IVIG ameliorate inflammation in collagen-induced arthritis: projection for IVIG therapy in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease that leads to joint destruction and disability. Despite a significant progress in administration of biological agents for RA patients, there is still a need for improved therapy. Intravenous immunoglobulins (IVIG), a pooled polyspecific immunoglobulin (Ig)G extracted from 5000 to 20 000 healthy subjects, showed beneficial therapeutic effect in patients with immune deficiency, sepsis and autoimmune diseases. The current study aimed to investigate the beneficial effect of treatment with IVIG in established collagen-induced arthritis in DBA/1j mice. Murine arthritis was induced in DBA/1j mice. Treatment with IVIG began when the disease was established. The clinical score was followed twice a week until day 48. The mice were bled for plasma and the paws were hematoxylin and eosin (H&E)-stained. Cytokine profile in the plasma was analyzed by Luminex technology and titers of circulating anti-collagen antibodies in the plasma was tested by enzyme-linked immunosorbent assay. Our results show that treatment with IVIG in murine significantly reduced the clinical arthritis score (P < 0·001). Moreover, mode of action showed that IVIG significantly reduced circulating levels of inflammatory cytokines [interferon (IFN)-γ, interleukin (IL)-1ß, IL-17, IL-6, tumor necrosis factor (TNF)-α, P < 0·001], inhibiting anti-collagen antibodies (P < 0·001) in the plasma of collagen-induced arthritis mice. Importantly, histopathological examination revealed that IVIG treatment prevented the migration of inflammatory immune cells into the cartilage and synovium, reduced the extent of joint damage and preserved joint architecture. Our results proved for the first time the valuable anti-inflammatory treatment of IVIG in experimental RA. We propose IVIG therapy for a subgroup of patients with rheumatologically related diseases.

"Watch Me Grow- Electronic (WMG-E)" surveillance approach to identify and address child development, parental mental health, and psychosocial needs: study protocol.

BACKGROUND: The COVID-19 pandemic and the associated economic recession has increased parental psychosocial stress and mental health challenges. This has adversely impacted child development and wellbeing, particularly for children from priority populations (culturally and linguistically diverse (CALD) and rural/regional communities) who are at an already increased risk of health inequality. The increased mental health and psychosocial needs were compounded by the closure of in-person preventive and health promotion programs resulting in health organisations embracing technology and online services. Watch Me Grow- Electronic (WMG-E) - developmental surveillance platform- exemplifies one such service. WMG-E was developed to monitor child development and guide parents towards more detailed assessments when risk is identified. This Randomised Controlled Trial (RCT) aims to expand WMG-E as a digital navigation tool by also incorporating parents' mental health and psychosocial needs. Children and families needing additional assessments and supports will be electronically directed to relevant resources in the 'care-as-usual' group. In contrast, the intervention group will receive continuity of care, with additional in-person assessment and 'warm hand over' by a 'service navigator' to ensure their needs are met. METHODS: Using an RCT we will determine: (1) parental engagement with developmental surveillance; (2) access to services for those with mental health and social care needs; and (3) uptake of service recommendations. Three hundred parents/carers of children aged 6 months to 3 years (recruited from a culturally diverse, or rural/regional site) will be randomly allocated to the 'care-as-usual' or 'intervention' group. A mixed methods implementation evaluation will be completed, with semi-structured interviews to ascertain the acceptability, feasibility and impact of the WMG-E platform and service navigator. CONCLUSIONS: Using WMG-E is expected to: normalise and de-stigmatise mental health and psychosocial screening; increase parental engagement and service use; and result in the early identification and management of child developmental needs, parental mental health, and family psychosocial needs. If effective, digital solutions such as WMG-E to engage and empower parents alongside a service navigator for vulnerable families needing additional support, will have significant practice and policy implications in the pandemic/post pandemic period. TRIAL REGISTRATION: The trial (Protocol No. 1.0, Version 3.1) was registered with ANZCTR (registration number: ACTRN12621000766819 ) on July 21st, 2021 and reporting of the trial results will be according to recommendations in the CONSORT Statement.

Decrease in 14-3-3η protein levels is correlated with improvement in disease activity in patients with rheumatoid arthritis treated with Tofacitinib.

