Host-specific genetic variation of highly pathogenic avian influenza viruses (H5N1)

The complete genome sequences of two isolates A/chicken/Egypt/CL6/07 (CL6/07) and A/duck/Egypt/D2br10/07 (D2br10/07) of highly pathogenic avian influenza virus (HPAI) H5N1 isolated at the beginning of 2007 outbreak in Egypt were determined and compared with all Egyptian HPAI H5N1 sequences available in the GenBank. Sequence analysis utilizing the RNA from the original tissue homogenate showed amino acid substitutions in seven of the viral segments in both samples. Interestingly, these changes were different between the CL6/07 and D2br10/07 when compared to other Egyptian isolates. Moreover, phylogenetic analysis showed independent sub-clustering of the two viruses within the Egyptian sequences signifying a possible differential adaptation in the two hosts. Further, pre-amplification analysis of H5N1 might be necessary for accurate data interpretation and identification of distinct factor(s) influencing the evolution of the virus in different poultry species.     

Diagnostic implications of transcription factor Pax 2 protein and transmembrane enzyme complex carbonic anhydrase IX immunoreactivity in adult renal epithelial neoplasms

Pax 2, expressed by metanephric mesenchyme is vital for renal tubule formation and development. Carbonic anhydrase IX (CA IX) is implicated in cell proliferation, adhesion, and invasion. Data regarding expression in renal epithelial tumors other than clear cell renal cell carcinoma (RCC) are limited, conflicting, from tissue microarrays, and do not encompass the entire spectrum or novel uncommon variants. Conventional sections from 200 renal tumors comprising clear cell RCC (n=30), oncocytoma (n=17), papillary RCC (n=30), chromophobe RCC (n=50), urothelial carcinomas (n=30), collecting duct carcinomas (n=5), renal tumors with Xp11.2 translocation (n=15), tubulocystic carcinoma (n=19), and mucinous tubular spindle cell carcinoma (n=4) were immunostained for Pax 2 and CA IX. Clear cell RCC (28/30, 93%), oncocytoma (17/17, 100%), papillary RCC (16/30, 53%), and mucinous tubular spindle cell carcinoma (3/4, 75%) demonstrated nuclear immunoreactivity with Pax 2, whereas the other subtypes were nonreactive. Clear cell RCC (30/30, 100%), urothelial carcinoma (27/30, 90%), papillary RCC (17/30, 57%), and renal tumors with Xp11.2 translocation (6/15, 40%) exhibited membranous immunoreactivity with CA IX, whereas the other subtypes were nonreactive. This suggests potential diagnostic utility of Pax 2 in distinction of (i) oncocytoma (positive) from chromophobe RCC (negative), (ii) clear cell RCC and papillary RCC (positive) from renal tumors with Xp11.2 translocation (negative), and (iii) high-grade clear cell RCC (positive) from urothelial carcinoma (negative). CA IX expression has potential diagnostic implications including (i) clear cell RCC (positive) versus chromophobe RCC (negative) and (ii) urothelial carcinoma (positive) versus collecting duct carcinoma (negative). These antibodies may reliably discriminate between clinically significant subtypes of RCC with overlapping cytoarchitectural features.     

Persistent bacteraemia due to methicillin-resistant Staphylococcus aureus with reduced susceptibility to vancomycin in a patient with erythrodermic psoriasis

A 49-y-old male with erythrodermic psoriasis developed persistent bacteraemia for 3 months due to methicillin-resistant Staphylococcus aureus despite antimicrobial therapy. The skin was the likely focus. Three consecutive isolates from the blood and 1 from the nose were identical and had vancomycin MIC of 4 mg/l.     

Surgical treatment of bilateral aneurysmal coronary to pulmonary artery fistulas associated with severe atherosclerosis

A 39-year-old diabetic patient with an old inferior wall infarction presented with disabling angina pectoris, despite medical treatment. Coronary angiography showed severe triple-vessel coronary artery disease, and bilateral coronary to pulmonary fistulas originating from the right coronary artery and the left anterior descending coronary artery. Both coronary artery saphenous vein bypass grafting and ligation of the fistulas was performed.     

