Gulf War Illness: lessons from medically unexplained symptoms

Service in the Persian Gulf in 1991 is associated with increased reporting of symptoms and distress in a proportion of those who served there. Yet despite clear evidence of an increase in symptom burden and a decrease in well being, exhaustive clinical and laboratory based scientific research has failed to document many reproducible biomedical abnormalities in this group. Likewise, there has been no evidence of an increase in disease related mortality. Formal psychiatric disorders are twice as common in Gulf War veterans, as might be expected in the aftermath of any conflict, but this too is insufficient to explain the ill-health observed. Many service personnel who returned unwell believe that they have Gulf War Syndrome, and that their ill-health is due to exposures that they encountered in theatre. Research on multiple exposures to date has not generated a plausible aetiological mechanism for veterans' ill-health. Even if medical research has failed to provide a satisfactory explanation, it remains the case that many of those affected continue to be unwell and disabled some 15 years after returning from combat. For this reason, it is time that more attention is given to developing effective interventions to relieve their ill-health and distress. In this review we discuss the importance of the wider social context, individual illness beliefs and attributions and go on to outline a model of continuing ill-health in Gulf veterans. The review concludes with some suggestions for future research priorities, in particular the need for further qualitative studies to further our understanding of the illness, in order that better treatments may be developed.     

Antisense peptide-phosphorodiamidate morpholino oligomer conjugate: dose-response in mice infected with Escherichia coli

OBJECTIVES: Phosphorodiamidate morpholino oligomers (PMOs) are DNA analogues that inhibit translation by an antisense mechanism. Membrane-penetrating peptides attached to PMOs increase PMO efficacy by enhancing penetration through bacterial membranes. The objectives of these experiments are to demonstrate gene-specific efficacy and establish a dose-response relationship of a peptide-PMO conjugate. METHODS: An 11-base PMO (AcpP) targeted at acpP (an essential gene) of Escherichia coli was synthesized and conjugated with the cell-penetrating peptide RFFRFFRFFRXB (X is 6-aminohexanoic acid and B is beta-alanine). Mice were infected by intraperitoneal (i.p.) injection with K-12 E. coli W3110, and treated i.p. at 15 min and 12 h post-infection with various amounts of AcpP peptide-PMO conjugate, AcpP PMO without attached peptide, scrambled base sequence PMOs or ampicillin. A strain (LT1) of E. coli was constructed by replacing acpP with an allele that has four wobble base substitutions in the region targeted by the PMO. RESULTS: Twelve hours after a single treatment, 30 microg of AcpP peptide-PMO or 3 mg of AcpP PMO reduced bacteraemia by 3 orders of magnitude compared with treatment with water. Neither scrambled base sequence PMO controls nor 30 microg of ampicillin reduced bacteraemia. Two treatments with 30 microg of AcpP peptide-PMO reduced cfu significantly more than four treatments with 15 microg at 15 min, 4, 8 and 12 h. Mice treated with doses of AcpP peptide-PMO > 30 microg showed further reductions in plasma cfu. Survival 48 h after treatment with 2 x 30 microg (3 mg/kg) of AcpP peptide-PMO or 2 x 3 mg (300 mg/kg) of AcpP PMO was 100%, compared with 20% for mice treated with water or scrambled base sequence PMO controls. However, survival was reduced to 75% and 0% for mice treated with 2 x 300 microg and 2 x 1 mg of AcpP peptide-PMO, respectively. A conjugate made from the D-isomeric form of each amino acid was less effective than the L-amino acid equivalent, and required 2 x 300 microg treatments for significant reduction in bacteria and survival. Mice infected with LT1 and treated with AcpP peptide-PMO did not survive and had the same amount of bacteria in the blood as mice treated with water, whereas those treated with 2 x 100 microg of AcpPmut4 peptide-PMO (complementary to the mutated allele) survived, and had a 3 orders of magnitude reduction in bacteria in the blood at 24 h post-infection. CONCLUSIONS: Both AcpP peptide-PMO and AcpP PMO significantly reduced bacteraemia and promoted survival of mice infected with E. coli W3110. The conjugate was about 50-100 times more potent than the PMO without attached peptide. The L-isomeric peptide-PMO was 10 times more potent than the D-isomeric equivalent. The conjugate apparently was toxic at doses > or = 2 x 300 microg/mouse (30 mg/kg). PMOs produced a sequence-specific antibiotic effect and the conjugate had a therapeutic index (toxic dose/effective dose) approximately equal to 10 in a mouse model of infection.     

ERG Protein Expression in Diagnostic Specimens Is Associated with Increased Risk of Progression During Active Surveillance for Prostate Cancer

Background

Compelling biomarkers identifying prostate cancer patients with a high risk of progression during active surveillance (AS) are needed.

Objective

To examine the association between ERG expression at diagnosis and the risk of progression during AS.

Design, setting, and participants

This study included 265 patients followed on AS with prostate-specific antigen (PSA) measurements, clinical examinations, and 10–12 core rebiopsies from 2002 to 2012 in a prospectively maintained database. ERG immunohistochemical staining was performed on diagnostic paraffin-embedded formalin-fixed sections with a ready-to-use kit (anti-ERG, EPR3864). Men were characterised as ERG positive if a minimum of one tumour focus demonstrated ERG expression.

Outcome measurements and statistical analysis

Overall AS progression was defined as clinical progression: increased clinical tumour category ≥cT2b by digital rectal examination and ultrasound, and/or histopathologic progression: upgrade of Gleason score, more than three positive cores or bilateral positive cores, and/or PSA progression: PSA doubling time <3 yr. Risk of progression was analysed using multiple cause-specific Cox regression and stratified cumulative incidences (Aalen-Johansen method). Curatively intended treatment, watchful waiting, and death without progression were treated as competing events.

Results and limitations

A total of 121 of 142 ERG-negative and 96 of 123 ERG-positive patients had complete diagnostic information. In competing risk models, the ERG-positive group showed significantly higher incidences of overall AS progression (p < 0.0001) and of the subgroups PSA progression (p < 0.0001) and histopathologic progression (p < 0.0001). The 2-yr cumulative incidence of overall AS progression was 21.7% (95% confidence interval [CI], 14.3–29.1) in the ERG-negative group compared with 58.6% (95% CI, 48.7–68.5) in the ERG-positive group. ERG positivity was a significant predictor of overall AS progression in multiple Cox regression (hazard ratio: 2.45; 95% CI, 1.62–3.72; p < 0.0001). The main limitation of this study is its observational nature.

Conclusions

In our study, ERG positivity at diagnosis can be used to estimate the risk of progression during AS. If confirmed, ERG status can be used to individualise AS programmes.

Patient summary

The tissue biomarker ERG identifies active surveillance patients with an increased risk of disease progression.