Brain network hypersensitivity underlies pain crises in sickle cell disease.

Sickle cell disease (SCD) is a genetic disorder causing painful and unpredictable Vaso-occlusive crises (VOCs) through blood vessel blockages. In this study, we propose explosive synchronization (ES) as a novel approach to comprehend the hypersensitivity and occurrence of VOCs in the SCD brain network. We hypothesized that the accumulated disruptions in the brain network induced by SCD might lead to strengthened ES and hypersensitivity. We explored ES's relationship with patient reported outcome measures (PROMs) as well as VOCs by analyzing EEG data from 25 SCD patients and 18 matched controls. SCD patients exhibited lower alpha frequency than controls. SCD patients showed correlation between frequency disassortativity (FDA), an ES condition, and three important PROMs. Furthermore, stronger FDA was observed in SCD patients with a higher frequency of VOCs and EEG recording near VOC. We also conducted computational modeling on SCD brain network to study FDA's role in network sensitivity. Our model demonstrated that a stronger FDA could be linked to increased sensitivity and frequency of VOCs. This study establishes connections between SCD pain and the universal network mechanism, ES, offering a strong theoretical foundation. This understanding will aid predicting VOCs and refining pain management for SCD patients.

Inflammation and autoimmunity are interrelated in patients with sickle cell disease at a steady-state condition: implications for vaso-occlusive crisis, pain, and sensory sensitivity.

This study aimed to comprehensively analyze inflammatory and autoimmune characteristics of patients with sickle cell disease (SCD) at a steady-state condition (StSt) compared to healthy controls (HCs) to explore the pathogenesis of StSt and its impact on patients' well-being. The study cohort consisted of 40 StSt participants and 23 HCs enrolled between July 2021 and April 2023. StSt participants showed elevated white blood cell (WBC) counts and altered hematological measurements when compared to HCs. A multiplex immunoassay was used to profile 80 inflammatory cytokines/chemokines/growth factors in plasma samples from these SCD participants and HCs. Significantly higher plasma levels of 35 analytes were observed in SCD participants, with HGF, IL-18, IP-10, and MCP-2 being among the most significantly affected analytes. Additionally, autoantibody profiles were also altered, with elevated levels of anti-SSA/Ro60, anti-Ribosomal P, anti-Myeloperoxidase (MPO), and anti-PM/Scl-100 observed in SCD participants. Flow cytometric analysis revealed higher rates of red blood cell (RBC)/reticulocyte-leukocyte aggregation in SCD participants, predominantly involving monocytes. Notably, correlation analysis identified associations between inflammatory mediator levels, autoantibodies, RBC/reticulocyte-leukocyte aggregation, clinical lab test results, and pain crisis/sensitivity, shedding light on the intricate interactions between these factors. The findings underscore the potential significance of specific biomarkers and therapeutic targets that may hold promise for future investigations and clinical interventions tailored to the unique challenges posed by SCD. In addition, the correlations between vaso-occlusive crisis (VOC)/pain/sensory sensitivity and inflammation/immune dysregulation offer valuable insights into the pathogenesis of SCD and may lead to more targeted and effective therapeutic strategies. Clinical Trial Registration: ClinicalTrials.gov, Identifier: NCT05045820.

Differential clinical characteristics across traditional Chinese medicine (TCM) Syndromes in patients with sickle cell disease.

Background: Pain is a common, debilitating, and poorly understood complication of sickle cell disease (SCD). The need for clinical pain management of SCD is largely unmet and relies on opioids as the main therapeutic option, which leads to a decreased quality of life (QoL). According to the literature, acupuncture has shown certain therapeutic effects for pain management in SCD. However, these clinical studies lack the guidance of Traditional Chinese Medicine (TCM) Syndrome Differentiation principles for treatment. Aim: To characterize differences in clinical presentation amongst TCM diagnosed Syndromes in SCD patients. Method: Fifty-two patients with SCD and 28 age- and sex-matched healthy controls (HCs) were enrolled in an ongoing trial of acupuncture. Each participant completed a series of questionnaires on pain, physical function, fatigue, sleep, anxiety, depression and QoL and underwent cold- and pressure-based quantitative sensory testing at baseline. Data on prescription opioid use over the 12 months prior to study enrollment was used to calculate mean daily morphine milligram equivalents (MME). Differences among the three TCM Syndromes were analyzed by one-way ANOVA followed by Tukey post hoc testing. Two-sample t-tests were used to compare SCD and HC groups. Results: TCM diagnosis criteria classified SCD patients into one of three TCM Syndromes: (a) Equal; (b) Deficiency; and (c) Stagnation. The Stagnation group exhibited higher pain interference, physical dysfunction, nociplastic pain, fatigue, anxiety, depression, MME consumption and lower sleep quality and QoL compared to the Equal group. Few differences were observed between HCs and the Equal SCD group across outcomes. Deficiency and Stagnation groups were differentiated with observed- and patient-reported clinical manifestations. Conclusion: These findings suggest that TCM diagnosed Syndromes in SCD can be differentially characterized using validated objective and patient-reported outcomes. Because characteristics of pain and co-morbidities in each SCD patient are unique, targeting specific TCM "Syndromes" may facilitate treatment effectiveness with a Syndrome-based personalized treatment plan that conforms to TCM principles. These findings lay the foundation for the development of tailored acupuncture interventions based on TCM Syndromes for managing pain in SCD. Larger samples are required to further refine and validate TCM diagnostic criteria for SCD.

