Lipid Profile and Cardiovascular Risk Modification after Hepatitis C Virus Eradication.

The eradication of the hepatitis C virus (HCV) has revolutionized the hepatology paradigm, halting the progression of advanced liver disease in patients with chronic infection and reducing the risk of hepatocarcinoma. In addition, treatment with direct-acting antivirals can reverse the lipid and carbohydrate abnormalities described in HCV patients. Although HCV eradication may reduce the overall risk of vascular events, it is uncertain whether altered lipid profiles increase the risk of cerebrovascular disease in certain patients. We have conducted a review on HCV and lipid and carbohydrate metabolism, as well as new scientific advances, following the advent of direct-acting antivirals.

Effect of ambulation following 18F-fluorodeoxyglucose injection on standing positron emission tomography of the healthy equine digit.

OBJECTIVE: Measure 18F-FDG uptake in digital tissues of healthy horses subjected to different ambulatory conditions between the time of injection and positron emission tomography (PET) scan acquisition. ANIMALS: 8 healthy adult horses. METHODS: Horses were walked (AMB) or tied in stalls (NONAMB) immediately after injection with ∼1.5 MBq/kg 18F-FDG until scan acquisition using a randomized crossover design. Steps were quantified using accelerometers. Standardized uptake values (SUV; mean and maximum) in digital tissues including the dorsal lamellae (proximal, middle, and distal), quarter lamellae (medial and lateral), and coronary band were analyzed using a mixed-effects linear regression model. RESULTS: Mean (95% CI) step count for AMB (569[484-653]) was higher than NONAMB (88[24-152]) P = <.001. The SUVmax (but not SUVmean) was increased in AMB compared with NONAMB in the proximal (2.74[2.52-2.98] vs 2.42[2.05-2.78]; P = .04) and middle (2.74[2.37-3.11] vs 2.36[2.05-2.68]; P = .03) dorsal lamellae but was not different in the distal lamellae or coronary band. In the medial quarter lamellae, both SUVmax (2.53[1.58-3.48] vs 2.07[0.81-3.33]; P = .01) and SUVmean (1.90[1.55-2.25] vs 1.49[0.91-2.06]; P = .007) were increased in AMB compared with NONAMB. The medial quarter lamellae also had lower SUVmax (P = .002) and SUVmean (P = .04) compared with the lateral quarter and lower SUVmax compared with the mid-dorsal lamellae (P = .01). CLINICAL RELEVANCE: Lamellar 18F-FDG uptake was affected by ambulatory activity mostly in the medial quarter; however, this effect was relatively small and unlikely to interfere with clinical detection of laminitis.

HLA-DQA1*05 Was Not Associated With Primary Nonresponse or Loss of Response to First Anti-TNF in Real-World Inflammatory Bowel Disease Patients.

BACKGROUND: We lack predictors of response to biologics in the management of patients with inflammatory bowel disease (IBD). A recent study has shown a significant association between HLA-DQA1*05 carriers and the development of loss of response to anti-tumor necrosis factor (TNF) mediated by immunogenicity. METHODS: Retrospective single-center cohort study including IBD patients who had received anti-TNF therapy as a first biologic and whose HLA-DQA1*05 had been determined. Primary nonresponse and secondary failure (assessed by survival analysis) have been evaluated as well as safety outcomes. RESULTS: A total of 199 IBD patients (161 [81%] with Crohn's disease and 38 [19%] with ulcerative colitis) were included. A total of 42.4% were HLA-DQA1*05 carriers and 60% received combination therapy at the start of anti-TNF treatment. Median follow-up was 24 (interquartile range, 11-66) months. No statistically significant differences were found in primary nonresponse to anti-TNF (89.3% vs 87.8%; P = .825), depending on HLA carriers and noncarriers. No differences in secondary loss of response according to HLA variant in any of the analyses performed (full cohort, according to IBD or anti-TNF type) were observed. Again, no differences were observed in patients treated with combination therapy. In terms of safety, no significant differences were found in the rate of infusion reactions or serious adverse events. CONCLUSION: In our real-life cohort of IBD patients treated for the first time with anti-TNF, being an HLA-DQA1*05 carrier did not act as a predictor of response failure, either primary or secondary. The safety of anti-TNF treatment has also not been influenced by the variant.

