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Biomedical subjects

M Goldberg

Publications and source records attributed to M Goldberg.

At least 19 recordsLinked to original sources
PubMed2007

Cellular uptake of amelogenin, and its localization to CD63, and Lamp1-positive vesicles.

Proteins of the developing enamel matrix include amelogenin, ameloblastin and enamelin. Of these three proteins amelogenin predominates. Protein-protein interactions are likely to occur at the ameloblast Tomes' processes between membrane-bound proteins and secreted enamel matrix proteins. Such protein-protein interactions could be associated with cell signaling or endocytosis. CD63 and Lamp1 are ubiquitously expressed, are lysosomal integral membrane proteins, and localize to the plasma membrane. CD63 and Lamp1 interact with amelogenin in vitro. In this study our objective was to study the molecular events of intercellular trafficking of an exogenous source of amelogenin, and related this movement to the spatiotemporal expression of CD63 and Lamp1 using various cell lineages. Exogenously added amelogenin moves rapidly into the cell into established Lamp1-positive vesicles that subsequently localize to the perinuclear region. These data indicate a possible mechanism by which amelogenin, or degraded amelogenin peptides, are removed from the extracellular matrix during enamel formation and maturation.

Amelogenesis↗
PubMed2006

Amelogenin gene splice products A+4 and A-4 implanted in soft tissue determine the reorientation of CD45-positive cells to an osteo-chondrogenic lineage.

Several molecules such as bone morphogenetic protein-7, bone sialoprotein (BSP), or amelogenin gene splice products (A+4 or A-4) have been shown to induce reparative dentin formation in a rat model. However, at the moment, the origin and the mechanism of differentiation of the pulp cells stimulated by the bioactive molecules remain poorly understood. The present investigation was undertaken to validate an ectopic oral mucosal mouse model to evaluate the effects of amelogenin gene splice product implantation in a non-mineralizing tissue. Agarose beads, alone or coated with amelogenin gene splice products, were implanted in the mucosa of the cheeks in mouse. An immunohistochemical characterization of the recruited cells was undertaken for 3 days, 8 days, and 30 days after the implantation. The results showed that the implantation of agarose beads in mucosa induced the recruitment of inflammatory CD45 positive cells. When the beads were coated with amelogenin gene splice products (A+4 or A-4), the expression of osteo-chondrogenic markers (RP59, Sox9, or BSP) was also observed. However, no mineralization nodule was observed, even after 30 days of implantation. The present investigation suggests that amelognin gene splice products have the capacity of recruiting among inflammatory cell mesenchymal progenitors that eventually differentiate into osteo-chondrogenic cells. Altogether, the results obtained in the pulp model and the present data suggest the existence of different pathways of cell recruitment and differentiation in different cellular environments.

Absorbable Implants↗
PubMed2006

Dentin alteration of deciduous teeth in human hypophosphatemic rickets.

Familial hypophosphatemic rickets is in most cases transmitted as an X-linked dominant trait and results from mutation of the PHEX gene, predominantly expressed in osteoblast and odontoblast. Patients have been reported to display important dentin defects, and therefore, we explored the dentin structure, composition, and distribution of extracellular matrix (ECM) molecules in hypophosphatemic human deciduous teeth. Compared to age-matched controls, the dentin from hypophosphatemic patients exhibited major differences: presence of large interglobular spaces resulting from the lack of fusion of calcospherites in the circumpulpal dentin; defective mineralization in the interglobular spaces contrasting with normal Ca-P levels in the calcospherites on X-ray microanalysis; abnormal presence of low-molecular weight protein complexes recognized on Western blots by antibodies against matrix extracellular phosphoglycoprotein (MEPE), dentin sialoprotein, osteopontin, and reduced osteocalcin (OC) level; and accumulation in the interglobular spaces of immunolabeling with antibodies against DSP, dentin matrix protein, bone sialoprotein, MEPE and OC, while chondroitin/dermatan sulfate glycosaminoglycans were exclusively located inside calcospherites. Alterations of the post-translational processing or partial degradation of some ECM appear as key factors in the formation of the defective hypophosphatemic dentin.

