Conformation-regulated mechanosensory control via titin domains in cardiac muscle

The giant filamentous protein titin is ideally positioned in the muscle sarcomere to sense mechanical stimuli and transform them into biochemical signals, such as those triggering cardiac hypertrophy. In this review, we ponder the evidence for signaling hotspots along the titin filament involved in mechanosensory control mechanisms. On the way, we distinguish between stress and strain as triggers of mechanical signaling events at the cardiac sarcomere. Whereas the Z-disk and M-band regions of titin may be prominently involved in sensing mechanical stress, signaling hotspots within the elastic I-band titin segment may respond primarily to mechanical strain. Common to both stress and strain sensor elements is their regulation by conformational changes in protein domains

Intensive Care Unit Sluice Room Sinks as Reservoirs and Sources of Potential Transmission of Carbapenem-Resistant Bacteria in a South African Tertiary Care Hospital

Khelan R Dheda,1 Chad M Centner,2 Lindsay Wilson,3,4 Anil Pooran,3,4 Shireen Grimwood,2 Yonas T Ghebrekristos,2 Suzette Oelofse,3,4 Ivan A Joubert,5 Aliasgar Esmail,3,4 Michele Tomasicchio3,4 1Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa; 2Division of Medical Microbiology, National Health Laboratory Services (NHLS)/Groote Schuur Hospital, Microbiology, University of Cape Town, Cape Town, South Africa; 3Division of Pulmonology, Department of Medicine, Centre for Lung Infection and Immunity, University of Cape Town and UCT Lung Institute, Cape Town, South Africa; 4South African MRC/UCT Centre for the Study of Antimicrobial Resistance, University of Cape Town, Cape Town, South Africa; 5Division of Critical Care, Department of Anaesthesia and Perioperative Medicine, University of Cape Town, Cape Town, South AfricaCorrespondence: Michele Tomasicchio, Division of Pulmonology, Department of Medicine, Centre for Lung Infection and Immunity, University of Cape Town and UCT Lung Institute, Cape Town, South Africa, Tel +27 21 650 4331, Fax +27 21  650 3824, Email [email protected]: Carbapenem-resistant bacteria (CRB) pose a major health risk to patients in intensive care units (ICU) across African hospitals. There are hardly any data about the role of hospital sinks as reservoirs of CRB in resource-poor African settings. Furthermore, the specific within-sink location of the highest concentration of pathogens and the role of splash back as a transmission mechanism remains poorly clarified.Methods: We swabbed ICU sluice room sinks in a tertiary hospital in Cape Town, South Africa. Swabs were taken from four different parts of the sluice room sinks (tap-opening, trap, below the trap, and u-bend). Dilutions were prepared and plated on carbapenem-infused agar. Colonies were identified and drug resistance profiles were determined using a biochemical analyser. To evaluate the potential transmission from the sink, similar plates were placed at fixed distances from the sink when the tap was turned on and off.Results: CRB were isolated from the trap, water interface below the trap, and the u-bend (the latter harboured the highest density of CRB species). Five CRB, resistant to at least 7 antibiotic classes, were isolated including Pseudomonas, Klebsiella, Citrobacter, Serratia, and Providencia. CRB could be cultured from droplets that fell on agar-containing plates placed at a varying distance from the trap.Conclusion: There is a higher density of CRB in the u-bend of ICU sluice room sinks which can act as a potential source of transmission. The data inform targeted CRB transmission-interruption strategies in resource-poor settings.Keywords: carbapenem-resistant bacteria, multi drug resistant bacteria, sluice room sink, intensive care units, antimicrobial resistanc

Improving the microbiological diagnosis of tuberculous meningitis: A prospective, international, multicentre comparison of conventional and modified Ziehl–Neelsen stain, GeneXpert, and culture of cerebrospinal fluid

Objectives Tuberculous meningitis (TBM) is the severest form of tuberculosis, but current diagnostic tests are insensitive. Recent reports suggest simple modifications to conventional cerebrospinal fluid (CSF) Ziehl–Neelsen (ZN) staining may greatly improve sensitivity. We sought to define the performance of modified and conventional ZN stain for TBM diagnosis. Methods In hospitals in Vietnam, South Africa and Indonesia we conducted a prospective study of modified ZN with or without cytospin, conventional ZN smear, GeneXpert, and culture on CSF in adults with suspected TBM. Results A total of 618 individuals were enrolled across 3 sites. Compared with the TBM clinical diagnostic gold standard for research (definite probable or possible TBM), sensitivity of conventional ZN and modified ZN with cytospin were 33.9% and 34.5% respectively (p = 1.0 for the difference between tests), compared with culture 31.8% and Xpert 25.1%. Using culture as a reference, sensitivities of conventional ZN, modified ZN with cytospin, and Xpert were 66.4%, 67.5%, and 72.3%, respectively. Higher CSF volume and lactate, and lower CSF:blood glucose ratio were independently associated with microbiologically confirmed TBM. Conclusions Modified ZN stain does not improve diagnosis of TBM. Currently available tests are insensitive, but testing large CSF volumes improves performance. New diagnostic tests for TBM are urgently required