Somatosensation in OA: exploring the relationships of pain sensitization, vibratory perception and spontaneous pain

Abstract Background Pain in osteoarthritis (OA) remains poorly understood. Different types of somatosensory alterations exist in OA including hyperesthesia and increased sensitivity to painful stimuli as well as those of decreased sensitivity to cutaneous stimuli including vibratory perception threshold. The relationship between these different somatosensory measures has not been previously evaluated in OA. In this observational study, we evaluated relationships between vibratory perception (VPT), pressure pain detection thresholds (PPT), allodynia and subjective pain in knee OA. Methods Forty-two persons with moderate to severe knee OA and 12 controls without OA were evaluated. VPT was measured using a biothesiometer. Allodynia was measured by application of a 60 g Von Frey monofilament repeatedly to predetermined sites. PPTs were measured using a pressure algometer. Results Increased vibratory acuity was associated with lower PPTs and presence of allodynia. Allodynia was more common in OA than controls (54.8% vs 16.6%, p = 0.024 in the ipsilateral knee, and 42.9% vs 0%, p = 0.005 in the contralateral knee). OA participants with allodynia had lower PPTs than those without allodynia. In those with OA, spontaneous knee pain was associated with lower PPTs and with allodynia. Conclusion This study confirms the presence of somatosensory alterations in OA. Sensory alterations (vibratory perception) were shown to be related to nociceptive alterations (sensitization) in OA, showing a general increased sensitivity to cutaneous mechanical stimulation. Understanding these relationships is an important step in delineating the complicated pathophysiology of pain processing in OA

Symptoms of Knee Instability are Risk Factors for Recurrent Falls.

OBJECTIVES: Whether knee instability contributes to the increased risk of falls and fractures observed in persons with knee osteoarthritis (OA) has not been studied. We examined the association of knee buckling with the risk of falling and fall-related consequences in older adults with, or at high risk for, knee OA. METHODS: At the 60 month visit of the Multicenter Osteoarthritis Study, men and women ages 55 to 84 were asked about knee buckling in the past 3 months and whether they fell when a knee buckled. Falls and fall-related injuries in the past 12 months and balance confidence were assessed at 60 and 84 months. Multivariate logistic regression was used to assess the association of knee buckling with falls and their consequences. RESULTS: 1,842 subjects (59% women, mean [SD] age= 66.9 [7.8] and BMI= 30.3 [5.7]) were included. At 60 months 16.8% reported buckling and at 84 months 14.1% had recurrent (≥2) falls. Bucklers at 60 months had a 1.6 to 2.5-fold greater odds of recurrent falls, fear of falling and poor balance confidence at 84 months. Those who fell when a knee buckled at baseline had a 4.5-fold, 2-fold and 3-fold increased odds two years later of recurrent falls, significant fall injuries and fall injuries that limited activity, respectively, and were 4 times more likely to have poor balance confidence. CONCLUSION: Interventions that reduce knee buckling may help prevent falls, fall-related injuries and adverse psychological consequences of falls in persons with knee OA

Variants associated with bedaquiline (BDQ) resistance identified in Rv0678 and efflux pump genes in mycobacterium tuberculosis isolates from BDQ naïve TB patients in Pakistan

Background: Mutations in the Rv0678, pepQ and atpE genes of Mycobacterium tuberculosis (MTB) have been reported to be associated with reduced antimycobacterial susceptibility to bedaquiline (BDQ). Resistance conferring mutations in treatment naïve MTB strains is likely to have implications for BDQ based new drug regimen that aim to shorten treatment duration. We therefore investigated the genetic basis of resistance to BDQ in MTB clinical isolates from BDQ naïve TB patients from Pakistan. In addition, mutations in genes associated with efflux pumps were investigated as an alternate mechanism of resistance. Methods: Based on convenience sampling, we studied 48 MTB clinical isolates from BDQ naïve TB patients. These isolates (from our strain bank) included 38 MDR/pre-XDR/XDR (10 BDQ resistant, 8 BDQ intermediate and 20 BDQ susceptible) and 10 pan drug susceptible MTB isolates. All strains were subjected to whole genome sequencing and genomes were analysed to identify variants in Rv0678, pepQ, atpE, Rv1979c, mmpLS and mmpL5 and drug resistance associated efflux pump genes. Results: Of the BDQ resistant and intermediate strains 44% (8/18) had variants in Rv0678 including; two reported mutations S63R/G, six previously unreported variants; L40F, R50Q and R107C and three frameshift mutations; G25fs, D64fs and D109fs. Variants in efflux pumps; Rv1273c (G462K), Rv0507c (R426H) and Rv1634c (E198R) were found to be present in drug resistant isolates including BDQ resistant and intermediate isolates. E198R in efflux pump gene Rv1634c was the most frequently occurring variant in BDQ resistant and intermediate isolates (n = 10). Conclusion: We found RAVs in Rv0678 to be commonly associated with BDQ resistance. Further confirmation of the role of variants in efflux pump genes in resistance is required so that they may be incorporated in genome-based diagnostics for drug resistant MTB

Variants associated with Bedaquiline (BDQ) resistance identified in Rv0678 and efflux pump genes in Mycobacterium tuberculosis isolates from BDQ naïve TB patients in Pakistan

Abstract Background Mutations in the Rv0678, pepQ and atpE genes of Mycobacterium tuberculosis (MTB) have been reported to be associated with reduced antimycobacterial susceptibility to bedaquiline (BDQ). Resistance conferring mutations in treatment naïve MTB strains is likely to have implications for BDQ based new drug regimen that aim to shorten treatment duration. We therefore investigated the genetic basis of resistance to BDQ in MTB clinical isolates from BDQ naïve TB patients from Pakistan. In addition, mutations in genes associated with efflux pumps were investigated as an alternate mechanism of resistance. Methods Based on convenience sampling, we studied 48 MTB clinical isolates from BDQ naïve TB patients. These isolates (from our strain bank) included 38 MDR/pre-XDR/XDR (10 BDQ resistant, 8 BDQ intermediate and 20 BDQ susceptible) and 10 pan drug susceptible MTB isolates. All strains were subjected to whole genome sequencing and genomes were analysed to identify variants in Rv0678, pepQ, atpE, Rv1979c, mmpLS and mmpL5 and drug resistance associated efflux pump genes. Results Of the BDQ resistant and intermediate strains 44% (8/18) had variants in Rv0678 including; two reported mutations S63R/G, six previously unreported variants; L40F, R50Q and R107C and three frameshift mutations; G25fs, D64fs and D109fs. Variants in efflux pumps; Rv1273c (G462K), Rv0507c (R426H) and Rv1634c (E198R) were found to be present in drug resistant isolates including BDQ resistant and intermediate isolates. E198R in efflux pump gene Rv1634c was the most frequently occurring variant in BDQ resistant and intermediate isolates (n = 10). Conclusion We found RAVs in Rv0678 to be commonly associated with BDQ resistance. Further confirmation of the role of variants in efflux pump genes in resistance is required so that they may be incorporated in genome-based diagnostics for drug resistant MTB