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1.
Ir Med J ; 113(7): 123, 2020 Jul 30.
Article in English | MEDLINE | ID: mdl-35575598

ABSTRACT

Aim Outpatient parenteral antimicrobial therapy (OPAT) is an option in patients who require parenteral antimicrobial administration and are clinically well enough for hospital discharge. This is an update of the Irish National OPAT guidelines which were last reviewed in 2011. Methods The guideline was devised through a collaborative process with the national OPAT Working Group and a review of the literature. It is intended for clinicians who prescribe any intravenous (IV) antimicrobials outside of the inpatient setting in the Republic of Ireland. Results Patient care while on OPAT should be provided by a designated OPAT service, with clear managerial and clinical governance lines of responsibility. It should be conducted using a team approach with a clinical lead on each site either as an infection specialist, or a general medical physician with infection specialist input and an OPAT nurse. An antimicrobial pharmacist is also desirable. Several factors must be considered when assessing patient's suitability for OPAT including exclusion criteria, infection-specific factors, and patient specific factors such as physical, social and logistic criteria. Conclusion This updated guideline advocates a more individualised OPAT approach, with the recognition that specific antimicrobials and/or specific delivery models may be more appropriate for certain patient groups. Full guidelines are available through www.opat.ie.

2.
Cell Metab ; 2022 Apr 23.
Article in English | MEDLINE | ID: mdl-35504291

ABSTRACT

The tumor microenvironment (TME) contains a rich source of nutrients that sustains cell growth and facilitate tumor development. Glucose and glutamine in the TME are essential for the development and activation of effector T cells that exert antitumor function. Immunotherapy unleashes T cell antitumor function, and although many solid tumors respond well, a significant proportion of patients do not benefit. In patients with KRAS-mutant lung adenocarcinoma, KEAP1 and STK11/Lkb1 co-mutations are associated with impaired response to immunotherapy. To investigate the metabolic and immune microenvironment of KRAS-mutant lung adenocarcinoma, we generated murine models that reflect the KEAP1 and STK11/Lkb1 mutational landscape in these patients. Here, we show increased glutamate abundance in the Lkb1-deficient TME associated with CD8 T cell activation in response to anti-PD1. Combination treatment with the glutaminase inhibitor CB-839 inhibited clonal expansion and activation of CD8 T cells. Thus, glutaminase inhibition negatively impacts CD8 T cells activated by anti-PD1 immunotherapy.

3.
Zootaxa ; 5100(1): 73-88, 2022 Feb 17.
Article in English | MEDLINE | ID: mdl-35391088

ABSTRACT

Hagenulopsis diptera Ulmer, type species of the genus Hagenulopsis, was originally described based on imagos from Santa Catarina State, Southern Brazil. Misconceptions of H. diptera circumscription led to erroneous attribution of material from Minas Gerais and Esprito Santo, Southeastern Brazil, to H. diptera. Despite the increase in the number of species attributed to Hagenulopsis, little attention has been given to the type species. After comparative examination of photographs of the holotype and fresh material of H. diptera from Southeastern Brazil, we conclude that many specimens previously assigned to H. diptera represent a new species. Thus, we redescribe H. diptera and describe a new species Hagenulopsis perere sp. nov. based on eggs, nymphs and imagos. Diagnostic features of Hagenulopsis perere sp. nov. include cross veins between C and RP1 strongly clouded with brown and outer surface of mid femur with a brown spot at midlength. Finally, comments and new records are presented for Hagenulopsis minuta Spieth.


