Hepatocellular carcinoma (HCC) represents an increasing fraction of liver transplant indications; the role of living donor liver transplant (LDLT) remains unclear. Recurrence and post-transplant mortality rates were compared in LDLT and deceased donor liver transplant (DDLT) patients with at least one potential living donor evaluated. HCC recurrence and post-transplant mortality were evaluated among 100 LDLT and 97 DDLT recipients in the Adult-to-Adult Living Donor Liver Transplantation Cohort Study. Mortality from date of evaluation of each recipient’s first potential living donor was analyzed. LDLT recipients had shorter time to transplant, were more likely to have tumors exceeding Milan criteria, higher alpha-fetoprotein levels, and less likely to have received pre-operative loco-regional therapy than DDLT recipients. Unadjusted 5-year HCC recurrence was significantly higher after LDLT (38%) than DDLT (11%), (p=0.0004). After adjustment for tumor characteristics, HCC recurrence remained significantly different between LDLT and DDLT recipients (hazard ratio (HR) = 2.35; p=0.04) for the overall cohort but not for recipients transplanted following the introduction of MELD prioritization. Five-year post-transplant survival was similar in LDLT and DDLT recipients from time of transplant (HR=1.32; p=0.27) and from date of LDLT evaluation (HR=0.73; p=0.36). We conclude that the higher recurrence observed after LDLT is likely due to differences in tumor characteristics, pre-transplant HCC management, and waiting time.
Recurrence; MELD score; Milan criteria; loco-regional therapy; survival
Clinical complications of sickle cell anemia begin in infancy. BABY HUG (ClinicalTrials.gov, NCT00006400) was a NHLBI-NICHD supported randomized phase III placebo-controlled trial of hydroxyurea (HU) in infants (recruited at 9–18 months) unselected for clinical severity with sickle cell anemia. This secondary analysis of data from BABY HUG examines the influence of anemia on the incidence of sickle cell related complications, and the impact of hydroxyurea therapy in altering these events by comparing children with lower (<25th percentile) and higher (>75th percentile) hemoglobin concentrations at study entry.
Infants were categorized by: 1) age-adjusted hemoglobin quartiles as determined by higher (Hi) and lower (Lo) hemoglobin concentrations at study entry (9 to12 months old: <8.0 gm/dL and >10.0gm/dL; 12 to 18 months old: <8.1 gm/dL and >9.9gm/dL) and 2) treatment arm (hydroxyurea or placebo). Four subgroups were created: placebo (PL) LoHb (n=25), PL HiHb (n=27), hydroxyurea (HU) LoHb (n=21), and HU HiHb (n=18). The primary and secondary endpoints of BABY HUG were analyzed by subgroup.
Infants with lower hemoglobin at baseline were more likely to have a higher incidence of clinical events (acute chest syndrome, pain crisis, fever) as well as higher TCD velocities and lower neuropsychological scores at study exit. Hydroxyurea reduced the incidence of these findings.
Infants with more severe anemia are at risk for increased clinical events that may be prevented by early initiation of hydroxyurea.
Sickle Cell Anemia; Hydroxyurea; Acute Chest Syndrome; Pain; Transcranial Doppler; Renal; Spleen
Ovarian cancer is the most lethal gynaecological cancer. Progression-free and overall survival is significantly related to surgical success and residual disease volume. It is unclear whether this survival advantage is due to an intrinsic biological element of the tumour cells which enables successful surgery and improved prognosis, or alternatively the number of tumour sustaining cells remaining irrespective of differences in biology.
A systematic review of the literature was performed identifying studies that have investigated the association between biomarkers and surgical outcomes. We attempted validation of these results using The Cancer Genome Atlas ovarian cancer data sets.
Thirty studies were identified of which sixteen determined protein expression, eight gene expression and one DNA methylation in association with surgical debulking. Individualised linear models adjusting for batch, stage and age identified only expression of the genes MTDH and insulin-like growth factor-1 receptor (IGF1R) to be significantly associated with debulking surgery (P<0.05, false discovery rate (FDR)<5%), although in the case of IGF1R this was in the opposite direction to previous findings.
