Circadian variability of blood pressure in obese children

Background and aimsThe aim of the present study was to evaluate the circadian rhythm of blood pressure pattern in obese children, and to investigate if the lack of normal diurnal rhythm of blood pressure is associated with cardiovascular risk factors.Methods and results73 obese children (body weight [mean ± SD]: 89.0 ± 17.8 kg; age [mean ± SD]: 14.2 ± 2.3 years), 42 dippers and 31 non-dippers were investigated. Following ambulatory blood pressure monitoring (ABPM), physical fitness testing was performed on a treadmill. Physical working capacity at 130, -150, -170 beat/min (PWC-130, -150, -170), resting and peak oxygen consumption (VO₂rest, VO₂peak) were determined.Forty-two percent of obese children were non-dipper. PWC-130 (74.8 ± 48.8 watts; 48.0 ± 38.5 watts), PWC-150 (132.9 ± 52.1 watts; 104.2 ± 49.3 watts), PWC-170 (185.9 ± 49.5 watts; 154.9 ± 53.4 watts) and VO₂rest, ([mean ± SD]: 0.29 ± 0.08 L/min; 0.26 ± 0.07 L/min), and VO₂ peak (2.77 ± 0.61 L/min; 2.44 ± 0.62 L/min) were significantly lower in the non-dipper group, as compared to dippers (p < 0.05). The prevalence of hypertension, on the basis of ABPM, was significantly higher in the non-dipper group (45.2% vs 83.9%, p < 0.001). This is due to increased prevalence of masked hypertension in the non-dipper group (19.0% vs 32.3%, p < 0.001).ConclusionThe normal circadian variation of the blood pressure is frequently absent in obese children. Most of the non-dipper obese children are hypertensive, and their physical fitness is decreased.     

Characterization of the DialGuard device for endotoxin removal in hemodialysis

Bacterial pyrogens, capable of penetrating dialyzer membranes, are responsible for a systemic inflammatory reaction in hemodialysis patients. Dialyzer reuse, involving rinsing of the dialyzer with pyrogen-containing water, may exacerbate this situation. Studies of the mechanism of action of endotoxin suggest that it irreversibly damages the vascular endothelium. The novel endotoxin removal method described here, is based on affinity-binding of endotoxin by the adsorbent ClarEtox, a USP Class VI-certified resin that is the active component of the medical device DialGuard. Under standard hemodialysis operating conditions, challenge of DialGuard with Pseudomonas maltophilia supernatant-spiked dialysate, containing 35-193 EU/ml endotoxin, resulted in endotoxin levels below 0.05 EU/ml in the treated dialysate. DialGuard was able to decrease endotoxin concentrations in the dialysate from a range of 2.39-8.49 to <0.005 EU/ml. DialGuard supports high fluid velocities at low back pressures and can be sanitized using the heat sanitization cycle of hemodialysis machines. DialGuard offers a simple, user-friendly way to reduce the concentration of endotoxin in dialysate and water for dialysis at a low cost.     

Profound loss of T-cell receptor repertoire complexity in cutaneous T-cell lymphoma

Cutaneous T-cell lymphoma (CTCL) is a malignancy of skin-homing T cells. A major feature of CTCL is profound immunosuppression, such that patients with advanced mycosis fungoides or Sézary syndrome have been compared with patients with advanced HIV disease and are susceptible to opportunistic infection. The etiology of this immunosuppression is unclear. We analyzed peripheral blood T cells of patients with CTCL with stage I to IV disease, using a sensitive beta-variable complementarity-determining region 3 spectratyping approach. Our data revealed a profound disruption of the complexity of the T-cell repertoire, which was universally observed in patients with advanced disease (stages III and IV), and present in up to 50% of patients with early-stage disease (stages I and II). In most patients, multiple monoclonal and oligoclonal complementarity-determining region 3 (CDR3) spectratype patterns in many different beta-variable families were seen. Equally striking was a reduction of normal T cells (as judged by absolute CD4 counts) across multiple beta-variable families. In general, CTCL spectratypes were reminiscent of advanced HIV spectratypes published elsewhere. Taken together, these data are most consistent with a global assault on the T-cell repertoire in patients with CTCL, a process that can be observed even in early-stage disease.     

