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PubMed2002

Variations of basal cell carcinomas according to gender, age, location and histopathological subtype.

BACKGROUND: Most published series of basal cell carcinomas (BCCs) do not take into account the histopathological subtype. Recent studies suggest that the nodular and superficial types could be induced by different causal factors. OBJECTIVES: To analyse the three major subtypes of BCC with regard to sex, age and anatomical distribution. METHODS: We retrospectively included all cases of BCC diagnosed at a single centre of dermatopathology during 1967-96. The diagnosis and subtype (nodular, superficial, morphoeiform) were confirmed by two dermatopathologists. Gender, age at excision, number of tumours and location were recorded, and analysed by histopathological subtype. RESULTS: We recorded 13 457 cases in 10 245 patients (M/F ratio 0.92) of mean age 65 years. Of the BCCs, 78.7% were nodular, 15.1% superficial and 6.2% morphoeiform. Nodular tumours occurred at a mean age of 66.3 years, whereas superficial tumours were excised earlier (63.0 years) and more frequently in women (M/F ratio 0.96). Patients with morphoeiform BCC had a mean age of 65.8 years and were predominantly women (M/F ratio 0.73). Both nodular and morphoeiform types predominated on the head (89.6% and 94.8%), whereas the trunk was the most common location for the superficial type (45.9%). Superficial carcinomas were predominantly located on the head in women (44.8% vs. 34.7% in men), whereas they predominated on the trunk in men (49.9% vs. 42% in women). Tumours of the trunk were excised earlier than those of the face, whatever their histological subtype, in both men and women. CONCLUSIONS: This is the largest series of BCCs in the literature, and shows striking differences in anatomical distribution, sex and mean age according to histological type. The results suggest that the tumours of the trunk, and not only those of the superficial type, could represent a particular subtype of BCC. The analysis also suggests that the hypothesis of chronic vs. intermittent sun exposure cannot be simply extrapolated to BCC. Other causal factors, such as a genetic predisposition, could be involved in the development of carcinomas located on the trunk.

Adolescent↗
PubMed2003

Thirty-four novel mutations detected in factor VIII gene by multiplex CSGE: modeling of 13 novel amino acid substitutions.

Detection of causal mutations is required for genetic counseling. Molecular modeling combined with patients' phenotype provides significant insight into structure-function relationship of factor (F)VIII molecule. Our objective was to identify defects in the gene of FVIII by a sensitive and simple scanning technique with high throughput in order to study molecular mechanisms by which novel amino acid substitutions may lead to hemophilia A. A cohort of 81 families with mild, moderate and severe hemophilia A negative in intron 22 inversion was studied. For detection of mutations in the FVIII gene a conformation sensitive gel electrophoresis (CSGE) was modified by multiplexing. Thirteen novel amino acid substitutions were studied by molecular modeling and a correlation with the cross-reactive material (CRM) phenotype was performed. In 74 families, 59 different mutations were detected. Six different mutations were recurrent in 21 unrelated families. Thirty-four novel mutations included 19 point mutations, four small insertions, nine small deletions and two complex mutations. Thirteen novel amino acid substitutions occurred at residues conserved in FVIII orthologs. Five of them were associated with a discrepancy between FVIII activity and antigen; another five with CRM reduced phenotype and one with undetectable FVIII antigen. Multiplexing of the CSGE significantly increased its throughput without substantial loss of sensitivity. Molecular modeling suggested mechanisms by which substitutions at residues 382 and 569, located outside the proposed FIXa-binding region, may influence FVIII/FIXa interaction. His2155 was predicted to participate in FVIII/VFW binding.

Amino Acid Substitution↗
PubMed2001

Increased activity in the biliary Con A-binding fraction accounts for the difference in crystallization behavior in bile from Chilean gallstone patients compared with Dutch gallstone patients.

