Mitochondria are highly motile organelles that constantly undergo fission and fusion. Impairment of mitochondrial dynamics is associated with mitochondrial dysfunction and is frequently linked to the pathogenesis of neurodegenerative diseases and cancer. We have previously shown that biallelic inactivation of the suppressor of cytokine signaling 6 (SOCS6) gene is a frequent event in human gastric cancer. In this study, we recapitulated the event of SOCS6 loss using a Lentivirus-based knockdown approach, and demonstrated the linkage between SOCS6 depletion and the suppression of programmed cell death. SOCS6 promotes intrinsic apoptosis, with increased Bax conformational change, mitochondrial targeting, and oligomerization. Most importantly, SOCS6 is targeted to mitochondria and induces mitochondrial fragmentation mediated through an increase in DRP1 fission activity. Here, we show that SOCS6 forms complex with DRP1 and the mitochondrial phosphatase PGAM5, attenuates DRP1 phosphorylation, and promotes DRP1 mitochondrial translocation. Based on mutation analyses, SOCS6-mediated apoptosis is tightly coupled to its ability to induce mitochondrial fission. This study demonstrates an important role for SOCS6 in modulating mitochondrial dynamics and apoptosis.
apoptosis; DRP1; mitochondrial dynamic; PGAM5; SOCS6
We aimed to investigate the mechanism of shaking as a prenatal stressor impacting the development of the offspring and Chinese medicines correcting the alterations. Pregnant rats were randomized into earthquake simulation group (ESG), herbal group (HG) which received herbal supplements in feed after shaking, and control group (CG). Findings revealed body weight and open field test (OFT) score of ESG offspring were statistically inferior to the CG and HG offspring. The corticosterone levels of ESG were higher than those of CG but not than HG. The dopamine level of ESG was slightly lower than that of the CG and of HG was higher than that of ESG. The 5-HT of ESG was higher than CG and HG. The growth hormone level of the ESG was significantly lower than ESG but not than CG. Gene expression profile showed 81 genes upregulated and 39 genes downregulated in ESG versus CG, and 60 genes upregulated and 28 genes downregulated in ESG versus HG. Eighty-four genes were found differentially expressed in ESG versus CG comparison and were normalized in ESG versus HG. We conclude that maternal shaking negatively affected physical and nervous system development, with specific alterations in neurohormones and gene expression. Chinese herbal medicine reduced these negative outcomes.
Barrett’s oesophagus is associated with abdominal obesity. Adiponectin is a peptide that is secreted from adipocytes and circulates in three multimeric forms: low molecular weight (LMW), middle molecular weight (MMW), and high molecular weight (HMW). The anti-inflammatory effects of adiponectin are specific to individual multimers, with LMW being most anti-inflammatory. We postulated that circulating levels of adiponectin and its multimers would be associated with the risk of Barrett’s oesophagus.
Outpatient clinic in North Carolina, USA.
Cases of Barrett’s oesophagus and controls undergoing upper endoscopy for gastro-oesophageal reflux disease (GORD).
Main outcome measures
Adjusted odds ratios of plasma adiponectin levels and its multimers for Barrett’s oesophagus.
There were 112 cases of Barrett’s oesophagus and 199 GORD controls. Total adiponectin was not associated with Barrett’s oesophagus (3rd tertile vs 1st tertile adjusted odds ratio (aOR) = 0.88; 95% confidence interval (CI) = 0.44 to 1.78). High levels of LMW adiponectin were associated with a decreased risk of Barrett’s oesophagus (3rd tertile vs 1st tertile aOR = 0.33; 95% CI, 0.16 to 0.69), and a high LMW/total ratio appeared particularly inversely associated with Barrett’s oesophagus (3rd tertile vs 1st tertile aOR = 0.27; 95% CI, 0.13 to 0.58).
High levels of LMW adiponectin are associated with a decreased risk of Barrett’s oesophagus among patients with GORD. Further human studies are required to confirm these findings, and in vitro studies are needed to understand if there is a mechanism whereby adiponectin may affect Barrett’s metaplasia.
