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1.  Three-dimensional mechanical evaluation of joint contact pressure in 12 periacetabular osteotomy patients with 10-year follow-up 
Acta orthopaedica  2009;80(2):155-161.
Background and purpose
Because of the varying structure of dysplastic hips, the optimal realignment of the joint during periacetabular osteotomy (PAO) may differ between patients. Three-dimensional (3D) mechanical and radiological analysis possibly accounts better for patient-specific morphology, and may improve and automate optimal joint realignment.
Patients and methods
We evaluated the 10-year outcomes of 12 patients following PAO. We compared 3D mechanical analysis results to both radiological and clinical measurements. A 3D discrete-element analysis algorithm was used to calculate the pre- and postoperative contact pressure profile within the hip. Radiological angles describing the coverage of the joint were measured using a computerized approach at actual and theoretical orientations of the acetabular cup. Quantitative results were compared using postoperative clinical evaluation scores (Harris score), and patient-completed outcome surveys (q-score) done at 2 and 10 years.
The 3D mechanical analysis indicated that peak joint contact pressure was reduced by an average factor of 1.7 subsequent to PAO. Lateral coverage of the femoral head increased in all patients; however, it did not proportionally reduce the maximum contact pressure and, in 1 case, the pressure increased. This patient had the lowest 10-year q-score (70 out of 100) of the cohort. Another hip was converted to hip arthroplasty after 3 years because of increasing osteoarthritis.
The 3D analysis showed that a reduction in contact pressure was theoretically possible for all patients in this cohort, but this could not be achieved in every case during surgery. While intraoperative factors may affect the actual surgical outcome, the results show that 3D contact pressure analysis is consistent with traditional PAO planning techniques (more so than 2D analysis) and may be a valuable addition to preoperative planning and intraoperative assessment of joint realignment.
PMCID: PMC2689368  PMID: 19404795
2.  Three-dimensional mechanical evaluation of joint contact pressure in 12 periacetabular osteotomy patients with 10-year follow-up 
Acta Orthopaedica  2009;80(2):155-161.
Background and purpose Because of the varying structure of dysplastic hips, the optimal realignment of the joint during periacetabular osteotomy (PAO) may differ between patients. Three-dimensional (3D) mechanical and radiological analysis possibly accounts better for patient-specific morphology, and may improve and automate optimal joint realignment.
Patients and methods We evaluated the 10-year outcomes of 12 patients following PAO. We compared 3D mechanical analysis results to both radiological and clinical measurements. A 3D discrete-element analysis algorithm was used to calculate the pre- and postoperative contact pressure profile within the hip. Radiological angles describing the coverage of the joint were measured using a computerized approach at actual and theoretical orientations of the acetabular cup. Quantitative results were compared using postoperative clinical evaluation scores (Harris score), and patient-completed outcome surveys (q-score) done at 2 and 10 years.
Results The 3D mechanical analysis indicated that peak joint contact pressure was reduced by an average factor of 1.7 subsequent to PAO. Lateral coverage of the femoral head increased in all patients; however, it did not proportionally reduce the maximum contact pressure and, in 1 case, the pressure increased. This patient had the lowest 10-year q-score (70 out of 100) of the cohort. Another hip was converted to hip arthroplasty after 3 years because of increasing osteoarthritis.
Interpretation The 3D analysis showed that a reduction in contact pressure was theoretically possible for all patients in this cohort, but this could not be achieved in every case during surgery. While intraoperative factors may affect the actual surgical outcome, the results show that 3D contact pressure analysis is consistent with traditional PAO planning techniques (more so than 2D analysis) and may be a valuable addition to preoperative planning and intraoperative assessment of joint realignment.
PMCID: PMC2689368  PMID: 19404795
3.  A Histopathological Feature of EGFR-Mutated Lung Adenocarcinomas with Highly Malignant Potential – An Implication of Micropapillary Element - 
PLoS ONE  2016;11(11):e0166795.
The purpose of this study was to define histological features determining the malignant potential of EGFR-mutated lung adenocarcinoma (LADC). Surgically resected tumors (EGFR-mutated LADCs with (21) and without (79) lymph node metastasis and EGFR wild-type LADCs with (26) and without (108) lymph node metastasis) and biopsy samples from inoperably advanced tumors (EGFR-mutated LADCs (78) and EGFR wild-type LADCs (99)) were examined. In surgically resected tumors, the EGFR-mutated LADCs with lymph node metastasis had the micropapillary element in a significantly greater proportion than others (Mann-Whitney tests P ≤0.026). The proportion of micropapillary element was higher in the EGFR-mutated LADC at the advanced stage (stage II, III, or IV) than in the tumor at the early stage (stage I) (Mann-Whitney test, P<0.0001). In the biopsy samples from inoperably advanced LADCs (177), EGFR-mutated tumors also had micropapillary element at a higher frequency than EGFR-wild type tumors (53/78 (68%), versus 30/99 (30%), Pearson x2 test, P<0.0001). In stage I EGFR-mutated LADCs (84), the tumors with the micropapillary element (34) exhibited a significantly higher recurrence rate than tumors without micropapillary element (50) (5-year Recurrence-free survival 64.4% versus 93.3%, log-rank test P = 0.028). The micropapillary element may be an exclusive determinant of malignant potential in EGFR-mutated LADC. It is suggested that EGFR-mutated LADC may develop through a distinct histogenesis, in which the micropapillary element is important for promoting progression.
