Phosphorus-Containing Bis-allenes: Synthesis and Heterocyclization Reactions Mediated by Iodine or Copper Dibromide.

Bisphosphorylallenes were easily obtained in multigram scale from the Wittig-type rearrangement of bispropargyl alcohols. Unlike other conjugated bis-allenes, these reagents underwent a double cyclization mediated by iodine or copper dibromide leading to the formation of bis-1,2-oxaphospholenes.

A case of autochthonous Plasmodium vivax malaria, Corsica, August 2006.

A case of Plasmodium vivax malaria was diagnosed in Corsica in summer 2006. This is the first case of autochthonous transmission of malaria to be reported in Corsica since 1972. Corsica is a well-known malaria endemic region characterised, for several years now by an anophelism situation without malaria disease, due to the presence of An. labranchiae and An. saccharovi able to transmit P. vivax. The occurring sequence of malaria signs in an imported case on 9 July and in an autochthonous case on 5 August, both in Porto, implies a transmission by local Anopheles. This suspicion is reinforced by the results of entomological investigations. However, from June to September 2006, no other P. vivax malaria case and no other autochthonous case were detected in Corsica. Therefore, it seems that no permanent malaria transmission occurs in this island. Mosquito eradication actions and anti-vectorial measures have been reinforced as well as individual prevention measures against imported diseases while travelling in tropical countries. Obviously, detection of one exceptional autochthonous transmission of one malaria case in Corsica does not justify proposing malaria protection to tourists.

Malaria prophylaxis policy for travellers from Europe to the Indian Subcontinent.

Analysis of malaria imported into eight European countries from the Indian Sub-continent (ISC) (India, Pakistan, Bangladesh and Sri Lanka) led to a consensus statement on the use of chemoprophylaxis within TropNetEurop. The proportion of cases from the ISC in 2004 ranged from 1.4%-4.6% of total imported cases. Plasmodium falciparum cases reported from the eight countries was only 23 (13% of all cases from the region). Total malaria reports between 1999-2004 fell from 317 to 180. The risk of malaria in UK residents visiting the region was > 1 case per 1,000 years exposed. The group recommended non-selective prescribing of chemoprophylaxis for visitors to India, Pakistan, Bangladesh and Sri Lanka should be dropped.

[Imported malaria in children in France]. / Paludisme d'importation de l'enfant en France.

UNLABELLED: Among the European countries, France is the most affected by imported malaria. The aim of this study was to take stock of the situation of imported malaria in children in France. METHODS: Attacks of malaria in children less than 15-year-old which have been notified to Centre National de Référence des Maladies d'Importation (CNRMI) were reviewed retrospectively between 1995 and 1997 and 1995 and 1998 for severe malaria. RESULTS: Over a period of 3 years, 1256 malaria attacks were notified in children including 90.9% without signs of severity. The mean age was 7 years. Sex ratio was 1.19. About 44.5% were French. Most of the cases were acquired in Africa. Plasmodium falciparum was involved in 79.2% of the cases. About 61.8% of children have been under prophylaxis but only 37.9% admit good compliance. Chemoprophylaxis was frequently inadequate. Halofantrine was prescribed for 76% of these children. Over a 4-year period, 51 children were notified as severe malaria attacks. Among them, 17 had severe malaria as defined by the World Health Organisation criteria. Most of these patients (73%) were treated by quinine by intravenous route. Two children died. CONCLUSION: Paediatric malaria is not rare in France. Only the improvement of prophylaxis could decrease the incidence of malaria in France.

[Current data on malaria in metropolitan France]. / Donnees actuelles sur le paludisme en France metropolitaine.

