Sacroiliac joint syndrome 10 years after lumbar arthroplasty: the importance of spinopelvic alignment.

INTRODUCTION: Sagittal balance is an independent predictor of outcomes in spinal care and several authors focused their attention on the lumbar lordosis restoration as the key point to prevent secondary sacroiliac joint dysfunction (SIJD) after fusion. On the other hand, lumbar disc arthroplasty allows preservation of motion avoiding increased stress on the spinopelvic junction and preventing iatrogenic sagittal imbalance. METHODS: We analyze the incidence of a secondary SIJD and the spinopelvic alignment on a series of 31 consecutive lumbar disc prosthesis with a 10-year follow-up. RESULTS: Sagittal balance assessment showed no significant variation of preoperative spinopelvic parameters. Four patients (12 %) presented a symptomatic SIJD. Only two of them required a percutaneous SIJ fixation. Both of them presented a fused L5-S1 prosthesis. CONCLUSIONS: The low rate of SIJD 10 years after lumbar arthroplasty might be explained by the preservation of the spinopelvic balance.

A prospective study of percutaneous balloon kyphoplasty with calcium phosphate cement in traumatic vertebral fractures: 10-year results.

STUDY DESIGN: This is a prospective study to investigate the clinical and radiological results 10 years after percutaneous balloon kyphoplasty and cement augmentation with calcium phosphate cement (CPC) in traumatic vertebral fractures type A. OBJECTIVES: Evaluation of a 10-year follow-up with radiological and computed tomography results, calculated by 2 independent radiologists, VAS, Roland Morris score, Oswestry Disability Index (ODI) score and Denis work scale and clinical examination in patients with traumatic compression fractures type A, who were treated with a balloon kyphoplasty with CPC (Calcibon™ from Biomed). METHODS: In this study, we evaluated 21 patients (8 female and 13 male) clinically and radiologically 10 years postoperative and compared them with the same group of 28 patients we operated between August 2002 and August 2003 for traumatic vertebral fractures type A with balloon kyphoplasty and CPC. Over the 10 years, 7 patients were lost to follow-up. 3 of them were not clinically impaired but did not want to participate in the study and 4 patients were untraceable. All 21 patients underwent standard X-ray (standing) and a CT. We measured the volume of the cement, the resorption the last 10 years and the disc height in the CT and the segmental and vertebral kyphosis angle in the X-ray and compared them with the X-ray (standing) and CT done directly postoperatively. To assess the pain level we used the VAS, ODI score, Roland Morris score and the Denis work scale and compared them with the same scores we recorded in the past. RESULTS: The VAS score demonstrated an increase over time from a mean of 1 (0-5) at the 2-year follow-up to 2.3 (0-8) at the 10-year follow-up. The Roland Morris disability score also increased over time from 2 (0-8) 2 years postoperative to a mean of 3.6 (0-18) at the 10 years follow-up. We recognized no complications and no reoperations were necessary. We recognized an increase of the median value for the vertebral kyphosis angle about 1° (0°-4°) (p < 0.0001). The median value of the disc height diminution over the 10 years was 0.7 mm (0-3.9) (p < 0.0001). For the anterior wall of the fractured VB the decrease of the median value was about 1 mm (0-3) (p < 0.0001) and for the posterior wall it was 0 mm (0-2) (p < 0.0039). So the beck index decreased from 0.80 (0.65-0.97) to 0.77 (0.62-0.97) at the 10-year follow-up, which means a decrease of the median value of 0.03 (0-0.07) (p < 0.0039). We noticed a median value for the cement volume of 4.2 cc (2.0-8.6) postoperative and at the 10-year follow-up of 3.2 cc (1.3-7.8), which means a resorption of the cement volume about 22.9 % (0.8-55.5 %) (p < 0.0001). CONCLUSIONS: In our 10-year follow-up, we did not recognize any high loss of correction of the vertebral and segmental kyphosis angle. We also did not recognize a high diminution of the disc height without degeneration of the disc over the last 10 years. There was a partial resorption of the cement but not as much as we expected with variable bone formation. In summary, the long follow-up about 10 years of kyphoplasty show us very good clinical and radiological results and in our opinion we consider this to be a treatment option for traumatic selected vertebral type A fractures also in young patients.

Zinc-mediated carboxylations of allylic and propargylic halides in flow: synthesis of ß-lactones via subsequent bromolactonization.

Zinc-mediated carboxylation of allylic halides under flow conditions delivered ß,γ-unsaturated carboxylic acids and subsequent bromolactonization provides a streamlined process for the synthesis of γ-bromo-ß-lactones. The described process further demonstrates the utility of organozinc reagents prepared by passage of allylic halides through a metallic zinc column integrated into a flow process. Use of a tube-in-tube reactor for efficient CO2 introduction led to improvements in conversion compared to a batch process and improved overall yields of ß-lactones. The described flow process was also applied to propargylic bromides for the synthesis of allenic and propargylic acids.

Randomized, controlled trial comparing Rhodococcus equi and poly-N-acetyl glucosamine hyperimmune plasma to prevent R equi pneumonia in foals.

