Macrophage immunomodulation through new polymers that recapitulate functional effects of itaconate as a power house of innate immunity.

Itaconate (ITA) is an emerging powerhouse of innate immunity with therapeutic potential that is limited in its ability to be administered in a soluble form. We developed a library of polyester materials that incorporate ITA into polymer backbones resulting in materials with inherent immunoregulatory behavior. Harnessing hydrolytic degradation release from polyester backbones, ITA polymers resulted in the mechanism specific immunoregulatory properties on macrophage polarization in vitro. In a functional assay, the polymer-released ITA inhibited bacterial growth on acetate. Translation to an in vivo model of biomaterial associated inflammation, intraperitoneal injection of ITA polymers demonstrated a rapid resolution of inflammation in comparison to a control polymer silicone, demonstrating the value of sustained biomimetic presentation of ITA.

Kidney Transplantation in a Recipient with Positive RT-PCR for SARS-CoV-2.

When it is safe to proceed with transplantation after coronavirus disease 2019 (COVID-19) infection is still unknown. We describe the clinical course and management of immunosuppression in a patient with positive real-time polymerase chain reaction (RT-PCR) for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in a nasopharyngeal swab at the time of kidney transplantation, and with positive antibodies for SARS-CoV-2. The patient had no complications and was discharged with a functioning graft.

Biomimetic approach to cardiac tissue engineering.

Here, we review an approach to tissue engineering of functional myocardium that is biomimetic in nature, as it involves the use of culture systems designed to recapitulate some aspects of the actual in vivo environment. To mimic the capillary network, subpopulations of neonatal rat heart cells were cultured on a highly porous elastomer scaffold with a parallel array of channels perfused with culture medium. To mimic oxygen supply by haemoglobin, the culture medium was supplemented with a perfluorocarbon (PFC) emulsion. Constructs cultivated in the presence of PFC contained higher amounts of DNA and cardiac markers and had significantly better contractile properties than control constructs cultured without PFC. To induce synchronous contractions of cultured constructs, electrical signals mimicking those in native heart were applied. Over only 8 days of cultivation, electrical stimulation induced cell alignment and coupling, markedly increased the amplitude of synchronous construct contractions and resulted in a remarkable level of ultrastructural organization. The biomimetic approach is discussed in the overall context of cardiac tissue engineering, and the possibility to engineer functional human cardiac grafts based on human stem cells.

Risk factors for Pneumocystis carinii pneumonia in kidney transplant recipients: a case-control study.

OBJECTIVE: To analyze risk factors for Pneumocystis carinii pneumonia (PCP) in kidney transplant recipients. STUDY DESIGN: In a case-control study, 17 PCP cases diagnosed between July 1994 and July 2000 were matched with two controls each (previous and subsequent kidney transplant recipients who did not develop PCP during the same follow-up period). Demographics, organ origin, human leukocyte antigen (HLA) mismatches, use of poly- or monoclonal anti-CD3 antibodies (Po/MoAb) for induction or rejection treatment, rejection episodes, cumulative steroid dose for rejection treatment, immunosuppressive regimens, and other infections were analyzed. RESULTS: No significant differences were seen in gender (male 10 vs. 15), mean age (39.7 vs. 35.4 years), organ origin (cadaver donor 13 vs. 19), HLA mismatches, or Po/MoAb use in induction treatment. Significant differences were observed in PCP cases for rejection history (P=0.02), and median and total number of rejection episodes (P=0.0018). The relative risks for PCP for 1, 2, and > or =3 rejection treatments vs. no such treatment were 1, 1.05, and 6.30, respectively (P=0.021). The relative risk for PCP for steroid-resistant rejection was 4.34 (95% confidence interval [CI], 1.04-18.89) (P=0.019), and that for the use of Po/MoAb for rejection treatment was 7.23 (95% CI, 1.28-49.34) (P=0.006). The relative risk for PCP for 0, 1, and > or =2 previous or concomitant cytomegalovirus (CMV) infection vs. no such infections were 1.0, 2.32, and 13.0, respectively (P=0.012). The relative risks for PCP for tuberculosis (TB) was 18 (95% CI, 1.76-852.03), that for bacterial pneumonia was 14.22 (95% CI, 2.16-150.23), and that for hepatitis C virus infection was 5.25 (95% CI, 1.03-28.91). Immunosuppressive regimens with tacrolimus, mycophenolate mofetil (MMF), steroids (P=0.06), and MMF as a single variable (P=0.05) were more frequently used in cases. Primary trimethoprim-sulfamethoxazole prophylaxis failure was observed in 12 patients in association with heavy immunosuppression and concomitant infections. CONCLUSIONS: The risk of PCP in kidney transplant recipients is related to the number and type of rejection treatments. It is also related to the occurrence of CMV infection, and to other immunomodulating infections such as TB and hepatitis C, and might also be increased with the use of newer and more potent immunosuppressive agents. Primary prophylaxis failure may occur in association with some of these risk factors.