14-3-3η protein is a proinflammatory mediator that may represent a novel diagnostic and prognostic biomarker for rheumatoid arthritis (RA). We assessed the correlation between changes in serum 14-3-3η levels and changes in clinical disease activity measures in RA patients treated with Tofacitinib (TOF). Paired serum samples from 35 patients with RA were obtained at baseline and 5 months after the initiation of treatment with TOF. The levels of 14-3-3η were measured by JOINT stat 14-3-3η ELISA test kits (Augurex Life Sciences Corp.). The cut-off was defined as 0.19 ng/ml. 14-3-3η positivity was found in 57% of the patients at baseline and in 37% of the patients after 5 months of treatment. Mean ± SD baseline 14-3-3η levels [4.92 ± 8.86 ng/ml] were significantly higher (p < 0.005) than 14-3-3η levels following treatment [1.97 ± 4.59 ng/ml]. A statistically significant improvement (p < 0.001) of CDAI, SDAI, DAS4ESR and DAS4CRP was achieved after 5 month of treatment. Decrease in 14-3-3η protein levels was highly correlated with improvement in DAS4ESR (r = 0.50, p < 0.01), DAS4CRP (r = 0.46, p < 0.01) and ESR (r = 0.36, p = 0.03) and moderately correlated with improvement in CDAI (r = 0.32, p = 0.065) and SDAI (r = 0.33, p = 0.051). The correlation between decrease in 14-3-3η levels and improvement in DAS4ESR remained significant in a partial correlation analysis controlling for ESR (r = 0.39, p = 0.02). This study demonstrates that in RA patients who were treated with TOF, decrease in 14-3-3η levels is correlated with improvement in clinical disease activity parameters. The 14-3-3η protein may serve as an objective biomarker for monitoring of TOF therapy response.

Massive in Silico Study of Noble Gas Binding to the Structural Proteome.

Noble gases are chemically inert, and it was therefore thought they would have little effect on biology. Paradoxically, it was found that they do exhibit a wide range of biological effects, many of which are target-specific and potentially useful and some of which have been demonstrated in vivo. The underlying mechanisms by which useful pharmacology, such as tissue and neuroprotection, anti-addiction effects, and analgesia, is elicited are relatively unexplored. Experiments to probe the interactions of noble gases with specific proteins are more difficult with gases than those with other chemicals. It is clearly impractical to conduct the large number of gas-protein experiments required to gain a complete picture of noble gas biology. Given the simplicity of atoms as ligands, in silico methods provide an opportunity to gain insight into which noble gas-protein interactions are worthy of further experimental or advanced computational investigation. Our previous validation studies showed that in silico methods can accurately predict experimentally determined noble gas binding sites in X-ray structures of proteins. Here, we summarize the largest reported in silico reverse docking study involving 127 854 protein structures and the five nonradioactive noble gases. We describe how these computational screening methods are implemented, summarize the main types of interactions that occur between noble gases and target proteins, describe how the massive data set that this study generated can be analyzed (freely available at group18.csiro.au), and provide the NDMA receptor as an example of how these data can be used to understand the molecular pharmacology underlying the biology of the noble gases. We encourage chemical biologists to access the data and use them to expand the knowledge base of noble gas pharmacology, and to use this information, together with more efficient delivery systems, to develop "atomic drugs" that can fully exploit their considerable and relatively unexplored potential in medicine.

Large protein as a potential target for use in rabies diagnostics.

Rabies is a zoonotic viral disease that remains a serious threat to public health worldwide. The rabies lyssavirus (RABV) genome encodes five structural proteins, multifunctional and significant for pathogenicity. The large protein (L) presents well-conserved genomic regions, which may be a good alternative to generate informative datasets for development of new methods for rabies diagnosis. This paper describes the development of a technique for the identification of L protein in several RABV strains from different hosts, demonstrating that MS-based proteomics is a potential method for antigen identification and a good alternative for rabies diagnosis.

Biotechnology advances: a perspective on the diagnosis and research of Rabies Virus.

