UNASSIGNED: Sickle cell disease, a common genetic disorder in African Americans, manifests an increased risk of sudden death, the basis of which is incompletely understood. Prolongation of heart rate-corrected QT (QTc) interval on the electrocardiogram, a standard clinical measure of cardiac repolarization, may contribute to sudden death by predisposing to torsades de pointes ventricular tachycardia.
UNASSIGNED: We established a cohort study of 293 adult and 121 pediatric sickle cell disease patients drawn from the same geographic region as the Jackson Heart Study (JHS) cohort, in which significant correlates of QT duration have been characterized and quantitatively modeled. Herein, we establish clinical and laboratory correlates of QTc duration in our cohort using stepwise multivariate linear regression analysis. We then compared our adult sickle cell disease data to effect-size predictions from the published JHS statistical model of QT interval duration.
UNASSIGNED: In adult sickle cell disease, gender, diuretic use, QRS duration, serum ALT levels, anion gap, and diastolic blood pressure show positive correlation; hemoglobin levels show inverse correlation; in pediatric sickle cell disease, age, hemoglobin levels, and serum bicarbonate and creatinine levels show inverse correlation. The mean QTc in our adult sickle cell disease cohort is 7.8 milliseconds longer than in the JHS cohort, even though the JHS statistical model predicts that the mean QTc in our cohort should be > 11 milliseconds shorter than in the much older JHS cohort, a differential of > 18 milliseconds.
UNASSIGNED: Sickle cell disease patients have substantial QTc prolongation relative to their age, driven by factors some overlapping, in adult and pediatric sickle cell disease, and distinct from those that have been defined in the general African American community.

The root cause of sickle cell disease (SCD) is the polymerization of sickle hemoglobin (HbS) leading to sickling of red blood cells (RBC). Earlier studies showed that in patients with SCD, high-dose nitrite inhibited sickling, an effect originally attributed to HbS oxidation to methemoglobin-S even though the anti-sickling effect did not correlate with methemoglobin-S levels. Here, we examined the effects of nitrite on HbS polymerization and on methemoglobin formation in a SCD mouse model. In vitro, at concentrations higher than physiologic (>1 μM), nitrite increased the delay time for polymerization of deoxygenated HbS independently of methemoglobin-S formation, which only occurred at much higher concentrations (>300 μM). In vitro, higher nitrite concentrations oxidized 100% of normal hemoglobin A (HbA), but only 70% of HbS. Dimethyl adipimidate, an anti-polymerization agent, increased the fraction of HbS oxidized by nitrite to 82%, suggesting that polymerized HbS partially contributed to the oxidation-resistant fraction of HbS. At low concentrations (10 μM-1 mM), nitrite did not increase the formation of reactive oxygen species but at high concentrations (10 mM) it decreased sickle RBC viability. In SCD mice, 4-week administration of nitrite yielded no significant changes in methemoglobin or nitrite levels in plasma and RBC, however, it further increased leukocytosis. Overall, these data suggest that nitrite at supra-physiologic concentrations has anti-polymerization properties in vitro and that leukocytosis is a potential nitrite toxicity in vivo. Therefore, to determine whether the anti-polymerization effect of nitrite observed in vitro underlies the decreases in sickling observed in patients with SCD, administration of higher nitrite doses is required.

Programed cell death (PCD) plays fundamental roles in plant development and responses to environmental stresses. Here, we report a protein, SICKLE (SIC), which represses PCD. In Arabidopsis (Arabidopsis thaliana), the loss-of-function mutant of SIC, sic-4, hyperaccumulated lariat intronic RNAs (lariRNAs) and exhibited PCD. The gene encoding an RNA debranching enzyme 1 (DBR1), a rate-limiting enzyme for lariRNAs decay, was overexpressed to reduce the level of lariRNAs in the sic-4 mutant, which led to suppression of PCD. Meanwhile, another lariRNAs hyper-accumulating mutant, dbr1-2, also exhibited PCD, further indicating that sic-4 PCD is caused by hyper-accumulation of lariRNAs. Transcriptional profiling analyses revealed that the sic-4 mutation disturbed alternative splicing and decay of mRNAs associated with salicylic acid (SA) homeostasis, a well-known molecule functioning in PCD regulation. Moreover, SA is dramatically increased in sic-4 and the disruption of SA biosynthesis and signaling suppressed PCD in the mutant, demonstrating that SA functions downstream of sic-4. Taken together, our results demonstrate that SIC is involved in regulating SA-triggered PCD.