The goal of this project was to identify key effective components of ADVANCE, a family-centred preoperative intervention programme, through the use of a dismantling approach. ADVANCE was previously demonstrated to be more effective than parental presence and just as effective as midazolam in reducing children's preoperative anxiety. The total programme, however, may be difficult to implement in hospitals across the country.
Subjects in this follow-up dismantling report were 96 children aged 2–10 who were part of the original study and who underwent anaesthesia and surgery. Baseline characteristics, parental adherence to the components of ADVANCE, and child and parent anxiety were assessed.
We found that greater parental adherence to the ADVANCE intervention was associated with lower child anxiety before surgery. The two components of ADVANCE that emerged as having a significant impact on children's anxiety were practising with the anaesthesia mask at home and parental planning and use of distraction in the preoperative holding area. In fact, not only did children experience significantly less preoperative anxiety when their parents were adherent to mask practise and use of distraction, their anxiety tended to remain stable and relatively low throughout the preoperative period.
Shaping and exposure (i.e. practise with the anaesthesia mask) and parental use of distraction in the surgical setting are two beneficial components that could be included in preoperative preparation programmes that will be designed in the future.
children; surgery, paediatric; surgery, preoperative period
Patients with high-grade gliomas are treated with surgery followed by chemoradiation. The risk factors and implications of neurological side effects are not known.
Acute and late ⩾ grade 3 neurological toxicities (NTs) were analysed among 2761 patients from 14 RTOG trials accrued from 1983 to 2003. The association between acute and late toxicity was analysed using a stepwise logistic regression model. The association between the occurrence of acute NT and survival was analysed as an independent variable.
There were 2610 analysable patients (86% glioblastoma, 10% anaplastic astrocytoma). All received a systemic agent during radiation (83% chemotherapy, 17% biological agents). Median radiation dose was 60 Gy. There were 182 acute and 83 late NT events. On univariate analysis, older age, poor performance status, aggressive surgery, pre-existing neurological dysfunction, poor mental status and twice-daily radiation were associated with increased acute NT. In a stepwise logistic regression model the occurrence of acute NT was significantly associated with late NT (OR=2.40; 95% CI=1.2–4.8; P=0.014). The occurrence of acute NT predicted poorer overall survival, independent of recursive partitioning analysis class (median 7.8 vs 11.8 months).
Acute NT is significantly associated with both late NT and overall survival.
glioblastoma; toxicity; normal tissue effects; radiation therapy
Although protein expression is regulated both temporally and spatially, most proteins have an intrinsic, “typical” range of functionally effective abundance levels. These extend from a few molecules per cell for signaling proteins, to millions of molecules for structural proteins. When addressing fundamental questions related to protein evolution, translation and folding, but also in routine laboratory work, a simple rough estimate of the average wild type abundance of each detectable protein in an organism is often desirable. Here, we introduce a meta-resource dedicated to integrating information on absolute protein abundance levels; we place particular emphasis on deep coverage, consistent post-processing and comparability across different organisms. Publicly available experimental data are mapped onto a common namespace and, in the case of tandem mass spectrometry data, re-processed using a standardized spectral counting pipeline. By aggregating and averaging over the various samples, conditions and cell-types, the resulting integrated data set achieves increased coverage and a high dynamic range. We score and rank each contributing, individual data set by assessing its consistency against externally provided protein-network information, and demonstrate that our weighted integration exhibits more consistency than the data sets individually. The current PaxDb-release 2.1 (at http://pax-db.org/) presents whole-organism data as well as tissue-resolved data, and covers 85,000 proteins in 12 model organisms. All values can be seamlessly compared across organisms via pre-computed orthology relationships.
