Safe administration of etoposide phosphate after hypersensitivity reaction to intravenous etoposide

Etoposide is commonly used in a variety of malignancies. A well known but rare toxicity are hypersensitivity reactions, usually manifested by chest discomfort, dyspnoea, bronchospasm and hypotension. We report the details of a patient who developed hypersensitivity reactions to intravenous etoposide, but subsequently tolerated the administration of intravenous etoposide phosphate with no sequalae

Platelet Transfusion Practices in Critically Ill Children

Rationale: The epidemiology, indications, and outcomes for critically ill children transfused red blood cells or plasma have been described recently in large multicenter studies. This information is not known regarding platelet transfusions in this population. Objectives: To describe the epidemiology, indications, and outcomes of platelet transfusions among critically ill children. Methods: This point-prevalence study was conducted in 82 pediatric intensive care units in 16 countries during six assigned weeks. All children included received a platelet transfusion prescribed during one of the screening days. Measurements and Main Results: During six weeks of screening, 16,934 patients were eligible, of whom 559 received at least one platelet transfusion (prevalence 3.3%). The indications for transfusion included prophylaxis in 67%, minor bleeding in 21% and major bleeding in 12%. Thirty-four percent of prophylactic platelet transfusions were prescribed when the platelet count was ≥ 50 x 109 cells/L. The median (IQR) change in platelet count was 48 x 109 cells/L (17-82) for major bleeding, 42 x 109 cells/L (16-80) for prophylactic transfusions, 38 x 109 cells/L (17-72) for minor bleeding, and 25 x 109 cells/L (10-47) for prophylaxis in patients at risk of bleeding from a device. Overall mortality for all patients was 25%. Conclusions: The majority of platelet transfusions prescribed are given as prophylaxis to non-bleeding children and significant variation in platelet thresholds exists. Studies are needed to clarify appropriate indications, with a particular focus on prophylactic transfusions

Effects of ABO Matching of Platelet Transfusions in Critically Ill Children.

OBJECTIVES: To determine if transfusing ABO compatible platelets has a greater effect on incremental change in platelet count as compared to ABO incompatible platelets in critically ill children. DESIGN: Secondary analysis of a prospective, observational study. Transfusions were classified as either ABO compatible, major incompatibility, or minor incompatibility. The primary outcome was the incremental change in platelet count. Transfusion reactions were analyzed as a secondary outcome. SETTING: Eighty-two PICUs in 16 countries. PATIENTS: Children (3 d to 16 yr old) were enrolled if they received a platelet transfusion during one of the predefined screening weeks. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Five-hundred three children were enrolled and had complete ABO information for both donor and recipient, as well as laboratory data. Three-hundred forty-two (68%) received ABO-identical platelets, 133 (26%) received platelets with major incompatibility, and 28 (6%) received platelets with minor incompatibility. Age, weight, proportion with mechanical ventilation or underlying oncologic diagnosis did not differ between the groups. After adjustment for transfusion dose, there was no difference in the incremental change in platelet count between the groups; the median (interquartile range) change for ABO-identical transfusions was 28 × 10 cells/L (8-68 × 10 cells/L), for transfusions with major incompatibility 26 × 10 cells/L (7-74 × 10 cells/L), and for transfusions with minor incompatibility 54 × 10 cells/L (14-81 × 10 cells/L) (p = 0.37). No differences in count increment between the groups were noted for bleeding (p = 0.92) and nonbleeding patients (p = 0.29). There were also no differences observed between the groups for any transfusion reaction (p = 0.07). CONCLUSIONS: No differences were seen in the incremental change in platelet count nor in transfusion reactions when comparing major ABO incompatible platelet transfusions with ABO compatible transfusions in a large study of critically ill children. Studies in larger, prospectively enrolled cohorts should be performed to validate whether ABO matching for platelet transfusions in critically ill children is necessary

The crystal structure of human Rogdi provides insight into the causes of Kohlschutter-Tonz Syndrome

