Trypanosomatid parasites are notorious for the human diseases they cause throughout Africa and South America. However, non-pathogenic trypanosomatids are also found worldwide, infecting a wide range of hosts. One example is Trypanosoma (Megatrypanum) theileri, a ubiquitous protozoan commensal of bovids, which is distributed globally. Exploiting knowledge of pathogenic trypanosomatids, we have developed Trypanosoma theileri as a novel vehicle to deliver vaccine antigens and other proteins to cattle. Conditions for the growth and transfection of T. theileri have been optimised and expressed heterologous proteins targeted for secretion or specific localisation at the cell interior or surface using trafficking signals from Trypanosoma brucei. In cattle, the engineered vehicle could establish in the context of a pre-existing natural T. theileri population, was maintained long-term and generated specific immune responses to an expressed Babesia antigen at protective levels. Building on several decades of basic research into trypanosomatid pathogens, Trypanosoma theileri offers significant potential to target multiple infections, including major cattle-borne zoonoses such as Escherichia coli, Salmonella spp., Brucella abortus and Mycobacterium spp. It also has the potential to deliver therapeutics to cattle, including the lytic factor that protects humans from cattle trypanosomiasis. This could alleviate poverty by protecting indigenous African cattle from African trypanosomiasis.
Single-celled parasites of the order Kinetoplastida are responsible for devastating diseases of humans and animals, including African trypanosomiasis, Chagas' disease and leishmaniasis. However, there are also many species of trypanosomatids that do not cause disease and are distributed globally. One example is Trypanosoma (Megatrypanum) theileri, which is restricted to bovids and ubiquitous in cattle herds worldwide. This organism is maintained extracellularly in the blood and tissues long-term without any observed ill effects on host health or productivity. Using knowledge of gene expression and protein trafficking in pathogenic trypanosomatids, we have successfully developed, from first principles, Trypanosoma theileri as a delivery system for vaccine antigens and therapeutics. Procedures for the growth, transfection and heterologous gene expression of T. theileri have been developed, and the delivery of a vaccine antigen derived from Babesia divergens evaluated in vivo. Our results demonstrate the ability of T. theileri to be used as a flexible and easily manipulated protein delivery system suitable for the control of cattle pathogens and cattle-borne zoonoses. In one notable application, we propose that the system could allow the expression of serum trypanolytic factors in cattle, with the potential to alleviate poverty in Africa through the killing of pathogenic trypanosomatids in livestock.
In morphology, coloration, and size, Pseudabispa wasps (Hymenoptera: Vespidae: Eumeninae) closely resemble mason wasps in the genus Abispa, and their distributions overlap. Although these two genera are among the largest solitary wasps in Australia, the biology of Pseudabispa was not previously known. Field observations from near Katherine, Northern Territory, strongly suggest that P. paragioides (Meade-Waldo) females attack and kill female A. ephippium (Fabricius) and usurp their nests, then appropriate cells, mass provision them with caterpillars acquired by theft from still other nests, and close them with mud taken from the host nest. Despite an abundance of potentially available cells in nests of three other large solitary wasps common at the same site, P. paragioides was found associated only with nests of A. ephippium. This unusual report of apparently forcible and lethal interspecific nest takeover for a non-social wasp parallels behaviors previously known only from socially parasitic eusocial Hymenoptera. Exploitation by P. paragioides may help explain why its host displays some of the most highly developed parental care known in any solitary eumenid, and why its nests are spaced widely from one another.
exploitation; interspecific competition; kleptoparasitism; lethal fighting; prey theft; provisioning; social parasitism; usurpation
Projections of health and social care need are highly sensitive to assumptions about cohort trends in health and disability. We use a repeated population-based cross-sectional study from the Cambridgeshire centre of the UK Medical Research Council Cognitive Function and Ageing Study to investigate trends in the health of the young-old UK population
Non-overlapping cohorts of men and women aged 65–69 years in 1991/2 (n = 689) and 1996/7 (n = 687) were compared on: self-reported diseases and conditions; self-rated health; mobility limitation; disability by logistic regression and four-year survival by Cox Proportional Hazards Regression models, with adjustments for differences in socio-economic and lifestyle factors.
