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AbstractBackgroundWe previously reported that in our autopsy‐confirmed cohort of Dementia with Lewy Bodies (DLB), Parkinson’s Disease Dementia (PDD) and Alzheimer’s Disease (AD), DLB with parkinsonism (DLB+Park) predicted faster progression of UPDRS‐III scores compared to PDD, DLB without parkinsonism (DLB‐Park), and AD. This study examined annualized rate of change of UPDRS‐III subscales in our cohort.MethodsData included were from participants in Arizona Study of Aging and Neurodegenerative Diseases (AZSAND) with clinicopathologic diagnosis of DLB (n = 48), PDD (n = 98) or pure AD (n = 48), and longitudinal movement exams. Mixed effects model (accounting for age, education, and sex) was used to determine predicted mean UPDRS‐III and subscale scores (0‐4) for all groups. Individual UPDRS‐III subscale scores were derived for: Body Bradykinesia, Limb Bradykinesia, Gait, Postural Instability, Limb Rest Tremor, Neck Rigidity and Limb Rigidity. Where applicable, scores for multiple limbs involved were averaged.ResultsLongitudinal data was analyzed for over 1430‐participant years. Parkinsonism was present in 65.6% of DLB participants. PDD participants were more likely to be treated with dopaminergic agents (87.8%) compared to (p<0.001) DLB+Park (57.6%), DLB‐park (0%) and AD (2.1%). Frequency (29.4% vs. 29.0%) and severity (mean±SE = 0.4±0.07 and 0.4±0.12) of Limb Rest Tremor was similar for PDD and DLB+park. Limb Bradykinesia frequency and severity were PDD: 100%, 2.4±0.11, DLB+Park: 96.8%, 2.1±0.18, DLB‐Park: 20%, 0.4±0.23, and AD: 62%, 1.1±0.16. Frequency of gait abnormality was 98.5% in PDD, 90.3% in DLB+park, 60% in DLB‐Park and 57.8% in AD. Rigidity was most frequent in the PDD group (88.2%), followed by DLB+Park (71%), AD (19.6%), and none DLB‐park (0%). Over 8 years trajectories for limb bradykinesia and gait were greater for DLB+park than PDD (Figure 1, Cohen’s d range 0.89‐2.18 and 0.63‐1.99 over 8 years, p<0.001).ConclusionOur results suggest that DLB+Park group have faster motor progression predominantly related to gait abnormalities and limb bradykinesia. Future analyses will explore more convergent data, integrated effects of various measures and their differential contributions in this cohort.

Hexanucleotide G 4 C 2 repeat expansions in the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Dipeptide repeat proteins (DPRs) generated by translation of repeat-containing RNAs show toxic effects in vivo as well as in vitro and are key targets for therapeutic intervention. We generated human antibodies that bind DPRs with high affinity and specificity. Anti-GA antibodies engaged extra- and intra-cellular poly-GA and reduced aggregate formation in a poly-GA overexpressing human cell line. However, antibody treatment in human neuronal cultures synthesizing exogenous poly-GA resulted in the formation of large extracellular immune complexes and did not affect accumulation of intracellular poly-GA aggregates. Treatment with antibodies was also shown to directly alter the morphological and biochemical properties of poly-GA and to shift poly-GA/antibody complexes to more rapidly sedimenting ones. These alterations were not observed with poly-GP and have important implications for accurate measurement of poly-GA levels including the need to evaluate all centrifugation fractions and disrupt the interaction between treatment antibodies and poly-GA by denaturation. Targeting poly-GA and poly-GP in two mouse models expressing G 4 C 2 repeats by systemic antibody delivery for up to 16 mo was well-tolerated and led to measurable brain penetration of antibodies. Long-term treatment with anti-GA antibodies produced improvement in an open-field movement test in aged C9orf72 450 mice. However, chronic administration of anti-GA antibodies in AAV-(G 4 C 2 ) 149 mice was associated with increased levels of poly-GA detected by immunoassay and did not significantly reduce poly-GA aggregates or alleviate disease progression in this model.

