The impact of CFTR modulator triple therapy on type 2 inflammatory response in patients with cystic fibrosis.

BACKGROUND: Treatment of cystic fibrosis (CF) has been revolutionized by the use of cystic fibrosis transmembrane conductance regulator (CFTR) protein modulators such as elexacaftor/tezacaftor/ivacaftor (ETI) triple therapy. Prior studies support a role for type 2 (T2) inflammation in many people with CF (PwCF) and CF-asthma overlap syndrome (CFAOS) is considered a separate clinical entity. It is unknown whether initiation of ETI therapy impacts T2 inflammation in PwCF. We hypothesized that ETI initiation decreases T2 inflammation in PwCF. METHODS: A single center retrospective chart review was conducted for adult PwCF. As markers of T2 inflammation, absolute eosinophil count (AEC) and total immunoglobulin E (IgE) data were collected longitudinally 12 months prior to ETI therapy initiation and 12 months following therapy initiation. Multivariable analyses adjusted for the age, gender, CFTR mutation, disease severity, inhaled steroid use, and microbiological colonization. RESULTS: There was a statistically significant reduction (20.10%, p < 0.001) in 12-month mean total IgE following ETI initiation; this change remained statistically significant in the multivariate model. The longitudinal analysis demonstrated no change in AEC following therapy initiation. CONCLUSION: This study demonstrates that there is a statistically significant percent reduction in mean total IgE but no change in AEC following ETI initiation. ETI may lead to decreased antigen and superantigen load in the airway as a result of improved mucociliary clearance and these changes may drive the decline in total IgE, without influencing the epigenetic drivers of eosinophilic inflammation. Further studies are warranted to determine the underlying mechanism of ETI impact on T2 inflammation and possible role for asthma immunomodulator therapy post ETI initiation in CFAOS.

A functional outcome study comparing total ankle arthroplasty (TAA) subjects with pain to subjects with absent level of pain by means of videofluoroscopy.

BACKGROUND: Total ankle arthroplasty (TAA) subjects often suffer pain on the anteromedial side of their ankle joint. Whether this prevalent pain is caused by a changed motion pattern of the TAA is unclear. Therefore, this study assessed the kinematic differences in the motion of the TAA components during gait, comparing TAA subjects with elevated versus absent levels of pain. METHODS: Eleven TAA subjects (5 with pain vs. 6 without pain), all with unilateral Mobility™ TAA and at least two years post-operation, were recruited and stratified based on standard clinical assessed patient data. The 3D motion of the TAA was assessed by means of videofluoroscopy during level, uphill and downhill walking. RESULTS: The hypothesis that the pain group shows a different kinematic motion pattern than the no pain group could not be confirmed. CONCLUSIONS: The same kinematic motion pattern causes pain in some patients, but not in others. Further investigation concerning ligament stresses is needed.

Can tibio-femoral kinematic and kinetic parameters reveal poor functionality and underlying deficits after total knee replacement? A systematic review.

BACKGROUND: Extensive efforts have been made to understand joint kinematics and kinetics in total knee arthroplasty (TKA) in subjects with satisfactory outcomes during daily functional activities and clinical tests, but it remains unclear whether such movement characteristics hold the potential to indicate the underlying aetiology of unsatisfactory or bad TKA outcomes. PURPOSE: To investigate which kinematic and kinetic parameters assessed during passive clinical tests and functional activities of daily living are associated with poor functionality and underlying deficits after total knee replacement. METHODS: We focused on studies characterizing the kinematic or kinetic parameters of the knee joint that are associated with poor clinical outcome after TKA. Seventeen articles were included for the review, and kinematic and kinetic data from 719 patients with minimal follow up of 6 months were extracted and analyzed. RESULTS: Passive posterior translation at 90°flexionexhibited good potential for differentiating stable and unstable TKAs. Anterior-posterior (A-P) translation of the medial condyle at 0-30° and 30-60° flexion, A-P translation of the lateral condyle at 60-90°during closed chain exercises, as well asknee extension moment during stair ascent and descent, knee abduction moment during stair descent, knee internal rotation moment and plantar flexion moment during walking, 2ndpeak ground reaction force during stair ascent and walkingshowed the greatest promise as functional biomarkers for a dissatisfied/poor outcome knee after TKA. CONCLUSION: In this study, we systematically reviewed the state-of-the-art knowledge of kinematics and kinetics associated with functional deficits, and found 11 biomechanical parameters that showed promise for supportingdecision making in TKA.

In Vivo Elongation Patterns of the Collateral Ligaments in Healthy Knees During Functional Activities.