Survival was similar between cohorts (HR: 0.91, 95% CI: 0.62 to 1.32). There was a significant increase in the number of conditions reported between cohorts, with more participants reporting 3 or more conditions in the new cohort (14.2% vs. 10.1%). When individual conditions were considered, there was a 10% increase in the reporting of arthritis and a significant increase in the reporting of chronic airways obstruction (OR: 1.36, 95% CI: 1.04 to 1.78).
This study provides evidence of rising levels of ill-health, as measured by the prevalence of self-reported chronic conditions, in the newer cohorts of the young-old. Though changes in diagnosis or reporting of disease cannot, as yet, be excluded, to better understand whether our findings reflect real increases in ill-health, investment should be made into improved population-based databases, linking self-report and objective measures of health and function, and including those in long-term care.
FlyBase is a database of genetic and molecular data concerning Drosophila. FlyBase is maintained as a relational database (in Sybase) and is made available as html documents and flat files. The scope of FlyBase includes: genes, alleles (and phenotypes), aberrations, transposons, pointers to sequence data, clones, stock lists, Drosophila workers and bibliographic references. The Encyclopedia of Drosophila is a joint effort between FlyBase and the Berkeley Drosophila Genome Project which integrates FlyBase data with those from the BDGP.
This study examines the relation between cerebral O2 consumption (CMRO2) and the O2 consumption of the rest of the body (BVO2) after severe head injury. Seventy nine serial measurements of whole body O2 consumption, CMRO2, plasma adrenaline, T3, and glucagon concentrations were made in 15 children with severe head injuries receiving neurointensive care. Body O2 consumption was measured with indirect calorimetry and CMRO2 with the Kety-Schmidt technique. There was no evidence of a significant relation between CMRO2 and BVO2. Within each child there were statistically significant positive relations between BVO2 and adrenaline, T3, and glucagon. By contrast, there was only a weak significant positive relation between CMRO2 and T3. In conclusion, CMRO2 and BVO2 seem to be determined independently after severe head injury. Thus therapeutic measures aiming to reduce CMRO2 need to be specific to the brain and it should not be assumed that measures which decrease whole body energy expenditure will necessarily have the same effect on CMRO2.
This study examines the relationship between core temperature and whole body energy expenditure, cerebral oxygen consumption (CMRO2), cerebral blood flow (CBF), and intracranial pressure (ICP) in severely head injured children. A total of 107 serial measurements of temperature, energy expenditure, CMRO2, CBF, and ICP were made in 18 head injured children receiving neurointensive care. Energy expenditure was measured using indirect calorimetry, and CMRO2 and CBF using the Kety-Schmidt technique. The mean rectal temperature was 37.8 degrees C (34-39.1 degrees C) despite modification with paracetamol. Within each child there was a positive relationship between rectal temperature and energy expenditure, energy expenditure increasing by a mean of 7.4% per degree C. There was no evidence of significant relationships between rectal temperature and CMRO2, CBF, or ICP. Mild induced hypothermia in two children did not result in decreased CMRO2 or CBF measurements. The efficacy of interventions aiming to modify cerebral energy metabolism by changing core temperature cannot be readily assessed by the response of the whole body.
Semantic memory impairment is common in both Mild Cognitive Impairment (MCI) and early Alzheimer’s disease (AD), and the ability to recognize familiar people is particularly vulnerable. A time-limited temporal gradient (TG) in which well known people from decades earlier are better recalled than those learned recently is also reported in both AD and MCI. In this study, we hypothesized that the TG pattern on a famous name recognition task (FNRT) administered to cognitively intact elders would predict future episodic memory decline, and would also show a significant correlation with hippocampal volume.
78 healthy elders (ages 65-90) with normal cognition and episodic memory at baseline were administered a FNRT. Follow-up episodic memory testing 18 months later produced two groups: Declining (≥ 1 SD reduction in episodic memory) and Stable (< 1 SD).
