A series of new furoxan derivatives of praziquantel have been synthesized and evaluated for antis... more A series of new furoxan derivatives of praziquantel have been synthesized and evaluated for antischistosomal activity. The newly synthesized hybrid compounds have structural modifications at amide and aromatic rings and thus offer broad structure-activity variations. All the compounds have been tested against adult as well as immature Schistosoma mansoni. Compounds 15 and 18 show moderate activity against adult schistosomes. On immature worms, only compound 15 shows substantial activity whereas the standard drug PZQ is practically inactive at this stage.
The American Journal of Tropical Medicine and Hygiene, 1980
Various numbers of 25- to 28-day-old schistosomes of both sexes were surgically transferred into ... more Various numbers of 25- to 28-day-old schistosomes of both sexes were surgically transferred into the mesenteric veins of mice. Recipient animals (plus sham-operated controls) were percutaneously challenged with cercariae at various times after transfer, and the number of surviving worms was subsequently determined by portal perfusion. Significantly fewer challenge parasites were recovered from mice which had received a worm transfer than from sham controls; the reduction was comparable to that observed in mouse recipients of a percutaneous primary infection with cercariae. Resistance of mice to cercarial challenge was dependent upon the number of schistosome pairs transferred, and upon the time interval between transfer and challenge.
The American Journal of Tropical Medicine and Hygiene, 1981
Lung stage schistosomula exposed to 50 kilorads of gamma irradiation induced significant resistan... more Lung stage schistosomula exposed to 50 kilorads of gamma irradiation induced significant resistance to challenge infection with Schistosoma mansoni following intravenous (tail or mesenteric vein), intramuscular, or intraperitoneal injection into mice. Similar or higher levels were induced with irradiated cercariae, while irradiated 3- or 4-week-old worms induced little resistance. Non-irradiated day 6 and day 12 lung schistosomula injected into mice immunized with irradiated cercariae were susceptible to elimination, though to a lesser extent than a challenge infection administered at the cercarial stage. Day 20 liver worms injected into a mesenteric vein were not susceptible to irradiated cercaria-induced resistance. In contrast, cercariae, day 6 lung schistosomula, day 12 lung schistosomula and day 20 liver worms were all susceptible to the resistance induced by a chronic (non-irradiated) infection.
The American Journal of Tropical Medicine and Hygiene, 1986
Normal and passively immunized Fischer rats were infected with 75Se-selenomethionine-labeled cerc... more Normal and passively immunized Fischer rats were infected with 75Se-selenomethionine-labeled cercariae of Schistosoma mansoni. Migration of the parasites from skin to lungs to liver was monitored by autoradiographic analyses of these sites. Labeled parasites migrated from skin to lungs with high efficiency in normal and immune rats; disappearance of labeled parasites from the lungs was slower in immune rats. Labeled parasites accumulated in the liver, reaching maximal values by 11 days post-infection in both groups and remaining constant through day 21. Half the number of labeled parasites were detected in the liver of immune rats. The total number of labeled parasites detected in the skin, lungs, and liver was constant through day 5, then declined to about 60% of this value by day 11 in both groups. Over the next 10 days, the rate of decline decreased significantly in normal rats but did not change in immune rats. By day 21 post-infection, nearly 50% fewer labeled parasites were detectable in immune rats. We conclude that a subpopulation of parasites in the lungs is the target of protective antibody in the serum used for passive immunization. Target parasites, retained longer in the lungs, were probably prevented from migrating successfully to the liver. Another parasite subpopulation migrated to the liver with normal kinetics. Lung schistosomula isolated from normal and passively immunized rats were transferred by intravenous injection into recipient rats and their continued migration from lungs to liver compared. No differences in portal perfusion worm yields were detected in normal recipients; equally reduced yields were detected in passively immunized recipients. We conclude that the effects of antibodies during week 1 post-infection were insignificant or reversible.
