Diamond Blackfan anemia treatment: past, present, and future

Despite significant improvements in our understanding of the pathophysiology of Diamond Blackfan anemia (DBA), there have been few advances in therapy. The cornerstones of treatment remain corticosteroids, chronic red blood cell transfusions, and hematopoietic stem cell transplantation, each of which is fraught with complications. In this article, we will review the history of therapies that have been offered to patients with DBA, summarize the current standard of care, including management of side effects, and discuss novel therapeutics that are being developed in the context of the research into the roles of ribosomal haplo-insufficiency and p53 activation in Diamond Blackfan anemia.     

Markedly disturbed sleep in medically refractory compared to controlled epilepsy - a clinical and polysomnography study

PurposeTo evaluate sleep disturbances or sleep related events and their characteristics among patients with medically refractory epilepsy, compared to those with controlled epilepsy.MethodsIn a prospective case-controlled study, patients of medically refractory and controlled epilepsy were recruited and history pertaining to epilepsy and sleep related events and Epworth sleepiness scores were recorded and all patients underwent over night polysomnography.ResultsAmong 40 patients, 20 with medically refractory (Group 1) and 20 with controlled epilepsy (Group 2) (median age 18, range 10–35 years), the self reported sleep parameters in Group 1 patients were found to be significantly different as compared to Group 2, in terms of the duration of night time sleep, day time sleep, day time nap frequency, total sleep hours per day, excessive daytime sleepiness (EDS)(45% vs. 15%) and average sleep hours over the week prior to polysomnography. On PSG, Group 1 patients showed significantly less total sleep time [340.4 min (147–673) vs. 450.3 min (330–570)] with delayed sleep latency and REM latency, poor sleep efficiency [80.45 (40.5–98.0) vs. 95.45 (88.4–99.7)] and frequent arousals and wake after sleep onset (WASO) compared to Group 2 patients. Four patients (20%) in Group 1 compared to none in Group 2 were found to have mild obstructive sleep apnea.ConclusionsOur results indicate that medically refractory epilepsy patients believe that they spend more time sleeping, in contrast to the documented shorter sleep duration on polysomnography. This difference between perceived and actual sleep seems, by their data, to arise mainly from sleep fragmentation, disturbed architecture and the interesting finding of associated sleep apnea among the medically refractory epilepsy patients.     

Indirect Magnetic Resonance Arthrography May Help Avoid Second Look Arthroscopy for Assessment of Healing After Bucket Handle Medial Meniscus Repairs: A Prospective Clinico-Radiological Observational Study

ObjectivesThe objectives were: (1) to analyze the MRI healing rates of bucket-handle meniscus repair; (2) to compare the accuracy of assessment of meniscus healing for conventional MRI and Indirect Magnetic Resonance Arthrography (IMRA); and (3) to identify patients who may require second-look arthroscopy after meniscus repair.MethodsThis is a prospective observational case series of thirty-seven patients with repaired bucket-handle medial meniscus tear with a minimum one year follow-up. Meniscus healing rates were assessed on direct MRI and IMRA using Henning’s criteria. At the same time, patients’ symptoms were evaluated according to Barrett’s criteria and functional outcomes were recorded using International Knee Documentation Committee (IKDC) score, Knee Osteoarthritis and Outcomes Score (KOOS) and Tegner–Lysholm scores. A further clinical review was performed 18 months after the imaging to assess the evolution of symptoms.ResultsAt a mean of 22.3 ± 7.8 months after the meniscus repair, 56.7% patients showed complete healing and 40.5% patients demonstrated incomplete repair healing on IMRA. 52% patients with complete healing and 40% patients with incomplete healing demonstrated meniscus symptoms. At the second clinical review, 19% patients with complete healing and 20% patients with incomplete healing had meniscus symptoms. There was no co-relation between symptoms, PROMs and healing on MRI.ConclusionIndirect MR arthrography offers distinct advantages over direct MRI for assessment of meniscus healing, especially in symptomatic patients. Patient-reported outcome measures and symptomatology are not co-related with the healing status of the meniscus and they resolve in the majority on longer follow-up. A more conservative approach guided by IMRA to assess meniscus healing will avoid early re-operations.     

Actinomycotic Endocarditis of the Eustachian Valve: A Rare Case and a Review of the Literature

Eustachian valve endocarditis caused by Actinomyces species is extremely rare. A literature review revealed only one reported case—caused by Actinomyces israelii in an intravenous drug abuser.Our patient, a 30-year-old woman who at first appeared to be in good health, presented with fever, a large mobile mass on the eustachian valve, and extensive intra-abdominal and pelvic masses that looked malignant. Histopathologic examination of tissue found in association with an intrauterine contraceptive device revealed filamentous, branching microorganisms consistent with Actinomyces turicensis. This patient was treated successfully with antibiotic agents.In addition to presenting a new case of a rare condition, we discuss cardiac actinomycotic infections in general and eustachian valve endocarditis in particular: its predisposing factors, clinical course, sequelae, and our approaches to its management.     

Logical Analysis of Data (LAD) model for the early diagnosis of acute ischemic stroke

Background  

Strokes are a leading cause of morbidity and the first cause of adult disability in the United States. Currently, no biomarkers are being used clinically to diagnose acute ischemic stroke. A diagnostic test using a blood sample from a patient would potentially be beneficial in treating the disease.     

