Identification of a Novel Hypoxia-induced Inflammatory Cell Death Pathway.

Hypoxic cancer cells resist many anti-neoplastic therapies and can seed recurrence. We found previously that PTP1B deficiency promotes HER2+ breast cancer cell death in hypoxia by activating RNF213, an ∼600kDa protein containing AAA-ATPase domains and two ubiquitin ligase domains (RING and RZ) that also is implicated in Moyamoya disease (MMD), lipotoxicity, and innate immunity. Here we report that PTP1B and ABL1/2 reciprocally control RNF213 phosphorylation on tyrosine-1275. This phosphorylation promotes RNF213 oligomerization and RZ domain activation. The RZ domain ubiquitylates CYLD/SPATA2, and together with the LUBAC complex, induces their degradation. Decreased CYLD/SPATA2 causes NF-κB activation, which together with hypoxia-induced ER-stress triggers GDSMD-dependent pyroptosis. Mutagenesis experiments show that the RING domain negatively regulates the RZ domain. CYLD -deleted HER2+ cell-derived xenografts phenocopy the effects of PTP1B deficiency, and reconstituting RNF213 knockout lines with RNF213 mutants shows that the RZ domain mediates PTP1B-dependent tumor cell death. Our results identify a novel, potentially targetable PTP1B/RNF213/CYCLD/SPATA pathway critical for controlling inflammatory cell death in hypoxic tumors that could be exploited to target hypoxic tumor cells, potentially turning "cold" tumors "hot". Our findings also reveal new insights into RNF213 regulation, and have potentially important implications for the pathogenesis of MMD, atherosclerosis, and inflammatory and auto-immune disorders.

Urate-lowering therapy for patients with gout on hemodialysis.

OBJECTIVE: Gout is the most common form of inflammatory arthritis and is caused by deposition of monosodium urate crystals resulting from a high burden of uric acid (UA). High UA burden also has been associated with increased morbidity and mortality in the general population and progression to chronic kidney disease. In persons with gout and end-stage renal disease (ESRD), prior studies suggest that UA levels decrease after initiation of hemodialysis (HD). We evaluated UA level and the use of urate-lowering therapies (ULTs) in patients with gout and ESRD on HD. METHODS: We performed a retrospective review of patients with gout and ESRD seen at a large urban public hospital (The MetroHealth System). We extracted data from the medical record (Epic) for patients diagnosed with gout and ESRD on HD. The main outcomes were the UA level and the use of ULTs before and after HD initiation. RESULTS: We identified 131 patients with gout on HD. Of these, 21 patients had crystal proven gout diagnosis, 10 of whom had data on UA level pre-HD and post-HD and were included in the analysis. For the total sample (N = 21), the mean age was 65 years, 7 were female and 20 were African American. Mean pre-HD and post-HD UA levels were 8.4 and 3.98 mg/dL respectively. Twenty-one patients were receiving ULT pre-HD, 11 discontinued post-HD. CONCLUSION: Among patients with gout and ESRD, we observed a decrease in UA level associated with initiation of HD. For this group, discontinuation of ULTs may be appropriate.

Effects of Biochar on the Growth and Development of Tomato Seedlings and on the Response of Tomato Plants to the Infection of Systemic Viral Agents.