The majority of studies are limited by design, include heterogeneous samples and lack adjustment for major confounding factors. High quality detailed clinical annotations should be routinely collected in future to more accurately evaluate biomarkers of surgical outcome.
ovarian cancer; debulking surgery; molecular biomarkers
The promise of epigenome-wide association studies and cancer-specific somatic DNA methylation changes in improving our understanding of cancer, coupled with the decreasing cost and increasing coverage of DNA methylation microarrays, has brought about a surge in the use of these technologies. Here, we aim to provide both a review of issues encountered in the processing and analysis of array-based DNA methylation data and a summary of the advantages of recent approaches proposed for handling those issues, focusing on approaches publicly available in open-source environments such as R and Bioconductor. We hope that the processing tools and analysis flowchart described herein will facilitate researchers to effectively use these powerful DNA methylation array-based platforms, thereby advancing our understanding of human health and disease.
DNA methylation; microarray; processing; analysis; bioconductor and R packages
Despite improved outcomes in multiple myeloma (MM), a cure remains elusive. However, even before the current therapeutic era, 5% of patients survived >10 years and we propose that immune factors contribute to this longer survival. We identified patients attending our clinic, who had survived >10 years (n=20) and analysed their blood for the presence of T-cell clones, T-regulatory cells (Tregs) and T helper 17 (Th17) cells. These results were compared with MM patients with shorter follow-up and age-matched healthy control donors. The frequency of cytotoxic T-cell clonal expansions in patients with <10 years follow-up (MM patients) was 54% (n=144), whereas it was 100% (n=19/19) in the long-survivors (LTS-MM). T-cell clones from MM patients proliferated poorly in vitro, whereas those from LTS-MM patients proliferated readily (median proliferations 6.1% and 61.5%, respectively (P<0.0001)). In addition, we found significantly higher Th17 cells and lower Tregs in the LTS-MM group when compared with the MM group. These results indicate that long-term survival in MM is associated with a distinct immunological profile, which is consistent with decreased immune suppression.
myeloma; T-cell clones; Tregs; Th17 cells
Peroxisome proliferator-activated receptor (PPAR)-γ modulates substrate metabolism and inflammatory responses. In experimental rats subjected to myocardial ischemia-reperfusion (I/R), thiazolidinedione PPAR-γ activators reduce infarct size and preserve left ventricular function. Troglitazone is the only PPAR-γ activator that has been shown to be protective in I/R in large animals. However, because troglitazone contains both α-tocopherol and thiazolidinedione moieties, whether PPAR-γ activation per se is protective in myocardial I/R in large animals remains uncertain. To address this question, 56 pigs were treated orally for 8 wk with troglitazone (75 mg·kg−1 ·day−1), rosiglitazone (3 mg·kg−1 ·day−1), or α-tocopherol (73 mg·kg−1 ·day−1, equimolar to troglitazone dose) or received no treatment. Pigs were then anesthetized and subjected to 90 min of low-flow regional myocardial ischemia and 90 min of reperfusion. Myocardial expression of PPAR-γ, determined by ribonuclease protection assay, increased with troglitazone and rosiglitazone compared with no treatment. Rosiglitazone had no significant effect on myocardial contractile function (Frank-Starling relations), substrate uptake, or expression of proinflammatory cytokines during I/R compared with untreated pigs. In contrast, preservation of myocardial contractile function and lactate uptake were greater and cytokine expression was attenuated in pigs treated with troglitazone or α-tocopherol compared with untreated pigs. Multivariate analysis indicated that presence of an α-tocopherol, but not a thiazolidinedione, moiety in the test compound was significantly related to greater contractile function and lactate uptake and lower cytokine expression during I/R. We conclude that PPAR-γ activation is not protective in a porcine model of myocardial I/R. Protective effects of troglitazone are attributable to its α-tocopherol moiety. These findings, in conjunction with prior rat studies, suggest interspecies differences in the response to PPAR-γ activation in the heart.
nuclear receptor; thiazolidinedione; energy metabolism; cytokine; ventricular function
Women with polycystic ovary syndrome (PCOS) have increased prevalence of cardiovascular (CV) risk factors. However, data on the incidence of CV events are lacking in this population.