Subject(s)
Ephemeroptera , Animals , Brazil , Nymph
4.
J Stroke Cerebrovasc Dis ; 31(5): 106346, 2022 05.
Article in English | MEDLINE | ID: mdl-35193026

ABSTRACT

BACKGROUND: Cervical Artery Dissection is an important cause of stroke in the young. Data on incidence and associations of recurrence in patients with cervical artery dissection are lacking. Increased Vertebral Artery Tortuosity Index has been reported in patients with cervical artery dissection and associated with earlier age of arterial dissection in patients with connective tissue disease. OBJECTIVE: To test the hypothesis that increased vertebral artery tortuosity is associated with recurrent cervical artery dissection. METHODS: We reviewed data from a single-center registry of cervical artery dissection patients enrolled between 2011-2021. CT angiography was reviewed for neck length, vertebral artery dominance, and vertebral artery tortuosity index. Incidence rate of recurrent dissection was calculated using Poisson regression. Differences between groups were analyzed using the Kruskal-Wallis rank sum test and Fisher's exact test. RESULTS: The cohort included 155 patients: women (56%), mean (SD) age 42 (±10) years, and 116 single and 39 multiple artery dissections. Eleven (7.1%) had a recurrence with an incidence rate (95% CI) of 1.91 (1.06, 3.44) per 100 person-years. Vertebral artery tortuosity did not differ significantly between single and recurrent groups (median (IQR) 46.81 (40.85, 53.91) vs 44.97 (40.68, 50.62) p = 0.388). Morphometric characteristics of height, neck length, and BMI were not associated with recurrence. There was no difference in vertebral artery tortuosity by dissection location (carotid vs vertebral). CONCLUSION: In this single center cohort of patients with cervical artery dissection, there was no difference in VTI between single and recurrent groups.


Subject(s)
Aneurysm, Dissecting , Carotid Artery, Internal, Dissection , Stroke , Vertebral Artery Dissection , Adult , Aneurysm, Dissecting/complications , Carotid Artery, Internal, Dissection/etiology , Computed Tomography Angiography/adverse effects , Female , Humans , Incidence , Stroke/diagnostic imaging , Stroke/epidemiology , Stroke/etiology , Vertebral Artery/diagnostic imaging , Vertebral Artery Dissection/complications , Vertebral Artery Dissection/diagnostic imaging , Vertebral Artery Dissection/epidemiology
5.
Curr Opin Endocr Metab Res ; 15: 8-14, 2020 Dec.
Article in English | MEDLINE | ID: mdl-35128145

ABSTRACT

Breast cancers are a diverse group of diseases and are often characterized by their expression of receptors for hormones such as estrogen and progesterone. Recently another steroid hormone receptor, the glucocorticoid receptor (GR) has been shown to be a key player in breast cancer progression, metastasis, and treatment. These receptors bind to chromatin to elicit transcriptional changes within cells, which are often inhibited by the structure of chromatin itself. Chromatin remodeling proteins, such as Brahma-related gene 1 (BRG1), function to overcome this physical inhibition of transcription factor function and have been linked to many cancers including breast cancer. Recent efforts to understand the interactions of BRG1 and GR, including genomic and single cell analyses, within breast cancers may give insight into personalized medicine and other potential treatments.

6.
Arch Sex Behav ; 51(3): 1541-1557, 2022 04.
Article in English | MEDLINE | ID: mdl-35119568

ABSTRACT

The quality of communication between romantic partners has consistently been found to be associated with relationship well-being and stability. Studies on sexual and nonsexual communication, however, have typically assessed communication skills and behaviors using self-report measures. The use of observational methods has several advantages, including the ability to capture and allow for the independent coding of both partners' communication behaviors. With few exceptions, research applying observational methods has not distinguished between sexual and nonsexual communication behaviors. In the present study, we asked 126 young, mixed-sex couples to engage in sexual and nonsexual conflict discussions. The two 7-min discussions were videotaped and rated by trained coders on nine behavioral dimensions using an adaptation of the specific affect coding system (Gottman & Krokoff, 1989) and the system for coding interactions and family functioning (Lindahl & Malik, 2001). Coder ratings applied to the discussion as a whole. Analyses included factor analysis on the behavioral dimensions and multilevel modeling incorporating the actor-partner interdependence model (APIM). We found significant differences in how couples interacted during the two discussions, with more positive (affectionate and validating) and less negative behaviors during sexual discussions as compared to nonsexual discussions. In both women and men, expressions of positivity during the two types of conflict discussions were associated with higher relationship satisfaction. Gender differences were found in the association between negative behaviors during sexual discussions and relationship satisfaction, with men but not women's negative behaviors being associated with lower relationship satisfaction. These findings point at distinct qualities of sexual communication and its association with couples' relational well-being and contribute to a better scientific understanding, with clinical relevance, of sexual and nonsexual communication.