PMCID: PMC5115808  PMID: 27861549
4.  Pathoadaptive Mutations of Escherichia coli K1 in Experimental Neonatal Systemic Infection 
PLoS ONE  2016;11(11):e0166793.
Although Escherichia coli K1 strains are benign commensals in adults, their acquisition at birth by the newborn may result in life-threatening systemic infections, most commonly sepsis and meningitis. Key features of these infections, including stable gastrointestinal (GI) colonization and age-dependent invasion of the bloodstream, can be replicated in the neonatal rat. We previously increased the capacity of a septicemia isolate of E. coli K1 to elicit systemic infection following colonization of the small intestine by serial passage through two-day-old (P2) rat pups. The passaged strain, A192PP (belonging to sequence type 95), induces lethal infection in all pups fed 2–6 x 106 CFU. Here we use whole-genome sequencing to identify mutations responsible for the threefold increase in lethality between the initial clinical isolate and the passaged derivative. Only four single nucleotide polymorphisms (SNPs), in genes (gloB, yjgV, tdcE) or promoters (thrA) involved in metabolic functions, were found: no changes were detected in genes encoding virulence determinants associated with the invasive potential of E. coli K1. The passaged strain differed in carbon source utilization in comparison to the clinical isolate, most notably its inability to metabolize glucose for growth. Deletion of each of the four genes from the E. coli A192PP chromosome altered the proteome, reduced the number of colonizing bacteria in the small intestine and increased the number of P2 survivors. This work indicates that changes in metabolic potential lead to increased colonization of the neonatal GI tract, increasing the potential for translocation across the GI epithelium into the systemic circulation.
PMCID: PMC5115809  PMID: 27861552
5.  High Diversity and Variability in the Vaginal Microbiome in Women following Preterm Premature Rupture of Membranes (PPROM): A Prospective Cohort Study 
PLoS ONE  2016;11(11):e0166794.
To characterize the vaginal microbiota of women following preterm premature rupture of membranes (PPROM), and determine if microbiome composition predicts latency duration and perinatal outcomes.
A prospective cohort study
Women with PPROM between 24+0 and 33+6 weeks gestational age (GA).
Microbiome profiles, based on pyrosequencing of the cpn60 universal target, were generated from vaginal samples at time of presentation with PPROM, weekly thereafter, and at delivery.
Main Outcome Measures
Vaginal microbiome composition, latency duration, gestational age at delivery, perinatal outcomes.
Microbiome profiles were generated from 70 samples from 36 women. Mean GA at PPROM was 28.8 wk (mean latency 2.7 wk). Microbiome profiles were highly diverse but sequences representing Megasphaera type 1 and Prevotella spp. were detected in all vaginal samples. Only 13/70 samples were dominated by Lactobacillus spp. Microbiome profiles at the time of membrane rupture did not cluster by gestational age at PPROM, latency duration, presence of chorioamnionitis or by infant outcomes. Mycoplasma and/or Ureaplasma were detected by PCR in 81% (29/36) of women, and these women had significantly lower GA at delivery and correspondingly lower birth weight infants than Mycoplasma and/or Ureaplasma negative women.
Women with PPROM had mixed, abnormal vaginal microbiota but the microbiome profile at PPROM did not correlate with latency duration. Prevotella spp. and Megasphaera type I were ubiquitous. The presence of Mollicutes in the vaginal microbiome was associated with lower GA at delivery. The microbiome was remarkably unstable during the latency period.
PMCID: PMC5115810  PMID: 27861554
6.  The Association of EGFR Mutations with Stage at Diagnosis in Lung Adenocarcinomas 
PLoS ONE  2016;11(11):e0166821.
The prognostic role of epidermal growth factor receptor (EGFR) mutations in patients with lung adenocarcinomas remains controversial and the association between EGFR mutations and stage at the time of the initial diagnosis is debatable. In this study, we evaluated the association of EGFR mutations with stage at diagnosis in lung adenocarcinomas.
Materials and Methods
We retrospectively analyzed 1004 consecutive patients who were diagnosed with lung adenocarcinomas and tested for EGFR mutations between June 2011 and December 2014.
EGFR mutations were detected in 49.2% of 1004 patients with lung adenocarcinomas. In multivariable analysis, EGFR mutations were significantly associated with early stage disease (stage I to II) at diagnosis (odds ratio [OR], 0.65; 95% confidence interval [CI], 0.49–0.87; P = 0.003). When adjusted for age, sex, smoking status, and screening, the adjusted proportion of EGFR mutations significantly decreased according to stage. The adjusted proportions of EGFR mutations were 57.6% (95% CI, 51.7%–63.3%) for stage I, 47.9% (95% CI, 36.9%–59.0%) for stage II, 47.5% (95% CI, 39.6%–55.5%) for stage III, and 43.4% (95% CI, 38.3%–48.6%) for stage IV (P = 0.0082).
