French summaries of product characteristics: content in relation to therapeutic monitoring of psychotropic drugs.

The prescription information (summary of product characteristics, SPC) is compiled by the pharmaceutical industry as required by the national regulatory authorities. They vary in their content about the properties of drugs and about the usefulness of therapeutic drug monitoring (TDM) in the blood of patients. Based on a previous study carried out in Germany, the degree of agreement of French SPC for 59 psychotropic drugs with the existing medico-scientific evidence in the area of TDM was examined using a recently developed instrument. A summary score of SPC content (SPCC) related to TDM (SPCC(TDM)) has been calculated and compared with the level of recommendation of TDM of the AGNP-TDM expert group consensus guidelines for TDM in psychiatry [AGNP: Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (Association for neuropsychopharmacology and pharmacopsychiatry)]. Among the antidepressants, antipsychotics, tranquillizers/hypnotic agents and mood stabilizers, the highest SPCC(TDM) scores in the French SPC were reached for imipramine (16), haloperidol (6), clonazepam (8) and lithium (23), respectively. Results were similar to those obtained from the analysis of German SPC, and considerable disagreement was found between the information on TDM in SPC and existing medico-scientific evidence, albeit less in the case of mood stabilizers. Taking into account the recommendations of the AGNP-TDM expert group guidelines, there is a deficit in the French SPC concerning TDM-relevant information. An amelioration of this situation could help to improve the clinical practice of TDM of psychotropic drugs, as the SPC is a widely used tool.

Cancer survival from the incident cases of the Registry of Vaud, Switzerland.

Survival statistics from the incident cases of the Vaud Cancer Registry over the period 1974-1980 were computed on the basis of an active follow-up based on verification of vital status as to December 31, 1984. Product-moment crude and relative 5 to 10 year rates are presented in separate strata of sex, age and area of residence (urban or rural). Most of the rates are comparable with those in other published series from North America or Europe, but survival from gastric cancer (24% 5-year relative rates) tended to be higher, and that from bladder cancer (about 30%) lower than in most other datasets. No significant difference in survival emerged according to residence in urban Lausanne vs surrounding (rural) areas. Interesting indications according to subsite (higher survival for the pyloric region vs the gastric fundus, but absence of substantial differences for various colon subsites), histology (higher rates for squamous carcinomas of the lung, seminomas of the testis or chronic lymphatic leukemias as compared with other histotypes), or site of origin (higher survival for lower limb melanomas), require further quantitative assessment from other population-based series. A Cox proportional hazard model applied to melanomatous skin cancers showed an independent favorable effect on long-term prognosis of female gender and adverse implications for advanced age, stage at diagnosis and tumor site other than lower limb.

Long sequence duplications, repeats, and palindromes in HIV-1 gp120: length variation in V4 as the product of misalignment mechanism.

We have shown that indels in gp120 V4 are associated to the presence of duplicated and palindromic sequences, suggesting that they may be produced by strand-slippage misalignment mechanism. Indels in V4 involved region-specific duplications 9 to 15 bp long, and repeats of various lengths, associated to trinucleotides AAT. No duplications were found in V3 and C3. The frequency of palindromic sequences in individual genes was found to be significantly higher in gp120 (p < or = 3.00E-7), and significantly lower in Tat (p < or = 9.00E-7) than the average frequency calculated over the full genome. The finding of elements of misalignment in association with indels in V4 suggests that these mutations may occur in proviral DNA after integration of HIV into the host genome. It also implies that occurrence of large indels in gp120 is not random but is directed by the presence and distribution of elements of misalignment in the HIV genome.

