Purpose
Implementation of morphometric reference data from the contralateral, unaffected lower limb is suggested when reconstructing the coronal plane alignment in TKA. Limited information, however, ...is available which confirms this left-to-right symmetry in coronal alignment based upon radiographs. The purpose of the study was, therefore, (1) to verify if a left-to-right symmetry is present and (2) to assess whether the contralateral lower limb would be a reliable reference for reconstructing the frontal plane alignment.
Methods
Full-leg standing radiographs of 250 volunteers (male, 125; female,125) were reviewed for three alignment parameters (Hip–Knee–Ankle angle (HKA), Femoral Mechanical Angle (FMA) and Tibial Mechanical Angle (TMA)). Evaluation of assumed left-to-right symmetry was performed according to two coronal alignment classifications (HKA subdivisions (HKA) and limb, femoral and tibial phenotypes (HKA, FMA and TMA)). Inter- and within-subject variability was calculated, along with correlations coefficients (
r
) and coefficients of determination (
r
2
). Reliability of the contralateral limb as a personalized reference to reconstruct the constitutional alignment was investigated by intervals, expanding by 1° increments (0.5° increment both to varus and valgus) around the right knee alignment parameters. Subsequently, it was verified whether or not the left knee parameters fell within this interval.
Results
Symmetrical distribution in coronal alignment was found in 79% (HKA subdivision) and 59% (limb phenotype) of the cohort. Gender differences were present for the most common symmetric limb phenotypes (VAR
HKA
3° (23.2%) in males and NEU
HKA
0° (38.4%) in females). Inter-subject variability was more prominent than the within-subject side differences for all parameters. Correlations analyses revealed mostly moderate correlations between the alignment measurements. Coefficients of determination showed overall weak left-to-right relationship, except for a moderate predictability for HKA (
r
2
= 0.538,
p
< 0.001) and FMA (
r
2
= 0.618,
p
< 0.001) in females. FMA and TMA marked weak predictive values for contralateral HKA. Only 60% of left knees were referenced within a 3° interval around the right knee.
Conclusion
No strict left-to-right symmetry was observed in coronal alignment measurements. There is insufficient left-to-right agreement to consider the concept of the contralateral unaffected limb as an idealized reference for frontal plane alignment reconstruction based upon full-leg standing radiographs.
Level of evidence
I.
Purpose
The role of neutral alignment in total knee arthroplasty (TKA) on short- and long-term outcomes has become controversial. Based on the concept of constitutional varus, it has been suggested ...that under-correction in TKA in a varus osteoarthritis (OA) population might lead to better clinical outcomes. However, it is still unknown what the relationship between constitutional varus and the development of end-stage OA is. The goal of this study was to analyse the contribution of constitutional varus in a medial OA population and to define a correlation between the constitutional alignment and end-stage varus OA.
Methods
Based on full-length radiographs, corrected for the intra-articular deformity of the knee, of 315 patients with unilateral end-stage medial OA of the knee (Charnley type A), a correlation in the coronal plane was made between medial end-stage OA and the contralateral non-arthritic side.
Results
With increasing varus alignment in the arthritic limb, the physiologic limb alignment also became more varus. The proportion of constitutional varus rose with increasing overall alignment and was found to be continuous for males. Constitutional varus was three times higher in men when the overall arthritic alignment was greater more than 6° varus.
Conclusion
Constitutional varus significantly contributes to varus osteoarthritis and was found to be higher than in the general population.
Level of evidence
III.
Abstract Background Coronal plane alignment is one of the contributing factors to polyethylene wear in total knee arthroplasty. Methods Based on 95 retrieved polyethylene inserts, wear and damage ...patterns were analyzed in relationship to the overall mechanical alignment and to the position of the tibial component. Results A progression of wear was observed with progressively mechanical varus alignment. However, there was significantly more damage in the lateral compartment in the mild and moderate varus group compared to the valgus group. No difference in damage was seen between all groups for tibial component positioning in valgus or varus. Conclusion Progressive wear was observed with progressively varus alignment with more damage at the lateral side. This observation is unique and might be explained by lateral condylar lift-off inducing impact and shear loading in the varus group.
Purpose
It remains unclear what the contribution of the PCL is in total knee arthroplasty (TKA). The goal of this study was to investigate the influence of the PCL in TKA in relationship to clinical ...outcome, strength and proprioception.
