An essential role for the IL-2 receptor in Treg cell function.

Regulatory T cells (Treg cells), which have abundant expression of the interleukin 2 receptor (IL-2R), are reliant on IL-2 produced by activated T cells. This feature indicates a key role for a simple network based on the consumption of IL-2 by Treg cells in their suppressor function. However, congenital deficiency in IL-2R results in reduced expression of the Treg cell lineage-specification factor Foxp3, which has confounded experimental efforts to understand the role of IL-2R expression and signaling in the suppressor function of Treg cells. Using genetic gain- and loss-of-function approaches, we found that capture of IL-2 was dispensable for the control of CD4+ T cells but was important for limiting the activation of CD8+ T cells, and that IL-2R-dependent activation of the transcription factor STAT5 had an essential role in the suppressor function of Treg cells separable from signaling via the T cell antigen receptor.

An Oral Interleukin-23-Receptor Antagonist Peptide for Plaque Psoriasis.

BACKGROUND: The use of monoclonal antibodies has changed the treatment of several immune-mediated inflammatory diseases, including psoriasis. However, these large proteins must be administered by injection. JNJ-77242113 is a novel, orally administered interleukin-23-receptor antagonist peptide that selectively blocks interleukin-23 signaling and downstream cytokine production. METHODS: In this phase 2 dose-finding trial, we randomly assigned patients with moderate-to-severe plaque psoriasis to receive JNJ-77242113 at a dose of 25 mg once daily, 25 mg twice daily, 50 mg once daily, 100 mg once daily, or 100 mg twice daily or placebo for 16 weeks. The primary end point was a reduction from baseline of at least 75% in the Psoriasis Area and Severity Index (PASI) score (PASI 75 response; PASI scores range from 0 to 72, with higher scores indicating greater extent or severity of psoriasis) at week 16. RESULTS: A total of 255 patients underwent randomization. The mean PASI score at baseline was 19.1. The mean duration of psoriasis was 18.2 years, and 78% of the patients across all the trial groups had previously received systemic treatments. At week 16, the percentages of patients with a PASI 75 response were higher among those in the JNJ-77242113 groups (37%, 51%, 58%, 65%, and 79% in the 25-mg once-daily, 25-mg twice-daily, 50-mg once-daily, 100-mg once-daily, and 100-mg twice-daily groups, respectively) than among those in the placebo group (9%), a finding that showed a significant dose-response relationship (P<0.001). The most common adverse events included coronavirus disease 2019 (in 12% of the patients in the placebo group and in 11% of those across the JNJ-77242113 dose groups) and nasopharyngitis (in 5% and 7%, respectively). The percentages of patients who had at least one adverse event were similar in the combined JNJ-77242113 dose group (52%) and the placebo group (51%). There was no evidence of a dose-related increase in adverse events across the JNJ-77242113 dose groups. CONCLUSIONS: After 16 weeks of once- or twice-daily oral administration, treatment with the interleukin-23-receptor antagonist peptide JNJ-77242113 showed greater efficacy than placebo in patients with moderate-to-severe plaque psoriasis. (Funded by Janssen Research and Development; FRONTIER 1 ClinicalTrials.gov number, NCT05223868.).

HLA-DRB1 genes and the expression dynamics of HLA CIITA determine the susceptibility to T2DM.