Epidemiology of end-stage renal disease and current status of hemodialysis in Yugoslavia.

Maintenance hemodialysis (HD) in Yugoslavia started in the sixties and followed the dialysis trends in the Western Europe. However, in the last decade the development of renal replacement therapy (RRT) slowed down. In this report the epidemiology of ESRD from 1997-1999 and the survey of the status of HD treatment in Yugoslavia in 1999 are presented. Epidemiological data are obtained by the annual center questionnaires (response rate: 92.6 -94.2%). The survey of HD status is based on a specific questionnaire and covered 2108 patients (65%). At the end of 1999 there were 56 RRT centers in Yugoslavia treating 3939 patients: 3232 (82%) patients by HD, 248 (6.3%) by peritoneal dialysis, and 459 (11.7%) living with transplanted kidney. In a three year period, incidence of ESRD ranged from 108-128 pmp, point prevalence from 435-463 pmp and mortality rate from 20.7-17.9. Numerous refugee patients were treated over the last 10 years. Main causes of ESRD were glomerulonephritis (30%); Balkan nephropathy represented 11% and diabetic nephropathy 7% of all primary renal diseases. Cardiovascular and cerebrovascular diseases were the most common causes of death of RRT patients. Most centers are overcrowded and HD machines are worn out. Mean Kt/V was 1.19+/-0.08, mean URR% 58.8+/-7.4. The shortage of drugs prevented adequate management: 83% of HD patients had hemoglobin level less than 100 g/L but only 10.3 -17.8% were treated with rHuEpo; 64.5% of patients had phosphate levels higher than 1.7 mmol/L but only 33.5% used phosphate binders; 47% of patients had hypertension despite the antihypertensive therapy. The prevalence of hepatitis B remained unchanged (about 14%) in HD population during the last three years, but the prevalence of anti-HCV positive patients decreased (31-23%). In conclusion, there is a well developed dialysis service in Yugoslavia but insufficient conditions for adequate treatment.

Severe acute lung injury caused by Mycoplasma pneumoniae: potential role for steroid pulses in treatment.

Published evidence of pathogenetic mechanisms of acute respiratory distress syndrome (ARDS) in mycoplasmal lung infections suggests that the pulmonary injury is related to a cell-mediated immune response. Therefore, steroids may play a role in the treatment of severe cases. We describe a patient who had Mycoplasma pneumoniae pneumonia that progressed to severe ARDS requiring mechanical ventilation and who had improvement with prednisolone pulses.

Tuberculosis in renal transplant recipients.

