Genomic profiling in GIST: Implications in clinical outcome and future challenges.

Gastrointestinal Stromal Tumors (GIST) are the most frequent mesenchymal neoplasia of the digestive tract. Genomic alterations in KIT, PDFGRA, SDH, and BRAF genes are essential in GIST oncogenesis. Therefore, the mutations in these genes have demonstrated clinical implications. Tumors with deletions in KIT-exon 11 or duplications in exon 9 are associated with a worse prognosis. In contrast, KIT-exon 11 substitutions and duplications are associated with a better clinical outcome. Moreover, mutations in Kit exon 9 and 11 are actionable, due to their response to imatinib, while mutations in PDGFRA respond to sunitinib and/or avapritinib. Although, molecular testing on tissue samples is effective; it is invasive, requires adequate amounts of tissue, and a long experimental process is needed for results. In contrast, liquid biopsy has been proposed as a simple and non-invasive method to test biomarkers in cancer. The most common molecule analyzed by liquid biopsy is circulating tumor DNA (ctDNA). GISTs ctDNA testing has been demonstrated to be effective in identifying known and novel KIT mutations that were not detected using traditional tissue DNA testing and have been useful in determining progression risk and response to TKI therapy. This allows the clinician to have an accurate picture of the genetic changes of the tumor over time. In this work, we aimed to discuss the implications of mutational testing in clinical outcomes, the methods to test ctDNA and the future challenges in the establishment of alternatives of personalized medicine.

Latin American young patients with gastric adenocarcinoma: worst prognosis and outcomes.

Background: Incidence of young patients (aged 40 years or younger) diagnosed with gastric carcinoma has increased worldwide. Young GC diagnosis, have clinicopathological features that differ from elderly, and is correlated with bad prognosis factors. The purpose of this work is to describe the prevalence, clinic-pathological features, and prognosis of overall survival (OS) of young Latin-American patients with GC. Methods: Retrospective, observational study. Included patients treated at the National Cancer Institute [2004-2020]. Statistical analysis: χ2 and t-test, Kaplan-Meier, Log-Rank and Cox-Regression. Statistical significance differences were assessed when P was bilaterally <0.05. Results: A total of 2,543 patients fulfilled the inclusion criteria. Young-patients were predominantly female (54%), with diffuse-type adenocarcinoma (68%), signet-ring-cell (72%), poor-differentiation (90%), and metastatic (79%). In OS analysis, patients with metastatic disease, showed differences regarding age, young patients reported a median-OS of 8 versus 13 months for elderly patients (P=0.001). Among young patients, differences were also observed regarding gender, young-female patients had a median-OS of 5 versus 11 months for young-man (P=0.001). Conclusions: This is one of the pioneer studies correlating age with gender and the prognostic features of bad prognosis in Latin-American population. Besides, supports the idea that a global effort is required to improve awareness, prevention, and early diagnosis of GC.

TLR8 escapes X chromosome inactivation in human monocytes and CD4+ T cells.

BACKGROUND: Human endosomal Toll-like receptors TLR7 and TLR8 recognize self and non-self RNA ligands, and are important mediators of innate immunity and autoimmune pathogenesis. TLR7 and TLR8 are, respectively, encoded by adjacent X-linked genes. We previously established that TLR7 evades X chromosome inactivation (XCI) in female immune cells. Whether TLR8 also evades XCI, however, has not yet been explored. METHOD: In the current study, we used RNA fluorescence in situ hybridization (RNA FISH) to directly visualize, on a single-cell basis, primary transcripts of TLR7 and TLR8 relative to X chromosome territories in CD14+ monocytes and CD4+ T lymphocytes from women, Klinefelter syndrome (KS) men, and euploid men. To assign X chromosome territories in cells lacking robust expression of a XIST compartment, we designed probes specific for X-linked genes that do not escape XCI and therefore robustly label the active X chromosome. We also assessed whether XCI escape of TLR8 was associated with sexual dimorphism in TLR8 protein expression by western blot and flow cytometry. RESULTS: Using RNA FISH, we show that TLR8, like TLR7, evades XCI in immune cells, and that cells harboring simultaneously TLR7 and TLR8 transcript foci are more frequent in women and KS men than in euploid men, resulting in a sevenfold difference in frequency. This transcriptional bias was again observable when comparing the single X of XY males with the active X of cells from females or KS males. Interestingly, TLR8 protein expression was significantly higher in female mononuclear blood cells, including all monocyte subsets, than in male cells. CONCLUSIONS: TLR8, mirroring TLR7, escapes XCI in human monocytes and CD4+ T cells. Co-dependent transcription from the active X chromosome and escape from XCI could both contribute to higher TLR8 protein abundance in female cells, which may have implications for the response to viruses and bacteria, and the risk of developing inflammatory and autoimmune diseases.