Methods
Two arthroplasty designs were compared: a posterior cruciate-substituting (PS) and a posterior cruciate-retaining (CR) TKA. A retrospective analysis was performed of 27 CR and 18 PS implants with a minimum of 1 year in vivo. Both groups were compared in terms of clinical outcome (range of motion, visual analogue scale for pain, Hospital for Special Surgery Knee Scoring system, Lysholm score and Knee Injury and Osteoarthritis Outcome Score), strength (Biodex System 3 Dynamometer
®
) and proprioception (balance and postural control using the Balance Master system
®
). Each design was also compared to the non-operated contralateral side in terms of strength and proprioception.
Results
There were no significant differences between both designs in terms of clinical outcome and strength. In terms of proprioception, only the rhythmic weight test at slow and moderate speed shifting from left to right was significant in favour of the CR design. None of the unilateral stance tests showed any significant difference between both designs. There was no difference in terms of strength and proprioception between the operated side and the non-operated side.
Conclusion
Retaining the PCL in TKA does not result in an improved performance in terms of clinical outcome and proprioception and does not show any difference in muscle strength.
Level of evidence
III.
γδ and αβ T cells have unique roles in immunity and both originate in the thymus from T‐lineage committed precursors through distinct but unclear mechanisms. Here, we show that Notch1 activation is ...more stringently required for human γδ development compared to αβ‐lineage differentiation and performed paired mRNA and miRNA profiling across 11 discrete developmental stages of human T cell development in an effort to identify the potential Notch1 downstream mechanism. Our data suggest that the miR‐17–92 cluster is a Notch1 target in immature thymocytes and that miR‐17 can restrict BCL11B expression in these Notch‐dependent T cell precursors. We show that enforced miR‐17 expression promotes human γδ T cell development and, consistently, that BCL11B is absolutely required for αβ but less for γδ T cell development. This study suggests that human γδ T cell development is mediated by a stage‐specific Notch‐driven negative feedback loop through which miR‐17 temporally restricts BCL11B expression and provides functional insights into the developmental role of the disease‐associated genes BCL11B and the miR‐17–92 cluster in a human context.
Synopsis
Human γδ and αβ T cells have unique roles in immunity, but originate from the same precursors. Notch1 and BCL11B have differential roles during αβ and γδ T cell development, and these are likely mediated via miR‐17.
Human αβ and γδ T cell development is marked by specific and dynamic changes in miRNA expression.
miR17 promotes human γδ T cell development.
Notch1 activation is more stringently required for human γδ development.
γδ T cell development is less dependent on BCL11B expression compared to αβ T cell development.
Human γδ and αβ T cells have unique roles in immunity, but originate from the same precursors. Notch1 and BCL11B have differential roles during αβ and γδ T cell development, and these are likely mediated via miR‐17.
Aims
To describe the baseline characteristics of participants in the Acetazolamide in Decompensated Heart Failure with Volume Overload (ADVOR) trial and compare these with other contemporary diuretic ...trials in acute heart failure (AHF).
Methods and results
ADVOR recruited 519 patients with AHF, clinically evident volume overload, elevated N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) and maintenance loop diuretic therapy prior to admission. All participants received standardized loop diuretics and were randomized towards once daily intravenous acetazolamide (500 mg) versus placebo, stratified according to study centre and left ventricular ejection fraction (LVEF) (≤40% vs. >40%). The primary endpoint was successful decongestion assessed by a dedicated score indicating no more than trace oedema and no other signs of congestion after three consecutive days of treatment without need for escalating treatment. Mean age was 78 years, 63% were men, mean LVEF was 43%, and median NT‐proBNP 6173 pg/ml. The median clinical congestion score was 4 with an EuroQol‐5 dimensions health utility index of 0.6. Patients with LVEF ≤40% were more often male, had more ischaemic heart disease, higher levels of NT‐proBNP and less atrial fibrillation. Compared with diuretic trials in AHF, patients enrolled in ADVOR were considerably older with higher NT‐proBNP levels, reflecting the real‐world clinical situation.
Conclusion
ADVOR is the largest randomized diuretic trial in AHF, investigating acetazolamide to improve decongestion on top of standardized loop diuretics. The elderly enrolled population with poor quality of life provides a good representation of the real‐world AHF population. The pragmatic design will provide novel insights in the diuretic treatment of patients with AHF.
Baseline characteristics of ADVOR trial participants. ACEi, angiotensin‐converting enzyme inhibitor; AHF, acute heart failure; ARB, angiotensin receptor blocker; IV, intravenous; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide.
