DMOG protects against murine IL-33-induced pulmonary type 2 inflammation through HIF-1 pathway in innate lymphoid cells.

One of the traditional methods of treating allergy is to avoid the allergen, protocol that has long been used in high altitude clinics. It has been hypothesized that the therapeutic effect of high altitude on allergy is due to allergen avoidance, exposure to sunlight and reduced stress. However, the contribution of environmental elements like low oxygen pressure and hypoxia remains underexplored. In this study, we examined the role of hypoxia in the development of type 2 lung inflammation. Mice were administered with papain or recombinant IL-33 intra-nasally to induce type 2 lung inflammation. Some of them were treated additionally with the prolyl hydroxylase (PHD) inhibitor DMOG, which mimics hypoxia. DMOG treatment exhibited an inhibitory effect on the lung inflammation induced by papain or IL-33, operating in a manner independent of T and B cells. The anti-inflammatory effect of DMOG was accompanied by a downregulation of IL-5 and IL-13 in innate lymphoid cells (ILCs), which was abolished in HIF-1α deficient mice. Collectively, our findings suggest that DMOG's modulatory effect on IL-5 and IL-13 operates through the HIF-1 pathway, resulting in a reduction in type 2 lung inflammation. These findings underscore the role of the PHD-HIF pathway in IL-5 and IL-13 expression in lung ILCs and pharmacological inhibition of PHD might be a novel therapeutic candidate for type 2 lung inflammation.

mTORC1 Deficiency Prevents the Development of MC903-Induced Atopic Dermatitis through the Downregulation of Type 2 Inflammation.

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by eczema and itching. Recently, mTORC, a central regulator of cellular metabolism, has been reported to play a critical role in immune responses, and manipulation of mTORC pathways has emerged as an effective immunomodulatory drug. In this study, we assessed whether mTORC signaling could contribute to the development of AD in mice. AD-like skin inflammation was induced by a 7-day treatment of MC903 (calcipotriol), and ribosomal protein S6 was highly phosphorylated in inflamed tissues. MC903-induced skin inflammation was ameliorated significantly in Raptor-deficient mice and exacerbated in Pten-deficient mice. Eosinophil recruitment and IL-4 production were also decreased in Raptor deficient mice. In contrast to the pro-inflammatory roles of mTORC1 in immune cells, we observed an anti-inflammatory effect on keratinocytes. TSLP was upregulated in Raptor deficient mice or by rapamycin treatment, which was mediated by hypoxia-inducible factor (HIF) signaling. Taken together, these results from our study indicate the dual roles of mTORC1 in the development of AD, and further studies on the role of HIF in AD are warranted.

CD4+ T cells play an essential role in chronic MC903-induced skin inflammation.

MC903 skin inflammation model is one of well-characterized murine models of atopic dermatitis and driven by TSLP-mediated type 2 inflammation. Since it can be prepared simply by repetitive applications of MC903 and shows consistent clinical results, this model has been widely used. However, in contrast to human atopic dermatitis which is chronic and closely related to TH2 cells, MC903 induces inflammations temporarily and even in the absence of T cells. Here, we modified the MC903 treatment schedule and developed a chronic MC903-induced skin inflammation model. Mice were sensitized with a high dose of MC903 and challenged with a low dose of MC903. Prior to challenge, mice were allowed to recover completely from the inflammation which occurred during the sensitization. The challenge of MC903 induced skin swelling and type 2 inflammations more rapidly, which was dependent on CD4+ T cells and IL-33. We expect that our mouse model will be beneficial for studying the late course of atopic dermatitis.

Blood Products, Crystalloids, and Rapid Infusion: An Experimental Study With Magnesium.

OBJECTIVES: Calcium and magnesium are concentration-dependent pro- and anticoagulant cofactors, and magnesium behaves similarly to calcium in the presence of citrate. The authors hypothesized that magnesium can cause clot formation (primary objective) when mixed with coagulation factor-containing blood products diluted with different crystalloids in a rapid- infuser reservoir. A secondary objective was the observation of any infuser alarms and stops in the event of clotting. DESIGN: An experimental in vitro study with blood products, crystalloids, magnesium, and calcium in a rapid infuser with a reservoir using a closed-loop system. SETTING: Anesthesia research laboratory at an urban academic tertiary medical center PARTICIPANTS: Not applicable. INTERVENTIONS: Exposure of fresh frozen plasma (FFP) and packed red blood cells alone (control) or in combination with either normal saline (NS), lactated Ringer's solution (LR), or Plasma-Lyte A (PL) to increasing concentrations of magnesium sulphate (MgSO4) up to 1 g. After each incremental MgSO4 change, the authors applied a specific pump-flow sequence in a closed-loop system with a rapid-infuser reservoir, and if no clot was observed, the authors incrementally added calcium chloride (CaCl2) up to 1 g. MEASUREMENTS AND MAIN RESULTS: Observation of macroscopic clot and time to event, as well as occurrence and type of any pump alarms or stops. LR experiments resulted in clot observation in the reservoir by a dedicated observer after MgSO4 275 ± 206 mg (95% confidence interval [CI], 9-541). Adding MgSO4 1 g in the NS, PL, or the control experiments did not result in clot observation. Only when CaCl2 166.7 ± 51.64 mg (95% CI, 112.0-22.01) was added to the combination of blood products alone or mixed with NS and PL, clotting occurred. The mean FFP volume was 281 ± 48.6 mL (range, 204-340 mL) and was not different between groups (p = 0.44). Pump alarms and stops were inconsistent. CONCLUSIONS: The addition of magnesium to a combination of LR with coagulation factor- containing blood products consistently resulted in a visible blood clot in the rapid-infuser reservoir in the authors' experimental setup. In addition to MgSO4 1 g in the control, NS, and PL experiments, CaCl2 is needed before a clot can be observed.

