The impact of sperm DNA damage in assisted conception and beyond: recent advances in diagnosis and treatment

Abstract Sperm DNA damage is a useful biomarker for male infertility diagnosis and prediction of assisted reproduction outcomes.
It is associated with reduced fertilization rates, embryo quality and pregnancy rates, and higher rates of spontaneous miscarriage
and childhood diseases. This review provides a synopsis of the most recent studies from each of the authors, all of whom have major
track records in the field of sperm DNA damage in the clinical setting. It explores current laboratory tests and the accumulating body
of knowledge concerning the relationship between sperm DNA damage and clinical outcomes. The paper proceeds to discuss the
strengths, weaknesses and clinical applicability of current sperm DNA tests. Next, the biological significance of DNA damage in
the male germ line is considered. Finally, as sperm DNA damage is often the result of oxidative stress in the male reproductive tract,
the potential contribution of antioxidant therapy in the clinical management of this condition is discussed. DNA damage in human spermatozoa is an important attribute of semen quality. It should be part of the clinical work up and properly controlled trials
addressing the effectiveness of antioxidant therapy should be undertaken as a matter of urgency.

Contribution of primary motor cortex to compensatory balance reactions

Background: Rapid compensatory arm reactions represent important response strategies following an unexpected loss of balance. While it has been assumed that early corrective actions arise largely from sub-cortical networks, recent findings have prompted speculation about the potential role of cortical involvement. To test the idea that cortical motor regions are involved in early compensatory arm reactions, we used continuous theta burst stimulation (cTBS) to temporarily suppress the hand area of primary motor cortex (M1) in participants prior to evoking upper limb balance reactions in response to whole body perturbation. We hypothesized that following cTBS to the M1 hand area evoked EMG responses in the stimulated hand would be diminished. To isolate balance reactions to the upper limb participants were seated in an elevated tilt-chair while holding a stable handle with both hands. The chair was held vertical by a magnet and was triggered to fall backward unpredictably. To regain balance, participants used the handle to restore upright stability as quickly as possible with both hands. Muscle activity was recorded from proximal and distal muscles of both upper limbs.

Results: Our results revealed an impact of cTBS on the amplitude of the EMG responses in the stimulated hand muscles often manifest as inhibition in the stimulated hand. The change in EMG amplitude was specific to the target hand muscles and occasionally their homologous pairs on the non-stimulated hand with no consistent effects on the remaining more proximal arm muscles.

Conclusions: Present findings offer support for cortical contributions to the control of early compensatory arm reactions following whole-body perturbation.

Community-acquired infections and their association with myeloid malignancies

Introduction: Antigenic stimulation is a proposed aetiologic mechanism for many haematological malignancies. Limited evidence suggests that community-acquired infections may increase the risk of acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS). However, associations with other myeloid malignancies including chronic myeloid leukaemia (CML) and myeloproliferative neoplasms (MPNs) are unknown.

Materials and methods: Using the Surveillance, Epidemiology and End Result (SEER)-Medicare database, fourteen community-acquired infections were compared between myeloid malignancy patients [AML (n=8489), CML (n=3626) diagnosed 1992-2005; MDS (n=3072) and MPNs (n=2001) diagnosed 2001-2005; and controls (200,000 for AML/CML and 97,681 for MDS/MPN]. Odds ratios (ORs) and 95% confidence intervals were adjusted for gender, age and year of selection excluding infections diagnosed in the 13-month period prior to selection to reduce reverse causality.

