Chondrocyte Invasion May Be a Mechanism for Persistent Staphylococcus Aureus Infection In Vitro.

BACKGROUND: Recurrent bone and joint infection with Staphylococcus aureus is common. S. aureus can invade and persist in osteoblasts and fibroblasts, but little is known about this mechanism in chondrocytes. If S. aureus were able to invade and persist within chondrocytes, this could be a difficult compartment to treat. QUESTION/PURPOSE: Can S. aureus infiltrate and persist intracellularly within chondrocytes in vitro? METHODS: Cell lines were cultured in vitro and infected with S. aureus. Human chondrocytes (C20A4) were compared with positive controls of human osteoblasts (MG63) and mouse fibroblasts (NIH3T3), which have previously demonstrated S. aureus invasion and persistence (human fibroblasts were not available to us). Six replicates per cell type were followed for 6 days after infection. Cells were treated daily with antibiotic media for extracellular killing. To determine whether S. aureus can infiltrate chondrocytes, fluorescence microscopy was performed to qualitatively assess the presence of intracellular bacteria, and intracellular colony-forming units (CFU) were enumerated 2 hours after infection. To determine whether S. aureus can persist within chondrocytes, intracellular CFUs were enumerated from infected host cells each day postinfection. RESULTS: S. aureus invaded human chondrocytes (C20A4) at a level (2.8 x 105 ± 5.5 x 104 CFUs/mL) greater than positive controls of human osteoblasts (MG63) (9.5 x 102 ± 2.5 x 102 CFUs/mL; p = 0.01) and mouse fibroblasts (NIH3T3) (9.1 x 104 ± 2.5 x 104 CFUs/mL; p = 0.02). S. aureus also persisted within human chondrocytes (C20A4) for 6 days at a level (1.4 x 103 ± 5.3 x 102 CFUs/mL) greater than that of human osteoblasts (MG63) (4.3 x 102 ± 3.5 x 101 CFUs/mL; p = 0.02) and mouse fibroblasts (NIH3T3) (0 CFUs/mL; p < 0.01). S. aureus was undetectable within mouse fibroblasts (NIH3T3) after 4 days. There were 0 CFUs yielded from cell media, confirming extracellular antibiotic treatment was effective. CONCLUSION: S. aureus readily invaded human chondrocytes (C20A4) in vitro and persisted viably for 6 days after infection, evading extracellular antibiotics. Chondrocytes demonstrated a greater level of intracellular invasion and persistence by S. aureus than positive control human osteoblast (MG63) and mouse fibroblast (NIH3T3) cell lines. CLINICAL RELEVANCE: Chondrocyte invasion and persistence may contribute to recurrent bone and joint infections. Additional research should assess longer periods of persistence and whether this mechanism is present in vivo.

Static Versus Articulating Spacer: Does Infectious Pathogen Type Affect Treatment Success?