Chile has one of the highest prevalences of cholesterol gallstone disease in the world. Recent data indicate that this is partly caused by genetic (Indian) factors. However, the causal factors inducing increased gallstone formation have not been elucidated. The aim of this study was to compare biliary composition and cholesterol crystallization in bile from patients of high and moderate risk areas (Chile and The Netherlands) for gallstone disease. Bile was sampled at cholecystectomy from 30 Chilean and 26 Dutch gallstone patients. The Con A-binding fraction (CABF) was extracted from fresh native bile samples by incubation with Con A-sepharose. Reconstitution of the CABF to the Con A-extracted native bile induced almost full recovery of crystallization confirming the validity of this technique. There was no difference between the two groups regarding sex and age. Chilean bile nucleated significantly faster (3.5 +/- 0.6 vs. 7.9 +/- 1.5 days) despite the fact that Dutch bile had a significantly higher cholesterol saturation index (CSI) (1.6 vs. 1.2, P = .01). The total lipid content was not different. Chilean bile contained more total protein (5 vs. 2.9 mg/mL, P = .008). IgG, IgM, Haptoglobin and alpha-1-acid glycoprotein were not different between the two groups. IgA, though, was significantly higher in the Chilean samples (0.44 vs. 0.19 mg/mL, P < .001). Extraction of CABF increased crystal observation time (COT) and decreased crystal growth in both groups. However, the effects were much more pronounced in the Chilean samples. Compared with Dutch bile, Chilean bile crystallizes much faster despite a lower CSI. Chilean bile contains an increased content of Con A-binding nucleation promoting activity.

Bile↗
PubMed2006

A mutation in the human phospholamban gene, deleting arginine 14, results in lethal, hereditary cardiomyopathy.

The sarcoplasmic reticulum Ca(2+)-cycling proteins are key regulators of cardiac contractility, and alterations in sarcoplasmic reticulum Ca(2+)-cycling properties have been shown to be causal of familial cardiomyopathies. Through genetic screening of dilated cardiomyopathy patients, we identified a previously uncharacterized deletion of arginine 14 (PLN-R14Del) in the coding region of the phospholamban (PLN) gene in a large family with hereditary heart failure. No homozygous individuals were identified. By middle age, heterozygous individuals developed left ventricular dilation, contractile dysfunction, and episodic ventricular arrhythmias, with overt heart failure in some cases. Transgenic mice overexpressing the mutant PLN-R14Del recapitulated human cardiomyopathy exhibiting similar histopathologic abnormalities and premature death. Coexpression of the normal and mutant-PLN in HEK-293 cells resulted in sarcoplasmic reticulum Ca(2+)-ATPase superinhibition. The dominant effect of the PLN-R14Del mutation could not be fully removed, even upon phosphorylation by protein kinase A. Thus, by chronic suppression of sarcoplasmic reticulum Ca(2+)-ATPase activity, the nonreversible superinhibitory function of mutant PLN-R14Del may lead to inherited dilated cardiomyopathy and premature death in both humans and mice.

Adult↗
PubMed2003

Social anxiety disorder.

Although social anxiety disorder (SAD) is a common and disabling disorder that may occur in different cultural settings, it is under-diagnosed by clinicians. In order to facilitate accurate diagnosis, the clinical features and differential diagnosis of SAD are described, together with useful assessment instruments for clinicians. Aetiological evidence suggests that the causal pathways for SAD include genetic, neurobiological, temperamental and cognitive factors. A range of effective treatments for SAD are available: current findings suggest that the selective serotonin reuptake inhibitors (SSRIs) are the first-line choice of pharmacotherapy for SAD, while several other agents show promise in treating refractory cases; furthermore, SAD responds well to psychotherapeutic interventions such as exposure therapy and cognitive restructuring.

Humans↗
PubMed2003

Exposing the MYtH about base excision repair and human inherited disease.

Base excision repair (BER) protects against damage to DNA from reactive oxygen species, methylation, deamination, hydroxylation and other by-products of cellular metabolism. Until last year, inherited deficiencies in the BER pathway had not been causally linked with any human genetic disorder. An apparent explanation was functional redundancy between proteins in this and other pathways. However, it was recently discovered that biallelic mutations in the BER DNA glycosylase MYH lead to an autosomal recessive syndrome of adenomatous colorectal polyposis and very high colorectal cancer risk. We review the molecular mechanism of tumourigenesis in MYH polyposis, the preliminary delineation of the MYH polyposis phenotype and the functional overlap of MYH with other repair proteins.

Adenomatous Polyposis Coli↗
PubMedDate not supplied

Translational research in ovarian cancer: a must.

