Fc multimers effectively treat murine models of multiple sclerosis.

Multiple Sclerosis (MS) is a chronic neurodegenerative disease with limited therapeutic options. Recombinant Fc multimers (rFc), designed to mirror many of the anti-inflammatory activities of Intravenous Immunoglobulin (IVIG), have been shown to effectively treat numerous immune-mediated diseases in rodents. In this study we used the experimental autoimmune encephalomyelitis (EAE) murine model of MS to test the efficacy of a rFc, M019, that consists of multimers of the Fc portion of IgG2, in inhibiting disease severity. We show that M019 effectively reduced clinical symptoms when given either pre- or post-symptom onset compared to vehicle treated EAE induced mice. M019 was effective in reducing symptoms in both SJL model of relapsing remitting MS as well as the B6 model of chronic disease. M019 binds to FcγR bearing-monocytes both in vivo and in vitro and prevented immune cell infiltration into the CNS of treated mice. The lack of T cell infiltration into the spinal cord was not due to a decrease in T cell priming; there was an equivalent frequency of Th17 cells in the spleens of M019 and vehicle treated EAE induced mice. Surprisingly, there was an increase in chemokines in the sera but not in the CNS of M019 treated mice compared to vehicle treated animals. We postulate that M019 interacts with a FcγR rich monocyte intermediary to prevent T cell migration into the CNS and demyelination.

Complement component C1q is an immunological rheostat that regulates Fc:Fc[Formula: see text]R interactions.

Though binding sites for the complement factor C1q and the canonical fragment crystallizable (Fc) gamma receptors (Fc[Formula: see text]Rs) on immunoglobulin G (IgG) molecules overlap, how C1q decoration of immune complexes (ICs) influences their ability to engage Fc[Formula: see text]Rs remains unknown. In this report, we use recombinant human Fc multimers as stable IC mimics to show that C1q engagement of ICs directly and transiently inhibits their interactions with Fc[Formula: see text]RIII (CD16) on human natural killer (NK) cells. This inhibition occurs by C1q engagement alone as well as in concert with other serum factors. Furthermore, the inhibition of Fc[Formula: see text]RIII engagement mediated by avid binding of C1q to ICs is directly associated with IC size and dependent on the concentrations of both C1q and Fc multimers present. Functionally, C1q-mediated Fc blockade limits the ability of NK cells to induce the upregulation of the cosignaling molecule, 4-1BB (CD137), and to mediate antibody-dependent cell-mediated cytotoxicity (ADCC). Although C1q is traditionally viewed as a soluble effector molecule, we demonstrate that C1q may also take on the role of an "immunologic rheostat," buffering Fc[Formula: see text]R-mediated activation of immune cells by circulating ICs. These data define a novel role for C1q as a regulator of immune homeostasis and add to our growing understanding that complement factors mediate pleiotropic effects.

The effects of an ergonomic chinrest among professional violin players. A biomechanical investigation in a randomised crossover design.

This study aimed to compare violinists' upper body kinematics and muscle activity while playing with different supportive equipment: their usual chinrest (UC) or an ergonomic chinrest (EC), each mounted on the violin. Three-dimensional motion capture and electromyographic data were acquired from the upper body while 38 pain-free professional violinists performed an excerpt of a music piece. There were only minor differences between the two set-ups tested. The EC resulted in less left rotation of the head (3.3°), slightly more neck extension (1.3°) and less muscle activity (0.5-1.0 %MVE). However, the overall high static muscle activity (4-10 %MVE across all muscles) was maintained using EC. For both setups, the head posture was left-rotated >15°, ≤6° flexed and left-bent 90% of the time. The EC did not produce a substantial difference in biomechanical load. Instead, future studies may focus on aspects other than chinrest design to lower the static workload demands.

Mortality Not Increased in Patients With Nonfunctional Adrenal Adenomas: A Matched Cohort Study.

