[Systemic manifestations of Parvovirus B19 infections]. / Manifestations systémiques des infections à Parvovirus B19.

PURPOSE: Parvovirus B19 (B19) causes many clinical disorders, of which the most common are erythema infectiosum, aplastic crisis complicating chronic hemolytic anemia, and hydrops fetalis. In young adults, the skin eruption caused by B19 is accompanied by polyarthritis and polyarthralgia in 60% of the cases. Rheumatoid factors and other antibodies including antinuclear antibodies, anti-ADN, and antiphospholipids can be produced in the wake of B19 infection. CURRENT KNOWLEDGE AND KEY POINTS: These features may simulate systemic diseases as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) (lupus-like eruption over the cheeks, cytopenia, etc.) or vasculitis (purpura, renal involvement). In addition, there have been a few reports of SLE, vasculitis and other connective tissue diseases developing shortly after a B19 infection associated with virus clearance suggesting that B19 can act as a trigger of systemic disease. However, studies in large series indicate that in fact B19 is probably an extremely rare cause of RA, SLE or vasculitis. FUTURE PROSPECTS AND PROJECTS: In fundamental studies B19 interacts with inflammatory cells by regulation of cytokines. More recently, two studies suggest that viral infection due to B19 may affect the course of SLE, leading to specific biological subsets. These preliminary findings require confirmation to elucidate the significance of the presence of B19 in systemic disease.

[Pharmacologic interactions in chronic treatments: corrective measures for its prevention in a basic area of rural health]. / Interacciones farmacológicas en tratamientos crónicos: medidas correctoras para su prevención en un área básica de salud rural.

OBJECTIVES: To identify the pharmacological interactions of clinical relevance (PICR) in the medication authorization cards (MAC) of the chronically ill and to establish strategies to minimise their appearance. DESIGN: Cross-sectional descriptive study. SETTING: Rural primary care centre. PATIENTS: Random sample of 626 MAC out of a total of 1306. MEASUREMENTS AND MAIN RESULTS: In December 1998, the following was gathered for every MAC with more than one drug treatment: age, sex, number of drugs, intrinsic value, drugs prescribed, daily dose and pharmacological interactions (PI), classified (using the scale of Hansten 1996) into light and clinically relevant. STATISTICAL ANALYSIS: Mantel-Haenszel (alpha = 0.05). Patients' mean age was 69.1 (95% CI, +/- 1.2). Mean number of drugs per MAC was 4 (95% CI, +/- 0.2). 341 PI affecting 197 patients (31.5%, 95% CI, +/- 3.6) were identified. 24.9% (95% CI, +/- 4.5) were PICR, detected in 11.7% (95% CI, +/- 2.5) of the MAC. The existence of PI was related to the number of drugs prescribed to each patient (p < 0.01). There were 26 PI with drugs of low intrinsic value (7.6%; 95% CI, +/- 2.8). 74.1% (95% CI, +/- 9.3) of the total PICR could be avoided by simple recommendations; and the remaining 25.9% (95% CI, +/- 9.3) by monitoring and follow-up of patients. CONCLUSIONS: It is important to identify the medications most commonly involved in the PICR so as to establish corrective measures to minimise the risks arising from multiple medication. Four educational messages advise on over 60% of the PICR detected.

Interacciones farmacológicas en tratamientos crónicos: medidas correctoras para su prevención en un área básica de salud rural / Corrective measures in a rural health district to prevent pharmacological interactions in chronic treatments