Acute ethanol intoxication increases the production of reactive oxygen species (ROS). Hemorrhagic shock with subsequent resuscitation (H/R) also induces ROS resulting in cellular and hepatic damage in vivo. We examined the role of acute ethanol intoxication upon oxidative stress and subsequent hepatic cell death after H/R. 14 h before H/R, rats were gavaged with single dose of ethanol or saline (5 g/kg, EtOH and ctrl; H/R_EtOH or H/R_ctrl, resp.). Then, rats were hemorrhaged to a mean arterial blood pressure of 30 ± 2 mmHg for 60 min and resuscitated. Two control groups underwent surgical procedures without H/R (sham_ctrl and sham_EtOH, resp.). Liver tissues were harvested at 2, 24, and 72 h after resuscitation. EtOH-gavage induced histological picture of acute fatty liver. Hepatic oxidative (4-hydroxynonenal, 4-HNE) and nitrosative (3-nitrotyrosine, 3-NT) stress were significantly reduced in EtOH-gavaged rats compared to controls after H/R. Proapoptotic caspase-8 and Bax expressions were markedly diminished in EtOH-gavaged animals compared with controls 2 h after resuscitation. EtOH-gavage increased antiapoptotic Bcl-2 gene expression compared with controls 2 h after resuscitation. iNOS protein expression increased following H/R but was attenuated in EtOH-gavaged animals after H/R. Taken together, the data suggest that acute EtOH-gavage may attenuate H/R-induced oxidative stress thereby reducing cellular injury in rat liver.
The role of secondary refrigerants is expected to grow as the focus on the reduction of greenhouse gas emissions increases. The effectiveness of secondary refrigerants can be improved when phase changing media are introduced in place of single phase media. Operating at temperatures below the freezing point of water, ice slurry facilitates several efficiency improvements such as reductions in pumping energy consumption as well as lowering the required temperature difference in heat exchangers due to the beneficial thermo-physical properties of ice slurry. Research has shown that ice slurry can be engineered to have ideal ice particle characteristics so that it can be easily stored in tanks without agglomeration and then be extractable for pumping at very high ice fraction without plugging. In addition ice slurry can be used in many direct contact food and medical protective cooling applications. This paper provides an overview of the latest developments in ice slurry technology.
Ice slurry; cold storage; food industry; surgery; protective hypothermia
Activation of the vagal afferents by noxious gastrointestinal stimuli suggests that vagal afferents may play a complex role in visceral pain processes. The contribution of the vagus nerve to visceral pain remains unresolved. Previous studies reported that patients following chronic vagotomy have lower pain thresholds. The patient with irritable bowel syndrome has been shown alteration of vagal function. We hypothesize that vagal afferent nerves modulate visceral pain. Visceromotor responses (VMR) to graded colorectal distension (CRD) were recorded from the abdominal muscles in conscious rats. Chronic subdiaphragmatic vagus nerve sections induced 470, 106, 51, and 54% increases in VMR to CRD at 20, 40, 60 and 80 mmHg, respectively. Similarly, at light level of anesthesia, topical application of lidocaine to the subdiaphragmatic vagus nerve in rats increased VMR to CRD. Vagal afferent neuronal responses to low or high-intensity electrical vagal stimulation (EVS) of vagal afferent Aδ or C fibers were distinguished by calculating their conduction velocity. Low-intensity EVS of Aδ fibers (40 μA, 20 Hz, 0.5 ms for 30 s) reduced VMR to CRD at 40, 60, and 80 mmHg by 41, 52, and 58%, respectively. In contrast, high-intensity EVS of C fibers (400 μA, 1 Hz, 0.5 ms for 30 s) had no effect on VMR to CRD. In conclusion, we demonstrated that vagal afferent nerves modulate visceral pain. Low-intensity EVS that activates vagal afferent Aδ fibers reduced visceral pain. Thus EVS may potentially have a role in the treatment of chronic visceral pain.