Rabies is a widespread zoonotic disease responsible for approximately 55,000 human deaths/year. The direct fluorescent antibody test (DFAT) and the mouse inoculation test (MIT) used for rabies diagnosis, have high sensitivity and specificity, but are expensive and time-consuming. These disadvantages and the identification of new strains of the virus encourage the use of new techniques that are rapid, sensitive, specific and economical for the detection and research of the Rabies Virus (RABV). Real-time RT-PCR, phylogeographic analysis, proteomic assays and DNA recombinant technology have been used in research laboratories. Together, these techniques are effective on samples with low virus titers in the study of molecular epidemiology or in the identification of new disease markers, thus improving the performance of biological assays. In this context, modern advances in molecular technology are now beginning to complement more traditional approaches and promise to revolutionize the diagnosis of rabies. This brief review presents some of the recent molecular tools used for RABV analysis, with emphasis on rabies diagnosis and research.

The impact of bedside wipes in multi-patient rooms: a prospective, crossover trial evaluating infections and survival.

BACKGROUND: Multidrug-resistant organisms (MDROs) are prevalent on high-touch surfaces in multi-patient rooms. AIM: To quantify the impact of hanging single-use cleaning/disinfecting wipes next to each bed. Pre-specified outcomes were: (1) hospital-acquired infections (HAIs), (2) cleaning frequency, (3) MDRO room contamination, (4) new MDRO acquisitions, and (5) mortality. METHODS: Clustered randomized crossover trial at Shamir Medical Center, Israel (October 2016 to January 2018). Clusters were randomly assigned to use for cleaning either single-use quaternary ammonium wipes (Clinell) or standard practices (reusable cloths and buckets with bleach). Six-month intervention periods were implemented in alternating sequence, separated by a washout period. Five high-touch surfaces were monitored by fluorescent markers. Study outcomes were compared between periods using generalized estimating equations, Poisson regression, and Cox proportional hazards models. FINDINGS: Overall, 7725 patients were included (47,670 person-days), 3793 patients in rooms with intervention cleaning and 3932 patients in rooms with standard practices. During the intervention, there was no significant difference in HAI rates (incidence rate ratio: 1.6; 95% confidence interval (CI): 0.7-3.5; P = 0.3). However, in intervention rooms, the frequency of environmental cleaning was higher (odds ratio: 3.73; 95% CI: 2.0-7.1; P < 0.0001), MDRO environmental contamination rate was insignificantly lower (odds ratio: 0.7; 95% CI: 0.5-1.0; P = 0.06), new MDRO acquisition rate was lower (hazard ratio: 0.4; 95% CI: 0.2-1.0; P = 0.04), and in-hospital mortality rate was lower (incidence rate ratio: 0.8; 95% CI: 0.7-1.0; P = 0.03). CONCLUSION: Hanging single-use cleaning/disinfecting wipes next to each bed did not affect the HAI rates but did improve the frequency of cleaning, reduce MDRO environmental contamination, and was associated with reduced incidence of new MDRO acquisitions and reduced mortality. This is a feasible, recommended practice to improve patient outcomes in multi-patient rooms.

Growth of SJL/J-derived transplantable reticulum cell sarcoma as related to its ability to induce T-cell proliferation in the host. I. Dominant negative genetic influences of other parent haplotype in F1 hybrids of SJL/J mice.

