Divergent Profile of Emerging Cutaneous Leishmaniasis in Subtropical Brazil: New Endemic Areas in the Southern Frontier

Background

Although known to be highly endemic in the Amazon regions of Brazil, the presence of cutaneous leishmaniasis (CL) in the subtropical southern part of the country has largely been ignored. This study was conducted to demonstrate CL is emerging in the Brazilian state of Santa Catarina, as well as to characterize the epidemiological profile and Leishmania species involved.

Methodology/Principal Findings

For this cross-sectional study, data from all CL cases from Santa Catarina, Brazil, reported to the Brazilian National Notifiable Diseases Information System from 2001 to 2009 were investigated. Amplification of the kDNA minicircle conserved region followed by restriction fragment length polymorphism (PCR-RFLP) was conducted to screen for Leishmania species present in patient biopsy. Overall, 542 CL cases were reported, with majority resulting from autochthonous transmission (n = 401, 73.99%) and occurring in urban zones (n = 422, 77.86%). Age, gender, zone of residence, origin of case, clinical form and case outcome were found to differ significantly by region. Imported cases were over seven times more likely to relapse (95% CI 2.56–21.09). Mapping of cases revealed new endemic areas in northeastern Santa Catarina with two species present. With the exception of three L. (Leishmania) amazonensis cases (1.20%), majority of PCR positive samples were found to be L. (Viannia) braziliensis (n = 248, 98.80%).

Conclusions/Significance

CL is now endemic in the state of Santa Catarina, Brazil, with case profiles varying significantly by region. L. (V.) braziliensis has been identified as the predominant species in the region.     

Wood use in a medieval village: the contribution of wood charcoal analysis to the history of land use during the 13th and 14th centuries a.d. at Pobla d’Ifach, Calp, Alicante, Spain

Excavations on the Rock of Ifach, Alicante, Spain have revealed the remains of a medieval settlement that flourished between a.d. 1297 and 1359. Wood charcoal analysis combined with archaeological evidence and historical records allow an assessment of the local vegetation of the area during the medieval period, the obtaining and use of firewood and the commercial routes for supplying timber. Pinus halepensis and to a lesser degree various matorral taxa were used for fuel during the main occupation phases at the settlement. The resource exploitation network of the settlement expanded over the adjacent coastal area, with firewood obtained from pine woodlands there. The timbers used in the construction of the settlement were mainly from pines that originated nearby (P. halepensis) or which were transported by river from woodland areas to the north which were controlled by the Crown of Aragon (P. nigra/sylvestris, P. pinaster). The partial destruction of the village in a.d. 1359 and its gradual abandonment are reflected in changes observed in fuel supplying practices that then concentrated on the local matorral vegetation of the rock itself.     

Fertility Desires among Men and Women Living with HIV/AIDS in Nairobi Slums: A Mixed Methods Study

Objectives

Fertility desires require new understanding in a context of expanding access to antiretroviral therapy for people living with HIV/AIDS in Sub-Saharan Africa. This paper studies the fertility desires and their rationales, of slum-dwelling Kenyan men and women living with HIV/AIDS who know their serostatus, but have different antiretroviral therapy treatment statuses. It addresses two research questions: How do people living with HIV/AIDS consider their future fertility? What factors contribute to an explanation of fertility desires among people living with HIV/AIDS.

Methods

A mixed methods study (survey [n = 513] and in-depth interviews [n = 41]) with adults living with HIV/AIDS living in Nairobi slums was conducted in 2010. Regression analyses assess independent relationships between fertility desires and socio-demographic factors. Analyses of in-depth interviews are used to interpret the statistical analyses of fertility desires.

Results

Our analyses show that fertility desires are complex and ambivalent, reflecting tensions between familial and societal pressures to have children versus pressures for HIV (re-)infection prevention. More than a third (34%) of men and women living with HIV expressed future fertility desires; however, this is significantly lower than in the general population. Factors independently associated with desiring a child among people living with HIV/AIDS were age, sex, number of surviving children, social support and household wealth of the respondent.

