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1.
Mol Psychiatry ; 2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38383769

RESUMO

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.

2.
Artigo em Inglês | MEDLINE | ID: mdl-38662927

RESUMO

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.

3.
Artigo em Inglês | MEDLINE | ID: mdl-38662933

RESUMO

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.

4.
J Arthroplasty ; 39(2): 490-493, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37619801

RESUMO

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.


Assuntos
Artrite Infecciosa , Artroplastia do Joelho , Prótese do Joelho , Infecções Relacionadas à Prótese , Humanos , Estudos Retrospectivos , Infecções Relacionadas à Prótese/etiologia , Infecções Relacionadas à Prótese/cirurgia , Infecções Relacionadas à Prótese/tratamento farmacológico , Articulação do Joelho/cirurgia , Artroplastia do Joelho/efeitos adversos , Artroplastia do Joelho/métodos , Antibacterianos/uso terapêutico , Resultado do Tratamento , Artrite Infecciosa/etiologia , Reoperação/métodos , Prótese do Joelho/efeitos adversos
5.
J Formos Med Assoc ; 2023 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-37978028

RESUMO

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.

6.
J Shoulder Elbow Surg ; 32(6): 1323-1332, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36610477

RESUMO

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.


Assuntos
Artroplastia do Ombro , Hemiartroplastia , Articulação do Ombro , Humanos , Ombro/cirurgia , Articulação do Ombro/diagnóstico por imagem , Articulação do Ombro/cirurgia , Hemiartroplastia/efeitos adversos , Seguimentos , Artroplastia do Ombro/efeitos adversos , Resultado do Tratamento , Estudos Retrospectivos , Amplitude de Movimento Articular
7.
Mol Psychiatry ; 26(10): 5620-5635, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-32792660

RESUMO

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.


Assuntos
Doença de Alzheimer , Microglia , Doença de Alzheimer/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Camundongos , Microglia/metabolismo , Fosforilação , Presenilina-1/genética , Presenilina-1/metabolismo
8.
Proc Natl Acad Sci U S A ; 116(13): 6385-6390, 2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30850537

RESUMO

The mechanism by which γ-secretase activating protein (GSAP) regulates γ-secretase activity has not yet been elucidated. Here, we show that knockout of GSAP in cultured cells directly reduces γ-secretase activity for Aß production, but not for Notch1 cleavage, suggesting that GSAP may induce a conformational change contributing to the specificity of γ-secretase. Furthermore, using an active-site-directed photoprobe with double cross-linking moieties, we demonstrate that GSAP modifies the orientation and/or distance of the PS1 N-terminal fragment and the PS1 C-terminal fragment, a region containing the active site of γ-secretase. This work offers insight into how GSAP regulates γ-secretase specificity.


Assuntos
Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Presenilina-1/química , Proteínas/metabolismo , Sistemas CRISPR-Cas , Domínio Catalítico , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Cinética , Fragmentos de Peptídeos/metabolismo , Proteínas/genética , Receptor Notch1
9.
Occup Environ Med ; 78(12): 849-858, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34108255

RESUMO

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.


Assuntos
Fazendeiros , Doenças Profissionais/epidemiologia , Insuficiência Renal Crônica/epidemiologia , Adolescente , Adulto , Estudos Transversais , Desidratação/epidemiologia , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Profissionais/etiologia , Prevalência , Insuficiência Renal Crônica/etiologia , Taiwan/epidemiologia
10.
J Integr Neurosci ; 20(4): 1067-1078, 2021 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-34997730

RESUMO

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.


Assuntos
Degeneração Corticobasal , Demência Frontotemporal , Doença por Corpos de Lewy , Atrofia de Múltiplos Sistemas , Dor Musculoesquelética , Neuralgia , Paralisia Supranuclear Progressiva , Degeneração Corticobasal/complicações , Degeneração Corticobasal/epidemiologia , Degeneração Corticobasal/fisiopatologia , Demência Frontotemporal/complicações , Demência Frontotemporal/epidemiologia , Demência Frontotemporal/fisiopatologia , Humanos , Doença por Corpos de Lewy/complicações , Doença por Corpos de Lewy/epidemiologia , Doença por Corpos de Lewy/fisiopatologia , Atrofia de Múltiplos Sistemas/complicações , Atrofia de Múltiplos Sistemas/epidemiologia , Atrofia de Múltiplos Sistemas/fisiopatologia , Dor Musculoesquelética/epidemiologia , Dor Musculoesquelética/etiologia , Dor Musculoesquelética/fisiopatologia , Neuralgia/epidemiologia , Neuralgia/etiologia , Neuralgia/fisiopatologia , Prevalência , Paralisia Supranuclear Progressiva/complicações , Paralisia Supranuclear Progressiva/epidemiologia , Paralisia Supranuclear Progressiva/fisiopatologia
11.
BMC Fam Pract ; 21(1): 209, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-33059587

