Neurocutaneous melanocytosis-associated malignant melanoma presenting with peritoneal seeding.

Neurocutaneous melanocytosis (NCM) is characterized by melanocyte deposition in the leptomeninges and brain parenchyma, primarily occurring in children with large or giant congenital melanocytic nevi (LCMN) or multiple congenital melanocytic nevi. Patients with NCM may develop hydrocephalus and increased intracranial pressure, which can be managed with ventriculoperitoneal (VP) shunting. We present the case of a 16-month-old girl who developed peritoneal carcinomatosis and malignant ascites following VP shunting for hydrocephalus secondary to NCM to increase awareness of this rare, but serious, complication of cerebrospinal fluid diversion.

DNA Repair Mechanisms and Therapeutic Targets in Glioma.

PURPOSE OF REVIEW: This review discusses current and investigative strategies for targeting DNA repair in the management of glioma. RECENT FINDINGS: Recent strategies in glioma treatment rely on the production of overwhelming DNA damage and inhibition of repair mechanisms, resulting in lethal cytotoxicity. Many strategies are effective in preclinical glioma models while clinical feasibility remains under investigation. The presence of glioma biomarkers, including IDH mutation and/or MGMT promoter methylation, may confer particular susceptibility to DNA damage and inhibition of repair. These biomarkers have been adopted as eligibility criteria in the design of multiple ongoing clinical trials. Targeting DNA repair mechanisms with novel agents or therapeutic combinations is a promising approach to the treatment of glioma. Further investigations are underway to optimize this approach in the clinical setting.

Biomechanical measures in participants with shoulder pain: Intra-rater reliability.

Biomechanical measures are used to characterize the mechanisms of treatment for shoulder pain. The objective was to characterize test-retest reliability and measurement error of shoulder surface electromyographic(sEMG) and kinematic measures. Individuals(n = 12) with subacromial pain syndrome were tested at 2 visits. Five repetitions of shoulder scapular plane elevation were performed while collecting sEMG of the upper trapezius(UT), middle trapezius(MT), lower trapezius(LT), serratus anterior(SA) middle-deltoid, and infraspinatus muscles during ascending and descending phases. Simultaneously, electromagnetic sensors measured 3-dimensional kinematics of scapular internal/external rotation, upward/downward rotation, posterior/anterior tilt, and clavicular elevation/depression and clavicular protraction/retraction. Kinematic and sEMG variables were reduced for the total phase of ascending and descending elevation (30°-120°, 120°-30°), at 30° intervals for sEMG, and at every 30° discrete kinematic angle. The intraclass correlation coefficients(ICC) ranged from 0.08 to 0.99 for sEMG and 0.23-0.95 for kinematics. Correspondingly, the standard error of the measurement(SEM) and minimal detectable change(MDC) for sEMG measures varied from 2.3% to 103.8% of a reference contraction(REF-contraction). For kinematics, the SEM and MDC varied from 1.4° to 5.9°. Between-day reliability was good to very good, except for scapular internal/external rotation kinematics, and sEMG for the LT, UT, and SA. sEMG error values were highest (>25%REF-contraction) for most of the LT, UT, and SA variables. Kinematic error values indicate changes or differences of 2°-3° are meaningful, except for upward/downward rotation and internal/external rotation with MDCs of 4°-6°. Generally, data from the total phase of movement had better reliability and lower error than the data from sEMG interval or kinematic discrete angles.

The effects of alternating electric fields in glioblastoma: current evidence on therapeutic mechanisms and clinical outcomes.

Glioblastoma is both the most common and most lethal primary CNS malignancy in adults, accounting for 45.6% of all malignant CNS tumors, with a 5-year survival rate of only 5.0%, despite the utilization of multimodal therapy including resection, chemotherapy, and radiation. Currently available treatment options for glioblastoma often remain limited, offering brief periods of improved survival, but with substantial side effects. As such, improvements in current treatment strategies or, more likely, the implementation of novel strategies altogether are warranted. In this topic review, the authors provide a comprehensive review on the potential of alternating electric fields (AEFs) in the treatment of glioblastoma. Alternating electric fields-also known as tumor-treating fields (TTFs)-represent an entirely original therapeutic modality with preliminary studies suggesting comparable, and at times improved, efficacy to standard chemotherapeutic agents in the treatment of recurrent glioblastoma. A recent multicenter, Phase III, randomized clinical trial comparing NovoTTF-100A monotherapy to physician's best choice chemotherapy in patients with recurrent glioblastoma revealed that AEFs have similar efficacy to standard chemotherapeutic agents with a more favorable side-effects profile and improved quality of life. In particular, AEFs were shown to have limited systemic adverse effects, with the most common side effect being contact dermatitis on the scalp at the sites of transducer placement. This study prompted FDA approval of the NovoTTF-100A system in April 2011 as a standalone therapy for treatment of recurrent glioblastoma refractory to surgical and radiation treatment. In addition to discussing the available clinical evidence regarding the utilization of AEFs in glioblastoma, this article provides essential information regarding the supposed therapeutic mechanism as well as modes of potential tumor resistance to such novel therapy, delineating future perspectives regarding basic science research on the issue.