Biochar is a rich carbon product obtained by pyrolysis of biomass under a limited supply of oxygen. It is composed mainly of aromatic molecules, but its agronomic value is hard to evaluate and difficult to predict due to its great variable characteristics depending on the type of starting biomass and the conditions of pyrolysis. Anyway, it could be used as soil amendment because it increases the soil fertility of acidic soils, increases the agricultural productivity, and seems to provide protection against some foliar and soilborne diseases. In this study, the effects of biochar, obtained from olive pruning, have been evaluated on tomato seedlings growth and on their response to systemic agents' infection alone or added with beneficial microorganisms (Bacillus spp. and Trichoderma spp.). First, experimental data showed that biochar seems to promote the development of the tomato seedlings, especially at concentrations ranging from 1 to 20% (w/w with peat) without showing any antimicrobial effects on the beneficial soil bacteria at the tomato rhizosphere level and even improving their growth. Thus, those concentrations were used in growing tomato plants experimentally infected with tomato spotted wilt virus (TSWV) and potato spindle tuber viroid (PSTVd). The biochar effect was estimated by evaluating three parameters, namely, symptom expression, number of infected plants, and pathogen quantification, using RT-qPCR technique and -ΔΔCt analysis. Biochar at 10-15% and when added with Trichoderma spp. showed that it reduces the replication of PSTVd and the expression of symptoms even if it was not able to block the start of infection. The results obtained on TSWV-infected plants suggested that biochar could contribute to reducing both infection rate and virus replication. For systemic viral agents, such as PSTVd and TSWV, there are no curative control methods, and therefore, the use of prevention means, as can be assumed the use biochar, for example, in the nursery specialized in horticultural crops, can be of great help. These results can be an encouraging starting point to introduce complex biochar formulates among the sustainable managing strategies of plant systemic diseases.

Thyroid Disease in Lupus: An Updated Review.

In the following review, we seek to provide an overview of the current understanding of various thyroid manifestations affecting patients with systemic lupus erythematosus (SLE), including topics ranging from thyroid-related complications to SLE in pregnancy. Autoimmune diseases tend to coincide, and an association between thyroid disease and SLE has been reported for more than 50 years. There is no evidence that the coexistence of thyroid disease and lupus alters the disease course or manifestations of either. Both hypothyroidism and thyroid nodules are seen more frequently in patients with SLE than in the general population. The rate of thyroid cancer is twice as prevalent in patients with SLE compared with those without SLE. Several forms of thyroid disease are more common among patients with SLE, with adverse consequences in pregnancy. Future work will require delineating the mechanism behind these associations and understanding the role of antirheumatic agents with concomitant thyroid disease.

Sacroiliitis mimics: a case report and review of the literature.

BACKGROUND: Radiographic sacroiliitis is the hallmark of ankylosing spondylitis (AS), and detection of acute sacroiliitis is pivotal for early diagnosis of AS. Although radiographic sacroiliitis is a distinguishing feature of AS, sacroiliitis can be seen in a variety of other disease entities. CASE PRESENTATION: We present an interesting case of sacroiliitis in a patient with Paget disease; the patient presented with inflammatory back pain which was treated with bisphosphonate. This case demonstrates comorbidity with Paget disease and possible ankylosing spondylitis. We also present a review of the literature for other cases of Paget involvement of the sacroiliac joint. CONCLUSIONS: In addition, we review radiographic changes to the sacroiliac joint in classical ankylosing spondylitis as well as other common diseases. We compare and contrast features of other diseases that mimic sacroiliitis on a pelvic radiograph including Paget disease, osteitis condensans ilii, diffuse idiopathic skeletal hyperostosis, infections and sarcoid sacroiliitis. There are some features in the pelvic radiographic findings which help distinguish among mimics, however, one must also rely heavily on extra-pelvic radiographic lesions. In addition to the clinical presentation, various nuances may incline a clinician to the correct diagnosis; rheumatologists should be familiar with the imaging differences among these diseases and classic spondylitis findings.

It's time to redefine inflammation.

Inflammation has been defined for many years as the response to tissue injury and infection. We are now forced to reconsider this definition by the avalanche of reports that molecules and cells associated with inflammation are activated or expressed in high concentration in a large variety of states in the absence of tissue injury or infection. Modest increases in concentration of C-reactive protein, a circulating marker of inflammation, have been reported to be associated with an astounding number of conditions and lifestyles felt to be associated with poor health; these conditions represent or reflect minor metabolic stresses. In recent years we have learned that inflammation is triggered by sentinel cells that monitor for tissue stress and malfunction-deviations from optimal homeostasis-and that molecules that participate in the inflammatory process play a role in restoring normal homeostasis. Accordingly, we suggest that inflammation be redefined as the innate immune response to potentially harmful stimuli such as pathogens, injury, and metabolic stress.-Antonelli, M., Kushner, I. It's time to redefine inflammation.