colorectal distension; vagal afferent Aδ or C fibers; visceromotor responses
Second Generation high-throughput sequencing technologies have revolutionized the genome sequencing applications and will ultimately have great impact on personalized medicine. The increase in capacity of both the AB/Life Technologies SOLiD 4.0 and Illumina HiSeq instrumentation and the ability of the platforms to multiplex samples has led to process innovations impacting many ongoing projects at the HGSC. Applications have ranged from regional and whole exome capture sequencing to the use of whole genome shotgun for deep coverage and determining structural rearrangements. Internal advancements have complemented the higher capacity instrumentation through the implementation of library automation, low DNA input samples, capture hybridization multiplexing and application of read mapping tools such as BFAST and BWA. Development of sample intake procedures, LIMS tracking and defined reporting metrics has enabled NexGen sequencing pipelines that can effectively deliver targeted and whole genome shotgun data for thousands of samples. These technical advancements to the pipeline have allowed us to achieve a rate of ∼1500 libraries/captures per month. To date the center has completed over 5000 exome and regional capture libraries for The Cancer Genome Atlas (TCGA), NIMH Autism, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE-S) and 1000 Genomes Project. Development of these applications and methods will be discussed along with key data metrics, process management and pipeline organization.
Novel therapeutic approaches for endometriosis based on molecular strategies may prove to be useful. Conditionally replicative adenoviruses (CRAds) are designed to exploit key differences between target and normal cells. The wild-type adenovirus (Adwt) promoter can be replaced by tissue-specific promoters, allowing viral replication only in target cells. Viral infectivity can be enhanced by altering Ad tropism via fiber modification. We investigated whether CRAds can be used to target endometriosis and determined the most efficient transcriptional- and transductional-targeting strategy.
An in vitro study was carried out using human endometriotic cell lines, 11Z (epithelial) and 22B (stromal), normal human ovarian surface epithelial cell line (NOSE006) and primary human endometriosis cells. A total of 9 promoters and 12 Ad tropism modifications were screened by means of a luciferase reporter assay. From this screening data, three CRAds (CRAd-S-pK7, CRAd-S-RGD, CRAd-S-F5/3σ1, all incorporating the survivin promoter but with different fiber modifications) were selected to perform experiments using Adwt and a replication-deficient virus as controls. CRAds were constructed using a plasmid recombination system. Viral-binding capacity, rates of entry and DNA replication were evaluated by quantitative real-time PCR of viral genome copy. Cell-killing effects were determined by crystal violet staining and a cell viability assay for different concentrations of viral particles per cell.
Comparison of promoters demonstrated that the survivin promoter exhibited the highest induction in both endometriotic cell lines. Among the fiber-modified viruses, the polylysine modification (pK7) showed the best infection enhancement. CRAd-S-pK7 was validated as the optimal CRAd to target endometriosis in terms of binding ability, entry kinetics, DNA replication and cell-killing effect. CRAd-S-pK7 also exhibited a high level of DNA replication in primary endometriosis cells.
CRAd-S-pK7 has the best infection and cell-killing effect in the context of endometriosis. It could prove to be a useful novel method to target refractory cases of endometriosis.
endometriosis; gene therapy; replicative adenovirus; survivin; targeting
To determine the role of Smad1 in bone development and postnatal bone formation.
Col2a1-Cre transgenic mice were bred with Smad1fx/fx mice to produce chondrocyte-specific Smad1 conditional knockout (cKO) mice. Embryonic skeletal preparation and staining were performed, alkaline phosphatase activity (ALP) and relative gene expression were examined in isolated primary cells. Smad1fx/fx mice were also bred with Col1a1-Cre transgenic mice to produce osteoblast-specific Smad1 cKO mice. Postnatal bone formation was assessed by micro-computed tomography (μCT) and histological analyses in 2-month-old mice. Mineralized bone nodule formation assay, 5-bromo-2′-deoxy-uridine (BrdU) labeling and gene expression analysis were performed.
Mice with chondrocyte- and osteoblast-specific deletion of the Smad1 gene are viable and fertile. Calvarial bone development was delayed in chondrocyte-specific Smad1 cKO mice. In osteoblast-specific Smad1 cKO mice, BMP signaling was partially inhibited and mice developed an osteopenic phenotype. Osteoblast proliferation and differentiation were impaired in osteoblast-specific Smad1 cKO mice.
Smad1 plays an essential role in bone development and postnatal bone formation.
