Recent updates and perspectives on approaches for the development of vaccines against visceral leishmaniasis

All rights reserved. Visceral leishmaniasis (VL) is one of the most important tropical diseases worldwide. Although chemotherapy has been widely used to treat this disease, problems related to the development of parasite resistance and side effects associated with the compounds used have been noted. Hence, alternative approaches for VL control are desirable. Some methods, such as vector control and culling of infected dogs, are insufficiently effective, with the latter not ethically recommended. The development of vaccines to prevent VL is a feasible and desirable measure for disease control, for example, some vaccines designed to protect dogs against VL have recently been brought to market. These vaccines are based on the combination of parasite fractions or recombinant proteins with adjuvants that are able to induce cellular immune responses, however, their partial efficacy and the absence of a vaccine to protect against human leishmaniasis underline the need for characterization of new vaccine candidates. This review presents recent advances in control measures for VL based on vaccine development, describing extensively studied antigens, as well as new antigenic proteins recently identified using immuno-proteomic techniquesThis work was supported by grants from Instituto Nacional de Ciência e Tecnologia em Nano-Biofarmacêutica, Rede Nanobiotec/Brasil-Universidade Federal de Uberlândia/CAPES, PRONEX-FAPEMIG (APQ-01019-09), FAPEMIG (CBB-APQ-00819-12 and CBB-APQ-01778-2014), and CNPq (APQ-482976/2012-8, APQ-488237/2013-0, and APQ-467640/2014-9). EAFC and LRG are recipients of the grant from CNPq. MACF is the recipient of grants from FAPEMIG/CAPE

Metformin reduces liver glucose production by inhibition of fructose-1-6-bisphosphatase.

Metformin is a first-line drug for the treatment of individuals with type 2 diabetes, yet its precise mechanism of action remains unclear. Metformin exerts its antihyperglycemic action primarily through lowering hepatic glucose production (HGP). This suppression is thought to be mediated through inhibition of mitochondrial respiratory complex I, and thus elevation of 5'-adenosine monophosphate (AMP) levels and the activation of AMP-activated protein kinase (AMPK), though this proposition has been challenged given results in mice lacking hepatic AMPK. Here we report that the AMP-inhibited enzyme fructose-1,6-bisphosphatase-1 (FBP1), a rate-controlling enzyme in gluconeogenesis, functions as a major contributor to the therapeutic action of metformin. We identified a point mutation in FBP1 that renders it insensitive to AMP while sparing regulation by fructose-2,6-bisphosphate (F-2,6-P2), and knock-in (KI) of this mutant in mice significantly reduces their response to metformin treatment. We observe this during a metformin tolerance test and in a metformin-euglycemic clamp that we have developed. The antihyperglycemic effect of metformin in high-fat diet-fed diabetic FBP1-KI mice was also significantly blunted compared to wild-type controls. Collectively, we show a new mechanism of action for metformin and provide further evidence that molecular targeting of FBP1 can have antihyperglycemic effects

Orbital cellulitis and massive chemosis as first sign of a cilio-choroidal malignant melanoma without extraocular extension: A case report

Purpose: To describe a case of cilio-choroidal melanoma presenting as aseptic orbital cellulitis with massive conjunctival chemosis. Methods: Case report. Results: A 51-year-old man with a left retro-iris pigmented lesion had acute lid edema, conjunctival chemosis, and extensive hyphema. Ultrasound revealed a large, lobulated, wide-base choroidal-starting lesion affecting the ciliary bodies and vitreous chamber. MRI revealed low-intermediate T2-signal and intermediate-high T1-signal, with substantial post-contrastographic enhancement. After one week of systemic corticosteroids, the chemosis reduced significantly, and the patient was referred for enucleation, even without histologic confirmation. Post-surgical histopathology found 90% necrotic tissue, few viable cells, and no scleral or vascular invasion, with genetic analysis showing monosomy of chromosome 3 and 8q gain. Conclusion: Choroidal melanoma, particularly if necrotic, may occasionally present as aseptic orbital cellulitis, even without extraocular spread

Frequency doubling technology, optical coherence technology and pattern electroretinogram in ocular hypertension

<p>Abstract</p> <p>Background</p> <p>To assess which of three methods, namely, optical coherence tomography (OCT), pattern electroretinogram (PERG) or frequency-doubling technology (FDT), is the most sensitive and specific for detecting early glaucomatous damage in ocular hypertension (OH).</p> <p>Methods</p> <p>Fifty-two patients with OH (24 men and 28 women, mean age of 56 ± 9.6 years) with an intraocular pressure (IOP) > 21 mmHg and fifty-two control patients (25 men and 27 women, mean age of 54.8 ± 10.4 years) with IOP < 21 mmHg, were assessed. All the patients had normal visual acuity, normal optic disk and normal perimetric indices.</p> <p>All subjects underwent OCT, FDT and PERG. Data were analyzed with unpaired <it>t</it>-tests, Chi-square test and Receiver Operating Characteristic (ROC) curve analyses.</p> <p>Results</p> <p>In patients with OH, OCT showed retinal nerve fiber layer (RNFL) thinner than in control group in the superior quadrant (130.16 ± 10.02 vs 135.18 ± 9.27 μm, respectively; p < 0.011) and inferior quadrant (120.14 ± 11.0 vs 132.68 ± 8.03 μm; p < 0.001). FDT showed a significantly higher pattern standard deviation (PSD) (3.46 ± 1.48 vs 1.89 ± 0.7 dB; p < 0.001). With respect to PERG, only the amplitude showed significant differences (p < 0.044) between the two groups. ROC curve analysis revealed a sensitivity and specificity of 92% and 86%, respectively, for FDT-PSD (with an area under the ROC curve of 0.940), whereas with OCT, a sensitivity of 82% and a specificity of 74% was recorded in the inferior RNFL quadrant (with an area under the ROC curve of 0.806) finally with PERG amplitude we found a sensitivity of 52% and specificity of 77% (with an area under the ROC curve of 0.595).</p> <p>Conclusions</p> <p>FDT is the most sensitive and specific method for detecting early glaucomatous damage in eyes with OH, and together with OCT, can be useful in identifying those patients who may develop glaucoma.</p> <p>Trial registration</p> <p>ISRCT number: ISRCTN70295497</p