DLD
Dihydrolipoyl dehydrogenase, mitochondrial precursor (EC 1.8.1.4) (Dihydrolipoamide dehydrogenase) (Glycine cleavage system L protein) [GCSL] [LAD] [PHE3]
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People with Down syndrome (DS) develop Alzheimer's disease (AD) at an earlier age of onset than those with sporadic AD. AD neuropathology is typically present in DS by 40 years of age with an onset of dementia approximately 10 years later. This early onset is due to the overexpression of amyloid precursor protein from the third copy of chromosome 21. Cerebrovascular neuropathology is thought to contribute in 40-60% of cases sporadic AD. However, the vascular contribution to dementia in people with DS has been relatively unexplored. We hypothesised that vascular perfusion is compromised in older adults with DS relative to younger individuals and is further exacerbated in those with dementia. Cerebral blood flow (CBF) was measured using pulsed arterial spin labelling in 35 cognitively characterised adults with DS (26-65 years). DS participants were also compared with 15 control subjects without DS or dementia (26-65 years). Linear regression evaluated the difference in CBF across groups and diagnosis along with assessing the association between CBF and cognitive measures within the DS cohort. Cerebral blood flow was significantly lower among DS participants with probable AD compared with controls (P = 0.02) and DS participants with no dementia (P = 0.01). Within the DS cohort, CBF was significantly associated with the Severe Impairment Battery (SIB) measure and the Dementia Questionnaire for People with Learning Disabilities (DLD) rating (F = 5.13; P = 0.007). Both the SIB (β = 0.74; t = 2.71; P = 0.01) and DLD (β = -0.96; t = -3.87; P < 0.001) indicated greater impairment as global CBF decreased. Age was significantly associated with CBF among participants with DS. There was a non-linear effect of age, whereby CBF declined more rapidly after 45 years of age. This preliminary study of CBF in DS indicates that cerebrovascular pathology may be a significant contributor to dementia in DS. CBF was associated with diagnosis, cognition and age. Notably, CBF decreases at a greater rate after age 45 and may represent a significant prodromal event in AD progression.
Keywords
- Alzheimer's disease
- Down syndrome
- aging
- cerebral blood flow
- neuroimaging
Cancer, and particularly colon cancer, is associated with an increasing number of cases resistant to chemotherapy. One approach to overcome this, and to improve the prognosis and outcome of patients, is the use of adjuvant therapy alongside the standard chemotherapy regiment. In the present study, the effect of deuterium-depleted water (DDW) as a potential modulator of adjuvant therapy on DLD-1 colorectal cancer models was assessed. A number of functionality assays were performed, including MTT, apoptosis and autophagy, and mitochondrial activity and senescence assays, in addition to assessing the capacity to modify the pattern of released miRNA via microarray technology. No significant effect on cell viability was identified, but an increase in mitochondrial activity and a weak pro-apoptotic effect were observed in the treated DLD-1 cells cultured in DDW-prepared medium compared with those grown in standard conditions (SC). Furthermore, the findings revealed the capacity of DDW medium to promote senescence to a higher degree compared with SC. The exosome-released miRNA pattern was significantly modified for the cells maintained in DDW compared with those maintained in SC. These findings suggest that DDW may serve as an adjuvant treatment; however, a better understanding of the underlying molecular mechanism of action will be useful for developing novel and efficient therapeutic strategies, in which the transcriptomic pattern serves an important role.
Keywords
- adjuvant therapy
- cell death
- colorectal cancer
- exosomal miRNAs pattern
- senescence
Immature auditory processing has been proposed to underlie language impairments in children with developmental language disorder (DLD; also known as specific language impairment). Using newly available normative auditory evoked potential (AEP) waveforms, we estimated AEP maturity in individual children with DLD and explored whether this maturational index was related to their language abilities. AEPs were elicited by 225 trials of a 490-Hz pure tone. Using intraclass correlation and our previously established normative AEP waveforms of 7- to 10-year-old children with typical development, we estimated the age equivalent of the AEPs (AEP-age) from 21 children with DLD. The relation between AEP maturity and language was explored through regression analysis. AEP-age predicted 31% of the variance in the language abilities of children with DLD. The AEP-age of children with mild DLD was similar to their chronological age, whereas children with moderate-severe DLD showed, on average, a 1.3-year delay in their neural responses. AEP-age predicted receptive, but not expressive, language performance. Maturation in auditory neural responses is a significant predictor of language ability, particularly in children with moderate-severe DLD.
