Pseudomonas aeruginosa mutants defective in glucose uptake have pleiotropic phenotype and altered virulence in non-mammal infection models

Pseudomonas spp. are endowed with a complex pathway for glucose uptake that relies on multiple transporters. In this work we report the construction and characterization of Pseudomonas aeruginosa single and multiple mutants with unmarked deletions of genes encoding outer membrane (OM) and inner membrane (IM) proteins involved in glucose uptake. We found that a triple \u394gltKGF \u394gntP \u394kguT mutant lacking all known IM transporters (named GUN for Glucose Uptake Null) is unable to grow on glucose as unique carbon source. More than 500 genes controlling both metabolic functions and virulence traits show differential expression in GUN relative to the parental strain. Consistent with transcriptomic data, the GUN mutant displays a pleiotropic phenotype. Notably, the genome-wide transcriptional profile and most phenotypic traits differ between the GUN mutant and the wild type strain irrespective of the presence of glucose, suggesting that the investigated genes may have additional roles besides glucose transport. Finally, mutants carrying single or multiple deletions in the glucose uptake genes showed attenuated virulence relative to the wild type strain in Galleria mellonella, but not in Caenorhabditis elegans infection model, supporting the notion that metabolic functions may deeply impact P. aeruginosa adaptation to specific environments found inside the host

Fusarium Infection: Report of 26 Cases and Review of 97 Cases From the Literature

Abstract Fusarium species is a ubiquitous fungus that causes opportunistic infections. We present 26 cases of invasive fusariosis categorized according to the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria of fungal infections. All cases (20 proven and 6 probable) were treated from January 2000 until January 2010. We also review 97 cases reported since 2000. The most important risk factors for invasive fusariosis in our patients were compromised immune system, specifically lung transplantation (n = 6) and hematologic malignancies (n = 5), and burns (n = 7 patients with skin fusariosis), while the most commonly infected site was the skin in 11 of 26 patients. The mortality rates among our patients with disseminated, skin, and pulmonary fusariosis were 50%, 40%, and 37.5%, respectively. Fusarium solani was the most frequent species, isolated from 49% of literature cases. Blood cultures were positive in 82% of both current study and literature patients with disseminated fusariosis, while the remaining 16% had 2 noncontiguous sites of infection but negative blood cultures. Surgical removal of focal lesions was effective in both current study and literature cases. Skin lesions in immunocompromised patients should raise the suspicion for skin or disseminated fusariosis. The combination of medical monotherapy with voriconazole or amphotericin B and surgery in such cases is highly suggested

Peripheral complement interactions with amyloid β peptide in Alzheimer's disease: 2. Relationship to amyloid β immunotherapy

IntroductionOur previous studies have shown that amyloid β peptide (Aβ) is subject to complement-mediated clearance from the peripheral circulation, and that this mechanism is deficient in Alzheimer's disease. The mechanism should be enhanced by Aβ antibodies that form immune complexes (ICs) with Aβ, and therefore may be relevant to current Aβ immunotherapy approaches.MethodsMultidisciplinary methods were employed to demonstrate enhanced complement-mediated capture of Aβ antibody immune complexes compared with Aβ alone in both erythrocytes and THP1-derived macrophages.ResultsAβ antibodies dramatically increased complement activation and opsonization of Aβ, followed by commensurately enhanced Aβ capture by human erythrocytes and macrophages. These in vitro findings were consistent with enhanced peripheral clearance of intravenously administered Aβ antibody immune complexes in nonhuman primates.DiscussionTogether with our previous results, showing significant Alzheimer's disease deficits in peripheral Aβ clearance, the present findings strongly suggest that peripheral mechanisms should not be ignored as contributors to the effects of Aβ immunotherapy

Effect of shelter-in-place on emergency department radiology volumes during the COVID-19 pandemic.