The Declining group (N=27) recognized fewer recent famous names than the Stable group (N=51), while recognition for remote names was comparable. Baseline MRI volumes for both the left and right hippocampus was significantly smaller in the Declining group than the Stable group. Smaller baseline hippocampal volume was also significantly correlated with poorer performance for recent, but not remote famous names. Logistic regression analyses indicated that baseline TG performance was a significant predictor of group status (Declining versus Stable) independent of chronological age and APOE ε4 inheritance.
Famous name recognition may serve as an early pre-clinical cognitive marker of episodic memory decline in older individuals.
Famous names; episodic memory; hippocampus; semantic memory; temporal gradient
African trypanosomes cause disease in humans and livestock, generating significant health and welfare problems throughout sub-Saharan Africa. When ingested in a tsetse fly bloodmeal, trypanosomes must detect their new environment and initiate the developmental responses that ensure transmission. The best-established environmental signal is citrate/cis aconitate (CCA), this being transmitted through a protein phosphorylation cascade involving two phosphatases: one that inhibits differentiation (TbPTP1) and one that activates differentiation (TbPIP39). Other cues have been also proposed (mild acid, trypsin exposure, glucose depletion) but their physiological relevance and relationship to TbPTP1/TbPIP39 signalling is unknown. Here we demonstrate that mild acid and CCA operate through TbPIP39 phosphorylation, whereas trypsin attack of the parasite surface uses an alternative pathway that is dispensable in tsetse flies. Surprisingly, glucose depletion is not an important signal. Mechanistic analysis through biophysical methods suggests that citrate promotes differentiation by causing TbPTP1 and TbPIP39 to interact.
African trypanosomes are important pathogens transmitted by tsetse flies in sub-Saharan Africa. Upon transmission, trypanosomes detect citrate and cis-aconitate in the bloodmeal, this inactivating a negative regulator of differentiation, the tyrosine phosphatase TbPTP1. One TbPTP1 substrate is another phosphatase, TbPIP39, which is more active when phosphorylated (after TbPTP1 inhibition) and promotes differentiation. These differentiation regulators have provided tools to monitor whether one or more environmental signals are used to initiate trypanosome development and their relevance in vivo. This is important because different studies over the last 30 years have disputed the physiological importance of different signals. Here we have, firstly, compared the efficacy of the different reported differentiation signals, establishing their relative importance. We then monitored TbPIP39 phosphorylation to show that two signalling pathways operate: one signalled by citrate or mild acid, the other stimulated by external protease activity. Thereafter, we showed that, of these different signals, protease activity is dispensable for differentiation in tsetse flies. Finally, we used biophysical methods to investigate how citrate causes TbPIP39 and TbPTP1 to interact, enabling their regulatory cross-talk. These studies have established the importance of different developmental signals in trypanosomes, providing molecular insight into how the development signal is transduced within the pathogen.
Expression of microRNAs (miRNAs) is under stringent regulation at both transcriptional and post-transcriptional levels. Disturbance at either level could cause dysregulation of miRNAs. Here we show that MLL fusion proteins negatively regulate production of miR-150, an miRNA widely repressed in acute leukemia, by blocking miR-150 precursors from being processed to mature miRNAs through MYC/LIN28 functional axis. Forced expression of miR-150 dramatically inhibited leukemic cell growth and delayed MLL-fusion-mediated leukemogenesis, likely through targeting FLT3 and MYB and thereby interfering with the HOXA9/MEIS1/FLT3/MYB signaling network, which in turn caused downregulation of MYC/LIN28. Collectively, we revealed a MLL-fusion/MYC/LIN28⊣miR-150⊣FLT3/MYB/HOXA9/MEIS1 signaling circuit underlying the pathogenesis of leukemia, where miR-150 functions as a pivotal gatekeeper and its repression is required for leukemogenesis.