Using Rochester Epidemiology Project resources, we conducted a retrospective cohort study comparing CV events in women with PCOS with those of women without PCOS in Olmsted County, Minnesota.
Between 1966 and 1988, 309 women with PCOS and 343 without PCOS were identified. Mean (SD) age at PCOS diagnosis was 25.0 (5.3) years; mean age at last follow-up was 46.7 years. Mean (SD) follow-up was 23.7 (13.7) years. Women with PCOS had a higher body mass index (29.4 kg/m2 vs 28.3 kg/m2; p=.01). Prevalence of type 2 diabetes mellitus and hypertension and levels of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and triglycerides were similar in the two groups. We observed no increase in CV events, including myocardial infarction (adjusted hazard ratio [HR] 0.74; 95% confidence interval [CI] 0.32 to 1.72; p=.48); coronary artery bypass graft surgery (adjusted HR 1.52; 95% CI 0.42 to 5.48; p=.52); death (adjusted HR 1.03; 95% CI, 0.29 to 3.71; p=.96); death due to CV disease (adjusted HR 5.67; 95% CI 0.51 to 63.7; p=.16); or stroke (adjusted HR 1.05; 95% CI 0.28 to 3.92; p=.94).
Although women with PCOS weighed more than controls, there was no increased prevalence of other CV risk factors. Furthermore, we found no increase in CV events. While prospective studies are needed to confirm these findings, women with PCOS do not appear to have adverse CV outcomes in midlife.
Cardiovascular disease; polycystic ovary syndrome; Rochester Epidemiology Project
Mutations that perturb the function of photoreceptor cyclic nucleotide-gated (CNG) channels are associated with several human retinal disorders, but the molecular and cellular mechanisms leading to photoreceptor dysfunction and degeneration remain unclear. Many loss-of-function mutations result in intracellular accumulation of CNG channel subunits. Accumulation of proteins in the endoplasmic reticulum (ER) is known to cause ER stress and trigger the unfolded protein response (UPR), an evolutionarily conserved cellular program that results in either adaptation via increased protein processing capacity or apoptotic cell death. We hypothesize that defective trafficking of cone photoreceptor CNG channels can induce UPR-mediated cell death. To test this idea, CNGA3 subunits bearing the R563H and Q655X mutations were expressed in photoreceptor-derived 661W cells with CNGB3 subunits. Compared to wild type, R563H and Q655X subunits displayed altered degradation rates and/or were retained in the ER. ER retention was associated with increased expression of UPR-related markers of ER stress and with decreased cell viability. Chemical and pharmacological chaperones (TUDCA, 4PBA, and the cGMP analog CPT-cGMP) differentially reduced degradation and/or promoted plasma-membrane localization of defective subunits. Improved subunit maturation was concordant with reduced expression of ER stress markers and improved viability of cells expressing localization-defective channels. These results indicate that ER stress can arise from expression of localization defective CNG channels, and may represent a contributing factor for photoreceptor degeneration.
Retinal disease; misfolding; chaperone; UPR; membrane localization; ion channel subunit
Memory decline commonly occurs among elderly individuals. This observation is often attributed to early neurodegenerative changes in the hippocampus and related brain regions. However, the contribution of vascular lesions, such as brain infarcts, to hippocampal integrity and age-associated memory decline remains unclear.
We studied 658 elderly participants without dementia from a prospective, community-based study on aging and dementia who received high-resolution structural MRI. Cortical and subcortical infarcts were identified, and hippocampal and relative brain volumes were calculated following standard protocols. Summary scores reflecting performance on tasks of memory, language, processing speed, and visuospatial function were derived from a comprehensive neuropsychological battery. We used multiple regression analyses to relate cortical and subcortical infarcts, hippocampal and relative brain volume, to measures of cognitive performance in domains of memory, language, processing speed, and visuospatial ability.
