - Vehmas S
TI -
Is it wrong to deliberately conceive or give birth to a child with
mental retardation?
SO - J Med Philos 2002 Feb;27(1):47-63
AD - Uni
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