Contribution of cuproptosis and Cu metabolism-associated genes to chronic obstructive pulmonary disease

Airway epithelial cell injury plays a crucial role in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, a novel form of Cu-induced programmed cell death known as cuproptosis has not yet been thoroughly investigated in the context of COPD. Clinical reports have suggested that high copper exposure may increase the risk of COPD. In this study, we aimed to determine the expression and potential functions of cuproptosis-related genes and genes associated with copper metabolism in COPD. We initially identified 52 copper metabolism-related genes based on a review of the literature. Subsequently, we calculated the expression levels of these genes using data from four GEO datasets. To gain insights into the activated signalling pathways and underlying mechanisms in COPD patients, we conducted Gene Ontology (GO) and KEGG pathway analyses, examined protein–protein interactions, and performed weighted correlation network analysis. Our findings revealed that 18 key copper metabolism-related genes, including 5 cuproptosis-related genes, were significantly enriched in signalling pathways and biological processes associated with the development of COPD. Further analysis of clinical data and animal experiments confirmed the high expression of certain cuproptosis key regulators, such as DLD and CDKN2A, in both healthy smokers and COPD smokers. Additionally, these regulators exhibited abnormal expression in a COPD rat model. Notably, copper content was found to be elevated in the lung tissues of COPD rats, suggesting its potential involvement in cuproptosis. These findings provide an experimental foundation for further research into the role of cuproptosis in COPD. Targeting copper metabolism-related genes may represent an effective approach for the treatment of COPD.     

Complexities of assessing the disease burden attributable to leishmaniasis

Among parasitic diseases, morbidity and mortality caused by leishmaniasis are surpassed only by malaria and lymphatic filariasis. However, estimation of the leishmaniasis disease burden is challenging, due to clinical and epidemiological diversity, marked geographic clustering, and lack of reliable data on incidence, duration, and impact of the various disease syndromes. Non-health effects such as impoverishment, disfigurement, and stigma add to the burden, and introduce further complexities. Leishmaniasis occurs globally, but has disproportionate impact in the Horn of Africa, South Asia and Brazil (for visceral leishmaniasis), and Latin America, Central Asia, and southwestern Asia (for cutaneous leishmaniasis). Disease characteristics and challenges for control are reviewed for each of these foci. We recommend review of reliable secondary data sources and collection of baseline active survey data to improve current disease burden estimates, plus the improvement or establishment of effective surveillance systems to monitor the impact of control efforts.     

Contribution to the study of periodic chronic myelogenous leukemia

The period (in the order of 40 to 80 days) in periodic chronic myelogenous leukemia (PCML) oscillations is quite long compared with the duration of the cell cycle of the hematopoietic stem cells from which the oscillations are presumed to originate (in the order of one or two days). Our objective is to understand the origin of these long-period oscillations using a G0 model for stem cell dynamics. We determine the local stability conditions and show under what conditions the Hopf bifurcation may occur. We interpret the role of each parameter in the loss of stability, and then examine a simpler model to try to deduce possible changes at the stem-cell level that might be responsible for the characteristics PCML.     

Malaria: burden of disease

Despite more than 100 years since Laveran described plasmodium species and Ross confirmed that they were transmitted by female anopheline mosquitoes, malaria remains a leading cause of morbidity and mortality worldwide. Although the areas where transmission takes place have reduced, and they are by now confined to the inter tropical areas, the number of people living at risk has grown to about 3 billion, and is expected to go on increasing. Not only does malaria cause around 500 million cases every year, and between 1 and 3 million deaths, but it also carries a huge burden that impairs the economic and social development of large parts of the planet. The failed attempt to eradicate malaria gave way to the control policy that was followed by a huge resurgence of malaria during the late 70s and 80s. Together with the emergence and spread of resistance to chloroquine and the weak health infrastructure in many of the endemic countries, particularly in Africa, the malaria situation worsened worldwide. The last decade of the 20th century was witness to the international community becoming increasingly aware of the unacceptable situation that the burden of malaria represented to large parts of the world. Renewed efforts to describe the problem, design and evaluate new control strategies, design and develop new drugs, better understand the biology of the parasite and the immunity it induces in the human host, develop candidate vaccines, together with new financial support constitute renewed hope that may lead to new trends in global health.     

