Mitochondrial energy deficit is considered a key element of different clinical pathologies - from inherited disorders of energy metabolism to drug-induced mitochondrial toxicity, to cardiometabolic and neurodegenerative diseases. However, clinical manifestations of impaired bioenergetics are not easy to recognize, with patient-reported features usually include non-pathognomonic fatigue and weakness, or exercise intolerance, while specific lab tests are missing. Although it is not clear whether poor energetics is a primary deficit or a secondary consequence of specific disorders, improving mitochondrial viability remains a challenging task in both experimental and clinical medicine. In this review, biochemical and clinical evidence of energy deficits were reviewed, along with possible therapeutic options to tackle energy failure and restore bioenergetics.

Age estimation is a crucial part of forensic investigations. Because different parts of the body are often found at crime scenes, it is important to explore the regions that can be used for age estimation. Previous studies have used simple X-ray to analyze changes in costal cartilage calcification as a measure of age. Here, we tested whether age could be better estimated using measurements of costal cartilage calcification on postmortem CT images. In this study, male and female decedents (n = 10 each) from autopsy cases were grouped into 10-year incremental age groups (20-29 y; 30-39 y; up to 89 y). We found that the mean Hounsfield unit (CT number) and percentage calcification (the ratio of the ossified area to the whole area) increased with age for both sexes. However, there were marked individual differences within many of the groups, and this led to a statistically significant difference (P < 0.05) only between the 20-29 y group and the older age groups. To improve the ability to correctly assign cases to age groups, we introduced and reanalyzed the data using Bayesian statistics. This improved the classifications rates, with 40% of males and 35% of females correctly assigned into their age groups. Broadening the age range could further improve the number of matches. Thus, combining Bayesian statistics with CT imaging can be used to estimate age at death from costal cartilage calcification, and could be used as an adjunct in forensic investigations.

Atypical femoral fractures (AFFs) are defined as atraumatic or low-trauma fractures located in the subtrochanteric or diaphyseal sites. Long-term bisphosphonates (BPs) are administered to prevent fragility fractures in patients with primary osteoporosis or collagen diseases who are already taking glucocorticoids (GCs). Long-term BP use is one of the most important risk factors for AFFs. Its pathogenesis is characterized by severely suppressed bone turnover (SSBT), but whether the characteristics of patients are different regarding to location of fracture site remains unknown. In this study, we compared the characteristics and bone histomorphometric findings between subtrochanteric and diaphyseal sites in patients with BP-associated AFFs. Nine women with BP-associated AFFs were recruited, including 3 with systemic lupus erythematosus, 2 with rheumatoid arthritis, 2 with primary osteoporosis, 1 with polymyalgia rheumatica, and 1 with sarcoidosis. Patients were divided into the subtrochanteric group (n = 5; average age, 52 years; BP treatment, 5.9 years) and the diaphyseal group (n = 4; average age, 77 years; BP treatment, 2.6 years). Compared with the diaphyseal group, the subtrochanteric group had significantly higher daily GC doses (average, 10.9 vs. 2.3 mg/day) and significantly lower serum 25-hydroxyvitamin-D levels (17.8 vs. 25.6 ng/mL). Bone histomorphometry of the biopsied iliac bone showed SSBT in 3 cases (subtrochanteric, n = 1; diaphyseal, n = 2). Osteoid volume and trabecular thickness were significantly lower in the subtrochanteric group than in the diaphyseal group. Bone formation was inhibited more severely in subtrochanteric than in the diaphyseal group due to the higher GC doses used.