Type 2 diabetes mellitus (T2DM) is a disease with polygenic inheritance. The expression of major histocompatibility complex class II genes are regulated by several trans-activators. We have studied the expression of HLA-DRB1, RFX, CIITA-P1, PIV transactivators, immunophenotyping of cells, SNPs in CIITA-168 (A/G) and IFN-γ + 874 (T/A) in T2DM patients and controls (n = 201 each). We observed increased frequencies of DRB1*03, DRB1*04 and DRB1*07 and decreased frequencies of DRB1*10, DRB1*14, and DRB1*15 alleles among patients. Significant up-regulations of HLA-DRB1 genes were observed in patients (p < 0.0001). Down-regulated expressions were documented in DRB1*03-homo (p < 0.002) and DRB1*04-homo (p < 0.009) patients. No significant differences were observed for CIITA-P1 expression except DRB1*04-pooled (p < 0.0113). The CIITA-PIV was up-regulated in overall (p < 0.0001), DRB1*03-pooled (p < 0.0006), DRB1*03-hetero (p < 0.0006) and DRB1*03-homo (p < 0.001) T2DM patients. However, significant down-regulations were documented for DRB1*04-pooled (p < 0.040), DRB1*04-hetero (p < 0.060), and DRB1*04-homo (p < 0.027) combinations. Further, significant down-regulations of RFX5 were observed in overall (p < 0.0006), DRB1*04-pooled (p < 0.0022), and DRB1*04-hetero (p < 0.0004) combinations. Immunophenotyping studies revealed significant increase of CD45+ CD14-, CD19+, CD14- and CD8 cells and elevated level of expression of IFN-γ (p < 0.0001) in patients. A significant increase of TT (p < 3.35 × 10-6) and decrease of TA (p < 4.57 × 10-4) genotypes of IFN-γ + 874 (T/A) and an increase of GG (p < 0.001) and decrease of AG (p < 8.24 × 10-5) genotypes of CIITA-168 A/G SNPs were observed. The combinatorial analysis revealed susceptible associations for DRB1*03 + AA, *03 + AG, *03 + GG and *04 + GG and protective associations for DRB1*10 + AG, *10 + GG, *15 + AG, and *14 + GG combinations. Thus, the present study corroborated the effect of differential expressions of promoters of risk alleles in the pathogenesis of T2DM.

The possible role of sirtuins in male reproduction.

Global influence of male infertility is increasing in recent decades. Proper understanding of genetics, anatomy, physiology and the intricate interrelation of male reproductive system are much needed for explaining the etiology of male infertility; and a detailed study on the epigenetics, indeed, will reveal the molecular mechanism behind its etiology. Sirtuins, the molecular sensors, are NAD+ dependent histone deacetylases and ADP- ribosyl transferases, participate in the chief events of epigenetics. In mammals, sirtuin family comprises seven members (SIRT1-SIRT7), and they all possess a conserved NAD+ binding catalytic domain, termed the sirtuin core domain which is imperative for their activity. Sirtuins exert a pivotal role in cellular homeostasis, energy metabolism, apoptosis, age-related disorders and male reproductive system. However, their exact role in male reproduction is still obscure. This article specifically reviews the role of mammalian sirtuins in male reproductive function, thereby, prompting further research to discover the restorative methods and its implementation in reproductive medicine.

Do Fixed or Mobile Bearing Implants Have Better Survivorship in Medial Unicompartmental Knee Arthroplasty? A Study From the Australian Orthopaedic Association National Joint Replacement Registry.