Controlled Cohort Study of Serum Gonadal and Adrenocortical Steroid Levels in Males Prior to Onset of Rheumatoid Arthritis (pre-RA): A Comparison to pre-RA Females and Sex Differences among the Study Groups.

Serum testosterone levels are generally reported to be lower in male rheumatoid arthritis (RA) patients, but it is not determined if a deficiency may occur before clinical onset of disease (pre-RA). Lower testosterone levels were recently reported in males many years before RA onset but were predictive only of rheumatoid factor (RF)-negative disease. A preceding prospective study did not reveal androgenic-anabolic hormone association with risk of RA in men or women. This cohort study of males analyzed baseline serum levels of gonadal and adrenocortical steroids, luteinizing hormone, and prolactin in 18 pre-RA versus 72 matched non-RA control (CN) subjects. Findings in males were compared to those in female pre-RA and CN subjects in the same cohort, and sex differences were analyzed. Steroidal and hormonal levels, including total testosterone, were similar between male study groups. In females, mean (±SE) serum androstenedione (nmol/L) was slightly (P = 0.048) lower in 36 pre-RA (6.7 ± 0.36) than 144 CN (7.6 ± 0.22). With the exception of 3 partial correlations of hormonal variables observed to differ between pre-RA versus CN subjects, the patterns were similar overall. However, partial correlations of hormonal variables differed frequently by sex, both within and between study groups.

Lower Serum Androstenedione Levels in Pre-Rheumatoid Arthritis versus Normal Control Women: Correlations with Lower Serum Cortisol Levels.

Serum adrenal androgens (AAs), including androstenedione (Δ4A) and dehydroepiandrosterone sulfate (DHEAS), have been reported to be lower in female rheumatoid arthritis (RA) patients with early disease. Few data are available on hormonal status of women before the onset of clinical rheumatoid arthritis (pre-RA). A broad baseline panel of serum adrenal and sex steroids was compared in 36 female pre-RA to 144 matched cohort control (CN) subjects to determine differences in their mean values and in patterns of hormonal correlations. Study subjects having lower versus higher baseline serum cortisol levels than the total group's mean value were also analyzed separately to investigate differences in their hormonal levels and correlational patterns. In total subjects, mean (±SE) Δ4A level (nmol/L) was lower (P = 0.018) in 28 pre-RA cases (6.4 ± 0.40) versus 108 CN (7.8 ± 0.28). The significant (P = 0.013) difference was restricted to 9 pre-RA versus 53 CN subjects having lower cortisol levels (5.6 ± 0.73 versus 8.0 ± 0.42 nmol/L, resp.). In total subjects, no significant difference was found between study subjects in their bivariate correlations of the hormonal panel variables, unlike results found in the subgroups stratified by lower versus higher cortisol levels. A subgroup of pre-RA females may have relative adrenal cortical insufficiency, as reflected by lower Δ4A, especially observed among those subjects with lower cortisol levels.

Serum acute phase protein and inflammatory cytokine network correlations: comparison of a pre-rheumatoid arthritis and non-rheumatoid arthritis community cohort.

Serum concentrations of acute phase proteins, inflammatory cytokines, and other immunological components were individually assayed using high-sensitivity ELISA in a com-munity-based cohort of preclinical rheumatoid arthritis (pre-RA) and matched non-RA control (CN) subjects. Bivariate correlations of the biomarker panel concentrations were compared in pre-RA versus CN and female versus male subjects. Clinically elevated CRP levels (8+ mg/l) occurred in a higher (p = 0.010) frequency in 46 pre-RA (n = 8, 17.4%) subjects than in 179 CN (n = 9, 5.0%), and were independent of age, gender, smoking behaviors, and serum rheumatoid factor. Selected age and gender differences were found in levels of the immunological network factors. In each study group, the ratio of sTNF-RI to IL-2sRα mean concentrations was 2-fold higher in men than in women. Aging correlated positively with CRP, ASAA, and TNF-α levels, but negatively with IL-1ß. Bivariate correlations were similar in pre-RA subjects versus CN and by gender, with few exceptions. Factor loadings in principal component analysis of the total subjects indicated that age- and gender-related variables constituted the two main components. Using multiple regression analyses, an integrative working model of all variable interrelations was generated. The tentative, directional model supports a concept of gender dimorphism of the ratio of sTNF-RI to IL-2sRα serum concentrations and displays differing effects of age on TNF-α versus IL-1ß levels. These findings indicate complex age, gender, and cytokine interrelations in control of the immune systems network. Future research in testing such inflammatory pathways promises a better understanding of predisposition to diseases, like RA.

