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Although the notion that tumors are heterogeneous is well rooted in diagnostic pathology, the extent of this heterogeneity at the molecular level and its impact on (targeted) treatment choice will certainly influence the practice of pathology. Even though the consequences of tumor heterogeneity for cancer care are as yet incompletely understood, pathologists can contribute to solving major scientific and clinical problems related to tumor heterogeneity by rethinking guidelines for tumor sampling, to have a more comprehensive covering of intratumor heterogeneity in the available tumor tissue samples. They should develop guidelines and/or technology to adequately document sample characteristics such as percentage of tumor cells in a sample. They need to contribute to training of bioinformaticians in the field of cancer pathobiology and integrate such well-trained bioinformaticians in the workflow leading to a final pathology report. They also need to redefine postgraduate training programs in diagnostic pathology to address the need for in-depth training in molecular cancer pathobiology. Pathologists might contribute more to making the public at large aware of the importance of data sharing. Finally, pathologists should support the creation of consortia in which clinical and molecular data are shared with the translational research community.

Only 1% of all tendon injuries affect the triceps tendon, making triceps ruptures very rare. An acute rupture can therefore easily be missed due to a low degree of suspicion. A palpable gap, inability to flex the elbow against resistance and a positive modified Thompson test are indicative for a complete triceps tendon rupture. The mechanism of injury is most commonly a sudden eccentric muscle contraction. We present the case of a 48-year-old man with an acute complete triceps tendon rupture, after a fall from an unstable chair while performing a one arm push-up. The rupture was surgically treated with Krackow sutures tunneled through drill holes in the olecranon. Postoperative treatment consisted of gradually increasing elbow flexion for six weeks with a brace. Three months following the operation, 150 degree flexion was possible with a 5 degree extension limitation. The Disabilities of the Arm, Shoulder and Hand score was 10.5. We demonstrate that early diagnosis and treatment facilitate excellent functional outcome.

A 14-year-old boy presented with a painful knee following a distorsion. He was unable to actively extend his lower leg. Conventional radiography showed no signs of a fracture. Both ultrasound imaging and MRI, however, demonstrated haemarthrosis and an osteochondral defect of the lateral femoral condyle. Apparently, an osteochondral lesion had developed due to patellar luxation. The osteochondral fragment was fixated using absorbable compression screws.

BACKGROUND: Although colon cancer (CC) with microsatellite instability (MSI) has a more favorable prognosis than microsatellite stable (MSS) CC, the impact varies according to clinicopathological parameters. We studied how MSI status affects prognosis in a trial-based cohort of stage II and III CC patients treated with 5-fluorouracil (5-FU)/leucovorin or FOLFIRI. MATERIALS AND METHODS: Tissue specimens of 1254 patients were tested for 10 different loci and were classified as MSI-high (MSI-H) when three or more loci were unstable and MSS otherwise. Study end points were overall survival (OS) and relapse-free survival (RFS). RESULTS: In stage II, RFS and OS were better for patients with MSI-H than with MSS CC [hazard ratio (HR) 0.26, 95% CI 0.10-0.65, P = 0.004 and 0.16, 95% CI 0.04-0.64, P = 0.01). In stage III, RFS was slightly better for patients with MSI-H CC (HR 0.67, 95% CI 0.46-0.99, P = 0.04), but the difference was not statistically significant for OS (HR 0.70, 95% CI 0.44-1.09, P = 0.11). Outcomes for patients with MSI-H CC were not different between the two treatment arms. RFS was better for patients with MSI-H than with MSS CC in the right and left colon, whereas for OS this was significant only in the right colon. For patients with KRAS- and BRAF-mutated CC, but not for double wild-type patients, RFS and OS were significantly better when the tumors were also MSI-H. An interaction test was statistically significant for KRAS and MSI status (P = 0.005), but not for BRAF status (P = 0.14). CONCLUSIONS: Our results confirm that for patients with stage II CC but less so for those with stage III MSI-H is strongly prognostic for RFS and OS. In the presence of 5-FU treatment, stage II patients with MSI-H tumors maintain their survival advantage in comparison with MSS patients and adding irinotecan has no added benefit. CLINICALTRIALSGOV IDENTIFIER: NCT00026273.

Summary Because of the high variability of seasonal influenza viruses and the eminent threat of influenza viruses with pandemic potential, there is great interest in the development of vaccines that induce broadly protective immunity. Most probably, broadly protective influenza vaccines are based on conserved proteins, such as nucleoprotein (NP). NP is a vaccine target of interest as it has been shown to induce cross-reactive antibody and T cell responses. Here we tested and compared various NP-based vaccine preparations for their capacity to induce humoral and cellular immune responses to influenza virus NP. The immunogenicity of protein-based vaccine preparations with Matrix-M™ adjuvant as well as recombinant viral vaccine vector modified Vaccinia virus Ankara (MVA) expressing the influenza virus NP gene, with or without modifications that aim at optimization of CD8+ T cell responses, was addressed in BALB/c mice. Addition of Matrix-M™ adjuvant to NP wild-type protein-based vaccines significantly improved T cell responses. Furthermore, recombinant MVA expressing the influenza virus NP induced strong antibody and CD8+ T cell responses, which could not be improved further by modifications of NP to increase antigen processing and presentation.