Presence of brain infarcts was associated with a smaller hippocampus. Smaller hippocampus volume was associated with poorer memory specifically. Brain infarcts were associated with poorer memory and cognitive performance in all other domains, which was independent of hippocampus volume.
Both hippocampal volume and brain infarcts independently contribute to memory performance in elderly individuals without dementia. Given that age-associated neurodegenerative conditions, such as Alzheimer disease, are defined primarily by impairment in memory, these findings have clinical implications for prevention and for identification of pathogenic factors associated with disease symptomatology.
Delimitation of species is an important and controversial area within evolutionary biology. Many species boundaries have been defined using morphological data. New genetic approaches now offer more objective evaluation and assessment of the reliability of morphological variation as an indicator that speciation has occurred. We examined geographic variation in morphology of the continuously distributed skink Chalcides mionecton from Morocco and used Bayesian analyses of nuclear and mitochondrial DNA (mtDNA) loci to examine: (i) their concordance with morphological patterns, (ii) support for species delimitation, (iii) timing of speciation, and (iv) levels of gene flow between species. Four digit individuals were found at sites between Cap Rhir (in the south) and the northern extreme of the range, whereas five-digit individuals were found in two disjunct areas: (i) south of Cap Rhir and (ii) the north of the range where they were often syntopic with four-digit individuals. The pattern of variation in generalized body dimensions was largely concordant with that in digit number, suggesting two general morphotypes. Bayesian analyses of population structure showed that individuals from sites south of Cap Rhir formed one genetic cluster, but that northern four- and five-digit individuals clustered together. Statistical support for delimitation of these genetic clusters into two species was provided by a recent Bayesian method. Phylogenetic–coalescent dating with external time calibrations indicates that speciation was relatively recent, with a 95% posterior interval of 0.46–2.66 mya. This postdates equivalent phylogenetic dating estimates of sequence divergence by approximately 1 Ma. Statistical analyses of a small number of independent loci provide important insights into the history of the speciation process in C. mionecton and support delimitation of populations into two species with distributions that are spatially discordant with patterns of morphological variation.
Methods; molecular ecology; population genetics
Approximately 215,000 people younger than 20 yr of age, or 1 in 500 children and adolescents, had diabetes in the United States in 2010 – and the incidence is rising. We still have insufficient knowledge about the precise mechanisms leading to the autoimmune mediated β-cell destruction in Type 1 diabetes, and the β-cell failure associated with insulin resistance in Type 2 diabetes. Long-term complications are similar: micro-and macrovascular disease occurs prematurely and presents an enormous burden on affected individuals, often as early as in middle age. In Type 1 diabetes, technological advances have clearly improved blood glucose management, but chronic peripheral over-insulinization remains a problem even with the most advanced systems. Thus, in Type 1 diabetes our research must focus on 1) finding the stimulus that ignites the immune response and 2) developing treatments that avoid hyperinsulinemia. In Type 2 diabetes in youth, the challenges start much earlier: most young patients do not even benefit from existing therapies due to non-compliance. Therefore, prevention of Type 2 diabetes and improvement of compliance, especially with non-pharmacological interventions, are the greatest challenges.
Autoimmunity; chronic stress; genetic; leptin; obesity; prevention; sleep deprivation; socioeconomic status; Vitamin D
The visual pigment melanopsin is expressed in intrinsically photosensitive retinal ganglion cells (ipRGCs) in the mammalian retina, where it is involved in non-image forming light responses including circadian photoentrainment, pupil constriction, suppression of pineal melatonin synthesis, and direct photic regulation of sleep. It has recently been shown that the melanopsin-based light response in ipRGCs is attenuated by the neurotransmitter dopamine. Here, we use a heterologous expression system to demonstrate that mouse melanopsin can be phosphorylated by protein kinase A, and that phosphorylation can inhibit melanopsin signaling in HEK cells. Site-directed mutagenesis experiments revealed that this inhibitory effect is primarily mediated by phosphorylation of sites T186 and S287 located in the second and third intracellular loops of melanopsin, respectively. Furthermore, we show that this phosphorylation can occur in vivo using an in situ proximity-dependent ligation assay (PLA). Based on these data, we suggest that the attenuation of the melanopsin-based light response by dopamine is mediated by direct PKA phosphorylation of melanopsin, rather than phosphorylation of a downstream component of the signaling cascade.