miR-150; MLL-associated leukemia; MYC; LIN28; FLT3; MYB; HOXA9; MEIS1; microRNA maturation; signaling axis; leukemogenesis
North American Indian Childhood Cirrhosis (NAIC) is a rare, autosomal recessive, progressive cholestatic disease of infancy affecting the Cree-Ojibway first Nations of Quebec. All NAIC patients are homozygous for a missense mutation (R565W) in CIRH1A, the human homolog of the yeast nucleolar protein Utp4. Utp4 is part of the t-Utp subcomplex of the small subunit (SSU) processome, a ribonucleoprotein complex required for ribosomal RNA processing and small subunit assembly. NAIC has thus been proposed to be a primary ribosomal disorder (ribosomopathy); however, investigation of the pathophysiologic mechanism of this disease has been hindered by lack of an animal model. Here, using a morpholino oligonucleotide (MO)-based loss-of-function strategy, we have generated a model of NAIC in the zebrafish, Danio rerio. Zebrafish Cirhin shows substantial homology to the human homolog, and cirh1a mRNA is expressed in developing hepatocytes and biliary epithelial cells. Injection of two independent MOs directed against cirh1a at the one-cell stage causes defects in canalicular and biliary morphology in 5 dpf larvae. In addition, 5 dpf Cirhin-deficient larvae have dose-dependent defects in hepatobiliary function, as assayed by the metabolism of an ingested fluorescent lipid reporter. Previous yeast and in vitro studies have shown that defects in ribosome biogenesis cause stabilization and nuclear accumulation of p53, which in turn causes p53-mediated cell cycle arrest and/or apoptosis. Thus, the nucleolus appears to function as a cellular stress sensor in some cell types. In accordance with this hypothesis, transcriptional targets of p53 are upregulated in Cirhin-deficient zebrafish embryos, and defects in biliary function seen in Cirhin-deficient larvae are completely abrogated by mutation of tp53. Our data provide the first in vivo evidence of a role for Cirhin in biliary development, and support the hypothesis that congenital defects affecting ribosome biogenesis can activate a cellular stress response mediated by p53.
To survey the Society for Vascular Surgery (SVS) membership with regard to type of practice, employment status, work effort, and productivity criteria.
A survey questionnaire was developed to gather information about member demographics, academic versus private practice, employment status, time in practice, measures of work, and productivity criteria.
Two-thirds of members were in private practice, 24% were employed by hospitals/health systems and 21% were in solo practice. Only 50.3% said they or their group kept record of relative value units/work relative value units (RVUs/WRVUs). Of those tracking RVUs, significantly greater number of private practice VS reported annual RVUs >10 000 compared to academic VS (P < .01). Net collections were the most common measure of productivity (51%) followed by WRVUs (36%).
With a changing environment and employment status of VS, tracking measures of productivity and proper benchmarking become vitally important. The SVS should consider positioning itself to collect, store, manage, and provide such information to assist members in practice transition.
productivity; WRVU; compensation; RVU
Parental bereavement is associated with increased risk for psychiatric illness and functional impairment in youth. Dysregulated hypothalamic-pituitary-adrenal (HPA) axis functioning may be one pathway through which bereaved children experience increased risk for poor outcomes. However, few studies have prospectively examined the association between parental bereavement and cortisol response while accounting for psychiatric disorders in both youth and their caregivers.
One-hundred and eighty-one bereaved and nonbereaved offspring and their caregivers were assessed at multiple time points over a 5-year period after parental death. Offspring participated in an adaptation of the Trier Social Stress Task (TSST), and salivary cortisol samples were collected before and after exposure to social stressors. Mixed models for repeated measures were used to analyze the effects of bereavement status, psychiatric disorder in both offspring and caregiver, and demographic indices on trajectories of cortisol response.
After controlling for demographic variables and offspring depression, bereaved offspring demonstrated significantly different trajectories of cortisol response compared with nonbereaved offspring, characterized by higher total cortisol output and an absence of cortisol reactivity to acute social stress. Within the bereaved group, offspring of parents who died by sudden natural death demonstrated significant cortisol reactivity to social stress compared with offspring whose parents died by suicide, who demonstrated more blunted trajectory of cortisol response.
Parentally bereaved youth demonstrate higher cortisol output than nonbereaved youth but are less able to mount an acute response in the face of social stressors.
