Switching dual therapy with dolutegravir (DTG) plus rilpivirine (RPV) was assessed in the SWORD-1 and SWORD-2 studies. Real-life data regarding the immunological impact of this approach on CD4+ and ...CD8+ T lymphocyte counts and the CD4/CD8 ratio are scarce. We evaluated this strategy on the basis of clinical practice data. A multicentric retrospective cohort study. Treatment-experienced virologically suppressed HIV-1-infected patients who were switched to DTG plus RPV were included. Using different models for paired data, we evaluated the efficacy and immune status in terms of CD4+ and CD8+ T-cell counts and CD4/CD8 ratio at 24 and 48 weeks of treatment. The study population comprised of 524 patients from 34 centers in Spain. Men accounted for 76.9% of patients, with a median age of 53 years. Patients receiving DTG plus RPV reached weeks 24 and 48 in 99.4% and 83.8% of cases, respectively, with only three (0.57%) virological failures. We found a significant decrease in CD8+ T-cell count (log OR –40) at week 24 and an increase in CD4+ T-cell count at week 48 (log OR +22.8). In acquired immunodeficiency syndrome-diagnosed patients, we found a significant increase in the CD4+ T-cell count at week 48 (log OR = 41.7, P = .0038), but no significant changes in the CD8+ T-cell count (log OR = –23.4, P = .54). No differences were found in the CD4/CD8 ratio between the acquired immunodeficiency syndrome subgroup and sex or age. In patients with controlled treatment, dual therapy with DTG plus RPV slightly improved the immune status during the first 48 weeks after switching, not only in terms of CD4+ T-cell count but also in terms of CD8+ T-cell count, with persistently high rates of viral control.
Gastric cancer (GC) stands as a prominent cause of cancer-related mortality and ranks second among the most frequently diagnosed malignancies in individuals with common variable immunodeficiency ...(CVID).
We sought to conduct a comprehensive, large-scale genetic analysis to explore the CVID-associated germline variant landscape within gastric adenocarcinoma samples and to seek to delineate the transcriptomic similarities between GC and CVID.
We investigated the presence of CVID-associated germline variants in 1591 GC samples and assessed their impact on tumor mutational load. The progression of GC was evaluated in patients with and without these variants. Transcriptomic similarities were explored by matching differentially expressed genes in GC to healthy gastric tissue with a CVID transcriptomic signature.
CVID-associated germline variants were found in 60% of GC samples. Our analysis revealed a significant association between the presence of CVID-related genetic variants and higher tumor mutational load in GC (P < .0001); high GC mutational load seems to be linked to immunotherapy response and worse prognosis. Transcriptomic similarities unveiled key genes and pathways implicated in innate immune responses and tumorigenesis. We identified upregulated genes related to oncogene drivers, inflammation, tumor suppression, DNA repair, and downregulated immunomodulatory genes shared between GC and CVID.
Our findings contribute to a deeper understanding of potential molecular modulators of GC and shed light on the intricate interplay between immunodeficiency and cancer. This study underscores the clinical relevance of CVID-related variants in influencing GC progression and opens avenues for further exploration into novel therapeutic approaches.
Background Cartilage-hair hypoplasia (CHH) is characterized by metaphyseal dysplasia, bone marrow failure, increased risk of malignancies, and a variable degree of immunodeficiency. CHH is caused by ...mutations in the RNA component of the mitochondrial RNA processing (RMRP) endoribonuclease gene, which is involved in ribosomal assembly, telomere function, and cell cycle control. Objectives We aimed to define thymic output and characterize immune function in a cohort of patients with molecularly defined CHH with and without associated clinical immunodeficiency. Methods We studied the distribution of B and T lymphocytes (including recent thymic emigrants), in vitro lymphocyte proliferation, cell cycle, and apoptosis in 18 patients with CHH compared with controls. Results Patients with CHH have a markedly reduced number of recent thymic emigrants, and their peripheral T cells show defects in cell cycle control and display increased apoptosis, resulting in poor proliferation on activation. Conclusion These data confirm that RMRP mutations result in significant defects of cell-mediated immunity and provide a link between the cellular phenotype and the immunodeficiency in CHH.
