[en] Highlights: • Nidovirus replication is inhibited by cyclophilin inhibitors. • Arterivirus replication depends on cyclophilin A. • Cyclosporin A blocks arterivirus RNA synthesis. • Using cyclophilin inhibitors against nidoviruses in vivo needs more investigation. Cyclophilins (Cyps) belong to the family of peptidyl-prolyl isomerases (PPIases). The PPIase activity of most Cyps is inhibited by the immunosuppressive drug cyclosporin A and several of its non-immunosuppressive analogs, which can also block the replication of nidoviruses (arteriviruses and coronaviruses). Cyclophilins have been reported to play an essential role in the replication of several other RNA viruses, including human immunodeficiency virus-1, hepatitis C virus, and influenza A virus. Likewise, the replication of various nidoviruses was reported to depend on Cyps or other PPIases. This review summarizes our current understanding of this class of nidovirus-host interactions, including the potential function of in particular CypA and the inhibitory effect of Cyp inhibitors. Also the involvement of the FK-506-binding proteins and parvulins is discussed. The nidovirus data are placed in a broader perspective by summarizing the most relevant data on Cyp interactions and Cyp inhibitors for other RNA viruses.

[en] Objective: To examine the use of anti-cytokine treatment in critical COVID-19 patients and their association with the frequency of CMV cases, viral load level, and mortality in these patients. Methods: This is a retrospective study. A total of 170 critical and/or intensive care patients with COVID-19 admitted to Hisar Hospital Intercontinental from March 15, 2020, to December 31, 2021 were divided into the use of anti-cytokine treatment group and the no anti-cytokine treatment group. Furthermore, the relationship between CMV reactivation, mortality and anti-cytokine treatment in patients was also examined. Results: A total of 170 critical COVID-19 patients were included in the study, three of them were excluded. One hundred sixty seven were included in the study of which 38 (22.7%) were found to be CMV DNA positive. As an anticytokine treatment, it was observed that tocilizumab was used in 53 patients, anakinra was used in 27 patients, and no anti-cytokine treatment was used in 77 patients. CMV positivity in patients treated with anti-cytokines (31.11%) was found to be significantly higher than in patients who were not treated with it (16.88%) (p:0.033). Furthermore, it was determined that anti-cytokine treatment significantly decreased mortality (p: 0.003) and that there was no significant relationship between CMV reactivation and mortality (p: 0.399). Conclusion: Even though CMV reactivation was high in critical COVID-19 patients who received anti-cytokine treatment, decrease in mortality were observed with early diagnosis and effective treatment. Therefore, CMV infection should be considered in patients receiving immunosuppressive treatment. (author)

[en] Highlights: • Klotho can inhibit DEX-induced apoptosis of MC3T3-E1 osteoblasts by inhibiting the expression of caspase-3. • NF-κB inhibitor PDTC reduced the number of DEX-induced apoptotic cells and attenuated the activity of caspase-3. • Klotho can inhibit IκB degradation, NF-κB nuclear translocation, and p65 phosphorylation in DEX-induced MC3T3-E1 apoptosis. Dexamethasone (DEX) is a commonly used anti-inflammatory drug and an immunosuppressive drug used in clinical practice to treat a variety of diseases. Glucocorticoid-induced osteoporosis (GIOP) is a consequence of high dose, or a long-term low dose use of glucocorticoids (GCs). These treatment regimens can cause a variety of bone-related adverse effects, leading to increased osteoblast and bone cell apoptosis. Evidence suggests that klotho (KL) can inhibit GIOP. It is unknown whether KL attenuates DEX-induced apoptosis in MC3T3-E1 cells or the underlying mechanisms involved. In the present study, we found that MC3T3-E1 cells pretreated with DEX led to the up-regulation of cleaved-caspase-3, and down-regulation of caspase-3, which were inhibited by KL transfection. Furthermore, flow cytometry and western blot analysis revealed that the NFκB inhibitor pyrrolidine dithiocarbamate (PDTC) could restore the DEX-induced caspase-3 decrease and inhibit the DEX-induced cleaved caspase-3 increase. We observed that DEX stimulated the degradation of IκBα(NFκB inhibitor α) and the translocation of NFκB, which were suppressed by KL transfection. These findings therefore, indicate a protective role for KL against osteoblastic cell apoptosis induced by DEX, via the NF-κB signaling pathway.

