Zhx2 (Zinc Fingers and Homeoboxes 2) Regulates Major Urinary Protein Gene Expression in the Mouse Liver

The mouse major urinary proteins (Mups) are encoded by a large family of highly related genes clustered on chromosome 4. Mups, synthesized primarily and abundantly in the liver and secreted through the kidneys, exhibit male-biased expression. Mups bind a variety of volatile ligands; these ligands, and Mup proteins themselves, influence numerous behavioral traits. Although urinary Mup protein levels vary between inbred mouse strains, this difference is most pronounced in BALB/cJ mice, which have dramatically low urinary Mup levels; this BALB/cJ trait had been mapped to a locus on chromosome 15. We previously identified Zhx2 (zinc fingers and homeoboxes 2) as a regulator of numerous liver-enriched genes. Zhx2 is located on chromosome 15, and a natural hypomorphic mutation in the BALB/cJ Zhx2 allele dramatically reduces Zhx2 expression. Based on these data, we hypothesized that reduced Zhx2 levels are responsible for lower Mup expression in BALB/cJ mice. Using both transgenic and knock-out mice along with in vitro assays, our data show that Zhx2 binds Mup promoters and is required for high levels of Mup expression in the adult liver. In contrast to previously identified Zhx2 targets that appear to be repressed by Zhx2, Mup genes are positively regulated by Zhx2. These data identify Zhx2 as a novel regulator of Mup expression and indicate that Zhx2 activates as well as represses expression of target genes

Secret origins of the state: the structural basis of raison d'état

The Italian city-state system occupies a special place in the canon of orthodox international relations. For, as Martin Wight says, ‘it was among the Italian powers that feudal relationships first disappeared and the efficient, self-sufficient secular state was evolved, and the Italian powers invented the diplomatic system’. And of course this was not all they invented. In addition to the earliest modern discourse of Realpolitik (‘Machiavelli’, Carr tells us, ‘is the first important political realist’), it is in the Italian city-states that we find the first routine use of double-entry book-keeping, of publicly traded state debt, of marine insurance, of sophisticated instruments of credit (such as the bill of exchange), of commercial and banking firms coordinating branch activity across the continent, and so on. Here, too, the citizen militias gave way earliest to the mercenary armies that would later characterize European Absolutism; and within the town walls, a population given over increasingly to commerce and manufacture elaborated new forms of urban class conflict

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Acquired left ventricular outflow tract obstruction and cardiogenic shock treated with β-blockers

β-Blockers are normally contraindicated in the treatment of cardiogenic shock. A 70-year-old lady presents with an acute coronary syndrome complicated by critical cardiogenic shock. Coronary angiography shows an ulcerated nonobstructing plaque in the left anterior descending artery. She fails to improve with standard treatment with inotrope and intraaortic balloon pump. Echocardiography revealed acquired left ventricular outflow tract (LVOT) obstruction and secondary mitral regurgitation. Treatment with intravenous β-blockers produced both clinical and hemodynamic improvement as well as resolution of LVOT obstruction. Echocardiography is essential in defining the mechanism of cardiogenic shock in patients with acute coronary syndrome. Inotropic support exacerbates cardiogenic shock due to acquired LVOT obstruction that is best treated with β-blockers

Hospital Value-Based Purchasing and Trauma-Certified Hospital Performance

Introduction:Hospital Value-Based Purchasing (HVBP) is an initiative that rewards acute-care hospitals with incentive payments for the quality of care they provide. A hospital\u27s trauma certification has the potential to influence HVBP scores as attaining the certification provides indication of the service quality offered by the hospital. As such, this study focuses on hospitals\u27 level of trauma certification attainment through the American College of Surgeons and whether this certification is associated with greater HVBP.Methods:A retrospective review of the 2015 HVBP database, 2015 Area Health Resources Files (AHRF) database, and the 2015 American Hospital Association (AHA) database is utilized, and propensity score matching was employed to determine the association between level of trauma certification and scores on HVBP dimensions.Results:Results reveal trauma certification is associated with lower HVBP domain scores when compared to hospitals without trauma certification. In addition, hospitals with a greater degree of trauma specialization were associated with lower total performance score and efficiency domain scores.Conclusions:Although payers attempt to connect hospital reimbursements with quality and outcomes, unintended consequences may occur. In response to these results, HVBP risk adjustment and scoring methods should receive further scrutiny