Objetivo. Identificar las interacciones farmacológicas de relevancia clínica (IFRC) existentes en las tarjetas de autorización de medicación (TAM) de crónicos y establecer estrategias para minimizar su aparición. Diseño. Estudio descriptivo, transversal. Emplazamiento. Centro rural de atención primaria. Pacientes. Muestra aleatoria de 626 TAM de un total de 1.306.Mediciones y resultados principales. En diciembre de 1998 de cada TAM con más de un tratamiento farmacológico se recogió: edad, sexo, número de fármacos, valor intrínseco (VIF), fármacos prescritos, dosis diaria e interacciones farmacológicas (IF), clasificadas en leves y de relevancia clínica según Hansten (1996). Análisis estadístico: Mantel-Haenszel (alfa = 0,05). La edad media de los pacientes fue de 69,1 años (IC del 95 por ciento ñ 1,2). La media del número de fármacos por TAM fue de 4 (IC del 95 por ciento ñ 0,2). Se identificaron 341 IF que afectaron a 197 pacientes (31,5 por ciento; IC del 95 por ciento ñ 3,6 por ciento). Un 24,9 por ciento (IC del 95 por ciento ñ 4,5 por ciento) fueron IFRC, detectadas en el 11,7 por ciento (IC del 95 por ciento ñ 2,5 por ciento) de las TAM. La existencia de IF se relacionó con el número de fármacos prescritos a cada paciente (p < 0,01). Hubo 26 IF con fármacos de VIF bajo (7,6 por ciento; IC del 95 por ciento ñ 2,8 por ciento). Pueden prevenirse el 74,1 por ciento (IC del 95 por ciento ñ 9,3 por ciento) del total de IFRC mediante recomendaciones sencillas y un 25,9 por ciento (IC del 95 por ciento ñ 9,3 por ciento) restante con la monitorización y seguimiento de los pacientes. Conclusiones. Es importante identificar los medicamentos más comúnmente implicados en las IFRC para establecer medidas correctoras que permitan minimizar los riesgos derivados de la polimedicación. Cuatro mensajes educativos permiten prevenir más del 60 por ciento de las IFRC detectadas (AU)

Synthesis, structure-activity relationships, and pharmacological profile of 9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino[6, 7,1-hi]indoles: discovery of potent, selective phosphodiesterase type 4 inhibitors.

The synthesis, structure-activity relationships, and biological properties of a novel series of potent and selective phosphodiesterase type 4 (PDE4) inhibitors are described. These new aminodiazepinoindoles displayed in vitro PDE4 activity with submicromolar IC(50) values and PDE4 selectivity vs PDE1, -3, and -5. Specifically, one compound (CI-1044, 10e) provided efficient in vitro inhibition of TNFalpha release from hPBMC and hWB with IC(50) values of 0.34 and 0.84 microM, respectively. This compound was found to exhibit potent in vivo activity in antigen-induced eosinophil recruitment in Brown-Norway rats (ED(50) = 3.2 mg/kg po) and in production of TNFalpha in Wistar rats (ED(50) = 2.8 mg/kg po). No emetic side effects at therapeutic doses were observed in ferrets.

Dermatomyositis associated with the presence of parvovirus B19 DNA in muscle.

We report a case of dermatomyositis associated with molecular evidence of parvovirus B19 DNA in two muscle biopsies collected 5 months apart. IgG- but not IgM-specific antibodies were detected in serum. None of four serum samples was positive for parvovirus B19 DNA. The two biopsies contained B19 VP1 sequences and the second one was also positive for NS1. This is the first report of viral parvovirus B19 DNA in muscle of a patient with dermatomyositis. Latent muscle infection may contribute to the clinical picture.

Synthesis and structure-activity relationships of 4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indoles: novel PDE4 inhibitors.

A novel series of benzodiazepine derivatives have been discovered as inhibitors of PDE4 enzymes. We have found that our compounds are selective versus other PDE enzymes, and that the activity can be modulated by specific structural modifications. One compound exhibited a strong eosinophilic infiltration inhibiting action on sensitized Brown-Norway rats (compound 9, 5.1 mg/kg p.o.), moreover this compound is not emetic at 3 mg/kg i.v.

Parvovirus B19 infection in thoracic organ transplant recipients.

