The Association Between Gender and Clinical Outcomes in Patients With Moderate to Severe Traumatic Brain Injury: A Systematic Review and Meta-Analysis.

INTRODUCTION: Traumatic brain injuries (TBIs) are a significant cause of morbidity and mortality in the United States. but have a disproportionate impact on patients based on gender. This systematic review and meta-analysis aim to compare gender differences in clinical outcomes between male and female adult trauma patients with moderate and severe TBI. METHODS: Studies assessing gender differences in outcomes following TBIs on PubMed, Google Scholar, EMBASE, and ProQuest were searched. Meta-analysis was performed for outcomes including in-hospital mortality, hospital length of stay, intensive care unit length of stay, and Glasgow outcome scale (GOS) at 6 mo. RESULTS: Eight studies were included for analysis with 26,408 female and 63,393 male patients. Meta-analysis demonstrated that males had a significantly lower risk of mortality than females (RR: 0.88; 95% CI 0.78, 0.99; P = 0.0001). Females had a shorter hospital length of stay (mean difference -1.4 d; 95% CI - 1.6 d, -1.2 d). No significant differences were identified in intensive care unit length of stay (mean difference -3.0 d; 95% CI -7.0 d, 1.1 d; P = 0.94) or GOS at 6 mo (mean difference 0.2 d; 95% CI -0.9 d, 1.4 d; P = 1). CONCLUSIONS: Compared to male patients, female patients with moderate and severe TBI had a significantly higher in-hospital mortality risk. There were no significant differences in long-term outcomes between genders based on GOS at 6 mo. These findings warrant further investigation into the etiology of these gender disparities and their impact on additional clinical outcome measures.

Single cell analysis of host response to helminth infection reveals the clonal breadth, heterogeneity, and tissue-specific programming of the responding CD4+ T cell repertoire.

The CD4+ T cell response is critical to host protection against helminth infection. How this response varies across different hosts and tissues remains an important gap in our understanding. Using IL-4-reporter mice to identify responding CD4+ T cells to Nippostrongylus brasiliensis infection, T cell receptor sequencing paired with novel clustering algorithms revealed a broadly reactive and clonally diverse CD4+ T cell response. While the most prevalent clones and clonotypes exhibited some tissue selectivity, most were observed to reside in both the lung and lung-draining lymph nodes. Antigen-reactivity of the broader repertoires was predicted to be shared across both tissues and individual mice. Transcriptome, trajectory, and chromatin accessibility analysis of lung and lymph-node repertoires revealed three unique but related populations of responding IL-4+ CD4+ T cells consistent with T follicular helper, T helper 2, and a transitional population sharing similarity with both populations. The shared antigen reactivity of lymph node and lung repertoires combined with the adoption of tissue-specific gene programs allows for the pairing of cellular and humoral responses critical to the orchestration of anti-helminth immunity.

Outcomes of Transfusion With Whole Blood, Component Therapy, or Both in Adult Civilian Trauma Patients: A Systematic Review and Meta-Analysis.

INTRODUCTION: This systematic review and meta-analysis was conducted to compare outcomes, including transfusion volume, complications, intensive care unit length of stay, and mortality for adult civilian trauma patients transfused with whole blood (WB), components (COMP), or both (WB + COMP). METHODS: A systematic review and meta-analysis were conducted using studies that evaluated outcomes of transfusion of WB, COMP, or WB + COMP for adult civilian trauma patients. A search of PubMed, Embase, and Cochrane from database inception to March 3, 2022 was conducted. The search resulted in 18,400 initial articles with 16 studies remaining after the removal of duplicates and screening for inclusion and exclusion criteria. RESULTS: This study identified an increased risk of 24-h mortality with COMP versus WB + COMP (relative risk: 1.40 [1.10, 1.78]) and increased transfusion volumes of red blood cells with COMP versus WB at 6 and 24 h, respectively (-2.26 [-3.82, -0.70]; -1.94 [-3.22, -0.65] units). There were no differences in the calculated rates of infections or intensive care unit length of stay between WB and COMP, respectively (relative risks: 1.35 [0.53, 3.46]; -0.91 [-2.64, 0.83]). CONCLUSIONS: Transfusion with WB + COMP is associated with lower 24-h mortality versus COMP and transfusion with WB is associated with a lower volume of red blood cells transfused at both 6 and 24 h. Based on these findings, greater utilization of whole blood in civilian adult trauma resuscitation may lead to improved mortality and reduced transfusion requirements.