The presence of EGFR mutations is significantly associated with early stage disease at initial diagnosis in lung adenocarcinomas after adjusting for age, sex, smoking status, and screening. This finding implies that EGFR mutations may play a role as a positive prognostic marker.
PMCID: PMC5115811  PMID: 27861565
7.  Binge Drinking in Young University Students Is Associated with Alterations in Executive Functions Related to Their Starting Age 
PLoS ONE  2016;11(11):e0166834.
Our aim was to evaluate whether or not alcohol consumption in the form of binge drinking is associated with alterations of memory and executive functions in a population of university students. At the same time, we have studied the role of potential modulating factors, such as the APOE genotype or physical exercise.University students enrolled in academic year 2013–2014 at Escuelas Universitarias Gimbernat-Cantabria, affiliated with the University of Cantabria, were invited to participate in the study. We gathered sociodemographic data and details regarding the lifestyle of 206 students (mean age 19.55 ± 2.39; 67.5% women). We evaluated memory and executive functions via a series of validated cognitive tests. Participants were classified as binge drinkers (BD) and non-BD. Using Student's t-distribution we studied the association between cognitive tests and BD patterns. Multivariate analyses were carried out via multiple linear regression. 47.6% of the students were found to be BD. The BD differed significantly from the non-BD in their results in the executive functions test TMT B (43.41 ± 13.30 vs 37.40 ± 9.77; p = 0.0003). Adjusting by age, sex, academic records, age at which they started consuming alcohol, cannabis consumption, level of physical activity and other possible modifying variables, the association was statistically significant (p = 0.009). We noticed a statistically significant inverse correlation (Pearson’s r2 = -0.192; p = 0.007) between TMT B and starting age of alcohol consumption. Differences were observed in another executive functions test, TMT A, but only in the group of women (19.73±6.1 BD vs 17.78±5.4 non-BD p = 0.05). In spite of the young age of our participants, BD was associated with a lower performance in the executive functions test (TMT B). These deficits were related to the age at which they started drinking alcohol, suggesting an accumulative effect.
PMCID: PMC5115818  PMID: 27861563
8.  Fruit Size Determines the Role of Three Scatter-Hoarding Rodents as Dispersers or Seed Predators of a Fleshy-Fruited Atacama Desert Shrub 
PLoS ONE  2016;11(11):e0166824.
Scatter-hoarding rodents can act as both predators and dispersers for many large-seeded plants because they cache seeds for future use, but occasionally forget them in sites with high survival and establishment probabilities. The most important fruit or seed trait influencing rodent foraging behavior is seed size; rodents prefer large seeds because they have higher nutritional content, but this preference can be counterbalanced by the higher costs of handling larger seeds. We designed a cafeteria experiment to assess whether fruit and seed size of Myrcianthes coquimbensis, an endangered desert shrub, influence the decision-making process during foraging by three species of scatter-hoarding rodents differing in body size: Abrothrix olivaceus, Phyllotis darwini and Octodon degus. We found that the size of fruits and seeds influenced foraging behavior in the three rodent species; the probability of a fruit being harvested and hoarded was higher for larger fruits than for smaller ones. Patterns of fruit size preference were not affected by rodent size; all species were able to hoard fruits within the entire range of sizes offered. Finally, fruit and seed size had no effect on the probability of seed predation, rodents typically ate only the fleshy pulp of the fruits offered and discarded whole, intact seeds. In conclusion, our results reveal that larger M. coquimbensis fruits have higher probabilities of being harvested, and ultimately of its seeds being hoarded and dispersed by scatter-hoarding rodents. As this plant has no other dispersers, rodents play an important role in its recruitment dynamics.
PMCID: PMC5115819  PMID: 27861550
9.  An Alteration in the Cecal Microbiota Composition by Feeding of 1-Kestose Results in a Marked Increase in the Cecal Butyrate Content in Rats 
PLoS ONE  2016;11(11):e0166850.
Functional food ingredients, including prebiotics, have been ardently developed for improving the intestinal environment. Fructooligosaccarides (FOS), including fructans, are the well researched and commercialized prebiotics. However, to our knowledge, few studies have been conducted on the physiological effects of each component of FOS as prebiotics. 1-Kestose, a component of FOS, is composed of one glucose and two fructose molecules, and is considered as a key prebiotic component in short-chain FOS. In the present study, we examined the effects of dietary 1-kestose using 0.5–5% 1-kestose diets on cecal microbiota composition and cecal contents of short-chain fatty acids and lactate in rats. The findings indicate that dietary 1-kestose induced cecal hypertrophy and alterations in the cecal microbiota composition, including a marked increase in the cell number of Bifidobacterium spp. These alterations were associated with significant increases in acetate and lactate, and a marked increase in butyrate in cecal contents. Furthermore, dietary 1-kestose induced a significant decrease in serum insulin concentration in rats fed 2.5–5% 1-kestose diet. These findings suggest a potential of 1-kestose to be a prebiotic for improving the metabolism of the host.
PMCID: PMC5115820  PMID: 27861621
10.  Propagated but Topologically Distributed Forebrain Neurons Expressing Alpha-Synuclein in Aged Macaques 
PLoS ONE  2016;11(11):e0166861.