RESUMO

BACKGROUND: The Family Practice Integrated Care Project (FPICP) is a team-based program in Taiwan initiated in 2003. This study investigates the influence of FPICP on the quality of diabetes care. METHODS: This population-based cohort study used Taiwan's National Health Insurance Administration data on FPICP (fiscal year 2015-2016, with follow-up duration of one year). Participants included diabetic patients aged ≥30 in primary care clinics. We used conditional logistic regression modeling of patient characteristics and annual diabetes examinations and compared FPICP participants with non-participating candidates. Main outcome measures included completion of annual diabetes examinations, including glycated hemoglobin (A1c), low-density lipoprotein (LDL), urine microalbumin (MAU), routine urinalysis (UR), and fundus examination (FE). RESULTS: The sample included 298,208 FPICP participants and 478,778 non-participating candidates. After 1:1 propensity score matching, the examination completion rates for FPICP participants and non-participants, respectively, were 94.4% versus 93.6% in A1c, 84.2% versus 83.8% in LDL, 61.9% versus 60.1% in MAU, 59.2% versus 58.0% in UR, and 30.1% versus 32.4% in FE. CONCLUSION: Our findings indicate that a program like FPICP helps improve the quality of diabetes care through regular examinations of Alc, LDL, MAU, and UR.


Assuntos
Prestação Integrada de Cuidados de Saúde , Diabetes Mellitus Tipo 2 , Diabetes Mellitus , Estudos de Coortes , Diabetes Mellitus/terapia , Medicina de Família e Comunidade , Hemoglobinas Glicadas/análise , Humanos , Taiwan
12.
Proc Natl Acad Sci U S A ; 113(19): 5412-7, 2016 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-27114525

RESUMO

The components involved in cellular trafficking and protein recycling machinery that have been associated with increased Alzheimer's disease (AD) risk belong to the late secretory compartments for the most part. Here, we hypothesize that these late unavoidable events might be the consequence of earlier complications occurring while amyloid precursor protein (APP) is trafficking through the early secretory pathway. We investigated the relevance to AD of coat protein complex I (COPI)-dependent trafficking, an early step in Golgi-to-endoplasmic reticulum (ER) retrograde transport and one of the very first trafficking steps. Using a complex set of imaging technologies, including inverse fluorescence recovery after photobleaching (iFRAP) and photoactivatable probes, coupled to biochemical experiments, we show that COPI subunit δ (δ-COP) affects the biology of APP, including its subcellular localization and cell surface expression, its trafficking, and its metabolism. These findings demonstrate the crucial role of δ-COP in APP metabolism and, consequently, the generation of amyloid-ß (Aß) peptide, providing previously nondescribed mechanistic explanations of the underlying events.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Membrana Celular/metabolismo , Proteína Coatomer/metabolismo , Neurônios/metabolismo , Frações Subcelulares/metabolismo , Animais , Linhagem Celular , Humanos , Camundongos , Transporte Proteico/fisiologia
15.
Support Care Cancer ; 25(2): 357-364, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27655559

RESUMO

AIM: Patients treated with allogeneic hematopoietic stem cell transplantation (HSCT) may experience oral complications associated with chronic graft-versus-host disease (cGVHD). These complications may significantly affect quality of life, even many years post-HSCT. Current treatment options for oral cGVHD are limited and often include steroid or other immunomodulatory medications, which may not adequately control the oral condition. A non-immunosuppressive intervention for symptomatic relief in oral cGVHD would thus be a welcome addition to the treatment paradigm. MATERIALS AND METHODS: We report seven cases of oral cGVHD that were treated with photobiomodulation therapy (PBM), previously known as low-level laser therapy (LLLT). Patients underwent at least two PBM treatments per week in addition to local treatment with steroids, and if on systemic therapies, these were either unchanged or dosage was reduced during the period of PBM therapy. Follow-up data is presented for 4 weeks of treatment. RESULTS: Oral pain, sensitivity, and dry mouth improved in most patients. These findings suggest PBM therapy may represent an additional approach for management of oral cGVHD, and suggest that controlled studies should be conducted to confirm the efficacy and safety of PBM therapy in oral cGVHD and to determine optimal PBM therapy protocols.


