Scholarships for Students with Intellectual Disabilities

Paying for college is hard. However, there are scholarships available for students with intellectual disability who want to go to college. This resource was created to help families and others locate scholarship money to help pay for college. There are scholarships listed that any student is eligible for, and many that are for students with specific disabilities. The information included in this document is up-to-date as of January 2023. The information will be reviewed and updated every year

Effect of N-Acetyl-L-Cysteine on Cysteine Redox Status in Patients with Thrombotic Thrombocytopenic Purpura: Protein Disulfide Bound Cysteine As a Biomarker of Oxidative Stress

Abstract N-Acetyl-L-Cysteine (NAC), an antioxidant drug, has been used to treat many diseases associated with oxidative stress. Nevertheless, its molecular mechanism of action in vivo remains to be understood. In an ongoing pilot study of NAC to treat thrombotic thrombocytopenic purpura (TTP), we found that NAC treatment following plasma exchange was safe in two TTP patients accompanying with rapid recovery. To explore whether the effectiveness of NAC is linked to plasma redox status, we developed a mass spectrometry based approach to measure cysteine (Cys) and Cys-containing disulfides including protein-bound cysteine (p-ss-Cys) in plasma, and measured these molecular species in plasma from patients with TTP before or after treatment with NAC. We propose that effect of NAC on p-ss-Cys may serve as an indicator for NAC action on redox sensitive proteins in plasma. Methods: Free thiols in plasma were blocked by N-ethylamaleimide (NEM), which also stops further disulfide exchange. NEM blocked thiols and small-molecule disulfides were extracted by methanol with isotopically-labeled internal standards and analyzed by liquid chromatography-tandem mass spectrometry with multiple reaction monitoring (LC-MS/MS-MRM). To determine total Cys including p-ss-Cys, we revaluated a parallel aliquot of plasma first reducing all disulfide-bound Cys with dithiothreitol (DTT) and then blocking the thiols with NEM before methanol extraction. Blood samples from TTP patients and normal donors were collected under protocols approved by IRB. Citrated Blood was collected daily from two patients with relapsed TTP before, during, andafter NAC treatment. Results: We first compared the concentrations of free-thiol Cys and Cys-containing disulfides in the plasma from two TTP patients before plasma exchange to plasma from normal donors. The concentrations of free-thiol Cys were in the low µM range and there were no significant differences between normal donor and TTP patients. However, the concentration of p-ss-Cys was greatly increased in the plasma from both TTP patients (337±33 µM) compared to normal heathy controls (181±27 µM, n=15). After plasma exchange prior to NAC infusion, the concentrations of p-ss-Cys in plasma from both patients decreased to the normal range. During a 4-day NAC treatment at doses of 300 mg/kg/day, p-ss-Cys further decreased to less than 80 µM in both TTP patients. The decreased p-ss-Cys was associated with increased the total free thiol concentration in patient plasma. Interestingly, we observed the lowest level of p-ss-Cys after the 3rd day of NAC treatment in patient 1, while it reached the lowest concentration after only one day of NAC treatment in patient 2. The different response to NAC treatment in the two patients may reflect that the patients are under different extent of oxidative stress. Conclusions: Our results suggest that TTP is associated with a high level of oxidative stress, as determined by accumulation of protein-bound Cys in plasma. NAC effectively reduces the disulfides that attach Cys to proteins, an effect that can be monitored by mass spectrometry. These results indicate that protein-ss-Cys can serve as a plasma biomarker for oxidative stress and effectiveness of antioxidant therapy. Disclosures No relevant conflicts of interest to declare. </jats:sec

Quantitative Analysis of Small Molecular Weight Thiols and Disulfides in Blood from a Sickle Cell Disease Patient Infused with N-Acetyl-L-Cysteine

