Encapsulating peritoneal sclerosis: experience of a tertiary referral center.

AIM: Encapsulating peritoneal sclerosis (EPS) is arguably the most serious complication of chronic peritoneal dialysis (PD) therapy with extremely high mortality rates. We aimed to establish the rates of EPS and factors associated with its development in a single center. METHODS: We retrospectively reviewed the records of all our PD patients from 1 January 1989 until 31 December 2008. All suspected cases were confirmed at laparotomy. Multifactorial models adjusted for potentially confounding variables such as age and sex. RESULTS: Eleven cases of EPS were identified giving a prevalence rate of 1.98%. Median duration on PD was substantially longer in affected versus unaffected patients (42.5 months versus 13.8 months; p = 0.0002). EPS patients had experienced a mean of 3.54 previous cases of peritonitis (1 infection per year versus 0.71 per year in unaffected patients; p = 0.075). Six patients died (54.5%) due to intra-abdominal sepsis including all five who presented with small bowel obstruction. Three patients had an omentectomy and adhesiolysis performed with a successful outcome. CONCLUSION: Our study reinforces the link between duration on PD and EPS. While mortality was high in our cohort, emerging surgical techniques demonstrate a favorable outcome that can be achieved even in severely affected cases.

Altered sensitivity to d-methylamphetamine, apomorphine, and haloperidol in rhesus monkeys depleted of caudate dopamine by repeated administration of d-methylamphetamine.

The long-term neurochemical and behavioral effects of repeated d-methylamphetamine (d-MA) administration were investigated using four male rhesus monkeys trained to lever-press for food on a DRL-40s schedule of reinforcement. Dose-response curves for d-MA (0.0625-2.0 mg/kg), apomorphine (0.025-0.4 mg/kg), and haloperidol (0.005-0.04 mg/kg) on responding showed that repeated d-MA administration (0.5-16.0 mg/kg/day) decreased sensitivity to d-MA and to apomorphine but increased sensitivity to haloperidol. At 3-6 months after the last injection of d-MA, a 48.1% decrease in caudate dopamine (DA) was observed, with the frontal cortex, midbrain, and pons-medulla showing no significant change. A trend toward increasing concentrations of norepinephrine was noted in the same brain areas, but only in the frontal cortex did this change reach significance. Specific binding of 3H-spiroperidol to caudate membrane preparations was not changed, while the Vmax of the caudate DA re-uptake process declined 32%, with no change in Km. These results suggest that exposure of DA neurons in the caudate nucleus to high concentrations of d-MA can lead to nerve terminal degeneration.

Role for protein synthesis in the neurotoxic effects of methamphetamine in mice and rats.

The mechanism by which the amphetamines damage selectively nigrostriatal dopaminergic neurons in experimental animals remains uncertain. The observation that neuronal cell death during embryogenesis involves an activation of gene expression and new protein synthesis, coupled with recent reports indicating that the amphetamines are capable of inducing neuropeptide biosynthesis, offers a possible clue as to their neurotoxic mechanism of action. Based on these considerations, we evaluated the effects of two different inhibitors of protein synthesis, cycloheximide and anisomycin, on the long-term, amine-depleting effects of methamphetamine (METH) in mice and rats. Both inhibitors were found to block the amine-depleting effects of METH in these species. In other experiments, cycloheximide did not affect the functional integrity of dopaminergic or glutamatergic neurons, transmitter systems previously implicated in the neurotoxic mechanism of action of METH. These findings raise the possibility that the neuronal-damaging effects of METH are mediated via a synthesis of 'neurotoxic' proteins.

Blockade of behavioral sensitization to cocaine and amphetamine by inhibitors of protein synthesis.

Anisomycin and cycloheximide were used to investigate the role of protein synthesis in the mechanism of behavioral sensitization to the stereotypic effects of cocaine and amphetamine in mice. The drugs completely antagonize induction and partially block expression of the sensitization. Because these drugs were found to be neither antidopaminergic nor antiglutamatergic, it seems that they disrupt sensitization at a novel locus. The antagonism of expression is limited to that quantitative fraction of the response derived from the sensitization reaction; the acute response is unaffected by the inhibitors of protein synthesis. The results differ from those obtained with haloperidol which can completely block either the acute or sensitized response to the stimulants. These results suggest that the sensitized response is functionally different from that of the acute response. The blockage of sensitization induction by the protein synthesis inhibitors may be related to other reports that the stimulants induce the transcription of immediate early genes; however, the relationship between the activation of immediate early genes and behavioral sensitization remains to be determined.

