Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis.

The acute phase of sepsis is characterized by a strong inflammatory reaction. At later stages in some patients, immunoparalysis may be encountered, which is associated with a poor outcome. By transcriptional and metabolic profiling of human patients with sepsis, we found that a shift from oxidative phosphorylation to aerobic glycolysis was an important component of initial activation of host defense. Blocking metabolic pathways with metformin diminished cytokine production and increased mortality in systemic fungal infection in mice. In contrast, in leukocytes rendered tolerant by exposure to lipopolysaccharide or after isolation from patients with sepsis and immunoparalysis, a generalized metabolic defect at the level of both glycolysis and oxidative metabolism was apparent, which was restored after recovery of the patients. Finally, the immunometabolic defects in humans were partially restored by therapy with recombinant interferon-γ, which suggested that metabolic processes might represent a therapeutic target in sepsis.

Structural mechanism of cGAS inhibition by the nucleosome.

The DNA sensor cyclic GMP-AMP synthase (cGAS) initiates innate immune responses following microbial infection, cellular stress and cancer1. Upon activation by double-stranded DNA, cytosolic cGAS produces 2'3' cGMP-AMP, which triggers the induction of inflammatory cytokines and type I interferons 2-7. cGAS is also present inside the cell nucleus, which is replete with genomic DNA8, where chromatin has been implicated in restricting its enzymatic activity9. However, the structural basis for inhibition of cGAS by chromatin remains unknown. Here we present the cryo-electron microscopy structure of human cGAS bound to nucleosomes. cGAS makes extensive contacts with both the acidic patch of the histone H2A-H2B heterodimer and nucleosomal DNA. The structural and complementary biochemical analysis also find cGAS engaged to a second nucleosome in trans. Mechanistically, binding of the nucleosome locks cGAS into a monomeric state, in which steric hindrance suppresses spurious activation by genomic DNA. We find that mutations to the cGAS-acidic patch interface are sufficient to abolish the inhibitory effect of nucleosomes in vitro and to unleash the activity of cGAS on genomic DNA in living cells. Our work uncovers the structural basis of the interaction between cGAS and chromatin and details a mechanism that permits self-non-self discrimination of genomic DNA by cGAS.

A novel TASK channel antagonist nasal spray reduces sleep apnea severity in physiological responders: a randomized, blinded, trial.

Preclinical and human physiological studies indicate that topical, selective TASK 1/3 K+ channel antagonism increases upper airway dilator muscle activity and reduces pharyngeal collapsibility during anesthesia and nasal breathing during sleep. The primary aim of this study was to determine the effects of BAY2586116 nasal spray on obstructive sleep apnea (OSA) severity and whether individual responses vary according to differences in physiological responses and route of breathing. Ten people (5 females) with OSA [apnea-hypopnea index (AHI) = 47 ± 26 events/h (means ± SD)] who completed previous sleep physiology studies with BAY2586116 were invited to return for three polysomnography studies to quantify OSA severity. In random order, participants received either placebo nasal spray (saline), BAY2586116 nasal spray (160 µg), or BAY2586116 nasal spray (160 µg) restricted to nasal breathing (chinstrap or mouth tape). Physiological responders were defined a priori as those who had improved upper airway collapsibility (critical closing pressure ≥2 cmH2O) with BAY2586116 nasal spray (NCT04236440). There was no systematic change in apnea-hypopnea index (AHI3) from placebo versus BAY2586116 with either unrestricted or nasal-only breathing versus placebo (47 ± 26 vs. 43 ± 27 vs. 53 ± 33 events/h, P = 0.15). However, BAY2586116 (unrestricted breathing) reduced OSA severity in physiological responders compared with placebo (e.g., AHI3 = 28 ± 11 vs. 36 ± 12 events/h, P = 0.03 and ODI3 = 18 ± 10 vs. 28 ± 12 events/h, P = 0.02). Morning blood pressure was also lower in physiological responders after BAY2586116 versus placebo (e.g., systolic blood pressure = 137 ± 24 vs. 147 ± 21 mmHg, P < 0.01). In conclusion, BAY2586116 reduces OSA severity during sleep in people who demonstrate physiological improvement in upper airway collapsibility. These findings highlight the therapeutic potential of this novel pharmacotherapy target in selected individuals.NEW & NOTEWORTHY Preclinical findings in pigs and humans indicate that blocking potassium channels in the upper airway with topical nasal application increases pharyngeal dilator muscle activity and reduces upper airway collapsibility. In this study, BAY2586116 nasal spray (potassium channel blocker) reduced sleep apnea severity in those who had physiological improvement in upper airway collapsibility. BAY2586116 lowered the next morning's blood pressure. These findings highlight the potential for this novel therapeutic approach to improve sleep apnea in certain people.