CONTEXT: Mild autonomous cortisol secretion (MACS) is associated with increased mortality in patients with adrenal incidentalomas, but little is known regarding the potential risk associated with nonfunctional adrenal adenomas (NFAA), which constitute the majority of adrenal incidentalomas. OBJECTIVE: Compare mortality risk in patients with NFAA, and different levels of MACS, to matched controls. METHOD: This was a retrospective matched cohort study. All patients referred to 2 endocrine centers in southern Sweden because of an adrenal incidentaloma between 2005 and 2015 were enrolled. Controls (3:1) matched for sex, age, and residency were included. Primary endpoint was all-cause mortality. Outcome data were obtained from the Cause of Death Register. Patients were grouped according to cortisol level post 1-mg dexamethasone suppression test (cortisolDST) (<50 (NFAA), 50-82, 83-137, and ≥138 nmol/L). RESULTS: 1154 patients and 3462 matched controls were included. During a median follow-up of 6.6 years, 210 patients and 505 controls died. There were no statistically significant differences in mortality between patients with NFAA and their controls (HR 1.13 [0.87-1.46]) whereas mortality was increased compared to controls in patients with cortisolDST 83-137 (HR 1.99 [1.38-2.88]) and ≥138 nmol/L (HR 4.09 [2.41-6.93]). Likewise, the mortality risk was increased in patients younger than 65 years with cortisolDST 50-82 nmol/L compared with controls (HR 2.33 [1.30-4.17]). CONCLUSION: NFAA does not seem to pose a clinically relevant risk for increased mortality in patients with adrenal incidentalomas while patients with MACS, and especially younger patients and those with cortisolDST ≥83 nmol/L, have significantly increased mortality risk compared with matched controls.

Effects of low load exercise with and without blood-flow restriction on microvascular oxygenation, muscle excitability and perceived pain.

This paper aimed to examine the acute effect of low-load (LL) exercise with blood-flow restriction (LL-BFR) on microvascular oxygenation and muscle excitability of the vastus medialis (VM) and vastus lateralis (VL) muscles during a single bout of unilateral knee extension exercise performed to task failure. Seventeen healthy recreationally resistance-trained males were enrolled in a within-group randomized cross-over study design. Participants performed one set of unilateral knee extensions at 20% of one-repetition maximum (1RM) to task failure, using a LL-BFR or LL free-flow (LL-FF) protocol in a randomized order on separate days. Changes in microvascular oxygenation and muscle excitability in VL and VM were assessed using near-infrared spectroscopy (NIRS) and surface electromyography (sEMG), respectively. Pain measures were collected using the visual analog scale (VAS) before and following set completion. Within- and between- protocol comparisons were performed at multiple time points of set completion for each muscle. During LL-BFR, participants performed 43% fewer repetitions and reported feeling more pain compared to LL-FF (p<0.05). Normalized to time to task failure, LL-BFR and LL-FF generally demonstrated similar progression in microvascular oxygenation and muscle excitability during exercise to task failure. The present results demonstrate that LL-BFR accelerates time to task failure, compared with LL-FF, resulting in a lower dose of mechanical work to elicit similar levels of oxygenation, blood-pooling, and muscle excitability. LL-BFR may be preferable to LL-FF in clinical settings where high workloads are contraindicated, although increased pain experienced during BFR may limit its application.HighlightsCompared to free flow (FF), neuromuscular fatigue mechanisms are accelerated during blood flow restricted (BFR) training. This can be observed as changes in microvascular oxygenation and muscle excitability occurring at a ∼43% faster mean rate during BFR compared to FF.BFR exercise seems to elicit the same level of neuromuscular fatigue as FF training within a shorter timeframe. This reduces total joint load and may be especially helpful in cases where high training volumes may be contraindicated (e.g. recovering from a sports injury or orthopedic surgery).

An ACE2-IgG4 Fc Fusion Protein Demonstrates Strong Binding to All Tested SARS-CoV-2 Variants and Reduced Lung Inflammation in Animal Models of SARS-CoV-2 and Influenza.