Human endosomal Toll-like receptors TLR7 and TLR8, encoded by two adjacent X-linked genes, recognize self and non-self RNA ligands, and are important mediators of innate immunity and autoimmune pathogenesis. We previously reported that TLR7 evades X chromosome inactivation (XCI) in female immune cells, correlating with enhanced functional properties in B cells harboring biallelic expression of this gene. Here, we conducted a comprehensive single-cell resolution analysis of the transcriptional regulation of both TLR7 and TLR8, in CD14⁺ monocytes and CD4⁺ T lymphocytes. We unequivocally demonstrated that TLR8, like TLR7, escapes XCI in immune cells from female and Klinefelter syndrome males. When we analyzed TLR7 and TLR8 transcripts together, cells from women and KS men exhibited higher frequencies of cells co-transcribing the two genes. Surprisingly, these differences were attributable not only to the ability of TLR7 and TLR8 to be expressed on the Xi, but also to the joint transcriptional behavior of the TLR7­TLR8 gene pair on the active X chromosome specifically. This contrasted with a striking pattern of mutually exclusive transcription on the single X of euploid men. Corroborating our RNA FISH results, we found higher TLR8 protein expression in female than in male leukocytes, including all monocyte subpopulations. In summary, our data suggest that sex-biased co-regulation of the Toll-like receptor locus and XCI escape of TLR8 contribute to the sexual dimorphism in TLR8 expression, which may have important consequences for the functional make-up of monocyte and T cell populations.

Impact of ileostomy in the adjuvant treatment and outcome of colon cancer.

BACKGROUND: After tumor resection, a preventive diverting loop ileostomy creation is a routine surgical procedure to prevent anastomotic leakage and infections and to preclude secondary surgeries. Despite its benefits, several studies have proposed potential complications that extend the disease course by impairing the feasibility of adjuvant chemotherapy and adherence. PURPOSE: The aim of this study was to evaluate the impact of ileostomy complications on the adherence to adjuvant treatment and overall survival (OS) of colon cancer (CC) patients. METHODS: Retrospective, observational study. Patients diagnosed with colon adenocarcinoma were treated between January 2010 and December 2020 at the National Cancer Institute in Mexico. STATISTICAL ANALYSIS: χ2 and t-test, Kaplan-Meier, log-rank, and Cox regression. Statistical significance differences were assessed when p was bilaterally < 0.05. RESULTS: The most frequent complications of loop-derived ileostomy were hydro-electrolytic dehydration (50%), acute kidney injury (AKI) (26%), grade 1-2 diarrhea (28%), and grade 3-4 diarrhea (21%) (p = 0.001). Patients with complete chemotherapy did not reach the median OS. In contrast, the median OS for patients with non-complete chemotherapy was 56 months (p = 0.023). Additionally, 5-year OS reached to 100% in the early restitution group, 85% in the late restitution group, and 60% in the non-restitution group (p = 0.016). Finally, AKI (p = 0.029; 95% confidence interval (CI) 3.348 [1.133-9.895]), complete chemotherapy (p = 0.028; 95% CI 0.376 [0.105-0.940]), and reversed ileostomy (p = 0.001; 95% CI 0.125 [0.038-0.407]) remained as predictors of overall survival for patients with CC treated with a loop ileostomy. CONCLUSIONS: Our results emphasize the early stoma reversal restitution as a safe and feasible alternative to prevent severe complications related to ileostomies which improve chemotherapy adherence and overall survival of colon cancer patients. This is one of the pioneer studies analyzing the impact of ileostomy on treatment adherence and outcome of Latin American patients with colon cancer. TRIAL REGISTRATION: Retrospective study No. 2021/045, in April 2021.

