Search

Summary: Aging and lipotoxicity are two major risk factors for gout that are linked by the activation of the NLRP3 inflammasome. Neutrophil-mediated production of interleukin-1β (IL-1β) drives gouty flares that cause joint destruction, intense pain, and fever. However, metabolites that impact neutrophil inflammasome remain unknown. Here, we identified that ketogenic diet (KD) increases β-hydroxybutyrate (BHB) and alleviates urate crystal-induced gout without impairing immune defense against bacterial infection. BHB inhibited NLRP3 inflammasome in S100A9 fibril-primed and urate crystal-activated macrophages, which serve to recruit inflammatory neutrophils in joints. Consistent with reduced gouty flares in rats fed a ketogenic diet, BHB blocked IL-1β in neutrophils in a NLRP3-dependent manner in mice and humans irrespective of age. Mechanistically, BHB inhibited the NLRP3 inflammasome in neutrophils by reducing priming and assembly steps. Collectively, our studies show that BHB, a known alternate metabolic fuel, is also an anti-inflammatory molecule that may serve as a treatment for gout. : NLRP3 inflammasome activation in macrophages and neutrophils drives painful inflammation during gout. Goldberg et al. report that ketogenic diet prevents systemic inflammation and joint damage in a rat model of gouty flare. Mechanistically, the ketone body β-hydroxybutyrate, the most abundant ketone in vivo, inhibits NLRP3/caspase-1-dependent IL-1β secretion from neutrophils. Keywords: NLRP3 inflammasome, gout, β-hydroxybutyrate, inflammation, aging, neutrophil, IL-1

A replication study of a previous genome-wide association study (GWAS) suggested that a SNP linked to the POLB gene is associated with systemic lupus erythematosus (SLE). This SNP is correlated with decreased expression of Pol β, a key enzyme in the base excision repair (BER) pathway. To determine whether decreased Pol β activity results in SLE, we constructed a mouse model of POLB that encodes an enzyme with slow DNA polymerase activity. We show that mice expressing this hypomorphic POLB allele develop an autoimmune pathology that strongly resembles SLE. Of note, the mutant mice have shorter immunoglobulin heavy-chain junctions and somatic hypermutation is dramatically increased. These results demonstrate that decreased Pol β activity during the generation of immune diversity leads to lupus-like disease in mice, and suggest that decreased expression of Pol β in humans is an underlying cause of SLE.

Coexpression of the macrophage colony-stimulating factor (CSF-1) and its receptor (CSF-1R) in metastatic ovarian cancer specimens is a predictor of poor outcome in epithelial ovarian cancer. This suggests that an autocrine loop is produced by which ovarian tumors can secrete CSF-1 stimulating the CSF-1R resulting in a more aggressive phenotype. Our current work sought to validate this autocrine stimulation model using stable transfection of a 4-kb CSF-1 construct into otherwise nonvirulent Bix3 ovarian cancer cells. A representative clone, Bix3T8.2, produced a 72-fold increase in CSF-1 gene transcription rate (by nuclear run-off assays) and a 57-fold increase in secreted CSF-1 protein (by sandwich ELISA), compared to parent cells. Comparison of Bix3T8.2 invasion, adhesion, and motility in vitro and metastasis in vivo were made to parental and transfectant controls. Up to 12-fold higher invasiveness was seen with Bix3T8.2 and 2- and 6-fold higher adhesion and motility, respectively, over controls in vitro. In nude mice, i.p. injection of Bix3T8.2 produced a wide array of visceral, nodal, and distant metastasis with a degree of enhanced tumor burden not seen in any of the 10 mice inoculated with transfectant control cells. Complete absence of tumor take distinguished 40% of mice implanted with transfectant control cells. Disruption of this autocrine loop using antisense oligomer therapy against CSF-1R and 3′ untranslated region knockdown of CSF-1 protein resulted in reversal of in vitro and in vivo tumor phenotypes. This CSF-1 feedback loop offers a model by which novel biologic therapies can potentially target multiple levels of this pathway.

Magnetic resonance (MR) examination of 42 normal wrists was performed for evaluation of anomalous musculature. A total of 23 muscle variations were found. An accessory abductor digiti minimi was found in 10 wrists (24%), an absent palmaris longus was found in seven wrists (16%), a muscular palmaris longus tendon was found in three wrists (7%), a muscular flexor digitorum superficialis was found in two wrists (5%), and an aberrant lumbrical muscle originating from within the carpal tunnel was found in one wrist (2.4%). Such muscle variations can be distinguished by MR from other mass lesions at the wrist and a knowledge of their frequency, appearance, and location can be of help in this regard.