Ovarian cancer discovered at late clinical stage continues to be a fatal disease. It seems self-evident that if we are to make an impact on the survival of advanced ovarian cancer patients, we must begin to understand the disease more completely. This should improve the diagnosis of the disease at an early stage when it is curable by surgery or develop better/targeted drug treatments. Modern molecular techniques have provided insights into many of the molecular changes that occur when ovarian cancer develops, but one must understand that changes seen in this way can only be said to correlate with disease. It would be helpful to have a way to test candidate changes for causality. In many cancer types, genetically engineered animals are beginning to be used for this purpose and as a means to study the disease process in greater detail. To date, there has been no way to study ovarian cancer by this means. Efforts to model human ovarian cancer have been delayed by a general lack of understanding both of the disease process in humans and of the cells widely believed to be the precursors of epithelial ovarian cancer, the ovarian surface epithelial (OSE) cells. Here, we present recent progress in modeling ovarian cancer using genetically modified mice.

Animals↗
PubMed1995

Comorbid Tourette's disorder and bipolar disorder: an etiologic perspective.

OBJECTIVE: Using an epidemiologic approach, the authors attempt to elucidate relationships between Tourette's disorder and bipolar disorder. METHOD: Of 205 patients with Tourette's disorder in the North Dakota Longitudinal Tourette Syndrome Surveillance Project, 15 had comorbid bipolar disorder. A subset of the patients with Tourette's disorder had been included in earlier population-based prevalence studies of Tourette's disorder in children, adolescents, and adults. Minimal risk ratios were calculated for the patients with Tourette's disorder plus bipolar disorder by age group (children/adolescents and adults). This information was used to estimate genetic risk indicators for comorbid Tourette's disorder and bipolar disorder. RESULTS: The estimated risk of developing bipolar disorder among the study group of children, adolescents, and adults with Tourette's disorder was more than four times higher than the level expected by chance, but this finding did not reach statistical significance. It was indicative of trends, however. CONCLUSIONS: Comorbidity between Tourette's disorder and bipolar disorder does not appear to be due to chance co-occurrence of the two disorders. Although a genetic mechanism may play a causal role, in the absence of family studies an explanatory model involving the concept of canalization of basal-ganglia-mediated dysfunctions is offered. In such a construct, Tourette's disorder would be a likely accompaniment to other conditions, including bipolar disorder, whose pathogenic determinants might channel through neural pathways involving the basal ganglia. The presence of significant developmental disabilities may further enhance factors culminating in comorbid Tourette's disorder and bipolar disorder.

Adolescent↗
PubMed2004

Possible roles for activating RAS mutations in the MGUS to MM transition and in the intramedullary to extramedullary transition in some plasma cell tumors.

To assess a possible role in tumor progression, the occurrence and type of K- and N-RAS mutations were determined in purified tumor cells, including samples from patients with premalignant monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM), and extramedullary plasma cell (PC) tumors (ExPCTs). Immunophenotypic aberrant PCs were flow sorted from 20 MGUS, 58 MM, and 13 ExPCT patients. One RAS mutation was identified in 20 MGUS tumors (5%), in contrast to a much higher prevalence of RAS mutations in all stages of MM (about 31%). Further, oncogene analyses showed that RAS mutations are not evenly distributed among different molecular subclasses of MM, with the prevalence being increased in MM-expressing cyclin D1 (P = .015) and decreased in MM with t(4;14) (P = .055). We conclude that RAS mutations often provide a genetic marker if not a causal event in the evolution of MGUS to MM. Surprisingly, RAS mutations were absent in bone marrow tumor cells from all patients with ExPCT, a result significantly different from intramedullary MM (P = .001). From 3 of 6 patients with paired intramedullary and extramedullary PCs and identical immunoglobulin heavy chain gene (IgH) sequences, RAS mutations were identified only in extramedullary PCs, suggesting a role for RAS mutations in the transition from intramedullary to extramedullary tumor.

Base Sequence↗
PubMed2000

Epidemiologic contributions to understanding the etiology of uterine leiomyomata.

