Zinc Gluconate Induces Potentially Cancer Chemopreventive Activity in Barrett's Esophagus: A Phase 1 Pilot Study.

BACKGROUND: Chemopreventive effects of zinc for esophageal cancer have been well documented in animal models. This prospective study explores if a similar, potentially chemopreventive action can be seen in Barrett's esophagus (BE) in humans. AIMS: To determine if molecular evidence can be obtained potentially indicating zinc's chemopreventive action in Barrett's metaplasia. METHODS: Patients with a prior BE diagnosis were placed on oral zinc gluconate (14 days of 26.4 mg zinc BID) or a sodium gluconate placebo, prior to their surveillance endoscopy procedure. Biopsies of Barrett's mucosa were then obtained for miRNA and mRNA microarrays, or protein analyses. RESULTS: Zinc-induced mRNA changes were observed for a large number of transcripts. These included downregulation of transcripts encoding proinflammatory proteins (IL32, IL1ß, IL15, IL7R, IL2R, IL15R, IL3R), upregulation of anti-inflammatory mediators (IL1RA), downregulation of transcripts mediating epithelial-to-mesenchymal transition (EMT) (LIF, MYB, LYN, MTA1, SRC, SNAIL1, and TWIST1), and upregulation of transcripts that oppose EMT (BMP7, MTSS1, TRIB3, GRHL1). miRNA arrays showed significant upregulation of seven miRs with tumor suppressor activity (-125b-5P, -132-3P, -548z, -551a, -504, -518, and -34a-5P). Of proteins analyzed by Western blot, increased expression of the pro-apoptotic protein, BAX, and the tight junctional protein, CLAUDIN-7, along with decreased expression of BCL-2 and VEGF-R2 were noteworthy. CONCLUSIONS: When these mRNA, miRNA, and protein molecular data are considered collectively, a cancer chemopreventive action by zinc in Barrett's metaplasia may be possible for this precancerous esophageal tissue. These results and the extensive prior animal model studies argue for a future prospective clinical trial for this safe, easily-administered, and inexpensive micronutrient, that could determine if a chemopreventive action truly exists.

Ivacaftor for cystic fibrosis: An evaluation of real world utilisation and expenditure in the Irish Healthcare Setting.

In Ireland, Ivacaftor is reimbursed, on the High-Tech Drug Scheme, for the treatment of cystic fibrosis in patients age 6 years and older who have the G551D mutation. The aim of this study was to analyse the utilisation and expenditure of Ivacaftor on this scheme in the 12 month period post-reimbursement. All patients who had received Ivacaftor (regardless of General Medical Services Scheme eligibility/ineligibility) were included. A total of 140 individuals (male=74; 53%) received Ivacaftor over the defined 12 month study period (from January 2015 to December 2015 inclusive). The cohort ranged in age from 6 years to 61 years. The mean age was 22 years; a positive skew in age distribution indicated that a greater number of the cohort were in the younger age groups. No statistically significant difference was detected in the mean ages of the male and female subgroups. Drug acquisition expenditure by the Health Services Executive on Ivacaftor over the 12 month study period was €29.81 million.

Piperlongumine promotes autophagy via inhibition of Akt/mTOR signalling and mediates cancer cell death.

BACKGROUND: The Akt/mammalian target of rapamycin (mTOR) signalling pathway serves as a critical regulator of cellular growth, proliferation and survival. Akt aberrant activation has been implicated in carcinogenesis and anticancer therapy resistance. Piperlongumine (PL), a natural alkaloid present in the fruit of the Long pepper, is known to exhibit notable anticancer effects. Here we investigate the impact of PL on Akt/mTOR signalling. METHODS: We examined Akt/mTOR signalling in cancer cells of various origins including prostate, kidney and breast after PL treatment. Furthermore, cell viability after concomitant treatment with PL and the autophagy inhibitor, Chloroquine (CQ) was assessed. We then examined the efficacy of in vivo combination treatment using a mouse xenograft tumour model. RESULTS: We demonstrate for the first time that PL effectively inhibits phosphorylation of Akt target proteins in all tested cells. Furthermore, the downregulation of Akt downstream signalling resulted in decrease of mTORC1 activity and autophagy stimulation. Using the autophagy inhibitor, CQ, the level of PL-induced cellular death was significantly increased. Moreover, concomitant treatment with PL and CQ demonstrated notable antitumour effect in a xenograft mouse model. CONCLUSIONS: Our data provide novel therapeutic opportunities to mediate cancer cellular death using PL. As such, PL may afford a novel paradigm for both prevention and treatment of malignancy.

