A multi-institutional comparison of mitoxantrone,etoposide, and cytarabine vs high-dose cytarabine and mitoxantrone therapy for patients with relapsed or refractory acute myeloid leukemia

Relapsed or refractory acute myeloid leukemia (R/R AML) has a poor prognosis and is best treated with salvage chemotherapy as a bridge to allogeneic stem cell transplant (alloSCT). However, the optimal salvage therapy remains unknown. Here we compared two salvage regimens; mitoxantrone, etoposide, and cytarabine (MEC) and mitoxantrone and high-dose Ara-C (Ara-C couplets). We analyzed 155 patients treated at three academic institutions between 1998 and 2017; 87 patients received MEC and 68 received Ara-C couplets. The primary endpoint was overall response (OR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of hospitalization, hematologic and nonhematologic toxicities, and success in proceeding to alloSCT. Baseline characteristics of the cohorts were well matched, though patients receiving Ara-C couplets had more co-morbidities (48.5% vs 33%; P = .07). OR was achieved in 43.7% of MEC and 54.4% of Ara-C couplets patients (P = .10). Ara-C couplets patients also trended towards a longer OS and PFS, more frequently proceeded to alloSCT (31% vs 54.4%; P = .003), and experienced less febrile neutropenia (94% vs 72%; P < .001) and grade 3/4 gastrointestinal toxicities (17.2% vs 2.94%; P = .005). No significant differences in other toxicities or median duration of hospitalization were noted. This is the first multi-institutional study directly comparing these regimens in a racially diverse population of R/R AML patients. Although these regimens have equivalent efficacy in terms of achieving OR, Ara-C couplets use is associated with significant reductions in toxicities, suggesting it should be used more frequently in these patients.     

Osteocyte‐Secreted Wnt Signaling Inhibitor Sclerostin Contributes to Beige Adipogenesis in Peripheral Fat Depots

Cells of the osteoblast lineage are increasingly identified as participants in whole‐body metabolism by primarily targeting pancreatic insulin secretion or consuming energy. Osteocytes, the most abundant bone cells, secrete a Wnt‐signaling inhibitor called sclerostin. Here we examined three mouse models expressing high sclerostin levels, achieved through constitutive or inducible loss of the stimulatory subunit of G‐proteins (Gsα in mature osteoblasts and/or osteocytes). These mice showed progressive loss of white adipose tissue (WAT) with tendency toward increased energy expenditure but no changes in glucose or insulin metabolism. Interestingly beige adipocytes were increased extensively in both gonadal and inguinal WAT and had reduced canonical β‐catenin signaling. To determine if sclerostin directly contributes to the increased beige adipogenesis, we engineered an osteocytic cell line lacking Gsα which has high sclerostin secretion. Conditioned media from these cells significantly increased expression of UCP1 in primary adipocytes, and this effect was partially reduced after depletion of sclerostin from the conditioned media. Similarly, treatment of Gsα‐deficient animals with sclerostin‐neutralizing antibody partially reduced the increased UCP1 expression in WAT. Moreover, direct treatment of sclerostin to wild‐type mice significantly increased UCP1 expression in WAT. These results show that osteocytes and/or osteoblasts secrete factors regulating beige adipogenesis, at least in part, through the Wnt‐signaling inhibitor sclerostin. Further studies are needed to assess metabolic effects of sclerostin on adipocytes and other metabolic tissues. © 2016 American Society for Bone and Mineral Research.     

Survival estimates and risk factors for failure of palatal and buccal mini-implants

ObjectivesThe primary objective was to compare the success and survival rates of palatal and buccal mini-implants for different locations and treatment requirements. The secondary objective was to evaluate risk factors influencing the survival of mini-implants.Materials and MethodsIn this retrospective cohort, records of 127 orthodontic patients with 257 mini-implants were included after imposing inclusion/exclusion criteria. Along with the implant failure data, factors such as age, sex, transverse location, anteroposterior location, and purpose of mini-implants were recorded. Kaplan–Meier survival analysis was used to draw the curves and a Nathan Mantel-David Cox test to compare variables.ResultsThe failure rate of palatal mini-implants was 8.5%, whereas the failure rate for buccal shelf mini-implants was 68.7% (P < .0001). A significant difference was that the survival rates of palatal mini-implants were dependent on the purpose of the mini-implants and, for the buccal mini-implants, they were dependent on the skeletal malocclusion and location type of mini-implants (P < .05).ConclusionsThe overall survival rate of palatal mini-implants was high, at 91.5%. Of the buccal mini-implants, inter-radicular mini-implants had the highest survival rate for 12 (75.5%) and 24 (71.9%) months, while buccal shelf mini-implants had the lowest success and survival rates for 12 (31.3%) and 24 (20.8%) months. Class III malocclusion had the lowest survival rate for the buccal mini-implants (65.3% and 54.2%) for 12 and 24 months.     

In vitro antiviral activity of neem (Azardirachta indica L.) bark extract against herpes simplex virus type‐1 infection

Herpes simplex virus type 1 (HSV‐1) causes significant health problems from periodical skin and corneal lesions to encephalitis. We report here that an aqueous extract preparation from the barks of neem plant Azardirachta indica acts as a potent entry inhibitor against HSV‐1 infection into natural target cells. The neem bark extract (NBE) significantly blocked HSV‐1 entry into cells at concentrations ranging from 50 to 100 μg/ml. The blocking activity of NBE was observed when the extract was pre‐incubated with the virus but not with the target cells, suggesting a direct antiHSV‐1 property of the neem bark. Further, virions treated with NBE failed to bind the cells which implicate a role of NBE as an attachment step blocker. Cells treated with NBE also inhibited HSV‐1 glycoprotein‐mediated cell–cell fusion and polykaryocytes formation suggesting an additional role of NBE at the viral fusion step. These findings open a potential new avenue for the development of NBE as a novel antiherpetic microbicide. Copyright © 2009 John Wiley & Sons, Ltd.     

