Single-donor spray-dried plasma.

BACKGROUND: Dried plasma is logistically superior for hemostasis management because it can be transported and stored under nonfrozen conditions and quickly reconstituted at the point of care, enabling prehospital administration. Velico Medical has developed a spray-drying system to be integrated into routine blood center work streams for spray drying single donor plasma units. This study compared the quality of the spray-dried plasma (on-demand plasma [ODP]) with fresh frozen plasma (FFP). STUDY DESIGN AND METHODS: ODP units (n = 60) were manufactured from never frozen fresh plasma, which was pretreated with glycine-hydrochloric acid and stored at 1to 6°C. Paired aliquots were frozen and stored at -18°C or less. After 31 to 33 days, ODP samples were reconstituted with water for injection and comprehensively characterized in parallel with paired FFP. The quantities of plasma dried and rehydration fluid were predetermined, ensuring comparable total protein concentration in ODP and paired FFP. RESULTS: ODP is comparable to FFP in global coagulation function as assessed by activated partial thromboplastin time and prothrombin time and in clot formation evaluated by thrombelastography. Compared to FFP, ODP had greater than 80% levels of functional coagulation factors and related proteins and chemistry analytes except for Factor XIII (74%). Pretreatment mitigated cleavage of high-molecular-weight von Willebrand factor multimers by spray drying and resulted in 60% vWF:ristocetin cofactor activity in ODP compared to FFP. CONCLUSIONS: ODP demonstrates coagulation function comparable to that of FFP. The spray drying system can be implemented in blood centers and is capable of producing units of ODP.

Prevalence and factors associated with renal dysfunction in patients on tenofovir disoproxil fumarate-based antiretroviral regimens for HIV infection in Southern India.

OBJECTIVES: Tenofovir disoproxil fumarate (TDF) is a nucleotide reverse transcriptase inhibitor commonly used in the treatment of HIV infection. This retrospective study aims to establish the prevalence of abnormal renal function among patients with HIV receiving TDF, and to investigate the risks for TDF-related renal dysfunction in this population. METHODS: Patients at the YRGCARE Medical Centre, Voluntary Health Services, receiving TDF-containing antiretroviral (ART) regimens between January 2002 and March 2017, were assessed for renal dysfunction using creatinine level and eGFR (DAIDS/NIH) during continuum of care. Demographic data and comorbidities were analysed for association with TDF toxicity. Data were obtained from the Natural History Study Database. Other causes of renal dysfunction were excluded. RESULTS: From the 14,118 patients on ART between 2002 and 2017 seen in the clinic, 7171 (50.8%) were initiated on TDF-containing regimens. Among these, 4400 were on a first-line NNRTI regimen, and 2771 on a second-line PI/r regimen, initiated after failure of first-line therapy. The majority of patients on ART were male, with a median age for the whole sample of 36 years (IQR 30-42). At ART initiation, the median CD4 cell count was 277 cells/mm3 (IQR 165-421) and the viral load (VL) 31,198 HIV-1 copies/mL (IQR 400-226,690). Median duration of follow-up was 5.1 years (IQR 2.3-9.5). The prevalence of renal dysfunction in patients taking TDF was 5.6%. Increased age, low BMI, low baseline CD4 cell count, hypertension and diabetes were associated with tenofovir toxicity (P<0.05). Concomitant PI use was not associated with increased risk for renal dysfunction (P>0.05). CONCLUSIONS: The prevalence of renal dysfunction associated with TDF in our study population was higher than in other well-resourced settings, suggesting the need for increased renal parameter monitoring in patients in resource-limited settings. Treatment with ART should be initiated earlier and BMI should be maintained ≥18.5 kg/m2 through adequate nutrition and prevention of opportunistic infections. For patients with multiple comorbidities, tenofovir alafenamide (TAF) should be considered, instead of TDF, to avoid renal dysfunction.

N,N-Dimethylacetamide Significantly Attenuates LPS- and TNFα-Induced Proinflammatory Responses Via Inhibition of the Nuclear Factor Kappa B Pathway.