Maintenance of the plasma cell pool is independent of memory B cells

Humoral memory to an antigen (Ag) is maintained for several decades in the form of memory B cells and serum Ab. In fact, plasma cells (PCs) that secrete Ab are known to be long-lived and could be solely responsible for maintaining the long-lived Ab titers. Alternatively, it has been proposed that the PC compartment is maintained for long periods by the differentiation of memory cells into long-lived PCs as a result of nonspecific stimulation. This model predicts accelerated decay of PC numbers in the absence of memory cells for the same Ag. To address this prediction, we have developed a mouse model system that combined the ability to deplete B cells with the ability to detect Ag-specific memory and PCs. After establishing an immune response, we depleted Ag-specific memory B cells with an anti-hCD20 mAb and determined the effect on the PC compartment over 16 weeks. Using a combination of surface markers, we demonstrated that memory B cells remained depleted over the course of the experiment. However, despite this absence of memory cells for an extended duration, PC numbers in spleen and bone marrow did not decline, which indicates that the PC compartment does not require a significant contribution from memory B cells for its maintenance and instead that PCs are sufficiently long-lived to maintain Ab titers over a long period without renewal. This observation settles an important controversy in B cell biology and has implications for the design of vaccines and for B cell depletion therapy in patients.     

Tannic acid prevents azidothymidine (AZT) induced hepatotoxicity and genotoxicity along with change in expression of PARG and histone H3 acetylation

Azidothymidine (AZT) is known to decrease HIV virus replication and is one of the most frequently prescribed antiretroviral drugs used for AIDS treatment. Dose-limiting toxicities are the major curse associated with AZT therapy. Recently, we have reported that tannic acid; a PARG inhibitor prevents cisplatin induced nephrotoxicity. The present work was conceived to study the effect of tannic acid on AZT induced hepatotoxicity and genotoxicity. AZT induces increase in plasma levels of ALT, AST and alkaline phosphatase along with increase in micronucleus (MN) count in peripheral blood. Suggesting, AZT is hepatotoxic and genotoxic to mice. Treatment of tannic acid protects AZT induced hepatotoxicity by decreasing the ALT, AST and alkaline phosphatase levels. It also significantly reduces the oxidative damage by preventing reduction in glutathione and decreasing the level of malondialdehyde in liver of AZT treated mice. In addition, tannic acid decreases the PARG expression, PARP cleavage and histone H3 acetylation in liver of AZT treated mice. Moreover, treatment of tannic acid also decreases MN count in peripheral blood, suggesting its anti-mutagenic effect. In light of these findings we suggest the potential role of tannic acid treatment in preventing AZT induced toxicity.     

Outcomes of patients with borderline resectable and resectable pancreatic adenocarcinoma treated with neoadjuvant three-week course chemoradiotherapy using capecitabine-based versus gemcitabine-based concurrent chemotherapy

BackgroundNeoadjuvant chemoradiotherapy can provide downstaging and improve margin negativity for borderline resectable and resectable pancreatic adenocarcinoma [(B)RPC]. Little is known about the relative efficacy of capecitabine (CAPE)-based vs. gemcitabine (GEM)-based 3-week chemoradiation (3WCRT) with 36 Gy in 15 fractions. This study aimed to compare the odds of achieving surgical resection, time to progression (TTP), and overall survival (OS) of patients treated with 3WCRT with concurrent CAPE versus GEM.MethodsA retrospective cohort study was conducted, examining medical records from a single center for patients with (B)RPC treated with 3WCRT between 1/2009–12/2020. Odd ratios (OR) of achieving surgical resection were estimated using logistic regression for univariable and multivariable analyses. Median TTP (mTTP) and median OS (mOS) were estimated using the Kaplan-Meier method. Cox proportional hazards analysis was conducted to estimate hazard ratios (HR) of progression and survival in univariable and multivariable analyses.ResultsThirty-one patients were included in the analysis. Twenty-two (71%) patients were treated with CAPE, while 9 (29%) were treated with GEM. All patients in the GEM group were borderline resectable, vs. 18 (82%) patients in the CAPE group, P=0.30. Nineteen (86%) patients in the CAPE group were treated with neoadjuvant FOLFIRINOX, vs. 4 (44%) patients in the GEM group, P=0.03. The CAPE group had higher odds of achieving surgical resection [OR =9.33; 95% confidence interval (CI): 1.50–58.20]. Adjusting for covariates, the odds of achieving surgical resection were still statistically higher in the CAPE group vs. the GEM group (OR =25.34; 95% CI: 1.14–563.72). The CAPE group had superior mTTP compared to the GEM group (15.4 months, 95% CI: 4.9–71.1 vs. 4.0 months, 95% CI: 0.4–14.5; P=0.01), corresponding to a hazard ratio of 0.33 (95% CI: 0.14–0.81). Adjusting for covariates this effect persisted; the adjusted hazard ratio (AHR) for progression was 0.24 (95% CI: 0.08–0.77). Cox proportional hazards analysis also demonstrated that the CAPE group had superior OS compared to the GEM group in unadjusted (HR =0.13; 95% CI: 0.04–0.40) and adjusted models (HR =0.13, 95% CI: 0.03–0.52).ConclusionsFor neoadjuvant 3WCRT, this hypothesis-generating study suggests concurrent CAPE may be a more effective radiosensitizer than GEM for patients with (B)RPC.