IL-6 prevents Th2 cell polarization by promoting SOCS3-dependent suppression of IL-2 signaling.

Defective interleukin-6 (IL-6) signaling has been associated with Th2 bias and elevated IgE levels. However, the underlying mechanism by which IL-6 prevents the development of Th2-driven diseases remains unknown. Using a model of house dust mite (HDM)-induced Th2 cell differentiation and allergic airway inflammation, we showed that IL-6 signaling in allergen-specific T cells was required to prevent Th2 cell differentiation and the subsequent IgE response and allergic inflammation. Th2 cell lineage commitment required strong sustained IL-2 signaling. We found that IL-6 turned off IL-2 signaling during early T-cell activation and thus inhibited Th2 priming. Mechanistically, IL-6-driven inhibition of IL-2 signaling in responding T cells was mediated by upregulation of Suppressor Of Cytokine Signaling 3 (SOCS3). This mechanism could be mimicked by pharmacological Janus Kinase-1 (JAK1) inhibition. Collectively, our results identify an unrecognized mechanism that prevents the development of unwanted Th2 cell responses and associated diseases and outline potential preventive interventions.

Creating a Chest Wall Injury and Reconstructive program: A single center experience with rib fractures.

BACKGROUND: New Chest Wall Injury and Reconstructive Centers (CWIRC) are emerging; this study aims to investigate the potential benefits of implementing a CWIRC at a single institution. We hypothesized that patients treated at CWIRC will have improved outcomes. METHODS: We instituted a CWIRC in 2019 at our American College of Surgeons (ACS) Level One Trauma Center. We retrospectively compared trauma patients with rib fractures who presented to our center 18 months before (PRE-C) and 18 months after CWIRC implementation (POST-C). Outcomes measured included mortality, length of stay (LOS), intensive care unit (ICU-LOS), readmission rates, and unplanned ICU admission. RESULTS: There were 192 PRE-C patients, compared to 388 POST-C. The mortality in PRE-C was not significantly different compared to the POST-C group (11.46% vs 8.8%, p=0.308). There were also no differences in LOS, ICU-LOS, readmission, and unplanned ICU admission. ICU utilization was dramatically different: PRE-C 17.8% were admitted to ICU compared to 35.6% POST-C (p<0.0001). CONCLUSIONS: The number of patients admitted with rib fractures to our center nearly doubled after CWIRC establishment. Early diagnosis and triage led to significantly more admissions to higher levels of care. There are trends toward improved outcomes using practice management protocols, albeit with higher ICU utilization. Establishment of a CWIRC should be considered for level 1 ACS trauma centers and as utilization of established CWIRC protocols are increased, patients will have improved outcomes. LEVEL OF EVIDENCE: IV STUDY TYPE: Retrospective chart review.

Victims of Violence and Post-Discharge Adverse Events: A Prospective Modified Trauma Quality Improvement Program (TQIP) Study.

Introduction Trauma patients frequently return to an emergency department (ED) soon after discharge; often for non-urgent reasons. Social factors contribute to higher ED usage. At present, there is no standardized system for reporting of ED visits and readmissions among trauma care. We hypothesized that victims of violent crime suffer from many early post-discharge adverse events that has not been captured by current methods. Methods We prospectively consented and enrolled injured patients from January 1st, 2019 to December 31st, 2019. We documented 30-day post-discharge events using post-discharge phone calls and detailed chart abstraction. Patients were categorized as victims of violence (VV) or unintentional traumatic injury (UT). Results During the study period, 444 patients were enrolled. Fifty-one (11.5%) were victims of violence and 393 (88.5%) experienced unintentional injuries. The VV patients were younger (40.10 vs 60.36; p<0.0001), and more predominantly male (92.16% vs 57.51%; p<0.0001). Total injury severity score (ISS), critical care length of stay (LOS), and total LOS were similar. VV patients were more likely discharged home (70.59% vs 55.47%; p=0.0403). They were significantly more likely to return to an emergency department (47.06% vs 23.16%; p<0.0005) and had more total number of ED visits per patient. Readmission rates, however, were not different (21.57% vs 16.28%; p=NS). The VV patients more frequently were underinsured (72.5%, vs 20.6%, p<0.005). Discussion Victims of violence presented to the ED significantly more often, despite similar injury scores, LOS, and being of younger age. Of these patients, only 26.2% of ED presentations resulted in readmission, suggesting the majority of patient complaints may have been able to be managed in an office-based setting. VV had significantly more underinsured or subsidized patients. Victims of violence are vulnerable and may benefit from more resources provided in the early post-discharge period.