MeSH Terms
- Age Factors
- Aging
- Child
- Child Language
- Electroencephalography
- Evoked Potentials, Auditory
- Female
- Humans
- Language Development Disorders
- Male
- Regression Analysis
A number of patients exhibit peritoneal dissemination of gastric or colorectal cancer, which is a predominant cause of cancer-associated mortality. Currently, there is no markedly effective treatment available. The present study was designed to determine the efficacy of trifluridine/tipiracil (TFTD), formerly known as TAS-102, which is used for the treatment of patients with unresectable advanced or recurrent colorectal cancer refractory to standard therapies. Four colorectal cancer cell lines and one gastric cancer cell line were intraperitoneally inoculated into nude mice, as models of peritoneal dissemination. TFTD (200 mg/kg/day) was orally administered for 5 consecutive days followed by 2 drug-free days for 6 weeks. The increase in the lifespan (ILS) of the TFTD-treated mice compared with that of the drug-free control mice was 66.7, 43.3, 106.3, 98.3 and 133.3% for DLD-1, DLD-1/5-fluorouracil [5-fluorouracil (5FU)-resistant subline of DLD-1], HT-29 and HCT116 colorectal cancer cell lines, and MKN45 gastric cancer cell line, respectively. This ILS was similar to that of the irinotecan-treated mice (ILS, 70-84%), but was significantly (P<0.05) increased compared with that of the 5FU-, tegafur, gimeracil and potassium oxonate- and cisplatin-treated mice (ILS, 1-53%, 0.8-60% and 85%, respectively). No significant increase in body weight loss was observed during the dosing periods with any of the drugs used. The increase in CEA levels with progressive peritoneal dissemination was inhibited by TFTD treatment. TFTD also exhibited marked anticancer effects against Kirsten rat sarcoma viral oncogene homolog-mutated tumors and 5FU-resistant tumors. The results of the present study indicate that TFTD may be a potential drug against peritoneal dissemination of colorectal and/or gastric cancer in humans and may be utilized for chemo-naïve tumors and recurrent tumors following 5FU treatment.
Keywords
- TAS-102
- colorectal cancer
- gastric cancer
- increase in lifespan
- tipiracil
- trifluridine
Mit mutations that disrupt function of the mitochondrial electron transport chain can, inexplicably, prolong Caenorhabditis elegans lifespan. In this study we use a metabolomics approach to identify an ensemble of mitochondrial-derived α-ketoacids and α-hydroxyacids that are produced by long-lived Mit mutants but not by other long-lived mutants or by short-lived mitochondrial mutants. We show that accumulation of these compounds is dependent on concerted inhibition of three α-ketoacid dehydrogenases that share dihydrolipoamide dehydrogenase (DLD) as a common subunit, a protein previously linked in humans with increased risk of Alzheimer's disease. When the expression of DLD in wild-type animals was reduced using RNA interference we observed an unprecedented effect on lifespan - as RNAi dosage was increased lifespan was significantly shortened, but, at higher doses, it was significantly lengthened, suggesting that DLD plays a unique role in modulating length of life. Our findings provide novel insight into the origin of the Mit phenotype.