BACKGROUND: During the last 5 years, there has been an increase in the use of unicompartmental knee arthroplasty (UKA) to treat knee osteoarthritis in Australia, and these account for almost 6% of annual knee replacement procedures. However, there is debate as to whether a fixed bearing or a mobile bearing design is best for decreasing revision for loosening and disease progression as well as improving survivorship. Small sample sizes and possible confounding in the studies on the topic may have masked differences between fixed and mobile bearing designs. QUESTIONS/PURPOSES: Using data from the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR), we selected the four contemporary designs of medial compartment UKA: mobile bearing, fixed modular, all-polyethylene, and fixed molded metal-backed used for the treatment of osteoarthritis to ask: (1) How do the different designs of unicompartmental knees compare with survivorship as measured by cumulative percentage revision (CPR)? (2) Is there a difference in the revision rate between designs as a function of patient sex or age? (3) Do the reasons for revision differ, and what types of revision procedures are performed when these UKA are revised? METHODS: The AOANJRR longitudinally maintains data on all primary and revision joint arthroplasties, with nearly 100% capture. The study population included all UKA procedures undertaken for osteoarthritis between September 1999 and December 2018. Of 56,628 unicompartmental knees recorded during the study period, 50,380 medial UKA procedures undertaken for osteoarthritis were included in the analysis after exclusion of procedures with unknown bearing types (31 of 56,628), lateral or patellofemoral compartment UKA procedures (5657 of 56,628), and those performed for a primary diagnosis other than osteoarthritis (560 of 56,628). There were 50,380 UKA procedures available for analysis. The study group consisted of 40% (20,208 of 50,380) mobile bearing UKA, 35% (17,822 of 50,380) fixed modular UKA, 23% (11,461 of 50,380) all-polyethylene UKA, and 2% (889 of 50,380) fixed molded metal-backed UKA. There were similar sex proportions and age distributions for each bearing group. The overall mean age of patients was 65 ± 9.4 years, and 55% (27,496 of 50,380) of patients were males. The outcome measure was the CPR, which was defined using Kaplan-Meier estimates of survivorship to describe the time to the first revision. Hazard ratios from Cox proportional hazards models, adjusted for sex and age, were performed to compare the revision rates among groups. The cohort was stratified into age groups of younger than 65 years and 65 years and older to compare revision rates as a function of age. Differences among bearing groups for the major causes and modes of revision were assessed using hazard ratios. RESULTS: At 15 years, fixed modular UKA had a CPR of 16% (95% CI 15% to 17%). In comparison, the CPR was 23% (95% CI 22% to 24%) for mobile bearing UKA, 26% (95% CI 24% to 27%) for all-polyethylene UKA, and 20% (95% CI 16% to 24%) for fixed molded metal-backed UKA. The lower revision rate for fixed modular UKA was seen through the entire period compared with mobile bearing UKA (hazard ratio 1.5 [95% CI 1.4 to 1.6]; p < 0.001) and fixed molded metal-backed UKA (HR 1.3 [95% CI 1.1 to 1.6]; p = 0.003), but it varied with time compared with all-polyethylene UKA. The findings were consistent when stratified by sex or age. Although all-polyethylene UKA had the highest revision rate overall and for patients younger than 65 years, for patients aged 65 years and older, there was no difference between all-polyethylene and mobile bearing UKA. When compared with fixed modular UKA, a higher revision risk for loosening was shown in both mobile bearing UKA (HR 1.7 [95% CI 1.5 to 1.9]; p < 0.001) and all-polyethylene UKA (HR 2.4 [95% CI 2.1 to 2.7]; p < 0.001). The revision risk for disease progression was higher for all-polyethylene UKA at all time points (HR 1.4 [95% CI 1.3 to 1.6]; p < 0.001) and for mobile bearing UKA after 8 years when each were compared with fixed modular UKA (8 to 12 years: HR 1.4 [95% CI 1.2 to 1.7]; p < 0.001; 12 or more years: HR 1.9 [95% CI 1.5 to 2.3]; p < 0.001). The risk of revision to TKA was higher for mobile bearing UKA compared with fixed modular UKA (HR 1.4 [95% CI 1.3 to 1.5]; p < 0.001). CONCLUSION: If UKA is to be considered for the treatment of isolated medial compartment osteoarthritis, the fixed modular UKA bearing has the best survivorship of the current UKA designs. LEVEL OF EVIDENCE: Level III, therapeutic study.

Role of Aquaporins in Spermatogenesis and Testicular Steroidogenesis.

The transport of water and several other small molecules across cell membranes is vital in many of the processes underlying reproduction. Fluid transport in cells and tissues inclusive of male reproductive organs are regulated by disparate isoforms of aquaporins (AQPs) in living organisms. Alteration in the expression, function and/or regulation of AQPs leads to some forms of male subfertility and infertility. The emerging role of AQPs in male and female reproductive function has been revealed in recent times. However, the role of AQPs with reference to male reproductive system needs to be explored in greater detail. This review emphasizes the distribution of AQPs and their physiological and pathophysiological role in spermatogenesis and steroidogenesis; and understanding the molecular mechanisms behind AQPs mediated regulation of spermatogenesis and steroidogenesis will help us in developing treatment strategies towards improved reproductive health.