Background: The continued emergence of SARS-CoV-2 variants has caused concern that a constantly evolving virus will escape vaccines and antibody therapies. New approaches are needed. Methods: We created and manufactured an ACE2 extracellular domain (ECD) fragment Fc fusion drug candidate, G921, and engineered the compound for enhanced delivery of drug to peripheral tissues by minimizing the size of the ACE2 ECD and by incorporating an Fc domain to enhance transcytosis. G921 was assessed for binding, neutralization, in vivo anti-inflammatory effect, and pharmacokinetic profile. Results: G921 was expressed as an IgG4 Fc fusion protein presenting two ACE2 domains to ACE2 ligands while avoiding risk of infection via antibody-dependent enhancement. G921 strongly binds to the SARS-CoV-2 Wuhan-Hu-1 spike protein and demonstrates further diminished off rate to the spike protein from each of the currently identified variants of concern. G921 demonstrates ACE2 enzymatic activity comparable to positive control and binding to the neonatal Fc receptor (FcRn) without binding to low affinity Fc-gamma receptors (FcγRs). G921 is effective in a concentration-dependent manner in a focus reduction neutralization assay with EC50=16.3±4.2 µg/mL without cytotoxicity in Vero E6 cells when tested at 200 µg/mL in an MTS cell proliferation assay. G921 demonstrates statistically significant reduction of lung inflammation in relevant models of both SARS-CoV-2 and influenza. The pharmacokinetic profile demonstrated dose-dependent exposure with a multi-day half-life in monkeys and rats. Conclusion: G921 data are consistent with both antiviral and anti-inflammatory modes of action. G921 is a novel approach for the prevention and treatment of COVID-19 and possible other diseases characterized by deficiency of ACE2.

Assessment of shoulder rotation strength, muscle co-activation and shoulder pain in tetraplegic wheelchair athletes - A methodological study.

Objective: To develop a feasible protocol for testing maximum shoulder rotation strength in tetraplegic wheelchair athletes, and investigate concurrent validity of maximum isometric handheld dynamometer (HHD) towards maximum isokinetic dynamometer (ID) strength measurements; secondly, to study shoulder muscle activation during maximum shoulder rotation measurements, and the association between shoulder strength and shoulder pain.Design: Descriptive methodological.Setting: Danish Wheelchair Rugby (WCR) association for WCR tetraplegic athletes from local WCR-clubs.Participants: Twelve adult tetraplegics.Interventions: N/A.Outcome measures: Wheelchair User's Shoulder Pain Index (WUSPI) and Visual Analog Scale (VAS) measured shoulder pain, isometric HHD and ID (60°/s) measured maximum internal (IR) and external (ER) shoulder rotation strength. Surface Electromyography normalized to maximum EMG measured muscle activity (mm Infraspinatus and Latissimus Dorsi) during maximum shoulder rotation strength.Results: Concurrent validity of isometric HHD towards ID showed Concordance Correlation Coefficients of left and right arms 0.90 and 0.86 (IR), and 0.89 and 0.91 (ER), with no difference in muscle activity between isometric HHD and ID, but larger co-activation during ER. There was no association between shoulder strength and pain, except for significantly weak negative associations between ID and pain during ER for left and right arms (P = 0.03; P = 0.04).Conclusion: Standardized feasible protocol for tetraplegic wheelchair athletes for measuring maximum shoulder rotation strength was established. Isometric HHD is comparable with ID on normalized peak torques and muscle activity, but with larger co-activation. Strength was not clearly associated with shoulder pain.

Associations of age, BMI, and renal function to cortisol after dexamethasone suppression in patients with adrenal incidentalomas.

Introduction: The specificity of cortisol after 1 mg dexamethasone (cortisolDST) ≥50 nmol/L as a criterion for mild autonomous cortisol secretion (MACS) is approximately 85% in patients with adrenal incidentalomas (AI). The aim was to study the associations of cortisolDST to age, BMI, and renal function. Methods: We studied 1,129 patients with AI examined from 2005 to 2015 at Skåne University Hospital and Helsingborg Hospital. The covariates studied were gender, age, BMI, estimated glomerular filtration rate (eGFR), treatment with inhalation steroids, size of the AI, and size of the smallest AI in patients with bilateral AI (set to 0 in unilateral AI). We used machine learning models to uncover potential nonlinear associations. They were trained to fit the data and examined using feature importance analysis and partial dependence plots. Partial dependence plots show the marginal effect on cortisolDST of a covariate averaging over other covariates. Results: CortisolDST was strongly associated with the size of the AI and weakly associated with age, BMI, and eGFR according to the feature importance analysis. The partial dependence plots indicated relatively linear relationships for cortisolDST to age (positively) and eGFR (negatively). The association between cortisolDST and BMI was nonlinear. At BMI below 30 kg/m2, cortisolDST was negatively associated with BMI, but it was unchanged at higher BMI levels. Using linear regression, we found that cortisolDST increased by 11% (95% CI, 7%-14%) for each 10-year increase in age. In patients with a BMI below 30 kg/m2, cortisolDST increased by 23% (95% CI, 16%-31%) for each 5 kg/m2 decrease in BMI. We found no association at BMI levels above 30 kg/m2. CortisolDST increased by 9% (95% CI, 6%-11%) for each 10 ml/min/1.73m2 decrease in eGFR. Conclusions: CortisolDST is positively associated with age, negatively with BMI if below 30 kg/m2, and negatively with eGFR. These associations should be considered before diagnosing MACS.

