Prevalence and impact of constipation and bowel dysfunction induced by strong opioids: a cross-sectional survey of 520 patients with cancer pain: DYONISOS study.

OBJECTIVE: To describe the prevalence of opioid-induced constipation (OIC) in patients with cancer pain according to the Knowles-Eccersley-Scott symptom score (KESS), the different symptoms of opioid-induced bowel dysfunction (OIBD), and to assess the impact of OIBD on patient's quality-of-life. METHODS: A cross-sectional observational study, using the KESS questionnaire and the physician's subjective assessment of constipation, and other questionnaires and questions on constipation, OIBD, and quality-of-life, carried out on 1 day at oncology day centres and hospitals. RESULTS: Five hundred and twenty patients were enrolled at 77 centres in France; 61.7% of patients (n = 321) showed a degree of constipation that is problematic for the patient according to KESS (between 9-39). Even more patients, 85.7% (n = 438), were considered constipated according to the physician's subjective assessment-despite laxative use (84.7% of patients). Quality-of-life was significantly reduced in constipated vs non-constipated patients for both PAC-QoL (p < 0.0001 for total score and each dimension) and the SF-12 questionnaires (statistically significant for all dimensions except physical state and role physical). OIC and OIBD led to hospitalization (16% of patients), pain (75% of patients), and frequent changes in opioid and laxative treatment. KEY LIMITATIONS: This cross-sectional study, in a selected population of cancer patients, has measured prevalence and impact of OIBD. Further confirmation could be sought through the use of longitudinal studies, and larger populations, such as non-cancer pain patients treated with opioids. CONCLUSIONS: Cancer patients taking opioids for pain are very frequently constipated, even if they are prescribed laxatives. This leads to relevant impairments of quality-of-life.

Further validation of the psychometric properties of the Bowel Function Index for evaluating opioid-induced constipation (OIC).

OBJECTIVE: The BFI † (Bowel Function Index) is a 3-item questionnaire for assessing opioid-induced constipation (OIC). The aim of this study was to contribute to the validation of the psychometric properties of the BFI by confirming a constipation threshold, and through correlation with other validated tools: KESS (Knowles Eccersley Scott Symptom) score and generic (12-Item Short Form Health Survey, SF-12) and specific (Patient Assessment of Constipation-Quality of Life, PAC-QoL *) quality-of-life scores. METHODS: A survey on opioid-requiring cancer-patients was carried out in France. A questionnaire was filled out for all patients that recorded their demographic characteristics, an assessment of their constipation using BFI and KESS scores, and included a self-assessment of quality-of-life using PAC-QoL and SF-12. Correlation of BFI with KESS, PAC-QoL, and SF-12 was investigated. RESULTS: Five hundred and twenty patients participated in the entire data collection with no loss. BFI was shown to be statistically correlated (r = 0.571; p < 0.0001) with the KESS score and matches up with PAC-QoL and to a lesser extent with the SF-12 generic quality-of-life questionnaire. A BFI threshold of 27-29 to discriminate constipated from non-constipated patients was confirmed. KEY LIMITATIONS: This cross-sectional study in a selected population of cancer pain patients has validated the psychometric properties of the BFI. Further confirmation of the validity of the BFI could be sought through the use of longitudinal studies, and larger populations, such as non-cancer pain patients treated with opioids. CONCLUSION: This study contributes to the validation of the psychometric properties of the BFI. It confirms the BFI as an easy-to-use tool to assess constipation and its impact on quality-of-life in chronic pain patients.

[Observational study of the initial prescription of level 3 analgesics in cancer patients.]. / Enquête observationnelle sur la primoprescription d'antalgiques de palier 3 chez les patients cancéreux.

To evaluate pain management in cancer patients, a study was conducted examining the treatment circumstances and modalities of initial prescription level 3 analgesics used by 122 French cancer specialists. The rationale for moving to level 3, the implementation and the follow-up were evaluated in 1,038 patients. The reasons underlying the initial prescription were in line with recommendations for clinical practice (WHO, SOR) and the professionals generally preferred molecules with which they were already familiar. Though pain intensity was reduced in 67% of patients, treatment follow-up could have been improved in a number of cases. In particular, titration was not systematically performed, and the interruption of the prescribed treatment (owing to inefficacy or negative side-effects) was not sufficiently timely. The awareness-raising campaigns performed over the past few years should be continued, underlining the importance of early follow-up, notably during the titration phase of level 3 analgesic initiation.

