First-line treatment of malignant glioma with carmustine implants followed by concomitant radiochemotherapy: a multicenter experience

Randomized phase III trials have shown significant improvement of survival 1, 2, and 3 years after implantation of 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) wafers for patients with newly diagnosed malignant glioma. But these studies and subsequent non-phase III studies have also shown risks associated with local chemotherapy within the central nervous system. The introduction of concomitant radiochemotherapy with temozolomide (TMZ) has later demonstrated a survival benefit in a phase III trial and has become the current treatment standard for newly diagnosed malignant glioma patients. Lately, this has resulted in clinical protocols combining local chemotherapy with BCNU wafers and concomitant radiochemotherapy with TMZ although this may carry the risk of increased toxicity. We have compiled the treatment experience of seven neurosurgical centers using implantation of carmustine wafers at primary surgery followed by 6 weeks of radiation therapy (59–60 Gy) and 75 mg/m2/day TMZ in patients with newly diagnosed glioblastoma followed by TMZ monochemotherapy. We have retrospectively analyzed the postoperative clinical course, occurrence and severity of adverse events, progression-free interval, and overall survival in 44 patients with newly diagnosed glioblastoma multiforme. All patients received multimodal treatment including tumor resection, BCNU wafer implantation, and concomitant radiochemotherapy. Of 44 patients (mean age 59 ± 10.8 years) with glioblastoma who received Gliadel wafer at primary surgery, 28 patients (64%) had died, 16 patients (36%) were alive, and 15 patients showed no evidence of clinical or radiographic progression after a median follow-up of 15.6 months. At time of analysis of adverse events in this patient population, the median overall survival was 12.7 months and median progression-free survival was 7.0 months. Surgical, neurological, and medical adverse events were analyzed. Twenty-three patients (52%) experienced adverse events of any kind including complications that did not require treatment. Nineteen patients (43%) experienced grade 3 or grade 4 adverse events. Surgical complications included cerebral edema, healing abnormalities, cerebral spinal fluid leakage, meningitis, intracranial abscess, and hydrocephalus. Neurological adverse events included newly diagnosed seizures, alteration of mental status, and new neurological deficits. Medical complications were thromboembolic events (thrombosis, pulmonary embolism) and hematotoxicity. Combination of both treatment strategies, local chemotherapy with BCNU wafer and concomitant radiochemotherapy, appears attractive in aggressive multimodal treatment schedules and may utilize the sensitizing effect of TMZ and carmustine on MGMT and AGT on their respective drug resistance genes. Our data demonstrate that combination of local chemotherapy and concomitant radiochemotherapy carries a significant risk of toxicity that currently appears underestimated. Adverse events observed in this study appear similar to complication rates published in the phase III trials for BCNU wafer implantation followed by radiation therapy alone, but further add the toxicity of concomitant radiochemotherapy with systemic TMZ. Save use of a combined approach will require specific prevention strategies for multimodal treatments

Skin prick testing in patients using beta-blockers: a retrospective analysis

<p>Abstract</p> <p>Rationale</p> <p>The use of beta-blockers is a relative contraindication in allergen skin testing yet there is a paucity of literature on adverse events in this circumstance. We examined a population of skin tested patients on beta-blockers to look for any adverse effects.</p> <p>Methods</p> <p>Charts from 2004-2008 in a single allergy clinic were reviewed for any patients taking a beta-blocker when skin tested. Data was examined for skin test reactivity, type of skin test, concomitant asthma diagnosis, allergens tested, and adverse events.</p> <p>Results</p> <p>One hundred and ninety-one patients were taking beta-blockers when skin testing occurred. Seventy-two patients had positive skin tests. No tests resulted in an adverse event.</p> <p>Conclusions</p> <p>This data demonstrates the relative safety of administrating of skin prick tests to patients on beta-blocker treatment. Larger prospective studies are needed to substantiate the findings of this study.</p