BACKGROUND: Treatment with a static or an articulating antibiotic-containing spacer is a common strategy for treating periprosthetic joint infection (PJI), yet many patients have persistent infections after spacer treatment. Although previous studies have compared the efficacy of a static and articulating spacer for treating PJI, few studies have assessed infection control from the time of spacer implantation, or they defined treatment failure as including reinfection, reoperation, or chronic suppressive therapy. Additionally, few studies have examined whether there is an interaction between spacer and pathogen type with respect to treatment success. QUESTIONS/PURPOSES: (1) Is there a difference in failure-free survival (defined as no reoperation, reinfection, or suppressive antibiotic therapy) between static and articulating spacers after spacer implantation for PJI? (2) Did the relationship between spacer type and failure-free survival differ by pathogen type (staphylococcal versus nonstaphylococcal and difficult-to-treat [including methicillin-resistant Staphylococcus aureus, methicillin-susceptible S. aureus, Corynebacterium, Mycobacterium, Enterococcus spp, and other gram-negative bacterium] versus not-difficult-to-treat organisms)? METHODS: Between January 2014 and January 2022, a convenience sample of 277 patients was identified as having knee PJIs treated with an articulating (75% [208 of 277]) or static (25% [69 of 277]) antibiotic spacer and potentially eligible for this study. During that time, providers at our institution generally used spacers for later-presenting or chronic infections. Spacer choice was determined by surgeon preference, with static spacers used more often in instances of higher bone loss and poor soft tissue coverage. Thirty-one patients (8 static and 23 articulating spacers) were considered lost to follow-up or had incomplete datasets and were excluded from the analysis, resulting in a final analysis cohort of 246 patients: 25% (61 of 246) received a static spacer and 75% (185 of 246) received an articulating spacer. The mean ± standard deviation age of patients was 66 ± 9.9 years, BMI was 33.3 ± 6.9 kg/m2, and Elixhauser score was 18.1 ± 16.9. Demographic and clinical characteristics were similar between the two groups. Pathogen type was collected and categorized as staphylococcal versus nonstaphylococcal, and difficult-to-treat (including methicillin-resistant Staphylococcus aureus, methicillin-susceptible S. aureus, Corynebacterium, Mycobacterium, Enterococcus spp, and other gram-negative bacterium) versus not-difficult-to-treat, as defined by an infectious disease physician. Other variables we collected included sex, age, American Society of Anesthesiologists classification, BMI, and Elixhauser score. The primary outcome of interest was failure-free survival, which was a composite time-to-event outcome, with failure defined as reoperation, reinfection, death owing to infection, or chronic antibiotic use at a minimum of 1 year after the completion of the patient's Stage 1 postoperative antibiotic course, whichever came first. Reinfection was determined by the treating physicians in accordance with the Musculoskeletal Infection Society guidelines and included an evaluation of infectious laboratory values, cultures, and clinical signs of infection. We compared static and articulating spacers using a Cox proportional hazards model, with spacer type as the primary predictor variable. We compared staphylococcal versus nonstaphylococcal and difficult-to-treat versus not-difficult-to-treat infections by running additional models with interaction terms between spacer type and pathogen type. RESULTS: No difference was observed in the cause-specific hazard ratio for static versus articulating (reference) spacers (HR 1.45 [95% confidence interval 0.94 to 2.22]; p = 0.09), after adjusting for covariates. Additionally, no difference in the association between spacer type and failure-free survival was found between pathogen types or treatment difficulty after evaluating interactions (staphylococcal HR 0.37 [95% CI 0.15 to 0.91], nonstaphylococcal HR 0.79 [95% CI 0.49 to 1.28]; p value for interaction = 0.14; difficult-to-treat HR 0.37 [95% CI 0.14 to 0.99], not-difficult-to-treat HR 0.75 [95% CI 0.47 to 1.20]; p value for interaction = 0.20). CONCLUSION: The lack of a difference in failure-free survival and insufficient evidence of a difference in the association between spacer type and treatment failure by pathogen type suggests that infectious organism may not be an important consideration in the decision about spacer treatment type. Further studies should aim to elucidate which patient factors are the most influential in surgeon decision-making when choosing a spacer type in patients with PJI of the knee.Level of Evidence Level III, therapeutic study.

Total Joint Arthroplasty Is a Viable Treatment Option for Patients With Osteonecrosis and Osteoarthritis After Bone Marrow Transplantation.

Background: Long-term survival in patients who receive bone marrow transplantation (BMT) is increasing. However, osteonecrosis and secondary osteoarthritis (OA) of the hip and knee are common complications in this population due to post-transplant steroid treatment to prevent graft vs host disease. The purpose of this study was to evaluate the outcomes of total joint arthroplasty (TJA) in patients with prior BMT and compare them to those of patients undergoing TJA for primary OA. Methods: Patients with a history of BMT undergoing primary TJA from 2013 to 2021 were retrospectively reviewed. Patients were matched 1:1 by surgical site, sex, age, body mass index, American Society of Anesthesiologists score, and Elixhauser Comorbidity Index to patients undergoing TJA for primary OA. Demographics, intraoperative blood loss, perioperative transfusion requirements, hospital length of stay, 90-day emergency department visits and readmissions, all-cause revisions, and 2-year mortality were compared between cohorts. Results: There were 17 patients undergoing total knee arthroplasty (TKA) after BMT (TKA-BMT) and 43 patients undergoing total hip arthroplasty (THA) after BMT (THA-BMT). More TKA-BMT and THA-BMT patients were immunosuppressed preoperatively compared to 17 matched TKA-OA and 43 THA-OA patients (P = .018 and P < .001). There were no other significant perioperative differences between BMT and OA groups. Two-year patient and implant survivorship for TKA-BMT and THA-BMT patients were high and not statistically different from TKA-OA and THA-OA cohorts. Conclusions: TJA after BMT provides satisfactory perioperative and short-term outcomes and is a viable treatment option for patients with osteonecrosis and secondary OA after BMT treatment.