Association Between Mortality and Levels of Autonomous Cortisol Secretion by Adrenal Incidentalomas : A Cohort Study.

BACKGROUND: Autonomous cortisol secretion in patients with adrenal incidentalomas is associated with increased mortality, but detailed information about the risk associated with specific levels of autonomous cortisol secretion is not available. OBJECTIVE: To measure the association between mortality and levels of autonomous cortisol secretion in patients with adrenal incidentalomas. DESIGN: Retrospective cohort study. (ClinicalTrials.gov: NCT03919734). SETTING: Two hospitals in southern Sweden. PATIENTS: Consecutive patients who had adrenal incidentalomas identified between 2005 and 2015 and were followed for up to 14 years. Outcome data were collected from national registers. MEASUREMENTS: Patients were grouped according to plasma cortisol level after a 1-mg dexamethasone suppression test (cortisolDST; <50, 50 to 82, 83 to 137, or ≥138 nmol/L). RESULTS: During a median follow-up of 6.4 years, 170 of 1048 patients died. Compared with a cortisolDST less than 50 nmol/L, a cortisolDST of 50 to 82 nmol/L was not associated with increased mortality (hazard ratio [HR], 1.15 [95% CI, 0.78 to 1.70]). However, a cortisolDST of 83 to 137 nmol/L (n = 119) had an HR of 2.30 (CI, 1.52 to 3.49), and a cortisolDST of 138 nmol/L or higher (n = 82) had an HR of 3.04 (CI, 1.86 to 4.98). Analyses using restricted cubic splines indicated that the association between cortisolDST and mortality was linear up to a cortisolDST of 200 nmol/L. LIMITATION: The results are not based on verified autonomous cortisol secretion; thus, the association may be underestimated. CONCLUSION: The association between mortality and cortisolDST increased linearly until cortisolDST reached 200 nmol/L. A cortisolDST of 83 to 137 nmol/L was associated with a 2-fold increase in mortality, and a cortisolDST of 138 nmol/L or higher was associated with a 3-fold increase in mortality. Additional studies should be done, and until those studies are completed some clinicians may consider these findings when deciding which patients to recommend for surgery. PRIMARY FUNDING SOURCE: Lisa and Johan Grönberg Foundation and Gyllenstiernska Krapperup Foundation.

Emergence of network effects and predictability in the judicial system.

As courts strive to simultaneously remain self-consistent and adapt to new legal challenges, a complex network of of citations between decided cases is established. Using network science methods to analyze the underlying patterns of citations between cases can help us understand the large-scale mechanisms which shape the judicial system. Here, we use the case-to-case citation structure of the Court of Justice of the European Union to examine this question. Using a link-prediction model, we show that over time the complex network of citations evolves in a way which improves our ability to predict new citations. Investigating the factors which enable prediction over time, we find that the content of the case documents plays a decreasing role, whereas both the predictive power and significance of the citation network structure itself show a consistent increase over time. Finally, our analysis enables us to validate existing citations and recommend potential citations for future cases within the court.

ACTH following overnight dexamethasone suppression can be used in the verification of autonomous cortisol secretion in patients with adrenal incidentalomas.

