A cytotoxic ribonuclease variant with a discontinuous nuclear localization signal constituted by basic residues scattered over three areas of the molecule.

Nuclear import of proteins is determined by specific signals that allow them to bind to receptors that mediate their energy-dependent transport through the nuclear pore. These signals are termed nuclear localization signals and do not constitute a specific consensus sequence. Among them, the most characterized correspond to monopartite and bipartite nuclear localization signals, which interact with the importin alpha/beta heterodimer. We previously described a cytotoxic variant of human pancreatic-ribonuclease that is actively transported into the nucleus. Here, we show that this protein interacts with importin alpha through different basic residues, including Lys1 and the arginine clusters 31-33 and 89-91. Although these residues are scattered along the sequence, they are close in the three-dimensional structure of the protein and their topological disposition strongly resembles that of a classical bipartite nuclear localization signal.

Power and weakness of spontaneous reporting: a probabilistic approach.

It has been clearly demonstrated that spontaneous reporting remains one of the best ways for picking up new adverse drug reactions (ADRs) once a drug is on the market. The probability of revealing a new ADR by spontaneous reporting was studied as a function of reporting rate, strength of drug-event association (relative risk), background incidence of the event and number of patients treated. The model included determination of (i) the probability of reporting at least one drug-event association case and (ii) the overall probability of concluding that the drug-event association is not coincidental. Both probabilities were generally low. The results suggest that the identification of a new risk by spontaneous reporting implies a strong association between the drug treatment and the occurrence of the event.

Joint effect of gestational age and maternal lead exposure on psychomotor development of the child at six years.

A prospective study has been carried out to assess the psychomotor deficit resulting from a moderate decrease in gestational age and pre-natal lead exposure. The general cognitive index of the McCarthy psychometric scale (adjusted for confounders) in six-year-old children was related to gestational age. Most of the psychomotor scores showed smoothing variations with gestational age ranging from 37 to 39 weeks, whereas sharp changes occurred between 39 to 40 weeks, with plateau values above such a cut-off for all spheres of development examined. Maternal hair lead content, used as an indicator of lead exposure during pregnancy, was found to be negatively related to general cognitive, verbal, quantitative, and memory subscales (p less than 0.01), whereas its relationship with perceptual and motor subscales was close to 0.05 significance level. Control for gestational age did not change the significance level of the associations. When controlling for maternal hair lead levels, the significance of the association between gestational age and the McCarthy subscales also remained stable, only the general cognitive index and verbal subscale reaching the conventional significance level.

Spontaneous reporting: how many cases are required to trigger a warning?

A statistical method is proposed to aid decisions on the recognition of new adverse drug reactions on the basis of spontaneous reports. The maximal number of associations between drug exposure and event is calculated from an independence test between drug and event, taking into account the expected incidence of that particular event in the general population. An example is given which illustrates the method.

Random models for margins of a 2 x 2 contingency table and application to pharmacovigilance.

The identification of new adverse drug reactions is often tricky. For a given case, the relationship between drug exposure and symptom occurrence is usually questionable. It could be investigated statistically from a series of drug-event association cases with an independence test between the two variables. Analysing the related 2 x 2 contingency table obviously requires knowledge of its margins. However this information is often not available. We develop a calculation of the P-value by choosing some random models for the unknown margins. Under the hypothesis of independence, a negative binomial distribution for the frequency of the drug-event association cell is obtained, exactly or approximately. This method allows investigation of the causal relationship when some parameters, as incidence of the symptom in the population, are uncertain. An example is presented.

Age and cohort effects in adult handedness.

A systematic increase with age of the strong right-handers/mixed right-handers ratio, in normal adults, was found in Algeria, Greece, Italy, France and Spain. This age effect on adult handedness is not easily explained by variations in the social pressure against left-hand use, differential mortality, or information bias. There was no systematic decrease in the frequency of left-handedness with age. Left-hand writing among left-handers was common in the youngest age group and rare after 40 years of age.