Cost of Nosocomial Outbreak Caused by NDM-1-Containing Klebsiella pneumoniae in the Netherlands, October 2015-January 2016.

During October-December 2015, 29 patients in a hospital in the Netherlands acquired nosocomial infection with a multidrug-resistant, New Delhi-metallo-β-lactamase-positive Klebsiella pneumoniae strain. Extensive infection control measures were needed to stop this outbreak. The estimated economic impact of the outbreak was $804,263; highest costs were associated with hospital bed closures

The CD40-CD40L Dyad in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis

The CD40-CD40L dyad is an immune checkpoint regulator that promotes both innate and adaptive immune responses and has therefore an essential role in the development of inflammatory diseases, including multiple sclerosis (MS). In MS, CD40 and CD40L are expressed on immune cells present in blood and lymphoid organs, affected resident central nervous system (CNS) cells, and inflammatory cells that have infiltrated the CNS. CD40-CD40L interactions fuel the inflammatory response underlying MS, and both genetic deficiency and antibody-mediated inhibition of the CD40-CD40L dyad reduce disease severity in experimental autoimmune encephalomyelitis (EAE). Both proteins are therefore attractive therapeutic candidates to modulate aberrant inflammatory responses in MS. Here, we discuss the genetic, experimental and clinical studies on the role of CD40 and CD40L interactions in EAE and MS and we explore novel approaches to therapeutically target this dyad to combat neuroinflammatory diseases

Cathepsin K Deficiency Prevents the Aggravated Vascular Remodeling Response to Flow Cessation in ApoE^-/- Mice

Cathepsin K (catK) is a potent lysosomal cysteine protease involved in extracellular matrix (ECM) degradation and inflammatory remodeling responses. Here we have investigated the contribution of catK deficiency on carotid arterial remodeling in response to flow cessation in apoE-/- and wild type (wt) background. Ligation-induced hyperplasia is considerably aggravated in apoE-/- versus wt mice. CatK protein expression was significantly increased in neointimal lesions of apoE-/- compared with wt mice, suggesting a role for catK in intimal hyperplasia under hyperlipidemic conditions. Surprisingly, CatK deficiency completely blunted the augmented hyperplastic response to flow cessation in apoE-/-, whereas vascular remodeling in wt mice was unaffected. As catK deficiency did neither alter lesion collagen content and elastic laminae fragmentation in vivo, we focused on effects of catK on (systemic) inflammatory responses. CatK deficiency significantly reduced circulating CD3 T-cell numbers, but increased the regulatory T cell subset in apoE-/- but not wt mice. Moreover, catK deficiency changed CD11b+Ly6G-Ly6C high monocyte distribution in apoE-/- but not wt mice and tended to favour macrophage M2a polarization. In conclusion, catK deficiency almost completely blunted the increased vascular remodeling response of apoE-/- mice to flow cessation, possibly by correcting hyperlipidemia-associated pro-inflammatory effects on the peripheral immune response

Injury Surveillance in Elite New Zealand Track Cyclists

Introduction: Injury surveillance is an essential component of elite sport. Little data is available on injury rates in track cyclists, with the majority of cycling research focussed on road cycling, and suggesting cyclists are at highest risk of overuse knee, back and neck injuries, and acute injuries involving the shoulder/clavicle, lower back and knee. Purpose: This research aims to establish the baseline incidence and prevalence of injury, and its effect on training and competition for elite New Zealand track-cyclists. Methods: All members of Cycling New Zealand’s elite track squad were invited to take part in this prospective, longitudinal study. Participants completed two baseline questionnaires detailing current and past injury status, current training volume, and other baseline characteristics. They then completed an online self-reporting injury survey every week for 52 consecutive weeks in the form of the Programme for Injury and Illness Surveillance (PILLS) tool. Injuries were classified using the OSICS-10 classification system. Key outcome measures were injury incidence and prevalence. Also recorded were self-reported measures of training exposures and intensity, injury classification, treatment received, duration of injury and where (geographical location) the injury occurred. Comparison of participant and therapist injury classification were made, and all outcome measures were calculated for the squad as a whole, as well as with breakdown for gender and squad. Results: Data were collected from 33 members of the elite NZ track cycling squad, comprising 17 males (17-32 years - mean 22.71, SD: 4.45), and 16 females (17-31 years - mean 21.5 years, SD: 4.82). 21 of the 33 participants sustained an injury during the period of inclusion in the study. Four reported injuring multiple body sites at one time, with one participant reporting two multi-site incidents during the period of data collection. 13 participants sustained multiple injuries, and 12 reported no incidence of injury. 11 injuries occurred in sports specific training, 20 in the gym, six in competition and seven other (mean 11, SD 6.38). 82% of injuries were recorded as being acute, 18% recurrent, with no overuse injuries reported. 8962 training exposures were planned (mean 689 exposures per four-weeks, SD 142), with 60 sessions (0.67%) missed and 84 (0.94%) modified due to injury, totalling 144/8962 (1.6%) training exposures affected by injury (mean 11.1, SD 7) per four-week block of surveys. Injury Incidence was 4.9 injuries per 1000 training and competition exposures. For all injuries sustained (53 body parts injured from 44 events), the injury incidence was 5.9 per 1000 exposures. Point prevalence ranged from one injury per four-week block to seven (mean 3.38, SD 1.80). No significant relationships were found between squad, gender, previous injury, years in sport, new injuries or injury frequency, or number of treatments. Conclusion: This research provides the first descriptive injury profile for the elite New Zealand track cycling cohort. 64% of participants sustained an injury over the study period, however injury incidence and prevalence was low with rapid return to training and competition. Greatest number of injuries was seen in the lower back, hip/buttock/pelvis region, and the knee, possibly reflecting the biomechanical requirements of cycling and the nature of the training required for this cohort. Previous studies investigating road cycling describe similar body sites injured, but with a large proportion classified as overuse whereas no overuse injuries were self-reported in this study. Further research is required to determine any reason for this. Total training exposures were recorded however little detail was documented on the intensity, nature and load of each specific training session and warrants more detailed investigation through future research