The American Journal of Tropical Medicine and Hygiene, 1985
Adult Schistosoma mansoni were incubated for 1 hour in vitro with various drugs and then returned... more Adult Schistosoma mansoni were incubated for 1 hour in vitro with various drugs and then returned into the mesenteric veins of permissive animal hosts. Survival of schistosomes was assessed 3-4 weeks later by portal perfusion. Under these conditions, oxamniquine and hycanthone proved effective in killing S. mansoni, whereas UK-3883, lucanthone and lucanthone-4-desmethyl had no lethal activity. The same drugs which were schistosomicidal in vitro also persistently inhibited DNA, RNA, and protein synthesis in S. mansoni, whereas they were only transiently inhibitory against Schistosoma japonicum, against hycanthone-resistant S. mansoni and against immature worms. When drugs were administered in vivo to infected mice and the synthesis of macromolecules was assayed in vitro on worms obtained 1 or 3 days after treatment, not only oxamniquine and hycanthone, but also UK-3883 and lucanthone, proved effective in inhibiting the synthesis of macromolecules in sensitive--but not in resistant--S. mansoni. It is suggested that oxamniquine, like hycanthone, may exert its schistosomicidal activity by inhibiting nucleic acid synthesis in the parasite.
The antischistosomal pro-drug oxamniquine is activated by a sulfotransferase (SULT) in the human ... more The antischistosomal pro-drug oxamniquine is activated by a sulfotransferase (SULT) in the human parasite Schistosoma mansoni Of the three main human blood fluke species, only S. mansoni is sensitive to oxamniquine therapy despite the presence of SULT orthologs in S. haematobium and S. japonicum The reason for this species-specific drug action has remained a mystery for decades. Here we present the crystal structures of S. haematobium and S. japonicum SULTs, including S. haematobium SULT in complex with oxamniquine. Our finding that all three enzymes show activity toward oxamniquine in vitro reveals differences in catalytic efficiency that implicate kinetics as the determinant for species-specific toxicity. These results support the initiative for designing oxamniquine derivatives to treat infection caused by all species of blood fluke to combat emerging resistance to current therapy.
methylsilane as a reference. The spectra gave evidence (chemical shift in values of 8) for three ... more methylsilane as a reference. The spectra gave evidence (chemical shift in values of 8) for three olefinic protons (8, 5.40), two methylene protons adjacent to an acetate oxygen atom (8, 4.06), ten methylene protons adjacent to doublebonded carbon atoms (8, 2.03), three acetyl methyl protons (8, 2.03), eight methylene protons adjacent to either methylene or methyl groups (8, 1.34), and six terminal methyl protons (8, 0.89) that appeared to be separated from a double-bonded carbon by at least two methylene groups. Double resonance studies indicated at least three methylene groups between the acetate group and a double bond, and only two methylene groups between the double bonds. The only structure for the attractant consistent with the foregoing data is 10-propyl-trans-5, 9-tridecadienyl acetate (I), and this structure was confirmed by an 11-step synthesis. CH3CH2CH2 C=CH(CH2)2CH=CH(CH.) ,OCCH3 I 11 CH3CH2CH2 0 I Compound I was synthesized in 0.2percent overall yield by the following procedure. Condensation of 4-heptanone with ethyl bromoacetate in the presence of zinc (14) gave ethyl 3-hydroxy-3-propylcaproate (75 percent; bp, 85?C at 1.5 mm-Hg), which was dehydrated with phosphorus oxychloride in pyridine to a mixture (88 percent; bp, 105? to 109?C at 20 mm; nD5, 1.4412) consisting of approximately 50 percent of ethyl 3-propyl-2-hexenoate and 50 percent of ethyl 3-propyl-3-hexenoate. Distillation through a spinning band column gave the pure a,fl-isomer (bp, 116.5?C at 28 mm) and the pure /3,y-isomer (bp, 113.5?C at 28 mm) as colorless liquids. Ethyl 3-propyl-2-hexenoate was reduced with lithium aluminum hydride to 3-propyl-2-hexen-l-ol (15) (80 percent; bp, 125?C at 25 mm; nD23.5, 1.4520), which was converted with phosphorus tribromide in pentane to 1-bromo-3-propyl-2-hexene (72 percent; bp, 105?C at 40 mm and 63?C at 3.3 mm; nD27, 1.4805). Stirring this compound for 6 days at room temperature with sodium cyanide in ethanol and hydrolysis of the crude product with alcoholic alkali gave crude 4-propyl-3-methylsilane as a reference. The spectra gave evidence (chemical shift in values of 8) for three olefinic protons (8, 5.40), two methylene protons adjacent to an acetate oxygen atom (8, 4.06), ten methylene protons adjacent to doublebonded carbon atoms (8, 2.03), three acetyl methyl protons (8, 2.03), eight methylene protons adjacent to either methylene or methyl groups (8, 1.34), and six terminal methyl protons (8, 0.89) that appeared to be separated from a double-bonded carbon by at least two methylene groups. Double resonance studies indicated at least three methylene groups between the acetate group and a double bond, and only two methylene groups between the double bonds. The only structure for the attractant consistent with the foregoing data is 10-propyl-trans-5, 9-tridecadienyl acetate (I), and this structure was confirmed by an 11-step synthesis. CH3CH2CH2 C=CH(CH2)2CH=CH(CH.) ,OCCH3
