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1.
medRxiv ; 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38883710

RESUMO

The causative agent of typhoid fever, Salmonella enterica serovar Typhi, is a human restricted pathogen. Human carriers, 90% of whom have gallstones in their gallbladder, continue to shed the pathogen after treatment. The genetic mechanisms involved in establishing the carrier state are poorly understood, but S. Typhi is thought to undergo specific genetic changes within the gallbladder as an adaptive mechanism. In the current study, we aimed to identify biofilm forming ability and the genetic differences in longitudinal clinical S. Typhi isolates from asymptomatic carriers with gallstones in Nairobi, Kenya. Whole genome sequences were analyzed from 22 S. Typhi isolates, 20 from stool and 2 from blood samples, all genotype 4.3.1 (H58). Nineteen strains were from four patients also diagnosed with gallstones, of whom, three had typhoid symptoms and continued to shed S. Typhi after treatment. All isolates had point mutations in the quinolone resistance determining region (QRDR) and only sub-lineage 4.3.1.2EA3 encoded multidrug resistance genes. There was no variation in antimicrobial resistance patterns among strains from the same patient/household. Non-multidrug resistant (MDR), isolates formed significantly stronger biofilms in vitro than the MDR isolates, p<0.001. A point mutation within the treB gene (treB A383T) was observed in strains isolated after clinical resolution from patients living in 75% of the households. Missense mutations in Vi capsular polysaccharide genes, tviE P263S was also observed in 18% of the isolates. This study provides insights into the role of typhoid carriage, biofilm formation, AMR genes and genetic variations in S. Typhi from asymptomatic carriers.

2.
Death Stud ; : 1-11, 2024 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-38709641

RESUMO

The present study sought to explore motivations (affective, relationships, life events, injury/medical diagnosis) in suicide notes (N = 49) from the U.S. Authors ranged in age from 18 to 74 years and were majority male (73.5%). Four raters analyzed the notes and, through a series of meetings, came to a consensus on the motives behind each note writers' suicide in terms of the broader motivational themes and the narrower second-level themes. All notes were primarily affectional in nature, with some gender and age differences. For example, suicide notes from males frequently refer to financial hardships whereas suicide notes from females were more focused on lowered self-worth and notes written by younger persons focused more on affect and relationships, while notes written by older adults focused on life events and marriage difficulties and separation. Findings illuminate the varied nature of suicide motivations but also highlight important patterns across groups.

3.
Psychol Rep ; : 332941241255323, 2024 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-38802302

RESUMO

The surge in firearm sales from the onset of the COVID-19 pandemic have been linked to increases in firearm violence, which is of public concern given that having firearms in one's home is associated with increased risk for domestic violence and suicide. Consistent with pre-pandemic trends, individuals tended to purchase firearms for self-protection during COVID-19. Prior work indicates that protective firearm ownership is motivated not only by perceptions that the world (and one's local environment) is dangerous, but also by one's endorsement of masculinity norms found in U.S. cultures of honor (primarily southern and western states). Honor-based masculinity norms emphasis reputation defense, toughness, and an absolute intolerance of disrespect. The present research examined the relative motivating influences of various threat perceptions and masculine honor endorsement in predicting reasons for non-COVID-19 firearm ownership, firearm purchasing during COVID-19, and purchase intentions. Three separate samples (total N = 2483) of mostly White U.S. men completed online surveys during different months of the first year of the COVID-19 pandemic. Participants completed measures of their endorsement of masculine honor norms, factors associated with firearm purchasing (e.g., dangerous world beliefs, intolerance of uncertainty), and firearm purchasing behaviors. Results indicated that masculine honor endorsement was higher among (1) protective firearm owners compared to non-owners and non-protective owners, (2) firearm owners who purchased a firearm during COVID-19 compared to non-owners and non-purchasing owners, and (3) firearm owners with intentions to purchase firearms in the next year compared to those without intentions and undecided owners. Relative to other predictors (e.g., COVID-19 concerns, dangerous world beliefs), masculine honor endorsement was consistently the strongest predictor of these outcomes. Findings add to the literature by highlighting the strength of masculine honor endorsement in motivating (protective) firearm ownership. Implications for interpersonal violence and suicide are discussed.

