Reversibility of severe metabolic stress in stored platelets after in vitro plasma rescue or in vivo transfusion: restoration of secretory function and maintenance of platelet survival

BACKGROUND: Determining reversible aspects of the platelet storage lesion may result in improved function and survival of transfused platelets. STUDY DESIGN AND METHODS: Using a model of high-dose (apheresis-derived) platelet concentrates (PC), functional changes imposed by transient adverse metabolic conditions (pH < 6.0 for 1-2 hr) that could be reversed by autologous plasma rescue followed by standard platelet storage were investigated. Whole-blood-derived PCs were transfused into a small number of normal volunteers to determine platelet recovery and survival. RESULTS: Without rescue, high-dose PCs developed severe in vitro functional derangements at the time of the pH nadir including 1) loss of resting morphology; 2) complete abrogation of osmotic recovery and platelet aggregation and glycoprotein IIb/IIIa up-regulation to agonist; and 3) decreased alpha-granule release. By contrast, spontaneous and agonist-induced binding of annexin V were unaffected by adverse metabolic conditions. Plasma rescue to an optimal pH improved morphology scores, stabilized osmotic recovery, and completely restored platelet secretory responses, as measured by aggregation, glycoprotein IIb/IIIa up-regulation, and alpha-granule release. In a limited number of studies, plasma rescue was accompanied by preserved in vivo platelet recovery and survival after autologous transfusion after 5 days of storage. CONCLUSION: Transient derangement of platelet metabolism, which does not increase membrane phosphatidylserine exposure, causes in vitro functional abnormalities that are fully reversed or stabilized by metabolic rescue. Preliminary data suggest that such rescued platelets may have normal posttransfusion recovery and survival.     

Vertebral Body Infarct and Ventral Cauda Equina Enhancement: Two Confirmatory Findings of Acute Spinal Cord Infarct

Two valuable confirmatory MRI findings of acute spinal cord infarct are highlighted and discussed: concomitant vertebral body infarct and ventral cauda equina nerve root enhancement.     

Structure-Based Design of Type II Inhibitors Applied to Maternal Embryonic Leucine Zipper Kinase

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Microbiota That Affect Risk for Shigellosis in Children in Low-Income Countries

Pathogens in the gastrointestinal tract exist within a vast population of microbes. We examined associations between pathogens and composition of gut microbiota as they relate to Shigella spp./enteroinvasive Escherichia coli infection. We analyzed 3,035 stool specimens (1,735 nondiarrheal and 1,300 moderate-to-severe diarrheal) from the Global Enteric Multicenter Study for 9 enteropathogens. Diarrheal specimens had a higher number of enteropathogens (diarrheal mean 1.4, nondiarrheal mean 0.95; p<0.0001). Rotavirus showed a negative association with Shigella spp. in cases of diarrhea (odds ratio 0.31, 95% CI 0.17–0.55) and had a large combined effect on moderate-to-severe diarrhea (odds ratio 29, 95% CI 3.8–220). In 4 Lactobacillus taxa identified by 16S rRNA gene sequencing, the association between pathogen and disease was decreased, which is consistent with the possibility that Lactobacillus spp. are protective against Shigella spp.–induced diarrhea. Bacterial diversity of gut microbiota was associated with diarrhea status, not high levels of the Shigella spp. ipaH gene.     

Inhibition of platelet activation prevents the P‐selectin and integrin‐dependent accumulation of cancer cell microparticles and reduces tumor growth and metastasis in vivo

Venous thromboembolism constitutes one of the main causes of death during the progression of a cancer. We previously demonstrated that tissue factor (TF)‐bearing cancer cell‐derived microparticles accumulate at the site of injury in mice developing a pancreatic cancer. The presence of these microparticles at the site of thrombosis correlates with the size of the platelet‐rich thrombus. The objective of this study was to determine the involvement of TF expressed by cancer cell‐derived microparticles on thrombosis associated with cancer. We observed that pancreatic cancer cell derived microparticles expressed TF, its inhibitor tissue factor pathway inhibitor (TFPI) as well as the integrins αvβ1 and αvβ3. In mice bearing a tumor under‐expressing TF, a significant decrease in circulating TF activity associated with an increase bleeding time and a 100‐fold diminished fibrin generation and platelet accumulation at the site of injury were observed. This was mainly due to the interaction of circulating cancer cell‐derived microparticles expressing TFPI with activated platelets and fibrinogen. In an ectopic model of cancer, treatment of mice with Clopidogrel, an anti‐platelet drug, decreased the size of the tumors and restored hemostasis by preventing the accumulation of cancer cell‐derived microparticles at the site of thrombosis. In a syngeneic orthotopic model of pancreatic cancer Clopidogrel also significantly inhibited the development of metastases. Together, these results indicate that an anti‐platelet strategy may efficiently treat thrombosis associated with cancer and reduce the progression of pancreatic cancer in mice.     

Impairment‐ and activity/participation‐directed interventions in progressive language impairment: Clinical and theoretical issues

Abstract

The most salient and discussed features of agrammatism are the omission and substitution of grammatical morphemes, whether bound or free, in speech production. Cross-linguistic studies have shown that language-specific features determine the pattern of omissions and substitutions found; morphological markers are almost never omitted if the resulting form is a non-word; substitutions are mis-selections from existing paradigms. In the present paper we investigate the ways in which agrammatism is manifested in Algerian Arabic, a Semitic language where simple (Ø-prefixed and Ø-suffixed) words are described as consisting of three morphemes: the discontinuous consonantal root, the discontinuous vocalic base and a CV template or skeleton (McCarthy 1975). Our findings are comparable to those previously reported, in that the three agrammatic subjects who participated in this study do omit and substitute free-standing and bound grammatical markers, and never produce non-words. More specifically, their performance is characterized by omissions of linear bound morphemes in prefixed and suffixed words, as well as substitutions of morphologically complex forms by simpler and more frequent ones. An interpretation of the subjects' performance in the light of current linguistic and psycholinguistic theories on the lexicon is proposed.