Using Gap-Induced Inhibition of the Post-Auricular Muscle Response as an Objective Measure of Tinnitus in Humans

A widely used method for detecting tinnitus in rodents is the gap pre-pulse inhibition of the acoustic startle (GPIAS). One variant uses the Preyer reflex to assess the startle response and a component of this can be measured as a small muscle potential generated by the post-auricular muscle reflex (PAMR). The question was whether the GPIAS method could also be used to identify tinnitus in humans using the PAMR response. We recruited 19 participants with chronic tinnitus and 18 age-matched controls, but 12 tinnitus participants were unable to contribute data to the final result due to hyperacusis or lack of a PAMR. A majority of those tinnitus participants with a detectable PAMR showed some evidence of GPIAS (71%, 5/7). In the control group, most showed a PAMR response (67%, 12/18) and most of these demonstrated GPIAS (67%, 8/12). Our stimulus parameters were not completely optimal for showing a PAMR response so, with further refinement it may be possible to use the PAMR response and GPIAS as an objective method for demonstrating tinnitus in humans

Collective consciousness and its pathologies: Understanding the failure of AIDS control and treatment in the United States

We address themes of distributed cognition by extending recent formal developments in the theory of individual consciousness. While single minds appear biologically limited to one dynamic structure of linked cognitive submodules instantiating consciousness, organizations, by contrast, can support several, sometimes many, such constructs simultaneously, although these usually operate relatively slowly. System behavior remains, however, constrained not only by culture, but by a developmental path dependence generated by organizational history, in the context of market selection pressures. Such highly parallel multitasking – essentially an institutional collective consciousness – while capable of reducing inattentional blindness and the consequences of failures within individual workspaces, does not eliminate them, and introduces new characteristic malfunctions involving the distortion of information sent between workspaces and the possibility of pathological resilience – dysfunctional institutional lock-in. Consequently, organizations remain subject to canonical and idiosyncratic failures analogous to, but more complicated than, those afflicting individuals. Remediation is made difficult by the manner in which pathological externalities can write images of themselves onto both institutional function and corrective intervention. The perspective is applied to the failure of AIDS control and treatment in the United States

Early subretinal allograft rejection is characterized by innate immune activity

Successful subretinal transplantation is limited by considerable early graft loss, despite pharmacological suppression of adaptive immunity. We postulated that early innate immune activity is a dominant factor in determining graft survival and chose a non-immunosuppressed mouse model of retinal pigment epithelial (RPE) cell transplantation to explore this. Expression of almost all measured cytokines by DH01 RPE cells increased significantly following graft preparation and the neutrophil chemoattractant, KC/GRO/CINC, was most significantly increased. Subretinal allografts of DH01 cells (C57BL/10 origin) into healthy, non-immunosuppressed C57BL/6 murine eyes were harvested and fixed at 1, 3, 7 and 28 days post-operatively and subsequently cryosectioned and stained. Graft cells were detected using SV40 large T antigen (SV40T) immunolabeling and apoptosis/necrosis by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). Sections were also immunolabeled for macrophage (CD11b & F4/80), neutrophil (Gr1 Ly-6G), and T-lymphocyte (CD3-ε) infiltration. Images captured with an Olympus FV1000 confocal microscope were analyzed using Imaris software. The proportion of the subretinal bolus comprising graft cells (SV40T+) was significantly (p<0.001) reduced between post-operative day (POD) 3 (90% ± 4%) and POD 7 (20% ± 7%). CD11b+, F4/80+ and Gr1 Ly-6G+ cells increased significantly (p<0.05) from POD 1 and predominated over SV40T+ cells by POD 7. Co-labeling confocal microscopic analysis demonstrated graft engulfment by neutrophils and macrophages at POD 7 and reconstruction of z-stacked confocal images confirmed SV40T inside Gr1 Ly-6G+ cells. Expression of CD3-ε was low and did not differ significantly between time-points. By POD 28, no graft cells were detectable and few inflammatory cells remained. These studies reveal for the first time a critical role for innate immune mechanisms early in subretinal graft rejection. The future success of subretinal transplantation will require more emphasis on techniques to limit innate immune-mediated graft loss, rather than focusing exclusively on suppression of the adaptive immune response

Early dissemination of bevacizumab for advanced colorectal cancer: a prospective cohort study

<p>Abstract</p> <p>Background</p> <p>We describe early dissemination patterns for first-line bevacizumab given for metastatic colorectal cancer treatment.</p> <p>Methods</p> <p>We analyzed patient surveys and medical records for a population-based cohort with metastatic colorectal cancer treated in multiple regions and health systems in the United States (US). Eligible patients were diagnosed with metastatic colorectal cancer and initiated first-line chemotherapy after US Food & Drug Administration (FDA) bevacizumab approval in February 2004. First-line bevacizumab therapy was defined as receiving bevacizumab within 8 weeks of starting chemotherapy for metastatic colorectal cancer. We evaluated factors associated with first-line bevacizumab treatment using logistic regression.</p> <p>Results</p> <p>Among 355 patients, 31% received first-line bevacizumab in the two years after FDA approval, including 26% of men, 41% of women, and 16% of those ≥ 75 years. Use rose sharply within 6 months after FDA approval, then plateaued. 20% of patients received bevacizumab in combination with irinotecan; 53% received it with oxaliplatin. Men were less likely than women to receive bevacizumab (adjusted OR 0.55; 95% CI 0.32-0.93; p = 0.026). Patients ≥ 75 years were less likely to receive bevacizumab than patients < 55 years (adjusted OR 0.13; 95% CI 0.04-0.46; p = 0.001).</p> <p>Conclusions</p> <p>One-third of eligible metastatic colorectal cancer patients received first-line bevacizumab shortly after FDA approval. Most patients did not receive bevacizumab as part of the regimen used in the pivotal study leading to FDA approval.</p