Abstract N-acetyl-L-cysteine (NAC) is an FDA approved drug used to treat acetaminophen overdose or as a mucolytic agent in respiratory disorders. The commonly accepted mechanism of action is that NAC undergoes deacetylation to cysteine, which is then used to synthesize glutathione (GSH), a major intracellular antioxidant. Like other thiol-containing compounds, NAC can also act as a reducing agent to break protein disulfide bonds or as a scavenger of reactive oxygen species. Due to its antioxidant properties, NAC has been proposed as a potential treatment for many diseases associated with oxidative stress, including sickle cell disease (SCD), neurological disorders, infectious diseases, and cancers. Though NAC has been widely studied, a full understanding of the mechanism by which NAC is effective in vivo has been limited by challenges in accurately quantifying NAC and its metabolites. As part of a clinical trial of NAC therapy in SCD, we have developed a liquid chromatography-mass spectrometry (LC-MS) based assay to quantify small molecule free thiols and disulfides using isotopically labeled internal standards. We applied this method to quantify small molecular thiols and disulfides in whole blood, red blood cells, and plasma from a SCD patient before (pre) and at 1, 8, 24 and 72 hr time points of intravenous administration of NAC at a dose of 300 mg/kg (a bolus infusion of 150 mg/kg for 1 hour followed by 150 mg/kg given over the next 7 hr). The cysteine concentration in whole blood increased to 286 μM at 1 hr from 97 μM at baseline, indicating that NAC is indeed rapidly metabolized (deacetylated) to cysteine. Interestingly, although cysteine concentration in RBCs increased over 4 fold at 1 hr and remained high compared to baseline, the highest concentration of total GSH in blood was observed at 24 hr (743 μM compared to 494 μM at baseline). Intracellular availability of cysteine is known as a rate-limiting step for GSH synthesis, and the delayed accumulation of GSH may suggest that NAC is involved in the extracellular deficit of reducing equivalents before it serves as a substrate in GSH synthesis. To explore this possibility, we quantitated NAC and its oxidation products, homo- and mixed disulfides. We found that total NAC concentration reached 1.58 mM in whole blood at 1 hr, but 44% of NAC was oxidized to N-acetyl-cystine (NAC-ss) or formed mixed disulfides with GSH (GS-ss-NAC) and Cys (Cys-ss-NAC), whereas the NAC used for infusion contained less than 0.5% in the oxidized form (NAC-ss). Concurrent with the formation of NAC disulfides, the levels of oxidized GSH (GSSG, GS-ss-Cys) and cysteine (cystine) were significantly decreased. These observations suggest that NAC administration of SCD not only increases GSH levels by raising the cysteine concentration, but also directly functions as an antioxidant to reduce oxidative stress. SCD patients are known to have low levels of GSH and frequently experience oxidative stress. NAC treatment is likely to address both issues. We plan to analyze the effects of NAC on blood small molecule thiol concentrations in several more SCD patients. Disclosures No relevant conflicts of interest to declare. </jats:sec

Effects of N-Acetylcysteine in Patients with Sickle Cell Disease

Abstract We previously showed that the plasma of patients with sickle cell disease (SCD) contains an elevated quantity of von Willebrand factor (VWF) with high specific adhesive activity (as measured by the binding of nanobody AU/VWFa-11). Total active VWF (VWF antigen multiplied by VWF specific activity) correlated with the extent of hemolysis in these patients (Chen J. et al., Blood, 2011, 117:3680). In another study, we showed that N-acetylcysteine (NAC) reduced VWF size and activity ex vivo and broke down platelet–VWF aggregates in vivo in mice (Chen J. et al, JCI, 2011, 121:522). Given the possibility that VWF is involved in the pathophysiology of sickle cell disease, we are examining whether NAC can benefit these patients. We are first conducting a pilot clinical trial to determine the safety profile of infused NAC and its effects on laboratory endpoints. Five SCD patients at disease baseline and not recently transfused will be enrolled. To date, two patients have completed intravenous infusion of NAC at a low dose of 150 mg/kg with a bolus infusion of 75 mg/kg for the 1st hr and 75 mg/kg for 7 hr. Approximately one month after the low-dose infusion, these patients received another infusion of 300 mg/kg given as a bolus infusion of 150 mg/kg for the 1st hr and 150 mg/kg for 7 hr. Blood was collected for analysis immediately before the infusion, at 1 hr (after bolus infusion), 8 hr, 24 hr, and 72 hr after infusion. Among the parameters examined were plasma VWF, red blood cell concentration, density, and size (to look for fragments), and the concentrations of NAC, cysteine and glutathione and their oxidized and mixed disulfide forms. In these two patients, the NAC infusion was well tolerated except that both patients experienced pruritus during the higher-dose bolus infusion. We measured the concentrations of reduced and oxidized NAC, cysteine, and glutathione in whole blood in the first study subject by mass spectrometry. NAC concentrations were 725 μM and 1.58 mM at the 1 hr time point at the low and high doses, respectively. Compared to the baseline (before NAC infusion), the concentration of total cysteine in blood was increased 2.4 fold for low dose and 2.9 fold for high dose at 1 hr and returned to baseline at 8 hr. The concentration of total glutathione in whole blood was increased 1.5 fold and 1.3 fold at 24, and 72 hr, respectively, for the high dose infusion but did not change much at the low dose infusion. The size of high molecular weight VWF multimers decreased with the high dose infusion, the effect being obvious at 1 hr. In addition, NAC infusion markedly reduced the concentration of red cell fragments and dense cells. Both of these effects were very rapid, being observable at the 1 hr time point. In summary, NAC infusion in sickle cell patients at disease baseline appears safe. NAC increases the concentrations of total cysteine and glutathione in blood, reduces high molecular weight VWF multimers, and decreases the number of dense red blood cells and the extent of red cell fragmentation. Disclosures No relevant conflicts of interest to declare. </jats:sec