Subject(s)
Personal Satisfaction , Sexual Partners , Communication , Female , Humans , Interpersonal Relations , Male , Pleasure , Sexual Behavior
7.
Tetrahedron ; 1052022 Jan 22.
Article in English | MEDLINE | ID: mdl-35095120

ABSTRACT

The scientific community has found deep interest in anthraquinone-based compounds due to their therapeutic properties and challenging structural elements. Various architecturally beautiful natural products have been successfully synthesized in recent decades utilizing two main strategies: either an early-stage synthesis of the anthraquinone and further elongation of the system, or a late-stage introduction of the anthraquinone ring moiety. Select syntheses of complex anthraquinone monomers and dimers within the past 20 years are described with an emphasis on the retrosynthetic disconnections that shape the anthraquinone-installation strategy.

8.
Mol Cell ; 82(4): 803-815.e5, 2022 02 17.
Article in English | MEDLINE | ID: mdl-35077705

ABSTRACT

The hormone-stimulated glucocorticoid receptor (GR) modulates transcription by interacting with thousands of enhancers and GR binding sites (GBSs) throughout the genome. Here, we examined the effects of GR binding on enhancer dynamics and investigated the contributions of individual GBSs to the hormone response. Hormone treatment resulted in genome-wide reorganization of the enhancer landscape in breast cancer cells. Upstream of the DDIT4 oncogene, GR bound to four sites constituting a hormone-dependent super enhancer. Three GBSs were required as hormone-dependent enhancers that differentially promoted histone acetylation, transcription frequency, and burst size. Conversely, the fourth site suppressed transcription and hormone treatment alleviated this suppression. GR binding within the super enhancer promoted a loop-switching mechanism that allowed interaction of the DDIT4 TSS with the active GBSs. The unique functions of each GR binding site contribute to hormone-induced transcriptional heterogeneity and demonstrate the potential for targeted modulation of oncogene expression.


Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Dexamethasone/pharmacology , Enhancer Elements, Genetic , Gene Expression Regulation, Neoplastic/drug effects , Receptors, Glucocorticoid/agonists , Transcription Factors/metabolism , Transcription, Genetic/drug effects , Binding Sites , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Line, Tumor , Female , Humans , Receptors, Glucocorticoid/genetics , Receptors, Glucocorticoid/metabolism , Signal Transduction , Transcription Factors/genetics
9.
BMC Anesthesiol ; 22(1): 26, 2022 01 18.
Article in English | MEDLINE | ID: mdl-35042468

ABSTRACT

BACKGROUND: Epidural analgesia is conventionally used as the mainstay of analgesia in open abdominal surgery but has a small life-changing risk of complications (epidural abscesses or haematomas). Local wound-infusion could be a viable alternative and are associated with fewer adverse effects. METHODS: A retrospective observational analysis of individuals undergoing open hepato-pancreato-biliary surgery over 1 year was undertaken. Patients either received epidural analgesia (EP) or continuous wound infusion (WI) + IV patient controlled anaesthesisa (PCA) with an intraoperative spinal opiate. Outcomes analyzed included length of stay, commencement of oral diet and opioid use. RESULTS: Between Jan 2016- Dec 2016, 110 patients were analyzed (WI n=35, EP n=75). The median length of stay (days) was 8 in both the WI and EP group (p=0.846), the median time to commencing oral diet (days) was 3 in WI group and 2 in EP group (p=0.455). There was no significant difference in the amount of oromorph, codeine or tramadol (mg) between WI and EP groups (p=0.829, p=0.531, p=0.073, respectively). CONCLUSIONS: Continuous wound infusion + IV PCA provided adequate analgesia to patients undergoing open hepato-pancreato-biliary surgery. It was non-inferior to epidural analgesia with respect to hospital stay, commencement of oral diet and opioid use.