Tropical Medicine & International Health, 2010
To determine whether praziquantel (PZQ) has retained its efficacy against Schistosoma haematobium... more To determine whether praziquantel (PZQ) has retained its efficacy against Schistosoma haematobium on Pemba Island after 20 years of mass administration--albeit discontinuous--and to analyse retrospectively the performance of schistosomiasis control programmes. A sample of Pemba schoolchildren was examined before and after PZQ treatment by urine filtration, macro- and micro-haematuria and viability of excreted eggs. Although 5% of treated children continued to pass some eggs in the urine up to the seventh week after PZQ administration, none of these eggs was viable, indicating an effective schistosomicidal activity followed by a slow release of dead eggs from host tissues. No signs of PZQ resistance could be detected in the population under study. An overall retrospective analysis of schistosomiasis control activities in Pemba Island revealed that mass drug administration is clearly effective in reducing infection prevalence, but soon after interruption of drug distribution prevalence returns rapidly to pre-intervention levels.
A method is described for preparing immunoglobulin nascent chains from mouse myeloma cells. Nasce... more A method is described for preparing immunoglobulin nascent chains from mouse myeloma cells. Nascent chains are isolated by ion-exchange chromatography based on the strongly acidic charge conferred to peptidyl-tRNA by its nucleic acid moiety. The method is rapid, simple, gives essentially quantitative recoveries, and permits the subsequent serological isolation of a single protein species. Peptidyl-tRNAs isolated in this way have chromatographic
Testing the hypothesis This is the essence of the scienti ic approach and when I do this I am con... more Testing the hypothesis This is the essence of the scienti ic approach and when I do this I am conscious of a highly exciting intellectual activity. I am also conscious that I may be attaching some emotion to my commitment to this hypothesis. I may feel "certain" that I am on the right track-this can mislead the scientist and often scientists are unwilling to renounce their own ideas. In this activity, an "Act of faith" is necessary for the immense intellectual and physical effort required to complete the necessary work. The formulation of the hypothesis often has involved a creative intuition and the choice of subject may involve a great feeling of compassion and emotion. This idea has been well described and discussed in Michael Polanyi's "Personal Knowledge" (especially under "Intellectual Passions" Polanyi) So the scientist is certainly using spiritual qualities, committing the whole of him/her self. Scienti ic colleagues The interaction with friends and colleagues is an essential activity during the agony of 2 INTRODUCTION 06
SUMMARY. The tunnel of the Roman aqueduct of Saldae, Algeria. The unique feature of the Saldae aq... more SUMMARY. The tunnel of the Roman aqueduct of Saldae, Algeria. The unique feature of the Saldae aqueduct consists in the fact that its chief engineer, Nonius Datus, wrote a long inscription describing the history of the work, the problems encountered during the excavation of a tunnel and the success he inally obtained in solving these problems. In so doing, Nonius gives us precious clues regarding the basic principles and the technical procedures that were adopted in his time in order to accomplish this type of challenging engineering tasks. The story begins in AD 137, when the Saldae authorities ask the commander of a neighboring legion to send an expert surveyor to design the city aqueduct. The military librator Nonius Datus comes to Saldae, makes his project, delivers a detailed plan to the city manager and leaves. Twelve years later, however, he is asked to return for further consultation, because the aqueduct is not completed. But that does not solve the problem, because four years later he has to go back again, since the two teams of diggers that were excavating the aqueduct tunnel from opposite sides of the mountain have failed to meet, in spite of extensive unproductive tunneling. Nonius makes a rapid diagnosis, gives precise directions and pretty soon the water can triumphantly rush through the tunnel. We are not told how the problem was solved, but we could probably understand Nonius' strategy from an accurate inspection of the tunnel. It seems, however, that the tunnel –although walkable– has remained locked since 1875 and no researcher has yet been able to adequately survey it. Thus, the little secret of Nonius Datus remains to be discovered.
