Publications

Stress exacerbates both experimental and clinical pain, most well-characterized in irritable bowel and fibromyalgia syndromes. Since it has been hypothesized that cytokines play an etiopathogenic role in fibromyalgia and other chronic widespread pain conditions, we investigated the relationship between stress and cytokines in a model of stress-induced chronic somatic pain. A series of experiments were performed to evaluate the impact of stress on the hyperalgesia-induced by endotoxin (lipopolysaccharide, LPS) and the role of two pro-inflammatory cytokines, interleukin-6 (IL-6) and tumor necrosis α (TNFα). Fourteen days after exposure to a 4-day protocol of unpredictable sound stress, the ability of systemic LPS (100 μg/kg, i.p) to elicit cytokine-mediated mechanical hyperalgesia was measured in gastrocnemius muscle. LPS-induced hyperalgesia was significantly greater in stressed rats, but when rats were treated intrathecally with antisense oligodeoxynucleotide (ODN), to decrease either the gp130 subunit of the IL-6 receptor or the TNFα receptor, in nociceptors, skeletal muscle hyperalgesia in sound stressed, but not control, rats was prevented. These data suggest that chronic stress alters signaling in the primary afferent nociceptor for the hyperalgesia induced by endogenously produced pro-inflammatory cytokines.

Many viruses have developed mechanisms to evade the IFN response. Here, HIV-1 was shown to induce a distinct subset of IFN-stimulated genes (ISGs) in monocyte-derived dendritic cells (DCs), without detectable type I or II IFN. These ISGs all contained an IFN regulatory factor 1 (IRF-1) binding site in their promoters, and their expression was shown to be driven by IRF-1, indicating this subset was induced directly by viral infection by IRF-1. IRF-1 and -7 protein expression was enriched in HIV p24 antigen-positive DCs. A HIV deletion mutant with the IRF-1 binding site deleted from the long terminal repeat showed reduced growth kinetics. Early and persistent induction of IRF-1 was coupled with sequential transient up-regulation of its 2 inhibitors, IRF-8, followed by IRF-2, suggesting a mechanism for IFN inhibition. HIV-1 mutants with Vpr deleted induced IFN, showing that Vpr is inhibitory. However, HIV IFN inhibition was mediated by failure of IRF-3 activation rather than by its degradation, as in T cells. In contrast, herpes simplex virus type 2 markedly induced IFNβ and a broader range of ISGs to higher levels, supporting the hypothesis that HIV-1 specifically manipulates the induction of IFN and ISGs to enhance its noncytopathic replication in DCs.

BACKGROUND

A patent foramen ovale (PFO) is a risk factor for cerebral events such as cryptogenic stroke, transient ischemic attacks, and migraine headaches. Far less commonly, PFO is associated with non-cerebral, paradoxical systemic embolic events such as myocardial infarction (MI), renal infarct, and limb ischemia. This report details the incidence of systemic paradoxical emboli at our institution.

METHODS

416 patients were referred for evaluation of PFO related conditions from 2001 to 2009. Clinical history and medical records of the patients were reviewed for incidence of cryptogenic stroke, transient ischemic attack (TIA), migraine headache, arterial desaturation, and noncerebral systemic embolism.

RESULTS

As the primary presenting symptom, 219 patients had a diagnosis of cryptogenic stroke, 38 patients had migraine headaches, and 80 patients had transient neurologic deficits consistent with a TIA or complex headache. Twelve patients (2.9% of the total population) presented with a presumptive diagnosis of systemic embolism. Eight of these patients had acute MI diagnosed by elevated cardiac biomarkers, electrocardiogram changes, and/or imaging evidence of a left ventricular wall motion abnormality, without evidence of obstructive coronary disease on angiography. Four patients had evidence of peripheral embolism to a systemic artery, including the popliteal artery, ophthalmic artery, and brachial artery. PFO closure was performed in 197 patients (47.4% of the total population), including eight patients in the systemic embolism group. All closure procedures were successful.

CONCLUSION

Although most paradoxical emboli travel to the brain, noncerebral paradoxical embolism is also associated with PFO. In addition to embolism of thrombus, there may be paradoxical passage of vasoactive chemicals that induce intense coronary spasm and myocardial infarction. Diagnosis is often challenging, given the lack of definitive criteria and the need to exclude other potential etiologies.

BACKGROUND

Colonoscopy insertion is difficult to teach due to the inability of current training models to provide realistic tactile sensation with simultaneous three-dimensional (3D) colonoscope display.

AIMS

To assess the influence of a simulator consisting of a colon model coupled with 3D instrument visualization on trainee colonoscopy performance.

METHODS

Pilot study using the simulator model with three trainees who were not proficient in colonoscopy. At random times over a 6-week period, trainees participated in an individualized half-day session using the Colonoscope Training Model and a colonoscope equipped with a 3D magnetic probe imaging system (ScopeGuide) in six standardized cases. A blinded supervising instructor graded patient-based colonoscopy performance over the 6-week period, and we independently analyzed the 2-week period before and after the intervention. We also measured cecal intubation and withdrawal times and medication requirements.

RESULTS

Trainees performed 86 patient-based colonoscopies. Following the intervention, the colonoscopy performance score improved from 4.4 ± 2.3 to 5.9 ± 2.4 (p = 0.005). Trainees had a 76% cecal intubation rate following the session as compared to 43% before training (p = 0.004), while utilizing less time, 14 ± 7 versus 18 ± 11 min (p = 0.056) and less medication (p > 0.05).