Results: Risk of AML and MDS respectively, were significantly associated with respiratory tract infections, bronchitis (ORs 1.20 [95% CI: 1.14-1.26], 1.25 [95% CI: 1.16-1.36]), influenza (ORs 1.16 [95% CI: 1.07-1.25], 1.29 [95% CI: 1.16-1.44]), pharyngitis (ORs 1.13 [95% CI: 1.06-1.21], 1.22 [95% CI: 1.11-1.35]), pneumonia (ORs 1.28 [95% CI: 1.21-1.36], 1.52 [95% CI: 1.40-1.66]), sinusitis (ORs 1.23 [95% CI: 1.16-1.30], 1.25 [95% CI: 1.15-1.36]) as was cystitis (ORs 1.13 [95% CI: 1.07-1.18], 1.26 [95% CI: 1.17-1.36]). Cellulitis (OR 1.51 [95% CI: 1.39-1.64]), herpes zoster (OR 1.31 [95% CI: 1.14-1.50]) and gastroenteritis (OR 1.38 [95% CI: 1.17-1.64]) were more common in MDS patients than controls. For CML, associations were limited to bronchitis (OR 1.21 [95% CI: 1.12-1.31]), pneumonia (OR 1.49 [95% CI: 1.37-1.62]), sinusitis (OR 1.19 [95% CI: 1.09-1.29]) and cellulitis (OR 1.43 [95% CI: 1.32-1.55]) following Bonferroni correction. Only cellulitis (OR 1.34 [95% CI: 1.21-1.49]) remained significant in MPN patients. Many infections remained elevated when more than 6 years of preceding claims data were excluded.

Discussion: Common community-acquired infections may be important in the malignant transformation of the myeloid lineage. Differences in the aetiology of classic MPNs and other myeloid malignancies require further exploration.

Tracking down the cause of proteinuria in primary care

Proteinuria originates from the kidney and occurs as a result of injury to either the glomerulus or the renal tubule or both. It is relatively common in the general population with reported point prevalence of up to 8% but the prevalence falls to around 2% on repeated testing. Chronic glomerular injury resulting in proteinuria may be secondary to prolonged duration of diabetes or hypertension. A tubular origin of proteinuria may be associated with inflammation of renal tubules triggered by prescribed drugs or ingested toxins. In the absence of obvious clues to the cause of persistent proteinuria on history or clinical examination it is worthwhile reviewing the patient's prescribed drugs to identify any potentially nephrotoxic agents e.g. NSAIDs. NICE guidelines recommend screening for proteinuria in individuals at higher risk for chronic kidney disease (CKD). These include patients with diabetes, hypertension, cardiovascular disease, connective tissue disorders, a family history of renal disease and those prescribed potentially nephrotoxic drugs. Patients with sudden onset of lower limb oedema and associated proteinuria should have a serum albumin level measured to exclude the nephrotic syndrome. Renal tract ultrasound will measure kidney size, and detect scarring associated with chronic pyelonephritis or prior renal stone disease which can cause proteinuria.

MRI diffusion tractography study in individuals with schizotypal features: A pilot study

Diffusion tensor imaging (DTI) studies have identified changes in white matter tracts in schizophrenia patients and those at high risk of transition. Schizotypal samples represent a group on the schizophrenia continuum that share some aetiological risk factors but without the confounds of illness. The aim of the current study was to compare tract microstructural coherence as measured by
fractional anisotropy (FA) between 12 psychometrically defined schizotypes and controls. We investigated bilaterally the uncinate and arcuate fasciculi (UF and AF) via a probabilistic tractography algorithm (PICo), with FA values compared between groups. Partial correlations were also examined between measures of subclinical hallucinatory/delusional experiences and FA values. High schizotypes
were found to have significantly higher FA values in bilateral UF only, but failed to reach significance in each hemisphere. In the whole sample there was a positive correlation between increasing FA values and measures of hallucinatory experience in the right AF. These findings suggest subtle changes in microstructural coherence are present in schizotypes. Correlations between mild hallucinatory experience and increasing FA values could indicate increasing coherence could be associated with symptom formation.

In vitro bactericidal activity of diterpenoids isolated from Aframomum melegueta K.Schum against strains of Escherichia coli, Listeria monocytogenes and Staphylococcus aureus

Ethnopharmacological relevance: The ethnobotanical use of Aframomum melegueta in the treatment of urinary tract and soft tissue infection suggested that the plant has antimicrobial activity.

