A population genetics study of the familial Mediterranean fever gene: evidence of balancing selection under an overdominance regime.

Familial Mediterranean Fever (FMF) is a recessively inherited systemic autoinflammatory disease caused by mutations in the MEFV gene. The frequency of different disease alleles is extremely high in multiple populations from the Mediterranean region, suggesting heterozygote advantage. Here, we characterize the sequence variation and haplotype structure of the MEFV 3' gene region (from exon 5 to the 3' UTR) in seven human populations. In non-African populations, we observed high levels of nucleotide variation, an excess of intermediate-frequency alleles, reduced population differentiation and a genealogy with two common haplotypes separated by deep branches. These features are suggestive of balancing selection having acted on this region to maintain one or more selected alleles. In line with this finding, an excess of heterozygotes was observed in Europeans and Asians, suggesting an overdominance regime. Our data, together with the earlier demonstration that the MEFV exon 10 has been subjected to episodic positive selection over primate evolution, provide evidence for an adaptive role of nucleotide variation in this gene region. Our data suggest that further studies aimed at clarifying the role of MEFV variants might benefit from the integration of molecular evolutionary and functional analyses.

[Preoperative platelet count as index of the grading in endometrial carcinoma]. / Conta piastrinica preoperatoria come indice del grading nel carcinoma endometriale.

AIM: To investigate a possible relationship between preoperative platelet count and following clinicopathological variables of the endometrial carcinoma: age, stage, histological type, histological grading (G), myometrial invasion, lymphovascular space involvement, cervical involvement, lymph node metastasis. In particular the existence of a possible relationship between elevated preoperative platelet count (=or>300 000 microL) and negative prognostic factors. METHODS: The authors analyzed retrospectively 120 patients with endometrial carcinoma underwent to surgery as the initial treatment. All the patients were subjected to radical surgical procedure: peritoneal cytology, total abdominal hysterectomy, bilateral salpingo-oophorectomy, systematic pelvic lymphadenectomy and omentectomy. Blood platelet count was taken from the patients three days prior to the surgery. RESULTS: The patients with platelet count<300000/microL whom they had a G1, G2, G3 they were respectively the 23.1%, 44.2% and 32.7% versus the 0%, 12.5% and 87.5%, respectively for G1, G2, G3, of the patients with platelet count>300000/microL (P=0.024). Only considering the patients to the stage I of the Federazione Internazionale dei Ginecologi ed Ostetrici (FIGO). The patients with platelet count<300000/microL whom they had a G1, G2, G3 they were respectively the 27.3%, 43.2% and 29.5% versus the 0%, 0% and 100%, respectively for G1, G2, G3, of the patients with platelet count=or>300000/microL (P=0.008). There were no differences respect to age, stage, histological type, myometrial invasion, lymphovascular space involvement and cervical involvement. CONCLUSION: Elevated preoperative platelet count, in the patients with endometrial carcinoma, may reflect poor prognostic factor such as higher histological grade. This study allowed to observe: a significant correlation between elevated preoperative platelet count (=or>300000/microL) and tumoral grading (G3) of general population submitted to study; for the patients to the stage I FIGO a more significant correlation between elevated preoperative platelet count (=or>300000/microL) and tumoral grading: the 100% of the patients with platelet count=or>300 000/microL had a histological grading G3.

Association of short-term memory with a variant within DYX1C1 in developmental dyslexia.

A substantial genetic contribution in the etiology of developmental dyslexia (DD) has been well documented with independent groups reporting a susceptibility locus on chromosome 15q. After the identification of the DYX1C1 gene as a potential candidate for DD, several independent association studies reported controversial results. We performed a family-based association study to determine whether the DYX1C1 single nucleotide polymorphisms (SNPs) that have been associated with DD before, that is SNPs '-3GA' and '1249GT', influence a broader phenotypic definition of DD. A significant linkage disequilibrium was observed with 'Single Letter Backward Span' (SLBS) in both single-marker and haplotype analyses. These results provide further support to the association between DD and DYX1C1 and it suggests that the linkage disequilibrium with DYX1C1 is more saliently explained in Italian dyslexics by short-term memory, as measured by 'SLBS', than by the categorical diagnosis of DD or other related phenotypes.

New pyrazolo[3,4-d]pyrimidines endowed with A431 antiproliferative activity and inhibitory properties of Src phosphorylation.

New 4-aminopyrazolo[3,4-d]pyrimidines bearing various substituents at the position 1 and 6, were synthesized. The new compounds showed antiproliferative activity toward A431 cells, were found to be inhibitors of Src phosphorylation, and induced apoptotic cell death. In particular, 2h was a better inhibitor of Src phosphorylation than the reference compound PP2.