Defence Engagement (Health) between the UK and Ireland since the Good Friday Agreement in 1998.

This paper describes the range of Defence Engagement (Health) (DE(H)) activities between Northern Ireland and Ireland following the Good Friday Agreement in April 1998. Although the Agreement made provision for cross-border cooperation in health, the Omagh bombing of August 1998 energised the discussion to provide greater co-ordination of future responses to mass casualty events. The paper describes these DE(H) activities at the Strategic, Operational and Tactical levels to show the integration across these levels and between the agencies of both governments. The paper shows how a DE(H) programme can have a successful strategic effect by finding topics of mutual interest that can bring together two countries in order to provide an effective health and social care provision. This paper forms part of a special issue of BMJ Military Health dedicated to Defence Engagement (.

Practices and perspectives on advanced diagnostic and interventional bronchoscopy among pediatric pulmonologists in the United States.

INTRODUCTION: Advanced diagnostic bronchoscopy includes endobronchial ultrasound (EBUS) guided transbronchial lung and lymph node biopsies, CT navigation and robotic bronchoscopy. Interventional bronchoscopy refers to procedures performed for therapeutic purposes such as balloon dilation of the airway, tissue debulking, cryotherapy, removal of foreign bodies and insertion of endobronchial valves [1]. For adult patients, these procedures are standard of care [2, 3]. Despite a lack of formalized training, there are numerous case reports and case series describing the use of advanced diagnostic and interventional bronchoscopy techniques in children. The safety and feasibility of EBUS-TBNA, cryotherapy techniques, endobronchial valves among other techniques have been demonstrated in these publications [1, 4-9]. METHODS: We sought to better understand the current practices and perspectives on interventional and advanced bronchoscopy among pediatric pulmonologists through surveys sent to pediatric teaching hospitals across the United States. RESULTS: We received 43 responses representing 28 programs from 25 states. The highest bronchoscopy procedure volume occurred in the 0-5 years age group. Among our respondents, 31% self-identified as a pediatric interventional/advanced bronchoscopist. 79% believe that advanced and interventional training is feasible in pediatric pulmonology and 77% believe it should be offered to pediatric pulmonary fellows. DISCUSSION: This is the first study to characterize current practices and perspectives regarding advanced diagnostic and interventional bronchoscopy procedures among pediatric pulmonologists in the United States. Pediatric interventional pulmonology (IP) is in its infancy and its beginnings echo those of the adult IP where only certain centers were performing these procedures.

Audit of Ireland's first manual vacuum aspiration service.

INTRODUCTION: Manual vacuum aspiration (MVA) is a safe and effective alternative option for the management of first-trimester miscarriage, termination of pregnancy, or retained pregnancy tissue. Ireland's first MVA clinic was set up in the Rotunda Hospital in April 2020. OBJECTIVE: To identify the number of women who have undergone MVA since establishing our service, to assess the efficacy and safety of MVA in that service, and to develop local Irish studies that further support the safety of MVA, adding to the international body of evidence. METHODS: With the approval and assistance of the Clinical Audit Committee, we obtained a log of all patients who underwent MVA in the first 18 months of the service. We performed a retrospective electronic chart review using Maternal and Newborn Clinical Management System. We collected the data and preformed a descriptive analysis. RESULTS: In total, 86 women underwent MVA, 85 (98.8%) of which were successfully completed. There were no immediate procedural complications, inter-hospital transfers, or emergency electric vacuum aspiration (EVA) required. We obtained an incomplete evacuation rate of 4.7% (n = 4). CONCLUSION: We have demonstrated that the MVA service in the Rotunda Hospital is a safe, effective management option with advantages for both the patient and the healthcare system. We recommend consideration for provision of funding and resources to enable expansion of this service nationally in order to give women greater autonomy of choice in the management of early pregnancy complications and termination of pregnancy.

