Multiple endocrine neoplasia type 1 (MEN-1) and neuroendocrine neoplasms (NENs).

Neuroendocrine neoplasms (NENs) are relatively rare neoplasms with 6.4-times increasing age-adjusted annual incidence during the last four decades. NENs arise from neuroendocrine cells, which release hormones in response to neuronal stimuli and they are distributed into organs and tissues. The presentation and biological behaviour of the NENs are highly heterogeneous, depending on the organ. The increased incidence is mainly due to increased awareness and improved detection methods both in the majority of sporadic NENs (non-inherited), but also the inherited groups of neoplasms appearing in at least ten genetic syndromes. The most important one is multiple endocrine neoplasia type 1 (MEN-1), caused by mutations in the tumour suppressor gene MEN1. MEN-1 has been associated with different tumour manifestations of NENs e.g. pancreas, gastrointestinal tract, lungs, thymus and pituitary. Pancreatic NENs tend to be less aggressive when arising in the setting of MEN-1 compared to sporadic pancreatic NENs. There have been very important improvements over the past years in both genotyping, genetic counselling and family screening, introduction and validation of various relevant biomarkers, as well as newer imaging modalities. Alongside this development, both medical, surgical and radionuclide treatments have also advanced and improved morbidity, quality of life and mortality in many of these patients. Despite this progress, there is still space for improving insight into the genetic and epigenetic factors in relation to the biological mechanisms determining NENs as part of MEN-1. This review gives a comprehensive update of current evidence for co-occurrence, diagnosis and treatment of MEN-1 and neuroendocrine neoplasms and highlight the important progress now finding its way to international guidelines in order to improve the global management of these patients.

Radiomics and radiogenomics in head and neck squamous cell carcinoma: Potential contribution to patient management and challenges.

The application of imaging biomarkers in oncology is still in its infancy, but with the expansion of radiomics and radiogenomics a revolution is expected in this field. This may be of special interest in head and neck cancer, since it can promote precision medicine and personalization of treatment by overcoming several intrinsic obstacles in this pathology. Our goal is to provide the medical oncologist with the basis to approach these disciplines and appreciate their main uses in clinical research and clinical practice in the medium term. Aligned with this objective we analyzed the most relevant studies in the field, also highlighting novel opportunities and current challenges.

ImmunoPET imaging of human CD8+ T cells with novel 68Ga-labeled nanobody companion diagnostic agents.

BACKGROUND: Although immunotherapy has revolutionized treatment strategies for some types of cancers, most patients failed to respond or obtain long-term benefit. Tumor-infiltrating CD8+ T lymphocytes are closely related to the treatment outcome and prognosis of patients. Therefore, noninvasive elucidation of both systemic and tumor-infiltrating CD8+ T lymphocytes is of extraordinary significance for patients during cancer immunotherapy. Herein, a panel of 68Ga-labeled Nanobodies were designed and investigated to track human CD8+ T cells in vivo through immuno-positron emission tomography (immunoPET). RESULTS: Among the screened Nanobodies, SNA006a showed the highest binding affinity and specificity to both human CD8 protein and CD8+ cells in vitro, with the equilibrium dissociation constant (KD) of 6.4 × 10-10 M and 4.6 × 10-10 M, respectively. 68Ga-NOTA-SNA006 was obtained with high radiochemical yield and purity, and stayed stable for at least 1 h both in vitro and in vivo. Biodistribution and Micro-PET/CT imaging studies revealed that all tracers specifically concentrated in the CD8+ tumors with low accumulation in CD8- tumors and normal organs except the kidneys, where the tracer was excreted and reabsorbed. Notably, the high uptake of 68Ga-NOTA-SNA006a in CD8+ tumors was rapid and persistent, which reached 24.41 ± 1.00% ID/g at 1.5 h after intravenous injection, resulting in excellent target-to-background ratios (TBRs). More specifically, the tumor-to-muscle, tumor-to-liver, and CD8+ to CD8- tumor was 28.10 ± 3.68, 5.26 ± 0.86, and 19.58 ± 2.70 at 1.5 h, respectively. Furthermore, in the humanized PBMC-NSG and HSC-NPG mouse models, 68Ga-NOTA-SNA006a accumulated in both CD8+ tumors and specific tissues such as liver, spleen and lung where human CD8 antigen was overexpressed or CD8+ T cells located during immunoPET imaging. CONCLUSIONS: 68Ga-NOTA-SNA006a, a novel Nanobody tracer targeting human CD8 antigen, was developed with high radiochemical purity and high affinity. Compared with other candidates, the long retention time, low background, excellent TBRs of 68Ga-NOTA-SNA006a make it precisely track the human CD8+ T cells in mice models, showing great potential for immunotherapy monitoring and efficacy evaluation.