BACKGROUND: Clinical manifestations of parvovirus B19 infection in immunocompromised patients are mostly reported as acute or chronic hematologic disorders. More recently, respiratory or renal involvement has been described. OBJECTIVE: We started in 1994 a prospective study of parvovirus B19 infection in a group of lung (LTP) and heart-lung (HLTP) transplanted patients, including occasionally heart transplanted (HTP) patients. STUDY DESIGN: 62 patients (49 LTP, 11 HLTP, 2 HTP) were included in a serological survey and DNA detection by PCR was performed on each serum sample of the first 29 patients; later we performed it only when serology could suggest an acute episode, or when parvovirus infection could be suspected on clinical or biological observations. A total of 1655 sera were examined by serological tests and DNA detection was done in 500 samples. Specific IgM, seroconversion, significant increase of specific IgG levels, and/or parvovirus B19 DNA detection, were considered as markers of viral infection. RESULTS: We observed the presence of both markers of infection in 24 patients (39%), with an individual combination of positive antibody and PCR results. Acute or chronic anaemia, neutropenia were associated to these laboratory findings in 19 patients, but in five cases, an asymptomatic clinical infection suggested viral persistence. CONCLUSIONS: We report parvovirus associated acute or chronic anaemia and pancytopenia in a group of LTP, HLTP and HTP patients, as well as asymptomatic cases of infection. In the hypothesis of a parvoviral persistent or latent infection, current diagnosis methods may be unreliable to identify any other clinical manifestations.

[The pediatric prescription according to its origin and the motive for the consultation in a basic rural health area]. / Prescripción pediátrica según origen y motivo de consulta en un área básica de salud rural.

OBJECTIVE: To describe the paediatric prescription in a rural health district in terms of the origin and reason for consultation. DESIGN: Cross-sectional descriptive study. SETTING: Garraf Rural Health District, Barcelona. PARTICIPANTS: The 3 basic care paediatrics units in the district. MEASUREMENTS AND MAIN RESULTS: 1068 attendances of children of both sexes under 15 were collected. Recorded on each visit to the paediatrics clinic were: age, sex, reason for consultation (RC), and, if medicine was given, the product prescribed and the origin of the prescription. The number of children receiving treatment increased progressively with age. 87% +/- 2.8% of prescriptions originated with the paediatrician. Therapeutic groups of respiratory apparatus and systemic anti-infection drugs accounted for 69% +/- 2.9% of all prescriptions. Only 2.3% +/- 0.5% had fixed-dose associations. The most common RC was upper-tract respiratory infection, mainly treated with a single therapy (76.6% +/- 6.1%). In the case of the second most common RC, acute bronchitis, 94.6% +/- 4.2% of all cases received drugs treatment with single therapy or two simultaneous treatments. Acute tonsillitis was mainly treated with antibiotics (86.4% +/- 6.6%). CONCLUSIONS: The frequencies of the pathology groups detected in the Health District correlate with other studies' findings. Analysis of the origin of prescriptions shows the high decision-making capacity of the Health District's paediatricians. The pharmacological profile employed is good, though it could be improved.

Giant cell arteritis, polymyalgia rheumatica, and viral hypotheses: a multicenter, prospective case-control study. Groupe de Recherche sur l'Artérite à Cellules Géantes.

OBJECTIVE: Although suspected, a viral etiology has never been proven in giant cell arteritis (GCA). We tested for viruses known to induce multinucleated giant cells in human pathology, which include the parainfluenza viruses (HPIV), respiratory syncytial virus, measles virus, herpesviruses type 1 and 2, and the Epstein-Barr virus. METHODS: A multicenter case-control study on incident cases of temporal arteritis (TA) and polymyalgia rheumatica (PMR). Population based age and sex matched controls were randomly selected. Serological tests for IgG and IgM directed against the viruses listed above were performed, on blood samples taken at the time of clinical diagnosis. RESULTS: Three hundred five new patients were included over a 5 year period, of whom 159 presented with positive biopsy TA, 70 with negative biopsy TA, and 76 with negative biopsy PMR. Thirty-eight percent of cases versus 20.9% of controls were positive for IgM directed against HPIV (p = 0.00005). The association was stronger in the positive TA subgroup [positivity rate 43.31%; odds ratio with controls 2.89 (95% CI 1.82-4.60, p = 0.000006)] than in the PMR or negative biopsy TA subgroups. Only HPIV type 1 was associated with the disease, regardless of the season or the geographical origin of the cases. Positivity rates for HPIV types 2 and 3 and for the other viruses tested were similar in cases and controls. CONCLUSION: Our findings suggest that reinfection with HPIV type 1 is associated with the onset of GCA in a subset of patients, particularly in cases with positive TA biopsy.

