[Organophosphorus poisoning: Towards enzymatic treatments]. / Intoxication aux organophosphorés : vers des traitements enzymatiques.

Organophosphorus compounds (OP) are toxic molecules developed as insecticides and chemical warfare nerve agents (CWNAs). Most OP are neurotoxic and act as nervous system disruptors by blocking cholinergic transmission. They are therefore responsible for many poisonings worldwide. OP toxicity may result either from acute or chronic exposure, and their poisoning effect were evaluated using several animal models. These latter were also used for evaluating the efficacy of antidotes. Strategies based on enzymes that can trap (stoichiometric bioscavengers) or degrade (catalytic bioscavengers) OP, were particularly studied since they allow effective decontamination, without toxicity or environmental impact. This review summarizes the results obtained in vivo with enzymes through three levels: prophylaxis, treatment and external decontamination. The efficiency of enzymatic treatments in different animal models is presented and the relevance of these models is also discussed for a better extrapolation to humans.

[Decontamination of organophosphorus compounds: Towards new alternatives]. / La décontamination des organophosphorés : vers de nouvelles alternatives.

Organophosphorus coumpounds (OP) are toxic chemicals mainly used for agricultural purpose such as insecticides and were also developed and used as warfare nerve agents. OP are inhibitors of acetylcholinesterase, a key enzyme involved in the regulation of the central nervous system. Chemical, physical and biological approaches have been considered to decontaminate OP. This review summarizes the current and emerging strategies that are investigated to tackle this issue with a special emphasis on enzymatic remediation methods. During the last decade, many studies have been dedicated to the development of biocatalysts for OP removal. Among these, recent reports have pointed out the promising enzyme SsoPox isolated from the archaea Sulfolobus solfataricus. Considering both its intrinsic stability and activity, this hyperthermostable enzyme is highly appealing for the decontamination of OP.

Developmental defects and genomic instability after x-irradiation of wild-type and genetically modified mouse pre-implantation and early post-implantation embryos.

Results obtained from the end of the 1950s suggested that ionizing radiation could induce foetal malformations in some mouse strains when administered during early pre-implantation stages. Starting in 1989, data obtained in Germany also showed that radiation exposure during that period could lead to a genomic instability in the surviving foetuses. Furthermore, the same group reported that both malformations and genomic instability could be transmitted to the next generation foetuses after exposure of zygotes to relatively high doses of radiation. As such results were of concern for radiation protection, we investigated this in more detail during recent years, using mice with varying genetic backgrounds including mice heterozygous for mutations involved in important cellular processes like DNA repair, cell cycle regulation or apoptosis. The main parameters which were investigated included morphological development, genomic instability and gene expression in the irradiated embryos or their own progeny. The aim of this review is to critically reassess the results obtained in that field in the different laboratories and to try to draw general conclusions on the risks of developmental defects and genomic instability from an exposure of early embryos to moderate doses of ionizing radiation. Altogether and in the range of doses normally used in diagnostic radiology, the risk of induction of embryonic death and of congenital malformation following the irradiation of a newly fertilised egg is certainly very low when compared to the 'spontaneous' risks for such effects. Similarly, the risk of radiation induction of a genomic instability under such circumstances seems to be very small. However, this is not a reason to not apply some precaution principles when possible. One way of doing this is to restrict the use of higher dose examinations on all potentially pregnant women to the first ten days of their menstrual cycle when conception is very unlikely to have occurred (the so-called ten-day rule), as already recommended by the Health Protection Agency. Such a precautionary attitude would also be supported by the uncertainties associated with later changes in gene expression which might result from irradiation or early embryos with moderate doses.

Variability in repeated economic games: comparing trust game decisions to other social trust measures.