BACKGROUND: Hyperimmune plasma raised against ß-1→6-poly-N-acetyl glucosamine (PNAG HIP) mediates more opsonophagocytic killing of Rhodococcus equi (R equi) than does R equi hyperimmune plasma (RE HIP) in vitro. The relative efficacy of PNAG HIP and RE HIP to protect foals against R equi pneumonia, however, has not been evaluated. HYPOTHESIS: Transfusion with PNAG HIP will be superior to RE HIP in foals for protection against R equi pneumonia in a randomized, controlled, blinded clinical trial. ANIMALS: Four hundred sixty Quarter Horse and Thoroughbred foals at 5 large breeding farms in the United States. METHODS: A randomized, controlled, blinded clinical trial was conducted in which foals were transfused within 24 hours after birth with 2 L of either RE HIP or PNAG HIP. Study foals were monitored through weaning for clinical signs of pneumonia by farm veterinarians. The primary outcome was the proportion of foals that developed pneumonia after receiving each type of plasma. RESULTS: The proportion of foals that developed pneumonia was the same between foals transfused with RE HIP (14%; 32/228) and PNAG HIP (14%; 30/215). CONCLUSIONS AND CLINICAL IMPORTANCE: Results indicate that PNAG HIP was not superior to a commercially available, United States Department of Agriculture-licensed RE HIP product for protecting foals against R equi pneumonia under field conditions.

Antibody activities in hyperimmune plasma against the Rhodococcus equi virulence -associated protein A or poly-N-acetyl glucosamine are associated with protection of foals against rhodococcal pneumonia.

The efficacy of transfusion with hyperimmune plasma (HIP) for preventing pneumonia caused by Rhodococcus equi remains ill-defined. Quarter Horse foals at 2 large breeding farms were randomly assigned to be transfused with 2 L of HIP from adult donors hyperimmunized either with R. equi (RE HIP) or a conjugate vaccine eliciting antibody to the surface polysaccharide ß-1→6-poly-N-acetyl glucosamine (PNAG HIP) within 24 hours of birth. Antibody activities against PNAG and the rhodococcal virulence-associated protein A (VapA), and to deposition of complement component 1q (C՛1q) onto PNAG were determined by ELISA, and then associated with either clinical pneumonia at Farm A (n = 119) or subclinical pneumonia at Farm B (n = 114). Data were analyzed using multivariable logistic regression. Among RE HIP-transfused foals, the odds of pneumonia were approximately 6-fold higher (P = 0.0005) among foals with VapA antibody activity ≤ the population median. Among PNAG HIP-transfused foals, the odds of pneumonia were approximately 3-fold (P = 0.0347) and 11-fold (P = 0.0034) higher for foals with antibody activities ≤ the population median for PNAG or C՛1q deposition, respectively. Results indicated that levels of activity of antibodies against R. equi antigens are correlates of protection against both subclinical and clinical R. equi pneumonia in field settings. Among PNAG HIP-transfused foals, activity of antibodies with C՛1q deposition (an indicator of functional antibodies) were a stronger predictor of protection than was PNAG antibody activity alone. Collectively, these findings suggest that the amount and activity of antibodies in HIP (i.e., plasma volume and/or antibody activity) is positively associated with protection against R. equi pneumonia in foals.

Targeting AML-associated FLT3 mutations with a type I kinase inhibitor.

Tyrosine kinase domain (TKD) mutations contribute to acquired resistance to FMS-like tyrosine kinase 3 (FLT3) inhibitors used to treat FLT3-mutant acute myeloid leukemia (AML). We report a cocrystal structure of FLT3 with a type I inhibitor, NCGC1481, that retained potent binding and activity against FLT3 TKD and gatekeeper mutations. Relative to the current generation of advanced FLT3 inhibitors, NCGC1481 exhibited superior antileukemic activity against the common, clinically relevant FLT3-mutant AML cells in vitro and in vivo.

Overcoming adaptive therapy resistance in AML by targeting immune response pathways.

Targeted inhibitors to oncogenic kinases demonstrate encouraging clinical responses early in the treatment course; however, most patients will relapse because of target-dependent mechanisms that mitigate enzyme-inhibitor binding or through target-independent mechanisms, such as alternate activation of survival and proliferation pathways, known as adaptive resistance. Here, we describe mechanisms of adaptive resistance in FMS-like receptor tyrosine kinase (FLT3)-mutant acute myeloid leukemia (AML) by examining integrative in-cell kinase and gene regulatory network responses after oncogenic signaling blockade by FLT3 inhibitors (FLT3i). We identified activation of innate immune stress response pathways after treatment of FLT3-mutant AML cells with FLT3i and showed that innate immune pathway activation via the interleukin-1 receptor-associated kinase 1 and 4 (IRAK1/4) complex contributes to adaptive resistance in FLT3-mutant AML cells. To overcome this adaptive resistance mechanism, we developed a small molecule that simultaneously inhibits FLT3 and IRAK1/4 kinases. The multikinase FLT3-IRAK1/4 inhibitor eliminated adaptively resistant FLT3-mutant AML cells in vitro and in vivo and displayed superior efficacy as compared to current targeted FLT3 therapies. These findings uncover a polypharmacologic strategy for overcoming adaptive resistance to therapy in AML by targeting immune stress response pathways.