The Parallel Structure-Activity Relationship Screening of Three Compounds Identifies the Common Agonist Pharmacophore of Pyrrolidine Bis-Cyclic Guanidine Melanocortin-3 Receptor (MC3R) Small-Molecule Ligands.

The melanocortin receptors are involved in numerous physiological pathways, including appetite, skin and hair pigmentation, and steroidogenesis. In particular, the melanocortin-3 receptor (MC3R) is involved in fat storage, food intake, and energy homeostasis. Small-molecule ligands developed for the MC3R may serve as therapeutic lead compounds for treating disease states of energy disequilibrium. Herein, three previously reported pyrrolidine bis-cyclic guanidine compounds with five sites for molecular diversity (R1-R5) were subjected to parallel structure-activity relationship studies to identify the common pharmacophore of this scaffold series required for full agonism at the MC3R. The R2, R3, and R5 positions were required for full MC3R efficacy, while truncation of either the R1 or R4 positions in all three compounds resulted in full MC3R agonists. Two additional fragments, featuring molecular weights below 300 Da, were also identified that possessed full agonist efficacy and micromolar potencies at the mMC5R. These SAR experiments may be useful in generating new small-molecule ligands and chemical probes for the melanocortin receptors to help elucidate their roles in vivo and as therapeutic lead compounds.

Evaluating Clinical Outcomes of Laparoscopic Subtotal and Total Cholecystectomy for Complicated Acute Cholecystitis: A Systematic Review and Meta-Analysis.

INTRODUCTION: This systematic review and meta-analysis aimed to compare clinical outcomes in patients with complicated acute cholecystitis undergoing laparoscopic total vs subtotal cholecystectomy. METHODS: This systematic review and meta-analysis was conducted according to PRISMA guidelines and queried PubMed, Embase, ProQuest, Google Scholar, and Cochrane databases from inception to May 2023. The primary outcome was complication rates including common bile duct injury, wound infection, reoperation, bile leak, retained stones, and subhepatic collection, whereas secondary outcomes were in-hospital mortality and hospital length of stay. RESULTS: A total of 7 studies with 135,233 cases were included for meta-analysis. Patients who underwent laparoscopic total cholecystectomy had a significantly lower risk of postoperative bile leaks (RR: .15; 95% CI: .03, .80) and subhepatic fluid collection (RR: 0.19; 95% CI: .06, .63) and were 2.94 times less likely to die compared to those who underwent subtotal cholecystectomy (RR .34; 95% CI: .15, .77). Patients who underwent subtotal cholecystectomy had significantly longer hospital length of stay (mean difference 1.0 days; 95% CI: .5 days, 1.4 days). CONCLUSIONS: In adult patients presenting with complicated cholecystitis, management with laparoscopic subtotal cholecystectomy presents a unique complication profile with increased risk of postoperative bile leak and subhepatic fluid collection, in-hospital mortality, and longer hospital length-of-stay when used as an alternative approach to laparoscopic total cholecystectomy. Further research into the most appropriate clinical scenarios and patient populations for the use of the subtotal cholecystectomy approach may prove useful in improving its associated outcomes.

Outcomes of Preperitoneal Packing and Angioembolization for Hemorrhage Control in Hemodynamically Unstable Pelvic Fractures: A Systematic Review and Meta-Analysis.