Discussion

Increasing access to ART is changing the context of future childbearing for people living with HIV/AIDS. Prevailing values mean that, for many people living with HIV/AIDS, having children is seen as necessary for a “normal” and healthy adult life. However, the social rewards of childbearing conflict with moral imperatives of HIV prevention, presenting dilemmas about the “proper” reproductive behaviour of people living with HIV/AIDS. The health policy and service delivery implications of these findings are explored.     

PTHrP, PTH, and the PTH/PTHrP receptor in endochondral bone development

Endochondral bone development is a fascinating story of proliferation, maturation, and death. An understanding of this process at the molecular level is emerging. In particular, significant advances have been made in understanding the role of parathyroid-hormone-related peptide (PTHrP), parathyroid hormone (PTH), and the PTH/PTHrP receptor in endochondral bone development. Mutations of the PTH/PTHrP receptor have been identified in Jansen metaphyseal chondrodysplasia, Blomstrand's lethal chondrodysplasia, and enchondromatosis. Furthermore, genetic manipulations of the PTHrP, PTH, and the PTH/PTHrP receptor genes, respectively, have demonstrated the critical role of these proteins in regulating both the switch between proliferation and differentiation of chondrocytes, and their replacement by bone cells. A future area of investigation will be the identification of downstream effectors of PTH, PTHrP, and PTH/PTHrP receptor activities. Furthermore, it will be of critical importance to study how these proteins cooperate and integrate with other molecules that are essential for growth plate development.     

Severe Extracellular Matrix Abnormalities and Chondrodysplasia in Mice Lacking Collagen Prolyl 4-Hydroxylase Isoenzyme II in Combination with a Reduced Amount of Isoenzyme I

Collagen prolyl 4-hydroxylases (C-P4H-I, C-P4H-II, and C-P4H-III) catalyze formation of 4-hydroxyproline residues required to form triple-helical collagen molecules. Vertebrate C-P4Hs are α₂β₂ tetramers differing in their catalytic α subunits. C-P4H-I is the major isoenzyme in most cells, and inactivation of its catalytic subunit (P4ha1^−/−) leads to embryonic lethality in mouse, whereas P4ha1^+/− mice have no abnormalities. To study the role of C-P4H-II, which predominates in chondrocytes, we generated P4ha2^−/− mice. Surprisingly, they had no apparent phenotypic abnormalities. To assess possible functional complementarity, we established P4ha1^+/−;P4ha2^−/− mice. They were smaller than their littermates, had moderate chondrodysplasia, and developed kyphosis. A transient inner cell death phenotype was detected in their developing growth plates. The columnar arrangement of proliferative chondrocytes was impaired, the amount of 4-hydroxyproline and the T_m of collagen II were reduced, and the extracellular matrix was softer in the growth plates of newborn P4ha1^+/−;P4ha2^−/− mice. No signs of uncompensated ER stress were detected in the mutant growth plate chondrocytes. Some of these defects were also found in P4ha2^−/− mice, although in a much milder form. Our data show that C-P4H-I can to a large extent compensate for the lack of C-P4H-II in proper endochondral bone development, but their combined partial and complete inactivation, respectively, leads to biomechanically impaired extracellular matrix, moderate chondrodysplasia, and kyphosis. Our mouse data suggest that inactivating mutations in human P4HA2 are not likely to lead to skeletal disorders, and a simultaneous decrease in P4HA1 function would most probably be required to generate such a disease phenotype.     

Pregnancy Augments G Protein Estrogen Receptor (GPER) Induced Vasodilation in Rat Uterine Arteries via the Nitric Oxide - cGMP Signaling Pathway

Background

The regulation of vascular tone in the uterine circulation is a key determinant of appropriate uteroplacental blood perfusion and successful pregnancy outcome. Estrogens, which increase in the maternal circulation throughout pregnancy, can exert acute vasodilatory actions. Recently a third estrogen receptor named GPER (G protein-coupled estrogen receptor) was identified and, although several studies have shown vasodilatory effects in several vascular beds, nothing is known about its role in the uterine vasculature.

Aim

The aim of this study was to determine the function of GPER in uterine arteries mainly during pregnancy. Uterine arteries were isolated from nonpregnant and pregnant rats.

Methods

Vessels were contracted with phenylephrine and then incubated with incremental doses (10⁻¹²–10⁻⁵ M) of the selective GPER agonist G1.

