Bismuth coordination networks containing deferiprone: synthesis, characterisation, stability and antibacterial activity

A series of bismuth–dicarboxylate–deferiprone coordination networks have been prepared and structurally characterised. The new compounds have been demonstrated to release the iron overload drug deferiprone on treatment with PBS and have also been shown to have antibacterial activity against H. pylori

Iron status and Helicobacter pylori infection in symptomatic children: an international multi-centered study

Objective:Iron deficiency (ID) and iron deficiency anaemia (IDA) are global major public health problems, particularly in developing countries. Whilst an association between H. pylori infection and ID/IDA has been proposed in the literature, currently there is no consensus. We studied the effects of H. pylori infection on ID/IDA in a cohort of children undergoing upper gastrointestinal endoscopy for upper abdominal pain in two developing and one developed country.Methods:In total 311 children (mean age 10.7±3.2 years) from Latin America - Belo Horizonte/Brazil (n = 125), Santiago/Chile (n = 105) - and London/UK (n = 81), were studied. Gastric and duodenal biopsies were obtained for evaluation of histology and H. pylori status and blood samples for parameters of ID/IDA.Results:The prevalence of H. pylori infection was 27.7% being significantly higher (p<0.001) in Latin America (35%) than in UK (7%). Multiple linear regression models revealed H. pylori infection as a significant predictor of low ferritin and haemoglobin concentrations in children from Latin-America. A negative correlation was observed between MCV (r = -0.26; p = 0.01) and MCH (r = -0.27; p = 0.01) values and the degree of antral chronic inflammation, and between MCH and the degree of corpus chronic (r = -0.29, p = 0.008) and active (r = -0.27, p = 0.002) inflammation.Conclusions:This study demonstrates that H. pylori infection in children influences the serum ferritin and haemoglobin concentrations, markers of early depletion of iron stores and anaemia respectively

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

The impact of immediate breast reconstruction on the time to delivery of adjuvant therapy: the iBRA-2 study

Background: Immediate breast reconstruction (IBR) is routinely offered to improve quality-of-life for women requiring mastectomy, but there are concerns that more complex surgery may delay adjuvant oncological treatments and compromise long-term outcomes. High-quality evidence is lacking. The iBRA-2 study aimed to investigate the impact of IBR on time to adjuvant therapy. Methods: Consecutive women undergoing mastectomy ± IBR for breast cancer July–December, 2016 were included. Patient demographics, operative, oncological and complication data were collected. Time from last definitive cancer surgery to first adjuvant treatment for patients undergoing mastectomy ± IBR were compared and risk factors associated with delays explored. Results: A total of 2540 patients were recruited from 76 centres; 1008 (39.7%) underwent IBR (implant-only [n = 675, 26.6%]; pedicled flaps [n = 105,4.1%] and free-flaps [n = 228, 8.9%]). Complications requiring re-admission or re-operation were significantly more common in patients undergoing IBR than those receiving mastectomy. Adjuvant chemotherapy or radiotherapy was required by 1235 (48.6%) patients. No clinically significant differences were seen in time to adjuvant therapy between patient groups but major complications irrespective of surgery received were significantly associated with treatment delays. Conclusions: IBR does not result in clinically significant delays to adjuvant therapy, but post-operative complications are associated with treatment delays. Strategies to minimise complications, including careful patient selection, are required to improve outcomes for patients

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Bismuth coordination networks containing deferiprone:synthesis, characterisation, stability and antibacterial activity

A series of bismuth-dicarboxylate-deferiprone coordination networks have been prepared and structurally characterised. The new compounds have been demonstrated to release the iron overload drug deferiprone on treatment with PBS and have also been shown to have antibacterial activity against H. pylori.</p

Characterization of Cinnamyl Alcohol Dehydrogenase of Helicobacter Pylori. An Aldehyde Dismutating Enzyme

Cinnamyl alcohol dehydrogenases (CAD; 1.1.1.195) catalyse the reversible conversion of p-hydroxycinnamaldehydes to their corresponding alcohols, leading to the biosynthesis of lignin in plants. Outside of plants their role is less defined. The gene for cinnamyl alcohol dehydrogenase from Helicobacter pylori (HpCAD) was cloned in Escherichia coli and the recombinant enzyme characterized for substrate specificity. The enzyme is a monomer of 42.5 kDa found predominantly in the cytosol of the bacterium. It is specific for NADP(H) as cofactor and has a broad substrate specificity for alcohol and aldehyde substrates. Its substrate specificity is similar to the well-characterized plant enzymes. High substrate inhibition was observed and a mechanism of competitive inhibition proposed. The enzyme was found to be capable of catalysing the dismutation of benzaldehyde to benzyl alcohol and benzoic acid. This dismutation reaction has not been shown previously for this class of alcohol dehydrogenase and provides the bacterium with a means of reducing aldehyde concentration within the cell

Helicobacter pylori-associated hypochlorhydria in children, and development of iron deficiency

Aims Acute Helicobacter pylori infection is associated with transient hypochlorhydria. In H pylori-associated atrophy, hypochlorhydria has a role in iron deficiency (ID) through changes in the physiology of iron-complex absorption. The aims were to evaluate the association between H pylori-associated hypochlorhydria and ID in children. Methods Symptomatic children (n=123) were prospectively enrolled. Blood, gastric juice and gastric biopsies were taken, respectively, for haematological analyses, pH assessment and H pylori determination, and duodenal biopsies for exclusion of coeliac disease. Stool samples were collected for parasitology/microbiology. Thirteen children were excluded following parasitology and duodenal histopathology, and five due to impaired blood analysis. Results Ten children were hypochlorhydric (pH&gt;4) and 33 were H pylori positive. In H pylori-positive children with pH&gt;4 (n=6) serum iron and transferrin saturation levels % were significantly lower (p&lt;0.01) than H pylori-positive children with pH&le;4. No differences in ferritin, or total iron binding capacity, were observed. In H pylori-negative children with pH&gt;4, iron and transferrin saturation were not significantly different from children with pH&le;4. Conclusions Low serum iron and transferrin in childhood H pylori infection is associated with hypochlorhydria. In uninfected children, hypochlorhydria was not associated with altered serum iron parameters, indicating a combination of H pylori infection and/or inflammation, and hypochlorhydria has a role in the aetiology of ID. Although H pylori-associated hypochlorhydria is transient during acute gastritis, this alters iron homeostasis with clinical impact in developing countries with a high H pylori prevalence