Growth of three transplantable reticulum cell sarcomas (RCS) was studied in a variety of F1 hybrids of SJL/J mice by determination of lymph node (LN) and spleen: body weights ratios 7 and 14 d after intravenous injection of RCS cells. Comparison of BIO.S x SJL and A.SW x SJL with SJL/J showed a negative effect of both the A and the BIO non-H-2 genes, particularly on growth in LN. F1 hybrid resistance was noted with F1 hybrids that carried H-2Dd and was much more evident with F1 hybrids from BIO- than from A-background mice. This resistance was less marked at 14 than at 7 d and was partially overcome by injection of higher tumor doses. Changing the I region in the F1 parent from H-2d to H-2b or H-2f had no effect on growth, but changing to H-2k or H-2d virtually abolished the ability to support tumor growth. This effect appeared partially as a result of the I-E/C and partially of the I-A(B) region and was not overcome by higher tumor dose or longer intervals after injection. There also appeared to be a negative influence on growth of H-2Kk, but this was difficult to differentiate from the I-Ak effect with the available strains. The known proliferative responsiveness that SJL/J Lyt-1 T cells exhibit to Ia determinants on gamma-irradiated RCS cells in vitro was also compared with that of cells from various F1 hybrids. Responsiveness of F1 LN cells was expressed as a percentage of the response in SJL/J LN cells to the same RCS cells, measured as [3H]thymidine incorporation. There was a striking degree of correlation between proliferative responsiveness of F1 LN cells to RCS and the ability of the F1 mice to support tumor growth. This correlation was especially clear with respect to the negative influences of non-H-2 genes, and of H-2 loci in the I region, particularly of I-Ak or -d and of I-E/Ck or -d, but there also appeared to be a (smaller) negative effect of I-Ab or -f. Negative influence of H-2Dd on growth, however, was not reflected in a similarly large effect on the proliferative response. Additional findings showed that LN cells from all F1 hybrids exhibited equivalent syngeneic mixed lymphocyte responses in the presence of polyethylene glycol to mitomycin-treated spleen cells from both the SJL/J and the other parent. The extra high response of F1 cells to RCS cells, as compared with SJL spleen cells, however, was always absent when Ik or -d was contributed by one of the F1 parents. The results suggest a promoting effect of the proliferative response on RCS growth in vivo and, furthermore, an interesting effect of I-A and I-E/C genes, possibly via an interaction product, on the ability of LN cells to be stimulated by Ia determinants on RCS cells.

Is there a need for early detection programs for chronic kidney disease?

The aims of this paper are to examine whether early detection programs are needed to assist in detecting and managing chronic kidney disease (CKD). It draws on existing material which indicates that CKD and its precursor risk factors or illnesses such as hypertension, diabetes mellitus and HIV infection are very clearly major challenges faced by health systems worldwide. This paper evaluates whether CKD meets the epidemiological criteria to justify early screening. More compelling evidence is becoming available which indicates that the prevalence of CKD is significant in both developing and developed countries and that CKD can be easily detected and treated with only small changes to existing practice and this may be improved through screening programs. A brief evaluation of the challenges of establishing early detection programs is provided, as well as an examination of the capacity which exists for establishing such programs. It concludes that, despite the lack of randomized studies, these programs appear to provide an opportunity to integrate CKD management with common chronic illnesses and, through this approach, provide clinical and cost-effective management of both CKD and cardiovascular disease.

Characterization of the Th17 profile immune response in cases of human rabies transmitted by dogs and its interference in the disease pathogenesis.

The Th17 profile immune response is influenced by the presence of cytokines such as IL-1, IL-6, TGF-ß, IL-17, and IL-23. We sought to characterize the Th17 profile in CNS samples from human rabies cases transmitted by dogs and examine its possible influence on disease pathogenesis. We observed a high expression of TGF-ß, followed by IL-23, IL-17 and IL-6, and a low expression of IL-1ß and IFN-γ. Those results suggest the participation of Th17 in rabies virus neuroinfection transmitted by dogs. IL-23 probably plays a role in maintaining the Th17 profile, but it can also interfere with the establishment of the Th1 profile and viral clearance.

Fluorochrome-labeled deoxyribonuclease: specific stain for cell nuclei.

Nuclei of cells in tissue culture may be stained with deoxyribonuclease labeled with fluoresceitn isothiocyatnate; this is a simple, rapid, and specific process which is useful in localizing DNA in situ.

Clear-air turbulence: simultaneous observations by radar and aircraft.

Ultrasensitive radars and uninstrumented jet aircraft in concert have probed regions of the clear atmosphere in search of clear-air turbulence. All sources of clear-air radar echoes above 6 kilometers that were probed simultaneously by the aircraft were found to be turbulent.

Tropopause detected by radar.

The tropopause has been detected by ultrasensitive, narrow-beam, microwave (10.7-centimeter) and ultrahigh-frequency (71.5-cm) radars. Its reflectivity is consistent with that expected theoretically for a refractively turbulent medium. Indications are that the layer is also mechanically turbulent, and that electromagnetic scatter techniques may be used to detect high-altitude clear-air turbulence.

High flow nasal cannula: Influence of gas type and flow rate on airway pressure and CO2 clearance in adult nasal airway replicas.

