COVID-19 severity in kidney transplant recipients is similar to nontransplant patients with similar comorbidities

Higher rates of severe COVID-19 have been reported in kidney transplant recipients (KTRs) compared to nontransplant patients. We aimed to determine if poorer outcomes were specifically related to chronic immunosuppression or underlying comorbidities. We used a 1:1 propensity score-matching method to compare survival and severe disease-free survival (defined as death and/or need for intensive care unit [ICU]) incidence in hospitalized KTRs and nontransplant control patients between February 26 and May 22, 2020. Patients were matched for risk factors of severe COVID-19: age, sex, body mass index, diabetes mellitus, preexisting cardiopathy, chronic lung disease, and basal renal function. We included 100 KTRs (median age [interquartile range (IQR)]) 64.7 years (55.3–73.1) in three French transplant centers. After a median follow-up of 13 days (7–30), transfer to ICU was required for 34 patients (34%) and death occurred in 26 patients (26%). Overall, 43 patients (43%) developed a severe disease during a median follow-up of 8.5 days (2–14). Propensity score matching to a large French cohort of 2017 patients hospitalized in 24 centers, revealed that survival was similar between KTRs and matched nontransplant patients with respective 30-day survival of 62.9% and 71% (p = .38) and severe disease-free 30-day survival of 50.6% and 47.5% (p = .91). These findings suggest that severity of COVID-19 in KTRs is related to their associated comorbidities and not to chronic immunosuppression.     

Induction of NKG2D ligands by gamma radiation and tumor necrosis factor-alpha may participate in the tissue damage during acute graft-versus-host disease

Immunopathology of acute graft-versus-host disease (aGVHD) involves secretion of proinflammatory cytokines with subsequent expression of danger signals by injured host tissues. This explanation, however, does not explain the cluster of aGVHD target organs (skin, gut, and liver). NKG2D ligands (MICA/B and ULBP1-3 proteins) are stress-induced molecules that act as danger signals to alert NK and alphabeta or gammadelta CD8 T cells through engagement of the activating NKG2D receptor. We observed a strong and reversible induction of MICA/B expression in skin and liver sections during aGVHD. Tumor necrosis factor-alpha and gamma-radiation up-regulated expression of MICA/B and ULBP proteins in vitro on skin and intestine epithelial cell lines and ex vivo in normal skin explants. This NKG2D-ligand induction was regulated by a complex interplay between NFkB and JNK activation pathways. Our data suggest that NKG2D ligand induction might participate in the amplification loop that leads to tissue damage during aGVHD.     

Effects of fenbufen and other anti-inflammatory drugs on rat liver lysosomes

Fenbufen, biphenylacetic acid and other non-steroidal anti-inflammatory drugs were found to labilize the lysosomal membrane of liver lysosomes in vitro. The extent of labilization was pH dependent. All the non-steroidal drugs labilized to a much greater extent at pH 5.0 than at pH 7.4. The two steroids tested, cholesterol and cortisone, stabilized the lysosomes at both pH 5.0 and 7.4. Oral administration of fenbufen and indomethacin caused no change in lysosomal membrane stability when assayed in vitro. Hydrocortisone showed a small degree of stabilization under these conditions. It is concluded that lysosomal membrane stabilization cannot account for the anti-inflammatory activity of fenbufen, biphenylacetic acid or other non-steroidal anti-inflammatory drugs.     

Fungal thrombus of the right atrium on a central venous catheter. Apropos of a case]

The authors report the case of a 9 year old child in an intensive care unit after multiple trauma, presenting with a candida septicaemia and a central venous catheter. Echocardiography, performed because of the inefficacy of medical treatment, showed a right atrial thrombus. Surgical ablation was decided because of its extreme mobility and persisting infection, and resulted in cure of the patient.     