BACKGROUND: Hemodynamically unstable pelvic fractures are often life-threatening injuries; however, the optimal management remains uncertain. This systematic review and meta-analysis aim to evaluate the most appropriate primary management of hemorrhage in adult patients with hemodynamically unstable pelvic fractures by comparing outcomes following the initial use of preperitoneal packing (PPP) vs angioembolization (AE). METHODS: A systematic search of PubMed, Embase, Google Scholar, and ProQuest databases was conducted following PRISMA guidelines. Studies assessing hemorrhage management in trauma patients with hemodynamically unstable pelvic fractures were included. The data extracted from selected articles included patient demographics, study design, and outcomes such as 24-hour PRBC transfusions, in-hospital mortality, and DVT rate. RESULTS: Eight articles were included in the systematic review. Among the included studies, 2040 patients with hemodynamically unstable pelvic fractures were analyzed. Meta-analyses revealed that treatment with PPP was associated with fewer 24-hour PRBC transfusions (mean difference = -1.0, 95% CI: -1.8 to -.2) than AE. However, no significant differences were noted in in-hospital mortality (RR: .91, 95% CI: .80-1.05) and the rate of deep vein thrombosis (RR: .89, 95% CI: .62-1.28) between groups. CONCLUSION: The findings of this study suggest that primary management with PPP was associated with fewer 24-hour PRBC transfusions compared to AE. The choice of primary management with PPP or AE did not significantly impact in-hospital mortality. Future studies should address clinical outcomes and the factors that affect them to better understand the impact of different management strategies and direct the creation of practice management guidelines.

Antigen-driven CD8 + T cell clonal expansion is a prominent feature of MASH in humans and mice.

Background and Aims: Chronic liver disease due to metabolic dysfunction-associated steatohepatitis (MASH) is a rapidly increasing global epidemic. MASH progression is a consequence of the complex interplay between inflammatory insults and dysregulated hepatic immune responses. T lymphocytes have been shown to accumulate in the liver during MASH, but the cause and consequence of T cell accumulation in the liver remain unclear. Our study aimed to define the phenotype and T cell receptor diversity of T cells from human cirrhotic livers and an animal model of MASH to begin resolving their function in disease. Approach and Results: In these studies, we evaluated differences in T cell phenotype in the context of liver disease we isolated liver resident T cell populations from individuals with cirrhosis and a murine model of MASH. Using both 5' single cell sequencing and flow cytometry we defined the phenotype and T cell receptor repertoire of liver resident T cells during health and disease. Conclusions: MASH-induced cirrhosis and diet-induced MASH in mice resulted in the accumulation of activated and clonally expanded T cells in the liver. The clonally expanded T cells in the liver expressed markers of chronic antigenic stimulation, including PD1 , TIGIT and TOX . Overall, this study establishes for the first time that T cells undergo antigen-dependent clonal expansion and functional differentiation during the progression of MASH. These studies could lead to the identification of potential antigenic targets that drive T cell activation, clonal expansion, and recruitment to the liver during MASH.

Selective agonists and antagonists of formylpeptide receptors: duplex flow cytometry and mixture-based positional scanning libraries.

The formylpeptide receptor (FPR1) and formylpeptide-like 1 receptor (FPR2) are G protein-coupled receptors that are linked to acute inflammatory responses, malignant glioma stem cell metastasis, and chronic inflammation. Although several N-formyl peptides are known to bind to these receptors, more selective small-molecule, high-affinity ligands are needed for a better understanding of the physiologic roles played by these receptors. High-throughput assays using mixture-based combinatorial libraries represent a unique, highly efficient approach for rapid data acquisition and ligand identification. We report the superiority of this approach in the context of the simultaneous screening of a diverse set of mixture-based small-molecule libraries. We used a single cross-reactive peptide ligand for a duplex flow cytometric screen of FPR1 and FPR2 in color-coded cell lines. Screening 37 different mixture-based combinatorial libraries totaling more than five million small molecules (contained in 5,261 mixture samples) resulted in seven libraries that significantly inhibited activity at the receptors. Using positional scanning deconvolution, selective high-affinity (low nM K(i)) individual compounds were identified from two separate libraries, namely, pyrrolidine bis-diketopiperazine and polyphenyl urea. The most active individual compounds were characterized for their functional activities as agonists or antagonists with the most potent FPR1 agonist and FPR2 antagonist identified to date with an EC50 of 131 nM (4 nM K(i)) and an IC50 of 81 nM (1 nM K(i)), respectively, in intracellular Ca²âº response determinations. Comparative analyses of other previous screening approaches clearly illustrate the efficiency of identifying receptor selective, individual compounds from mixture-based combinatorial libraries.