BACKGROUND: Improved knowledge of in vivo function of the collateral ligaments is essential for enhancing rehabilitation and guiding surgical reconstruction as well as soft-tissue balancing in total knee arthroplasty. The aim of this study was to quantify in vivo elongation patterns of the collateral ligaments throughout complete cycles of functional activities. METHODS: Knee kinematics were measured using radiographic images captured with a mobile fluoroscope while healthy subjects performed level walking, downhill walking, and stair descent. The registered in vivo tibiofemoral kinematics were then used to drive subject-specific multibody knee models to track collateral ligament elongation. RESULTS: The elongation patterns of the medial collateral ligament varied distinctly among its bundles, ranging from lengthening of the anterior fibers to shortening of the posterior bundle with increases in the knee flexion angle. The elongation patterns of the lateral collateral ligament varied considerably among subjects. It showed an average 4% shortening with increasing flexion until 60% to 70% of the gait cycle, and then recovered during the terminal-swing phase until reaching its reference length (defined at heel strike). CONCLUSIONS: The observed nonuniform elongation of the medial collateral ligament bundles suggests that single-bundle reconstruction techniques may not fully restore healthy ligament function. Moreover, the observed ligament elongation patterns indicate greater varus than valgus laxity in the loaded knee. CLINICAL RELEVANCE: Through providing key knowledge about the in vivo elongation patterns of the collateral ligaments throughout complete cycles of functional activities, this study offers in vivo evidence for benchmarking ligament reconstruction and soft-tissue balancing in total knee arthroplasty.

Length-Change Patterns of the Collateral Ligaments During Functional Activities After Total Knee Arthroplasty.

This study aimed to quantify the elongation patterns of the collateral ligaments following TKA during functional activities of daily living. Using mobile video-fluoroscopy to capture radiographic images of the knee in a group of six patients, each with an ultra-congruent knee implant, tibiofemoral kinematics were reconstructed throughout complete cycles of level gait, downhill walking, stair descent, and squat activities. Kinematic data were then used to drive subject-specific multibody knee models to estimate length-change patterns of the LCL as well as three bundles of the MCL. In addition, a sensitivity analysis examined the role of the attachment site in the elongation patterns. Our data indicate a slackening of the LCL but non-uniform length-change patterns across the MCL bundles (ranging from lengthening of the anterior fibers to shortening of the posterior fibers) with increasing knee flexion angle. Near-isometric behavior of the intermediate fibers was observed throughout the entire cycle of the studied activities. These length-change patterns were found to be largely consistent across different activities. Importantly, length-change patterns were critically sensitive to the location of the femoral attachment points relative to the femoral component. Thus, in TKA with ultra-congruent implants, implantation of the femoral component may critically govern post-operative ligament function.

Superconducting gap in bi-sr-ca-cu-o by high-resolution angle-resolved photoelectron spectroscopy.

Detailed studies indicate a superconducting gap in the high-temperature superconductor Bi(2)Sr(2)CaCu(2)O(8). Photoemission measurements with high energy and angle resolution isolate the behavior of a single band as it crosses the Fermi level in both the normal and superconducting states, giving support to the Fermi liquid picture. The magnitude of the gap is 24 millielectron volts.

Tibio-Femoral Contact Force Distribution is Not the Only Factor Governing Pivot Location after Total Knee Arthroplasty.

Total knee arthroplasty aims to mimic the natural knee kinematics by optimizing implant geometry, but it is not clear how loading relates to tibio-femoral anterior-posterior translation or internal-external pivoting. We hypothesised that the point of pivot in the transverse plane is governed by the location of the highest axial force. Tibio-femoral loading was measured using an instrumented tibial component in six total knee arthroplasty patients (aged 65-80y, 5-7y post-op) during 5-6 squat repetitions, while knee kinematics were captured using a mobile video-fluoroscope. In the range of congruent tibio-femoral contact the medial femoral condyle remained approximately static while the lateral condyle translated posteriorly by 4.1 mm (median). Beyond the congruent range, the medial and lateral condyle motions both abruptly changed to anterior sliding by 4.6 mm, and 2.6 mm respectively. On average, both the axial loading and pivot position were more medial near extension, and transferred to the lateral side in flexion. However, no consistent relationship between pivoting and load distribution was found across all patients throughout flexion, with R2 values ranging from 0.00 to 0.65. Tibio-femoral kinematics is not related to the load distribution alone: medial loading of the knee does not necessarily imply a medial pivot location.

Author Correction: Tibio-Femoral Contact Force Distribution is Not the Only Factor Governing Pivot Location after Total Knee Arthroplasty.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Tympanoplasty graft preparation using ear drops containing polyethylene glycol, flumethasone and clioquinol.

