Multiorgan involvement and circulating IgG1 predict hypocomplementaemia in IgG4-related disease.

OBJECTIVES: Hypocomplementaemia is common in patients with IgG4-related disease (IgG4-RD). We aimed to determine the IgG4-RD features associated with hypocomplementaemia and investigate mechanisms of complement activation in this disease. METHODS: We performed a single-centre cross-sectional study of 279 patients who fulfilled the IgG4-RD classification criteria, using unadjusted and multivariable-adjusted logistic regression to identify factors associated with hypocomplementaemia. RESULTS: Hypocomplementaemia was observed in 90 (32%) patients. In the unadjusted model, the number of organs involved (OR 1.42, 95% CI 1.23 to 1.63) and involvement of the lymph nodes (OR 3.87, 95% CI 2.19 to 6.86), lungs (OR 3.81, 95% CI 2.10 to 6.89), pancreas (OR 1.66, 95% CI 1.001 to 2.76), liver (OR 2.73, 95% CI 1.17 to 6.36) and kidneys (OR 2.48, 95% CI 1.47 to 4.18) were each associated with hypocomplementaemia. After adjusting for age, sex and number of organs involved, only lymph node (OR 2.59, 95% CI 1.36 to 4.91) and lung (OR 2.56, 95% CI 1.35 to 4.89) involvement remained associated with hypocomplementaemia while the association with renal involvement was attenuated (OR 1.6, 95% CI 0.92 to 2.98). Fibrotic disease manifestations (OR 0.43, 95% CI 0.21 to 0.87) and lacrimal gland involvement (OR 0.53, 95% CI 0.28 to 0.999) were inversely associated with hypocomplementaemia in the adjusted analysis. Hypocomplementaemia was associated with higher concentrations of all IgG subclasses and IgE (all p<0.05). After adjusting for serum IgG1 and IgG3, only IgG1 but not IgG4 remained strongly associated with hypocomplementaemia. CONCLUSIONS: Hypocomplementaemia in IgG4-RD is not unique to patients with renal involvement and may reflect the extent of disease. IgG1 independently correlates with hypocomplementaemia in IgG4-RD, but IgG4 does not. Complement activation is likely involved in IgG4-RD pathophysiology.

Platelet function testing and clinical outcomes in peripheral arterial disease: Systematic review and narrative synthesis.

OBJECTIVE: This systematic review aims to comprehensively assess the contemporary literature on platelet function testing (PFT) in individuals undergoing revascularization therapy for peripheral arterial disease (PAD). The goal is to identify whether PFT can aid in detecting antiplatelet resistance, predicting post-procedural thrombotic complications, and informing tailored treatment strategies. METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a literature review was conducted using PubMed databases. Search terms included relevant medical subject headings (MeSH) terms. Eligible articles published in English between 1990 and 2023 were analyzed. Studies that examined PFT outcomes in patients with PAD after lower extremity revascularization were included. RESULTS: Ten studies met the inclusion criteria. Various PFT methods were used, including thromboelastography with platelet mapping, multiplate analyzer, Cytochrome P450 2C19 testing, VerifyNow, corrected whole blood aggregometry, platelet function analyzer-100, and light transmission aggregometry. PFT identified individuals who were resistant or non-sensitive to antiplatelet therapy, with such patients facing increased risks of graft/stent thrombosis, amputation, and reintervention. However, substantial heterogeneity in surgical procedures, drug regimens, and testing methods was observed among the studies. CONCLUSIONS: PFTs can play a crucial role in detecting resistance and non-sensitivity to antiplatelet drugs in patients with PAD post-revascularization. However, heterogeneity of data and methods underlines the need for standardized protocols and consensus-building among PFTs. Enhancing clinical utility and reliability could help optimize antiplatelet thromboprophylaxis, minimize thrombotic complications, and improve treatment strategies in vascular surgery. Further research is necessary to solidify the role of PFTs in guiding antiplatelet therapy post-revascularization in patients with PAD.

Preoperative Anemia is Associated with Poorer Postoperative Outcomes in Patients Undergoing Infrainguinal Bypass Surgery.