Uterine leiomyomata are hormonally dependent tumors that are a major source of gynecologic morbidity among women of reproductive age. Relatively few studies have attempted to identify specific risk factors for these neoplasms. In this review of epidemiologic contributions to the etiology of uterine leiomyomata, we begin by outlining methodologic issues in epidemiologic studies that arise from the fact that a large proportion of uterine leiomyomata does not come to medical attention. We then review the major findings from published epidemiologic studies, which to date have focused primarily on menstrual and childbearing history, exogenous hormone use, obesity, cigarette smoking, and other lifestyle and behavioral characteristics that may in part reflect aspects of a woman's hormonal milieu. None of the potential risk factors studied have demonstrated sufficiently consistent associations to guide decisions on the primary prevention of uterine leiomyomata. Clarifying the etiology and natural history of uterine leiomyomata will require studies designed to address methodologic issues and test hypotheses involving environmental and lifestyle influences on endocrine function, as well as on other possible etiologic mechanisms. Recent advances in molecular genetics present opportunities for epidemiologic studies of uterine leiomyomata to incorporate biomarkers of somatic changes found in these tumors and to examine inherited genetic factors related to possible causal physiologic mechanisms.

Disease Progression↗
PubMed2005

Historical perspectives on plant developmental biology.

The early studies of plant growth and development focused on embryogenesis. In the past twenty five years, it became possible to successfully analyze many more developmental processes, hence plant developmental biology became the generally accepted terminology. It refers to a multidisciplinary approach using expertise and tools from genetics, molecular biology and cell biology to study processes in development also beyond the formation of the embryo. Around that time, initiatives were taken to address biological questions in just a few model systems, such as Arabidopsis thaliana, Zea mays, Antirrhinum majus and Petunia hybrida, while the < > model systems, i.e. potato, tobacco, used in regeneration and grafting experiments, were increasingly abandoned. International research programs were initiated in Arabidopsis at first to create stock centers and databases to proceed faster with the scientific research and to get deeper insight into plant biology. During the last five years the maize community made tremendous progress in developing tools and resources for their system. Milestones in plant developmental biology discussed relate to the molecular-genetic approach to study embryogenesis, autoregulation of meristems, leaf and flower initiation, leaf and flower formation and cell specification in the root. Developmental biology changed the research from descriptive to causal resulting in a number of genetic models. Future developments in research will focus on the study of a specific gene activity in a genome-wide context. The building of molecular networks will allow computer modeling of biological processes and its use for predictions and further experimentation. Sequence information derived from the multiple genome projects will be exploited in comparative biology.

DNA, Plant↗
PubMed2006

The incidence of second primary tumors in thyroid cancer patients is increased, but not related to treatment of thyroid cancer.

OBJECTIVE: The aim of the present study is to assess the prevalence of second primary tumors in patients treated for thyroid cancer. Furthermore, we wanted to assess the standardized risk rates for all second primary tumors, but especially for breast cancer, as data in the literature indicate an excessive risk in differentiated thyroid cancer (DTC) patients for this tumor. MATERIALS AND METHODS: We included consecutive patients, who received ablation treatment with I-131 at the Leiden University Medical Center between January 1985 and December 1999 (n = 282). The mean period of follow-up was 10.6 +/- 4.1 years. RESULTS: Thirty-five of the 282 patients (12.4%) had a second primary tumor (SPT), either preceding or following the diagnosis of thyroid cancer. Five other patients had three primary tumors, including DTC. As a result, 40 additional tumors were found in this group, revealing an overall prevalence of 14.2%. Twenty tumors (7.1%) preceded the thyroid cancer with a mean interval of 5.7 years (range: 0.5-22.0 years), whereas 20 tumors (7.1%) occurred after this tumor with a mean interval of 6.7 years (range: 1.0-15.0 years). In 13 female patients, breast cancer was found as SPT. The standardized incidence rate (SIR) for all cancers after the diagnosis of DTC in this study population was not increased (1.13; confidence interval (CI): 0.68-1.69). However, we found an increased SIR of 2.26 (CI: 1.60-3.03) for all cancers either following or preceding DTC, which is mainly caused by a SIR of 3.95 (CI: 2.06-6.45) for breast cancer. CONCLUSION: Patients with DTC have an overall increased standardized incidence rate for second primary tumors, but not for second primary tumors following I-131 therapy. These findings suggest a common etiologic and/or genetic mechanism instead of a causal relation.

Adenocarcinoma, Follicular↗
PubMedDate not supplied

Aicardi-Goutières syndrome: differential diagnosis and aetiopathogenesis.

