Coronal Knee Alignment 40 Years after Total Meniscectomy in Adolescents: A Prospective Cohort Study

Introduction: Meniscectomies result in altered knee biomechanics and increase contact forces on the operated knee joint. Methods: We assessed coronal knee alignment in relation to radiological osteoarthritis grading, clinical range of movement and patient reported outcome measures 40 years after total open meniscectomies in adolescence. Thirty eight knees (30 patients) that underwent total open meniscectomy were assessed on standardised weight-bearing anteroposterior radiographs for deviation from ‘physiological valgus angle’ in either direction (magnitude of malalignment). These values were analysed as per site of meniscectomy for correlations with radiographic scoring systems, range of motion and patient reported outcome measures. Results: Tibiofemoral angle was significantly more varus, and the magnitude of malalignment was significantly higher for the medial meniscectomy patients. The range of flexion was lower for those patients who underwent medial and lateral meniscectomies of the same knee. The patients who underwent meniscectomies of both knees had worse scores for IKDC and KOOS quality of life. Tibiofemoral angle, magnitude of malalignment and range of flexion strongly correlated with Ahlback, and Kellgren and Laurence scores, but patient reported that outcome measures did not correlate. Conclusion: Meniscectomy induced malalignment corresponds to the site of meniscectomy and the radiographic degree of osteoarthritis. While malalignment and reduced range of movement correlate well with worsening radiographic signs of arthritis, patient reported outcome measures do not correlate

MMP-3 in the peripheral serum as a biomarker of knee osteoarthritis, 40 years after open total knee meniscectomy.

BACKGROUND: To explore potential biomarkers in a meniscectomy-induced knee osteoarthritis model, at forty years after meniscectomy. METHODS: We carried out a forty-year study of 53 patients who, as adolescents, underwent open total meniscectomy and assessed two potential synovial and serum biomarkers, namely glycosaminoglycan (GAG) and matrix metalloproteinase-3 (MMP-3). Of the 30 patients available for review, 8 had contralateral knee operations and were excluded. Of the remaining 22 patients, 17 had successful operated knee synovial fluid aspirations and 8 also had successful contralateral control knee aspirations. GAG and MMP3 levels in the synovial fluid and peripheral serum was measured using Alcian blue precipitation and ELISA quantification, respectively. Patients also had their knee radiographs assessed and their radiographic osteoarthritis classified as per the Kellgren-Lawrence and Ahlbӓck systems. RESULTS: At forty years after meniscectomy, synovial MMP-3 levels remain increased (p = 0.0132) while GAG levels were reduced (p = 0.0487) when compared to controls and these two levels correlate inversely. Furthermore, levels of synovial MMP-3 significantly correlated (p = 0.0032, r = 0.7734; p = 0.0256, r = 0.5552) and GAG levels significantly inversely correlated (p = 0.0308, r = - 0.6220; p = 0.0135, r = - 0.6024), respectively, with both radiological scoring systems. Interestingly, we found that the levels of serum MMP-3 correlated only with the synovial fluid levels of MMP-3 in the operated knee and not with the non-operated joint (p = 0.0252, r = 0.7706 vs. p = 0.0764, r = 0.6576). Multiple regression analysis for patient's quality of life based on these biomarkers revealed an almost perfect result with an R2 of 0.9998 and a p value = 0.0087. CONCLUSION: Our results suggest that serum levels of MMP3 could be used as a potential biomarker for knee osteoarthritis, using a simple blood test. Larger cohorts are desirable in order to prove or disprove this finding

Long-term morphological and hormonal follow-up in a single unit on 115 patients with adrenal incidentalomas

We investigated the natural course of adrenal incidentalomas in 115 patients by means of a long-term endocrine and morphological (CT) follow-up protocol (median 4 year, range 1–7 year). At entry, we observed 61 subclinical hormonal alterations in 43 patients (mainly concerning the ACTH–cortisol axis), but confirmatory tests always excluded specific endocrine diseases. In all cases radiologic signs of benignity were present. Mean values of the hormones examined at last follow-up did not differ from those recorded at entry. However in individual patients several variations were observed. In particular, 57 endocrine alterations found in 43 patients (37.2%) were no longer confirmed at follow-up, while 35 new alterations in 31 patients (26.9%) appeared de novo. Only four alterations in three patients (2.6%) persisted. Confirmatory tests were always negative for specific endocrine diseases. No variation in mean mass size was found between values at entry (25.4±0.9 mm) and at follow-up (25.7±0.9 mm), although in 32 patients (27.8%) mass size actually increased, while in 24 patients (20.8%) it decreased. In no case were the variations in mass dimension associated with the appearance of radiological criteria of malignancy. Kaplan–Meier curves indicated that the cumulative risk for mass enlargement (65%) and for developing endocrine abnormalities (57%) over time was progressive up to 80 months and independent of haemodynamic and humoral basal characteristics. In conclusion, mass enlargement and the presence or occurrence over time of subclinical endocrine alterations are frequent and not correlated, can appear at any time, are not associated with any basal predictor and, finally, are not necessarily indicative of malignant transformation or of progression toward overt disease

TReatIng Urinary symptoms in Men in Primary Healthcare using non-pharmacological and non-surgical interventions (TRIUMPH) compared with usual care: Study protocol for a cluster randomised controlled trial