SummaryThe Wnt pathway is abnormally activated in the majority of colorectal cancers, and significant knowledge has been gained in understanding its role in tumor initiation. However, the mechanisms of metastatic outgrowth in colorectal cancer remain a major challenge. We report that autophagy-dependent metabolic adaptation and survival of metastatic colorectal cancer cells is regulated by the target of oncogenic Wnt signaling, homeobox transcription factor PROX1, expressed by a subpopulation of colon cancer progenitor/stem cells. We identify direct PROX1 target genes and show that repression of a pro-apoptotic member of the BCL2 family, BCL2L15, is important for survival of PROX1+ cells under metabolic stress. PROX1 inactivation after the establishment of metastases prevented further growth of lesions. Furthermore, autophagy inhibition efficiently targeted metastatic PROX1+ cells, suggesting a potential therapeutic approach. These data identify PROX1 as a key regulator of the transcriptional network contributing to metastases outgrowth in colorectal cancer.

Olecranon fractures are common and typically require surgical fixation due to displacement generated by the pull of the triceps muscle. The most common techniques for repairing olecranon fractures are tension-band wiring or plate fixation, but these methods are associated with high rates of implant-related soft-tissue irritation. Another treatment option is fixation with an intramedullary screw, but less is known about surgical results using this strategy. Thus, the purpose of this study was to report the clinical and functional outcomes of olecranon fractures treated with an intramedullary cannulated screw.We identified 15 patients (average age at index procedure 44 years, range 16-83) with a Mayo type I or IIA olecranon fracture who were treated with an intramedullary cannulated screw at a single level 2 trauma center between 2012 and 2017. The medical record was reviewed to assess radiographic union, postoperative range of motion and complications (including hardware removal). Patient-reported outcome was evaluated using the Disabilities of the Arm, Shoulder and Hand (DASH) score. Average follow-up was 22 months (range 8-36 months).By the 6th month post-operative visit, 14 patients had complete union of their fracture and 1 patient had an asymptomatic non-union that did not require further intervention. Average flexion was 145° (range 135-160) and the average extension lag was 11° (range 0-30). Implants were removed in 5 patients due to soft-tissue irritation. Average DASH score (± standard deviation) by final follow-up was 16 ± 10.Fixation of simple olecranon fractures with an intramedullary screw is a safe and easy fixation method in young patients, leading to good functional and radiological results. Compared to available data, less hardware removal is necessary than with tension-band wiring or plate fixation.

BACKGROUND We conducted a randomized, phase II, multicenter study to evaluate the anti-epidermal growth factor receptor (EGFR) mAb panitumumab (P) in combination with chemoradiotherapy (CRT) with standard-dose capecitabine as neoadjuvant treatment for wild-type KRAS locally advanced rectal cancer (LARC). PATIENTS AND METHODS Patients with wild-type KRAS, T3-4 and/or N+ LARC were randomly assigned to receive CRT with or without P (6 mg/kg). The primary end-point was pathological near-complete or complete tumor response (pNC/CR), defined as grade 3 (pNCR) or 4 (pCR) histological regression by Dworak classification (DC). RESULTS Forty of 68 patients were randomly assigned to P + CRT and 28 to CRT. pNC/CR was achieved in 21 patients (53%) treated with P + CRT [95% confidence interval (CI) 36%-69%] versus 9 patients (32%) treated with CRT alone (95% CI: 16%-52%). pCR was achieved in 4 (10%) and 5 (18%) patients, and pNCR in 17 (43%) and 4 (14%) patients. In immunohistochemical analysis, most DC 3 cells were not apoptotic. The most common grade ≥3 toxic effects in the P + CRT/CRT arm were diarrhea (10%/6%) and anastomotic leakage (15%/4%). CONCLUSIONS The addition of panitumumab to neoadjuvant CRT in patients with KRAS wild-type LARC resulted in a high pNC/CR rate, mostly grade 3 DC. The results of both treatment arms exceeded prespecified thresholds. The addition of panitumumab increased toxicity.

This research note analyses the experiences of Dutch Muslim soldiers during peace operations in Muslim societies. It is based on 19 in-depth interviews with soldiers and (non-commissioned) officers of different services, for the large part of Moroccan descent. It focuses on their interaction with the local population, mostly Muslims. The findings indicate four types of interactions with the local population: positive encounters, encounters with conflicting loyalties, masked encounters and hostile encounters.

In this study a digital measurement technique has been proposed to quantify bone formation on histological images. Two standard parietal defects were created in 30 adult rabbits. The animals were divided into six groups. Four animals of each group were randomly chosen as experimental group in which osteopontin-coated hydroxyapatite (OPN-HA) and hydroxyapatite (HA) were inserted alternatively in created defects. To observe the spontaneous healing process of defects, one animal of each group was used as control animal and these created defects did not receive any implants. The animals were sacrificed after 1, 2, 6, 12, 18 and 30 weeks. The histological sections were magnified (×100) and scanned digitally. The newly formed bone surfaces within the healing area were indicated and quantified by means of Adobe Photoshop® 7 software. This measuring technique was found to be reliable and reproducible. The results of this study show no significant differences in bone formation between the OPN-HA and non-coated HA defects, although a significant difference in bone formation was measured at the margins of the defects treated with OPN-HA.