Subject(s)
Analgesia, Epidural/methods , Analgesics, Opioid/administration & dosage , Anesthetics, Local/administration & dosage , Digestive System Surgical Procedures/methods , Pain, Postoperative/drug therapy , Aged , Analgesia, Patient-Controlled/methods , Female , Humans , Infusions, Parenteral , Length of Stay/statistics & numerical data , Male , Middle Aged , Pain Management/methods , Patient Satisfaction/statistics & numerical data , Retrospective Studies , Treatment Outcome
10.
Osteoarthritis Cartilage ; 30(4): 605-612, 2022 04.
Article in English | MEDLINE | ID: mdl-35032627

ABSTRACT

OBJECTIVE: The human meniscus is essential in maintaining proper knee joint function. The meniscus absorbs shock, distributes loads, and stabilizes the knee joint to prevent the onset of osteoarthritis. The extent of its shock-absorbing role can be estimated by measuring the energy dissipated by the meniscus during cyclic mechanical loading. METHODS: Samples were prepared from the central and horn regions of medial and lateral human menisci from 8 donors (both knees for total of 16 samples). Cyclic compression tests at several compression strains and frequencies yielded the energy dissipated per tissue volume. A GEE regression model was used to investigate the effects of compression, meniscal side and region, and water content on energy dissipation in order to account for repeated measures within samples. RESULTS: Energy dissipation by the meniscus increased with compressive strain from ∼0.1 kJ/m3 (at 10% strain) to ∼10 kJ/m3 (at 20% strain) and decreased with loading frequency. Samples from the anterior region provided the largest energy dissipation when compared to central and posterior samples (P < 0.05). Water content for the 16 meniscal tissues was 77.9 (C.I. 72.0-83.8%) of the total tissue mass. A negative correlation was found between energy dissipation and water content (P < 0.05). CONCLUSION: The extent of energy dissipated by the meniscus is inversely related to loading frequency and meniscal water content.


Subject(s)
Menisci, Tibial , Meniscus , Humans , Knee , Knee Joint , Water
11.
Sci Adv ; 7(46): eabi8178, 2021 Nov 12.
Article in English | MEDLINE | ID: mdl-34757788

ABSTRACT

Aptamer-based proteomics revealed differentially abundant proteins in Alzheimer's disease (AD) brains in the Baltimore Longitudinal Study of Aging and Religious Orders Study (mean age, 89 ± 9 years). A subset of these proteins was also differentially abundant in the brains of young APOE ε4 carriers relative to noncarriers (mean age, 39 ± 6 years). Several of these proteins represent targets of approved and experimental drugs for other indications and were validated using orthogonal methods in independent human brain tissue samples as well as in transgenic AD models. Using cell culture­based phenotypic assays, we showed that drugs targeting the cytokine transducer STAT3 and the Src family tyrosine kinases, YES1 and FYN, rescued molecular phenotypes relevant to AD pathogenesis. Our findings may accelerate the development of effective interventions targeting the earliest molecular triggers of AD.

12.
Proc Natl Acad Sci U S A ; 118(43)2021 10 26.
Article in English | MEDLINE | ID: mdl-34686593

ABSTRACT

Many viruses directly engage and require the dynein-dynactin motor-adaptor complex in order to transport along microtubules (MTs) to the nucleus and initiate infection. HIV type 1 (HIV-1) exploits dynein, the dynein adaptor BICD2, and core dynactin subunits but unlike several other viruses, does not require dynactin-1 (DCTN1). The underlying reason for HIV-1's variant dynein engagement strategy and independence from DCTN1 remains unknown. Here, we reveal that DCTN1 actually inhibits early HIV-1 infection by interfering with the ability of viral cores to interact with critical host cofactors. Specifically, DCTN1 competes for binding to HIV-1 particles with cytoplasmic linker protein 170 (CLIP170), one of several MT plus-end tracking proteins (+TIPs) that regulate the stability of viral cores after entry into the cell. Outside of its function as a dynactin subunit, DCTN1 also functions as a +TIP that we find sequesters CLIP170 from incoming particles. Deletion of the Zinc knuckle (Zn) domain in CLIP170 that mediates its interactions with several proteins, including DCTN1, increased CLIP170 binding to virus particles but failed to promote infection, further suggesting that DCTN1 blocks a critical proviral function of CLIP170 mediated by its Zn domain. Our findings suggest that the unique manner in which HIV-1 binds and exploits +TIPs to regulate particle stability leaves them vulnerable to the negative effects of DCTN1 on +TIP availability and function, which may in turn have driven HIV-1 to evolve away from DCTN1 in favor of BICD2-based engagement of dynein during early infection.


