87 research outputs found
Serum IgG2 levels are specifically associated with whole-body insulin-mediated glucose disposal in non-diabetic offspring of type 2 diabetic individuals. a cross-sectional study
.Preclinical studies suggested that IgG2c isotype may specifically impair skeletal muscle insulin
sensitivity in mice. In this study we investigated the association between serum levels of the four IgG
subclasses and insulin sensitivity in non-diabetic individuals. Total IgG, IgG1, IgG2, IgG3 and IgG4
levels were measured in 262 subjects. Whole-body insulin sensitivity was assessed by euglycemic
hyperinsulinemic clamp. IgG2 levels were positively correlated with BMI, waist circumference, 2-h postload
glucose levels and complement C3. Serum IgG2, but not IgG1, IgG3 and IgG4 levels were negatively
correlated with whole-body insulin sensitivity (r = â0.17; P = 0.003) and muscle insulin sensitivity index
(r = â0.16; P = 0.03) after adjustment for age and gender. No significant correlation was found between
IgG2 levels and hepatic insulin resistance assessed by HOMA-IR and liver IR index. In a multivariable
regression analysis including variables known to affect insulin sensitivity such as age, gender, BMI,
smoking, lipids, inflammatory markers, fasting and 2-h post-load glucose levels, IgG2 levels were
independently associated with insulin-stimulated glucose disposal (ÎČ = â0.115, 95% CI: â0.541 to
â0.024; P = 0.03). These data demonstrate the independent association between higher levels of IgG2
and decreased whole-body insulin sensitivity, thus confirming in humans the animal-based evidence
indicating the pathogenic role of IgG2 in insulin resistance
Probing the interaction interface of the GADD45ÎČ/MKK7 and MKK7/DTP3 complexes by chemical cross-linking mass spectrometry
GADD45ÎČ is selectively and constitutively expressed in Multiple Myeloma cells, and this expression correlates with an unfavourable clinical outcome. GADD45ÎČ physically interacts with the JNK kinase, MKK7, inhibiting its activity to enable the survival of cancer cells. DTP3 is a small peptide inhibitor of the GADD45ÎČ/MKK7 complex and is able to restore MKK7/JNK activation, thereby promoting selective cell death of GADD45ÎČ-overexpressing cancer cells. Enzymatic MS foot-printing and diazirine-based chemical cross-linking MS (CX-MS) strategies were applied to study the interactions between GADD45ÎČ and MKK7 kinase domain (MKK7_KD) and between DTP3 and MKK7_KD. Our data show that the binding between GADD45ÎČ and MKK7 largely occurs between GADD45ÎČ loop 2 (region 103â117) and the kinase enzymatic pocket. We also show that DTP3 interferes with this GADD45ÎČ/MKK7 interaction by contacting the MKK7 peptides, 113â136 and 259â274. Accordingly, an MKK7_KD Î(101â136) variant lacking Trp135 did not produce a fluorescence quenching effect upon the binding of DTP3. The assessment of the interaction between GADD45ÎČ and MKK7 and the elucidation of the recognition surfaces between DTP3 and MKK7 significantly advance the understanding of the mechanism underlying the inhibition of the GADD45ÎČ/MKK7 interaction by DTP3 and pave the way to the design of small-molecule DTP3 analogues
Predictors of poor retention on antiretroviral therapy as a major HIV drug resistance early warning indicator in Cameroon: results from a nationwide systematic random sampling
Retention on lifelong antiretroviral therapy (ART) is essential in sustaining treatment success while preventing HIV drug resistance (HIVDR), especially in resource-limited settings (RLS). In an era of rising numbers of patients on ART, mastering patients in care is becoming more strategic for programmatic interventions. Due to lapses and uncertainty with the current WHO sampling approach in Cameroon, we thus aimed to ascertain the national performance of, and determinants in, retention on ART at 12Â months
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 nonâcritically 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 (nâ=â257), ARB (nâ=â248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; nâ=â10), or no RAS inhibitor (control; nâ=â264) for up to 10 days.
MAIN OUTCOMES AND MEASURES The primary outcome was organ supportâfree 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 supportâfree days among critically ill patients was 10 (â1 to 16) in the ACE inhibitor group (nâ=â231), 8 (â1 to 17) in the ARB group (nâ=â217), and 12 (0 to 17) in the control group (nâ=â231) (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 supportâfree 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
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