BACKGROUND: Preoperative anemia is an important, modifiable risk factor among surgical patients. However, data are scarce on the impact of preoperative anemia on postoperative outcomes after infrainguinal bypass. METHODS: In this multi-institutional analysis, data were retrospectively collected on all infrainguinal bypass procedures performed between 2010 and 2020. Patients were grouped by preoperative hemoglobin as per the National Cancer Institute anemia scale (mild, 10 g/dL-lower limit of normal; moderate, 8.0-9.9 g/dL; severe, 6.5-7.9 g/dL). Multivariable comparisons were performed using logistic regression analysis. RESULTS: A total of 492 patients underwent bypass for peripheral artery disease over the 10-year study period. Median preoperative hemoglobin was 11.0 g/dL (interquartile range 9.5-12.7) and median follow-up was 1.7 years. Preoperative anemia was prevalent among bypass patients (mild 52.4% [n = 258], moderate 26.4% [n = 130], and severe 5.1% [n = 25]). Women were more likely to have moderate (49.2% [women] vs. 50.8% [men]) or severe anemia (52.0% [women] vs. 48.0% [men]) compared with normal hemoglobin (17.7% [women] vs. 82.3% [men]) (P < 0.001). Patients with preoperative anemia were more likely to present with tissue loss (22.8% [normal] vs. 47.7% [moderate] vs. 52.0% [severe], P = 0.01). Bypass target and conduit types were similar between groups. Anemic patients had longer median hospital length of stay compared with nonanemic patients (4 days [normal] vs. 5 days [mild] vs. 6 days [moderate] vs. 7 days [severe], P < 0.001). Postoperative mortality at 30 days was similar across anemia groups (2.5% [normal] vs. 4.6% [moderate] vs. 8.0% [severe], P = 0.23). On multivariable analysis, however, postoperative mortality was independently associated with severe anemia (odds ratio 7.5 [1.2-48.8], P = 0.04) and male gender (odds ratio 7.5 [1.2-26.4], P = 0.03). CONCLUSIONS: Preoperative anemia is common among patients undergoing infrainguinal bypass surgery and is an independent risk factor for postoperative mortality. Future investigation is needed to determine whether correction of anemia improves postoperative outcomes in these high-risk patients.

Neutralizing anti-IL-1 receptor antagonist autoantibodies induce inflammatory and fibrotic mediators in IgG4-related disease.

BACKGROUND: IgG4-related disease (IgG4-RD) is a fibroinflammatory condition involving loss of B-cell tolerance and production of autoantibodies. However, the relevant targets and role of these aberrant humoral immune responses are not defined. OBJECTIVE: Our aim was to identify novel autoantibodies and autoantigen targets that promote pathogenic responses in IgG4-RD. METHODS: We sequenced plasmablast antibody repertoires in patients with IgG4-RD. Representative mAbs were expressed and their specificities characterized by using cytokine microarrays. The role of anti-IL-1 receptor antagonist (IL-1RA) autoantibodies was investigated by using in vitro assays. RESULTS: We identified strong reactivity against human IL-1RA by using a clonally expanded plasmablast-derived mAb from a patient with IgG4-RD. Plasma from patients with IgG4-RD exhibited elevated levels of reactivity against IL-1RA compared with plasma from the controls and neutralized IL-1RA activity, resulting in inflammatory and fibrotic mediator production in vitro. IL-1RA was detected in lesional tissues from patients with IgG4-RD. Patients with anti-IL-1RA autoantibodies of the IgG4 subclass had greater numbers of organs affected than did those without anti-IL-1RA autoantibodies. Peptide analyses identified IL-1RA epitopes targeted by anti-IL-1RA antibodies at sites near the IL-1RA/IL-1R interface. Serum from patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) also had elevated levels of anti-IL-1RA autoantibodies compared with those of the controls. CONCLUSION: A subset of patients with IgG4-RD have anti-IL-1RA autoantibodies, which promote proinflammatory and profibrotic meditator production via IL-1RA neutralization. These findings support a novel immunologic mechanism underlying the pathogenesis of IgG4-RD. Anti-IL-1RA autoantibodies are also present in a subset of patients with SLE and RA, suggesting a potential common pathway in multiple autoimmune diseases.

Role of solute carrier transporters SLC25A17 and SLC27A6 in acquired resistance to enzalutamide in castration-resistant prostate cancer.

