A Potent Kalihinol Analogue Disrupts Apicoplast Function and Vesicular Trafficking in P. falciparum Malaria.

Here we report the discovery of MED6-189, a new analogue of the kalihinol family of isocyanoterpene (ICT) natural products. MED6-189 is effective against drug-sensitive and -resistant P. falciparum strains blocking both intraerythrocytic asexual replication and sexual differentiation. This compound was also effective against P. knowlesi and P. cynomolgi. In vivo efficacy studies using a humanized mouse model of malaria confirms strong efficacy of the compound in animals with no apparent hemolytic activity or apparent toxicity. Complementary chemical biology, molecular biology, genomics and cell biological analyses revealed that MED6-189 primarily targets the parasite apicoplast and acts by inhibiting lipid biogenesis and cellular trafficking. Genetic analyses in P. falciparum revealed that a mutation in PfSec13, which encodes a component of the parasite secretory machinery, reduced susceptibility to the drug. The high potency of MED6-189 in vitro and in vivo, its broad range of efficacy, excellent therapeutic profile, and unique mode of action make it an excellent addition to the antimalarial drug pipeline.

Verapamil: prevention and treatment of cardio-renal syndromes in diabetic hypertensive patients?

Patients with diabetes mellitus (DM) often present other chronic comorbidities including arterial hypertension (AH), chronic kidney disease (CKD), ischemic heart disease (IHD) and heart failure with preserved ejection fraction (HFpEF). The frequent association of the latter conditions is considered part of the spectrum of cardio-renal syndromes (CRS), a group of disorders of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other. Verapamil is a non-dihydropyridine calcium channel blocker (CCB) widely used in the treatment of hypertension, chronic stable angina, secondary prevention of reinfarction, paroxysmal supra-ventricular tachycardia and for rate control in atrial fibrillation/flutter. In addition to its antihypertensive and anti-ischemic actions verapamil exerts favorable effects also on glycemic control, proteinuric diabetic nephropathy, left ventricular diastolic dysfunction and sympathetic nervous system overactivity which may potentially benefit patients with DM and CRS. In this narrative review, we summarize the current evidence on the potential role of verapamil in the prevention and treatment of CRS in diabetic hypertensive patients.

[Use of dried blood spots in early diagnosis of HIV-1 infection in children born to HIV-infected mothers as part of the prevention of mother-to-child transmission in Benin]. / Utilisation des prélèvements capillaires sur buvard dans le diagnostic précoce de l'infection à VIH-1 chez des enfants nés de mères infectées dans le cadre de la prévention de la transmission mère-enfant au Bénin.

The goal of this study was to evaluate using the molecular diagnosis, infection transmission rate of HIV in children born to HIV-1 positive mothers as part of the prevention of mother-to-child transmission (PMTCT) in Benin. The sample consisted of 524 dried blood spots (DBS) of children born to HIV-1 positive mothers, from 30 sites (PMTCT) taken between October 2009 and June 2010. The diagnosis of HIV-1 was performed by the qualitative detection of viral nucleic acids (RNA and DNA) in DBS on filter paper using the Abbott RealTime(®) HIV-1 Qualitative assay. We found that 51 DBS were positive (9.7%) and 473 were negative (90.3%). The failure rate of PMTCT among 420 mothers who received antiretroviral prophylaxis was 6.7% (28/420). This failure rate was significantly higher among children born to infected mothers on antiretroviral monotherapy than on triple therapy (HAART). The results of our study enrich the data in the literature on highly active antiretroviral chemoprophylaxis to reduce the transmission of HIV-1 from mother to child.

Erythrocyte invasion profiles are associated with a common invasion ligand polymorphism in Senegalese isolates of Plasmodium falciparum.