Materials and methods: To substantiate the folkloric claims, an acetone, 50:50 acetone:methanol and 2:1 chloroform:methanol extracts were tested against Escherichia coli K12; acetone extract and the fractions of acetone extracts were tested against Listeria monocytogenes. Bioassay-guided fractionation was performed on the extract using L. monocytogenes as the test organism to isolate the bioactive compounds which were then tested against all the other organisms.

Results: Four known labdane diterpenes (G3 and G5) were isolated for the first time from the rhizomes of A. melegueta and purified. These were tested against E. coli, L. monocytogenes, methicillin resistant Staphylococus aureus (MRSA) and S. aureus to determine antibacterial activity. The result showed that two compounds G3 and G5 exhibited more potent antibacterial activity compared to the current clinically used antibiotics ampicillin, gentamicin and vancomycin and can be potential antibacterial lead compounds. The structure of the labdane diterpenes were elucidated using nuclear magnetic resonance (NMR) spectroscopy and Mass spectrometry. A possible mode of action of the isolated compound G3 and its potential cytotoxicity towards mammalian cells were also discussed.

Conclusion: The results confirmed the presence of antibacterial compounds in the rhizomes of A. melegueta with a favourable toxicity profile which could be further optimized as antibacterial lead compounds.

Field-Isolated Genotypes of Mycobacterium bovis Vary in Virulence and Influence Case Pathology but Do Not Affect Outbreak Size

Strains of many infectious agents differ in fundamental epidemiological parameters including transmissibility, virulence and pathology. We investigated whether genotypes of Mycobacterium bovis (the causative agent of bovine tuberculosis, bTB) differ significantly in transmissibility and virulence, combining data from a nine-year survey of the genetic structure of the M. bovis population in Northern Ireland with detailed records of the cattle population during the same period. We used the size of herd breakdowns as a proxy measure of transmissibility and the proportion of skin test positive animals (reactors) that were visibly lesioned as a measure of virulence. Average breakdown size increased with herd size and varied depending on the manner of detection (routine herd testing or tracing of infectious contacts) but we found no significant variation among M. bovis genotypes in breakdown size once these factors had been accounted for. However breakdowns due to some genotypes had a greater proportion of lesioned reactors than others, indicating that there may be variation in virulence among genotypes. These findings indicate that the current bTB control programme may be detecting infected herds sufficiently quickly so that differences in virulence are not manifested in terms of outbreak sizes. We also investigated whether pathology of infected cattle varied according to M. bovis genotype, analysing the distribution of lesions recorded at post mortem inspection. We concentrated on the proportion of cases lesioned in the lower respiratory tract, which can indicate the relative importance of the respiratory and alimentary routes of infection. The distribution of lesions varied among genotypes and with cattle age and there were also subtle differences among breeds. Age and breed differences may be related to differences in susceptibility and husbandry, but reasons for variation in lesion distribution among genotypes require further investigation. © 2013 Wright et al.

A single-component multidrug transporter of the major facilitator superfamily is part of a network that protects Escherichia coli from bile salt stress

Resistance to high concentrations of bile salts in the human intestinal tract is vital for the survival of enteric bacteria such as Escherichia coli. Although the tripartite AcrAB-TolC efflux system plays a significant role in this resistance, it is purported that other efflux pumps must also be involved. We provide evidence from a comprehensive suite of experiments performed at two different pH values (7.2 and 6.0) that reflect pH conditions that E. coli may encounter in human gut that MdtM, a single-component multidrug resistance transporter of the major facilitator superfamily, functions in bile salt resistance in E. coli by catalysing secondary active transport of bile salts out of the cell cytoplasm. Furthermore, assays performed on a chromosomal ΔacrB mutant transformed with multicopy plasmid encoding MdtM suggested a functional synergism between the single-component MdtM transporter and the tripartite AcrAB-TolC system that results in a multiplicative effect on resistance. Substrate binding experiments performed on purified MdtM demonstrated that the transporter binds to cholate and deoxycholate with micromolar affinity, and transport assays performed on inverted vesicles confirmed the capacity of MdtM to catalyse electrogenic bile salt/H(+) antiport.