Literature reviews of cancer trials have highlighted the need for better understanding of phase II statistical designs. Understanding the key elements associated with phase II design and knowledge of available statistical designs is necessary to enable appropriate phase II trial design.
A systematic literature review was performed to identify phase II trial designs applicable to oncology trials. The results of the review were used to create a library of currently available designs, and to develop a structured approach to phase II trial design outlining key points for consideration.
A total of 122 papers describing new or adapted phase II trial designs were obtained. These were categorised into nine levels, reflecting the practicalities of implementation, and form a library of phase II designs. Key design elements were identified by data extraction. Along with detailed description of the key elements and the library of designs, a structured thought process was developed to form a guidance document for choice of phase II oncology trial design.
The guidance offers researchers a structured and systematic approach to identifying phase II trial designs, highlighting key issues to be considered by both clinicians and statisticians and encouraging an interactive approach to more informed trial design.
phase II; methodology; systematic review; trial design; guidance manual
Laser scanning technology is one of the most integral parts of today's scientific research, manufacturing, defense, and biomedicine. In many applications, high-speed scanning capability is essential for scanning a large area in a short time and multi-dimensional sensing of moving objects and dynamical processes with fine temporal resolution. Unfortunately, conventional laser scanners are often too slow, resulting in limited precision and utility. Here we present a new type of laser scanner that offers ∼1,000 times higher scan rates than conventional state-of-the-art scanners. This method employs spatial dispersion of temporally stretched broadband optical pulses onto the target, enabling inertia-free laser scans at unprecedented scan rates of nearly 100 MHz at 800 nm. To show our scanner's broad utility, we use it to demonstrate unique and previously difficult-to-achieve capabilities in imaging, surface vibrometry, and flow cytometry at a record 2D raster scan rate of more than 100 kHz with 27,000 resolvable points.
To examine changes in breast cancer knowledge, attitudes, beliefs and behaviors following implementation of a tribal run CDC Breast and Cervical Cancer Program (BCCP), we report 2006 survey results from Hopi women and contrast findings with 1993 survey data and BCCP reports.
Community meetings, focus groups, and researchers jointly developed a culturally appropriate survey instrument. Hopi women randomly selected from Tribal enrollment lists were interviewed in-person by Hopi interviewers; 250 women ≥ age 18 participated (87% response) between June and December, 2006.
Among women 40+, 77.5 % reported ever having had a mammogram and 68.9% reported having done so within the past two years, an increase from 45.2% and 46% self-reported in 1993. Compared to 1993, more women in 2006 (88.1% vs. 59%) believed that a mammogram can detect cancer and more than 90% now believe that early detection of cancer can save lives. Women reported a preference (60%) for receiving health care at the Hopi BCCP. Survey results were validated using programmatic data which estimated 76.6% of Hopi women had received mammography screening.
Implementation of a tribal run BCCP has resulted in a substantial increase in mammography screening on the Hopi reservation.
American Indian; breast cancer; mammography; cancer screening
Photoreceptor cyclic nucleotide-gated (CNG) channels are the principal ion channels responsible for transduction of the light-induced change in cGMP concentration into an electrical signal. The ligand sensitivity of photoreceptor CNG channels is subject to regulation by intracellular signaling effectors, including calcium-calmodulin, tyrosine kinases and phosphoinositides. Little is known, however, about regulation of channel activity by modification to extracellular regions of CNG channel subunits. Extracellular proteases MMP9 and -2 are present in the interphotoreceptor matrix adjacent to photoreceptor outer segments. Given that MMPs have been implicated in retinal dysfunction and degeneration, we hypothesized that MMP activity may alter the functional properties of photoreceptor CNG channels. For heterologously expressed rod and cone CNG channels, extracellular exposure to MMPs dramatically increased the apparent affinity for cGMP and the efficacy of cAMP. These changes to ligand sensitivity were not prevented by destabilization of the actin cytoskeleton or by disruption of integrin mediated cell adhesion, but could be attenuated by inhibition of MMP catalytic activity. MMP-mediated gating changes exhibited saturable kinetic properties consistent with enzymatic processing of the CNG channels. In addition, exposure to MMPs decreased the abundance of full-length expressed CNGA3 subunits, with a concomitant increase in putative degradation products. Similar gating effects and apparent proteolysis were observed also for native rod photoreceptor CNG channels. Furthermore, constitutive apparent proteolysis of retinal CNGA1 and retinal MMP9 levels were both elevated in aged mice compared with young mice. Together, these results provide evidence that MMP-mediated proteolysis can regulate the ligand sensitivity of CNG channels.
