Mitochondrial Complex Abundance, Mitophagy Proteins, and Physical Performance in People With and Without Peripheral Artery Disease.

Background Mitochondrial abnormalities exist in gastrocnemius muscle of people with peripheral artery disease (PAD). Whether abnormalities in mitochondrial biogenesis and autophagy are associated with greater ischemia or walking impairment in PAD is unknown. Methods and Results Protein markers of mitochondrial biogenesis and autophagy and the abundance of mitochondrial electron transport chain complexes were quantified in gastrocnemius muscle biopsies from people with and without PAD. Their 6-minute walk distance and 4-m gait speed were measured. Sixty-seven participants (mean age 65.0 years [±6.8], 16 [23.9%] women, 48 [71.6%] Black) were enrolled, including 15 with moderate to severe PAD (ankle brachial index [ABI] <0.60), 29 with mild PAD (ABI 0.60-0.90), and 23 without PAD (ABI 1.00-1.40). Abundance of all electron transport chain complexes was significantly higher in participants with lower ABI (eg, complex I: 0.66, 0.45, 0.48 arbitrary units [AU], respectively, P trend=0.043). Lower ABI values were associated with a higher LC3A/B II-to-LC3A/B I (microtubule-associated protein 1A/1B-light chain 3) ratio (2.54, 2.31, 2.15 AU, respectively, P trend=0.017) and reduced abundance of the autophagy receptor p62 (0.71, 0.69, 0.80 AU, respectively, P trend=0.033). The abundance of each electron transport chain complex was positively and significantly associated with 6-minute walk distance and 4-m gait speed at usual and fast pace only among participants without PAD (eg, complex I: r=0.541, P=0.008; r=0.477, P=0.021; r=0.628, P=0.001, respectively). Conclusions These results suggest that accumulation of electron transport chain complexes in gastrocnemius muscle of people with PAD may be because of impaired mitophagy in the setting of ischemia. Findings are descriptive, and further study in larger sample sizes is needed.

Let the Kid Speak: Dynamics of Triadic Medical Interactions Involving Pediatric Patients.

Communication in healthcare represents the complex interplay between multiple individual and contextual factors unfolding over the course of the medical encounter. Despite significant improvements in patient-centered care delivery, studies of health communication typically focus exclusively on clinical interactions between adult patients and their clinicians. Much less is known about non-dyadic interactions, such as pediatric triads involving a child patient and accompanying parent. Understanding the dynamics of triadic pediatric healthcare communication is the first step toward evaluating and ultimately optimizing these healthcare interactions. Thus, we undertook a mixed-method analysis of 28 audio-recorded triadic medical interactions between healthcare providers, pediatric asthma and allergy patients, and their parents to explore the prevalence of various features of these interactions. Our findings point to mechanisms through which healthcare providers and parents may facilitate or hinder children's involvement in their own asthma and allergy care, including interruptions, unclarified technical medical language, the flow of information exchange, and the formation of dyadic conversational partnerships (coalitions) between providers and parents. Our analyses further reveal that children's participation during their medical visits was minimal (13% of the interaction). Providers in our sample elicited input directly from pediatric patients more often than from parents, though the difference was small. Taken together, these findings provide a foundation on which to develop training and communication interventions to ensure that children have a voice in their medical care.

Dysregulated Genes, MicroRNAs, Biological Pathways, and Gastrocnemius Muscle Fiber Types Associated With Progression of Peripheral Artery Disease: A Preliminary Analysis.