The HLA variant DQA1*05 has been identified as a risk factor for the development of antibodies to anti-tumor necrosis factor drugs. We observed that its presence has no impact on clinical outcomes, such as secondary loss of response. These data suggest that caution is required before making decisions based on this HLA variant.

Equine Granulocytic Anaplasmosis.

Equine granulocytic anaplasmosis is a clinically significant and common disease of equids that has a broader prevalence than was once thought. The most common clinical signs include high fever and edema, with mild to mderate thrombocytopenia and lymphopenia typically noted on complete blood count. Subclinical cases are reported and many are self-limiting. Rare clinical presentations include neurologic disease, vasculitis, dysphagia, rhabdomyolysis, or bicavitary effusion. Most cases resolve rapidly with appropriate antimicrobial intervention.

Incidence, Management Experience and Characteristics of Patients with Giardiasis and Common Variable Immunodeficiency.

Common variable immunodeficiency (CVID) is an antibody immunodeficiency with a wide variety of clinical and immunological manifestations, and whose genetic cause is found in about 25% of diagnosed cases. Giardia lamblia is one of the main causes of gastrointestinal infections in CVID. 5-Nitroimidazoles are the most used first-line treatment, but nitroimidazole-refractory giardiasis is increasing. Nevertheless, only a few cases of refractory giardiasis in CVID have been reported. This study aimed to determine the incidence of Giardia infection in our CVID cohort, shows our management experience and describes patients' phenotypic features. Clinical data collection, immunological, immunogenetics and microbiology assays were performed, and previous cases of giardiasis in CVID were reviewed. The incidence of symptomatic giardiasis was 12.9%. The main immunological features were undetectable or decreased IgA levels and reduced switched memory B cells. A probable PTEN pathogenic variant was detected in one. Three patients responded to metronidazole but suffered reinfections, and one was a refractory giardiasis eradicated with innovative quinacrine plus paromomycin combination. This work could contribute to the decision-making and therapeutic management of future patients with CVID and giardiasis, highlighting the importance of the early detection and treatment of infections in patients with CVID to ensure a good quality of life.

Common Variable Immunodeficiency Associated with a De Novo IKZF1 Variant and a Low Humoral Immune Response to the SARS-CoV-2 Vaccine.

BACKGROUND AND AIMS: Common variable immunodeficiency (CVID) comprises a group of diseases with heterogeneous clinical and immunological manifestations. Several mutations have been identified in genes encoding proteins essential for immune function. Our aim was to phenotypically and genotypically characterize a patient diagnosed with CVID and study his response to the SARS-CoV-2 vaccine. METHODS: We performed a next-generation sequencing analysis, a CMIA, and an ELISA to analyze the humoral and cellular response to the SARS-CoV-2 vaccine, respectively. We also employed flow cytometry and immunoturbidimetry to assess the patient's global immune status. RESULTS: We found a low humoral but positive cellular response to the SARS-CoV-2 vaccine. NGS screening revealed a transition from guanine to adenine at position c.485 of the IKZF1 gene in heterozygosity, giving rise to the R162Q variant, which was not present in his parents. CONCLUSIONS: The R162Q variant of the IKZF1 gene has been associated with CVID type 13, but always with an autosomal dominant inheritance with high penetrance. Therefore, we present for the first time a case of CVID associated with a de novo heterozygous R162Q variant in the IKZF1 gene in a patient with a low humoral immune response to the complete COVID-19 vaccination program.

References Values of Soluble α-Klotho Serum Levels Using an Enzyme-Linked Immunosorbent Assay in Healthy Adults Aged 18-85 Years.