4.
Vaccine ; 42(9): 2171-2180, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38461051

RESUMO

Tularemia is caused by subspecies of Francisella tularensis and can manifest in a variety of disease states, with the pneumonic presentation resulting in the greatest mortality. Despite decades of research, there are no approved vaccines against F. tularensis in the United States. Traditional vaccination strategies, such as live-attenuated or subunit vaccines, are not favorable due to inadequate protection or safety concerns. Because of this, novel vaccination strategies are needed to combat tularemia. Here we discuss the current state of and challenges to the tularemia vaccine field and suggest novel vaccine approaches going forward that might be better suited for protecting against F. tularensis infection.


Assuntos
Francisella tularensis , Tularemia , Humanos , Tularemia/prevenção & controle , Vacinas Bacterianas/uso terapêutico , Vacinas Atenuadas , Vacinação
5.
Int J Aging Hum Dev ; : 914150231208688, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38291615

RESUMO

Using a sample of middle-aged and older adults, this research explores associations between generativity and two key risk factors for suicide: thwarted belonging (T.B.) and perceived burdensomeness (P.B.). These variables are typically studied as predictors of suicide; the current study is unique in examining their psychosocial correlates. Erikson described, generativity as a psychosocial construct that characterizes adult well-being in mid-life, conceptualized as the sense one has successfully guided and contributed to the younger generation through mentoring. Using the Midlife in the United States Survey (MIDUS), the current analyses indicate that generativity is associated with lower levels of P.B. and T.B., even after accounting for measures of hopelessness, depressive symptoms, financial stability, perceived neighborhood quality, chronic health conditions, and respondent's demographic characteristics including gender and age. Results are discussed in terms of applications for suicide-risk prevention, and with regard to the promotion of positive psychosocial development across the lifespan.

6.
Environ Toxicol Chem ; 43(4): 833-846, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38146911

RESUMO

Arsenic can accumulate in freshwater biota, sometimes reaching potentially harmful levels. However, the toxicity of arsenic strongly depends on which arsenic species are present. Although organic species are considered less harmful than inorganic ones, they have not been extensively studied in freshwater environments, and drivers of variation in arsenic speciation among sites and taxa remain unclear. We assessed concentrations of two organic arsenic species, arsenobetaine (AsB) and dimethylarsinic acid (DMA), in fish and invertebrates from three lakes near Sudbury, Ontario, Canada-a region with widespread mining impacts. Both AsB and DMA were detected in most samples (n = 212), varying across a wide range of concentrations (<0.001-30.144 and <0.006-5.262 mg/kg dry wt, respectively). The lake with the most severe mining impacts typically had the highest concentrations (designated by square brackets []) of AsB and DMA. In contrast, the percentage of total arsenic made up by AsB (%AsB) and DMA (%DMA) did not vary significantly between lakes. Arsenic speciation in fish muscle varied with fish size, selenium concentrations, and trophic elevation (inferred from nitrogen stable isotope ratios δ15N), but relationships with dietary carbon source (inferred from carbon stable isotope ratios δ13C) were more varied. Within all three lake food webs, [AsB] and [DMA] typically underwent biodilution, decreasing with trophic elevation (i.e., δ15N). Although the aforementioned factors explained some variation in arsenic speciation, there remains considerable unexplained variation. Further studies on arsenic speciation in freshwater biota should target a wider diversity of taxa to better understand drivers of variation in arsenic speciation. In addition, research emphasizing the percentage of inorganic arsenic and other organic arsenic species is needed to improve environmental and human health risk assessments. Environ Toxicol Chem 2024;43:833-846. © 2024 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.


Assuntos
Arsênio , Arsenicais , Animais , Humanos , Arsênio/análise , Cadeia Alimentar , Ácido Cacodílico , Peixes , Lagos , Ontário , Isótopos , Carbono
7.
Artigo em Inglês | MEDLINE | ID: mdl-37933468