Background Peripheral artery disease (PAD) is associated with gastrocnemius muscle abnormalities. However, the biological pathways associated with gastrocnemius muscle dysfunction and their associations with progression of PAD are largely unknown. This study characterized differential gene and microRNA (miRNA) expression in gastrocnemius biopsies from people without PAD compared with those with PAD. Participants with PAD included those with and without PAD progression. Methods and Results mRNA and miRNA sequencing were performed to identify differentially expressed genes, differentially expressed miRNAs, mRNA-miRNA interactions, and associated biological pathways for 3 sets of comparisons: (1) PAD progression (n=7) versus non-PAD (n=7); (2) PAD no progression (n=6) versus non-PAD; and (3) PAD progression versus PAD no progression. Immunohistochemistry was performed to determine gastrocnemius muscle fiber types and muscle fiber size. Differentially expressed genes and differentially expressed miRNAs were more abundant in the comparison of PAD progression versus non-PAD compared with PAD with versus without progression. Among the top significant cellular pathways in subjects with PAD progression were muscle contraction or development, transforming growth factor-beta, growth/differentiation factor, and activin signaling, inflammation, cellular senescence, and notch signaling. Subjects with PAD progression had increased frequency of smaller Type 2a gastrocnemius muscle fibers in exploratory analyses. Conclusions Humans with PAD progression exhibited greater differences in the number of gene and miRNA expression, biological pathways, and Type 2a muscle fiber size compared with those without PAD. Fewer differences were observed between people with PAD without progression and control patients without PAD. Further study is needed to confirm whether the identified transcripts may serve as potential biomarkers for diagnosis and progression of PAD.

Time-Restricted Eating Regimen Differentially Affects Circulatory miRNA Expression in Older Overweight Adults.

Time-restricted eating (TRE), a popular form of intermittent fasting, has been demonstrated to provide multiple health benefits, including an extension of healthy lifespan in preclinical models. While the specific mechanisms remain elusive, emerging research indicates that one plausible mechanism through which TRE may confer health benefits is by influencing the expression of the epigenetic modulator circulatory miRNAs, which serve as intercellular communicators and are dysregulated in metabolic disorders, such as obesity. Therefore, the goal of this pilot study is to examine the effects of a 4-week TRE regimen on global circulatory miRNA from older (≥65 years) overweight participants. Pre- and post-TRE regimen serum samples from nine individuals who participated in the Time to Eat clinical trial (NCT03590847) and had a significant weight loss (2.6 kg, p < 0.01) were analyzed. The expressions of 2083 human miRNAs were quantified using HTG molecular whole transcriptome miRNA assay. In silico analyses were performed to determine the target genes and biological pathways associated with differentially expressed miRNAs to predict the metabolic effects of the TRE regimen. Fourteen miRNAs were differentially expressed pre- and post-TRE regimen. Specifically, downregulated miRNA targets suggested increased expression of transcripts, including PTEN, TSC1, and ULK1, and were related to cell growth and survival. Furthermore, the targets of downregulated miRNAs were associated with Ras signaling (cell growth and proliferation), mTOR signaling (cell growth and protein synthesis), insulin signaling (glucose uptake), and autophagy (cellular homeostasis and survival). In conclusion, the TRE regimen downregulated miRNA, which, in turn, could inhibit the pathways of cell growth and activate the pathways of cell survival and might promote healthy aging. Future mechanistic studies are required to understand the functional role of the miRNAs reported in this study.

Effectiveness of Yoga on Quality of Life of Breast Cancer Patients Undergoing Chemotherapy: A Randomized Clinical Controlled Study.

BACKGROUND: Cancer of breast is most common cancer among women in India and vast majority of countries worldwide. While undergoing chemotherapy for carcinoma management, women encounter side effects, which affects their quality of life (QOL). A randomized controlled study with quantitative research approach and time series design was conducted, to study the effectiveness of yoga on QOL of breast cancer patients undergoing chemotherapy. METHODOLOGY: One hundred breast cancer patients scheduled for 3-weekly, day-care adjuvant chemotherapy (CEF regimen) were enrolled with consecutive sampling technique, into control (n = 52) and experiment (n = 48) groups, by concealed randomization following written informed consent. Baseline data on QOL were collected before first-cycle chemotherapy using the European Organization for Research and Treatment of Cancer QLQ C30. Patients in the experimental group were taught diaphragmatic breathing techniques, systematic relaxation, and alternate nostril breathing, and Joints and Glands neck and shoulder exercises were instructed to practice twice daily at home. They were supervised in practicing these techniques while they received second, third, fourth, fifth, and sixth cycles of chemotherapy in the day-care facility. Participants in the control group received only routine care. All participants received standard post chemotherapy prescription. Data on QOL were collected from all patients during the second, third, fourth, fifth, and sixth cycles of chemotherapy. RESULTS: The analysis revealed that at the baseline (first chemotherapy cycle), breast cancer patients in control and experimental groups were homogeneous in terms of their sociodemographic and clinical variables and QOL score. Yoga practices were effective in improving the QOL of breast cancer patients in the experimental group in the areas of global health status, physical function, role function, and emotional function and decreasing the symptoms of fatigue, insomnia, loss of appetite, and constipation, during the period of chemotherapy. CONCLUSION: Yoga practices comprising of relaxation techniques reduce many side effects and improve the QOL of women undergoing chemotherapy for breast cancer.