Impact of self-assessment on dental student's performance in pre-clinical conservative dentistry course.

BACKGROUND: Self-assessment (SA) is an interactive course that endorses the accomplishment of learning objectives through learners' identification of insufficiencies in their didactic knowledge and pre-clinical skills. This study was planned to determine whether there is any improvement in the faculty assessment (FA) score following the implementation of SA in the Pre-clinical Conservative Dentistry Course. METHODS: Fifty-four first-semester dental students were given an introductory lecture followed by a demonstration for Class I Cavity Preparation in typhodont mandibular first molar. At the end of the demonstration, the Scoring Rubric (SR) was explained point-wise in the prepared cavities. During the next session, all students performed Class I cavity preparation and they were given an assessment sheet to enter their scores (SA1). All teeth were evaluated by the Grading Faculties in a blinded manner (FA1). Each participant was explained the difference in their respective SA1 from FA1 and their queries were resolved individually. During the next sessions, Students and Grading Faculties followed the same protocol and scores were recorded as SA2, FA2, SA3 and FA3. RESULTS: The mean score of SA1 was significantly higher than that of FA1 (p < 0.001). However, no significant difference was obtained between SA and FA in the second (p = 0.352) and third (p = 0.434) assessments. In contrast with first assessment, mean marks obtained in FA were higher compared to SA in both second and third assessments. There was a statistically significant improvement in mean marks obtained by the students over time (p < 0.001). CONCLUSION: SA endorsed student-faculty communication and enhanced student's poise and technical skills in operative pre-clinical dentistry.

Biomimetic approach to strengthen the incisal fracture composite build-up: an in vitro study.

OBJECTIVE: Incisal composite build-up shows a high failure susceptibility. The incorporation of fiber-reinforced composite (FRC) during composite restoration could improve its strength. Hence the study was planned to compare the effect of various positions of FRC on the strength of composite resin incisal build-ups. METHODS: In maxillary incisors (n = 90), 3 mm of the incisal edge was cut and teeth were categorized into three groups based on the location and number of fibers used during incisal composite build-up - Group I: composite resin; Group II: composite resin and a single fiber palatally and Group III: composite resin along with two fibers palatally. RESULTS: The data showed that group II had the maximum load-bearing values followed by group I and group III. CONCLUSION: Within the confines of our study, it can be concluded that the addition of FRC to the conventional incisal composite build-up increased the overall strength restoration. Such composite restoration reinforced with a single fiber on the palatal side showed the highest load-bearing capacity compared to two fibers reinforced and unreinforced composites. The common mode of failure in group I was in composite resin, in two fibers reinforced at fibers-composite junction, and in one fiber reinforced composite was in the remaining part of the tooth.

Combined Cardiac and Respiratory Monitoring from a Single Signal: A Case Study Employing the Fantasia Database.

This study proposes a novel method for obtaining the electrocardiogram (ECG) derived respiration (EDR) from a single lead ECG and respiration-derived cardiogram (RDC) from a respiratory stretch sensor. The research aims to reconstruct the respiration waveform, determine the respiration rate from ECG QRS heartbeat complexes data, locate heartbeats, and calculate a heart rate (HR) using the respiration signal. The accuracy of both methods will be evaluated by comparing located QRS complexes and inspiration maxima to reference positions. The findings of this study will ultimately contribute to the development of new, more accurate, and efficient methods for identifying heartbeats in respiratory signals, leading to better diagnosis and management of cardiovascular diseases, particularly during sleep where respiration monitoring is paramount to detect apnoea and other respiratory dysfunctions linked to a decreased life quality and known cause of cardiovascular diseases. Additionally, this work could potentially assist in determining the feasibility of using simple, no-contact wearable devices for obtaining simultaneous cardiology and respiratory data from a single device.

Comparative evaluation of effect of sodium hypochlorite and chlorhexidine in dental unit waterline on aerosolized bacteria generated during dental treatment.