Economic games are well-established tools that offer a convenient approach to study social behaviour. Although widely used, recent evidence suggests that decisions made in the context of standard economic games are less predictive of real-world behaviour than previously assumed self-reported questionnaires. A possible explanation for this discrepancy is that economic games decisions in the laboratory are more likely to be influenced by the current situation, while questionnaires are specifically designed to measure people's average behaviour across a long period of time. To test this hypothesis, we performed a longitudinal study where 275 respondents played 16 Trust games every two days within a three-week period, and filled out a questionnaire that measures social trust. This study confirmed the instability of our measure of trust behaviour over time and the substantial stability of questionnaire responses. However, we found a significant association between self-reported social trust and participants' average behaviour in the trust game measured across sessions, but also with participants' behaviour measured only in Session 1. Nevertheless, analysis of behavioural changes in the Trust games over time revealed different behavioural profiles, highlighting how economic games and questionnaires can complement each other in the study of social trust.

Childhood environmental adversity is not linked to lower levels of cooperative behaviour in economic games.

Cooperation is a universal phenomenon, it is present in all human cultures from hunter-gatherers to industrialised societies, and it constitutes a fundamental aspect of social relationships. There is, however, variability in the amount of resources people invest in cooperative activities. Recent findings indicate that this variability may be partly explained as a contextually appropriate response to environmental conditions. Specifically, adverse environments seem to be associated with less cooperation and recent findings suggest that this effect is partly mediated by differences in individuals' life-history strategy. In this paper, we set out to replicate and extend these findings by measuring actual cooperative behaviour in three economic games - a Dictator game, a Trust game and a Public Goods game - on a nationally representative sample of 612 people. Although we found that the cooperation and life-history strategy latent variables were adequately captured by the models, the hypothesised relationship between childhood environmental adversity and adult cooperation and the mediation effect by life-history strategy were not found.

Correction: Environmental adversity is associated with lower investment in collective actions.

[This corrects the article DOI: 10.1371/journal.pone.0236715.].

Transgenerational developmental effects and genomic instability after X-irradiation of preimplantation embryos: studies on two mouse strains.

Recent results have shown that irradiation of a single cell, the zygote or 1-cell embryo of various mouse strains, could lead to congenital anomalies in the fetuses. In the Heiligenberger strain, a link between the radiation-induced congenital anomalies and the development of a genomic instability was also suggested. Moreover, further studies showed that in that strain, both congenital anomalies and genomic instability could be transmitted to the next generation. The aim of the experiments described in this paper was to investigate whether such non-targeted transgenerational effects could also be observed in two other radiosensitive mouse strains (CF1 and ICR), using lower radiation doses. Irradiation of the CF1 and ICR female zygotes with 0.2 or 0.4Gy did not result in a decrease of their fertility after birth, when they had reached sexual maturity. Moreover, females of both strains that had been X-irradiated with 0.2Gy exhibited higher rates of pregnancy, less resorptions and more living fetuses. Additionally, the mean weight of living fetuses in these groups had significantly increased. Exencephaly and dwarfism were observed in CF1 fetuses issued from control and X-irradiated females. In the control group of that strain, polydactyly and limb deformity were also found. The yields of abnormal fetuses did not differ significantly between the control and X-irradiated groups. Polydactyly, exencephaly and dwarfism were observed in fetuses issued from ICR control females. In addition to these anomalies, gastroschisis, curly tail and open eye were observed at low frequencies in ICR fetuses issued from X-irradiated females. Again, the frequencies of abnormal fetuses found in the different groups did not differ significantly. In both CF1 and ICR mouse strains, irradiation of female zygotes did not result in the development of a genomic instability in the next generation embryos. Overall, our results suggest that, at the moderate doses used, developmental defects observed after X-irradiation of female zygotes of these two sensitive mouse strains should not be transmitted to the next generation. Paradoxically, other studies would be needed to address the question of a potential increase of fertility after doses lower than 0.2Gy in both strains.

Environmental adversity is associated with lower investment in collective actions.

