Presence and clinical impact of human herpesvirus-6 infection in patients with moderate to critical coronavirus disease-19.

Human herpesvirus-6 (HHV-6) may cause serious diseases in immunocompromised individuals. SARS-CoV-2/HHV-6 coinfection has been emphasized in previous works, mostly case reports, small series, or epidemiological studies, but few are known about its real clinical outcomes. Here we present a real-world pilot study aiming to understand the frequency and the clinical impact of HHV-6 coinfection in moderate to critically ill patients hospitalized due to COVID-19. SARS-CoV-2 and HHV-6 were evaluated in nasopharyngeal samples at the hospital admission of suspected COVID-19 patients. From 173 consecutive cases, 60 were SARS-CoV-2 positive and 13/60 (21.7%) were HHV-6 positive after identified as the HHV-6B species by a Sanger sequencing. The SARS-CoV-2+/HHV-6+ group was younger but not significant for cardiovascular diseases, diabetes, obesity, and cancer, but significant among therapeutic immunosuppressed patients (as systemic lupus erythematosus and kidney transplant patients). In the medical records, only sparse data on cutaneous or neurological manifestations were found. Biochemical and hematological data showed only a trend towards hyperferritinemic status and lymphopenia. In conclusion, despite the impressive high frequency of HHV-6 coinfection in SARS-CoV-2 positive cases, it did not impact general mortality. We suggest larger future prospective studies to better elucidate the influence of HHV-6 reactivation in cases of COVID-19, designed to specific assessment of clinical outcomes and viral reactivation mechanisms.

Differential impacts of TNFα inhibitors on the transcriptome of Th cells.

BACKGROUND: Targeting TNFα is beneficial in many autoimmune and inflammatory diseases, including rheumatoid arthritis. However, the response to each of the existing TNFα inhibitors (TNFis) can be patient- and/or disease-dependent. In addition, TNFis can induce the production of type 1 interferons (IFNs), which contribute to their non-infection side effects, such as pustular psoriasis. Thus far, the molecular mechanisms mediating the drug-specific effects of TNFis and their induction of type 1 IFNs are not fully understood. METHODS: Peripheral blood mononuclear cells (PBMCs) were collected from healthy donors and stimulated in vitro with anti-CD3 and anti-CD28 in the absence or presence of adalimumab, etanercept, or certolizumab. Th cells were isolated from the stimulated PBMCs, and their RNA was subjected to RNA-seq and quantitative polymerase chain reaction. RESULTS: Adalimumab and etanercept, which contain Fc, but not certolizumab, which does not contain Fc, inhibited the expression of several effector cytokines by Th cells within anti-CD3/anti-CD28-stimulated PBMCs. Transcriptomic analyses further showed that adalimumab, but not certolizumab, reciprocally induced type 1 IFN signals and the expression of CD96 and SIRPG in Th cells. The unique effects of adalimumab were not due to preferential neutralization of soluble TNFα but instead were mediated by several distinct mechanisms independent or dependent of Fc-facilitated physical interaction between Th cells and CD14+ monocytes. CONCLUSIONS: TNFis can have drug-specific effects on the transcriptional profile of Th cells.

Utilizing a PTPN22 gene signature to predict response to targeted therapies in rheumatoid arthritis.

Despite the development of several targeted therapies for rheumatoid arthritis (RA), there is still no reliable drug-specific predictor to assist rheumatologists in selecting the most effective targeted therapy for each patient. Recently, a gene signature caused by impaired induction of PTPN22 in anti-CD3 stimulated peripheral blood mononuclear cells (PBMC) was observed in healthy at-risk individuals. However, the downstream target genes of PTPN22 and the molecular mechanisms regulating its expression are still poorly understood. Here we report that the PTPN22 gene signature is also present in PBMC from patients with active RA and can be reversed after effective treatment. The expression of PTPN22 correlates with that of more than 1000 genes in Th cells of anti-CD3 stimulated PBMC of healthy donors and is inhibited by TNFα or CD28 signals, but not IL-6, through distinct mechanisms. In addition, the impaired induction of PTPN22 in PBMC of patients with active RA can be normalized in vitro by several targeted therapies. More importantly, the in vitro normalization of PTPN22 expression correlates with clinical response to the targeted therapies in a longitudinal RA cohort. Thus, in vitro normalization of PTPN22 expression by targeted therapies can potentially be used to predict clinical response.