Exosomes are released by cultured cortical neurones.

Accumulating evidence shows that several cell types have the capacity to secrete membrane proteins by incorporating them into exosomes, which are small lipid vesicles derived from the intralumenal membranes of multivesicular bodies (MVBs) of the endocytic pathway. Exosomes are expelled in the extracellular space upon fusion of the MVB with the plasma membrane. Exosomal release is a way of secreting membrane proteins meant to be discarded, or to be passed on to other cells. Here, we demonstrate, using primary cortical cultures, that neurones and astrocytes can secrete exosomes. We find that exosomes released by cortical neurones contain the L1 cell adhesion molecule, the GPI-anchored prion protein, and the GluR2/3 but not the NR1 subunits of glutamate receptors. We also show that exosomal release is regulated by depolarisation. Our observation suggests that exosomes may have a regulatory function at synapses and could also allow intercellular exchange of membrane proteins within the brain.

Venous disease and ergonomics of female employment.

AIM: The aim of this study was to describe the employment conditions of women with chronic venous disorders of the lower limbs. METHODS: Cross sectional study conducted by general practitioners who describe the first 3 women, between 18 and 65 years of age, who were employed and who presented with at least CEAP stage I venous disorders. RESULTS: Occupations held by these women indicate significant departures from the general population with an over representation of industrial workers (18.6% vs 11.9%) and an under representation of intermediate professions (12.5% vs 26.6%), (P<0.001). At work, 78.2% (n=4,143) of the women remained standing for 6.2+/-2.4 hours per day and/or 52.3% (n=2,771) were seated for prolonged periods, 28.9% (n=1 503) were exposed to sources of high heat on the legs and 18.2% (n=947) wore garments that compressed the abdomen Conditions favorable to the ergonomic evolution of their workstation are limited: only 9.2% (n=397) thought it possible to reduce the time they spend standing; 10.1% (n=319) the time they spend sitting; 12.9% (n=189) their exposure to heat. Combating these factors appears difficult: 74.3% (n=3 883) state that they do not have sufficient breaks to rest their legs, 38.9% (n=2,053) that they do not have the opportunity to stretch their legs and 42.5% (n=1,395) that compression stockings would be permitted, but would be a hindrance in their work (85.6%, n=4,503). For 27% (n=1,424) of respondents, these problems significantly increase the arduousness of their work and 73.7% (n=3,870) think their working conditions have worsened their venous distress. CONCLUSIONS: Women who consult for venous problems are employed in work which are characterized by unavoidable conditions constituting undeniable venous risk factors for venous disease and occupational medicine does not pay enough attention to the ''ladies legs'' at work.

Pharmaco-epidemiology of the treatment of chronic venous insufficiency in general medicine.

BACKGROUND: A report is presented of a multicenter pharmaco-epidemiological study on chronic venous insufficiency conducted in France on 5043 patients. METHODS: It was based on a questionnaire that included the demographic characteristics of the patients, their risk factors for venous disease, history of venous insufficiency, physical and functional symptoms, and clinical stage according to the CEAP classification, as well as modalities of treatment and professional practice of the participating doctors. The various treatment modalities (phlebotonics, compression stockings, sclerotherapy and surgery) were related to the stage of the venous insufficiency and to the satisfaction expressed by the patients. RESULTS: The results of the study showed a minimum annual sick leave rate of 7.2%. CONCLUSIONS: In conclusion, this study brings to the fore the change in treatment modalities for venous insufficiency according to its severity stage, principally as regards medico-economics.

[Frequency and detection rate of silent myocardial ischemia by Holter monitoring in patients with stable coronary insufficiency under treatment. Study of 95,725 recorded hours]. / Fréquence et taux de dépistage de l'ischémie myocardique silencieuse en fonction de la durée du Holter chez les coronariens stables sous traitement. Etude sur 95,725 heures d'enregistrement.

