Sahel, savana, riverine and urban malaria in West Africa: Similar control policies with different outcomes

The study sites for the West African ICEMR are in three countries (The Gambia, Senegal, Mali) and are located within 750 km of each other. In addition, the National Malaria Control Programmes of these countries have virtually identical policies: (1) Artemisinin Combination Therapies (ACTs) for the treatment of symptomatic Plasmodium falciparum infection, (2) Long-Lasting Insecticide-treated bed Nets (LLINs) to reduce the Entomololgic Inoculation Rate (EIR), and (3) sulfadoxine-pyrimethamine for the Intermittent Preventive Treatment of malaria during pregnancy (IPTp). However, the prevalence of P. falciparum malaria and the status of malaria control vary markedly across the four sites with differences in the duration of the transmission season (from 4-5 to 10-11 months), the intensity of transmission (with EIRs from unmeasurably low to 4-5 per person per month), multiplicity of infection (from a mean of 1.0 to means of 2-5) and the status of malaria control (from areas which have virtually no control to areas that are at the threshold of malaria elimination). The most important priority is the need to obtain comparable data on the population-based prevalence, incidence and transmission of malaria before new candidate interventions or combinations of interventions are introduced for malaria control.     

Stimulation of bone formation in the expanding premaxillary suture with a GSK‐3β inhibitor

Oral Diseases (2012) 19 , 73–79 Objectives: Glycogen synthase kinase‐3β (GSK‐3β)/β‐catenin signaling mediates osteogenesis in response to mechanical loading. We tested the hypothesis that local administration of a GSK‐3β inhibitor could stimulate new bone formation in the expanding premaxillary suture. Materials and methods: Thirty‐five Sprague–Dawley rats were subjected to premaxillary suture expansion using a helix spring. The experimental rats were given one or two local injections of SB‐415286, a small‐molecule GSK‐3β inhibitor. Animals were administered calcein and sacrificed on day 7 to quantify new bone formation. To evaluate the proliferation and differentiation of osteoblasts, rats were labeled with bromodeoxyuridine on day 1 and sacrificed on day 2 or 4. β‐catenin expression was evaluated by immunohistochemical staining. Results: Two injections of SB‐415286 led to an elevation of β‐catenin expression and an increase in the number of proliferating osteoblasts in expanding sutures on day 2 and day 4. Consequently, new bone formation in the suture increased significantly on day 7. Conclusions: These results suggest that local delivery of a GSK‐3β inhibitor could stimulate bone formation in the expanding premaxillary suture by eliciting β‐catenin signaling. GSK‐3β could be a pharmaceutical target for improving the effect of orthodontic treatments such as rapid palatal expansion.     

A Survey of Patients' Preferences for the Treatment of Teeth with Apical Periodontitis

Introduction

This research aimed to investigate the preference of patients in Toronto, Canada for management of a tooth affected by painful apical periodontitis when considering its retention via root canal treatment (RCT) and its extraction followed by no replacement, replacement with an implant-supported crown, fixed, or removable partial prostheses.

Methods

Data were collected through a mail-out survey of the University of Toronto Faculty of Dentistry patients, which was complemented by a convenience sample of patients in 10 community practices in Toronto (n = 1000, response rate = 43%). Participants were asked to select their general preference for anterior and posterior teeth with apical periodontitis between saving the tooth or extraction and their specific preference for tooth retention via RCT or extraction. By using bivariate and logistic regression analyses, we applied the Gelberg-Andersen Behavioral Model for Vulnerable Populations to the preference questions to understand the influential factors (P ≤ .05).

Results

Participants' specific preference for tooth retention via RCT was slightly but significantly lower than their general preference (anterior tooth, 93.7% versus 97.2%; posterior tooth, 83.8% versus 89.6%; P < .005). Higher annual income, previous RCT, functional dentition, good/excellent self-rated oral health, and regular dental visits were associated with higher preferences for tooth retention in response to different questions.

Conclusions

The high preference for retaining a tooth in general was moderated by the specific consideration of RCT to retain the tooth. When RCT and extraction are viable options, patients should be advised about the treatment options in an impartial manner and encouraged to communicate their preferences.     