Altered Expression of Mitoferrin and Frataxin, Larger Labile Iron Pool and Greater Mitochondrial DNA Damage in the Skeletal Muscle of Older Adults.

Mitochondrial dysfunction and iron (Fe) dyshomeostasis are invoked among the mechanisms contributing to muscle aging, possibly via a detrimental mitochondrial-iron feed-forward loop. We quantified the labile Fe pool, Fe isotopes, and the expression of mitochondrial Fe handling proteins in muscle biopsies obtained from young and older adults. The expression of key proteins of mitochondrial quality control (MQC) and the abundance of the mitochondrial DNA common deletion (mtDNA4977) were also assessed. An inverse association was found between total Fe and the heavier Fe isotope (56Fe), indicating an increase in labile Fe abundance in cells with greater Fe content. The highest levels of labile Fe were detected in old participants with a Short Physical Performance Battery (SPPB) score ≤ 7 (low-functioning, LF). Protein levels of mitoferrin and frataxin were, respectively, higher and lower in the LF group relative to young participants and older adults with SPPB scores ≥ 11 (high-functioning, HF). The mtDNA4977 relative abundance was greater in old than in young participants, regardless of SPPB category. Higher protein levels of Pink1 were detected in LF participants compared with young and HF groups. Finally, the ratio between lipidated and non-lipidated microtubule-associated protein 1A/1B-light chain 3 (i.e., LC3B II/I), as well as p62 protein expression was lower in old participants regardless of SPPB scores. Our findings indicate that cellular and mitochondrial Fe homeostasis is perturbed in the aged muscle (especially in LF older adults), as reflected by altered levels of mitoferrin and frataxin, which, together with MQC derangements, might contribute to loss of mtDNA stability.

Mitochondrial DNA damage in calf skeletal muscle and walking performance in people with peripheral artery disease.

BACKGROUND: Peripheral artery disease (PAD) is associated with mitochondrial dysfunction in calf skeletal muscle and a greater abundance of mitochondrial DNA (mtDNA) heteroplasmy. However, it is unknown whether calf skeletal muscle mtDNA of PAD participants harbors a greater abundance of mitochondrial DNA 4977-bp common deletion (mtDNA4977), strand breaks and oxidative damage (i.e., oxidized purines) compared to non-PAD participants and whether these mtDNA abnormalities are associated with poor walking performance in participants with PAD. METHODS: Calf muscle biopsies were obtained from 50 PAD participants (ankle-brachial index (ABI) < 0.95) and 25 non-PAD participants (ABI = 0.99-1.40) matched by age, sex, and race. The abundance of mtDNA copy number, mtDNA4977 deletion, strand breaks, and oxidized purines in selected mtDNA regions coding for electron transport chain (ETC) constituents and the non-coding D-Loop region was determined in calf muscle. All participants completed measurement of 6-min walk and usual and fast-paced 4-m walking velocity test. RESULTS: Participants with PAD (mean age = 65.4 years, SD = 6.9; 14 (28%) women, 38 (76%) black) and without PAD (mean age = 65.2 years, SD = 6.7; 7 (28%) women, 16 (64%) black) did not differ in the abundance of calf muscle mtDNA4977 deletion, mtDNA strand breaks, and oxidized purines. Though, a greater abundance of mtDNA strand breaks within ND4/5 genes was significantly associated with poorer 6-min walk distance, lower usual-paced 4-m walking velocity, and lower fast-paced 4-m walking velocity in non-PAD participants. Significant associations were also found in the density of strand break damage (i.e., damage per mtDNA copy) within ND1/2, ND4/5 and COII/ATPase 6/8 region with 6-min walk distance, usual-paced 4-m walking velocity and fast-paced 4-m walking velocity in non-PAD participants. Significant interactions were found between PAD presence vs. absence and density of strand break damage within ND1/2, ND4/5, COII/ATPase 6/8 regions for the associations with 6-min walk distance, usual-paced 4-m walking velocity, fast-paced 4-m walking velocity. Conversely, of the three walking performance measures only the usual-paced 4-m walking velocity showed a significant, although modest, negative association with the abundance of oxidized purines in the D-Loop (P = 0.031) and ND4/5 (P = 0.033) regions in the calf skeletal muscle of people with PAD. CONCLUSION: Overall, these data suggest that the abundance of calf muscle mtDNA strand breaks and mtDNA4977 common deletion are not associated with walking performance in people with PAD and may not be directly involved in the pathophysiology of PAD. Conversely, strand breaks in specific mtDNA regions may contribute to poor walking performance in people without PAD. Further study is needed to confirm whether usual-paced 4-m walking velocity is associated significantly with a greater abundance of oxidized purines in the D-loop, a "mutational hotspot" for oxidative damage, and why this association may differ from the association with 6-min walk distance and fast-paced 4-m walking velocity.