An aberrant muscle is demonstrated by magnetic resonance (MR) imaging in a patient presenting with focal wrist swelling and compression neuropathy of median and ulnar nerves following 4 months of carpentry work. The muscle originated from the palmaris longus tendon and ulnar antebrachial fascia at the lower half of the forearm as a single belly, then diverged medially from palmaris longus tendon and bifurcated. Both portions of the split muscle extended into the distal ulnar tunnel or Guyon's canal. One segment joined with the abductor digiti minimi muscle and the other with the flexor retinaculum. MR was able to clearly delineate this hypertrophied, symptomatic muscle anomaly. It may be helpful when mass effect is suspected in either tunnel, or in patients with atypical work-related carpal tunnel syndrome with evidence of significant ulnar neuropathy for evaluation of underlying anomalous musculature. Normal MR images of the wrist are included for comparison and the literature is reviewed.

A lobulated mass in the suprapatellar bursa of the knee is presented with MRI findings simulating the features of focal pigmented villonodular synovitis (PVS). Microscopic examination demonstrated a nonspecific, inflammatory mass of hypertrophied synovium. The MRI features of various forms of synovitis are reviewed from recent literature and differential considerations of a suprapatellar, intrabursal mass are discussed.

Three cross-sectional imaging modalities are compared in the evaluation of a patient with Superior Vena Cava Syndrome. The apparent and potential advantages of magnetic resonance imaging (MRI) over computer tomography (CT) and ultrasound (US) are discussed.

An abnormal chest roentgenogram is essential for the diagnosis of ventilator-associated pneumonia. The diagnostic accuracy of various roentgenographic signs of pneumonia has not been assessed previously in the portable anteroposterior roentgenograms obtained in ventilated patients. Seven roentgenographic signs (air bronchograms, alveolar infiltrates, silhouette sign, cavities, fissure abutment, atelectasis, and asymmetric infiltrates superimposed on diffuse bilateral infiltrates) were evaluated for their accuracy in predicting pneumonia alone, in combination with other signs, or in combination with clinical parameters. The last roentgenogram prior to autopsy of 69 ventilated patients was interpreted by three reviewers and the above signs were correlated with autopsy evidence of pneumonia. Pneumonia was present in 24 (35 percent) of the 69 autopsies. No roentgenographic sign had a diagnostic efficiency of greater than 68 percent. By stepwise logistic regression, the presence of air bronchograms was the only roentgenographic sign that correlated with pneumonia in the total group, correctly predicting 64 percent of pneumonias. In patients without adult respiratory distress syndrome (ARDS), the presence of air bronchograms or alveolar infiltrates correlated with pneumonia, while in patients with ARDS, no roentgenographic sign and only the clinical parameter of purulent sputum correlated with pneumonia. Only a minority (7/22) of worsening alveolar infiltrates in all groups were due to pneumonia and were often confused with ARDS. Alveolar hemorrhage occurred with a surprising frequency (38 percent of autopsies), including 13/45 (29 percent) patients without pneumonia. Alveolar hemorrhage was associated with 29 percent of multiple air bronchograms and 30 percent of bilateral alveolar infiltrates in patients without pneumonia. We conclude that in intubated patients with diffuse bilateral roentgenographic infiltrates, no roentgenographic sign correlates well with pneumonia. No clinical parameter added to the accuracy of either an alveolar infiltrate or an air bronchogram in patients without diffuse infiltrates. Pulmonary hemorrhage and/or infarction are frequent autopsy findings in intubated patients and may be confused radiologically with pneumonia.

Magnetic resonance imaging was done on the wrists of 14 volunteer subjects with the wrists in the neutral position, then flexed and extended at 45 degrees. Computer enhanced cross-sectional areas were measured on each subject at the level of the hook of the hamate. In the neutral position the distance between confining structures around the median nerve is 2.0 +/- 0.2 mm in the anteroposterior direction, and the mean cross-sectional area of the carpal tunnel is 1.52 cm2. With the wrist in the extended position the distance available for the median nerve measures 2.2 +/- 0.4 mm and the cross-sectional area increases to 1.75 cm2. When the wrist is flexed, the distance available for the median nerve between the flexor tendons and transverse carpal ligament decreases to 1.1 +/- 0.4 mm, and the cross-sectional tunnel area decreases to 1.36 cm2. Flexion of the wrist and/or fingers both produces a palmar rearrangement of the flexor tendons creating potential compression of the median nerve. The nerve responds to these forces by becoming interposed in various positions between the superficial flexor tendons.

In a patient suspected of having tarsal tunnel syndrome by clinical and electrophysiological exam, magnetic resonance imaging (MRI) was performed in an attempt to define the cause. Transverse and sagittal T1 and T2 images were obtained which demonstrated tubular T2 enhancing masses felt to be abnormally dilated and tortuous veins with slow flow. The nerve was displaced posteriorly from its usual position. Surgery confirmed these findings and the retinaculum was released with good results. In certain cases, therefore, MRI can be of help in the tarsal tunnel although its overall role has yet to be defined.