Reentrant para-Hisian ventricular tachycardia eliminated from the noncoronary cusp: Importance of regional anatomy for vantage-point ablation.

We present a rare case of reentrant ventricular tachycardia proven by entrainment maneuvers that was successfully ablated from the noncoronary cusp. The case highlights regional anatomy, pacing maneuvers with multi-modality images from fluoroscopy, intracardiac echo, and electroanatomical mapping.

IL-36 receptor antagonistic antibodies inhibit inflammatory responses in preclinical models of psoriasiform dermatitis.

Psoriasis vulgaris (PV) results from activation of IL-23/Th17 immune pathway and is further amplified by cytokines/chemokines from skin cells. Among skin-derived pro-inflammatory cytokines, IL-36 family members are highly upregulated in PV patients and play a critical role in general pustular psoriasis. However, there is limited data showing crosstalk between the IL-23 and IL-36 pathways in PV. Herein, potential attenuation of skin inflammation in the IL-23-induced mouse model of psoriasiform dermatitis by functional inhibition of IL-36 receptor (IL-36R) was interrogated. Anti-mouse IL-36R monoclonal antibodies (mAbs) were generated and validated in vitro by inhibiting IL-36α-induced secretion of CXCL1 from NIH 3T3 cells. Antibody target engagement was demonstrated by inhibition of CXCL1 production in a novel acute model of IL-36α systemic injection in mice. In addition, anti-IL-36R mAbs inhibited tissue inflammation and inflammatory gene expression in an IL-36α ear injection model of psoriasiform dermatitis demonstrating engagement of the target in the ear skin. To elucidate the possible role of IL-36 signalling in IL-23/Th17 pathway, the ability of anti-IL-36R mAbs to inhibit skin inflammation in an IL-23 ear injection model was assessed. Inhibiting the IL-36 pathway resulted in significant attenuation of skin thickening and psoriasis-relevant gene expression. Taken together, these data suggest a role for IL-36 signalling in the IL-23/Th17 signalling axis in PV.

Diversity and association of HLA/KIR receptors with type 2 diabetes in South India.

The present study was undertaken to delineate the association(s) of KIR-HLA combination in South Indian Type 2 diabetes mellitus (T2DM) patients. The T2DM patients (n = 343) and healthy controls (n = 309) were genotyped for KIR/HLA ligands by PCR-SSP method. The increased frequency of activatory KIR (aKIR) 2DS2 (OR = 1.91; p < 2.91 × 10-4 ) was observed in patients suggesting a susceptible association. The frequencies of iKIR 2DL2 (OR = 0.38; p < 1.55 × 10-5 ) and aKIRs 2DS1 (OR = 0.60; p < 0.001) and 3DS1 (OR = 0.52; p < 5.83 × 10-5 ) were decreased in patients suggesting protective associations. The C1/C2 combinatorial analysis has revealed an increased frequency of C1+ /C2- in T2DM patients (OR = 1.62; p < 0.014). The KIR "AB" genotype (OR = 2.41; p < 3.87 × 10-5 ) was observed to be higher in patients. However, the "BB" genotype (OR = 0.32; p < 4.71 × 10-7 ) was increased in controls. The KIR motifs, "Tel-B/B" (OR = 1.84; p < 0.007), were observed higher among patients. However, the frequency of "Tel-A/B" motif genotype was decreased in patients (OR = 0.56; p < 3.13 × 10-4 ). The iKIR/HLA combinations such as 2DL2/3 +C1 and 3DL2+A3/A11 were increased in patients (OR = 3.90; p < 7.5 × 10-5 ) suggesting susceptible associations. On the contrary, the aKIR+HLA combinations such as 2DS2+C1, 2DS1+C2 and 3DS1+Bw4 were less frequent in patients (OR = 0.32; p < 4.2 × 10-4 ) suggesting protective associations. Thus, the present study clearly establishes the positive and negative associations of different KIR-HLA receptor combinations with T2DM in South India.