Synthesis and biological evaluation of azole derivatives, analogues of bifonazole, with a phenylisoxazolyl or phenylpyrimidinyl moiety.

A series of azole derivatives, isoxazole or pyrimidine analogues of the antifungal drug bifonazole, were synthesized and tested in vitro against representative human pathogenic fungi (Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus). They were also evaluated as antibacterial agents against Staphylococcus aureus and Salmonella spp. Only 5-(imidazol-1-yl-phenylmethyl)-2,4-diphenyl-pyrimidine 7c showed weak antimicrobial activity (MIC = 66 microM) against C. albicans, C. neoformans and S. aureus. Results of biological tests proved, therefore, that replacement of the biphenyl portion of the bifonazole with a phenylisoxazolyl or phenylpyrimidinyl moiety is not profitable for antimicrobial properties.

Synthesis and biological data of 4-amino-1-(2-chloro-2-phenylethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl esters, a new series of A1-adenosine receptor (A1AR) ligands.

The synthesis of a new family of A1-adenosine receptor (A1AR) ligands 3a-n has been performed in a straightforward way. Affinity data at A1AR, A2AAR and A3AR in bovine membranes show that these new compounds bind the A1AR in a selective way over A2AAR and A3AR and one of them (3j) presents a very high affinity, probably due to the phenethylamine substituent at C-4.

4-Dialkylamino-1-(5-substituted or unsubstituted 1-phenyl-1H-pyrazol-4-yl)butan-1-ols: synthesis and evaluation of analgesic, anti-inflammatory and platelet anti-aggregating activities.

A number of 4-dialkylamino-1-(5-substituted or unsubstituted 1-phenyl-1H-pyrazol-4-yl)butan-1-ols 2a-n were synthesized and tested in vivo for anti-inflammatory and analgesic activities and in vitro for platelet anti-aggregating activity. Dimethylaminoderivatives 2b, e, g showed good analgesic activity; almost all of them had strong platelet anti-aggregating properties at a final concentration of 1 x 10(-3) M; pyrazoles 2c, d, f-h showed weak anti-inflammatory activity.

Synthesis and preliminary biological evaluation of novel N-substituted 1-amino-3-[1-methyl(phenyl)-1H-indazol-4-yloxy]-propan-2-ols interesting as potential antiarrhythmic, local anaesthetic and analgesic agents.

A series of indazoloxypropanolamines 7 and 8, pindolol isosteres, were synthesized to extend the structure activity relationship (SAR) which was observed in an earlier series of related derivatives. Compounds 7, characterized by methyl substitution on the N-1 indazole nucleus, generally exhibited significant antiarrhythmic, local anaesthetic and analgesic activities. The preliminary radioligand binding assay highlighted, in compounds 7, an interesting beta 1-affinity which can be well correlated to their antiarrhyhtmic activity. Analogues 8 characterized by a phenyl group on the N-1 indazole nucleus, were generally less active as antiarrhyhtmic agents but generally interesting as local anaesthetics. Due to the importance of the indazole moiety as a carrier of antiphlogistic activity, the two classes of derivatives 7 and 8 were evaluated for their NSAID behaviour. Once again, compounds 7 resulted having more interesting analgesic and antipyretic effects than analogues 8.

3-Acetyl-5-acylpyridin-2(1H)-ones and 3-acetyl-7,8-dihydro-2,5(1H,6H)-quinolinediones: synthesis, cardiotonic activity and computational studies.

A series of milrinone analogues, namely 6-substituted 3-acetyl-5-acylpyridin-2(1H)-ones 4a-c, e, f and 7-substituted or unsubstituted 3-acetyl-7,8-dihydro-2,5(1H,6H)-quinolinediones 4g-j, in which the cyano group was replaced by the acetyl function, was prepared. In a preliminary pharmacological investigation on spontaneously beating atria from reserpine-treated guinea-pigs, all new compounds did not induce any inotropic effect equivalent or higher than that of the milrinone chosen as the reference compound. In order to rationalise how the structure modifications influence the activity and the selectivity of the title compounds, a computational study has been performed. The important role of the substituents in positions-3 and -6 on the pyridone nucleus has been highlighted.

Synthesis and biological evaluation of [alpha-(1,5-disubstituted 1H-pyrazol-4-yl)benzyl]azoles, analogues of bifonazole.