Effects of L-type calcium channel antagonists on the serotonin-depleting actions of MDMA in rats.

The calcium channel antagonists verapamil nifedipine and flunarizine all increased the threshold for convulsions induced by N-methyl-D-aspartate in rats. By contrast, only flunarizine blocked the long-term serotonin-depleting effects of 3,4-methylenedioxymethamphetamine. Flunarizine was also the only drug that antagonized methamphetamine-induced stereotypy. These findings suggest that calcium influx through L-type channels does not participate in the neurotoxic mechanism of MDMA, and that the neuroprotective actions of flunarizine are probably related to its anti-dopaminergic activity.

Dextromethorphan protects against the neurotoxic effects of p-chloroamphetamine in rats.

Dextromethorphan, an agent that blocks the neuronal-damaging effects of hypoxemia in vitro, was tested for its ability to prevent the neurotoxic effects of p-chloroamphetamine (PCA). Rats were treated with either saline, PCA, dextromethorphan, or the combination of PCA and increasing doses of dextromethorphan. Dextromethorphan provided a dose-related protection against the serotonin (5-HT)-depleting effects of PCA. These observations may offer a clue as to the mechanism responsible for PCA-induced neurotoxicity.

The relationships between aging, monoamine oxidase, striatal dopamine and the effects of MPTP in C57BL/6 mice: a critical reassessment.

Although the effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice have been reported to increase with age, they have not been characterized in the full spectrum of ages. Thus, in spite of a considerable body of scientific literature on the subject, previous reports leave unanswered the question of whether or not the increased susceptibility of fully mature mice is part of the aging process or simply a consequence of maturation. In the present study, the age-related effects of MPTP on striatal dopamine were studied in groups of C57BL/6 mice from young maturity to old age. The major increase in the effects of MPTP occurred between 2 and 10 months of age (equivalent to adolescence and young adulthood in humans). A slight additional increase was observed between 10 and 16 months (young adulthood and middle age) and the dopamine-depleting effects of MPTP significantly declined in truly aged animals (24 months). Of note also is the fact that normal concentrations of striatal dopamine did not decline in the later ages. Additional studies indicated that while neuronal sensitivity to the effects of 1-methyl-4-phenylpyridinium (MPP+; the putative toxic metabolite of MPTP) appears to remain constant, age-related changes in the activity of striatal monoamine oxidase type B (MAO B) paralleled the dopamine-depleting effects of MPTP in the 4 age groups. Indeed, MAO B activity increased between 2 and 16 months and declined slightly, but significantly, between 16 and 24 months. This pattern of age-related changes in MAO B, striatal dopamine and the sensitivity of the nigrostriatal system to toxic insult may provide insights into factors which have been implicated in age-related neurodegeneration and idiopathic Parkinson's disease.

The dopamine-depleting effect of 6-hydroxydopamine does not increase with aging.

The dopamine-depleting effects of intracerebroventricularly administered 6-hydroxydopamine (6-OHDA) were studied in young mature (6-8 weeks), older (8-12 months) and aged (18-24 months) mice. No differences were noted between age groups. To rule out the possibility that higher levels of monoamine oxidase (which degrades 6-OHDA) in older animals might be masking an increased sensitivity of older neurons to 6-OHDA, experiments were repeated after treatment with pargyline (50 mg/kg). Again, no differences between age groups were noted. We conclude that aging does not increase the sensitivity of dopaminergic neurons to 6-OHDA.

The amine-depleting effects of 5,7-dihydroxytryptamine (5,7-DHT) in C57BL/6 mice do not increase with age.

