Synthesis and evaluation of NS5A inhibitors containing diverse heteroaromatic cores.

Inhibitors of the HCV NS5A nonstructural protein are showing promising clinical potential in the treatment of hepatitis C when used in combination with other direct-acting antiviral agents. Current NS5A clinical candidates such as daclatasvir, ledipasvir, and ombitasvir share a common pharmacophore that features a pair of (S)-methoxycarbonylvaline capped pyrrolidines linked to various cores by amides, imidazoles and/or benzimidazoles. In this Letter, we describe the evaluation of NS5A inhibitors which contain alternative heteroaromatic replacements for these amide mimetics. The SAR knowledge gleaned in the optimization of scaffolds containing benzoxazoles was parlayed toward the identification of potent NS5A inhibitors containing other heteroaromatic replacements such as indoles and imidazopyridines.

Benzimidazole-containing HCV NS5A inhibitors: effect of 4-substituted pyrrolidines in balancing genotype 1a and 1b potency.

The treatment of HCV with highly efficacious, well-tolerated, interferon-free regimens is a compelling clinical goal. Trials employing combinations of direct-acting antivirals that include NS5A inhibitors have shown significant promise in meeting this challenge. Herein, we describe our efforts to identify inhibitors of NS5A and report on the discovery of benzimidazole-containing analogs with subnanomolar potency against genotype 1a and 1b replicons. Our SAR exploration of 4-substituted pyrrolidines revealed that the subtle inclusion of a 4-methyl group could profoundly increase genotype 1a potency in multiple scaffold classes.

Discovery of thienoimidazole-based HCV NS5A inhibitors. Part 1: C2-symmetric inhibitors with diyne and biphenyl linkers.

The discovery of C2-symmetric bis-thienoimidazoles HCV NS5A inhibitors is herein reported. Two straightforward approaches to access the requisite diyne and biphenyl linker moieties are described. This study revealed the paramount importance of the aromatic character of the linker to achieve high genotype 1a potency.

Discovery of thienoimidazole-based HCV NS5A inhibitors. Part 2: non-symmetric inhibitors with potent activity against genotype 1a and 1b.

The discovery of non-symmetric thienoimidazole-containing HCV NS5A inhibitors is described. The inhibitors herein reported display high potencies against both genotype 1a and 1b. In this follow-up manuscript, we discuss the importance of the linker aromaticity to achieve high potency, particularly against genotype 1a.

Serotypes of carriage and invasive isolates of Streptococcus pneumoniae in Brazilian children in the era of pneumococcal vaccines.

Nasopharyngeal carriage of Streptococcus pneumoniae is a key factor in the development of invasive disease and the spread of resistant strains within the community. A single nasopharyngeal swab was obtained from 648 unvaccinated children aged <5 years, either healthy or with acute respiratory tract infection or meningitis, during the winters of 2000 and 2001. The overall pneumococcal carriage rate was 35.8% (95% CI 32.1-39.6). The pneumococcal serotypes found most frequently in the nasopharynx were 14, 6B, 6A, 19F, 10A, 23F and 18C, which included five of the seven serotypes in the currently licensed seven-valent conjugate vaccine (PCV7); serotypes 4 and 9V were less common. Serotypes 1 and 5 were isolated rarely from the nasopharynx. A comparison of 222 nasopharyngeal isolates with 125 invasive isolates, matched for age and time to the carrier isolates, showed a similar prevalence of penicillin non-susceptible pneumococci (PNSp) (19.8% and 19.2%, respectively). PNSp serotypes were similar (6B, 14, 19F, 19 A, 23B and 23F) for carriage and invasive disease isolates. The coverage of PCV7 for carriage isolates (52.2%) and invasive isolates (62.4%) did not differ significantly (p 0.06); similarly, there was no significant difference in PCV7 coverage for carriage isolates (34.5%) and invasive isolates (28.2%) of PNSp. These data suggest that PCV7 has the potential to reduce pneumococcal carriage and the number of carriers of PNSp belonging to vaccine serotypes.

Serious adverse events associated with yellow fever 17DD vaccine in Brazil: a report of two cases.