A series of pyrazole analogues of bifonazole, an antifungal drug used in clinical practice, 2a-h and 4a-h were synthesized and tested in vitro against Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus, with no significant results. Imidazoles 2a-h were also tested in vivo for antiarrhythmic and antihypertensive activities; two of these compounds showed moderate activity against ventricular fibrillation caused by aconitine in rats. The above compounds were prepared by reaction of phenyl-[5 substituted 1-phenyl (or 1-methyl)-1H-pyrazol-4-yl]methanols with N,N'-carbonyldiimidazole (2a-h) or of the respective chloro derivatives with 1H-1,2,4-triazole (4a-h).

[The effect of hormone substitution therapy on body weight]. / L'influenza sul peso corporeo della terapia ormonale sostitutiva.

BACKGROUND: The influence of hormone replacement therapy on the body weight has been studied. METHODS: For this purpose, a group of 205 women in spontaneous menopause, were selected at the Menopause Centre in Suzzara: they were given a continuative replacement therapy for a period of 12 months (estradiol 50/60 micrograms and medroxyprogesterone acetate, 5/10 micrograms twelve days a month). RESULTS: After twelve months, 30% of the 200 patients who completed the study, showed a weight increase which was significant only in 20%, with no variation of the Body Mass Index. CONCLUSIONS: From the data obtained, two remarks can be done: the HRT contributes in an insignificant way to the body weight and probably these results must also be ascribed to the choice of neutral progestinics which do not possess androgenical mineralcorticoid effects.

Synthesis of angelicin heteroanalogues: preliminary photobiological and pharmacological studies.

A series of angelicin heteroanalogues, in which the furan was replaced by thiophene or a 1-substituted pyrazole moiety, was synthesised in order to obtain potential therapeutic agents with antiproliferative and/or other biological activities. In general, the antiproliferative activity of the new thioangelicin, tested in different biological substrates, appeared to be higher than that of the angelicin, the natural parent compound, but lower than that of 8-MOP, the furocoumarin ordinarily used in PUVA therapy and photopheresis. Thioangelicin 6 induced strong inhibition of T2 bacteriophage infectivity and was able to significantly repress the DNA synthesis in Ehrlich ascites cells and the clonal growth in HeLa cells. The pyrazolocoumarins did not show any noticeable effect upon UVA irradiation in all the biological systems considered. All the new angelicin heteroanalogues appeared to be free of the known phototoxicity of furocoumarins on the skin. The pyrazolocoumarins have also been tested as anti-inflammatory, analgesic, antipyretic, local anaesthetic, anti-arrhythmic and platelet anti-aggregating agents by standard procedures. In this class of derivatives, 10a showed good anti-inflammatory and antipyretic properties, while 9a and 11a showed significant local anaesthetic activity.

[Effects of PGE1 (alprostadil alpha-cyclodestrin) in a case of probable paraneoplastic thrombocytopenic purpura]. / Effetti della PGE1 (alprostadil alpha-ciclodestrina) in un caso di porpora trombocitopenica verosimilmente paraneoplastica.

The authors report the case of a severely vasculopathic patient with pulmonary mediastinal tumour who presented, probably on a paraneoplastic basis, the onset of severe thrombocytopenic purpura persisting for several months. The syndrome was not classifiable in any of the forms known to the authors and was completely resolved by treatment with PGE1 (alprostadil-alpha-cyclodextrine (Prostavasin, Schwarz Pharma).

Synthesis and photobiological properties of 3-acylangelicins, 3-alkoxycarbonylangelicins and related derivatives.

Convenient synthesis of 3-acyl-2H-furo[2,3-h]-1-benzopyran-2-ones, esters of 2-oxo-2H-furo[2,3-h]-1-benzopyran-3-carboxylic acid and 2H-furo[2,3-h]-1-benzopyran-3-carboxamides was accomplished via aromatization of the adducts obtained by a reaction between (E)-5-dimethyl-aminomethylene-6,7-dihydrobenzofuran-4(5H)-one and the appropriate acylacetate or dialkyl malonate. These compounds are angelicin derivatives which were prepared with the aim of obtaining intrinsically monofunctional drugs for photochemotherapy, with only one photoreactive site in their molecule. The new angelicins appear to be free of the known phototoxicity of furocoumarins on the skin and at a genetic level. The 3-carboxylic esters showed significant antiproliferative activity in Ehrlich ascites cells and T2 bacteriophage; the other derivatives were only slightly effective. The features of these compounds are such that they represent a new model for non-toxic agents for photochemotherapy.

[Recurrence of Crohn disease, complicated by intestinal perforation, during pregnancy. Discussion of a clinical case]. / Morbo di Crohn riacutizzato nel corso della gravidanza e complicato da perforazione intestinale libera. Discussione di un caso clinico.