BACKGROUND: In dentistry, nosocomial infection poses a great challenge to clinicians. The microbial contamination of water in dental unit waterlines (DUWLs) is ubiquitous. Such infected DUWLs can transmit oral microbes in the form of aerosols. Previous studies have suggested treating DUWLs with various disinfectants to reduce cross-contamination. The literature lacks a comparative evaluation of the effect of the use of 0.2% chlorhexidine (CHX) and 0.1% sodium hypochlorite (NaOCl) in DUWLs on aerosolized bacteria generated during dental procedures. OBJECTIVE: To compare the effect of NaOCl and CHX in DUWLs on aerosolized bacteria generated during restorative and endodontic procedures. MATERIALS AND METHODS: A total of 132 patients were equally divided into three groups (n = 44 in each group) according to the content of DUWL as follows. Group I-0.1% NaOCl Group II-0.2% CHX Group III-distilled water (Positive control) One-way ANOVA was performed and the Kruskal-Wallis test was used for intergroup comparison. RESULTS: For the restorative procedure, inter-group comparison of mean colony-forming units (CFU) scores showed a statistically significant difference between the groups (p - .001) with the score of group 3 higher than group 2 followed by group 1. For the endodontics, an inter-group comparison of CFU scores showed a statistically significant difference between the groups (p - .003) with the mean score in group 1 being the lowest and group 3 being the highest. CONCLUSION: The addition of NaOCl or CHX in DUWLs shows an effective reduction in aerosolized bacteria compared to distilled water.

Current management of appendicular mas - a narrative review.

Appendicular mass is considered as one of the complications of acute appendicitis but there is no consensus on the optimal management of this condition. The management of this condition has always been conservative management with interval appendectomy as popularized by Oschner and Sheerin. The need for interval appendectomy has now been questioned, and an emerging trend has been early appendectomy by laparoscopic method. There are no guidelines on the management of appendicular mass and treatment is decided by the surgeon. We have conducted a narrative review to investigate what is the current practice in the management of appendicular mass.

Morpho-molecular diversity and avirulence genes distribution among the diverse isolates of Magnaporthe oryzae from Southern India.

AIMS: To investigate the diversity of eco-distinct isolates of Magnaporthe oryzae for their morphological, virulence and molecular diversity and relative distribution of five Avr genes. METHODS AND RESULTS: Fifty-two M. oryzae isolates were collected from different rice ecosystems of southern India. A majority of them (n = 28) formed a circular colony on culture media. Based on the disease reaction on susceptible cultivar (cv. HR-12), all 52 isolates were classified in to highly virulent (n = 28), moderately virulent (n = 11) and less-virulent (13) types. Among the 52 isolates, 38 were selected for deducing internal transcribed spacer (ITS) sequence diversity. For deducing phylogeny, another set of 36 isolates from other parts of the world was included, which yielded two distinct phylogenetic clusters. We identified eight haplotype groups and 91 variable sites within the ITS sequences, and haplotype-group-2 (Hap_2) was predominant (n = 24). The Tajima's and Fu's Fs neutrality tests exhibited many rare alleles. Furthermore, PCR analysis for detecting the presence of five Avr genes in the different M. oryzae isolates using Avr gene-specific primers in PCR revealed that Avr-Piz-t, Avr-Pik, Avr-Pia and Avr-Pita were present in 73.68%, 73.68%, 63.16% and 47.37% of the isolates studied, respectively; whereas, Avr-Pii was identified only in 13.16% of the isolates. CONCLUSIONS: Morpho-molecular and virulence studies revealed the significant diversity among eco-distinct isolates. PCR detection of Avr genes among the M. oryzae population revealed the presence of five Avr genes. Among them, Avr-Piz-t, Avr-Pik and Avr-Pia were more predominant. SIGNIFICANCE AND IMPACT OF THE STUDY: The study documented the morphological and genetic variability of eco-distinct M. oryzae isolates. This is the first study demonstrating the distribution of the Avr genes among the eco-distinct population of M. oryzae from southern India. The information generated will help plant breeders to select appropriate resistant gene/s combinations to develop blast disease-resistant rice cultivars.

Analytical Method Validation for Estimation of Neurotransmitters (Biogenic Monoamines) from Cerebrospinal Fluid Using High Performance Liquid Chromatography.

