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The fibrin-derived gamma377-395 peptide inhibits microglia activation and suppresses relapsing paralysis in central nervous system autoimmune disease.
Perivascular microglia activation is a hallmark of inflammatory demyelination in multiple sclerosis (MS), but the mechanisms underlying microglia activation and specific strategies to attenuate their activation remain elusive. Here, we identify fibrinogen as a novel regulator of microglia activation and show that targeting of the interaction of fibrinogen with the microglia integrin receptor Mac-1 (alpha(M)beta(2), CD11b/CD18) is sufficient to suppress experimental autoimmune encephalomyelitis in mice that retain full coagulation function. We show that fibrinogen, which is deposited perivascularly in MS plaques, signals through Mac-1 and induces the differentiation of microglia to phagocytes via activation of Akt and Rho. Genetic disruption of fibrinogen-Mac-1 interaction in fibrinogen-gamma(390-396A) knock-in mice or pharmacologically impeding fibrinogen-Mac-1 interaction through intranasal delivery of a fibrinogen-derived inhibitory peptide (gamma(377-395)) attenuates microglia activation and suppresses relapsing paralysis. Because blocking fibrinogen-Mac-1 interactions affects the proinflammatory but not the procoagulant properties of fibrinogen, targeting the gamma(377-395) fibrinogen epitope could represent a potential therapeutic strategy for MS and other neuroinflammatory diseases associated with blood-brain barrier disruption and microglia activation
Indium oxide diffusion barriers for Al/Si metallizations
Indium oxide (In2O3) films were prepared by reactive rf sputtering of an In target in O2/Ar plasma. We have investigated the application of these films as diffusion barriers in Si/In2O3/Al and Si/TiSi2.3/In2O3/Al metallizations. Scanning transmission electron microscopy together with energy dispersive analysis of x ray of cross-sectional Si/In2O3/Al specimens, and electrical measurements on shallow n + -p junction diodes were used to evaluate the diffusion barrier capability of In2O3 films. We find that 100-nm-thick In2O3 layers prevent the intermixing between Al and Si in Si/In2O3/Al contacts up to 650°C for 30 min, which makes this material one of the best thin-film diffusion barriers on record between Al and Si. (The Si-Al eutectic temperature is 577°C, Al melts at 660°C.) When a contacting layer of titanium silicide is incorporated to form a Si/TiSi2.3/In2O3/Al metallization structure, the thermal stability of the contact drops to 600°C for 30 min heat treatment
Characterizing and prognosticating chronic lymphocytic leukemia in the elderly: prospective evaluation on 455 patients treated in the United States.
BACKGROUND: Median age at diagnosis of patients with chronic lymphocytic leukemia (CLL) is \u3e 70 years. However, the majority of clinical trials do not reflect the demographics of CLL patients treated in the community. We examined treatment patterns, outcomes, and disease-related mortality in patients ≥ 75 years with CLL (E-CLL) in a real-world setting.
METHODS: The Connect® CLL registry is a multicenter, prospective observational cohort study, which enrolled 1494 adult patients between 2010-2014, at 199 US sites. Patients with CLL were enrolled within 2 months of initiating first line of therapy (LOT1) or a subsequent LOT (LOT ≥ 2). Kaplan-Meier methods were used to evaluate overall survival. CLL- and infection-related mortality were assessed using cumulative incidence functions (CIF) and cause-specific hazards. Logistic regression was used to develop a classification model.
RESULTS: A total of 455 E-CLL patients were enrolled; 259 were enrolled in LOT1 and 196 in LOT ≥ 2. E-CLL patients were more likely to receive rituximab monotherapy (19.3 vs. 8.6%; p \u3c 0.0001) and chemotherapy-alone regimens (p \u3c 0.0001) than younger patients. Overall and complete responses were lower in E-CLL patients than younger patients when given similar regimens. With a median follow-up of 3 years, CLL-related deaths were higher in E-CLL patients than younger patients in LOT1 (12.6 vs. 5.1% p = 0.0005) and LOT ≥ 2 (31.3 vs. 21.5%; p = 0.0277). Infection-related deaths were also higher in E-CLL patients than younger patients in LOT1 (7.4 vs. 2.7%; p = 0.0033) and in LOT ≥ 2 (16.2 vs. 11.2%; p = 0.0786). A prognostic score for E-CLL patients was developed: time from diagnosis to treatment \u3c 3 months, enrollment therapy other than bendamustine/rituximab, and anemia, identified patients at higher risk of inferior survival. Furthermore, higher-risk patients experienced an increased risk of CLL- or infection-related death (30.6 vs 10.3%; p = 0.0006).
CONCLUSION: CLL- and infection-related mortality are higher in CLL patients aged ≥ 75 years than younger patients, underscoring the urgent need for alternative treatment strategies for these understudied patients.