Enzalutamide (XTANDI®), an antiandrogen, is used for the treatment of advanced-stage prostate cancer. Approximately, 60% of patients receiving enzalutamide show initial remission followed by disease relapse with the emergence of highly aggressive castration-resistant prostate cancer. Solute carrier (SLC) proteins play a critical role in the development of drug resistance by altering cellular metabolism. Transcriptome analysis revealed the predominance of SLC25A17 and SLC27A6 in enzalutamide-resistant prostate cancer cells; however, their role in antiandrogen resistance has not been elucidated. sgRNA-mediated knockdown of SLC25A17 and SLC27A6 suppressed cell proliferation and migration in enzalutamide-resistant cells. An induction of G1/S cell cycle arrest and abundance of hypo-diploid cells along with the reduction in the protein expression CyclinD1 and CDK6, the checkpoint factors, was observed including increased cell death as evident by BAX upregulation in knockdown cells. Inhibition of SLC25A17 and SLC27A6 resulted in downregulation of fatty acid synthase and acetyl-CoA carboxylase with parallel decrease in the levels of lactic acid in enzalutamide resistant cells. However, downregulation of triglyceride and citric acid was only observed in SLC25A17 silenced cells. The protein-protein interaction of SLC25A17 and SLC27A6 revealed alteration in some common drug-resistant and metabolism-related genes. Analysis of The Cancer Genome Atlas database exhibiting high SLC25A17 and SLC27A6 gene expression in prostate cancer patients were associated with poor survival than those with low expression of these proteins. In conclusion, SLC25A17 and SLC27A6 and its interactive network play an essential role in the development of enzalutamide resistance through metabolic reprogramming and may be identified as therapeutic target(s) to circumvent drug resistance.

Impact of anticoagulation/antiplatelet therapy on femoropopliteal bypass graft outcomes.

BACKGROUND: Anticoagulant and antiplatelet (AC/AP) medications have been reported to improve bypass graft patency, however, the optimal AC/AP strategy remains unclear in the heterogenous peripheral artery disease population. METHODS: A multi-institutional retrospective review utilizing the Research Patient Data Registry database from 1995 to 2020 was performed for all patients who underwent femoropopliteal bypass procedures. Electronic medical records were used to obtain demographic information, comorbidities, smoking status, operative details (bypass target), postoperative AC/AP medications, postoperative complications, and long-term outcomes and were reviewed for the cohort. Cox proportional hazards model was used to determine independent risk factors for major adverse limb events (MALE) after bypass. MALE was defined as reintervention for patency or major amputation of index limb (above- or below-knee amputation). RESULTS: A total of 1421 patients underwent femoropopliteal bypass between 1995 and 2020 throughout five institutions included in this study. Complete data were available for 1292 of the 1421 patients (90.9%). The indications for bypass included intermittent claudication (21.4%), rest pain (30.3%), tissue loss (33.5%), and nonatherosclerotic disease (14.8%). Distal bypass targets comprised above-knee (38.6%) and below-knee (61.4%) popliteal arteries. Patients were divided into six groups based on postoperative AC/AP use including none (n = 57 [4.4%]), monoantiplatelet therapy (n = 587 [45.4%]), dual AP therapy (n = 214 [16.6%]), AC alone (n = 73 [5.7%]), AC + monoantiplatelet therapy (n = 319 [24.7%]), and AC + dual AP therapy (n = 42 [3.3%]). Postoperative bleeding complications were low for both hematoma (3.7%) and pseudoaneurysm (0.7%). There was no difference in bleeding complications across AC/AP groups (hematoma, P = .61; pseudoaneurysm, P = .31). After adjusting for patient factors, below-knee bypass target (hazard ratio [HR], 1.25; 95% confidence interval [CI], 1.04-1.52; P = .019) and bypass for tissue loss (HR, 1.40; 95% CI, 1.04-1.88; P = .028) were independent predictors for MALE. Great saphenous vein conduit trended toward protection for MALE, compared with prosthetic grafts (HR, 0.84; 95% CI, 0.70-1.01; P = .06). No AC/AP regimen was associated with of MALE, even stratifying by above-knee and below-knee bypass cohorts. The median follow-up period was 2 years. CONCLUSIONS: Among patients undergoing femoropopliteal bypass grafting, no combination of AC or AP medications was associated with improved graft patency; however, a below-knee target and tissue loss were associated with adverse limb events. AC and AP regimen may be individualized after bypass with regard to other concomitant medical comorbidities.

Risk factors and consequences of graft infection after femoropopliteal bypass: A 25-year experience.