OBJECTIVE: During the investigation of adrenal incidentalomas, it is important to accurately diagnose autonomous cortisol secretion (ACS) but the specificity of cortisol ≥50 nmol/L after overnight dexamethasone suppression (cortisolONDST ) is low. Therefore, ACTH following overnight dexamethasone suppression (ACTHONDST ) and cortisol following a 2-day dexamethasone suppression test (cortisol2-DAYDST ) were examined as markers of HPA axis suppression during ONDST. DESIGN: This cross-sectional study examined patients with adrenal incidentalomas and basal ACTH ≥ 2.0 pmol/L who underwent ONDST. MEASUREMENTS: ACTHONDST /ACTH ratio (ACTH ratio) was calculated for all patients. To define cut-off levels for ACTHONDST and ACTH ratio as markers of HPA axis suppression, ROC curves were used to separate patients with cortisolONDST <50 and ≥50 nmol/L. RESULTS: CortisolONDST was ≥50 nmol/L in 140 out of 373 patients. In patients with cortisolONDST <50 nmol/L, ACTHONDST was 0.28 pmol/L (<0.23-2.7). DHEAS was positively correlated to ACTHONDST , demonstrating a 9% increase with a doubling in ACTHONDST , p = 0.02. The best cut-off levels for ACTHONDST and ACTH ratio to detect cortisolONDST ≥50 nmol/L were ≥0.6 pmol/L and ≥18% respectively. These cut-off levels were tested on patients with cortisolONDST <50 nmol/L, considered to have adequate suppression (n = 233), and patients with reduction of ≥50 nmol/L from cortisolONDST to cortisol2-DAYDST , who were considered to have inadequate suppression (n = 16). ACTHONDST ≥0.6 pmol/L and ACTH ratio ≥18% had a sensitivity of 75% and 81% respectively, and a specificity of 78% and 85% respectively, for detecting patients with inadequate suppression. CONCLUSIONS: ACTHONDST and ACTH ratio can be markers of HPA axis suppression in the investigation of adrenal incidentalomas. CortisolONDST ≥50 nmol/L with ACTHONDST <0.6 pmol/L or ACTH ratio <18% should lead to the suspicion of ACS.

High prevalence of smoking in patients with adrenal incidentalomas: causality or case selection?

OBJECTIVE: Autonomous cortisol secretion and possible autonomous cortisol secretion (ACS/pACS) are associated to an increase of cardiovascular risk factors such as hypertension, diabetes mellitus and dyslipidaemia. To our knowledge, the prevalence of smoking, another well-established risk factor for cardiovascular disease, has not been studied in detail in people with ACS/pACS or adrenal incidentalomas. METHODS: Patients with adrenal incidentalomas were examined with the 1-mg overnight dexamethasone suppression test (cortisolONDST). Information about current smoking was collected from the patient's records. RESULTS: We studied 1044 patients, of whom 370 (35%) were current smokers. Of these, 22% had bilateral AI compared to 12% of the non-smokers (P < 0.001). Among patients with unilateral adrenal incidentalomas, smokers had larger adrenal incidentalomas than non-smokers (22 mm vs 19 mm, P < 0.001). Smokers also more often had cortisolONDST ≥50 nmol/L than non-smokers, 54% vs 40% (P < 0.001), a finding independent of the size of the adrenal incidentaloma in patients with unilateral adrenal incidentalomas. CONCLUSIONS: In the present study of patients with adrenal incidentalomas, the prevalence of current smoking was higher than in the general population. Furthermore, smokers had larger unilateral adrenal incidentalomas, more often bilateral adrenal incidentalomas, and more frequently ACS/pACS. Whether smoking is a risk factor for adrenal incidentalomas and ACS/pACS or our findings are due to case selection needs to be further studied.

A recombinant human IgG1 Fc multimer designed to mimic the active fraction of IVIG in autoimmunity.