3' Untranslated Region Structural Elements in CYP24A1 Are Associated With Infantile Hypercalcemia Type 1.

Loss-of-function mutations in the CYP24A1 protein-coding region causing reduced 25 hydroxyvitamin D (25OHD) and 1,25 dihydroxyvitamin D (1,25(OH)2 D) catabolism have been observed in some cases of infantile hypercalcemia type 1 (HCINF1), which can manifest as nephrocalcinosis, hypercalcemia and adult-onset hypercalciuria, and renal stone formation. Some cases present with apparent CYP24A1 phenotypes but do not exhibit pathogenic mutations. Here, we assessed the molecular mechanisms driving apparent HCINF1 where there was a lack of CYP24A1 mutation. We obtained blood samples from 47 patients with either a single abnormality of no obvious cause or a combination of hypercalcemia, hypercalciuria, and nephrolithiasis as part of our metabolic and stone clinics. We used liquid chromatography tandem mass spectrometry (LC-MS/MS) to determine serum vitamin D metabolites and direct sequencing to confirm CYP24A1 genotype. Six patients presented with profiles characteristic of altered CYP24A1 function but lacked protein-coding mutations in CYP24A1. Analysis upstream and downstream of the coding sequence showed single nucleotide variants (SNVs) in the CYP24A1 3' untranslated region (UTR). Bioinformatics approaches revealed that these 3' UTR abnormalities did not result in microRNA silencing but altered the CYP24A1 messenger RNA (mRNA) secondary structure, which negatively impacted translation. Our experiments showed that mRNA misfolding driven by these 3' UTR sequence-dependent structural elements was associated with normal 25OHD but abnormal 1,25(OH)2 D catabolism. Using CRISPR-Cas9 gene editing, we developed an in vitro mutant model for future CYP24A1 studies. Our results form a basis for future studies investigating structure-function relationships and novel CYP24A1 mutations producing a semifunctional protein. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Influence of X chromosome in sex-biased autoimmune diseases.

Females have better ability to resolve infections, compared to males, but also, a greater susceptibility to develop autoimmunity. Besides the initial interest on the contribution of sex-steroid hormone signaling, the role of genetic factors linked to X chromosome has recently focused much attention. In human and mouse, the number of X chromosomes, rather than sex-steroid hormones, have been found associated with higher risk or susceptibility to develop autoimmunity, particularly rheumatic diseases, such as SLE, Sjögren's syndrome or Scleroderma. For all of these diseases, the Toll-like receptor TLR7 and TLR8, encoded on the same locus in the human Xp, have been demonstrated to be causal in disease development through gene dosage effect or gain of function mutations. During embryonic development in female mammals, one X chromosome is stochastically inactivated to balance X-linked gene expression between males and females, a process known as X chromosome inactivation (XCI). Nevertheless, some genes including immune related genes can escape XCI to variable degree and penetrance, resulting in a bi-allelic expression in some immune cells, such as TLR7. Because tight regulation of TLR expression is necessary for a healthy, self-tolerant immune environment, XCI escape has been proposed as a mechanism contributing to this sexual dimorphism. In this review, we will summarize general mechanisms of XCI, and describe the known escapee's genes in immune cells, the cellular diversity created by such mechanisms and its potential implication in autoimmune diseases, with a particular focus on the X-linked genes and immune cell populations involved in SLE. Whether dysregulated expression of X-linked genes could contribute to the enhanced susceptibility of females to develop such diseases remains to be proven. Shedding lights onto the X-linked genetic mechanisms contributing to modulation of immune cell functions will undoubtedly provide new insights into the intricate mechanisms underlying sex differences in immunity and autoimmunity.

The workload of a medical examiner service at an acute National Health Service hospital during the COVID-19 pandemic: The Norfolk & Norwich University Hospital experience.