AIM OF THE STUDY: To determine in standard living conditions the circadian variation of the symptomatic and silent electrocardiographic ischaemia in patients with chronic stable coronary insufficiency. To evaluate the influence of the past history of the patients on the circadian variations of the symptomatic and silent ischaemic events. METHODS: The patients included in the study presented with stable angina pectoris and have undergone a 96 hours Ambulatory ECG (AECG) monitoring with a low-weight and compact material which did not modify their daily activities (R-test). The system records the trace that the patient has initiated it himself following the onset of symptoms and makes possible to distinguish between silent and symptomatic ischaemia. The same experienced cardiologist validated all the AECG records. RESULTS: 1,022 patients aged 64.6 +/- 11.0 years suffering of coronary insufficiency from 5.8 +/- 6.0 years have undergone an electrocardiographic record by an R-test for a total duration of 95,725 hours. Of the 1,022 records, 3,258 ischaemic events have been validated: 295 (9.1%) were symptomatic and 2,963 (90.9%) were silent which correspond to a ratio of 1 versus 9 while this ratio is usually described as 1 versus 4. By 26.5% (n = 271) of the patients, ischaemia have been detected and among them more than a half (54.6%, n = 148) were presenting only silent ischaemia. Of these patients who present silent ischaemia, it was recorded during the first 24 hours by only 63.7% of them which is the usual duration of an ambulatory ECG monitoring. This percentage increases to 83.1% after 48 hours and to 94.1% after 72 hours. CONCLUSION: By more than one third (36.3%) of the patients with stable coronary insufficiency, an ambulatory ECG monitoring recorded during only 24 hours is insufficient to detect a silent ischaemia which will happen later. A record duration of 48 hours reduces this risk to 20% of the patients and of 72 hours to less than 5%.

Mini mutagenicity test: a miniaturized version of the Ames test used in a prescreening assay for point mutagenesis assessment.

The bacterial reverse mutagenicity test on Salmonella typhimurium, known as the Ames test, is widely used by regulatory agencies, academic institutions and chemical companies to assess the mutagenic potential of raw compounds. Several attempts have been made to miniaturise the Ames test in order to fit the industrial constraint of screening more products at the low quantities available. The major limitation of these miniaturised versions of the Ames test lies in the impossibility to work with all the six strains used in the regular Ames test, especially with those showing a low spontaneous revertant frequency. We describe here a mini version of the regulatory Ames test protocol that allows a significant reduction of the quantity of test substance needed (300 mg) but remains applicable to all Salmonella strains used in the regulatory protocol. In a preliminary study, 10 in-house chemical compounds have been evaluated in the Mini Mutagenicity Test (MMT) together with some positive control substances. A first set of historical data obtained in 1999 as well as the predictivity and the sensitivity of the MMT are presented and compared to those of the regular Ames test.

Fluoroquinolones as chemical tools to define a strategy for photogenotoxicity in vitro assessment.

Today's lifestyle is often associated with frequent exposure to sunlight, but some xenobiotics used in drugs, cosmetics or food chemicals can produce adverse biological effects when irradiated. In particular, they can increase the risk of photogenotoxicity already due to UV radiation itself. There is thus a need to design appropriate approaches in order to obtain relevant data at the molecular and cellular level in this field. For ethical and practical reasons, in vitro models can be very convenient at least for first evaluation tests. Here, we propose a strategy based on complementary experiments to study the photogenotoxic potential of a compound. The fluoroquinolones BAYy3118 and lomefloxacin were used as standards to demonstrate the performance of each test: photoinduced interaction with supercoiled circular DNA, photomutagenicity in the yeast Saccharomyces cerevisae, induction of DNA photodamage in cultured human skin cells as revealed by comet assay, and finally induction of specific phototoxic stress responses such as p53 activation or melanogenesis stimulation. Such a strategy should help to ensure the safety of products likely to undergo environmental sunlight exposure.

Differences in the photogenotoxic potential of two fluoroquinolones as shown in diploid yeast strain (Saccharomyces cerevisae) and supercoiled plasmid DNA.