AbstractIntroductionInfections are known complications of solid‐organ transplant. Treatment for rejection may increase risk of infection. We aimed to study frequency of infection and identify the risk factors for infections in solid organ transplant (SOT) (liver and kidney) recipients treated for rejection.MethodsThis is a retrospective chart review of all liver and kidney transplant recipients treated for rejection at our institution from 2014 to 2020. We collected information on episodes of acute rejection in the first year of transplant and infections within 6 months following rejection treatment.ResultsWe identified 257 transplant patients treated for rejection. One hundred twelve (43.6%) developed infections, with a total of 226 infections. Urinary tracts infections were the most common, 72 (31.9%), followed by cytomegalovirus viremia in 37 (16.4%), bacteremia in 24 (10.6%), and BK virus in 14 (6.2%). Female sex (p = .047), elevated neutrophil count at rejection (p = .002), and increased number of rejection episodes (p = .022) were predictors of infection in kidney and simultaneous liver‐kidney recipients. No specific type of induction or rejection therapy was identified as a risk factor for infection, likely due to the prophylaxis protocols at our institution. Infection post rejection treatment was associated with higher graft loss (p = .021) and mortality (p = .031) in kidney transplant recipients.ConclusionsInfections are common complications after treatment of SOT rejection. Female gender, higher neutrophil at time of rejection, and increased numbers of rejection episodes were predictors of infections after rejection in simultaneous liver‐kidney and kidney transplant patients. Infections were predictors of graft loss at 6 months and mortality at any point in follow‐up in kidney transplant patients. image

The intrinsic healing following tendon injury is ideal, in which tendon progenitor cells proliferate and migrate to the injury site to directly bridge or regenerate tendon tissue. However, the mechanism determining why and how those cells are attracted to the injury site for tendon healing is not understood. Since the tenocytes near the injury site go through apoptosis or necrosis following injury, we hypothesized that secretions from injured tenocytes might have biological effects on cell proliferation and migration to enhance tendon healing. Tenocyte apoptosis was induced by 24 h cell starvation. Apoptotic body-rich media (T-ABRM) and apoptotic body-depleted media (T-ABDM) were collected from culture media after centrifuging. Tenocytes and bone marrow-derived stem cells (BMDSCs) were isolated and cultured with the following four media: (1) T-ABRM, (2) T-ABDM, (3) GDF-5, or (4) basal medium with 2% fetal calf serum (FCS). The cell activities and functions were evaluated. Both T-ABRM and T-ABDM treatments significantly stimulated the cell proliferation, migration, and extracellular matrix synthesis for both tenocytes and BMDSCs compared to the control groups (GDF-5 and basal medium). However, cell proliferation, migration, and extracellular matrix production of T-ABRM-treated cells were significantly higher than the T-ABDM, which indicates the apoptotic bodies are critical for cell activities. Our study revealed the possible mechanism of the intrinsic healing of the tendon in which apoptotic bodies, in the process of apoptosis, following tendon injury promote tenocyte and stromal cell proliferation, migration, and production. Future studies should analyze the components of the apoptotic bodies that play this role, and, thus, the targeting of therapeutics can be developed.

AbstractBackgroundThe pleiotropic effects of statin therapy on inflammation and coagulation may reduce the risk of venous thromboembolism. This study evaluated whether statin therapy is associated with decreased venous thromboembolic (VTE) events following kidney transplantation.MethodsWe performed a retrospective analysis of all primary kidney transplants performed between January 2014 and December 2019 at Mayo Clinic Arizona. Patients were divided into two groups depending on sustained statin therapy during the first year following transplantation. Recipient and donor clinical and demographic data were collected. The primary outcome was admission for symptomatic VTE events (deep vein thrombosis [DVT] or pulmonary embolism [PE]).ResultsSustained statin therapy in the first year following transplant was observed in 16.1% (n = 223) of 1384 kidney transplants. The overall incidence of VTE events in the year following kidney transplant was 3.8%. VTE occurred in 4.1% of recipients treated with statins and 3.8% of the controls – (hazard ratio [HR] .92, 95% confidence interval [95% CI] .39, 2.21, p = .86). However, there were significant differences between the groups in terms of age, sex, race/ethnicity, body mass index, indication for transplant, diagnosis of diabetes and discharge antiplatelet or anticoagulant therapy. Following sensitivity analysis in which cohort matching was performed to account for these differences, there was no difference in VTE event‐free survival (HR .89, 95% CI .41, 1.96, p = .78) or overall survival (HR .54, 95% CI .15, 1.94, p = .35) between patients treated with statins compared to controls.ConclusionStatin therapy in the year following successful kidney transplant was not associated with a reduction in risk of VTE.