Plasmodium falciparum parasites use multiple ligand-receptor interactions to invade human erythrocytes. Variant expression levels of members of the PfRh and PfEBA ligand families are associated with the use of different erythrocyte receptors, defining invasion pathways. Here we analyse a major polymorphism, a large sequence deletion in the PfRh2b ligand, and erythrocyte invasion profiles in uncultured Senegalese isolates. Parasites vary considerably in their use of sialic acid-containing and protease-sensitive erythrocyte receptors for invasion. The erythrocyte selectivity index was not related to invasion pathway usage, while parasite multiplication rate was associated with enhanced use of a trypsin-resistant invasion pathway. PfRh2b protein was expressed in all parasite isolates, although the PfRh2b deletion was present in a subset (approximately 68%). Parasites with the PfRh2b deletion were found to preferentially utilize protease-resistant pathways for erythrocyte invasion. Sialic acid-independent invasion is reduced in parasites with the PfRh2b deletion, but only in isolates derived from blood group O patients. Our results suggest a significant role for PfRh2b sequence polymorphism in discriminating between alternative erythrocyte receptors for invasion and as a possible determinant of virulence.

Effect of tryptophan on the early tri-iodothyronine uptake in mouse thymocytes.

OBJECTIVE: We have studied the effect of tryptophan on cellular [(125)I]tri-iodothyronine (T3) uptake by mouse thymocytes. MATERIALS AND METHODS: Mouse thymocytes (20 x 10(6 )cells/ml) were suspended in Krebs-Ringer solution buffered by Tris-HCl and incubation (23 degrees C at pH7.45+/-0.6), in the presence or absence of 1mM tryptophan, was started by adding 25 pM [(125)I]T3. At the end of incubation, samples were cooled in ice, centrifuged over a 30% sucrose cushion and the cell-associated radioactivity was measured in the pellet. RESULTS: Tryptophan reduced both the total and the saturable fraction of [(125)I]T3 uptake by 44% (P=0.0009) and 60% (P=0.0006) respectively, following 1 min of incubation. This effect was specific and dose-dependent, being maximal at 5mM concentration (-82%). In contrast, the pre-exposure of cells to tryptophan for up to 2h had no effect on the subsequent uptake of [(125)I]T3, in the absence of tryptophan. The effect of D-tryptophan on saturable T3 uptake was not different from that obtained using the L-stereoisomer. Tryptophan reduced the V(max) of the initial rate of saturable [(125)I]T3 uptake by two-thirds without affecting the apparent K(m) (2.2 nM) of the process, thus indicating the non-competitive nature of the inhibition. In sodium-free medium the saturable [(125)I]T3 uptake was reduced by 43%. The inhibitory effect of tryptophan on [(125)I]T3 uptake was exerted in both the presence and the absence of sodium. In fact, the inhibitory effect of tryptophan on T3 transport was greater and significantly different (P=0.0046) from that obtained by sodium depletion alone. CONCLUSIONS: Tryptophan interferes with both the sodium-dependent and -independent components of [(125)I]T3 uptake by a dose-dependent, non-competitive mechanism which operates in cis-modality at the plasma membrane level of mouse thymocytes.

[Microsurgical repair after excision of large cancers. Apropos of 14 cases]. / Réparation microchirurgicale après exérèse des cancers étendus. A propos de 14 cas.

The specialty which has benefited the most from the rapid development of reconstructive microsurgery over the last decade, has been plastic surgery. In particular, the authors refer to reconstructive microsurgery after malignant tumor resection. Resections which used to cause serious psychological problems or which required multiple reconstructive procedures, can now be performed as a single stage procedure with good oncological, functional and aesthetic results. This experience concerns the treatment of 14 primary or recurrent malignant tumors of the skin and soft tissues using microsurgical techniques. The free latissimus dorsi musculocutaneous flap was the flap most commonly used. The authors also used the groin flap, the scapular flap, the tensor fasciae latae flap, the dorsalis pedis flap and finally the jejunum combined with the second metatarsus to reconstruct the mandible and the floor of the mouth. Complications consisted of complete necrosis of a dorsalis pedis flap and two revisions were performed for venous thrombosis. With a minimum follow-up of 5 years, one patient has developed a local recurrence and another has developed regional lymph node metastases. The functional and aesthetic results were quite satisfactory. The authors believe that microsurgery is a very valuable technique to treat difficult reconstructive problems.