Child↗
PubMed2006

Synthesis of complement proteins in the human chorion is differentially regulated by cytokines.

The aim of the current paper was to determine the chorion's contribution to complement synthesis in the placenta and its regulation by cytokines. Biosynthetic labeling followed by immunoprecipitation with polyclonal antibodies was performed in chorionic tissue and chorion-derived cells. Eight complement proteins, factor B, C3, C1r, C1s, C1 inhibitor, factor H, C4 and C2 were detected in chorionic tissue and were secreted extracellularly. In chorion-derived cells, IL-1beta stimulated factor B synthesis but had no effect on C1r, C1 inhibitor, C1s, factor H and C4. TNFalpha had no stimulative effect on any of the complement proteins tested. In contrast, both IL-1beta and TNFalpha highly induced IL-6 secretion in chorion-derived cells, demonstrating the overall responsiveness of these cells to these stimuli. Interestingly, IFN-gamma increased the synthesis of C1s, C1r, C1 inhibitor, C4 and factor H in chorion-derived cells. The fact that the latter two complement proteins have opposing effects on immune activation of the complement cascade demonstrates the complex balance required to both maintain an ability to ward off infections but simultaneously suppress the immune response to enable tolerance of the allograft fetus.

Cells, Cultured↗
PubMed2006

Why are manual workers at high risk of upper limb disorders? The role of physical work factors in a random sample of workers in France (the Pays de la Loire study).

OBJECTIVE: To investigate the reasons for the excess risk of upper limb musculoskeletal disorders among manual workers compared with other workers in a random sample of 2656 French men and women (20-59 years old) participating in a study on the prevalence of work related upper limb disorders conducted by France's National Institute of Health Surveillance. METHODS: Prevalence ratios (PR) of physician-diagnosed musculoskeletal disorders of the shoulder, elbow, wrist, and hand (any of six leading disorders, rotator cuff syndrome, carpal tunnel syndrome) in manual versus non-manual workers were calculated using Cox regression models with a constant time of follow up and robust variance. RESULTS: 11.3% of men and 15.1% of women were diagnosed with an upper limb disorder. The risk was especially high in manual workers (PRs: 1.40 to 2.10). Physical work factors accounted for over 50% of occupational disparities overall, 62% (men) to 67% (women) for rotator cuff syndrome, and 96% (women) for carpal tunnel syndrome. The authors calculated that under lower levels of physical work exposures, up to 31% of cases among manual workers could have been prevented. CONCLUSIONS: In working men and women, upper limb musculoskeletal disorders are frequent. Physical work exposures, such as repetitive and forceful movements, are an important source of risk and in particular account for a large proportion of excess morbidity among manual workers.

Adult↗
PubMed2006

The French National Mesothelioma Surveillance Program.

OBJECTIVES: The French National Mesothelioma Surveillance Program (NMSP) was established in 1998 by the National Institute for Health Surveillance (InVS). Its objectives are to estimate the trends in mesothelioma incidence and the proportion attributable to occupational asbestos exposure, to help improve its pathology diagnosis, to assess its compensation as an occupational disease, and to contribute to research. METHODS: The NMSP records incident pleural tumours in 21 French districts that cover a population of approximately 16 million people (a quarter of the French population). A standardised procedure of pathological and clinical diagnosis ascertainment is used. Lifetime exposure to asbestos and to other factors (man made mineral fibres, ionising radiation, SV40 virus) is reconstructed, and a case-control study was also conducted. The proportion of mesothelioma compensated as an occupational disease was assessed. RESULTS: Depending on the hypothesis, the estimated number of incident cases in 1998 ranged from 660 to 761 (women: 127 to 146; men: 533 to 615). Among men, the industries with the highest risks of mesothelioma are construction and ship repair, asbestos industry, and manufacture of metal construction materials; the occupations at highest risk are plumbers, pipe-fitters, and sheet-metal workers. The attributable risk fraction for occupational asbestos exposure in men was 83.2% (95% CI 76.8 to 89.6). The initial pathologist's diagnosis was confirmed in 67% of cases, ruled out in 13%, and left uncertain in the others; for half of the latter, the clinical findings supported a mesothelioma diagnosis. In all, 62% applied for designation of an occupational disease, and 91% of these were receiving workers' compensation. CONCLUSIONS: The NMSP is a large scale epidemiological surveillance system with several original aspects, providing important information to improve the knowledge of malignant pleural mesothelioma, such as monitoring the evolution of its incidence, of high risk occupations and economic sectors, and improving pathology techniques.