Sizing Up Allometric Scaling Theory

Metabolic rate, heart rate, lifespan, and many other physiological properties vary with body mass in systematic and interrelated ways. Present empirical data suggest that these scaling relationships take the form of power laws with exponents that are simple multiples of one quarter. A compelling explanation of this observation was put forward a decade ago by West, Brown, and Enquist (WBE). Their framework elucidates the link between metabolic rate and body mass by focusing on the dynamics and structure of resource distribution networks—the cardiovascular system in the case of mammals. Within this framework the WBE model is based on eight assumptions from which it derives the well-known observed scaling exponent of 3/4. In this paper we clarify that this result only holds in the limit of infinite network size (body mass) and that the actual exponent predicted by the model depends on the sizes of the organisms being studied. Failure to clarify and to explore the nature of this approximation has led to debates about the WBE model that were at cross purposes. We compute analytical expressions for the finite-size corrections to the 3/4 exponent, resulting in a spectrum of scaling exponents as a function of absolute network size. When accounting for these corrections over a size range spanning the eight orders of magnitude observed in mammals, the WBE model predicts a scaling exponent of 0.81, seemingly at odds with data. We then proceed to study the sensitivity of the scaling exponent with respect to variations in several assumptions that underlie the WBE model, always in the context of finite-size corrections. Here too, the trends we derive from the model seem at odds with trends detectable in empirical data. Our work illustrates the utility of the WBE framework in reasoning about allometric scaling, while at the same time suggesting that the current canonical model may need amendments to bring its predictions fully in line with available datasets

Thioredoxin-binding protein-2 (TBP-2/VDUP1/TXNIP) regulates T-cell sensitivity to glucocorticoid during HTLV-I-induced transformation

Although glucocorticoid (GC) is widely used for treating hematopoietic malignancies including adult T-cell leukemia (ATL), the mechanism by which leukemic cells become resistant to GC in the clinical course remains unclear. Using a series of T-cell lines infected with human T lymphotropic virus type-I (HTLV-I), the causative virus of ATL, we have dissected the transformation from interleukin (IL)-2-dependent to -independent growth stage. The transformation associates the loss of thioredoxin-binding protein-2 (TBP-2), a tumor suppressor and regulator of lipid metabolism. Here we show that TBP-2 is responsible for GC-induced apoptosis in ATL cells. In the IL-2-dependent stage, dexamethasone induced TBP-2 expression and apoptosis, both of which were blocked by GC receptor (GR) antagonist RU486. Knockdown of TBP-2 consistently reduced the amount of GC-induced apoptosis. In IL-2-independent stage, however, expression of GR and TBP-2 was suppressed and GC failed to induce apoptosis. Forced expression of GR led the cells to mild sensitivity to GC, which was also accomplished by treatment with suberoylanilide hydroxamic acid, a TBP-2 inducer. A transfection experiment showed that TBP-2 expression induced apoptosis in IL-2-independent ATL cells. Thus, TBP-2 is likely to be one of the key molecules for GC-induced apoptosis and a potential target for treating the advanced stage of ATL

Mechanism of and Threshold Biomechanical Conditions for Falsetto Voice Onset

The sound source of a voice is produced by the self-excited oscillation of the vocal folds. In modal voice production, a drastic increase in transglottal pressure after vocal fold closure works as a driving force that develops self-excitation. Another type of vocal fold oscillation with less pronounced glottal closure observed in falsetto voice production has been accounted for by the mucosal wave theory. The classical theory assumes a quasi-steady flow, and the expected driving force onto the vocal folds under wavelike motion is derived from the Bernoulli effect. However, wavelike motion is not always observed during falsetto voice production. More importantly, the application of the quasi-steady assumption to a falsetto voice with a fundamental frequency of several hundred hertz is unsupported by experiments. These considerations suggested that the mechanism of falsetto voice onset may be essentially different from that explained by the mucosal wave theory. In this paper, an alternative mechanism is submitted that explains how self-excitation reminiscent of the falsetto voice could be produced independent of the glottal closure and wavelike motion. This new explanation is derived through analytical procedures by employing only general unsteady equations of motion for flow and solids. The analysis demonstrated that a convective acceleration of a flow induced by rapid wall movement functions as a negative damping force, leading to the self-excitation of the vocal folds. The critical subglottal pressure and volume flow are expressed as functions of vocal fold biomechanical properties, geometry, and voice fundamental frequency. The analytically derived conditions are qualitatively and quantitatively reasonable in view of reported measurement data of the thresholds required for falsetto voice onset. Understanding of the voice onset mechanism and the explicit mathematical descriptions of thresholds would be beneficial for the diagnosis and treatment of voice diseases and the development of artificial vocal folds