N-Acetylcysteine Treatment in Two Patients with Relapsed Thrombotic Thrombocytopenic Purpura Increased ADAMTS13 Activity, Free Thiol Concentration in Plasma, and Inhibited Platelet Activation

Abstract Introduction: Thrombotic thrombocytopenic purpura (TTP) is a catastrophic and potentially fatal disorder caused by systemic microvascular thrombosis due to von Willebrand factor (VWF)-platelet thrombi. TTP is caused by congenital or acquired deficiency of the plasma metalloprotease ADAMTS13. Based on an earlier study (Chen J et al., J Clin Invest 2011, 121:593-603), we proposed N-acetylcysteine (NAC) as an adjunct treatment for TTP. This study showed that NAC reduced the size and activity of VWF in vitro in human plasma and in vivo in a TTP mouse model. In 2013 and 2014, two case reports described treatment of refractory TTP patients with NAC, one receiving a low dose of NAC [300 mg/kg (total 15 g) for the 1st 24 hrs, followed by 2.5 g/day for two weeks concurrently with plasma exchange] (Shortt J et al., N Engl J Med 2013, 368: 90-92; Shortt J et al., Transfusion 2014, 54:2362-2363) and the other receiving high-dose NAC [300 mg/kg/day (11 g/day) for 10 days between plasma exchanges] (Li GW et al. Transfusion 2014, 54: 1221-1224). The patient treated with high-dose NAC improved rapidly (the patient woke up from coma 18 hr after NAC treatment was initiated), but the patient treated with lower dose NAC did not appear to respond. Thus, it is as yet unclear whether NAC is an effective treatment for TTP. Therefore, more clinical studies and detailed analyses are required to examine the effects of NAC in TTP patients. Here we report the results of clinical and biochemical studies on two patients with relapsed TTP treated with NAC. Before, during, and after NAC treatment, we determined the concentrations of NAC, cysteine, and glutathione in plasma; VWF concentration, multimer structure, and functions; ADAMTS13 concentration and activity; and platelet counts and activation status (P-selectin expression and phosphatidylserine exposure). Methods: Two females with a history of prior episodes of TTP presented with acute TTP [ADAMTS13 &lt; 10%, positive for ADAMTS13 inhibitors, platelet count ≤ 10,000/uL, lactate dehydrogenase (LDH) &gt; 600 IU/L] and both were treated with NAC per IRB-approved protocol [150 mg/kg bolus over 1 hr and 150 mg/kg as continuous infusion until the next therapeutic plasma exchange (TPE)]. They received daily TPE until their platelet counts normalized, and intravenous NAC during days 2-5. Blood was collected daily for 8 days for research assays. ADAMTS13 concentrations in patient plasma were measured by ELISA. ADAMTS13 activity was measured using HRP-conjugated A2 peptide substrate (Wu J-J et al. J Thromb Haemost 2006, 4:129-136). Concentrations of NAC, total cysteine, and total free thiols (free thiol cysteine and free thiol NAC) in plasma were determined by mass spectrometry. Plasma VWF multimer patterns were analyzed by 1.5% agarose gel electrophoresis followed by western blotting with an HRP-conjugated polyclonal VWF antibody. Platelets in whole blood were labeled for platelet markers (CD41a or CD42b) together with one of the activation markers, P-selectin or phosphatidylserine (lactadherin). The labeled platelets were analyzed by flow cytometry. Results: Platelet counts in both patients started to increase 1 day after NAC infusion and continued to increase after discontinuation of NAC and TPE. After NAC infusion, the free thiol concentration (NAC and cysteine) in plasma increased 4 and 59 fold in patients 1 and 2, respectively. This was accompanied by increasing ADAMTS13 specific activity (ADAMTS13 activity/ADAMTS13 antigen). In patient 1, the specific activity increased from 127% (prior to NAC infusion but after TPE) to 270% during NAC infusion; in patient 2, the specific activity increased from 56% to 86%. In patient 1, the VWF multimer size decreased during NAC treatment and the VWF multimers migrated slightly faster. NAC also appeared to inhibit platelet activation. Before NAC infusion, the platelets in both patients were positive for phosphatidylserine (PS, &gt; 30%) and P-selectin (&gt; 15%), compared to 2% and 5%, respectively, in a normal control. The percentages of PS- and P-selectin-positive platelets decreased to less than 18% and 10% respectively, during NAC treatment. Summary: NAC treatment of two patients with TTP in conjunction with TPE was well tolerated and associated with recovery of platelet count and LDH, increased ADAMTS13 specific activity and total free thiol concentration in plasma, reduced platelet activation, and decreased VWF multimer size in one patient. Disclosures Konkle: CSL Behring: Consultancy; Pfizer: Consultancy; Baxalta: Consultancy, Research Funding; Biogen: Consultancy, Research Funding; Octapharma: Research Funding; Novo Nordisk: Consultancy. </jats:sec