Aged↗
PubMed2006

Different genetic pathways in the development of periocular sebaceous gland carcinomas in presumptive Muir-Torre syndrome patients.

Periocular sebaceous gland carcinomas (SGCs) occur in the eyelids either sporadically or as a phenotypic feature of Muir-Torre syndrome (MTS). In knockout mice mismatch-repair (MMR) defects or inactivation of the fragile histidine triad (FHIT) gene are associated with MTS-like signs, including SGC. To dissect the genetic alterations associated with microsatellite instability (MSI) and inactivation of the FHIT gene, we studied nine periocular SGC specimens from MTS patients. Immunohistochemistry was performed for FHIT, MSH2, MLH1, and MSH6. We assessed MSI as well as loss of heterozygosity (LOH) at the FHIT locus with polymorphic markers and genomic multiplex PCR. Epigenetic silencing was detected by methylation-specific PCR (MSP) and combined bisulfite restriction analysis (COBRA). Our analyses identified two SGCs with FHIT positivity and high-grade MSI, and seven cases with loss of FHIT and microsatellite stability (MSS). MSI correlated with loss of MSH2 and MLH1 immunostaining. Loss-of-function mechanisms affecting the FHIT gene were identified as intragenic deletions eliminating the coding exons 5 and 6 on one hand, and complete biallelic methylation of the FHIT transcription regulatory region on the other hand. Germinal FHIT mutations as a predisposing factor for MTS were excluded in two index patients with cancer in three generations, including an FHIT-negative SGC. Our data suggest that either somatic inactivation of the FHIT gene associated with MSS or inactivation of the MMR system resulting in MSI contribute to the development of periocular SGCs in presumptive MTS.

Acid Anhydride Hydrolases↗
PubMed2006

[Comparison of the French DRG based information system (PMSI) with the National Mesothelioma Surveillance Program database].

BACKGROUND: One of the main purposes of the French National Mesothelioma Surveillance Program is to estimate and follow the national incidence of pleural mesothelioma. We wanted to study the contribution of the French hospital national database as a valid source of mesothelioma incident cases. METHODS: From the 1998 and 1999 hospital national database, medical records with a diagnosis code of mesothelioma or pleural cancer where selected among patients who resided in one of the 17 administrative divisions covered by the National Mesothelioma Surveillance Program in 1998. From these records, 506 patients in 1998 and 474 patients in 1999 where identified and matched with the National Mesothelioma Surveillance Program cases over the same period using indirect criteria of identification (sex, age, place of residence). Medical records of cases unknown by the National Mesothelioma Surveillance Program where consulted in one of the administrative divisions. RESULTS: Only two-thirds of the registered cases of the National Mesothelioma Surveillance Program could be matched with a patient identified in the hospital national database with a diagnosis of mesothelioma registered during the same year. Consultation of the medical records showed that 1) certified cases registered in the National Mesothelioma Surveillance Program where often (83%) found in the hospital national database with a code of mesothelioma but 10 to 15% of the patients with a code of mesothelioma in the national hospital databases had a different diagnosis according to their medical records; 2) 65% of the patients with a code of mesothelioma in the national hospital databases that where unknown from the National Mesothelioma Surveillance Program in 1998 and 55% in 1999 where prevalent cases; 3) 3 suspected cases had not been reported to the National Mesothelioma Surveillance Program. CONCLUSION: Because of lack of diagnosis certification, mistakes in encoding diagnosis and the fact that incident and prevalent cases cannot be distinguished in the hospital national database make it impossible to estimate the mesothelioma incidence solely from this source of data. However, the hospital claim databases constitute a complementary source of information for the active search of incident cases performed by the National Mesothelioma Surveillance Program.