In neurodegenerative disorders, such as Parkinson's disease (PD), alpha-synuclein (α-syn) accumulates to induce cell death and/or form a cytoplasmic inclusion called Lewy body (LB). This α-syn-related pathology is termed synucleinopathy. It remains unclear how α-syn accumulation expands during the progress of synucleinopathy in the human brain. In our study, we investigated the patterns of distribution and propagation of forebrain neurons expressing α-syn in aged macaques. It was found that the occurrence of α-syn-positive neurons proceeded topologically based on the midbrain dopamine pathways arising from the substantia nigra and the ventral tegmental area where they were primarily observed. In the nigrostriatal or mesolimbic dopamine pathway, the age-dependent increase in α-syn-positive neurons was evident in the striatum or the nucleus accumbens, respectively. Concerning the nigrostriatal pathway, a mediolateral or rostrocaudal gradient was seen in the substantia nigra or the striatum, respectively, and a compensatory increase in dopamine transporter occurred in the striatum regardless of the decreased dopamine level. In the mesocortical dopamine pathway, α-syn-positive neurons appeared in the prefrontal and then motor areas of the frontal lobe. Given that neither LB formation nor clinical phenotype manifestation was detected in any of the monkeys examined in the present study, aged macaques may be useful as a potential presymptomatic model for PD and LB-related neuropsychiatric disorders.
PMCID: PMC5115821  PMID: 27861638
11.  Symptoms of Dry Eye Disease and Personality Traits 
PLoS ONE  2016;11(11):e0166838.
The essential targets of dry eye disease (DED) treatments include both objective signs and subjective symptoms. However, due to the numerous subjective symptoms, it is understandable why little association has been found between the signs and symptoms. Although psychological influences on the subjective symptoms have been reported, little is known about the influence of personality traits. The present study analyzed the relationship between the signs/symptoms of DED and the personality traits of patients using a cross-sectional design. We examined 56 DED patients (mean age; 62.4 ± 12.9, range 34–85 years) visiting the outpatient clinic of the Department of Ophthalmology at the Nippon Medical School Hospital in Tokyo, Japan. Objective signs evaluated included the Schirmer I test, tear breakup time (BUT), fluorescein and lissamine green staining, and tear osmolality. Subjective symptoms were assessed by the Ocular Surface Disease Index (OSDI) and Dry Eye-Related Quality-of-Life Score (DEQS) questionnaires. For personality traits, the Big Five personality traits model analysis was used. Correlations between the objective signs, subjective symptoms, and personality traits were analyzed. A significant correlation was found between the neuroticism in the Big Five Personality Inventory and the symptoms assessed by the DEQS (r = -0.35, p < 0.01), and the OSDI (r = -0.28, p < 0.05). There was no significant correlation observed between the signs and the symptoms, or between the signs and any personality traits. The results of our current study suggest that the personality of the patient, which appears to be the basis of various psychological factors, can have some impact on the subjective symptoms. This may be one of the reasons why there has been little association noted between the signs and symptoms of DED.
PMCID: PMC5115822  PMID: 27861642
12.  Modulation of Type-1 and Type-2 Cannabinoid Receptors by Saffron in a Rat Model of Retinal Neurodegeneration 
PLoS ONE  2016;11(11):e0166827.
Experimental studies demonstrated that saffron (Crocus sativus) given as a dietary supplement counteracts the effects of bright continuous light (BCL) exposure in the albino rat retina, preserving both morphology and function and probably acting as a regulator of programmed cell death [1]. The purpose of this study was to ascertain whether the neuroprotective effect of saffron on rat retina exposed to BCL is associated with a modulation of the endocannabinoid system (ECS). To this aim, we used eight experimental groups of Sprague-Dawley rats, of which six were exposed to BCL for 24 hours. Following retinal function evaluation, retinas were quickly removed for biochemical and morphological analyses. Rats were either saffron-prefed or intravitreally injected with selective type-1 (CB1) or type-2 (CB2) cannabinoid receptor antagonists before BCL. Prefeeding and intravitreally injections were combined in two experimental groups before BCL. BCL exposure led to enhanced gene and protein expression of retinal CB1 and CB2 without affecting the other ECS elements. This effect of BCL on CB1 and CB2 was reversed by saffron treatment. Selective CB1 and CB2 antagonists reduced photoreceptor death, preserved morphology and visual function of retina, and mitigated the outer nuclear layer (ONL) damage due to BCL. Of interest, CB2-dependent neuroprotection was more pronounced than that conferred by CB1. These data suggest that BCL modulates only distinct ECS elements like CB1 and CB2, and that saffron and cannabinoid receptors could share the same mechanism in order to afford retinal protection.
PMCID: PMC5115823  PMID: 27861558
13.  Survival Benefits of Statins for Primary Prevention: A Cohort Study 
PLoS ONE  2016;11(11):e0166847.
Estimate the effect of statin prescription on mortality in the population of England and Wales with no previous history of cardiovascular disease.
