Deoxypodophyllotoxin suppresses tumor vasculature in HUVECs by promoting cytoskeleton remodeling through LKB1-AMPK dependent Rho A activation

Angiogenesis plays a critical role in the growth and metastasis of tumors, which makes it an attractive target for anti-tumor drug development. Deoxypodophyllotoxin (DPT), a natural product isolated from Anthriscus sylvestris, inhibits cell proliferation and migration in various cancer cell types. Our previous studies indicate that DPT possesses both anti-angiogenic and vascular-disrupting activities. Although the RhoA/ RhoA kinase (ROCK) signaling pathway is implicated in DPT-stimulated cytoskeleton remodeling and tumor vasculature suppressing, the detailed mechanisms by which DPT mediates these effects are poorly understood. In the current study, we found that DPT promotes cytoskeleton remodeling in human umbilical vein endothelial cells (HUVECs) via stimulation of AMP-activated protein kinase (AMPK) and that this effect is abolished by either treatment with a selective AMPK inhibitor or knockdown. Moreover, the cellular levels of LKB1, a kinase upstream of AMPK, were enhanced following DPT exposure. DPT-induced activation of AMPK in tumor vasculature effect was also verified by transgenic zebrafish (VEGFR2:GFP), Matrigel plug assay, and xenograft model in nude mice. The present findings may lay the groundwork for a novel therapeutic approach in treating cancer.     

Acute hepatitis secondary to parenteral amiodarone does not preclude subsequent oral therapy

Amiodarone chlorhydrate is a diiodated benzofuran derivative used to treat cardiac rhythm abnormalities. Hepatotoxicity is a relatively uncommon side effect of amiodarone and symptomatic hepatic dysfunction occurs in less than 1% to 3% of patients taking amiodarone. We report here on an unusual case of amiodarone-induced hepatotoxicity. A 29 year old woman with normal liver function was given amiodarone intravenously to treat her atrial fibrillation. She developed acute toxic hepatitis after 24 h. The intravenous form of amiodarone was immediately avoided and replaced by the oral form, using conventional loading doses as soon as the deranged liver function tests had normalized, without recurrence of the hepatitis. These observations show that the occurrence of acute hepatic impairment with intravenous amiodarone does not necessarily preclude the use of this drug by mouth and the necessity of monitoring the hepatic function of patients treated with amiodarone.     

Maternal effect and familial aggregation in a type 2 diabetic Moroccan population

The aim of this study is to evaluate the degree of familial aggregation of type 2 diabetes mellitus in Morocco and to investigate transmission patterns of the disease and their relationships with patients' clinical profiles. Family history of diabetes and clinical data were collected from 232 unrelated type 2 diabetic Moroccan patients. Diabetes status was recorded for first degree (parents, siblings) and second degree relatives (aunts and uncles from both maternal and paternal sides). Among studied subjects, 50% reported at least one relative with diabetes and 24% had at least one parent with diabetes. Familial aggregation of type 2 diabetes was prominent and more important among first degree relatives than second degree relatives (P < 0.01). Moreover, diabetes was more frequent among mothers than fathers of probands (P = 0.02), but this maternal effect was not observed in second degree relatives. There are no significant differences in clinical and metabolic profiles between patients according to the transmission pattern of the disease. In conclusion, these results suggest familial aggregation and excess maternal transmission of type 2 diabetes in the Moroccan studied population.     

Plasma expansion by polyethylene-glycol-modified albumin

Systemic inflammatory response conditions are associated with capillary leak and haemodynamic compromise. Fluid resuscitation to reverse the ensuing hypovolaemia is, however, complicated by the decreased endothelium reflection coefficient to albumin and other colloids. We developed PEG-Alb (albumin covalently linked to polyethylene glycol) as a potential resuscitative agent. PEG was covalently linked to human albumin at multiple sites on the protein. The modified protein was heterogeneous when examined by SDS/PAGE, size-exclusion chromatography and SELDI-TOF MS (surface-enhanced laser-desorption ionization-time of flight MS). Based on size-exclusion chromatography and osmotic pressure data, the effective volume of PEG-Alb is increased 13- to 16-fold compared with unmodified albumin. In an LPS (lipopolysaccharide) model of shock, rats treated with PEG-Alb showed better blood pressure, lower Hct (haematocrit) consistent with haemodilution and less lung injury than rats treated with unmodified albumin or saline. In a CLP (caecal ligation and puncture) model of sepsis, PEG-Alb was more effective than albumin or saline in maintaining blood pressure and in decreasing Hct. When fluorescein-labelled PEG-Alb and Texas Red-labelled albumin were administered to rats with LPS- or CLP-induced shock, PEG-Alb was retained within blood vessels, whereas albumin extravasates into the interstitial space. Based on these data, PEG-Alb appears to be retained within blood vessels in models of capillary leak. PEG-Alb may ultimately be effective in the clinical treatment of shock associated with capillary leak.     

Disseminated blastomycosis

A 26-year-old veiled Saudi-Arabian woman presented with hemoptysis, and multiple nodules and abscesses. A skin biopsy specimen revealed yeast forms consistent with Blastomyces dermatitidis. Fungal cultures from bronchoscopy and skin specimens also grew B dermatitidis. She was treated with oral itraconazole (200 mg twice a day). Both lung and skin lesions showed improvement within 6 weeks.