Environmental adversity is associated with a wide range of biological outcomes and behaviors that seem to fulfill a need to favor immediate over long-term benefits. Adversity is also associated with decreased investment in cooperation, which is defined as a long-term strategy. Beyond establishing the correlation between adversity and cooperation, the channel through which this relationship arises remains unclear. We propose that this relationship is mediated by a present bias at the psychological level, which is embodied in the reproduction-maintenance trade-off at the biological level. We report two pre-registered studies applying structural equation models to test this relationship on large-scale datasets (the European Values Study and the World Values Survey). The present study replicates existing research linking adverse environments (both in childhood and in adulthood) with decreased investment in adult cooperation and finds that this association is indeed mediated by variations in individuals' reproduction-maintenance trade-off.

[How to differentiate schizophrenia from bipolar disorder using cognitive assessment?]. / L'évaluation cognitive permet-elle de distinguer la schizophrénie du trouble bipolaire ?

BACKGROUND: Historical aspects of the dichotomy between manic-depressive disorders and schizophrenia raise the question of a continuum between the two entities. Griesinger (1817-1868) proposed a unitary concept of psychosis: "Einheitspsychose", adaptations of which have survived until the present day. Although Kraepelin's traditional dichotomy is still a common base for clinicians every day: diagnosis, prognosis and treatment of psychotic disorders, recent epidemiological and neurobiological data are congruent with a dimensional aspect of psychosis. Epidemiological data are consistent with the existence of an individual and a familial overlap between bipolar disorder and schizophrenia. Schizophrenia is probably the most debilitating psychological disorder. It was primarily considered as a behavioural disorder, characterized by socially inappropriate and bizarre behaviour, but much attention has been focussed nowadays on the cognitive component and the cognitive pathology underlying schizophrenia. On the other hand, bipolar, or manic depressive disorder has been primarily considered as a mood or affective disorder, characterized by excessive swings of emotion and motivation. Manic depression is more about recurrent dimensions. However, symptoms associated with the diagnosis of schizophrenia can be associated with psychotic mood disorders: hallucinations and delusions (50%), disorganised speech and behaviour (all patients with moderate to severe mania or mixed episode), negative symptoms (all patients with moderate to severe depression). The social and job dysfunction may be due to disturbances in the volitional system in patients with schizophrenia or severe bipolar disorder. LITERATURES FINDINGS: A considerable body of literature exists concerning the relationship between cognitive impairment in schizophrenia, but there is less data about cognition in bipolar disorder. However, there are some notable similarities between data observed in schizophrenia and bipolar disorder. Many domains of cognition are disrupted in schizophrenia with varying degrees of deficit. Concerning mood disorders, cognitive dysfunction could be considered as a state marker. Globally some studies indicate that, compared with schizophrenia, those with bipolar disorder display a similar but less severe neuropsychological pattern of impairment. However, it is only recently that cognitive dysfunction has been recognized as a primary and enduring core deficit in schizophrenia and further studies in bipolar disorder are needed. DISCUSSION: In this way, it has been suggested that psychotic symptoms may be distributed along a continuum that extends from schizophrenia to psychotic mood disorders with increasing level of severity. An explicative theory has to explain the evolution and the similarities between those affections including genetic and environmental liability. Some individuals, who are at high risk for psychosis, can even develop bipolar disorder or schizophrenia. Likewise, common factors can explain cognitive and social disorders in psychosis. So, there are various arguments for the dimensional approach of psychosis. These data are not completely in contradiction with Kraepelin: schizophrenia is a chronic affection and bipolar disorder is a cyclic pathology. However, common symptoms are not in favour of a strict categorization.

Imprinting of the G(s)alpha gene GNAS1 in the pathogenesis of acromegaly.

Approximately 40% of growth hormone-secreting pituitary adenomas have somatic mutations in the GNAS1 gene (the so-called gsp oncogene). These mutations at codon 201 or codon 227 constitutively activate the alpha subunit of the adenylate cyclase-stimulating G protein G(s). GNAS1 is subject to a complex pattern of genomic imprinting, its various promoters directing the production of maternally, paternally, and biallelically derived gene products. Transcripts encoding G(s)alpha are biallelically derived in most human tissues. Despite this, we show here that in 21 out of 22 gsp-positive somatotroph adenomas, the mutation had occurred on the maternal allele. To investigate the reason for this allelic bias, we also analyzed GNAS1 imprinting in the normal adult pituitary and found that G(s)alpha is monoallelically expressed from the maternal allele in this tissue. We further show that this monoallelic expression of G(s)alpha is frequently relaxed in somatotroph tumors, both in those that have gsp mutations and in those that do not. These findings imply a possible role for loss of G(s)alpha imprinting during pituitary somatotroph tumorigenesis and also suggest that G(s)alpha imprinting is regulated separately from that of the other GNAS1 products, NESP55 and XLalphas, imprinting of which is retained in these tumors.