OBJECTIVE: In this multi-institutional series, we aimed to determine the incidence, risk factors, and long-term outcomes of graft infection in patients post-femoropopliteal bypass. METHODS: A multi-institutional database was retrospectively queried for all femoropopliteal bypass procedures from 1995 through 2020. Cumulative incidence function estimated the long-term rate of bypass graft infection (BGI), and the Fine-Gray model was used to determine independent risk factors for BGI to account for death as a competing risk. RESULTS: Over the 25-year period, 1315 femoral popliteal bypasses were identified with a median follow-up of 2.89 years (interquartile range, 0.75-6.55 years). BGI was diagnosed in 34 patients (2.6%). BGI occurred between 9 days and 11.2 years postoperatively, with a median of 109 days. Estimated 1- and 5-year incidence of BGI was 2.1% (95% confidence interval [CI], 1.4%-3.1%) and 2.8% (95% CI, 1.9%-3.9%), respectively. Medical comorbidities, indications for bypass, and popliteal bypass targets (above- vs below-knee) were similar between patients with BGI and all patients (P = not significant for each). Patients with BGI were more frequently complicated by postoperative hematoma (14.7% vs 3.7%), superficial wound infection (38.2% vs 19.2%), lymphocele/lymphorrhea (8.8% vs 2.1%), and 30-day readmission rates (47.1% vs 21.3%) (P < .05 for each). Most commonly isolated pathogens were Staphylococcus aureus (n = 19; 55.9%) and polymicrobial cultures (n = 5; 14.7%). Reoperation for BGI involved incision and drainage (n = 7; 20.6%), graft excision without reconstruction (n = 12; 35.3%), graft excision with in-line reconstruction (n = 11; 32.4%), and graft excision with extra-anatomic reconstruction (n = 2; 5.9%). Nine patients with BGI (26.5%) ultimately required major amputation. Prosthetic bypass (subdistribution hazard ratio [SHR], 3.73; 95% CI, 1.64-8.51; P = .002), postoperative hematoma (SHR, 3.44; 95% CI, 1.23-9.61; P = .018), and 30-day readmission (SHR, 2.75; 95% CI, 1.27-5.44; P = .010) were independently associated with BGI. One-year amputation-free survival was 50% (95% CI, 31.9%-65.7%) after BGI. CONCLUSIONS: BGI is a rare complication of femoral-popliteal bypass with significant morbidity. Graft infection is associated with the use of prosthetic grafts, postoperative hematoma, and unplanned hospital readmission. Mitigation of these risk factors may decrease the risk of this dreaded complication.

A systematic review of thromboelastography utilization in vascular and endovascular surgery.

OBJECTIVE: Thromboelastography (TEG) is diagnostic modality that analyzes real-time blood coagulation parameters. Clinically, TEG primarily allows for directed blood component resuscitation among patients with acute blood loss and coagulopathy. The utilization of TEG has been widely adopted in among other surgical specialties; however, its use in vascular surgery is less prominent. We aimed to provide an up-to-date review of TEG utilization in vascular and endovascular surgery. METHODS: Using Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, a literature review with the Medical Subject Headings (MeSH) terms "TEG and arterial events", "TEG and vascular surgery", "TEG and vascular", "TEG and endovascular surgery", "TEG and endovascular", "TEG and peripheral artery disease", "TEG and prediction of arterial events", "TEG and prediction of complications ", "TEG and prediction of thrombosis", "TEG and prediction of amputation", and "TEG and amputation" was performed in Cochrane and PubMed databases to identify all peer-reviewed studies of TEG utilization in vascular surgery, written between 2000 and 2021 in the English language. The free-text and MeSH subheadings search terms included diagnosis, complications, physiopathology, surgery, mortality, and therapy to further restrict the articles. Studies were excluded if they were not in humans or pertaining to vascular or endovascular surgery. Additionally, case reports and studies with limited information regarding TEG utilization were excluded. Each study was independently reviewed by two researchers to assess for eligibility. RESULTS: Of the 262 studies identified through the MeSH strategy, 15 studies met inclusion criteria and were reviewed and summarized. Literature on TEG utilization in vascular surgery spanned cerebrovascular disease (n = 3), peripheral arterial disease (n = 3), arteriovenous malformations (n = 1), venous thromboembolic events (n = 7), and perioperative bleeding and transfusion (n = 1). In cerebrovascular disease, TEG may predict the presence and stability of carotid plaques, analyze platelet function before carotid stenting, and compare efficacy of antiplatelet therapy after stent deployment. In peripheral arterial disease, TEG has been used to predict disease severity and analyze the impact of contrast on coagulation parameters. In venous disease, TEG may predict hypercoagulability and thromboembolic events among various patient populations. Finally, TEG can be utilized in the postoperative setting to predict hemorrhage and transfusion requirements. CONCLUSIONS: This systematic review provides an up-to-date summarization of TEG utilization in multiple facets of vascular and endovascular surgery.

Outcomes of Femoropopliteal Bypass for Lifestyle-Limiting Claudication in the Endovascular Era.

