Effect of Pluronic L-81 on intestinal lipoprotein secretion in the rat

The hydrophobic nonionic detergent Pluronic L-81 has been shown to lower plasma very-low-and low-density lipoprotein cholesterol, thus preventing diet-induced atherogenesis. The major effect of this agent is a pronounced interference with intestinal lipid metabolism. For studying mesenteric lymph lipoproteins during detergent exposure, a combined micromorphological and biochemical assessment of mucosa and lymph during steady-state lipid absorption was performed. Pluronic L-81 was infused intraduodenally at a constant rate in combination with mixed micellar solutions or saline in mesenteric lymph fistula rats. Pluronic L-81 impairs transepithelial lipid flux during fat absorption, trapping export lipids within the enterocytes and leading to a cytosolic and endoplasmic reticulum lipid accumulation sparing the Golgi region. Pluronic L-81 markedly (P<0.001) reduces mesenteric triglyceride, phospholipid, and total cholesterol secretion almost exclusively by a reduction of chylomicron formation. Chylomicron and very-low-density lipoprotein lipid composition was only insignificantly altered, except for somewhat higher phospholipid/triglyceride ratios. The chylomicron apoprotein pattern was almost unaffected. Thus, chylomicron formation decreased dramatically without major compositional alterations. The reduction of lipid and apoprotein secretion without particle augmentation is not in favour of a selective interference of Pluronic L-81 with intestinal apoprotein B-48 secretion.Parts of this work have been presented at the Annual Meeting of the American Gastroenterological Association, Washington, DC, May 1989, and published in abstract form (1).     

Management of tandem occlusions in patients who receive rtPA

Journal of Thrombosis and Thrombolysis - Tandem occlusions exist in 17–32% of large vessel occlusion (LVO) strokes. A significant concern is bleeding when carotid stenting is performed in...     

Répartition spatio-temporelle des cas de tuberculose dans la ville de Saint-Louis du Sénégal entre 2008–2011

BackgroundWe studied the incidence of tuberculosis in the health district of Saint-Louis, Senegal over a period of 4 years (2008–2011). One thousand three hundred and eighty-six cases were identified, producing an annual standardized incidence ratio of 129 cases per 100,000 inhabitants.ResultsMen in the 15–24-year old age group were more likely to be affected, and diagnosis was more common in the second half of the year. Treatment compliance was excellent (96%), and the cure rate of patients with a TB-positive microscopic examination was 95%. The overall treatment failure rate was 1% and the 6-month morality was 2%. Seropositivity, measured in volunteer patients (48%) was 3%.ConclusionA spatial and temporal map of tuberculosis in the city of Saint-Louis, Senegal has been established. A cluster appears to be very likely in Guet Ndar, a particularly dense population zone in a fishing area. There is also a possible secondary cluster at Pikine.     

Transgenic over expression of ectonucleotide triphosphate diphosphohydrolase-1 protects against murine myocardial ischemic injury

Modulation of purinergic signaling is critical to myocardial homeostasis. Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD-1; CD39) which converts the proinflammatory molecules ATP or ADP to AMP is a key regulator of purinergic modulation. However, the salutary effects of transgenic over expression of ENTPD-1 on myocardial response to ischemic injury have not been tested to date. Therefore we hypothesized that ENTPD-1 over expression affords myocardial protection from ischemia–reperfusion injury via specific cell signaling pathways. ENTPD-1 transgenic mice, which over express human ENTPDase-1, and wild-type (WT) littermates were subjected to either ex vivo or in vivo ischemia–reperfusion injury. Infarct size, inflammatory cell infiltrate and intracellular signaling molecule activation were evaluated. Infarct size was significantly reduced in ENTPD-1 versus WT hearts in both ex vivo and in vivo studies. Following ischemia–reperfusion injury, ENTPD-1 cardiac tissues demonstrated an increase in the phosphorylation of the cellular signaling molecule extracellular signal-regulated kinases 1/2 (ERK 1/2) and glycogen synthase kinase-3β (GSK-3β). Resistance to myocardial injury was abrogated by treatment with a non-selective adenosine receptor antagonist, 8-SPT or the more selective A_2B adenosine receptor antagonist, MRS 1754, but not the A₁ selective antagonists, DPCPX. Additionally, treatment with the ERK 1/2 inhibitor PD98059 or the mitochondrial permeability transition pore opener, atractyloside, abrogated the cardiac protection provided by ENTPDase-1 expression. These results suggest that transgenic ENTPDase-1 expression preferentially conveys myocardial protection from ischemic injury via adenosine A_2B receptor engagement and associated phosphorylation of the cellular protective signaling molecules, Akt, ERK 1/2 and GSK-3β that prevents detrimental opening of the mitochondrial permeability transition pore.     

