Biomedical subjects

Christian Hirsch

Publications and source records attributed to Christian Hirsch.

15 recordsLinked to original sources

PubMed2006

Coping with stress: cellular relaxation techniques.

Proteins damaged by stressors such as heat, oxidizing conditions or toxic agents are deleterious to cells and must be properly taken care of. Accordingly, misfolded proteins trigger a cellular stress response that aims to either repair defective polypeptides or eliminate faulty elements when salvage is not possible. This stress response provides time for additional stressor-specific pathways that adapt the cell to the changed environment if necessary. Recent studies have investigated how proteins that frustrate the folding machinery are recognized and cleared from the cell. Surprisingly, these clearance mechanisms are not restricted to the protein level. The stress response can also eliminate the mRNA of polypeptides that are refractory to folding.

Animals↗

PubMed2006

A complex of Yos9p and the HRD ligase integrates endoplasmic reticulum quality control into the degradation machinery.

A quality-control system surveys the lumen of the endoplasmic reticulum for terminally misfolded proteins. Polypeptides singled out by this system are ultimately degraded by the cytosolic ubiquitin-proteasome pathway. Key components of both the endoplasmic reticulum quality-control system and the degradation machinery have been identified, but a connection between the two systems has remained elusive. Here, we report an association between the endoplasmic reticulum quality-control lectin Yos9p and Hrd3p, a component of the ubiquitin-proteasome system that links these pathways. We identify designated regions in the luminal domain of Hrd3p that interact with Yos9p and the ubiquitin ligase Hrd1p. Binding of misfolded proteins occurs through Hrd3p, suggesting that Hrd3p recognises proteins that deviate from their native conformation, whereas Yos9p ensures that only terminally misfolded polypeptides are degraded.

Blotting, Western↗

PubMed2006

Mandibular jaw movement capacity in 10-17-yr-old children and adolescents: normative values and the influence of gender, age, and temporomandibular disorders.

The aims of this study were, first, to report normative values for jaw movements in Caucasian children and adolescents (maximum opening, laterotrusion, and protrusion) and, second, to investigate the influence of age, gender, and temporomandibular disorders (TMD) on jaw movement capacity. The population-based study included 1,011 randomly selected German children and adolescents, aged 10-17 yr. Case histories, as well as mandibular movements and the presence of TMD, were assessed according to the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD). The mean +/- standard deviation for maximum opening was 50.6 +/- 6.4 mm, for laterotrusion to the right was 10.2 +/- 2.2 mm, for laterotrusion to the left was 10.6 +/- 2.3 mm, and for protrusion was 8.2 +/- 2.5 mm. Bivariable (t-test) and multivariable (linear regression) analyses showed that normative values for jaw opening capacity were influenced by age and gender. No influence on jaw movement capacity was seen when TMD were present. Based on the distribution of the measurements in the population (lowest decentile), the mandibular mobility of subjects with a maximum opening of < 43 mm and laterotrusive movements < 8 mm or protrusive movements < 5 mm might be considered as being limited. However, these limitations do not necessarily require treatment.

Adolescent↗

PubMed2006

Translating the research diagnostic criteria for temporomandibular disorders into German: evaluation of content and process.

AIMS: To develop a German-language version of the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) through a formal translation/back-translation process, to summarize available data about their psychometric properties, and to provide new data about psychometric testing of components of the RDC/TMD. METHODS: To cross-culturally adapt the instrument, the RDC/TMD were translated using a forward-backward method, except for measures of somatization and depression, because German-specific instruments of these already existed. The psychometric properties of the RDC/TMD were examined, and the literature on this topic was reviewed. RESULTS: The available literature about reliability of clinical examination methods (4 studies) showed at least acceptable results, with a median intraclass correlation coefficient (ICC) of 0.60. Reliability of RDC/TMD components Jaw Disability List (JDL) and Graded Chronic Pain Scale (GCPS) was sufficient (ICC for retest reliability [n = 27] was 0.76 for JDL and 0.92 for GCPS; Cronbach's alpha for internal consistency [n = 378] was 0.72 and 0.88, respectively). A priori hypothesized associations between GCPS or JDL summary scores and self-report of general health, oral health, oral health-related quality of life, or dysfunctional pain, which were measured by means of the Multidimensional Pain Inventory, were confirmed in a convenience sample of clinical TMD patients (n = 378). These correlations were interpreted as support for the validity of the GCPS and JDL. The original RDC/TMD include measures for somatization and depression (SCL-90-R); however, equivalent German instruments to assess these constructs ("Beschwerdenliste," "Allgemeine Depressionsskala") have well-established validity and reliability in the German cultural environment. CONCLUSION: The psychometric properties and international comparability of the German version of the RDC/TMD (RDC/TMD-G) make this instrument suitable for the assessment of TMD in Germany.