Mass Screening for Celiac Disease: The Autoimmunity Screening for Kids Study.

INTRODUCTION: The Autoimmunity Screening for Kids (ASK) study is a large scale pediatric screening study in Colorado for celiac disease (CD) and type 1 diabetes. This is a report of the CD outcomes for the first 9,973 children screened through ASK. METHODS: ASK screens children aged 1-17 years for CD using 2 highly sensitive assays for tissue transglutaminase autoantibodies (TGA): a radiobinding (RBA) assay for IgA TGA and an electrochemiluminescence (ECL) assay that detects all TGA isotypes. Children who test positive on either assay are asked to return for confirmatory testing. Those with a confirmed RBA TGA level ≥ 0.1 (twice the upper limit of normal) are referred to the Colorado Center for Celiac Disease for further evaluation; all others are referred to primary care. RESULTS: Of the initial 9,973 children screened, 242 children were TGA+ by any assay. Of those initially positive, 185 children (76.4%) have completed a confirmation blood draw with 149 children (80.5%) confirming positive by RBA TGA. Confirmed RBA TGA+ was associated with a family history of CD (odds ratio [OR] = 1.83; 95% confidence interval 1.06-3.16), non-Hispanic white ethnicity (OR = 3.34; 2.32-4.79), and female sex (OR = 1.43; 1.03-1.98). Gastrointestinal symptoms of CD, assessed at the initial screening, were reported equally often among the RBA TGA+ vs TGA- children (32.1% vs 30.5%, P = 0.65). DISCUSSION: The initial results of this ongoing mass-screening program confirm a high prevalence of undiagnosed CD autoimmunity in a screened US population. Symptoms at initial screening were not associated with TGA status (see Visual abstract, Supplementary Digital Content 5, http://links.lww.com/AJG/B587).

Radiotracers for positron emission tomography (PET) targeting tumour-associated carbonic anhydrase isoforms.

The tumour-associated, cell membrane-bound isoforms IX and XII of human carbonic anhydrase (CA, EC 4.2.1.1) are overexpressed in cancer cells contributing to the hypoxic tumour pH/metabolism regulating machinery and as thus, can serve as markers of malignant neoplastic tissue. Inhibitors of CAs can be employed both for the treatment of hypoxic tumours and in the design of radiotracers for positron emission tomography and imaging of such cancers. The present review provides a comprehensive summary of the progress achieved to-date in the field of developing PET-tracers based on monoclonal antibodies, biomolecules, and small-molecule ligands of CA IX and XII.

18F-labeled radiotracers for in vivo imaging of DREADD with positron emission tomography.

Designer Receptors Exclusively Activated by Designer Drugs (DREADD) are a preclinical chemogenetic approach with clinical potential for various disorders. In vivo visualization of DREADDs has been achieved with positron emission tomography (PET) using 11C radiotracers. The objective of this study was to develop DREADD radiotracers labeled with 18F for a longer isotope half-life. A series of non-radioactive fluorinated analogs of clozapine with a wide range of in vitro binding affinities for the hM3Dq and hM4Di DREADD receptors has been synthesized for PET. Compound [18F]7b was radiolabeled via a modified 18F-deoxyfluorination protocol with a commercial ruthenium reagent. [18F]7b demonstrated encouraging PET imaging properties in a DREADD hM3Dq transgenic mouse model, whereas the radiotracer uptake in the wild type mouse brain was low. [18F]7b is a promising long-lived alternative to the DREADD radiotracers [11C]clozapine ([11C]CLZ) and [11C]deschloroclozapine ([11C]DCZ).