MeSH Terms
- Animals
- Caenorhabditis elegans
- Caenorhabditis elegans Proteins
- Dihydrolipoamide Dehydrogenase
- Longevity
- Mutation
The aim of this study was to assess the accuracy of ultrasound measurements for predicting carcass traits in 124 Spanish pascual-type lambs (13 to 16 kg carcass weight). Ultrasound images were taken transversal and longitudinal to the vertebral column and at thoracic (TV; between 12th and 13th ribs) and lumbar (LV; between first and second lumbar vertebrae) locations. Skin thickness, subcutaneous backfat thickness (BFT), and depth (DLD), width (WLD), and area (ALD) of longissimus dorsi were obtained with ImageJ 1.42q software. After slaughter, BFT (TV, 2.30 ± 0.06 mm; LV, 2.46 ± 0.06 mm), DLD (TV, 2.47 ± 0.03 cm; LV, 2.48 ± 0.03 cm), WLD (TV, 4.50 ± 0.04 cm; LV, 4.60 ± 0.04 cm), and ALD (TV, 9.96 ± 0.12 cm(2); LV, 10.19 ± 0.13 cm(2)) were directly measured on the lamb carcass. Correlations between ultrasound and direct carcass measurements were greater than 0.61 for DLD, WLD, and ALD (P < 0.05) whereas they fluctuated between 0.32 and 0.60 for BFT (P < 0.05); moreover, correlations were significantly (P < 0.05) greater for transversal than for longitudinal views. In a similar way, linear regression analyses suggested a moderate underestimation for BFT and lumbar DLD when using real-time ultrasound technologies whereas WLD, ALD, and thoracic DLD suffered from under- and overestimation for small and large values of carcass traits, respectively. After decomposing the mean square prediction error (MSPE) for the different ultrasound measurements, we found that the error due to disturbance contributed most to the MSPE followed by the error of central tendency and the error due to regression. The SE of prediction (SEP) was also calculated as an additional precision indicator, obtaining estimates less than that in previous studies with larger lambs. In conclusion, transversal ultrasound measurements at the thoracic and lumbar levels could be a useful tool for predicting DLD, WLD, and ALD in light lambs, perhaps suffering from worse prediction properties when focusing on BFT. This information could be of special relevance for light lamb producers worldwide, with a special emphasis in the Mediterranean basin where this kind of production system accounts for a large percentage of the sheep industry.
MeSH Terms
- Adipose Tissue
- Aging
- Animal Husbandry
- Animals
- Female
- Linear Models
- Male
- Muscle, Skeletal
- Sheep, Domestic
- Ultrasonography
To elucidate the involvement of NO in pain transmission in humans, we measured NO metabolites (nitrite/nitrate) in the CSF of patients with painful diseases using an NO analyzer based on the Griess method. The nitrite/nitrate levels in patients with degenerative lumbar disease (DLD), but not those with fracture or appendicitis, were significantly higher than those in an age-matched control group. The duration of pain in the DLD group was much longer than that in the fracture or appendicitis group. The nitrite/nitrate levels in the middle-aged and elderly DLD patients depended on the duration of pain. These data probably suggest that the duration of pain is critical for the elevation in nitrite/nitrate levels.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Appendicitis
- Female
- Fractures, Bone
- Humans
- Lumbosacral Region
- Male
- Middle Aged
- Nitrates
- Nitrites
- Osmolar Concentration
- Pain
- Spinal Diseases
- Time Factors
The area occupied by Sertoli cell lipid inclusions--electron-lucent lipid vacuoles (LLV) and electron-dense lipid droplets (DLD)--at each stage of the cycle of the seminiferous epithelium was measured on electron micrographs in young adults and elderly men, and expressed as the ratio "area occupied by lipid inclusions/area occupied by the Sertoli cell cytoplasm". For LLV this ratio increased from stage I to stage III, and decreased from stage IV to stage VI in young adults. These results suggest that the development of LLV is synchronized with the spermatogenic process: the residual bodies released in stages I and II are phagocytized by Sertoli cells and transformed into LLV; the amounts of LLV decrease in the subsequent stages of the cycle and increase again when new residual bodies appear. In elderly men the ratio LLV/Sertoli cell cytoplasm was 1.9-2.9 times higher than in young adults at each stage of the cycle. This increase may be related to the increased germ-cell degeneration observed in ageing testes, DLD were less abundant than LLV and the DLD/Sertoli cell cytoplasm ratio did not undergo cyclic changes in young adults or elderly men.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Cytoplasm
- Humans
- Inclusion Bodies
- Male
- Microscopy, Electron
- Middle Aged
- Seminiferous Epithelium
- Sertoli Cells
- Testis