The COVID-19 pandemic commenced in March 2020. In May 2019, a new Medical Examiner system was introduced to scrutinise deaths of patients dying within acute National Health Service Trusts. The Coronavirus Act 2020 which came into force in March 2020 modified certification of death requirements. Newly formed Medical Examiner Services were advised they could suspend scrutiny during the pandemic. The Norfolk & Norwich University Hospital Medical Examiner Service (NNUH MES) continued to scrutinise patient deaths throughout. This study summarises the workload of the NNUH MES from 1st June 2020 to 31st May 2021 over which period 2856 deaths were recorded and 2687 scrutinised by the Medical Examiners.

A microRNA panel that regulates proinflammatory cytokines as diagnostic and prognosis biomarkers in colon cancer.

Colon cancer (CC) is the third most common neoplasm and the fourth cause of cancer-related death worldwide in both sexes. It has been established that inflammation plays a critical role in tumorigenesis and progression of CC. Immune, stromal and tumor cells supply the tumor microenvironment with pro-inflammatory cytokines such as interleukin 1ß, TNFα, IL-6 and IL-11, to hyperactivate signaling pathways linked to cancerous processes. Recent findings suggest a putative role of microRNAs (miRNAs) in the progression and management of the inflammatory response in intestinal diseases. Moreover, miRNAs are able to regulate expression of molecular mediators that are linking inflammation and cancer. In this work a miRNA panel differentially expressed between healthy, inflammatory bowel disease (IBD) and CC tissue was established. Identified miRNAs regulate signaling pathways related to inflammation and cancer progression. An inflammation associated-miRNA panel composed of 11-miRNAs was found to be overexpressed in CC but not in inflamed or normal tissues (miR-21-5p, miR-304-5p, miR-577, miR-335-5p, miR-21-3p, miR-27b-5p, miR-335-3p, miR-215-5p, miR-30b-5p, miR-192-5p, miR-3065-5p). The association of top hit miRNAs, miR-3065-5p and miR-30b-5p expression with overall survival of CC patients was demonstrated using Kaplan-Meier tests. Finally, differential miRNA expression was validated using an inflammation-associated CC model induced by Azoxymethane/Dextran Sodium Sulfate (AOM/DSS) to compare miRNA expression in normal and inflamed tissue versus CC tissues. Based on these findings we propose the identified inflammatory miRNA panel as a potent diagnostic tool for CC determination.

Cociente ganglionar como factor pronóstico de recurrencia tumoral en pacientes con carcinoma escamoso de cavidad oral.

BACKGROUND: The lymph node ratio (LNR) is a recent tool, but its predictive value for recurrence is uncertain. OBJECTIVE: To evaluate LNR as a prognostic factor for disease-free survival (DFS) in patients with oral squamous cell carcinoma. METHOD: Retrospective observational study. Patients with oral squamous cell carcinoma undergoing resection and lymph node dissection. Chi squared, Kaplan-Meier, log rank and Cox regression tests were run; bilateral p ≤ 0.05 determined statistical significance. RESULTS: 88 patients were included, 45% (n = 40) men and 54% (n = 48) women, mean age of 60.42 (± 14.28) years. Main tumor location in tongue (75%); 61% in clinical stage I-III and 39% in clinical stage IV. Population was divided into LNR < 0.06 (58%) and LNR ≥ 0.06 (42%). The median DFS was not reached for both groups (p = 0.018). Predictors of DFS were the LNR (p = 0.024; hazard ratio [HR]: 2.20; confidence interval of 95% [95% CI]: 1.11-4.39) and the clinical stage (p = 0.004; HR: 1.76; 95% CI: 1.19-2.59). In the multivariate analysis, predictors were not maintained (p = 0.227 and 0.191, respectively). CONCLUSIONS: Significant differences were observed in the DFS analysis, however, they were not predictive of local recurrence in the multivariate analysis.

