Hyperinflammatory syndromes are life-threatening disorders caused by overzealous immune cell activation and cytokine release, often resulting from defects in negative feedback mechanisms. In the ...quintessential hyperinflammatory syndrome familial hemophagocytic lymphohistiocytosis (HLH), inborn errors of cytotoxicity result in effector cell accumulation, immune dysregulation and, if untreated, tissue damage and death. Here, we describe a human case with a homozygous nonsense R688* RC3H1 mutation suffering from hyperinflammation, presenting as relapsing HLH. RC3H1 encodes Roquin-1, a posttranscriptional repressor of immune-regulatory proteins such as ICOS, OX40 and TNF. Comparing the R688* variant with the murine M199R variant reveals a phenotypic resemblance, both in immune cell activation, hypercytokinemia and disease development. Mechanistically, R688* Roquin-1 fails to localize to P-bodies and interact with the CCR4-NOT deadenylation complex, impeding mRNA decay and dysregulating cytokine production. The results from this unique case suggest that impaired Roquin-1 function provokes hyperinflammation by a failure to quench immune activation.
Radiation-induced proctitis (RIP) is a debilitating adverse event that occurs commonly during lower abdominal radiotherapy. The lack of prophylactic treatment strategies leads to diminished patient ...quality of life, disruption of radiotherapy schedules, and limitation of radiotherapy efficacy due to dose-limiting toxicities. Semisynthetic glycosaminoglycan ethers (SAGE) demonstrate protective effects from RIP. However, low residence time in the rectal tissue limits their utility. We investigated controlled delivery of GM-0111, a SAGE analogue with demonstrated efficacy against RIP, using a series of temperature-responsive polymers to compare how distinct phase change behaviors, mechanical properties and release kinetics influence rectal bioaccumulation. Poly(lactic acid)-co-(glycolic acid)-block-poly(ethylene glycol)-block-poly(lactic acid)-co-(glycolic acid) copolymers underwent macroscopic phase separation, expelling >50% of drug during gelation. Poloxamer compositions released GM-0111 cargo within 1 h, while silk-elastinlike copolymers (SELPs) enabled controlled release over a period of 12 h. Bioaccumulation was evaluated using fluorescence imaging and confocal microscopy. SELP-415K, a SELP analogue with 4 silk units, 15 elastin units, and one elastin unit with lysine residues in the monomer repeats, resulted in the highest rectal bioaccumulation. SELP-415K GM-0111 compositions were then used to provide localized protection from radiation induced tissue damage in a murine model of RIP. Rectal delivery of SAGE using SELP-415K significantly reduced behavioral pain responses, and reduced animal mass loss compared to irradiated controls or treatment with traditional delivery approaches. Histological scoring showed RIP injury was ameliorated for animals treated with GM-0111 delivered by SELP-415K. The enhanced bioaccumulation provided by thermoresponsive SELPs via a liquid to semisolid transition improved rectal delivery of GM-0111 to mice and radioprotection in a RIP model.
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Purpose To compare the effectiveness of imaging techniques in aiding and confirming the diagnosis of complex regional pain syndrome (CRPS) type I. Methods We conducted a meta-analysis of randomized ...controlled studies that evaluated the effectiveness of 3 different imaging techniques in aiding the diagnosis of CRPS type I. A systematic search in bibliographical databases resulted in 24 studies with 1,916 participants. Results To determine the effectiveness of each imaging technique, we determined the average specificity, sensitivity, negative predictive value, and positive predictive value and then statistically compared them using the analysis of variance statistical test, which indicated that compared with magnetic resonance imaging and plain film radiography, triple-phase bone scan had a significantly better sensitivity and negative predictive values. However, there appeared to be no statistical significance between imaging techniques when we evaluated specificity and positive predictive value using the analysis of variance test. Conclusions The findings of this meta-analysis support the use of triple-phase bone scan in ruling out CRPS type I, owing to its greater sensitivity and higher negative predictive value than both magnetic resonance imaging and plain film radiography. Type of study/level of evidence Diagnostic I.
The purpose of this study was to investigate the potential of silk-elastinlike protein polymers (SELPs) in controlling the release rate of adenoviruses in vitro and in vivo while preserving their ...bioactivity.
A hydrogel system composed of SELP/adenovirus mixture was prepared. The release of the adenovirus particles from the hydrogels was quantified by Real Time-PCR and the bioactivity of the released viruses was evaluated using confocal microscopy and beta-galactosidase assay. To demonstrate the ability of SELP in entrapping virus cargo and releasing it over a prolonged period of time in vivo, a SELP/adenovirus mixture was prepared and injected directly into xenograft tumor models of breast and head and neck cancer in mice. At various time points mice were sacrificed, tumors dissected, and tissue sections studied under confocal microscope.
In vitro studies demonstrated that SELP hydrogels release viruses over a period of 4 weeks while preserving their bioactivity. After intratumoral injection, a prolonged and localized expression of adenoviruses was observed.
These results suggest the potential of SELPs in local adenoviral delivery to solid tumors as an alternative approach to intratumoral virus infusion.