Primary care records from The Health Improvement Network 1987–2011 were used. Four cohorts of participants aged 60, 65, 70, or 75 years at baseline included 118,700, 199,574, 247,149, and 194,085 participants; and 1.4, 1.9, 1.8, and 1.1 million person-years of data, respectively. The exposure was any statin prescription at any time before the participant reached the baseline age (60, 65, 70 or 75) and the outcome was all-cause mortality at any age above the baseline age. The hazard of mortality associated with statin prescription was calculated by Cox’s proportional hazard regressions, adjusted for sex, year of birth, socioeconomic status, diabetes, antihypertensive medication, hypercholesterolaemia, body mass index, smoking status, and general practice. Participants were grouped by QRISK2 baseline risk of a first cardiovascular event in the next ten years of <10%, 10–19%, or ≥20%.
There was no reduction in all-cause mortality for statin prescription initiated in participants with a QRISK2 score <10% at any baseline age, or in participants aged 60 at baseline in any risk group. Mortality was lower in participants with a QRISK2 score ≥20% if statin prescription had been initiated by age 65 (adjusted hazard ratio (HR) 0.86 (0.79–0.94)), 70 (HR 0.83 (0.79–0.88)), or 75 (HR 0.82 (0.79–0.86)). Mortality reduction was uncertain with a QRISK2 score of 10–19%: the HR was 1.00 (0.91–1.11) for statin prescription by age 65, 0.89 (0.81–0.99) by age 70, or 0.79 (0.52–1.19) by age 75.
The current internationally recommended thresholds for statin therapy for primary prevention of cardiovascular disease in routine practice may be too low and may lead to overtreatment of younger people and those at low risk.
PMCID: PMC5115824  PMID: 27861639
14.  The Relationship between Endothelial Dysfunction and Endothelial Cell Markers in Peripheral Arterial Disease 
PLoS ONE  2016;11(11):e0166840.
The endothelial function plays key roles in both promoting and protecting against atherosclerotic disease. Several methods, including peripheral arterial tonometry (PAT), have been reported to be useful for investigating endothelial dysfunction. Furthermore, the level of thrombomodulin (TM) is assumed to reflect the endothelial dysfunction. In the present study, we investigated endothelial dysfunction in patients with peripheral arterial disease (PAD) by measuring their TM levels, and evaluated the correlation between TM and various parameters.
Materials and Methods
We measured the TM levels and performed PAT in 17 patients with PAD. We also recorded the patients’ demographic information, including comorbidities, and investigated their hemodynamic status by measuring the ankle brachial pressure index (ABI). The PAT results were used to calculate the reactive hyperemia index (RHI), which reflected the patients’ level of endothelial dysfunction.
The RHI and ABI values and the serum level of creatinine were found to be significantly correlated with the TM level (P = 0.040, 0.041 and 0.005, respectively). After setting an RHI value of 1.67 as the cut-off, the patients with RHI values of <1.67 were found to have significantly higher TM levels (median, 20.3 U/mL) than the patients with RHI values of ≥1.67 (median, 13.7 U/mL) (P = 0.023).
The degree of endothelial dysfunction, as calculated by the TM level, might influence the prognostic value of the RHI, which is determined by PAT. The measurement of the TM level and PAT might both be useful methods of measuring endothelial dysfunction in patients with PAD.
PMCID: PMC5115826  PMID: 27861629
15.  The Expression of the Endogenous mTORC1 Inhibitor Sestrin 2 Is Induced by UVB and Balanced with the Expression Level of Sestrin 1 
PLoS ONE  2016;11(11):e0166832.
Sestrin 2 (SESN2) is an evolutionarily conserved regulator of mechanistic target of rapamycin complex 1 (mTORC1) which controls central cellular processes such as protein translation and autophagy. Previous studies have suggested that SESN2 itself is subjected to regulation at multiple levels. Here, we investigated the expression of SESN2 in the skin and in isolated skin cells. SESN2 was detected by immunofluorescence analysis in fibroblasts and keratinocytes of human skin. Differentiation of epidermal keratinocytes was not associated with altered SESN2 expression and siRNA-mediated knockdown of SESN2 did not impair stratum corneum formation in vitro. However, SESN2 was increased in both cell types when the expression of its paralog SESN1 was blocked by siRNA-mediated knock down, indicating a compensatory mechanism for the control of expression. Irradiation with UVB but not with UVA significantly increased SESN2 expression in both keratinocytes and fibroblasts. Upregulation of SESN2 expression could be completely blocked by suppression of p53. These results suggest that SESN2 is dispensable for normal epidermal keratinization but involved in the UVB stress response of skin cells.
PMCID: PMC5115827  PMID: 27861561
16.  Caspase-Dependent and Caspase-Independent Pathways Are Involved in Cadmium-Induced Apoptosis in Primary Rat Proximal Tubular Cell Culture 
PLoS ONE  2016;11(11):e0166823.
