SPI-CI and SPI-6 cooperate in the protection from effector cell-mediated cytotoxicity

Tumors have several mechanisms to escape from the immune system. One of these involves expression of intracellular anticytotoxic proteins that modulate the execution of cell death. Previously, we have shown that the serine protease inhibitor (serpin) SPI-6, which inactivates the cytotoxic protease granzyme B (GrB), is capable of preventing cytotoxic T lymphocyte (CTL)-mediated apoptosis. Despite its potent antiapoptotic activity, SPI-6 does not prevent membranolysis induced by cytotoxic lymphocytes. We now provide evidence that several colon carcinoma cell lines do resist membranolysis and that this protection is dependent on SPI-6 but also requires expression of a closely related serpin called SPI-CI (serine protease inhibitor involved in cytotoxicity inhibition). Expression of SPI-CI is absent from normal colon but observed in placenta, testis, early during embryogenesis, and in cytotoxic lymphocytes. SPI-CI encodes a chymotrypsin-specific inhibitor and irreversibly interacts with purified granzyme M. Moreover, SPI-CI can protect cells from purified perforin/GrM-induced lysis. Our data therefore indicate that SPI-CI is a novel immune escape molecule that acts in concert with SPI-6 to prevent cytotoxic lymphocyte-mediated killing of tumor cells.     

Magnetic resonance imaging as a tool to image neuroinflammation in a rat model of Parkinson's disease – phagocyte influx to the brain is promoted by bilberry‐enriched diet

Neuroinflammation is a chronic event in neurodegenerative disorders. In the rat model of Parkinson's disease, including a striatal injection of the neurotoxin 6‐hydroxydopamine (6‐OHDA), antioxidant treatment affects the inflammatory process. Despite a heavy accumulation of microglia early after the injury, dopamine nerve fibre regeneration occurs. It remains unclear why this heavy accumulation of microglia is found early after the lesion in antioxidant‐treated animals, or even more, what is the origin of these microglia. In this study magnetic resonance imaging (MRI) was used to elucidate whether the inflammatory response was generated from the blood or from activated brain microglia. Superparamagnetic iron oxide (SPIO) nanoparticles were injected intravenously prior to a striatal 6‐OHDA injection to tag phagocytes in the blood. Rats were fed either with bilberry‐enriched or control diet. T2*‐weighted MRI scans were performed 1 week after the lesion, and hypointense areas were calculated from T2*‐weighted images, to monitor the presence of SPIO particles. The results revealed that feeding the animals with bilberries significantly promoted accumulation of blood‐derived immune cells. Gadolinium‐enhanced MRI demonstrated no difference in leakage of the blood–brain barrier independent of diets. To conclude, bilberry‐enriched diet promotes an influx of periphery‐derived immune cells to the brain early after injury.     

Quinidine in the treatment of KCNT1‐positive epilepsies

We report 2 patients with drug‐resistant epilepsy caused by KCNT1 mutations who were treated with quinidine. Both mutations manifested gain of function in vitro, showing increased current that was reduced by quinidine. One, who had epilepsy of infancy with migrating focal seizures, had 80% reduction in seizure frequency as recorded in seizure diaries, and partially validated by objective seizure evaluation on EEG. The other, who had a novel phenotype, with severe nocturnal focal and secondary generalized seizures starting in early childhood with developmental regression, did not improve. Although quinidine represents an encouraging opportunity for therapeutic benefits, our experience suggests caution in its application and supports the need to identify more targeted drugs for KCNT1 epilepsies. Ann Neurol 2015;78:995–999     

Clarithromycin as an Adjunct to One‐Stage Full‐Mouth Ultrasonic Periodontal Debridement in Generalized Aggressive Periodontitis: A Randomized Controlled Clinical Trial

Background: The aim of the present study is to evaluate the periodontal clinical and microbiologic responses and possible adverse effects of clarithromycin (CLM) combined with periodontal mechanical therapy in the treatment of patients with generalized aggressive periodontitis. Methods: Forty patients were selected and randomly assigned into one of two groups: 1) CLM (n = 20): one‐stage full‐mouth ultrasonic debridement (FMUD) associated with CLM (500 mg, every 12 hours for 3 days); and 2) placebo (n = 20): FMUD associated with placebo pills. Clinical and microbiologic parameters were evaluated at baseline and 3 and 6 months postoperatively. Results: Both treatments presented statistically significant clinical and microbiologic improvements. However, the CLM group presented lower means of probing depth for pockets ≥7 mm at 6 months (4.0 ± 1.7 mm) compared with the placebo group (4.7 ± 1.3 mm) (P = 0.04). In addition, the CLM group also presented greater reduction of Porphyromonas gingivalis (Pg) DNA counts at 6 months (P = 0.0001). Conclusion: Results from this study suggest both treatments are effective; however, adjunct use of CLM to FMUD leads to better reduction of deep pockets and Pg at 6 months compared with FMUD alone.     

Immunostimulatory capacity of dental casting alloys on endotoxin responsiveness

Statement of problem

Oral metal exposure has been associated with systemic and local adverse reactions, probably due to elemental release from the alloys. Although supraphysiological concentrations of salts from dentally applied metals can activate innate cells through TLR4 (Ni, Co, Pd) and TLR3 (Au), whether direct exposure to solid alloys can also trigger innate immune reactivity is still unknown.

Diagnostic accuracy of magnetic resonance imaging and clinical signs of temporomandibular joint disorders: a 10-year research update review

Objectives

To review the past 10 years of research in the diagnostic accuracy of magnetic resonance imaging (MRI) and clinical signs of temporomandibular joint (TMJ) disorders with pain, sound, and function limitation in the existing literature.

Methods

A review of the literature was performed to search for all articles published between 2006 and 2016, and those that met the selection criteria were examined.

Results

The MRI results ranged from 25.3 to 69% for findings in TMJ with sound, 17–74.5% for findings in TMJ with function limitation, and 13.3–77% for findings in TMJ with pain. The reasons for the TMJ symptoms were variable and MRI findings for temporomandibular disorders were seen in asymptomatic patients as well as symptomatic patients. No singular outcome measure can be suggested as a predictor for TMJ symptoms on MRI images.

Conclusions

To increase study comparability with MRI, a standardized terminology and evidence-based guidelines are required for correlations of clinical symptoms and MRI findings.