Kohlschutter-Tönz syndrome (KTS) is a rare autosomal-recessive disorder of childhood onset characterized by global developmental delay, spasticity, epilepsy, and amelogenesis imperfecta. Rogdi, an essential protein, is highly conserved across metazoans, and mutations in Rogdi are linked to KTS. However, how certain mutations in Rogdi abolish its physiological functions and cause KTS is not known. In this study, we determined the crystal structure of human Rogdi protein at atomic resolution. Rogdi forms a novel elongated curved structure comprising the ?? domain, a leucine-zipper-like four-helix bundle, and a characteristic ??-sheet domain. Within the ?? domain, the N-terminal H1 helix (residues 19-45) pairs with the C-terminal H6 helix (residues 252-287) in an antiparallel manner, indicating that the integrity of the four-helix bundle requires both N- and C-terminal residues. The crystal structure, in conjunction with biochemical data, indicates that the ?? domain might undergo a conformational change and provide a structural platform for protein-protein interactions. Disruption of the four-helix bundle by mutation results in significant destabilization of the structure. This study provides structural insights into how certain mutations in Rogdi affect its structure and cause KTS, which has important implications for the development of pharmaceutical agents against this debilitating neurological disease

Automated operant assessments of Huntington's Disease mouse models

Huntington’s disease (HD) presents clinically with a triad of motor, cognitive, and psychiatric symptoms. Cognitive symptoms often occur early within the disease progression, prior to the onset of motor symptoms, and they are significantly burdensome to people who are affected by HD. In order to determine the suitability of mouse models of HD in recapitulating the human condition, these models must be behaviorally tested and characterized. Operant behavioral testing offers an automated and objective method of behaviorally profiling motor, cognitive, and psychiatric dysfunction in HD mice. Furthermore, operant testing can also be employed to determine any behavioral changes observed after any associated interventions or experimental therapeutics. We here present an overview of the most commonly used operant behavioral tests to dissociate motor, cognitive, and psychiatric aspects of mouse models of HD

Increased Serum and Musculotendinous Fibrogenic Proteins following Persistent Low-Grade Inflammation in a Rat Model of Long-Term Upper Extremity Overuse.

We examined the relationship between grip strength declines and muscle-tendon responses induced by long-term performance of a high-repetition, low-force (HRLF) reaching task in rats. We hypothesized that grip strength declines would correlate with inflammation, fibrosis and degradation in flexor digitorum muscles and tendons. Grip strength declined after training, and further in weeks 18 and 24, in reach limbs of HRLF rats. Flexor digitorum tissues of reach limbs showed low-grade increases in inflammatory cytokines: IL-1β after training and in week 18, IL-1α in week 18, TNF-α and IL-6 after training and in week 24, and IL-10 in week 24, with greater increases in tendons than muscles. Similar cytokine increases were detected in serum with HRLF: IL-1α and IL-10 in week 18, and TNF-α and IL-6 in week 24. Grip strength correlated inversely with IL-6 in muscles, tendons and serum, and TNF-α in muscles and serum. Four fibrogenic proteins, TGFB1, CTGF, PDGFab and PDGFbb, and hydroxyproline, a marker of collagen synthesis, increased in serum in HRLF weeks 18 or 24, concomitant with epitendon thickening, increased muscle and tendon TGFB1 and CTGF. A collagenolytic gelatinase, MMP2, increased by week 18 in serum, tendons and muscles of HRLF rats. Grip strength correlated inversely with TGFB1 in muscles, tendons and serum; with CTGF-immunoreactive fibroblasts in tendons; and with MMP2 in tendons and serum. Thus, motor declines correlated with low-grade systemic and musculotendinous inflammation throughout task performance, and increased fibrogenic and degradative proteins with prolonged task performance. Serum TNF-α, IL-6, TGFB1, CTGF and MMP2 may serve as serum biomarkers of work-related musculoskeletal disorders, although further studies in humans are needed

Loss-of-Function Variants in HOPS Complex Genes VPS16 and VPS41 Cause Early Onset Dystonia Associated with Lysosomal Abnormalities.