Aicardi-Goutières syndrome (AGS) is a progressive encephalopathy with onset in the first year of life and a recessive autosomal pattern of inheritance. The syndrome is characterised by acquired microcephaly, basal ganglia calcifications, white matter abnormalities, chronic cerebrospinal fluid (CSF) lymphocytosis and raised interferon-alpha (INF-alpha) in the CSF. AGS is diagnosed on the basis of a clinical picture characterised by microcephaly and by the onset of encephalopathy associated with severe psychomotor delay, spasticity and extrapyramidal signs. CT is very important in the diagnosis of AGS, demonstrating clearly the presence of calcifications at basal ganglia level: these are often bilateral and symmetrical. CT scan and MRI reveal leukodystrophy and progressive cerebral atrophy. A raised level of INF-alpha in the CSF constitutes a marker of the syndrome: this level, which falls with age, is higher in the CSF than in the serum, suggesting intrathecal synthesis. Differential diagnosis in AGS is carried out to exclude the presence of other neurological and endocrinological pathologies characterised by the presence of intracranial calcification; considering the white matter abnormalities, it is necessary to exclude forms of leukodystrophy associated with metabolic defects, known or otherwise. One fundamental aspect that remains to be clarified is the aetiopathogenetic mechanism underlying AGS: the most well-founded hypotheses are reported. There does not exist, to date, any causal therapy for AGS, although genetic studies, particularly those focusing on interferon-regulating genes, may well provide some therapeutic indications.

Basal Ganglia Diseases↗
PubMed1992

Nonconvulsive electrocorticographic paroxysms (absence epilepsy) in rat strains.

Rat strains were screened for evidence of unresponsive periods associated with high-voltage spike and wave paroxysms on electroencephalography--a rodent model of human absence epilepsy. Five commonly used strains were newly noted to express the spike and wave phenomenon. Only an inbred Sprague Dawley rat strain did not exhibit such episodes. The existence of the phenomenon in many and unrelated inbred rat strains suggests that both genetic and environmental factors are causal.

Animals↗
PubMed2005

Detailed histopathologic characterization of the retinopathy, globe enlarged (rge) chick phenotype.

PURPOSE: The purpose of this study was to characterize the morphological abnormalities in the retinas of chicks (Gallus gallus) suffering from the autosomal recessive disease, retinopathy, globe enlarged (rge/rge). METHODS: rge/rge affected and age matched control retinas were examined from hatch up to 730 days of age. Thickness of retinal layers at six retinal regions was measured from plastic embedded sections. Morphological features were examined on semi-thin sections by light microscopy and on ultra-thin sections by transmission electron microscopy. Immunohistochemistry was performed using a panel of several different antibodies. Additionally, comparative counting of rod outer segments, rows of cells in the inner nuclear layer, and ganglion cells per unit length was performed. RESULTS: The earliest changes observed in rge/rge retinas were disorganization of the outer plexiform layer and abnormal location of the endoplasmic reticulum of the photoreceptors. In rge/rge retinas, cone pedicles were larger, irregular in shape, and usually contained multivesicular bodies. In addition, synaptic ribbons of the cone pedicles and rod spherules in rge/rge retinas were less numerous compared to controls. Large glycogen deposits progressively accumulated in the perinuclear cytoplasm associated with the abnormally located endoplasmic reticuli in accessory cones and rods. Total retinal thickness progressively decreased with age in rge/rge birds. This was accompanied by a decrease in the number of cells in the inner nuclear layer and a decrease in the number of rod outer segments (OSs). Several changes were detected in the rge/rge retinas using immunohistochemistry, including mislocalized opsin immunoreactivity of rod photoreceptors, a decrease in number and disorganization of opsin positive rod OSs (especially in the peripheral regions), a decrease in number of tyrosine hydroxylase positive neurites in the distal inner plexiform layer, and activation of macroglial and microglial cells. CONCLUSIONS: As we previously reported, the rge/rge chick has vision loss that is not the result of photoreceptor loss and is unusual in that electroretinographic responses, although abnormal, are maintained until well after vision loss has developed. The phenotype is associated with a developmental disruption of both rod and cone photoreceptor synaptic terminals that progresses with age. It is possible that these changes may be indicative of abnormal circuitry within the outer plexiform layer, and that they underlie the progressive loss of vision in rge/rge birds. Other early changes suggesting photoreceptor abnormality are dilation of photoreceptor cell bodies, abnormal positioning of endoplasmic reticulum in the perinuclear region that is associated with abnormal glycogen deposition, and mislocalization of opsin immunoreactivity in rods. The rge/rge birds develop globe enlargement after the morphological and electroretinographic abnormalities. Globe enlargement in chicks can be induced by a number of different environmental factors. It is possible that abnormal signaling of photoreceptors to inner retinal cells could induce excessive ocular growth in the rge/rge birds. Many of the morphological changes such as retinal thinning seen in older rge/rge birds may be partly the result of the considerable globe enlargement that occurs later in the disease process. Molecular genetic studies to identify the causal gene mutation should help explain the morphological features of the rge/rge phenotype and clarify their association with vision loss and electroretinographic abnormalities.