Effectiveness of physiotherapy exercise following total knee replacement: Systematic review and meta-analysis

© 2015 Artz et al. Background: Rehabilitation, with an emphasis on physiotherapy and exercise, is widely promoted after total knee replacement. However, provision of services varies in content and duration. The aim of this study is to update the review of Minns Lowe and colleagues 2007 using systematic review and meta-analysis to evaluate the effectiveness of post-discharge physiotherapy exercise in patients with primary total knee replacement. Methods: We searched MEDLINE, Embase, PsycInfo, CINAHL and Cochrane CENTRAL to October 4th 2013 for randomised evaluations of physiotherapy exercise in adults with recent primary knee replacement. Outcomes were: patient-reported pain and function, knee range of motion, and functional performance. Authors were contacted for missing data and outcomes. Risk of bias and heterogeneity were assessed. Data was combined using random effects meta-analysis and reported as standardised mean differences (SMD) or mean differences (MD). Results: Searches identified 18 randomised trials including 1,739 patients with total knee replacement. Interventions compared: physiotherapy exercise and no provision; home and outpatient provision; pool and gym-based provision; walking skills and more general physiotherapy; and general physiotherapy exercise with and without additional balance exercises or ergometer cycling. Compared with controls receiving minimal physiotherapy, patients receiving physiotherapy exercise had improved physical function at 3-4 months, SMD -0.37 (95% CI -0.62, -0.12), and pain, SMD -0.45 (95% CI -0.85, -0.06). Benefit up to 6 months was apparent when considering only higher quality studies. There were no differences for outpatient physiotherapy exercise compared with home-based provision in physical function or pain outcomes. There was a short-term benefit favouring home-based physiotherapy exercise for range of motion flexion. There were no differences in outcomes when the comparator was hydrotherapy, or when additional balancing or cycling components were included. In one study, a walking skills intervention was associated with a long-term improvement in walking performance. However, for all these evaluations studies were under-powered individually and in combination. Conclusion: After recent primary total knee replacement, interventions including physiotherapy and exercise show short-term improvements in physical function. However this conclusion is based on meta-analysis of a few small studies and no long-term benefits of physiotherapy exercise interventions were identified. Future research should target improvements to long-term function, pain and performance outcomes in appropriately powered trials

Liver Stiffness Measurement and Biochemical Markers in Senegalese Chronic Hepatitis B Patients with Normal ALT and High Viral Load

Despite the high prevalence of chronic hepatitis B (CHB) in Africa, few studies have been performed among African patients. We sought to evaluate liver stiffness measurement by FibroScan® (LSM) and two biochemical scores (FibroTest®, Fibrometer®) to diagnose liver fibrosis in Senegalese CHB patients with HBV plasma DNA load ≥3.2 log(10) IU/mL and normal alanine aminotransferase (ALT) values.LSM and liver fibrosis biochemical markers were performed on 225 consecutive HBV infected Senegalese patients with high viral load. Patients with an LSM range between 7 and 13 kPa underwent liver biopsy (LB). Two experienced liver pathologists performed histological grading using Metavir and Ishak scoring.225 patients were evaluated (84% male) and LB was performed in 69 patients, showing F2 and F3 fibrosis in 17% and 10% respectively. In these patients with a 7-13 kPa range of LSM, accuracy for diagnosis of significant fibrosis according to LB was unsatisfactory for all non-invasive markers with AUROCs below 0.70. For patients with LSM values below 7 kPa, FibroTest® (FT), and Fibrometer® (FM) using the cut-offs recommended by the test promoters suggested a fibrosis in 18% of cases for FT (8% severe fibrosis) and 8% for FM. For patients with LSM values greater than 13 kPa, FT, FM suggested a possible fibrosis in 73% and 70%, respectively.In highly replicative HBV-infected African patients with normal ALT and LSM value below 13 kPa, FibroScan®, FibroTest® or Fibrometer® were unsuitable to predict the histological liver status of fibrosis

How to Minimize the Attack Rate during Multiple Influenza Outbreaks in a Heterogeneous Population

