Protein Quantitative Trait Loci Analysis Identifies Genetic Variation in the Innate Immune Regulator TOLLIP in Post-Lung Transplant Primary Graft Dysfunction Risk.

The authors previously identified plasma plasminogen activator inhibitor-1 (PAI-1) level as a quantitative lung injury biomarker in primary graft dysfunction (PGD). They hypothesized that plasma levels of PAI-1 used as a quantitative trait could facilitate discovery of genetic loci important in PGD pathogenesis. A two-stage cohort study was performed. In stage 1, they tested associations of loci with PAI-1 plasma level using linear modeling. Genotyping was performed using the Illumina CVD Bead Chip v2. Loci meeting a p < 5 × 10(-4) cutoff were carried forward and tested in stage 2 for association with PGD. Two hundred ninety-seven enrollees were evaluated in stage 1. Six loci, associated with PAI-1, were carried forward to stage 2 and evaluated in 728 patients. rs3168046 (Toll interacting protein [TOLLIP]) was significantly associated with PGD (p = 0.006). The increased risk of PGD for carrying at least one copy of this variant was 11.7% (95% confidence interval 4.9-18.5%). The false-positive rate for individuals with this genotype who did not have PGD was 6.1%. Variants in the TOLLIP gene are associated with higher circulating PAI-1 plasma levels and validate for association with clinical PGD. A protein quantitative trait analysis for PGD risk prioritizes genetic variations in TOLLIP and supports a role for Toll-like receptors in PGD pathogenesis.

Gene set enrichment analysis identifies key innate immune pathways in primary graft dysfunction after lung transplantation.

We hypothesized alterations in gene expression could identify important pathways involved in transplant lung injury. Broncho alveolar lavage fluid (BALF) was sampled from donors prior to procurement and in recipients within an hour of reperfusion as part of the NIAID Clinical Trials in Organ Transplantation Study. Twenty-three patients with Grade 3 primary graft dysfunction (PGD) were frequency matched with controls based on donor age and recipient diagnosis. RNA was analyzed using the Human Gene 1.0 ST array. Normalized mRNA expression was transformed and differences between donor and postreperfusion values were ranked then tested using Gene Set Enrichment Analysis. Three-hundred sixty-two gene sets were upregulated, with eight meeting significance (familywise-error rate, FWER p-value <0.05), including the NOD-like receptor inflammasome (NLR; p < 0.001), toll-like receptors (TLR; p < 0.001), IL-1 receptor (p = 0.001), myeloid differentiation primary response gene 88 (p = 0.001), NFkB activation by nontypeable Haemophilus influenzae (p = 0.001), TLR4 (p = 0.008) and TLR 9 (p = 0.018). The top five ranked individual transcripts from these pathways based on rank metric score are predominantly present in the NLR and TLR pathways, including IL1ß (1.162), NLRP3 (1.135), IL1α (0.952), IL6 (0.931) and CCL4 (0.842). Gene set enrichment analyses implicate inflammasome-mediated and innate immune signaling pathways as key mediators of the development of PGD in lung transplant patients.

Retinoids for preventing the progression of cervical intra-epithelial neoplasia.

BACKGROUND: Invasive cervical carcinoma is preceded by a precancerous phase, cervical intra-epithelial neoplasia (CIN), which can be detected on cervical smears and confirmed by colposcopy and biopsy. Moderate and severe intra-epithelial neoplasia (CIN2 and CIN3) are treated mainly with surgery to prevent progression to invasive carcinoma. Medical methods of preventing the progression or inducing regression of CIN are needed. Retinoids are potent modulators of epithelial cell growth and differentiation and may have potential for the treatment of CIN. OBJECTIVES: To ascertain whether retinoids can cause regression or prevent progression of CIN. SEARCH STRATEGY: Cochrane Gynaecological Cancer Review Group's Specialised Register and Non-Trials Database, Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 2,2007),MEDLINE and EMBASE (June 2007). SELECTION CRITERIA: Randomized controlled trials (RCTs) and non-RCTs of retinoids for treating CIN in women. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data from the trials. Adverse effects information was also collected from the trials. MAIN RESULTS: Five RCTs comparing the efficacy of four different retinoids were identified. Two studies examined the effect on CIN2 and CIN3 of retinoids N-(4-hydroxyphenyl)retinamide (fenretinide) (Follen 2001) and 9-cis-retinoic acid (aliretinoin) (Alvarez 2003) given orally and two examined the effect of all-trans-retinoic acid given topically to the cervix (Meyskens 1994; Ruffin 2004). The fifth study investigated the use of 13-cis-retinoic acid (isotretinoin) given orally in HIV positive patients with CIN1 and condyloma (Robinson 2002).Four studies reported no significant effect of retinoids on the progression to higher grades of CIN, whilst the fifth did not report data on progression. In all studies retinoids had no significant effect on regression of CIN3. Two studies reported that retinoids were associated with regression of CIN2. One reported a greater complete regression of CIN2 over placebo, which was of borderline statistical significance, odds ratio(OR) = 0.5 (95% confidence interval (CI) 0.25 to 1.02). The other study reported a non-significant dose-related trend towards increased rates of complete and partial regression compared with placebo. One study reported a significantly worse outcome in women receiving retinoid, OR for regression = 6.00 (95% CI 1.00 to 35.91). In general, the retinoid medications were well tolerated. AUTHORS' CONCLUSIONS: The retinoids studied are not effective at causing regression of CIN3 but may have some effect on CIN2. The data on CIN1 is inadequate. Retinoids are not effective at preventing progression of CIN of any grade. At the doses given and duration of treatment studied, the retinoids were reasonably well-tolerated.

Traumatic unilateral avulsion of the anterior superior and inferior iliac spines with anterior dislocation of the hip: a case report.

A sixteen-year-old boy involved in a high-speed motor vehicle accident sustained an anterior hip dislocation and avulsion of the anterior ilium extending from the anterior superior iliac spine to the anterior inferior iliac spine. The hip was emergently reduced, and further imaging was obtained to evaluate the bony injury. Computed tomography confirmed the presence of a large displaced bony fragment representing avulsion of the anterior superior and inferior iliac spines and a smaller fragment from the reflected head of the rectus femoris. The patient underwent open reduction and internal fixation of the ilium two days after the initial injury. Postoperatively, he was allowed to bear weight as tolerated with crutches but to avoid active hip flexion. He went on to an uneventful recovery, and at last report (approximately six months after injury), he had returned to full activity. An extensive review of the literature failed to show a similar injury of ipsilateral avulsion of the anterior superior and inferior iliac spines and reflected head of the rectus femoris.

Distal radial metaphyseal forces in an extrinsic grip model: implications for postfracture rehabilitation.

The purpose of this study was to establish the relationship between force at the distal radius and power grip force of the hand, a common functional and rehabilitation maneuver. This information will provide limits of allowable grip forces during postfixation rehabilitation and guide design requirements for fixation systems. By designing a model of power grip using the extrinsic hand musculotendinous units, we were able to compare grip force with force at the distal radius. Our results show that to obtain 10 N of grip force, approximately 26.3 N of force is transmitted through the distal radius, 52.4 N is transmitted through the radius and ulna combined, and 30.0 N needs to be applied to the flexor tendons. Fifty-one percent of the total forearm force was transmitted through the distal radius in this model. If all forearm forces were transmitted through the radius, 52 N of force would be transmitted through the distal radius to obtain 10 N of grip force. The clinical application of this model suggests that since failure forces of tested distal radius fixation systems range from 55 to 825 N, rehabilitation grip force should not exceed 10 to 159 N, depending on the type of fixation.