Safety profile of intravenous and subcutaneous siplizumab,an anti‐CD2 monoclonal antibody,for the treatment of plaque psoriasis: results of two randomized,double‐blind,placebo‐controlled studies

Several biologics targeting different cytokines and receptors, including T‐cell receptors, have been approved for psoriasis treatment. Siplizumab, a humanized anti‐CD2 monoclonal antibody, may potentially provide an alternative therapy for psoriasis. Its safety profile and immunogenicity was examined in adults with plaque psoriasis. Two multicenter phase II randomized, double‐blind, placebo‐controlled studies: one tested two intravenous (I.V.) doses (0.012 and 0.04 mg/kg) of siplizumab every 2 weeks × 8 doses (124 patients); the second study tested three subcutaneous (S.C.) dose regimens of siplizumab (5 mg × 12 weeks, 5 mg × 6 weeks + placebo × 6 weeks, 7 mg × 4 weeks + placebo × 8 weeks), and placebo × 12 weeks (420 patients). Adverse events (AEs) and laboratory values were monitored. Immunogenicity was determined by anti‐siplizumab antibodies quantification. In both studies, siplizumab exhibited an acceptable safety profile; most common AEs judged to be siplizumab related were lymphopenia, chills, and headache, reported at a higher frequency in the siplizumab‐treated vs. placebo group. Siplizumab‐related reductions in absolute lymphocyte count did not result in clinical evidence of immune suppression. Anti‐siplizumab antibodies were detected after exposure to siplizumab; however, there was no evidence of an association between antibody development and AEs. Siplizumab exhibited an acceptable safety profile in adult patients with plaque psoriasis when administered as multiple I.V. or S.C. doses. Higher, clinically relevant doses of siplizumab would need to be tested to fully assess its safety.     

Attainment of local drug delivery with paclitaxel-eluting balloon in porcine coronary arteries

OBJECTIVE: Our purpose was to confirm the local drug delivery of a paclitaxel-eluting balloon by percutaneous intervention of single arterial segments or bifurcations of porcine coronary arteries. METHODS: Eight domestic pigs were subjected to 2 x 30 s Dior balloon dilatation of the mid left anterior descending, left circumflex and proximal right coronary arteries. Bifurcation intervention was performed in six arteries. The dilated, and the distal and proximal reference segments were prepared for tissue paclitaxel concentration measurement. Tissue samples were harvested at mean 1.5, 12, 24 and 48 h after balloon dilatation and plasma samples were taken at various time points. RESULTS: The tissue paclitaxel concentration of the single dilated segment was at 1.5 h postdilatation 1.82+/-1.60 micromol/l, which decreased significantly to 0.73+/-0.27 (P=0.032), 0.62+/-0.34 and 0.44+/-0.31 micromol/l at 12, 24 and 48 h. The bifurcation intervention resulted in 5.10+/-1.80 micromol/l tissue paclitaxel amount in the main branch, which at 12 h had diminished to 1.41+/-1.23 micromol/l (P=0.004). The bifurcation side contained 7.00+/-4.80 micromol/l paclitaxel at 1.5 h postdilatation, which lowered to 2.72+/-0.40 micromol/l (P=0.034). The mean paclitaxel concentration of the reference segments decreased gradually from 0.84+/-0.99 to 0.34+/-0.36 micromol/l (P=0.09), 0.28+/-0.16 and 0.19+/-0.18 micromol/l tissue at 1.5, 12, 24 and 48 h postdilatation, respectively. No paclitaxel was found in the peripheral blood at any time point. CONCLUSION: Short exposure of the coronary artery to paclitaxel with a coated balloon is sufficient for the attainment of an adequate tissue concentration of paclitaxel, which is known to be efficient in inhibiting neointimal growth.     