Objective To review and summarize published information on the effectiveness and safety of rituximab (RTX) in adult patients with refractory neuropsychiatric systemic lupus erythematosus (NPSLE). ...Methods We describe a patient with persistently active NPSLE, despite conventional therapy, who responded dramatically to RTX. Current evidence on the therapeutic use of RTX in this complex situation is also analyzed through a systematic review of the English-language literature, based on a PubMed search. Results Available data on the use of RTX in refractory NPSLE come from a large number of case reports and some open-label studies. Including our case, 35 patients have been well documented. A complete or partial therapeutic response was achieved in 85% of patients after 1 cycle of treatment. A positive correlation between serological markers of disease activity and clinical outcome has also been demonstrated in some of these patients. Clinical improvement was accompanied by a significant reduction in the daily dose of oral corticosteroids. Relapse after RTX treatment was noted in 45% of cases (median 9.5 months; range, 4-33 months). Infections were observed in 29% of patients. Conclusion Evidence for the effectiveness of RTX as induction therapy in NPSLE is based solely on several case reports and noncontrolled trials. Although it is not yet possible to make definite recommendations, the global analysis of these cases supports the off-label use of RTX in cases of severe refractory NPSLE.
Long QT syndrome (LQTS) is characterized by a prolonged QT interval that can lead to severe ventricular arrhythmias (torsades de pointes) and sudden death. Congenital LQTS type 2 (LQT2) is due to ...loss-of-function mutations in the KCNH2 gene encoding Kv11.1 channels responsible for the rapid component of the delayed rectifier current.
The purpose of this study was to determine the functional properties of the LQT2-associated mutation p.E637G found in a Spanish family.
Wild-type (WT) and p.E637G Kv11.1 channels were transiently transfected in Chinese hamster ovary cells, and currents were recorded using the patch-clamp technique.
The p.E637G channels lost inward rectification and K(+) selectivity, generating small but measurable slowly activating, noninactivating currents. These important alterations were corrected neither by cotransfection with WT channels nor by incubation at low temperatures or with pharmacological chaperones. As a consequence of its effects on channel gating, the mutation significantly reduced the outward repolarizing current during the action potential (AP), resulting in a marked lengthening of the duration of a simulated human ventricular AP.
We have identified and characterized an LQT2-associated mutation that through removal of C-type inactivation and reduction of K(+) selectivity causes the QT prolongation observed in the patients carrying the mutation. Moreover, the results obtained demonstrate the importance of the glutamic acid at position 637 for the inactivation process and K(+) selectivity of Kv11.1 channels.
Pancreatitis, Panniculitis, and Polyarthritis Narváez, Javier, MD, PhD; Bianchi, Maria Marta, MD; Santo, Pilar, MD ...
Seminars in arthritis and rheumatism,
04/2010, Letnik:
39, Številka:
5
Journal Article
Recenzirano
Background and Objective Lobular panniculitis, together with polyarthritis and intraosseous fat necrosis, may occasionally complicate pancreatic disease. This triad is known in the literature as the ...pancreatitis, panniculitis, and polyarthritis (PPP syndrome). We describe a case of the PPP syndrome and review the available literature to summarize the clinical characteristics of patients with this condition. Methods A patient with the PPP syndrome, with evidence of extensive intraosseous fat necrosis in the joints involved revealed by magnetic resonance imaging, is described and the relevant literature based on a PubMed search from 1970 to February 2008 is reviewed. The keywords used were pancreatitis or pancreatic disease, panniculitis, arthritis, and intraosseous fat necrosis. Results Including our case, 25 well-documented patients with the PPP syndrome have been reported. Our patient had few abdominal symptoms despite high serum levels of pancreatic enzymes. In our review of the literature, almost 2/3 of patients had absent or mild abdominal symptoms, leading to misdiagnosis. The delay in diagnosis and specific treatment of the underlying pancreatitis worsens the prognosis of this condition, which has a mortality rate as high as 24%. In nearly 45% of the patients, the arthritis follows a chronic course with a poor response to nonsteroidal anti-inflammatory drugs and corticosteroids, and the rapid development of radiographic joint damage. Conclusion Certain forms of pancreatic disease can very occasionally cause arthritis and panniculitis. Although uncommon, physicians should be alert to the possible presence of this syndrome for 2 reasons: first, unrecognized pancreatic disease can be fatal if not treated promptly; second, to avoid inappropriate and risky therapy to improve joint symptoms.
