Enhanced Pseudomonas aeruginosa biofilm development mediated by human neutrophils

Cystic fibrosis (CF) lung disease features persistent neutrophil accumulation to the airways from the time of infancy. CF children are frequently exposed to Pseudomonas aeruginosa, and by adulthood, 80% of CF patients are chronically infected. The formation of biofilms is a particularly important phenotypic characteristic of P. aeruginosa that allows for bacterial survival despite aggressive antibiotic therapy and an exuberant immune response. Here, we show that the presence of neutrophils enhances initial P. aeruginosa biofilm development over a period of 72 h through the formation of polymers comprised of actin and DNA. F-actin was found to be a site of attachment for P. aeruginosa. These actin and DNA polymers are present in CF sputum, and disruption of the polymers dispersed the associated P. aeruginosa cells and reduced biofilm development. These findings demonstrate a potential maladaptation of the primary innate response. When the host fails to eradicate the infection, cellular components from necrotic neutrophils can serve as a biological matrix to facilitate P. aeruginosa biofilm formation.     

LPS binding protein is important in the airway response to inhaled endotoxin

BACKGROUND: Inhaled endotoxin is a risk factor for asthma exacerbation, and endotoxin inhalation by itself recapitulates many of the classical features of asthma in mice, including reversible airflow obstruction and inflammation, airways hyperresponsiveness, and airway remodeling. OBJECTIVE: Our objective was to determine the importance of LPS binding protein (LBP) in the response to inhaled LPS. METHODS: We challenged LBP-deficient mice (C57BL/6(LBP-/-)) and C57BL/6 mice with inhaled endotoxin for 4 hours, 5 days, or 4 weeks, followed by 3 days of recovery. RESULTS: LBP in the lung was significantly increased in LPS-exposed C57BL/6 mice from all 3 groups. Only LPS-exposed C57BL/6 mice had significantly enhanced airway responsiveness to inhaled methacholine. Total lavage cells in LPS-exposed C57BL/6(LBP-/-) mice were significantly reduced compared with those seen in LPS-exposed C57BL/6 mice; however, the percentage of PMNs was similarly increased in both the C57BL/6 and C57BL/6(LBP-/-) mice. TNF-alpha, IL-1 beta, and IL-6 protein concentrations in whole-lung lavage fluid from C57BL/6(LBP-/-) mice were also significantly reduced when compared with those seen in C57BL/6 mice. In C57BL/6(LBP-/-) mice submucosal cell proliferation was significantly reduced in the 1-week group when compared with that seen in similarly exposed C57BL/6 mice. The 4-week exposed C57BL/6 mice had significantly thickened airway submucosa and significantly increased lavaged TGF-beta(1) protein compared with that seen in C57BL/6(LBP-/-) mice. CONCLUSIONS: These findings indicate that LBP is one of the critical molecules regulating the acute and chronic airway response to inhaled LPS.     

A genetic and clinical study of individuals with nonsyndromic retinopathy consequent upon sequence variants in HGSNAT,the gene associated with Sanfilippo C mucopolysaccharidosis

Pathogenic variants in the gene HGSNAT (heparan‐α‐glucosaminide N‐acetyltransferase) have been reported to underlie two distinct recessive conditions, depending on the specific genotype, mucopolysaccharidosis type IIIC (MPSIIIC)—a severe childhood‐onset lysosomal storage disorder, and adult‐onset nonsyndromic retinitis pigmentosa (RP). Here we describe the largest cohort to‐date of HGSNAT‐associated nonsyndromic RP patients, and describe their retinal phenotype, leukocyte enzymatic activity, and likely pathogenic genotypes. We identified biallelic HGSNAT variants in 17 individuals (15 families) as the likely cause of their RP. None showed any other symptoms of MPSIIIC. All had a mild but significant reduction of HGSNAT enzyme activity in leukocytes. The retinal condition was generally of late‐onset, showing progressive degeneration of a concentric area of paramacular retina, with preservation but reduced electroretinogram responses. Symptoms, electrophysiology, and imaging suggest the rod photoreceptor to be the cell initially compromised. HGSNAT enzymatic testing was useful in resolving diagnostic dilemmas in compatible patients. We identified seven novel sequence variants [p.(Arg239Cys); p.(Ser296Leu); p.(Phe428Cys); p.(Gly248Ala); p.(Gly418Arg), c.1543‐2A>C; c.1708delA], three of which were considered to be retina‐disease‐specific alleles. The most prevalent retina‐disease‐specific allele p.(Ala615Thr) was observed heterozygously or homozygously in 8 and 5 individuals respectively (7 and 4 families). Two siblings in one family, while identical for the HGSNAT locus, but discordant for retinal disease, suggest the influence of trans‐acting genetic or environmental modifying factors.     

Breast cancer prediction and the Wolfe classification of mammograms

Mammographic parenchymal patterns have been proposed as a method of determining women at high risk of developing breast cancer. Wolfe's original report of relative risks as high as 37:1 for "dysplastic" breasts (DY) as compared with adipose breasts (N1), with intermediate values of P1 and P2, were not uniformly confirmed by others. (Relative risks are used here as the equivalent of odds ratios.) A case-control study of 706 breast cancers, each with two matching controls, drawn from 40,000 participants in four Breast Cancer Detection Demonstration Project clinics, was conducted to assess the role of the Wolfe classification of breast parenchymal patterns as a breast-cancer risk factor together with a set of well-established risk factors for breast cancer. Relative risks of 3.1 for DY to N1, 3.5 for P2 to N1, and 2.0 for P1 to N1 were determined. These are comparable to or greater than other known risk factors found in the same population. The Wolfe classification of parenchymal patterns strengthens the basis for clinical judgment, but should not be used exclusively to determine intervention in an individual patient's care.     

High density lipoprotein cholesterol is not a major risk factor for ischaemic heart disease in British men

The concentration of high density lipoprotein cholesterol (HDL cholesterol) in serum was measured at initial examination in a large prospective study of men aged 40-59 drawn from general practices in 24 British towns. After an average follow up of 4.2 years 193 cases of major ischaemic heart disease had been registered in 7415 men in whom both HDL cholesterol and total cholesterol values had been measured. The mean HDL cholesterol concentration was lower in the men with ischaemic heart disease ("cases") compared with other men, but the difference became small and non-significant after adjustment for age, body mass index, blood pressure, cigarette smoking, and concentration of non-HDL cholesterol. The higher mean concentration of non-HDL cholesterol in "cases" remained highly significant after adjustment for other factors. Men in the highest fifth of non-HDL cholesterol values had over three times the risk of major ischaemic heart disease compared with men in the lowest fifth. Multivariate analysis showed that non-HDL cholesterol was a more powerful predictor of risk than the HDL to total cholesterol ratio. These British findings were compared with six other prospective studies. All the larger studies showed similar results, suggesting that HDL cholesterol is not a major risk factor in the aetiology of ischaemic heart disease.     

Variations in Safe Sleep Practices and Beliefs: Knowledge is not Enough

Maternal and Child Health Journal - Sleep-related infant deaths in the District of Columbia (DC) varies, with rates in certain geographical areas three times higher than DC and seven times higher...     

Evaluating the Impact of a Youth-Led Sexual Violence Prevention Program: Youth Leadership Retreat Outcomes

Prevention Science - Involving youth in developing and implementing prevention programs to reduce sexual violence (SV) has the potential to improve prevention outcomes. However, there has been...     

Letter to the editor re: the effect of pelvic floor exercise program on incontinence and sexual dysfunction in multiple sclerosis patients Altunan et al., IJUN, (2021) 53:1059

International Urology and Nephrology -