Fluoroquinolones are antibiotics with a potential clinical side effect of phototoxicity and some are suspected to enhance UVA-induced tumorigenesis. The present study was designed to evaluate the recombinogenic and mutagenic potential of two highly photoreactive compounds, lomefloxacin and BAYy3118 when exposed to complete UVA (320-400 nm). In order to possibly increase the sensitivity of the test, we used a diploid mutant (D7-rad3) deficient in nucleotide excision repair and deriving from the tester strain D7 of the yeast Saccharomyces cerevisae. In agreement with previous reports, lomefloxacin had no effect in this system. Moreover, BAYy3118 was highly photocytotoxic and genotoxic especially when yeast cells were incubated in its presence in the dark before exposure to UVA radiation. Both fluoroquinolones were comparable in their ability to photo-induce DNA strand breaks or oxidative damage to purines and pyrimidines in supercoiled plasmid DNA, but agarose gel electrophoresis showed that BAYy3118 photoproducts could tightly interact with supercoiled plasmid DNA while lomefloxacin ones only induced strand breaks. These data suggest that phototoxicity of BAYy3118 was the result of a multistep mechanism: first, local photo oxidative stress is induced and secondly some of the photoproducts exerted genotoxic effects. This work also shows that very simple and complementary in vitro approaches can be very informative in the understanding of drug-induced phototoxicity.

Tiaprofenic acid-photosensitized damage to nucleic acids: a mechanistic study using complementary in vitro approaches.

In order to determine whether or not tiaprofenic acid (TPA) could cause cellular DNA damage, human fibroblasts were irradiated in the presence of the drug and subsequently examined by means of the comet assay. This led to the observation that TPA actually sensitizes cellular DNA to the subsequent irradiation. When TPA was irradiated in the presence of supercoiled plasmid DNA, it produced large amounts of single-strand breaks (SSB); this is consistent with the effects observed on cellular genomic DNA by the comet assay. More importantly, low concentrations of TPA, unable to produce direct SSB, caused photo-oxidative damage to DNA as revealed by the use of excision-repair enzymes. The fact that TPA-irradiated DNA was a substrate of formamidopyrimidine glycosylase as well as endonuclease III revealed that both purine and pyrimidine bases were oxidized. This was further supported by the TPA-photosensitized oxidation of 2'-deoxyguanosine which led to a product mixture characteristic of mixed type-I/II mechanisms. Thymidine was less reactive under similar conditions, but it also decomposed to give a typical type-I product pattern. Accordingly, the TPA triplet was quenched by the two nucleosides with clearly different rate constants (10(8) vs 10(7) M-1 s-1, respectively). As cellular RNA also contains oxidizable bases, it could be the target of similar processes, thus interfering with the biosynthesis of proteins by the cells. Extraction of total RNA from TPA-irradiated human fibroblasts, followed by gel electrophoresis and PCR analysis, confirmed this hypothesis. Finally, photosensitization experiments with Saccharomyces cerevisiae showed that, in spite of an efficient drug-yeast interaction leading to cytotoxicity, neither intergenic recombination nor gene conversion took place. Thus, while TPA-photosensitized damage to nucleic acids can result in genotoxicity, the risk of mutagenicity does not appear to be significant.

[Frequency of silent and painful ischemia in patients with treated stable coronary insufficiency]. / Etude de la fréquence des ischémies silencieuses et douloureuses chez les patients présentant une insuffisance coronaire stable traitée.