The DNA sequence and biological annotation of human chromosome 1.

The reference sequence for each human chromosome provides the framework for understanding genome function, variation and evolution. Here we report the finished sequence and biological annotation of human chromosome 1. Chromosome 1 is gene-dense, with 3,141 genes and 991 pseudogenes, and many coding sequences overlap. Rearrangements and mutations of chromosome 1 are prevalent in cancer and many other diseases. Patterns of sequence variation reveal signals of recent selection in specific genes that may contribute to human fitness, and also in regions where no function is evident. Fine-scale recombination occurs in hotspots of varying intensity along the sequence, and is enriched near genes. These and other studies of human biology and disease encoded within chromosome 1 are made possible with the highly accurate annotated sequence, as part of the completed set of chromosome sequences that comprise the reference human genome.

Thymoma With Triple Threat: Pure Red Cell Aplasia, Autoimmune Hemolytic Anemia, and T-Cell Large Granular Lymphocytic Leukemia.

Thymomas are a rare neoplasm of the anterior mediastinum and often associated with paraneoplastic syndromes. Though myasthenia gravis is the most common and well-known, the list of reported paraneoplastic syndromes occurring with thymoma is extensive and ever-growing. Paraneoplastic syndromes can involve nearly every organ system, including hematologic abnormalities affecting any or all cell lines. This can present challenges to the clinician in terms of diagnosis, prognostic impact, and management. We present the case of a previously healthy 41-year-old female who was diagnosed with thymoma and three rare hematologic paraneoplastic syndromes: pure red cell aplasia (PRCA), autoimmune hemolytic anemia (AIHA), and T-cell large granular lymphocytic leukemia (T-LGLL). To the best of our knowledge, there have been only four other reported cases of PRCA and AIHA in a single patient with thymoma, all of which were treated with thymectomy. Upfront surgical resection was not possible in the present case and thus the patient was alternatively treated with corticosteroids and octreotide, which proved successful in resolving the anemia. The authors present this case to share these findings of an alternative treatment strategy for thymoma-associated PRCA and AIHA and to highlight the importance of careful monitoring with routine blood work for these complex patients.

The effect of tape type, taping method and tape storage temperature on the retrieval rate of fibres from various surfaces: An example of data generation and analysis to facilitate trace evidence recovery validation and optimisation.