Cutting Edge: Drebrin-Regulated Actin Dynamics Regulate IgE-Dependent Mast Cell Activation and Allergic Responses.

Mast cells play critical roles in allergic responses. Calcium signaling controls the function of these cells, and a role for actin in regulating calcium influx into cells has been suggested. We have previously identified the actin reorganizing protein Drebrin as a target of the immunosuppressant 3,5-bistrifluoromethyl pyrazole, which inhibits calcium influx into cells. In this study, we show that Drebrin(-/-) mice exhibit reduced IgE-mediated histamine release and passive systemic anaphylaxis, and Drebrin(-/-) mast cells also exhibit defects in FcεRI-mediated degranulation. Drebrin(-/-) mast cells exhibit defects in actin cytoskeleton organization and calcium responses downstream of the FcεRI, and agents that relieve actin reorganization rescue mast cell FcεRI-induced degranulation. Our results indicate that Drebrin regulates the actin cytoskeleton and calcium responses in mast cells, thus regulating mast cell function in vivo.

Itk signals promote neuroinflammation by regulating CD4+ T-cell activation and trafficking.

Here we demonstrate that interleukin-2-inducible T-cell kinase (Itk) signaling in cluster of differentiation 4-positive (CD4(+)) T cells promotes experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). We show that Itk(-/-) mice exhibit reduced disease severity, and transfer of Itk(-/-) CD4(+) T cells into T cell-deficient recipients results in lower disease severity. We observed a significant reduction of CD4(+) T cells in the CNS of Itk(-/-) mice or recipients of Itk(-/-) CD4(+) T cells during EAE, which is consistent with attenuated disease. Itk(-/-) CD4(+) T cells exhibit defective response to myelin antigen stimulation attributable to displacement of filamentous actin from the CD4(+) coreceptor. This results in inadequate transmigration of Itk(-/-) CD4(+) T cells into the CNS and across brain endothelial barriers in vitro. Finally, Itk(-/-) CD4(+) T cells show significant reduction in production of T-helper 1 (Th1) and Th17 cytokines and exhibit skewed T effector/T regulatory cell ratios. These results indicate that signaling by Itk promotes autoimmunity and CNS inflammation, suggesting that it may be a viable target for treatment of MS.

Anti-CD25 monoclonal antibody Fc variants differentially impact regulatory T cells and immune homeostasis.

Interleukin-2 (IL-2) is a critical regulator of immune homeostasis through its non-redundant role in regulatory T (Treg) cell biology. There is major interest in therapeutic modulation of the IL-2 pathway to promote immune activation in the context of tumour immunotherapy or to enhance immune suppression in the context of transplantation, autoimmunity and inflammatory diseases. Antibody-mediated targeting of the high-affinity IL-2 receptor α chain (IL-2Rα or CD25) offers a direct mechanism to target IL-2 biology and is being actively explored in the clinic. In mouse models, the rat anti-mouse CD25 clone PC61 has been used extensively to investigate the biology of IL-2 and Treg cells; however, there has been controversy and conflicting data on the exact in vivo mechanistic function of PC61. Engineering antibodies to alter Fc/Fc receptor interactions can significantly alter their in vivo function. In this study, we re-engineered the heavy chain constant region of an anti-CD25 monoclonal antibody to generate variants with highly divergent Fc effector function. Using these anti-CD25 Fc variants in multiple mouse models, we investigated the in vivo impact of CD25 blockade versus depletion of CD25(+) Treg cells on immune homeostasis. We report that immune homeostasis can be maintained during CD25 blockade but aberrant T-cell activation prevails when CD25(+) Treg cells are actively depleted. These results clarify the impact of PC61 on Treg cell biology and reveal an important distinction between CD25 blockade and depletion of CD25(+) Treg cells. These findings should inform therapeutic manipulation of the IL-2 pathway by targeting the high-affinity IL-2R.

Sirtuin 4 Regulates Lipopolysaccharide Mediated Leydig Cell Dysfunction.