Preoperative detection and management of immune heparin-induced thrombocytopenia in patients undergoing heart surgery with iloprost

OBJECTIVE: The objective of this study was to evaluate our protocol for the identification and management of patients with immune heparin-induced thrombocytopenia undergoing cardiac surgery. METHODS: Among 1518 patients who underwent cardiac surgery between June 1998 and May 2001, 32 (2.1%) presented with platelet counts less than 150,000/mm3 preoperatively or a history of prolonged (>3 days) intravenous exposure to heparin or both. These 32 patients were evaluated with an enzyme-linked immunosorbent assay for antibodies against heparin-platelet factor 4 complex. Platelets of patients with detected antibodies were tested with the prostacyclin analog iloprost for inhibition of heparin aggregation and determination of the inhibiting concentration and corresponding intravenous infusion rate of iloprost. Patients with antibodies received heparin after complete platelet inhibition with iloprost infusion. Hypotension was prevented or treated with intravenous noradrenaline. Ten randomly selected patients with similar preoperative characteristics, no previous extended exposure to heparin, and normal platelet counts served as controls. RESULTS: Ten of the 32 patients (group A, 31.3%) and none of the controls had antibodies against heparin-platelet factor 4 complex. Patients in group A underwent surgery with iloprost (6-24 ng.kg(-1).min(-1)) and had their blood pressure maintained at greater than 95 mm Hg with norepinephrine infusion (1-4 microg.kg(-1).min(-1)). Operative mortality was zero. There were no thrombotic complications or bleeding requiring exploration. One patient in group A bled 1310 mL/6 hours but did not need exploration. There was no difference in postoperative blood loss and morbidity between groups. Platelet counts were reduced by 12.5% +/- 8.7% (group A) and 38.1% +/- 15.2% (control) (P <.001) 1 hour postoperatively and reached preoperative values by the fifth postoperative day. CONCLUSIONS: Immune heparin-induced thrombocytopenia can be detected preoperatively among patients with a low platelet count or a history of prolonged heparin exposure or both. Cardiac surgery can be safely undertaken using iloprost-induced platelet inhibition during heparinization.     

Axon tracing in the adult rat optic nerve and tract after intravitreal injection of MnDPDP using a semiautomatic segmentation technique

PURPOSE: To develop and validate an objective technique for 3D segmentation of manganese-enhanced MR images of the optic nerve/tract (ON) in adult rats to improve contrast-to-noise (CNR) calculations and use the technique to ascertain if manganese dipyridoxyl diphosphate (MnDPDP) gives sufficient Mn(2+) enhancement compared to MnCl(2) when used for functional imaging of the visual pathway. MATERIALS AND METHODS: Intravitreous injection of the manganese-releasing MR contrast agent MnDPDP (30 nmol Mn(2+)) was performed to trace the ON in adult rats (n = 4). A positive control group of rats (n = 5) received a standard preparation of MnCl(2) (200 nmol Mn(2+)), while gadodiamide (1500 nmol Gd(3+)) was administered in negative control rats (n = 2). An objective technique for 3D segmentation of the enhanced ON was developed. CNR profiles along the ON were calculated by resampling the 3D image-volume in 2D planes perpendicular to the Mn(2+) enhanced ON in 0.2 mm steps, 4 mm along the segmented ON measured from the lamina cribrosa. RESULTS: The ON was successfully segmented and CNR calculated accurately within 2 minutes in a representative 3D MR image volume. Intravitreal MnDPDP injection resulted in significant MRI contrast enhancement of the retina and ON after 12-24 hours similar to that of MnCl(2) injection. CONCLUSION: 3D semiautomated image segmentation and the use of MnDPDP can improve in vivo axon tracing based on MRI. Mn(2+) was found to be released from MnDPDP after intravitreal injection in sufficient amounts to obtain functional tracing of the adult rat primary visual pathway.     

A critical function for transforming growth factor-beta, interleukin 23 and proinflammatory cytokines in driving and modulating human T(H)-17 responses

Interleukin 17 (IL-17)-producing T helper 17 cells (T(H)-17 cells) have been described as a T helper cell subset distinct from T helper type 1 (T(H)1) and T(H)2 cells, with specific functions in antimicrobial defense and autoimmunity. The factors driving human T(H)-17 differentiation remain controversial. Using a systematic approach combining experimental and computational methods, we show here that transforming growth factor-beta, interleukin 23 (IL-23) and proinflammatory cytokines (IL-1beta and IL-6) were all essential for human T(H)-17 differentiation. However, individual T(H)-17 cell-derived cytokines, such as IL-17, IL-21, IL-22 and IL-6, as well as the global T(H)-17 cytokine profile, were differentially modulated by T(H)-17-promoting cytokines. Transforming growth factor-beta was critical, and its absence induced a shift from a T(H)-17 profile to a T(H)1-like profile. Our results shed new light on the regulation of human T(H)-17 differentiation and provide a framework for the global analysis of T helper responses.