Scleredema adultorum of Buschke: an under recognized skin complication of diabetes.

Scleredema of Buschke or scleredema diabetorum is a skin complication of diabetes with deposits of collagen and aminoglycans in the dermis. This disease characterized by thickening and hardening of the skin, is usually localized in nape, back and shoulder areas. Consequences could be a decrease in motility of the shoulders and an impairment of respiratory function. Other possible complications are sleep apnoea syndrome and monoclonal gammapathy. Type 1 or type 2 diabetes may be associated with scleredema of Buschke in more than 50% of cases. Diabetes-related risk factors are long duration of the disease, presence of microangiopathy, overweight and need of insulin. Various specific treatments proposed in the literature are poorly validated. In most severe cases, radiation therapy may be useful.

Melatonin has dose-dependent effects on folliculogenesis, oocyte maturation capacity and steroidogenesis.

Chemo and/or radiotherapy applied to young cancer patients most often have severe effects upon female fertility. Today, few options are available to protect ovarian function in females. However, these options are either ineffective, belong to the field of experimental research or/and are not applicable to all patients. Drugs that could protect the oocyte and its surrounding feeder cells from damage can be of great importance. Melatonin, being an important indirect antioxidant and a powerful direct free radical scavenger could be such a reagent. This paper reports the direct effects of different melatonin concentrations (range: 1 nM to 2 mM) on folliculogenesis and oogenesis of in vitro cultured mouse ovarian follicles. Early secondary mouse follicles were cultured in vitro for 12 days under different melatonin regimes. Every fourth day, survival rates were scored, follicles were morphologically evaluated and medium was collected for steroid analyses. On day 12, in vitro ovulation was induced by hCG/EGF. Eighteen hours later, oocytes were measured, oocyte maturation was evaluated and normality of spindle and chromosomes ascertained. Results obtained in this study indicated that 2mM melatonin is toxic. One mM negatively influenced oocyte maturation capacity. In the presence of 100 microM melatonin, androstenedione and progesterone were increased whereas estradiol was not influenced. Lower melatonin concentrations had no effect on the evaluated parameters. These data indicate an effect of melatonin on theca cell steroidogenesis. For prophylactic use, a dose of 10 microM could be suitable to reduce oxidative stress in cultured follicles.

Cytogenetic studies in mouse oocytes irradiated in vitro at different stages of maturation, by use of an early preantral follicle culture system.

In vivo studies on X-irradiated mice have shown that structural chromosome aberrations can be induced in female germ cells and that the radiation-induced chromosomal damage strongly depends on the stage of maturation reached by the oocytes at the time of irradiation. In the present study, the sensitivity of oocytes to induction of chromosome damage by radiation was evaluated at two different stages, by use of a recently developed method of in vitro culture covering a crucial period of follicle/oocyte growth and maturation. A key feature of this system is that growth and development of all follicles is perfectly synchronized, due to the selection of a narrow class of follicles in the start-off culture. This allows irradiation of well-characterized and homogenous populations of follicles, in contrast to the situation prevailing in vivo. Follicles were X-irradiated with either 2 or 4 Gy, on day 0 of culture (early preantral follicles with one to two cell layers) or on day 12, 3h after hormonal stimulation of ovulation (antral Graafian follicles). Ovulated oocytes, blocked in metaphase I (MI) by colchicine, were fixed 16 h after hormonal stimulation and analyzed for chromosome aberrations. The results confirm the high radiosensitivity of oocytes at 2 weeks prior to ovulation and the even higher radiosensitivity of those irradiated a few hours before ovulation, underlining the suitability of the in vitro system for further studies on the genetic effects of ionising radiation in female mammals.