Osteopontin (OPN) is one of the major non-collagen proteins in extracellular bone matrix. To elucidate the function of OPN in bone metabolism, a cellular defect was created in parietal bone and tibia of 12 rats. In Group 1, the left defects were filled with OPN-coated hydroxyapatite (OPN-H). In Group 2, the right defects were filled with non-coated hydroxyapatite (N-H). In both groups, the contra lateral defects were used as control defects. In Group 3, OPN-H was inserted in the left defects and N-H in the right defects. Bone metabolism was measured by (45)Ca and technetium-99m methylene diphosphonate scintigraphy for 4 weeks. Scintigraphy did not show any significant differences in bone metabolism between the defects filled with OPN-H and N-H. A higher bone metabolism was measured between the parietal defects filled with OPN-H or N-H in comparison with the parietal control defects. This difference, however, was not significant and was less for tibia defects. Histological observation (7th week) shows less inflammatory cells at the tibia defects filled with OPN-H compared to the tibia defects filled with N-H. This study did not show any acceleration or inhibition of bone metabolism in parietal or tibia bone in rats, but there is some evidence that OPN might influence inflammatory cells in bone matrix.

More than 50 years have passed since Barrett described a case of peptic ulcer disease of the esophagus and the condition that would carry his name [1]. It is now generally accepted that Barrett esophagus is the result of long-standing gastroesophageal reflux disease leading to replacement of the normal stratified squamous epithelial lining of the esophagus by glandular epithelium of various types [24, 32]. The importance of a diagnosis of Barrett esophagus is its association with the development of an esophageal adenocarcinoma. In contrast to what Norman Barrett originally thought, Barrett esophagus is a premalignant condition, and the incidence of Barrett carcinoma has increased dramatically since his publication in 1950 [12]. Barrett adenocarcinoma is preceded by a well-defined premalignant lesion, i.e., dysplasia (intraepithelial neoG. J. A. Offerhaus · S. van Eeden · F. J. W. ten Kate · A. Bosma Department of Pathology, Academic Medical Center Amsterdam, The Netherlands

The type of attachment that is used in oral rehabilitation by means of implant-retained mandibular overdentures may influence the retention and the stability of the denture. In this study, we examined the hypothesis that a better retention and stability of the denture improve the oral function. Eighteen edentulous subjects received 2 permucosal implants, a new denture, and, successively, 3 suprastructure modalities. Maximum bite force and electrical activity of the masseter and temporalis muscles were measured. The maximum bite force nearly doubled after treatment for each of the 3 attachments. However, the average bite force after treatment was still only two-thirds of the value obtained for dentate subjects. No large differences in maximum bite force and muscle activity were found among the 3 attachment types. Temporalis activity was significantly lower than masseter activity when subjects clenched without implant support. There was no difference in activity when subjects clenched with implant support.

Lactobacillus amylovorus LMG P-13139, isolated from corn steep liquor, produces two bactericidal peptides with respective estimated molecular masses of 4.5 and 6.0 kDa upon denaturing sodium dodecyl sulfatepolyacrylamide gel electrophoresis. The antimicrobial activity detected in the fermentation supernatant fraction of L. amylovorus LMG P-13139 was heat stable (20 min, 121 degrees C), displayed a narrow inhibitory spectrum, and was sensitive to proteinase K, trypsin, and alpha-chymotrypsin but insensitive to alpha-amylase, lysozyme, catalase, and lipase. The 4.5-kDa bacteriocin was purified and characterized and designated lactobin A. Lactobin A was isolated as a floating pellicle from culture supernatant brought to 35% saturation with ammonium sulfate. Upon this ammonium sulfate treatment, crude lactobin A was incorporated, together with Tween 80 as a major contaminant, in high-molecular-mass complexes sized at approximately 670 kDa by gel filtration chromatography. Contaminating fatty acids were removed from these micelles by a simple one-step methanol-chloroform extraction without loss of activity. Both inhibitory peptides were separated in an isocratic isopropanol gradient on a PepRPC 5/5 reversed-phase column, and both peptides retained activity towards Lactobacillus helveticus ATCC 15009 upon separation. Lactobin A has a molecular mass determined by electrospray mass spectrometry of 4,879 +/- 0.69 Da. Its peptide chain contains 50 unmodified amino acids, of which 26% are glycine residues and 40% are hydrophobic residues (A, V, L, I, and P). It displays the highest structural homology (42% identity and 28% similarity) with the lafX gene product, encoded by the second open reading frame of the lactacin F operon. These data strongly indicate that lactobin A belongs to the class IIb bacteriocins according to the classification of Klaenhammer.

The Tile Calorimeter, covering the central region of the ATLAS experiment up to pseudorapidities of +/-1.7, is a sampling device built with scintillating tiles that alternate with iron plates. The light is collected in wave-length shifting (WLS) fibers and is read out with photomultipliers. In the characteristic geometry of this calorimeter the tiles lie in planes perpendicular to the beams, resulting in a very simple and modular mechanical and optical layout. This paper focuses on the procedures applied in the optical instrumentation of the calorimeter, which involved the assembly of about 460,000 scintillator tiles and 550,000 WLS fibers. The outcome is a hadronic calorimeter that meets the ATLAS performance requirements, as shown in this paper.