Trace Element Abundance and Renal Disease

This research investigates the relationship between elevated trace elements in soils, stream sediments and stream water and the prevalence of Chronic Kidney Disease (CKD). The study uses a collaboration of datasets provided from the UK Renal Registry Report (UKRR) on patients with renal diseases requiring treatment including Renal Replacement Therapy (RRT), the soil geochemical dataset for Northern Ireland provided by the Tellus Survey, Geological Survey of Northern Ireland (GSNI) and the bioaccessibility of Potentially Toxic Elements (PTEs) from soil samples which were obtained from the Unified Barge Method (UBM). The relationship between these factors derives from the UKRR report which highlights incidence rates of renal impaired patients showing regional variation with cases of unknown aetiology. Studies suggest a potential cause of the large variation and uncertain aetiology is associated with underlying environmental factors such as the oral bioaccessibility of trace elements in the gastrointestinal tract.
As previous research indicates that long term exposure is related to environmental factors, Northern Ireland is ideally placed for this research as people traditionally live in the same location for long periods of time. Exploratory data analysis and multivariate analyses are used to examine the soil, stream sediments and stream water geochemistry data for a range of key elements including arsenic, lead, cadmium and mercury identified from a review of previous renal disease literature. The spatial prevalence of patients with long term CKD is analysed on an area basis. Further work includes cluster analysis to detect areas of low or high incidences of CKD that are significantly correlated in space, Geographical Weighted Regression (GWR) and Poisson kriging to examine locally varying relationship between elevated concentrations of PTEs and the prevalence of CKD.

Biomolecular Mechanisms of Pseudomonas aeruginosa and Escherichia coli Biofilm Formation

Pseudomonas aeruginosa and Escherichia coli are the most prevalent Gram-negative biofilm forming medical device associated pathogens, particularly with respect to catheter associated urinary tract infections. In a similar manner to Gram-positive bacteria, Gram-negative biofilm formation is fundamentally determined by a series of steps outlined more fully in this review, namely adhesion, cellular aggregation, and the production of an extracellular polymeric matrix. More specifically this review will explore the biosynthesis and role of pili and flagella in Gram-negative adhesion and accumulation on surfaces in Pseudomonas aeruginosa and Escherichia coli. The process of biofilm maturation is compared and contrasted in both species, namely the production of the exopolysaccharides via the polysaccharide synthesis locus (Psl), pellicle Formation (Pel) and alginic acid synthesis in Pseudomonas aeruginosa, and UDP-4-amino-4-deoxy-l-arabinose and colonic acid synthesis in Escherichia coli. An emphasis is placed on the importance of the LuxR homologue sdiA; the luxS/autoinducer-II; an autoinducer-III/epinephrine/norepinephrine and indole mediated Quorum sensing systems in enabling Gram-negative bacteria to adapt to their environments. The majority of Gram-negative biofilms consist of polysaccharides of a simple sugar structure (either homo- or heteropolysaccharides) that provide an optimum environment for the survival and maturation of bacteria, allowing them to display increased resistance to antibiotics and predation.

Common infection-related conditions and risk of lymphoid malignancies in older individuals