尿毒症非透析患者心瓣膜钙化危险因素分析

目的 探讨尿毒症非透析患者心脏瓣膜钙化的临床相关危险因素及胎球蛋白A与心瓣膜钙化的关系.方法 通过彩色多普勒超声心动图检查观察88例尿毒症非透析患者心脏瓣膜钙化的情况,根据心脏彩超结果将其分为瓣膜钙化组和未钙化组.收集患者的血生化指标,放射免疫法测定全段甲状旁腺激素(iPTH);同时选择我院体检中心健康体检者30例为正常对照组,ELISA法测定研究组及对照组血清胎球蛋白A.采用二分类Lo-gistic回归方法分析瓣膜钙化的危险因素.结果 88例患者中发现心脏瓣膜钙化25例,其中主动脉瓣钙化(AVC)21例,二尖瓣钙化(MVC)4例,联合瓣膜钙化2例;研究组胎球蛋白A水平明显低于对照组;瓣膜钙化组患者的年龄、血磷、钙磷乘积、C反应蛋白、iPTH明显高于未钙化组,胎球蛋白A水平明显低于未钙化组(P＜0.05),Logistic 回归分析显示年龄(B =3.732,P-0.015)、炎症(B=1.503,P=0.025)、血磷(B=1.774,P=0.003)、钙磷乘积(B=1.255,P=0.003)、血iPTH(B=0.832,P=0.017)是心脏瓣膜钙化的危险因素,胎球蛋白A是心脏瓣膜钙化的抑制剂(B=-0.59,P=0.043);直线相关分析显示胎球蛋白A与CRP呈负相关(r=-0.545,P=0.000).结论 尿毒症非透析患者心脏瓣膜钙化的发生率高,以主动脉瓣钙化多见.年龄、炎症、高磷、高钙磷乘积、血iPTH是瓣膜钙化的危险因素.胎球蛋白A是瓣膜钙化的抑制剂,胎球蛋白A水平与CRP呈负相关.     

Change in fibrosis score as a predictor of mortality among HIV-infected patients with viral hepatitis

Noninvasive markers of liver fibrosis, measured at baseline, have been shown to predict liver-related mortality. It remains unknown if a change in the value of the scores over time predicts mortality in patients with HIV and viral hepatitis. In this retrospective study, survival in HIV/hepatitis B virus (HBV; n = 67), HIV/hepatitis C virus (HCV; n = 43), and HIV/HBV/HCV (n = 41) patients was examined using Kaplan-Meier life table analysis. Aspartate aminotransferase (AST)-to-platelet ratio index (APRI) and FIB-4 scores, two noninvasive markers of liver fibrosis, were calculated at baseline and at last available clinical follow-up to determine the change in fibrosis score. Factors associated with mortality were assessed by Cox proportional hazards, including the change in the noninvasive marker score between the two time points. All-cause mortality was determined by Social Security Death Index and chart review. Sixty-seven were coinfected with HIV/HBV, 43 with HIV/HCV, and 41 were triply infected (HIV/HBV/HCV). Kaplan-Meier analysis showed similar survival for the three groups at 7 years of follow-up (p = 0.10). However, median length of follow-up was lower in HIV/HCV (60.5; range 0-102) compared to HIV/HBV (75.7; 12.3-126.5) and HIV/HBV/HCV (80.0; 2.7-123) months, respectively, p = 0.02. Baseline fibrosis score (p = 0.002), an increase in the value for noninvasive measurements for fibrosis (p < 0.001), and the presence of HIV/HCV coinfection (p = 0.041) were each associated with higher risk for mortality. Baseline fibrosis score (p = 0.03) and an increase in FIB-4 score (p = 0.05) were independent predictors of all-cause mortality, but liver-related mortality was not evaluated. In this study, baseline fibrosis score was predictive of 7-year all-cause mortality. Further studies are needed in a prospective cohort to evaluate the predictive value of monitoring changes in fibrosis scores over time to predict mortality in patients with viral hepatitis.     

A Functional Variant in APOA5/A4/C3/A1 Gene Cluster Contributes to Elevated Triglycerides and Severity of CAD by Interfering With MicroRNA 3201 Binding Efficiency

Background

Recent genome-wide association studies identified the APOA5/A4/C3/A1 gene cluster polymorphisms influencing triglyceride level and risk of coronary artery disease (CAD).

Objectives

The purposes of this study were to fine-map triglyceride association signals in the APOA5/A4/C3/A1 gene cluster and then explore the clinical relevance in CAD and potential underlying mechanisms.

Methods

We resequenced the APOA5/A4/C3/A1 gene cluster in 200 patients with extremely high triglyceride levels (≥10 mm/l) and 200 healthy control subjects who were ethnically matched and genotyped 20 genetic markers among 4,991 participants with Chinese Han ethnicity. Subsequently, 8 risk markers were investigated in 917 early-onset and 1,149 late-onset CAD patients, respectively. The molecular mechanism was explored.

Results

By resequencing, a number of newly and potentially functional variants were identified, and both the common and rare variants have remarkable cumulative effects on hypertriglyceridemia risk. Of note, gene dosage of rs2266788 demonstrated a robust association with triglyceride level (p = 1.39 × 10⁻¹⁹), modified Gensini scores (p = 1.67 × 10⁻³), and numbers of vascular lesions in CAD patients (odds ratio: 1.96, 95% confidence interval: 1.31 to 2.14, p = 8.96 × 10⁻⁴). Functional study demonstrated that the rs2266788 C allele destroyed microRNA 3201 binding to the 3′ UTR of APOA5, resulting in prolonging the half-life of APOA5 messenger RNA and increasing its expression levels.

Conclusions

Genetic variants in APOA5/A4/C3/A1 gene cluster play an important role in the regulation of plasma triglyceride levels by an increased APOA5 concentration and contribute to the severity of CAD.     