Epidemiological data from the French National Reference Center for Imported Diseases showed that the estimated number of cases of imported malaria in France increased from 5,940 in 1998 to 7,127 in 1999 and 8,056 in 2000. This three-year progression ended in 2001 when the number of estimated cases fell back to 7,223. It was due mainly to the concomitant increase in the number of people traveling to endemic zones especially in Africa. In 2000 the median age of patients with imported malaria in France was 29.5 years and the sex ratio was 1.78. Sixty-three percent of cases involved people of African origin and 37% involved "Westerners". The countries in which contamination occurred were located in tropical Africa (95%), Asia (2.2%), and Latin America (2.7%). During the three year period from 1998 to 2000, there were a total of 13 accidental autochtonous cases of malaria involving patients with no history of travel to tropical areas. The distribution of Plasmodium species involved in imported malaria in France was stable with 83% of cases involving Plasmodium falciparum, 6% involving Plasmodium vivax, 6.5% involving Plasmodium ovale and 1.3% involving Plasmodium malariae. Attacks were clinically uncomplicated in 90 to 95% of cases and severe in 2 to 5% including fatal Plasmodium falciparum malaria in 0.49 to 0.37% of cases. Less than 10% of the 45% of patients claiming use of prophylaxis complied properly. Analysis of the drugs used for curative treatment in 2000 showed an increase in the use of quinine and mefloquine and decrease in the use of halofantrine. The main objectives remain reduction of mortality and improvement of prevention.

Functional characterization of novel mutations in the human cytochrome b gene.

The great variability of the human mitochondrial DNA (mtDNA) sequence induces many difficulties in the search for its deleterious mutations. We illustrate these pitfalls by the analysis of the cytochrome b gene of 21 patients affected with a mitochondrial disease. Eighteen different sequence variations were found, five of which were new mutations. Extensive analysis of the cytochrome b gene of 146 controls found 20 supplementary mutations, thus further demonstrating the high variability of the cytochrome b sequence. We fully evaluated the functional relevance of 36 of these 38 mutations using indirect criteria such as the nature of the mutation, its frequency in controls, or the phylogenetic conservation of the mutated amino acid. When appropriate, the mtDNA haplotype, the heteroplasmic state of the mutation, its tissue distribution or its familial transmission were also assessed. The molecular consequences of the mutations, which appeared possibly deleterious in that first step of evaluation, were evaluated on the complex III enzymological properties and protein composition using specific antibodies that we have generated against four of its subunits. Two original deleterious mutations were found in the group of seven patients with overt complex III defect. Both mutations (G15150A (W135X) and T15197C (S151P)) were heteroplasmic and restricted to muscle. They had significant consequences on the complex III structure. In contrast, only two homoplasmic missense mutations with dubious clinical relevance were found in the patients without overt complex III defect.

Imported Plasmodium vivax malaria in France: geographical origin and report of an atypical case acquired in Central or Western Africa.

A total of 73 cases of Plasmodium vivax infections acquired in Western or Central Africa were diagnosed on microscopical criteria in French travellers from 1995 to 1998. We report a case of P. vivax infection in a non immune traveller confirmed by polymerase chain reaction and presenting an atypical P. ovale morphology. The infection was acquired in Western or Central Africa. These microscopical observations, together with the molecular evidence for P. vivax in Western and Central Africa suggest that P. vivax is transmitted in this area despite lacking the Duffy receptor in autochthonous population.

N-acetylcysteine decreases severity of acute pancreatitis in mice.

Oxidative stress plays a major role in the early stage of acute pancreatitis. This study assessed the effects of N-acetylcysteine (NAC), a reduced glutathione (GSH) provider and a direct scavenger of reactive oxygen intermediates, in the course of acute pancreatitis in mice. Acute pancreatitis (AP) was induced by intraperitoneal (i.p.) injections of cerulein. Mice received NAC (1,000 mg/kg, i.p.) every 3 h, starting either 1 h before the first cerulein injection (prophylactic group) or 1 h after the first cerulein injection (therapeutic group), or i.p. saline injections for controls. Severity of AP was evaluated by histology, serum hydrolase levels, and serum and intrapancreatic levels of MCP-1 and interleukin 6 (IL-6). Pancreatic conjugated dienes and intrapancreatic and intrahepatic GSH levels were measured to assess the local and systemic oxidative processes. Acute pancreatitis was also induced with a CDE diet in controls and mice receiving either both NAC ad libidum in drinking water and 1,000 mg/kg i.p. injection once daily. The severity of pulmonary lesions was assessed by arterial blood gases (pO2) and intrapulmonary myeloperoxidase (MPO content) measurements as well as the survival of mice. The severity of cerulein-induced AP was significantly decreased in the prophylactic group compared with the therapeutic and control groups. Prophylactic administration of NAC also decreased the intrapancreatic levels of conjugated dienes compared with controls. The intrapancreatic and systemic release of MCP- 1 and IL-6 was also decreased in the prophylactic group 3 and 6 hours after AP induction. In addition, NAC pretreatment also reduced hepatic IL-6 production at 3 and 6 hours after starting cerulein challenge. In CDE-induced AP, the severity of lung injury (hypoxemia, MPO content) was decreased, and survival was improved by NAC. NAC administered in a prophylactic protocol limits the severity of experimental acute pancreatitis in mice, as well as its systemic complications and related mortality.

