Agricultural use of Burkholderia (Pseudomonas) cepacia: a threat to human health?

In the past 2 decades, Burkholderia cepacia has emerged as a human pathogen causing numerous outbreaks, particularly among cystic fibrosis (CF) patients. One highly transmissible strain has spread across North America and Britain, and another between hospitalized CF and non-CF patients. Meanwhile, the organism has been developed as a biopesticide for protecting crops against fungal diseases and has potential as a bioremediation agent for breaking down recalcitrant herbicides and pesticides. However, B. cepacia is inherently resistant to multiple antibiotics; selection of strains "safe" for environmental application is not at present possible phenotypically or genotypically; molecular epidemiology and phylogenetic studies demonstrate that highly transmissible strains emerge randomly; and the organism has a capacity for rapid mutation and adaptation (facilitated by numerous insertion sequences), and a large, complex genome divided into separate chromosomes. Therefore, the widespread agricultural use of B. cepacia should be approached with caution

Therapeutic immunisation of rabbits with cottontail rabbit papillomavirus (CRPV) virus-like particles (VLP) induces regression of established papillomas

There is overwhelming evidence that persistent infection with high-risk human papillomaviruses (HR-HPV) is the main risk factor for invasive cancer of the cervix. Due to this global public health burden, two prophylactic HPV L1 virus-like particles (VLP) vaccines have been developed. While these vaccines have demonstrated excellent type-specific prevention of infection by the homologous vaccine types (high and low risk HPV types), no data have been reported on the therapeutic effects in people already infected with the low-risk HPV type. In this study we explored whether regression of CRPV-induced papillomas could be achieved following immunisation of out-bred New Zealand White rabbits with CRPV VLPs. Rabbits immunised with CRPV VLPs had papillomas that were significantly smaller compared to the negative control rabbit group (P ≤ 0.05). This data demonstrates the therapeutic potential of PV VLPs in a well-understood animal model with potential important implications for human therapeutic vaccination for low-risk HPVs

Filling the intervention gap: service evaluation of an intensive nonsurgical weight management programme for severe and complex obesity

Background: Weight management including formula total diet replacement (TDR) is emerging as an effective intervention for severe and complex obesity, particularly with respect to type 2 diabetes (T2DM). However, no prospective audit and service evaluation of such programmes have been reported. Methods: Following initial feasibility piloting, the Counterweight‐Plus programme was commissioned across a variety of healthcare providers. The programme includes: Screening, TDR (formula low energy diet), food reintroduction and weight loss maintenance, all delivered by staff with 8 h of training, in‐service mentoring, ongoing specialist support and access to medical consultant expertise. Anonymised data are returned centrally for clinical evaluation. Results: Up to December 2016, 288 patients commenced the programme. Mean (SD) baseline characteristics were: age 47.5 (12.7) years, weight 128.0 (32.0) kg, body mass index 45.7 (10.1) kg m−2, n = 76 (26.5%) were male and n = 99 (34.5%) had T2DM. On an intention‐to‐treat (ITT) basis, a loss of ≥15 kg at 12 months was achieved by 48 patients, representing 22.1% of all who started and 40% of those who maintained engagement. For complete cases, mean (95% confidence interval) weight loss was 13.3 (12.1–14.4) kg at 3 months, 16.0 (14.4–17.6) kg at 6 months and 14.2 (12.1–16.3) kg at 12 months (all P < 0.001), with losses to follow‐up of 10.8%, 29.3% and 44.2%, respectively. Mean loss at 12 months by ITT analyses was: single imputation –10.5 (9.5) kg, last observation carried forward –10.9 (11.6) kg and baseline observation carried forward –7.9 (11.1) kg. The presence of diabetes had no significant impact on weight change outcomes. Conclusions: This nonsurgical approach is effective for many individuals with severe and complex obesity, representing an option before considering surgery. The results are equally effective in terms of weight loss for people with T2DM

Ethnic differences in allelic distribution of IFN-g in South African women but no link with cervical cancer

BACKGROUND: The failure of specific types of human papillomaviruses (HPV) to raise effective immune responses may be important in the pathogenesis of cervical cancer, the second most common cancer in South African women. Polymorphisms of a number of cytokine genes have been implicated in inducing susceptibility or resistance to cancers caused by infectious agents owing to their role in determining host immune response. Polymorphisms of IL-10 and IFN-γ genes are believed to influence the expression and/or secretion levels of their respective cytokines. METHODS AND RESULTS: In this study, women with histologically proven cancer of the cervix (n = 458) and hospital-based controls (n = 587) were investigated for bi-allelic -1082 (A/G) polymorphisms of IL-10 and the bi-allelic +874(A/T) polymorphisms of IFN-γ. In addition, the distributions of the allelic frequencies were stratified in both the African and mixed race population groups of South Africa. We found striking differences in the allele distribution of IFN-γ (X(2 )= 0.02) among the two ethnic groups. A significant increase in the allele distribution of the IFN-γ AA genotype was found in the African group compared to the mixed population group (OR, 0.5; 95% CI, 0.2–1.0). For IL-10 there were no significant allelic differences between the two South African ethnic groups. Furthermore, when the ethnic groups were combined the IL-10 allelic frequencies in the combined South African data were similar to those observed in an Oriental population from Southern China and in an Italian population. However, the allele frequencies of the IFN-γ genotype among the two South African ethnic groups were different when compared to an Italian Caucasoid group. While crude analysis of these data showed both statistically significantly increased and diminished risks of cervical cancer among high producers of INF-γ and low producers of IL-10 respectively, these associations were no longer significant when the data were adjusted for confounding factors. CONCLUSION: These findings demonstrate a clear correlation between ethnicity and IFN-γ polymorphism across different population groups. However, these differences in ethnicity and gene polymorphisms in the aforementioned cytokines are suggested not to influence the development of invasive cervical cancer but may represent an important susceptibility biomarker for other diseases and should be explored further