Patient Perceptions and Interest in Robotic-Assisted Total Joint Arthroplasty.

Background: Robotic-assisted total joint arthroplasty (rTJA) has growing interest among patients and surgeons. However, patient interest in and perceptions of rTJA have not been well explored. We sought to investigate the influence of patient demographics on interest in rTJA and patient perceptions regarding rTJA. Methods: Patients presenting for their initial adult reconstruction consultation received an optional anonymous survey prior to seeing the provider. Patient sociodemographic parameters were recorded. Additional questions assessed interest in and perceptions surrounding rTJA. Results were analyzed to determine whether patient factors correlated with survey responses. Results: A total of 360 patients participated. Analysis of responses revealed 77.8% of patients were interested in rTJA. Interest level positively correlated with patient age (Rs = 0.139, P = .010), education level (Rs = 0.168, P = .002), household income (Rs = 0.274, P < .001), and White race (F = 4.157, P = .016). At least 100 patients believed rTJA was easier and more accurate, but more expensive and had a significant learning curve for the surgeon. Over 100 patients believed robots were capable of independently performing most or all of the rTJA operation. Conclusions: Patient interest in rTJA varies between patients. Many patients have an incomplete understanding of rTJA, and orthopaedic surgeons should address patient perceptions during surgical consultation. Level of Evidence: IV, Cross-sectional study.

HuM195 and its single-chain variable fragment increase Aß phagocytosis in microglia via elimination of CD33 inhibitory signaling.

CD33 is a transmembrane receptor expressed on cells of myeloid lineage and regulates innate immunity. CD33 is a risk factor for Alzheimer's disease (AD) and targeting CD33 has been a promising strategy drug development. However, the mechanism of CD33's action is poorly understood. Here we investigate the mechanism of anti-CD33 antibody HuM195 (Lintuzumab) and its single-chain variable fragment (scFv) and examine their therapeutic potential. Treatment with HuM195 full-length antibody or its scFv increased phagocytosis of ß-amyloid 42 (Aß42) in human microglia and monocytes. This activation of phagocytosis was driven by internalization and degradation of CD33, thereby downregulating its inhibitory signal. HumM195 transiently induced CD33 phosphorylation and its signaling via receptor dimerization. However, this signaling decayed with degradation of CD33. scFv binding to CD33 leads to a degradation of CD33 without detection of the CD33 dimerization and signaling. Moreover, we found that treatments with either HuM195 or scFv promotes the secretion of IL33, a cytokine implicated in microglia reprogramming. Importantly, recombinant IL33 potentiates the uptake of Aß42 in monocytes. Collectively, our findings provide unanticipated mechanistic insight into the role of CD33 signaling in both monocytes and microglia and define a molecular basis for the development of CD33-based therapy of AD.

Inferior Outcomes for Patients Transferred Between Surgical Stages for Knee Periprosthetic Joint Infection.

BACKGROUND: Periprosthetic joint infection (PJI) in total knee arthroplasty may result in 2-stage revision surgery. There are limited data describing outcomes when the first stage is completed at an outside hospital and the patient is referred to a tertiary center. We hypothesized that patients have greater success when both surgeries occur at a single center. METHODS: There were 25 knee PJI patients who presented with an antibiotic spacer and had a minimum 2-year follow-up who were retrospectively identified at a single tertiary referral center from 2014 to 2021. A cohort matched for age, sex, body mass index, Elixhauser comorbidity measure, spacer type, infectious organism, and year of surgery was established with patients who had both stages completed at the investigating institution. Modified Delphi success criteria of no subsequent surgery or reinfection with any species were compared. RESULTS: The transferred group demonstrated a treatment success of 40% compared to 84% in the continuous group (P < .01). The transferred group was more likely to have an additional procedure between stages (44 versus 8%, P < .01), with a higher number of surgeries after primary total knee arthroplasty (4.8 versus 3.0, P < .01), between stages (1.4 versus 0.2, P < .01), and after second stage (0.8 versus 0.2, P = .03). The transferred group had longer durations between stages (20.1 versus 7.0 weeks, P < .01). CONCLUSION: Patients who have PJIs transferred between stages demonstrated higher treatment failure. Surgeons should consider transfer early with a goal of continuous management by a single institution.