Conditional probabilistic analysis for prediction of the activity landscape and relative compound activities.

Structure-property relationships and structure-activity relationships play an important role in many research areas, such as medicinal chemistry and drug discovery. Such methods, however, have focused on providing post-hoc descriptions of such relationships based on known data. The ability for these descriptions to remain relevant when considering compounds of unknown activity, and thus the prediction of activity and property landscapes using existing data, remains little explored. In this study, we present a novel method of evaluating the ability of a compound comparison methodology to provide accurate information about a set of unknown compounds and also explore the ability of these predicted activity landscapes to prioritize active compounds over inactive. These methods are applied to three distinct and diverse sets of compounds, each with activity data for multiple targets, for a total of eight target-compound set pairs. Six methodologically distinct compound comparison methods were evaluated. We show that overall, all compound comparison methods provided an improvement in structure-activity relationship prediction over random and were able to prioritize compounds in a superior manner to random sampling, but the degree of success and therefore applicability varied markedly.

Rapid scanning structure-activity relationships in combinatorial data sets: identification of activity switches.

We present a general approach to describe the structure-activity relationships (SAR) of combinatorial data sets with activity for two biological endpoints with emphasis on the rapid identification of substitutions that have a large impact on activity and selectivity. The approach uses dual-activity difference (DAD) maps that represent a visual and quantitative analysis of all pairwise comparisons of one, two, or more substitutions around a molecular template. Scanning the SAR of data sets using DAD maps allows the visual and quantitative identification of activity switches defined as specific substitutions that have an opposite effect on the activity of the compounds against two targets. The approach also rapidly identifies single- and double-target R-cliffs, i.e., compounds where a single or double substitution around the central scaffold dramatically modifies the activity for one or two targets, respectively. The approach introduced in this report can be applied to any analogue series with two biological activity endpoints. To illustrate the approach, we discuss the SAR of 106 pyrrolidine bis-diketopiperazines tested against two formylpeptide receptors obtained from positional scanning deconvolution methods of mixture-based libraries.

The mathematics of a successful deconvolution: a quantitative assessment of mixture-based combinatorial libraries screened against two formylpeptide receptors.

In the past 20 years, synthetic combinatorial methods have fundamentally advanced the ability to synthesize and screen large numbers of compounds for drug discovery and basic research. Mixture-based libraries and positional scanning deconvolution combine two approaches for the rapid identification of specific scaffolds and active ligands. Here we present a quantitative assessment of the screening of 32 positional scanning libraries in the identification of highly specific and selective ligands for two formylpeptide receptors. We also compare and contrast two mixture-based library approaches using a mathematical model to facilitate the selection of active scaffolds and libraries to be pursued for further evaluation. The flexibility demonstrated in the differently formatted mixture-based libraries allows for their screening in a wide range of assays.

