MME
Neprilysin (EC 3.4.24.11) (Atriopeptidase) (Common acute lymphocytic leukemia antigen) (CALLA) (Enkephalinase) (Neutral endopeptidase 24.11) (NEP) (Neutral endopeptidase) (Skin fibroblast elastase) (SFE) (CD10 antigen) [EPN]
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Opioid harm reduction is increasingly important in the care of the older adults, who are at higher risk for negative opioid-related outcomes due to high prevalence of pain, multimorbidity, polypharmacy, and age-changes in metabolism. Our project aims to develop, implement, and evaluate an interprofessional opioid harm reduction service training. This evaluation occurs in context of the Richmond Health and Wellness Program (RHWP), a community-based interprofessional wellness care coordination equity initiative, within buildings designated for low-income and disabled older adults. The geriatric opioid harm reduction training was delivered online and inperson, and followed up with case-discussions and practice. Pre ([i]n[/i] = 69)/post ([i]n[/i] = 62) student assessments indicated that after the training, there was an increase in knowledge. At follow-up, 60% recognized tramadol as an opioid, 50% at baseline. About 97% correctly indicated that MME represents morphine milligram equivalent, 80% at baseline. About 93% indicated that 50 MME level greatly increases opioid overdose risk, 62% at baseline. Only 20%, change from 60% at baseline, reported not being able to calculate MME at post assessment. Findings indicate that geriatric opioid harm reduction training within community-based wellness care coordination is feasible. Future works need to explore the impact on student practice in clinical settings and resident health.
Keywords
- aging
- older adults
- opioid harm reduction
- overdose risk
Geriatric fracture patients are at risk for poorly controlled pain and side effects of opioid medications. The arthroplasty literature has demonstrated that infiltration of long-acting local anesthetic or anesthetic cocktails improves pain control and reduces post-operative opioid use resulting in better postoperative mobility without the deleterious effects of narcotics. Despite having a higher risk for adverse events, there is limited data among geriatric trauma patients. The aim this study was to evaluate whether local anesthetic infiltration (LAI) into the soft tissues surrounding the surgical field reduces narcotic use or pain scores in patients undergoing surgical management of proximal and diaphyseal femur fractures. A retrospective review was performed of patients age >65 undergoing operative intervention for proximal and diaphyseal femur fracture. The electronic record was utilized to determine if local anesthetic was injected into the surgical wound, the amount of narcotics administered over 48 h in four-hour intervals, and to obtain visual analog scale (VAS) pain scores associated with patients post-operative course in four-hour intervals. The amount of narcotics was converted to morphine milligram equivalents (MME). Among 477 patients with femur fracture, 358 did not receive LAI and 119 patients received LAI. Baseline demographics, fracture types, and surgical procedure were equivalent between the groups. In the first 28 h following surgery, compared with those who did not receive LAI, those who did required significantly less opioid (57.8 MME versus 94.3 MME, p = 0.034) and despite decreased narcotics, had equal pain scores (mean difference 0.37, p = 0.22). There was no difference in rates of post-operative complications. LAI is associated with a reduction in opioid consumption in geriatric fracture patients with equivalent pain scores. Optimizing pain control is a critical issue in caring for geriatric fracture patients since both under-treated pain and opioid medications are implicated in postoperative delirium, complications, and ability to mobilize early. More research is needed to identify effective ways to optimize pain management in this at-risk patient population.