In our aging world, increasing numbers of people are suffering from calcific aortic valve disease (CAVD). In this study, we used integrated bioinformatics analysis to predict several key genes that are involved in the initiation and progression of CAVD. Expression profiles of 15 calcific and 14 normal human aortic valve samples were generated from two gene expression datasets (GSE12644 and GSE51472). Dataset GSE26953 from the human aortic valve fibrosa-derived endothelial cells cultured under laminar or oscillatory shear stress was also evaluated. Related R packages were used to process the data. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed for functional annotation. Hub genes were identified based on the protein-protein interaction network. CAVD-related gene modules were identified by Weighted Gene Co-expression Network Analysis (WGCNA). The predicted key genes were manually reviewed. In our present work, complex connections among mechano-response, oxidative stress, inflammation and extracellular remodeling pathways in the etiology of CAVD were revealed. The key genes, thus identified, encode a transcription factor KLF2 and phospholipid phosphatase 3 (PLPP3) that are involved in mechano-responses; eNOS involved in oxidative stress; IL-8 involved in inflammation; and collagen triple helix repeat containing 1 (CTHRC1) and secretogranin II (SCG2) involved in extracellular remodeling. These gene products are predicted to play critical roles in CAVD development and progression. The present study provides valuable information for future research and drug development.

Acid sphingomyelinase (ASM) is a lysosomal enzyme that hydrolyzes sphingomyelin into ceramide, a bioactive lipid to regulate cellular physiological functions. Thus, ASM activation has been reported as a key event in pathophysiological reactions including inflammation, cytokine release, oxidative stress, and endothelial damage in human diseases. Since ASM activation is associated with extracellular ASM secretion through unknown mechanisms, it can be detected by recognizing the elevation of secretory ASM (S-ASM) activity. Serum S-ASM activity has been reported to increase in chronic diseases, acute cardiac diseases, and systemic inflammatory diseases. However, the serum S-ASM has not been investigated in common acute illness. This study was designed to evaluate serum S-ASM activity in children with common acute illness. Fifty children with common acute illness and five healthy children were included in this study. The patients were categorized into five groups based on clinical diagnoses: acute respiratory syncytial virus (RSV) bronchiolitis, adenovirus infection, streptococcal infection, asthma, and other infections due to unknown origin. The serum S-ASM activity was significantly elevated at 6.9 ± 1.6 nmol/0.1 mL/6 h in the group of acute RSV bronchiolitis patients compared with healthy children who had a mean level of 1.8 ± 0.8 nmol/0.1 mL/6 h (p < 0.05). In the other illness groups, the serum S-ASM activity was not significantly elevated. The results suggest an association of ASM activation with RSV infection, a cause for common acute illness. This is the first report to describe the elevation of serum S-ASM activity in respiratory tract infection.

Individuals with prehypertension have a greater risk of developing hypertension and cardiovascular disease than those with normal blood pressure. Good cardiorespiratory fitness has been associated with a reduced risk for cardiovascular diseases, but whether it is related to slower progression of early atherosclerosis is unclear. We evaluated 442 women, aged 40-60 years, with resting systolic blood pressure 120-139 mmHg and diastolic blood pressure 80-89 mmHg, defined as prehypertension in cross-sectional study. Blood glucose, blood lipids and carotid intima-media thickness (CIMT) were measured at rest. Cardiorespiratory fitness (VO₂peak) was measured by respiratory gas exchange during a treadmill exercise test. Participants were divided into three cardiorespiratory fitness levels: low, moderate, and high. The prevalence of subclinical carotid atherosclerosis was defined as a mean carotid intima-media thickness greater than the 75^th percentile. After adjustment for various confounders, a high cardiorespiratory fitness level was associated with significantly lower SBP, DBP and CIMT compared with low and moderate fitness (p < 0.05). After adjustment for established risk factors, high and moderate fitness were each associated with significantly lower odds ratios for carotid atherosclerosis 0.74 (95% CI 0.45-0.92) and 0.70 (95% CI 0.46-0.95), respectively, compared with low fitness. Our results indicate that good cardiorespiratory fitness is associated with a slower progression of early atherosclerosis in middle-aged women. These findings are important, because they emphasize that middle-aged women can be evaluated for cardiorespiratory fitness to estimate their future risk for atherosclerotic vascular diseases.