ANTECEDENTES: El cociente ganglionar (LNR) es una herramienta reciente, pero su valor predictivo de recurrencia es incierto. OBJETIVO: Evaluar el LNR como factor pronóstico de supervivencia libre de enfermedad (SLE) en pacientes con carcinoma oral de células escamosas. MÉTODO: Estudio retrospectivo observacional. Pacientes con carcinoma oral de células escamosas sometidos a resección y disección ganglionar. Se aplicaroon las pruebas de ji al cuadrado, Kaplan-Meier, log rank y regresión de Cox; se consideró estadísticamente significativo p ≤ 0.05 bilateral. RESULTADOS: Fueron incluidos 88 pacientes, el 45% (n = 40) hombres y el 54% (n = 48) mujeres, con una edad media de 60.42 (± 14.28) años. La principal localización tumoral fue la lengua (75%); el 61% en etapa I-III y el 39% en etapa IV. Se dividió en LNR < 0.06 (58%) y LNR ≥ 0.06 (42%). La mediana de SLE no fue alcanzada para ambos grupos (p = 0.018). Resultaron predictores de SLE el LNR (p = 0.024; hazard ratio [HR]: 2.20; intervalo de confianza del 95% [IC95%]: 1.11-4.39) y la etapa clínica (p = 0.004; HR: 1.76; IC95%: 1.19-2.59). En el análisis multivariado no se mantuvieron predictores (p = 0.227 y p = 0.191, respectivamente). CONCLUSIONES: Se observaron diferencias significativas en el análisis de SLE, pero no se mantuvieron como predictoras de recurrencia local en el análisis multivariado.

A Dual Role for Macrophages in Modulating Lung Tissue Damage/Repair during L2 Toxocara canis Infection.

Macrophages that are classically activated (M1) through the IFN-γ/STAT1 signaling pathway have a major role in mediating inflammation during microbial and parasitic infections. In some cases, unregulated inflammation induces tissue damage. In helminth infections, alternatively activated macrophages (M2), whose activation occurs mainly via the IL-4/STAT6 pathway, have a major role in mediating protection against excessive inflammation, and has been associated with both tissue repair and parasite clearance. During the lung migratory stage of Toxocara canis, the roles of M1 and M2 macrophages in tissue repair remain unknown. To assess this, we orally infected wild-type (WT) and STAT1 and STAT6-deficient mice (STAT1-/- and STAT6-/-) with L2 T. canis, and evaluated the role of M1 or M2 macrophages in lung pathology. The absence of STAT1 favored an M2 activation pattern with Arg1, FIZZ1, and Ym1 expression, which resulted in parasite resistance and lung tissue repair. In contrast, the absence of STAT6 induced M1 activation and iNOS expression, which helped control parasitic infection but generated increased inflammation and lung pathology. Next, macrophages were depleted by intratracheally inoculating mice with clodronate-loaded liposomes. We found a significant reduction in alveolar macrophages that was associated with higher lung pathology in both WT and STAT1-/- mice; in contrast, STAT6-/- mice receiving clodronate-liposomes displayed less tissue damage, indicating critical roles of both macrophage phenotypes in lung pathology and tissue repair. Therefore, a proper balance between inflammatory and anti-inflammatory responses during T. canis infection is necessary to limit lung pathology and favor lung healing.

Carcinoma epidermoide puro-combinado de vesícula biliar / Gallbladder epidermoid carcinoma

Background: Gallbladder epidermoid carcinoma is rare and more common in women over 55 years of age. Aim: To report the features of 15 patients with gallbladder epidermoid carcinoma. Material and Methods: Review of medical records of patients with gallbladder cancer in an oncology service. Results: Of 207 patients with gallbladder cancer, 15patients aged 53-72years, 93% women had an epidermoid component in their cancer. Forty percent were diabetic and 33% had cholelithiasis. All had locoregional extension of the tumor. A cholecystectomy was done in nine patients (using open surgery in six). In six patients, only a biopsy was done. Median survival was 4.2 months. Conclusions: Gallbladder epidermoid carcinoma is uncommon and has a bad prognosis.

Carcinoma epidermoide primario del estómago: reporte de tres casos / Primary squamous cell carcinoma of the stomach: report of three cases

Gastric squamous cell carcinoma (SCC) is a rare type of cancer. We report three patients with the tumor. A 65 years old male presenting with weight los and heartburn. An upper gastrointestinal endoscopy revealed an ulcerated tumor whose biopsy disclosed a gastric epidermoid carcinoma. The patient was operated and chemotherapy was attempted, but he died five months later. A 39 years old male with an antral tumor corresponding to an epidermoid carcinoma. He was operated and received chemotherapy and radiotherapy and died one year later. A 79 years old female with a distal antral tumor corresponding to a undifferentiated epidermoid carcinoma. She received palliative therapy and died two months later.