La sinoviortesis radioisotópica en el control de la sinovitis refractaria en Castilla La-Mancha. Una experiencia de 10 años / Radioisotope synoviorthesis in the control of refractory synovitis in Castilla-La Mancha. A 10-year experience

Nuestro hospital es el hospital de referencia en medicina nuclear para la realización de la sinoviortesis radioisotópica para toda Castilla La-Mancha. OBJETIVO: Describir la experiencia en la realización de la sinoviortesis radioisotópica en las artritis refractarias a otros tratamientos en nuestro hospital. METODOLOGÍA: Estudio observacional, descriptivo y transversal protocolizado a través de la revisión de la base de datos de las sinoviortesis radioisotópicas realizadas entre 2007 y 2017. Se recopilaron datos clínicos previos (edad, sexo, proceso patológico, tratamientos previos, infiltración previa y articulación afectada) y evolutivos a los 6 meses tras administrar el isótopo. Se creó una base de datos Excel para un análisis de frecuencias con SPSS 21. RESULTADOS: Se realizaron 30 radiosinoviortesis, siendo las enfermedades más frecuentes, por este orden: sinovitis villonodular pigmentada (40%), artritis reumatoide (23,3%), espondiloartritis (13,3%), osteoartritis (10%) y artritis inespecíficas (6,7%), seguido de lupus eritematoso sistémico y gota. Tras 6 meses un 56,7% de los pacientes mejoraron frente a un 36,7% que seguían igual. Así mismo, ninguno de ellos presentó complicaciones relacionadas con el procedimiento. A un 6,6% de los pacientes se les perdió el seguimiento. DISCUSIÓN Y CONCLUSIONES: En los pacientes con episodios de artritis de repetición con derrame articular asociado en una o 2 articulaciones, refractarias a tratamientos sistémicos, a las infiltraciones locales con corticoides y en aquellos pacientes en los que otros tratamientos puedan estar contraindicados, debemos considerar la posibilidad de realizar una radiosinoviortesis isotópica, pues es una técnica sencilla, segura y con una tasa de éxito superior al 50%

Our hospital is the nuclear medicine referral hospital for radioisotopic synoviorthesis for all of Castilla-La Mancha. OBJECTIVE: To describe the experience in the performance of radioisotopic synoviorthesis for arthritis refractory to other treatments in our hospital. METHODOLOGY: Observational, descriptive and cross-sectional study protocolised through the review of the database of radioisotopic synoviorthesis performed between 2007 and 2017. Previous clinical data were collected (age, sex, pathology, previous treatments, previous infiltration and affected joint), and progress at 6 months after administering the isotope. An Excel database was created for a frequency analysis with SPSS 21. RESULTS: 30 radiosynovitis interventions were performed. The most frequent pathologies in this order were: pigmented villonodular synovitis (40%), rheumatoid arthritis (23.3%), spondyloarthritis (13.3%), osteoarthritis (10%) and nonspecific arthritis (6.7%), followed by systemic lupus erythematosus and gout. After 6 months, 56.7% of the patients improved compared to 36.7% who remained the same. Likewise, none of them presented complications related to the procedure. Six point six percent of the patients were lost to follow-up. DISCUSSION AND CONCLUSIONS: In patients with episodes of recurrent arthritis with associated joint effusion in one or two joints, refractory to systemic treatments, to local infiltrations with corticosteroids and for patients for whom other treatments may be contraindicated, we must consider the possibility of performing an isotope radiosinoviortesis, as it is a simple, safe technique with a success rate of more than 50%

Diagnostic value of radionuclide in bone metastasis after breast cancer surgery: A protocol of systematic review.

BACKGROUND: The objective of this study is to evaluate the accuracy of radionuclide in diagnosis of bone metastasis (BM) after breast cancer surgery (BCS). METHODS: The electronic databases (Cochrane Library, MEDLINE, EMBASE, Web of Science, CBM, and CNKI) will be systematically and comprehensively searched until June 1, 2020 for eligible studies that reported the diagnosis of radionuclide in BM after BCS. In addition, we will also identify grey literatures, such as conference abstracts, and reference lists of included studies. All process of study identification, data extraction, and study methodological quality evaluation will be performed by 2 independent authors. All divergences will be settled by a third author through discussion. All data analysis will be carried out by RevMan 5.3 software (London, UK). RESULTS: This study will scrutinize the most recent evidence of radionuclide in detection of BM after BCS. CONCLUSION: This study may provide evidence of accuracy of radionuclide in diagnosis of BM following BCS. STUDY REGISTRATION NUMBER: PROSPERO CRD42020187646.