Effect of curcuma on radiation-induced apoptosis in human cancer cells.

There have been considerable efforts to search for naturally occurring substances for the intervention of carcinogenesis. Many components from dietary or medicinal plants have been identified that possess substantial chemopreventive properties. Curcuma, a yellow pigment from Curcuma longa, exhibits anti-inflammatory, antitumor, and antioxidative properties. Although its precise mode of action has not been elucidated so far, studies have shown that chemopreventive action of curcuma might be due to its ability to induce apoptosis (programmed cell death) in cancer cells. This original study was conducted in order to estimate whether curcuma enhances the radiation sensitivity of cancer cells. For this purpose, curcuma (concentrations ranging from 0 to 200 microM) was applied to human cancer cell cultures (HeLa, K-562 and IM-9) with or without X-irradiation (doses comprised between 0 and 8 Gy). Cell proliferation was monitored by trypan blue exclusion. For the estimation of apoptosis, changes in cell morphology and flow cytometry analysis (DNA content and presence of the sub-G1 peak) were performed. Microscopic examination of the curcuma-treated cells (with concentrations above 100 microM) showed a characteristic morphology of apoptosis. Furthermore, cells treated with curcuma exhibited a sub-G1 peak from which the magnitude was proportional to the concentration of curcuma. X-irradiation alone induced polyploidisation and apoptosis of the three cell lines, proportional to the doses of irradiation with a marked difference in radiation sensitivity between the cell lines (IM-9 < K-562 < HELA). However, when radiation and curcuma were applied together, our results showed that in HELA, K-562 and IM-9, curcuma showed a radiation sensitising effect only at the dose of 200 micro M. This result may open a perspective of synergical therapy at the condition to also address the intrinsic toxicity of curcuma on normal cells.

Absence of activating mutations in the GnRH receptor gene in human pituitary gonadotroph adenomas.

The monoclonal origin of gonadotropin-secreting pituitary adenomas has been well demonstrated but only few molecular abnormalities have so far been recognized in these tumors. For many years, several authors have suggested a role for GnRH and/or GnRH receptors (GnRH-R) in the development of these pituitary adenomas. To test the hypothesis that mutant genes encoding a constitutively activated GnRH-R might be involved in the pathogenesis of these tumors, the sequence of the GnRH-R gene was analyzed in tumoral pituitary tissue obtained from ten patients (six female, four male). The pituitary gonadotropin-secreting adenoma was associated with in vivo hypersecretion of FSH, LH and/or free alpha-subunit (n = 7) or was clinically silent (normal plasma levels of gonadotropins or free alpha-subunit, n = 3). In all cases, immunocytochemical studies of the removed adenoma confirmed their gonadotroph nature by revealing positivity for FSH, LH and/or alpha-subunit. Genomic DNA was extracted from the pathological tissue obtained at neurosurgery. Eight sequencing primers were used to amplify the three exons of the GnRH-R gene from tumoral DNA. The entire coding sequence of the GnRH-R gene was sequenced in the ten adenomas. No mutation was found in any of the tumor specimens examined. In conclusion, mutations in the GnRH receptor coding sequence occur infrequently if at all in gonadotropin-secreting pituitary adenomas.

Hyperthermic intraperitoneal doxorubicin: pharmacokinetics, metabolism, and tissue distribution in a rat model.

