Comparison of a Low-Cost Miniature Inertial Sensor Module and a Fiber-Optic Gyroscope for Clinical Balance and Gait Assessments.

Objective: To investigate whether a microelectromechanical system (MEMS) inertial sensor module is as accurate as fiber-optic gyroscopes when classifying subjects as normal for clinical stance and gait balance tasks. Methods: Data of ten healthy subjects were recorded simultaneously with a fiber-optic gyroscope (FOG) system of SwayStar™ and a MEMS sensor system incorporated in the Valedo® system. Data from a sequence of clinical balance tasks with different angle and angular velocity ranges were assessed. Paired t-tests were performed to determine significant differences between measurement systems. Cohen's kappa test was used to determine the classification of normal balance control between the two sensor systems when comparing the results to a reference database recorded with the FOG system. Potential cross-talk errors in roll and pitch angles when neglecting yaw axis rotations were evaluated by comparing 2D FOG and 3D MEMS recordings. Results: Statistically significant (α=0.05) differences were found in some balance tasks, for example, "walking eight tandem steps" and various angular measures (p < 0.03). However, these differences were within a few percent (<2.7%) of the reference values. Tasks with high dynamic velocity ranges showed significant differences (p=0.002) between 2D FOG and 3D MEMS roll angles but no difference between 2D FOG and 2D MEMS roll angles. An almost perfect agreement could be obtained for both 2D FOG and 2D MEMS (κ=0.97) and 2D FOG and 3D MEMS measures (κ=0.87) when comparing measurements of all subjects and tasks. Conclusion: MEMS motion sensors can be used for assessing balance during clinical stance and gait tasks. MEMS provides measurements comparable to values obtained with a highly accurate FOG. When assessing pitch and roll trunk sway measures without accounting for the effect of yaw, it is recommended to use angle and angular velocity measures for stance, and only angular velocity measures for gait because roll and pitch velocity measurements are not influenced by yaw rotations, and angle errors are low for stance.

Hypoxia-inducible factor-1α activation in HPV-positive head and neck squamous cell carcinoma cell lines.

PURPOSE: Human papillomavirus (HPV) is a causative agent for a rising number of head and neck squamous cell carcinomas (HNSCC), which are characterized by distinct tumor biology. Hypoxia inducible-factor (HIF) signaling influences initiation and progression of carcinogenesis and HPV oncoproteins have evolved to highjack cellular pathways for viral reproduction. Therefore, we investigated whether HPV activates HIF-1α expression in HNSCC. EXPERIMENTAL TECHNIQUE: HPV-positive and -negative HNSCC cells were examined for adaptive responses to hypoxia. Expression of HIF-1α, prolyl hydroxylase-domain protein 2 (PHD2) and E-cadherin was analyzed by Western blotting, immunofluorescence (IF) microscopy and migration/wound healing assays. RESULTS: HPV-positive HNSCC cells showed higher HIF-1α and PHD2 protein levels under normoxia and hypoxia. HIF-1α hydroxylation was reduced in HPV-positive HNSCC cell lines under PHD and proteasomal inhibition. In vitro wound healing assays showed impairment of migration and proliferation by HIF-1α pathway activation in HPV-negative cell lines only. In contrast, migration and proliferation in HPV-positive cell lines was impaired by HIF-1α specific siRNA. CONCLUSIONS: HPV-positive HNSCC cells show activation of the HIF pathway and adaptation to HIF-1α upregulation, representing potential therapeutic targets in this emerging tumor entity.

Frey's syndrome after superficial parotidectomy: role of the sternocleidomastoid muscle flap: a prospective nonrandomized controlled trial.

BACKGROUND: The prevalence of Frey's syndrome (FS) after superficial parotidectomy in correlation to the sternocleidomastoid muscle flap (SCMMF) interposition is analyzed. METHODS: A prospective nonrandomized controlled multicenter trial included 130 patients. During superficial parotidectomy, SCMMF was dissected, if excised specimens' volume exceeded 25 mL (SCMMF group). Follow-up examinations took place after 6, 12, and 24 months and included a Minor's test. RESULTS: SCMMF was dissected in 30 (23.1%) patients. A total of 104, 80, and 68 patients completed the 1st, 2nd, and the 3rd follow-up, respectively. FS was detectable with nonvarying prevalence (46.3%, 45.6%, and 43.4%, respectively) during follow-up. The prevalence was higher in the SCMMF group (59.9%) than in the non-SCMMF group (41.8%; P = .92). The sweating area increased during follow-up (P = .12). Overall, 89.5% of patients characterized FS as not disturbing after 2 years. CONCLUSIONS: FS occurred with a steady and high prevalence after superficial parotidectomy. In particular, SCMMF did not lower the risk of FS.

