Prior immunization against an intracellular antigen enhances subsequent red blood cell alloimmunization in mice.

Antibodies against red blood cell (RBC) alloantigens can increase morbidity and mortality among transfusion recipients. However, alloimmunization rates can vary dramatically, as some patients never generate alloantibodies after transfusion, whereas others not only become alloimmunized but may also be prone to generating additional alloantibodies after subsequent transfusion. Previous studies suggested that CD4 T-cell responses that drive alloantibody formation recognize the same alloantigen engaged by B cells. However, because RBCs express numerous antigens, both internally and externally, it is possible that CD4 T-cell responses directed against intracellular antigens may facilitate subsequent alloimmunization against a surface RBC antigen. Here, we show that B cells can acquire intracellular antigens from RBCs. Using a mouse model of donor RBCs expressing 2 distinct alloantigens, we demonstrate that immune priming to an intracellular antigen, which would not be detected by any currently used RBC compatibility assays, can directly influence alloantibody formation after exposure to a subsequent distinct surface RBC alloantigen. These findings suggest a previously underappreciated mechanism whereby transfusion recipient responders may exhibit an increased rate of alloimmunization because of prior immune priming toward intracellular antigens.

MPYS Modulates Fatty Acid Metabolism and Immune Tolerance at Homeostasis Independent of Type I IFNs.

MPYS/STING (stimulator of IFN genes) senses cyclic dinucleotides (CDNs), generates type I IFNs, and plays a critical role in infection, inflammation, and cancer. In this study, analyzing genotype and haplotype data from the 1000 Genomes Project, we found that the R71H-G230A-R293Q (HAQ) MPYS allele frequency increased 57-fold in East Asians compared with sub-Saharan Africans. Meanwhile, the G230A-R293Q (AQ) allele frequency decreased by 98% in East Asians compared with sub-Saharan Africans. We propose that the HAQ and AQ alleles underwent a natural selection during the out-of-Africa migration. We used mouse models of HAQ and AQ to investigate the underlying mechanism. We found that the mice carrying the AQ allele, which disappeared in East Asians, had normal CDN-type I IFN responses. Adult AQ mice, however, had less fat mass than did HAQ or wild-type mice on a chow diet. AQ epididymal adipose tissue had increased regulatory T cells and M2 macrophages with protein expression associated with enhanced fatty acid oxidation. Conditional knockout mice and adoptive cell transfer indicate a macrophage and regulatory T cell-intrinsic role of MPYS in fatty acid metabolism. Mechanistically, AQ/IFNAR1-/- mice had a similar lean phenotype as for the AQ mice. MPYS intrinsic tryptophan fluorescence revealed that the R71H change increased MPYS hydrophilicity. Lastly, we found that the second transmembrane (TM) and the TM2-TM3 linker region of MPYS interact with activated fatty acid, fatty acyl-CoA. In summary, studying the evolution of the human MPYS gene revealed an MPYS function in modulating fatty acid metabolism that may be critical during the out-of-Africa migration.

Impact of Nicotine Replacement Therapy on Breast Surgery Outcomes.

BACKGROUND: Smoking cessation therapy, including nicotine replacement therapy (NRT), is used perioperatively to assist patients to reduce their tobacco smoke intake and consequently decrease their risk of smoking-associated complications. There are, however, theoretical concerns that nicotine-induced peripheral vasoconstriction could impair wound healing. This study investigated the effect of NRT on postoperative outcomes in patients undergoing breast surgery. METHODS: A retrospective chart review of patients undergoing breast surgery within the Yale New Haven Health System from the years 2014 to 2020 was performed. Documented smoking status within 6 months before surgery, use or prescription of NRT, type of surgery, and surgical complications of infection, wound dehiscence, tissue necrosis, hematoma, seroma, fat necrosis, and return to operating room within 30 days were recorded. Demographic and complication data were compared between patients with NRT usage and those without using t-tests and chi-square analyses. Multivariable logistic regression models were created to predict the effect of NRT usage on the occurrence of any complication. RESULTS: A total of 613 breast procedures met inclusion criteria, of which 105 (17.2%) had documented NRT use. The NRT cohort and the non-NRT cohort were well balanced with respect to demographics and procedural variables. Upon multivariable modeling for risk of any surgical complication, NRT was not a significant predictor (odds ratio [OR]: 1.199, p = 0.607 and OR: 0.974, p = 0.912, respectively), whereas procedure type, increased body mass index, and increased age were. CONCLUSION: NRT use was not associated with an increased risk of postoperative complications compared with not using NRT as part of smoking cessation therapy prior to operation.