RESUMO

BACKGROUND: Suicide rates among Black and Hispanic youth have been increasing over the past decade in the United States. The objective of this study was to identify risk factors for suicide ideation and attempt among Black and Hispanic youth in the United States using intersectionality theory and minority stress theory as a framework. METHODS: Data from the CDC Youth Risk Behavior Surveillance System (YRBSS; 2015-2019) were analyzed and delimited to include only Black and Hispanic youth. RESULTS: About 37% of the subsample identified as Black and 63% of the subsample identified as Hispanic; mean age was 16 years (SE = 0.02). Weighted multivariate logistic regressions were used to explore associations between suicide ideation and attempt, depressive symptoms, bullying, dating violence, and being threatened with a weapon. Black and Hispanic youth who had depressive symptoms, experienced bullying, dating violence, or threatened with a weapon all had increased odds of having suicide ideation and suicide attempt. Hispanic youth had the higher odds of suicide ideation and attempt than Black youth. Girls in the study also had elevated odds of suicide ideation. CONCLUSION: This study adds to the literature on risk factors of suicide in Black and Hispanic youth and bringing to awareness the gender disparities in suicide ideation and attempt among youth.

8.
Biofilm ; 6: 100158, 2023 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-37790732

RESUMO

The ESKAPE pathogens are a group of bacteria that are a leading cause of health-care associated infections and are known to be agents of chronic, biofilm-mediated infections. These chronic bacterial infections often respond poorly to antibiotics and in some cases may require surgical intervention in order to cure the infection. As biofilms are often the critical mediator of a chronic infection, it is essential to develop therapies that target bacteria within the biofilm state. Herein, we report the development of a rapid, 96-well plate-based assay that employs conditions specific for each species to optimize biofilm production and allow for easy identification of differences in biofilm mass after treatment with anti-biofilm candidates. We used these ESKAPE-specific biofilm assays to test our previously identified Salmonella anti-biofilm small molecule compounds, JG-1 and M4, for anti-biofilm activity. The results demonstrated that JG-1 and M4 have anti-biofilm activity against Enterobacter spp., S. aureus, E. faecium, P. aeruginosa, and A. baumannii. In addition, we identified that M4 has significant antimicrobial activity against S. aureus and E. faecium at concentrations >10 µM (X µg/mL). These findings support the claim that JG-1 and M4 have broad-spectrum anti-biofilm activity, while M4 has antimicrobial activity against the Gram-positive members of the ESKAPE pathogens. Thus, these compounds have the potential to have a significant impact on treating multiple types of commonly encountered biofilm-mediated infections.

9.
Infect Immun ; 91(5): e0013523, 2023 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-37129526

RESUMO

Non-typhoidal Salmonella (NTS) serovars have a broad host range and cause gastroenteritis in humans. However, invasive NTS (iNTS) bloodstream infections have increased in the last decade, causing 60,000 deaths annually. Human-specific typhoidal Salmonella colonizes and forms biofilms on gallstones, resulting in chronic, asymptomatic infection. iNTS lineages are undergoing genomic reduction and may have adapted to person-to-person transmission via mutations in virulence, bile resistance, and biofilm formation. As such, we sought to determine the capacity of iNTS lineages for biofilm formation and the development of chronic infections in the gallbladder in our mouse model. Of the lineages tested (L1, L2, L3 and UK), only L2 and UK were defective for the rough, dry and red (RDAR) morphotype, correlating with the known bcsG (cellulose) mutation but not with csgD (curli) gene mutations. Biofilm-forming ability was assessed in vitro, which revealed a biofilm formation hierarchy of L3 > ST19 > UK > L1 = L2, which did not correlate directly with either the bcsG or the csgD mutation. By confocal microscopy, biofilms of L2 and UK had significantly less curli and cellulose, while L1 biofilms had significantly lower cellulose. All iNTS strains were able to colonize the mouse gallbladder, liver, and spleen in a similar manner, while L3 had a significantly higher bacterial load in the gallbladder and increased lethality. While there was iNTS lineage variability in biofilm formation, gallbladder colonization, and virulence in a chronic mouse model, all tested lineages were capable of colonization despite possessing biofilm-related mutations. Thus, iNTS strains may be unrecognized chronic pathogens in endemic settings.