cyclic nucleotide-gated channel; cone; rod; photoreceptor; extracellular protease; matrix metalloproteinase; gating
Genetic changes have been widely reported in association with cholangiocarcinoma (CCA), while epigenetic changes are poorly characterised. We aimed to further evaluate CpG-island hypermethylation in CCA at candidate loci, which may have potential as diagnostic or prognostic biomarkers.
We analysed methylation of 26 CpG-islands in 102 liver fluke related-CCA and 29 adjacent normal samples using methylation-specific PCR (MSP). Methylation of interest loci was confirmed using pyrosequencing and/or combined bisulfite restriction analysis, and protein expression by immunohistochemistry.
A number of CpG-islands (OPCML, SFRP1, HIC1, PTEN and DcR1) showed frequency of hypermethylation in >28% of CCA, but not adjacent normal tissues. The results showed that 91% of CCA were methylated in at least one CpG-island. The OPCML was the most frequently methylated locus (72.5%) and was more frequently methylated in less differentiated CCA. Patients with methylated DcR1 had significantly longer overall survival (Median; 41.7 vs 21.7 weeks, P=0.027). Low-protein expression was found in >70% of CCA with methylation of OPCML or DcR1.
Aberrant hypermethylation of certain loci is a common event in liver fluke-related CCA and may potentially contribute to cholangiocarcinogenesis. The OPCML and DcR1 might serve as methylation biomarkers in CCA that can be readily examined by MSP.
DNA methylation; cholangiocarcinoma; liver fluke; OPCML; DcR1; biomarkers
Sickle cell anaemia (SCA) is associated with significant morbidity from acute complications and organ dysfunction beginning in the first year of life. In the first multicenter randomised double-blinded trial in very young children with SCA, the impact of hydroxyurea (hydroxycarbamide) therapy on organ dysfunction, clinical complications, and laboratory findings, and its toxicity, were examined.
Eligible subjects had HbSS or Sβ0thalassaemia, were age 9–18 months at randomisation, and were not selected for clinical severity. Subjects received liquid hydroxyurea, 20 mg/kg/day, or placebo for two years. Primary study endpoints were splenic function (qualitative uptake on 99Tc spleen scan) and renal function (glomerular filtration rate by 99mTc-DTPA clearance). Additional evaluations included: blood counts, HbF, chemistry profiles, spleen function biomarkers, urine osmolality, neurodevelopment, transcranial Doppler ultrasonography, growth, and mutagenicity. Study visits occurred every two to four weeks.
Ninety-six subjects received hydroxyurea and 97 placebo; 86% completed the study. Significant differences were not seen for the primary endpoints, but suggestive benefit was noted in quantitative measures of spleen function. Hydroxyurea significantly decreased pain and dactylitis with trends for decreased acute chest syndrome, hospitalisation and transfusion. Hydroxyurea increased haemoglobin and HbF and decreased WBC count. Toxicity was limited to mild-moderate neutropaenia.
Although hydroxyurea treatment did not reduce splenic and renal dysfunction assessed by primary endpoint measures, it resulted in major clinical benefit because of diminished acute complications, favorable haematologic results, and a lack of unexpected toxicities. Based on the safety and efficacy data from this trial, hydroxyurea can now be considered for all very young children with SCA.