α-Klotho protein is a powerful predictor of the aging process and lifespan. Although lowered circulating soluble α-Klotho levels have been observed in aged non-healthy individuals, no specific reference values across a wide range of ages and sex using an enzyme-linked immunosorbent assay (ELISA) are available for larger cohorts of healthy individuals. The present analytical cross-sectional study was aimed to establish the reference values of soluble α-Klotho serum levels in healthy adults by age and sex groups. A total of 346 (59% women) healthy individuals aged from 18 to 85 years were recruited. Subjects were divided by sex and age as: (i) young (18−34.9 years), (ii) middle-aged (35−54.9 years), and (iii) senior (55−85 years) individuals. The soluble α-Klotho levels were measured in serum using ELISA. Senior adults were the age-group that presented the lowest soluble α-Klotho serum levels (p < 0.01), with age showing a negative association with soluble α-Klotho serum levels (p < 0.001). No differences between sexes were observed. Therefore, soluble α-Klotho levels were especially decreased­regardless of sex­in our cohort of healthy individuals because of the physiological decline derived from the aging process. We recommend routine assessments of soluble α-Klotho levels using ELISA as a simple and cheap detectable marker of aging that improves quality of life in the elderly.

Enhanced recovery after surgery (ERAS®) protocol adapted to the Brazilian reality: a prospective cohort study for thoracic patients.

BACKGROUND: In Low-Middle Income Countries (LMICs), resource optimization and infrastructure availability are recurrently in debate. In order to assist the development and implementation of guidelines, LMICs often exemplify from High-Income Countries protocols. At the final, it will be: content adaption is often needed. In this study, we demonstrated the preliminary analysis of the Brazilian experience by adapting the ERAS® Protocol for thoracic surgery patients (PROSM). METHODS: Patients' data were extracted from the surgical group database that operated in the city of Sao Paulo. Patients' data were organized for analysis after the institution's ethics committee gave their approval. Patients' variables were analyzed and compared to a control group. Subgroup analysis included patients without ICU Admission. RESULTS: PROSM patients had reduced ICU length of stay (LOS) (Mean of 0.3±0.58 days, 1.2±1.65 days, P=0.001), Hospital LOS (Mean of 1.6±1.32 days, 3.9±3.25 days, P=0.001) and Chest Drain duration (Median 1.0±1.00 days, 3.0±3.00 days, P=0.001). Analyses of patients that were not admitted to the ICU demonstrated reduced Hospital LOS and Chest drain duration. Cost analysis, such as procedure, daily, and post-surgical costs were also significantly lower towards PROSM group. CONCLUSIONS: This study revealed important aspects for improvement of the delivered care quality and opportunity for expenditure management. We expect to assist more countries to improve knowledge under the implementation of enhanced protocols.

Macrophage Activation in the Synovium of Healthy and Osteoarthritic Equine Joints.

Synovitis is a major component of osteoarthritis and is driven primarily by macrophages. Synovial macrophages are crucial for joint homeostasis (M2-like phenotype), but induce inflammation (M1-like) when regulatory functions become overwhelmed. Macrophage phenotypes in synovium from osteoarthritic and healthy joints are poorly characterized; however, comparative knowledge of their phenotypes during health and disease is paramount for developing targeted treatments. This study compared patterns of macrophage activation in healthy and osteoarthritic equine synovium and correlated histology with cytokine/chemokine profiles in synovial fluid. Synovial histology and immunohistochemistry for M1-like (CD86), M2-like (CD206, IL-10), and pan macrophage (CD14) markers were performed on biopsies from 29 healthy and 26 osteoarthritic equine joints. Synovial fluid cytokines (MCP-1, IL-10, PGE2, IL-1ß, IL-6, TNF-α, IL-1ra) and growth factors (GM-CSF, SDF-1α+ß, IGF-1, and FGF-2) were quantified. Macrophage phenotypes were not as clearly defined in vivo as they are in vitro. All macrophage markers were expressed with minimal differences between OA and normal joints. Expression for all markers increased proportionate to synovial inflammation, especially CD86. Synovial fluid MCP-1 was higher in osteoarthritic joints while SDF-1 and IL-10 were lower, and PGE2 concentrations did not differ between groups. Increased CD14/CD86/CD206/IL-10 expression was associated with synovial hyperplasia, consistent with macrophage recruitment and activation in response to injury. Lower synovial fluid IL-10 could suggest that homeostatic mechanisms from synovial macrophages became overwhelmed preventing inflammation resolution, resulting in chronic inflammation and OA. Further investigations into mechanisms of arthritis resolution are warranted. Developing pro-resolving therapies may provide superior results in the treatment of OA.

