Publications by authors named "Timothy R Braun"

Objective: The desired therapeutic effect of Arthrokinex™ autologous conditioned serum (ACS) is facilitated by the ability of IL-1-Ra to limit the destructive inflammatory intra-articular (IA) actions of IL-1β. Previous studies have proven the capacity of Arthrokinex™ (ACS) to induce the anti-inflammatory cytokine, IL-1-Ra. The primary purpose of this retrospective study was to investigate the effect of Arthrokinex™ (ACS) to reduce pain, improve joint function and enhance quality of life in patients with knee osteoarthritis.

Methods: Venous blood from 100 patients with symptomatic knee osteoarthritis (KOA) was conditioned and injected into the affected joint in this treatment protocol. Each patient received a total of six ultrasound-guided IA injections at day 0, 7, 14, 90, 180, and 270 and followed for up to one year. Treatment outcome measures were assessed by three different patient-administered surveys at each visit. Using the Visual Analog Pain Scale (VAS), participants were asked to classify pain in the previous 24 h. The Extra Short Musculoskeletal Functional Assessment (XSMFA-D) survey is a series of 16 questions designed to determine the functionality of the OA-affected joint. Finally, the patient completed a patient global impression of change (PGIC) survey to assess their individual level of satisfaction with the treatment regimen.

Results: Compared to baseline, a total of 84% of patients reported better pain control at 6 months with 91% reporting improvement at 12 months. A robust and statistically significant improvement in each XSMFA-D subscale was observed in KOA patients over 12 months. The overall reduction of pain and enhanced joint function was observed within 1 week and sustained 3, 6 and even 12 months after the initial injection. In addition to symptomatic control of OA, 92% of patients reported satisfaction with the treatment regimen 12 months after the initial injection.

Conclusion: Given the favorable safety profile, reduction in pain and enhanced quality of life experienced by patients enrolled in this joint health program, Arthrokinex™ (ACS) has the potential to offer an alternative, chondroprotective, natural, molecular approach to treating pain and functionality in patients with mild, moderate or severe knee osteoarthritis.

Objective: Current orthopedic therapies, aimed solely at symptomatic control, are unable to restore the cytokine imbalance that produces the hallmark clinical profile of osteoarthritis. While a myriad of chemical factors in the cytokine network stimulate local joint inflammation and pain, Interleukin 1 (IL-1) is widely recognized as a key offender and a potential therapeutic target. The purpose of this article is to describe a novel, on-site, point of service process (Arthrokinex™) to induce Interleukin 1 Receptor Antagonist Protein (IL-1-Ra or IRAP) from whole blood aimed at inhibiting the destructive intra-articular effects of IL-1.

Methods: 53 patient charts were included in this retrospective chart review study. Venous blood from the selected participants had been harvested and centrifuged to isolate Platelet Rich Plasma and Platelet Poor Plasma. These layers were extracted and incubated for 30 min in a specialized syringe containing medical grade concentrator beads. After centrifuge filtration, the supernatant containing IL-1-Ra was extracted. Anti-inflammatory (IL-1-Ra, IL-10) and pro-inflammatory (TNF α, IL-1 β) cytokines of baseline whole blood were compared to the conditioned serum following quantification using ELISA.

Results: On average, a 32-fold increase (baseline, 550 pg/mL; post conditioning 17,537 pg/mL) in IL-1-Ra concentration was observed after the brief interaction of blood with the concentrator bead surface. IL-1-Ra, if present in concentrations that are 10-100 times higher than IL-1β, will block the interaction of IL-1β with cell surface receptors. At these increased concentrations, Arthrokinex™ induced IL-1-Ra joint injections produce an IL-1-Ra to IL-1β ratio of 999:1. Post conditioning levels of IL-1β and TNF α were not clinically significant.

Conclusion: The Arthrokinex™ blood conditioning process has the ability to rapidly induce IL-1-Ra without increasing the pro-inflammatory cytokine profile.