Abstract An 81-year-old woman was referred for primary angioplasty due to a myocardial infarction. Upon her arrival, the patient was in cardiogenic shock. Coronarography revealed a large filling ...defect within the left main coronary artery. Thromboaspiration was performed, obtaining thrombotic material and tissue of different consistencies. Balloon angioplasty in the left anterior descending and left main arteries was performed, resulting in incomplete reperfusion, leading to irreversible electromechanical dissociation. Analysis of the aspirated material was consistent with thrombus, atheroma, and calcified tissue. Autopsy revealed a heavily calcified mitral valve, and distal embolization of amorphous material in the microvasculature identical to that found in the mitral valve subapparatus. < Learning objective: Acute myocardial infarction due to left main embolization of tissue from mitral valve subapparatus is a rare condition but lethal. Early recognition of this condition is important for establishing the best option of treatment, between a percutaneous or surgical approach.>
Dietary quality indices (DQI) are widely used in nutritional epidemiology. However, how they might change over time in a Mediterranean population is not well understood.
To evaluate ...within-participant longitudinal changes in scores for nine a priori–defined DQIs: Fat Quality Index (FQI), Carbohydrate Quality Index (CQI), Pro-vegetarian Dietary Pattern (PVG), Mediterranean Diet Adherence Screener (MEDAS), Mediterranean Diet Score (MDS), Dietary Approaches to Stop Hypertension (DASH), Mediterranean-DASH Intervention for Neurodegenerative Delay Diet (MIND), Prime Diet Quality Score (PDQS) and Alternate Healthy Eating Index (AHEI-2010) in the “Seguimiento Universidad de Navarra” (SUN) cohort, a well-known Mediterranean cohort of university graduates, and to identify baseline predictors of improvement in MEDAS and AHEI-2010 after 10 years of follow-up.
In this longitudinal cohort study, DQI scores were calculated based on responses from a validated semiquantitative food-frequency questionnaire (FFQ).
Spanish university graduates enrolled in the SUN cohort before March 2008, who completed the 10-year FFQ and reported total dietary intake at baseline and after 10 years of follow-up, included 2,244 men and 3,271 women, whose mean age at baseline was 36.3 years (standard deviation SD, 10.7).
Main outcome measures were within-participant longitudinal changes for FQI, CQI, PVG, MEDAS, MDS, DASH, MIND, PDQS, and AHEI-2010.
Adjusted logistic regression models were used to evaluate within-participant longitudinal changes and to identify baseline predictors of improvements ≥10% in MEDAS and AHEI-2010 scores after 10 years of follow-up.
The comparison of the nine scores of DQI calculated at baseline and after 10 years of follow-up showed an improvement in all DQI scores except for PDQS. The greatest changes in DQIs were found for MEDAS (from 6.2 to 7.2, +22.9%) and MDS (from 4.3 to 4.4, +15.4%). The strongest predictors at baseline for ≥10% improvements in MEDAS or AHEI-2010 scores varied across indices. Being female, ≥35 years old, and more physically active at baseline were associated with improvement, whereas snacking between meals was associated with <10% improvements in both indices.
In this cohort, the changes in nine a priori-defined DQI scores suggested modest improvements in diet quality, in which MEDAS and MDS scores showed the largest improvements. Additional longitudinal studies, especially intervention trials with long follow-up, are warranted to establish the most appropriate DQIs to assess long-term changes in diet quality in adult populations.
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