Results

G1 induced a dose-dependent vasodilation which was: 1) significantly increased in pregnancy, 2) endothelium-dependent, 3) primarily mediated by NO/cGMP pathway and 4) unaffected by BK_ca channel inhibition.

Conclusion

This is the first study to show the potential importance of GPER signaling in reducing uterine vascular tone during pregnancy. GPER may therefore play a previously unrecognized role in the regulation of uteroplacental blood flow and normal fetus growth.     

Proteasome inhibitors sensitize ovarian cancer cells to TRAIL induced apoptosis

In the present study we have explored the sensitivity of ovarian cancer cells to TRAIL and proteasome inhibitors. Particularly, we have explored the capacity of proteasome inhibitors to bypass TRAIL resistance of ovarian cancer cells. For these studies we have used the A2780 ovarian cancer cell line and its chemoresistant derivatives A2780/DDP and A2780/ADR, providing evidence that: (i) the three cell lines are either scarcely sensitive (A2780 and A2780/ADR) or moderately sensitive (A2780/DDP) to the cytotoxic effects of TRAIL; (ii) the elevated c-FLIP expression observed in ovarian cancer cells is a major determinant of TRAIL resistance of these cells; (iii) proteasome inhibitors (PS-341 or MG132) are able to exert a significant pro-apoptotic effect and to greatly enhance the sensitivity of both chemosensitive and chemoresistant A2780 cells to TRAIL; (iv) proteasome inhibitors damage mitochondria through stabilization of BH3-only proteins, Bax and caspase activation and significantly enhance TRAIL-R2 expression; (v) TRAIL-R2, but not TRAIL-R1, mediates the apoptotic effects of TRAIL on ovarian cancer cells. Importantly, studies on primary ovarian cancer cells have shown that these cells are completely resistant to TRAIL and proteasome inhibitors markedly enhance the sensitivity of these cells to TRAIL. Given the high susceptibility of ovarian cancer cells to proteasome inhibitors, our results further support the experimental use of these compounds in the treatment of ovarian cancer.     

Evaluation of DNA extraction methods of rumen microbial populations

The dynamism of microbial populations in the rumen has been studied with molecular methods that analyze single nucleotide polymorphisms of ribosomal RNA gene fragments (rDNA). Therefore DNA of good quality is needed for this kind of analysis. In this work we report the evaluation of four DNA extraction protocols (mechanical lysis or chemical lysis with CTAB, ethylxanthogenate or DNAzol^®) from ruminal fluid. The suitability of two of these protocols (mechanical lysis and DNAzol^®) was tested on single-strand conformation polymorphism (SSCP) of rDNA of rumen microbial populations. DNAzol^® was a simple method that rendered good integrity, yield and purity. With this method, subtle changes in protozoan populations were detected in young bulls fed with slightly different formulations of a supplement of multinutritional blocks of molasses and urea. Sequences related to Eudiplodinium maggi and a non-cultured Entodiniomorphid similar to Entodinium caudatum, were related to major fluctuating populations in an SSCP assay.     

The HIF signaling pathway in osteoblasts directly modulates erythropoiesis through the production of EPO

Osteoblasts are an important component of the hematopoietic microenvironment in bone. However, the mechanisms by which osteoblasts control hematopoiesis remain unknown. We show that augmented HIF signaling in osteoprogenitors results in HSC niche expansion associated with selective expansion of the erythroid lineage. Increased red blood cell production occurred in an EPO-dependent manner with increased EPO expression in bone and suppressed EPO expression in the kidney. In contrast, inactivation of HIF in osteoprogenitors reduced EPO expression in bone. Importantly, augmented HIF activity in osteoprogenitors protected mice from stress-induced anemia. Pharmacologic or genetic inhibition of prolyl hydroxylases1/2/3 in osteoprogenitors elevated EPO expression in bone and increased hematocrit. These data reveal an unexpected role for osteoblasts in the production of EPO and modulation of erythropoiesis. Furthermore, these studies demonstrate a molecular role for osteoblastic PHD/VHL/HIF signaling that can be targeted to elevate both HSCs and erythroid progenitors in the local hematopoietic microenvironment.