Alto rendimiento de la Cardiología Nuclear hoy en el diagnóstico cardiológico / High performance of Nuclear Cardiology today in cardiac diagnosis

No disponible

Comparing the intra-tumoral distribution of Gemcitabine, 5-Fluorouracil, and Capecitabine in a murine model of pancreatic ductal adenocarcinoma.

PURPOSE: To develop a technique to compare the intra-tumoral distribution of the drug gemcitabine, its surrogate [18F]-fluoroarabinocytosine ([18F]-FAC) and related chemotherapeutics 5-FU and capecitabine in a pre-clinical model of pancreatic ductal adenocarcinoma (PDAC). EXPERIMENTAL DESIGN: Using a KPC-organoid derived model of PDAC, we obtained autoradiographic images of the tumor distribution of, [14C]-gemcitabine, [14C]-5-FU, [3H]-capecitabine. These were compared indirectly by co-administering [18F]-FAC, a close analog of gemcitabine with a proven equivalent intra-tumor distribution. The short half-life of 18F allows for clean separation of 3H/14C labeled drugs in specimens by dual isotope digital autoradiography. Autoradiographic images of [14C]-gemcitabine, [3H]-capecitabine and [14C]-5-FU were each correlated to [18F]-FAC on a pixel-by-pixel basis. The tumor drug penetration was compared using cumulative histograms. RESULTS: Gemcitabine distribution correlated strongly with FAC as expected. 5-FU also gave a similar microdistribution to that of FAC, whereas no correlation was found between capecitabine or its metabolic products and FAC distribution. Accumulation of Gemcitabine and 5-FU was lower in hypoxic regions of the tumor, whereas no such correlation was observed for capecitabine and its metabolites. CONCLUSIONS: Gemcitabine and 5-FU target the same regions of the tumor, leaving hypoxic cells untreated. Capecitabine metabolites penetrate further into the tumor but it is yet to be determined whether these metabolites are the active form of the drug.

Usage des Rayonnements ionisants en milieu médical à Cotonou (Benin)

Objectif : Faire l'état des lieux des applications médicales des rayonnements ionisants dans la ville de Cotonou.Matériels et méthode : Etude prospective du 16 avril au 22 juin 2018 dans les structures sanitaires disposant de générateurs ou sources de rayonnements ionisants utilisés à des fins médicales dans la ville de Cotonou. Les paramètres étudiés étaient : les caractéristiques des structures sanitaires utilisant les rayonnements ionisants, les infrastructures techniques et ressources humaines impliquées, et la mise en oeuvre des mesures de radioprotection.Résultats : Les rayonnements ionisants étaient utilisés respectivement dans 22 services pour les rayons X, et 1 service pour les rayons gamma. Ces services ne couvraient que les 2/3 des arrondissements. Les générateurs de rayons X comprenaient les appareils de radiologie classique (52,1%), de mammographie (19,6%), de radiologie dentaire (15,2%) et de scanner (8,7%). Ces appareils étaient acquis à l'état neuf dans 52,1% et utilisés dans 63,1% dans les structures privées. Ils étaient dominés par les marques Siemens (20,8%), Schimadzu (12,5%) pour la radiologie classique. Les scanners avaient un âge compris entre 5 et 9 ans et étaient de 16 barrettes dans 50%. Quatorze radiologues et 65 manipulateurs étaient recensés. Près des 2/3 des manipulateurs avaient moins de dix années d'expérience. Aucune structure n'utilisait de dosimètre. Seulement 2 structures sanitaires disposaient de pictogramme et de règlement de zone. Un peu plus de 1500 patients étaient exposés aux rayons X par semaine et 150 dosages radio immunologiques étaient réalisés par semaine.Conclusion : L'usage des rayonnements ionisants était exclusivement à but diagnostique à Cotonou avec des mesures de radioprotection peu satisfaisantes

SPECT/CT imaging of apoptosis in aortic aneurysm with radiolabeled duramycin.