Revised estimates of leprosy disability weights for assessing the global burden of disease: A systematic review and individual patient data meta-analysis

BackgroundLeprosy is a chronic bacterial infection caused by Mycobacterium leprae, which may lead to physical disability, stigma, and discrimination. The chronicity of the disease and disabilities are the prime contributors to the disease burden of leprosy. The current figures of the disease burden in the 2017 global burden of disease study, however, are considered to be under-estimated. In this study, we aimed to systematically review the literature and perform individual patient data meta-analysis to estimate new disability weights for leprosy, using Health-Related Quality of Life (HRQOL) data.Methodology/principal findingsThe search strategy included all major databases with no restriction on language, setting, study design, or year of publication. Studies on human populations that have been affected by leprosy and recorded the HRQOL with the Short form tool, were included. A consortium was formed with authors who could share the anonymous individual-level data of their study. Mean disability weight estimates, sorted by the grade of leprosy disability as defined by WHO, were estimated for individual participant data and pooled using multivariate random-effects meta-analysis. Eight out of 14 studies from the review were included in the meta-analysis due to the availability of individual-level data (667 individuals). The overall estimated disability weight for grade 2 disability was 0.26 (95%CI: 0.18–0.34). For grade 1 disability the estimated weight was 0.19 (95%CI: 0.13–0.26) and for grade 0 disability it was 0.13 (95%CI: 0.06–0.19). The revised disability weight for grade 2 leprosy disability is four times higher than the published GBD 2017 weights for leprosy and the grade 1 disability weight is nearly twenty times higher.Conclusions/significanceThe global burden of leprosy is grossly underestimated. Revision of the current disability weights and inclusion of disability caused in individuals with grade 0 leprosy disability will contribute towards a more precise estimation of the global burden of leprosy.     

Contribution of allergic inflammatory response to the pathogenesis of malaria disease

Plasmodium falciparum, the aetiological agent of human lethal malaria, is responsible for over 2 million deaths per year and malaria episodes may vary considerably in their severity and clinical manifestations. Dysregulated balance of the inflammatory response and a defect in the anti-Plasmodium parasite immune response represent the hallmarks of malaria disease. Among the many possible mechanisms, it is now widely recognized that the production of pro-inflammatory mediators and cytokines and upregulation of endothelial cell adhesion molecules play important roles in malaria pathogenesis. We and others provided evidence that some components of allergic inflammatory response to malaria parasites or elicited by by-products of parasite infection may contribute to malaria pathogenesis. This review provides some clue regarding these mechanisms where mast cells and histamine, an inflammatory mediator generated following IgE-independent or IgE-mediated immune response, were found to play a major role in parasite transmission and malaria pathogenesis, respectively. This article is part of a Special Issue entitled: Mast cells in inflammation.     

Contribution of vaccines to our understanding of pneumococcal disease

Pneumonia is the leading cause of mortality in children in developing countries and is also the leading infectious cause of death in adults. The most important cause of pneumonia is the Gram-positive bacterial pathogen, Streptococcus pneumoniae, also known as the pneumococcus. It has thus become the leading vaccine-preventable cause of death and is a successful and diverse human pathogen. The development of conjugate pneumococcal vaccines has made possible the prevention of pneumococcal disease in infants, but has also elucidated aspects of pneumococcal biology in a number of ways. Use of the vaccine as a probe has increased our understanding of the burden of pneumococcal disease in children globally. Vaccination has also elucidated the clinical spectrum of vaccine-preventable pneumococcal infections; the identification of a biological niche for multiple pneumococcal serotypes in carriage and the differential invasiveness of pneumococcal serotypes; the impact of pneumococcal transmission among children on disease burden in adults; the role of carriage as a precursor to pneumonia; the plasticity of a naturally transformable pathogen to respond to selective pressure through capsular switching and the accumulation of antibiotic-resistance determinants; and the role of pneumococcal infections in hospitalization and mortality associated with respiratory viral infections, including both seasonal and pandemic influenza. Finally, there has been a recent demonstration that pneumococcal pneumonia in children may be an important cause of hospitalization for those with underlying tuberculosis.     

NIH disease funding levels and burden of disease

Background

An analysis of NIH funding in 1996 found that the strongest predictor of funding, disability-adjusted life-years (DALYs), explained only 39% of the variance in funding. In 1998, Congress requested that the Institute of Medicine (IOM) evaluate priority-setting criteria for NIH funding; the IOM recommended greater consideration of disease burden. We examined whether the association between current burden and funding has changed since that time.

Methods

We analyzed public data on 2006 NIH funding for 29 common conditions. Measures of US disease burden in 2004 were obtained from the World Health Organization''s Global Burden of Disease study and national databases. We assessed the relationship between disease burden and NIH funding dollars in univariate and multivariable log-linear models that evaluated all measures of disease burden. Sensitivity analyses examined associations with future US burden, current and future measures of world disease burden, and a newly standardized NIH accounting method.

Results

In univariate and multivariable analyses, disease-specific NIH funding levels increased with burden of disease measured in DALYs (p = 0.001), which accounted for 33% of funding level variation. No other factor predicted funding in multivariable models. Conditions receiving the most funding greater than expected based on disease burden were AIDS ($2474 M), diabetes mellitus ($390 M), and perinatal conditions ($297 M). Depression ($719 M), injuries ($691 M), and chronic obstructive pulmonary disease ($613 M) were the most underfunded. Results were similar using estimates of future US burden, current and future world disease burden, and alternate NIH accounting methods.