<div><h3>Background</h3><p>If repeated interventions against multiple outbreaks are not feasible, there is an optimal level of control during the first outbreak. Any control measures above that optimal level will lead to an outcome that may be as sub-optimal as that achieved by an intervention that is too weak. We studied this scenario in more detail.</p> <h3>Method</h3><p>An age-stratified ordinary-differential-equation model was constructed to study infectious disease outbreaks and control in a population made up of two groups, adults and children. The model was parameterized using influenza as an example. This model was used to simulate two consecutive outbreaks of the same infectious disease, with an intervention applied only during the first outbreak, and to study how cumulative attack rates were influenced by population composition, strength of inter-group transmission, and different ways of triggering and implementing the interventions. We assumed that recovered individuals are fully immune and the intervention does not confer immunity.</p> <h3>Results/Conclusion</h3><p>The optimal intervention depended on coupling between the two population sub-groups, the length, strength and timing of the intervention, and the population composition. Population heterogeneity affected intervention strategies only for very low cross-transmission between groups. At more realistic values, coupling between the groups led to synchronization of outbreaks and therefore intervention strategies that were optimal in reducing the attack rates for each subgroup and the population overall coincided. For a sustained intervention of low efficacy, early intervention was found to be best, while at high efficacies, a delayed start was better. For short interventions, a delayed start was always advantageous, independent of the intervention efficacy. For most scenarios, starting the intervention after a certain cumulative proportion of children were infected seemed more robust in achieving close to optimal outcomes compared to a strategy that used a specified duration after an outbreak’s beginning as the trigger.</p> </div

Inter- and intrachromosomal asynchrony of cell division cycle events in root meristem cells of Allium cepa: possible connection with gradient of cyclin B-like proteins

Alternate treatments of Allium cepa root meristems with hydroxyurea (HU) and caffeine give rise to extremely large and highly elongated cells with atypical images of mitotic divisions, including internuclear asynchrony and an unknown type of interchromosomal asynchrony observed during metaphase-to-anaphase transition. Another type of asynchrony that cannot depend solely on the increased length of cells was observed following long-term incubation of roots with HU. This kind of treatment revealed both cell nuclei entering premature mitosis and, for the first time, an uncommon form of mitotic abnormality manifested in a gradual condensation of chromatin (spanning from interphase to prometaphase). Immunocytochemical study of polykaryotic cells using anti-β tubulin antibodies revealed severe perturbations in the microtubular organization of preprophase bands. Quantitative immunofluorescence measurements of the control cells indicate that the level of cyclin B-like proteins reaches the maximum at the G2 to metaphase transition and then becomes reduced during later stages of mitosis. After long-term incubation with low doses of HU, the amount of cyclin B-like proteins considerably increases, and a significant number of elongated cells show gradients of these proteins spread along successive regions of the perinuclear cytoplasm. It is suggested that there may be a direct link between the effects of HU-mediated deceleration of S- and G2-phases and an enhanced concentration of cyclin B-like proteins. In consequence, the activation of cyclin B-CDK complexes gives rise to an abnormal pattern of premature mitotic chromosome condensation with biphasic nuclear structures having one part of chromatin decondensed, and the other part condensed

Influenza Virus in Human Exhaled Breath: An Observational Study

Background: Recent studies suggest that humans exhale fine particles during tidal breathing but little is known of their composition, particularly during infection. Methodology/Principal Findings: We conducted a study of influenza infected patients to characterize influenza virus and particle concentrations in their exhaled breath. Patients presenting with influenza-like-illness, confirmed influenza A or B virus by rapid test, and onset within 3 days were recruited at three clinics in Hong Kong, China. We collected exhaled breath from each subject onto Teflon filters and measured exhaled particle concentrations using an optical particle counter. Filters were analyzed for influenza A and B viruses by quantitative polymerase chain reaction (qPCR). Twelve out of thirteen rapid test positive patients provided exhaled breath filter samples (7 subjects infected with influenza B virus and 5 subjects infected with influenza A virus). We detected influenza virus RNA in the exhaled breath of 4 (33%) subjects-three (60%) of the five patients infected with influenza A virus and one (14%) of the seven infected with influenza B virus. Exhaled influenza virus RNA generation rates ranged from <3.2 to 20 influenza virus RNA particles per minute. Over 87% of particles exhaled were under 1 μm in diameter. Conclusions: These findings regarding influenza virus RNA suggest that influenza virus may be contained in fine particles generated during tidal breathing, and add to the body of literature suggesting that fine particle aerosols may play a role in influenza transmission. © 2008 Fabian et al.published_or_final_versio