Medical Malpractice Litigation Following Hindfoot Arthrodesis.

Given high patient expectations in the setting of complex surgeries, orthopedic surgeons are at risk of being subject to malpractice claims which can impose significant economic and psychological burden. This study investigates malpractice claims against orthopedic surgeons and podiatrists performing hindfoot arthrodesis and determine factors associated with plaintiff verdicts and settlements using the Westlaw legal database. The database was queried for all cases involving hindfoot arthrodesis using the terms "malpractice" and either "ankle fusion," "arthrodesis," "subtalar fusion," "tibiotalar fusion," "tibiotalocalcaneal fusion," "TTC fusion," or "tibiofibular fusion" from 1987 to 2023. Data regarding patient demographics, causes cited for litigation, case outcomes, and indemnity settlements were collected. Cases were excluded if the defendant was not an orthopedic surgeon or a podiatrist, the procedure involved was not a hindfoot arthrodesis, or if the patient was a minor. Forty-five cases of hindfoot arthrodesis met the inclusion criteria. The mean plaintiff age was 51.5 ± 13.8 years with 51.1% male. Thirty-three cases (73%) were in favor of the defendant, with an average inflation-adjusted payout of $853,863 (±456,179). The most alleged category of negligence was procedural/intraoperative error (75%) followed by postsurgical error (38%) and failure to inform (31%). The most common specific damages included functional/ROM limitation (49%), need for additional surgery (47%), continuing/worsened pain (27%), and nonunion/malunion (29%). Given the frequency of hindfoot arthrodesis performed, this study highlights the importance of effective communication with patients concerning potential postoperative complications, prognosis of their injury, and risks and benefits associated with each treatment modality.

An antagonistic monoclonal anti-Plexin-B1 antibody exerts therapeutic effects in mouse models of postmenopausal osteoporosis and multiple sclerosis.

Osteoporosis and multiple sclerosis are highly prevalent diseases with limited treatment options. In light of these unmet medical needs, novel therapeutic approaches are urgently sought. Previously, the activation of the transmembrane receptor Plexin-B1 by its ligand semaphorin 4D (Sema4D) has been shown to suppress bone formation and promote neuroinflammation in mice. However, it is unclear whether inhibition of this receptor-ligand interaction by an anti-Plexin-B1 antibody could represent a viable strategy against diseases related to these processes. Here, we raised and systematically characterized a monoclonal antibody directed against the extracellular domain of human Plexin-B1, which specifically blocks the binding of Sema4D to Plexin-B1. In vitro, we show that this antibody inhibits the suppressive effects of Sema4D on human osteoblast differentiation and mineralization. To test the therapeutic potential of the antibody in vivo, we generated a humanized mouse line, which expresses transgenic human Plexin-B1 instead of endogenous murine Plexin-B1. Employing these mice, we demonstrate that the anti-Plexin-B1 antibody exhibits beneficial effects in mouse models of postmenopausal osteoporosis and multiple sclerosis in vivo. In summary, our data identify an anti-Plexin-B1 antibody as a potential therapeutic agent for the treatment of osteoporosis and multiple sclerosis.

Marginal zone B cells mediate a CD4 T-cell-dependent extrafollicular antibody response following RBC transfusion in mice.

Red blood cell (RBC) transfusions can result in alloimmunization toward RBC alloantigens that can increase the probability of complications following subsequent transfusion. An improved understanding of the immune mechanisms that underlie RBC alloimmunization is critical if future strategies capable of preventing or even reducing this process are to be realized. Using the HOD (hen egg lysozyme [HEL] and ovalbumin [OVA] fused with the human RBC antigen Duffy) model system, we aimed to identify initiating immune factors that may govern early anti-HOD alloantibody formation. Our findings demonstrate that HOD RBCs continuously localize to the marginal sinus following transfusion, where they colocalize with marginal zone (MZ) B cells. Depletion of MZ B cells inhibited immunoglobulin M (IgM) and IgG anti-HOD antibody formation, whereas CD4 T-cell depletion only prevented IgG anti-HOD antibody development. HOD-specific CD4 T cells displayed similar proliferation and activation following transfusion of HOD RBCs into wild-type or MZ B-cell-deficient recipients, suggesting that IgG formation is not dependent on MZ B-cell-mediated CD4 T-cell activation. Moreover, depletion of follicular B cells failed to substantially impact the anti-HOD antibody response, and no increase in antigen-specific germinal center B cells was detected following HOD RBC transfusion, suggesting that antibody formation is not dependent on the splenic follicle. Despite this, anti-HOD antibodies persisted for several months following HOD RBC transfusion. Overall, these data suggest that MZ B cells can initiate and then contribute to RBC alloantibody formation, highlighting a unique immune pathway that can be engaged following RBC transfusion.