Protocol for the Foot in Juvenile Idiopathic Arthritis trial (FiJIA): a randomised controlled trial of an integrated foot care programme for foot problems in JIA

&lt;b&gt;Background&lt;/b&gt;: Foot and ankle problems are a common but relatively neglected manifestation of juvenile idiopathic arthritis. Studies of medical and non-medical interventions have shown that clinical outcome measures can be improved. However existing data has been drawn from small non-randomised clinical studies of single interventions that appear to under-represent the adult population suffering from juvenile idiopathic arthritis. To date, no evidence of combined therapies or integrated care for juvenile idiopathic arthritis patients with foot and ankle problems exists. &lt;b&gt;Methods/design&lt;/b&gt;: An exploratory phase II non-pharmacological randomised controlled trial where patients including young children, adolescents and adults with juvenile idiopathic arthritis and associated foot/ankle problems will be randomised to receive integrated podiatric care via a new foot care programme, or to receive standard podiatry care. Sixty patients (30 in each arm) including children, adolescents and adults diagnosed with juvenile idiopathic arthritis who satisfy the inclusion and exclusion criteria will be recruited from 2 outpatient centres of paediatric and adult rheumatology respectively. Participants will be randomised by process of minimisation using the Minim software package. The primary outcome measure is the foot related impairment measured by the Juvenile Arthritis Disability Index questionnaire's impairment domain at 6 and 12 months, with secondary outcomes including disease activity score, foot deformity score, active/limited foot joint counts, spatio-temporal and plantar-pressure gait parameters, health related quality of life and semi-quantitative ultrasonography score for inflammatory foot lesions. The new foot care programme will comprise rapid assessment and investigation, targeted treatment, with detailed outcome assessment and follow-up at minimum intervals of 3 months. Data will be collected at baseline, 6 months and 12 months from baseline. Intention to treat data analysis will be conducted. A full health economic evaluation will be conducted alongside the trial and will evaluate the cost effectiveness of the intervention. This will consider the cost per improvement in Juvenile Arthritis Disability Index, and cost per quality adjusted life year gained. In addition, a discrete choice experiment will elicit willingness to pay values and a cost benefit analysis will also be undertaken

Preparation of Pre-Confluent Retinal Cells Increases Graft Viability In Vitro and In Vivo: A Mouse Model

PURPOSE: Graft failure remains an obstacle to experimental subretinal cell transplantation. A key step is preparing a viable graft, as high levels of necrosis and apoptosis increase the risk of graft failure. Retinal grafts are commonly harvested from cell cultures. We termed the graft preparation procedure "transplant conditions" (TC). We hypothesized that culture conditions influenced graft viability, and investigated whether viability decreased following TC using a mouse retinal pigment epithelial (RPE) cell line, DH01. METHODS: Cell viability was assessed by trypan blue exclusion. Levels of apoptosis and necrosis in vitro were determined by flow cytometry for annexin V and propidium iodide and Western blot analysis for the pro- and cleaved forms of caspases 3 and 7. Graft viability in vivo was established by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and cleaved caspase 3 immunolabeling of subretinal allografts. RESULTS: Pre-confluent cultures had significantly less nonviable cells than post-confluent cultures (6.6%±0.8% vs. 13.1%±0.9%, p<0.01). Cell viability in either group was not altered significantly following TC. Caspases 3 and 7 were not altered by levels of confluence or following TC. Pre-confluent cultures had low levels of apoptosis/necrosis (5.6%±1.1%) that did not increase following TC (4.8%±0.5%). However, culturing beyond confluence led to progressively increasing levels of apoptosis and necrosis (up to 16.5%±0.9%). Allografts prepared from post-confluent cultures had significantly more TUNEL-positive cells 3 hours post-operatively than grafts of pre-confluent cells (12.7%±3.1% vs. 4.5%±1.4%, p<0.001). Subretinal grafts of post-confluent cells also had significantly higher rates of cleaved caspase 3 than pre-confluent grafts (20.2%±4.3% vs. 7.8%±1.8%, p<0.001). CONCLUSION: Pre-confluent cells should be used to maximize graft cell viability

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Ribosome-associated vesicles: A dynamic subcompartment of the endoplasmic reticulum in secretory cells

The endoplasmic reticulum (ER) is a highly dynamic network of membranes. Here, we combine live-cell microscopy with in situ cryo–electron tomography to directly visualize ER dynamics in several secretory cell types including pancreatic β-cells and neurons under near-native conditions. Using these imaging approaches, we identify a novel, mobile form of ER, ribosome-associated vesicles (RAVs), found primarily in the cell periphery, which is conserved across different cell types and species. We show that RAVs exist as distinct, highly dynamic structures separate from the intact ER reticular architecture that interact with mitochondria via direct intermembrane contacts. These findings describe a new ER subcompartment within cells