The objective of this research was to estimate whether a [99mTc]duramycin probe can be used for apoptosis imaging in patients with aortic aneurysm (AA). Vascular smooth muscle cell (SMC) apoptosis has an important influence on AA development. Thus, non-invasive imaging of SMC apoptosis may be able to evaluate AA progress and risk stratification. SMCs were treated with hydrogen peroxide (H2O2; 200 µΜ) or culture medium as a control. Apoptosis was measured using flow cytometry and [99mTc]duramycin to detect the binding efficiency to apoptotic SMCs. C57/BL6 mice were administered angiotensin-II and beta-aminopropionitrile (BAPN) subcutaneously to establish an AA model, or saline for controls. Aortic specimens underwent pathological evaluation and their aortic diameters were measured after 6 weeks. Micro-SPECT/CT scanning of [99mTc]duramycin and 18F-FDG PET detection were performed. SMCs treated with H2O2 showed more apoptosis compared with the control group (67.2 ± 3.8% vs. 16.1 ± 0.6%, P < 0.01). The experimental group showed a high rate of AA formation (70%) compared with no AA formation in the control group. The average aorta diameter was higher and [99mTc]duramycin uptake at the AA site was higher in the experimental group compared with the control group. Compared with the normal aorta in the control group, AA in experiment group had more severe medial degeneration, elastic fiber reduction and fracture, and collagen degeneration. TUNEL staining verified the higher apoptosis rate at the AA site in experiment group compared with the control group (63.9 ± 3.7% in ascending AA, 66.4 ± 4.0% in thoracic AA, vs. 3.5 ± 0.3% in normal aorta, P < 0.01). [99mTc]Duramycin may be an effective probe to evaluate apoptosis in AA.

Determination of the geographical origin of marine mussels (Mytilus spp.) using 143Nd/144Nd ratios.

Geographical traceability of marine bivalves is critical to guarantee their quality and safeguard the interest of both consumers and producers. The neodymium isotopic ratio (143Nd/144Nd) of the coastal water mainly reflects the geology of its neighboring watershed, displaying the distinct and systematic variability at high level of geographical detail and thereby shedding light on its potential as a geochemical tracer. For the first time, the present study investigated the utility and robustness of 143Nd/144Nd archived in mytilid mussel shells for geographical traceability purposes. The reproducibility of 143Nd/144Nd ratios maintained in mussels shells from the same cohort demonstrates that the Nd isotopic ratio meets the major requirement for an ideal geochemical tracer, i.e., the biologically induced variation should be rather minimal. The distribution and variability of mussel shell 143Nd/144Nd patterns were subsequently mapped along the Japanese and Chinese coastal waters. Neodymium isotopes of mussel shells record 143Nd/144Nd variations among local regions and between the two countries, which are rather compatible with the ages and lithology of the continental bedrocks. These findings highlight the great potential of 143Nd/144Nd for tracing the geographical origin of marine bivalves.

Radioluminescence Microscopy: A Quantitative Method for Radioisotopic Imaging of Metabolic Fluxes in Living Cancer Cells.

Radionuclide imaging with cellular-scale resolution allows characterization of biological processes and metabolic fluxes in single live cells. In this protocol, we describe how to image radiotracer uptake with single-cell resolution and compare the method to conventional bulk-scale gamma counting. We describe the utility of both techniques, give examples where each technique is recommended, and provide detailed side-by-side instructions for both techniques.

Determination of intracellular pH in phytoplankton using the fluorescent probe, SNARF, with detection by fluorescence spectroscopy.

The maintenance of pH homeostasis is critical for a variety of cellular metabolic processes. Although ocean acidification is likely to influence cellular metabolism and energy balance, the degree to which intracellular pH in phytoplankton differs from the external environment under varying environmental pH levels is not well characterized. While there are numerous existing methods for the determination of intracellular pH in the form of single peak emission (e.g., BCECF) and radioisotopic (e.g., 14C-DMO) indicators for use with phytoplankton, the fluorescent pH indicator seminaphtharhodafluor (SNARF) has not been established as a robust method for measuring in vivo pH in phytoplankton. SNARF has superior accuracy and sensitivity since it exhibits dual emission peaks from a single excitation wavelength and the ratio of the two are related to pH. The use of a ratio limiting variations in fluorescence due to dye loading, photobleaching, and instrument variation; moreover, like other fluorescence-based assays, it does not require the specialized equipment and permits that radioisotopic methods do. As a first step, we tested the performance of SNARF for measuring intracellular pH in vivo in a number of phytoplankton taxa. SNARF detection was accomplished using fluorescence spectroscopy (FS) and laser scanning microscopy (LSM). Since SNARF fluorescence is activated by cleavage of an ester group from the core fluorophore by non-specific esterases, we measured esterase activity using fluorescein diacetate (FDA) to characterize variability in esterase activity among phytoplankton taxa, with a view towards its influence on assay performance. Esterase activity cell volume; however, there was no indication that enzyme specificity and differences in individual esterase profiles adversely affected SNARF performance in phytoplankton. Assays of intracellular pH using SNARF were comparable to those made with 14C-labeled DMO, an accepted standard method. Thus, SNARF provides robust measurements of intracellular pH in phytoplankton, constituting a useful tool in investigations of the effects of ocean acidification and fluctuations in environmental pH on cellular physiology.