Blood Products, Crystalloids, and Rapid Infusion: An Experimental Study.

BACKGROUND: Electromagnetic coil overheating, deformation, occlusion, and rupture during rapid infuser use have been previously reported. Although the etiology is unclear, prolonged machine use and reconstitution of citrated blood components with crystalloid solutions in the reservoir have been implicated. Lactated Ringer's (LR) solution is of particular concern as a diluent because of its calcium content. We sought to reproduce this failure mode using different infusion rates and different combinations of fluids for blood product reconstitution in the reservoir. We also introduced calcium chloride (CaCl2) to the mix to determine its role in macroscopic clot formation. METHODS: In this in vitro study, we conducted 2 series of experiments using the Belmont FMS 2000 rapid infuser and a reservoir. In series I, we submitted a mix of 1 U fresh thawed plasma (FTP) and 1 U red blood cells (RBC) with 500 mL of LR solution, normal saline, Plasma-Lyte A, or albumin 5% to a specific pump flow sequence. If neither a pump failure mode or self-shutoff (primary outcome) nor macroscopic clot (secondary outcome) was observed during a pump flow sequence, the sequences were repeated after first adding an additional 500 mL of the initially used crystalloid or albumin and then CaCl2 beginning with 200 mg and up to 1 g to the reservoir. In series II, 7 different crystalloid-blood product combinations were tested by using a variety of pump flow sequences with the same end points. Descriptive statistics and analysis of variance were used, and data were reported as means ± SD. RESULTS: We did not observe a Belmont pump failure mode (coil deformation, occlusion, or rupture) as previously described. In series I, the addition of CaCl2 200 mg resulted in macroscopic clots in 9 of 10 experiments (95% confidence interval, 0.55-0.99). The time to clot formation was 9.1 ± 2.3 minutes (99% confidence interval, 6.74-11.46) and did not differ between solutions used for component reconstitution. In series II, adding variable amounts of CaCl2 to 4 different combinations of FTP/RBC with Plasma-Lyte A or LR solution led to clot formation. The use of only FTP in 2 experiments with either LR solution or normal saline resulted in formation of a fibrin clot. In 1 experiment of LR solution mixed with RBCs alone, no clot was observed even after addition of 1 g CaCl2. After the observation of clot in the reservoir, the fluid empty alarm occurred once in series I, the overheating alarm occurred once in series II, and the high-pressure alarms occurred 3 times in each series, all accompanied by self-shutoff. CONCLUSIONS: In this in vitro study, we were unable to reproduce the failure mode characterized by coil overheating, deformation, and rupture previously reported with use of the FMS 2000. Addition of CaCl2 in the range of 200 mg caused macroscopic coagulation in the reservoir when added to crystalloids or albumin mixed with different combinations of blood products containing FTP.

Acute trauma and multiple injuries in the elderly population.

PURPOSE OF REVIEW: Traumatic injuries in the rapidly growing elderly population pose a significant challenge to the healthcare community. These injuries are associated with significant morbidity and mortality, and as a result cause a financial burden on the medical system. Although normal decline in physiologic reserve can provide some explanation for these poor outcomes, there is significant room for improvement. This review will summarize recent literature around the evaluation and management of elderly trauma patients with a particular focus on those with hip fractures. RECENT FINDINGS: It is becoming increasingly evident that customized evaluation and management of elderly trauma patients is a key factor in improving outcomes. Geriatric-specific triage and assessment criteria have been developed and initial results are encouraging. In particular, the use of frailty as an assessment tool in these patients has been shown to be an independent predictor of outcomes. Further, assessment of these tools in elderly trauma patients with hip fractures has provided a wealth of information about their use and limitations. SUMMARY: Differentiated, geriatric-specific triaging, assessment and treatment pathways in the care of elderly trauma patients will ultimately lead to improvements in outcomes. These improvements have already started to be seen in the realm of orthogeriatrics.

Prolyl hydroxylase inhibition protects against murine MC903-induced skin inflammation by downregulating TSLP.