Potential for therapeutic targeting of tumor stem cells

Recent developments in isolation and characterization of tumor stem cells (TSCs) have opened new possibilities for developing TSC-targeted therapies. Extensive efforts have been made to ascertain markers of TSCs, including cell surface, enzymatic, gene expression profile, and functional markers. These markers and the technologies used to identify and isolate TSCs are discussed in this review. TSC characteristics, such as quiescence, multidrug resistance, enhanced DNA repair ability, and anti-apoptotic mechanisms, and various features of the in vivo niche, which may make them resistant to conventional therapy, are also discussed here. The increasing understanding of aberrantly expressed molecules and signaling pathways in TSCs may provide the foundation for design of therapeutic strategies for TSC ablation. ( Cancer Sci 2009)     

Ophthalmic Complication Following Posterior Superior Alveolar Nerve Block for Tooth Extraction! A Rare Occurrence

One of the most commonly asked question by a patient who comes for extraction especially in the rural areas is whether the procedure will cause problems to the eye!! In reality however, ophthalmic complications following routine maxillary molar extractions are practically unheard of. When they occur they can be extremely unnerving not just to the patient but also to the surgeon. Patients generally panic which makes it tougher for the clinician to assess the situation. We present a case of a 26 year old female patient developing ophthalmic complication following local anesthesia administration during extraction of upper left maxillary third molar. In this article, ophthalmic complications arising from posterior superior alveolar nerve block are discussed and management guidelines are highlighted.     

Virostatic potential of micro-nano filopodia-like ZnO structures against herpes simplex virus-1

Herpes simplex virus type-1 (HSV-1) entry into target cell is initiated by the ionic interactions between positively charged viral envelop glycoproteins and a negatively charged cell surface heparan sulfate (HS). This first step involves the induction of HS-rich filopodia-like structures on the cell surface that facilitate viral transport during cell entry. Targeting this initial first step in HSV-1 pathogenesis, we generated different zinc oxide (ZnO) micro-nano structures (MNSs) that were capped with multiple nanoscopic spikes mimicking cell induced filopodia. These MNSs were predicted to target the virus to compete for its binding to cellular HS through their partially negatively charged oxygen vacancies on their nanoscopic spikes, to affect viral entry and subsequent spread. Our results demonstrate that the partially negatively charged ZnO-MNSs efficiently trap the virions via a novel virostatic mechanism rendering them unable to enter into human corneal fibroblasts - a natural target cell for HSV-1 infection. The anti-HSV-1 activity of ZnO MNSs was drastically enhanced after creating additional oxygen vacancies under UV-light illumination. Our results provide a novel insight into the significance of ZnO MNSs as the potent HSV-1 inhibitor and rationalize their development as a novel topical agent for the prevention of HSV-1 infection.     

Effect of complicated ocular surgery in stress-related parameters: A novel outlook into surgeon’s health

Purpose:To assess the stress-related physiological parameters of ophthalmic surgeons during complicated cataract surgery and compare them with uncomplicated routine cataract surgery.Methods:In this cross-sectional observational study, 110 patients of various types of cataract were divided into two groups: Group 1 included 55 patients with simple cataract (Grade ≤3) with no ocular or systemic comorbidities, whereas Group 2 included 55 patients with complicated cataracts (Grade >3) and ocular/systemic comorbidities. All patients underwent phacoemulsification with intraocular lens implantation in the right eye only. The outcome measures were systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), heart rate (HR), and saturation of peripheral oxygen (SpO₂).Results:The average SBP, DBP, MAP, and HR were significantly higher in the surgeon operating Group 2 (complicated cataract) compared with Group 1 (uncomplicated cataract; P < 0.05). The average SBP of the surgeon while operating Group 1 patients preoperatively and postoperatively was 125.42 ± 2.49 mmHg and 122.45 ± 2.10 mmHg, respectively, whereas in Group 2, the average SBP of the surgeon taken preoperatively and postoperatively was 145.98 ± 3.80 mmHg and 137.44 ± 3.45 mmHg, respectively (P < 0.05). The surgeon’s SpO₂ showed no significant difference between the two groups.Conclusion:There is a significant level of increase in stress-related parameters of operating surgeons while doing complicated cataract surgery.     

Limb lead interchange in thorough QT/QTc studies

The investigators analyzed 85,133 electrocardiograms (ECGs) recorded in 484 subjects from 5 thorough QT/QTc studies (3 using Holter devices, 2 using 12-lead ECGs) for inadvertent limb lead interchanges using a dedicated quality control process in a central ECG laboratory. Limb lead interchanges were present in 2919 (3.4%) ECGs in 17.9% of subjects and were more frequent with Holter devices (7.5% vs 0.8%, P < .0001), where leads remain connected for prolonged periods, affecting data from several time points. Left arm-left leg interchange was seen in 54% of 12-lead ECGs and right arm-left arm interchange in 38%. The ECG device itself could identify 21.7% of interchanges, whereas experienced readers blinded to subject and visit identified 79% of interchanges; 21% of interchanges were identified only during the quality control process. If correctly identified, QT measurement could be performed in a precordial lead. If undiagnosed, incorrect QT interval measurements and morphological diagnosis may confound results.