Depression↗

PubMed2006

Pain-related impairment and health care utilization in children and adolescents: a comparison of orofacial pain with abdominal pain, back pain, and headache.

OBJECTIVE: The purpose was to compare orofacial (temporomandibular) pain with other pain complaints regarding impairment and health care utilization in a sample of 1,011 children and adolescents from a metropolitan area in Germany. METHOD AND MATERIALS: Individuals aged 10 to 18 years were sampled in schools using a 2-stage cluster technique. Orofacial pain in the previous month was assessed according to the Research Diagnostic Criteria for Temporomandibular Disorders. Additionally, participants were questioned about headache, back pain, abdominal pain, pain-related impairment, and health care utilization (visits to doctors, analgesic consumption) in the previous month. RESULTS: Headache was reported by 50% (95% CI: 45% to 56%) of participants, stomach pain by 36% (95% CI: 32% to 41%), back pain by 31% (95% CI: 25% to 36%), and orofacial pain by 15% (95% CI: 12% to 18%). Girls were more affected than boys. The range of "severe" and "very severe" impairment lay between 8% (orofacial pain) and 22% (headache). The range of treatment demand was between 10% and 17% (orofacial pain: 15%), and the range for analgesic consumption between 18% and 24% (orofacial pain: 22%). The more pain experienced, the more impairment, doctor consultations, and analgesic consumption were reported (Chi2test: P < 0.05). Risk of orofacial pain was 60% higher for subjects with head, back, and/or abdominal pain (odds ratio: 1.6; 95% CI: 1.3 to 1.9). CONCLUSION: In children and adolescents, orofacial pain occurs about half as often as other pain complaints. However, relative to their prevalence the different pain complaints are similar regarding impairment and health care utilization.

Abdominal Pain↗

PubMed2005

San1p, checking up on nuclear proteins.

Cellular quality control mechanisms perform vital tasks by ensuring that the proteome reflects precisely the information encoded by the genome. In this issue of Cell, Gardner et al. (2005) report the discovery of a novel protein quality control system that resides in the nucleus. Central to this system is the E3 ligase San1p, which monitors nuclear proteins and targets aberrant species for destruction.

Cell Nucleus↗

PubMed2005

ERAD: the long road to destruction.

Endoplasmic reticulum (ER)-associated protein degradation (ERAD) eliminates misfolded or unassembled proteins from the ER. ERAD targets are selected by a quality control system within the ER lumen and are ultimately destroyed by the cytoplasmic ubiquitin-proteasome system (UPS). The spatial separation between substrate selection and degradation in ERAD requires substrate transport from the ER to the cytoplasm by a process termed dislocation. In this review, we will summarize advances in various aspects of ERAD and discuss new findings on how substrate dislocation is achieved.

Animals↗

PubMed2005

Research diagnostic criteria for temporomandibular disorders: a calibration and reliability study.