Background: Chronic antigenic stimulation may initiate non-Hodgkin (NHL) and Hodgkin lymphoma (HL) development. Antecedent, infection-related conditions have been associated, but evidence by lymphoproliferative subtype is limited. Methods: From the US SEER-Medicare database, 44 191 NHL, 1832 HL and 200 000 population-based controls, frequency-matched to all SEER cancer cases, were selected. Logistic regression models, adjusted for potential confounders, compared infection-related conditions in controls with HL and NHL patients and by the NHL subtypes diffuse large B-cell, T-cell, follicular and marginal zone lymphoma (MZL). Stratification by race was undertaken. Results: Respiratory tract infections were broadly associated with NHL, particularly MZL. Skin infections were associated with a 15–28% increased risk of NHL and with most NHL subtypes, particularly cellulitis with T-cell lymphoma (OR 1.36, 95%CI 1.24–1.49). Only herpes zoster remained associated with HL following Bonferroni correction (OR 1.55, 95% CI 1.28–1.87). Gastrointestinal and urinary tract infections were not strongly associated with NHL or HL. In stratified analyses by race, sinusitis, pharyngitis, bronchitis and cellulitis showed stronger associations with total NHL in blacks than whites (P<0.001). Conclusions: Infections may contribute to the aetiologic pathway and/or be markers of underlying immune modulation. Precise elucidation of these mechanisms may provide important clues for understanding how immune disturbance contributes to lymphoma.

Community-acquired infections associated with increased risk of lymphoplasmacytic lymphoma/Waldenström macroglobulinaemia

Emerging evidence supports the role of immune stimulation in the development of lymphoplasmacytic lymphoma/Waldenström Macroglobulinaemia (LPL/WM). Using the population-based Surveillance, Epidemiology End Results-Medicare database we investigated the exposure to 14 common community-acquired infections and subsequent risk of LPL/WM in 693 LPL/WM cases and 200 000 controls. Respiratory tract infections, bronchitis [odds ratio (OR) 1·56], pharyngitis (OR 1·43), pneumonia (OR 1·42) and sinusitis (OR 1·33) and skin infection, herpes zoster (OR 1·51) were all significantly associated with subsequent increased risk of LPL/WM. For each of these infections, the findings remained significantly elevated following the exclusion of more than 6 years of Medicare claims data prior to LPL/WM diagnosis. Our findings may support a role for infections in the development of LPL/WM or could reflect an underlying immune disturbance that is present several years prior to diagnosis and thereby part of the natural history of disease progression.

The effect of inhaled IFN-β on worsening of asthma symptoms caused by viral infections. a randomized trial

Rationale: Ex vivo, bronchial epithelial cells from people with asthma are more susceptible to rhinovirus infection caused by deficient induction of the antiviral protein, IFN-b. Exogenous IFN-b restores antiviral activity.

Objectives: To compare the efficacy and safety of inhaled IFN-b with placebo administered to people with asthma after onset of cold symptoms to prevent or attenuate asthma symptoms caused by respiratory viruses.

Methods: A total of 147 people with asthma on inhaled corticosteroids (British Thoracic Society Steps 2–5), with a history of virus-associated exacerbations, were randomized to 14-day treatment with inhaled IFN-b (n = 72) or placebo (n = 75) within 24 hours of developing cold symptoms and were assessed clinically, with relevant samples collected to assess virus infection and antiviral responses.

Measurements and Main Results: A total of 91% of randomized patients developed a defined cold. In this modified intention-to-treat population, asthma symptoms did not get clinically significantly worse
(mean change in six-item Asthma Control Questionnaire ,0.5) and IFN-b treatment had no significant effect on this primary endpoint, although it enhanced morning peak expiratory flow recovery (P = 0.033), reduced the need for additional treatment, and boosted innate immunity as assessed by blood and sputum biomarkers. In an exploratory analysis of the subset ofmore difficult-to-treat, Step 4-5 peoplewith asthma (n = 27 IFN-b; n = 31 placebo), Asthma Control Questionnaire-6 increased significantly on placebo; this was prevented by IFN-b (P = 0.004).

Conclusions: Although the trial did not meet its primary endpoint, it suggests that inhaled IFN-b is a potential treatment for virus-induced deteriorations of asthma in difficult-to-treat people with asthma and supports the needforfurther, adequately powered, trialsin this population. Clinical trial registered with www.clinicaltrials.gov (NCT 01126177).

Are early life factors considered when managing respiratory disease?:A British Thoracic Society survey of current practice

We hypothesised that early life events are not routinely considered by most respiratory specialists.