Enhanced neutrophil extravasation and rapid progression of proteoglycan-induced arthritis in TSG-6-knockout mice

OBJECTIVE: To gain insight into the mechanisms of the antiinflammatory effect of tumor necrosis factor alpha (TNFalpha)-induced protein 6 (Tnfip6) in arthritis, using Tnfip6-deficient animals. METHODS: TNFalpha-stimulated gene 6 (TSG-6) coding for Tnfip6 was disrupted. Tnfip6-deficient mice were backcrossed into proteoglycan-induced arthritis (PGIA)-susceptible BALB/c mice, and arthritis was induced by systemic immunization with cartilage proteoglycan (PG). Thioglycollate-induced sterile peritonitis was also assessed, to monitor the early events of neutrophil extravasation in wild-type and Tnfip6-deficient mice in the presence or absence of treatment with recombinant murine Tnfip6. RESULTS: The onset of PGIA was similar, but progression and severity were significantly greater, in Tnfip6-deficient mice compared with wild-type BALB/c mice. However, this was not associated with enhanced T or B cell responses to cartilage PGs, but rather, an early and more extensive infiltration of the synovium with neutrophil leukocytes was the most prominent histopathologic feature of PGIA in Tnfip6-deficient mice. This was accompanied by elevated serum levels of interleukin-6 and amyloid A, and significantly increased activities of the enzymes plasmin, myeloperoxidase, and neutrophil elastase in the inflamed paw joints of Tnfip6-null mice, when compared with that of the wild-type littermates. Loss of control over several components of inflammation resulted in extensive and rapid cartilage degradation, bone erosion, joint ankylosis, and deformities in Tnfip6-null animals. In support of the antiinflammatory effect of Tnfip6 via the inhibition of polymorphonuclear (PMN) cell efflux, neutrophil invasion during thioglycollate-induced peritonitis was 2-fold higher in Tnfip6-deficient animals than in wild-type animals, but was dramatically suppressed by intravenous injection of recombinant murine Tnfip6. CONCLUSION: Tnfip6 is a multifunctional antiinflammatory protein that is produced at the site of inflammation and can be retained by the hyaluronan-rich extracellular matrix. A major effect of Tnfip6 is the inhibition of the extravasation of PMN cells, predominantly neutrophils, into the site of inflammation, most likely via a CD44/hyaluronan/Tnfip6-mediated blocking mechanism.     

Relationship of SARS-CoV-2–specific CD4 response to COVID-19 severity and impact of HIV-1 and tuberculosis coinfection

T cells are involved in control of coronavirus disease 2019 (COVID-19), but limited knowledge is available on the relationship between antigen-specific T cell response and disease severity. Here, we used flow cytometry to assess the magnitude, function, and phenotype of SARS coronavirus 2–specific (SARS-CoV-2–specific) CD4⁺ T cells in 95 hospitalized COVID-19 patients, 38 of them being HIV-1 and/or tuberculosis (TB) coinfected, and 38 non–COVID-19 patients. We showed that SARS-CoV-2–specific CD4⁺ T cell attributes, rather than magnitude, were associated with disease severity, with severe disease being characterized by poor polyfunctional potential, reduced proliferation capacity, and enhanced HLA-DR expression. Moreover, HIV-1 and TB coinfection skewed the SARS-CoV-2 T cell response. HIV-1–mediated CD4⁺ T cell depletion associated with suboptimal T cell and humoral immune responses to SARS-CoV-2, and a decrease in the polyfunctional capacity of SARS-CoV-2–specific CD4⁺ T cells was observed in COVID-19 patients with active TB. Our results also revealed that COVID-19 patients displayed reduced frequency of Mycobacterium tuberculosis–specific CD4⁺ T cells, with possible implications for TB disease progression. These results corroborate the important role of SARS-CoV-2–specific T cells in COVID-19 pathogenesis and support the concept of altered T cell functions in patients with severe disease.     

Malignant Mesothelioma—A Connective Tissue Tumor with Proteoglycan-Dependent Differentiation

Malignant mesothelioma (MM) is a connective tissue tumor with partial epithelioid differentiation. The pattern of proteoglycan (PG) expression by epithelioid and fibroblast-like (sarcomatoid) MM cells differ; cell surface PGs being more abundant in the former phenotype and matrix PGs in the latter. The differentiation as well as much of the malignant nature of these tumors is dependent on the expression of surface PGs. The syndecans, however, also translocate to the nucleus for an as yet unknown function.     

Late-Onset Suicide: A Dementia Prodrome?

ObjectivesThis study examined whether late-onset (versus early-onset) suicidal behavior is associated with worse cognition.MethodsParticipants included 278 adults aged 50+ years (56 nonpsychiatric comparison group; 67 nonsuicidal depressed older adults; 63 depressed suicide ideators; and 44 late-onset (55+ years) and 48 early-onset suicide attempters (<55 years). Using a case-control design, this study examined group differences in global cognition, episodic memory, information processing speed, and executive functioning, assessed using the Repeatable Battery of Neuropsychological Status and the Trail Making Test from the Delis-Kaplan Executive Function System. Linear regression was used for data analyses.ResultsBoth attempter groups displayed worse executive functioning than nonsuicidal depressed older adults. Late-onset attempters additionally displayed poorer global cognition and processing speed than nonsuicidal depressed older adults and poorer memory than early-onset attempters.ConclusionsLate-onset suicidal behavior is associated with worse performance in a broad range of cognitive domains, possibly reflective of a dementia prodrome.