Effects of Dietary Components During and After Concomitant Chemoradiotherapy, Radiotherapy, or Sequential Chemoradiotherapy to the Abdominopelvic Area.

Radiotherapy is a fundamental part of the treatment of pelvic neoplasms. Up to 90% of patients develop gastrointestinal symptoms as a result of acute injury to the small and large intestine, particularly in the mucosa. Radiotherapy leads to atrophy of the intestinal epithelium, acute crypt inflammation, inflammatory infiltration of the epithelium, malabsorption of lactose, and biliary salts as well as alterations in pancreatic enzymes and biliary salts, resulting in the malabsorption syndrome and dysbiosis. The most commonly reported symptoms of pelvic radiation disease include changes in bowel habits (94%), decreased fecal consistency (80%), frequency of bowel movements (74%), bowel urgency (39%), and fecal incontinence (37%). Although nutritional interventions with dietary modifications have been reported to prevent and treat gastrointestinal symptoms, the evidence remains inconclusive.

[Primary squamous cell carcinoma of the stomach. Report of three cases]. / Carcinoma epidermoide primario del estómago. Reporte de tres casos.

Gastric squamous cell carcinoma (SCC) is a rare type of cancer. We report three patients with the tumor. A 65 years old male presenting with weight los and heartburn. An upper gastrointestinal endoscopy revealed an ulcerated tumor whose biopsy disclosed a gastric epidermoid carcinoma. The patient was operated and chemotherapy was attempted, but he died five months later. A 39 years old male with an antral tumor corresponding to an epidermoid carcinoma. He was operated and received chemotherapy and radiotherapy and died one year later. A 79 years old female with a distal antral tumor corresponding to a undifferentiated epidermoid carcinoma. She received palliative therapy and died two months later.

[Gallbladder epidermoid carcinoma]. / Carcinoma epidermoide puro-combinado de vesícula biliar.

BACKGROUND: Gallbladder epidermoid carcinoma is rare and more common in women over 55 years of age. AIM: To report the features of 15 patients with gallbladder epidermoid carcinoma. MATERIAL AND METHODS: Review of medical records of patients with gallbladder cancer in an oncology service. RESULTS: Of 207 patients with gallbladder cancer, 15patients aged 53-72years, 93% women had an epidermoid component in their cancer. Forty percent were diabetic and 33% had cholelithiasis. All had locoregional extension of the tumor. A cholecystectomy was done in nine patients (using open surgery in six). In six patients, only a biopsy was done. Median survival was 4.2 months. CONCLUSIONS: Gallbladder epidermoid carcinoma is uncommon and has a bad prognosis.

Development of guidance on the timeliness in response to acute kidney injury warning stage test results for adults in primary care: an appropriateness ratings evaluation.

OBJECTIVES: Tackling the harm associated with acute kidney injury (AKI) is a global priority. In England, a national computerised AKI algorithm is being introduced across the National Health Service (NHS) to drive this change. The study sought to maximise its clinical utility and minimise the potential for burden on clinicians and patients in primary care. DESIGN: An appropriateness ratings evaluation using the RAND/UCLA Appropriateness Method. SETTING: Clinical scenarios were developed to test the timeliness in (1) communication of AKI warning stage test results from clinical pathology services to primary care, and (2) primary care clinician response to an AKI warning stage test result. PARTICIPANTS: A 10-person panel was purposively sampled with representation from clinical biochemistry, acute and emergency medicine and general practice. General practitioners (GPs) represented typical practice in relation to rural and urban practice, out of hours care, GP commissioning and those interested in reducing the impact of medicalisation and 'overdiagnosis'. RESULTS: There was agreement that delivery of AKI warning stage test results through interruptive methods of communication (ie, telephone) from laboratories to primary care was the appropriate next step for patients with an AKI warning stage 3 test result. In the context of acute illness, waiting up to 72 hours to respond to an AKI warning stage test result was deemed an inappropriate action in 62 out of the 65 (94.5%) cases. There was agreement that a clinician response was required within 6 hours, or less, in 39 out of 40 (97.5%) clinical cases relating AKI warning stage test results in the presence of moderate hyperkalaemia. CONCLUSIONS: The study has informed national guidance to support a timely and calibrated response to AKI warning stage test results for adults in primary care. Further research is needed to support effective implementation, with a view to examine the effect on health outcomes and costs.