Databases, Factual↗
PubMed2006

Epigenetic silencing contributes to frequent loss of the fragile histidine triad tumour suppressor in basal cell carcinomas.

BACKGROUND: Extensive exposure to ultraviolet radiation is associated with genetic alterations in basal cell carcinomas (BCCs), which represent some 75% of skin cancers. OBJECTIVES: As recent data suggested the fragile histidine triad (FHIT) gene product to participate in DNA damage responses we wished to address whether functional deletion of this tumour suppressor participates in the development of BCC. Our study focused on epigenetic inactivation of the FHIT gene. METHODS: Paraffin-embedded specimens from 17 patients with BCC were available for methylation-specific polymerase chain reaction (MSP), combined bisulphite-dependent restriction analysis (COBRA) of the FHIT gene and immunohistochemistry of its product. RESULTS: We report for the first time that 100% of BCCs are negative for FHIT by immunostaining. Aberrant methylation of the FHIT promoter occurred in a significant portion of BCCs. MSP detected hypermethylation of the FHIT/FRA3B locus in nine of nine (100%) periocular BCCs and in six of eight (75%) BCCs from other body regions. COBRA yielded similar results, confirming that some 88% of the 17 BCCs analysed harbour epigenetic silencing of the FHIT gene. Loss of FHIT protein was demonstrated immunohistochemically, confirming that promoter hypermethylation correlated with loss of gene expression. CONCLUSIONS: We have identified epigenetic silencing of the FHIT tumour suppressor gene as a frequent inactivation mechanism which is likely to contribute to functional deficiencies in DNA damage response of BCCs.

Acid Anhydride Hydrolases↗
PubMed2006

Lifelong socioeconomic trajectory and premature mortality (35-65 years) in France: findings from the GAZEL Cohort Study.

BACKGROUND: Studies conducted in the UK and Scandinavia show an inverse association between lifetime socioeconomic position and adult mortality. However, there are virtually no data from other countries and few investigations have examined non-cardiovascular mortality in men and women. METHODS: Lifelong socioeconomic trajectories (father's occupation, own occupation in young adulthood and in mid-life) and premature (< or = 65 years) mortality (all-cause, smoking-related cancer, diseases of the circulatory system and external causes) in the French GAZEL Cohort Study (14,972 men and 5,598 women, followed up between 1990 and 2004) were studied. Hazard ratios (HRs) were estimated using Cox's regression models adjusted for age, marital status, tobacco smoking, alcohol consumption, body mass index, and fruit and vegetable consumption. RESULTS: Men and women who experienced lifelong disadvantage or downward intergenerational mobility were at high risk of dying prematurely compared with those with a favourable trajectory (age-adjusted HRs for all-cause mortality: cumulative disadvantage: HR 1.61, 95% confidence interval (CI) 1.26 to 2.06 in men and HR 1.95, 95% CI 1.10 to 3.47 in women; downward mobility: HR 1.87, 95% CI 1.35 to 2.58 in men and HR 2.05, 95% CI 1.12 to 3.75 in women). Associations were strongest for mortality due to chronic diseases (smoking-related cancers and diseases of the circulatory system). These associations were partly explained by marital status, body mass index, alcohol consumption, cigarette smoking, and fruit and vegetable consumption. CONCLUSIONS: In France, where the leading cause of premature death is cancer, lifelong socioeconomic position is associated with the risk of dying before the age of 65 years. Adult factors seem more relevant than childhood socioeconomic circumstances.

Adult↗
PubMed2006

The role of matrix metalloproteinases (MMPs) in human caries.

The objective of this review is to summarize our understanding of the role of host matrix metalloproteinases (MMPs) in the caries process and to discuss new therapeutic avenues. MMPs hydrolyze components of the extracellular matrix and play a central role in many biological and pathological processes. MMPs have been suggested to play an important role in the destruction of dentin organic matrix following demineralization by bacterial acids and, therefore, in the control or progression of carious decay. Host-derived MMPs can originate both from saliva and from dentin. They may be activated by an acidic pH brought about by lactate release from cariogenic bacteria. Once activated, they are able to digest demineralized dentin matrix after pH neutralization by salivary buffers. Furthermore, the degradation of SIBLINGs (Small Integrin-binding Ligand N-linked Glycoproteins) by the caries process may potentially enhance the release of MMPs and their activation. This review also explores the different available MMP inhibitors, natural or synthetic, and suggests that MMP inhibition by several inhibitors, particularly by natural substances, could provide a potential therapeutic pathway to limit caries progression in dentin.