We designed this study to investigate whether cadmium induces caspase-independent apoptosis and to investigate the relationship between the caspase-dependent and caspase-independent apoptotic pathways. Cadmium (1.25–2.5 μM) induced oxidative stress in rat proximal tubular (rPT) cells, as seen in the reactive oxygen species levels; N-acetylcysteine prevented this. Cyclosporin A (CsA) prevented mitochondrial permeability transition pore opening and apoptosis; there was mitochondrial ultrastructural disruption, mitochondrial cytochrome c (cyt c) translocation to the cytoplasm, and subsequent caspase-9 and caspase-3 activation. Z-VAD-FMK prevented caspase-3 activation and apoptosis and decreased BNIP-3 (Bcl-2/adenovirus E1B 19-kDa interacting protein 3) expression levels and apoptosis-inducing factor/endonuclease G (AIF/Endo G) translocation. Simultaneously, cadmium induced prominent BNIP-3 expression in the mitochondria and cytoplasmic AIF/Endo G translocation to the nucleus. BNIP-3 silencing significantly prevented AIF and Endo G translocation and decreased the apoptosis rate, cyt c release, and caspase-9 and caspase-3 activation. These results suggest that BNIP-3 is involved in the caspase-independent apoptotic pathway and is located upstream of AIF/Endo G; both the caspase-dependent and caspase-independent pathways are involved in cadmium-induced rPT cell apoptosis and act synergistically.
PMCID: PMC5115828  PMID: 27861627
17.  Digitor/dASCIZ Has Multiple Roles in Drosophila Development 
PLoS ONE  2016;11(11):e0166829.
In this study we provide evidence that the spindle matrix protein Skeletor in Drosophila interacts with the human ASCIZ (also known as ATMIN and ZNF822) ortholog, Digitor/dASCIZ. This interaction was first detected in a yeast two-hybrid screen and subsequently confirmed by pull-down assays. We also confirm a previously documented function of Digitor/dASCIZ as a regulator of Dynein light chain/Cut up expression. Using transgenic expression of a mCitrine-labeled Digitor construct, we show that Digitor/dASCIZ is a nuclear protein that is localized to interband and developmental puff chromosomal regions during interphase but redistributes to the spindle region during mitosis. Its mitotic localization and physical interaction with Skeletor suggest the possibility that Digitor/dASCIZ plays a direct role in mitotic progression as a member of the spindle matrix complex. Furthermore, we have characterized a P-element insertion that is likely to be a true null Digitor/dASCIZ allele resulting in complete pupal lethality when homozygous, indicating that Digitor/dASCIZ is an essential gene. Phenotypic analysis of the mutant provided evidence that Digitor/dASCIZ plays critical roles in regulation of metamorphosis and organogenesis as well as in the DNA damage response. In the Digitor/dASCIZ null mutant larvae there was greatly elevated levels of γH2Av, indicating accumulation of DNA double-strand breaks. Furthermore, reduced levels of Digitor/dASCIZ decreased the resistance to paraquat-induced oxidative stress resulting in increased mortality in a stress test paradigm. We show that an early developmental consequence of the absence of Digitor/dASCIZ is reduced third instar larval brain size although overall larval development appeared otherwise normal at this stage. While Digitor/dASCIZ mutant larvae initiate pupation, all mutant pupae failed to eclose and exhibited various defects in metamorphosis such as impaired differentiation, incomplete disc eversion, and faulty apoptosis. Altogether we provide evidence that Digitor/dASCIZ is a nuclear protein that performs multiple roles in Drosophila larval and pupal development.
PMCID: PMC5115829  PMID: 27861562
18.  Seasonal and Inter-Annual Variations in Carbon Dioxide Exchange over an Alpine Grassland in the Eastern Qinghai-Tibetan Plateau 
PLoS ONE  2016;11(11):e0166837.
This work analyzed carbon dioxide exchange and its controlling factors over an alpine grassland on the eastern Qinghai-Tibetan Plateau. The main results show that air temperature and photosynthetically active radiation are two dominant factors controlling daily gross primary production. Soil temperature and soil water content are the main factors controlling ecosystem respiration. Canopy photosynthetic activity is also responsible for the variation of daily ecosystem respiration other than environmental factors. No clear correlation between net ecosystem exchange and environmental factors was observed at daily scale. Temperature sensitive coefficient was observed to increase with larger soil water content. High values of temperature sensitive coefficient occurred during the periods when soil water content was high and grass was active. Annual integrated net ecosystem exchange, gross primary production and ecosystem respiration were -191, 1145 and 954 g C m-2 for 2010, and -250, 975 and 725 g C m-2 for 2011, respectively. Thus, this alpine grassland was a moderate carbon sink in both of the two years. Compared to alpine grasslands on the Qinghai-Tibetan Plateau, this alpine grassland demonstrated a much greater potential for carbon sequestration than others. Annual precipitation is a dominant factor controlling the variation of annual net ecosystem exchange over this grassland. The difference in gross primary production between the two years was not caused by the variation in annual precipitation. Instead, air temperature and the length of growing season had an important impact on annual gross primary production. Variation of annual ecosystem respiration was closely related to annual gross primary production and soil water content during the growing season.
PMCID: PMC5115830  PMID: 27861616
19.  Multiplex Real-Time PCR Assay Targeting Eight Parasites Customized to the Korean Population: Potential Use for Detection in Diarrheal Stool Samples from Gastroenteritis Patients 
PLoS ONE  2016;11(11):e0166957.