INTRODUCTION: Outcomes after femoropopliteal bypass for intermittent claudication (IC) remain unclear in the endovascular era. METHODS: A multi-institutional database was retrospectively queried for all femoropopliteal bypass procedures performed between 1995 and 2020. Demographics, operative details, and outcomes were documented. A statistical analysis included Kaplan-Meier curves and Cox proportional hazards ratios (HR). RESULTS: A total of 282 patients underwent femoropopliteal bypass surgery for IC. Median age was 68 y (interquartile range, 61-73 y). Bypass conduits included great saphenous vein (GSV) (48.2%), prosthetic grafts (48.9%), and non-GSV autogenous grafts (2.8%). Distal bypass target was above-knee in 62.1% and below-knee in 37.9% of patients. The most common postoperative complications were wound infections (14.2%) followed by unplanned 30-d hospital readmissions (12.4%). Mortality rates were low at 0.4% (30 d) and 3.2% (1 y). Five-year primary patency rates trended highest for claudicants undergoing above-knee bypass with GSV conduit (log-rank P = 0.065). Five-year amputation-free survival rates were highest using GSV conduit regardless of distal bypass target (log-rank P = 0.017). On a multivariable analysis, age (HR 1.02 [1.00-1.04], P = 0.023) and active smoking (HR 1.48 [1.06-2.06], P = 0.021) were identified as risk factors for diminished primary graft patency. Risk factors for amputation-free survival included age (HR 1.03 [1.01-1.05], P < 0.001) and GSV conduit type (HR 0.65 [0.46-0.90], P = 0.011). CONCLUSIONS: Femoropopliteal bypass among claudicants is associated with high rates of wound infection and hospital readmission. Active smoking portends worse outcomes in this population. These data may inform clinical decision-making regarding surgical intervention for claudication in the endovascular era.

Metabolic Pathways for S-Metolachlor Detoxification Differ Between Tolerant Corn and Multiple-Resistant Waterhemp.

Herbicide resistance in weeds can be conferred by target-site and/or non-target-site mechanisms, such as rapid metabolic detoxification. Resistance to the very-long-chain fatty acid-inhibiting herbicide, S-metolachlor, in multiple herbicide-resistant populations (CHR and SIR) of waterhemp (Amaranthus tuberculatus) is conferred by rapid metabolism compared with sensitive populations. However, enzymatic pathways for S-metolachlor metabolism in waterhemp are unknown. Enzyme assays using S-metolachlor were developed to determine the specific activities of glutathione S-transferases (GSTs) and cytochrome P450 monooxygenases (P450s) from CHR and SIR seedlings to compare with tolerant corn and sensitive waterhemp (WUS). GST activities were greater (∼2-fold) in CHR and SIR compared to WUS but much less than corn. In contrast, P450s in microsomal extracts from CHR and SIR formed O-demethylated S-metolachlor, and their NADPH-dependent specific activities were greater (>20-fold) than corn or WUS. Metabolite profiles of S-metolachlor generated via untargeted and targeted liquid chromatography-mass spectrometry from CHR and SIR differed from WUS, with greater relative abundances of O-demethylated S-metolachlor and O-demethylated S-metolachlor-glutathione conjugates formed by CHR and SIR. In summary, our results demonstrate that S-metolachlor metabolism in resistant waterhemp involves Phase I and Phase II metabolic activities acting in concert, but the initial O-demethylation reaction confers resistance.

Resistance to a nonselective 4-hydroxyphenylpyruvate dioxygenase-inhibiting herbicide via novel reduction-dehydration-glutathione conjugation in Amaranthus tuberculatus.

Metabolic resistance to 4-hydroxyphenylpyruvate dioxygenase (HPPD)-inhibiting herbicides is a threat in controlling waterhemp (Amaranthus tuberculatus) in the USA. We investigated resistance mechanisms to syncarpic acid-3 (SA3), a nonselective, noncommercial HPPD-inhibiting herbicide metabolically robust to Phase I oxidation, in multiple-herbicide-resistant (MHR) waterhemp populations (SIR and NEB) and HPPD inhibitor-sensitive populations (ACR and SEN). Dose-response experiments with SA3 provided ED50 -based resistant : sensitive ratios of at least 18-fold. Metabolism experiments quantifying parent SA3 remaining in excised leaves during a time course indicated MHR populations displayed faster rates of SA3 metabolism compared to HPPD inhibitor-sensitive populations. SA3 metabolites were identified via LC-MS-based untargeted metabolomics in whole plants. A Phase I metabolite, likely generated by cytochrome P450-mediated alkyl hydroxylation, was detected but was not associated with resistance. A Phase I metabolite consistent with ketone reduction followed by water elimination was detected, creating a putative α,ß-unsaturated carbonyl resembling a Michael acceptor site. A Phase II glutathione-SA3 conjugate was associated with resistance. Our results revealed a novel reduction-dehydration-GSH conjugation detoxification mechanism. SA3 metabolism in MHR waterhemp is thus atypical compared to commercial HPPD-inhibiting herbicides. This previously uncharacterized detoxification mechanism presents a unique opportunity for future biorational design by blocking known sites of herbicide metabolism in weeds.