Tenofovir monotherapy for hepatitis B after 1 year does not produce renal dysfunction, but is associated with hyperparathyroidism not related to vitamin D.

INTRODUCTION: Viral hepatitis B (VHB) represents a major public health problem. Studies from HIV multidrug patients have associated the use of tenofovir disoproxil fumarate (TDF) with renal dysfunction and phosphate wasting. OBJECTIVE: The aim of this study was to examine the effect of year-long TDF monotherapy on renal function in VHB patients. PATIENTS AND METHODS: We evaluated adult patients diagnosed with VHB before treatment initiation (T0), and after 3 and 12 months (T3 and T12) of TDF initiation. Estimated glomerular filtration rate (eGFR) was estimated by serum cystatin C and creatinine. In addition, urinary electrolytes and tubular biomarkers (cystatin C, ß2-microglobulin and neutrophil gelatinase-associated lipocalin) were analyzed, as well as parathyroid hormone (PTH) and 25(OH)vitamin D levels. RESULTS: After 1 year, 32 patients completed the study, 22 (68.7%) men and 12 (37.5%) Whites, mean age 44.1±12.0 years. We found that serum electrolytes were similar at baseline and 3 or 12 months after initiation of TDF monotherapy. In addition, urinary fractional excretions of electrolytes as well as proteinuria, albuminuria, urinary ß2-microglobulin, and urinary cystatin C showed no significant differences across the treatment timeline. There were also no statistical differences in the eGFR. There was a statistically significant increase in the PTH (Friedman's test, P=0.012), but the 25(OH)vitamin D levels were in the normal range in the beginning and did not change at the follow-up. Moreover, there was no correlation between the initial levels of vitamin D and the corresponding increases in the PTH values. CONCLUSION: If used as monotherapy in hepatitis B patients for a 12-month period, TDF is not associated with changes in either eGFR or a panel of urinary biomarkers. Serum and urinary electrolytes also remained unchanged. Of note, a significant increase in the PTH was found, although not related to the 25(OH)vitamin D initial status.

Hypertrophy and neuron loss: structural changes in sheep SCG induced by unilateral sympathectomy.

Recently, superior cervical ganglionectomy has been performed to investigate a variety of scientific topics from regulation of intraocular pressure to suppression of lingual tumour growth. Despite these recent advances in our understanding of the functional mechanisms underlying superior cervical ganglion (SCG) growth and development after surgical ablation, there still exists a need for information concerning the quantitative nature of the relationships between the removed SCG and its remaining contralateral ganglion and between the remaining SCG and its modified innervation territory. To this end, using design-based stereological methods, we have investigated the structural changes induced by unilateral ganglionectomy in sheep at three distinct timepoints (2, 7 and 12 weeks) after surgery. The effects of time, and lateral (left-right) differences, were examined by two-way analyses of variance and paired t-tests. Following removal of the left SCG, the main findings were: (i) the remaining right SCG was bigger at shorter survival times, i.e. 74% at 2 weeks, 55% at 7 weeks and no increase by 12 weeks, (ii) by 7 weeks after surgery, the right SCG contained fewer neurons (no decrease at 2 weeks, 6% fewer by 7 weeks and 17% fewer by 12 weeks) and (iii) by 7 weeks, right SCG neurons were also larger and the magnitude of this increase grew substantially with time (no rise at 2 weeks, 77% by 7 weeks and 215% by 12 weeks). Interaction effects between time and ganglionectomy-induced changes were significant for SCG volume and mean perikaryal volume. These findings show that unilateral superior cervical ganglionectomy has profound effects on the contralateral ganglion. For future investigations, it would be interesting to examine the interaction between SCGs and their innervation targets after ganglionectomy. Is the ganglionectomy-induced imbalance between the sizes of innervation territories the milieu in which morphoquantitative changes, particularly changes in perikaryal volume and neuron number, occur? Mechanistically, how would those changes arise? Are there any grounds for believing in a ganglionectomy-triggered SCG cross-innervation and neuroplasticity?

