Knockdown of leptin A expression dramatically alters zebrafish development

Using morpholino antisense oligonucleotide (MO) technology, we blocked leptin A or leptin receptor expression in embryonic zebrafish, and analyzed consequences of leptin A knock-down on fish development. Embryos injected with leptin A or leptin receptor MOs (leptin A or leptin receptor morphants) had smaller bodies and eyes, undeveloped inner ear, enlarged pericardial cavity, curved body and/or tail and larger yolk compared to control embryos of the same stages. The defects persisted in 6-9days old larvae. We found that blocking leptin A function had little effect on the development of early brain (1day old), but differentiation of both the morphant dorsal brain and retinal cells was severely disrupted in older (2days old) embryos. Despite the enlarged pericardial cavity, differentiation of cardiac cells appeared to be similar to control embryos. Formation of the morphants' inner ear is also severely disrupted, which corroborates existing reports of leptin receptor expression in inner ear of both zebrafish and mammals. Co-injection of leptin A MO and recombinant leptin results in partial rescue of the wild-type phenotype. Our results suggest that leptin A plays distinct roles in zebrafish development.     

Patient Education and Engagement through Social Media

This review addresses the demographics of social media users and their relative health literacy. Means of overcoming health inequities via social media and the role of social media in patient education and engagement are explored. This review discusses forms of appropriate patient engagement, including the pitfalls of social media use.     

Mortality in patients with microvascular disease

Patients with chest pain/ischemic cardiac disease and normal coronary arteriography are thought to have a benign prognosis despite diminished quality of life. Many patients with hypertension fall into this group, at least in the early stage of their disease. Whether abnormalities in coronary flow reserve in these patients are associated with increased morbidity and mortality is unknown. One hundred sixty-eight patients with chest pain/ischemic cardiac disease and normal coronary angiograms who underwent invasive measures of coronary flow reserve were followed longitudinally. Mortality and quality of life were ascertained by query of the national death index and telephone administration of standardized questionnaires. Patient follow-up occurred at a mean of 8.5 years. In the abnormal coronary flow reserve group, 12 deaths (20%) were documented in 60 patients compared with eight out of 108 patients (7%; p=0.016) with normal coronary flow reserve. Coronary flow reserve did not predict impairment in functional health status in long-term follow-up. Thus, invasive measures of coronary flow reserve in patients with chest pain/ischemic cardiac disease and normal coronary angiograms predicted increased mortality. Surviving patients with chest pain/ischemic cardiac disease and normal coronary angiograms have significant morbidity.     

Non Calcifying Type of Calcifying Epithelial Odontogenic Tumor: An Unusual Case Report with Special Emphasis on Histogenesis of Calcifications

Calcifying epithelial odontogenic tumour also known as Pindborg tumour, is a rare benign odontogenic neoplasm of locally aggressive behavior. It is thought to arise from the epithelial element of the enamel origin which are reminiscent of the cells in the stratum intermedium layer of enamel organ in tooth development. The tumour is characterized histologically by the presence of polygonal epithelial cells, calcifications and eosinophilic deposits resembling amyloid. Non-calcifying epithelial odontogenic tumours are very rare and unusual. Only five cases have been reported in the English literature till date. Here, we present an additional case of non calcifying type along with a review of previously reported cases. It has a much lower recurrence and malignant transformation rate.     

Arrhythmias in neurofibromatosis. A case report and review of the literature

Patients with neurofibromatosis have a higher incidence of anatomic cardiac abnormalities. However, there is little data regarding incidence of arrhythmias in this population. It is known that these patients have a higher mortality than the normal population, and it is possible that some deaths may be due to preventable causes such as cardiac arrhythmias. We report a patient with neurofibromatosis who was treated for a refractory seizure disorder for 8 years. However, video/EEG monitoring demonstrated that the patient had recurrent syncopal seizures secondary to sinus node dysfunction. Complete resolution of symptoms occurred after a permanent pacemaker implantation. We believe this is the first reported case of sinus node dysfunction associated with neurofibromatosis.     

Differential requirement of signal transducer and activator of transcription-4 (Stat4) and Stat6 in a thyrotropin receptor-289-adenovirus-induced model of Graves' hyperthyroidism

T helper type 1 (Th1) and Th2 cells have critical roles in the development of cell-mediated and humoral immune responses, respectively. This division of function predicts that Th1 cells mediate inflammatory diseases and Th2 cells promote antibody (Ab)-mediated autoimmunity. Our previous studies using HEK-293 cells expressing the extracellular domain of the TSH receptor (TSHR) showed that Stat4-/- mice, which lack Th1 cells, are susceptible, whereas Stat6-/- mice, which lack Th2 cells, are resistant to the induction of Graves' hyperthyroidism. To investigate the role of Stat4 and Stat6 genes in other murine models of hyperthyroidism, we injected wild-type BALB/c, Stat4-/-, and Stat6-/- mice with an adenovirus expressing amino acid residues 1-289 of TSHR (TSHR-289-ad or 289-ad). The viral system induces a much stronger immune response with much more rapid onset of disease. Our results showed that 56% of wild-type, 75% of Stat4-/-, and 39% of Stat6-/- mice developed hyperthyroidism. Hyperthyroid mice exhibited thyroid stimulatory Abs. The Stat4-/- mice developed a higher incidence and greater severity of hyperthyroidism compared with wild-type and Stat6-/- mice. BALB/c and Stat4-/- mice showed significantly higher TSHR Abs of the IgG1 subclass and IL-4 compared with Stat6-/- mice. In contrast, Stat6-/- mice had predominantly the IgG2a subclass of TSHR Ab and produced significantly higher amounts of IFN-gamma than BALB/c and Stat4-/- mice. All hyperthyroid mice showed enlarged thyroid glands with hyperactivity. These results suggest that in the TSHR-289-ad model, the Th2 cells are more efficient in mediating disease, but in the absence of Th2 cells, Th1 cells may still initiate a reduced incidence of Graves' hyperthyroidism.     

Vital roles of mTOR complex 2 in Notch-driven thymocyte differentiation and leukemia

Notch plays critical roles in both cell fate decisions and tumorigenesis. Notch receptor engagement initiates signaling cascades that include a phosphatidylinositol 3-kinase/target of rapamycin (TOR) pathway. Mammalian TOR (mTOR) participates in two distinct biochemical complexes, mTORC1 and mTORC2, and the relationship between mTORC2 and physiological outcomes dependent on Notch signaling is unknown. In this study, we report contributions of mTORC2 to thymic T-cell acute lymphoblastic leukemia (T-ALL) driven by Notch. Conditional deletion of Rictor, an essential component of mTORC2, impaired Notch-driven proliferation and differentiation of pre-T cells. Furthermore, NF-κB activity depended on the integrity of mTORC2 in thymocytes. Active Akt restored NF-κB activation, a normal rate of proliferation, and differentiation of Rictor-deficient pre-T cells. Strikingly, mTORC2 depletion lowered CCR7 expression in thymocytes and leukemic cells, accompanied by decreased tissue invasion and delayed mortality in T-ALL driven by Notch. Collectively, these findings reveal roles for mTORC2 in promoting thymic T cell development and T-ALL and indicate that mTORC2 is crucial for Notch signaling to regulate Akt and NF-κB.