Effects of rituximab-based B-cell depletion therapy on skin manifestations of lupus erythematosus--report of 17 cases and review of the literature

Cutaneous manifestations occur frequently in systemic lupus erythematosus (SLE) and are pathognomonic in subacute-cutaneous lupus erythematosus (SCLE) and chronic cutaneous lupus erythematosus (CCLE). Although B-cell depletion therapy (BCDT) has demonstrated efficacy in SLE with visceral involvement, its usefulness for patients with predominant skin manifestations has not been fully established. In this single-centre, retrospective study 14 consecutive SLE, one CCLE and two SCLE patients with recalcitrant skin involvement were treated with 2 × rituximab 1 g, and 1 × cyclophosphamide 750 mg. Six months after BCDT, nine of 17 (53%) patients were in complete (CR) or partial remission (PR). Relapses occurred in 12 patients (71%) at a mean time of 10 ± 1.8 months after BCDT. A second cycle of BCDT achieved a more sustained remission in seven of nine patients (78%) lasting for a mean time of 18.4 ± 2.7 months. Minor adverse events were experienced by three patients. Mean follow-up was 30 months. Our own results and the literature review demonstrate that BCDT based on rituximab is well tolerated and may be effective for cutaneous lesions of lupus erythematosus. Randomized controlled trials are necessary to further evaluate the value of BCDT for this group of patients

Survival with Treated and Well-Controlled Blood Pressure: Findings from a Prospective Cohort Study.

AIM: To compare survival and incident cardiovascular disease between normotensive, untreated hypertensive, treated and poorly-controlled hypertensive and treated and well-controlled hypertensive adults. METHODS AND RESULTS: Data from the British Regional Heart Study (men) and British Women's Heart and Health Study (women) were used (N = 6476). Blood pressure and treatment were assessed at baseline (1998-2001) when participants were aged 60-79 years and participants were followed up for a median of 8 years. Date and cause of death were obtained from death certificates and non-fatal cardiovascular disease events were obtained from repeat detailed medical record reviews. Of the whole cohort 52% of women and 49% of men had untreated hypertension and a further 22% and 18%, respectively, had poorly treated hypertension. Just 3% of women and 4% of men had treated and well controlled hypertension and 23% and 29%, respectively, were normotensive. Compared to normotensive individuals, incident cardiovascular disease (fatal and non-fatal) was increased in those with poorly-controlled hypertension (Hazard Ratio (HR): 1.88; 95%CI: 1.53, 2.30), those with untreated hypertension (HR 1.46; 95%CI 1.22, 1.75) and those who were well-controlled hypertension (HR 1.38; 95%CI 0.94, 2.03). Adjustment for baseline differences in mean blood pressure between the groups resulted in attenuation of the increased risk in the poorly-controlled (1.52 (1.18, 1.97) and untreated groups (1.21 (0.97, 1.52), but did not change the association in the well-controlled group. All-cause mortality was also increased in all three hypertension groups but estimates were imprecise with wide confidence intervals. CONCLUSIONS: Half of women and men aged 60-79 in Britain had untreated hypertension and only a very small proportion of those with diagnosed and treated hypertension were well controlled. Those with hypertension, irrespective of whether this was treated and controlled or not, were at greater risk of future cardiovascular disease than those who are normotensive

Can analyses of electronic patient records be independently and externally validated? The effect of statins on the mortality of patients with ischaemic heart disease: a cohort study with nested case-control analysis

Objective To conduct a fully independent and external validation of a research study based on one electronic health record database, using a different electronic database sampling the same population. Design Using the Clinical Practice Research Datalink (CPRD), we replicated a published investigation into the effects of statins in patients with ischaemic heart disease (IHD) by a different research team using QResearch. We replicated the original methods and analysed all-cause mortality using: (1) a cohort analysis and (2) a case-control analysis nested within the full cohort. Setting Electronic health record databases containing longitudinal patient consultation data from large numbers of general practices distributed throughout the UK. Participants CPRD data for 34 925 patients with IHD from 224 general practices, compared to previously published results from QResearch for 13 029 patients from 89 general practices. The study period was from January 1996 to December 2003. Results We successfully replicated the methods of the original study very closely. In a cohort analysis, risk of death was lower by 55% for patients on statins, compared with 53% for QResearch (adjusted HR 0.45, 95% CI 0.40 to 0.50; vs 0.47, 95% CI 0.41 to 0.53). In case-control analyses, patients on statins had a 31% lower odds of death, compared with 39% for QResearch (adjusted OR 0.69, 95% CI 0.63 to 0.75; vs OR 0.61, 95% CI 0.52 to 0.72). Results were also close for individual statins. Conclusions Database differences in population characteristics and in data definitions, recording, quality and completeness had a minimal impact on key statistical outputs. The results uphold the validity of research using CPRD and QResearch by providing independent evidence that both datasets produce very similar estimates of treatment effect, leading to the same clinical and policy decisions. Together with other non-independent replication studies, there is a nascent body of evidence for wider validity