Smad1; Conditional knockout; BMP signaling; Chondrocyte; Osteoblast
The GG genotype of the interleukin (IL)-10 promoter polymorphism in position -1082 (-1082GG) has been associated with increased IL-10 production. The current authors hypothesised that the -1082GG genotype is associated with the development of, and outcomes in, acute respiratory distress syndrome (ARDS).
A nested case-control study was conducted in 211 Caucasian cases of ARDS and 429 controls who were admitted to an intensive care unit with sepsis, trauma, aspiration or massive transfusions. Cases were followed for organ failure and 60-day mortality.
The -1082GG genotype was associated with the development of ARDS, but only in the presence of a significant interaction between the -1082GG genotype and age. Among patients with ARDS, the -1082GG genotype was associated with decreased severity of illness on admission, lower daily organ dysfunction scores and lower 60-day mortality.
In conclusion, the high interleukin-10-producing -1082GG genotype may be associated with variable odds for acute respiratory distress syndrome development depending on age. Among those with acute respiratory distress syndrome, the -1082GG genotype is associated with lower mortality and organ failure. Further studies are needed to confirm these findings.
Acute respiratory distress syndrome; interleukin-10; mortality; polymorphism
Multimodality treatments that combine conventional cancer therapies with antigen-specific immunotherapy have emerged as promising approaches for the control of cancer. In the current study, we have explored the effect of doxorubicin on the antigen-specific immune responses generated in mice vaccinated with calreticulin (CRT)/E6 and/or Ii-PADRE DNA. We observed that pretreatment with doxorubicin suppressed the E6-specific CD8+ T-cell immune responses generated by CRT/E6 DNA vaccination in vaccinated mice. In contrast, pretreatment with doxorubicin enhanced the PADRE-specific CD4+ T-cell immune responses generated by Ii-PADRE DNA vaccination. Furthermore, coadministration of Ii-PADRE DNA could not only reverse the suppression, but also enhanced the E6-specific CD8+ T-cell responses in CRT/E6-vaccinated mice pretreated with doxorubicin. Finally, treatment with doxorubicin followed by CRT/E6 combined with Ii-PADRE DNA vaccination led to enhanced antitumor effects and prolonged survival in TC-1 tumor-bearing mice. The clinical implications of the current study are discussed.
doxorubicin; DNA vaccine; calreticulin; E6; human papillomavirus
Structural chromosome aberrations are known hallmarks of many solid tumors. In the papillary form of thyroid cancer (PTC), for example, activation of the receptor tyrosine kinase (RTK) genes, ret or the neurotrophic tyrosine kinase receptor type I (NTRK1) by intra- or interchromosomal rearrangements have been suggested as a cause of the disease. The 1986 accident at the nuclear power plant in Chernobyl, Ukraine, led to the uncontrolled release of high levels of radioisotopes. Ten years later, the incidence of childhood papillary thyroid cancer (chPTC) near Chernobyl had risen by two orders of magnitude. Tumors removed from some of these patients showed aberrant expression of the ret RTK gene due to a ret/PTC1 or ret/PTC3 rearrangement involving chromosome 10. However, many cultured chPTC cells show a normal G-banded karyotype and no ret rearrangement. We hypothesize that the “ret-negative“ tumors inappropriately express a different oncogene or have lost function of a tumor suppressor as a result of chromosomal rearrangements, and decided to apply molecular and cytogenetic methods to search for potentially oncogenic chromosomal rearrangements in Chernobyl chPTC cases. Knowledge of the kind of genetic alterations may facilitate the early detection and staging of chPTC as well as provide guidance for therapeutic intervention.
thyroid cancer; radiation; Chernobyl; gene expression; chromosome aberration; translocation
To investigate the ability of high-field (9.4 T) magnetic resonance (MR) imaging to delineate porcine knee meniscal tissue structure and meniscal tears.
Materials and methods
Porcine knees were obtained from a local abattoir, and eight medial menisci with no visible defects were dissected. Lesions simulating longitudinal tears were created on two of the menisci. MR images of the menisci were obtained at 9.4 T using a three-dimensional (3D)-FLASH sequence. A detailed 3D internal architecture of the intact and injured menisci was demonstrated on high-resolution MR images.