Clinical results and complications following surgical management of symptomatic os acromiale: a systematic review

Abstract Background This review compares the outcomes and complication rates of three surgical strategies used for the management of symptomatic os acromiale. The purpose of this study was to help guide best practice recommendations. Methods A systematic review of nine prospective studies, seven retrospective studies, and three case studies published across ten countries between 1993 and 2018 was performed. Adult patients (i.e., ≥ 18 years of age) with a symptomatic os acromiale that failed nonoperative management were included in this review. Surgical techniques utilized within the included studies include excision, acromioplasty, and open reduction and internal fixation (ORIF). The primary outcomes of interest included patient satisfaction. Range of motion and several standardized outcome measurement tools were also included in the final analysis. Results Patient satisfaction was highest in the excision and ORIF groups, with 92% and 82% of patients reporting good to excellent postoperative results, respectively, compared to 63% in the acromioplasty group. All three patient groups experienced improvements in postoperative outcomes (i.e., active range of motion and patient-reported outcome scores). The excision group experienced a complication rate of 1%, while the acromioplasty group experienced a complication rate of 11% and the ORIF group a rate of 67%. Conclusion This study reports on the largest sample of patients who underwent surgical treatment for a symptomatic os acromiale. We have demonstrated that excision of the os with meticulous repair of the deltoid resulted in the best clinical outcomes with the least complications. In healthy adult patients with a large os fragment and a normal rotator cuff, surgical fixation may provide increased preservation of deltoid function while offering good to excellent patient satisfaction. However, patients must be informed that a second procedure may be required to remove symptomatic hardware

Selective Inhibition of Matrix Metalloproteinase-9 Attenuates Secondary Damage Resulting from Severe Traumatic Brain Injury

<div><p>Traumatic brain injury (TBI) is a leading cause of death and long-term disability. Following the initial insult, severe TBI progresses to a secondary injury phase associated with biochemical and cellular changes. The secondary injury is thought to be responsible for the development of many of the neurological deficits observed after TBI and also provides a window of opportunity for therapeutic intervention. Matrix metalloproteinase-9 (MMP-9 or gelatinase B) expression is elevated in neurological diseases and its activation is an important factor in detrimental outcomes including excitotoxicity, mitochondrial dysfunction and apoptosis, and increases in inflammatory responses and astrogliosis. In this study, we used an experimental mouse model of TBI to examine the role of MMP-9 and the therapeutic potential of SB-3CT, a mechanism-based gelatinase selective inhibitor, in ameliorating the secondary injury. We observed that activation of MMP-9 occurred within one day following TBI, and remained elevated for 7 days after the initial insult. SB-3CT effectively attenuated MMP-9 activity, reduced brain lesion volumes and prevented neuronal loss and dendritic degeneration. Pharmacokinetic studies revealed that SB-3CT and its active metabolite, <i>p</i>-OH SB-3CT, were rapidly absorbed and distributed to the brain. Moreover, SB-3CT treatment mitigated microglial activation and astrogliosis after TBI. Importantly, SB-3CT treatment improved long-term neurobehavioral outcomes, including sensorimotor function, and hippocampus-associated spatial learning and memory. These results demonstrate that MMP-9 is a key target for therapy to attenuate secondary injury cascades and that this class of mechanism-based gelatinase inhibitor–with such desirable pharmacokinetic properties–holds considerable promise as a potential pharmacological treatment of TBI.</p></div