Slowed Diffusion and Excluded Volume Both Contribute to the Effects of Macromolecular Crowding on Alcohol Dehydrogenase Steady-State Kinetics.

To understand the consequences of macromolecular crowding, studies have largely employed in vitro experiments with synthetic polymers assumed to be both pure and "inert". These polymers alter enzyme kinetics by excluding volume that would otherwise be available to the enzymes, substrates, and products. Presented here is evidence that other factors, in addition to excluded volume, must be considered in the interpretation of crowding studies with synthetic polymers. Dextran has a weaker effect on the Michaelis-Menten kinetic parameters of yeast alcohol dehydrogenase (YADH) than its small molecule counterpart, glucose. For glucose, the decreased Vmax values directly correlate with slower translational diffusion and the decreased Km values likely result from enhanced substrate binding due to YADH stabilization. Because dextran is unable to stabilize YADH to the same extent as glucose, this polymer's ability to decrease Km is potentially due to the nonideality of the solution, a crowding-induced conformational change, or both. Chronoamperometry reveals that glucose and dextran have surprisingly similar ferricyanide diffusion coefficients. Thus, the reduction in Vmax values for glucose is partially offset by an additional macromolecular crowding effect with dextran. Finally, this is the first report that supplier-dependent impurities in dextran affect the kinetic parameters of YADH. Taken together, our results reveal that caution should be used when interpreting results obtained with inert synthetic polymeric agents, as additional effects from the underlying monomer need to be considered.

Scholl Cyclizations of Aryl Naphthalenes: Rearrangement Precedes Cyclization.

In 1910, Scholl, Seer, and Weitzenbock reported the AlCl3-catalyzed cyclization of 1,1'-binaphthyl to perylene. We provide evidence that this classic organic name reaction proceeds through sequential and reversible formation of 1,2'- and 2,2'-binaphthyl isomers. Acid-catalyzed isomerization of 1,1'-binaphthyl to 2,2'-binaphthyl has been noted previously. The superacid trifluoromethanesulfonic acid (TfOH), 1 M in dichloroethane, catalyzes these rearrangements, with slower cyclization to perylene. Minor cyclization products are benzo[k]fluoranthene and benzo[j]fluoranthene. At ambient temperature, the observed equilibrium ratio of 1,1'-binaphthyl, 1,2'-binaphthyl, and 2,2'-binaphthyl is <1:3:97. DFT calculations with the inclusion of solvation support a mechanistic scheme in which ipso-arenium ions are responsible for rearrangements; however, we cannot distinguish between arenium ion and radical cation mechanisms for the cyclization steps. Under similar reaction conditions, 1-phenylnaphthalene interconverts with 2-phenylnaphthalene, with the latter favored at equilibrium (5:95 ratio), and also converts slowly to fluoranthene. Computations again support an arenium ion mechanism for rearrangements.

A nationwide 2010-2012 analysis of U.S. health care utilization in inflammatory bowel diseases.

BACKGROUND: Implementation of the 2010 Affordable Care Act (ACA) calls for a collaborative effort to transform the U.S. health care system toward patient-centered and value-based care. To identify how specialty care can be improved, we mapped current U.S. health care utilization in patients with inflammatory bowel diseases (IBD) using a national insurance claims database. METHODS: We performed a cross-sectional study analyzing U.S. health care utilization in 964,633 patients with IBD between 2010 and 2012 using insurance claims data, including pharmacy and medical claims. Frequency of IBD-related care utilization (medication, tests, and treatments) and their charges were evaluated. Subsequently, outcomes were put into the framework of current U.S. guidelines to identify areas of improvement. RESULTS: A disproportionate usage of aminosalicylates in Crohn's disease (42%), frequent corticosteroid use (46%, with 9% long-term users), and low rates of corticosteroid-sparing drugs (thiopurines 15%; methotrexate 2.7%) were observed. Markers for inflammatory activity, such as C-reactive protein or fecal calprotectin were not commonly used (8.8% and 0.13%, respectively). Although infrequently used (11%), anti-TNF antibody therapy represents a major part of observed IBD charges. CONCLUSIONS: This analysis shows 2010-2012 utilization and medication patterns of IBD health care in the United States and suggests that improvement can be obtained through enhanced guidelines adherence.