CONCLUSIONS

Colonoscopy simulation using the Colonoscope Training Model and the ScopeGuide produced an immediate and large effect on trainee colonoscopy performance.

BACKGROUND

The transmission of sexually transmitted infections (STIs) is closely related to the sexual transmission of human immunodeficiency virus (HIV). Similar risk behaviours, such as frequent unprotected intercourse with different partners, place people at high risk of HIV and STIs, and there is clear evidence that many STIs increase the likelihood of HIV transmission. STI control, especially at the population or community level, may have the potential to contribute substantially to HIV prevention.This is an update of an existing Cochrane review. The review's search methods were updated and its inclusion and exclusion criteria modified so that the focus would be on one well-defined outcome. This review now focuses explicitly on population-based biomedical interventions for STI control, with change in HIV incidence being an outcome necessary for a study's inclusion.

OBJECTIVES

To determine the impact of population-based biomedical STI interventions on the incidence of HIV infection.

SEARCH STRATEGY

We searched PubMed, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science/Social Science, PsycINFO, and Literatura Latino Americana e do Caribe em Ciências da Saúde (LILACS), for the period of 1 January1980 - 16 August 2010. We initially identified 6003 articles and abstracts. After removing 776 duplicates, one author (TH) removed an additional 3268 citations that were clearly irrelevant. Rigorously applying the inclusion criteria, three authors then independently screened the remaining 1959 citations and abstracts. Forty-six articles were chosen for full-text scrutiny by two authors. Ultimately, four studies were included in the review.We also searched the Aegis database of conference abstracts, which includes the Conference on Retroviruses and Opportunistic Infections (CROI), the International AIDS Conference (IAC), and International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS) meetings from their inception dates (1993, 1985 and 2001, respectively) through 2007. We manually searched the web sites of those conferences for more recent abstracts (up to 2010, 2010 and 2009, respectively)  In addition to searching the clinical trials registry at the US National Institutes of Health, we also used the metaRegister of Controlled Trials.We checked the reference lists of all studies identified by the above methods.

SELECTION CRITERIA

Randomised controlled trials involving one or more biomedical interventions in general populations (as opposed to occupationally or behaviourally defined groups, such as sex workers) in which the unit of randomisation was either a community or a treatment facility and in which the primary outcome was incident HIV infection. The term "community" was interpreted to include a group of villages, an arbitrary geographical division, or the catchment population of a group of health facilities.

DATA COLLECTION AND ANALYSIS

Three authors (BN, LB, TH) independently applied the inclusion criteria to potential studies, with any disagreements resolved by discussion. Trials were examined for completeness of reporting. Data were abstracted independently using a standardised abstraction form.

MAIN RESULTS

We included four trials. One trial evaluated mass treatment of all individuals in a particular community. The other three trials evaluated various combinations of improved syndromic STI management in clinics, STI counselling, and STI treatment.In the mass treatment trial in rural southwestern Uganda, after three rounds of treatment of all community members for STIs, the adjusted rate ratio (aRR) of incident HIV infection was 0.97 (95% CI 0.81 - 1.2), indicating no effect of the intervention. The three STI management intervention studies were all conducted in rural parts of Africa. One study, in northern Tanzania, showed that the incidence of HIV infection in the intervention groups (strengthened syndromic management of STIs in primary care clinics) was 1.2% compared with 1.9% in the control groups (aRR = 0.58, 95% CI 0.42 - 0.79), corresponding to a 42% reduction (95% CI 21.0% - 58.0%) in HIV incidence in the intervention group. Another study, conducted in rural southwestern Uganda, showed that the aRR of behavioural intervention and STI management compared to control on HIV incidence was 1.00 (95% CI 0.63 - 1.58). In the third STI management trial, in eastern Zimbabwe, there was no effect of the intervention on HIV incidence (aRR = 1.3, 95% CI 0.92 - 1.8). These are consistent with data from the mass treatment trial showing no intervention effect. Overall, pooling the data of the four studies showed no significant effect of any intervention (rate ratio [RR] = 0.97, 95% CI 0.78 - 1.2).Combining the mass treatment trial and one of the STI management trials, we find that there is a significant 12.0% reduction in the prevalence of syphilis for those receiving a biomedical STI intervention (RR 0.88, 95% CI 0.80 - 0.96). For gonorrhoea, we find a statistically significant 51.0% reduction in its prevalence in those receiving any of these interventions (RR 0.49, 95% CI 0.31 - 0.77). Finally, for chlamydia, we found no significant difference between any biomedical intervention and control (RR 1.03, 95% CI 0.77 - 1.4).

AUTHORS' CONCLUSIONS

We failed to confirm the hypothesis that STI control is an effective HIV prevention strategy. Improved STI treatment services were shown in one study to reduce HIV incidence in an environment characterised by an emerging HIV epidemic (low and slowly rising prevalence), where STI treatment services were poor and where STIs were highly prevalent; Incidence was not reduced in two other settings. There is no evidence for substantial benefit from a presumptive treatment intervention for all community members. There are, however, other compelling reasons why STI treatment services should be strengthened, and the available evidence suggests that when an intervention is accepted it can substantially improve quality of services provided.