Isolation and immunological characterization of a novel Cladosporium herbarum allergen structurally homologous to the alpha/beta hydrolase fold superfamily.

Because the ascomycete Cladosporium herbarum embodies one of the most important, world-wide occurring fungal species responsible for eliciting typical IgE-mediated hypersensitivity reactions ranging from rhinitis and ocular symptoms to severe involvement of the lower respiratory tract, a more comprehensive definition of its detailed allergen repertoire is unquestionably of critical medical as well as therapeutic significance. By screening a C. herbarum cDNA library with IgE antibodies pooled from 3 mold-reactive sera, we were able to identify, clone and affinity-purify a novel allergen candidate (29.9 kDa) exhibiting considerable (three-dimensional) homology to the alpha/beta hydrolase fold superfamily. The latter covers a collection of hydrolytic enzymes of widely differing phylogenetic origin as well as catalytic activity (operating in countless biological contexts) that in general exhibit only little sequence similarity yet show a remarkable conservation of structural topology. Our present study (i) characterizes recombinant non-fusion C. herbarum hydrolase as a natively folded, minor mold allergen that displays a prevalence of IgE reactivity of approximately 17% in our in vitro immunoblot experiments, (ii) proposes the existence of several putative (speculatively cross-reactive) ascomycete orthologues as determined via genome-wide in silico predictions, and (iii) finally implies that C. herbarum hydrolase could be included in forthcoming minimal testing sets when fungal allergy is suspected.

Difference in the relative distribution of CD4+ T-cell subsets in B-CLL with mutated and unmutated immunoglobulin (Ig) VH genes: implication for the course of disease.

B-cell chronic lymphocytic leukemia (B-CLL) is a clinically heterogeneous disease in which the clinical course is influenced by the presence or absence of immunoglobulin (Ig) variable heavy chain (VH) gene mutations. The poor clinical outcome of the subgroup with unmutated Ig VH genes has been linked to the persistent ability of the B-cell receptor in tumor cells from these cases to respond to antigen. As B-cell receptor signaling generally relies on T-cell help, we hypothesized that the course of B-CLL might not only be influenced by the Ig VH mutational status but also by the activation/differentiation status of T cells. We assessed the relative distribution of naive and memory T-cell subsets in peripheral blood from patients with mutated (M-CLL, n=71) and unmutated Ig VH genes (UM-CLL, n=42) and correlated it with the course of disease. We also compared the prosurvival potential of naive and memory T cells cocultured with B-CLL cells in vitro. A significant increase in relative numbers of central and effector memory T cells was observed in the CD4 T-cell pool from UM-CLL as compared with M-CLL cases and was associated with high Rai stage, progressive disease and shorter treatment-free survival (TFS). In a multivariate analysis, the relative number of CD4 central and effector memory T cells remained a significant prognostic parameter for TFS after correction for CD38 expression, Ig VH status, genomic aberrations, and Rai stage. The inverse correlation of memory CD4 T cells with TFS might be explained by their potential to support survival of B-CLL cells.

PKCbeta is essential for the development of chronic lymphocytic leukemia in the TCL1 transgenic mouse model: validation of PKCbeta as a therapeutic target in chronic lymphocytic leukemia.

The development and the propagation of chronic lymphocytic leukemia (CLL) has been linked to signaling via the B-cell receptor (BCR). Protein kinase C beta (PKCbeta) is an essential signaling element of the BCR and was recently shown to be overexpressed in human CLL. We used the TCL1 transgenic mouse model to directly target PKCbeta in the development of murine CLL. TCL1 overexpression did restore the CD5(+) B-cell population that is absent in PKCbeta-deficient mice. However, PKCbeta-deleted TCL1 transgenic mice did not develop a CLL disease, suggesting a role of PKCbeta in the establishment of the malignant clone. Moreover, targeting of PKCbeta with the specific inhibitor enzastaurin led to killing of human CLL samples in vitro. We thus propose that PKCbeta may be a relevant target for the treatment of CLL.

