Introduction: Similar to pediatric regimens, multiple doses of L-asparaginase (PEG-Asp) are being increasingly used in adults with newly diagnosed acute lymphoblastic leukemia (ALL) with promising results. One of the most common side effects of the drug in adults is high-grade hyperbilirubinemia and transaminitis. Despite being almost always reversible and may not recur, clinicians may still be reluctant to continue with PEG-Asp in patients with liver toxicity, losing the benefit from multiple doses of the drug. Case Report: We describe a case of adult ALL who developed PEG-Asp-related high grade liver toxicity. The rising hyperbilirubinemia and transaminitis rapidly and permanently reversed using the amino-acid derivative L-carnitine. This case goes in line with similar observations in animal models and humans. Conclusion:L-Carnitine may show therapeutic benefit in PEG-Asp-related hepatotoxicity and should be considered in clinical trials of the drug.

Tropomyosin is a component of thin filaments that constitute myofibrils, the contractile apparatus of striated muscles. In vertebrates, except for fish, four TPM genes TPM1, TPM2, TPM3, and TPM4 are known. In zebrafish, there are six TPM genes that include the paralogs of the TPM1 (TPM1-1 & TPM1-2), the paralogs of the TPM4 gene (TPM4-1 & TPM4-2), and the two single copy genes TPM2 and TPM3. In this study, we have identified, cloned, and sequenced the TPM1-1κ isoform of the TPM1-1 gene and also discovered a new isoform TPM1-2ν of the TPM1-2. Further, we have cloned and sequenced the sarcomeric isoform of the TPM4-2 gene designated as TPM4-2α. Using conventional RT-PCR, we have shown the expression of the sarcomeric isoforms of TPM1-1, TPM1-2, TPM2, TPM3, TPM4-1, and TPM4-2 in heart and skeletal muscles. By qRT-PCR using both relative expression as well as the absolute copy number, we have shown that TPM1-1α, TPM1-2α, and TPM1-2ν are expressed mostly in skeletal muscle; the level of expression of TPM1-1κ is significantly lower compared to TPM1-1α in skeletal muscle. In addition, both TPM4-1α and TPM4-2α are predominantly expressed in heart. 2D Western blot analyses using anti-TPM antibody followed by Mass Spectrometry of the proteins from the antibody-stained spots show that TPM1-1α and TPM3α are expressed in skeletal muscle whereas TPM4-1α and TPM3α are expressed in zebrafish heart. To the best of our knowledge, this is by far the most comprehensive analysis of tropomyosin expression in zebrafish, one of the most popular animal models for gene expression study.

In order to better understand the training and athletic activity of horses, we must have complete understanding of the isoform diversity of various myofibrillar protein genes like tropomyosin. Tropomyosin (TPM), a coiled-coil dimeric protein, is a component of thin filament in striated muscles. In mammals, four TPM genes (TPM1, TPM2, TPM3, and TPM4) generate a multitude of TPM isoforms via alternate splicing and/or using different promoters. Unfortunately, our knowledge of TPM isoform diversity in the horse is very limited. Hence, we undertook a comprehensive exploratory study of various TPM isoforms from horse heart and skeletal muscle. We have cloned and sequenced two sarcomeric isoforms of the TPM1 gene called TPM1α and TPM1κ, one sarcomeric isoform of the TPM2 and one of the TPM3 gene, TPM2α and TPM3α respectively. By qRT-PCR using both relative expression and copy number, we have shown that TPM1α expression compared to TPM1κ is very high in heart. On the other hand, the expression of TPM1α is higher in skeletal muscle compared to heart. Further, the expression of TPM2α and TPM3α are higher in skeletal muscle compared to heart. Using western blot analyses with CH1 monoclonal antibody we have shown the high expression levels of sarcomeric TPM proteins in cardiac and skeletal muscle. Due to the paucity of isoform specific antibodies we cannot specifically detect the expression of TPM1κ in horse striated muscle. To the best of our knowledge this is the very first report on the characterization of sarcmeric TPMs in horse striated muscle.

In mammals, tropomyosin is encoded by four known TPM genes (TPM1, TPM2, TPM3, and TPM4) each of which can generate a number of TPM isoforms via alternative splicing and/or using alternate promoters. In humans, the sarcomeric isoform(s) of each of the TPM genes, except for the TPM4, have been known for a long time. Recently, on the basis of computational analyses of the human genome sequence, the predicted sequence of TPM4α has been posted in GenBank. We designed primer-pairs for RT-PCR and showed the expression of the transcripts of TPM4α and a novel isoform TPM4δ in human heart and skeletal muscle. qRT-PCR shows that the relative expression of TPM4α and TPM4δ is higher in human cardiac muscle. Western blot analyses using CH1 monoclonal antibodies show the absence of the expression of TPM4δ protein (~28 kDa) in human heart muscle. 2D western blot analyses with the same antibody show the expression of at least nine distinct tropomyosin molecules with a mass ~32 kD and above in adult heart. By Mass spectrometry, we determined the amino acid sequences of the extracted proteins from these spots. Spot “G” reveals the putative expression of TPM4α along with TPM1α protein in human adult heart.

Background Rosai–Dorfman–Destombes disease (RDD) is a rare histiocytic disorder with heterogeneous clinical manifestations and rare neurologic involvement. The existing clinical literature about neurologic RDD has yet to be critically examined. Methods We performed a four-database English-language systematic literature search for cases of RDD neurohistiocytosis, excluding secondary literature. Individual patient data for neurologic symptoms, disease sites, treatments, and responses were captured. Responses to first-line and second-line surgical interventions, post-surgical radiotherapy, and systemic therapies were analyzed. Results Among 4769 articles yielded by literature search, 154 articles were fully reviewed, containing data on 224 patients with neurologic RDD. 128 (83.1%) articles were single case reports. 149 (66.5%) patients were male, 74 (33.5%) female, with a median age of 37.6 years (range 2–79). Presenting neurologic symptoms included headache (45.1%), focal neurological deficits (32.6%), visual symptoms (32.1%), and seizures (24.6%). RDD involvement was multifocal in 32 (14.3%) cases. First-line treatment involved resection in 200 (89.6%) patients, with subsequent progression in 52 (26%), including 41 (78.8%) with unifocal disease. No difference was observed in progression-free survival comparing post-operative radiotherapy to no radiotherapy following partial resection. Chemotherapy given alone as first-line treatment led to complete or partial response in 3/7(43%) patients. Second-line treatments led to complete or partial response in 18/37(37.5%) patients. Mutational data were reported on 10 patients (4.46%). Conclusions This review highlights the limited published data about neurologic RDD, which presents with varied symptomatology and outcome. Further study is needed about its mutational landscape, and more effective therapies are needed for recurrent and refractory disease.