Comparing Outcomes of Appendectomy Versus Non-operative Antibiotic Therapy for Acute Appendicitis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

BACKGROUND: Acute appendicitis is one of the most common etiologies of an acute abdomen in the emergency department and first-line standard surgical care for the condition has recently been reconsidered. We aim to evaluate the effectiveness and outcomes of surgical intervention versus non-operative antibiotic therapy in the treatment of acute appendicitis in adult and pediatric patients. METHODS: A literature search was conducted using PubMed, Google Scholar, and EMBASE. The search included all studies until January 15th, 2022. Preferred Reporting Items for Systematic reviews and Meta-Analysis guidelines were followed for abstracting data and assessing data quality and validity. Data were independently extracted by the authors of the study. Meta-analysis was performed and Cohen's Q test for heterogeneous effects was performed to determine if fixed or random-effects models were appropriate for use. RESULTS: Twelve randomized controlled trials investigating a total of 3703 acute appendicitis patients met inclusion criteria and were included in the meta-analysis. In the systematic review, eleven RCTs demonstrated that appendectomy had improved effectiveness compared to non-operative antibiotic management. The meta-analysis demonstrated that patients undergoing appendectomy had significantly higher treatment effectiveness compared with antibiotics-only treatment (98.4% vs. 73.3%, P < .0001). The meta-analysis did demonstrate a significant .54-day reduction in hospital length of stay for the appendectomy group compared to the non-operative antibiotic therapy group. CONCLUSIONS: Surgical intervention is associated with increased effectiveness of treatment and reduced in-hospital length of stay among patients with acute appendicitis. Guidelines established by institutions and surgical organizations should indicate appendectomy as the standard and superior treatment option for patients presenting with acute appendicitis.

Beta-Blocker Therapy in Patients With Severe Traumatic Brain Injury: A Systematic Review and Meta-Analysis.

INTRODUCTION: Traumatic brain injury (TBI), a leading cause of morbidity and mortality among trauma patients worldwide, poses the risk of secondary neurological insult due to significant catecholamine surge. We aim to investigate the effectiveness and outcomes of beta-blocker administration in patients with severe TBI. METHODS: A search through PubMed, EMBASE, JAMA network, and Google Scholar databases was conducted for relevant peer-reviewed original studies published before February 15, 2022. A standard random-effects model was used, as justified by a high Cohen's Q test. RESULTS: Twelve studies met inclusion criteria and were included in the meta-analysis. Severe TBI patients who were administered beta-blockers had a significantly reduced incidence of in-hospital mortality compared to the non-beta-blocker group (14.5% vs 19.2%). However, the beta-blocker group was reported to have a significantly greater number of ventilator days (5.58 vs 2.60 days). Similarly, intensive care unit (9.00 vs 6.84 days) and hospital (17.30 vs 11.02 days) lengths of stay (LOS) were increased in the beta-blocker group compared to those who were not administered beta-blocker therapy, but only the difference in hospital-LOS was significant. CONCLUSIONS: Beta-blockers have significantly decreased in-hospital mortality in patients with severe TBI despite being associated with an increase in ventilator days and hospital-LOS. The administration of beta-blocker therapy in the management of severe TBI may be warranted and should be discussed in future guidelines.

Assessing the ecological risk of heavy metal sediment contamination from Port Everglades Florida USA.

Port sediments are often contaminated with metals and organic compounds from anthropogenic sources. Remobilization of sediment during a planned expansion of Port Everglades near Fort Lauderdale, Florida (USA) has the potential to harm adjacent benthic communities, including coral reefs. Twelve sediment cores were collected from four Port Everglades sites and a control site; surface sediment was collected at two nearby coral reef sites. Sediment cores, sampled every 5 cm, were analyzed for 14 heavy metals using inductively coupled plasma-mass spectrometry. Results for all three locations yielded concentration ranges (µg/g): As (0.607-223), Cd (n/d-0.916), Cr (0.155-56.8), Co (0.0238-7.40), Cu (0.004-215), Pb (0.0169-73.8), Mn (1.61-204), Hg (n/d-0.736), Mn (1.61-204), Ni (0.232-29.3), Se (n/d-4.79), Sn (n/d-140), V (0.160-176), and Zn (0.112-603), where n/d = non-detected. The geo-accumulation index shows moderate-to-strong contamination of As and Mo in port sediments, and potential ecological risk indicates moderate-to-significantly high overall metal contamination. All four port sites have sediment core subsamples with As concentrations above both threshold effect level (TEL, 7.24 µg/g) and probable effect level (PEL, 41.6 µg/g), while Mo geometric mean concentrations exceed the background continental crust level (1.5 µg/g) threshold. Control site sediments exceed TEL for As, while the reef sites has low to no overall heavy metal contamination. Results of this study indicate there is a moderate to high overall ecological risk from remobilized sediment due to metal contamination. Due to an imminent dredging at Port Everglades, this could have the potential to harm the threatened adjacent coral communities and surrounding protected habitats.