ADOLESCENT AMENORRHEA

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73937/1/j.1749-6632.1967.tb14694.x.pd

PTSD and Alcohol Use Disorders Predict the Pace of Cellular Aging

Advanced epigenetic age is associated with psychopathology and may help to explain the link between psychopathology and physical health morbidity and mortality. Using a longitudinal sample of 171 trauma-exposed Veterans, we modeled the rate of change in epigenetic age across two time points (averaging 5.58 years apart) using two epigenetic age algorithms (GrimAge and Horvath) and tested associations with posttraumatic stress disorder (PTSD), alcohol use disorder (AUD), and depression. Results showed that PTSD (β = .199) and AUD (β = .186) were associated with a quickened pace of epigenetic aging over time (ps \u3c .021). Results replicate and extend prior work and offer foundational support for identifying interventions that slow the pace of biological aging among those with psychopathology

Structural and functional characterization of Pseudomonas aeruginosa CupB chaperones

Pseudomonas aeruginosa, an important human pathogen, is estimated to be responsible for,10% of nosocomial infections worldwide. The pathogenesis of P. aeruginosa starts from its colonization in the damaged tissue or medical devices (e. g. catheters, prothesis and implanted heart valve etc.) facilitated by several extracellular adhesive factors including fimbrial pili. Several clusters containing fimbrial genes have been previously identified on the P. aeruginosa chromosome and named cup [1]. The assembly of the CupB pili is thought to be coordinated by two chaperones, CupB2 and CupB4. However, due to the lack of structural and biochemical data, their chaperone activities remain speculative. In this study, we report the 2.5 A crystal structure of P. aeruginosa CupB2. Based on the structure, we further tested the binding specificity of CupB2 and CupB4 towards CupB1 (the presumed major pilus subunit) and CupB6 (the putative adhesin) using limited trypsin digestion and strep-tactin pull-down assay. The structural and biochemical data suggest that CupB2 and CupB4 might play different, but not redundant, roles in CupB secretion. CupB2 is likely to be the chaperone of CupB1, and CupB4 could be the chaperone of CupB4:CupB5:CupB6, in which the interaction of CupB4 and CupB6 might be mediated via CupB5

Factors influencing acquisition of Burkholderia cepacia complex organisms in patients with cystic fibrosis

Burkholderia cepacia complex organisms are important transmissible pathogens found in cystic fibrosis (CF) patients. In recent years, the rates of cross-infection of epidemic strains have declined due to effective infection control efforts. However, cases of sporadic B. cepacia complex infection continue to occur in some centers. The acquisition pathways and clinical outcomes of sporadic B. cepacia complex infection are unclear. We sought to determine the patient clinical characteristics, outcomes, incidence, and genotypic relatedness for all cases of B. cepacia complex infection at two CF centers. We also sought to study the external conditions that influence the acquisition of infection. From 2001 to 2011, 67 individual organisms were cultured from the respiratory samples of 64 patients. Sixty-five percent of the patients were adults, in whom chronic infections were more common (68%) (P = 0.006). The incidence of B. cepacia complex infection increased by a mean of 12% (95% confidence interval [CI], 3 to 23%) per year. The rates of transplantation and death were similar in the incident cases who developed chronic infection compared to those in patients with chronic Pseudomonas aeruginosa infection. Multilocus sequence typing revealed 50 individual strains from 65 isolates. Overall, 85% of the patients were infected with unique strains, suggesting sporadic acquisition of infection. The yearly incidence of nonepidemic B. cepacia complex infection was positively correlated with the amount of rainfall in the two sites examined: subtropical Brisbane (r = 0.65, P = 0.031) and tropical Townsville (r = 0.82, P = 0.002). This study demonstrates that despite strict cohort segregation, new cases of unrelated B. cepacia complex infection continue to occur. These data also support an environmental origin of infection and suggest that climate conditions may be associated with the acquisition of B. cepacia complex infections

Intracellular trafficking and replication of Burkholderia cenocepacia in human cystic fibrosis airway epithelial cells

We investigated the trafficking of Burkholderia cenocepacia , an opportunistic respiratory pathogen of persons with cystic fibrosis (CF), in immortalized CF airway epithelial cells in vitro . Our results indicate that bacteria enter cells in a process involving actin rearrangement. Whereas both live and heat-killed bacteria reside transiently in early endosomes, only live bacteria escape from late endosomes to colocalize in vesicles positive for lysosomal membrane marker LAMP1, endoplasmic reticulum (ER) membrane marker calnexin, and autophagosome marker monodansylcadavarine (MDC). Twenty-four hours after infection, microcolonies of live bacteria were observed in the perinuclear area colocalizing with calnexin. In contrast, after ingestion, dead bacteria colocalized with late endosome marker Rab7, and lysosome markers LAMP1 and cathepsin D, but not with calnexin or MDC. Six to eight hours after ingestion of dead bacteria, degraded bacterial particles were observed in the cytoplasm and in vesicles positive for cathepsin D. These results indicate that live B. cenocepacia gain entry into human CF airway cells by endocytosis, escape from late endosomes to enter autophagosomes that fail to fuse with mature lysosomes, and undergo replication in the ER. This survival and replication strategy may contribute to the capacity of B. cenocepacia to persist in the lungs of infected CF patients.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75744/1/j.1462-5822.2006.00724.x.pd