Procalcitonin Reveals Early Dehiscence in Colorectal Surgery: The PREDICS Study.

OBJECTIVES: We designed a multicentric, observational study to test if Procalcitonin (PCT) might be an early and reliable marker of anastomotic leak (AL) after colorectal surgery (ClinicalTrials.govIdentifier:NCT01817647). BACKGROUND: Procalcitonin is a biomarker used to monitor bacterial infections and guide antibiotic therapy. Anastomotic leak after colorectal surgery is a severe complication associated with relevant short and long-term sequelae. METHODS: Between January 2013 and September 2014, 504 patients underwent colorectal surgery, for malignant colorectal diseases, in elective setting. White blood count (WBC), C-reactive protein (CRP) and PCT levels were measured in 3rd and 5th postoperative day (POD). AL and all postoperative complications were recorded. RESULTS: We registered 28 (5.6%) anastomotic leaks. Specificity and negative predictive value for AL with PCT less than 2.7 and 2.3 ng/mL were, respectively, 91.7% and 96.9% in 3rd POD and 93% and 98.3% in 5th POD. Receiver operating characteristic curve for biomarkers shows that in 3rd POD, PCT and CRP have similar area under the curve (AUC) (0.775 vs 0.772), both better than WBC (0.601); in 5th POD, PCT has a better AUC than CRP and WBC (0.862 vs 0.806 vs 0.611). Measuring together PCT and CRP significantly improves AL diagnosis in 5th POD (AUC: 0.901). CONCLUSIONS: PCT and CRP demonstrated to have a good negative predictive value for AL, both in 3rd and in 5th POD. Low levels of PCT, together with low CRP values, seem to be early and reliable markers of AL after colorectal surgery. These biomarkers might be safely added as additional criteria of discharge protocols after colorectal surgery.

Red cell distribution width: a measure of cardiovascular risk in rheumatoid arthritis patients?

This study aims to evaluate if myocardial infarction (MI) is more frequent in rheumatoid arthritis (RA) patients with elevated levels of red cell distribution width (RDW). Utilizing a secure cloud based platform, Explorys, we searched de-identified US patient data between 1999 and 2014. RA patients were identified by serologic positivity and ICD9 diagnosis code. Patients were stratified into high (≥15.6 %) RDW and low (<13.5 %) RDW groups (and excluding any patient with prior episode of RDW >15.6 %). The proportion of patients with diagnosis of MI in each RDW group was collected. For comparison, patients were divided into high and low CRP groups (≥2.5 and ≤0.8 mg/dL) and high and low ESR groups (≥50 and ≤30 mm/h), and MI data were collected. Statistical comparison between high and low laboratory test groups was performed with chi-square test, and odds ratios were calculated. The patient population included 20,810 patients with RA. The proportion of RA patients with MI was significantly increased in the high compared to low RDW, ESR, and CRP groups (p < 0.001 for each). The odds ratios of MI were greater in the high than in the low group for each parameter: RDW (OR1.5, 95 % CI 1.3 to 1.6); ESR (OR2.0, 95 % CI 1.8-2.3); and CRP (OR1.9, 95 % CI 1.7 to 2.2). These data from a large unselected population suggest that elevated RDW levels in RA patients should prompt physicians to aggressively screen and treat their patients for modifiable cardiovascular (CVS) risk factors, in addition to treating RA inflammation.

Technical characteristics can make the difference in a surgical linear stapler. Or not?