Reduced transmission of human schistosomiasis after restoration of a native river prawn that preys on the snail intermediate host

Eliminating human parasitic disease often requires interrupting complex transmission pathways. Even when drugs to treat people are available, disease control can be difficult if the parasite can persist in nonhuman hosts. Here, we show that restoration of a natural predator of a parasite’s intermediate hosts may enhance drug-based schistosomiasis control. Our study site was the Senegal River Basin, where villagers suffered a massive outbreak and persistent epidemic after the 1986 completion of the Diama Dam. The dam blocked the annual migration of native river prawns (Macrobrachium vollenhoveni) that are voracious predators of the snail intermediate hosts for schistosomiasis. We tested schistosomiasis control by reintroduced river prawns in a before-after-control-impact field experiment that tracked parasitism in snails and people at two matched villages after prawns were stocked at one village’s river access point. The abundance of infected snails was 80% lower at that village, presumably because prawn predation reduced the abundance and average life span of latently infected snails. As expected from a reduction in infected snails, human schistosomiasis prevalence was 18 ± 5% lower and egg burden was 50 ± 8% lower at the prawn-stocking village compared with the control village. In a mathematical model of the system, stocking prawns, coupled with infrequent mass drug treatment, eliminates schistosomiasis from high-transmission sites. We conclude that restoring river prawns could be a novel contribution to controlling, or eliminating, schistosomiasis.Multiply just (US) $0.32, the annual cost to treat a child infected with schistosomiasis (1), by the 114 million children requiring treatment (2), and cheap drug-based treatment can become too costly to sustain. Drug-based control programs for human helminth diseases, termed preventive chemotherapy, have led to spectacular improvements in health and reductions of many worm infections (3). The success has led to new challenges in devising strategies to eliminate these parasites over the long-term, sometimes called the “end game” of infectious disease control (4). For schistosomiasis, this new focus on elimination has sparked a debate over the best strategies to complement drug treatment and interrupt the transmission cycle (5–7). In its May 2012 resolution to eliminate schistosomiasis (World Health Assembly Resolution 65.21) (8), the World Health Assembly called for new procedures to interrupt transmission. Here, we offer evidence that the restoration of a natural predator of the obligate snail hosts of schistosomiasis could be an effective strategy to eliminate disease when performed along with drug treatment. We present the results of a recent pilot program to control schistosomiasis after the construction of the Diama Dam on the Senegal River as an example.The Diama Dam is only 18 m high, but that is enough to keep the tide from pushing brackish water up the Senegal River. The impounded river is now a stable reservoir of freshwater for people in Dakar and Saint-Louis, Republic of Senegal, and for irrigating surrounding farmland. Unfortunately, just after the dam was built in 1986, an unprecedented, massive, and persistent schistosomiasis epidemic swept through the villages along the river and its tributaries (9, 10). As some had predicted (11), the dam created an ideal freshwater habitat for the snail intermediate hosts of schistosomiasis by reducing flows and saltwater intrusion and increasing algal and plant growth (12). Moreover, the dam extirpated a chief snail predator (13), whose role in the control of schistosomiasis is the focus of our current study.Schistosomiasis infects an estimated 220–240 million people globally, and 790 million are at risk for infection, more than 90% of whom are in Sub-Saharan Africa (14). Infected humans contaminate water sources with urine or feces containing schistosome eggs that release larvae (miracidia) infectious to snails in the genus Biomphalaria (for Schistosoma mansoni) or Bulinus (for Schistosoma hematobium) (Fig. 1). Each infected snail sheds thousands of cercariae, which seek and penetrate human skin. After entering the skin, the parasites migrate to the blood vessels of the intestines (S. mansoni) or urinary bladder (S. hematobium), where female worms lay 350–2,200 eggs per day (15). Eggs have sharp spines that promote passage through the tissues across the intestines or the urinary bladder. Nonetheless, many eggs do not complete their passage, lodging in the liver, bladder, or other organs, where they trigger chronic inflammatory processes (16). Death from liver failure or bladder cancer can be preceded by chronic anemia, cognitive impairment in children, growth stunting, infertility, and a higher risk of contracting HIV in women (17, 18). These effects, combined with the poverty of its victims, make schistosomiasis one of the world’s most important, but most neglected, human diseases (19). Three decades after the Diama Dam’s completion, schistosomiasis is still the chief health concern among the region’s rural poor (20).Open in a separate windowFig. 1.(A) Adult M. vollenhovenii prawn. (B) Evidence of prawn predation via characteristic damage on snail shells (arrows). (C) Net enclosure for prawns at Lampsar village.Our current research was inspired by an experimental study showing persistent and cost-effective schistosomiasis control in Kenyan villages following snail predation by the exotic North American crayfish (Procambarus clarkii) (21). Although crayfish are not present in Senegal, a large river prawn, Macrobrachium vollenhovenii (Fig. 1), is native to the Atlantic coast of Africa and was reported in fishery catches before the construction of the Diama Dam in Senegal (22). River prawns, like crayfish, feed on the snails that transmit schistosomiasis (Fig. 1), and, as reported in laboratory experiments, captive prawns can control snail abundance (23).Ecological theory supports the idea that the river prawn can eliminate the parasite. The prawn acts as an “intraguild predator” of the schistosome because it both preys on the larval worm when eating infected snails and competes with it by eating the parasite’s host. An intraguild predator can extirpate an intraguild prey, such as the schistosome, when the intraguild predator, like the river prawn, is a generalist and its competitor prey, the larval schistosome, is a specialist (24).The natural history of the region also supports the hypothesis that river prawns can control snails. Before the dam, when river prawns were more common, human schistosomiasis prevalence was low (25). The Diama Dam impeded the annual downstream female migration to the estuary and blocked the upstream return of larvae, after which the river prawn fishery collapsed (13, 23). Prawn extirpation upriver of the dam was concurrent with a dramatic escalation in the prevalence and intensity of human schistosomiasis in the Lower Senegal River Basin (9, 10). It is plausible that the consequent release of snail populations from predation contributed to snail population expansion and to the schistosomiasis epidemic. If so, restoring prawn populations could reduce snail populations and help curb schistosomiasis transmission. Moreover, this hypothesis raises three questions: (i) Can prawns reduce snail abundance at a village water-contact site as they do in aquaria, (ii) can snail population reduction by prawns control schistosomiasis in humans, and (iii) how might the combination of prawn stocking and chemotherapy affect snail populations and parasite elimination?We addressed these questions with the combination of a field experiment and a mathematical model (Materials and Methods). Logistical constraints limited our field experiment to a single control and experimental village (we discuss the limitations imposed by lack of replication below). Briefly, after recruiting two similar villages upriver of the dam, screening participants for schistosomiasis, and confirming (through trapping) that prawns were scarce in nature (13), we stocked prawns at the downstream village in the pair into a 10-m × 20-m net that enclosed an opening in the reeds along the shoreline that villagers used to access the river (Fig. 1). The other village was a control site without prawns. Then, we tracked snail infection prevalence and abundance at these two sites over 18 mo after adding prawns. Unfortunately, there were no comparable snail data collected before the prawn intervention. After treating the village residents enrolled in the study at both intervention and control sites with the anthelminthic praziquantel in three follow-up visits, we measured schistosomiasis reinfection rates. Finally, we created a mathematical model, parameterized with independent data derived from the literature, as well as published and unpublished laboratory data, to simulate the effect of prawn stocking on schistosome transmission dynamics and to compare model outcomes with those outcomes observed in the field.     