The aim of tympanoplasty graft preparation is to stiffen the fascia or perichondrium and thereby to optimise ease of manipulation. We report 39 cases utilising a novel technique in which the graft is prepared in ear drops containing polyethylene glycol, flumetasone pivalate (0.02 per cent) and clioquinol (1 per cent). This technique is useful in reducing the risk of desiccation if placement is delayed, and may pose less risk of infection and mechanical damage than alternative methods.

Antigenic heterogeneity in high- and low-virulence strains of Rickettsia rickettsii revealed by monoclonal antibodies.

Previously it has been reported that strains of Rickettsia rickettsii that differ greatly in their ability to cause disease in guinea pigs are similar by serological and sodium dodecyl sulfate-polyacrylamide gel electrophoresis analyses. In this study, we used monoclonal antibodies to the virulent R and the relatively avirulent HLP strains to investigate strain differences which might account for the disparate behavior of the strains in guinea pigs. Coomassie blue-stained sodium dodecyl sulfate-polyacrylamide gel electrophoresis profiles of the R and HLP strains were nearly identical for polypeptides with apparent molecular weights greater than 32 kilodaltons (kDa). All of the monoclonal antibodies to a lipopolysaccharide-like antigen reacted equally well with antigen from both strains by immunoblotting. None of the antibodies to the lipopolysaccharide-like antigen protected mice against challenge with viable rickettsiae. Some antibodies reacted with both 120- and 155-kDa polypeptides of both strains in radioimmune precipitation and immunoblotting tests, and other antibodies reacted only with the homologous strain. The monoclonal antibodies cross-reacted with the heterologous strain in the enzyme-linked immunosorbent assay essentially either completely or not at all. The ability of the monoclonal antibodies to the 120- and 155-kDa polypeptides to protect mice against the two strains was correlated with the ability of the antibodies to react with the antigens in the enzyme-linked immunosorbent assay and radioimmune precipitation or immunoblotting tests. These results demonstrate that R and HLP antigens which appear identical in molecular weight differ in their compositions of antigenic determinants.

Neutralizing activity of monoclonal antibodies to heat-sensitive and heat-resistant epitopes of Rickettsia rickettsii surface proteins.

Antiprotein monoclonal antibodies derived from mice inoculated with Rickettsia rickettsii heated at 56 degrees C for 15 min are of two types: one is type specific for epitopes denatured by moderate temperatures, and the other is specific for epitopes resistant to 100 degrees C for 5 min. The heat-resistant epitopes are found by immunoblotting on multiple polypeptides after solubilization of the rickettsiae at temperatures of 56 degrees C or higher. Most, but not all, antibodies to the heat-sensitive epitopes passively protected mice against two 50% lethal doses of R. rickettsii, whereas none of the antibodies to heat-resistant epitopes did.

Effective nonliving vaccine against experimental tuberculosis in mice.

Ribi, Edgar (Rocky Mountain Laboratory, Hamilton, Mont.), Carl Larson, William Wicht, Robert List, and Granville Goode. Effective nonliving vaccine against experimental tuberculosis in mice. J. Bacteriol. 91:975-983. 1966.-Antituberculosis vaccines were prepared in one of three manners: lyophilized BCG suspended in light mineral oil was disrupted in a Sorvall pressure cell and the "oil disruption product" was collected by centrifugation; BCG was disrupted in water, lyophilized, and worked into a paste with a small amount of oil (about 0.16 ml per 50 mg); BCG was disrupted in water, and the cell wall fraction was isolated, lyophilized, and prepared in an oil paste. These vaccines were suspended in Tween-saline to a concentration of 5 mg/ml and heated at 65 C for 30 min. In protection tests based on pulmonary infection with Mycobacterium tuberculosis H37Rv, the median number of virulent organisms in lung tissue of mice immunized with a few hundred micrograms of these three vaccines was 3 to 4 logs lower than in unvaccinated control mice. A similar dose of viable BCG standard vaccine reduced the lung count 1 to 2 logs below the controls. Protection afforded by nonviable, whole BCG, with or without oil, was of only borderline significance. Since oil-treated fractions containing cell walls produced effective immunity, while the oil-treated protoplasm or whole cells were not active, the protective antigen appeared to be an inner component of the cell wall, exposed when the cell was disrupted, and activated by oil. Extraction of oil from immunogenic disruption products resulted in loss of ability of the products to confer protection against the aerosol challenge, whereas high protection against the conventional challenge by intravenous infection with up to 1.4 x 10(8) cells of M. tuberculosis H37Rv was retained. Retreatment with oil of these nonimmunogenic products restored the immunogenicity if the oil was applied to dried products. The consistent finding that moisture interferes with the enhancement of the vaccine potency by oil suggested that such enhancement may not be the same as that ordinarily produced by water-in-oil emulsions.