High-resolution 3D MR imaging allowed visualisation of internal architecture of the meniscus and disruption to the internal structural network in damage models. The architecture of the porcine knee meniscus revealed by the MR scans appeared similar to the structures visualised by histology in previously reported studies.
High-field MRI is a non-destructive technique to examine the internal structural components and damage/wear of meniscal tissue. It has tremendous potential in the field of functional cartilage/meniscus biomechanics and biotribology.
Meniscus; MRI; Structure
We report the results of anatomical and vibrometric studies of the middle ear of the African clawed frog, Xenopus laevis. The cartilaginous tympanic disk of Xenopus shows pronounced sexual dimorphism, that of male frogs being much larger than that of females, relative to body size. The stapes footplate, however, is not enlarged in males. The cucullaris muscle was found to insert on the stapes in frogs of both sexes. Using laser interferometry to examine the response of middle ear structures to airborne sound, the stapes footplate was found to vibrate close to 180° out-of-phase with the tympanic disk across a range of frequencies, this resembling the relationship between tympanic membrane and footplate movement previously described in ranid frogs. By contrast, whereas there is a pronounced difference in vibration velocity between tympanic membrane and footplate in ranids, the footplate vibration velocity in Xenopus was found to be similar to that of the tympanic disk. This may be interpreted as an adaptation to improve the detection of sound underwater.
In general, measurements of solar ultraviolet (UV) radiation are related to horizontal surfaces. While the humans walking and standing outdoors expose to the natural solar UV radiation, their eyes, cheeks, extremities, trunks, or many other anatomical sites are close to vertical plane and random orient to different directions. In this study, we characterized the diurnal variations in solar UV on horizontal and vertical plane which may be helpful to obtain more relevant information on UV exposure of humans.
The UV exposure on vertical and horizontal plane were measured using Solar-UV Sensors in Shenyang (41°51″N, 123°27″E) and Sanya (18°19′N, 109°42′E), PR China.
As the well known, the diurnal variations in solar UV on horizontal plane in a sunny day exhibited unimodal distributions, reached a single UV peak exposure at around solar noon. However, the diurnal variations on vertical plane presented bimodal distributions, with two peaks in summer in Shenyang and Sanya, and a unimodal distribution in winter in Shenyang. In spring and autumn in Shenyang, the UV exposure around noon were slightly flat with no significant peaks but relative high. When the Solar Elevation Angle (SEA) is about 40°, the vertical plane may potentially receiving maximal unweighted total solar UV radiation exposures.
The results potentially showed that the protection of some vertical and near-vertical anatomical sites of human body from high UV exposure should not only focused on the periods of before and after noon especially in high SEA places.
UV radiation; Solar radiation; UV exposure; Horizontal plane; Vertical plane
The Affymetrix Gene 1.0 ST arrays provide an alternative platform for performing expression analysis than traditional 3' gene expression analysis arrays. These arrays offers several advantages, including updated content, lower cost, and probe sets designed to span the entire length of a given transcript. However, since its release in 2007, adoption of this platform has been limited and questions remain as to optimal approaches for sample labeling and subsequent data analysis. To address these issues we compared two labeling chemistries to generate the biotinylated sense DNA using the Microarray Quality Control Consortium (MAQC) total RNA titration samples: Stratagene Universal Reference RNA (A), Ambion Human Brain RNA (B) and the two titration samples (C and D, consisting of 3:1 and 1:3 ratios of A to B, respectively). Samples were labeled in triplicate, using either the Affymetrix GeneChip® WT Sense Target Labeling kit or the NuGEN WT-Ovation™ Pico RNA Amplification System, and hybridized to the Human Gene 1.0 ST Array. We next evaluated different data preprocessing approaches for background correction, normalization and probe set summarization, including the RMA, PLIER and dCHIP methods. Statistical analysis was performed using the LIMMA package in R, to generate lists of significantly differentially expressed genes (P < 0.001) and a fold change > 2. Dependent upon the preprocessing method used, the Affymetrix labeling chemistry consistently identified 30-50% more significantly differentially expressed genes than were detected with the NuGEN chemistry. Analysis of titration data showed that both chemistries had similar performance, and enabled us to determine optimal data preprocessing approaches. Our data demonstrate that even though the NuGEN chemistry provides a solution for sample labeling limited amounts of starting material, it results in significant data compression. However, higher quality data is obtained with the Affymetrix WT Sense Target Labeling kit if sufficient starting material (100 ng) is available.