The seroepidemiology of isolated core antibody against hepatitis B among Taiwanese adults - A large hospital-based study.

BACKGROUND/PURPOSE: This study aims to investigate the prevalence of isolated core antibodies against hepatitis B (IAHBc) in different birth cohorts using a large medical record database. METHODS: Hepatitis B viral serological test data were collected from a chart cloud database at a medical center in Taiwan between January 2006 and December 2018. The data collected included birth year, sex, hepatitis B viral markers (HBsAg, anti-HBs or anti-HBc), and hepatitis B vaccination records. Enrolled patients were grouped according to their birth year into three categories: ≤ 1986, 1987-1992, and ≥ 1993, which correspond to no neonatal hepatitis B immunization, plasma-derived HB vaccine (PDHBV), and recombinant hepatitis B vaccine (RHBV), respectively. Prevalence of hepatitis B viral seromarkers, including IAHBc, was calculated by sex, age groups, and birth cohorts. Those who underwent repeated hepatitis B serology tests were included for further analysis to follow up their serostatus. RESULTS: A total of 117,335 adults with complete hepatitis B serologic data were analyzed. Among them, 6641 individuals (5.7 %) were found to have IAHBc. The prevalence of IAHBc was 11.4 %, 0.8 %, and 0.3 % among those born before 1986, between 1987 and 1992, and after 1992, respectively. Among the 690 subjects with repeated blood tests and complete hepatitis B serologic data, 551 cases (79.9 %) remained IAHBc. The other cases included resolved infection status (13.9 %), seronegativity for three HB seromarkers (3 %), and carrier of hepatitis B virus (2.3 %). CONCLUSION: The management of individuals with IAHBc should be tailored to their age, vaccination status, and risk factors for occult hepatitis B viral infection.

Feature-enhanced adversarial semi-supervised semantic segmentation network for pulmonary embolism annotation.

This study established a feature-enhanced adversarial semi-supervised semantic segmentation model to automatically annotate pulmonary embolism (PE) lesion areas in computed tomography pulmonary angiogram (CTPA) images. In the current study, all of the PE CTPA image segmentation methods were trained by supervised learning. However, when CTPA images come from different hospitals, the supervised learning models need to be retrained and the images need to be relabeled. Therefore, this study proposed a semi-supervised learning method to make the model applicable to different datasets by the addition of a small number of unlabeled images. By training the model with both labeled and unlabeled images, the accuracy of unlabeled images was improved and the labeling cost was reduced. Our proposed semi-supervised segmentation model included a segmentation network and a discriminator network. We added feature information generated from the encoder of the segmentation network to the discriminator so that it could learn the similarities between the prediction label and ground truth label. The HRNet-based architecture was modified and used as the segmentation network. This HRNet-based architecture could maintain a higher resolution for convolutional operations to improve the prediction of small PE lesion areas. We used a labeled open-source dataset and an unlabeled National Cheng Kung University Hospital (NCKUH) (IRB number: B-ER-108-380) dataset to train the semi-supervised learning model, and the resulting mean intersection over union (mIOU), dice score, and sensitivity reached 0.3510, 0.4854, and 0.4253, respectively, on the NCKUH dataset. Then we fine-tuned and tested the model with a small number of unlabeled PE CTPA images in a dataset from China Medical University Hospital (CMUH) (IRB number: CMUH110-REC3-173). Comparing the results of our semi-supervised model with those of the supervised model, the mIOU, dice score, and sensitivity improved from 0.2344, 0.3325, and 0.3151 to 0.3721, 0.5113, and 0.4967, respectively. In conclusion, our semi-supervised model can improve the accuracy on other datasets and reduce the labor cost of labeling with the use of only a small number of unlabeled images for fine-tuning.

Primary Aortoenteric Fistula in a Patient With Prior Abdominopelvic Surgery and Opioid-Induced Constipation.