Subject(s)
Dynactin Complex/physiology , HIV Infections/physiopathology , HIV Infections/virology , HIV-1/physiology , Host Microbial Interactions/physiology , Microtubule-Associated Proteins/physiology , Neoplasm Proteins/physiology , Binding, Competitive , Cell Line , Dynactin Complex/antagonists & inhibitors , Dynactin Complex/genetics , Gene Knockdown Techniques , HEK293 Cells , HIV-1/pathogenicity , HeLa Cells , Humans , Jurkat Cells , Microglia/virology , Microtubule-Associated Proteins/chemistry , Models, Biological , Neoplasm Proteins/chemistry , Protein Domains , RNA, Small Interfering/genetics
14.
Environ Entomol ; 50(6): 1276-1285, 2021 12 17.
Article in English | MEDLINE | ID: mdl-34554252

ABSTRACT

Reducing the use of synthetic fertilizers and pesticides can limit negative impacts of agriculture on insects and is a crucial step towards sustainable agriculture. In the United States, organic agriculture has the potential to reduce greenhouse gas emissions, pollutant runoff, and biodiversity loss in the Midwestern Corn Belt-an area extending over 500,000 km2 devoted to intensive production of corn Zea mays (Linnaeus 1753) (Poales: Poaceae), often in rotation with soy Glycine max (Linnaeus 1753) (Fabales: Fabaceae) or wheat Triticum aestivum (Linnaeus 1753) (Poales: Poaceae). Working in 30-yr-long landscape experiments in this region, we tested for impacts of conventional versus organic agriculture on ant communities (Hymenoptera: Formicidae) and potential ecosystem services they provide. Organic fields supported higher ant diversity and a slightly more species-rich ant assemblage than conventionally managed fields but did not otherwise differ in community composition. Despite similar community composition, organic and conventional fields differed in seasonal patterns of ant foraging activity and potential for natural pest suppression. Conventional plots experienced higher overall ant foraging activity, but with the timing skewed towards late in the growing season such that 75% of ant foraging occurred after crop harvest in a wheat year and was therefore unavailable for pest suppression. Organic fields, in contrast, experienced moderate levels of ant foraging activity throughout the growing season, with most foraging occurring during crop growth. Organic fields thus supported twice as much pest suppression potential as conventional fields. Our results highlight the importance of timing in mediating ecosystem services in croplands and emphasize the value of managing landscapes for multiple services rather than yield alone.


Subject(s)
Ants , Zea mays , Agriculture , Animals , Biodiversity , Ecosystem , Organic Agriculture , United States
15.
Kathmandu Univ Med J (KUMJ) ; 17(58): 185-187, 2017.
Article in English | MEDLINE | ID: mdl-34547855

ABSTRACT

Abdominal wall scar endometrioma is an uncommon clinical entity, which presents with lump and cyclical abdominal pain during menstruation, which develops after caesarean section or gynaecological procedures. Differential diagnosis includes a haematoma, desmoid tumour, incisional hernia, sarcoma, metastatic malignancies and suture granuloma. Adenocarcinoma developing from abdominal wall scar endometrioma are aggressive and carry poor prognosis. An awareness of this clinical entity is important to establish its diagnosis early and ultrasound scan, magnetic resonance scan, or a computerised tomographic-guided localization followed by surgical excision provides best outcome. Here in, a case of abdominal wall scar endometrioma is reported and review of pertinent literature is presented.