Molecular dynamics of NPY Y1 receptor activation.

A three-dimensional model of the human neuropeptide Y(NPY)Y1 receptor (hY1) was constructed, energy refined and used to simulate molecular receptor interactions of the peptide ligands NPY, [L31, P34]NPY, peptide YY (PYY) and pancreatic polypeptide (PP), and of the nonpeptide antagonist R-N2-(diphenylacetyl)-N-(4-hydroxyphenyl)methyl-argininamide (BIBP3226) and its S-enantiomer BIBP3435. The best complementarity in charges between the receptor and the peptides, and the best structural accordance with experimental studies, was obtained with amino acid 1-4 of the peptides interacting with Asp194, Asp200, Gln201, Phe202 and Trp288 in the receptor. Arg33 and Arg35 of the peptides formed salt bridges with Asp104 and Asp287, respectively, while Tyr36 interacted in a binding pocket formed by Phe41, Thr42, Tyr100, Asn297, His298 and Phe302. Calculated electrostatic potentials around NPY and hY1 molecules indicated that ligand binding is initiated by electrostatic interactions between a highly positive region in the N- and C-terminal parts of the peptides, and a negative region in the extracellular receptor domains. Molecular dynamics simulations of NPY and BIBP3226 interactions with the receptor indicated rigid body motions of TMH5 and TMH6 upon NPY binding as mechanisms of receptor activation, and that BIBP3226 may act as an antagonist by constraining these motions.

The ligand binding site of NPY at the rat Y1 receptor investigated by site-directed mutagenesis and molecular modeling.

The ligand binding site of neuropeptide Y (NPY) at the rat Y1 (rY1,) receptor was investigated by construction of mutant receptors and [3H]NPY binding studies. Expression levels of mutant receptors that did not bind [3H]NPY were examined by an immunological method. The single mutations Asp85Asn, Asp85Ala, Asp85Glu and Asp103Ala completely abolished [3H]NPY binding without impairing the membrane expression. The single mutation Asp286Ala completely abolished [3H]NPY binding. Similarly, the double mutation Leu34Arg/Asp199Ala totally abrogated the binding of [3H]NPY, whereas the single mutations Leu34Arg and Asp199Ala decreased the binding of [3H]NPY 2.7- and 5.2-fold, respectively. The mutants Leu34Glu, Pro35His as well as Asp193Ala only slightly affected [3H]NPY binding. A receptor with a deletion of the segment Asn2-Glu20 or with simultaneous mutations of the three putative N-terminal glycosylation sites, displayed no detectable [3H]NPY binding, due to abolished expression of the receptor at the cell surface. Taken together, these results suggest that amino acids in the N-terminal part as well as in the first and second extracellular loops are important for binding of NPY, and that Asp85 in transmembrane helix 2 is pivotal to a proper functioning of the receptor. Moreover, these studies suggest that the putative glycosylation sites in the N-terminal part are crucial for correct expression of the rY1 receptor at the cell surface.

Solid-supported syntheses of 3-thio-1,2,4-triazoles.

Two solid-supported synthesis strategies for the preparation of 3-thio-1,2,4-triazoles are described. In the first, Rink amide resin is combined with Fmoc-protected omega-amino acids, acid hydrazides, and alkyl halides to provide diverse sets of starting materials from which numerous triazoles may be prepared. The second employs t-alkylcarbamate resin (Boc resin) which permits the use of additional pools of starting materials, including isothiocyanates and alpha- and omega-amino esters, resulting in triazoles with patterns of functional groups that are not possible from the initial route. The combination of multiple resins and resin attachment sites allows the preparation of a diverse library based upon the 3-thio-1,2,4-triazole scaffold and avoids the pitfall of having a single linker functionality present at the same position in all library members. General synthetic procedures and representative products from each route are presented. A similarity analysis of representative sublibraries from each synthesis strategy concludes that variation of the solid-phase linker chemistry and attachment site can enhance molecular diversity of the combined triazole library.

[Ascites with "activated" lymphocytes in a case of hydrops fetalis related to a parvovirus B19 infection]. / Ascite avec lymphocytes "activés" dans un cas d'anasarque foetale liée à une infection par le parvovirus B19.