Storage differentially impacts alloimmunization to distinct red cell antigens following transfusion in mice.

INTRODUCTION: The impact of blood storage on red blood cell (RBC) alloimmunization remains controversial, with some studies suggesting enhancement of RBC-induced alloantibody production and others failing to observe any impact of storage on alloantibody formation. Since evaluation of storage on RBC alloimmunization in patients has examined antibody formation against a broad range of alloantigens, it remains possible that different clinical outcomes reflect a variable impact of storage on alloimmunization to specific antigens. METHODS: RBCs expressing two distinct model antigens, HEL-OVA-Duffy (HOD) and KEL, separately or together (HOD × KEL), were stored for 0, 8, or 14 days, followed by detection of antigen levels prior to transfusion. Transfused donor RBC survival was assessed within 24 h of transfusion, while IgM and IgG antibody production were assessed 5 and 14 days after transfusion. RESULTS: Stored HOD or KEL RBCs retained similar HEL or KEL antigen levels, respectively, as fresh RBCs, but did exhibit enhanced RBC clearance with increased storage age. Storage enhanced IgG antibody formation against HOD, while the oppositive outcome occurred following transfusion of stored KEL RBCs. The distinct impact of storage on HOD or KEL alloimmunization did not appear to reflect intrinsic differences between HOD or KEL RBCs, as transfusion of stored HOD × KEL RBCs resulted in increased IgG anti-HOD antibody development and reduced IgG anti-KEL antibody formation. CONCLUSIONS: These data demonstrate a dichotomous impact of storage on immunization to distinct RBC antigens, offering a possible explanation for inconsistent clinical experience and the need for additional studies on the relationship between RBC storage and alloimmunization.

NCCN Guidelines® Insights: Hematopoietic Cell Transplantation, Version 3.2022.

The NCCN Guidelines for Hematopoietic Cell Transplantation (HCT) provide an evidence- and consensus-based approach for the use of autologous and allogeneic HCT in the management of malignant diseases in adult patients. HCT is a potentially curative treatment option for patients with certain types of malignancies; however, recurrent malignancy and transplant-related complications often limit the long-term survival of HCT recipients. The purpose of these guidelines is to provide guidance regarding aspects of HCT, including pretransplant recipient evaluation, hematopoietic cell mobilization, and treatment of graft-versus-host disease-a major complication of allogeneic HCT-to enable the patient and clinician to assess management options in the context of an individual patient's condition. These NCCN Guidelines Insights provide a summary of the important recent updates to the NCCN Guidelines for HCT, including the incorporation of a newly developed section on the Principles of Conditioning for HCT.

The Use of Medical Chaperones During Physical Examinations: The Perceptions of Adolescents and Their Caregivers.

PURPOSE: A medical chaperone serves as a witness for a patient and health care practitioner during a medical examination. We sought to better understand the preferences of parents and children toward the use of chaperones during pediatric physical examinations. METHODS: This cross-sectional study surveyed patients aged 8 to 18 years and their parents presenting primarily to the emergency department as well as primary care ambulatory clinic and inpatient units. Participants were asked which individuals (patient alone, parent, or medical chaperone) should be present for each aspect of the child's physical examination. RESULTS: The survey was completed by 121 patients (mean age 14 years, 58.5% girls) and 122 parents (mean age 42 years, 82.8% women) in a variety of clinical settings (17 in inpatient, 17 in outpatient clinic, and 87 emergency department admissions). Significant differences existed between male and female patients regarding preferred presence for every body part being examined ( P ≤ 0.002). Female patients preferred to have a same-sex parent in the room, particularly for examination of the breasts, genitalia, or rectum and when the examination was performed by a male provider. Male patients preferred to be alone or with either parent for any body part being examined, regardless of provider sex. CONCLUSIONS: Adolescents have significant differences in who they prefer to be in the room for the physical examination based on patient and provider sex in settings where they are unfamiliar with the health care examiner. Few patients and parents preferred a medical chaperone; most preferred a parent to be in the room. Patient and parent considerations should be prioritized when creating policies for the use of medical chaperones.