This paper summarises the mechanical construction and installation of the Tile Calorimeter for the ATLAS experiment at the Large Hadron Collider in CERN, Switzerland. The Tile Calorimeter is a sampling calorimeter using scintillator as the sensitive detector and steel as the absorber and covers the central region of the ATLAS experiment up to pseudorapidities ±1.7. The mechanical construction of the Tile Calorimeter occurred over a period of about 10 years beginning in 1995 with the completion of the Technical Design Report and ending in 2006 with the installation of the final module in the ATLAS cavern. During this period approximately 2600 metric tons of steel were transformed into a laminated structure to form the absorber of the sampling calorimeter. Following instrumentation and testing, which is described elsewhere, the modules were installed in the ATLAS cavern with a remarkable accuracy for a structure of this size and weight. © CERN 2013 for the benefit of the ATLAS collaboration.

Cancer omics data are exponentially created and associated with clinical variables, and important findings can be extracted based on bioinformatics approaches which can then be experimentally validated. Many of these findings are related to a specific class of non-coding RNA molecules called microRNAs (miRNAs) (post-transcriptional regulators of mRNA expression). The related research field is quite heterogeneous and bioinformaticians, clinicians, statisticians and biologists, as well as data miners and engineers collaborate to cure stored data and on new impulses coming from the output of the latest Next Generation Sequencing technologies.Here we review the main research findings on miRNA of the first 10years in colon cancer research with an emphasis on possible uses in clinical practice. This review intends to provide a road map in the jungle of publications of miRNA in colorectal cancer, focusing on data availability and new ways to generate biologically relevant information out of these huge amounts of data.

A 17-year-old woman was hit on the left ankle during hockey. There was pain over the dorsal fibula, though no swelling. During dorsiflexion the tendon of the M. peroneus could be luxated over the lateral malleolus towards the front. This was consistent with a peroneal tendon dislocation at the level of the lateral malleolus.

Il presente lavoro lia lo scopo di fornire dei criteri praticidi progetto per il rivestimento termico di ugelli per razzi ad elevatedurate di combustione.Lo sviluppo die lia condotto alla formulazione di detti criteri lia richiestoin una prima fase lo studio della propagazione del flusso di caloreattraverso una parete doppia costituita da materiali differenti (isolante emetallo); tale studio si è concluso definendo gli elementi base che caratterizzanoil fenomeno.Successivamente si è svolta una ricerca numerica allo scopo di esplorareil campo di variabilità di tali parametri caratteristici in vista di applicaredeterminati materiali e per l'involucro metallico e per il rivestimento.Tale indagine è stata effettuata mediante calcoli eseguiti con il computatoredigitale IBM 1620.A questo punto si è proceduto alla soluzione numerica del problemain forma adimensionale, la soluzione è stata effettuata per un certo numerodei parametri caratteristici allo scopo di ricoprire, dando valori determinati,t u t to il campo di variabilità di questi.Queste diverse soluzioni sono state ricavate mediante calcolatriceanalogica (DONNER) simulando il fenomeno della propagazione del calore.Diagrammati questi risultati si è infine definito un criterio per ottenererapidamente, in base alle caratteristiche dei gas, dei materiali usati e deglispessori relativi, i parametri caratteristici per i quali il calcolo già è staff)eseguito.

HCVs constitute a genus within the Flaviviridae, with closest homology to the hepatitis G and GB viruses, and Pestiviruses. The positive-stranded RNA genome encodes at least nine proteins. Core, El, and E2 constitute the structural proteins; NS2, NS3, NS4A, NS4B, NS5A, and NS5B are nonstructural (NS) proteins. HCV isolates display high levels of sequence heterogeneity allowing classification into at least 11 types and 90 subtypes (1). HCV infection of the human liver is often clinically benign, with mild icterus in the acute phase, the disease may even go unnoticed in some cases of acute resolving hepatitis C. In the majority (70%) of cases, however, HCV infection leads to chronic persistent or active infection, often with complications of liver cirrhosis and auto-immune disorders. Hepatocellular carcinoma may occur after about 20-35 yr (2); sometimes even without the intermediate phase of cirrhosis. No prophylaxis is available today and treatment with interferon-alpha (IFN-α) only leads to long-term resolution in about 4-36% of treated cases, depending on the HCV genotype (1).

A discriminant analysis has been applied on several electromyographic (EMG) parameters of the masseter and the anterior temporal muscles, related to clenching and the jaw-jerk reflex, to characterize jaw muscle function of patients with craniomandibular disorder (CMD) with respect to controls. The subject samples, matched for age, consisted of 20 females with myogenous CMD, and 20 symptom-free females. The jaw-jerk reflex was elicited by a downward-directed mandibular load, transmitted by a bite-fork causing a similar occlusion and bite-rise as a splint. The patients differed mainly from the controls by smaller maximum EMG activity in both muscle groups (P less than 0.05 with the bite-fork inserted). This finding was related to a smaller muscle strength as the EMG level did not improve with pain-free jaw muscles after therapy using a relaxation splint. Discriminating factors of secondary importance were an enhanced bilateral asymmetry in the muscle activity of the patients, and in the reflex amplitude normalized for background EMG activity. In all subject samples, the activity of the anterior temporal muscles decreased with respect to the masseter muscles when the bite-fork was inserted (P less than 0.05-0.001). The therapeutic effect of a relaxation splint may, in part, be related to a relief of the temporal muscles.