We describe a case of Crohn's disease which came up before pregnancy and which is responsible of an acute abdomen picture caused by intestinal reacutation and perforation to the 38th week of amenorrhea. The relations between the disease and the pregnancy state are analyzed from the clinical, diagnostic and therapeutical aspect.

1-Aryl-1H-pyrazole-5-acetic acids with antiinflammatory, analgesic and other activities.

Reaction of methyl 4-methoxy-2-dimethylaminomethylene-3-oxobutanoate with arylhydrazines gave methyl 1-aryl-5-(methoxymethyl)-1H-pyrazole-4-carboxylates 1 in high yields. Esters 1 were hydrolyzed to the relative carboxylic acids, which were converted by heating to 1-aryl-5-(methoxymethyl)-1H-pyrazoles 3 in good yields. Reaction of 3 with hydrobromic acid afforded the intermediate 1-aryl-5-(bromomethyl)-1H-pyrazoles, which were converted with potassium cyanide to 1-aryl-1H-pyrazole-5- acetonitriles, whose hydrolysis gave the required 1-aryl-1H-pyrazole-5-acetic acids. Some acids 5 showed a strong antiinflammatory and analgesic activity in rats and mice, respectively, as well as moderate antipyretic and in vito platelet antiaggregating effects.

5-substituted 4-isoxazoleacetic acids with analgesic activity.

The synthesis of some 5-substituted 4-isoxazoleacetic acids starting from 5-substituted 4-isoxazolemethanols via their conversion to 4-(bromomethyl)isoxazoles, 4-isoxazoleacetonitriles and acid hydrolysis of the latter is described. 5-Ethyl- and 5-propyl-4-isoxazoleacetic acids showed in the writhing test an analgesic activity comparable to that of aspirin.

Ethyl or methyl 6-substituted 3-(benzoylamino)-2-oxo-2H-pyran-5-carboxylates and 3-(benzoylamino)-7,8-dihydro-2H-1-benzopyran-2,5(6H)-diones with local anesthetic, platelet antiaggregating and other activities.

The synthesis of ethyl or methyl 6-substituted 3-(benzoylamino)-2-oxo-2H-pyran-5-carboxylates 2 and 3-(benzoylamino)-7,8-dihydro-2H-1-benzopyran-2,5(6H)-diones 4 by reaction of hippuric acid in acetic anhydride with ethyl or methyl 2-dimethylaminomethylene-3-oxoalkanoates and 2-dimethylaminomethylene-1,3-cyclohexanediones, respectively, is described. Some compounds 2 and 4 showed a strong local anesthetic activity in mice and a platelet antiaggregating activity in vitro comparable to that of acetylsalicylic acid, as well as moderate analgesic, antiinflammatory and antiarrhythmic activities in rats and mice.

N-substituted 4-carboxy-1-phenyl-1H-pyrazole-5-propanamides with antiinflammatory, analgesic, antipyretic and platelet antiaggregating activities.

The synthesis of a series of N-substituted 4-carboxy-1-phenyl-1H-pyrazole-5-propanamides by reaction of 1-phenyl-1H-oxepino[4,3-c]pyrazole-4(8H),6(7H)-dione with aromatic primary amines is described. Some amides showed a platelet antiaggregating activity in vitro superior or comparable to that of acetylsalicylic acid, as well as moderate antiinflammatory, analgesic and antipyretic activities in rats or mice.

Synthesis, antiviral (HSV-1) and antimycotic activities of ethyl or methyl 2,4-disubstituted 5-pyrimidinecarboxylates, 2,4-disubstituted 5-pyrimidinecarboxylic acids and 2,4-disubstituted pyrimidines.

The synthesis of ethyl or methyl 4-substituted or unsubstituted 2-methylthio-5-pyrimidinecarboxylates 3 a-i and 8 o mainly by reaction of ethyl or methyl 2-dimethylaminomethylene-3-oxoalkanoates with 2-methylisothiourea is described. Also some ethyl 2-substituted (NH2, CH3, C6H5) 4-trifluoromethyl-5-pyrimidinecarboxylates were prepared. Some of the above esters were hydrolyzed to the relative carboxylic acids, which were decarboxylated to the corresponding 2,4-disubstituted pyrimidines. Esters 3 a-i and 8 o were tested for their toxicity on Vero cultured cells and for their inhibitory activity against herpes simplex virus type 1 (HSV-1) infectivity in a short-term plaque assay. At non toxic concentrations, each ester was found to be active, the most interesting compound being 3 h, which achieved a 80.9% inhibition of HSV-1 infectivity at 12 micrograms/ml. Moreover, esters 3 f, 8 l and acid 9 o were active against some fungal strains.