The antiinflammatory effects of i.v. Ig (IVIG) in the treatment of autoimmune disease are due, in part, to the Fc fragments of Ig aggregates. In order to capitalize on the known antiinflammatory and tolerogenic properties of Ig Fc aggregates, we created a recombinant human IgG1 Fc multimer, GL-2045. In vitro, GL-2045 demonstrated high-avidity binding to Fc receptors, blocked the binding of circulating immune complexes from patients with rheumatoid arthritis to human Fcγ receptors (FcγRs), and inhibited antibody-mediated phagocytosis at log order-lower concentrations than IVIG. In vivo, administration of GL-2045 conferred partial protection against antibody-mediated platelet loss in a murine immune thrombocytopenic purpura (ITP) model. GL-2045 also suppressed disease activity in a therapeutic model of murine collagen-induced arthritis (CIA), which was associated with reduced circulating levels of IL-6. Furthermore, GL-2045 administration to nonhuman primates (NHPs) transiently increased systemic levels of the antiinflammatory cytokines IL-10 and IL-1RA, reduced the proinflammatory cytokine IL-8, and decreased surface expression of CD14 and HLA-DR on monocytes. These findings demonstrate the immunomodulatory properties of GL-2045 and suggest that it has potential as a treatment for autoimmune and inflammatory diseases, as a recombinant alternative to IVIG.

Suppressed ACTH Is Frequently Unrelated to Autonomous Cortisol Secretion in Patients With Adrenal Incidentalomas.

Objective: ACTH is considered a weak marker for autonomous cortisol secretion (ACS) in patients with adrenal incidentalomas (AIs). Our aim was to investigate suppressed basal ACTH as a marker of ACS and to elucidate why this criterion is of limited value. Methods: Basal ACTH and cortisol after overnight dexamethasone suppression test (cortisolONDST) were measured in 198 patients with unilateral AI and at 2-year follow-up. Basal ACTH was measured in 100 control subjects. Results: In patients with cortisolONDST <50 nmol/L (n = 145), ACTH was <2 pmol/L in 19%, compared with 4% in control subjects (P < 0.001). ACTH and size of AI correlated negatively (P = 0.002). Among patients with cortisolONDST ≥50 nmol/L, ACTH was <2 pmol/L in 53%. The patients were grouped according to whether cortisolONDST was <50 or ≥50 nmol/L and whether ACTH was <2.0 or ≥2.0 or pmol/L. At follow-up, these four groups were still separated with statistically significant differences in ACTH and cortisolONDST. Conclusions: This study identifies a previously unrecognized group of patients defined by suppressed ACTH despite normal cortisolONDST. This suppression of ACTH by a factor other than ACS may explain the limitation of suppressed ACTH as a marker for ACS. We suggest increased cortisol secretion in response to ACTH by the AI to be an additional factor.

Recombinant human IgG1 based Fc multimers, with limited FcR binding capacity, can effectively inhibit complement-mediated disease.

There is a lack of effective targeted therapies for the treatment of complement dependent diseases. We developed two recombinant Fc multimers, G207 and G211, with limited ability to interact with low/moderate affinity FcγRs, but with high avidity for C1q. These drugs effectively inhibited complement dependent cytotoxicity (CDC) in vitro, and prevented the deposition of C1q, C3b and MAC, on the surface of Ab-opsonized cells. Importantly, these inhibitory effects were both C1q dependent and independent. In order to determine the biologic relevance of our findings, we evaluated the clinical efficacy of these drugs in three different animal models, acute RBC hemolysis, anti-Thy-1 nephritis and passive Heymann's nephropathy (PHN), in which disease pathophysiology relies preferentially on complement activation. While G207 was protective in the anti-Thy-1 nephritis and PHN models, G211 was protective in all of the models tested and could effectively treat PHN. In the anti-Thy-1 nephritis model, G211 prevented the characteristic histologic changes associated with the disease and limited glomerular deposition of C3. Collectively, these data suggest that "complement preferential" Fc multimers offer a novel approach to the treatment of complement mediated diseases.

A fully recombinant human IgG1 Fc multimer (GL-2045) inhibits complement-mediated cytotoxicity and induces iC3b.