The aim of this study was to investigate the reliability between different examiners when using the axis I of the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD). The hypothesis was that the standardized RDC/TMD examination protocol enables calibrated examiners to evaluate all examination items reliably. After calibration training by the RDC/TMD calibration team including the calibration of palpation pressure and the performance of the standardized examination protocol, four examiners, blinded to the patients' medical histories examined 24 subjects in a randomized sequence. One experienced examiner was the standard (hierarchical calibration). The recorded measurements strictly followed the RDC/TMD. Intraclass correlation coefficients (ICC), bias and precision were calculated to estimate interrater reliability. Acceptable (0.75 > or = CC > 0.4) to excellent (ICC > 0.75) reliability was found for 20 of the 23 (87%) examinations. Only sub-retromandibular muscle palpation and joint sound vibration recordings on lateral excursion showed poor-results (ICC < or = 0.4). The RDC/TMD examination protocol enables calibrated examiners to perform most (87%) examination items with satisfactory reliability. Therefore multi-site studies based on the RDC/TMD examination protocol may become feasible, keeping in mind the unsatisfactory reliability of 13% of the items (clicking during laterotrusion to the ipsilateral side, palpation of the posterior and submandibular region).

Adolescent↗

PubMed2005

Relationship between overbite/overjet and clicking or crepitus of the temporomandibular joint.

AIMS: Since occlusal variables such as overbite and overjet have been thought to be associated with temporomandibular disorders (TMD), and joint sounds are some of the most prevalent signs of TMD, the aim of this study was to determine whether overbite and overjet are risk factors for temporomandibular joint (TMJ) sounds. METHODS: A population-based cross-sectional study of 3,033 subjects (age range, 10 to 75 years; 53% female) was conducted in Germany. Overbite/overjet, reproducible reciprocal clicking (RRC) during open-close jaw movements that did not occur in the protrusive jaw position, and joint crepitus were assessed according to the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD). RESULTS: When age and gender were controlled for, high or low values of overbite and overjet were not associated with a greater risk of RRC and crepitus as compared to a reference category of a normal overbite and overjet of 2 to 3 mm (multiple logistic regression; odds ratios 0.7 to 1.3; P > .05 for all). CONCLUSION: This study showed that higher or lower overbite or overjet jaw relationships, even extreme values, are not risk factors for TMJ sounds as assessed by clinical examination.

Adolescent↗

PubMed2004

Endoplasmic reticulum-associated protein degradation--one model fits all?

The endoplasmic reticulum (ER) is the eukaryotic organelle where most secretory proteins are folded for subsequent delivery to their site of action. Proper folding of newly synthesized proteins is monitored by a stringent ER quality control system. This system recognizes misfolded or unassembled proteins and prevents them from reaching their final destination. Instead, they are extracted from the ER, polyubiquitinated and degraded by the cytosolic proteasome. With the identification of novel components and substrates, a more and more complex picture of this process emerges in which distinct pathways target different sets of substrates for destruction.

Animals↗

PubMed2004

Dissection of the dislocation pathway for type I membrane proteins with a new small molecule inhibitor, eeyarestatin.

The mammalian endoplasmic reticulum (ER)-to-cytosol degradation pathway for disposal of misfolded proteins is an attractive target for therapeutic intervention in diseases that are characterized by impaired protein degradation. The ability to do so is hampered by the small number of specific inhibitors available and by our limited understanding of the individual steps involved in this pathway. Cells that express a class I major histocompatibility complex (MHC) heavy chain-enhanced green fluorescent protein (EGFP) fusion protein and the human cytomegalovirus protein US11, which catalyzes dislocation of the class I MHC EGFP reporter, show only little fluorescence. Treatment with proteasome inhibitors increases their fluorescence by stabilizing EGFP-tagged MHC class I molecules. We used this change in signal intensity as a readout to screen a chemical library of 16,320 compounds and identified two structurally related compounds (eeyarestatin I and II) that interfered with the degradation of both EGFP-heavy chain and its endogenous unmodified class I MHC heavy chain counterpart. Eeyarestatin I also inhibited degradation of a second misfolded type I membrane protein, T-cell receptor alpha. Both compounds stabilize these dislocation substrates in the ER membrane, without preventing proteasomal turnover of cytosolic substrates. The new inhibitors must therefore interfere with a step that precedes proteasomal degradation. The use of eeyarestatin I thus allows the definition of a new intermediate in dislocation.

Catalysis↗

PubMed2004

A glycosylated type I membrane protein becomes cytosolic when peptide: N-glycanase is compromised.