Association of fruit, pericarp, and epidermis traits with surface autofluorescence in green peppers.

We investigated the association of blue fluorescence (excitation at 365 nm) with the traits of the fruit, pericarp, and epidermis in green peppers. The fruits were manually classified into two groups based on fluorescence brightness. The dark fluorescence group showed the accumulation of blue-absorbing pigments and a thicker cuticular structure, suggesting epidermal development.

Inflamed synovial fluid induces a homeostatic response in bone marrow mononuclear cells in vitro: Implications for joint therapy.

Synovial inflammation is a central feature of osteoarthritis (OA), elicited when local regulatory macrophages (M2-like) become overwhelmed, activating an inflammatory response (M1-like). Bone marrow mononuclear cells (BMNC) are a source of naïve macrophages capable of reducing joint inflammation and producing molecules essential for cartilage metabolism. This study investigated the response of BMNC to normal (SF) and inflamed synovial fluid (ISF). Equine BMNC cultured in autologous SF or ISF (n = 8 horses) developed into macrophage-rich cultures with phenotypes similar to cells native to normal SF and became more confluent in ISF (~100%) than SF (~25%). BMNC cultured in SF or ISF were neither M1- nor M2-like, but exhibited aspects of both phenotypes and a regulatory immune response, characterized by increasing counts of IL-10+ macrophages, decreasing IL-1ß concentrations and progressively increasing IL-10 and IGF-1 concentrations. Changes were more marked in ISF and suggest that homeostatic mechanisms were preserved over time and were potentially favored by progressive cell proliferation. Collectively, our data suggest that intra-articular BMNC could increase synovial macrophage counts, potentiating the macrophage- and IL-10-associated mechanisms of joint homeostasis lost during the progression of OA, preserving the production of cytokines involved in tissue repair (PGE2 , IL-10) generally impaired by frequently used corticosteroids.

Autologous bone marrow mononuclear cells modulate joint homeostasis in an equine in vivo model of synovitis.

Osteoarthritis (OA) is characterized by macrophage-driven synovitis. Macrophages promote synovial health but become inflammatory when their regulatory functions are overwhelmed. Bone marrow mononuclear cells (BMNCs) are a rich source of macrophage progenitors used for treating chronic inflammation and produce essential molecules for cartilage metabolism. This study investigated the response to autologous BMNC injection in normal and inflamed joints. Synovitis was induced in both radiocarpal joints of 6 horses. After 8 h, 1 inflamed radiocarpal and 1 normal tarsocrural joint received BMNC injection. Contralateral joints were injected with saline. Synovial fluid was collected at 24, 96, and 144 h for cytology, cytokine quantification, and flow cytometry. At 144 h, horses were euthanatized, joints were evaluated, and synovium was harvested for histology and immunohistochemistry. Four days after BMNC treatment, inflamed joints had 24% higher macrophage counts with 10% more IL-10+ cells than saline-treated controls. BMNC-treated joints showed gross and analytical improvements in synovial fluid and synovial membrane, with increasing regulatory macrophages and synovial fluid IL-10 concentrations compared with saline-treated controls. BMNC-treated joints were comparable to healthy joints histologically, which remained abnormal in saline-treated controls. Autologous BMNCs are readily available, regulate synovitis through macrophage-associated effects, and can benefit thousands of patients with OA.-Menarim, B. C., Gillis, K. H., Oliver, A., Mason, C., Ngo, Y., Werre, S. R., Barrett, S. H., Luo, X., Byron, C. R., Dahlgren, L. A. Autologous bone marrow mononuclear cells modulate joint homeostasis in an equine in vivo model of synovitis.