Bacterial lipopolysaccharide (LPS) is the most important contributing factor in pathogenesis of bacterial infection in male accessory glands; and it has shown to inhibit testicular steroidogenesis and induce apoptosis. The present study demonstrates that LPS causes mitochondrial dysfunction via suppression of sirtuin 4 (SIRT4); which in turn affects Leydig cell function by modulating steroidogenesis and apoptosis. LC-540 Leydig cells treated with LPS (10 µg/ml) showed impaired steroidogenesis and increased cellular apoptosis. The mRNA and protein expression of SIRT4 were decreased in LPS treated cells when compared to controls. The obtained data suggest that the c-Jun N-terminal kinase (JNK) activation suppresses SIRT4 expression in LPS treated Leydig cells. Furthermore, the overexpression of SIRT4 prevented LPS induced impaired steroidogenesis and cellular apoptosis by improving mitochondrial function. These findings provide valuable information that SIRT4 regulates LPS mediated Leydig cell dysfunction.

Allele-sensitive mutant, Itkas, reveals that Itk kinase activity is required for Th1, Th2, Th17, and iNKT-cell cytokine production.

Itk(-/-) mice exhibit defects in the activation, development, and function of CD4(+) and CD8(+) T cells and iNKT cells. These and other defects in these mice make it difficult to uncouple the developmental versus functional requirement of Itk signaling. Here, we report an allele-sensitive mutant of Itk (Itkas) whose catalytic activity can be selectively inhibited by analogs of the PP1 kinase inhibitor. We show that Itkas behaves like WT Itk in the absence of the inhibitor and can rescue the development of Itk(-/-) T cells in mice. Using mice carrying Itkas, we show using its inhibitor that Itk activity is required not only for Th2, Th17, and iNKT-cell cytokine production, but also surprisingly, for Th1 cytokine production. This work has important implications for understanding the role of Itk signaling in the development versus function of iNKT cells, Th1, Th2, and Th17 cells.

Perioperative Management of Anticoagulation-Review of Latest Evidence.

Periprocedural anticoagulation bridging is recommended to reduce the risk of thromboembolic events in patients at a higher risk of developing thromboembolism during the perioperative period. The optimal periprocedural anticoagulation strategy has not been established. Unfractionated heparin and low molecular heparin are used in preventing thromboembolism in the special population. Novel oral anticoagulants that directly inhibit thrombin (dabigatran) or factor Xa (rivaroxaban, apixaban) are shown as effective anticoagulants in preventing thromboembolism (venous thromboembolism) in various medical conditions. They have the advantage of having a faster onset, shorter half-lives, easier monitoring, and predicable doses. But there are disadvantages to newer anticoagulants such as the unavailability of definitive reversal agents and lack of data in patients with renal insufficiency. We review the latest evidence on the effects of newer oral anticoagulants in preventing thromboembolism and its bleeding risks.

Coronary Revascularization in Chronic and End-Stage Renal Disease: A Systematic Review and Meta-analysis.

Patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) on dialysis have an increased risk for cardiovascular mortality and morbidity secondary to occlusive coronary artery disease. Optimal revascularization strategy is unclear in this high-risk population. We have performed a meta-analysis to compare coronary artery bypass grafting (CABG) versus percutaneous coronary intervention (PCI) in patients with ESRD and CKD. We searched PubMed, Ovid, MEDLINE, CINAHL, and EMBASE (1980-2013) and found 17 trials (N = 33,584) in the ESRD arm and 6 studies (n = 15,493) in the CKD arm. Two investigators independently collected the data. All the studies were retrospective trials. In the ESRD and CKD groups, we found significantly reduced early mortality with the PCI group with the odds ratio of 2.08 (1.90-2.26; P < 0.00001) and 2.55 (1.45-4.51; P = 0.001), respectively. Contrary to the early mortality results, we found decreased late mortality with the CABG group when compared with the PCI group [odds ratio: 0.86 (0.83-0.89; P < 0.000001) and 0.82 (0.76-0.88; P < 0.00001)] in the ESRD and CKD arm, respectively. When compared with PCI, there was decreased cardiovascular mortality with an odds ratio of 0.61 (0.40-0.92; P = 0.02) in patients who underwent CABG in ESRD population. Similar trends were observed in the incidence of myocardial infarction and repeat revascularization. There is a strong trend for decreased risk of stroke with PCI when compared with CABG in ESRD and CKD populations.