Background: Lower urinary tract symptoms (LUTS) can relate to urinary storage or voiding. In men, the prevalence and severity of LUTS increases with age, with a significant impact on quality of life. The majority of men presenting with LUTS are managed by their general practitioner (GP) in the first instance, with conservative therapies recommended as the initial treatment. However, the provision of conservative therapies in primary care is variable and can be time and resource limited. GPs require practical resources to enhance patient engagement with such interventions. TRIUMPH aims to determine whether a standardised and manualised care intervention delivered in primary care achieves superior symptomatic outcome for LUTS versus usual care.Methods/design: TRIUMPH is a two-arm, cluster randomised controlled trial (RCT) being conducted in 30 National Health Service (NHS) general practices in England. The TRIUMPH intervention comprises a standardised LUTS advice booklet developed for the trial with patient and healthcare professional (HCP) consultation. The booklet is delivered to patients by nurses/healthcare assistants following assessment of their urinary symptoms. Patients are directed to relevant sections of the booklet, providing the manualised element of the intervention. To encourage adherence, HCPs provide follow-up contacts over 12 weeks. Practices are randomised 1:1 to either deliver the TRIUMPH intervention or a usual care pathway. The patient-reported International Prostate Symptom Score (IPSS) at 12 months post consent is the primary outcome. Secondary outcomes include cost-effectiveness, patient-reported outcomes on LUTS, quality of life, and patient and HCP acceptability and experience of the intervention. Primary analyses will be conducted on an intention-to-treat basis.Discussion: It is unclear whether conservative therapies for male LUTS are effectively delivered in primary care using current approaches. This can lead to men being inappropriately referred to secondary care or experiencing persistent symptoms. Primary care, therefore, holds the key to effective treatment for these men. The TRIUMPH intervention, through its standardised and manualised approach, has been developed to support GP practices in delivering effective conservative care. This pragmatic, cluster RCT should provide robust evidence in a primary-care setting to inform future guidelines

Structure of the stationary phase survival protein YuiC from B.subtilis

- Background: Stationary phase survival proteins (Sps) were found in Firmicutes as having analogous domain compositions, and in some cases genome context, as the resuscitation promoting factors of Actinobacteria, but with a different putative peptidoglycan cleaving domain. - Results: The first structure of a Firmicute Sps protein YuiC from B. subtilis, is found to be a stripped down version of the cell-wall peptidoglycan hydrolase MltA. The YuiC structures are of a domain swapped dimer, although some monomer is also found in solution. The protein crystallised in the presence of pentasaccharide shows a 1,6-anhydrodisaccharide sugar product, indicating that YuiC cleaves the sugar backbone to form an anhydro product at least on lengthy incubation during crystallisation. - Conclusions: The structural simplification of MltA in Sps proteins is analogous to that of the resuscitation promoting factor domains of Actinobacteria, which are stripped down versions of lysozyme and soluble lytic transglycosylase proteins

Modulation of epithelial sodium channel (ENaC) expression in mouse lung infected with Pseudomonas aeruginosa

BACKGROUND: The intratracheal instillation of Pseudomonas aeruginosa entrapped in agar beads in the mouse lung leads to chronic lung infection in susceptible mouse strains. As the infection generates a strong inflammatory response with some lung edema, we tested if it could modulate the expression of genes involved in lung liquid clearance, such as the α, β and γ subunits of the epithelial sodium channel (ENaC) and the catalytic subunit of Na(+)-K(+)-ATPase. METHODS: Pseudomonas aeruginosa entrapped in agar beads were instilled in the lung of resistant (BalB/c) and susceptible (DBA/2, C57BL/6 and A/J) mouse strains. The mRNA expression of ENaC and Na(+)-K(+)-ATPase subunits was tested in the lung by Northern blot following a 3 hours to 14 days infection. RESULTS: The infection of the different mouse strains evoked regulation of α and β ENaC mRNA. Following Pseudomonas instillation, the expression of αENaC mRNA decreased to a median of 43% on days 3 and 7 after infection and was still decreased to a median of 45% 14 days after infection (p < 0.05). The relative expression of βENaC mRNA was transiently increased to a median of 241%, 24 h post-infection before decreasing to a median of 43% and 54% of control on days 3 and 7 post-infection (p < 0.05). No significant modulation of γENaC mRNA was detected although the general pattern of expression of the subunit was similar to α and β subunits. No modulation of α(1)Na(+)-K(+)-ATPase mRNA, the catalytic subunit of the sodium pump, was recorded. The distinctive expression profiles of the three subunits were not different, between the susceptible and resistant mouse strains. CONCLUSIONS: These results show that Pseudomonas infection, by modulating ENaC subunit expression, could influence edema formation and clearance in infected lungs

Structural and functional insight into human O-GlcNAcase.

O-GlcNAc hydrolase (OGA) removes O-linked N-acetylglucosamine (O-GlcNAc) from a myriad of nucleocytoplasmic proteins. Through co-expression and assembly of OGA fragments, we determined the three-dimensional structure of human OGA, revealing an unusual helix-exchanged dimer that lays a structural foundation for an improved understanding of substrate recognition and regulation of OGA. Structures of OGA in complex with a series of inhibitors define a precise blueprint for the design of inhibitors that have clinical value