Barrett's esophagus (BE) is an acquired condition in which the normal lining of the esophagus is replaced by intestinal metaplastic epithelium. BE can evolve to esophageal adenocarcinoma (EAC) through low-grade dysplasia (LGD) and high-grade dysplasia (HGD). The only generally accepted marker for increased risk of EAC is the presence of HGD, diagnosed on endoscopic biopsies. More specific markers for the prediction of EAC risk are needed. A tissue microarray was constructed comprising tissue samples from BE, LGD, HGD, and EAC. Marker expression was studied by immunohistochemistry using antibodies against CD44, DKK1, CDX2, COX2, SOX9, OCT1, E-cadherin, and beta-catenin. Immunostaining was evaluated semi-quantitatively. CD44 expression decreased in HGD and EAC relative to BE and LGD. DKK1 expression increased in HGD and EAC relative to BE and LDG. CDX2 expression increased in HGD but decreased in EAC. COX2 expression decreased in EAC, and SOX9 expression increased only in the upper crypt epithelial cells in HGD. E-cadherin expression decreased in EAC. Nuclear beta-catenin was not significantly different between BE, LGD, and HGD. Loss of CD44 and gain of DKK1 expression characterizes progression from BE and LGD to HGD and EAC, and their altered expression might indicate an increased risk for developing an EAC. This observation warrants inclusion of these immunohistochemically detectable markers in a study with a long patient follow-up.

An experimental rat model to study acute cytomegalovirus infections is described. Eight-week old male Brown Norway rats, immunosuppressed by total body irradiation, were infected with rat cytomegalovirus (RCMV). The effects of infection were determined by survival rates and the presence of virus or viral components in different organs was assayed by plaque test, immunoperoxidase staining, dot-blot DNA hybridization and in situ DNA hybridization. At days 10-post infection nearly 90% of the animals had died. Spleen, liver and bone marrow were heavily infected. Interstitial pneumonia was observed. Pathological findings strongly resembled the full scale of lesions in human CMV infections. Anti-RCMV hyperimmune serum was effective against mortality from RCMV infection and viral spread to lungs and liver was prevented. This model is appropriate for studies on the pathogenesis and antiviral therapy of CMV infections in the immunocompromised host.

Determinants of mandibular movements, like condylar inclination and incisal guidance, should be considered in the fabrication of restorations in occlusion to prevent posterior excursive occlusal interferences. The aim of this study was to investigate differences in the occlusal morphology of the right mandibular molar resulting from high, average, and low values of settings for determinants of anteroposterior and transverse mandibular movement using a virtual articulation model.The articulation functionalities of computer integrated restorative technology by imaging and new acquisition (CYRTINA, Oratio B.V., Zwaag, The Netherlands) were used as a tool to examine the potential effect of determinants of mandibular movement on occlusal molar design. High, average, and low values for condylar guide inclination, incisal guide angle, and intercuspal contact area (antero-posterior determinants) and laterotrusion, mandibular lateral translation and intercuspal contact area (transverse determinants) were introduced and differences in molar morphology studied. The latter was done by comparing mesiodistal and buccolingual sections of the occlusal designs. These interocclusal differences were quantified as differences in frequency of occlusal distance intervals in an interocclusal range of 1 mm, measured from the occlusal surface of the molar model. The vertical distance with which a standard crown in occlusion had to be corrected to avoid interferences was calculated.Among all parameters, the ipsilateral and contralateral mandibular lateral translation, sagittal condylar guide inclination, the ipsilateral laterotrusion and the incisal guide angle give substantial occlusal surface corrections. The high setting for the ipsilateral mandibular lateral translation required most correction.High and low setting values of mandibular movement determinants require considerable adaptation of the occlusal surface of a crown to prevent occlusal disturbances.

Hepatocyte paraffin 1 (Hep Par 1) and neprilysin (CD10) are well-known markers of hepatocellular carcinoma (HCC). To assess their potential prognostic role, we conducted a retrospective analysis of 97 formalin-fixed and paraffin-embedded HCC from patients treated by surgery with curative intent, using standard immunohistochemical procedures and semiquantitative analysis. Strong Hep Par 1 expression and canalicular CD10 staining pattern were significantly correlated with smaller tumor size (p=0.007 and 0.04, respectively). On univariate analysis, longer overall survival was observed in patients with strong Hep Par 1 expression (p=0.0005) and in patients with a CD10can staining pattern (p=0.02). On multivariate analysis, the combined immunohistochemical score (CIS) obtained by addition of Hep Par 1 and CD10can scores and subtraction of cytoplasmic CD10 score was retained as the single most important prognostic factor (p=0.001). Patients with a CIS or=4. In conclusion, strong Hep Par 1 expression, presence of CD10can labeling, and absence of CD10cyt staining are favorable prognostic factors in HCC, which can be easily combined into a single immunohistochemical score for routine clinical use.

Non-collagen proteins such as bone sialoprotein and osteopontin (OPN) form 10% of the extracellular bone matrix. In this study, the influence of OPN on bone repair was investigated. Human OPN (Innogenetics ® ) was produced by a recombinant technique and bonded onto the surface of hydroxyapatite (Interpore 200 ® ). Thirty rabbits were divided into six equal groups. A circular defect (10mm) was prepared in each parietal bone. In four rabbits of each group the left and right defects were filled with either OPN-coated hydroxyapatite (OPN-HA) or non-coated hydroxyapatite (HA). One sham animal of each group received no implants. The animals were killed after 1, 2, 6, 12, 18 and 30 weeks. The histological sections were scanned and analysed digitally. There were no statistically significant differences in total bone formation between defects filled with OPN-HA and HA. Bone formation at the borders of the healing area was significantly higher in defects filled with OPN-HA than in those filled with HA. Less bone formation was noted in the OPN-HA and HA groups at the centre of the healing area than at the borders of the healing area and the dural area. Although some animals in the sham group showed a high level of bone formation in the dural area, this was not significantly different to that in the dural area of the other groups. There was no sign of infection or tissue rejection of the graft.