The Impact of Social Determinants of Health on Pressure Injury Progression: A Retrospective Chart and Scoping Review.

OBJECTIVE: To understand the effects of nutrition security and social determinants of health (SDOHs) on pressure injury (PI) progression through a scoping review and retrospective review of patients reporting to New England's largest healthcare system. METHODS: Authors performed a scoping review for full-text, original articles reporting outcomes data specific to PIs in patients with socially informed nutrition insecurity. Investigators also performed a retrospective review of all patients from 2012 to 2021 to search for patients with PI documentation and International Classification of Diseases, Tenth Revision Z codes related to the SDOHs. RESULTS: A full-text review of 2,323 articles from 1965 to 2020 failed to locate any eligible studies. Investigators identified 1,044 patients who met the inclusion criteria; 50.7% were men, 74.3% were White, and 13.3% had evidence of detrimental SDOHs. The average PI duration was 12.13 days (interquartile range, 6 days). Multivariate regression analysis revealed that PI duration was longer in men, Black patients, and patients with evidence of detrimental SDOHs compared with their converse counterparts (P < .0001). The presence of detrimental SDOHs independently predicted an increased duration of disease by 13.07 days (95% CI, 8.99-17.15; t = 6.29, P < .0001). CONCLUSIONS: A patient's SDOH history has a significant and considerably stronger correlation with disease progression than predictors that are traditionally studied such as sex, race, or body mass index. These findings are novel, as highlighted by the absence of data uncovered in the literature. These data carry relevance for plastic surgeons wishing to prevent early recurrence following operative closure of PI-related wounds.

Clodronate inhibits alloimmunization against distinct red blood cell alloantigens in mice.

BACKGROUND: Alloimmunization can be a significant barrier to red blood cell (RBC) transfusion. While alloantigen matching protocols hold promise in reducing alloantibody formation, transfusion-dependent patients can still experience RBC alloimmunization and associated complications even when matching protocols are employed. As a result, complementary strategies capable of actively preventing alloantibody formation following alloantigen exposure are warranted. STUDY DESIGN AND METHODS: We examined whether pharmacological removal of macrophages using clodronate may provide an additional strategy to actively inhibit RBC alloimmunization using two preclinical models of RBC alloimmunization. To accomplish this, mice were treated with clodronate, followed by transfusion of RBCs expressing the HOD (HEL, OVA, and Duffy) or KEL antigens. On days 5 and 14 post transfusion, anti-HOD or anti-KEL IgM and IgG antibodies were evaluated. RESULTS: Low dose clodronate effectively eliminated key marginal zone macrophage populations from the marginal sinus. Prior treatment with clodronate, but not empty liposomes, also significantly inhibited IgM and IgG anti-HOD alloantibody formation following transfusion of HOD RBCs. Similar exposure to clodronate inhibited IgM and IgG antibody formation following KEL RBC transfusion. CONCLUSIONS: Clodronate can inhibit anti-HOD and anti-KEL antibody formation following RBC transfusion in preclinical models. These results suggest that clodronate may provide an alternative approach to actively inhibit or prevent the development of alloantibodies following RBC transfusion, although future studies will certainly be needed to fully explore this possibility.

NCCN Guidelines® Insights: Hematopoietic Growth Factors, Version 1.2022.

The NCCN Guidelines for Hematopoietic Growth Factors provide recommendations for the appropriate use of growth factors in the clinical management of febrile neutropenia (FN), chemotherapy-induced thrombocytopenia (CIT), and chemotherapy-induced anemia (CIA). Management and prevention of these sequelae are an integral part of supportive care for many patients undergoing cancer treatment. The purpose of these guidelines is to operationalize the evaluation, prevention, and treatment of FN, CIT, and CIA in adult patients with nonmyeloid malignancies and to enable the patient and clinician to assess management options for FN, CIT, and CIA in the context of an individual patient's condition. These NCCN Guidelines Insights provide a summary of the important recent updates to the NCCN Guidelines for Hematopoietic Growth Factors, with particular emphasis on the incorporation of a newly developed section on CIT.