BACKGROUND: High flow nasal cannula therapy is a form of respiratory support which delivers high flow rates of heated, humidified gas to the nares via specialized cannula. Two primary mechanisms of action attributed to the therapy are the provision of positive airway pressure as well as clearance of CO2-rich exhaled gas from the upper airways. METHODS: Physiologically accurate nose-throat airway replicas were connected at the trachea to a lung simulator, where CO2 was supplied to mimic the CO2 content in exhaled gas. Cannula delivered either air, oxygen or heliox (80/20%volume helium/oxygen) to the replicas at flow rates ranging from 0 to 60 l/min. Five replicas and three cannulas were compared. Tracheal pressure and CO2 concentration were continuously measured. The lung simulator provided breaths with tidal volume of 500 ml and frequency of 18 breaths/min. Additional clearance measurements were conducted for tidal volume and breathing frequency of 750 ml and 27 breaths/min, respectively. FINDINGS: Cannula flow rate was the dominant factor governing CO2 concentration. Average CO2 concentration decreased with increasing cannula flow rate, but above 30 L/min this effect was less pronounced. Tracheal positive end-expiratory pressure increased with flow rate and was lower for heliox than for air or oxygen. A predictive correlation was developed and used to predict positive end-expiratory pressure for a given cannula size as a function of supplied flow rate and occlusion of the nares. INTERPRETATION: Compared with administration of air or oxygen, administration of heliox is expected to result in similar CO2 clearance from the upper airway, but markedly lower airway pressure.

Predicted airway obstruction distribution based on dynamical lung ventilation data: A coupled modeling-machine learning methodology.

In asthma and chronic obstructive pulmonary disease, some airways of the tracheobronchial tree can be constricted, from moderate narrowing up to closure. Those pathological patterns of obstructions affect the lung ventilation distribution. While some imaging techniques enable visualization and quantification of constrictions in proximal generations, no noninvasive technique exists to provide the airway morphology and obstruction distribution in distal areas. In this work, we propose a method that exploits lung ventilation measures to access positions of airway obstructions (restrictions and closures) in the tree. This identification approach combines a lung ventilation model, in which a 0D tree is strongly coupled to a 3D parenchyma description, along with a machine learning approach. On the basis of synthetic data generated with typical temporal and spatial resolutions as well as reconstruction errors, we obtain very encouraging results of the obstruction distribution, with a detection rate higher than 85%.

Chronic kidney disease in human immunodeficiency virus infection.

The number of people living with human immunodeficiency virus (HIV) worldwide was estimated to be 39.5 million in 2006, 2.6 million more than in 2004. The manifestations of HIV infection in the kidney are multiple and varied, highlighting the complexity of the disease process. There is a wide spectrum of renal disease that occurs in the course of HIV infection. Biopsy studies reveal varying frequencies of histological patterns. HIV-associated nephropathy (HIVAN) is most common. A biopsy study at Chris Baragwanath Hospital in Soweto, South Africa showed that HIVAN was present in 27% and immune complex disease in 21%. Han et al. studied HIV-positive patients in Durban, South Africa and screened for proteinuria, including microalbuminuria. They found persistent proteinuria in 6%; HIVAN in 21/30 (72.4%) and the prevalence of HIVAN in patients with persistent microalbuminuria was 85.7%. Studies in black patients have shown a higher prevalence of both severe glomerular lesions (focal glomerulosclerosis) and nephrotic range proteinuria with renal dysfunction in the presence of normo-hypotension. There have been no prospective randomised controlled studies with any form of therapy for HIVAN to date. Therapy of HIVAN has included corticosteroids, cyclosporine and antiretroviral therapy (ART). ART appears to be a logical choice in the management of HIV-associated renal disease. Regimens containing protease inhibitors have been shown to be associated with significant slowing of the decline in creatinine clearance. Both peritoneal dialysis and haemodialysis are appropriate treatment modalities for HIV-infected patients with end stage renal disease. The choice of dialysis modality between haemodialysis and peritoneal dialysis is not a factor in predicting survival, if patients are stable on ART. Preliminary short-term data in case reports and small cohorts of liver, kidney, and heart transplant recipients suggest that patient survival rates may be similar to those in HIV-uninfected transplant recipients. However, high rates of acute and chronic rejection have been observed among HIV-infected kidney transplant recipients. The Infectious Diseases Society of America (IDSA) published guidelines in 2005, recommending that all individuals be assessed for kidney disease at the time of diagnosis of HIV infection with a screening urinalysis for proteinuria and a calculated estimate of renal function. Therefore any patient with persistent proteinuria, persistent haematuria or glomerular filtration rate < 60 mL/min per 1.73 m(2) should be referred to an institution where a specialist can evaluate this patient for further investigations. An integrated plan to reduce the progression to kidney failure together with lifestyle measures, focusing also on high risk groups with effective management at all levels of chronic kidney disease remains essential.