[Plastic surgery of the eyelids after tumoral excision. Apropos of 299 cases]. / La chirurgie réparatrice palpébrale après exérèses tumorales. A propos de 299 cas.

Plastic surgery of the peri-orbital area after tumor resection is a special and interesting field of reconstructive surgery. Our experience concerns the surgical treatment of 299 malignant tumors of the skin of the peri-orbital area in 291 patients. Basal cell carcinomas were the most common but we also had 8 squamous cell and 4 mixed carcinomas and 1 malignant melanoma. Among these tumors, 277 were primary and 22 were recurrences: 5 after X-Ray therapy, 9 after surgery elsewhere, 4 after electrocautery and 4 after combined treatments. The lower eyelids and the inner canthus areas were the most frequently involved in our series with relative infrequency in the outer canthus and upper eyelids. We used direct closure and local flaps in the repair of most of our patients, but we also used some full thickness skin grafts by preference for the upper eyelid. Complications consisted of 8 cases of ectropion and 2 flap necroses for which a revision was performed in some cases. Concerning our carcinological results among the 123 patients with one year minimum follow up we noticed 4 recurrences which represents a percentage of 3.2%.

[Cerebrospinal fluid in cysticercosis of the brain]. / Líquido cefalorraquiano na cisticercose encefalica.

Cerebrospinal fluid (CSF) changes in brain cysticercosis have long been known. Its characteristic features are a mild or moderate pleocytosis with eosinophils, a slight or moderate protein increase with an elevated gammaglobulin concentration, and a positive complement fixation test. Unfortunately all these abnormalities are not always present together and difficulties may be encountered in the diagnosis. This paper presents a study based on the experience acquired in the CSF Laboratory of the Neurological Department of Escola Paulista de Medicina (São Paulo, Brasil) after 35 years' work, and 120.000 CSF specimens examined. The material consists of 147 cases of brain cysticercosis confirmed by necropsy, surgery, subcutaneous or intraocular cysticercus, x ray of the skull, and of 509 clinical observation with suggestive CSF changes. It is the purpose of this paper to appreciate the importance of each of the CSF tests and to observe the CSF abnormalities during the course of this disease. The results of the study of the 79 cases varified by necropsy or surgery showed that the characteristic CSF changes that make the diagnosis of brain cysticercosis were observed in 54 percent of the cases. The eosinophils were present in 82 percent, protein changes in 78 percent, complement fixation test in 70 per cent, hypertension in 55 per cent, and decreased sugar content in 27 per cent of the cases. In two cases the CSF was normal. As the eosinophils and the protein abnormalities may be seen in several other diseases, the complement fixation test for cysticercus should be regarded as the most important CSF test in the diagnosis of brain cysticercosis. The successive CSF specimens withdrawn of 40 patients during the course of this disease have shown that the abnormalities went on for 4 to 18 years observation, suggesting that the parasites were alive. On the contrary, in 11 other cases it was varified the final CSF normalization after 5 to 14 years, suggesting that the parasites were dead. The CSF was normal in 31 out of 42 patients with opaque nodules visible in skull films (calcified cysticercus). In the remaining 11 cases, the characteristic CSF findings were observed in 3, but in 8 cases the only abnormalities were positive complement fixation test or eosinophils. In 14 out of 26 patients with subcutaneous or introacular cysticercus there were the usual CSF changes but in the other remaining cases the CSF was normal. The absence of treatment for brain cysticercosis is consistent with the persistence of CSF abnormalities in the specimens examined during the course of this disease. This calls for an integrated prophylactic to all Latin-American countries in order to exterminate this serious disease for the well-being of the next generation.