A case of non immunologic hydrops fetalis associated with parvovirus B19 infection is reported. Viral etiology was suspected by the pattern of overstimulated lymphocytes in fetal ascites and confirmed later by identification of parvovirus B19 by PCR. The cytologic finding center helps the precocious diagnosis.

[Infectious agents associated with exacerbations of chronic obstructive bronchopneumopathies and asthma attacks]. / Agents infectieux associés aux décompensations des bronchopathies chroniques obstructives et aux attaques d'asthme.

Infections of the respiratory airways are frequently responsible for exacerbations of chronic obstructive pulmonary disease (COPD) and attacks of asthma. However, the causal infectious agents in practice are rarely precisely identified. We have undertaken a prospective study with the aim of researching into the bacteria and viruses associated with these exacerbations. Forty-seven patients who were in hospital between 1987 and 1989 for attacks of asthma (13 episodes) or exacerbations of COPD (35 episodes) were included in this study. The microbiological analysis consisted of: 1) the bacteriology of expectorated material or the products aspirated by fibroscopy with direct examination, quantitative cytology and culture; 2) samples taken from the nasal airways to identify and isolate pneumotropic viruses and mycoplasma; 3) serial serology looking for antibodies against pneumotropic bacteria and viruses. One of more infectious agents were shown in 47% of the episode studies of which 57% were exacerbations of COPD and treated 23% attacks of asthma. In the cases COPD bacteria were identified in 13 cases including Haemophilus influenzae [3], Streptococcus pneumoniae [3], Pseudomonas aeruginosa [3]. Amongst the 14 viruses recovered, the influenza virus [8] and the respiratory syncytial virus (VRS) [4] predominated. In 14 cases of acute asthma only 4 infectious agents were shown; Mycoplasma pneumoniae, influenza A, VRS and parainfluenza virus. The influenza virus was the agent most frequently discovered (26%) during the course of exacerbation of COPD and of asthma.

Study of a new strain of paramyxoviruses isolated from wild ducks: antigenic and biological properties.

Among the different strains of avian paramyxoviruses isolated from migrating feral ducks, two were identified as Newcastle disease viruses (NDV) and the five others would correspond to a new serotype for which we suggest the name of Duck/Mississippi/75 virus. The characteristics of this new serotype are as follows: (1) Duck/Mississippi/75 virus is able to grow as well in allantoic as in amniotic cavities of embryonated hen's eggs; (2) the haemagglutinin and haemolytic activities can be detected with hen red blood cells; (3) the neuraminidase hydrolyses the alpha 2 leads to 3 bonds of the fetuin substrate and its pH activity could be species specific. Antigenically, this serotype is different from all human and animal paramyxoviruses, in spite of an antigenic relationship with NDV.

Electrocorticography of waves associated with eye movements in man during wakefulness.

Waves associated with horizontal saccadic eye movements were recorded from cortical occipital areas through multilead intracerebral electrodes implanted for a few days in 6 drug-resistant epileptic patients in order to localize epileptogenic foci. The waves were studied statistically when the EEG activity was not disturbed by interictal discharges. Cortical occipital waves related to free eye movements while scanning complex material started at the end of the eye movement, later in fact than the corresponding scalp parieto-occipital phenomena. The amplitude of the cortical waves increased with the complexity of the external field (contrasts having no marked effect) and was reduced in an unpatterned field and in dim light. Waves persisted in darkness. Their amplitude was independent of the size of the eye movement. The latency of the waves, calculated from the onset of eye movement, increased with the size of the movement, the complexity of the external field and also in darkness. Imposed eye movements induced cortical waves of larger amplitude and shorter latency and anticipatory potential changes beginning before onset of the eye movement. Waves related to eye movements differed from blinks and from responses to several types of light stimulation more strikingly in cortical records than in those from the scalp. These findings are discussed in relation to lambda waves, activation waves and eye movement potentials, expectancy waves and premotor potentials, and to the phenomena of perceptual blanks preceding normal perception after fixation of gaze. The importance of the subject's attention is emphasized.