Assuntos
Vesícula Biliar , Febre Tifoide , Camundongos , Animais , Humanos , Vesícula Biliar/microbiologia , Salmonella , Biofilmes , Celulose , Mutação
10.
Ecol Evol ; 13(1): e9725, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36636425

RESUMO

Actions to protect against biodiversity loss and climate change will require a framework that addresses synergies between these interrelated issues. In this study, we present methods for identifying areas important for the implementation of nature-based climate solutions and biodiversity conservation by intersecting high-resolution spatial data for carbon storage and landscape connectivity. We explored the spatial congruence of carbon and connectivity in Ontario, Canada and examined effectiveness of current protected areas coverage. We found a weak positive relationship between carbon stocks and landscape connectivity; however, our maps revealed large hotspots, with high values of both indices, throughout the boreal forest and northern peatlands and smaller, isolated hotspots, in the settled landscapes of the south. Location of hotspots varied depending on whether we considered forest or soil carbon. Further, our results show that current protected and conserved areas in Ontario only cover 13% of landscapes with the highest values for both carbon storage and connectivity. Protection or restoration of areas that maximize the co-benefits of carbon storage and connectivity would make significant contributions toward ambitious national targets to reduce greenhouse gas emissions and conserve biodiversity.

11.
Nat Chem Biol ; 19(4): 451-459, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36482094

RESUMO

Bacteria use two-component system (TCS) signaling pathways to sense and respond to peptides involved in host defense, quorum sensing and inter-bacterial warfare. However, little is known about the broad peptide-sensing capabilities of TCSs. In this study, we developed an Escherichia coli display method to characterize the effects of human antimicrobial peptides (AMPs) on the pathogenesis-regulating TCS PhoPQ of Salmonella Typhimurium with much higher throughput than previously possible. We found that PhoPQ senses AMPs with diverse sequences, structures and biological functions. We further combined thousands of displayed AMP variants with machine learning to identify peptide sub-domains and biophysical features linked to PhoPQ activation. Most of the newfound AMP activators induce PhoPQ in S. Typhimurium, suggesting possible roles in virulence regulation. Finally, we present evidence that PhoPQ peptide-sensing specificity has evolved across commensal and pathogenic bacteria. Our method enables new insights into the specificities, mechanisms and evolutionary dynamics of TCS-mediated peptide sensing in bacteria.


Assuntos
Proteínas de Bactérias , Escherichia coli , Humanos , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Bactérias/metabolismo , Bactérias/metabolismo , Salmonella typhimurium/metabolismo , Peptídeos Catiônicos Antimicrobianos/farmacologia , Regulação Bacteriana da Expressão Gênica
12.
Microorganisms ; 10(11)2022 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-36422346

RESUMO

Typhoid fever is caused by Salmonella enterica serovar Typhi (S. Typhi). Around 3-5% of individuals infected become chronic carriers, with the gallbladder (GB) as the predominant site of persistence. Gallstones (GS) aid in the development and maintenance of GB carriage, serving as a substrate to which Salmonellae attach and form a biofilm. This biofilm matrix protects bacteria from the host immune system and environmental stress. This shielded environment is an ideal place for the development of persister cells, a transient phenotype of a subset of cells within a population that allows survival after antibiotic treatment. Persisters can also arise in response to harsh environments such as the GB. Here we investigate if GB conditions affect the number of persisters in a Salmonella population. To simulate the chronic GB environment, we cultured biofilms in cholesterol-coated 96-well plates in the presence of ox or human bile. We then treated planktonic or biofilm Salmonella cultures with high concentrations of different antibiotics. This study suggests that biofilms provide a niche for persister cells, but GB conditions either play no role or have a negative influence on persister formation, especially after kanamycin treatment. The antibiotic target was important, as antimicrobials directed against DNA replication or the cell wall had no effect on persister cell formation. Interestingly, repeated treatment with ciprofloxacin increased the percentage of S. Typhimurium persisters in a biofilm, but this increase was abolished by GB conditions. On the other hand, repeated ciprofloxacin treatment of S. Typhi biofilms in GB conditions slightly increased the fraction of persisters. Thus, while the harsh conditions in the GB would be thought to give rise to increased persisters, therefore contributing to the development of chronic carriage, these data suggest persister cell formation is dampened in this environment.