Incidental findings in trauma patients: dedicated communication with the primary care physician ensures adequate follow-up.

BACKGROUND: Frequent use of computed tomography (CT) in trauma patients results in frequent detection of non-trauma-related incidental findings (IFs). Inpatient documentation and disclosure at discharge are infrequent, even when they are potentially serious. We aimed to not only identify the incidence of IFs but also to evaluate the effectiveness of an intervention to trigger follow-up. METHODS: In this before-after study, all trauma patients evaluated by the trauma surgery service who underwent CT were admitted for >24 h, had at least one IF requiring follow-up, and had a primary care physician (PCP) employed in our health care system were identified. The historical control period was from January 2006 to December 2008. The intervention period was from December 2011 to September 2012. Intervention consisted of notifying the PCP via email or postal letter. The outcome of interest-the rate of follow-up-was compared between both groups. RESULTS: During the historical period, 364 (20.5 %) of 1,774 eligible trauma patients had 434 IFs requiring follow-up. During the study period, 197 (26 %) of 692 trauma patients had 212 IFs requiring follow-up. Overall, 91 % of study patients with postdischarge PCP follow-up had documented follow-up of the IF. There was a significant improvement in the rate of follow-up in the study group compared to that of the control group (51 vs. 11 %; p < 0.0001). CONCLUSIONS: Detection of IFs is common in trauma patients. A dedicated effort of communicating the presence of an IF to the patient's PCP triggered a follow-up for 91 % of patients who saw their PCP after hospital discharge.

Phenyl shifts in substituted arenes via ipso arenium ions.

The isomerization of substituted arenes through ipso arenium ions is an important and general molecular rearrangement that leads to interconversions of constitutional isomers. We show here that the superacid trifluoromethanesulfonic acid (TfOH), ca. 1 M in dichloroethane (DCE), provides reliable catalytic reaction conditions for these rearrangements, easily applied at ambient temperature, reflux (84 °C), or in a microwave reactor for higher temperatures. Interconversion of terphenyl isomers in TfOH/DCE at 84 °C gives an ortho/meta/para equilibrium ratio of 0:65:35, nearly identical to values reported earlier by Olah with catalysis by AlCl(3). For the three triphenylbenzenes, TfOH-catalyzed equilibration strongly (>95%) favors the 1,3,5-triphenyl isomer. Equilibration of the three possible tetraphenylbenzenes gives a 61:39 mixture of the 1,2,3,5- and 1,2,4,5-substituted isomers. Under the reaction conditions explored, none of these structures undergoes significant Scholl cyclization. DFT calculations with inclusion of solvation support a mechanistic scheme in which all of the phenyl migrations occur among a series of ipso arenium ions. In every case studied, the preferred isomers at equilibrium are those that yield highly stable cations by the most exothermic, hence least reversible 1,2-H shift.

CC chemokine receptor-3 (CCR3) antagonists: improving the selectivity of DPC168 by reducing central ring lipophilicity.

DPC168, a benzylpiperidine-substituted aryl urea CCR3 antagonist evaluated in clinical trials, was a relatively potent inhibitor of the 2D6 isoform of cytochrome P-450 (CYP2D6). Replacement of the cyclohexyl central ring with saturated heterocycles provided potent CCR3 antagonists with improved selectivity against CYP2D6. The favorable preclinical profile of DPC168 was maintained in an acetylpiperidine derivative, BMS-570520.

Benzothiazole benzimidazole (S)-isothiazolidinone derivatives as protein tyrosine phosphatase-1B inhibitors.

Benzothiazole benzimidazole (S)-isothiazolidinone ((S)-IZD) derivatives 5 were discovered through a peptidomimetic modification of the tripeptide (S)-IZD protein tyrosine phosphatase 1B (PTP1B) inhibitor 1. These derivatives are potent, competitive, and reversible inhibitors of PTP1B with improved caco-2 permeability. An X-ray co-crystal structure of inhibitor 5/PTP1B at 2.2A resolution demonstrated that the benzothiazole benzimidazole forms bi-dentate H-bonds to Asp48, and the benzothiazole interacts with the surface of the protein in a solvent exposed region towards the C-site. The design, synthesis, and SAR of this novel series of benzothiazole benzimidazole containing (S)-IZD inhibitors of PTP1B are presented herein.