A Pilot Study of High-Dose N-Acetylcysteine Infusion in Patients with Sickle Cell Disease

Abstract We have completed a clinical trial evaluating the safety of N-acetylcysteine (NAC) infusion in adult patients with sickle cell disease (SCD) at disease baseline (NCT01800526). This trial was inspired by the hypothesis that von Willebrand factor (VWF) has an important role in the pathophysiology of vaso-occlusion and hemolysis in SCD and that NAC can reduce signs and symptoms of the disease by reducing the activity of VWF. A secondary hypothesis was that NAC could also act by reversing or preventing some of the oxidative changes associated with SCD. VWF is stored in the Weibel-Palade bodies of endothelial cells and α-granules of platelets and released from endothelial cells upon activation and mediates the attachment of platelets to the vessel wall, and secondarily, of erythrocytes and leukocytes. We previously showed that VWF levels and adhesive activity in SCD plasma were elevated and that total active VWF correlated with the extent of hemolysis (determined by plasma LDH levels), suggesting that VWF participates in the pathophysiology of SCD (Chen et al, Blood. 2011; 117:3680‐3). In another study, we showed that NAC was able to reduce VWF multimer size and platelet-binding activity ex vivo in human plasma and in vivo in mice (Chen et al, JCI, 2011, 121:522). In this clinical trial, we enrolled 5 subjects at disease baseline, 4 with SCD and 1 with sickle trait. All subjects received two high-dose NAC infusions: initially 150 mg/kg and 4 weeks later 300 mg/kg. NAC infusion was administered in subjects 1 and 2 as a bolus infusion of half of the dose in the 1sthour and the remaining half in 7 hr. Subjects 3-5 received NAC as constant infusion for 8 hr. Blood was collected immediately before infusion, during infusion (at 1 and 4 hr), immediately after infusion (8 hr), and 24 and 72 hr after infusion. We examined blood for red blood cell (RBC) fragments, dense cells, platelet activation status, platelet-monocyte complexes and the concentrations of reduced and oxidized glutathione. We also examined plasma for VWF concentration and multimer distribution, ADAMTS13 antigen and activity, and evaluated plasma redox status by measuring the concentrations of NAC and cysteine in their reduced, oxidized, and mixed disulfide forms, as well as the concentration of protein-bound cysteine. The small molecule thiols were measured by mass spectrometry. Results:1) All subjects tolerated NAC infusion well, except that subjects 1 and 2 experienced pruritus during the bolus infusion at the 300 mg/kg dose. We therefore changed the protocol to deliver the drug over 8 hr by continuous infusion for subjects 3 through 5. 2) During NAC infusion, the percentage of dense cells and concentration of RBC fragments decreased rapidly (average decrease: low dose 44%; high dose 31%) and the change persisted up to 72 hr. 3) Platelet activation also decreased, as determined by reduced P-selectin expression (low dose, 7.7 ± 0.7% to 5.0 ± 1.9%; high dose, 17.8 ± 0.07% to 7.3% ± 0.4), PAC-1 binding (evaluates activated αΙΙbβ3), and formation of platelet-monocyte complexes (monocytes with attached platelets: low dose, 52 ± 16% to 27 ± 12%; high dose, 77 ± 12% to 50 ± 17%). 4) The highest molecular weight VWF multimers transiently disappeared during the NAC infusion and recovered by 24 hr. There were no appreciable changes in VWF antigen or ADAMTS13 antigen or activity with NAC infusion. 5) With NAC infusion, the concentrations of Cys and NAC increased in plasma, both total and reduced forms, with a concomitant decrease in protein-bound Cys in the one patient studied (free thiol Cys increased 23 fold with the high dose infusion at 8 hr; protein-bound Cys decreased 87%). Similarly, the concentrations of reduced and oxidized glutathione increased in whole blood. Summary: NAC infusion in SCD patients at disease baseline appears safe and is well tolerated. NAC infusion decreases RBC fragments, dense cells, and the size of large VWF multimers, and inhibits platelet activation and formation of platelet-monocyte complexes. In addition, NAC infusion increases the total and free-thiol concentrations of cysteine and glutathione in blood, relieving oxidative stress in SCD. Our data suggest that NAC may be of benefit for SCD patients during vaso-occlusive crisis through a variety of mechanisms, which include improvements in red cell parameters, decreased platelet adhesion, reduced adhesive activity of VWF, and protection against oxidative damage. Disclosures No relevant conflicts of interest to declare. </jats:sec