Assuntos
Doença Enxerto-Hospedeiro/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Terapia com Luz de Baixa Intensidade/métodos , Condicionamento Pré-Transplante/efeitos adversos , Transplante Homólogo/efeitos adversos , Adolescente , Adulto , Idoso , Doença Crônica , Feminino , Doença Enxerto-Hospedeiro/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade
16.
J Foot Ankle Surg ; 56(1): 42-46, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27989346

RESUMO

Bone marrow aspirates (BMAs), owing to their innate osteogenic potential, are well-documented supplements to osteoconductive and/or osteoinductive materials. The calcaneal body provides foot and ankle surgeons a convenient harvest site with low morbidity and minimal cost. In the present study, we sought to identify and characterize multipotent mesenchymal stromal cells (MSCs) in BMAs harvested from the human calcaneal body. Ten healthy patients aged 18 to 65 years were enrolled in the present study. BMAs were harvested from the patients without any reported postoperative complications related to the harvest. Cells isolated from all the aspirates were adherent to culture plates and expressed positive MSC surface markers (CD105, CD90, and CD73) and a low level of negative MSC markers (CD34 and CD45). The cells maintained the ability to proliferate and differentiate into cells of mesenchymal lineages. The BMAs from the human calcaneal body offer a healthy source of multipotent MSCs.


Assuntos
Calcâneo/citologia , Células-Tronco Mesenquimais/citologia , Transplante de Células-Tronco , Coleta de Tecidos e Órgãos/métodos , Adulto , Idoso , Biópsia por Agulha/métodos , Células da Medula Óssea , Calcâneo/cirurgia , Estudos de Coortes , Feminino , Citometria de Fluxo/métodos , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade
18.
Proc Natl Acad Sci U S A ; 110(42): 17071-6, 2013 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-24067654

RESUMO

The hallmarks of Alzheimer's disease (AD) are the aggregates of amyloid-ß (Aß) peptides and tau protein. Autophagy is a major cellular pathway leading to the removal of aggregated proteins. We have reported recently that autophagy was responsible for amyloid precursor protein cleaved C-terminal fragment (APP-CTF) degradation and amyloid ß clearance in an Atg5-dependent manner. Here we aimed to elucidate the molecular mechanism by which autophagy mediates the degradation of APP-CTF and the clearance of amyloid ß. Through affinity purification followed by mass spectrum analysis, we identified adaptor protein (AP) 2 together with phosphatidylinositol clathrin assembly lymphoid-myeloid leukemia (PICALM) as binding proteins of microtubule-associated protein 1 light chain 3 (LC3). Further analysis showed that AP2 regulated the cellular levels of APP-CTF. Knockdown of AP2 reduced autophagy-mediated APP-CTF degradation. Immunoprecipitation and live imaging analysis demonstrated that AP2 and PICALM cross-link LC3 with APP-CTF. These data suggest that the AP-2/PICALM complex functions as an autophagic cargo receptor for the recognition and shipment of APP-CTF from the endocytic pathway to the LC3-marked autophagic degradation pathway. This molecular mechanism linking AP2/PICALM and AD is consistent with genetic evidence indicating a role for PICALM as a risk factor for AD.


Assuntos
Complexo 2 de Proteínas Adaptadoras/metabolismo , Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Autofagia , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Monoméricas de Montagem de Clatrina/metabolismo , Proteólise , Complexo 2 de Proteínas Adaptadoras/genética , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Proteína 5 Relacionada à Autofagia , Células HeLa , Humanos , Proteínas Associadas aos Microtúbulos/genética , Proteínas Monoméricas de Montagem de Clatrina/genética , Fatores de Risco
19.
Arthroplast Today ; 26: 101342, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38481560

RESUMO

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.

20.
Arthroplast Today ; 27: 101373, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38680846

RESUMO

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.

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