Role of Macrophages in the Repair Process during the Tissue Migrating and Resident Helminth Infections.

The Th1/Th2/Th17 balance is a fundamental feature in the regulation of the inflammatory microenvironment during helminth infections, and an imbalance in this paradigm greatly contributes to inflammatory disorders. In some cases of helminthiasis, an initial Th1 response could occur during the early phases of infection (acute), followed by a Th2 response that prevails in chronic infections. During the late phase of infection, alternatively activated macrophages (AAMs) are important to counteract the inflammation caused by the Th1/Th17 response and larval migration, limiting damage and repairing the tissue affected. Macrophages are the archetype of phagocytic cells, with the primary role of pathogen destruction and antigen presentation. Nevertheless, other subtypes of macrophages have been described with important roles in tissue repair and immune regulation. These types of macrophages challenge the classical view of macrophages activated by an inflammatory response. The role of these subtypes of macrophages during helminthiasis is a controversial topic in immunoparasitology. Here, we analyze some of the studies regarding the role of AAMs in tissue repair during the tissue migration of helminths.

Biological variation of cardiac troponin in stable haemodialysis patients.

BACKGROUND: Patients with end-stage renal failure exhibit a chronic elevation of serum cardiac troponin (cTn) concentration. In order to facilitate the diagnosis of myocardial infarction in these patients, it is necessary to distinguish an increased cTn concentration due to an acute event, from that being a manifestation of chronic elevation. The aim of this study was to gather biological variation data relating to two serum cTn assays, one, a hs-cTnT assay, the other a contemporary sensitive cTnI assay, among stable haemodialysis patients. It was hoped that this might inform as to the best way to use cTn assays to assist in the diagnosis of myocardial infarction in patients with end-stage renal failure. METHODS: Eighteen stable haemodialysis patients were recruited, of whom 16 completed the study. Predialysis blood samples were collected weekly for 10 weeks during the second dialysis session of the week. Analytical CV (CVA), within-subject biological variation (CVI), between-subject biological variation (CVG), reference change value (RCV) and index of individuality (II) were determined for both assays. RESULTS: All samples had a serum hs-cTnT concentration above the 99th percentile for a healthy population compared to 29.4% for cTnI. For hs-cTnT, the long-term CVA was 2.1%, CVI 10.5%, CVG 64.2%, RCV 28.1% and log-normal RCV (rise/fall) 34.4%/-25.6%. The corresponding values for cTnI were 7.1, 20.2, 100.5 and 79.8%/-44.4%. The II was 0.17 and 0.2 for hs-cTnT and cTnI, respectively. CONCLUSION: Long-term biological variation of cTn in stable haemodialysis patients is similar to that in healthy individuals and in patients with stable coronary arterial disease. The low II for cTnI and hs-cTnT in stable haemodialysis patients indicates that population-based decision points are of limited value. Serial measurements are required to detect significant changes in cTn concentrations and support diagnosis of myocardial infarction in these patients.

External quality assessment: best practice.

There is a requirement for accredited laboratories to participate in external quality assessment (EQA) schemes, but there is wide variation in understanding as to what is required by the laboratories and scheme providers in fulfilling this. This is not helped by a diversity of language used in connection with EQA; Proficiency testing (PT), EQA schemes, and EQA programmes, each of which have different meanings and offerings in the context of improving laboratory quality. We examine these differences, and identify what factors are important in supporting quality within a clinical laboratory and what should influence the choice of EQA programme. Equally as important is how EQA samples are handled within the laboratory, and how the information provided by the EQA programme is used. EQA programmes are a key element of a laboratory's quality assurance framework, but laboratories should have an understanding of what their EQA programmes are capable of demonstrating, how they should be used within the laboratory, and how they support quality. EQA providers should be clear as to what type of programme they provide - PT, EQA Scheme or EQA Programme.