White matter hyperintensity (WMH) may be a marker of an underlying cerebral microangiopathy. Therefore, we hypothesized that WMH would be most severe in patients with lacunar stroke and intracerebral hemorrhage (ICH), 2 types of stroke in which cerebral small vessel (SV) changes are pathophysiologically relevant.
We determined WMH volume (WMHV) in cohorts of prospectively ascertained patients with acute ischemic stroke (AIS) (Massachusetts General Hospital [MGH], n = 628, and the Ischemic Stroke Genetics Study [ISGS], n = 263) and ICH (MGH, n = 122).
Median WMHV was 7.5 cm3 (interquartile range 3.4–14.7 cm3) in the MGH AIS cohort (mean age 65 ± 15 years). MGH patients with larger WMHV were more likely to have lacunar stroke compared with cardioembolic (odds ratio [OR] = 1.87 per SD normally transformed WMHV), large artery (OR = 2.25), undetermined (OR = 1.87), or other (OR = 1.85) stroke subtypes (p < 0.03). These associations were replicated in the ISGS cohort (p = 0.03). In a separate analysis, greater WMHV was seen in ICH compared with lacunar stroke (OR = 1.2, p < 0.02) and in ICH compared with all ischemic stroke subtypes combined (OR = 1.34, p < 0.007).
Greater WMH burden was associated with SV stroke compared with other ischemic stroke subtypes and, even more strongly, with ICH. These data, from 2 independent samples, support the model that increasing WMHV is a marker of more severe cerebral SV disease and provide further evidence for links between the biology of WMH and SV stroke.
= atrial fibrillation;
= acute ischemic stroke;
= coronary artery disease;
= confidence interval;
= diabetes mellitus;
= diffusion-weighted imaging;
= fluid-attenuated inversion recovery;
= intracranial area;
= intraclass correlation coefficient;
= intracerebral hemorrhage;
= interquartile range;
= Ischemic Stroke Genetics Study;
= Massachusetts General Hospital;
= odds ratio;
= small vessel;
= Trial of Org 10172 in Acute Stroke Treatment;
= white matter hyperintensity;
= white matter hyperintensity volume.
Apoptosis of cardiac myocytes plays a key role in the pathogenesis of many cardiac diseases including viral myocarditis. The apoptotic signaling pathways that are activated during viral myocarditis and the role that these pathways play in disease pathogenesis have not been clearly delineated.
Methods and Results
We investigated the role of apoptotic signaling pathways following virus infection of primary cardiac myocytes. The death receptor associated initiator caspase, caspase 8, and the effector caspase, caspase 3, were significantly activated following infection of primary cardiac myocytes with myocarditic, but not non-myocarditic, reovirus strains. Furthermore, reovirus-induced cardiac myocyte apoptosis was significantly inhibited by soluble death receptors. In contrast, the mitochondrial membrane potential remained unaltered and caspase 9, the initiator caspase associated with mitochondrial apoptotic signaling, was only weakly activated in cardiac myocytes following infection with myocarditic reovirus strains. Inhibition of mitochondrial apoptotic signaling had no effect on reovirus-induced cardiac myocyte apoptosis. In accordance with our in vitro data, caspase 8, but not caspase 9, was significantly activated in the hearts of reovirus-infected mice.
Death receptor, but not mitochondrial, apoptotic signaling plays a key role in apoptosis following infection of cardiac myocytes with myocarditic reovirus strains.
Apoptosis; Myocarditis; Virus; Death Receptors
We examined mortality and recurrence of hepatocellular carcinoma (HCC) among 106 transplant candidates with cirrhosis and HCC who had a potential living donor evaluated between January 1998 and February 2003 at the nine centers participating in the Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL). Cox regression models were fitted to compare time from donor evaluation and time from transplant to death or HCC recurrence between 58 living donor liver transplant (LDLT) and 34 deceased donor liver transplant (DDLT) recipients. Mean age and calculated Model for End-Stage Liver Disease (MELD) scores at transplant were similar between LDLT and DDLT recipients (age: 55 vs. 52 years, p = 0.21; MELD: 13 vs. 15, p = 0.08). Relative to DDLT recipients, LDLT recipients had a shorter time from listing to transplant (mean 160 vs. 469 days, p < 0.0001) and a higher rate of HCC re currence within 3 years than DDLT recipients (29% vs. 0%, p = 0.002), but there was no difference in mortality or the combined outcome of mortality or recurrence. LDLT recipients had lower relative mortality risk than patients who did not undergo LDLT after the center had more experience (p = 0.03). Enthusiasm for LDLT as HCC treatment is dampened by higher HCC recurrence compared to DDLT.