13.
J Public Ment Health ; 21(1): 23-34, 2022 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-36185543

RESUMO

Purpose ­: Death by suicide among Black people in the USA have increased by 35.6% within the past decade. Among youth under the age of 24 years old, death by suicide among Black youth have risen substantially. Researchers have found that structural inequities (e.g. educational attainment) and state-specific variables (e.g. minimum wage, incarceration rates) may increase risk for suicide among Black people compared to White people in the USA. Given the limited understanding of how such factors systematically affect Black and White communities differently, this paper aims to examine these relationships across US states using publicly available data from 2015 to 2019. Design/methodology/approach ­: Data were aggregated from various national sources including the National Center for Education Statistics, the Department of Labor, the FBI's Crime in the US Reports and the Census Bureau. Four generalized estimating equations (GEE) models were used to examine the impact of state-level variables on suicide rates: Black adults suicide rate, Black youth (24 years and younger) suicide rate, White adult suicide rate and White youth suicide rate. Each model includes state-level hate group rates, minimum wage, violent crime rates, gross vacancy rates, and race-specific state-level poverty rates, incarceration rates and graduation rates. Findings ­: Across all GEE models, suicide rates rose between 2015-2019 (ß = 1.11 - 2.78; ß = 0.91 - 1.82; ß = 0.52 - 3.09; ß = 0.16 - 1.53). For the Black adult suicide rate, state rates increased as the proportion of Black incarceration rose (ß = 1.14) but fell as the gross housing vacancy rates increased (ß = -1.52). Among Black youth, state suicide rates rose as Black incarcerations increased (ß = 0.93). For the adult White suicide rate, state rates increased as White incarceration (ß = 1.05) and percent uninsured increased (ß = 1.83), but fell as White graduation rates increased (ß = -2.36). Finally, among White youth, state suicide rates increased as the White incarceration rate rose (ß = 0.55) and as the violent crime rate rose (ß = 0.55) but decreased as state minimum wages (ß = -0.61), White poverty rates (ß = -0.40) and graduation rates increased (ß = -0.97). Originality/value ­: This work underscores how structural factors are associated with suicide rates, and how such factors differentially impact White and Black communities.

14.
Chemosphere ; 308(Pt 1): 136140, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36041531

RESUMO

Elevated concentrations of total arsenic (As) have been reported in boreal freshwater fish in both human-impacted and relatively pristine areas. We assessed the arsenic speciation profiles in muscle tissue of six fish species (n = 300) sampled from nine locations across a remote freshwater watershed in northern Ontario, Canada, extending from inland headwater lakes to the coastal marine confluence. Of the five arsenic species measured, only arsenobetaine (AsB) and dimethylarsinic acid (DMA) were detected in these fish. Riverine fish had up to 10-fold higher total [As] when compared to lacustrine fish. On average, these riverine fish also had higher percentages of AsB (%AsB, 60 ± 26%) and lower percentages of unmeasured arsenic (%UNM, 20 ± 21%), compared to lacustrine fish (28 ± 18% and 52 ± 21% %AsB and %UNM, respectively). DMA percentages (%DMA) were relatively consistent across the watershed, averaging 20 ± 21% across all fish. We examined ecological drivers of As speciation and found that %AsB increased slightly with fish weight in large-body predatory fish, but not in forage fish or insectivores. Furthermore, %AsB was positively related to trophic elevation (inferred from δ15N) in lacustrine fish across 3 out of 4 communities and within some populations. Lastly, riverine fish with a more marine-based diet had markedly higher %AsB when compared to fish with more freshwater-based diets, indicating an effect of anadromy on arsenic speciation. Overall, knowledge on arsenic speciation in freshwater fish has been limited and these results indicate potential drivers that can be considered in future studies. Furthermore, the absence of toxic inorganic As species in these boreal fish is an important consideration for future environmental monitoring practices and risk assessments, some of which assume 10-20% of total [As] in fish is present as toxic inorganic As. Additional studies on As bioaccumulation and biotransformation are needed in freshwater systems, particularly at the base of aquatic food webs.


Assuntos
Intoxicação por Arsênico , Arsênio , Arsenicais , Animais , Arsênio/análise , Arsenicais/metabolismo , Ácido Cacodílico/metabolismo , Peixes/metabolismo , Humanos , Lagos , Músculos/química , Ontário
15.
Environ Res ; 213: 113740, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35750129

RESUMO

Fish total mercury concentration ([THg]) has been linked to various fish attributes, but the relative importance of these attributes in accounting for among-individual variation in [THg] has not been thoroughly assessed. We compared the contributions of ontogeny (age, length), growth (growth rate, body condition), and food web position (δ13C, δ15N) to among-individual variability in [THg] within populations of seven common fishes from 141 north temperate lakes. Ontogenetic factors accounted for most variation in [THg]; age was a stronger and less variable predictor than length for most species. Adding both indices of growth and food web position to these models increased explained variation (R2) in [THg] by 6-25% among species. Fish [THg] at age increased with growth rate, while fish [THg] at length decreased with growth rate, and the effect of body condition was consistently negative. Trophic elevation (inferred from δ15N) was a stronger predictor than primary production source (inferred from δ13C) for piscivores but not benthivores. Fish [THg] increased with δ15N in all species but showed a more variable relationship with δ13C. Among-individual variation in [THg] is primarily related to age or size in most temperate freshwater fishes, and effects of growth rate and food web position need to be considered in the context of these ontogenetic drivers.