Abstract Current discussion exists whether to position a total knee arthroplasty (TKA) in slight undercorrection in varus osteoarthritis. The goal of this study was to analyse the effect of wear and ...lateral lift-off in primary TKA on coronal plane alignment and the implication to future constrained revision TKA. Seventy-six retrieved tibial inserts were analysed for the ratio of wear (RW), lateral lift-off and implications for future constrained revision surgery according to the coronal plane alignment. The RW significantly affects the coronal plane alignment in TKA. Progressive wear and lateral lift-off were seen with progressive varus alignment. However, there was no difference in constrained revision between mild varus and moderate varus aligned TKAs.
Using a targeted peptide-centric proteomics approach, we performed in vitro protease substrate profiling of the apoptotic serine protease granzyme B resulting in the delineation of more than 800 ...cleavage sites in 322 human and 282 mouse substrates, encompassing the known substrates Bid, caspase-7, lupus La protein, and fibrillarin. Triple SILAC (stable isotope labeling by amino acids in cell culture) further permitted intra-experimental evaluation of species-specific variations in substrate selection by the mouse or human granzyme B ortholog. For the first time granzyme B substrate specificities were directly mapped on a proteomic scale and revealed unknown cleavage specificities, uncharacterized extended specificity profiles, and macromolecular determinants in substrate selection that were confirmed by molecular modeling. We further tackled a substrate hunt in an in vivo setup of natural killer cell-mediated cell death confirming in vitro characterized granzyme B cleavages next to several other unique and hitherto unreported proteolytic events in target cells.
Purpose
This study was designed to describe the clinical and radiographical outcome of the HemiCAP
®
resurfacing system as a salvage treatment for a failed index cartilage procedure.
Methods
Fourteen ...patients were treated consecutively and clinically prospectively followed for a mean period of 26.1 ± 12.8 months. All patients were previously treated for their cartilage lesion. Radiographical data were analysed based on the Kellgren and Lawrence system.
Results
The patients involved in this study demonstrated a gradual clinical improvement in time. However, radiographically significant osteoarthritic changes were observed during the follow-up period. The position of the HemiCAP
®
resurfacing system was adequate in all cases, and no signs of loosening were observed during the follow-up period.
Conclusions
The HemiCAP
®
resurfacing system is feasible as a salvage treatment for a failed index cartilage procedure and resulted in a gradual clinical improvement. However, the favourable clinical outcome was not confirmed by the radiographical findings.
Level of evidence
IV.
The impact of N(α)-terminal acetylation on protein stability and protein function in general recently acquired renewed and increasing attention. Although the substrate specificity profile of the ...conserved enzymes responsible for N(α)-terminal acetylation in yeast has been well documented, the lack of higher eukaryotic models has hampered the specificity profile determination of N(α)-acetyltransferases (NATs) of higher eukaryotes. The fact that several types of protein N termini are acetylated by so far unknown NATs stresses the importance of developing tools for analyzing NAT specificities. Here, we report on a method that implies the use of natural, proteome-derived modified peptide libraries, which, when used in combination with two strong cation exchange separation steps, allows for the delineation of the in vitro specificity profiles of NATs. The human NatA complex, composed of the auxiliary hNaa15p (NATH/hNat1) subunit and the catalytic hNaa10p (hArd1) and hNaa50p (hNat5) subunits, cotranslationally acetylates protein N termini initiating with Ser, Ala, Thr, Val, and Gly following the removal of the initial Met. In our studies, purified hNaa50p preferred Met-Xaa starting N termini (Xaa mainly being a hydrophobic amino acid) in agreement with previous data. Surprisingly, purified hNaa10p preferred acidic N termini, representing a group of in vivo acetylated proteins for which there are currently no NAT(s) identified. The most prominent representatives of the group of acidic N termini are γ- and β-actin. Indeed, by using an independent quantitative assay, hNaa10p strongly acetylated peptides representing the N termini of both γ- and β-actin, and only to a lesser extent, its previously characterized substrate motifs. The immunoprecipitated NatA complex also acetylated the actin N termini efficiently, though displaying a strong shift in specificity toward its known Ser-starting type of substrates. Thus, complex formation of NatA might alter the substrate specificity profile as compared with its isolated catalytic subunits, and, furthermore, NatA or hNaa10p may function as a post-translational actin N(α)-acetyltransferase.
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