Does anxiety moderate the effectiveness of mirtazapine in patients with treatment-resistant depression? A secondary analysis of the MIR trial

BACKGROUND: There is a lack of evidence to guide treatment of comorbid depression and anxiety. Preliminary evidence suggests mirtazapine may be effective in treating patients with both depression and anxiety symptoms. METHODS: We undertook a secondary analysis of mirtazapine (MIR): a placebo-controlled trial of the addition of mirtazapine to a selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor in treatment-resistant depression (TRD) in primary care. We subdivided participants into three groups by baseline generalized anxiety disorder score (GAD-7): severe (GAD-7 ⩾ 16), moderate (GAD-7 = 11-15), no/mild (GAD-7 ⩽ 10). We used linear regression including likelihood-ratio testing of interaction terms to assess how baseline anxiety altered the response of participants to mirtazapine as measured by 12-week GAD-7 and Beck Depression Inventory II (BDI-II) scores. RESULTS: Baseline generalized anxiety moderated mirtazapine's effect as measured by GAD-7 (p = 0.041) and BDI-II (p = 0.088) at 12 weeks. Participants with severe generalized anxiety receiving mirtazapine had lower 12-week GAD-7 score (adjusted difference between means (ADM) -2.82, 95% confidence interval (CI) -0.69 to -4.95) and larger decreases in BDI-II score (ADM -6.36, 95% CI -1.60 to -10.84) than placebo. Conversely, there was no anxiolytic benefit (ADM 0.28, 95% CI -1.05 to 1.60) or antidepressant benefit (ADM -0.17, 95% CI -3.02 to 2.68) compared with placebo in those with no/mild generalized anxiety. CONCLUSIONS: These findings extend the evidence for the effectiveness of mirtazapine to reduce generalized anxiety in TRD in primary care. These results may inform targeted prescribing in depression based on concurrent anxiety symptoms, although these conclusions are constrained by the post-hoc nature of this analysis

Eliciting a predatory response in the eastern corn snake (Pantherophis guttatus) using live and inanimate sensory stimuli: implications for managing invasive populations

North America's Eastern corn snake (Pantherophis guttatus) has been introduced to several islands throughout the Caribbean and Australasia where it poses a significant threat to native wildlife. Invasive snake control programs often involve trapping with live bait, a practice that, as well as being costly and labour intensive, raises welfare and ethical concerns. This study assessed corn snake response to live and inanimate sensory stimuli in an attempt to inform possible future trapping of the species and the development of alternative trap lures. We exposed nine individuals to sensory cues in the form of odour, visual, vibration and combined stimuli and measured the response (rate of tongue-flick [RTF]). RTF was significantly higher in odour and combined cues treatments, and there was no significant difference in RTF between live and inanimate cues during odour treatments. Our findings suggest chemical cues are of primary importance in initiating predation and that an inanimate odour stimulus, absent of simultaneous visual and vibratory cues, is a potential low-cost alternative trap lure for the control of invasive corn snake populations

Conserving, Distributing and Managing Genetically Modified Mouse Lines by Sperm Cryopreservation

Sperm from C57BL/6 mice are difficult to cryopreserve and recover. Yet, the majority of genetically modified (GM) lines are maintained on this genetic background.Reported here is the development of an easily implemented method that consistently yields fertilization rates of 70+/-5% with this strain. This six-fold increase is achieved by collecting sperm from the vas deferens and epididymis into a cryoprotective medium of 18% raffinose (w/v), 3% skim milk (w/v) and 477 microM monothioglycerol. The sperm suspension is loaded into 0.25 mL French straws and cooled at 37+/-1 degrees C/min before being plunged and then stored in LN(2). Subsequent to storage, the sperm are warmed at 2,232+/-162 degrees C/min and incubated in in vitro fertilization media for an hour prior to the addition of oocyte cumulus masses from superovulated females. Sperm from 735 GM mouse lines on 12 common genetic backgrounds including C57BL/6J, BALB/cJ, 129S1/SvImJ, FVB/NJ and NOD/ShiLtJ were cryopreserved and recovered. C57BL/6J and BALB/cByJ fertilization rates, using frozen sperm, were slightly reduced compared to rates involving fresh sperm; fertilization rates using fresh or frozen sperm were equivalent in all other lines. Developmental capacity of embryos produced using cryopreserved sperm was equivalent, or superior to, cryopreserved IVF-derived embryos.Combined, these results demonstrate the broad applicability of our approach as an economical and efficient option for archiving and distributing mice