16.
Bioorg Chem ; 116: 105250, 2021 11.
Article in English | MEDLINE | ID: mdl-34469833

ABSTRACT

1,2,3-triazole heterocycles stand out in medicinal chemistry for having great structural diversity and bioactivities. In this study, two series of triazoles were synthesized. One was obtained by the 1,3-dipolar cycloaddition reaction between ethyl cyanoacetate and several phenyl azides forming 1H-1,2,3-triazoles and the other by rearrangement of Dimroth forming and 2H-1,2,3-triazoles. Both series were shown to be active against the epimastigote form of Trypanosoma cruzi. The 1,2,3-triazoles 16d (S.I. between 100 and 200), 17d and 16f (S.I. > 200) were the most active compounds and capable of breaking the plasma membrane of trypomastigotes acting on CYP51 and inhibiting ergosterol synthesis. Candidate 16d exhibited the best and most favorable profile when interacting with CYP51.


Subject(s)
Chagas Disease/drug therapy , Triazoles/pharmacology , Trypanocidal Agents/pharmacology , Trypanosoma cruzi/drug effects , Animals , Dose-Response Relationship, Drug , Male , Mice , Molecular Structure , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/chemistry , Trypanocidal Agents/chemical synthesis , Trypanocidal Agents/chemistry
17.
J Org Chem ; 86(16): 11237-11262, 2021 08 20.
Article in English | MEDLINE | ID: mdl-34288689

ABSTRACT

This manuscript describes our studies of the class of natural products known as the rubellins, culminating in the total synthesis of (+)-rubellin C. These anthraquinone-based natural products contain a variety of stereochemical and architectural motifs, including a 6-5-6-fused ring system, 5 stereogenic centers, and a central quaternary center. Herein, we report our development of a strategy to target the stereochemically dense core and anthraquinone nucleus, including approaches such as a bifunctional allylboron and vinyl triflate reagent, an anthraquinone benzylic metalation strategy, and a late-stage anthraquinone introduction strategy. Our studies culminate in a successful route to highly functionalized anthraquinone-based natural product scaffolds and a stereoselective total synthesis of (+)-rubellin C. These strategies and outcomes will aid in synthetic planning toward anthraquinone-based natural products of high interest.


Subject(s)
Biological Products , Bufanolides , Indicators and Reagents , Stereoisomerism
18.
Afr. j. lab. med. (Online) ; 1(1): 1-5, 2012. ilus
Article in English | AIM (Africa), AIM (Africa) | ID: biblio-1257287

ABSTRACT

Objective: To determine if use of basic laboratory tests improves diagnosis and treatment outcomes in outpatients attending rural primary health care facilities. Setting: Six rural health centres in Kenya.Design: Cross-sectional study to observe change in diagnosis and treatment made by clinical officers after laboratory testing in outpatients attending six rural health centres in Kenya.Subject: The diagnosis and treatment of 1134 patients attending outpatient services in six rural health centres were compared before and after basic laboratory testing. Essential clinical diagnostic equipment and laboratory tests were established at each health centre. Clinical officers and laboratory technicians received on-site refresher training in good diagnostic practices and laboratory procedures before the study began. Results: Laboratory tests were ordered on 704 (62.1) patients. Diagnosis and treatment were changed in 45of tested patients who returned with laboratory results (21 of all patients attending the clinics). 166 (23.5 of all patients attending the clinics). 166 (23.5) patients did not return to the clinician for a final diagnosis and management decision after laboratory testing. Blood slide examination for malaria parasites; wet preparations; urine microscopy and stool microscopy resulted in most changes to diagnosis. There was no significant change in drug costs after laboratory testing. The greatest changes in numbers of recorded diseases following laboratory testing was for intestinal worms (53) and malaria (21). Conclusion: Effective use of basic laboratory tests at primary health care level significantly improves diagnosis and patient treatment. Use of laboratory testing can be readily incorporated into routine clinical practice. On-site refresher training is an effective means of improving the quality of patient care and communication between clinical and laboratory staff