GL-2045 is a recombinant human immunoglobulin G1 (IgG1)-based Fc multimer designed to recapitulate the anti-inflammatory activities of intravenous immunoglobulin (IVIG) on the innate and adaptive immune responses. We used functional in vitro studies to determine if GL-2045 could mimic the modulatory activity of IVIG on complement activation. GL-2045, at log-order lower concentrations than heat-aggregated IgG (HAGG) and IVIG, protected antibody-opsonized cells from complement-dependent cytotoxicity. These protective effects were completely mediated by the higher order multimer fractions of GL-2045 and were partially dependent upon sequestration of C1q. Exposure of serum to GL-2045 and, to a lesser extent, IVIG, resulted in high levels of C4a, limited levels of C3a, and no C5a. In contrast, HAGG induced high levels of C4a, C3a, and C5a. The means by which GL-2045 governed complement activation was dependent on its ability to augment the function of factor H, alone and in combination with factor I, to indirectly limit the alternative form of C3 convertase, with resultant increases in the anti-inflammatory molecule, the "inactive" form of C3b, called iC3b. Although IVIG, like GL-2045, potentiated factor H function, it also directly inhibited the alternative form of C3 convertase. Our findings help elucidate how IVIG, GL-2045, and HAGG regulate complement function. Furthermore, the capacity of GL-2045 to sequester C1q and augment factor H activity, in combination with its ability to generate activation-induced immunomodulatory complement split products, such as iC3b, make it a viable drug candidate for the treatment of diverse complement-mediated diseases.

Neck and shoulder muscle activity and posture among helicopter pilots and crew-members during military helicopter flight.

Neck pain among helicopter pilots and crew-members is common. This study quantified the physical workload on neck and shoulder muscles using electromyography (EMG) measures during helicopter flight. Nine standardized sorties were performed, encompassing: cruising from location A to location B (AB) and performing search and rescue (SAR). SAR was performed with Night Vision Goggles (NVG), while AB was performed with (AB+NVG) and without NVG (AB-NVG). EMG was recorded for: trapezius (TRA), upper neck extensors (UNE), and sternocleido-mastoid (SCM). Maximal voluntary contractions (MVC) were performed for normalization of EMG (MVE). Neck posture of pilots and crew-members was monitored and pain intensity of neck, shoulder, and back was recorded. Mean muscle activity for UNE was ∼10% MVE and significantly higher than TRA and SCM, and SCM was significantly lower than TRA. There was no significant difference between AB-NVG and AB+NVG. Muscle activity in the UNE was significantly higher during SAR+NVG than AB-NVG. Sortie time (%) with non-neutral neck posture for SAR+NVG and AB-NVG was: 80.4%, 74.5% (flexed), 55.5%, 47.9% (rotated), 4.5%, 3.7% (lateral flexed). Neck pain intensity increased significantly from pre- (0.7±1.3) to post-sortie (1.6±1.9) for pilots (p=0.028). If sustained, UNE activity of ∼10% MVE is high, and implies a risk for neck disorders.

Anti-CD20 Antibody with Multimerized Fc Domains: A Novel Strategy To Deplete B Cells and Augment Treatment of Autoimmune Disease.

We developed a fully recombinant anti-CD20 protein derived from cDNA encoding one Fab domain, two IgG1 Fc regions, the IgG2 hinge, and an isoleucine zipper. This protein, called GB4542, contained both the homodimer and higher-order multimers. Binding studies revealed that GB4542 preferentially bound CD20(+) cells yet also recognized CD20(-)FcγR(+) PBMC. In contrast, a control mAb containing the identical Fab region, GB4500, failed to bind CD20(-)FcγR(+) PBMC. Consistent with these findings, interactions between GB4542 and the canonical FcγRs had substantially lower KD values than correlate interfaces between GB4500 and these receptors. At low concentrations, GB4542 showed enhanced Ab-dependent cellular cytotoxicity, Ab-dependent cellular phagocytosis, and complement-dependent cytotoxicity compared with GB4500. However, at higher concentrations, an Fc analog of GB4542 inhibited anti-CD20 mAb-mediated B cell clearance through direct blocking of both Fc-FcγR interactions and C1q deposition on target cells. Furthermore, the higher-order multimer fraction of GB4542 demonstrated greater binding avidity with the canonical FcγRs and was associated with inhibitory effects observed in Ab-dependent cellular phagocytosis and complement-dependent cytotoxicity assays. These data suggest that GB4542 might have utility in the treatment of autoimmune diseases by combining both mAb-mediated B cell depletion and multimerized Fc-mediated tolerogenic effects.