Adult, immature and hycanthone-resistant schistosomes were allowed to incorporate tritiated precu... more Adult, immature and hycanthone-resistant schistosomes were allowed to incorporate tritiated precursors of maeromolecule ~ynthesis in vitro, either in the presence of various concentrations of hycanthone, o~" at various times after removal of the drug. The effect on worms was compared to that on Hel.a cells. The results show that hyeanthone markedly inhibited the incorporation of uridine in all the sy ,terns studied, while the incorporation of thymidine and leucine was only secondarily affected. TI~c inhibition of uridine incorporation reflected in part a decreased uptake of the radioactive precursor. 'f'z hycanthone-induced inhibition of uridine incorporation was essentially irreversible upon remo :~t[ of the dxug ill adult sehistosomes, while it was completely reversible in hycanthoneresistant wol.as, in immature worms and in HeLa cells. The effects of a hycanthone analog, IA-4, were largely comparable to the effects of the parent compound. These results suggest that the inhibition of RNA synthesis can be a possible explanation for the mechanism of the schistosomieidal action of hycantho~e.
Inbred rats were thymectomized, irradiated, and reconstituted with T cell-free bone marrow cells.... more Inbred rats were thymectomized, irradiated, and reconstituted with T cell-free bone marrow cells. Thymectomized-reconstituted (B rats) and control rats were infected with Schistosoma mansoni cercariae and the number of worms recovered was determined at various times after infection. The extent of immunosuppression was assessed by two criteria: 1) response to an injection of sheep erythrocytes (plaque assay, hemagglutination, hemolysis); 2) response to schistosome antigens (passive hemagglutination). Humoral responses to worm antigens were completely suppressed in almost all instances and anti-sheep erythrocyte responses showed a more variable but always very definite depression in B rats. The number of worms in B rats was about 4 times higher than in control animals at 5 weeks and about 3 times higher at 6 weeks. In a different experiment, rats were perfused at 4, 6, and 9 weeks after infection and the number of worms was found to be consistently higher in B rats, by a factor of about 2 at 4 weeks to a factor of about 4 or 6 at subsequent times. Although B rats had more worms than controls even at 9 weeks, a slow drop in their worm burden was noticeable with time in both experiments. Moreover, the size of worms in B rats was smaller than in controls and even 9-week-old worms failed to develop to normal size and appearance and could not be shown to produce fertile eggs. These experiments show a definite involvement of the immune system in the "self-cure" phenomenon, but may at the same time suggest that other non-immune mechanisms are involved in determining the pattern of S. mansoni infection in the rat.
Inbred rats were thymectomized, irradiated, and reconstituted with T cell-free bone marrow cells.... more Inbred rats were thymectomized, irradiated, and reconstituted with T cell-free bone marrow cells. Thymectomized-reconstituted (B rats) and control rats were infected with Schistosoma mansoni cercariae and the number of worms recovered was determined at various times after infection. The extent of immunosuppression was assessed by two criteria: 1) response to an injection of sheep erythrocytes (plaque assay, hemagglutination, hemolysis); 2) response to schistosome antigens (passive hemagglutination). Humoral responses to worm antigens were completely suppressed in almost all instances and anti-sheep erythrocyte responses showed a more variable but always very definite depression in B rats. The number of worms in B rats was about 4 times higher than in control animals at 5 weeks and about 3 times higher at 6 weeks. In a different experiment, rats were perfused at 4, 6, and 9 weeks after infection and the number of worms was found to be consistently higher in B rats, by a factor of about 2 at 4 weeks to a factor of about 4 or 6 at subsequent times. Although B rats had more worms than controls even at 9 weeks, a slow drop in their worm burden was noticeable with time in both experiments. Moreover, the size of worms in B rats was smaller than in controls and even 9-week-old worms failed to develop to normal size and appearance and could not be shown to produce fertile eggs. These experiments show a definite involvement of the immune system in the "self-cure" phenomenon, but may at the same time suggest that other non-immune mechanisms are involved in determining the pattern of S. mansoni infection in the rat.