Structural insights into the design of nonpeptidic isothiazolidinone-containing inhibitors of protein-tyrosine phosphatase 1B.

Structural analyses of the protein-tyrosine phosphatase 1B (PTP1B) active site and inhibitor complexes have aided in optimization of a peptide inhibitor containing the novel (S)-isothiazolidinone (IZD) phosphonate mimetic. Potency and permeability were simultaneously improved by replacing the polar peptidic backbone of the inhibitor with nonpeptidic moieties. The C-terminal primary amide was replaced with a benzimidazole ring, which hydrogen bonds to the carboxylate of Asp(48), and the N terminus of the peptide was replaced with an aryl sulfonamide, which hydrogen bonds to Asp(48) and the backbone NH of Arg(47) via a water molecule. Although both substituents retain the favorable hydrogen bonding network of the peptide scaffold, their aryl rings interact weakly with the protein. The aryl ring of benzimidazole is partially solvent exposed and only participates in van der Waals interactions with Phe(182) of the flap. The aryl ring of aryl sulfonamide adopts an unexpected conformation and only participates in intramolecular pi-stacking interactions with the benzimidazole ring. These results explain the flat SAR for substitutions on both rings and the reason why unsubstituted moieties were selected as candidates. Finally, substituents ortho to the IZD heterocycle on the aryl ring of the IZD-phenyl moiety bind in a small narrow site adjacent to the primary phosphate binding pocket. The crystal structure of an o-chloro derivative reveals that chlorine interacts extensively with residues in the small site. The structural insights that have led to the discovery of potent benzimidazole aryl sulfonamide o-substituted derivatives are discussed in detail.

Potent benzimidazole sulfonamide protein tyrosine phosphatase 1B inhibitors containing the heterocyclic (S)-isothiazolidinone phosphotyrosine mimetic.

Potent nonpeptidic benzimidazole sulfonamide inhibitors of protein tyrosine phosphatase 1B (PTP1B) were derived from the optimization of a tripeptide containing the novel (S)-isothiazolidinone ((S)-IZD) phosphotyrosine (pTyr) mimetic. An X-ray cocrystal structure of inhibitor 46/PTP1B at 1.8 A resolution demonstrated that the benzimidazole sulfonamides form a bidentate H bond to Asp48 as designed, although the aryl group of the sulfonamide unexpectedly interacts intramolecularly in a pi-stacking manner with the benzimidazole. The ortho substitution to the (S)-IZD on the aryl ring afforded low nanomolar enzyme inhibitors of PTP1B that also displayed low caco-2 permeability and cellular activity in an insulin receptor (IR) phosphorylation assay and an Akt phosphorylation assay. The design, synthesis, and SAR of this novel series of benzimidazole sulfonamide containing (S)-IZD inhibitors of PTP1B are presented herein.

Structure-based design and discovery of protein tyrosine phosphatase inhibitors incorporating novel isothiazolidinone heterocyclic phosphotyrosine mimetics.

Structure-based design led to the discovery of novel (S)-isothiazolidinone ((S)-IZD) heterocyclic phosphotyrosine (pTyr) mimetics that when incorporated into dipeptides are exceptionally potent, competitive, and reversible inhibitors of protein tyrosine phosphatase 1B (PTP1B). The crystal structure of PTP1B in complex with our most potent inhibitor 12 revealed that the (S)-IZD heterocycle interacts extensively with the phosphate binding loop precisely as designed in silico. Our data provide strong evidence that the (S)-IZD is the most potent pTyr mimetic reported to date.

Concise approach to novel isothiazolidinone phosphotyrosine mimetics: microwave-assisted addition of bisulfite to activated olefins.

[reaction: see text] A novel and efficient synthesis of isothiazolidinone protein tyrosine phosphatase mimetics is presented. A practical, regiospecific microwave-assisted addition of bisulfite to activated olefins, including unprecedented reactions with styrene derivatives, is highlighted.