Scanning optical pyrometer for measuring temperatures in hollow cathodes.

Life-limiting processes in hollow cathodes are determined largely by the temperature of the electron emitter. To support cathode life assessment, a noncontact temperature measurement technique which employs a stepper motor-driven fiber optic probe was developed. The probe is driven inside the hollow cathode and collects light radiated by the hot interior surface of the emitter. Ratio pyrometry is used to determine the axial temperature profile. Thermocouples on the orifice plate provide measurements of the external temperature during cathode operation and are used to calibrate the pyrometer system in situ with a small oven enclosing the externally heated cathode. The diagnostic method and initial measurements of the temperature distribution in a hollow cathode are discussed.

Medical cannabis: Another piece in the mosaic of autoimmunity?

Legalization of cannabis' medicinal use is rapidly increasing worldwide, raising the need to evaluate medical implications of cannabis. Currently, evidence supports cannabis and its active ingredients as immune-modulating agents, affecting T-cells, B-cells, monocytes, and microglia cells, causing an overall reduction in pro-inflammatory cytokine expression and an increase in anti-inflammatory cytokines. Due to the supporting evidence of cannabinoids as an immune-modulating agent, research focusing on cannabinoids and autoimmunity has emerged. Several clinical trials in multiple sclerosis, inflammatory bowel disease, and fibromyalgia suggest cannabis' effectiveness as an immune-modulator. However, contradicting results and lack of large-scale clinical trials obscure these results. Although lacking clinical research, in vitro and in vivo experiments in rheumatoid arthritis, diabetes type 1, and systemic sclerosis demonstrate a correlation between disease activity and cannabinoids.

The Roughton-Forster equation for DLCO and DLNO re-examined.

Roughton and Forster (RF) proposed to split the lung diffusing capacity into two contributions describing first, diffusion to red blood cells (RBC), and second, capture by diffusion from the RBC surface and reaction with haemoglobin. Solving the diffusion-reaction equations for simplified capillary-RBC structures, we investigate the RF interpretation. This reveals first that the conventional extrapolation to zero pressure of 1/DLCO on PO2 is not a correct measure of the diffusive component. Consequently the capillary volumes deduced from this extrapolation are erroneous. Secondly, capture mechanisms are different for CO and NO: while DLCO characterizes "volume absorption" in the RBC and is correlated with hematocrit, DLNO quantifies "surface absorption" and provide information about the morphology of the space between the alveolar surface and the RBC surfaces. In conclusion, the RF approach may lead to erroneous physiological interpretations of DLCO; nevertheless, the measurement of DLCO and DLNO bring different types of information that give the potential for a better understanding of respiratory diseases.

Calculated ventilation and effort distribution as a measure of respiratory disease and Heliox effectiveness.

In spite of numerous clinical studies, there is no consensus on the benefit Heliox mixtures can bring to asthmatic patients in terms of work of breathing and ventilation distribution. In this article we use a 3D finite element mathematical model of the lung to study the impact of asthma on effort and ventilation distribution along with the effect of Heliox compared to air. Lung surface displacement fields extracted from computed tomography medical images are used to prescribe realistic boundary conditions to the model. Asthma is simulated by imposing bronchoconstrictions to some airways of the tracheo-bronchial tree based on statistical laws deduced from the literature. This study illuminates potential mechanisms for patient responsiveness to Heliox when affected by obstructive pulmonary diseases. Responsiveness appears to be function of the pathology severity, as well as its distal position in the tracheo-bronchial tree and geometrical position within the lung.