A2ALL; DDLT; HCC; LDLT; MELD; recurrence
The rate-limiting step in the recovery of the photoreceptor light response is the hydrolysis of GTP by transducin, a reaction that is accelerated by the RGS9-Gβ5 complex, and its membrane anchor, R9AP. Similar complexes, including RGS7, RGS11, and Gβ5 are found in retinal ON-bipolar cell dendrites. Here we present evidence that R9AP is also expressed in the dendritic tips of ON-bipolar cells. Immunofluorescent staining for R9AP revealed a punctate pattern of labeling in the outer plexiform layer, where it co-localized with mGluR6. In photoreceptors, R9AP is required for proteolytic stability of the entire RGS complex, and we found that genetic deletion of R9AP also results in a marked reduction in the levels of RGS11 and Gβ5 in the bipolar cell dendrites; the level of RGS7 was unaffected, suggesting the presence of another interaction partner to stabilize RGS7. To determine the effect of R9AP deletion on the response kinetics of ON-bipolar cells, we compared the electroretinogram between wild type and R9AP deficient mice. The electroretinogram b-wave, reflecting ON-bipolar cell activity, was delayed and larger in the R9AP deficient mice. Our data indicate that R9AP is required for stable expression of RGS11-Gβ5 in ON-bipolar cell dendrites. Further, they suggest that the RGS11-Gβ5-R9AP complex accelerates the initial ON-bipolar cell response to light.
Electroretinogram; ERG b-wave; RGS proteins; retina
The microtubule-associated protein tau is thought to play a pivotal role in neurodegeneration. Mutations in the tau coding gene MAPT are a cause of frontotemporal dementia, and the H1/H1 genotype of MAPT, giving rise to higher tau expression levels, is associated with progressive supranuclear palsy, corticobasal degeneration, and Parkinson disease (PD). Furthermore, tau hyperphosphorylation and aggregation is a hallmark of Alzheimer disease (AD), and reducing endogenous tau has been reported to ameliorate cognitive impairment in a mouse model for AD. Tau hyperphosphorylation and aggregation have also been described in amyotrophic lateral sclerosis (ALS), both in human patients and in the mutant SOD1 mouse model for this disease. However, the precise role of tau in motor neuron degeneration remains uncertain.
The possible association between ALS and the MAPT H1/H2 polymorphism was studied in 3,540 patients with ALS and 8,753 controls. Furthermore, the role of tau in the SOD1G93A mouse model for ALS was studied by deleting Mapt in this model.
The MAPT genotype of the H1/H2 polymorphism did not influence ALS susceptibility (odds ratio = 1.08 [95% confidence interval 0.99–1.18], p = 0.08) and did not affect the clinical phenotype. Lowering tau levels in the SOD1G93A mouse failed to delay disease onset (p = 0.302) or to increase survival (p = 0.557).
These findings suggest that the H1/H2 polymorphism in MAPT is not associated with human amyotrophic lateral sclerosis, and that lowering tau levels in the mutant SOD1 mouse does not affect the motor neuron degeneration in these animals.
= Alzheimer disease;
= amyotrophic lateral sclerosis;
= analysis of variance;
= confidence interval;
= human amyloid precursor protein;
= corticobasal degeneration;
= enhanced green fluorescent protein;
= frontotemporal dementia;
= microtubule-associated protein tau;
= odds ratio;
= Parkinson disease;
= progressive supranuclear palsy;
= single nucleotide polymorphism;
= superoxide dismutase 1.