Airport malaria : four new cases in suburban Paris during summer 1999.

During the summer 1999, four clustered cases of airport malaria were observed in France. The cases analysis revealed that airport malaria, which is a rare disease whose diagnosis is difficult, can be observed outside occupations at risk, in people livin

A dose-response study of epidural liposomal bupivacaine in rabbits.

Liposomes are drug delivery systems used to prolong local effects of bupivacaine. We studied the relationships between motor and hemodynamic changes and epidural doses of plain bupivacaine (P) and liposomal bupivacaine (L) in rabbits equipped with chronical lumbar epidural and femoral arterial catheters. Liposomal (phosphatidylcholine-cholesterol) suspensions contained 20 mg ml-1 of lipid, and different doses of bupivacaine (Lipo 7.5=7.5-; Lipo 3.7=3. 75-; Lipo 2.5=2.5-; Lipo 1.2=1.25-; and Lipo 0.7=0.65-mg of bupivacaine per ml). Forty rabbits were randomly assigned to five groups to receive epidural anesthesia (1 ml) as follows: Groups I to V received 0.65 to 7.5 mg of bupivacaine as P then as L. Release rate of bupivacaine from liposome was significantly slower using Lipo 3.7 than after Lipo 2.5 (Td was 3.9 h and 1.7 h respectively). Increasing the doses of L and P resulted in faster onset time for complete motor blockade and in a prolonged duration of motor effects. Liposomal formulation appears to be a powerful delivery system to prolong the motor effects of bupivacaine since E50 was lower and Emax higher than after the use of plain solution (E50 4.49+/-1.81 mg and Emax 152+/-40 min for P; and E50 2.61+/-0.23 mg and Emax 202+/-9 min for L). Hemodynamic changes were linearly related to doses of bupivacaine injected. The best bupivacaine-to-lipid ratio to prolong motor effects using our model was 3.75 mg and 20.0 mg respectively (Lipo 3.7).

Surveillance of malaria in European Union countries.

The European Union countries are outside the endemic area for malaria, but many cases of malaria contracted elsewhere are imported into Europe each year. Several countries have reported high and increasing numbers of imported cases in recent years (France

Imported malaria in continental France in 1996.

Malaria ceased to be endemic in France in 1960, although sporadic cases were reported until 1970 in the department of Corse. No indigenous case of malaria have been reported since then. We report below the epidemiological data on imported malaria in 1996.

Neurotoxicological assessment after intracisternal injection of liposomal bupivacaine in rabbits.

UNLABELLED: Experiments were performed on rabbits randomly assigned to intracisternally receive 0.3 mL of plain bupivacaine 5 mg/mL, liposomal bupivacaine 5 mg/mL, bupivacaine-free liposomes, or isotonic phosphate-buffered saline. Mechanical ventilation was initiated or intravenous dopamine was infused when respiratory depression or hypotension occurred. Seven days after the injection, the whole spinal cord was removed and histopathologic characteristics were studied on transverse sections. All preparations were devoid of phosphatidylcholine hydrolysis or oxidation compounds. Solutions without bupivacaine produced transient irritative signs that required sedation in most rabbits. Despite the similar duration of respiratory depression in groups receiving liposomal or plain bupivacaine, liposomes produced significantly prolonged motor blockade (126 vs 70 min). Correction of hypotension after plain bupivacaine required a longer dopamine infusion and larger doses than after liposomal bupivacaine (28 vs 18 min and 74 vs 47 mg). Necrosis was observed in the cervical area of two rabbits (one in the liposomal bupivacaine group and another in the phosphate buffer group). No demyelinated areas were noted in spinal cord examinations. We conclude that liposomal bupivacaine leads to a less severe sympathetic block and to a prolonged motor block, whereas histologic changes are not significantly different among groups. IMPLICATIONS: Multilamellar liposomes containing bupivacaine administered intracisternally to rabbits produce spinal cord histopathologic changes not significantly different from those observed with plain bupivacaine. Sustained release of bupivacaine from liposomes is suggested by the prolonged motor blockade and the reduced severity of arterial hypotension. Use of these liposomes could prolong the local anesthetic effects of bupivacaine.