Divergent age-dependent peripheral immune transcriptomic profile following traumatic brain injury.

The peripheral immune system is a major regulator of the pathophysiology associated with traumatic brain injury (TBI). While age-at-injury influences recovery from TBI, the differential effects on the peripheral immune response remain unknown. Here, we investigated the effects of TBI on gene expression changes in murine whole blood using RNAseq analysis, gene ontology and network topology-based key driver analysis. Genome-wide comparison of CCI-injured peripheral whole blood showed a significant increase in genes involved in proteolysis and oxidative-reduction processes in juvenile compared to adult. Conversely, a greater number of genes, involved in migration, cytokine-mediated signaling and adhesion, were found reduced in CCI-injured juvenile compared to CCI-injured adult immune cells. Key driver analysis also identified G-protein coupled and novel pattern recognition receptor (PRR), P2RY10, as a central regulator of these genes. Lastly, we found Dectin-1, a c-type lectin PRR to be reduced at the protein level in both naïve neutrophils and on infiltrating immune cells in the CCI-injured juvenile cortex. These findings demonstrate a distinct peripheral inflammatory profile in juvenile mice, which may impact the injury and repair response to brain trauma.

Body Composition and S-Klotho Plasma Levels in Middle-Aged Adults: A Cross-Sectional Study.

The α-Klotho gene was identified as a possible "aging-suppressor" agent that extends life span when overexpressed. However, little is known about the association of the body composition with the secreted protein form of the α-Klotho gene (S-Klotho). Therefore, the aim of this study was to analyze the association of body composition, including lean and fat mass as well as bone mineral density (BMD), with S-Klotho plasma levels in middle-aged sedentary adults. A total of 74 (39 women) middle-aged sedentary adults (53.7 ± 5.1 years old; 75.7 ± 14.0 kg; 167.8 ± 9.8 cm) participated in the study. We measured weight and height, and we used dual-energy X-ray absorptiometry to measure fat mass and lean mass. We calculated the body mass index (BMI), fat mass index (FMI), and lean mass index (LMI). The S-Klotho plasma levels were measured in the ethylenediaminetetraacetic acid plasma using a solid-phase sandwich enzyme-linked immunosorbent assay. There was a strong positive association between LMI and S-Klotho plasma levels (ß = 74.794, R2 = 0.346, p < 0.001), which persisted after controlling for age and gender as well as after additionally controlling for FMI. Significantly positive associations of BMI and BMD were also found with S-Klotho plasma levels (ß = 33.981, R2 = 0.125, p = 0.002 and ß = 858.194, R2 = 0.058, p = 0.041, respectively), which disappeared after controlling for LMI (ß = 0.183, R2 = 0.611, p = 0.984 and ß = -379.426, R2 = 0.617, p = 0.290, respectively). FMI was not significantly associated with S-Klotho plasma levels. Our study shows that LMI is strongly associated with S-Klotho plasma levels and explains the associations of BMI and BMD with S-Klotho plasma levels in middle-aged sedentary adults.

Exercise training as S-Klotho protein stimulator in sedentary healthy adults: Rationale, design, and methodology.

AIMS: The secreted form of the α-Klotho gene (S-Klotho), which is considered a powerful biomarker of longevity, makes it an attractive target as an anti-ageing therapy against functional decline, sarcopenic obesity, metabolic and cardiovascular diseases, osteoporosis, and neurodegenerative disorders. The S-Klotho plasma levels could be related to physical exercise inasmuch physical exercise is involved in physiological pathways that regulate the S-Klotho plasma levels. FIT-AGEING will determine the effect of different training modalities on the S-Klotho plasma levels (primary outcome) in sedentary healthy adults. FIT-AGEING will also investigate the physiological consequences of activating the klotho gene (secondary outcomes). METHODS: FIT-AGEING will recruit 80 sedentary, healthy adults (50% women) aged 45-65 years old. Eligible participants will be randomly assigned to a non-exercise group, i.e. the control group, (n = 20), a physical activity recommendation from World Health Organization group (n = 20), a high intensity interval training group (n = 20), and a whole-body electromyostimulation group (n = 20). The laboratory measurements will be taken at the baseline and 12 weeks later including the S-Klotho plasma levels, physical fitness (cardiorespiratory fitness, muscular strength), body composition, basal metabolic rate, heart rate variability, maximal fat oxidation, health blood biomarkers, free-living physical activity, sleep habits, reaction time, cognitive variables, and health-related questionnaires. We will also obtain dietary habits data and cardiovascular disease risk factors.