A recent approach to identifying the factors that predispose neurons to an early death in Parkinson's or Alzheimer's disease has been to study how the effect of specific neurotoxins are altered by increasing maturity. We determined the dose-related serotonin and norepinephrine-depleting effects of the selective neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), in C57BL/6 mice of 2 different ages. Norepinephrine and serotonin in the hippocampus were assayed 1 week after the intracerebroventricular (i.c.v.) administration of 5,7-DHT. 5,7-DHT produced an equivalent, dose-related depletion of hippocampal norepinephrine in both age groups. Since the effects of 5,7-DHT on noradrenergic neurons may, at least in part, depend on the monoamine oxidase (MAO)-generated formation of hydrogen peroxide and associated oxy-radicals, this result suggests that noradrenergic neurons do not become more vulnerable to oxidative stress with aging. We also found that the noradrenergic-depleting effects of 5,7-DHT were blocked by the non-selective MAO inhibitor pargyline (50 mg/kg, i.p.), while the selective MAO B inhibitor deprenyl (10 mg/kg, i.p.) failed to prevent this depletion. These latter results suggest that it is the A form of MAO that plays an important role in the mechanism of 5,7-DHT-induced noradrenergic toxicity. Somewhat unexpectedly, older mice were found to be less susceptible to the serotonin-depleting effects of 5,7-DHT. Although the mechanism by which this compound damages serotonergic neurons is uncertain, our results show that the increased susceptibility of serotonergic neurons to 5,7-DHT in young animals extends well beyond the neonatal period.

Orally administered MDMA causes a long-term depletion of serotonin in rat brain.

Recent studies suggest that 3,4-methylenedioxymethylamphetamine (MDMA), when administered subcutaneously, is toxic to central serotonergic neurons in rats. Because humans typically self-administer this drug orally, we compared this route to the s.c. route of administration. Orally administered MDMA produced a dose-related depletion of serotonin comparable to that produced by the s.c. route. These findings suggest that MDMA, when given orally, retains it neurotoxic activity and that humans using MDMA may be at risk for developing a persistent depletion of brain serotonin.

The evolution of nigrostriatal neurochemical changes in the MPTP-treated squirrel monkey.

The MPTP-treated monkey has become an important model for the study of Parkinson's disease. However, studies on the acute evolution of the neurotoxic effects of MPTP in primates are lacking. In the present study, 17 squirrel monkeys were given a single subcutaneous injection of MPTP (2.5 mg/kg). The behavioral effects and the concentrations of dopamine (DA), dihydroxyphenylacetic acid and homovanillic acid were determined in caudate, putamen and substantia nigra 1, 3, 5 (n = 3/time point) and 10 days (n = 6) after drug administration. Two animals were studied neuropathologically 8 and 9 days after MPTP. Profound parkinsonism was evident in all animals after 1 day and neuropathological examination revealed severe nerve cell destruction in the substantia nigra. Surprisingly, although 50-75% reductions in nigral DA were observed 1 and 3 days after MPTP, caudate DA was not reduced and putaminal DA was increased at these time points. The temporal sequence of these events differs markedly from that which occurs in the MPTP-treated mouse and suggests that, in the monkey, nigral cell bodies may represent an important initial site of MPTP-induced damage. Five and 10 days after MPTP, nigral DA depletions remained greater than 60% of control and striatal DA was reduced 50-85%. At these time points, the putamen was always more affected than the caudate. This interregional pattern of striatal DA deficits is similar to that seen in idiopathic Parkinson's disease.

A comparison of the neurochemical and behavioral effects of clenbuterol and desipramine.

Because both long-term adrenoceptor agonist administration and antidepressant treatment in animals down-regulate CNS beta-adrenoceptors and attenuate brain adenylate cyclase activity, beta-adrenoceptor agonists may also possess antidepressant properties. We compared the effects of the centrally acting beta-adrenoceptor agonist clenbuterol (5, 10 and 35 mg/kg per day), and the combination of propranolol (5 mg/kg per day) and clenbuterol (10 mg/kg per day), with desipramine (15 mg/kg per day) on forced swim test performance and on cortical beta-adrenoceptors in rats following 7 days of drug administration. Desipramine (15 mg/kg per day), and clenbuterol (10 and 35 mg/kg per day, but not 5 mg/kg per day) both significantly reduced immobility in the forced swim test. Frontal cortex beta-adrenoceptors were significantly down-regulated after desipramine and all 3 doses of clenbuterol. The co-administration of propranolol (5 mg/kg per day) blocked both the reduction in immobility and down-regulation of cortical beta-receptors induced by clenbuterol (10 mg/kg per day). Propranolol (5 mg/kg per day) alone up-regulated frontal cortex beta-adrenoceptors, but had no significant effect on swimming performance. These data suggest that the physiological consequences of beta-adrenoceptor down-regulation are important in the mechanism of action of antidepressants. The results also suggest that clenbuterol may be useful in the treatment of depression.