OBJECTIVES: The majority of people with suspected genetic dystonia remain undiagnosed after maximal investigation, implying that a number of causative genes have not yet been recognized. We aimed to investigate this paucity of diagnoses. METHODS: We undertook weighted burden analysis of whole-exome sequencing (WES) data from 138 individuals with unresolved generalized dystonia of suspected genetic etiology, followed by additional case-finding from international databases, first for the gene implicated by the burden analysis (VPS16), and then for other functionally related genes. Electron microscopy was performed on patient-derived cells. RESULTS: Analysis revealed a significant burden for VPS16 (Fisher's exact test p value, 6.9 × 109 ). VPS16 encodes a subunit of the homotypic fusion and vacuole protein sorting (HOPS) complex, which plays a key role in autophagosome-lysosome fusion. A total of 18 individuals harboring heterozygous loss-of-function VPS16 variants, and one with a microdeletion, were identified. These individuals experienced early onset progressive dystonia with predominant cervical, bulbar, orofacial, and upper limb involvement. Some patients had a more complex phenotype with additional neuropsychiatric and/or developmental comorbidities. We also identified biallelic loss-of-function variants in VPS41, another HOPS-complex encoding gene, in an individual with infantile-onset generalized dystonia. Electron microscopy of patient-derived lymphocytes and fibroblasts from both patients with VPS16 and VPS41 showed vacuolar abnormalities suggestive of impaired lysosomal function. INTERPRETATION: Our study strongly supports a role for HOPS complex dysfunction in the pathogenesis of dystonia, although variants in different subunits display different phenotypic and inheritance characteristics. ANN NEUROL 2020;88:867-877

Immunosenescence and lymphomagenesis

One of the most important determinants of aging-related changes is a complex biological process emerged recently and called \u201cimmunosenescence\u201d. Immunosenescence refers to the inability of an aging immune system to produce an appropriate and effective response to challenge. This immune dysregulation may manifest as increased susceptibility to infection, cancer, autoimmune disease, and vaccine failure. At present, the relationship between immunosenescence and lymphoma in elderly patients is not defined in a satisfactory way. This review presents a brief overview of the interplay between aging, cancer and lymphoma, and the key topic of immunosenescence is addressed in the context of two main lymphoma groups, namely Non Hodgkin Lymphoma (NHL) and Hodgkin Lymphoma (HL). Epstein Barr Virus (EBV) plays a central role in the onset of neoplastic lymphoproliferation associated with immunological changes in aging, although the pathophysiology varies vastly among different disease entities. The interaction between immune dysfunction, immunosenescence and Epstein Barr Virus (EBV) infection appears to differ between NHL and HL, as well as between NHL subtypes

Gene Expression Profiles in Parkinson Disease Prefrontal Cortex Implicate FOXO1 and Genes under Its Transcriptional Regulation

Parkinson disease (PD) is a complex neurodegenerative disorder with largely unknown genetic mechanisms. While the degeneration of dopaminergic neurons in PD mainly takes place in the substantia nigra pars compacta (SN) region, other brain areas, including the prefrontal cortex, develop Lewy bodies, the neuropathological hallmark of PD. We generated and analyzed expression data from the prefrontal cortex Brodmann Area 9 (BA9) of 27 PD and 26 control samples using the 44K One-Color Agilent 60-mer Whole Human Genome Microarray. All samples were male, without significant Alzheimer disease pathology and with extensive pathological annotation available. 507 of the 39,122 analyzed expression probes were different between PD and control samples at false discovery rate (FDR) of 5%. One of the genes with significantly increased expression in PD was the forkhead box O1 (FOXO1) transcription factor. Notably, genes carrying the FoxO1 binding site were significantly enriched in the FDR–significant group of genes (177 genes covered by 189 probes), suggesting a role for FoxO1 upstream of the observed expression changes. Single-nucleotide polymorphisms (SNPs) selected from a recent meta-analysis of PD genome-wide association studies (GWAS) were successfully genotyped in 50 out of the 53 microarray brains, allowing a targeted expression–SNP (eSNP) analysis for 52 SNPs associated with PD affection at genome-wide significance and the 189 probes from FoxO1 regulated genes. A significant association was observed between a SNP in the cyclin G associated kinase (GAK) gene and a probe in the spermine oxidase (SMOX) gene. Further examination of the FOXO1 region in a meta-analysis of six available GWAS showed two SNPs significantly associated with age at onset of PD. These results implicate FOXO1 as a PD–relevant gene and warrant further functional analyses of its transcriptional regulatory mechanisms