Serum free light chains in the evaluation of the response to treatment and biological progression in primary amyloidosis / Cadenas ligeras libres séricas en la evaluación de la respuesta al tratamiento y progresión biológica en Amiloidosis Primaria

Primary amyloidosis is a rare condition characterised by the deposition of free light chains in different tissues and organs (e.g. kidney, heart, liver, gastrointestinal system). The aim of the therapy in patients with primary amyloidosis is to suppress the monoclonal plasma cells that produce the amyloidogenic free light chains and to preserve the organ function. Thus, the new criteria for the haematological disease response include the measurement of serum free light chains concentrations. The case is presented on a patient diagnosed with primary amyloidosis, where the difference between bound and free serum free light chains (dFLC) was used to evaluate the haematological response to the treatment, as well as any biological progression. In contrast to dFLC, Bence Jones Protein in urine was positive but ineffective to evaluate the response to the treatment (AU)

La amiloidosis primaria es una entidad rara caracterizada por el depósito de cadenas ligeras libres en diferentes tejidos y órganos (riñón, corazón, hígado, aparato gastrointestinal). El objetivo en la terapia de los pacientes con amiloidosis primaria consiste en suprimir las células plasmáticas monoclonales que producen las cadenas ligeras libres amiloidogénicas y preservar la función de los órganos afectados. Así, los nuevos criterios de respuesta hematológica de la enfermedad incorporan la medida de las concentraciones séricas de cadenas ligeras libres. Presentamos el caso de una paciente a quien se diagnosticó amiloidosis primaria y en la cual la diferencia de concentración en suero entre la cadena ligera libre monoclonal implicada y la no implicada (dFLC) nos permitió evaluar la respuesta hematológica al tratamiento y la presencia de progresión biológica. En contraste a la dFLC, la proteinuria de Bence Jones fue positiva pero ineficaz en la evaluación de la respuesta al tratamiento (AU)

Carcinoma de células pequeñas mixto: un desafío diagnóstico / A rare case of combined small-cell lung carcinoma: a challenging diagnosis

Los síndromes neurológicos paraneoplásicos constituyen un conjunto de manifestaciones neurológicas asociadas a la existencia de una tumor oculto no diagnosticado en un paciente. Los síndromes neurológicos paraneoplásicos están producidos por mecanismos inmunológicos donde tiene lugar una respuesta inmunológica frente a antígenos compartidos por el tumor y el tejido neuronal del paciente. La detección serológica de los anticuerpos onconeuronales (Hu, Yo, Ri, Ma-2, anfifisina, etc.) es de utilidad en el diagnóstico de los síndromes neurológicos paraneoplásicos asociados. Presentamos el caso de una paciente que acude a Urgencias por presentar alteraciones neurológicas y donde los resultados obtenidos por el laboratorio clínico permiten orientar el estudio diagnóstico de la paciente hacía la búsqueda de un tumor oculto de estirpe microcítica mixta (AU)

Paraneoplastic neurological syndromes are a set of neurological manifestations associated with the existence of a hidden tumour in a patient. Paraneoplastic neurological syndromes are produced by immunological mechanisms where an immune response occurs against antigens shared between tumour and neuronal tissue of the patient. Serological detection of onconeural antibodies (Hu, Yo, Ri, Ma-2, amphiphysin, etc.) is useful in the diagnosis of associated paraneoplastic neurological syndromes. The case is presented of a patient who was admitted to emergency room due to neurological disorders. With the results of the clinical laboratory, the study was oriented towards the search for a hidden tumour of microcytic mixed lineage (AU)