Wwox inactivation enhances mammary tumorigenesis

Breast cancer is the leading cause of cancer-related death in women worldwide. Expression of the WWOX tumor suppressor is absent or reduced in a large proportion of breast tumors suggesting that loss of WWOX may contribute to breast tumorigenesis. Wwox-deficient mice die by 3-4 weeks of age precluding adult tumor analysis. To evaluate the effect of WWOX-altered expression on mammary tumor formation, the Wwox-heterozygous allele was back crossed onto the C3H mammary tumor-susceptible genetic background (Wwox(C3H)+/-) and incidence of mammary tumor formation was evaluated. Although 50% of the female Wwox(C3H)+/- mice developed mammary carcinomas, only 7% of Wwox(C3H)+/+ mice did. Intriguingly, mammary tumors in Wwox(C3H)+/- mice frequently lost WWOX protein expression suggesting a genetic predisposition toward mammary tumorigenesis. Immunohistochemical staining of hormone receptors revealed loss of estrogen receptor-α (ER) and progesterone receptor in the majority of these tumors. In vitro, depletion of WWOX in MCF7 ER-positive cells led to reduced ER expression and reduced sensitivity to tamoxifen and estrogen treatment and was associated with enhanced survival and anchorage-independent growth. Finally, cDNA array analyses of murine normal mammary epithelial cells and mammary tumors identified 163 significantly downreguated and 129 upregulated genes in the tumors. The majority of differentially expressed genes were part of pathways involved in cellular movement, cell-to-cell signaling and interaction, cellular development, cellular growth and proliferation and cell death. These changes in gene expression of mouse mammary tumors in Wwox(C3H)+/- mice resemble, at least in part, human breast cancer development. Our findings demonstrate the critical role that the WWOX tumor suppressor gene has in preventing tumorigenesis in breast cancer.     

Synthesis of piperazino and morpholino derivatives of aryloxypropane with potential analgesic and possible antimigraine activities

Abstract  

Modeling studies demonstrate that aryl piperazines (I), aryloxyalkylamines (II), phenylalkykamines (III) and indolylalkylamines (VI) may interact at 5-HT receptors in a similar manner. Examination of these structures (I–VI) reveals that all possess an aromatic moiety and terminal amine binding sites (Glennon et al., J Med Chem 32(8):1921–1926, 1989). In the present investigation a new series of aryloxyalkylamines (4, 5, 8, and 9) was designed and synthesized, in which the aromatic moiety is a phenyl group substituted at the 2,3-, 2,4-, 2,5-, or 2,6-positions by halogens and the terminal amine is N-methylpiperazine, or morpholine. In addition, the alkyl side chain is ethyl, or substituted ethyl at the α- or β-carbon by a methyl group. The length of the alkyl chain that separates the terminal amine from the ether oxygen atom of the aryloxy group is of major importance, and two-carbon chain appears optimal. The structures of the new compounds were assessed by microanalyses, IR, and NMR. The analgesic activity of selected compounds was performed on experimental animals and proved to be in the range of 85–100% relative to aspirin.     

Blood Pressure-Lowering Response to Amlodipine as a Determinant of the Antioxidative Activity of Small, Dense HDL3

Background and Objective

High-density lipoproteins (HDLs) exert multiple antiatherogenic activities including protection of low-density lipoproteins (LDLs) from oxidative stress. Beneficial effects of calcium channel blockers on cardiovascular disease may in part be related to the reduction of oxidative stress, potentially enhancing the antioxidative activity (AOX) of HDLs. This study aimed to assess the effect of 1 month’s treatment with amlodipine on HDL AOX in hypertensive subjects.

Methods

This was a prospective trial of amlodipine 10 mg/day administered for 1 month in primary-care patients with hypertension (n = 28), 46% of whom were obese and 57% of whom displayed the metabolic syndrome. The main outcome measure was HDL AOX, assessed as the capacity of small, dense HDL3c particles to attenuate LDL oxidation induced in vitro by an azo initiator (AAPH).

Results

Mean (±SD) systolic (SBP) and diastolic (DBP) BP were reduced by amlodipine by 22.1mmHg (±13.2) and 10.4mmHg (±7.5), respectively (p<0.001). Body mass index, waist circumference, and plasma levels of triglycerides, cholesterol, and fasting blood glucose did not change significantly. Amlodipine treatment did not modify HDL3c AOX in the whole study population; changes in AOX were, however, positively correlated with SBP (r = 0.37, p = 0.05 for maximal diene concentration; r = 0.34, p = 0.08 for LDL oxidation rate). When the population was divided into two subgroups according to the BP response to amlodipine (change in SBP below or above the median), HDL3c AOX was significantly improved in hyperresponders (BP-lowering response >22/10 mmHg) as compared with hypo-responders (BP-lowering response <22/10mmHg: mean [± SD] change in the LDL oxidation rate in the presence of HDL3c, ?6.8% [± 11.2] vs +1.9% [±5.2], respectively, p = 0.04; maximal diene concentration, ?8.6% [±13.0] vs +1.9% [±8.2], respectively, p<0.05). By contrast, neither plasma concentrations of oxidized LDL, a marker of systemic oxidative stress, nor the chemical composition of HDL3c were modified between the subgroups.

Conclusions

In hypertensive patients, amlodipine treatment enhanced HDL AOX in subjects who had a BP reduction that exceeded the median response. This effect appears to be secondary to the hypotensive effect, rather than to the direct antioxidant properties, of the drug.