Intestinal parasitic diseases occur worldwide and can cause diarrhea or gastroenteritis; however, their diagnosis is quite difficult, especially in low-endemism countries. We developed a multiplex real-time PCR assay for detection of eight intestinal parasites and prospectively evaluated it for patients with gastroenteritis. The assay targeted Cryptosporidium parvum, Giardia lamblia, Entamoeba histolytica, Blastocystis hominis, Dientamoeba fragilis, Clonorchis sinensis, Metagonimus yokogawai, and Gymnophalloides seoi. Performance characteristics were evaluated based on recovery after DNA extraction, analytical sensitivity, specificity, reproducibility, cross-reactivity, and interference characteristics. Clinical performance was validated against microscopy on 123 diarrheal samples. The assay demonstrated strong correlations between DNA concentrations and Ct values (R2, 0.9924–0.9998), and had a high PCR efficiency (83.3%–109.5%). Polymerase chain reactions detected as few as 10–30 copies of genomic DNA, and coefficient of variance was 0–7%. There was no cross-reactivity to the other 54 microorganisms tested. Interference occurred only in presence of high concentrations of erythrocytes or leukocytes. This assay had a higher correct identification rate (100.0% vs. 90.2%) and lower incorrect ID rate (0.0% vs. 9.8%) when compared to microscopy. Overall, this assay showed a higher sensitivity (100.0%; 95% confidence interval [CI] of 80.5–100.0) than microscopy (29.4%; 95% CI 10.31–55.96), and the specificity levels were comparable for both methods (100.0%; 95% CI 96.58–100.0). This newly developed multiplex real-time PCR assay offers a potential use for detecting intestinal parasitic pathogens customized to the Korean population.
PMCID: PMC5115832  PMID: 27861635
20.  Do People Eat the Pain Away? The Effects of Acute Physical Pain on Subsequent Consumption of Sweet-Tasting Food 
PLoS ONE  2016;11(11):e0166931.
Sweet tasting foods have been found to have an analgesic effect. Therefore people might consume more sweet-tasting food when they feel pain. In Study 1, participants were randomly assigned to a pain or non-pain condition and their consumption of cheesecake was measured. Participants ate more cheesecake (a sweet-tasting food) following a painful experience than a non-painful one. In Study 2, participants were randomly assigned to a painful experience or a resource depleting experience (i.e., squeezing a handgrip) and then were asked to taste test two foods, one sweet and one not sweet. Participants ate more sweet-tasting food following a painful experience than a non-painful or a resource-depleting experience. These differences were not present for consumption of non-sweet food. Further, habitual self-control predicted consumption of sweet-tasting food when in pain, with those lower in self-control particularly likely to eat more. Results suggest that people do eat more sweet-tasting food when they feel pain, particularly if they are not in the habit of controlling their impulses. These findings have implications for health given rising rates of obesity and pain-related diagnoses.
PMCID: PMC5115833  PMID: 27861581
21.  Prazosin Can Prevent Glucocorticoid Mediated Capillary Rarefaction 
PLoS ONE  2016;11(11):e0166899.
Glucocorticoids (GC) elicit skeletal muscle capillary rarefaction, which can subsequently impair blood distribution and muscle function; however, the mechanisms have not been established. We hypothesized that CORT would inhibit endothelial cell survival signals but that treatment with the alpha-1 adrenergic receptor inhibitor prazosin, which leads to angiogenesis in skeletal muscle of healthy rats, would reverse these effects and induce angiogenesis within the skeletal muscle of corticosterone (CORT)-treated rats. Male Sprague Dawley rats were implanted subcutaneously with CORT pellets (400 mg/rat), with or without concurrent prazosin treatment (50mg/L in drinking water), for 1 or 2 weeks. Skeletal muscle capillary rarefaction, as indicated by a significant reduction in capillary-to-fiber ratio (C:F), occurred after 2 weeks of CORT treatment. Concurrent prazosin administration prevented this capillary rarefaction in CORT-treated animals but did not induce angiogenesis or arteriogenesis as was observed with prazosin treatment in control rats. CORT treatment reduced the mRNA level of Angiopoietin-1 (Ang-1), which was partially offset in the muscles of rats that received 2 weeks of co-treatment with prazosin. In 2W CORT animals, prazosin treatment elicited a significant increase in vascular endothelial growth factor-A (VEGF-A) mRNA and protein. Conversely prazosin did not rescue CORT-induced reductions in transforming growth factor beta-1 (TGFβ1 and matrix metalloproteinase-2 (MMP-2) mRNA. To determine if CORT impaired shear stress dependent signaling, cultured rat skeletal muscle endothelial cells were pre-treated with CORT (600nM) for 48 hours, then exposed to 15 dynes/cm2 shear stress or maintained with no flow. CORT blunted the shear stress-induced increase in pSer473 Akt, while pThr308 Akt, ERK1/2 and p38 phosphorylation and nitric oxide (NO) production were unaffected. This study demonstrates that GC-mediated capillary rarefaction is associated with a reduction in Ang-1 mRNA within the skeletal muscle microenvironment and that concurrent prazosin treatment effectively increases VEGF-A levels and prevents capillary loss.
PMCID: PMC5115834  PMID: 27861620
22.  Highlights in breast cancer from ASCO 2016 
ESMO Open  2016;1(5):e000106.