Identification of B Cell and T Cell Epitopes Using Synthetic Peptide Combinatorial Libraries.

This article presents a combinatorial library method that consists of the synthesis and screening of mixture-based synthetic combinatorial libraries of peptide molecules to identify B and T cell epitopes. The protocols employ peptide libraries to identify peptides recognized by MAbs and T cells. The first protocol uses a positional scanning peptide library made up of hexapeptides to identify antigenic determinants recognized by MAbs. The 120 mixtures in the hexapeptide library are tested for their inhibitory activity in a competitive ELISA. The second protocol uses a decapeptide library to identify T cell peptide ligands. The 200 mixtures of the decapeptide library are tested for their ability to induce T cell activation. Support protocols cover optimization of the assay conditions for each MAb or T cell, to achieve the best level of sensitivity and reproducibility, and preparation of a hexapeptide library, along with deconvolution approaches. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Screening peptide library for antibody inhibition Basic Protocol 2: Screening a peptide library to identify CD4+ Or CD8+ T cell ligands Support Protocol 1: Optimizing antigen and antibody concentrations for screening assay Support Protocol 2: Preparing a positional scanning peptide library.

Healthcare understanding of COVID-19 antibody.

OBJECTIVE: : The SARS-CoV-2 pandemic has shed light on the difficulties in spreading uniform information. We rely on national and international organizations to provide scientifically accurate information to the public at large. With so many different sources of information, often not scientific, there appears to be an incomplete understanding of many aspects of SARS-CoV-2 infection. We sought to gain information about healthcare worker understanding of the implications of a positive serum COVID-19 antibody test result. We identified a broad range of responses among all categories of healthcare workers in our facility. Most notably we found that there was not complete understanding that there can be asymptomatic spread of COVID-19 infection. METHODS: : We provided health literacy and opinion questions to the healthcare workers of our facility. RESULTS: : Upon analysis of the data, we identified many differences in level of understanding among our healthcare workers. CONCLUSION: : We identified a lack of consensus on important details leading to potentially growing uncertainty with respect to SARS-COV-2 antibody. A diminished health literacy with respect to antibody testing could potentially suggest future issues with understanding the importance of vaccination benefits.

Association of hypothermia with increased mortality rate in SARS-CoV-2 infection.

OBJECTIVE: Patients were observed to have variable temperatures. The objective of this study was to identify whether hypothermia in a patient infected with SARS-CoV-2 was associated with a higher than expected mortality. METHODS: In total, 331 charts from patients hospitalized with SARS-CoV-2 between March 9 and April 20, 2020 were reviewed. RESULTS: The probability of death was 2.06 times higher for those with hypothermia than for those without (95% CI 1.25-3.38)]. In ventilated patients, there were 32 deaths. Of these, 75% had been hypothermic. In a prior review of 10 000 non-SARS-CoV-2 patients with sepsis, the mortality rate in patients with hypothermia was 47%. A review of previous studies demonstrated a range of expected mortality rates in patients with ventilator-dependent respiratory failure and sepsis. In comparison, our study showed that within a group of critically ill patients with SARS-CoV-2 and hypothermia, the mortality rate exceeded those rates. CONCLUSION: Our review showed a significant association between hypothermia and death (p = 0.0033). Predictors of mortality in SARS-CoV-2 disease can expedite earlier aggressive care. Additionally, in areas with limited resources or overburdened healthcare systems, where there may be a need for resource allocation management, information about mortality risk may be helpful.