Conclusions

Current levels of NIH disease-specific research funding correlate modestly with US disease burden, and correlation has not improved in the last decade.     

Contribution of tuberculosis to slim disease in Africa.

OBJECTIVES--To assess the contribution of tuberculosis to the aetiology of the HIV wasting syndrome (slim) in Africa, a condition usually considered an enteropathy. METHODS--Clinical examination and representative necropsy study of adult patients positive for HIV. SETTING--Hospital medical wards in Abidjan, Ivory Coast. SUBJECTS--Adults positive for HIV. MAIN OUTCOME MEASURES--CD4 T lymphocyte counts before death, clinical and anthropometric data, and gross and microscopic pathology. RESULTS--Necropsy was done on 212 HIV positive adults. Tuberculosis was found in 41 of 93 with the clinical HIV wasting syndrome and in 32 of 119 without (odds ratio 2.1, 95% confidence interval 1.2 to 4.0). A significant association existed between the prevalence of tuberculosis at necropsy and the degree of cadaveric wasting (no wasting 25% (15/59); moderate wasting 40% (23/58); skeletal wasting 44% (42/95); P = 0.02). Wasting was also associated with a history of chronic diarrhoea, but no association existed between diarrhoea and tuberculosis. Median CD4 T lymphocyte counts were lowest in wasted patients irrespective of findings at necropsy and in those with chronic diarrhoea (< 60 x 10(6)/l). CONCLUSION--Wasting and chronic diarrhoea are late stage manifestations of HIV disease in Africa. The importance of tuberculosis as a contributing factor in the pathogenesis of the slim syndrome has been underestimated. In nearly half of patients dying with severe wasting, tuberculosis was the dominant pathological finding.     

Contribution of an aged microenvironment to aging-associated myeloproliferative disease

The molecular and cellular mechanisms of the age-associated increase in the incidence of acute myeloid leukemia (AML) remain poorly understood. Multiple studies support that the bone marrow (BM) microenvironment has an important influence on leukemia progression. Given that the BM niche itself undergoes extensive functional changes during lifetime, we hypothesized that one mechanism for the age-associated increase in leukemia incidence might be that an aged niche promotes leukemia progression. The most frequent genetic alteration in AML is the t(8;21) translocation, resulting in the expression of the AML1-ETO fusion protein. Expression of the fusion protein in hematopoietic cells results in mice in a myeloproliferative disorder. Testing the role of the age of the niche on leukemia progression, we performed both transplantation and in vitro co-culture experiments. Aged animals transplanted with AML1-ETO positive HSCs presented with a significant increase in the frequency of AML-ETO positive early progenitor cells in BM as well as an increased immature myeloid cell load in blood compared to young recipients. These findings suggest that an aged BM microenvironment allows a relative better expansion of pre-leukemic stem and immature myeloid cells and thus imply that the aged microenvironment plays a role in the elevated incidence of age-associated leukemia.     

Contribution of T cell subsets to the pathophysiology of Pneumocystis-related immunorestitution disease

Immune-mediated lung injury is an important component of Pneumocystis pneumonia (PcP)-related immunorestitution disease (IRD). However, the individual contribution of CD4(+) and CD8(+) T cells to the pathophysiology of IRD remains undetermined. Therefore, IRD was modeled in severe combined immunodeficient mice, and specific T cell depletion was used to determine how T cell subsets interact to affect the nature and severity of disease. CD4(+) cells were more abundant than CD8(+) cells during the acute stage of IRD that coincided with impaired pulmonary physiology and organism clearance. Conversely, CD8(+) cells were more abundant during the resolution phase following P. carinii clearance. Depletion of CD4(+) T cells protected mice from the acute pathophysiology of IRD. However, these mice could not clear the infection and developed severe PcP at later time points when a pathological CD8(+) T cell response was observed. In contrast, mice depleted of CD8(+) T cells efficiently cleared the infection but developed more severe disease, an increased frequency of IFN-gamma-producing CD4(+) cells, and a prolonged CD4(+) T cell response than mice with both CD4(+) and CD8(+) cells. These data suggest that CD4(+) T cells mediate the acute respiratory disease associated with IRD. In contrast, CD8(+) T cells contributed to neither lung injury nor organism clearance when CD4(+) cells were present, but instead served to modulate CD4 function. In the absence of CD4(+) cells, CD8(+) T cells produced a nonprotective, pathological immune response. These data suggest that the interplay of CD4(+) and CD8(+) T cells affects the ultimate outcome of PcP-related IRD.