Adolescent; bereavement; cortisol; depression; HPA axis; TSST
Neuromyelitis optica and its spectrum disorder (NMOSD) can present similarly to relapsing-remitting multiple sclerosis (RRMS). Using a quantitative lesion mapping approach, this research aimed to identify differences in MRI brain lesion distribution between aquaporin-4 antibody–positive NMOSD and RRMS, and to test their diagnostic potential.
Clinical brain MRI sequences for 44 patients with aquaporin-4 antibody–positive NMOSD and 50 patients with RRMS were examined for the distribution and morphology of brain lesions. T2 lesion maps were created for each subject allowing the quantitative comparison of the 2 conditions with lesion probability and voxel-wise analysis.
Sixty-three percent of patients with NMOSD had brain lesions and of these 27% were diagnostic of multiple sclerosis. Patients with RRMS were significantly more likely to have lesions adjacent to the body of the lateral ventricle than patients with NMOSD. Direct comparison of the probability distributions and the morphologic attributes of the lesions in each group identified criteria of “at least 1 lesion adjacent to the body of the lateral ventricle and in the inferior temporal lobe; or the presence of a subcortical U-fiber lesion; or a Dawson's finger-type lesion,” which could distinguish patients with multiple sclerosis from those with NMOSD with 92% sensitivity, 96% specificity, 98% positive predictive value, and 86% negative predictive value.
Careful inspection of the distribution and morphology of MRI brain lesions can distinguish RRMS and NMOSD.
Better health is a well-documented benefit of having a higher socioeconomic status (SES). Inflammation may be one pathway through which SES influences health. Using 2658 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) Study, we examine whether two measures of SES assessed at baseline (mean age, 32±4 years)—years of education and household income—predict change in C-reactive protein (CRP) concentrations over the course of 13 years. We also examine whether four health-related behaviors—smoking, fruit and vegetable consumption, physical activity, and alcohol consumption—mediate the prospective association of SES with CRP. Both higher education and household income predicted smaller increases in CRP over the 13 years of follow-up independent of age, sex, race, CARDIA center, body mass, medical diagnoses, medications, and hormone use (among women). Associations did not differ by race or sex. When examined in separate analyses, smoking and fruit and vegetable intake each accounted for a significant proportion of the respective effects of education and household income on CRP change, and physical activity a significant proportion of the effect of household income. These findings suggest that poor health behaviors among persons of lower socioeconomic status can have long-term effects on inflammation.
C-reactive protein; CARDIA Study; health behaviors; inflammatory markers; mediation; socioeconomic status
Non-dystrophic Myotonia (NDM) is characterized by myotonia without muscle wasting. A standardized quantitative myotonia assessment (QMA) is important for clinical trials.
Myotonia was assessed in 91 individuals enrolled in a natural history study using a commercially available computerized handgrip myometer and automated software. Average peak force and 90% to 5% relaxation times were compared to historical normal controls studied with identical methods.
30 subjects had chloride channel mutations, 31 sodium channel mutations, 6 DM2, and 24 no identified mutation. Chloride channel mutations were associated with prolonged 1st handgrip relaxation times, and warm up on subsequent handgrips. Sodium channel mutations were associated with prolonged 1st handgrip relaxation times and paradoxical myotonia or warm-up, depending on underlying mutations. DM2 subjects had normal relaxation times but decreased peak force. Sample size estimates are provided for clinical trial planning.
QMA is an automated, non-invasive technique for evaluating myotonia in NDM.
natural history; ion channel mutation; muscle disease; myotonia; non-dystrophic myotonia
Biological scaffolds must support a complex balance of resisting enzymatic degradation while promoting tissue remodeling. Thus, the purpose of this study was to evaluate the effects of in vitro enzymatic exposure on the mechanical properties of biological scaffolds. It was hypothesized that exposure to an enzyme solution would result in decreased tensile strength and that crosslinked scaffolds would resist enzymatic degradation more effectively than noncrosslinked scaffolds.