TRIAL REGISTRATION: The Connect CLL registry was registered at clinicaltrials.gov: NCT01081015 on March 4, 2010
The fibrin-derived γ377-395 peptide inhibits microglia activation and suppresses relapsing paralysis in central nervous system autoimmune disease
Perivascular microglia activation is a hallmark of inflammatory demyelination in multiple sclerosis (MS), but the mechanisms underlying microglia activation and specific strategies to attenuate their activation remain elusive. Here, we identify fibrinogen as a novel regulator of microglia activation and show that targeting of the interaction of fibrinogen with the microglia integrin receptor Mac-1 (αMβ2, CD11b/CD18) is sufficient to suppress experimental autoimmune encephalomyelitis in mice that retain full coagulation function. We show that fibrinogen, which is deposited perivascularly in MS plaques, signals through Mac-1 and induces the differentiation of microglia to phagocytes via activation of Akt and Rho. Genetic disruption of fibrinogen–Mac-1 interaction in fibrinogen-γ390-396A knock-in mice or pharmacologically impeding fibrinogen–Mac-1 interaction through intranasal delivery of a fibrinogen-derived inhibitory peptide (γ377-395) attenuates microglia activation and suppresses relapsing paralysis. Because blocking fibrinogen–Mac-1 interactions affects the proinflammatory but not the procoagulant properties of fibrinogen, targeting the γ377-395 fibrinogen epitope could represent a potential therapeutic strategy for MS and other neuroinflammatory diseases associated with blood-brain barrier disruption and microglia activation
Non-adiabatic and time-resolved photoelectron spectroscopy for molecular systems
We quantify the non-adiabatic contributions to the vibronic sidebands of
equilibrium and explicitly time-resolved non-equilibrium photoelectron spectra
for a vibronic model system of Trans-Polyacetylene. Using exact
diagonalization, we directly evaluate the sum-over-states expressions for the
linear-response photocurrent. We show that spurious peaks appear in the
Born-Oppenheimer approximation for the vibronic spectral function, which are
not present in the exact spectral function of the system. The effect can be
traced back to the factorized nature of the Born-Oppenheimer initial and final
photoemission states and also persists when either only initial, or final
states are replaced by correlated vibronic states. Only when correlated initial
and final vibronic states are taken into account, the spurious spectral weights
of the Born-Oppenheimer approximation are suppressed. In the non-equilibrium
case, we illustrate for an initial Franck-Condon excitation and an explicit
pump-pulse excitation how the vibronic wavepacket motion of the system can be
traced in the time-resolved photoelectron spectra as function of the pump-probe
delay
Journal of Clinical Monitoring and Computing end of year summary 2019:hemodynamic monitoring and management
Real-world clinical experience in the Connect® chronic lymphocytic leukaemia registry: a prospective cohort study of 1494 patients across 199 US centres.
The clinical course of chronic lymphocytic leukaemia (CLL) is heterogeneous, and treatment options vary considerably. The Connect® CLL registry is a multicentre, prospective observational cohort study that provides a real-world perspective on the management of, and outcomes for, patients with CLL. Between 2010 and 2014, 1494 patients with CLL and that initiated therapy, were enrolled from 199 centres throughout the USA (179 community-, 17 academic-, and 3 government-based centres). Patients were grouped by line of therapy at enrolment (LOT). We describe the clinical and demographic characteristics of, and practice patterns for, patients with CLL enrolled in this treatment registry, providing patient-level observational data that represent real-world experiences in the USA. Fluorescence in situ hybridization (FISH) analyses were performed on 49·3% of patients at enrolment. The most common genetic abnormalities detected by FISH were del(13q) and trisomy 12 (45·7% and 20·8%, respectively). Differences in disease characteristics and comorbidities were observed between patients enrolled in LOT1 and combined LOT2/≥3 cohorts. Important trends observed include the infrequent use of genetic prognostic testing, and differences in patient characteristics for patients receiving chemoimmunotherapy combinations. These data represent experiences of patients with CLL in the USA, which may inform treatment decisions in everyday practice
Beyond the caveman: Rethinking masculinity in relation to men’s help-seeking
publication-status: Publishedtypes: ArticleStatistically, men make less use of health-care services than women. This has been
interpreted as the result of the ‘hegemonic’ masculine code in which ‘real’ men are
understood to be physically fit, uninterested in their health and self-reliant. However,
less attention has been paid to understanding how hegemonic masculinity intersects
with the wider western socio-cultural contexts of men’s help-seeking, particularly
the valorization of health as a form of social achievement. This article presents the
results of interviews with 14 higher socio-economic status (SES) men to uncover their
‘interpretive repertoires’ in relation to health and illness, help-seeking and masculinity.
Although many interviewees drew on the stereotype of the ‘Neanderthal Man’ who
avoids the doctors to explain help-seeking by men ‘in general’, they constructed their
own experiences of help-seeking in terms of being responsible, problem-solving and in
control. It is argued that the framing of help-seeking in terms of ‘taking action’ chimes
with an increasingly pro-active ‘expert patient’ approach within western health-care.
This conceptual reconstruction of the dominant masculine code in relation to helpseeking,
from ‘Neanderthal Man’ to ‘Action Man’, may lead to greater gender equality
in terms of accessing health-care. However, it has the potential to exacerbate social
inequalities between men from different SES groups
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