BACKGROUND: The yellow fever vaccine is regarded as one of the safest attenuated virus vaccines, with few side-effects or adverse events. We report the occurrence of two fatal cases of haemorrhagic fever associated with yellow fever 17DD substrain vaccine in Brazil. METHODS: We obtained epidemiological, serological, virological, pathological, immunocytochemical, and molecular biological data on the two cases to determine the cause of the illnesses. FINDINGS: The first case, in a 5-year-old white girl, was characterised by sudden onset of fever accompanied by headache, malaise, and vomiting 3 days after receiving yellow fever and measles-mumps-rubella vaccines. Afterwards she decompensated with icterus and haemorrhagic signs and died after a 5-day illness. The second patient-a 22-year-old black woman-developed a sore throat and fever accompanied by headache, myalgia, nausea, and vomiting 4 days after yellow fever vaccination. She then developed icterus, renal failure, and haemorrhagic diathesis, and died after 6 days of illness. Yellow fever virus was recovered in suckling mice and C6/36 cells from blood in both cases, as well as from fragments of liver, spleen, skin, and heart from the first case and from these and other viscera fragments in case 2. RNA of yellow fever virus was identical to that previously described for 17D genomic sequences. IgM ELISA tests for yellow fever virus were negative in case 1 and positive in case 2; similar tests for dengue, hantaviruses, arenaviruses, Leptospira, and hepatitis viruses A-D were negative. Tissue injuries from both patients were typical of wild-type yellow fever. INTERPRETATION: These serious and hitherto unknown complications of yellow fever vaccination are extremely rare, but the safety of yellow fever 17DD vaccine needs to be reviewed. Host factors, probably idiosyncratic reactions, might have had a substantial contributed to the unexpected outcome.

Spinal cord abscess in a heroin addict: case report.

Spinal cord abscesses are extremely rare, even in intravenous drug abusers. They usually have a poor prognosis unless diagnosed and treated promptly. MRI is the best imaging modality for diagnosis and follow-up. We report a 42-year-old man, an active intravenous drug user, HIV negative, who developed subacute tetraplegia from an intramedullary abscess caused by Staphylococcus aureus. Immediate decompressive surgery and antibiotic treatment led to progressive recovery.

Intracranial vascular involvement of brain pathologies and venous occlusions.

In this paper, the authors present the contribution of CT and MRI to the diagnosis of acute stroke caused by arterial or venous occlusion. The term "early" used in this context means within 6 h of the onset of symptoms. Signs of early ischemic edema are subtle and sometimes difficult to detect by CT or MRI. The purpose of this presentation is to familiarize the clinician and the radiologist with the subtle brain parenchymal changes seen within the first 6 h after onset of symptoms, in order to improve detection of early ischemic infarction and to improve patient care.

Host and viral characteristics affecting the response to interferon therapy in chronic hepatitis C.

OBJECTIVE: To define parameters determined before and after 4 weeks of interferon therapy (3 MU three times per week for 24 weeks) which could be reliable predictors of a response to therapy. PATIENTS: Thirty-four patients with chronic hepatitis C virus (HCV) infection were investigated prospectively. METHODS: A complete response was defined as the normalization of serum alanine aminotransferase levels (ALT) at the end of treatment. The genotype of HCV was determined and the level of HCV-RNA was quantitated both before and after 4 weeks of treatment. RESULTS: After 4 weeks, 16 out of 20 responders [95% confidence interval (CI) 54-94%] and two out of 14 non-responders (95% CI 2-44%) normalized their ALT levels (P = 0.0002). The prevalence of genotype 1b was significantly (P < 0.04) higher among non-responders (eight out of 10; 95% CI 44-92%) than in responders (four out of 18; 95% CI 4-40%). Before treatment, the viraemia determined by branched DNA was significantly lower in responders than in non-responders (46.4 versus 116 x 10(5) eq virus/ml). After 4 weeks of treatment, the level of viraemia in responders was still significantly lower than that in non-responders (22.8 versus 66 x 10(5) eq virus/ml). In responders, a significant decrease in the level of viraemia was observed after 4 weeks of treatment. CONCLUSION: In a stepwise regression analysis only age and the normalization of ALT levels after 4 weeks of treatment were predictive of response to interferon at the end of treatment.

[The melancholy Spaniard: notes for the interpretation of a stereotype]. / La typologie des nations et l'Espagnol mélancolique: notes pour l'interprétation d'un cliché.