During their first two years at the medical faculty of the University of Lausanne, selection of medical students is based on their performance in tests in basic sciences. However, this carries the risk that scientifically talented students who perhaps do not necessarily possess the personal skills to make them a good doctor are given preferential admission to the clinical semesters. This study followed a student cohort (n = 115), which had passed the first part of their state examination at the end of the third year course. The examination included an oral examination in psychosocial medicine (PSM) that tested the student's skills with regard to patient-physician communication. The PSM grade is compared with the grade achieved in the written tests in physics and physiology taken at the end of the first year of study. The findings showed that the performance achieved in the basic science examination had no predicative value for the student's future performance in the PSM test. Moreover, it was found that the type of pre-graduate degree had no major influence on the student's progress in their preclinical years of medical school.

One of the functions of the masticatory system is to prepare food for swallowing by crushing it into small pieces to be moistened with saliva. The degree of fragmentation of the food particles depends on factors like the chewing force generated by the closer muscles, the jaw movement, and the morphological aspects of the teeth. The jaw movement is the result of a precise neuromuscular control of the various chewing muscles. Experimental research showed that the muscle activity needed to crush the food particles exists of two components: an anticipating component and a component evoked by the food resistance. The anticipating muscle activity is observed only if food resistance is expected. The muscle activity evoked by the food starts on average 25 ms after food contact. The amount of peripherally induced muscle activity linearly increases as a function of the food resistance. This part of the muscle activity is controlled by sensory information of the masticatory system.

A reflex is an involuntary response on a specific nerve stimulus. Several types of receptors are present in the masticatory system which can be involved in reflex activity. A short mechanical tap on an incisor, for example, evokes a specific pattern of several so-called exteroceptive reflexes in the electromyographic (EMG) activity of jaw-closing muscles, which includes periods with decreased activity (inhibitory reflex) as well as increased activity (excitatory reflex). In this case, periodontal mechanoreceptors are detecting the stimulus. The second type of reflex that is dealt with is the jaw-jerk reflex as an example of a proprioceptive reflex. A transient increase in length of a jaw-closing muscle, detected by length sensors (muscle spindles), evokes an excitatory reflex in the EMG. Dependent on the motor task, the amplitude of both reflexes is modified. The various reflex mechanisms play an important role in normal physiological functions such as posture control and chewing.

Comminution of food is the composite result of selection and breakage. Selection is characterised by the chance that a food particle will at least be damaged by the teeth during chewing. For any size, this chance equals the ratio between the weight of damaged or broken particles and that of all initial particles. The breakage process refers to fracturing of selected particles. The aim was to examine whether a reduced chewing performance of pre-orthognathic surgery patients is due to an impairment of selection, breakage or both. Eight cubes of 8.0 mm of the silicone-rubber Optosil " were used as a test food to determine chewing efficiency for 12 patients (skeletal Angle Class II and dental Angle Class II, subdivision 1) and 12 controls (class I molar relation). Selection and breakage were determined in one-chew experiments using various particle sizes. Chewing efficiency was significantly lower for the patients than for the controls. The selection chance was significantly smaller for the patients, in particular for smaller (or = 4.8 mm) particles. The degree of breakage was lower for the patients, in particular for medium-sized particles of 4.8 mm. These findings suggest that the reduced chewing performance of pre-orthognathic surgery patients is due to an impairment of both selection and breakage.

Mastication was evaluated in patients with bulbar myasthenia gravis and compared with that of patients with ocular myasthenia gravis, patients in remission who previously suffered from bulbar symptoms, and healthy controls. Bulbar myasthenia gravis may impair mastication due to weakness of the masticatory muscles. The aim of the study was to objectively evaluate the influence of myasthenia gravis on mastication. The subjects chewed a piece of breakfast cake and chewed 1 min on a piece of chewing gum. Surface EMG of the masseter muscle, temporalis muscle and jaw opener muscles was recorded. Statistical analysis revealed that bulbar patients produced significantly less EMG activity in the closing phase of a chewing cycle in both experiments. The EMG of the masseter muscle expressed as percentage of the maximum EMG during maximal clenching showed significantly higher values in the bulbar group than in the other groups. This was not found for the temporalis muscle. It was suggested that bulbar patients use a strategy of limited effort to produce a bolus that can be swallowed. The ocular patients and the patients in remission showed no subclinical impairments in muscle function during chewing.

The aim was to study tongue force in patients with bulbar myasthenia gravis and compare it with that of patients with ocular myasthenia gravis, patients in clinical remission who previously suffered from bulbar myasthenia gravis, and healthy subjects.Tongue force was measured with a tongue force transducer in cranial and lateral directions, which coincide with the directions in which the tongue exerts force during swallowing, speech, and mastication.Tongue force in lateral direction was significantly decreased in patients with bulbar myasthenia gravis. In addition, our findings suggest an incomplete recovery of lateral tongue force in the patients of the remission group.Our tongue force measurements may be useful for longitudinal evaluation of therapy in individual patients and also in studies of therapy efficacy in matched groups of patients if the influence of factors such as age, dental state, and sex is taken into account.