Nine scaffolds were evaluated (four porcine dermis: Permacol™, CollaMend™, Strattice™, XenMatrix™; two human dermis: AlloMax™, FlexHD®; two bovine pericardium: Veritas®, PeriGuard®; and one porcine small intestine submucosa: Surgisis™). Ten specimens (n = 10) were hydrated in saline at 37 °C and subjected to uniaxial testing to establish baseline properties. 50 specimens (n = 50) were incubated in collagenase solution at 37 °C for 2, 6, 12, 24, or 30 h (n = 10 each group) followed by uniaxial tensile testing.
Tensile strength was significantly reduced after 30 h for CollaMend™, AlloMax™, Veritas®, Strattice™, XenMatrix™, Permacol™, and FlexHD® (p < 0.01), while PeriGuard® demonstrated a slight increase in tensile strength (p = 0.0188). Crosslinked bovine pericardium (PeriGuard®) maintained greater tensile strength than noncrosslinked bovine pericardium (Veritas®) throughout all exposure periods (p < 0.0001). Similarly, crosslinked porcine dermis (Permacol™) maintained greater tensile strength than non-crosslinked porcine dermis (Strattice™ and XenMatrix™) throughout all exposure periods (p < 0.0001).
Materials that deteriorate rapidly after in vitro enzymatic exposure may also deteriorate rapidly in vivo, particularly when exposed to a wound environment with elevated levels of matrix metalloproteinases. Permacol™, CollaMend™, Strattice™, FlexHD®, and Peri-Guard® survived the longest incubation period (30 h) and withstood mechanical testing. XenMatrix™, AlloMax™, Veritas®, and Surgisis™ degraded more quickly and did not survive the longer exposure periods. Scaffolds that maintain strength characteristics after in vitro collagenase exposure may be advantageous for long-term hernia repair scenarios where elevated enzyme levels are expected.
Hernia repair; Biologic mesh; Tensile strength; Enzymes; Matrix metalloproteinases; Strain
Proteins that interact with voltage-gated sodium (Nav) channels are important in channel sorting and modulation. In this study, we identified the transcriptional regulator, Sin3B, as a novel binding partner of Nav channels in a yeast two-hybrid screen and confirmed the interaction using pull-down assays, co-immunoprecipitation, and immunofluorescence-colocalization. Because both long (~1100-residue) and short (N-terminal 293 residues) Sin3B variants interacted with Nav channels, binding occurred within the N-terminal region containing two paired-amphipathic helix domains. In Nav channels, Sin3B bound to a 132-residue portion of the cytoplasmic C-terminus. Expression of the short Sin3B variant strongly reduced native sodium current and Nav-channel gating charge in the neuronal cell line N1E-115, without affecting the voltage-dependence of activation. Because the total amount of channel protein was unchanged by Sin3B, binding of Sin3B likely decreases the number of channels in the plasma membrane, suggesting that interaction with Sin3B influences Nav-channel trafficking or stability in the membrane.
Short sleep duration has been associated with higher current body mass index (BMI) and subsequent weight gain. However, most prior longitudinal studies are limited by reliance on self-reported sleep duration, and none accounted for the potential confounding effect of sleep-disordered breathing. The associations of sleep duration with current BMI and BMI change were examined among 310 midlife women in the Study of Women’s Health Across the Nation (SWAN) Sleep Study (2003–2005). Sleep duration was assessed for approximately one month with concurrent wrist actigraphy and sleep diaries. The presence and severity of sleep-disordered breathing was quantified using the apnea-hypopnea index (AHI) based on in-home polysomnography. BMI was assessed annually through core SWAN visit 10 (2006 and 2008). Mean BMI increased from 29.6 (SD=7.8) kg/m2 to 30.0 (SD=8.0) kg/m2 over an average of 4.6 years (SD=1.0) of follow up. In cross-sectional analyses controlling for AHI, demographic variables, and several potential confounding variables, actigraphy (estimate=−1.22, 95%C.I.: −2.03, −.42) and diary (estimate=−.86, 95%C.I. −1.62, −.09) measures of sleep duration were inversely associated with BMI. Each hour of less sleep was associated with 1.22 kg/m2 greater BMI for actigraphy sleep duration, and a 0.86 kg/m2 greater BMI for diary sleep duration. Longitudinal associations between sleep duration and annual BMI change were non-significant in unadjusted and fully-adjusted models. In this cohort of midlife women, cross-sectional associations between sleep duration and current BMI were independent of sleep-disordered breathing, but sleep duration was not prospectively associated with weight change.