Psychosocial outcomes 1-year post total pancreatectomy and autologous islet cell transplant.

BACKGROUND: A paucity of research regarding the psychosocial outcomes after TPIAT exists. METHODS: Adults (>18 years), adolescents (13-18 years), and children (5-12 years) with their parents were administered questionnaires at the time of evaluation for TPIAT and 1-year postsurgery to assess psychosocial outcomes. RESULTS: A total of 13 adults (6 male, 46%; mean age 35.2 years) and 9 children/adolescents (4 female, 44.4%; mean age 11.78 years) with CP were included in the study. A total of 69.2% of the adults and 66.7% of the children and adolescents were insulin dependent at 1-year postsurgery. In adults, improvements on the SF-36 pain (p = .001) and general health (p = .045) subscales were generally observed 1-year postsurgery. Adult patients who underwent robotic-assisted surgery compared to open surgery specifically reported better general health on the SF-36 (p < .05) at 1 year. For children and adolescents, reductions in average pain in the last week (p < .05), pain interference (p < .001), and fatigue were observed (p < .05) at 1-year postsurgery. For the entire sample, using repeated measures ANOVA and covarying for age, significant differences were found 1-year postsurgery in average pain in the last week (p = .034) and pain interference with the following categories: general activity (p < .001), walking (p = .04), normal work (p = .003), sleep (p = .002), and enjoyment in life (p = .007). CONCLUSIONS: While few transplant centers offer this treatment, the improvement in quality of life suggests this may be a viable treatment option for those with CP complicated by intractable pain. (IRB Approval PRO 19080302).

Association of Vitamin D with Thyroid Status in a Tertiary Care Hospital in North India.

BACKGROUND: Vitamin D acts as immunomodulatory molecule and its deficiency has been implicated in various autoimmune diseases including immune mediated hypothyroidism. However, its association with thyroid hormones is ambiguous. The present study was therefore aimed to explore the relationship of vitamin D with thyroid hormone levels in a population enrolled for health care check up in a tertiary care hospital. METHODS: The present cross-sectional study included 664 subjects. Serum levels of 25(OH) vitamin D, free triiodothyronine, free thyroxine, and thyroid stimulating hormone (TSH) were measured. Serum vitamin 25(OH)D levels < 30 ng/mL and > 30 ng/mL were considered as vitamin D insufficient and vitamin D sufficient state, respectively. RESULTS: Vitamin D insufficiency was greater in females (89.6%) than in males (78.5%). Females were observed to have significantly lower serum 25(OH)D levels (18.7 ± 9.5 versus 20.62 ± 10.2 ng/mL) and higher serum TSH values (2.5 ± 1.25 versus 2.25 ± 1.16 mIU/L) as compared to males. The serum TSH level in the vitamin D sufficiency group were significantly lower than those in the vitamin D insufficiency group (2.39 ± 1.22 versus 2.12 ± 1.1 mIU/ L). Further, age was the only significant predictor of TSH levels. Meanwhile, no predictor was identified for vitamin D levels. CONCLUSIONS: Although no association was observed between TSH and vitamin D levels, TSH was observed to be significantly higher in the vitamin D insufficient group than the vitamin D sufficient group. It warrants further studies to ascertain the role of vitamin D in regulating thyroid hormones considering the thyroid autoimmune status of the individuals as well.

The experience of hearing loss in adult survivors of childhood and young adult cancer: A qualitative study.

BACKGROUND: Hearing loss is a prevalent late effect among cancer survivors. Despite the significant social costs, there is a noted delay in seeking care and to the authors' knowledge there are limited data regarding the lived experiences of cancer survivors with hearing loss. The objective of the current study was to explore the lived experience of hearing loss in survivors of childhood and young adult cancers to guide survivorship care. METHODS: A total of 24 survivors participated in semistructured telephone interviews. Inclusion criteria consisted of a clinical visit at the Adult Long-Term Follow-Up Program at Memorial Sloan Kettering Cancer Center in New York City between September 2005 and January 2019; exposure to cranial radiotherapy, platinum chemotherapy, or both; and hearing loss as evidenced by clinical notes, use of hearing aids, or audiogram levels consistent with severe ototoxicity. RESULTS: Three primary themes emerged from the interviews. First, posttreatment hearing loss is associated with isolation and feelings of exclusion. Second, clinicians play an important role in providing survivors with education regarding hearing loss and hearing aids. Finally, hearing loss for survivors may be deprioritized because it is a reminder of the cancer history and is interpreted within the context of other treatment-related late effects. CONCLUSIONS: Clinicians play an important role in initiating the discussion regarding hearing loss with survivors given the importance of hearing in maintaining social relationships, the availability of hearing care interventions, and the invisibility of hearing loss. Education regarding the value of treatment may have implications for how survivors choose to prioritize hearing loss and seek care.