Validation of the Fournier's gangrene severity index in a large contemporary series.

PURPOSE: In this study we identified prognostic factors for survival and validated the accuracy of the Fournier's gangrene severity index in patients with Fournier's gangrene. MATERIALS AND METHODS: We retrospectively reviewed medical records of patients diagnosed with Fournier's gangrene between 1996 and 2006. Fournier's gangrene severity index scores were assessed using a receiver operating characteristic curve. Using an outcome variable of inpatient mortality, univariate analyses were performed using the Mann-Whitney U, chi-square and Fisher exact tests. RESULTS: A total of 68 patients (79.4% male, mean age 55.8 +/- 15.2 years) diagnosed with Fournier's gangrene met the criteria for review. The inpatient mortality rate was 10% (7 patients). The mean Fournier's gangrene severity index score for survivors was 5.4 +/- 3.5 vs 10.9 +/- 4.7 for nonsurvivors (p = 0.006). Isolated Fournier's gangrene severity index and individual laboratory parameters associated with mortality included heart rate (p = 0.05), respiratory rate (p = 0.02), serum creatinine (p = 0.03), serum bicarbonate (p = 0.001), serum lactate (p = 0.001) and serum calcium (p = 0.03). Although mean total body surface area was only suggestive of an association (p = 0.169), abdominal wall (p = 0.004) or lower extremity (p = 0.005) involvement was associated with increased mortality. Using a Fournier's gangrene severity index score threshold of 9 (sensitivity 71.4%, specificity 90%) there was a 96% survival rate in patients with a Fournier's gangrene severity index of less than 9 and a 46% mortality rate in those with a Fournier's gangrene severity index of 9 or greater (p = 0.001, OR 22, 95% CI 3.5-139.7). CONCLUSIONS: The Fournier's gangrene severity index remains an objective and simple method to quantify the extent of metabolic aberration at presentation in patients with Fournier's gangrene. A Fournier's gangrene severity index threshold value of 9 is sensitive and specific for predicting mortality in this patient population.

Microbial acceleration of aerobic pyrite oxidation at circumneutral pH.

Pyrite (FeS2 ) is the most abundant sulfide mineral on Earth and represents a significant reservoir of reduced iron and sulfur both today and in the geologic past. In modern environments, oxidative transformations of pyrite and other metal sulfides play a key role in terrestrial element partitioning with broad impacts to contaminant mobility and the formation of acid mine drainage systems. Although the role of aerobic micro-organisms in pyrite oxidation under acidic-pH conditions is well known, to date there is very little known about the capacity for aerobic micro-organisms to oxidize pyrite at circumneutral pH. Here, we describe two enrichment cultures, obtained from pyrite-bearing subsurface sediments, that were capable of sustained cell growth linked to pyrite oxidation and sulfate generation at neutral pH. The cultures were dominated by two Rhizobiales species (Bradyrhizobium sp. and Mesorhizobium sp.) and a Ralstonia species. Shotgun metagenomic sequencing and genome reconstruction indicated the presence of Fe and S oxidation pathways in these organisms, and the presence of a complete Calvin-Benson-Bassham CO2 fixation system in the Bradyrhizobium sp. Oxidation of pyrite resulted in thin (30-50 nm) coatings of amorphous Fe(III) oxide on the pyrite surface, with no other secondary Fe or S phases detected by electron microscopy or X-ray absorption spectroscopy. Rates of microbial pyrite oxidation were approximately one order of magnitude higher than abiotic rates. These results demonstrate the ability of aerobic microbial activity to accelerate pyrite oxidation and expand the potential contribution of micro-organisms to continental sulfide mineral weathering around the time of the Great Oxidation Event to include neutral-pH environments. In addition, our findings have direct implications for the geochemistry of modern sedimentary environments, including stimulation of the early stages of acid mine drainage formation and mobilization of pyrite-associated metals.