Previously, we have shown that N,N-dimethylacetamide (DMA) prevents inflammation-induced preterm birth in a murine model, inhibits LPS-induced increases in placental pro-inflammatory cytokines and up-regulates the anti-inflammatory cytokine Interleukin-10 (IL-10). However, DMA's mechanism of action remains to be elucidated. In the current study we investigate how DMA produces its anti-inflammatory effect. Using in vitro and ex vivo models, we show that DMA suppresses secretion of pro-inflammatory cytokines in lipopolysaccharide (LPS)-induced RAW 264.7 cells, TNFα-challenged JEG-3 cells and LPS-stimulated human placental explants. DMA significantly attenuated the secretion of TNFα, IL-6, IL-10, and granulocyte macrophage colony stimulating factor (GM-CSF) from LPS-stimulated RAW 264.7 cells, IL-6 secretion from TNFα-stimulated JEG-3 cells and TNFα, IL-6, IL-10, GM-CSF and Interleukin-8 (IL-8) from LPS-stimulated human placental explants. We further investigated if DMA's effect on cytokine expression involves the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. DMA (10 mM) significantly inhibited nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) degradation in LPS-stimulated RAW 264.7 cells, but there was no significant change in the expression of phosphorylated or native forms of downstream proteins in the MAPK pathway. In addition, DMA significantly attenuated luciferase activity in cells co-transfected with NF-κB-Luc reporter plasmid, but not with AP-1-Luc or CEBP-Luc reporters. Overall, our findings suggest that the anti-inflammatory activity of DMA is mediated by inhibition of the NF-κB pathway via decreased IκBα degradation.

Inhibition of sphingosine kinase prevents lipopolysaccharide-induced preterm birth and suppresses proinflammatory responses in a murine model.

Premature delivery occurs in 12% of all births, and accounts for nearly half of long-term neurological morbidity, and 60% to 80% of perinatal mortality. Despite advances in obstetrics and neonatology, the rate of premature delivery has increased approximately 12% since 1990. The single most common cause of spontaneous preterm birth is infection. Several lines of evidence have demonstrated the role of endothelin-1 as both a constrictor of uterine myometrial smooth muscle and a proinflammatory mediator. Endothelin-1 activates the phospholipase C pathway, leading to activation of protein kinase C and, in turn, sphingosine kinase (SphK). The inhibition of SphK has been recently shown to control the proinflammatory response associated with sepsis. We show herein, for the first time, that SphK inhibition prevents inflammation-associated preterm birth in a murine model. Rescue of pups from premature abortion with an SphK inhibitor occurs by suppression of the proinflammatory cytokines tumor necrosis factor α, Il-1ß, and Il-6 and attenuation of polymorphonuclear inflammatory cells into the placental labyrinth. Moreover, we postulate that inhibition of SphK leads to suppression of endothelin-converting enzyme-1 expression, indicating the presence of an endothelin-converting enzyme 1/endothelin 1-SphK positive feedback loop. This work introduces a novel approach for the control of infection-triggered preterm labor, a condition for which there is no effective treatment.

N,N-dimethylacetamide regulates the proinflammatory response associated with endotoxin and prevents preterm birth.

The proinflammatory response leads to various types of pathologic pathways, including the development of preterm birth. Preterm birth occurs in 12% of deliveries in the United States and causes more than 70% of perinatal morbidity and mortality. The most common cause of spontaneous preterm birth is intrauterine infection in the mother. There is accumulating evidence indicating that the release of proinflammatory cytokines plays a critical role in the pathogenesis of inflammation-associated premature delivery. We found that the common organic solvent, N,N-dimethylacetamide (DMA), prevents endotoxin-induced preterm birth in timed pregnant C57BL/6 embryonic day (E)15.5 mice and rescues their pups from spontaneous abortion at doses many-fold lower than those currently used clinically and in a dose-dependent fashion. We also provide histologic evidence that DMA suppresses the endotoxin-triggered proinflammatory response by significantly attenuating inflammatory cell infiltration of placental tissue. Furthermore, immunoblotting analysis of placental tissue harvested from our murine models revealed DMA-mediated regulation of expression of the proinflammatory cytokines IL-1ß, tumor necrosis factor α, and IL-6, and increased expression of the regulatory inflammatory cytokine IL-10. By using in vitro studies, we provide evidence that DMA suppresses macrophage function and that this small molecule prevents nuclear translocation of nuclear factor-kB. These results suggest that DMA represents a newly discovered, nontoxic therapy for a broad range of inflammatory disorders.