Molecular insights into enhanced resistance of Papaver somniferum against downy mildew by application of endophyte bacteria Microbacterium sp. SMR1.

Downy mildew is one of the most serious diseases of Papaver somniferum. Endophytes isolated from different parts of P. somniferum were screened for their ability to enhance resistance against downy mildew caused by the obligate biotrophic oomycete Peronospora meconopsidis. Two endophytes (SMR1 and SMR2) reduced the downy mildew on three P. somniferum genotypes (Sampada, J-16, and I-14). SMR1 (Microbacterium sp.) also enhanced the resistance of P. somniferum against downy mildew under field conditions. The biochemical markers of plant susceptibility under biotic stresses (proline and malondialdehyde) were found to be reduced in P. somniferum upon SMR1 treatment. To understand the mechanisms underlying the enhanced resistance to downy mildew in SMR1 endophyte-treated P. somniferum genotype J-16, we compared the expression profiles using the next-generation RNA sequencing approach between P. somniferum pretreated with SMR1 and untreated endophyte-free control plants following exposure to downy mildew pathogen. Comparative transcriptome analysis revealed differential expression of transcripts belonging to broad classes of signal transduction, protein modification, disease/defense proteins, transcription factors, and phytohormones in SMR1-primed P. somniferum after infection with downy mildew pathogen. Furthermore, enhanced salicylic acid content was observed in SMR1-primed P. somniferum after exposure to downy mildew pathogen. This study sheds light on molecular mechanisms underlying enhanced resistance to downy mildew in SMR1-primed P. somniferum. Finally, we propose that the SA-dependent defense pathway, the hallmark of systemic acquired resistance, is activated in SMR1-primed P. somniferum, triggering the endophyte-induced resistance.

Low vasopressin and progression of neonatal sepsis to septic shock: a prospective cohort study.

The study objective was to analyze the association between low plasma vasopressin and progression of sepsis to septic shock in neonates < 34 weeks gestation. Septic neonates of < 34 weeks gestation were consecutively enrolled; moribund neonates and those with major malformations were excluded. Subjects were monitored for progression of sepsis to septic shock over the first 7 days from enrolment. Plasma vasopressin levels and inducible nitric oxide synthase levels were measured at the onset of sepsis (T0), severe sepsis (T1), and septic shock (T2). Primary outcome was plasma vasopressin levels at the point of sepsis in those who progressed to septic shock in comparison with matched nested controls in the non-progression group. Forty-nine (47%) enrolled subjects developed severe sepsis or septic shock. Plasma vasopressin levels (pg/ml) at the onset of sepsis were significantly low in those who progressed to septic shock (median (IQR), 31 (2.5-80) versus 100 (12-156); p = 0.02). After adjusting for confounders, vasopressin levels were independently associated with progression to septic shock (adjusted OR (95% CI), 0.97 (0.96, 0.99); p = 0.01).Conclusion: Preterm septic neonates who progressed to septic shock had suppressed vasopressin levels before the onset of shock. Low vasopressin levels were independently associated with progression to septic shock.What is known:• In animal sepsis models and adult septic patients, exuberant production of nitric oxide metabolites and low vasopressin levels have been reportedly associated with progression to septic shock.• Vasopressin levels have been variably reported as low as well as elevated in children with septic shock.What is New:• Preterm neonates who progressed from sepsis to septic shock had significantly lower levels of vasopressin before the onset of shock in comparison with those who did not progress.• Low vasopressin levels independently predicted the progression from sepsis to septic shock in this population.

Postpartum Cardiogenic Pulmonary Edema: The Initial Presentation of an Underlying Rheumatic Heart Disease.

How to cite this article: Shadrach BJ, Tiwari D, Shahi SS, Goel R. Postpartum Cardiogenic Pulmonary Edema: The Initial Presentation of an Underlying Rheumatic Heart Disease. Indian J Crit Care Med 2020;24(10):999-1000.

Deficiency of Interleukin-1 Receptor Antagonist (DIRA): Report of the First Indian Patient and a Novel Deletion Affecting IL1RN.