Utilisation de la méthode capture-marquage-recapture pour une évaluation quantitative des populations de mollusques dans deux sites à Lampsar (Vallée du Fleuve Sénégal)

The authors have made an estimate of the number of mollusc by the capture-mark-recapture method at two sites in the Valley of the Senegal River. This quantification is necessary to track the effect of the introduction in one of the sites of a native shrimp Machrobrachium vollenhovenii, predator of mollusc. The populations of two study sites were approximately 1,800 and 1,500 individuals with coefficients of variation of about 30%.     

Ectonucleotide triphosphate diphosphohydrolase-1 (CD39) mediates resistance to occlusive arterial thrombus formation after vascular injury in mice

Modulation of purinergic signaling, which is critical for vascular homeostasis and the response to vascular injury, is regulated by hydrolysis of proinflammatory ATP and/or ADP by ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD-1; CD39) to AMP, which then is hydrolyzed by ecto-5'-nucleotidase (CD73) to adenosine. We report here that compared with littermate controls (wild type), transgenic mice expressing human ENTPDase-1 were resistant to the formation of an occlusive thrombus after FeCl(3)-induced carotid artery injury. Treatment of mice with the nonhydrolyzable ADP analog, adenosine-5'-0-(2-thiodiphosphate) trilithium salt, Ado-5'-PP[S], negated the protection from thrombosis, consistent with a role for ADP in platelet recruitment and thrombus formation. ENTPD-1 expression decreased whole-blood aggregation after stimulation by ADP, an effect negated by adenosine-5'-0-(2-thiodiphosphate) trilithium salt, Ado-5'-PP[S] stimulation, and limited the ability to maintain the platelet fibrinogen receptor, glycoprotein α(IIb)/β(3), in a fully activated state, which is critical for thrombus formation. In vivo treatment with a CD73 antagonist, a nonselective adenosine-receptor antagonist, or a selective A(2A) or A(2B) adenosine-receptor antagonist, negated the resistance to thrombosis in transgenic mice expressing human ENTPD-1, suggesting a role for adenosine generation and engagement of adenosine receptors in conferring in vivo resistance to occlusive thrombosis in this model. In summary, our findings identify ENTPDase-1 modulation of purinergic signaling as a key determinant of the formation of an occlusive thrombus after vascular injury.