This paper aspires to assist those tasked with data generation and analysis for the purpose of the validation and/or optimisation of trace evidence recovery. It does so via a detailed report of the authors' approach to this problem in the context of target fibre retrieval using self-adhesive tapes. Textile fibres can provide valuable evidence at both source and activity levels. This ability stems from their near ubiquity in the man-made environment, their potential for high levels of discrimination (especially when found in combination) and their reproducible transfer and persistence behaviours. To realise this value for the criminal justice system, it is vital that police forces and forensic providers are collectively able to search for, recover and analyse fibres found at crime scenes and correctly evaluate their evidential value. ISO accreditation provides quality assurance for such activities. The work reported in this paper was part of a study to validate crime scene fibre retrieval processes for the purposes of ISO17020 accreditation. However, it is hoped that it will be of assistance to those wishing to validate and/or optimise forensic fibre recovery whether at the crime scene or in the laboratory. Further, the methods described may be of value to those who need to validate and/or optimise the recovery of other types of trace evidence. This paper outlines a series of experiments that investigated the effect of four factors on the rate at which target fibres could be recovered from surfaces by tape lifting. The factors were tape type (with two levels, namely: J-LAR and Crystal Tabs), tape storage temperature (three levels: -5 °C, room temperature [19 ±â€¯1 °C] and 35 °C), taping method (two levels: zonal and one-to-one) and surface (12 levels: each being a surface type commonly encountered at crime scenes). This resulted in 144 unique experimental conditions. For each of these, five repeat fibre recovery rate determinations were carried out, generating 720 data points. All surfaces were clean and dry prior to target fibres being transferred and recovered. In all cases, the tapes were applied to the surfaces at 19 ±â€¯1 °C. These experiments showed that the surfaces can be divided into three stable clusters based on the median and interquartile range of the fibre retrieval rate achieved from each of them. Also, they showed that, in terms of the proportion of the target fibres retrieved, typically and setting aside interaction effects: However, notably, a good degree of between-condition overlap was also apparent in the data. To understand this, a four-way factorial ANOVA model was built which revealed significant and substantive effects for all four main effects and for 10 of the 11 interactions. Importantly, the four-way interaction term was amongst those found to be significant. The interplay between the effects of the four factors was analysed by means of simple effects tests and pairwise contrasts. Tables and interactive parallel coordinate plots have been created. Using these it can easily be seen which of any given pair of levels of each of the four factors resulted in the higher fibre retrieval rate under any one of the unique conditions of the study, and the effect size and statistical significance of this observation. Qualitative evaluations of the effect of tape storage temperatures on tape pliability and its propensity to tear in use were also made.

Ammonia effects on microinvertebrates and fish in outdoor experimental streams.

Laboratory data on ammonia effects, the US EPA national water quality criteria for ammonia, and ammonia site-specific criteria were evaluated in four outdoor experimental streams (one control and three treatment streams) over a 76-week period. Calculated un-ionised ammonia concentrations varied daily and seasonally according to pH and temperature changes. Populations of four major microinvertebrate taxonomic groups (cladocerans, copepods, rotifers and protozoans) were monitored during a 4-week period early in the study, and six fish species (fathead minnows, bluegills, channel catfish, white suckers, walleyes, and rainbow trout) were tested for various time intervals, from 4 to 26 weeks, throughout the 76-week study period. Copepods and rotifers were unaffected in all three treatment streams, based on comparisons with the control stream. Cladoceran and protozoan populations were reduced in at least two treatment streams, but because of large variability, effects were considered to be inconclusive. However, complete mortality of cladocerans did occur in the high and medium treatments when placed in in situ biomonitor chambers. All six fish species were affected in one or more treatments. Generally, the fish effect values agreed with most laboratory effect values. Of 12 fish groups tested, one channel catfish group and one white sucker group were affected below the recommended protection levels of the national and site-specific criteria. The lowest effect concentrations tested for the other ten groups occurred above the criteria levels.

Treatment paradigms in heart failure.

Heart failure patients suffer very severe morbidity, high mortality and are common in medical practice. Their need for effective treatments is only partially answered by current options. Effective treatments often address cellular and pathophysiological mechanisms which are involved in the progression of heart failure. This article reviews those mechanisms and treatments.

Mutations at arginine 352 alter the pore architecture of CFTR.

Arginine 352 (R352) in the sixth transmembrane domain of the cystic fibrosis transmembrane conductance regulator (CFTR) previously was reported to form an anion/cation selectivity filter and to provide positive charge in the intracellular vestibule. However, mutations at this site have nonspecific effects, such as inducing susceptibility of endogenous cysteines to chemical modification. We hypothesized that R352 stabilizes channel structure and that charge-destroying mutations at this site disrupt pore architecture, with multiple consequences. We tested the effects of mutations at R352 on conductance, anion selectivity and block by the sulfonylurea drug glipizide, using recordings of wild-type and mutant channels. Charge-altering mutations at R352 destabilized the open state and altered both selectivity and block. In contrast, R352K-CFTR was similar to wild-type. Full conductance state amplitude was similar to that of wild-type CFTR in all mutants except R352E, suggesting that R352 does not itself form an anion coordination site. In an attempt to identify an acidic residue that may interact with R352, we found that permeation properties were similarly affected by charge-reversing mutations at D993. Wild-type-like properties were rescued in R352E/D993R-CFTR, suggesting that R352 and D993 in the wild-type channel may interact to stabilize pore architecture. Finally, R352A-CFTR was sensitive to modification by externally applied MTSEA+, while wild-type and R352E/D993R-CFTR were not. These data suggest that R352 plays an important structural role in CFTR, perhaps reflecting its involvement in forming a salt bridge with residue D993.