BACKGROUND: Anastomotic leak (AL) after gastrointestinal surgery is a severe complication associated with relevant short- and long-term sequelae. Most of the anastomosis are currently performed with a surgical stapler that is required to have appropriate characteristics to guarantee good performances. The aim of our study was to evaluate, in the laboratory, pressure resistance and tensile strength of anastomosis performed with different surgical linear staplers, available in the market. MATERIALS AND METHODS: We have been studying three linear staplers, with diverse cartridges and staple heights, of three different companies, used for gastrointestinal anastomosis and gastric or intestinal closure. We performed 50 anastomosis for each device, with the pertinent different cartridges, on fresh pig intestine, for a total of 350 anastomosis, then injected saline solution and recorded the pressure that provokes a leak on the staple line. There were no statistically significant differences between the mean pressure necessary to induce an AL in the various instruments (P > 0.05). For studying the tensile strength, we performed a total of 350 anastomosis with the different linear staplers on a special strong paper (Tyvek), then recorded the maximal tensile force that could open the anastomosis. RESULTS: There were no statistically significant differences between the different staplers about the strength necessary to open the staple line (P > 0.05). CONCLUSIONS: we demonstrated that different linear staplers of three companies available in the market give comparable anastomotic pressure resistance and tensile strength. This might suggest that small dissimilarities between different devices are not involved, at least as major parameters, in AL etiology.

Screening and treatment of osteoporosis after hip fracture: comparison of sex and race.

Most patients with osteoporosis (OP) are untreated and remain so even after hip fracture. Outcomes after osteoporotic hip fractures are worse among men and non-Caucasians compared with Caucasian women. We hypothesized that screening and treatment of OP after hip fracture remains low in men and non-Caucasian women. We identified all patients aged 65 yr or older with a primary diagnosis of hip fracture (ICD9-DM code 820.xx) discharged from an urban public hospital between January 1, 2000 and December 31, 2010. Patients with active malignancy (1 yr before or after the fracture) and Paget's disease were excluded. Also, patients were excluded if they had less than 2 encounters for post-event care at the hospital. Patient charts were reviewed to obtain information on demographics, post-fracture OP screening status (dual-energy X-ray absorptiometry [DXA] ordered or resulted), OP treatment status (prescription for oral bisphosphonates, raloxifene, zoledronic acid, calcitonin, or teriparatide), and referral to rheumatology clinic. Data were captured using Research Electronic Data Capture. Differences in frequency of patients who had been evaluated by DXA and/or prescribed antiosteoporotic therapy after hip fractures overall and stratified by sex and race were evaluated using Chi-squared tests. The study was approved by our hospital institutional review board. There were a total of 596 patients discharged with a primary diagnosis of hip fracture during the study period. After exclusions, 417 patients remained and were included in the analyses. The median age was 80yr (range: 65-95), 113 (27%) were men, and 243 were White women (57.9%). Overall, 10.3% of the patients were ordered DXA after their hospital discharge, 5.4% of men and 12.1% of women (p=0.05). A total of 19% received treatment for OP, and women were nearly 3 times more likely to receive treatment than men (23.2% vs 8%, p=0.004). The rates of DXA, treatment, and referral to rheumatology did not differ by race. The frequency of OP screening using DXA scan and the initiation of OP treatment was low in all patients after fragility fractures of hip. Women were more likely than men to receive DXA and significantly more likely to receive OP treatment. Although representative of only 1 hospital, these data suggest that more attention should be paid to possible OP among elderly patients hospitalized for hip fracture, and especially among men.

Polarimetric imaging of uterine cervix: a case study.

We present a preliminary investigation of macroscopic polarimetric imaging of uterine cervix. Orthogonal state contrast (OSC) images of healthy and anomalous cervices have been taken in vivo at 550 nm. Four ex vivo cervix samples have been studied in full Muller polarimetry, at 550 nm and 700 nm, and characterized in detail by standard pathology. One sample was totally healthy, another one carried CIN lesions at very early stage (CIN1) in its visible exocervical region, while for the other two samples more advanced (CIN3) lesions were present, together with visible glandular epithelium (ectropion). Significant birefringence has been observed in the healthy regions of all six samples, both in vivo and ex vivo. Standard treatments of the Mueller images of the ex vivo samples allowed to quantify both retardation and depolarization. Retardation reached 60° in healthy regions, and disappeared in the anomalous regions of the other three ex vivo samples. The depolarization power was largest in healthy regions, and lower in CINs and ectropion. Possible origins of the observed effects are briefly discussed.