PurposeThe coronavirus disease 2019 (COVID-19) pandemic has led to significant disruptions in the healthcare system including surges of infected patients exceeding local capacity, closures of primary care offices, and delays of non-emergent medical care. Government-initiated measures to decrease healthcare utilization (i.e., "flattening the curve") have included shelter-in-place mandates and social distancing, which have taken effect across most of the USA. We evaluate the immediate impact of the Public Health Messaging and shelter-in-place mandates on Emergency Department (ED) demand for radiology services.MethodsWe analyzed ED radiology volumes from the five University of California health systems during a 2-week time period following the shelter-in-place mandate and compared those volumes with March 2019 and early April 2019 volumes.ResultsED radiology volumes declined from the 2019 baseline by 32 to 40% (p < 0.001) across the five health systems with a total decrease in volumes across all 5 systems by 35% (p < 0.001). Stratifying by subspecialty, the smallest declines were seen in non-trauma thoracic imaging, which decreased 18% (p value < 0.001), while all other non-trauma studies decreased by 48% (p < 0.001).ConclusionTotal ED radiology demand may be a marker for public adherence to shelter-in-place mandates, though ED chest radiology demand may increase with an increase in COVID-19 cases

Effect of shelter-in-place on emergency department radiology volumes during the COVID-19 pandemic.

PurposeThe coronavirus disease 2019 (COVID-19) pandemic has led to significant disruptions in the healthcare system including surges of infected patients exceeding local capacity, closures of primary care offices, and delays of non-emergent medical care. Government-initiated measures to decrease healthcare utilization (i.e., "flattening the curve") have included shelter-in-place mandates and social distancing, which have taken effect across most of the USA. We evaluate the immediate impact of the Public Health Messaging and shelter-in-place mandates on Emergency Department (ED) demand for radiology services.MethodsWe analyzed ED radiology volumes from the five University of California health systems during a 2-week time period following the shelter-in-place mandate and compared those volumes with March 2019 and early April 2019 volumes.ResultsED radiology volumes declined from the 2019 baseline by 32 to 40% (p < 0.001) across the five health systems with a total decrease in volumes across all 5 systems by 35% (p < 0.001). Stratifying by subspecialty, the smallest declines were seen in non-trauma thoracic imaging, which decreased 18% (p value < 0.001), while all other non-trauma studies decreased by 48% (p < 0.001).ConclusionTotal ED radiology demand may be a marker for public adherence to shelter-in-place mandates, though ED chest radiology demand may increase with an increase in COVID-19 cases

Peripheral complement interactions with amyloid β peptide: Erythrocyte clearance mechanisms.

IntroductionAlthough amyloid β peptide (Aβ) is cleared from the brain to cerebrospinal fluid and the peripheral circulation, mechanisms for its removal from blood remain unresolved. Primates have uniquely evolved a highly effective peripheral clearance mechanism for pathogens, immune adherence, in which erythrocyte complement receptor 1 (CR1) plays a major role.MethodsMultidisciplinary methods were used to demonstrate immune adherence capture of Aβ by erythrocytes and its deficiency in Alzheimer's disease (AD).ResultsAβ was shown to be subject to immune adherence at every step in the pathway. Aβ dose-dependently activated serum complement. Complement-opsonized Aβ was captured by erythrocytes via CR1. Erythrocytes, Aβ, and hepatic Kupffer cells were colocalized in the human liver. Significant deficits in erythrocyte Aβ levels were found in AD and mild cognitive impairment patients.DiscussionCR1 polymorphisms elevate AD risk, and >80% of human CR1 is vested in erythrocytes to subserve immune adherence. The present results suggest that this pathway is pathophysiologically relevant in AD

Peripheral complement interactions with amyloid β peptide: Erythrocyte clearance mechanisms.

IntroductionAlthough amyloid β peptide (Aβ) is cleared from the brain to cerebrospinal fluid and the peripheral circulation, mechanisms for its removal from blood remain unresolved. Primates have uniquely evolved a highly effective peripheral clearance mechanism for pathogens, immune adherence, in which erythrocyte complement receptor 1 (CR1) plays a major role.MethodsMultidisciplinary methods were used to demonstrate immune adherence capture of Aβ by erythrocytes and its deficiency in Alzheimer's disease (AD).ResultsAβ was shown to be subject to immune adherence at every step in the pathway. Aβ dose-dependently activated serum complement. Complement-opsonized Aβ was captured by erythrocytes via CR1. Erythrocytes, Aβ, and hepatic Kupffer cells were colocalized in the human liver. Significant deficits in erythrocyte Aβ levels were found in AD and mild cognitive impairment patients.DiscussionCR1 polymorphisms elevate AD risk, and >80% of human CR1 is vested in erythrocytes to subserve immune adherence. The present results suggest that this pathway is pathophysiologically relevant in AD