Significantly elevated Helicobacter pylori density and different genotype distribution in erosions as compared with normal gastric biopsy specimen detected by quantitative real-time PCR

BACKGROUND AND AIM: Determination of the local densities of Helicobacter pylori and its genotypic variations in gastric biopsy specimens by using novel real-time PCR-based methods could support the precise diagnosis and understanding of H. pylori infections. METHODS: Serial dilutions of H. pylori (0.016-16 microg/microl), control, bacterial, and human DNA samples were prepared. Fresh-frozen gastric biopsy specimens were taken from 103 patients, and the DNA was isolated. Quantitative determination of the ureaseA gene using hybridization probes with parallel evaluation of an internal human control gene (beta-globin) was performed by real-time PCR. CagA and VacA s1 genotypic characterizations were also performed. The data were compared with urea breath test (UBT), histology, and serological testing. RESULTS: The presence of H. pylori could be detected by ureaseA-fluorescence energy transfer (53%), UBT (51%), serological testing (48%), and histology (52%) when compared with the gold standard (54%). A significant correlation was found between the quantitative real-time ureaseA/beta-globin ratio-based H. pylori frequency and the UBT results (P<0.01). Significantly increased bacterial density was found in the erosions when compared with the healthy part of the antrum and corpus (P<0.01). Real-time PCR VacA s1 results were in significant correlation (P<0.01) with those of serological tests, but CagA results were not. The genomic profiles (VAC/GAC) were different in 13.7% of the cases, which involved three different locations in the stomach. CONCLUSION: Real-time PCR was the most reliable method for H. pylori diagnosis. Furthermore, quantification and genotyping could also be performed using this technique. The density of H. pylori was significantly increased in macroscopic erosions.     

Traumatic brain injury-induced cerebral microbleeds in the elderly

Traumatic brain injury (TBI) was shown to lead to the development of cerebral microbleeds (CMBs), which are associated with long term cognitive decline and gait disturbances in patients. The elderly is one of the most vulnerable parts of the population to suffer TBI. Importantly, ageing is known to exacerbate microvascular fragility and to promote the formation of CMBs. In this overview, the effect of ageing is discussed on the development and characteristics of TBI-related CMBs, with special emphasis on CMBs associated with mild TBI. Four cases of TBI-related CMBs are described to illustrate the concept that ageing exacerbates the deleterious microvascular effects of TBI and that similar brain trauma may induce more CMBs in old patients than in young ones. Recommendations are made for future prospective studies to establish the mechanistic effects of ageing on the formation of CMBs after TBI, and to determine long-term consequences of CMBs on clinically relevant outcome measures including cognitive performance, gait and balance function.

     

Examination of pituitary adenylate cyclase-activating polypeptide in Parkinson’s disease focusing on correlations with motor symptoms

GeroScience - The neuroprotective effects of pituitary adenylate cyclase-activating polypeptide (PACAP) have been shown in numerous in vitro and in vivo models of Parkinson’s disease (PD)...     

Blocking protein farnesyltransferase improves nuclear blebbing in mouse fibroblasts with a targeted Hutchinson-Gilford progeria syndrome mutation

Hutchinson-Gilford progeria syndrome (HGPS), a progeroid syndrome in children, is caused by mutations in LMNA (the gene for prelamin A and lamin C) that result in the deletion of 50 aa within prelamin A. In normal cells, prelamin A is a "CAAX protein" that is farnesylated and then processed further to generate mature lamin A, which is a structural protein of the nuclear lamina. The mutant prelamin A in HGPS, which is commonly called progerin, retains the CAAX motif that triggers farnesylation, but the 50-aa deletion prevents the subsequent processing to mature lamin A. The presence of progerin adversely affects the integrity of the nuclear lamina, resulting in misshapen nuclei and nuclear blebs. We hypothesized that interfering with protein farnesylation would block the targeting of progerin to the nuclear envelope, and we further hypothesized that the mislocalization of progerin away from the nuclear envelope would improve the nuclear blebbing phenotype. To approach this hypothesis, we created a gene-targeted mouse model of HGPS, generated genetically identical primary mouse embryonic fibroblasts, and we then examined the effect of a farnesyltransferase inhibitor on nuclear blebbing. The farnesyltransferase inhibitor mislocalized progerin away from the nuclear envelope to the nucleoplasm, as determined by immunofluoresence microscopy, and resulted in a striking improvement in nuclear blebbing (P < 0.0001 by chi2 statistic). These studies suggest a possible treatment strategy for HGPS.     