PURPOSE: Deficiency of interleukin-1 receptor antagonist (DIRA) is a rare life-threatening autoinflammatory disease caused by autosomal recessive mutations in IL1RN. DIRA presents clinically with early onset generalized pustulosis, multifocal osteomyelitis, and elevation of acute phase reactants. We evaluated and treated an antibiotic-unresponsive patient with presumed DIRA with recombinant IL-1Ra (anakinra). The patient developed anaphylaxis to anakinra and was subsequently desensitized. METHODS: Genetic analysis of IL1RN was undertaken and treatment with anakinra was initiated. RESULTS: A 5-month-old Indian girl born to healthy non-consanguineous parents presented at the third week of life with irritability, sterile multifocal osteomyelitis including ribs and clavicles, a mild pustular rash, and elevated acute phase reactants. SNP array of the patient's genomic DNA revealed a previously unrecognized homozygous deletion of approximately 22.5 Kb. PCR and Sanger sequencing of the borders of the deleted area allowed identification of the breakpoints of the deletion, thus confirming a homozygous 22,216 bp deletion that spans the first four exons of IL1RN. Due to a clinical suspicion of DIRA, anakinra was initiated which resulted in an anaphylactic reaction that triggered desensitization with subsequent marked and sustained clinical and laboratory improvement. CONCLUSION: We report a novel DIRA-causing homozygous deletion affecting IL1RN in an Indian patient. The mutation likely is a founder mutation; the design of breakpoint-specific primers will enable genetic screening in Indian patients suspected of DIRA. The patient developed anaphylaxis to anakinra, was desensitized, and is in clinical remission on continued treatment.

Lesional CD4+ IFN-γ+ cytotoxic T lymphocytes in IgG4-related dacryoadenitis and sialoadenitis.

OBJECTIVES: IgG4-related disease (IgG4-RD) is a chronic, systemic, inflammatory condition of unknown aetiology. We have recently described clonally expanded circulating CD4+ cytotoxic T lymphocytes (CTLs) in IgG4-RD that infiltrate affected tissues where they secrete interleukin (IL)-1ß and transforming growth factor -ß1 (TGF-ß1). In this study, we sought to examine the role of CD4+ CTLs in the pathogenesis of IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS) and to determine whether these cells secrete interferon-gamma (IFN-γ) at lesional sites. METHODS: Salivary glands of 25 patients with IgG4-DS, 22 patients with Sjögren's syndrome (SS), 12 patients with chronic sialoadenitis (CS) and 12 healthy controls were analysed in this study. Gene expression analysis was performed on submandibular glands (SMGs) from five patients with IgG4-DS, three with CS and three healthy controls. Infiltrating CD4+ CTLs were examined by quantitative multicolour imaging in tissue samples from 20 patients with IgG4-DS, 22 patients with SS, 9 patients with CS and 9 healthy controls. RESULTS: In IgG4-DS tissues, nine genes associated with CD4+ CTLs were overexpressed. The expression of granzyme A (GZMA) mRNA was significantly higher in samples from patients with IgG4-RD compared with corresponding tissues from SS and healthy controls. Quantitative imaging showed that infiltrating CD4+ GZMA+ CTLs were more abundant in patients with IgG4-DS than in the other groups. The ratio of CD4+GZMA+ CTLs in SMGs from patients with IgG4-DS correlated with serum IgG4 concentrations and the number of affected organs. A large fraction of CD4+GZMA+ CTLs in SMGs from patients with IgG4-DS secreted IFN-γ. CONCLUSIONS: The pathogenesis of IgG4-DS is associated with tissue infiltration by CD4+GZMA+ CTLs that secrete IFN-γ.

Plant growth-promoting rhizobacteria enhance wheat salt and drought stress tolerance by altering endogenous phytohormone levels and TaCTR1/TaDREB2 expression.

Abiotic stresses such as salt and drought represent adverse environmental conditions that significantly damage plant growth and agricultural productivity. In this study, the mechanism of the plant growth-promoting rhizo-bacteria (PGPR)-stimulated tolerance against abiotic stresses has been explored. Results suggest that PGPR strains, Arthrobacter protophormiae (SA3) and Dietzia natronolimnaea (STR1), can facilitate salt stress tolerance in wheat crop, while Bacillus subtilis (LDR2) can provide tolerance against drought stress in wheat. These PGPR strains enhance photosynthetic efficiency under salt and drought stress conditions. Moreover, all three PGPR strains increase indole-3-acetic acid (IAA) content of wheat under salt and drought stress conditions. The SA3 and LDR2 inoculations counteracted the increase of abscisic acid (ABA) and 1-aminocyclopropane-1-carboxylate (ACC) under both salt and drought stress conditions, whereas STR1 had no significant impact on the ABA and ACC content. The impact of PGPR inoculations on these physiological parameters were further confirmed by gene expression analysis as we observed enhanced levels of the TaCTR1 gene in SA3-, STR1- and LDR2-treated wheat seedlings as compared to uninoculated drought and salt stressed plants. PGPR inoculations enhanced expression of TaDREB2 gene encoding for a transcription factor, which has been shown to be important for improving the tolerance of plants to abiotic stress conditions. Our study suggest that PGPR confer abiotic stress tolerance in wheat by enhancing IAA content, reducing ABA/ACC content, modulating expression of a regulatory component (CTR1) of ethylene signaling pathway and DREB2 transcription factor.