Aortoenteric fistulas (AEF) represent a rare, life-threatening cause of gastrointestinal bleeding with an incidence of 0.007 per million. Iliac artery-enteric fistulas represent an even more uncommon variant of AEFs. Prompt diagnosis and intervention are required to prevent associated morbidity and mortality. Herein, we report a rare case of iliac-enteric fistula in a patient with hematochezia.

Pyrocarbon hemiarthroplasty of the shoulder: a systematic review and meta-analysis of clinical results.

BACKGROUND: Hemiarthroplasty is often considered in the setting of preserved glenoid cartilage given the high risk of revision associated with total shoulder arthroplasty. Pyrocarbon (PyC) has been used as an implant material that theoretically allows for formation of a neo-membrane that would act like cartilage to reduce glenoid wear. The purpose of this study was to evaluate the clinical outcomes, radiographic outcomes, revision rates, and complication rates in the existing literature on shoulder hemiarthroplasty using PyC. METHODS: The MEDLINE, Embase, and Scopus databases were searched for articles relating to shoulder hemiarthroplasty using the terms "pyrocarbon" or "pyrolytic carbon." Abstracts and articles were screened against predefined inclusion and exclusion criteria, with a minimum of 24 months' follow-up required. Data on patient demographic characteristics, clinical outcome scores, complications, revision rates, and radiographic findings were recorded. Where appropriate, meta-analysis was performed. RESULTS: Twelve studies were selected for final inclusion, with a total of 536 patients. Among the studies reporting preoperative and postoperative range of motion (ROM), an overall improvement in ROM was observed. The mean Constant score was 70.9 points postoperatively, with a mean improvement of 36.2 points (n = 359, 9 studies). Radiographically, 22.8% of patients (n = 536, 8 studies) had evidence of glenoid erosion, 10.4% had changes in implant positioning, and 9.9% had tuberosity thinning. In addition, 1.5% of patients had radiographic subacromial space reduction, whereas 0.7% had an increase in tuberosity thickness. Across all studies, there was an 8.6% complication rate, with the most common cause being glenoid erosion (2.6%, n = 14). There was an overall 7.7% revision rate (n = 41), with 63% of revisions (n = 26) undergoing conversion to reverse or total shoulder arthroplasty. CONCLUSION: PyC hemiarthroplasty shows overall improvements in ROM and patient-reported outcomes for patients. However, there remains concern for glenoid erosion on radiographic evaluation at minimum 2-year follow-up. Although preliminary studies have shown encouraging results, this systematic review emphasizes the need for longer-term follow-up studies with further radiographic evaluation of the severity of glenoid erosion and the association with functional outcomes and failure risk.

Effectiveness of convolutional neural networks in the interpretation of pulmonary cytologic images in endobronchial ultrasound procedures.

BACKGROUND: Rapid on-site cytologic evaluation (ROSE) helps to improve the diagnostic accuracy in endobronchial ultrasound (EBUS) procedures. However, cytologists are seldom available to perform ROSE in many institutions. Recent studies have investigated the application of deep learning in cytologic image analysis. As such, the present study analyzed lung cytologic images obtained by EBUS procedures, and employed deep-learning methods to distinguish between benign and malignant cells and to semantically segment malignant cells. METHODS: Ninety-seven patients who underwent 104 EBUS procedures were enrolled. Four hundred and ninety-nine lung cytologic images obtained via ROSE, including 425 malignant and 74 benign, and most malignant were lung adenocarcinoma (64.3%). All the images were used to train a residual network model with 101 layers (ResNet101), with suitable hyperparameters selected to classify benign and malignant lung cytologic images. An HRNet model was also employed to mark the area of malignant cells. Automatic patch-cropping was adopted to facilitate dataset preparation. RESULTS: Malignant cells were successfully classified by ResNet101 with 98.8% classification accuracy, 98.8% sensitivity, and 98.8% specificity in patch-based classification; 95.5% classification accuracy in image-based classification; and 92.9% classification accuracy in patient-based classification. Malignant cell area was successfully marked by HRNet with a mean intersection over union of 89.2%. The automatic cropping method enabled the system to complete diagnosis within 1 s. CONCLUSIONS: This is the first study to combine lung cytologic image deep-learning classification with semantic segmentation. The model was optimized for high accuracy and the automatic cropping facilitates the clinical application of our model. The success in both lung cytologic images classification and semantic segmentation on our dataset shows a promising result for clinical application in the future.