Baculovirus expression of parvovirus B19 (B19V) NS1: utility in confirming recent infection.

BACKGROUND: The presence of anti-parvovirus B19 (B19V) IgM against viral capsid proteins (VP1 and VP2) has long been used to detect recent infection. The utility of antibodies directed against B19V NS1 protein has received less attention as a serological indicator of recent infection, although anti-B19V NS1 IgG has been associated with persistent infection. OBJECTIVES: To elucidate the role of anti-B19V NS1 antibody detection in recent infection, full-length B19V NS1 was expressed and purified. The resultant antigen was used to develop both Western blot assays and microplate ELISA for the detection of NS1 antibodies. STUDY DESIGN: Serum specimens were obtained from individuals recently infected with B19V (children (n=16), adults (n=40)) and from 17 individuals with no evidence of recent B19V infection. All specimens were screened for anti-B19V NS1 IgG and IgM. RESULTS: It was observed that 68.8% (11/16) of children recently infected with B19V were anti-B19V NS1 IgG seropositive. Furthermore, 27.5% (11/40) anti-B19V VP2 IgM positive specimens also contained anti-B19V NS1 IgM when tested by ELISA, while no reactivity was observed following Western blot analysis, possibly due to the absence of conformational epitopes. CONCLUSIONS: Anti-B19V NS1 IgM detection may have utility in the confirmation of recent infection with B19V.

Minimal tumor necrosis factor receptor binding protein: optimum biological activity of a truncated p55 soluble tumor necrosis factor receptor-IgG fusion protein.

We have previously demonstrated, using expressed deletion constructs, that the fourth membrane proximal cysteine-rich repeat of the p55 TNF receptor (TNF-R) is not required for binding of tumour necrosis factor-alpha (TNF) or lymphotoxin-alpha (LT; tumour necrosis factor-beta). We and others have also shown that the soluble p55 TNF-R, rendered dimeric by fusion to an IgG backbone is extremely effective at neutralizing the harmful effects of TNF overproduction, such as in toxic shock. Here we address the question of how the TNF binding properties of the truncated TNF-R comprising the three distal cysteine-rich repeats (delta4 TNF-R), when fused with an IgG backbone, compare with those of the full length soluble receptor. We constructed several versions of the soluble delta4 TNF-R, on a complete IgG heavy chain backbone and on an IgG lacking the CH1 (first constant region) domain. The constructs were expressed with an Ig or native TNF receptor leader sequence and altered or native N terminal sequence, to compare efficiency of expression. When compared with a full length, soluble receptor Ig fusion protein, the affinity of all for TNF was identical, as were their activities in in vitro binding and cytotoxicity assays. In vivo studies showed that the delta4 and wild type fusion proteins afforded equivalent protection against LPS-induced lethality. However, the delta4 proteins exhibited a significantly lower affinity for LT, and reduced activity in LT binding and cytotoxicity assays. We conclude that the truncated TNF receptor IgG fusion protein is as effective at neutralizing TNF activity as the full length soluble receptor fusion protein. Its lower affinity for LT may make it a more selective agent in blocking the action of TNF, while causing less interference with the action of LT. Also its smaller size may make it a more useful therapeutic agent as it may be less immunogenic than the full length receptor.

Fifteen years of child drowning--a 1967-1981 analysis of all fatal cases from the Brisbane Drowning Study and an 11 year study of consecutive near-drowning cases.