Tuberculosis (TB) has been described in kidney transplant recipients as an infection with predominantly pulmonary involvement. We report the impact of TB in kidney transplantation. Clinical records of adult kidney recipients, transplanted between 1 January 1986 and 31 December 1995 were analyzed for sex, age, graft origin, immunosuppressive therapy, TB sites, diagnostic methods and concomitant infections. Annual incidence, mean time of onset, relation to rejection treatment, tuberculin skin test (PPD) and outcome were analyzed. Patients with a history of TB or graft loss in the first month were excluded. TB was diagnosed in 14 of 384 (3.64%). Mean age at transplantation was 35 years. Twelve of these received the graft from a living donor. All had triple immunosuppression with cyclosporine. Ten had pulmonary TB, three extrapulmonary infection and one disseminated disease. In 13 cases an invasive diagnostic procedure was performed. Mycobacterium tuberculosis cultures were positive in all cases; microscopy revealed acid-fast bacilli (AFB) in 6, and adenosine deaminase was elevated in CSF and pleural effusion in 2. Annual incidence varied from 0% to 3.1%. At the time of TB presentation 8 patients had other concomitant infections (cytomegalovirus, nocardia, Pneumocystis carinii, disseminated herpes simplex virus). Median time of onset was 13 months. Diagnostic results became available post-mortem in 2 cases, and one had TB in a failing allograft. TB was treated with 4 drugs including rifampin in 10 patients. Cyclosporine was discontinued in one, lowered in one and increased in 8. During treatment 5 patients had rejection episodes. At 1 year, graft survival was 72.7% and patient survival 90.9%. TB was more prevalent when recipient and donor were both PPD positive. In summary: although TB is a growing threat in the transplant setting, early and aggressive diagnosis with meticulous monitoring of immunosuppression allows a successful outcome for both patient and graft. Optimal prophylaxis guidelines have yet to be completely defined.

Nitric oxide regulates oxygen uptake and hydrogen peroxide release by the isolated beating rat heart.

Isolated rat heart perfused with 1.5-7.5 microM NO solutions or bradykinin, which activates endothelial NO synthase, showed a dose-dependent decrease in myocardial O2 uptake from 3.2 +/- 0.3 to 1.6 +/- 0.1 (7.5 microM NO, n = 18, P < 0.05) and to 1.2 +/- 0.1 microM O2.min-1.g tissue-1 (10 microM bradykinin, n = 10, P < 0.05). Perfused NO concentrations correlated with an induced release of hydrogen peroxide (H2O2) in the effluent (r = 0.99, P < 0.01). NO markedly decreased the O2 uptake of isolated rat heart mitochondria (50% inhibition at 0.4 microM NO, r = 0.99, P < 0.001). Cytochrome spectra in NO-treated submitochondrial particles showed a double inhibition of electron transfer at cytochrome oxidase and between cytochrome b and cytochrome c, which accounts for the effects in O2 uptake and H2O2 release. Most NO was bound to myoglobin; this fact is consistent with NO steady-state concentrations of 0.1-0.3 microM, which affect mitochondria. In the intact heart, finely adjusted NO concentrations regulate mitochondrial O2 uptake and superoxide anion production (reflected by H2O2), which in turn contributes to the physiological clearance of NO through peroxynitrite formation.

[Adjunctive treatment with hyperbaric oxygen in a patient with rhino-sinuso-orbital mucormycosis]. / Tratamiento adyuvante con oxígeno hiperbárico en un paciente con mucormicosis rino-sinuso-orbitaria.

Mucormycosis (phycomycosis) is an acute and often fatal infection, mostly seen in diabetics and immunocompromised patients, and seldom in healthy people. Therapy includes aggressive surgical debridement, amphotericin B and control of underlying predisposing condition (diabetes, immunosuppression or immunodeficiency). The rhino-sinuso-orbital presentation is typically observed in insulin-dependent diabetes mellitus with ketoacidosis. This metabolic condition may impair the polymorphonuclear function in a reversible way and this may favour infection by a mucoral. These spores germinate into hyphae, which invade local arteries and arterioles, causing thrombosis, vascular insufficiency and tissue hypoxia and acidosis, conditions which further enhance fungal growth. Hyperbaric oxygen has theoretical value in treating mucormycosis, since it reduces tissue hypoxia caused by the vascular insufficiency. We report an insulin-dependent diabetic patient with rhino-sinuso-orbital mucormycosis, who after being treated with amphotericin B and surgical debridement on two occasions, maintained clinical and tomographic evidence of active infection, and mucoral persistence in the lesion. An aggressive surgical debridement, using microsurgical techniques, was performed. Amphotericin B was increased up to a total dose of 3900 mg. (he had previously received 2900 mg) and hyperbaric oxygen was added as adjunctive treatment. The outcome was successful. There was no evidence of relapse after a 16-month follow-up. This observation would confirm the usefulness of hyperbaric oxygen as adjunctive therapy in mucormycosis.