Length variation in HIV-1 gp120 as the product of DNA misalignment mechanism

Background: To determine whether misalignment structures such as duplications, repeats, and palindromes are associated to insertions/deletions (indels) in gp120, indicating that indels are indeed frameshift mutations generated by DNA misalignment mechanism. Methods: Cloning and sequencing of a fragment of HIV-1 gp120 spanning C2-C4 derived from plasma RNA in 12 patients with early chronic disease and naïve to antiretroviral therapy. Results: Indels in V4 involved always insertion and deletion of duplicated nucleotide segments, and AAT repeats, and were associated to the presence of palindromic sequences. No duplications were detected in V3 and C3. Palindromic sequences occurred with similar frequencies in V3, C3 and V4; the frequency of palindromes in individual genes was found to be significantly higher in structural (gp120, p ≤ 3.00E-7) and significantly lower in regulatory (Tat, p ≤ 9.00E-7) genes, as compared to the average frequency calculated over the full genome. Discussion: Indels in V4 are associated to misalignment structures (i.e. duplications repeat and palindromes) indicating DNA misalignment as the mechanism underlying length variation in V4. The finding that indels in V4 are caused by DNA misalignment has some very important implications: 1) indels in V4 are likely to occur in proviral DNA (and not in RNA), after integration of HIV into the host genome; 2) they are likely to occur as progressive modifications of the early founder virus during chronic infection, as more and more cells get infected; 3) frameshift mutations involving any number of base pairs are likely to occur evenly across gp120; however, only those mutants carrying a functional gp120 (indels as multiples of three base pairs) will be able to perpetuate the virus cycle and to keep spreading through the population.

Quantification of the relation between surface morphodynamics and subsurface sedimentological product in sandy braided rivers

This study uses digital elevation models and ground-penetrating radar to quantify the relation between the surface morphodynamics and subsurface sedimentology in the sandy braided South Saskatchewan River, Canada. A unique aspect of the methodology is that both digital elevation model and ground-penetrating radar data were collected from the same locations in 2004, 2005, 2006 and 2007, thus enabling the surface morphodynamics to be tied explicitly to the associated evolving depositional product. The occurrence of a large flood in 2005 also allowed the influence of discharge to be assessed with respect to the processproduct relationship. The data demonstrate that the morphology of the study reach evolved even during modest discharges, but more extensive erosion was caused by the large flood. In addition, the study reach was dominated by compound bars before the flood, but switched to being dominated by unit bars during and after the flood. The extent to which the subsurface deposits (the product') were modified by the surface morphodynamics (the process') was quantified using the changes in radar-facies recorded in sequential ground-penetrating radar surveys. These surveys reveal that during the large flood there was an increase in the proportion of facies associated with bar margin accretion and larger dunes. In subsequent years, these facies became truncated and replaced with facies associated with smaller dune sets. This analysis shows that unit bars generally become truncated more laterally than vertically and, thus, they lose the high-angle bar margin deposits and smaller scale bar-top deposits. In general, the only fragments that remain of the unit bars are dune sets, thus making identification of the original unit barform problematic. This novel data set has implications for what may ultimately become preserved in the rock record.

Neuropathic Pain Phenotype Does Not Involve the NLRP3 Inflammasome and Its End Product Interleukin-1β in the Mice Spared Nerve Injury Model.

The NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome is one of the main sources of interleukin-1β (IL-1β) and is involved in several inflammatory-related pathologies. To date, its relationship with pain has not been studied in depth. The aim of our study was to elucidate the role of NLRP3 inflammasome and IL-1β production on neuropathic pain. Results showed that basal pain sensitivity is unaltered in NLRP3-/- mice as well as responses to formalin test. Spared nerve injury (SNI) surgery induced the development of mechanical allodynia and thermal hyperalgesia in a similar way in both genotypes and did not modify mRNA levels of the NLRP3 inflammasome components in the spinal cord. Intrathecal lipopolysaccharide (LPS) injection increases apoptosis-associated speck like protein (ASC), caspase-1 and IL-1β expression in both wildtype and NLRP3-/- mice. Those data suggest that NLRP3 is not involved in neuropathic pain and also that other sources of IL-1β are implicated in neuroinflammatory responses induced by LPS.

Governance mode vs. governance fit: Performance implications of make-or-ally choices for product innovation in the worldwide aircraft industry, 1942-2000

We examine the impact of governance mode and governance fit on performance in make-or-ally decisions. We argue that while horizontal collaboration and autonomous governance have direct and countervailing performance implications, the alignment of make-or-ally choices with the focal firm's resource endowment and the activity's resource requirements leads to better performance. Data on the aircraft industry show that relative to aircraft developed autonomously, collaborative aircraft exhibit greater sales but require longer time-to-market. However, governance fit increases unit sales and reduces time-to-market. We contribute to the alliance and economic organization literatures. (Copyright © 2013 John Wiley & Sons, Ltd.)