Assuntos
Mercúrio , Poluentes Químicos da Água , Animais , Tamanho Corporal , Monitoramento Ambiental , Comportamento Alimentar , Peixes , Cadeia Alimentar , Lagos , Mercúrio/análise , Poluentes Químicos da Água/análise
16.
Microbiol Spectr ; 10(3): e0061922, 2022 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-35579463

RESUMO

Typhoid fever is caused primarily by the enteric microbe Salmonella enterica serovar Typhi and remains a major global health problem with approximately 14 million new infections and 136,000 fatalities annually. While there are antibiotic options available to treat the disease, the global increase in multidrug-resistant strains necessitates alternative therapeutic options. Host-targeted therapeutics present a promising anti-infective strategy against intracellular bacterial pathogens. A cell-based assay identified a compound that inhibits Salmonella proliferation in infected cells, 2-(3-hydroxypropyl)-1-(3-phenoxyphenyl)-1,2-dihydrochromeno[2,3-c]pyrrole-3,9-dione (KH-1), which is devoid of direct activity against Salmonella. The compound inhibits the growth of both antibiotic-sensitive and -resistant Salmonella strains inside macrophages and reduces lactate dehydrogenase (LDH) release from Salmonella-infected cells. Subsequent screening of KH-1 commercial analogs identified 2-(4-fluorobenzyl)-1-(3-phenoxyphenyl)-1,2-dihydrochromeno[2,3-c] pyrrole-3,9-dione (KH-1-2), which is more effective in controlling Salmonella growth inside macrophages. In vitro KH-1-2 treatment of Salmonella infection resulted in an 8- to 10-fold reduction in bacterial load in infected macrophages. In combination with suboptimal ciprofloxacin treatment, KH-1-2 further reduces Salmonella growth inside macrophages. The toxicity and efficacy of KH-1-2 in controlling Salmonella infection were examined in vivo using a mouse model of typhoid fever. No significant compound-related clinical signs and histological findings of the liver, spleen, or kidney were observed from uninfected mice that were intraperitoneally treated with KH-1-2. KH-1-2 significantly protected mice from a lethal dose of infection by an antibiotic-resistant Salmonella strain. Thus, our study provides support that this is a promising lead compound for the development of a novel host-targeted therapeutic agent to control typhoid fever. IMPORTANCESalmonella spp. cause significant morbidity and mortality worldwide. Typhoidal spp. (e.g., S. Typhi) cause a systemic disease typically treated with antibiotics. However, growing antibiotic resistance is resulting in increased treatment failures. We screened a compound library for those that would reduce Salmonella-induced macrophage toxicity, identifying compound KH-1. KH-1 has no direct effects on the bacteria but limits Salmonella survival in macrophages and protects against lethal infection in a mouse model of typhoid fever. A suboptimal concentration of ciprofloxacin worked in conjunction with the compound to further decrease Salmonella survival in macrophages. An analog (KH-1-2) was identified that possessed increased activity in vitro in macrophages and in vivo against both antibiotic-sensitive and -resistant strains. Thus, we report the identification of a lead compound that may be a useful scaffold as a host-directed antimicrobial against typhoid fever.