Previously, we reported an anti-inflammatory effect of mTORC1 in a mouse model of type 2 skin inflammation. TSLP, one of the epithelial cell-derived cytokines, was upregulated by Raptor deficiency or rapamycin treatment, which was inhibited by dimethyloxalylglycine (DMOG). However, it remains unclear how DMOG regulates TSLP expression and type 2 skin inflammation. In this study, we investigated the protective effect of DMOG on MC903 (calcipotriol)-induced type 2 skin inflammation. Morphological and immunological changes were assessed by H-E staining, flow cytometry and RT-qPCR. DMOG treatment attenuated MC903-induced skin inflammation in a T cell-independent manner. The anti-inflammatory effect of DMOG was accompanied by downregulation of TSLP and IL-33, and supplementation with recombinant TSLP and IL-33 abolished the effect of DMOG. MC903 increased ROS levels in skin tissue, which was prevented by DMOG. Furthermore, the ROS scavenger N-acetylcysteine (NAC) downregulated TSLP and ameliorated MC903-induced skin inflammation, as did DMOG. Finally, the effect of DMOG on ROS and TSLP was reduced by HIF knockdown. These results suggest that DMOG downregulates TSLP and ROS through the HIF pathway, which reduces MC903-induced skin inflammation.

Single glucose challenge test procedure for diagnosis of gestational diabetes mellitus: a Jammu cohort study.

AIM: To elucidate an evidence based Single Glucose Challenge test to diagnose Gestational Diabetes Mellitus (GDM). METHOD: This study included 500 pregnant women in 16-32 weeks of gestation. They underwent 75g Oral Glucose Challenge test irrespective of the last meal timing and 2 hr venous blood was drawn. After 3 days they underwent 75g OGTT in the fasting state and their 2 hr blood was drawn. Plasma glucose was estimated in both samples by GOD-POD method. GDM was diagnosed with 2hr Plasma glucose (PG) > or = 7.8 mmol/l (> or = 140 mg/dl) based on WHO criteria. The data was analysed by computer software Microsoft excel for windows and epi-info version 6.0, CDC, Atlanta, GA. RESULTS: Among 500 women, 55(11%) were diagnosed as GDM by WHO criteria. It was observed that there was no statistical difference (p > 0.05) between 2 hr PG of GCT and 2 hr PG of WHO recommended method. CONCLUSION: This Single Glucose Challenge test procedure is cost-effective, evidence based and patient friendly approach to diagnosis Gestational Diabetes Mellitus.

Lysophosphatidylcholine aggravates contact hypersensitivity by promoting neutrophil infiltration and IL17 expression.

Lysophosphatidylcholine (LPC) is a bioactive lysolipid known to contribute to the development of lung allergic diseases. However, it remains unknown whether LPC possesses proinflammatory properties in the skin as well. Here, we investigated this issue by injection of LPC into the murine contact hypersensitivity (CHS) model induced by 2,4-dinitrofluorobenzene (DNFB). LPC increased the expression of IL17, recruited more neutrophils, and eventually aggravated the CHS in the skins. Moreover, the effects of LPC diminished after neutralizing IL17 or depleting neutrophils. Mechanistically, LPC upregulated not only IL17 but also CXCL1 and CXCL2 in a G2A-dependent manner. Taken together, our study demonstrated that the upregulation of LPC could contribute to allergic skin inflammation by increasing IL17 expression and neutrophil recruitment via G2A receptor. [BMB Reports 2021; 54(4): 203-208].

Respiratory volume monitoring in an obese surgical population and the prediction of postoperative respiratory depression by the STOP-bang OSA risk score.

STUDY OBJECTIVE: To evaluate use of a respiratory volume monitor (RVM; ExSpiron, Respiratory Motion, Inc., Waltham, MA, USA) that provides minute ventilation (MV), tidal volume (TV) and respiratory rate (RR) measurements in obese surgical patients, hitherto undescribed. DESIGN: Prospective, IRB-approved observational study of RVM parameter accuracy in obese surgical patients, designed to test the ability of the RVM to detect predefined postoperative respiratory depression (PORD) and apneic events (POA) and to correlate STOP-Bang scores with PORD and POA. SETTING: Pre-, intra-, and post-op patient-care areas, including the post-anesthesia care unit (PACU) in 2 academic centers with bariatric populations. PATIENTS: 80 patients (47±12 years), BMI of 43±7 kg/m(2) undergoing elective surgery were enrolled. INTERVENTIONS: Data collected included patient characteristics, STOP-Bang scores and RVM data from immediately preoperatively through PACU completion without effecting standard clinical care. MEASUREMENTS: Low minute ventilation (LMV) was defined as 40% of predicted MV, and PORD was defined as sustained LMV for 5 minutes. Appropriate parametric and non-parametric statistical analyses were performed, P<.05 considered significant. MAIN RESULTS: In 56 patients with complete intraoperative ventilator data, correlation between RVM and ventilator MV measurements was r=0.89 (measurement bias 1.5%, accuracy 11%). Measurement error was 0.13 L/min (95% confidence interval-0.93 L/min - 1.20 L/min). In PACU, 16.3% and 31% of patients had PORD and POA respectively. There were no significant differences in the incidence of PORD and POA in 3 STOP-Bang risk categories (P>.2). CONCLUSIONS: There was excellent correlation and accuracy between the RVM and ventilator volumes in obese surgical patients. A considerable number of patients exhibited PORD and POA in the PACU. The STOP-Bang risk scores correlated poorly with PORD and POA which suggests that obese surgical patients remain at risk for early post-operative respiratory events irrespective of the STOP-Bang score.