BACKGROUND: The cytotoxic effect of several anticancer agents, including doxorubicin, can be enhanced by hyperthermia. The purpose of this study was to evaluate the effect of hyperthermia on the pharmacokinetics, metabolism, and tissue distribution of intraperitoneal (i.p.) doxorubicin in a rodent model. METHODS: Doxorubicin was given i.p. to 20 Sprague-Dawley rats at a dose of 2 mg/kg over 60 min. Rats were randomized into two groups according to the temperature of the peritoneal perfusate: group NT received normothermic (37 degrees C) i.p. doxorubicin; group HT received hyperthermic (43 degrees C) i.p. doxorubicin. During the course of i.p. chemotherapy, peritoneal fluid and blood were sampled every 10 min. At the end of the procedure, rats were sacrificed and tissue samples (liver, spleen, small bowel, omentum, bladder, diaphragm, abdominal wall, heart) were collected. Concentrations of doxorubicin and its aglycone metabolites were determined in peritoneal fluid, plasma, and tissues by HPLC. RESULTS: No significant differences in areas under the curve (AUC) of peritoneal fluid doxorubicin and plasma doxorubicin were found between group NT and group HT. AUC ratios (AUC peritoneal fluid/AUC blood) were 87.9 for group NT and 82.9 for group HT. Group HT exhibited increased doxorubicin concentrations for all intraabdominal tissues. These differences were significant for spleen (P = 0.03), small bowel (P = 0.03), and omentum (P = 0.03). Doxorubicin aglycone was detected in plasma of both groups within the first 10 min of the procedure. There was a significant (P < 0.001) increase in plasma aglycone AUC for group HT when compared with group NT. Group HT exhibited increased aglycone concentration for all tissues. This difference was significant for liver (P < 0.001) and bladder (P < 0.001). CONCLUSION: Hyperthermia did not affect significantly the pharmacokinetics of i.p. doxorubicin. Tissue concentrations of doxorubicin in small bowel, omentum, and spleen were significantly increased when the drug was administered by hyperthermic i.p. perfusion. Hyperthermia increased significantly the doxorubicin aglycone concentrations in plasma, liver, and bladder.

CT in the selection of patients with abdominal or pelvic sarcoma for reoperative surgery.

BACKGROUND: Retroperitoneal or visceral sarcoma may recur with disease limited to the abdomen and pelvis. In this clinical situation, further surgical treatments in an attempt to control the disease may be appropriate. CT is used to help select patients for additional surgical interventions. STUDY DESIGN: Preoperative abdominal and pelvic CT scans of 33 patients with recurrent sarcoma were reviewed retrospectively. All patients underwent reoperative surgery and, when appropriate, perioperative intraperitoneal chemotherapy. Patients were divided into two groups according to survival and disease status: alive with no evidence of disease (n = 7) and alive with disease or dead of disease (n = 26). Twenty-two CT indices were studied retrospectively for each patient and evaluated statistically. RESULTS: The presence of large (greater than 5 cm) tumor volume in 3 of the 13 abdominopelvic regions resulted in a significant difference in the prognosis between the groups of patients. These findings included tumor in the left lower quadrant (p = 0.032), tumor in the pelvis (p = 0.008), and tumor in the distal jejunum (p = 0.032). Two other CT indices that showed a significant difference in survival between the groups were involvement of five abdominopelvic regions or fewer (p = 0.008) and a peritoneal cancer index of 15 or less (p = 0.03). A statistical approach using a tree-structured diagram showed that patients with tumor diameter greater than 5 cm in the pelvis accompanied by tumor involvement of more than one segment of small bowel had a 0% probability of postoperative disease-free survival. In contrast, patients with tumor diameter less than 5 cm in the pelvis on CT had an 86% probability of disease-free survival. CONCLUSIONS: For patients with recurrent sarcoma, selection criteria were generated by a preoperative CT of the abdomen and pelvis. In this disease, CT was a reliable diagnostic test for predicting benefit from further surgical interventions and should be used in the future to help select patients for an aggressive versus a palliative approach.

Abdominal computed tomographic scan in the selection of patients with mucinous peritoneal carcinomatosis for cytoreductive surgery.