Animals↗
PubMed1988

[Hodgkin and Sternberg-Reed cells--cell origin, cell marker, cell function].

The controversy in literature with regard to the origin of Hodgkin's and Reed-Sternberg cells persists, however only two conceptions seem to be plausible at present: the first is based on the relation to histiocytic elements, the second postulates lymphocytic precursors. The significance of surface-markers of these malignant cells in cryostat-sections and in cell-cultures and the relevance of their functional properties are discussed with respect to pathophysiology, clinical appearance, diagnosis and prognosis of Hodgkin's disease. The authors present two tendencies in the classification of malignant lymphomas based on the present knowledge achieved especially by monoclonal antibodies: the first includes aspects of integration between non Hodgkin's lymphomas and Hodgkin's disease, illustrated by the Ki-1-lymphoma, the second is related to separation of entities of the group of Hodgkin's lymphomas (for example the nodular paragranuloma). The aetiopathogenesis of Hodgkin's disease is considered as a causal trinity of virus infection, genetic determination and immunologic predisposition.

Biomarkers, Tumor↗
PubMed1994

[Helicobacter pylori, a risk factor for stomach cancer and primary stomach lymphoma?].

Helicobacter pylori has been implicated as a possible etiologic factor in gastric cancer. Recent epidemiologic studies, in fact, have demonstrated that there is a significantly higher prevalence of H. pylori in patients with gastric cancer than in matched controls. In addition to these and other epidemiologic findings, there is evidence that several of the pathogenic consequences of H. pylori infection may be relevant to carcinogenesis. In accordance with the theory that the etiology of gastric cancer is likely to be multifactorial, it is believed that the overall risk is determined by dietary, genetic and other cofactors. A causal relationship between H. pylori and gastric cancer, however, remains to be proven by randomized intervention trials of the long-term effects of H. pylori eradication. Until conclusive results become available from these studies, bacterial eradication cannot be recommended as prophylactic measure to reducing the risk of gastric cancer. In patients with low-grade B-cell gastric lymphomas of the mucosa-associated lymphoid tissue type (MALT) a causal pathogenic association with H. pylori-associated gastritis was demonstrable not only in cell culture but also in preliminary clinical trials. Several investigators have reported that eradication of H. pylori results in complete regression of early stage gastric MALT lymphomas. Answers to the questions whether healing is permanent, whether lymphomas at a more advanced stage will respond as well, and how regression comes about will have to be established in future studies.

Cell Transformation, Neoplastic↗
PubMedDate not supplied

Genetic influences on aging.

Genetics is an important tool for identifying key molecular events that are involved in specifying biological functions. Genetic approaches have been used repeatedly to understand diverse biological phenomena: oncogenesis, development, and the cell cycle, but have only recently been applied to the analysis of organismic aging and senescence. The power of the genetic approach stems from two facts. First, genetic analyses allow the integration of phenomena that are analyzed at many levels of observation from the molecule to the intact organism, and second, genetics has the real power to reveal causality by factors that are not dependent upon the prejudice of the investigator. I discuss several areas where genetics has been fruitfully applied to the study of the aging processes: human genes identified by "segmental progeroid" mutations, neurological diseases of the elderly, the limited proliferative life span of human somatic cells in tissue culture, studies on the life span of the mouse, and genetic analysis of life span in shorter lived metazoans (Drosophila melanogaster and Caenorhabditis elegans), and the yeast Saccharomyces cerevisiae.

Aging↗