The purpose of this study was to examine the biological environment of the esophageal hiatus through analysis of the collagen content within the gastrohepatic ligament (GHL), gastrophrenic ligament (GPL), and phrenoesophageal ligament (PEL) in patients with type I hiatal hernias (HH) and type III paraesophageal hernias (PEH).
A control group (N = 10) and patients with type I HH (N = 10) and type III PEH (N = 10) were included in the analysis. Specimens of the GHL, PEL, and GPL were collected intraoperatively. Slides stained with sirius red/fast green were created and ten photos at 400 × magnification were taken of each specimen. Axiovision 4.7 (Zeiss) photo analysis software was employed for quantification of collagen I (red) and III (green) by calculating color area (μm2). Statistical significance (p < 0.05) was determined using a one-way ANOVA and Fisher’s LSD post-test.
Cross-polarization microscopy revealed that the collagen I content was similar in the three study groups for the GHL, greater in the type III PEH group and in the control group compared to the type I HH group for the PEL, and greater in the type III PEH group compared to control group for the GPL. Collagen III quantity was greater in the control group than in the type I HH group for each ligament, and greater in the GHL and PEL when compared to the type III PEH group. Type III PEH patients had greater collagen III quantity than did type I HH patients for each ligament. Collagen type I:III ratio of the GHL was greater in both hernia groups compared to the control group. Type III PEH patients contained a higher I:III ratio than both the control and type I HH groups with respect to the PEL. There was no difference in the ratio with evaluation of the GPL for the three groups.
Evaluation of the esophageal hiatus revealed that patients with PEH have a different biological environment with regard to collagen content compared to control patients. The collagen I:III ratio of the study groups was equal to or greater than the control group. Collagen deficiency in the GE junction supporting ligaments does not appear to be an etiology of PEH formation.
Paraesophageal hernia; Collagen ratio; Collagen I; Collagen III
To construct a maximally predictive model of the risk of severe acute esophagitis (AE) for patients who receive definitive radiation therapy (RT) for non–small-cell lung cancer.
Methods and Materials
The dataset includes Washington University and RTOG 93-11 clinical trial data (events/patients: 120/374, WUSTL = 101/237, RTOG9311 = 19/137). Statistical model building was performed based on dosimetric and clinical parameters (patient age, sex, weight loss, pretreatment chemotherapy, concurrent chemo-therapy, fraction size). Awide range of dose–volume parameters were extracted from dearchived treatment plans, including Dx, Vx, MOHx (mean of hottest x% volume), MOCx (mean of coldest x% volume), and gEUD (generalized equivalent uniform dose) values.
The most significant single parameters for predicting acute esophagitis (RTOG Grade 2 or greater) were MOH85, mean esophagus dose (MED), and V30. A superior–inferior weighted dose-center position was derived but not found to be significant. Fraction size was found to be significant on univariate logistic analysis (Spearman R = 0.421, p < 0.00001) but not multivariate logistic modeling. Cross-validation model building was used to determine that an optimal model size needed only two parameters (MOH85 and concurrent chemotherapy, robustly selected on bootstrap model-rebuilding). Mean esophagus dose (MED) is preferred instead of MOH85, as it gives nearly the same statistical performance and is easier to compute. AE risk is given as a logistic function of (0.0688 * MED+1.50 * ConChemo-3.13), where MED is in Gy and ConChemo is either 1 (yes) if concurrent chemotherapy was given, or 0 (no). This model correlates to the observed risk of AE with a Spearman coefficient of 0.629 (p < 0.000001).
Multivariate statistical model building with cross-validation suggests that a two-variable logistic model based on mean dose and the use of concurrent chemotherapy robustly predicts acute esophagitis risk in combined-data WUSTL and RTOG 93-11 trial datasets.
Acute esophagitis; Lung cancer; NTCP; Radiotherapy