Included in the traditional typology of nations, the image of the melancholy Spaniard is a cultural stereotype which appears with a remarkable continuity since the Spanish Golden Age. Developed by foreigners--particularly by the French--this stereotype is also adopted by the Spaniards themselves. It is then necessary to inquire about the persistance of this stereotype through-out the centuries and to examine how--and why--the Spaniards did adhere to the image given by foreigners and the typology of nations. The examination of this stereotype aims at analyzing its mechanism, at discovering its representations--sometimes very different--and the implications involved. The image of the melancholy Spaniard is deeply subjective representation which engages a complex work of the imagination: it concerns the representation of the other and the consciousness that every nation has of itself, revealing many elements about the one who produces it.

[Prevention and treatment of postmenopausal osteoporosis in women treated for cancer]. / Prévention et traitement de l'ostéoporose postménopausique chez la femme traitée pour cancer.

Among 50-year-old women, about 30%, will suffer from osteoporosis resulting in vertebral compression, pain, and possible disablement; this represents a cost of over 4 billion French franco, and therefore necessitates a prevention policy. It has been established that estrogens applied in a dose-dependent manner have a preventive action against bone loss during the treatment period. The action of nor-steroid progestatives and anti-estrogens is likely, although this has not been fully demonstrated. Estrogens, when administered alone, increase the risk of endometrial cancer; however, this risk seems to be reduced by the addition of progestatives over a minimal period of time. Regarding breast cancer, it seems that substitutional hormone treatments for menopause only increase the risk of the above cancer after a prolonged period of over 10 years. The role of progestatives in breast-cancer risk remains uncertain, and is a subject of controversy. It therefore seems justified to prescribe substitutional hormone treatments combining estrogens and progestatives for young women in whom treatment for non hormone-dependent cancers of the cervix, ovary, etc has resulted in castration. For women who have been treated for breast or endometrial cancer, we are of the opinion that the treatment of choice should consist of non-hormonal treatments for prevention of osteoporosis.

[Oral contraception and benign breast diseases]. / Contraception orale et mastopathies bénignes.

A benign mastopathy does not contra-indicate contraceptive pill, but has to meet stringent criteria. Hormonal composition needs case by case adjustment. A good choice can induce an improvement or a cure of benign mastopathy.

[Human papillomavirus infections of the cervix uteri. Clinical implications, indications of typing]. / Les infections à papillomavirus humains (HPV) du col utérin. Implications cliniques, indications due typage.

Recently, intense interest has focused on the relation between HPV infection and precancerous and cancerous lesions of the uterine cervix, as witnessed by the numerous publications on the subject. We carried out a prospective anatomo-clinical study on 224 HPV positive women followed in the Rene Huguenin Centre, from April 1984 to December 1988. Among these patients, cytology, colposcopy and biopsy were performed, when necessary, concurrently with the detection of HPV on cervical smears using a molecular hybridization method (G. ORTH). This study analysed the anatomo-clinical results and suggested the practical implications, taking into account the progress of the patients. These patients were followed up and treated when necessary for cervical intra-epithelial neoplasia (CIN) or carcinoma, associated or not with HPVs (oncogene in 70% of cases). 24% of this population was infected by an HPV, without any lesion. This virus disappeared spontaneously during follow-up; therefore, HPV infection even oncogene, did not necessarily carry onto CIN. Among CIN 1-2, associated or not with HPV, adequate treatment cured the patients with the virus disappearing. In some cases, a simple follow-up showed a spontaneous resolution of the lesion and of the virus. CIN 3 was removed when necessary with systematic pathological examination of the endocervix and of the surgical sample limits. In a few cases, the virus persisted without lesion. HPV infection did not modify our protocol for invasive carcinoma.(ABSTRACT TRUNCATED AT 250 WORDS)

[Human papillomaviruses in uterine cervix pathology: clinical implications, detection and type]. / Les papillomavirus humains (HPV) en pathologie cervicale utérine: implications cliniques, indications du typage.