A series of new furoxan derivatives of praziquantel have been synthesized and evaluated for antis... more A series of new furoxan derivatives of praziquantel have been synthesized and evaluated for antischistosomal activity. The newly synthesized hybrid compounds have structural modifications at amide and aromatic rings and thus offer broad structure-activity variations. All the compounds have been tested against adult as well as immature Schistosoma mansoni. Compounds 15 and 18 show moderate activity against adult schistosomes. On immature worms, only compound 15 shows substantial activity whereas the standard drug PZQ is practically inactive at this stage.
The American Journal of Tropical Medicine and Hygiene, 1980
Various numbers of 25- to 28-day-old schistosomes of both sexes were surgically transferred into ... more Various numbers of 25- to 28-day-old schistosomes of both sexes were surgically transferred into the mesenteric veins of mice. Recipient animals (plus sham-operated controls) were percutaneously challenged with cercariae at various times after transfer, and the number of surviving worms was subsequently determined by portal perfusion. Significantly fewer challenge parasites were recovered from mice which had received a worm transfer than from sham controls; the reduction was comparable to that observed in mouse recipients of a percutaneous primary infection with cercariae. Resistance of mice to cercarial challenge was dependent upon the number of schistosome pairs transferred, and upon the time interval between transfer and challenge.
The American Journal of Tropical Medicine and Hygiene, 1981
Lung stage schistosomula exposed to 50 kilorads of gamma irradiation induced significant resistan... more Lung stage schistosomula exposed to 50 kilorads of gamma irradiation induced significant resistance to challenge infection with Schistosoma mansoni following intravenous (tail or mesenteric vein), intramuscular, or intraperitoneal injection into mice. Similar or higher levels were induced with irradiated cercariae, while irradiated 3- or 4-week-old worms induced little resistance. Non-irradiated day 6 and day 12 lung schistosomula injected into mice immunized with irradiated cercariae were susceptible to elimination, though to a lesser extent than a challenge infection administered at the cercarial stage. Day 20 liver worms injected into a mesenteric vein were not susceptible to irradiated cercaria-induced resistance. In contrast, cercariae, day 6 lung schistosomula, day 12 lung schistosomula and day 20 liver worms were all susceptible to the resistance induced by a chronic (non-irradiated) infection.
The American Journal of Tropical Medicine and Hygiene, 1986
Normal and passively immunized Fischer rats were infected with 75Se-selenomethionine-labeled cerc... more Normal and passively immunized Fischer rats were infected with 75Se-selenomethionine-labeled cercariae of Schistosoma mansoni. Migration of the parasites from skin to lungs to liver was monitored by autoradiographic analyses of these sites. Labeled parasites migrated from skin to lungs with high efficiency in normal and immune rats; disappearance of labeled parasites from the lungs was slower in immune rats. Labeled parasites accumulated in the liver, reaching maximal values by 11 days post-infection in both groups and remaining constant through day 21. Half the number of labeled parasites were detected in the liver of immune rats. The total number of labeled parasites detected in the skin, lungs, and liver was constant through day 5, then declined to about 60% of this value by day 11 in both groups. Over the next 10 days, the rate of decline decreased significantly in normal rats but did not change in immune rats. By day 21 post-infection, nearly 50% fewer labeled parasites were detectable in immune rats. We conclude that a subpopulation of parasites in the lungs is the target of protective antibody in the serum used for passive immunization. Target parasites, retained longer in the lungs, were probably prevented from migrating successfully to the liver. Another parasite subpopulation migrated to the liver with normal kinetics. Lung schistosomula isolated from normal and passively immunized rats were transferred by intravenous injection into recipient rats and their continued migration from lungs to liver compared. No differences in portal perfusion worm yields were detected in normal recipients; equally reduced yields were detected in passively immunized recipients. We conclude that the effects of antibodies during week 1 post-infection were insignificant or reversible.
The American Journal of Tropical Medicine and Hygiene, 1985
Adult Schistosoma mansoni were incubated for 1 hour in vitro with various drugs and then returned... more Adult Schistosoma mansoni were incubated for 1 hour in vitro with various drugs and then returned into the mesenteric veins of permissive animal hosts. Survival of schistosomes was assessed 3-4 weeks later by portal perfusion. Under these conditions, oxamniquine and hycanthone proved effective in killing S. mansoni, whereas UK-3883, lucanthone and lucanthone-4-desmethyl had no lethal activity. The same drugs which were schistosomicidal in vitro also persistently inhibited DNA, RNA, and protein synthesis in S. mansoni, whereas they were only transiently inhibitory against Schistosoma japonicum, against hycanthone-resistant S. mansoni and against immature worms. When drugs were administered in vivo to infected mice and the synthesis of macromolecules was assayed in vitro on worms obtained 1 or 3 days after treatment, not only oxamniquine and hycanthone, but also UK-3883 and lucanthone, proved effective in inhibiting the synthesis of macromolecules in sensitive--but not in resistant--S. mansoni. It is suggested that oxamniquine, like hycanthone, may exert its schistosomicidal activity by inhibiting nucleic acid synthesis in the parasite.