Associations of Poly (ADP-Ribose) Polymerase1 abundance in calf skeletal muscle with walking performance in peripheral artery disease.

OBJECTIVE: This study investigated associations of markers of oxidative stress and mitochondrial function in calf muscle biopsies with walking performance in people with and without lower extremity peripheral artery disease (PAD). METHODS: Participants with PAD (ankle-brachial index (ABI) <0.90) and without PAD (ABI: 0.90-1.50) underwent calf muscle biopsy and measurement of 6-min walk and four-meter walking velocity. PARP1 (Poly (ADP-Ribose) Polymerase 1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), silent information regulator 1 (SIRT1) and 4-hydroxynonenal (4HNE) expression were measured in calf muscle using western blot. RESULTS: Among 15 participants with PAD mean age: 66.8 years (standard deviation (SD): 6.4) and six without PAD (age: 64.4 years, SD: 5.9), mean PARP1-abundance in calf muscle was 1.16 ± 0.92 AU and 0.96 ± 0.38 AU, respectively (P = 0.61). Among participants with PAD after adjustment with ABI, a greater abundance of PARP1 was associated with poorer 6-min walking distance (r = -0.65, P = 0.01), usual-paced 4-m walking velocity (r = -0.73, P = 0.003) and slower fast-paced four-meter walking velocity (r = -0.51, P = 0.07). Among participants with PAD, ABI was not associated with PARP1 abundance in calf muscle (r = 0.02, P = 0.93). Among participants without PAD, skeletal muscle PARP1 abundance was not significantly associated with 6-min walk distance (r = -0.58; P = 0.22), usual-paced walking velocity (r = -0.26; P = 0.62), or fast-paced walking velocity (r = -0.21; P = 0.69), perhaps due to lack of statistical power. There were no associations of remaining calf muscle measures with walking performance. CONCLUSIONS: These findings are consistent with the hypothesis that calf skeletal muscle characteristics are related to walking performance, independently of severity of lower extremity arterial obstruction in people with PAD.

Nicotinamide riboside-A missing piece in the puzzle of exercise therapy for older adults?

Maintaining physical mobility is important for preventing age-related comorbidities in older adults. Endurance and resistance training prevent mobility loss in aging, but exercise alone does not always achieve the expected improvements in physical and cardiopulmonary function. Recent preclinical evidence suggests that a reason for the variability in exercise training responses may be the age-related dysregulation of the nicotinamide adenine dinucleotide (NAD+) metabolome. NAD+ is an essential enzymatic cofactor in energetic and signaling pathways. Endogenous NAD+ pool is lower in several chronic and degenerative diseases (e.g., cardiovascular diseases, Alzheimer's and Parkinson's diseases, muscular dystrophies), and also in aging. Exercise requires a higher energy expenditure than a resting state, thus a state of NAD+ insufficiency with reduced energy metabolism, could result in an inadequate exercise response. Recently, the NAD+ precursor nicotinamide riboside (NR), a vitamin B3 derivate, showed an ability to improve NAD+ metabolome homeostasis, restoring energy metabolism and cellular function in various organs in animals. NR has also been tested in older humans and is considered safe, but the effects of NR supplementation alone on physical performance are unclear. The purpose of this review is to examine the preclinical and clinical evidence on the effect of NR supplementation strategies alone and in combination with physical activity on mobility and skeletal muscle and cardiovascular function.