Initial management of the acute pain crisis (APC) of sickle cell disease (SCD) is often unsatisfactory, and might be improved by developing a standardised analgesia protocol. Here, we report the first stages in developing a standard oral protocol for adolescents and adults. Initially, we performed a dose finding study to determine the maximal tolerated dose of sublingual fentanyl (MTD SLF) given on arrival in the acute care facility, when combined with repeated doses of oral oxycodone. We used a dose escalation algorithm with two dosing ranges based on patient\'s weight (<50 kg or >50 kg). We also made a preliminary evaluation of the safety and efficacy of the protocol. The study took place in a large tertiary centre in London, UK. Ninety patients in the age range 14-60 years were pre-consented and 31 treatment episodes were evaluated. The first 21 episodes constituted the dose escalation study, establishing the MTD SLF at 600 mcg (>50 kg) or 400 mcg (<50 kg). Further evaluation of the protocol indicated no evidence of severe opioid toxicity, nor increased incidence of acute chest syndrome (ACS). Between 0 and 6 hours, the overall gradient of reduction of visual analogue pain score (visual analogue scale (VAS)) was 0.32 centimetres (cm) per hour (95% confidence interval (CI) = 0.20 to 0.44, p < 0.001). For episodes on MTD SLF, there was median (interquartile range (IQR)) reduction in VAS score of 2.8 cm (0-4.2) and 59% had at least a 2.6-cm reduction. These results are supportive of further evaluation of this protocol for acute analgesia of APC in a hospital setting and potentially for supervised home management.

OBJECTIVE: The objective of this data set was to identify how interaction between temperature and the sickle-3 (sic-3) mutant alters the global messenger RNA (mRNA) content of Arabidopsis thaliana seedlings. The motivation was discovery of atypical mRNA splice variants in sic-3 that differed with seedling growth temperature. The expected outcome was identification of mRNA splice variants altered by sic-3, temperature, or the combination of temperature and genotype.
METHODS: The data set is RNAseq profiling of Arabidopsis (Col-0 ecotype) wild type and sic-3 seedlings under 16 °C or 28 °C. A comprehensive view of global mRNA sequences and their content was captured by deep sequencing of RNA pools made from sets of seedlings sampled every 4 h over 20 h. This data set contains sequences representing the spectrum of mRNA splice variants from individual genes, as well as from mRNA-related sequences like spliced introns. This data set enables detection of significant changes in gene-level expression and relative levels of mRNA splice variants caused by the different growth temperatures, the sic-3 mutation or both factors. This data set is useful to study production of mRNA splice variants and other mRNA-related RNAs in a range of plant species because Arabidopsis is a model plant.

BACKGROUND:  Sickle cell trait (SCT) has received attention as a cause of death in college athletes, leading to mandatory lab SCT screening in National Collegiate Athletic Association (NCAA) athletes. High-school athletes are commonly screened by self-report. There are no known studies for evaluating whether this method is effective as a screening tool.
OBJECTIVE:  The local prevalence rate of SCT as self-reported on the preparticipation evaluation (PPE) forms would be lower than the national accepted average.
METHODS: PPE forms from the Department of Orthopedics and Rehabilitation of the University of Florida (UF) were reviewed between January 1, 2017, and April 30, 2018. The Florida High School PPE form includes a yes/no question to assess the diagnosis of SCT. The prevalence established by self-report was then compared with the national prevalence for SCT in the comparable race/ethnicity groups reported by the CDC. The response rate of SCT questions was also compared to other common cardiac screening questions.
RESULTS:  A total of 401 forms were reviewed. Six (1.5%) students answered \"yes,\" 351 answered \"no,\" and 44 left the SCT question blank. All six athletes who self-reported \"yes\" were Black and made up 3.7% of the 162 known Black respondents. This self-report rate for Black/African Americans was well below the expected 7.3% described by the CDC. Response rates were also lower than the comparable cardiac screening questions.
CONCLUSIONS:  Self-report SCT status rates are lower than the accepted prevalence in a similar population. Significant inconsistencies in reporting were also determined.
CONCLUSIONS:  This is a rare study to evaluate the self-reported prevalence of SCT in high-school athletes. Below average reporting of SCT and inconsistency in completion of the forms increase the concern for accuracy and effectiveness of current high-school SCT screening methods relying on self-report.