Subject(s)
Diagnostic Techniques and Procedures , Laboratories , Primary Health Care , Rural Health , Treatment Outcome
19.
Injury ; 52(8): 2403-2406, 2021 Aug.
Article in English | MEDLINE | ID: mdl-34176637

ABSTRACT

INTRODUCTION: Evidence regarding recommendations for treatment of ballistic fractures remains limited. This paucity of literature has largely been attributed to gunshot wound victims being a difficult population to study secondary to loss to follow-up. The purpose of this study was to examine the epidemiology of operatively treated ballistic femur fractures at our institution, the frequency of outpatient follow-up and risk factors for loss to follow-up. METHODS: Inpatient consults from 2013-2018 were queried for femoral gunshot wounds treated operatively. Cases without internal or external fixation were excluded from the study. Postoperative visits where a patient was hospitalized or had expired were excluded from the analysis. Demographic information, length of hospital stay, and operative characteristics were compared for different fixation methods and examined as risk factors for loss to follow-up. RESULTS: A total of 194 patients met inclusion criteria. The average age was 27 years old and 94% of the patients were male. Patient's stayed a median of 5 days post-operatively with patients treated with external fixation staying longer than internal fixation (14 days vs 5 days p=0.01). 9.3% of ballistic fractures had a concomitant vascular injury necessitating repair. 70.4% of patients attended their 2-week postoperative visit, 55.7% of patients attended their 6 week follow-up visit and 31.3% attended their 3 month follow-up visit. Risk factors for loss to follow-up at 3 month visit included younger age (p=0.028), decreased hospital length of stay (p=0.025) and intramedullary fixation (p=0.00015). DISCUSSION AND CONCLUSION: This study reinforces the difficulty of studying ballistic fractures secondary to loss to follow-up. Younger age, shorter hospital stays and intramedullary fixation increased the risk for loss to follow-up at 3 months.


Subject(s)
Femoral Fractures , Fracture Fixation, Intramedullary , Wounds, Gunshot , Adult , Femoral Fractures/epidemiology , Femoral Fractures/surgery , Femur , Follow-Up Studies , Fracture Fixation, Intramedullary/adverse effects , Humans , Infant , Male , Retrospective Studies , Risk Factors , Wounds, Gunshot/epidemiology , Wounds, Gunshot/surgery
20.
Aging (Albany NY) ; 13(12): 15750-15769, 2021 06 08.
Article in English | MEDLINE | ID: mdl-34102611

ABSTRACT

Cellular senescence is linked to chronic age-related diseases including atherosclerosis, diabetes, and neurodegeneration. Compared to proliferating cells, senescent cells express distinct subsets of proteins. In this study, we used cultured human diploid fibroblasts rendered senescent through replicative exhaustion or ionizing radiation to identify proteins differentially expressed during senescence. We identified acid ceramidase (ASAH1), a lysosomal enzyme that cleaves ceramide into sphingosine and fatty acid, as being highly elevated in senescent cells. This increase in ASAH1 levels in senescent cells was associated with a rise in the levels of ASAH1 mRNA and a robust increase in ASAH1 protein stability. Furthermore, silencing ASAH1 in pre-senescent fibroblasts decreased the levels of senescence proteins p16, p21, and p53, and reduced the activity of the senescence-associated ß-galactosidase. Interestingly, depletion of ASAH1 in pre-senescent cells sensitized these cells to the senolytics Dasatinib and Quercetin (D+Q). Together, our study indicates that ASAH1 promotes senescence, protects senescent cells, and confers resistance against senolytic drugs. Given that inhibiting ASAH1 sensitizes cells towards senolysis, this enzyme represents an attractive therapeutic target in interventions aimed at eliminating senescent cells.


Subject(s)
Acid Ceramidase/metabolism , Cellular Senescence , Fibroblasts/cytology , Fibroblasts/enzymology , Acid Ceramidase/genetics , Cell Line , Cell Proliferation/genetics , Cell Survival , Ceramides/metabolism , Gene Silencing , Humans , Metabolome , Protein Biosynthesis/genetics , RNA Stability/genetics
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