GSAP regulates lipid homeostasis and mitochondrial function associated with Alzheimer's disease.

Biochemical, pathogenic, and human genetic data confirm that GSAP (γ-secretase activating protein), a selective γ-secretase modulatory protein, plays important roles in Alzheimer's disease (AD) and Down's syndrome. However, the molecular mechanism(s) underlying GSAP-dependent pathogenesis remains largely elusive. Here, through unbiased proteomics and single-nuclei RNAseq, we identified that GSAP regulates multiple biological pathways, including protein phosphorylation, trafficking, lipid metabolism, and mitochondrial function. We demonstrated that GSAP physically interacts with the Fe65-APP complex to regulate APP trafficking/partitioning. GSAP is enriched in the mitochondria-associated membrane (MAM) and regulates lipid homeostasis through the amyloidogenic processing of APP. GSAP deletion generates a lipid environment unfavorable for AD pathogenesis, leading to improved mitochondrial function and the rescue of cognitive deficits in an AD mouse model. Finally, we identified a novel GSAP single-nucleotide polymorphism that regulates its brain transcript level and is associated with an increased AD risk. Together, our findings indicate that GSAP impairs mitochondrial function through its MAM localization and that lowering GSAP expression reduces pathological effects associated with AD.

Epidemiology of chronic kidney disease of undetermined aetiology in Taiwanese farmers: a cross-sectional study from Changhua Community-based Integrated Screening programme.

OBJECTIVES: Chronic kidney disease of undetermined or non-traditional aetiology (CKDu or CKDnT) has been reported in Mesoamerica among farmers under heat stress. Epidemiological evidence was lacking in Asian countries with similar climatic conditions. The objective of this study was to investigate the prevalence of CKDu and possible risk factors. METHODS: We used the data from the Changhua Community-based Integrated Screening programme from 2005 to 2014, which is the annual screening for chronic diseases in Taiwan's largest rice-farming county since 2005. Our study population included farmers and non-farmers aged 15-60 years. CKDu was defined as an estimated glomerular filtration rate <60 mL/min/1.73 m2 at age under 60 years without hypertension, diabetes, proteinuria, haematuria or using Chinese herbal medicine. We estimated the adjusted prevalence OR (POR) of CKDu by farmers, age, sex, education, urbanisation, smoking, body mass index, hyperuricaemia, hyperlipidaemia, heart disease and chronic liver disease. RESULTS: 5555 farmers and 35 761 non-farmers were included in this study. CKDu accounted for 48.9% of all CKD cases. The prevalence of CKDu was 2.3% in the farmers and 0.9% in the non-farmers. The crude POR of CKDu in farmers compared with non-farmers was 2.73 (2.13-3.50), and the adjusted POR was 1.45 (1.10-1.90). Dehydration (blood urea nitrogen-to-creatinine ratio >20) was found in 22% of the farmers and 14% of the non-farmers. CONCLUSIONS: Farmers in subtropical Asian countries are at increased risk of CKDu. Governments should take the CKDu epidemics seriously and provide farmers with occupational health education programmes on thermal hazards.

Pain in neurodegenerative diseases with atypical parkinsonism: a systematic review on prevalence, clinical presentation, and findings from experimental studies.

Parkinson's disease-related pain has increasingly been investigated in research studies. Still, only a few studies have addressed the prevalence and clinical characteristics of pain in neurodegenerative disorders with atypical parkinsonism. The existing evidence, although scarce, suggests that, similarly as in Parkinson's disease, individuals with neurodegenerative diseases with atypical parkinsonism might be predisposed to the development of persistent pain. Today, as the global population is aging and we face an epidemic of neurodegenerative disorders, under-treated pain is taking a great toll on an ever-rising number of people. Here, we provide an up-to-date review of the current knowledge on the prevalence of pain, its clinical features, and findings from experimental studies that might signpost altered pain processing in the most prevalent neurodegenerative disorders with atypical parkinsonism: multiple system atrophy, progressive supranuclear palsy, corticobasal syndrome, frontotemporal dementia, and dementia with Lewy bodies. Finally, we point out the current gaps and unmet needs that future research studies should focus on. Large-scale, high-quality clinical trials, coupled with pre-clinical research, are urgently needed to reveal the exact pathophysiological mechanisms underpinning heightened pain and pave the path for mechanistically-driven analgesic interventions to be developed, ultimately leading to an improvement in the quality of life of individuals with neurodegenerative disorders.