In-stent fractional flow reserve variations and related optical coherence tomography findings: the FFR–OCT co-registration study

We sought to assess in-stent variations in fractional flow reserve (FFR) in patients with previous percutaneous coronary intervention (PCI) and to associate any drop in FFR with findings by optical coherence tomography (OCT) imaging. Suboptimal post-PCI FFR values were previously associated with poor outcomes. It is not known to which extent in-stent pressure loss contributes to reduced FFR. In this single-arm observational study, 26 patients who previously underwent PCI with drug-eluting stent or scaffold implantation were enrolled. Motorized FFR pullback during continuous intravenous adenosine infusion and OCT assessments was performed. Post-PCI FFR?<?0.94 was defined as suboptimal. At a median of 63 days after PCI (interquartile range: 59–64 days), 18 out of 26 patients (72%) had suboptimal FFR. The in-stent drop in FFR was significantly higher in patients with suboptimal FFR vs. patients with optimal FFR (0.08?±?0.07 vs. 0.01?±?0.02, p?<?0.001). Receiver operating characteristic curve analysis showed that an in-stent FFR variation of >?0.03 was associated with suboptimal FFR. In patients with suboptimal FFR, the OCT analyses revealed higher mean neointimal area (respectively: 1.06?±?0.80 vs. 0.51?±?0.23 mm²; p?=?0.018) and higher neointimal thickness of covered struts (respectively 0.11?±?0.07 vs. 0.06?±?0.01 mm; p?=?0.021). Suboptimal FFR values following stent-implantation are mainly caused by significant in-stent pressure loss during hyperemia. This finding is associated to a larger neointimal proliferation.     

Vital Signs: Estimated Effects of a Coordinated Approach for Action to Reduce Antibiotic-Resistant Infections in Health Care Facilities — United States

BackgroundTreatments for health care–associated infections (HAIs) caused by antibiotic-resistant bacteria and Clostridium difficile are limited, and some patients have developed untreatable infections. Evidence-supported interventions are available, but coordinated approaches to interrupt the spread of HAIs could have a greater impact on reversing the increasing incidence of these infections than independent facility-based program efforts.MethodsData from CDC’s National Healthcare Safety Network and Emerging Infections Program were analyzed to project the number of health care–associated infections from antibiotic-resistant bacteria or C. difficile both with and without a large scale national intervention that would include interrupting transmission and improved antibiotic stewardship. As an example, the impact of reducing transmission of one antibiotic-resistant infection (carbapenem-resistant Enterobacteriaceae [CRE]) on cumulative prevalence and number of HAI transmission events within interconnected groups of health care facilities was modeled using two distinct approaches, a large scale and a smaller scale health care network.ResultsImmediate nationwide infection control and antibiotic stewardship interventions, over 5 years, could avert an estimated 619,000 HAIs resulting from CRE, multidrug-resistant Pseudomonas aeruginosa, invasive methicillin-resistant Staphylococcus aureus (MRSA), or C. difficile. Compared with independent efforts, a coordinated response to prevent CRE spread across a group of inter-connected health care facilities resulted in a cumulative 74% reduction in acquisitions over 5 years in a 10-facility network model, and 55% reduction over 15 years in a 102-facility network model.ConclusionsWith effective action now, more than half a million antibiotic-resistant health care–associated infections could be prevented over 5 years. Models representing both large and small groups of interconnected health care facilities illustrate that a coordinated approach to interrupting transmission is more effective than historical independent facility-based efforts.Implications for Public HealthPublic health–led coordinated prevention approaches have the potential to more completely address the emergence and dissemination of these antibiotic-resistant organisms and C. difficile than independent facility–based efforts.