IL-2-inducible T cell kinase tunes T regulatory cell development and is required for suppressive function.

IL-2-inducible T cell kinase (ITK) is a key signaling mediator downstream of TCR, mediating T cell positive selection, as well as innate T cell and CD4(+) Th2/Th17 differentiation. In this article, we show that ITK also negatively tunes IL-2-induced expansion of conventional Foxp3-expressing regulatory T cells (Tregs). In vivo, Treg abundance is inversely correlated with ITK expression, and inducible Treg development is inversely dependent on ITK kinase activity. While Treg development normally requires both hematopoietic and thymic MHC class 2 (MHC2) expression, the absence of ITK allows Treg development with MHC2 expression in either compartment, with preference for selection by thymic MHC2, suggesting a gatekeeper role for ITK in ensuring that only Tregs selected by both thymic and hematopoietic MHC2 survive selection. Although ITK suppresses Treg development and is not required for maintenance of neuropilin-1-positive natural Tregs in the periphery, it is indispensable for Treg functional suppression of naive CD4(+) T cell-induced colitis in Rag(-/-) recipients. ITK thus regulates the development and function of Tregs.

Cardiovascular adverse effects of targeted antiangiogenic drugs: mechanisms and management.

Anticancer treatment has evolved enormously over the last decade. Drugs targeting receptor tyrosine kinases, VEGFR and EGFR have changed the treatment landscape of certain cancers and have shifted the theme of anticancer therapy toward personalized care. However, these newer agents also come with unique side-effect profiles not seen with conventional chemotherapy including serious cardiovascular adverse effects. Hence, meticulous understanding of the adverse effects is crucial in maximizing clinical benefits and minimizing detrimental effects of these newer drugs. We have reviewed the cardiovascular adverse effects of anti-VEGF therapy in this article.

Mild Renal Artery Stenosis Can Induce Renovascular Hypertension and is Associated with Elevated Renal Vein Renin Secretion.

Renovascular hypertension is a syndrome which encompasses the physiological response of the kidney to changes in renal blood flow and renal perfusion pressure. Such physiological changes can occur with renal artery occlusion irrespective of the severity of the lesion. We have analyzed hypertensive patients with mild renal artery stenosis and compared them to patients with no stenosis. Renal vein renin sampling from catheterization of the renal vein was performed in all these patients. Patients with mild stenosis had higher renal vein renin ratio (3.01 ± 1.5) than the patients with no stenosis (1.10 ± 0.29; p = 0.002). Patients with mild stenosis were also found to have higher diastolic blood pressure and renal artery resistive indices when compared to patients with no stenosis. We therefore conclude that mild stenosis can precipitate renin-mediated hypertension in renovascular stenosis and also emphasis that parameters pertinent to renal physiology need to be evaluated before considering treatment options in patients with renal artery stenosis and medical management with RAAS blockade is the preferred modality of therapy for patients with renin-mediated hypertension.

Revision TKA for Flexion Instability Improves Patient Reported Outcomes.

UNLABELLED: Instability is a major cause of early revision of total knee arthroplasty (TKA), of which flexion instability is a major subset. We analyzed radiologically evident corrections, patient reported outcome and complications associated with revision TKA for flexion instability in a retrospective cohort of 37 patients with minimum one year follow up. Following revision surgery, there was a significant increase in mean posterior condylar offset ratio and a significant decrease in tibial slope while the level of joint line was not significantly altered. Patient reported version of knee society score showed significant improvement with surgery and 26 of 37 patient reported perceptible improvement on a 7-point Likert scale. LEVEL OF EVIDENCE: Level IV, Case series. See the Guidelines for Authors for a complete description of levels of evidence.