[en] To ascertain the effectiveness of immunosuppressants along with ACEI and /or ARBS in proteinuria in patients with solitary kidney post nephrectomy. Study Design: Prospective quasi-experimental study. Place and Duration of Study: Combined Military Hospital Peshawar and Multan, from 2010 to 2016. Subjects and Methods: The sample population comprised of 07 cases of post nephrectomy solitary kidney developing proteinuria from 2010-2016 reporting to hospitals. Patients were given initially ACEI and/or ARBS to lower proteinuria for three months. They were followed up to see for complete or partial remission. Deltacortil 1mg/kg max 60mg/day along with ACEI and /or ARBS was added to patients who didn’t go into remission. Results: Out of 7 patients, 3 (42.9%) were males and 4 (57.1%) were female patients. Addition of deltacortil 1mg/kg max 60mg/day along with ACEI and /or ARBS reduced proteinuria to less than 1 gram in 3 patients (2 males and 1 female) and less than 300mg in 4 patients (1 male and 3 females).There was a reduction in the mean 24hrs urinary protein excretion as a whole from the baseline 2.33 ± 0.84 g/24 hrs to 0.48 +- 0.33 g/24 hrs. Remission was achieved on the average in three months and maintenance on tapering doses for 12 months. Cyclosporine was used in three cases who relapsed on tapering steroids and remission was achieved with 5-10mg steroids and 100-200mg of cyclosporine. Conclusion: Non respondent patients with solitary kidney developing proteinuria being treated with ACEI and /or ARBS had good chance to lower their proteinuria with steroids. Relapses even with steroids responded to cyclosporine. (author)

[en] A mathematical tumor response model has been developed, encompassing the interplay between immune cells and cancer cells initiated by either partial or full tumor irradiation. The iterative four-compartment model employs the linear–quadratic radiation response theory for four cell types: active and inactive cytotoxic T lymphocytes (immune cells, CD8⁺ T cells in particular), viable cancer cells (undamaged and reparable cells) and doomed cells (irreparably damaged cells). The cell compartment interactions are calculated per day, with total tumor volume (TV) as the main quantity of interest. The model was fitted to previously published data on syngeneic xenografts (67NR breast carcinoma and Lewis lung carcinoma; (Markovsky et al 2019 Int. J. Radiat. Oncol. Biol. Phys. 103 697–708)) subjected to single doses of 10 or 15 Gy by 50% (partial) or 100% (full) TV irradiation. The experimental data included effects from anti-CD8⁺ antibodies and immunosuppressive drugs. Using a new optimization method, promising fits were obtained where the lowest and highest root-mean-squared error values were observed for anti-CD8⁺ treatment and unirradiated control data, respectively, for both cell types. Additionally, predictive capabilities of the model were tested by using the estimated model parameters to predict scenarios for higher doses and different TV irradiation fractions. Here, mean relative deviations in the range of 19%–34% from experimental data were found. However, more validation data is needed to conclude on the model’s predictive capabilities. In conclusion, the model was found useful in evaluating the impact from partial and full TV irradiation on the immune response and subsequent tumor growth. The model shows potential to support and guide spatially fractionated radiotherapy in future pre-clinical and clinical studies. (paper)