CCL2/MCP-1 controls parasite burden, cell infiltration, and mononuclear activation during acute Trypanosoma cruzi infection.

CCL2/MCP-1 has emerged recently as a critical factor in infectious and autoimmune myocarditis. In fact, this chemokine is produced in great amounts in hearts from Trypanosoma cruzi-infected mice and is known to enhance parasite uptake and destruction by macrophages. Herein, we studied the involvement of CCL2 in tissue inflammation and resistance to T. cruzi. Infected CCL2(-/-) mice developed higher parasitemias and died earlier than WT mice. Close to their death, T. cruzi-infected CCL2(-/-) presented greater amounts of TNF, IFN-gamma, and IL-10 in plasma than WTs and clinical signs of systemic inflammatory response. Amastigote nests were more frequent in hearts and livers from infected CCL2(-/-) tissues than in WTs, and reduced numbers of leukocytes infiltrated their tissues. Leukocytes formed diffuse but not focal infiltrates in hearts from infected CCL2(-/-) mice, and perivascular cuffs could still be found in their livers. Infected CCL2(-/-) mice had smaller percentages of activated CD11b (Mac-1)+CD107b (Mac-3)+ macrophages and CD8+CD69(hi) cells among heart and liver infiltrates than WTs (flow cytometry), indicating that CCL2 controls subset migration/activation. CCL2 accumulated among focal heart infiltrates, suggesting that this chemokine is involved in retention of mononuclear cells in particular spots. Peritoneal macrophages from CCL2(-/-) mice displayed decreased trypanocidal activity. Our results demonstrate that CCL2 contributes to reduce parasite growth and indicate that it does so by controlling the distribution, cellular composition, and state of activation of inflammatory infiltrates in acute T. cruzi infection.

Anticorpos para componentes do sistema nervoso central em pacientes com esclerose múltipla crônica / Antibodies for components of the central nervous system in pacients with chronic multiple sclerosis

Esclerose múltipla (EM), uma doença inflamatória desmielinizante do sistema nervoso central , caracteriza-se pela destruiçäo total ou parcial dos componentes do sistema nervoso central, caracteriza-se pela destruiçåo total ou parcial dos componentes do sistema nervoso associado à mielina. A técnica de enzima imunoensaio (ELISA) foi utilizada para detecçåo pareada, no soro e líquido cefalorraquidiano (LCR), de auto-anticorpos para a proteína básica da mielina (PBM) e componentes lipídicos presentes na fraçåo VII (F-VII) do extrato de cérebro. Foram estudados 25 pacientes com esclerose múltipla na forma crônica. O grupo controle foi constituído por 26 doadores do banco de sangue e 10 pacientes com miastenia grave. Independente do aspecto evolutivo da doença, todos os pacientes com esclerose múltipla apresentavam níveis elevados de anticorpos para a F-VII no LCR, porém, somente 68 por cento apresentavam níveis elevados de auto-anticorpos para PBM. Os anticorpos séricos para PBM e V-II encontram-se geralmente-se em níveis abaixo daqueles observados no LCR correspondente. Os resultados sugerem que, além da proteína básica da mielina, os componentes líquidos presentes na F-VII do extrato de cérebro parecem desempenhar um papel importante na manutençåo da resposta imune local e na progressåo do processo desmielinizante em pacientes na forma crônica da esclerose múltipla