Masticatory muscle strength was quantified in patients with bulbar myasthenia gravis and compared with that of patients with ocular myasthenia gravis, patients in clinical remission (whether or not pharmacological) who previously suffered from bulbar myasthenia gravis, and healthy subjects. Maximal bite force and maximal activity of the masseter and temporalis muscles and of the submental muscle complex were measured. Bite force was decreased in the patients with bulbar myasthenia gravis, but was normal in the patients in the clinical remission group and in the ocular group. These findings were consistent with the results of electromyographic data. Although subjective reports of masticatory muscle weakness provide valuable information, quantitative measurements provide more information about the degree of muscle weakness of individual muscles. This is especially important for longitudinal evaluation of therapy in individual patients and for pharmacotherapeutic research.

Recent evidence suggests that evaluation of muscle tenderness in temporomandibular disorders (TMDs) patients might be improved by the use of pressure algometry; nevertheless, the evaluation of the diagnostic value of this tool has received little attention. The aim of this study was to assess the diagnostic value of pressure algometry in myofascial pain of the jaw muscles, by calculation of sensitivity (Se), specificity (Sp) and positive predictive values (PPV). Pressure pain thresholds (PPTs) of masseter and anterior temporalis muscles were assessed in 40 female myogenous TMD patients and 40 age-matched female controls. PPTs were significantly lower (P

The question of whether thread- and tangle-like inclusions of the choroid plexus (known as Biondi inclusions) are related to the cortical lesions in Alzheimer disease (AD) has been debated for almost a century, yet remains unanswered. Recently beta-amyloid protein was biochemically isolated from the plexus, indicating a possible pathogenetic relationship between the degenerative changes of the cerebral cortex and those of the plexus. The goal of the present study was to analyze whether or not a significant correlation exists between the occurrence of the cortical AD-type changes and those in the ependyma and choroid plexus. In 292 consecutive autopsy cases several cortical areas, the ependyma, and the choroid plexus were analyzed to look for AD-type changes and Biondi inclusions using histochemical staining techniques and immunohistochemistry. A semiquantitative analysis of the density of cortical AD-type changes showed that of the 292 cases, 63 had severe cortical changes, 23 moderate changes, and 142 discrete changes. In 64 cases no plaques or neurofibrillary tangles were found. The number of cases with thread- and tangle-like elements in the plexus and ependyma was more than 96% in the 3 groups with cortical AD-type lesions, but low in the group without AD-type cortical changes (19%). The pathological argyrophilic filaments accumulating in the ependymal layer and plexus had histochemical properties of amyloid and were immunoreactive with antibodies to P component, ubiquitin, fibronectin and Tau protein. They did not react with antibodies to neurofilament proteins. Ultrastructurally, they consisted of densely packed straight and paired helical filaments and closely resembled neurofibrillary tangles and neuropil threads. The highly significant correlation (chi2, p = 0.001; R = 0.85) between the occurrence of AD-type changes in the cortex and those in ependyma and plexus suggests a pathogenetic relationship.

Immunoscreening of an expression library constructed with Toxoplasma gondii tachyzoite mRNA with sera from toxoplasmosis-positive humans has led to the identification of a new parasite antigen. Sequence analysis of the gene encoding this antigen allowed the calculation of the theoretical molecular mass (25,857 Da) and showed that the protein contains a putative signal sequence. The C-terminal region contains two hydrophobic regions, the last of which has the characteristics of a membrane-spanning domain. When the protein was heterologously expressed in E. coli and tested by Western blot, it reacted with the human sera originally used for screening. The new antigen also reacted with a monoclonal antibody raised against the entire parasite. Ultrastructural analysis showed that the protein is localized in the dense granules. After host cell invasion, the protein is secreted into the vacuolar network, the parasitophorous vacuole membrane, and into extensions protruding in the cytoplasm. Therefore, it is suggested to designate this new dense granule protein GRA7, following the established nomenclature for this protein family.

In this study, we investigated whether the recently identified lectin-like domain of tumor necrosis factor (TNF) is implicated in its biological activities on mammalian cells. To this end, a mouse TNF (mTNF) triple mutant, T104A-E106A-E109A mTNF (referred to hereafter as triple mTNF), lacking the lectin-like affinity of mTNF for specific oligosaccharides, was compared with the wild-type molecule for various TNF effects in vitro and in vivo. The triple mTNF displayed a 50-fold-reduced TNF receptor 2 (TNFR2)-mediated bioactivity but only a 5-fold-reduced TNFR1-mediated bioactivity in vitro. The specific activity of the triple mutant on L929 fibrosarcoma cells was slightly reduced compared with that of the wild type. We subsequently assessed the systemic toxicity of triple versus wild-type mTNF, since TNFR2 is partially implicated in this activity. The triple mTNF had a significantly reduced toxicity compared with that of wild-type mTNF in vivo. Moreover, we compared the effects of the triple and the wild-type mTNFs in TNFR1-mediated phenomena, such as (i) induction of tolerance towards a lethal mTNF dose and (ii) protective activity in cecal ligation and puncture-induced septic peritonitis. No significant differences between the mutant and wild-type forms were observed. In conclusion, these results indicate that triple mTNF, lacking TNF's lectin-like binding capacity, has reduced systemic toxicity but retains the tolerance-inducing and peritonitis-protective activities of wild-type mTNF.