[Theoretical grounds of a structural and functional model for quality assurance of radiation diagnostics under conditions of development of the modern health care system in Ukraine].

OBJECTIVE: Introduction: Modern changes in the health care system of Ukraine are focused on financial support in providing medical and diagnostic care to the population and are based on deep and consistent structural and functional transformations. They are aimed at providing adequate quality care, which is the main target function and a principal criterion for operation of health care system. The urgency of this problem is increasing in the context of reforming the health care system and global changes in the governmental financial guarantees for the provision of medical services to the population. The aim of the work is to provide theoretical grounds for a structural and functional model of quality assurance of radiation diagnostics at all levels of medical care given to the population under the current health care reform in Ukraine. PATIENTS AND METHODS: Materials and methods: The object of the study is organizing the operation of the radiation diagnostic service; the information is based on the actual data on the characteristics of radiation diagnosis at different levels of medical care provision. Methods of systematic approach, system analysis and structural and functional analysis of the operating system of radiation diagnostics are used. RESULTS: Review: The basis of the quality assurance model is the cyclical process, which includes the stages of the problem identifition, planning of its solution, organization of the system for implementation of decisions, monitoring the quality management process of the radiation diagnostics, and factors influencing the quality of the radiation diagnostics service. These factors include the quality of the structure, process, results, organization of management and control of current processes and the results of radiation diagnostics management. CONCLUSION: Conclusions: The advantages of the proposed model for ensuring the quality of the radiation diagnostics service are its systemacy and complexity, elimination of identified defects and deficiencies, and achievement of profitability through modern redistribution and use of existing resources of the health care system. The results of adequate service quality management activities in radiation diagnostics are the improvement of organizational and economic principles along with legislative regulation, the implementation of a modern system of radiation diagnostics in the state health care at the national and regional levels, the increase of the accessibility, quality and efficiency of the radiation diagnostics service.

Gut Barrier Dysfunction-A Primary Defect in Twins with Crohn's Disease Predominantly Caused by Genetic Predisposition.

Background and Aims: The aetiology of Crohn's disease is poorly understood. By investigating twin pairs discordant for Crohn's disease, we aimed to assess whether the dysregulated barrier represents a cause or a consequence of inflammation and to evaluate the impact of genetic predisposition on barrier function. Methods: Ileal biopsies from 15 twin pairs discordant for Crohn's disease [monozygotic n = 9, dizygotic n = 6] and 10 external controls were mounted in Ussing chambers to assess paracellular permeability to 51Chromium [Cr]-EDTA and trancellular passage to non-pathogenic E. coli K-12. Experiments were performed with and without provocation with acetylsalicylic acid. Immunofluorescence and ELISA were used to quantify the expression level of tight junction proteins. Results: Healthy co-twins and affected twins displayed increased 51Cr-EDTA permeability at 120 min, both with acetylsalicylic acid [p < 0.001] and without [p < 0.001] when compared with controls. A significant increase in 51Cr-EDTA flux was already seen at 20 min in healthy monozygotic co-twins compared with controls [p≤0.05] when stratified by zygosity, but not in healthy dizygotic co-twins. No difference in E. coli passage was observed between groups. Immunofluorescence of the tight junction proteins claudin-5 and tricellulin showed lower levels in healthy co-twins [p < 0.05] and affected twins [p < 0.05] compared with external controls, while ELISA only showed lower tricellulin in Crohn's disease twins [p < 0.05]. Conclusion: Our results suggest that barrier dysfunction is a primary defect in Crohn's disease, since changes were predominantly seen in healthy monozygotic co-twins. Passage of E. coli seems to be a consequence of inflammation, rather than representing a primary defect.