The host metabolite D-serine contributes to bacterial niche specificity through gene selection

Escherichia coli comprise a diverse array of both commensals and niche-specific pathotypes. The ability to cause disease results from both carriage of specific virulence factors and regulatory control of these via environmental stimuli. Moreover, host metabolites further refine the response of bacteria to their environment and can dramatically affect the outcome of the host–pathogen interaction. Here, we demonstrate that the host metabolite, D-serine, selectively affects gene expression in E. coli O157:H7. Transcriptomic profiling showed exposure to D-serine results in activation of the SOS response and suppresses expression of the Type 3 Secretion System (T3SS) used to attach to host cells. We also show that concurrent carriage of both the D-serine tolerance locus (dsdCXA) and the locus of enterocyte effacement pathogenicity island encoding a T3SS is extremely rare, a genotype that we attribute to an ‘evolutionary incompatibility’ between the two loci. This study demonstrates the importance of co-operation between both core and pathogenic genetic elements in defining niche specificity

Non-invasive monitoring of Streptococcus pyogenes vaccine efficacy using biophotonic imaging.

Streptococcus pyogenes infection of the nasopharynx represents a key step in the pathogenic cycle of this organism and a major focus for vaccine development, requiring robust models to facilitate the screening of potentially protective antigens. One antigen that may be an important target for vaccination is the chemokine protease, SpyCEP, which is cell surface-associated and plays a role in pathogenesis. Biophotonic imaging (BPI) can non-invasively characterize the spatial location and abundance of bioluminescent bacteria in vivo. We have developed a bioluminescent derivative of a pharyngeal S. pyogenes strain by transformation of an emm75 clinical isolate with the luxABCDE operon. Evaluation of isogenic recombinant strains in vitro and in vivo confirmed that bioluminescence conferred a growth deficit that manifests as a fitness cost during infection. Notwithstanding this, bioluminescence expression permitted non-invasive longitudinal quantitation of S. pyogenes within the murine nasopharynx albeit with a detection limit corresponding to approximately 10(5) bacterial colony forming units (CFU) in this region. Vaccination of mice with heat killed streptococci, or with SpyCEP led to a specific IgG response in the serum. BPI demonstrated that both vaccine candidates reduced S. pyogenes bioluminescence emission over the course of nasopharyngeal infection. The work suggests the potential for BPI to be used in the non-invasive longitudinal evaluation of potential S. pyogenes vaccines

Use of Zebrafish to Probe the Divergent Virulence Potentials and Toxin Requirements of Extraintestinal Pathogenic Escherichia coli

Extraintestinal pathogenic E. coli (ExPEC) cause an array of diseases, including sepsis, neonatal meningitis, and urinary tract infections. Many putative virulence factors that might modulate ExPEC pathogenesis have been identified through sequencing efforts, epidemiology, and gene expression profiling, but few of these genes have been assigned clearly defined functional roles during infection. Using zebrafish embryos as surrogate hosts, we have developed a model system with the ability to resolve diverse virulence phenotypes and niche-specific restrictions among closely related ExPEC isolates during either localized or systemic infections. In side-by-side comparisons of prototypic ExPEC isolates, we observed an unexpectedly high degree of phenotypic diversity that is not readily apparent using more traditional animal hosts. In particular, the capacity of different ExPEC isolates to persist and multiply within the zebrafish host and cause disease was shown to be variably dependent upon two secreted toxins, α-hemolysin and cytotoxic necrotizing factor. Both of these toxins appear to function primarily in the neutralization of phagocytes, which are recruited in high numbers to sites of infection where they act as an essential host defense against ExPEC as well as less virulent E. coli strains. These results establish zebrafish as a valuable tool for the elucidation and functional analysis of both ExPEC virulence factors and host defense mechanisms