Electromyography (EMG) has been applied in studies on patients with temporomandibular dysfunction (TMD), usually with surface electrodes, focusing on rest position of the mandible, hyperactivity and hypo-activity of the muscles, muscle balance, muscle symmetry, reflex activity and parafunctional activity. The contribution of the use of EMG to the diagnostics of individual patients is considered to be marginal, at the most. However, EMG can be valuable in research on TMD if methodological pitfalls are avoided.

In a study of 118 patients with temporomandibular dysfunction treated with occlusal splint therapy, symptoms of pain and limited mobility of the mandible had decreased more distinct than clicking sounds of the temporomandibular joints. Interestingly, an untreated control group showed similar results after two years follow-up.

Masticatory movements in man are almost cyclic and mainly vertical. The precise movements depend on many factors, such as the amount of food, its consistency and the morphology of the occlusal planes. In normal function chewing forces range from 10 to 50 N. For solid food the chewing performance can be characterized by determining the particle size of the comminuted food. Chewing movements and chewing forces result from a coordinated pattern of muscle activities. The basic pattern results from a central pattern generator in the brain stem. The control of the precise timing and intensity of the muscle activity necessary for commuting the food is a result of anticipation and of sensoric information from the masticatory system. During chewing the tongue plays an important role in transporting the food.

Radiographs of dental implants in the edentulous mandible, which are suitable for evaluation studies, are difficult to obtain. This article describes the development of an aiming device for intraoral radiography of the crestal bone around the neck of dental implants. Error analysis of serial radiographs indicated only small deviations in reproducibility. Subsequently three methods of measurements of marginal bone level around the neck of dental implants are described, measurements with: 1. a computerized image analysis system, 2. a magnifying glass, and 3. a digital sliding gauge. The intra- and interobserver error analysis showed that determining the precise bone height on the image is responsible for a large standard deviation for each method. Measurements with a digital sliding gauge are preferable, since this method is easy to put into practice, whereas the accuracy matches the accuracy of the two other methods.

An overview is given of the most commonly investigated signs and symptoms associated with craniomandibular disorders as detected in a population of patients with craniomandibular disorders and in four defined diagnostic subgroups. The information was collected with a questionnaire and during an extensive clinical examination. Comparison of self-report and clinical data indicated that these two methods reveal different aspects of the patient's complaints and should be interpreted in their own way. The results showed that no statistically significant differences could be found between the four diagnostic subgroups with respect to occlusal factors, trauma, and clinically assessed parafunctional habits. The groups differed considerably with respect to general characteristics, pain variables, signs of craniomandibular disorders, self-reported para-functional habits, psychosocial factors, and general health factors. However, despite the reduction in clinical characteristics of the four subgroups, there was little reduction in the diversity of factors associated with craniomandibular disorders. This implicates that almost all factors associated with craniomandibular disorders may influence the initiation and perpetuation of the different disorders in the individual patient, and therefore, remain of interest in future research.

An overview is given of the following four well-defined diagnostic subgroups of patients who have craniomandibular disorders: those with a mainly myogenous component; those with internal derangement with reduction; those with internal derangement without reduction; and those with osteoarthrosis. Although it was inevitable that the subgroups were not completely homogeneous, symptom profiles differed considerably. There even seemed to be reasons to distinguish two osteoarthrosis groups in future research. Although the identification of clinically significant factors in a given patient with craniomandibular disorders remains a difficult clinical task, the symptom profiles provide a framework that may give more insight into the background of the complaint and into possible contributing factors. The symptom profiles also provide the possibility of a more directed choice of treatment and a treatment evaluation that is more aimed at the specific characteristics of the subgroups. It therefore may be concluded that, to increase insight into craniomandibular disorders, the evaluation of diagnostic subgroups has to be preferred in the assessment of a heterogeneous group of patients with craniomandibular disorders.

To standardize clinical history taking, a comprehensive anamnestic questionnaire was developed (Screen). Screen includes questions about (i) pain, (ii) other symptoms of CMD, (iii) correlates of CMD, (iv) psychosocial factors, and (v) general health. Variables discriminating between subgroups of clinical cases and controls were described successively. This study was performed to assess whether subgroups of patients with signs and symptoms of craniomandibular dysfunction (CMD), and a control group of dental patients with and without signs and symptoms of CMD, can be characterized by differential report of signs and symptoms of CMD, as reported in Screen. Results indicate that Screen can be used to discriminate between (i) subgroups of subjects with signs or symptoms of CMD (both clinical cases and controls) and controls without signs or symptoms of CMD; (ii) subgroups of clinical cases and controls with signs and/or symptoms of CMD; and (iii) patients with CMD with mainly a myogenous component and patients with CMD with mainly an arthrogenous component. Differences between patients and controls are interpreted with regard to the correct classification of patients with CMD with mainly a myogenous component and patients with CMD with mainly an arthrogenous component, and with regard to the subjective treatment need for CMD. The results of logistic regression analyses indicate that subsets of items of Screen correctly classified up to 80% of patients with myogenous or arthrogenous CMD. Implications for further research were discussed.