Biogenic amine neurotransmitters such as serotonin and dopamine are essential for signaling in both central and peripheral nervous system. Their metabolism is a multistep pathway and any defect in this results in alteration in metabolites of serotonin 5-Hydroxyindole acetic acid (5HIAA) and dopamine homovanillic acid (HVA) and 3-O-Methyl Dopa (3-OMD). Estimation of these metabolites in cerebrospinal fluid (CSF) assists in diagnosis of neurotransmitter defects. Their estimation is technically demanding and is currently available only in referral centers. We aimed to optimize a method for analysis of 5HIAA, HVA and 3-OMD. A high performance liquid chromatography (HPLC) method with electro chemical detector (ECD) was standardized for estimation. Analysis for method validation, reference range verification and clinical correlation was performed. Linearity obtained for 5-HIAA, HVA and 3-OMD was 65.35-2615.0 nmoles/l, 68.62-2745.0 nmoles/l and 236.5-4730.0 nmoles/l respectively. The coefficient of variation for internal quality controls ranged from 5 to 14% and the external proficiency testing samples (n = 16) were within peer group range. CSF metabolite levels of samples for reference range analysis overlapped with age matched ranges reported in literature. Among the 40 suspected patients analyzed for clinical testing four were found to have a neurotransmitter defect. These patients were then confirmed with molecular testing and clinical correlation. The method is validated and can be adapted in a clinical laboratory with analytical competence in HPLC.

Adsorptive removal of noxious atrazine using graphene oxide nanosheets: Insights to process optimization, equilibrium, kinetics, and density functional theory calculations.

Atrazine is a toxic herbicide whose alarming rate of contamination in the drinking water and wastewater poses a severe threat to the environment and human health. Here in this study, the graphene oxide (GO) nanosheets were prepared using Hummers' method with minor modification and studied as a potential adsorbent for atrazine removal from simulated wastewater. The spectroscopy and microscopic analysis confirmed the successful formation of GO with a multilayer structure resembling the crumpled sheets with random stacking. The Response Surface Methodology (RSM) employing Box Behnken design (BBD) was successfully developed to predict the optimal conditions for maximal atrazine removal as adsorbent dosage 121.45 mg/L; initial feed concentration 27.03 mg/L; temperature 27.69 °C, pH 5.37, and time 180 min. The atrazine adsorption onto GO was found to be higher in acidic pH and lower temperature. Density functional theory (DFT) calculation of adsorbent-adsorbate complex in the implicit solvent medium suggests adsorption affinity energy of -24.4 kcal/mol for atrazine. A careful observation of the molecules configuration and binding energy showed that the π-π interactions and hydrogen bonds played a significant role in the adsorption phenomena. Langmuir isotherm suited well to the adsorption process with a maximum adsorption capacity of 138.19 mg/g, at 318 K. The fitness of kinetic models for atrazine adsorption onto GO nanosheets were in following order Ho < Sobkowsk-Czerwi < Avrami model based on their correlation coefficient (R2) values. Reusability analysis showed that GO nanosheets could be effectively recycled using 0.01 N NaOH up to six cycles of atrazine removal. Thus, this study provided a theoretical and experimental basis for the potential application of GO nanosheets as a novel adsorbent for the removal of hazardous atrazine.

Biosignal-Based Human-Machine Interfaces for Assistance and Rehabilitation: A Survey.

As a definition, Human-Machine Interface (HMI) enables a person to interact with a device. Starting from elementary equipment, the recent development of novel techniques and unobtrusive devices for biosignals monitoring paved the way for a new class of HMIs, which take such biosignals as inputs to control various applications. The current survey aims to review the large literature of the last two decades regarding biosignal-based HMIs for assistance and rehabilitation to outline state-of-the-art and identify emerging technologies and potential future research trends. PubMed and other databases were surveyed by using specific keywords. The found studies were further screened in three levels (title, abstract, full-text), and eventually, 144 journal papers and 37 conference papers were included. Four macrocategories were considered to classify the different biosignals used for HMI control: biopotential, muscle mechanical motion, body motion, and their combinations (hybrid systems). The HMIs were also classified according to their target application by considering six categories: prosthetic control, robotic control, virtual reality control, gesture recognition, communication, and smart environment control. An ever-growing number of publications has been observed over the last years. Most of the studies (about 67%) pertain to the assistive field, while 20% relate to rehabilitation and 13% to assistance and rehabilitation. A moderate increase can be observed in studies focusing on robotic control, prosthetic control, and gesture recognition in the last decade. In contrast, studies on the other targets experienced only a small increase. Biopotentials are no longer the leading control signals, and the use of muscle mechanical motion signals has experienced a considerable rise, especially in prosthetic control. Hybrid technologies are promising, as they could lead to higher performances. However, they also increase HMIs' complexity, so their usefulness should be carefully evaluated for the specific application.