Glutathione transferase Kappa (GSTK1-1) also termed disulfide bond-forming oxidoreductase A-like protein (DsbA-L) has been implicated in the post-translational multimerization of adiponectin and has ...been negatively correlated with obesity in mice and humans. We investigated adiponectin in Gstk1(-/-) mice and surprisingly found no difference in the levels of total serum adiponectin or the level of high molecular weight (HMW) multimers when compared with normal controls. Non-reducing SDS-polyacrylamide gel electrophoresis and western blotting also showed a similar distribution of low, middle and HMW multimers in normal and Gstk1(-/-) mice. Variation in adiponectin has been correlated with glucose tolerance and with the levels of phosphorylated AMP-kinase but we found similar glucose tolerance and similar levels of phospho 5-AMP-activated protein kinase in normal and Gstk1(-/-) mice. Consequently, our findings suggest that GSTK1-1 is not absolutely required for adiponectin multimerization in vivo and alternate pathways may be activated in GSTK1-1 deficiency.
The purpose of this study was to evaluate the potential of a genetically engineered silk-elastinlike polymer (SELP) as a matrix for the controlled release of plasmid DNA.
The influences of SELP ...concentration, DNA concentration, SELP cure time, and buffer ionic strength on the release of DNA from SELP hydrogels were investigated. To calculate the average effective diffusivity of DNA within the hydrogels, the release data were fitted to a known equation.
DNA was released from SELP hydrogels by an ion-exchange mechanism. Under the conditions studied, the release rate was influenced by buffer ionic strength, SELP concentration, and SELP cure time but not DNA concentration. The apparent diffusivity of pRL-CMV plasmid DNA in SELP hydrogels ranged from 3.78 +/- 0.37 x 10(-10) cm2/s (for hydrogels containing 12% w/w SELP and cured for 4 h) to 4.69 +/- 2.81 x 10(-9) cm2/s (for hydrogels containing 8% w/w SELP and cured for 1 h).
The ability to precisely customize the structure and physicochemical properties of SELPs using recombinant techniques, coupled with their ability to form injectable, in situ hydrogel depots that release DNA, renders this class of polymers an interesting candidate for further evaluation in controlled gene delivery.
Objective
Studies have demonstrated improvement in Eustachian tube dysfunction (ETD) symptomatology after functional endoscopic sinus surgery (FESS); however, factors associated with ETD symptom ...alteration have not been elucidated. This study evaluated factors associated with improvement and normalization of ETD symptoms after FESS.
Methods
A case‐control study was performed of FESS patients who had clinically significant ETD symptoms based on the Eustachian Tube Dysfunction Questionnaire‐7 (ETDQ‐7 ≥ 2.1) without middle ear effusion (MEE) preoperatively. Study patients were identified as those with a normalized ETDQ‐7 at 2 months postoperatively. Controls were patients whose ETDQ‐7 did not normalize at 2 months. Demographics, surgery characteristics, chronic rhinosinusitis phenotype, Lund‐Mackay score, temporomandibular joint dysfunction (TMJD), preoperative ETDQ‐7 and SNOT‐22 scores, and tympanograms were analyzed. Univariate and multivariate analyses were performed comparing study cases and controls.
Results
Data were collected on 165 patients, with 46% patients having clinically significant preoperative ETD and 60 patients meeting final study inclusion/exclusion criteria. FESS was associated with both SNOT‐22 and ETDQ‐7 improvement (P < 0.001). Nasal polyposis was associated with a higher probability of ETDQ‐7 normalization (OR 4.429, P = 0.035). Factors associated with failure of ETDQ‐7 normalization included TMJD (OR 0.086, P < 0.001, 95% CI 0.019–0.391) and high preoperative ETDQ‐7 (OR 0.140, P = 0.006, 95% CI 0.032–0.613).
Conclusion
In patients with clinically significant ETD symptoms without MEE, FESS was associated with ETDQ‐7 improvement. Nasal polyposis was associated with an increased probability of normalization of ETD symptoms postoperatively, whereas TMJD had a negative association.
Level of Evidence
3b Laryngoscope, 2019
Objectives
Inadvertent intracranial injury from nasogastric tube (NGT) placement is a described and potentially fatal complication following endoscopic transsphenoidal hypophysectomy (TSH). This ...cadaver study assessed the role of middle turbinate (MT) preservation and medialization in preventing accidental skull base injury from NGT insertion after TSH. Methods: Standard approach for TSH was performed on 3 human cadavers. MTs were placed into neutral position (MTN), then medialized via suture pexy to the septum (MTP), and subsequently resected (MTR). After each stage, 3 blinded individuals passed a 10 F Dobhoff and a 16 F NGT on each side of each cadaver (5 passes per side). Using endoscopic visualization, each pass was scored by a blinded reviewer based on the first contact point of the tube (0 = nasopharynx, 1 = inferior sphenoid face, 2 = sphenoid sinus), with higher scores suggestive of increased risk of intracranial injury. Results: There were 270 Dobhoff and 270 NGT passes scored. Data was divided into 3 groups based on presence and position of the MT. Significant differences were demonstrated between all three groups one-way ANOVA: Dobhoff F(2,267) = 6.981, p = 0.001, NGT F(2,267) = 17.582, p < 0.001. There were significant differences between means for MTN versus MTP groups Dobhoff (0.43 vs 0.22, p = 0.007), NGT (0.73 vs 0.28, p < 0.001) and MTP versus MTR groups Dobhoff (0.22 vs 0.55, p < 0.001), NGT (0.28 vs 0.81, p < 0.001), indicating that the presence and position of the MT can significantly affect the accessibility of the sphenoid sinus interior after TSH. There was a trend toward lower means in the MTN group compared to the MTR group. Conclusion: MT preservation and deliberate medialization against the septum may reduce risk of inadvertent intracranial NGT injury in postop TSH patients. This simple maneuver should be considered in all routine TSH procedures.
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