Arsenic trioxide induces apoptosis preferentially in B-CLL cells of patients with unfavourable prognostic factors including del17p13.

In the last decade, arsenic trioxide (As2O3) has been used very successfully to treat acute promyelocytic leukaemia (APL). Much less is known about the effectiveness of As2O3 in other neoplastic disorders. In this paper, we report that after 18 h in vitro treatment with 4 microM As2O3, 75+/-18% of B cell chronic lymphocytic leukaemia (B-CLL) cells (n=52) underwent apoptosis. It is important to note that B-CLL cells harboring a deletion of chromosome 17p13, which predisposes to fludarabine resistance and has been identified as an important negative predictor of clinical outcome, were more susceptible to As2O3 toxicity than cells lacking this aberration. Furthermore, unfavourable risk profiles such as unmutated IgVH status, high CD38 expression and prior treatment were associated with significantly higher sensitivity of B-CLL cells to As2O3. As2O3 also preferentially killed B-CLL cells compared to B cells from healthy age-matched controls. Molecular analysis revealed that basal superoxide dismutase activity was positively correlated with the pro-apoptotic activity of As2O3 pointing to a role of reactive oxygen species in cell death induction. The high activity of As2O3 in B-CLL cells from high-risk patients makes it a promising drug for high-risk and/or fludarabine-refractory B-CLL patients.

Cladosporium herbarum translationally controlled tumor protein (TCTP) is an IgE-binding antigen and is associated with disease severity.

Cladosporium herbarum represents one of the most important world-wide occurring allergenic fungal species. The prevalence of IgE reactivity to C. herbarum in patients suffering from allergy varies between 5 and 30% in the different climatic zones. Since mold allergy has often been associated with severe asthma, along with other allergic symptoms, it is important to define more comprehensively the allergen repertoire of this ascomycete. In this context we are reporting our successful approach to identify, clone, produce as a recombinant protein, purify and further characterize a new C. herbarum allergen which is a close homolog of the human translationally controlled tumor protein (TCTP, also called histamine releasing factor, HRF). The immunoreactivity of both pure recombinant molecules was investigated by means of immunoblot analyses, enzyme-linked immunosorbent assays as well as histamine release studies. To summarize, IgE antibodies from five out of nine individuals recognized both the human and the fungal protein in immunoblots. The latter was able to cause histamine release from human basophils with about half the efficiency compared to its human homolog HRF. Cross-inhibition assays showed that the patients' IgEs recognize common epitopes on both the human and C. herbarum proteins, but however, only pre-incubation with C. herbarum TCTP could completely inhibit reactivity with HRF. Furthermore, it appears that patients reactive to TCTP have a higher probability to suffer from asthma than other allergic patients.

Expression levels of CD38 in T cells predict course of disease in male patients with B-chronic lymphocytic leukemia.

CD38 expression of tumor cells has been identified as an important prognostic factor in B-cell chronic lymphocytic leukemia (B-CLL). Although CD38 is involved in effector functions of T cells, the prognostic value of CD38+ T cells has not yet been addressed in B-CLL. In the present study, CD38-expression levels in B-CLL cells and T cells from 204 patients were analyzed by flow cytometry and correlated with clinical and molecular risk parameters. CD38 expression significantly differed in the neoplastic clone from patients with low versus advanced stage, irrespective of the sex of patients. In contrast, CD38 expression was generally higher in T cells from female compared with male patients but only increased in male patients in a stage-dependent manner. In male patients, combined analysis of CD38 in T cells and B-CLL cells identified 4 subgroups with significantly different treatment-free survival. Multivariate analysis including Rai stage and molecular risk parameters of the neoplastic clone identified CD38-expression levels in T cells as an independent prognostic factor in male patients. Combined analysis of CD38 in B-CLL and T cells is superior in predicting outcome of male B-CLL patients than either parameter alone. Further studies are needed to elucidate the underlying mechanisms of the sex-specific role of CD38+ T cells in B-CLL.