A high parasite density environment induces transcriptional changes and cell death in Plasmodium falciparum blood stages.

Transient regulation of Plasmodium numbers below the density that induces fever has been observed in chronic malaria infections in humans. This species transcending control cannot be explained by immunity alone. Using an in vitro system we have observed density dependent regulation of malaria population size as a mechanism to possibly explain these in vivo observations. Specifically, Plasmodium falciparum blood stages from a high but not low-density environment exhibited unique phenotypic changes during the late trophozoite (LT) and schizont stages of the intraerythrocytic cycle. These included in order of appearance: failure of schizonts to mature and merozoites to replicate, apoptotic-like morphological changes including shrinking, loss of mitochondrial membrane potential, and blebbing with eventual release of aberrant parasites from infected erythrocytes. This unique death phenotype was triggered in a stage-specific manner by sensing of a high-density culture environment. Conditions of glucose starvation, nutrient depletion, and high lactate could not induce the phenotype. A high-density culture environment induced rapid global changes in the parasite transcriptome including differential expression of genes involved in cell remodeling, clonal antigenic variation, metabolism, and cell death pathways including an apoptosis-associated metacaspase gene. This transcriptional profile was also characterized by concomitant expression of asexual and sexual stage-specific genes. The data show strong evidence to support our hypothesis that density sensing exists in P. falciparum. They indicate that an apoptotic-like mechanism may play a role in P. falciparum density regulation, which, as in yeast, has features quite distinguishable from mammalian apoptosis. DATABASE: Gene expression data are available in the GEO databases under the accession number GSE91188.

An extreme case of platypnoea-orthodeoxia syndrome.

An 80-year-old female presented with progressive breathlessness, worse on sitting or standing and relieved by lying flat. Subsequent investigations identified a patent foramen ovale (PFO) with right-to-left flow across the interatrial septum (IAS). A diagnosis of platypnoea orthodeoxia syndrome secondary to inter-atrial shunting was made. Technical features precluded a percutaneous PFO closure so an open surgical repair was performed with complete resolution of symptoms. We discuss the pathophysiology and management of platypnoea orthodeoxia syndrome.

Should surgical outcomes be published?

Despite publishing surgical outcomes being a positive step forwards in the progression of England's healthcare system, it has no doubt been faced with criticism and reservations. This review article aims to discuss the pros and cons of publishing individual surgical outcomes, as well as the challenges faced. Publishing outcomes requires data from a number of sources such as national clinical audits, hospital episode statistics, patient-reported outcomes, registers and information from revalidation. As yet, eight surgical specialties have begun publishing their data, including cardiac (coronary artery bypass graft, valve and aortic surgery), endocrine (thyroidectomy, lobectomy, isthmusectomy), orthopaedic (hip and knee replacement), urological (full and partial nephrectomies, nephroureterectomy), colorectal (bowel tumour removal), upper gastrointestinal (stomach cancer and oesophageal cancer removal, bariatric surgery), ear, nose and throat surgery (larynx, oral cavity, oropharynx, hypopharynx and salivary gland cancer removal), as well as vascular surgery (abdominal aortic aneurysm, carotid endarterectomy). However, not all procedures have been addressed. Despite the controversy surrounding the topic of publishing surgical outcomes, the advantages of reporting outcomes outweigh the disadvantages, and these challenges can be overcome, to create a more reliable, trustworthy and transparent NHS. Perhaps one of the main challenges has been the difficulty in collecting large amounts of clinically significant data able to quantify the performance of surgeons.

BLOC-1 is required for cargo-specific sorting from vacuolar early endosomes toward lysosome-related organelles.

Hermansky-Pudlak syndrome (HPS) is a genetic disorder characterized by defects in the formation and function of lysosome-related organelles such as melanosomes. HPS in humans or mice is caused by mutations in any of 15 genes, five of which encode subunits of biogenesis of lysosome-related organelles complex (BLOC)-1, a protein complex with no known function. Here, we show that BLOC-1 functions in selective cargo exit from early endosomes toward melanosomes. BLOC-1-deficient melanocytes accumulate the melanosomal protein tyrosinase-related protein-1 (Tyrp1), but not other melanosomal proteins, in endosomal vacuoles and the cell surface due to failed biosynthetic transit from early endosomes to melanosomes and consequent increased endocytic flux. The defects are corrected by restoration of the missing BLOC-1 subunit. Melanocytes from HPS model mice lacking a different protein complex, BLOC-2, accumulate Tyrp1 in distinct downstream endosomal intermediates, suggesting that BLOC-1 and BLOC-2 act sequentially in the same pathway. By contrast, intracellular Tyrp1 is correctly targeted to melanosomes in melanocytes lacking another HPS-associated protein complex, adaptor protein (AP)-3. The results indicate that melanosome maturation requires at least two cargo transport pathways directly from early endosomes to melanosomes, one pathway mediated by AP-3 and one pathway mediated by BLOC-1 and BLOC-2, that are deficient in several forms of HPS.