Summary:Electrocardiographic studies in patients with sickle-cell anemia have been performed during the normal resting state with routine twelve-lead ECGs. We studied 30 patients with sickle-cell disease in acute crisis with 24-hour continuous electrocardiographic monitoring. The standard ECG demonstrated a high incidence of abnormalities, but only three patients had arrhythmias. These findings contrasted sharply with the results of continuous monitoring, during which arrhythmias were detected in 24 of 30 patients. They were fairly evenly split between atrial (60%) and ventricular (67%). Nine of the patients had "complex arrhythmias" including two with episodes of ventricular tachycardia. Seventeen patients subsequently underwent equilibrium gated-blood pool scans. Eight patients had abnormal contractility and tended to have more arrhythmias on monitoring than those with normal contractility. Thus, continuous electrocardiographic monitoring of sickle-cell patients during crisis revealed a higher incidence of arrhythmias than previously thought.

BackgroundAutoimmune hemolytic anemia (AIHA) is a less recognized, potentially fatal condition. There is a scarcity of data on clinicoserological characteristics and response to therapy concerning this disease from South India.MethodsData for 33 patients with primary AIHA recorded from July 2009 to June 2015 were retrospectively analyzed for clinical presentation, response to frontline therapy, durability of response, time to next treatment (TTNT), and response to second-line agents.ResultsThe median follow-up period was 50 months. Among 33 patients, 48% of the cases were warm autoimmune hemolytic anemia (WAIHA), 46% were cold agglutinin disease (CAD), and 6% were atypical. Three-fourth of patients had severe anemia (<8 g/dL hemoglobin [Hb]) at onset; younger patients (age <40 yr) had more severe anemia. All of the patients who required treatment received oral prednisolone at 1.5 mg/kg/d as a frontline therapy, and the response rate was 90% (62% complete response [CR] and 28% partial response [PR]). The overall response to corticosteroids in WAIHA and CAD was 87% and 92%, respectively. The median corticosteroid duration was 14 months, and 50% of the patients required second-line agents. Fourteen patients received azathioprine as a second-line agent, and 11 of these patients responded well, with half of them not requiring a third agent. Four patients developed severe infections (pneumonia, sepsis, and soft tissue abscess) and two had life-threatening venous thrombosis. One case of death was recorded.ConclusionAIHA is a heterogeneous disease that requires care by physicians experienced in treating these patients.

Deregulated protein kinases play a very critical role in tumorigenesis, metastasis, and drug resistance of cancer. Although molecularly targeted small molecule kinase inhibitors (SMI) are effective against many types of cancer, point mutations in the kinase domain impart drug resistance, a major challenge in the clinic. A classic example is chronic myeloid leukemia (CML) caused by BCR-ABL fusion protein, wherein a BCR-ABL kinase inhibitor, imatinib (IM), was highly successful in the early chronic phase of the disease, but failed in the advanced stages due to amplification of oncogene or point mutations in the drug-binding site of kinase domain. Here, by identifying critical molecular pathways responsible for the drug-resistance in refractory CML patient samples and a model cell line, we have rationally designed an endogenous protein nanomedicine targeted to both cell surface receptors and aberrantly activated secondary kinase in the oncogenic network. Molecular diagnosis revealed that, in addition to point mutations and amplification of oncogenic BCR-ABL kinase, relapsed/refractory patients exhibited significant activation of STAT5 signaling with correlative overexpression of transferrin receptors (TfR) on the cell membrane. Accordingly, we have developed a human serum albumin (HSA) based nanomedicine, loaded with STAT5 inhibitor (sorafenib), and surface conjugated the same with holo-transferrin (Tf) ligands for TfR specific delivery. This dual-targeted "transferrin conjugated albumin bound sorafenib" nanomedicine (Tf-nAlb-Soraf), prepared using aqueous nanoprecipitation method, displayed uniform spherical morphology with average size of ∼150 nm and drug encapsulation efficiency of ∼74%. TfR specific uptake and enhanced antileukemic activity of the nanomedicine was found maximum in the most drug resistant patient sample having the highest level of STAT5 and TfR expression, thereby confirming the accuracy of our rational design and potential of dual-targeting approach. The nanomedicine induced downregulation of key survival pathways such as pSTAT5 and antiapoptotic protein MCL-1 was demonstrated using immunoblotting. This study reveals that, by implementing molecular diagnosis, personalized nanomedicines can be rationally designed and nanoengineered by imparting therapeutic functionality to endogenous proteins to overcome clinically important challenges like molecular drug resistance.

High-dose arabinoside cytarabine is used as an effective regimen for post-remission acute leukemia and refractory leukemia treatment. Most commonly used regimen is 3 g/m 2 IV over 1-3 h q12 h for a total of 8-12 doses. Major toxic effects associated with cytarabine are related to bone marrow, gastrointestinal tract, and nervous system. Acute cerebellar toxicity with ataxia and dysarthria is well-known adverse effect during high-dose cytarabine therapy. This case report describes about a patient with acute myeloid leukemia on high-dose cytarabine who developed ataxia and left-sided nystagmus as cerebellar toxicity. These symptoms persisted till 2 days after the termination of high-dose cytarabine the gradually improved with steroids. Patient's good response to methyl prednisolone illustrates immune-mediated mechanism of neurotoxicity.