Inhibition of CD40-TRAF6 interactions by the small molecule inhibitor 6877002 reduces neuroinflammation

Background: The influx of leukocytes into the central nervous system (CNS) is a key hallmark of the chronic neuro-inflammatory disease multiple sclerosis (MS). Strategies that aim to inhibit leukocyte migration across the blood-brain barrier (BBB) are therefore regarded as promising therapeutic approaches to combat MS. As the CD40L-CD40 dyad signals via TNF receptor-associated factor 6 (TRAF6) in myeloid cells to induce inflammation and leukocyte trafficking, we explored the hypothesis that specific inhibition of CD40-TRAF6 interactions can ameliorate neuro-inflammation. Methods: Human monocytes were treated with a small molecule inhibitor (SMI) of CD40-TRAF6 interactions (6877002), and migration capacity across human brain endothelial cells was measured. To test the therapeutic potential of the CD40-TRAF6-blocking SMI under neuro-inflammatory conditions in vivo, Lewis rats and C57BL/6J mice were subjected to acute experimental autoimmune encephalomyelitis (EAE) and treated with SMI 6877002 for 6 days (rats) or 3 weeks (mice). Results: We here show that a SMI of CD40-TRAF6 interactions (6877002) strongly and dose-dependently reduces trans-endothelial migration of human monocytes. Moreover, upon SMI treatment, monocytes displayed a decreased production of ROS, tumor necrosis factor (TNF), and interleukin (IL)-6, whereas the production of the anti-inflammatory cytokine IL-10 was increased. Disease severity of EAE was reduced upon SMI treatment in rats, but not in mice. However, a significant reduction in monocyte-derived macrophages, but not in T cells, that had infiltrated the CNS was eminent in both models. Conclusions: Together, our results indicate that SMI-mediated inhibition of the CD40-TRAF6 pathway skews human monocytes towards anti-inflammatory cells with reduced trans-endothelial migration capacity, and is able to reduce CNS-infiltrated monocyte-derived macrophages during neuro-inflammation, but minimally ameliorates EAE disease severity. We therefore conclude that SMI-mediated inhibition of the CD40-TRAF6 pathway may represent a beneficial treatment strategy to reduce monocyte recruitment and macrophage activation in the CNS and has the potential to be used as a co-treatment to combat MS

Cathepsin cysteine proteases in cardiovascular disease

Extracellular matrix (ECM) remodeling is one of the underlying mechanisms in cardiovascular diseases. Cathepsin cysteine proteases have a central role in ECM remodeling and have been implicated in the development and progression of cardiovascular diseases. Cathepsins also show differential expression in various stages of atherosclerosis, and in vivo knockout studies revealed that deficiency of cathepsin K or S reduces atherosclerosis. Furthermore, cathepsins are involved in lipid metabolism. Cathepsins have the capability to degrade low-density lipoprotein and reduce cholesterol efflux from macrophages, aggravating foam cell formation. Although expression studies also demonstrated differential expression of cathepsins in cardiovascular diseases like aneurysm formation, neointima formation, and neovascularization, in vivo studies to define the exact role of cathepsins in these processes are lacking. Evaluation of the feasibility of cathepsins as a diagnostic tool revealed that serum levels of cathepsins L and S seem to be promising as biomarkers in the diagnosis of atherosclerosis, whereas cathepsin B shows potential as an imaging tool. Furthermore, cathepsin K and S inhibitors showed effectiveness in (pre) clinical evaluation for the treatment of osteoporosis and osteoarthritis, suggesting that cathepsin inhibitors may also have therapeutic effects for the treatment of atherosclerosi

Minocycline Inhibits Apoptotic Cell Death in a Murine Model of Partial Flap Loss

For breast reconstruction, the deep inferior epigastric perforator (DIEP) flap has become standard therapy. A feared complication is partial or even total flap loss. In a novel murine model of partial DIEP flap loss, the contribution of apoptotis to flap loss was investigated. The clinically available apoptosis-inhibiting compound minocycline was tested for its ability to reduce cell death. The effect of minocycline on cell proliferation was studied in cell cultures of breast carcinoma. In 12 mice, pedicled DIEP flaps were raised, which were subjected to 15 minutes of ischemia and 4 days of reperfusion. Six mice were treated with minocycline 2 hours before surgery and every 24 hours for 4 days. Apoptosis was revealed by injecting annexin A5 30 minutes before sacrifice. Annexin A5 binds to phosphatidylserines, which are expressed on the cell membrane during apoptotis. Prior to sacrifice, necrosis was measured using planimetry. Minocycline reduced cell death after 4 days from 35.9% (standard deviation - 10.6) to 13.9% (standard deviation - 8.0; p <0.05). Apoptosis, as shown by annexin A5 binding in nontreated animals, was abundant. Minocycline did not influence tumor growth in cell cultures of human breast cancer. Minocycline treatment leads to increased DIEP flap viability in mice. This study widens the perspective in the improvement of free flap survival in patients