MeSH Terms
- Aged
- Aged, 80 and over
- Analgesics, Opioid
- Anesthetics, Local
- Delirium
- Female
- Femoral Fractures
- Fracture Fixation, Internal
- Geriatrics
- Humans
- Injections, Intra-Articular
- Intraoperative Care
- Male
- Pain Management
- Pain, Postoperative
- Retrospective Studies
Keywords
- Geriatrics
- Hip fracture
- Local anesthetic
- Narcotics
The hotspot mutation H1047R in the oncogenic PIK3CA gene is frequently detected in breast cancer and enhances the enzymatic activity of PI3K to activate AKT/mTOR signaling cascade. Aberrant elevated PI3K activation has been reported to promote the tumorigenesis of breast cancer, but the mechanisms underlying are still needed to be elucidated. Here, we found that continuously activating PIK3CA conferred human mammary epithelial MCF-10A cells to cellular senescence upon serum-starvation. Similarly, breast cancer T47D and HCC1954 cells harboring H1047R mutation were senescent when cells were deprived of serum. PI3K/AKT/mTOR axis but not p53 or RB might be required for the induction of senescence. Notably, membrane metallo-endopeptidase (MME) was identified as a downstream effector of PI3K to mediate the induction of senescence, which might be associated with its glycosylation. Senescent cells elicited a distinct secretome dependent on PI3K and MME. Specifically, IL-6 promoted the proliferation of normal cells and CCL2 induced the M2-like polarization of macrophages, which might create an immunosuppressive microenvironment during the initiation and/or development of breast cancer. This study shed new light on the tumorigenesis induced by hyper-activated PI3K and might provide new clues for the prevention and therapy of breast cancer.
MeSH Terms
- Animals
- Breast Neoplasms
- Cell Line, Tumor
- Cell Proliferation
- Cellular Senescence
- Chemokine CCL2
- Class I Phosphatidylinositol 3-Kinases
- Epithelial Cells
- Glycosylation
- Humans
- Interleukin-6
- Mammary Glands, Human
- Metalloendopeptidases
- Mice
- Mice, Inbred BALB C
- Proto-Oncogene Proteins c-akt
- TOR Serine-Threonine Kinases
- Tumor Suppressor Protein p53
Keywords
- PI3Kα
- breast cancer
- macrophage
- membrane metallo-endopeptidase
- senescence
Meniscus extrusion has always been described as an indirect sign of meniscus pathology and is associated with a loss of function of the affected meniscus. The current cut-off value of 3 mm displacement is indicated as abnormal and has been determined on magnetic resonance images (MRI) and ultrasound (US). However, it has to be considered that there is no description of the physiological meniscus extrusion in healthy knees depending on age or different weight-bearing conditions. It was hypothesized that in healthy knees there is a physiological age and BMI dependent meniscal extrusion, and meniscus extrusion depends on different loading conditions. Healthy volunteers with non-symptomatic knee, and no history of knee injuries or operations were included in this prospective cross-sectional study. Exclusion criteria were age < 18years, subjective or objective instability, malalignment and positive medial meniscus test. Secondary exclusion criteria were osteoarthritis ICRS grade 3-4 or signs of meniscus tear on MRI. Every patient underwent standard knee examination following measurement of medial meniscus extrusion (MME) using US. In US extrusion was determined in supine position (unloaded) and in standing position with full weight-bearing and 20° of flexion (loaded). MRI was performed in a neutral knee position to compare ultrasound measurements with the current gold standard. Based on the power calculation of preliminary results a minimum of 70 volunteers was needed. 75 patients were enrolled to this study. The mean US MME was 1.1 mm ± 0.5 mm in supine position and 1.9 mm ± 0.9 mm under full weight-bearing. The mean US Δ-extrusion was 0.8 mm ± 0.6 mm. With rising age, a significant increased MME in US and MRI could be demonstrated (p < 0.001). Furthermore, elevated BMI was significantly correlated to increased US MME under full weight-bearing (p = 0.002) and to US Δ-extrusion (p = 0.003). Based on the results of this study, medial meniscus extrusion is an age-depending phenomenon in healthy knees and depends on various load-bearing conditions. Ultrasound examination of the MME might be favorable compared to MRI due to the ability of dynamic evaluation. As a consequence, the current cut-off value of 3 mm for meniscus pathologies should be reconsidered. III.