The present study was aimed at determining the frequency and circadian variations in symptomatic or silent myocardial ischemia in ambulatory patients with stable coronary disease. A comparative analysis was then made of the recordings on symptomatic and asymptomatic patients according to their medical history. Three hundred and twenty-one cardiologists recruited a total of 1,088 patients who were monitored for 4 days with a new type of electrocardiographic recorder. The patients were able to voluntarily start up the recorder in the case of cardiac discomfort or pain. The results showed that over a total recording period of 95,725 hours, the following data, which were validated by an experienced cardiologist, were obtained: 3,258 ischemic episodes, 2,963 (or 91%) of which were cases of silent ischemia, and 295 (or 9%) which were symptomatic. All the ischemic episodes involved a limited number of subjects, i.e., 271 patients. Of these, 148 (54.6%) were completely asymptomatic; only 63% of these patients with silent ischemia would have been detected if the recording had just lasted 24 hours. Moreover, the medical history showed a correlation between certain factors (such as poorly managed arterial hypertension, cardiac insufficiency, renal failure, arteritis of the lower limbs, and a waist-hip relation of over one in men) and an increase in the number of cases of silent ischemia. However, no single factor was found to be linked more to silent ischemia than to symptomatic ischemia. This investigation therefore shows the significant numeric incidence of silent ischemia. It raises the question of the need to prescribe treatment in at-risk subjects which includes recordings of long duration, so that silent ischemia, which may increase the risk of mortality, can be more readily detected.

The phototumorigenic fluoroquinolone, lomefloxacin, photosensitises p53 accumulation and transcriptional activity in human skin cells.

The fluoroquinolone antibiotic, lomefloxacin, is phototoxic in human skin exposed to UVA radiation, photosensitises DNA strand breaks and pyrimidine dimers in human keratinocytes in vitro, and is phototumorigenic in mouse skin. The p53 tumour suppressor protein is activated by a variety of cellular insults including UV radiation, to become a transcription factor for downstream markers such as the cyclin-kinase inhibitor p21CIP1/WAF1 or cause caspase transactivation which cleaves poly ADP ribose polymerase (PARP) as an early step in apoptosis. We have investigated these molecular defence responses in human skin cells treated with lomefloxacin and UVA radiation in vitro. Western blots revealed that lomefloxacin photosensitised the stabilisation of p53 protein in human fibroblasts. Lomefloxacin also photosensitised p53 transcriptional activity in amelanotic melanoma cells expressing wild-type p53 and stably transfected with a construct containing a beta-galactosidase reporter gene downstream from a p53 consensus binding sequence. Neither photosensitised production of H2O2 nor the resultant DNA strand breaks, appeared to be involved in this effect. Interestingly, p21CIP1/WAFI protein was upregulated by lomefloxacin in the dark by a p53-independent mechanism. Lomefloxacin also photosensitised the degradation of nuclear PARP, suggestive of caspase mediated, early apoptotic events.

The human melanocyte as a particular target for UVA radiation and an endpoint for photoprotection assessment.

The induction of DNA breaks by UVA (320-400 nm) in the nucleus of normal human melanocytes in culture was investigated using single cell gel electrophoresis, also called the comet assay. Endogenous pigment and/or melanin-related molecules were found to enhance DNA breakage: comets were more intense in melanocytes than in fibroblasts, in cells with high melanin content or after stimulation of melanogenesis by supplying tyrosine in the culture medium. After UVA doses where strong comets were observed, neither cytotoxicity nor stimulation of tyrosinase activity were detected. However, the accumulation of p53 protein suggested that cells reacted to genotoxic stress under these experimental conditions. The same approach was used to compare two sunscreens with identical sun protection factors but different UVA protection factors. The results presented in this paper suggest that human melanocytes may be used as a target cell to evidence broadspectrum photoprotection. Moreover, these data appear to be helpful in getting a better understanding of the role of sunlight in the initiating steps of melanocyte transformation.

Comparative efficacy of a single daily dose of two capsules Cyclo 3 Fort in the morning versus a repeated dose of one capsule morning and noon. A one-month study.

BACKGROUND: The efficacy of Cyclo 3 Fort has previously been demonstrated in placebo-controlled trials on plethysmographic and clinical parameters. Its objective was to demonstrate that after one month of therapy, the efficacy and safety of a single dose of two capsules of Cyclo 3 Fort in the morning were comparable to that of a twice daily dose of Cyclo 3 Fort, one capsule morning and noon. METHODS: This single-center, randomised, double-blind study was conducted on 37 women with chronic lower-limb venous insufficiency, associating clinical or functional signs and abnormal plethysmographic values. Clinical parameters measured were those conventionally used to assess superficial venous insufficiency; the main laboratory parameter evaluated by plethysmography was the index of venous distensibility. RESULTS: The results data show that in each of the study groups, all of the patients attained a significant improvement in their clinical conditions, confirmed by laboratory tests, following one month of therapy with Cyclo 3 Fort. On the other hand, comparison of results data between the two groups did not objectify any significant difference between the two treatment modalities. CONCLUSIONS: Thus a single dose of two capsules of Cyclo 3 Fort in the morning appears as effective and as well-tolerated as a twice daily dose of one capsule of Cyclo 3 Fort morning and noon.