Endophytes of opium poppy differentially modulate host plant productivity and genes for the biosynthetic pathway of benzylisoquinoline alkaloids.

MAIN CONCLUSION: Endophytes reside in different parts of the poppy plant and perform the tissue-specific functions. Most leaf endophytes modulate photosynthetic efficiency, plant growth, and productivity while capsule endophytes modulate alkaloid biosynthesis. Endophytes promote plant growth, provide protection from environmental stresses and are the source of important secondary metabolites. Here, we established that the endophytes of opium poppy Papaver somniferum L. may play a role in the modulation of plant productivity and benzylisoquinoline alkaloid (BIA) biosynthesis. A total of 22 endophytes isolated from leaves, roots, capsules and seeds of the poppy plants were identified. Isolated endophytes were used to inoculate the endophytes free poppy seeds and screened for their ability to improve plant productivity and BIA production. It was evident that the endophytes from leaf were involved in improving photosynthetic efficiency, and thus crop growth and yield and the endophytes from capsule were involved in enhancing BIA biosynthesis. Capsule endophytes of alkaloid-rich P. somniferum cv. Sampada enhanced BIA production even in alkaloid-less cv. Sujata. Expression study of the genes involved in BIA biosynthesis conferred the differential regulation of their expression in the presence of capsule endophytes. The capsule endophyte SM1B (Acinetobacter) upregulated the expression of the key genes for the BIA biosynthesis except thebaine 6-O-demethylase (T6ODM) and codeine O-demethylase (CODM). On the other hand, another capsule endophyte SM3B (Marmoricola sp.) could upregulate both T6ODM and CODM. Colonization of poppy plant by endophytes isolated from leaves, roots and capsules found to be higher in their respective plant parts confirmed their tissue-specific role. Overall, the results demonstrate the specific role of endophytes in the modulation of host plant productivity and BIA production.

Distinct detoxification mechanisms confer resistance to mesotrione and atrazine in a population of waterhemp.

Previous research reported the first case of resistance to mesotrione and other 4-hydroxyphenylpyruvate dioxygenase (HPPD) herbicides in a waterhemp (Amaranthus tuberculatus) population designated MCR (for McLean County mesotrione- and atrazine-resistant). Herein, experiments were conducted to determine if target site or nontarget site mechanisms confer mesotrione resistance in MCR. Additionally, the basis for atrazine resistance was investigated in MCR and an atrazine-resistant but mesotrione-sensitive population (ACR for Adams County mesotrione-sensitive but atrazine-resistant). A standard sensitive population (WCS for Wayne County herbicide-sensitive) was also used for comparison. Mesotrione resistance was not due to an alteration in HPPD sequence, HPPD expression, or reduced herbicide absorption. Metabolism studies using whole plants and excised leaves revealed that the time for 50% of absorbed mesotrione to degrade in MCR was significantly shorter than in ACR and WCS, which correlated with previous phenotypic responses to mesotrione and the quantity of the metabolite 4-hydroxy-mesotrione in excised leaves. The cytochrome P450 monooxygenase inhibitors malathion and tetcyclacis significantly reduced mesotrione metabolism in MCR and corn (Zea mays) excised leaves but not in ACR. Furthermore, malathion increased mesotrione activity in MCR seedlings in greenhouse studies. These results indicate that enhanced oxidative metabolism contributes significantly to mesotrione resistance in MCR. Sequence analysis of atrazine-resistant (MCR and ACR) and atrazine-sensitive (WCS) waterhemp populations detected no differences in the psbA gene. The times for 50% of absorbed atrazine to degrade in corn, MCR, and ACR leaves were shorter than in WCS, and a polar metabolite of atrazine was detected in corn, MCR, and ACR that cochromatographed with a synthetic atrazine-glutathione conjugate. Thus, elevated rates of metabolism via distinct detoxification mechanisms contribute to mesotrione and atrazine resistance within the MCR population.