[en] Objectives: To compare new onset dyslipidaemia in live-related renal transplant recipients taking cyclosporine versus tacrolimus after 3 months of therapy. Methods: The randomised controlled trial was conducted at the Sindh Institute of Urology and Transplantation (SIUT) Karachi, from September 2010 to April 2011, and included 182 End Stage Renal Disease patients on maintenance haemodialysis with pre-transplant normal lipid profile. The patients, who had live-related renal transplant, were randomly allocated to two equal groups using lottery. Group A received cyclosporine (3mg/kg) and group B was treated with tacrolimus (0.1mg/kg). All patients had pre-transplant fasting lipid profile checked when they were on maintenance haemodialysis and 3 months after renal transplantation. Serum fasting lipid profile was collected by taking 5ml blood by venipuncture after an overnight fast of 9-12 hours. SPSS 10 was used for statistical analyses. Results: Of the 182 patients, 144(79.1%) were males and 38(20.9%) were females. The overall mean age was 30.18+-9.57 years, and the mean weight was 54.41+- 11.144kg. Significant difference was not observed between the two groups regarding age and weight of the patients. Dyslipidaemia was found in 115(63.2%) subjects; 61(67%) in group A and 54(59.3%) in group B. There was no statistical difference (p=0.28) when comparison was done after 3 months of therapy. Conclusions: The occurrence of new onset hyperlipidaemia is similar in renal transplant recipients receiving either cyclosporine or tacrolimus in first 3 months post-transplant, but there is room for more research in this field as dyslipidaemia following successful renal transplantation is a frequent and persistent complication. (author)

No abstract available

[en] CXCL10-CXCR3 axis plays a pivotal role in cardiac allograft rejection, so that targeting CXCL10 without inducing generalized immunosuppression may be of therapeutic significance in allotransplantation. Since the role of resident cells in cardiac rejection is still unclear, we aimed to establish reliable human cardiomyocyte cultures to investigate Th1 cytokine-mediated response in allograft rejection. We used human fetal cardiomyocytes (Hfcm) isolated from fetal hearts, obtained after legal abortions. Hfcm expressed specific cardiac lineage markers, specific cardiac structural proteins, typical cardiac currents and generated ventricular action potentials. Thus, Hfcm represent a reliable in vitro tool for allograft rejection research, since they resemble the features of mature cells. Hfcm secreted CXCL10 in response to IFNγ and TNFαα; this effect was magnified by cytokine combination. Cytokine synergy was associated to a significant TNFα-induced up-regulation of IFNγR. The response of Hfcm to some currently used immunosuppressive drugs compared to rosiglitazone, a peroxisome proliferator-activated receptor γ agonist and Th1-mediated response inhibitor, was also evaluated. Only micophenolic acid and rosiglitazone halved CXCL10 secretion by Hfcm. Given the pivotal role of IFNγ-induced chemokines in Th1-mediated allograft rejection, these preliminary results suggest that the combined effects of immunosuppressive agents and rosiglitazone could be potentially beneficial to patients receiving heart transplants

[en] Objective: To characterize the prevalence of latent tuberculosis infection (LTBI) in patients with interstitial lung diseases (ILDs) requiring immunosuppression. Only 5 to 10% of individuals infected with Mycobacterium tuberculosis develop tuberculosis, and certain groups of patients have an increased risk of illness, such as the immunocompromised. Patients with ILDs are frequently treated with immunosuppressants and, therefore, might have a higher risk of developing the disease. Methods: Prospective study conducted at the ILD reference center of the Federal University of Paraná from January 2019 to December 2020. The screening of LTBI was performed with the use of the tuberculin skin test (TST). Results: The sample consisted of 88 patients, of whom 64.8% were women, with a mean age of 61.4 years. The most frequent diagnoses were autoimmune rheumatic disease ILD (38.6%) and hypersensitivity pneumonitis (35.2%). The most common immunosuppressant in use at the time of the TST was prednisone, either in combination with mycophenolate (19.3%) or alone (17.1%). The majority of participants had fibrotic lung disease, characterized by a reticular interstitial pattern on chest computed tomography (79.5%) and moderate to severe functional impairment (mean FVC 69.2%). A prevalence of LTBI of 9.1% (CI 95%, 2.1%-15.1%) was found, with a TST median of 13. Conclusion: Patients with ILD who are treated with immunosuppressants are not commonly screened for LTBI, despite being under a greater risk of progression to active disease. This study suggests the need for a more cautious approach to these patients. (author)

No abstract available