Protection against DSP-4-induced neurotoxicity by deprenyl is not related to its inhibition of MAO B.

Clinical studies suggest that deprenyl may retard the progression of Parkinson's disease, an effect that may be related to its monoamine oxidase (MAO) inhibiting properties. Deprenyl also protects against the neurodegenerative effects of the noradrenergic toxin DSP-4. In this study we investigated the role of MAO B inhibition in this protection. C57BL/6 mice were given DSP-4 (50 mg/kg i.p.) 1 h. 24 h or 4 days after the administration of deprenyl (10 mg/kg i.p.) or the selective MAO B inhibitor MDL 72974 (1.25 mg/kg), and then killed 1 week later for assay of hippocampal norepinephrine. The MAO B inhibiting effects of deprenyl or MDL 72974 were also determined after these same intervals of time. Deprenyl and MDL 72974 produced comparable degrees of enzyme inhibition 1 h (greater than 95%), 24 h (greater than 90%) or 4 days (greater than 70%) after their administration. Given 1 h before, deprenyl totally blocked the norepinephrine-depleting effects of DSP-4, but this protection declined sharply when 24 h or 4 days was allowed to elapse between deprenyl and DSP-4 administration. MDL 72974 failed to protect at any time point. In vitro, we detected no activity using DSP-4 as a substrate for MAO. These findings suggest that the ability of deprenyl to protect against DSP-4-induced neuronal degeneration may not depend on its MAO B inhibiting properties.

3,4-Methylenedioxyethylamphetamine (MDE), a novel analogue of MDMA, produces long-lasting depletion of serotonin in the rat brain.

The present study was carried out to asses possible toxic effects of 3,4-methylenedioxyethylamphetamine (MDE) on serotonergic, dopaminergic or noradrenergic neurons in the rat brain. It was found that MDE produced a long-lasting, dose-related depletion of serotonin (5HT). However, even at high dosage, MDE did not reduce the concentration of either dopamine (DA) or norepinephrine (NE) on a long-term basis. When compared to 3,4-methylenedioxymethylamphetamine (MDMA), MDE was approximately one fourth as potent as producing a long-term depletion of 5HT. These results suggest that MDE, like MDMA, may be selectively toxic to central serotonergic neurons.

The N-methyl-D-aspartate (NMDA) receptor antagonist, dextrorphan, prevents the neurotoxic effects of 3,4-methylenedioxymethamphetamine (MDMA) in rats.

Using the systemically active, non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist dextrorphan, we explored the role of the NMDA receptor-calcium channel complex in the toxic mechanism of action of 3,4-methylenedioxymethamphetamine (MDMA). Rats were treated with MDMA, dextrorphan, or the combination of MDMA and increasing doses of dextrorphan, and then killed 10 days later for the assay of serotonin and dopamine in the striatum, hippocampus, and cortex. Dextrorphan totally prevented the serotonin-depleting effects of MDMA in the straitum, with a lessened but still significant blockade noted in the hippocampus and cortex. These findings may provide a clue to the molecular events underlying MDMA-induced neurotoxicity.

Phencyclidine-induced rotational behavior in rats with nigrostriatal lesions and its modulation by dopaminergic and cholinergic agents.