Histological chorioamnionitis (CAM) is one form of intrauterine inflammation that is often seen in cases of preterm birth and are usually confirmed based on pathological examination after delivery. Histological CAM is related to significant neonatal morbidity and mortality; however, its etiology is unknown. The objective of this study was to determine the risk factors for histological CAM, using medical background, including fetal heart rate (FHR) patterns in preterm birth cases. The preterm birth cases delivered between 28 and 36 weeks were categorized into two groups according to the presence of histological CAM. Ninety-five preterm infants were included: 48 infants without histological CAM and 47 cases with histological CAM. The odds ratio for histological CAM was adjusted for FHR patterns, gestational age, and delivery mode (vaginal delivery or Caesarean section). Logistic regression analysis showed that vaginal delivery and gestational age were associated with histological CAM (odds Ratio [OR]: 3.1, 95% confidence interval [CI]: 1.0-9.4, p < 0.05, and OR: 0.8, 95% CI: 0.6-0.9, p < 0.05, respectively). However, there were no specific FHR patterns associated with histological CAM. Our study indicates that in preterm birth cases, histological CAM is not related to any specific FHR pattern. However, labor uterine contraction and immature gestational age at the delivery are related to histological CAM. These results may provide better delivery management methods for preterm birth cases.

Intellectual disability (ID), occurs in approximately 1 to 3% of the population and tends to be higher in low-income countries and in inbred communities. Despite the high rates of consanguineous marriages and the likely enrichment for recessive forms of ID, the genetic bases of ID in Jordan are largely unstudied. In this study, whole exome sequencing (WES) and homozygosity mapping were used to identify the genetic causes of ID in ten families from Jordan. The studied families are characterized by consanguineous marriage and having one or more progeny with ID. Likely disease-causing missense mutations were identified in eight families; four families are due to mutations in genes previously implicated with ID and the other four families are due to mutations in genes that are not previously implicated with ID. The novel genes include: BSN (Protein Basson), PTCHD2 (Protein dispatched homolog 3), DHRS3 (Short-chain dehydrogenase/reductase 3), and LGI3 (Leucine-rich repeat LGI family member 3). In addition, copy number variant (CNV) deletion and/or duplication were identified in 2 families; one family with 3.5 mega base (Mb) deletion on chromosome17 previously implicated with Smith Magenis Syndrome, and the other family with a novel combination of deletion and duplication in chromosomes 5 and 11. In this pilot study, four genes and one CNV deletion/duplication are identified for the first time in association with ID. The finding of this study further demonstrates the power of WES and homozygosity mapping for clinical diagnostics of ID in consanguineous families in small populations.

Physiological adaptations to various types of prolonged and intensive physical activity, as seen in elite athletes from different sports, include changes in blood pressure (BP) response to acute exercise. Also, functional polymorphisms of the angiotensin I converting enzyme (ACE) and alfa-actinin-3 (ACTN3) genes are shown to be associated with BP parameters changes, both in athletes and sedentary population. In this study, an Alu insertion (I)/deletion (D) polymorphism in ACE gene, as well as nonsense mutation in the gene encoding ACTN3 have been scored in 107 elite Serbian athletes classified according to their sporting discipline to power/sprint (short distance runners/swimmers), endurance (rowers, footballers, middle-distance swimmers) or mixed sports (water polo, handball, volleyball players). Presence of nonfunctional allele in ACTN3 is associated with significantly increased maximal systolic BP (SBPmax, p = 0.04). Athletes with Alu insertion in ACE had significantly (p = 0.006) larger decline of systolic BP after 3 minutes of recovery (SBPR3), calculated as the percentage of maximal SBP response during exercise stress testing. Concomitant presence of non-functional variant in ACTN3 gene decreased this beneficiary effect of ACE mutation on SBPR3. Long term enrollment in power/sprint sports significantly increased resting diastolic BP (DBPrest: 74 mmHg) and SBPmax (197 mmHg) and improved SBPR3 (74.8%) compared to enrolment in endurance (72 mmHg; 178 mmHg; 81.1%) and mixed sports (69 mmHg; 185 mmHg; 80.0%). Lack of the effect of genotype by sport interaction on BP parameters suggests that the long-term effects of different disciplines on BP are not mediated by these two genes.

