Proteasome inhibition for antibody-mediated allograft rejection

Antibody-mediated rejection (AMR) is a major risk factor for graft loss following kidney transplantation. Traditional anti-humoral therapies provide suboptimal therapy and they do not deplete plasma cells, which are the source of antibody production. Proteasome inhibitors (PI) have been shown to deplete both transformed and nontransformed plasma cells in human transplant recipients and animal models; and therefore, offer a new paradigm for AMR, ie, plasma cell-targeted therapy. Bortezomib, a first in class proteasome inhibitor approved by the US Food and Drug Administration for treatment of multiple myeloma, has been used to treat AMR in several solid organ transplant recipients. The greatest experience with PI therapy for treating AMR is in kidney transplant recipients. Experiences to date with PI therapy have demonstrated that: (1) early AMR (within the first 6 months post-transplant) responds better than late AMR, and (2) the nature of the plasma cell clonal population influences sensitivity to PI therapy with plasma subsets greater than long-lived bone marrow niche-resident plasma cells. In conclusion, plasma cell-targeted therapy with PIs is a method for targeting plasma cells (the source of antibody production) with a well-elucidated mechanism of action and subsequent points of synergy, thereby providing an exciting new potential means for enhancing anti-humoral therapies.     

Spidroin in carbopol-based gel promotes wound healing in earthworm's skin model

Spider silk's regenerative, biocompatible, and antimicrobial properties render it a promising biomaterial for wound healing promotion. Spidroin as the main protein component of spider silks was used in this study to evaluate the potential effects on wound healing via topical application of novel spidroin-containing carbopol 934 (CP934) gel. Spidroin was extracted, formulated into CP934 gel, and characterized both in vitro and in vivo. Spidroin gel was translucent and brownish-yellow in color. An optimum viscosity was obtained at 0.6% CP934 at neutral pH. Optimized spidroin gel (0.6% CP934) effectively inhibited the growth of clinical bacterial isolates of methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA) and Escherichia coli at 440 μg/mL with MIC values of 0.98, 4.6, and 8.2 μg/mL, respectively. Optimized spidroin gel was evaluated for wound healing via topical application on wounds surgically induced in Allolobophora caliginosa earthworms used as a robust human skin model. After application for three consecutive days, dramatic reductions in wound closure and reepithelialization duration were observed macroscopically and via histological studies (light and electron microscopy) when compared with control. In conclusion, these results show that spidroin gel is a promising promoter for wound healing, and further studies would be directed toward investigating mechanisms underlying this effect.     

Relative neutralizing activity in polyspecific IgM, IgA, and IgG preparations against group A streptococcal superantigens.

In this study we compared the ability of different immunoglobulin (Ig) preparations containing IgG, IgM, and/or IgA to neutralize the activity of streptococcal pyrogenic exotoxin A (SpeA) or culture supernatant from a clinical group A streptococcal isolate. All Ig preparations markedly inhibited the mitogenic and cytokine-inducing activity of SpeA and culture supernatant at concentrations of 0.05-0.5 mg/mL, and at 0.5 mg/mL, most caused 95-100% inhibition of both stimuli. A significantly higher (P< or =.05) inhibition of SpeA was achieved by Pentaglobin (IgG, IgM, and IgA) and IgAbulin (IgA and IgG), as compared with pure IgG preparations. IgM- and IgA-enriched preparations had significantly higher inhibitory activity against SpeA than against culture supernatant, whereas the reverse was true for the IgG preparations (P< or =.05). The data show that IgM and IgA are potent inhibitors of specific streptococcal superantigens. These findings may have implications for the optimization of immunotherapy in invasive streptococcal infections.     

Blood stream infection is associated with cerebrovascular accident in patients with left ventricular assist device: a systematic review and meta-analysis

Cerebrovascular accident (CVA) is one of the major complications and a leading cause of death in patients with a left ventricular assist device (LVAD). Multiple studies of have shown that patients with blood stream infection (BSI) are more likely to develop CVA compared to patients without BSI. However, there is no meta-analysis to confirm this association. Studies were systematically acquired from MEDLINE and EMBASE electronic databases. Included studies assessed patients with heart failure requiring LVAD and reported the number of patients who had BSI post LVAD, incidence of ischemic CVA, hemorrhagic CVA, or any CVA. Pooled effect size was calculated with a random-effect model, weighted for the inverse of variance. Heterogeneity was assessed with I². Six studies were analyzed. Participants with LVAD who developed BSI were more likely to have a CVA compared to participants without BSI (RR 3.43, 95% CI 2.49–4.72, I²?=?0). In four studies, there was an association between BSI and increased incidence of hemorrhagic CVA post LVAD (RR 5.28, 95% CI 2.65–10.53) with minimal heterogeneity (I²?=?30%). In three studies, participants with BSI were more likely to develop ischemic CVA (RR 2.18, 95% CI 1.23–3.84) compared to patients without BSI. This meta-analysis suggested that there maybe an association between blood stream infection and cerebrovascular accident in patients with LVAD.     

Early weaning from CPAP to high flow nasal cannula in preterm infants is associated with prolonged oxygen requirement: a randomized controlled trial

Objective

To determine the better approach for weaning preterm infants from nasal continuous positive airway pressure (NCPAP) with or without transitioning to nasal cannula (NC).

Design/methods

This is a randomized, open label, controlled trial. Preterm infants born at ≥ 28 weeks gestation who were clinically stable on NCPAP of 5 cm H₂O with FiO₂ < 0.30 for at least 24 h were randomly assigned to one of 2 groups. The no-NC group were kept on NCPAP until they were on FiO₂ = 0.21 for 24 h, and then were weaned off NCPAP completely without any exposure to NC. If they met failing criteria, NCPAP was re-instituted. The NC-group was weaned off NCPAP when FiO₂ was ≤ 0.30 to NC (2 L/min) followed by gradual weaning from oxygen. Infants who failed NC were supported back with NCPAP for 24 h before making a second attempt of NC.

Results

Sixty neonates were enrolled; 30 in each group. The two groups were similar in birthweight, gestational age, sex, antenatal steroids, mode of delivery, use of surfactant and xanthines, and duration of mechanical ventilation. After randomization, the no-NC group had fewer days on oxygen [median (interquartile range): 5 (1-8) vs 14 (7.5-19.25) days, p < 0.001] and shorter duration of respiratory support [10.5 (4-21) vs 18 (11.5-29) days, p = 0.03]. There were no differences between groups regarding success of weaning from NCPAP.

Conclusions

Weaning preterm infants from NCPAP to NC is associated with increased exposure to oxygen and longer duration of respiratory support.     

Prevalence of factor V Leiden in south Tunisian blood donors

Venous thrombosis (VT) is a common disease with multifactorial pathogenesis. Factor V Leiden mutation (G1691A) (FVL) is the most common risk factor in venous thrombosis. The prevalence of FVL varies according to geography and ethnicity. Hence, in several countries there is a difference in the frequency of this mutation between the southern, central and north. In Tunisia, no data is available about prevalence of FVL mutation by geographical origin. For this reason, we sought the prevalence of FVL mutation in blood donor of south Tunisia population. FVL has been detected by APCR-test and confirmed by PCR-RFLP and sequencing. Two hundred fifty blood donors, different in age and sex were included in this study to determine the prevalence of FVL in blood donors. FVL mutation was found in 13.6% of the studied population. Thirty-one were heterozygous and three persons were homozygous with a rate of 12.4 and 1.2%, respectively. In conclusion, FVL mutation is very common in south Tunisian population.