Assuntos
Anti-Infecciosos , Febre Tifoide , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Anti-Infecciosos/uso terapêutico , Ciprofloxacina/farmacologia , Ciprofloxacina/uso terapêutico , Humanos , Pirróis/farmacologia , Pirróis/uso terapêutico , Salmonella , Salmonella typhi , Febre Tifoide/tratamento farmacológico , Febre Tifoide/microbiologia , Febre Tifoide/prevenção & controle
17.
Eur J Med Chem ; 232: 114203, 2022 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-35219950

RESUMO

Salmonella enterica serovars cause millions of infections each year that result either in typhoid fever or salmonellosis. Among those serovars that cause typhoid fever, Salmonella enterica subspecies Typhi can form biofilms on gallstones in the gallbladders of acutely-infected patients, leading to chronic carriage of the bacterium. These biofilms are recalcitrant to antibiotic-mediated eradication, leading to chronic fecal shedding of the bacteria, which results in further disease transmission. Herein, we report the synthesis and anti-biofilm activity of a 55-member library of small molecules based upon a previously identified hit that both inhibits and disrupts S. Typhi and S. Typhimurium (a nontyphoidal model serovar for S. Typhi) biofilms. Lead compounds inhibit S. Typhimurium biofilm formation in vitro at sub-micromolar concentrations, and disperse biofilms with five-fold greater potentency than the parent compound. Three of the most promising compounds demonstrated synergy with ciprofloxacin in a murine model of chronic Salmonella carriage. This work furthers the development of effective anti-biofilm agents as a promising therapeutic avenue for the eradication of typhoidal Salmonella.


Assuntos
Ciprofloxacina , Vesícula Biliar , Animais , Antibacterianos/farmacologia , Biofilmes , Ciprofloxacina/farmacologia , Humanos , Camundongos , Salmonella typhi
18.
Death Stud ; 46(8): 1801-1806, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-33357124

RESUMO

The Interpersonal Theory of Suicide (IPTS) proposes that suicide is the result of three constructs: perceived burdensomeness, thwarted belonging, and the acquired capability for suicide. To explore the presence of these constructs in suicides, two raters read 72 summaries of biographies of famous suicide for the extent to which each construct was present. Only 11 of the 72 (15.3%) suicides were judged to have perceived burdensomeness compared to 65 (90.3%) and 48 (66.7%) for thwarted belonging and the acquired capability, respectively, indicating that a sense of burdensomeness is not commonly found in suicides.


Assuntos
Pessoas Famosas , Suicídio , Humanos , Relações Interpessoais , Teoria Psicológica , Suicídio/psicologia
19.
Focus (Am Psychiatr Publ) ; 20(2): 232-240, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37153126

RESUMO

Recently, research has reported that the rates of suicide among Black children between the ages of 5 to 12-years-old are increasing as they are now more likely to commit suicide than White children. Yet, there are very few, if any, frameworks being used by researchers to explain the risks of suicide among Black children. Suicide research has overwhelmingly been focused on White youth thus leaving a critical gap in suicide research. This conceptual paper provides an integrated framework using the Interpersonal-Psychological Theory of Suicide and Intersectionality theory, as a guide for researchers, clinicians, and practitioners to incorporate culturally appropriate techniques in their work as a way to prevent suicide among Black children. This framework highlights racial discrimination, mental health, socioeconomic status, and sexual/gender minority status to be the most preeminent, yet understudied factors leading to suicide risk among Black children in the United States. Reprinted with permission of SAGE Publications; Opara et al. J Black Stud (51:611-631), copyright 2020.

20.
J Public Health (Oxf) ; 44(3): 614-624, 2022 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-33855435

RESUMO

Firearm violence is a major public health concern in the USA with firearm suicide and homicide accounting for the majority of gun deaths. The present work seeks to explore the role of firearm legislation in reducing suicide and homicide rates. Using the State Firearm Law Database (www.statefirearmlaws.org), suicide and homicide rates were compared across the 50 US states from 1991 to 2017. A firearm regulations index was computed to represent the total number of state firearm laws. Generalized estimating equations were used to explore population-level increases or decreases in firearm regulations and their association with state suicide and homicide rates after controlling for several state-level covariates. Even after accounting for several key covariates (US region; time; gun ownership; percent of the state population that was White, Black, below the poverty line and 25 years or older with a bachelor's degree; incarceration rate, unemployment rate and divorce rate), we found that firearm laws significantly predicted state firearm suicide and homicide rates. States with greater numbers of laws had reduced suicide and homicide rates compared with those with fewer laws. The present findings point to the role of firearm legislation in curbing rates of gun violence across the USA.


Assuntos
Armas de Fogo , Prevenção do Suicídio , Ferimentos por Arma de Fogo , Homicídio , Humanos , Desemprego , Estados Unidos/epidemiologia , Ferimentos por Arma de Fogo/prevenção & controle
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