The peripheral administration of the psychotomimetic drug phencyclidine (1-(phenylcyclohexyl) piperidine hydrochloride) (PCP) induces a dose-related ipsilateral rotation in unilateral substantia nigra electrolytically-lesioned rats. The intensity of this rotation can be modulated by administration of various dopaminergic and cholinergic agents. Injection of alpha-methylparatyrosine methylester (125 mg/kg) or haloperidol (1 mg/kg) inhibited the ipsilateral circling behavior. Pimozide (1 mg/kg) also inhibitied the rotation, but to a lesser extent. The injection of the anticholinergic agent trihexyphenidyl (5 mg/kg) potentiated, and the cholinomimetic drug arecoline (5 mg/kg), depressed the rotation induced by PCP (7.5 mg/kg), It is probable that PCP possesses significant dopaminergic and anticholinergic properties. The capacity of PCP to induce rotation in this model may be related to its effects on dopaminergic and cholingergic neurons in the rat striatum. Thus, PCP may induce rotational behavior by potentiating dopaminergic transmission, by blocking cholinergic activity, or both; both of these effects have been demonstrated to be important in the generation of circling behavior in rats with nigrostriatal lesions.

The presence and possible function of methylmalonyl CoA mutase and propionyl CoA carboxylase in Spirometra mansonoides.

Both spargana and adult forms of Spirometra mansonoides were shown to accumulate lactate, succinate, acetate, and propionate upon in vitro incubation. Adults differed markedly from the spargana in that quantitatively the most significant products of the former were acetate and propionate while the latter formed primarily acetate and lactate. The adults accumulated approximately 32 times more propionate than the spargana per gram of tissue. In accord with this propionate formation, propionyl CoA carboxylase and methylmalonyl CoA mutase have been found to be present in both stages of the parasite. As might be predicted, however, the activities of the carboxylase and mutase were 100-fold and 10-fold higher, respectively, in the adults as compared to the larvae. A possible physiological relationship between propionate formation and energy generation is suggested. Accordingly, inorganic 32P was incorporated into ATP upon incubation of methylmalonyl CoA with a homogenate obtained from adult S. mansonoides. Since methylmalonyl CoA mutase requires vitamin B12 coenzyme, a relationship between vitamin B12 content and propionate formation in helminths is suggested.

Career choices and professional attitudes of graduating clinical laboratory science students: a nationwide survey.

OBJECTIVE: To conduct a nationwide survey of graduating clinical laboratory science students in order to gather descriptive data and to determine how graduates felt about their profession and what their career goals were for the next 5 years. DESIGN: Survey PARTICIPANTS: A total of 866 clinical laboratory science seniors from hospital-based and university-based clinical laboratory science programs in the United States. OUTCOME MEASURES: Results of questions designed to gather descriptive data and professional goals as well as scales measuring professional attitudes about various aspects of the clinical laboratory science profession. RESULTS: Respondents indicated a high level of satisfaction with their chosen profession as indicated by the positive ratings of their clinical laboratory science program and immediate and long-term employment goals. CONCLUSION: Graduating clinical laboratory science students displayed satisfaction with their profession as evidenced by their career choices immediately following graduation, their professional goals 5 years after graduation, and their responses assessing professional attitudes.

Relationships among types of speech intelligibility in pediatric users of cochlear implants.

UNLABELLED: Twenty pediatric users of cochlear implants were administered three tests of speech intelligibility: (1) a test of contrast perception intelligibility, (2) a test of contrast production intelligibility, and (3) a test of production sentence intelligibility. Sixty adults with normal hearing served as listener judges for the two speech production tasks, and percent correct scores were generated for each of the three tasks. Correlational analyses showed significant correlations among overall scores for the three tasks. However, scores for individual feature classes from the contrast perception task were not correlated with their corresponding contrast production feature class scores, and only some of the feature class scores were correlated significantly with sentence intelligibility. We conclude that although these three types of intelligibility are related at a gross level, relationships are more tenuous at finer levels of analysis, suggesting that the separate skills may need to be addressed separately in remediation. EDUCATIONAL OBJECTIVES: As a result of this activity, the participant will be able to differentiate various methods for assessing speech intelligibility and describe the relationships among different types of speech intelligibility in pediatric users of cochlear implants.

Fostering interest in research: evaluation of an introductory research seminar at hospitals in rural Rwanda.