Soft tissue structures resisting anterior instability in a computational glenohumeral joint model.

The glenohumeral joint is the most dislocated joint in the body due to the lack of bony constraints and the dependence on soft tissue for stability. The roles that various structures provide to joint function are important for understanding injury treatment and orthopaedic device design purposes. The goal of this study was to develop a computational model of the glenohumeral joint whereby joint behaviour was dictated by articular contact, ligamentous constraints, muscle loading and external perturbations. The bone structure of the computational model consisted of assembled computer tomographic images of the scapula, humerus and clavicle. The soft tissue elements were composed of forces and tension-only springs that represented muscles and ligaments. Validation of this model was achieved by comparing computational predictions to the results of a cadaveric experiment in which the relative contribution of muscles and ligaments to anterior joint stability was examined. The computational model predicted an anterior subluxation force that was similar to the cadaveric experimental results in humeral external rotation. The individual structure results showed the subscapularis to be critical to stabilisation in both neutral and external rotations, the biceps stabilised the joint in neutral but not in external rotation, and the inferior glenohumeral ligament resisted anterior displacement only in external rotation. The model's predictions were similar to the conclusions of the cadaveric experiment and the literature. Knowledge gained from this type of model could assist in further understanding the contribution of soft tissue stabilisers to joint function, pre-operative planning or the design of orthopaedic implants.

Insertion domain within mammalian mitochondrial translation initiation factor 2 serves the role of eubacterial initiation factor 1.

Mitochondria have their own translational machineries for the synthesis of thirteen polypeptide chains that are components of the complexes that participate in the process of oxidative phosphorylation (or ATP generation). Translation initiation in mammalian mitochondria requires two initiation factors, IF2(mt) and IF3(mt), instead of the three that are present in eubacteria. The mammalian IF2(mt) possesses a unique 37 amino acid insertion domain, which is known to be important for the formation of the translation initiation complex. We have obtained a three-dimensional cryoelectron microscopic map of the mammalian IF2(mt) in complex with initiator fMet-tRNA(iMet) and the eubacterial ribosome. We find that the 37 amino acid insertion domain interacts with the same binding site on the ribosome that would be occupied by the eubacterial initiation factor IF1, which is absent in mitochondria. Our finding suggests that the insertion domain of IF2(mt) mimics the function of eubacterial IF1, by blocking the ribosomal aminoacyl-tRNA binding site (A site) at the initiation step.

Properties of the C-terminal tail of human mitochondrial inner membrane protein Oxa1L and its interactions with mammalian mitochondrial ribosomes.

In humans the mitochondrial inner membrane protein Oxa1L is involved in the biogenesis of membrane proteins and facilitates the insertion of both mitochondrial- and nuclear-encoded proteins from the mitochondrial matrix into the inner membrane. The C-terminal approximately 100-amino acid tail of Oxa1L (Oxa1L-CTT) binds to mitochondrial ribosomes and plays a role in the co-translational insertion of mitochondria-synthesized proteins into the inner membrane. Contrary to suggestions made for yeast Oxa1p, our results indicate that the C-terminal tail of human Oxa1L does not form a coiled-coil helical structure in solution. The Oxa1L-CTT exists primarily as a monomer in solution but forms dimers and tetramers at high salt concentrations. The binding of Oxa1L-CTT to mitochondrial ribosomes is an enthalpy-driven process with a K(d) of 0.3-0.8 microM and a stoichiometry of 2. Oxa1L-CTT cross-links to mammalian mitochondrial homologs of the bacterial ribosomal proteins L13, L20, and L28 and to mammalian mitochondrial specific ribosomal proteins MRPL48, MRPL49, and MRPL51. Oxa1L-CTT does not cross-link to proteins decorating the conventional exit tunnel of the bacterial large ribosomal subunit (L22, L23, L24, and L29).