A total population study of childhood fresh water drowning accidents (fatalities) for the 15 year period, 1967-1981, is reported. These data are from the ongoing Brisbane Drowning Study which has now also analysed 255 fresh water child immersions (both fatalities and near-fatalities) over the eleven year period, 1978-1981, and as such forms a consecutive unselected series for over one decade. The annual fatality (drowning) rate is 3.53 per 100,000. Details of immersion accidents by site, sex and by outcome (survivors versus fatalities) are presented. An analysis of secular trends revealed that one epidemic peak of child drownings in swimming pools and domestic baths (noted in the mid 1970s in Australia and other countries) is now passed. Evidence is presented to suggest that a vigorous education, and public awareness campaign can reduce the incidence of serious child immersion accidents by one-third. Such a campaign may have influence on all types of childhood household drownings (pools, baths, garden ponds), irrespective of site. Survival rates for unsupervised children who lose consciousness in fresh water are site-dependent, only 21% of such potential victims surviving after losing consciousness in rivers and creeks, compared with the survival rate of 65% for those in potential drowning incidents in their own backyard. Violent death continues to account for more than half of all deaths in childhood up to the age of 14 years [Gratz, 1979; Mayer, Walker and Johnson et al., 1981].(ABSTRACT TRUNCATED AT 250 WORDS)

Fatal and nonfatal accidents on the railways--a study of injuries to individuals, with particular reference to children and to nonfatal trauma.

This paper reports a five-year total population study of fatal railroad accidents involving individuals (that is, not including train crashes or derailments); and a consecutive unselected series of nonfatal isolated injuries in Queensland, Australia. There were 84 fatalities and 211 cases of significant nonfatal traumata. Fatal railway accidents involving children under 15 years of age are now more common in Australia than childhood poisonings and electrocutions. Two syndromes occur--(a) toddlers living near the tracks who simply wander onto the line; and (b) young teenage boys who are run down on level crossings, either as pedestrians or cyclists. Adult fatalities include (a) occupational deaths among railway workers (20%), (b) car-train collisions at level crossings (19%), (c) drunk pedestrians who walk into trains (17%), suicides (12%), and old folk who walk into trains (12%). Of 211 nonfatal cases studied, falls in and from both moving and stationary trains were the most common type of accident. Sudden jolting of the train (probably unpreventable) contributed to 26% of all falls. Twenty-two percent of nonfatal accidents resulted from a person being struck by a train. All persons who survived being struck by a train received serious injuries and required hospital admission. Fatalities involving adults include a high proportion of suicides. Some accidents, such as fingers being caught in windows and doors, can and are being overcome through improved design.

Hypokalemia: are elderly females more vulnerable?

This study was undertaken to evaluate the relationship between prevalence of hypokalemia and the age and sex of patients. Serum potassium concentrations of 872 patients were measured, and the prevalence of hypokalemia was compared between age and sex groups. Hypokalemia was more common in patients 65 years or older than in younger groups (P < .001), with a significantly higher frequency in female patients (P < .003). The finding was more common in elderly female patients than in elderly males (P < .002). No statistically significant difference was noted in the frequency of hypokalemia in elderly male patients compared with younger patients of either sex. The predominance of hypokalemia in elderly groups was chiefly attributable to a marked preponderance in elderly female patients over all other groups. Neither younger females nor elderly males were at increased risk. The preponderance in elderly females was not dependent on diuretic usage. It may have been due to age- and sex-associated differences in body mass composition, which result in a physiologically low total exchangeable body potassium in elderly females, placing this group at greater risk for developing hypokalemia.

Hypoxia-inducible factor signalling mechanisms in the central nervous system.