SETTINGS: Partners In Health Rwanda, in collaboration with the Ministry of Health, leads a multipronged approach to develop research capacity among health workers, particularly in rural areas. OBJECTIVES: To describe the characteristics of participants and to assess the impact of an introductory research seminar series in three district hospitals in rural Rwanda. DESIGN: This was a retrospective cohort study of seminar participants. Data were sourced from personnel records, assessment sheets and feedback forms. RESULTS: A total of 126 participants, including 70 (56%) clinical and 56 (44%) non-clinical staff, attended the research seminar series; 61 (48%) received certification. Among those certified, the median assessment score on assignments was 79%. Participants read significantly more articles at 6 and 12 months (median 2 and 4 respectively, compared to 1 at baseline, P < 0.01). There was also a significant increase (P ⩽ 0.05) in self-reported involvement in research studies (28%, baseline; 59%, 12 months) and attendance at other research training (36%, baseline; 65%, 12 months). CONCLUSION: The introductory research seminar series provided an important opportunity for engagement in research among clinical and non-clinical staff. Such an activity is a key component of a comprehensive research capacity building programme at rural sites, and serves as an entry point for more advanced research training.

Contexte : Partners In Health Rwanda, en collaboration avec le Ministère de la Santé, mène une approche multiple afin de développer les capacités de recherche du personnel de santé, surtout dans les zones rurales.Objectifs : Décrire les caractéristiques des participants et évaluer l'impact d'une série de séminaires d'introduction à la recherche dans trois hôpitaux de district ruraux du Rwanda.Schéma : Etude rétrospective de cohorte des participants au séminaire. Les données ont été recueillies à partir de dossiers personnels, de formulaires d'évaluation et de rétroaction.Résultats : Des 126 participants qui ont assisté à la série de séminaires de recherche, 70 (56%) étaient cliniciens et 56 (44%) personnel non-clinicien. Soixante et un (48%) ont obtenu leur certificat. Parmi ces derniers, le score médian d'évaluation des travaux était de 79%. Les participants lisaient beaucoup plus d'articles à 6 et 12 mois (médiane = 2 et 4 respectivement, comparé à 1 au départ, P < 0,01). On notait également une augmentation significative (P ⩽ 0,05) de l'implication dans des travaux de recherche rapportée par les intéressés eux-mêmes (28% au départ contre 59% à 12 mois) ainsi que de la participation à d'autres formations relatives à la recherche (36% au départ contre 65% à 12 mois).Conclusion : La série de séminaires d'introduction à la recherche a fourni une opportunité majeure d'engagement dans la recherche du personnel clinicien et non clinicien. Une telle activité est un élément clé d'un programme complet de renforcement des capacités de recherche dans les zones rurales et sert de point d'entrée pour des formations à la recherche plus avancées.

Marco de referencia: La organización Partners In Health de Rwanda, en colaboración con el Ministerio de Salud, dirige un proyecto multidimensional de creación de capacidad de investigación, dirigida a los profesionales que se ocupan de la salud, especialmente en las zonas rurales.Objetivos: Describir las características de los participantes y evaluar el efecto de la realización de una serie de seminarios introductorios a la investigación, en tres hospitales distritales de zonas rurales en Rwanda.Método: Fue este un estudio retrospectivo de cohortes de los participantes a los seminarios. Se obtuvieron datos a partir de los registros personales, las hojas de evaluación y los formularios de retroalimentación.Resultados: Participaron a la serie de seminarios 126 personas, de las cuales 70 pertenecían al personal asistencial (56%) y 56 a personal de otras esferas (44%). Sesenta y un participantes recibieron la certificación (48%). De las personas certificadas, la mediana de puntuación de la evaluación fue 79%. Los participantes leyeron más artículos a los seis y a los doce meses de la intervención (mediana = 1 y 4 respectivamente; P < 0,01) que al comienzo de la misma (mediana = 1; P ⩽ 0,05). Se observó además un aumento significativo de la intervención autorreferida en estudios de investigación (28% al comienzo y 59% a los 12 meses) y de la participación en otras capacitaciones científicas (36% al comienzo y 65% a los 12 meses).Conclusión: La serie de seminarios introductorios a la investigación ofreció al personal asistencial y a otros miembros del personal una importante oportunidad de participar en las actividades científicas. Este tipo de intervención constituye un componente primordial del programa integral de creación de capacidad de investigación en los centros rurales y representa una puerta de entrada a las capacitaciones científicas más avanzadas.