Mutational analysis confirms the presence of distal inhibitor-selectivity determining residues in B. stearothermophilus dihydrofolate reductase.

Many antibacterial and antiparasitic drugs work by competitively inhibiting dihydrofolate reductase (DHFR), a vital enzyme in folate metabolism. The interactions between inhibitors and DHFR active site residues are known in many homologs but the contributions from distal residues are less understood. Identifying distal residues that aid in inhibitor binding can improve targeted drug development programs by accounting for distant influences that may be less conserved and subject to frequent resistance causing mutations. Previously, a novel, homology-based, computational approach that mines ligand inhibition data was used to predict residues involved in inhibitor selectivity in the DHFR family. Expectedly, some inhibitor selectivity determining residue positions were predicted to lie in the active site and coincide with experimentally known inhibitor selectivity determining positions. However, other residues that group spatially in clusters distal to the active site have not been previously investigated. In this study, the effect of introducing amino acid substitutions at one of these predicted clusters (His38-Ala39-Ile40) on the inhibitor selectivity profile in Bacillus stearothermophilus dihydrofolate reductase (Bs DHFR) was investigated. Mutations were introduced into these cluster positions to change sidechain chemistry and size. We determined kcat and KM values and measured KD values at equilibrium for two competitive DHFR inhibitors, trimethoprim (TMP) and pyrimethamine (PYR). Mutations in the His38-Ala39-Ile40 cluster significantly impacted inhibitor binding and TMP/PYR selectivity - seven out of nine mutations resulted in tighter binding to PYR when compared to TMP. These data suggest that the His38-Ala39-Ile40 cluster is a distal inhibitor selectivity determining region that favors PYR binding in Bs DHFR and, possibly, throughout the DHFR family.

Lipid Risk Factors in Vitiligo: Homocysteine the Connecting Link?

BACKGROUND: Vitiligo is an acquired, depigmenting skin disease with unclear, multifactorial etiopathogenesis affecting not only skin but also connected with metabolic abnormalities, including glucose and lipid abnormalities, confirming the systemic nature of the disease. Vitamin B12 and folic acid deficiencies have also been implicated in vitiligo that can lead to increased homocysteine levels in the circulation, a finding that can be expected in vitiligo. Further, an association between hyperlipidemia and hyperhomocysteinemia has been suggested in vitiligo patients showing the eminent need of management of vascular risk factors especially in diseases with metabolic abnormalities. The present study was thus aimed to assess homocysteine levels and lipid risk factors in vitiligo patients and to study their interrelationship to predict the cardiometabolic risk in vitiligo and its management. METHODS: The present cross-sectional study included 54 case of generalized vitiligo and 54 age and gender-matched healthy adults as controls. Patients were assessed for disease activity and severity (VASI Score). All the subjects were evaluated for the lipid profile and serum homocysteine levels. RESULTS: Lipid profile analysis showed significantly higher LDL-cholesterol concentration (p = 0.010), significantly lower HDL-cholesterol concentration (p = 0.003) and significantly higher LDL/HDL ratio (p = 0.001) in patients with vitiligo in comparison with the control group. The mean serum homocysteine levels in vitiligo patients (18.76 ± 10.02 µmol/L) were significantly higher than in controls (10.04 ± 5.34 µmol/L) (p = 0.000). Serum homocysteine levels showed a positive correlation with the duration of disease which was near to significant (p = 0.064) and VASI score (p = 0.000). No significant correlation was observed between serum Hcy levels and lipid profile. CONCLUSIONS: The present study showed significantly higher Hcy levels in vitiligo patients than controls which may be a precipitating factor in the pathogenesis of vitiligo in predisposed individuals. The results of our study are also indicative of lipid disturbances in vitiligo. These findings may reflect some ongoing abnormal metabolic processes in patients with vitiligo. Therefore, we recommend routine estimation of homocysteine and lipid profile in vitiligo patients both of which should be regarded as independent significant contributing factors of cardiometabolic risk worth considering in the management of patients with vitiligo.