The antischistosomal pro-drug oxamniquine is activated by a sulfotransferase (SULT) in the human ... more The antischistosomal pro-drug oxamniquine is activated by a sulfotransferase (SULT) in the human parasite Schistosoma mansoni Of the three main human blood fluke species, only S. mansoni is sensitive to oxamniquine therapy despite the presence of SULT orthologs in S. haematobium and S. japonicum The reason for this species-specific drug action has remained a mystery for decades. Here we present the crystal structures of S. haematobium and S. japonicum SULTs, including S. haematobium SULT in complex with oxamniquine. Our finding that all three enzymes show activity toward oxamniquine in vitro reveals differences in catalytic efficiency that implicate kinetics as the determinant for species-specific toxicity. These results support the initiative for designing oxamniquine derivatives to treat infection caused by all species of blood fluke to combat emerging resistance to current therapy.
methylsilane as a reference. The spectra gave evidence (chemical shift in values of 8) for three ... more methylsilane as a reference. The spectra gave evidence (chemical shift in values of 8) for three olefinic protons (8, 5.40), two methylene protons adjacent to an acetate oxygen atom (8, 4.06), ten methylene protons adjacent to doublebonded carbon atoms (8, 2.03), three acetyl methyl protons (8, 2.03), eight methylene protons adjacent to either methylene or methyl groups (8, 1.34), and six terminal methyl protons (8, 0.89) that appeared to be separated from a double-bonded carbon by at least two methylene groups. Double resonance studies indicated at least three methylene groups between the acetate group and a double bond, and only two methylene groups between the double bonds. The only structure for the attractant consistent with the foregoing data is 10-propyl-trans-5, 9-tridecadienyl acetate (I), and this structure was confirmed by an 11-step synthesis. CH3CH2CH2 C=CH(CH2)2CH=CH(CH.) ,OCCH3 I 11 CH3CH2CH2 0 I Compound I was synthesized in 0.2percent overall yield by the following procedure. Condensation of 4-heptanone with ethyl bromoacetate in the presence of zinc (14) gave ethyl 3-hydroxy-3-propylcaproate (75 percent; bp, 85?C at 1.5 mm-Hg), which was dehydrated with phosphorus oxychloride in pyridine to a mixture (88 percent; bp, 105? to 109?C at 20 mm; nD5, 1.4412) consisting of approximately 50 percent of ethyl 3-propyl-2-hexenoate and 50 percent of ethyl 3-propyl-3-hexenoate. Distillation through a spinning band column gave the pure a,fl-isomer (bp, 116.5?C at 28 mm) and the pure /3,y-isomer (bp, 113.5?C at 28 mm) as colorless liquids. Ethyl 3-propyl-2-hexenoate was reduced with lithium aluminum hydride to 3-propyl-2-hexen-l-ol (15) (80 percent; bp, 125?C at 25 mm; nD23.5, 1.4520), which was converted with phosphorus tribromide in pentane to 1-bromo-3-propyl-2-hexene (72 percent; bp, 105?C at 40 mm and 63?C at 3.3 mm; nD27, 1.4805). Stirring this compound for 6 days at room temperature with sodium cyanide in ethanol and hydrolysis of the crude product with alcoholic alkali gave crude 4-propyl-3-methylsilane as a reference. The spectra gave evidence (chemical shift in values of 8) for three olefinic protons (8, 5.40), two methylene protons adjacent to an acetate oxygen atom (8, 4.06), ten methylene protons adjacent to doublebonded carbon atoms (8, 2.03), three acetyl methyl protons (8, 2.03), eight methylene protons adjacent to either methylene or methyl groups (8, 1.34), and six terminal methyl protons (8, 0.89) that appeared to be separated from a double-bonded carbon by at least two methylene groups. Double resonance studies indicated at least three methylene groups between the acetate group and a double bond, and only two methylene groups between the double bonds. The only structure for the attractant consistent with the foregoing data is 10-propyl-trans-5, 9-tridecadienyl acetate (I), and this structure was confirmed by an 11-step synthesis. CH3CH2CH2 C=CH(CH2)2CH=CH(CH.) ,OCCH3
Tropical Medicine & International Health, 2010
To determine whether praziquantel (PZQ) has retained its efficacy against Schistosoma haematobium... more To determine whether praziquantel (PZQ) has retained its efficacy against Schistosoma haematobium on Pemba Island after 20 years of mass administration--albeit discontinuous--and to analyse retrospectively the performance of schistosomiasis control programmes. A sample of Pemba schoolchildren was examined before and after PZQ treatment by urine filtration, macro- and micro-haematuria and viability of excreted eggs. Although 5% of treated children continued to pass some eggs in the urine up to the seventh week after PZQ administration, none of these eggs was viable, indicating an effective schistosomicidal activity followed by a slow release of dead eggs from host tissues. No signs of PZQ resistance could be detected in the population under study. An overall retrospective analysis of schistosomiasis control activities in Pemba Island revealed that mass drug administration is clearly effective in reducing infection prevalence, but soon after interruption of drug distribution prevalence returns rapidly to pre-intervention levels.