BACKGROUND: Cytoreductive surgery and intraperitoneal chemotherapy have been used to treat peritoneal carcinomatosis. A complete surgical resection is required for optimal results to be achieved. This study evaluated the preoperative computed tomographic (CT) findings in patients with mucinous peritoneal carcinomatosis in order to predict the probability of a complete resection. STUDY DESIGN: Computed tomographic scans of the abdomen and pelvis were reviewed retrospectively in 45 patients with a diagnosis of mucinous peritoneal carcinomatosis who were treated with surgery and intraperitoneal chemotherapy. According to the completeness of cytoreduction, patients were divided into two groups. Patients in the first group (n = 25) had complete cytoreduction (CR) with no tumor deposits 2.5 mm in diameter or larger left behind. The surgical resection of tumor was incomplete in the second group of patients (n = 20). Sixteen CT parameters were initially examined in each group of patients and statistically evaluated according to the completeness of the cytoreductive surgical procedure. RESULTS: The incidences of six CT findings were significantly different in the two groups of patients. These findings were: tumor volume in small bowel mesentery (p < 0.001), tumor volume in proximal jejunum (p = 0.003), tumor volume in distal jejunum (p = 0.002), tumor volume in proximal ileum (p = 0.003), mesentery configuration (p < 0.001), and obstruction of bowel segments by tumor (p < 0.001). A statistical approach using a tree-structured diagram showed that patients with both obstruction of bowel segments by tumor and tumor diameter greater than 0.5 cm on small bowel surfaces exclusive of distal ileum on preoperative CT scan, had an 88 percent probability of incomplete resection. Patients without these two CT findings had a 92 percent probability of complete resection. CONCLUSIONS: This study shows that selection criteria for patients with mucinous peritoneal carcinomatosis are available on a preoperative CT scan of the abdomen and pelvis. Patients whose scans show obstruction of bowel segments by tumor and tumor diameter greater than 0.5 cm on small bowel surfaces exclusive of distal ileum are unlikely to be candidates for cytoreductive surgery for the treatment of peritoneal carcinomatosis.

Efficacy of naftidrofuryl in patients with moderate senile dementia.

In a controlled double-blind study, 78 patients with moderate senile dementia were randomly assigned to 3-months' treatment with 200 mg naftidrofuryl twice daily in slow-release form or with placebo. The patients were selected on the basis of the EACG (Echelle d'Appréciation Clinique en Gériatrie), which was also used as main criterion for confirmatory analysis of the efficacy of naftidrofuryl. A further main criterion was the SGRS (Stockton Geriatric Rating Scale). Secondary criteria examined were visual memory as tested in the Benton test, verbal memory as tested in the Rey test and numerical memory as tested in the digit-span test. The patients' concentration was tested in the Zazzo test. The tests were performed before the patients were admitted to the study and after 1 and 3-months' treatment. Confirmatory analysis of the primary criteria showed a significant treatment difference in favour of naftidrofuryl in the form of improvement in the global symptoms of senile dementia both in the EACG and in the SGRS, the scores in the naftidrofuryl group improving by 15% compared with only 5% in the placebo group. This was paralleled by a significant improvement in visual and verbal memory in the naftidrofuryl group in comparison with placebo. The naftidrofuryl patients also showed a greater improvement in concentration than the placebo group. One patient in the naftidrofuryl group suffered briefly from gastro-intestinal symptoms. There were no changes in routine laboratory parameters studied.

Peritoneal-plasma barrier.

The peritoneal-plasma barrier is a pharmacologic entity of importance for treatment planning in patients with malignant tumours confined to the abdominal cavity. This physiologic barrier limits the resorption of drugs from the peritoneal cavity into the blood. The sequestration of chemotherapeutic agents improves their locoregional cytotoxicity and reduces their systemic toxicity. The physical nature of the peritoneal-plasma barrier has not been clearly defined. Further pharmacologic studies need to be performed in order to achieve a better understanding of this interesting metabolic phenomenom. At present, it is suspected that a diffusion barrier exists that consists of subserosal tissues or blood vessel walls. As postulated by Maher [29], the capillary wall appears to offer the dominant resistance to the transfer of larges solutes. The mesothelium and intersitium impede their movement to a lesser extent, and their removal during cytoreductive surgery does not affect the pharmacology of postoperative intraperitoneal chemotherapy.