HIV-1 infection of the kidney: mechanisms and implications.

People living with HIV are at higher risk for acute and chronic kidney disease compared with uninfected individuals. Kidney disease in this population is multifactorial, with several contributors including HIV infection of kidney cells, chronic inflammation, genetic predisposition, aging, comorbidities, and coinfections. In this review, we provide a summary of recent advancements in the understanding of the mechanisms and implications of HIV infection and kidney disease, with particular focus on the role of direct HIV infection of renal cells.

Presenilin 1 phosphorylation regulates amyloid-ß degradation by microglia.

Amyloid-ß peptide (Aß) accumulation in the brain is a hallmark of Alzheimer's Disease. An important mechanism of Aß clearance in the brain is uptake and degradation by microglia. Presenilin 1 (PS1) is the catalytic subunit of γ-secretase, an enzyme complex responsible for the maturation of multiple substrates, such as Aß. Although PS1 has been extensively studied in neurons, the role of PS1 in microglia is incompletely understood. Here we report that microglia containing phospho-deficient mutant PS1 display a slower kinetic response to micro injury in the brain in vivo and the inability to degrade Aß oligomers due to a phagolysosome dysfunction. An Alzheimer's mouse model containing phospho-deficient PS1 show severe Aß accumulation in microglia as well as the postsynaptic protein PSD95. Our results demonstrate a novel mechanism by which PS1 modulates microglial function and contributes to Alzheimer's -associated phenotypes.

HIV-1 diversity and compartmentalization in urine, semen, and blood.

HIV-1 persists indefinitely in multiple cellular reservoirs despite antiretroviral therapy. We previously demonstrated HIV-1 compartmentalization in kidney and urine. Here, we further characterized viruses in urine and when available, compared them to those present in semen from HIV-1 positive participants with detectable plasma viremia to further understand the viral dynamics in the upper and lower genitourinary tract.Blood and urine samples were obtained from 19 HIV-1 positive participants. Simultaneous semen samples were obtained from 16 of the 19 participants. HIV-1 envelope (env) gene sequences were obtained by single-genome amplification (SGA) and neighbor-joining trees were constructed using the Kimura 2-parameter model.HIV-1 env gene sequences were amplified from blood in 19/19 (100%) participants, urine in 18/19 (95%) participants, and semen in 12/16 (75%). In individuals from which both urine and semen samples were obtained, differences in viral shedding between the 2 sources were observed, where HIV-1 env sequences could only be amplified from either urine or semen. Longitudinal phylogenetic analysis of urine-derived env sequences from 1 participant demonstrated that urine clusters distinct from blood are maintained over time (20 weeks), consistent with viral compartmentalization and local replication. Comparison of urine and semen derived sequences demonstrated either virus compartmentalization or equilibration.Our results demonstrate that when present, viral compartmentalization in urine persists over time. Comparison of timing of viral shedding in urine and semen samples from our cohort suggest different viral kinetics between the upper and lower genitourinary tract and sequence analysis suggests that HIV-1 populations in urine and semen can either be imported from blood or produced locally.

Brain Permeable Tafamidis Amide Analogs for Stabilizing TTR and Reducing APP Cleavage.

Tafamidis, 1, a potent transthyretin kinetic stabilizer, weakly inhibits the γ-secretase enzyme in vitro. We have synthesized four amide derivatives of 1. These compounds reduce production of the Aß peptide in N2a695 cells but do not inhibit the γ-secretase enzyme in cell-free assays. By performing fluorescence correlation spectroscopy, we have shown that TTR inhibits Aß oligomerization and that addition of tafamidis or its amide derivative does not affect TTR's ability to inhibit Aß oligomerization. The piperazine amide derivative of tafamidis (1a) efficiently penetrates and accumulates in mouse brain and undergoes proteolysis under physiological conditions in mice to produce tafamidis.