The human cytomegalovirus-encoded glycoprotein US2 catalyzes proteasomal degradation of Class I major histocompatibility complex (MHC) heavy chains (HCs) through dislocation of the latter from the endoplasmic reticulum (ER) to the cytosol. During this process, the Class I MHC HCs are deglycosylated by an N-glycanase-type activity. siRNA molecules designed to inhibit the expression of the light chain, beta(2)-microglobulin, block the dislocation of Class I MHC molecules, which implies that US2-dependent dislocation utilizes correctly folded Class I MHC molecules as a substrate. Here we demonstrate it is peptide: N-glycanase (PNGase or PNG1) that deglycosylates dislocated Class I MHC HCs. Reduction of PNGase activity by siRNA expression in US2-expressing cells inhibits deglycosylation of Class I MHC HC molecules. In PNGase siRNA-treated cells, glycosylated HCs appear in the cytosol, providing the first evidence for the presence of an intact N-linked type I membrane glycoprotein in the cytosol. N-glycanase activity is therefore not required for dislocation of glycosylated Class I MHC molecules from the ER.

Cell Line, Tumor↗

PubMed2004

Yeast N-glycanase distinguishes between native and non-native glycoproteins.

N-glycanase from Saccharomyces cerevisiae (Png1) preferentially removes N-glycans from misfolded proteins. The ability of Png1 to distinguish between folded and misfolded glycoproteins is reminiscent of substrate recognition by UDP-glucose glycoprotein glucosyl transferase, an enzyme that possesses this trait. The only known in vivo substrates of Png1 are aberrant glycoproteins that originate in the endoplasmic reticulum, and arrive in the cytoplasm for proteasomal degradation. The substrate specificity of Png1 is admirably suited for this task.

Cell Line↗

PubMed2003

A role for N-glycanase in the cytosolic turnover of glycoproteins.

Successful maturation determines the intracellular fate of secretory and membrane proteins in the endoplasmic reticulum (ER). Failure of proteins to fold or assemble properly can lead to their retention in the ER and redirects them to the cytosol for degradation by the proteasome. Proteasome inhibitors can yield deglycosylated cytoplasmic intermediates that are the result of an N-glycanase activity, believed to act prior to destruction of these substrates by the proteasome. A gene encoding a yeast peptide:N-glycanase, PNG1, has been cloned, but this N-glycanase and its mammalian homolog were reported to be incapable of deglycosylating full-length glycoproteins. We show that both the yeast PNG1 enzyme and its mammalian homolog display N-glycanase activity towards intact glycoproteins. As substrates, cytosolic PNGase activity prefers proteins containing high-mannose over those bearing complex type oligosaccharides. Importantly, PNG1 discriminates between non-native and folded glycoproteins, consistent with a role for N-glycanase in cytoplasmic turnover of glycoproteins.

Amidohydrolases↗

PubMedDate not supplied

Incisal tooth wear and self-reported TMD pain in children and adolescents.

PURPOSE: Incisal tooth wear may be a sign of long-term bruxing behavior. Bruxism is purported to be a risk factor for temporomandibular disorders (TMD). The aim of this population-based cross-sectional study was to determine if anterior tooth wear is associated with the self-report of TMD pain in children and adolescents. MATERIALS AND METHODS: In a population sample of 1,011 children and adolescents (mean age 13.1 years, range 10 to 18 years; female 52%; response rate 85%), TMD cases were defined as subjects reporting pain in the face, jaw muscles, and temporomandibular joint during the last month according to RDC/TMD. All other subjects were considered controls. Incisal tooth wear was assessed in the clinical examination using a 0 to 2 scale (no wear, enamel wear, dentin wear) for every anterior permanent tooth. The mean wear score for the individuals was categorized into 0, 0.01 to 0.20, 0.21 to 0.40, and 0.41+. A multiple logistic regression analysis, controlling for the effects of age and gender, analyzed the association between the categorized summary wear score and TMD. Specifically, the hypothesis of a trend between higher tooth wear scores and higher risk of TMD was tested. RESULTS: An odds ratio of 1.1 indicated, after adjusting for gender and age, no statistically significantly higher risk of TMD pain with higher tooth wear scores. CONCLUSION: Incisal tooth wear was not associated with self-reported TMD pain in 10- to 18-year-old subjects.

Adolescent↗