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A critical review of the highlights in breast cancer research from the American Society of Clinical Oncology (ASCO) meeting 2016, held in June 2016 in Chicago, is presented in this podcast. Considering the most interesting and practice-changing studies reported at the meeting, in the advanced breast cancer setting several important confirmatory studies on the use of CDK inhibitors, and studies on using data on oestrogen receptor mutations to guide choices of endocrine therapy are discussed. The PHEREXA trial, in which a combination trastuzumab and pertuzumab was studied in the advanced setting is also considered. In the early breast cancer setting, the KRISTINE and ADAPT studies evaluated the potential of dual blockade in HER2-positive tumours. In HER2-negative early breast cancer several trials are also discussed with respect to types of adjuvant chemotherapy. The results of the MA.17R trial, which considered extending the duration of adjuvant endocrine therapy, are also discussed. The potential role of immunotherapy in breast cancer therapy is briefly mentioned.
PMCID: PMC5115812  PMID: 27900208
breast cancer
23.  Announcements 
Clinical Kidney Journal  2016;9(5):763.
PMCID: PMC5036912
24.  Optic Nerve Head Development in Healthy Infants and Children Using Handheld Spectral-Domain Optical Coherence Tomography 
Ophthalmology  2016;123(10):2147-2157.
To determine feasibility of optic nerve head (ONH) imaging and to characterize ONH development in full-term infants without sedation using handheld spectral-domain optical coherence tomography (SD OCT).
Prospective cross-sectional study.
Three hundred fifty-two children aged between 1 day and 13 years.
All participants were imaged using handheld SD OCT without sedation during a single scan session. The percentage of successful scans was calculated. Interexaminer reproducibility and differences between right and left eyes were assessed using intraclass correlation coefficients (ICCs). Images were analyzed using ImageJ software. The developmental trajectories over time for ONH parameters were calculated using fractional polynomial modelling.
Main Outcome Measures
Disc and cup diameter (expressed as distance in micrometers and visual angle in degrees), cup depth, Bruch's membrane opening–minimum rim width (BMO-MRW), retinal thickness, and retinal nerve fiber layer (RNFL; 1700 μm and 6° from the disc center).
On average, 70% of participants were imaged successfully. Interexaminer reliability was excellent (ICC, >0.89) for diametric and retinal thickness parameters. Right and left eyes were similar for diametric measurements (ICC, >0.79), but more variable for nasal BMO-MRW, RNFL, and retinal thickness. The mean disc and cup diameter increase by 30% and 40%, respectively, between birth and 13 years of age when expressed as a distance measure, but remained constant (at 5°–5.5° and 2°, respectively) when expressed as a visual angle with reference to the eye nodal point. The peripapillary temporal RNFL demonstrated a marked initial decrease of nearly 35% between birth and approximately 18 months of age. This was followed by a slow increase up to 12 years of age when measured at 1700 μm from the disc center, although there was little change when measured at 6° from the disc center.
We demonstrated feasibility of handheld SD OCT imaging of the ONH in full-term infants and children without anaesthesia or sedation. This is the first in vivo handheld SD OCT study to describe the development of ONH parameters during the critical early years of visual maturation. Our results provide a normative database for use in routine practice and further studies of ONH pathologic features.
PMCID: PMC5036922  PMID: 27521172
BMO-MRW, Bruch's membrane opening–minimum rim width; C/Dfund, cup-to-disc ratio described by fundoscopy; C/DOCT, cup-to-disc ratio defined using OCT measurements; D, diopter; ICC, intraclass correlation coefficient; ILM, inner limiting membrane; OCT, optical coherence tomography; ONH, optic nerve head; RNFL, retinal nerve fiber layer; SD, spectral-domain
25.  Investigating intra-host and intra-herd sequence diversity of foot-and-mouth disease virus☆ 
Due to the poor-fidelity of the enzymes involved in RNA genome replication, foot-and-mouth disease (FMD) virus samples comprise of unique polymorphic populations. In this study, deep sequencing was utilised to characterise the diversity of FMD virus (FMDV) populations in 6 infected cattle present on a single farm during the series of outbreaks in the UK in 2007. A novel RT–PCR method was developed to amplify a 7.6 kb nucleotide fragment encompassing the polyprotein coding region of the FMDV genome. Illumina sequencing of each sample identified the fine polymorphic structures at each nucleotide position, from consensus level changes to variants present at a 0.24% frequency. These data were used to investigate population dynamics of FMDV at both herd and host levels, evaluate the impact of host on the viral swarm structure and to identify transmission links with viruses recovered from other farms in the same series of outbreaks. In 7 samples, from 6 different animals, a total of 5 consensus level variants were identified, in addition to 104 sub-consensus variants of which 22 were shared between 2 or more animals. Further analysis revealed differences in swarm structures from samples derived from the same animal suggesting the presence of distinct viral populations evolving independently at different lesion sites within the same infected animal.
•NGS was used to characterise FMD viruses in clinical samples from cattle.•5 consensus and 104 sub-consensus level substitutions were identified.•Distinct virus swarms were found in different lesions within the same host.•Only 22 sub-consensus substitutions were shared between 2 or more animals.•Data suggest that FMDV evolves independently at different lesion sites.
PMCID: PMC5036933  PMID: 27421209
Foot-and-mouth disease; Next generation sequencing; Variant analysis; Phylogenetics; Viral diversity

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