Star-PAP RNA Binding Landscape Reveals Novel Role of Star-PAP in mRNA Metabolism That Requires RBM10-RNA Association.

Star-PAP is a non-canonical poly(A) polymerase that selects mRNA targets for polyadenylation. Yet, genome-wide direct Star-PAP targets or the mechanism of specific mRNA recognition is still vague. Here, we employ HITS-CLIP to map the cellular Star-PAP binding landscape and the mechanism of global Star-PAP mRNA association. We show a transcriptome-wide association of Star-PAP that is diminished on Star-PAP depletion. Consistent with its role in the 3'-UTR processing, we observed a high association of Star-PAP at the 3'-UTR region. Strikingly, there is an enrichment of Star-PAP at the coding region exons (CDS) in 42% of target mRNAs. We demonstrate that Star-PAP binding de-stabilises these mRNAs indicating a new role of Star-PAP in mRNA metabolism. Comparison with earlier microarray data reveals that while UTR-associated transcripts are down-regulated, CDS-associated mRNAs are largely up-regulated on Star-PAP depletion. Strikingly, the knockdown of a Star-PAP coregulator RBM10 resulted in a global loss of Star-PAP association on target mRNAs. Consistently, RBM10 depletion compromises 3'-end processing of a set of Star-PAP target mRNAs, while regulating stability/turnover of a different set of mRNAs. Our results establish a global profile of Star-PAP mRNA association and a novel role of Star-PAP in the mRNA metabolism that requires RBM10-mRNA association in the cell.

Single Nucleotide Polymorphisms of BMP2 Gene Association with Skeletal Class I Crowding: A PCR Study.

AIM AND OBJECTIVE: This study is conducted to find the association of BMP2 (bone morphogenic protein 2) gene variant rs1005464 and rs15705 with skeletal class I crowding cases. MATERIALS AND METHODS: Blood samples from 60 subjects who visited the Department of Orthodontics and Dentofacial Orthopaedics, D.A.P.M.R.V. Dental College, Bengaluru, were taken after written informed consent. These were divided into two groups: group A with 30 subjects having skeletal class I bases with crowding and group B with 30 subjects having skeletal class I bases without visible crowding or spacing (±2 mm). Around 2 mL of venous blood sample was procured from cases and controls after careful examination. All the samples were then subjected to polymerase chain reaction followed by DNA sequencing and capillary electrophoresis. BMP2 rs1005464 and rs15705 gene variants were assessed and Z-Test was used for statistical analysis. RESULT: GG (p = 0.001) and CC (p = 0.0024) genotype of BMP2 gene variant rs1005464 and rs15705, respectively, are significantly associated with skeletal class I crowding cases. CONCLUSION: This study concludes that BMP2 variants rs1005464 and rs15705 can be used as genetic markers for skeletal class I bases having crowding. CLINICAL SIGNIFICANCE: Predisposing genetic markers BMP2 can be identified prior and this would help in predicting the probability of potential crowding in the future and this would help in early prevention and intervention of crowding.

Levels of Vitamin D Are Low After Crohn's Disease Is Established But Not Before.