Recurrent event data analyses are usually conducted under the assumption that the censoring time is independent of the recurrent event process. In many applications the censoring time can be informative about the underlying recurrent event process, especially in situations where a correlated failure event could potentially terminate the observation of recurrent events. In this paper, we consider a semiparametric model of recurrent event data that allows correlations between censoring times and recurrent event process via frailty. This flexible framework incorporates both time-dependent and time-independent covariates in the formulation, while leaving the distributions of frailty and censoring times unspecified. We propose a novel semiparametric inference procedure that depends on neither the frailty nor the censoring time distribution. Large sample properties of the regression parameter estimates and the estimated baseline cumulative intensity functions are studied. Numerical studies demonstrate that the proposed methodology performs well for realistic sample sizes. An analysis of hospitalization data for patients in an AIDS cohort study is presented to illustrate the proposed method.
Comparable recurrence times; Frailty; Pairwise pseudolikelihood; Proportional rate model
Diffusion tensor imaging (DTI) studies have shown significant cross-sectional differences among normal controls (Bozzali et al., 2002), mild cognitive impairment (Robbins et al.) and Alzheimer’s disease (AD) patients in several fiber tracts in the brain, but longitudinal assessment is needed.
We studied 75 participants (25 NC, 25 amnestic MCI, and 25 mild AD) at baseline and 3 months later, with both imaging and clinical evaluations. Fractional anisotropy (Bozzali et al., 2002) was analyzed in regions of interest (ROIs) in: (1) fornix, (2) cingulum bundle, (3) splenium, and (4) cerebral peduncles. Clinical data included assessments of clinical severity and cognitive function. Cross-sectional and longitudinal differences in FA, within each ROI, were analyzed with generalized estimating equations (GEE).
Cross-sectionally, AD patients had lower FA than NC (p<0.05) at baseline and 3 months in the fornix and anterior portion of the cingulum bundle. Compared to MCI, AD cases had lower FA (p<0.05) in these regions and the splenium at 0 and 3 months. Both the fornix and anterior cingulum correlated across all clinical cognitive scores; lower FA in these ROIs corresponded to worse performance. Over the course of 3 months, when the subjects were clinically stable, the ROIs were also largely stable.
Using DTI, findings indicate FA is decreased in specific fiber tracts among groups of subjects that vary along the spectrum from normal to AD, and that this measure is stable over short periods of time. The fornix is a predominant outflow tract of the hippocampus and may be an important indicator of AD progression.
Periodontal disease is an inflammatory disorder with widespread morbidities involving both oral and systemic health. The primary goal of periodontal treatment is the regeneration of the lost or diseased periodontium. In this study, we retrospectively examined feasibility and safety of reconstructing the periodontal intrabony defects with autologous periodontal ligament progenitor (PDLP) implantation in three patients.
Materials and Methods
In this retrospective pilot study, we treated 16 teeth with at least one deep intrabony defect of probing depth (PD) ≥ 6 mm with PDLP transplantation and evaluated clinical outcome measures in terms of probing depth, gingival recession and attachment gain for a duration of 32–72 months. Furthermore, we compare PDLPs with standard PDL stem cells (PDLSCs) and confirmed that PDLPs possessed progenitor characters.
Clinical examination indicated that transplantation of PDLPs may provide therapeutic benefit for the periodontal defects. All treated patients showed no adverse effects during the entire course of follow up. We also found that PDLPs were analogous to PDLSCs in terms of high proliferation, expression of mesenchymal surface molecules, multipotent differentiation, and in vivo tissue regain. However, PDLPs failed to express scleraxis, a marker of tendon, as seen in PDLSCs.