Discovery of Nanomolar Melanocortin-3 Receptor (MC3R)-Selective Small Molecule Pyrrolidine Bis-Cyclic Guanidine Agonist Compounds Via a High-Throughput "Unbiased" Screening Campaign.

The central melanocortin-3 and melanocortin-4 receptors (MC3R, MC4R) are key regulators of body weight and energy homeostasis. Herein, the discovery and characterization of first-in-class small molecule melanocortin agonists with selectivity for the melanocortin-3 receptor over the melanocortin-4 receptor are reported. Identified via "unbiased" mixture-based high-throughput screening approaches, pharmacological evaluation of these pyrrolidine bis-cyclic guanidines resulted in nanomolar agonist activity at the melanocortin-3 receptor. The pharmacological profiles at the remaining melanocortin receptor subtypes tested indicated similar agonist potencies at both the melanocortin-1 and melanocortin-5 receptors and antagonist or micromolar agonist activities at the melanocortin-4 receptor. This group of small molecules represents a new area of chemical space for the melanocortin receptors with mixed receptor pharmacology profiles that may serve as novel lead compounds to modulate states of dysregulated energy balance.

Functional Mixture-Based Positional Scan Identifies a Library of Antagonist Tetrapeptide Sequences (LAtTeS) with Nanomolar Potency for the Melanocortin-4 Receptor and Equipotent with the Endogenous AGRP(86-132) Antagonist.

The melanocortin-4 receptor (MC4R) plays an important role in appetite. Agonist ligands that stimulate the MC4R decrease appetite, while antagonist compounds increase food consumption. Herein, a functional mixture-based positional scan identified novel MC4R antagonist sequences. Mixtures comprising a library of 12,960,000 tetrapeptides were screened in the presence and absence of the NDP-MSH agonist. These results led to the synthesis of 48 individual tetrapeptides, of which 40 were screened for functional activity at the melanocortin receptors. Thirteen compounds were found to possess nanomolar antagonist potency at the MC4R, with the general tetrapeptide sequence Ac-Aromatic-Basic-Aromatic-Basic-NH2. The most notable results include the identification of tetrapeptide 48 [COR1-25, Ac-DPhe(pI)-Arg-Nal(2')-Arg-NH2], an equipotent MC4R antagonist to agouti-related protein [AGRP(86-132)], more potent than miniAGRP(87-120), and possessing 15-fold selectivity for the MC4R versus the MC3R. These tetrapeptides may serve as leads for novel appetite-inducing therapies to treat states of negative energy balance, such as cachexia and anorexia.

CD4+ T cells in the lungs of acute sarcoidosis patients recognize an Aspergillus nidulans epitope.

Löfgren's syndrome (LS) is an acute form of sarcoidosis characterized by a genetic association with HLA-DRB1*03 (HLA-DR3) and an accumulation of CD4+ T cells of unknown specificity in the bronchoalveolar lavage (BAL). Here, we screened related LS-specific TCRs for antigen specificity and identified a peptide derived from NAD-dependent histone deacetylase hst4 (NDPD) of Aspergillus nidulans that stimulated these CD4+ T cells in an HLA-DR3-restricted manner. Using ELISPOT analysis, a greater number of IFN-γ- and IL-2-secreting T cells in the BAL of DR3+ LS subjects compared with DR3+ control subjects was observed in response to the NDPD peptide. Finally, increased IgG antibody responses to A. nidulans NDPD were detected in the serum of DR3+ LS subjects. Thus, our findings identify a ligand for CD4+ T cells derived from the lungs of LS patients and suggest a role of A. nidulans in the etiology of LS.