NLRP3 mutation and cochlear autoinflammation cause syndromic and nonsyndromic hearing loss DFNA34 responsive to anakinra therapy.

The NLRP3 inflammasome is an intracellular innate immune sensor that is expressed in immune cells, including monocytes and macrophages. Activation of the NLRP3 inflammasome leads to IL-1ß secretion. Gain-of-function mutations of NLRP3 result in abnormal activation of the NLRP3 inflammasome, and cause the autosomal dominant systemic autoinflammatory disease spectrum, termed cryopyrin-associated periodic syndromes (CAPS). Here, we show that a missense mutation, p.Arg918Gln (c.2753G > A), of NLRP3 causes autosomal-dominant sensorineural hearing loss in two unrelated families. In family LMG446, hearing loss is accompanied by autoinflammatory signs and symptoms without serologic evidence of inflammation as part of an atypical CAPS phenotype and was reversed or improved by IL-1ß blockade therapy. In family LMG113, hearing loss segregates without any other target-organ manifestations of CAPS. This observation led us to explore the possibility that resident macrophage/monocyte-like cells in the cochlea can mediate local autoinflammation via activation of the NLRP3 inflammasome. The NLRP3 inflammasome can indeed be activated in resident macrophage/monocyte-like cells in the mouse cochlea, resulting in secretion of IL-1ß. This pathway could underlie treatable sensorineural hearing loss in DFNA34, CAPS, and possibly in a wide variety of hearing-loss disorders, such as sudden sensorineural hearing loss and Meniere's disease that are elicited by pathogens and processes that stimulate innate immune responses within the cochlea.

TMEM173 variants and potential importance to human biology and disease.

TMEM173 gene encodes the protein STING (stimulator of interferon genes), a key player in host defense against pathogens. Mutations in the human TMEM173 gene cause a life-threatening auto-inflammatory disease called SAVI (STING-associated vasculopathy with onset in infancy). Human STING is also a promising therapeutic target for cancers and infectious diseases. Recently, Aduro Biotech and Novartis announced a $250M-plus initiative to develop STING-targeting cancer immunotherapies. Thus, understanding the genetics of the human TMEM173 gene is important for both basic and translational research. The human TMEM173 gene has great heterogeneity and population stratification. R232 of STING is the most common human TMEM173 allele. However, >50% of Americans are not R232/R232. HAQ (R71H-G230A-R293Q) is the second most common human TMEM173 allele. While R232/R232 is the dominant TMEM173 genotype in Europeans, R232/HAQ is the most common TMEM173 genotype in East Asians. Importantly, recent studies suggested that HAQ and H232 are likely loss-of-function TMEM173 alleles. In all, ~30% of East Asians and ~10% of Europeans are HAQ/HAQ, HAQ/H232, or H232/H232. Here, we reviewed human TMEM173 alleles, mutations and their potential impact on human health and medicine.

Bioactive peptides and proteins as alternative antiplatelet drugs.

Antiplatelet drugs reduce the risks associated with atherothrombotic events and show various applications in diverse cardiovascular diseases including myocardial infarctions. Efficacy of the current antiplatelet medicines including aspirin, clopidogrel, prasugrel and ticagrelor, and the glycoprotein IIb/IIIa antagonists, are limited due to their increased risks of bleeding, and antiplatelet drug resistance. Hence, it is important to develop new effective antiplatelet drugs, with fewer side-effects. The vast repertoire of natural peptides can be explored towards this goal. Proteins and peptides derived from snake venoms and plants represent exciting candidates for the development of novel and potent antiplatelet agents. Consequently, this review discusses multiple peptides that have displayed antiplatelet aggregation activity in preclinical drug development stages. This review also describes the antiplatelet mechanisms of the peptides, emphasizing the signaling pathways intervened by them. Also, the hurdles encountered during the development of peptides into antiplatelet drugs have been listed. Finally, hitherto unexplored peptides with the potential to prevent platelet aggregation are explored.