We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10(-11) to 5.0 × 10(-21)). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10(-6)). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.

Objective: The purpose of this investigation was to examine serum vitamin D status in a population of Punjabi ancestry from Northern India with a high prevalence of type 2 diabetes (T2D) and evaluate the effects of 25(OH)D levels on cardio-metabolic traits.

Research Design And Methods: We assessed cardiovascular risk factors and 25(OH)D levels in 1,765 participants (887 T2D cases, 878 normoglycemic controls).

Results: 76% of individuals were deficient (<50 nmol/L) in vitamin D. A higher percentage of T2D participants(83%) were vitamin D deficient compared to normoglycemic controls (68%)(p<0.0001).The prevalence of vitamin D deficiency increased progressively with body mass index (BMI) categories (p<0.0001): BMI<23 kg/m, 65%; BMI 23-27.5 kg/m, 75%; and BMI>27.5 kg/m, 81%. T2D participants had significantly decreased serum 25(OH)D levels (β=-0.41, p=2.8 × 10). Individuals with low serum 25(OH)D had elevated fasting glucose(β=-0.18, p=0.022), BMI (β=-0.71, p=1.4 × 10) and systolic blood pressure (β=-1.68, p=0.006). A positive association of increased 25(OH)D with HOMA-B (β=0.17, p=8.0×10), and C-peptide (β=0.09, 0.017) was observed. Non-medicated, normoglycemic, non-hypertensive individuals classified as vitamin D deficient (n=289) exhibited a significant increase in fasting glucose (p=0.02) and BMI (p<0.0001) as well as a significant decrease in C-peptide (p<0.0001) and amylin (p<0.0001) compared to vitamin D sufficient controls (n=150).

Conclusions: Vitamin D deficiency appears to be a significant risk factor for T2D severity and associated cardio-metabolic risk. Early intervention may be considered to improve prevention of T2D related cardiovascular complications.

Recent genome-wide association scans (GWAS) and meta-analysis studies on European populations have identified many genes previously implicated in lipid regulation. Validation of these loci on different global populations is important in determining their clinical relevance, particularly for development of novel drug targets for treating and preventing diabetic dyslipidemia and coronary artery disease (CAD). In an attempt to replicate GWAS findings on a non-European sample, we examined the role of six of these loci (CELSR2-PSRC1-SORT1 rs599839; CDKN2A-2B rs1333049; BUD13-ZNF259 rs964184; ZNF259 rs12286037; CETP rs3764261; APOE-C1-C4-C2 rs4420638) in our Asian Indian cohort from the Sikh Diabetes Study (SDS) comprising 3,781 individuals (2,902 from Punjab and 879 from the US). Two of the six SNPs examined showed convincing replication in these populations of Asian Indian origin. Our study confirmed a strong association of CETP rs3764261 with high-density lipoprotein cholesterol (HDL-C) (p = 2.03×10(-26)). Our results also showed significant associations of two GWAS SNPs (rs964184 and rs12286037) from BUD13-ZNF259 near the APOA5-A4-C3-A1 genes with triglyceride (TG) levels in this Asian Indian cohort (rs964184: p = 1.74×10(-17); rs12286037: p = 1.58×10(-2)). We further explored 45 SNPs in a ∼195 kb region within the chromosomal region 11q23.3 (encompassing the BUD13-ZNF259, APOA5-A4-C3-A1, and SIK3 genes) in 8,530 Asian Indians from the London Life Sciences Population (LOLIPOP) (UK) and SDS cohorts. Five more SNPs revealed significant associations with TG in both cohorts individually as well as in a joint meta-analysis. However, the strongest signal for TG remained with BUD13-ZNF259 (rs964184: p = 1.06×10(-39)). Future targeted deep sequencing and functional studies should enhance our understanding of the clinical relevance of these genes in dyslipidemia and hypertriglyceridemia (HTG) and, consequently, diabetes and CAD.