[Note on imported malaria in metropolitan France from 1993 to 1995]. / Note sur le paludisme d'importation en France métropolitaine de 1993 à 1995.

Concerning malaria, the role of the Reference National Centre on the Imported Diseases is to observe the cases that occur on the continent in order to describe their characteristics, assess their annual incidence and objectify the secular trend. The aim is to provide annual indicators to help to advise travellers. This surveillance is based on a voluntary network providing standardised informations on the epidemiologic, prophylactic, clinical, parasitologic and therapeutic data. After a noticeable increase between 1987 and 1988, the occurrence of the imported malaria cases in France decreased since 1989 then became stable since 1991, between 3,500 and 4,000 cases per year. From one year to another the characteristics of the cases are stable for most of the parameters. However, it is interesting to note: a progressive increase in the ratio of foreigners with a decrease of the median age, the average five days delay between the first symptoms and the diagnostic, the same ratio of severe cases for French people and foreigners, the average time of the stay at the hospital of 4.5 days for non severe malaria cases and the preferential use of halofantrine in first line treatment. The delay of the diagnostic and more precisely the delay of treatment turn-out to be the main factors leading to severe malaria sometimes leading to death. The limited interpretation of data is due to the lack of corresponding denominators required for measuring the rates and density of the incidence as well as the identification of risk factors.

Scintigraphic visualization of intrathecal liposome biodistribution.

BACKGROUND: Liposomes containing local anaesthetics have been administered intrathecally and in the epidural space. Poor attention has been given to the pharmacokinetics of liposomes as drug carriers. Therefore, we observed the biodistribution of liposomes after intrathecal injection in rats by scintigraphic imaging during 24 h. METHODS: We administered 99mTc-labeled multilamellar (MLV) and small unilamellar vesicles (SUV) of defined size and volume dispersities into the cerebrospinal fluid at the lumbar level. Those vesicles were free of contamination by radiolabeled colloids as visualized by light and electron microscopy and of neurotoxic products from phosphatidylcholine hydrolysis and peroxidation, both during the preparation process and after 24 h incubation in cerebrospinal fluid at 37 degrees C in vitro. RESULTS: SUV immediately diffused from the lumbar site of injection to the head and were cleared between 1 and 24 h after injection. MLV were cleared more slowly from the spinal space and appeared in the head region 1 h after injection where they accumulated up to 24 h. These differences were explained in terms of vesicle sizes and volumes. SUV with 0.05 micron diameters were rapidly absorbed into the blood through the arachnoid granulations. In contrast, particles larger than the upper size limit of the arachnoid granulations permeability (+/- 8 microns) could accumulate in the head with a slow elimination rate. CONCLUSION: This difference in clearance from the intrathecal space outlines the importance of defining the size of the liposomes, the distribution of a tracer or a drug inside the liposomal preparation, the chemical stability and the absence of toxic degradation products of liposome formulations before clinical use.

99mTechnetium-stannous oxinate as marker of liposome formulations.

Liposomes associated with tin(II) dioxinate were prepared from egg yolk phosphatidylcholine and cholesterol as sterile and pyrogen-free multilamellar or unilamellar vesicles. Complexing of liposomal tin(II) dioxinate with 99mTc attained 98% of the added radioactivity. Thirty percent 99mTc were released during 24-h incubation in biological fluids. The absence of tin colloids seen by electron microscopy and the stability of liposomal phospholipid and tin(II) dioxinate during 72-h incubation at 37 degrees C in plasma and cerebrospinal fluid would allow safe and reliable scintigraphic liposome pharmacokinetic studies.

Use of liposome-associated bupivacaine in a cancer pain syndrome.

Bupivacaine 0.25% encapsulated by multilamellar liposomes was administered epidurally to a patient suffering pain associated with lung cancer and the effect compared with a plain bupivacaine solution of the same concentration. Complete analgesia was produced for 4 h with the plain solution and 11 h with the liposomal formulation. No motor blockade or haemodynamic instability was observed with the liposome-associated bupivacaine.