Background and Novel Aspect of this Work: In the light of previous findings that inflammation predisposes to intercellular adhesion and microvascular occlusion in sickle cell disease (SCD), this study investigated the relationship between the number of vaso-occlusive events in SCD, plasma levels of the pro-inflammatory molecules 12-Hydroxyeicosatetraenoic acid (12-HETE), TNF-α and IL-1β; and single nucleotide polymorphisms (SNPs) in the gene 12-Lipooxygenase (ALOX-12), which encodes the enzyme 12-Lipoxygenase that catalyzes the biosynthesis of 12-HETE. Objective: To evaluate the relationship between vaso-occlusion in SCD and plasma concentrations of 12-HETE, TNF-α, and IL-1β; and single nucleotide polymorphisms (SNPs) in ALOX-12 gene. Participants and Methods: In 50 HbSS patients, the numbers of vaso-occlusive crisis requiring hospital treatment in the previous 1 year and the vaso-occlusive complications of SCD developed to date (e.g stroke) were added to obtain the vaso-occlusive events (VOE) score. In the HbSS patients and 30 healthy sibling control persons, plasma concentrations of 12-HETE, TNF-α and IL-1β were measured by ELISA, the ALOX12 SNPs rs2073438 and rs1126667 detected by DNA sequencing, and the accrued data statistically analyzed. Results: Compared to SCD patients with VOE score 0-1, those with scores ≥3 had higher plasma levels of 12-HETE (p < 0.0001) and TNF-α (p = 0.19), but not IL-1β (p = 0.27). VOE score showed strong direct correlation with plasma level of 12-HETE (r = 0.65, p < 0.0001), but not with TNF-α nor IL-1β. Neither VOE score nor plasma concentration of 12-HETE showed any relationship with the ALOX12 SNPs rs2073438 and rs1126667. Conclusion: The strong direct correlation of VOE score with plasma concentration of 12-HETE suggests that the clinical relevance of this pro-inflammatory molecule in SCD-associated vaso-occlusion needs to be evaluated in further studies.

Homicide by stab wound is common worldwide. However, the use of unusual edged weapons is rarely reported in the forensic literature. Here, we report two cases of homicide involving a Japanese sword, or katana, and a sickle. Both of these weapons can create either stab or incised wounds with some particularities. In our cases, characteristics of the external wounds, internal injuries, and the depth of penetration raised the possibility of an unusual weapon. Meticulous forensic examination of these injuries (morphological characteristics, depth of penetration, trajectories, and cut marks in the bone) may allow the forensic expert to determine the type of weapon used.

Sickle Cell Disease (SCD) is a chronic hemolytic disorder associated with frequent pain episodes, end organ damage and a shortened lifespan. Currently there exist no disease specific targeted therapies for the treatment of acute vaso-occlusive crisis (VOC) and management with analgesics and hydration is purely supportive. Improvement in understanding of disease pathophysiology has resulted in a great interest in disease modifying novel therapies and many are being evaluated in clinical trials. Here we report the results from the pre-specified mid-point analysis of the Phase 2 study of Intravenous Gamma Globulin (IVIG) for the treatment of acute VOC in patients with SCD and lessons learned.

Patients with sickle cell disease (SCD) can develop strokes and as a result, present neurologic and neurocognitive deficits. However, recent studies show that even without detectable cerebral parenchymal abnormalities on imaging studies, SCD patients can have significant cognitive and motor dysfunction, which can present as early as during infancy. As the cerebellum plays a pivotal role in motor and non-motor functions including sensorimotor processing and learning, we examined cerebellar behavior in humanized SCD mice using the Erasmus ladder. Homozygous (sickling) mice had significant locomotor malperformance characterized by miscoordination and impaired locomotor gait/stepping pattern adaptability. Conversely, Townes homozygous mice had no overall deficits in motor learning, as they were able to associate a conditioning stimulus (high-pitch warning tone) with the presentation of an obstacle and learned to decrease steptimes thereby increasing speed to avoid it. While these animals had no cerebellar strokes, these locomotor and adaptive gait/stepping patterns deficits were associated with oxidative stress, as well as cerebellar vascular endothelial and white matter abnormalities and blood brain barrier disruption, suggestive of ischemic injury. Taken together, these observations suggest that motor and adaptive locomotor deficits in SCD mice mirror some of those described in SCD patients and that ischemic changes in white matter and vascular endothelium and oxidative stress are biologic correlates of those deficits. These findings point to the cerebellum as an area of the central nervous system that is vulnerable to vascular and white matter injury and support the use of SCD mice for studies of the underlying mechanisms of cerebellar dysfunction in SCD.