An in vitro strategy to evaluate the phototoxicity of solar UV at the molecular and cellular level: application to photoprotection assessment.

Skin cancers are among the most common human cancers and have an increasing incidence. The ultraviolet radiation components of sunlight play a major role in skin tumor induction and development. Cellular DNA has been identified as a target for most of the biological effects of UV, and the induction of photodamage is considered as the initiating step of photocarcinogenesis. Thus, effective photoprotection of DNA against harmful overex-posure to solar UV is a critical issue. The efficiency of a sunscreen is usually tested with respect to its ability to prevent skin erythema, but conceivably, more data are required at the molecular and cellular level in order to ascertain protection against photocarcinogenic risk. In the present study, we define a strategy based on the use of various in vitro models and solar-simulated light to evaluate photodamage and photoprotection: -Supercoiled circular plasmid DNA for detection of structural alterations. -The yeast Saccharomyces cerevisiae to evaluate cytotoxicity and genotoxicity. -The single-cell gel electrophoresis or comet assay to determine DNA damage and DNA repair in human keratinocytes. -p53 expression as a hallmark for genotoxic stress. -Induction of pigmentation in human melanocytes. In conditions where light source, spectrum and control of radiation delivery were precisely defined, we have demonstrated that the wide spectrum UVA sunscreen Mexoryl SX protects from the cytotoxicity and genotoxicity of solar UV.

Striatal target-induced axonal branching of dopaminergic mesencephalic neurons in culture via diffusible factors.

The effects of striatal target cells on the morphological development of dopaminergic neurons were studied in dissociated cultures of embryonic rat mesencephalon. Mesencephalic neurons were cultured for four days in presence of target striatal cells or non target cerebellar ones. The outgrowth of dopaminergic neurons, visualized after tyrosine hydroxylase immunohistochemistry, was examined by quantitative morphometry. In cocultures, the increased complexity of dopaminergic neurites (branching) was the most striking pattern. It was dependent on the presence of target striatal cells as compared to non target ones. Cultures raised in presence or absence of serum lead to suggest the implication of striatal neurons rather than glia. Using MAP2 and phosphorylated neurofilaments immunohistochemistry in combination with tyrosine hydroxylase immunolabelling, it could be shown that the target-induced branching effect concerned only axonal and not dendritic processes. To further define whether diffusible factors from the striatal target would participate in the axonal branching effect, mesencephalic cells were cultured in conditioned medium from striatal neurons. Striatal conditioned medium enhanced dopamine uptake and dopamine neuron branching to the same extent as that observed in striatal cocultures. These findings demonstrate that soluble factors secreted by striatal neurons themselves selectively influence the branching of dopaminergic axons in vitro.

GDNF: existence of a second transcript in the brain.

The detection of the glial cell-line derived neurotrophic factor (GDNF) mRNA by RT-PCR in dissociated cell culture of rat embryonic or post-natal brain allowed the amplification of a doublet. The major band corresponded to the expected size and the minor one to a shorter product. We cloned and sequenced the latter product, and thus identified a mRNA potentially encoding for an isoform of the initially described precursor protein involved in GDNF synthesis.

Quaternary raised coral-reef terraces on sumba island, indonesia.

A spectacular sequence of coral-reef terraces (six steps broader than 500 meters and many minor substeps) is developed near Cape Laundi, Sumba Island, between an ancient patch reef 475 meters high and sea level. Several raised reefs have been dated with the electron spin resonance and the uranium-series dating methods. The uplift trend deduced from these reefs is 0.5 millimeter per year; most terraces, although polycyclic in origin, appear to correspond to specific interglacial stages, with the oldest terrace formed 1 million years ago. This puts them among the longest and most complete mid-Quaternary terrace sequences.