Recently, intense interest has been focused on the relation between HPV infection and the precancerous and cancerous lesions of the uterine cervix, as documented in numerous publications on the subject. We carried out a prospective anatomoclinical study on 224 women (HPV positive) in the René Huguenin Centre, from April 1984 to December 1988. Among these patients, cytology, colposcopy and biopsy, where necessary, were performed, concurrently with the detection of HPV on cervical smears using a molecular hybridization method (G Orth). We analysed the anatomo-clinical results and propose practical implications, in taking the evolution of the patients into account. These patients were followed up and treated when necessary for cervical intra-epithelial neoplasia (CIN) or carcinoma, associated or unassociated with HPVs (oncogene in 70% of cases). 24% of the patients where infected by an HPV, without any lesion. This virus disappeared spontaneously during the follow-up period. It can be concluded therefore that HPV infection, even oncogene, does not necessarily carry on CIN. Among CIN 1-2, associated or unassociated with HPV, the adequate treatment cured the patients and the virus disappeared. In some cases, a simple follow-up showed spontaneous regression of the lesion and the virus--CIN 3 was removed when necessary with a systematic pathological examination of the endocervix and the surgical sample limits. In a few cases, the virus persisted without lesion. HPV infection did not modify our protocol in the invasive carcinoma. These observations are available in a Centre with a well-trained anatomo-clinical team. In our opinion, the major priority involved in the recognition of cervical HPV infection is to perform a more systematic colposcopy (even for normal smears with subtle atypia), allowing the detection of early precancerous lesion, clinically occult. On the other hand, the oncogene HPV notion has caused us to take more aggressive action regarding treatment of some CIN 1-2, but may not be of benefit to the patient. We remain convinced that the CIN, with or without HPV, or not oncogene with HPV, must only be treated based on the clinical extension and the pathological gravity of the lesions.

[Ovarian seminoma and pregnancy. Apropos of a new case]. / Séminome ovarien et grossesse. A propos d'un nouveau cas.

The case of a 35-year-old primigravida with a 21-week intrauterine gestation and concurrent dysgerminoma of the ovary (stage Ic) is presented. A total hysterectomy with bilateral salpingo-oophorectomy was performed, followed by postoperative chemotherapy using cisplatin, bleomycin and vinblastine. The patient has done well since treatment, and is without evidence of recurrent disease 19 months later. Both radiation and chemotherapy are highly effective treatment modalities for dysgerminoma. For those patients with disease presenting in stages Ib, Ic, II and III who wish to maintain fertility, unilateral oophorectomy followed by combination chemotherapy may be curative and spare ovarian function.

[Human papillomaviruses in the epithelial cells of the cervix uteri: frequency of types 16 and 18. Preliminary results of a clinical, cytologic and viral study]. / Recherche de papillomavirus humains dans des cellules épithéliales du col utérin: fréquence des types 16 et 18. Résultats préliminaires d'une étude clinique, cytologique et virologique.

Between April 1 and June 30 1984, cervical scrapes were taken from 381 women attending the Gynecology Department of the Anticancer Center René-Huguenin. The scrapes were examined for the presence of human papillomavirus (HPV) DNA, by a molecular hybridization method, at the Pasteur Institute. The four HPV types involved in genital pathology, HPV 6, HPV 11, HPV 16 and HPV 18, were studied. Twenty four specimens (6.3%) were found positive: 19 for HPV 16, 3 for HPV 18, 2 for HPV 6 or HPV 11. Results of molecular hybridization were compared with cytological findings. HPV 6 or HPV 11 were detected in cases of mild dysplasia. HPV 16 or HPV 18 were mainly detected in cases diagnosed as severe dysplasia or carcinoma in situ (9 out of 14, i.e. 64.3%), and invasive carcinoma (3 out of 5 cases). The results were further confirmed when virological data obtained with cervical scrapes were compared with the histological diagnosis on biopsies: 14 out of 15 cases of severe dysplasia or carcinoma in situ (93%) and 3 out of 6 cases of invasive squamous carcinoma had been found positive for HPV 16 or HPV 18. Interestingly, four "normal" women (1.3%) with a negative cytology were found positive for HPV 16 or HPV 18. The data obtained by this sensitive and reliable method are useful to the clinician to identify women presenting a high risk of subsequent cervical intraepithelial neoplasia or invasive carcinoma, and, thus, to adapt the treatment and the follow-up of these patients.