Dental Caries↗
PubMed2006

Do respiratory symptoms predict job choices in teenagers?

Existing guidelines advise adolescents with asthma and allergies against high-risk occupations. The aim of the current authors' analyses was to investigate the resulting self-selection in a prospective cohort study. The participants of Phase II of the International Study of Asthma and Allergies in Childhood in Germany (aged 9-11 yrs at baseline) were re-contacted after 7 yrs (response rate was 77%) and were asked to complete a questionnaire, which included items on atopic diseases. The subjects were also asked about the type of job they would like to have in the future (preferred job choice). Exposure to agents with potential asthma risk was evaluated using a job exposure matrix. The analyses were restricted to those in school-based vocational training programmes without occupational exposures. A total of 33% of subjects chose jobs with high asthma risk, 23% selected low asthma risk jobs and the remaining adolescents indicated jobs without known asthma risk (reference category). There were no statistically significant associations between asthma, allergic rhinitis or atopic dermatitis and selecting jobs with asthma risk. Participants with allergic rhinitis tended to select high risk jobs less frequently. In conclusion, self-selection into low risk jobs seems to play a minor role in teenagers with asthma or allergies.

Adolescent↗
PubMed2005

Targeted disruption of two small leucine-rich proteoglycans, biglycan and decorin, excerpts divergent effects on enamel and dentin formation.

Small leucine-rich proteoglycans have been suggested to affect mineralization of dental hard tissues. To determine the functions of two of these small proteoglycans during the early stages of tooth formation, we characterized the dental phenotypes of biglycan (BGN KO) and decorin deficient (DCN KO) mice and compared them to that of wild type mice. Each targeted gene disruption resulted in specific effects on dentin and enamel formation. Dentin was hypomineralized in both knock out mice, although the effect was more prominent in the absence of decorin. Enamel formation was dramatically increased in newborn biglycan knockout mice but delayed in absence of decorin. Increased enamel formation in the former case resulted from an upregulation of amelogenin synthesis whereas delayed enamel formation in the later case was most probably an indirect consequence of the high porosity of the underlying dentin. Enamelin expression was unchanged in BGN KO, and reduced in DCN KO. Dentin sialoprotein (DSP), a member of the family of phosphorylated extracellular matrix proteins that play a role in dentinogenesis, was overexpressed in BGN-KO odontoblasts and in the sub-odontoblastic layer. In contrast, a decreased expression of DSP was detected in DCN KO. Dentin matrix protein-1 (DMP-1), bone sialoprotein (BSP) and osteopontin (OPN) were upregulated in BGN KO and downregulated in the DCN KO. Despite the strong effects induced by these deficiencies in newborn mice, no significant difference was detected between the three genotypes in adult mice, suggesting that the effects reported here in newborn mice are transient and subjected to self-repair.

Amelogenin↗
PubMed2005

[Quantitative assessment of the risk of lung cancer and pleural mesothelioma among automobile mechanics].

BACKGROUND: A quantitative assessment of the risk of lung cancer and pleural mesothelioma among mechanics exposed to dust released from automobile asbestos-containing parts was performed. METHODS: The population of automobile mechanics in France, according to profession and industrial sectors codes, was estimated from the data of the 1999 census. Risks were computed for a total male population of 242,360 automobile mechanics aged 16 to 60 years. Exposure to asbestos among these workers comes from maintenance tasks involving asbestos-containing parts produced before 1997 (date of the asbestos ban in France). Airborne asbestos concentration data available from the literature were highly variable. No data reporting the distribution of time spent for such tasks over a typical week of work were available. Therefore, different weekly exposure profiles were simulated, based on data from the 1994 SUMER survey. Risk models were those used for assessing asbestos health effects by all national and international agencies. Exposure scenarios mixed different levels of exposure, periods of time, proportions of exposed workers and dates of the "natural" disappearance of the automobile fleet built before asbestos was banned in brakes and other parts. The most realistic scenario hypothesizes that all automobile mechanics were exposed to asbestos, that the exposure levels ranged from 0.06 and 0.25 fibers/liter per week for the period before 1997, and between 0.01 and 0.06 fibers/liter per week afterwards until 2010. RESULTS: According to this scenario, the number of lifelong cancer deaths (lung and pleura) induced by asbestos exposure in this population is estimated at 602 "unavoidable" cases, due to exposure experienced before 2003; 43 other cases will occur if asbestos is not removed from existing automobiles.