Acute and chronic kidney disease in elderly patients with hip fracture: prevalence, risk factors and outcome with development and validation of a risk prediction model for acute kidney injury

Background Hip fracture is a common injury in older people with a high rate of postoperative morbidity and mortality. This patient group is also at high risk of acute kidney injury (AKI) and chronic kidney disease (CKD), but little is known of the impact of kidney disease on outcome following hip fracture. Methods An observational cohort of consecutive patients with hip fracture in a large UK secondary care hospital. Predictive modelling of outcomes using development and validation datasets. Inclusion: all patients admitted with hip fracture with sufficient serum creatinine measurements to define acute kidney injury. Main outcome measures – development of acute kidney injury during admission; mortality (in hospital, 30-365 day and to follow-up); length of hospital stay. Results Data were available for 2848 / 2959 consecutive admissions from 2007-2011; 776 (27.2%) male. Acute kidney injury occurs in 24%; development of acute kidney injury is independently associated with male sex (OR 1.48 (1.21 to 1.80), premorbid chronic kidney disease stage 3B or worse (OR 1.52 (1.19 to 1.93)), age (OR 3.4 (2.29 to 5.2) for >85 years) and greater than one major co-morbidities (OR 1.61 (1.34 to 1.93)). Acute kidney injury of any stage is associated with an increased hazard of death, and increased length of stay (Acute kidney injury: 19.1 (IQR 13 to 31) days; no acute kidney injury 15 (11 to 23) days). A simplified predictive model containing Age, CKD stage (3B-5), two or more comorbidities, and male sex had an area under the ROC curve of 0.63 (0.60 to 0.67). Conclusions Acute kidney injury following hip fracture is common and associated with worse outcome and greater hospital length of stay. With the number of people experiencing hip fracture predicted to rise, recognition of risk factors and optimal perioperative management of acute kidney injury will become even more important

Molecular Sites for the Positive Allosteric Modulation of Glycine Receptors by Endocannabinoids

Glycine receptors (GlyRs) are transmitter-gated anion channels of the Cys-loop superfamily which mediate synaptic inhibition at spinal and selected supraspinal sites. Although they serve pivotal functions in motor control and sensory processing, they have yet to be exploited as drug targets partly because of hitherto limited possibilities for allosteric control. Endocannabinoids (ECs) have recently been characterized as direct allosteric GlyR modulators, but the underlying molecular sites have remained unknown. Here, we show that chemically neutral ECs (e.g. anandamide, AEA) are positive modulators of α1, α2 and α3 GlyRs, whereas acidic ECs (e.g. N-arachidonoyl-glycine; NA-Gly) potentiate α1 GlyRs but inhibit α2 and α3. This subunit-specificity allowed us to identify the underlying molecular sites through analysis of chimeric and mutant receptors. We found that alanine 52 in extracellular loop 2, glycine 254 in transmembrane (TM) region 2 and intracellular lysine 385 determine the positive modulation of α1 GlyRs by NA-Gly. Successive substitution of non-conserved extracellular and TM residues in α2 converted NA-Gly-mediated inhibition into potentiation. Conversely, mutation of the conserved lysine within the intracellular loop between TM3 and TM4 attenuated NA-Gly-mediated potentiation of α1 GlyRs, without affecting inhibition of α2 and α3. Notably, this mutation reduced modulation by AEA of all three GlyRs. These results define molecular sites for allosteric control of GlyRs by ECs and reveal an unrecognized function for the TM3-4 intracellular loop in the allosteric modulation of Cys-loop ion channels. The identification of these sites may help to understand the physiological role of this modulation and facilitate the development of novel therapeutic approaches to diseases such as spasticity, startle disease and possibly chronic pain