MeSH Terms
- Adult
- Aged
- Aging
- Body Mass Index
- Cross-Sectional Studies
- Female
- Healthy Volunteers
- Humans
- Magnetic Resonance Imaging
- Male
- Menisci, Tibial
- Middle Aged
- Posture
- Prospective Studies
- Ultrasonography
- Weight-Bearing
- Young Adult
Keywords
- Dynamic extrusion
- Healthy knee
- MRI
- Meniscal extrusion
- Ultrasound
- Weight-bearing
Axonal polyneuropathies are a frequent cause of progressive disability in the elderly. Common etiologies comprise diabetes mellitus, paraproteinaemia, and inflammatory disorders, but often the underlying causes remain elusive. Late-onset axonal Charcot-Marie-Tooth neuropathy (CMT2) is an autosomal-dominantly inherited condition that manifests in the second half of life and is genetically largely unexplained. We assumed age-dependent penetrance of mutations in a so far unknown gene causing late-onset CMT2. We screened 51 index case subjects with late-onset CMT2 for mutations by whole-exome (WES) and Sanger sequencing and subsequently queried WES repositories for further case subjects carrying mutations in the identified candidate gene. We studied nerve pathology and tissue levels and function of the abnormal protein in order to explore consequences of the mutations. Altogether, we observed heterozygous rare loss-of-function and missense mutations in MME encoding the metalloprotease neprilysin in 19 index case subjects diagnosed with axonal polyneuropathies or neurodegenerative conditions involving the peripheral nervous system. MME mutations segregated in an autosomal-dominant fashion with age-related incomplete penetrance and some affected individuals were isolated case subjects. We also found that MME mutations resulted in strongly decreased tissue availability of neprilysin and impaired enzymatic activity. Although neprilysin is known to degrade β-amyloid, we observed no increased amyloid deposition or increased incidence of dementia in individuals with MME mutations. Detection of MME mutations is expected to increase the diagnostic yield in late-onset polyneuropathies, and it will be tempting to explore whether substances that can elevate neprilysin activity could be a rational option for treatment.
MeSH Terms
- Adipose Tissue
- Adult
- Age of Onset
- Aged
- Aged, 80 and over
- Aging
- Alleles
- Amyloid beta-Peptides
- Animals
- Axons
- Charcot-Marie-Tooth Disease
- DNA Mutational Analysis
- Databases, Genetic
- Dementia
- Exome
- Genes, Dominant
- Heterozygote
- Humans
- Mice
- Middle Aged
- Mutation
- Mutation, Missense
- Neprilysin
- Penetrance
- Polyneuropathies
- Skin
- Sural Nerve
Aging of the kidney is associated with renal damage, in particular mesangial matrix expansion (MME). Identifying the genes involved in this process will help to unravel the mechanisms of aging and aid in the design of novel therapeutic modalities aimed at prevention and regression. In this study, structural changes in glomeruli of 24 inbred mouse strains were characterized in male mice at 6, 12, and 20 months of age. Haplotype association mapping was used to determine genetic loci associated with the presence of MME at 20 months. This analysis identified a significant association with a 200-kb haplotype block on chromosome 6 containing Far2. Sequencing revealed that mouse strains with MME contain a 9-bp sequence in the 5' untranslated region of Far2 that is absent in most of the strains without MME. Real-time PCR showed a two-fold increase in the expression of Far2 in the kidneys of strains with the insert, and subsequent experiments performed in vitro with luciferase reporter vectors showed that this sequence difference causes differential expression of Far2. Overexpression of Far2 in a mouse mesangial cell line induced upregulation of platelet activating factor and the fibrotic marker TGF-β. This upregulation of MME-promoting factors may result, in part, from the FAR2-catalyzed reduction of fatty acyl-coenzyme A to fatty alcohols, which are possible precursors of platelet activating factor. Overall, these data suggest the identification of a novel pathway involved in renal aging that may yield therapeutic targets for reducing MME.
MeSH Terms
- Aging
- Aldehyde Oxidoreductases
- Animals
- Chromosome Mapping
- Haplotypes
- Kidney Glomerulus
- Male
- Mesangial Cells
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Mice, Inbred DBA
- Mice, Inbred MRL lpr
- Mice, Inbred NOD
- Species Specificity