A method is described for preparing immunoglobulin nascent chains from mouse myeloma cells. Nasce... more A method is described for preparing immunoglobulin nascent chains from mouse myeloma cells. Nascent chains are isolated by ion-exchange chromatography based on the strongly acidic charge conferred to peptidyl-tRNA by its nucleic acid moiety. The method is rapid, simple, gives essentially quantitative recoveries, and permits the subsequent serological isolation of a single protein species. Peptidyl-tRNAs isolated in this way have chromatographic
Testing the hypothesis This is the essence of the scienti ic approach and when I do this I am con... more Testing the hypothesis This is the essence of the scienti ic approach and when I do this I am conscious of a highly exciting intellectual activity. I am also conscious that I may be attaching some emotion to my commitment to this hypothesis. I may feel "certain" that I am on the right track-this can mislead the scientist and often scientists are unwilling to renounce their own ideas. In this activity, an "Act of faith" is necessary for the immense intellectual and physical effort required to complete the necessary work. The formulation of the hypothesis often has involved a creative intuition and the choice of subject may involve a great feeling of compassion and emotion. This idea has been well described and discussed in Michael Polanyi's "Personal Knowledge" (especially under "Intellectual Passions" Polanyi) So the scientist is certainly using spiritual qualities, committing the whole of him/her self. Scienti ic colleagues The interaction with friends and colleagues is an essential activity during the agony of 2 INTRODUCTION 06
SUMMARY. The tunnel of the Roman aqueduct of Saldae, Algeria. The unique feature of the Saldae aq... more SUMMARY. The tunnel of the Roman aqueduct of Saldae, Algeria. The unique feature of the Saldae aqueduct consists in the fact that its chief engineer, Nonius Datus, wrote a long inscription describing the history of the work, the problems encountered during the excavation of a tunnel and the success he inally obtained in solving these problems. In so doing, Nonius gives us precious clues regarding the basic principles and the technical procedures that were adopted in his time in order to accomplish this type of challenging engineering tasks. The story begins in AD 137, when the Saldae authorities ask the commander of a neighboring legion to send an expert surveyor to design the city aqueduct. The military librator Nonius Datus comes to Saldae, makes his project, delivers a detailed plan to the city manager and leaves. Twelve years later, however, he is asked to return for further consultation, because the aqueduct is not completed. But that does not solve the problem, because four years later he has to go back again, since the two teams of diggers that were excavating the aqueduct tunnel from opposite sides of the mountain have failed to meet, in spite of extensive unproductive tunneling. Nonius makes a rapid diagnosis, gives precise directions and pretty soon the water can triumphantly rush through the tunnel. We are not told how the problem was solved, but we could probably understand Nonius' strategy from an accurate inspection of the tunnel. It seems, however, that the tunnel –although walkable– has remained locked since 1875 and no researcher has yet been able to adequately survey it. Thus, the little secret of Nonius Datus remains to be discovered.