Quantum anticentrifugal force for wormhole geometry

We show the existence of an anticentrifugal force in a wormhole geometry in $R^3$. This counterintuitive force was shown to exist in a flat $R^2$ space. The role the geometry plays in the appearance of this force is discussed.Comment: to appear in Physics Letters

Cryo-EM reveals the conformation of a substrate analogue in the human 20S proteasome core

The proteasome is a highly regulated protease complex fundamental for cell homeostasis and controlled cell cycle progression. It functions by removing a wide range of specifically tagged proteins, including key cellular regulators. Here we present the structure of the human 20S proteasome core bound to a substrate analogue inhibitor molecule, determined by electron cryo-microscopy (cryo-EM) and single-particle analysis at a resolution of around 3.5 Å. Our map allows the building of protein coordinates as well as defining the location and conformation of the inhibitor at the different active sites. These results open new prospects to tackle the proteasome functional mechanisms. Moreover, they also further demonstrate that cryo-EM is emerging as a realistic approach for general structural studies of protein–ligand interactions

"Condoms Are Reliable but I Am Not": A Qualitative Analysis of AIDS-Related Beliefs and Attitudes of Young Heterosexual Adults in Budapest, Hungary and St. Petersburg, Russia

HIV and STD prevention is an essential component of public health initiatives in countries throughout Central and Eastern Europe. Liberalization in sexual values, declining age at first sex, higher levels of sexual activity, and inconsistent condom use have been well-documented among young people in the region following the political, economic, and cultural transitions after the end of the state socialism era. Less well-understood are the reasons for high-risk sexual behavior and psychosocial factors that must be addressed in the development of effective HIV/STD prevention programs. This study recruited members of 12 high-risk social networks of young adult men and women (n= 66 participants) in two cities, St. Petersburg, Russia, and Budapest, Hungary. In-depth focus groups were conducted with all members of each network, and qualitatively analyzed to examine factors surrounding high-risk sexual behavior. Main themes that emerged were that STDs are less known and less feared than AIDS, HIV risk factors were relatively well known among young adults in both countries but vulnerability is perceived differently, pregnancy prevention is a more immediate concern than protection from HIV or STDs, condom use declines quickly following first sex with a new partner, reintroducing condom use in a relationship is very difficult, and young adults report many barriers to condom use including those related to alcohol or other substance use. HIV/STD prevention programs are needed that extend beyond risk education alone and that also address critical psychological, social, and relationship factors related to sexual risk behavior

Fully coupled simulations of non-colloidal monodisperse sheared suspensions

In this work we investigate numerically the dynamics of sheared suspensions in the limit of vanishingly small fluid and particle inertia. The numerical model we used is able to handle the multi-body hydrodynamic interactions between thousands of particles embedded in a linear shear flow. The presence of the particles is modeled by momentum source terms spread out on a spherical envelop forcing the Stokes equations of the creeping flow. Therefore all the velocity perturbations induced by the moving particles are simultaneously accounted for. The statistical properties of the sheared suspensions are related to the velocity fluctuation of the particles. We formed averages for the resulting velocity fluctuation and rotation rate tensors. We found that the latter are highly anisotropic and that all the velocity fluctuation terms grow linearly with particle volume fraction. Only one off-diagonal term is found to be non zero (clearly related to trajectory symmetry breaking induced by the non-hydrodynamic repulsion force). We also found a strong correlation of positive/negative velocities in the shear plane, on a time scale controlled by the shear rate (direct interaction of two particles). The time scale required to restore uncorrelated velocity fluctuations decreases continuously as the concentration increases. We calculated the shear induced self-diffusion coefficients using two different methods and the resulting diffusion tensor appears to be anisotropic too. The microstructure of the suspension is found to be drastically modified by particle interactions. First the probability density function of velocity fluctuations showed a transition from exponential to Gaussian behavior as particle concentration varies. Second the probability of finding close pairs while the particles move under shear flow is strongly enhanced by hydrodynamic interactions when the concentration increases