DAO-9 (2,5-di(4-aryloylaryloxymethyl)-1,3,4-oxadiazole) exhibits p53 induced apoptogenesis through caspase-3 mediated endonuclease activity in murine carcinoma

One of the main strategies to inhibit the tumor growth is to promote the biochemical events leading to DNA degradation, which would eventually culminate in apoptosis. We have earlier reported that the 2,5-di(4-aryloylaryloxymethyl)-1,3,4-oxadiazole(DAO-9) possessed anti-cancer activity. To address the exact molecular mechanism underlying anti-cancer property, present study focused on evaluating the anti-tumor effect of the DAO-9 on murine ascites carcinoma cells using various in vivo and in vitro assays. The in vivo assays implicated a strong regression in tumor growth of ascites carcinoma after treatment which is due to apoptogenic efficacy as assessed through structural morphology of EAC cells by Giemsa, Acridine orange, Annexin V staining and FACS analysis. Nucleosomal DNA fragmentation induced by DAO-9 is due to activation of caspase-3 mediated DNAse as verified by endonuclease assays and immunoblot analysis. The caspase-3 activation mechanism is by induction of intrinsic cascade signaling molecules, such as p53, Bax, Bad and cytochrome c (cyt c) expression as verified by western blot. The results concluded that the tumor inhibiting activity of DAO-9 is due to activation of the apoptotic signaling cascade, which could be translated into targeted anti-cancer drug in the near future.     

Licorice‐Induced Severe Hypokalemia with Recurrent Torsade de Pointes

A 38‐year‐old obese woman presented with recurrent polymorphic ventricular tachycardia secondary to persistent hypokalemia necessitating more than 40 DC shocks. All endocrine investigations for hypokalemia were negative with impression of “mysterious hypokalemia.” On repeated inquiry, a hidden history of licorice use was elicited causing persistent hypokalemia. The case highlights a life threatening complication of licorice use. In addition, it reiterates the importance of repeated history taking in a patient with undiagnosed hypokalemia and torsade de pointes which avoided a device therapy.     

Analysis of end-of-life content in critical care nursing textbooks

Nurses have identified a need for improving their knowledge and skills in providing end-of-life care. Critical care nursing textbooks can serve as an important source of information on end-of-life care for critical care nurses. Hence, an analysis of end-of-life content in 14 critical care nursing textbooks was conducted. Critical care nursing textbooks used for review were published in 1995 or later and identified from the libraries at the University of Wisconsin-Madison and Brigham Young University. The end-of-life content areas identified by the American Association of Colleges of Nursing (AACN), under which the AACN end-of-life competencies for undergraduate nursing students can be taught, were used as a framework for assessing the presence or absence of end-of-life content in the textbooks. When end-of-life content was present, two reviewers judged whether the information was helpful. Four additional end-of-life content areas were identified in some textbooks during the study, and reviewers also judged whether these were helpful. None of the textbooks had end-of-life content in all the content areas used for the analysis. Three textbooks did not contain any end-of-life content.     

Tuberculous ulcer of tongue with oral complications of oral antituberculosis therapy.

Tuberculosis (TB) is an infectious disease affecting humans of all ages in all parts of the world. The dentist plays an important role in the identification and control of this condition by early recognition of oral lesions that may precede the detection of the pulmonary form. Occurrence of increased incidence of mycobacterial infections as a part of the spectrum of AIDS only emphasizes the importance of early diagnosis. A case of a tuberculous ulcer on the tongue along with oral ulcerations, which occurred as a consequence of oral antituberculosis therapy (ATT), is presented. Such complications have rarely been reported in the literature and the management of these is described herein. The tuberculous ulcer healed uneventfully in five weeks after institution of ATT and the other ATT-induced ulcers healed after a week of topical anesthetic application. The clinical presentations, differential diagnoses to be considered, and management of such oral manifestations is discussed. The occupational risk posed by TB to the dentist and appropriate precautions to be observed have been highlighted.     

Akt deficiency impairs normal cell proliferation and suppresses oncogenesis in a p53-independent and mTORC1-dependent manner

Akt contributes to tumorigenesis by inhibiting apoptosis. Here we establish that Akt is required for normal cell proliferation and susceptibility to oncogenesis independently of its antiapoptotic activity. Partial ablation of Akt activity by deleting Akt1 inhibits cell proliferation and oncogenesis. These effects are compounded by deleting both Akt1 and Akt2. In vivo, Akt1 null mice are resistant to MMTV-v-H-Ras-induced tumors and to skin carcinogenesis. Thus, partial ablation of Akt activity is sufficient to suppress tumorigenesis in vitro and in vivo. The effect of Akt deficiency on cell proliferation and oncogenesis is p53 independent but mTORC1 dependent. Surprisingly, upon mTORC1 hyperactivation, the reduction in Akt activity does not impair cell proliferation and susceptibility to oncogenic transformation; thus, Akt may mediate these processes exclusively via mTORC1.     

The Zebrafish fade out mutant: a novel genetic model for Hermansky-Pudlak syndrome

PURPOSE: To characterize retinal morphology and visual system function in the zebrafish mutant fade out (fad) and to establish the mutant as a lower vertebrate model for Hermansky-Pudlak syndrome (HPS). METHODS: Retinal morphology of fad larvae was examined between 3 and 9 days postfertilization (dpf) by standard histology, transmission electron microscopy, and immunohistochemistry examination. Apoptotic cells were visualized by TdT-mediated dUTP nick-end labeling (TUNEL) staining. Visual system function was probed by electroretinography and behavioral assessment by optokinetic response measurements. Blood clotting was evaluated by time to occlusion testing of blood vessels as an arterial thrombosis assay. The chromosomal location of fad was determined by simple sequence-length polymorphism mapping. Genomic fragments of candidate genes were cloned by standard molecular techniques and mapped to the zebrafish genome by radiation hybrid mapping. RESULTS: Mutant fad larvae are hypopigmented and show structural defects in the outer retina. Melanosomes of these larvae in the retinal pigment epithelium are hypopigmented, generally smaller, and progressively reduced in number compared to nonmutant larvae. Progressive microvilli protrusions into the photoreceptor cell layer are not detectable, and photoreceptor outer segments get shorter and are misaligned. Photoreceptors subsequently undergo apoptosis, with a peak of cell death at 6 dpf. Electrical responses of the retina and visual performance are severely reduced. Blood clotting is prolonged in mutant fad larvae. Genomic mapping of fad reveals distinct genomic positions of the mutant gene from known human HPS genes. CONCLUSIONS: The fad mutant shows syndromic defects in pigmentation, outer retinal structure and function, and blood clotting. This syndrome is characteristic of Hermansky-Pudlak syndrome (HPS), making fad a novel genetic model of HPS. The gene does not cosegregate with the known human HPS genes, suggesting a novel molecular cause of HPS.     

Extraperitoneal approach for closure of epithelized enterocutaneous fistulas following late removal of jejunostomy tube

Epithelized enterocutaneous fistulas will form if feeding jejunostomy tubes are kept for a lengthy period. Such fistulas may not close spontaneously, and thus surgical closure will be necessary. An intraperitoneal surgical approach is most commonly used but is often difficult and a major undertaking. A novel, simple, and safe technique to close such enterocutaneous fistulas extraperitoneally under local anesthesia is devised.