Advanced Age Is Associated with Iron Dyshomeostasis and Mitochondrial DNA Damage in Human Skeletal Muscle.

Whether disruption of iron metabolism is implicated in human muscle aging is presently unclear. We explored the relationship among iron metabolism, muscle mitochondrial homeostasis, inflammation, and physical function in older adults and young controls. Eleven young and 23 older men and women were included. Older adults were classified into high-functioning (HF) and low-functioning (LF) groups according to their Short Physical Performance Battery score. Vastus lateralis muscle biopsies were assayed for total iron content, expression of 8-oxoguanine and DNA glycosylase (OGG1), 3-nitrotyrosine (3-NT) levels, and mitochondrial DNA (mtDNA) content and damage. Circulating ferritin and hepcidin levels were also quantified. Muscle iron levels were greater in the old group. Protein expression of transferrin receptor 1, Zrt-Irt-like protein (ZIP) 8, and ZIP14 were lower in old participants. Circulating levels of ferritin, hepcidin, interleukin 6 (IL6), and C-reactive protein were higher in the old group. Old participants showed lower mtDNA content and greater mtDNA damage. OGG1 protein expression declined with age, whereas 3-NT levels were greater in old participants. Finally, a negative correlation was determined between ZIP14 expression and circulating IL6 levels in LF older adults. None of assayed parameters differed between HF and LF participants. Our findings suggest that muscle iron homeostasis is altered in old age, which might contribute to loss of mtDNA stability. Muscle iron metabolism may therefore represent a target for interventions against muscle aging.

Cancer Pain, Anxiety, and Depression in Admitted Patients at a Tertiary Care Hospital: A Prospective Observational Study.

CONTEXT: Pain is the most common symptom in admitted cancer patients. The association between the severity of cancer pain and distress symptoms such as depression and anxiety is a subject of research. AIMS: The aim is to study the prevalence of pain, anxiety, and depression in admitted cancer patients and determine the association between pain and anxiety and depression at a tertiary cancer care institute. SETTINGS AND DESIGN: This was prospective observational study. SUBJECTS AND METHODS: We enrolled 393 cancer inpatients prospectively after written informed consent. Their disease details, presence, severity, and character of pain were recorded. Numerical Pain Scale was used for pain scores, self-reporting Hospital Anxiety and Depression Scale for anxiety and depression. STATISTICAL ANALYSIS USED: Normal data were analyzed with parametric, nonnormal with nonparametric methods, and categorical with the Chi-square test. RESULTS: The prevalence of moderate-to-severe pain was 41.5%, anxiety 20.3%, and depression 24.8%. Proportion of patients with anxiety and depression was 9.2% and 17.7% in patients with no pain; about 32.8% and 36.7% with severe pain, respectively (P < 0.000). In patients with no depression 6% had anxiety; with depression 44.9% had anxiety (P < 0.000). Odd's ratio to have anxiety and depression was 4.44 (95% confidence interval [CI] 2.0318-9.7024) and 2.92 (95% CI 1.5739-5.4186), respectively, in patients with pain as compared to no pain (P < 0.00). There was a positive correlation between pain, anxiety, and depression scores. CONCLUSIONS: There is strong association between the presence and severity of pain and distress symptoms such as anxiety and depression in admitted cancer patients.

Carcinoma buccal mucosa underlying a giant cutaneous horn: a case report and review of the literature.

Cutaneous horn is a conical, dense, and hyperkeratotic protrusion that often appears similar to the horn of an animal. Giant cutaneous horns are rare; no incidence or prevalence has been reported. The significance of cutaneous horns is that they occur in association with, or as a response to, a wide variety of underlying benign, premalignant, and malignant cutaneous diseases. A case of giant cutaneous horn of left oral commissure along with carcinoma left buccal mucosa is reported here as an extremely rare oral/perioral pathology.