Adolescent↗
PubMed2005

Promoter methylation and loss of coding exons of the fragile histidine triad (FHIT) gene in intrahepatic cholangiocarcinomas.

AIMS: About 10-30% of primary liver cancers represent intrahepatic cholangiocarcinomas (IHCC). Since chromosomal losses of 3p are detectable in about 40% of cholangiocarcinomas our study aimed at the identification of mechanisms leading to functional deletion of tumor suppressor genes in this region. Our efforts focussed on genomic losses and epigenetic inactivation of two tumor suppressor genes, the fragile histidine triad (FHIT) and the ras association domain family 1 (RASSF1A) genes, both located on the short arm of chromosome 3. METHODS: Methylation-specific PCR (MSP) and combined bisulfite-dependent restriction analysis (COBRA) were applied to detect epigenetic silencing of gene promoters. Genomic duplex PCR was used to identify exon losses of the FHIT gene. Nineteen paraffin-embedded samples of intrahepatic cholangiocarcinomas were studied. RESULTS: Here we report for the first time that in addition to frequent losses of the exons 5 and 6, hypermethylation of the FHIT promoter occured in a significant portion of IHCC. Methylation specific PCR (MSP) detected epigenetic inactivation of the FHIT/FRA3B locus in 8 of 19 (42%) cases. Combined bisulfite restriction analysis (COBRA) revealed that high levels of methylated FHIT promoter sequences were present in 6 of the 8 methylation positive samples. In agreement with previous reports MSP identified hypermethylation of the RASSF1A gene in 13 of 19 (68%) IHCC specimens examined. CONCLUSIONS: Epigenetic silencing of the FHIT tumor suppressor gene is a novel inactivation mechanism to be considered in the development of intrahepatic cholangiocarcinomas. However, a statistically significant inverse correlation between K-Ras activation and RASSF1A inactivation was not found.

Acid Anhydride Hydrolases↗
PubMed2004

New cellular models for tracking the odontoblast phenotype.

Odontoblasts and osteoblasts differ functionally and histologically. Because of their close relationship, mesenchymal cells derived from teeth and bone are difficult to distinguish ex vivo. Indeed, the main non-collagenous components of the odontoblastic extracellular matrix, dentin sialoprotein (DSP) or dentin matrix protein 1 (DMP1), have also been detected in osteoblasts. The need to develop cellular models of odontoblast differentiation and to identify markers specific for the odontoblast lineage, has led us to establish clonal cell lines from tooth germs of day 18 mouse embryos transgenic for an adenovirus-SV40 recombinant plasmid. In this study, we analyzed the phenotypes of three independent clones by RT-PCR and Western blot. These clones synthesised DSP, DMP1 and other extracellular matrix proteins typical of the odontoblast and are therefore likely to be derived from the pulp. Transcripts encoding a set of homeobox proteins involved in craniofacial development, such as Pax9, Msx1, Cbfa1, Dlx2 and 5 were also expressed albeit at a different level. These features of the pulpal clones are shared by the C1 mesodermal cells that are capable of differentiating along osteogenic, chondrogenic or adipogenic lineages In contrast, transcripts for two LIM-domain homeobox family genes (Lhx6 and Lhx7) were only detected in the dental clones. Since these genes are preferentially expressed in the mesenchyme of the developing tooth, this suggests that our transgenic-derived cell lines retain intrinsic properties of odontoblastic cells. They may help to characterise genes specifying the odontoblast phenotype and the signalling pathways underlying odontoblast differentiation.

Adenoviridae↗