In the CNS, neurones are highly sensitive to the availability of oxygen. In conditions where oxygen availability is decreased, neuronal function can be altered, leading to injury and cell death. Hypoxia has been implicated in a number of central nervous system pathologies including stroke, head trauma and neurodegenerative diseases. Cellular responses to oxygen deprivation are complex and result in activation of short- and long-term mechanisms to conserve energy and protect cells. Failure of synaptic transmission can be observed within minutes following this hypoxia. The acute effects of hypoxia on synaptic transmission are primarily mediated by altering ion fluxes across membranes, pre-synaptic effects of adenosine and other actions at glutamatergic receptors. A more long-term feature of the response of neurones to hypoxia is the activation of transcription factors such as hypoxia-inducible factor. The activation of hypoxia-inducible factor is governed by a family of dioxygenases called hypoxia-inducible factor prolyl 4 hydroxylases (PHDs). Under hypoxic conditions, PHD activity is inhibited, thereby allowing hypoxia-inducible factor to accumulate and translocate to the nucleus, where it binds to the hypoxia-responsive element sequences of target gene promoters. Inhibition of PHD activity stabilizes hypoxia-inducible factor and other proteins thus acting as a neuroprotective agent. This review will focus on the response of neuronal cells to hypoxia-inducible factor and its targets, including the prolyl hydroxylases. We also present evidence for acute effects of PHD inhibition on synaptic transmission and plasticity in the hippocampus.

Improved detection of acute parvovirus B19 infection by immunoglobulin M EIA in combination with a novel antigen EIA.

BACKGROUND AND OBJECTIVES: Although parvovirus B19 is a significant blood product contaminant, few methods other than polymerase chain reaction (PCR) have been developed to detect the presence of the virus. MATERIAL AND METHODS: A B19 antigen enzyme immunoassay (EIA) has been developed and the sensitivity of detection is ascertained using dilutions of the B19 capsid protein VP2 and 10-fold dilutions of B19 viraemic serum. Once the assay cut-off was established, a panel of viraemic donations (n = 70) was screened by the antigen EIA. The B19 immunoglobulin M (IgM) and IgG status of these specimens was also determined. During screening of blood donor units by quantitative PCR, 70 individuals were identified with levels of B19 DNA greater than 10(6) IU/ml at the time of blood donation. RESULTS: The sensitivity of the B19 antigen EIA was estimated to be equivalent to between 10(8) and 10(9) IU/ml B19 DNA or 1-10 pg/ml of recombinant capsid protein. B19 detection was significantly enhanced when viraemic specimens were pretreated with a low pH proprietary reagent. Unlike other virus-detection assays, detection of the B19 antigen was not affected by the presence of B19 IgM or IgG antibodies. In addition, the assay was capable of detecting all three genotypes of human erythrovirus. Combined specimen analysis by the B19 antigen assay and a B19 IgM assay facilitated the detection of 91% of acute B19 infections in the test population. CONCLUSION: In combination with B19 IgM detection, application of the B19 antigen EIA is a flexible and efficient method of detecting recent B19 infection and can be used as an alternative to PCR.

Establishment of functional B cell memory against parvovirus B19 capsid proteins may be associated with resolution of persistent infection.

Parvovirus B19 (B19) infection can occur during acute lymphoblastic leukemia and persistent viral infection can occur despite intravenous immunoglobulin administration. Here, evidence is presented that resolution of persistent B19 infection in an acute lymphoblastic leukemia patient may be associated with the simultaneous strengthening of antigen-specific B cell memory against the B19 capsid protein VP2 and diminution in the memory response against the B19 non-structural protein 1 (NS1). Determination of antigen-specific B cell memory status may enhance the serological and molecular analyses of persistent B19 infection.

A very basic introduction to hearing aids.

A hearing aid is designed to bring sounds, especially speech, more effectively to the ear of a person with hearing loss. Typically a person with sensorineural deafness has a raising of thresholds of hearing and the basic principles of how the aid may overcome the loss is described.

A controlled study of tinnitus masking.

As part of a multi-centre study on tinnitus maskers, a controlled study with random allocation of patients to treatment groups was performed. The two therapists subdivided the patients according to whether or not they experienced hearing difficulties in addition to their tinnitus. Those with no hearing difficulties were randomly assigned to a control group with no instrumental treatment, or to treatment with one of two types of masker. Those with hearing difficulties were assigned to hearing aid, combination instrument, or masker treatment. No significant differences were found between treatment groups for those with no hearing difficulties. The differences between treatment groups for those fitted with maskers were small, but tended to indicate increased benefit derived from maskers. A number of interesting inter-therapist effects were found.