Characterization of monoclonal antibodies protecting mice against Rickettsia rickettsii.

Hybridomas producing monoclonal antibodies to Rickettsia rickettsii were prepared from mice to investigate the function of rickettsial antigens. Of the 31 reactive hybridoma lines thus far tested for immunoglobulin subclasses, 11 belonged to the IgG2A subclass, 9 to the IgG2B subclass, and 7 to the IgG3 subclass; four did not react with any of the isotyping sera. Five of the antibodies recognized epitopes present on molecules that were presumed to be polysaccharide and heterogeneous in molecular weight. Twenty monoclonal antibodies reacted with a 170,000-dalton antigen, and six precipitated both the 133,000- and 32,000-dalton polypeptides. Only those antibodies to the 170,000- and 133,000-dalton antigens protected mice from challenge with R. rickettsii. Antibodies to these same antigens were detected in sera from patients convalescing from Rocky Mountain spotted fever. All monoclonal antibodies reacted with antigens apparently located on the rickettsial surface. The protective activity of these antibodies was not correlated with their reactivity in complement fixation, enzyme-linked immunosorbent assay, and immunofluorescence tests.

Biochemical and immunochemical analysis of Rickettsia rickettsii strains of various degrees of virulence.

Six strains of Rickettsia rickettsii from Montana and North Carolina were examined in an effort to identify rickettsial constituents associated with virulence. Fever responses, scrotal reactions, and mortalities of male guinea pigs inoculated intraperitoneally with 1,000 PFU of rickettsial strains revealed that the two Montana patient strains ( Sheila Smith and Norgaard ) and one Montana strain ( Sawtooth female 2) from the wood tick, Dermacentor andersoni, could be placed in the group of highest virulence, the two North Carolina strains (Morgan and Simpson) in the group of lesser virulence, and the Montana strain (HLP) from the rabbit tick, Haemaphysalis leporispalustris , in the group of lowest virulence. The HLP strain was differentiated from the other strains by sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by staining with Coomassie brilliant blue or with silver. The patient strains could not be differentiated from each other by these procedures. All of the strains apparently had three heat-modifiable proteins. Analysis of proteinase K-digested rickettsial lysates by sodium dodecyl sulfate-polyacrylamide gel electrophoresis suggested that the strains had a complex mixture of polysaccharides. These putative polysaccharides probably were not related to the differences in virulence of the strains, since the patterns for all of the strains were identical. At least five antigens (molecular weights of 128,000, 105,000, 84,000, 30,500, and 20,500) were demonstrated by radioimmune precipitation tests employing extracts from radioiodine-labeled rickettsiae and antibodies from infected guinea pigs. With these same sera a minimum of 14 antigens was detected in these strains by an immunoblotting procedure. The apparent molecular weights of several of the HLP antigens differed from those of the presumed corresponding antigens of the other strains. The electrophoretic techniques utilized in this study were not sufficiently sensitive to demonstrate compositional differences in the patient strains which differed in their virulence for guinea pigs.

Factors influencing protection against experimental tuberculosis in mice by heat-stable cell wall vaccines.

Ribi, E. (Rocky Mountain Laboratory, Hamilton, Mont.), R. L. Anacker, W. Brehmer, G. Goode, C. L. Larson, R. H. List, K. C. Milner, and W. C. Wicht. Factors influencing protection against experimental tuberculosis in mice by heat-stable cell wall vaccines. J. Bacteriol. 92:869-879. 1966.-Studies of nonviable, heat-stable vaccines for active protection against experimental tuberculosis have been continued with a test involving aerosol challenge of intravenously vaccinated mice. The previously reported activating effect of light mineral oil on disrupted cells of the BCG strain was found to be shared by certain other mineral oils and a synthetic, 24-carbon hydrocarbon, but not by kerosene or any of several vegetable oils. Dry cell walls coated with a small amount of oil and dispersed in saline with aid of an emulsifier were suitable for intravenous administration and were effective in promoting resistance to challenge. Oil used in this manner, in contrast to water-in-oil emulsions of the Freund type which could not be administered intravenously, did not potentiate the tuberculin-sensitizing activity of the cell walls. Although the amount of oil required for full effect was small (< 0.5 ml/100 mg of dry antigen), there was a critical level below which optimal enhancement was not achieved. More stable suspensions than could be obtained with the other oils were readily prepared from cell walls treated with the synthetic hydrocarbon, 7-n-hexyloctadecane. Extended experience has shown that in this test system both the viable BCG standard vaccine and heated, oil-treated experimental vaccines gave highly reproducible results showing graded responses to graded doses.