Adult, immature and hycanthone-resistant schistosomes were allowed to incorporate tritiated precu... more Adult, immature and hycanthone-resistant schistosomes were allowed to incorporate tritiated precursors of maeromolecule ~ynthesis in vitro, either in the presence of various concentrations of hycanthone, o~" at various times after removal of the drug. The effect on worms was compared to that on Hel.a cells. The results show that hyeanthone markedly inhibited the incorporation of uridine in all the sy ,terns studied, while the incorporation of thymidine and leucine was only secondarily affected. TI~c inhibition of uridine incorporation reflected in part a decreased uptake of the radioactive precursor. 'f'z hycanthone-induced inhibition of uridine incorporation was essentially irreversible upon remo :~t[ of the dxug ill adult sehistosomes, while it was completely reversible in hycanthoneresistant wol.as, in immature worms and in HeLa cells. The effects of a hycanthone analog, IA-4, were largely comparable to the effects of the parent compound. These results suggest that the inhibition of RNA synthesis can be a possible explanation for the mechanism of the schistosomieidal action of hycantho~e.
Inbred rats were thymectomized, irradiated, and reconstituted with T cell-free bone marrow cells.... more Inbred rats were thymectomized, irradiated, and reconstituted with T cell-free bone marrow cells. Thymectomized-reconstituted (B rats) and control rats were infected with Schistosoma mansoni cercariae and the number of worms recovered was determined at various times after infection. The extent of immunosuppression was assessed by two criteria: 1) response to an injection of sheep erythrocytes (plaque assay, hemagglutination, hemolysis); 2) response to schistosome antigens (passive hemagglutination). Humoral responses to worm antigens were completely suppressed in almost all instances and anti-sheep erythrocyte responses showed a more variable but always very definite depression in B rats. The number of worms in B rats was about 4 times higher than in control animals at 5 weeks and about 3 times higher at 6 weeks. In a different experiment, rats were perfused at 4, 6, and 9 weeks after infection and the number of worms was found to be consistently higher in B rats, by a factor of about 2 at 4 weeks to a factor of about 4 or 6 at subsequent times. Although B rats had more worms than controls even at 9 weeks, a slow drop in their worm burden was noticeable with time in both experiments. Moreover, the size of worms in B rats was smaller than in controls and even 9-week-old worms failed to develop to normal size and appearance and could not be shown to produce fertile eggs. These experiments show a definite involvement of the immune system in the "self-cure" phenomenon, but may at the same time suggest that other non-immune mechanisms are involved in determining the pattern of S. mansoni infection in the rat.
Inbred rats were thymectomized, irradiated, and reconstituted with T cell-free bone marrow cells.... more Inbred rats were thymectomized, irradiated, and reconstituted with T cell-free bone marrow cells. Thymectomized-reconstituted (B rats) and control rats were infected with Schistosoma mansoni cercariae and the number of worms recovered was determined at various times after infection. The extent of immunosuppression was assessed by two criteria: 1) response to an injection of sheep erythrocytes (plaque assay, hemagglutination, hemolysis); 2) response to schistosome antigens (passive hemagglutination). Humoral responses to worm antigens were completely suppressed in almost all instances and anti-sheep erythrocyte responses showed a more variable but always very definite depression in B rats. The number of worms in B rats was about 4 times higher than in control animals at 5 weeks and about 3 times higher at 6 weeks. In a different experiment, rats were perfused at 4, 6, and 9 weeks after infection and the number of worms was found to be consistently higher in B rats, by a factor of about 2 at 4 weeks to a factor of about 4 or 6 at subsequent times. Although B rats had more worms than controls even at 9 weeks, a slow drop in their worm burden was noticeable with time in both experiments. Moreover, the size of worms in B rats was smaller than in controls and even 9-week-old worms failed to develop to normal size and appearance and could not be shown to produce fertile eggs. These experiments show a definite involvement of the immune system in the "self-cure" phenomenon, but may at the same time suggest that other non-immune mechanisms are involved in determining the pattern of S. mansoni infection in the rat.
Proceedings of the Third International Summer School “Water Management in arid and semiarid clima... more Proceedings of the Third International Summer School “Water Management in arid and semiarid climates in Roman time” (Feltre, 22nd - 26th August 2016)
Materiali della terza International Summer School “Water Management in arid and semiarid climates in Roman time” (Feltre, 22-26 Agosto 2016)
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Materiali della terza International Summer School “Water Management in arid and semiarid climates in Roman time” (Feltre, 22-26 Agosto 2016)
ISBN 978-88-33680-44-6