Tratamiento adyuvante con oxigeno hiperbarico en un paciente con mucormicosis rino-sinuso-orbitaria / Adjunctive treatment with hyperbaric oxygen in a patient with rhino-sinuso-orbital mucormycosis

Se presenta un paciente, diabético insulino-dependiente, portador de una mucormicosis rino-sinuso-orbitaria, que habiendo sido tratado con debridamiento quirúrgico en dos oportunidades y anfotericina B en una dosis totald e 2900 mg, mantenía signos clínicos y tomográficos de actividad infecciosa con persistencia del hongo en a lesión. Se realizó debridamiento amplio con técnica microquirúrgica, se incrementó la dosis de anfotericina B hasta 3900 mg agregándose terapéutica adyuvante con oxígenio hiperbárico. El resultado fue exitoso, sin evidencias de recaída en 16 meses de seguimiento. Esta observación confirma la utilidad del oxígeno hiperbárico como terapéutica adyuvante en mucormicosis

Tratamiento adyuvante con oxígeno hiperbárico en un paciente con mucormicosis rino-sinuso-orbitaria. / [Adjunctive treatment with hyperbaric oxygen in a patient with rhino-sinuso-orbital mucormycosis]

Mucormycosis (phycomycosis) is an acute and often fatal infection, mostly seen in diabetics and immunocompromised patients, and seldom in healthy people. Therapy includes aggressive surgical debridement, amphotericin B and control of underlying predisposing condition (diabetes, immunosuppression or immunodeficiency). The rhino-sinuso-orbital presentation is typically observed in insulin-dependent diabetes mellitus with ketoacidosis. This metabolic condition may impair the polymorphonuclear function in a reversible way and this may favour infection by a mucoral. These spores germinate into hyphae, which invade local arteries and arterioles, causing thrombosis, vascular insufficiency and tissue hypoxia and acidosis, conditions which further enhance fungal growth. Hyperbaric oxygen has theoretical value in treating mucormycosis, since it reduces tissue hypoxia caused by the vascular insufficiency. We report an insulin-dependent diabetic patient with rhino-sinuso-orbital mucormycosis, who after being treated with amphotericin B and surgical debridement on two occasions, maintained clinical and tomographic evidence of active infection, and mucoral persistence in the lesion. An aggressive surgical debridement, using microsurgical techniques, was performed. Amphotericin B was increased up to a total dose of 3900 mg. (he had previously received 2900 mg) and hyperbaric oxygen was added as adjunctive treatment. The outcome was successful. There was no evidence of relapse after a 16-month follow-up. This observation would confirm the usefulness of hyperbaric oxygen as adjunctive therapy in mucormycosis.

Tratamiento adyuvante con oxigeno hiperbarico en un paciente con mucormicosis rino-sinuso-orbitaria / Adjunctive treatment with hyperbaric oxygen in a patient with rhino-sinuso-orbital mucormycosis

Se presenta un paciente, diabético insulino-dependiente, portador de una mucormicosis rino-sinuso-orbitaria, que habiendo sido tratado con debridamiento quirúrgico en dos oportunidades y anfotericina B en una dosis totald e 2900 mg, mantenía signos clínicos y tomográficos de actividad infecciosa con persistencia del hongo en a lesión. Se realizó debridamiento amplio con técnica microquirúrgica, se incrementó la dosis de anfotericina B hasta 3900 mg agregándose terapéutica adyuvante con oxígenio hiperbárico. El resultado fue exitoso, sin evidencias de recaída en 16 meses de seguimiento. Esta observación confirma la utilidad del oxígeno hiperbárico como terapéutica adyuvante en mucormicosis (AU)