There is little epidemiological evidence linking subjective stress to objective etiologic indicators. To clarify an association between work-related stress and autonomic nervous function, we examined call center employees (167 males and 371 females) undergoing electrocardiography (ECG) at the time of annual health checkups. The questionnaire was composed of the Brief Job Stress Questionnaire based on the demand-control-support model and the Social Readjustment Rating Scale including detailed contents of home stress. The Bazett’s corrected QT (QTc) interval, QT index, and heart rate were obtained from the ECG data. The male employees showed significantly higher scores of job demand, job control, and supervisor support than the female ones. In the male employees, QT index indicating the extent of autonomic imbalance and heart rate were associated with high score of supervisor support and low score of coworker support (P < 0.05), but no significant relationships were seen between QTc interval and either job strain (i.e., job demand and job control) or home stress. By contrast, the female employees showed no significant links between any autonomic indicators and either work-related stress or home stress. These data suggest that work-related stress affected QT index in male employees suffering specific occupational stressors such as emotional abuse from unsatisfied customers. Specifically, supports from supervisors and coworkers were paradoxically associated with QT index, implying that supervisors may have failed to effectively support such male employees. Also, autonomic nervous function in male employees appears to be more vulnerable to work-related stress than that in female ones.

The Japanese national immunization programme for Human Papillomavirus (HPV) started in 2010. Vaccination rates increased up to 70% in women in the 1996-1999 birth. However, the proactive recommendation for HPV vaccine was suspended in 2013, following repeated media reports of adverse events. Vaccination rates plumped to less than 1% in women born since 2002. In this study, incidence of abnormal cytology and histology was examined in terms of HPV vaccination among 5,924 women aged 20 to 24 years in the fiscal year (FY) 2014 and 2015. The total rate of vaccination was 16.9% (1,002/5,924). In case of FY 2015, the rates of vaccination were 59.26%, 49.68%, 11.97%, 9.08%, and 4.58% in those aged 20, 21, 22, 23, and 24 years old, respectively. The rates of high-grade squamous intraepithelial lesion (HSIL) or worse were 0.20% (2/1,002) in women with HPV vaccination and 1.14% (56/4,922) in those without HPV vaccination, indicating a significant reduction of 82.46% with vaccination (P < 0.0001). The rates of cervical intraepithelial neoplasia (CIN) 1+ were 0.80% (8/1,002) in women with vaccination and 2.28% (112/4,922) in those without vaccination. The reduction rate of CIN1+ was 64.91% (P = 0.0025). The rates of CIN2+ were 0.10% (1/1,002) with vaccination and 0.69% (34/4,922) without vaccination. The reduction rate of CIN2+ was 85.51% (P = 0.0261). Our data are the first to demonstrate a significant reduction of CIN2+ cases in an Asian population. Scientific discussion is needed to restart the proactive recommendation for HPV vaccine in Japan.

Renal prognosis for anti-glomerular basement membrane (GBM) glomerulonephritis is poor. The greater the amount of anti-GBM antibody binding the antigen (type IV collagen of the glomerular basement membrane), the greater the number of crescents that develop in glomeruli, resulting in progression of renal impairment. Immunofluorescence staining reveals linear IgG depositions on glomerular capillary walls. Membranous nephropathy (MN) is one of the most common causes of nephrotic syndrome in middle-aged to elderly patients. Immune complex is deposited in the sub-epithelial space of the glomerulus resulting in the development of a membranous lesion. Immunofluorescence staining reveals granular IgG depositions on glomerular capillary walls. Coexisting anti-GBM glomerulonephritis and MN are rare and, here we report a case of coexisting anti-GBM glomerulonephritis and MN with preserved renal function. There are some cases of coexisting anti-GBM glomerulonephritis and MN do not show severely decreased renal function. A 76-year-old Japanese woman presented with nephrotic syndrome, microscopic hematuria, and was positive for anti-GBM antibody. Kidney biopsy revealed linear and granular IgG depositions in glomerular capillary walls, crescent formations, and electron-dense deposits in the sub-epithelial space. She was diagnosed with anti-GBM glomerulonephritis and MN. Steroid and cyclosporine therapy achieved complete remission, and kidney function was preserved. In conclusion, coexisting anti-GBM glomerulonephritis and MN can have preserved renal function. IgG subclass of deposited anti-GBM antibody may be associated with the severity of anti-GBM glomerulonephritis. In addition, in the case of nephrotic syndrome with hematuria, we should consider the possibility of coexisting anti-GBM glomerulonephritis and MN.