Hydroxycinnamic acid levels of various batches from mugwort flowering tops

Dried flowering tops of 24 harvested batches (Artemisia vulgaris: 13; Artemisia verlotiorum: 11) and 12 batches of mugwort from commercial origin were examined. The levels of principal compounds averaged respectively: total hydroxycinnamic acids 6.09; 10.29 and 9.13%, chlorogenic acid 0.79; 2.05 and 1.35%, 1,5-dicaffeoylquinic acid 0.51; 4.01 and 1.25%, 3,5-dicaffeoylquinic acid 2.21; 1.25 and 2.60%. Specifications were discussed for an European Pharmacopoeial monography.     

Angiotensinogen variants and human hypertension

The research on molecular genetics of human hypertension aims to identify the loci involved in the regulation o blood pressure, detect gene variants within the identifie loci, associate them with intermediate phenotypes, and ultimately estimate their quantitative effects on blood pressure level and their interaction with main environ mental factors. So far, the angiotensinogen (AGT) gene is one of the few candidate genes that has been investigated using these multiple statistical, clinical, and biochemical strategies. A highly polymorphic dinucleotide GT repeat (80% heterozygosity) has been used in several linkage studies. Other diallelic polymorphisms, located in the 59 regulatory region of the gene in intronic and exonic sequences, have been described, which were then used i association studies in different clinical settings. Positiv associations between the M235T and the G-6A polymor phisms and plasma angiotensinogen levels indicates a path way by which the AGT locus could be involved in essential hypertension.     

Deciphering the molecular basis of invasiveness in Sdhb-deficient cells

Metastatic pheochromocytomas and paragangliomas (PPGL) are malignant neuroendocrine tumors frequently associated with germline mutations in the SDHB gene. SDHB-mutated PPGL display a hypermethylator phenotype associated with hallmarks of epithelial-to-mesenchymal transition (EMT). In the present study, we report the characterization of a unique model of Sdhb knockout in mouse chromaffin cells. Sdhb deficient cells exhibit a metastatic phenotype as highlighted by increased individual cell migration (characterized by faster motility and increased persistence) as well as high invasive and adhesion abilities. This phenotype is associated with the modulation of Twist1, Twist2, Tcf3, Snai1, N-cadherin or Krt19 expression, reflecting an EMT-like reprogramming of cells. Krt19 is epigenetically silenced in Sdhb-deficient cells and re-expressed after treatment by the demethylating agent decitabine. Krt19 rescue by lentiviral transduction in Sdhb-deficient cells and Krt19 inhibition by RNA interference in wild-type cells were performed. Both studies revealed the involvement of KRT19 in the invasive phenotype by modulating collective and individual migration and cell/extra-cellular matrix adhesion properties. These findings underline the role of hypermethylation and EMT in the in vitro acquisition of metastatic properties, following SDHB loss of function.     

Recent advances in the genetics of phaeochromocytoma and functional paraganglioma

1. Recent clinical and fundamental research studies have revolutionized our understanding of the genetics of phaeochromocytoma (PH) and functional paraganglioma (FPGL). It was widely thought that only 10% of PH patients had familial disease and that the malignant phenotype of PH could not be diagnosed before occurrence of the first metastasis. 2. Human genetic studies have now shown that 25-30% of patients have hereditary PH due to a germline mutation in the SDHB, SDHD, VHL, RET or NF1 gene and that the identification of a germline SDHB mutation is associated with a high risk of malignancy and a poor prognosis in PH/PGL patients. 3. Fundamental research studies have shown that SDH genes are tumour suppressor genes and that succinate dehydrogenase inactivation induces abnormal stimulation of the hypoxia-angiogenesis pathway. 4. Finally various fundamental research studies, conducted through the Cortico and Medullo-surrenale: les Tumeurs Endocrines (COMETE) network in France and by other groups worldwide, have produced new recommendations for genetic counselling and testing and for the management of PH patients. They have also improved our understanding of the molecular mechanisms involved in PH tumorigenesis.     

Drugs associated with acute generalized exanthematic pustulosis

INTRODUCTION: Acute generalized exanthematous pustulosis is a severe eruption which is usually drug related. If the causative drug is discontinued, acute generalized exanthematous pustulosis resolves spontaneously in ten days. The aim of this study was to compare drugs suspected of causing acute generalized exanthematous pustulosis reported to French Pharmacovigilance centres and those reported in the literature. MATERIALS AND METHODS: All cases of "pustular eruption" qualified as "serious" reported to the French Pharmacovigilance Centers between January 1985 and December 2001 were analyzed. Cases for which the diagnosis of acute generalized exanthematous pustulosis was not clearly identified were reviewed by a dermatologist. The relationship between acute generalized exanthematous pustulosis and drug exposure was re-examined by one of us. An exhaustive review of the literature was also performed. RESULTS: Review of the data base revealed 207 cases of serious acute generalized exanthematous pustulosis leading to death in 4 cases (2%). Of these cases of acute generalized exanthematous pustulosis, only one drug was suspected in 107 cases (51.6%). The main drugs involved were: pristinamycin (18 cases), amoxicillin (+/- clavulanic acid) (16 cases), hydroxychloroquine (8 cases) and a combination of spiramycin + metronidazole (5 cases). DISCUSSION: The most frequent causal drugs in our study and in the literature are: amoxicillin +/- clavulanic acid, pristinamycin, hydroxychloroquine, ampicillin, diltiazem, co-trimoxazole, terbinafine, carbamazepine and spiramycin +/- metronidazole. Only pristinamycin and diltiazem have information in their summary of product characteristics regarding the risk of acute generalized exanthematous pustulosis. Because it is essential to discontinue the causative drug as soon as possible if a pustular eruption occurs, physicians must be informed of the risk, which should be added to the "adverse events", and "warnings" sections of the summary of product characteristics of the drugs concerned. CONCLUSION: Our results show the relevance of notification of side effects by physicians to pharmacovigilance centres, leading to the identification of a signal and public health dissemination of warnings.