This study demonstrated clinical and experimental evidences supporting a potential efficacy and safety of utilizing autologous PDL cells in the treatment of human periodontitis.
periodontal ligament progenitors; regeneration; periodontitis
The retinoic acid receptor-related orphan receptor (ROR) alpha has been demonstrated to regulate lipid metabolism. We were interested in the RORα1 dependent physiological functions in skeletal muscle. This major mass organ accounts for ∼40% of the total body mass and significant levels of lipid catabolism, glucose disposal and energy expenditure. We utilized the strategy of targeted muscle-specific expression of a truncated (dominant negative) RORα1ΔDE in transgenic mice to investigate RORα1 signaling in this tissue. Expression profiling and pathway analysis indicated that RORα influenced genes involved in: (i) lipid and carbohydrate metabolism, cardiovascular and metabolic disease; (ii) LXR nuclear receptor signaling and (iii) Akt and AMPK signaling. This analysis was validated by quantitative PCR analysis using TaqMan low-density arrays, coupled to statistical analysis (with Empirical Bayes and Benjamini–Hochberg). Moreover, westerns and metabolic profiling were utilized to validate the genes, proteins and pathways (lipogenic, Akt, AMPK and fatty acid oxidation) involved in the regulation of metabolism by RORα1. The identified genes and pathways were in concordance with the demonstration of hyperglycemia, glucose intolerance, attenuated insulin-stimulated phosphorylation of Akt and impaired glucose uptake in the transgenic heterozygous Tg-RORα1ΔDE animals. In conclusion, we propose that RORα1 is involved in regulating the Akt2-AMPK signaling pathways in the context of lipid homeostasis in skeletal muscle.
Feeding problems are an important area of neonatal morbidity that requires attention. We defined the feeding milestones related to transition to per oral feeding among premature infants based on gestational (GA) and postmenstrual ages (PMA), and elucidated the co-morbidity variables affecting with these skills.
Feeding progress was tracked during the first hospitalization in a retrospective study involving 186 infants. We measured the age at acquisition of first feedings, maximum gavage feedings and maximum oral feedings. Resource usage measures included the total length of hospital stay (LOS), duration of gavage tube and duration of respiratory support. Effects of perinatal and co-morbidity factors on the acquisition of feeding milestones were evaluated. ANOVA, t-test, Wilcoxon rank sum test, χ2 test, univariate and multivariate analysis, stepwise linear regression analysis and logistic regression analysis were applied as appropriate. Data were presented as mean±s.d., or as stated. P<0.05 was considered significant.
We stratified the data into three groups based on GA at birth: <28.0 weeks (group-1), 28.0 to 32.0 weeks (group-2) and 32.0 to 35.0 weeks (group-3). Compared with group-3, group-1 needed four-fold more ventilation and five-fold more continuous positive airway pressure (CPAP) duration (all P<0.001); whereas group-2 needed two-fold more CPAP duration. Age at first feed correlated with age at full gavage feedings and age at full oral feedings (r=0.53 and r=0.71, both P<0.0001). Age at full gavage feedings correlated with age at full oral feedings (r=0.81, P<0.0001). Univariate analysis was significant for GA age, hypotension, the effects of gastroesophageal reflux, and duration of ventilation and CPAP on the PMA at maximal oral feedings (all P<0.05); multivariate analysis for these variables was also significant (R
2=0.58, P<0.0001). The success rate for oral feedings at discharge accelerated with GA maturation and caffeine use; on the other hand, the need for respiratory support and management of positive blood culture were associated with failure rates (P<0.05).
Infants < 28 weeks GA have significant feeding delays with respect to initiation and progression to maximal gavage and oral feedings, as well as prolonged LOS. Infants >28 weeks GA attained successful feeding milestones by similar PMA. Specific aero-digestive co-morbidities significantly affected maximal oral feeding milestone. Delays in achieving maximum gavage and maximum oral feeding milestones suggest delays with the development of control and regulation of foregut motility.
feeding problems; prematurity; infant; milestones; morbidity