BACKGROUND & AIMS: Low serum levels of vitamin D have been associated with Crohn's disease (CD). However, it is unclear whether low vitamin D levels cause CD or CD reduces serum vitamin D. METHODS: United States military personnel with CD (n = 240) and randomly selected individuals without CD (controls, n = 240) were matched by age, sex, race, military branch, and geography. We measured 25-hydroxyvitamin D in sera 8-3 years (pre-2) and 3 years to 3 months before diagnosis (pre-1) and 3 months before through 21 months after diagnosis (pre-0). We genotyped VDR and GC vitamin D related polymorphisms. We used conditional logistic regression, including adjustments for smoking, season, enlistment status, and deployment, to estimate relative odds of CD according to vitamin D levels and interactions between genetic factors and levels of vitamin D. RESULTS: Levels of vitamin D before diagnosis were not associated with CD in pre-2 (P trend = .65) or pre-1 samples (P trend = .84). However, we found an inverse correlation between CD and highest tertile of vitamin D level in post-diagnosis samples (P trend = .01; odds ratio, 0.51; 95% CI, 0.30-0.86). Interactions were not detected between vitamin D levels and VDR or GC polymorphisms. We observed an association between VDR Taq1 polymorphism and CD (independent of vitamin D) (P = .02). CONCLUSIONS: In serum samples from military personnel with CD and matched controls, we found no evidence for an association between CD and vitamin D levels up to 8 years before diagnosis. However, we observed an inverse-association between post-diagnosis vitamin D levels and CD. These findings suggest that low vitamin D does not contribute to development of CD-instead, CD leads to low vitamin D.

Discovery of isoquinolinone and naphthyridinone-based inhibitors of poly(ADP-ribose) polymerase-1 (PARP1) as anticancer agents: Structure activity relationship and preclinical characterization.

The exploitation of GLU988 and LYS903 residues in PARP1 as targets to design isoquinolinone (I & II) and naphthyridinone (III) analogues is described. Compounds of structure I have good biochemical and cellular potency but suffered from inferior PK. Constraining the linear propylene linker of structure I into a cyclopentene ring (II) offered improved PK parameters, while maintaining potency for PARP1. Finally, to avoid potential issues that may arise from the presence of an anilinic moiety, the nitrogen substituent on the isoquinolinone ring was incorporated as part of the bicyclic ring. This afforded a naphthyridinone scaffold, as shown in structure III. Further optimization of naphthyridinone series led to identification of a novel and highly potent PARP1 inhibitor 34, which was further characterized as preclinical candidate molecule. Compound 34 is orally bioavailable and displayed favorable pharmacokinetic (PK) properties. Compound 34 demonstrated remarkable antitumor efficacy both as a single-agent as well as in combination with chemotherapeutic agents in the BRCA1 mutant MDA-MB-436 breast cancer xenograft model. Additionally, compound 34 also potentiated the effect of agents such as temozolomide in breast cancer, pancreatic cancer and Ewing's sarcoma models.

Detection of Atrial Fibrillation from Single Lead ECG Signal Using Multirate Cosine Filter Bank and Deep Neural Network.

Atrial fibrillation (AF) is a cardiac arrhythmia which is characterized based on the irregsular beating of atria, resulting in, the abnormal atrial patterns that are observed in the electrocardiogram (ECG) signal. The early detection of this pathology is very helpful for minimizing the chances of stroke, other heart-related disorders, and coronary artery diseases. This paper proposes a novel method for the detection of AF pathology based on the analysis of the ECG signal. The method adopts a multi-rate cosine filter bank architecture for the evaluation of coefficients from the ECG signal at different subbands, in turn, the Fractional norm (FN) feature is evaluated from the extracted coefficients at each subband. Then, the AF detection is carried out using a deep learning approach known as the Hierarchical Extreme Learning Machine (H-ELM) from the FN features. The proposed method is evaluated by considering normal and AF pathological ECG signals from public databases. The experimental results reveal that the proposed multi-rate cosine filter bank based on FN features is effective for the detection of AF pathology with an accuracy, sensitivity and specificity values of 99.40%, 98.77%, and 100%, respectively. The performance of the proposed diagnostic features of the ECG signal is compared with other existing features for the detection of AF. The low-frequency subband FN features found to be more significant with a difference of the mean values as 0.69 between normal and AF classes.

Continuing Medical Education Questions: December 2019.

Article Title: Colonic Manifestations and Complications Are Relatively Under-reported in Systemic Sclerosis: A Systematic Review.

Continuing Medical Education Questions: March 2019.

To receive CME/MOC credit for this activity, please go to: http://acgjournalcme.gi.org/Article Title: ACG Clinical Guideline: Ulcerative Colitis in Adults.

Continuing Medical Education Questions: July 2019.

Article Title: The Gut Microbiome in Other Chronic Immune Disease: Lessons for Inflammatory Bowel Disease.