Human natural killer cells control Plasmodium falciparum infection by eliminating infected red blood cells

Immunodeficient mouse–human chimeras provide a powerful approach to study host-specific pathogens, such as Plasmodium falciparum that causes human malaria. Supplementation of immunodeficient mice with human RBCs supports infection by human Plasmodium parasites, but these mice lack the human immune system. By combining human RBC supplementation and humanized mice that are optimized for human immune cell reconstitution, we have developed RBC-supplemented, immune cell-optimized humanized (RICH) mice that support multiple cycles of P. falciparum infection. Depletion of human natural killer (NK) cells, but not macrophages, in RICH mice results in a significant increase in parasitemia. Further studies in vitro show that NK cells preferentially interact with infected RBCs (iRBCs), resulting in the activation of NK cells and the elimination of iRBCs in a contact-dependent manner. We show that the adhesion molecule lymphocyte-associated antigen 1 is required for NK cell interaction with and elimination of iRBCs. Development of RICH mice and validation of P. falciparum infection should facilitate the dissection of human immune responses to malaria parasite infection and the evaluation of therapeutics and vaccines.Malaria is caused by infection with parasites of the Plasmodium species which are transmitted by bites of infected Anopheles mosquitoes. Plasmodium species are highly host specific. making it difficult to model human parasite infection in laboratory animals. So far, most in vivo experimental studies of malaria have been carried out with mouse and rat Plasmodium strains in rodents. Differences in invasion and disease pathology between human and rodent parasite species have impeded the translation of findings from rodents into human. The lack of appropriate small animal models also has hampered the evaluation of new drugs and vaccines before clinical trials (1).To overcome this challenge, one approach is to supplement SCID mice with human RBCs. The resulting mice support a limited blood-stage P. falciparum infection (2–4). The need to inject large volumes of human RBCs repeatedly and to treat mice with anti-neutrophil antibody and highly toxic clodronate liposomes to suppress the rapid clearance of the injected human RBCs by macrophages in the recipient mice makes working with this system difficult. More recently NOD-SCID Il2rg^−/− (NSG) mice have been shown to support a more efficient P. falciparum infection without the treatment of clodronate liposomes or anti-neutrophil antibody (5). Furthermore, a recent report shows the development of liver-stage P. falciparum infection in immunocompromised and fumarylacetoacetate hydrolase-deficient (Fah^−/−, Rag2^−/−, Il2rg^−/−) (FRG) mice. Backcrossing of FRG mice to the NOD background and supplementing the resulting mice with human RBCs led to reproducible transition from liver-stage infection to blood-stage infection (6). Despite such progress, none of the existing mouse models of human parasite infection has a human immune system.The immune system plays a critical role in the control of parasite infection. Studies in mice using mouse Plasmodium strains have shown that mouse immune cells such as natural killer (NK) cells, T cells, dendritic cells, and B cells all contribute to antiparasitic immunity (7–10). Notably, depletion of NK cells in a mouse model of Plasmodium chabaudi infection results in more severe disease associated with higher parasitemia and mortality (11). In vitro, P. falciparum-infected human RBCs are shown to interact with human NK cells, leading to the induction of IFN-γ (12). Compared with P. falciparum schizonts, live infected RBCs (iRBCs) induce more rapid activation and more production of IFN-γ by NK cells (13). More recently, it has been shown that, in addition to IFN-γ, activated human NK cells also produce perforin and granzyme against P. falciparum-infected RBCs (14). However, because of the lack of appropriate models, little is known about the role of human NK cells in the control of P. falciparum infection in vivo. NK cells are cytolytic and can lyse virus-infected cells and tumor cells (15). However, whether NK cells also can eliminate parasite-infected RBCs directly has not been demonstrated comprehensively.In our study of humanized mice, we previously had developed a simple and effective method of enhancing human cell reconstitution by hydrodynamic expression of human cytokines. Expression of human IL-15 and Flt-3/Flk-2 ligand (Flt-3L) enhances the reconstitution of human NK cells, monocytes, and macrophages (16). In this study, we have constructed humanized mice that have an optimized human immune cell reconstitution as well as high levels of human RBCs through supplementation. We show that such humanized mice support an efficient infection by P. falciparum. Depletion of human NK cells, but not macrophages, in these mice results in a significant increase in parasitemia. Our additional studies in vitro show that NK cells interact preferentially with iRBCs and become activated, resulting in the elimination of iRBCs in a contact-dependent manner. We further show that the cell adhesion molecules lymphocyte-associated antigen 1 (LFA-1) and to some extent DNAX accessory molecule 1 (DNAM-1) mediate NK cell interaction with and elimination of iRBCs. Development of humanized mice with robust reconstitution of human immune cells and human RBCs and validation of the model for P. falciparum infection should facilitate the dissection of human immune responses to malaria parasite infection and the evaluation of therapeutics and vaccines.     

Cartilage-specific β-catenin signaling regulates chondrocyte maturation, generation of ossification centers, and perichondrial bone formation during skeletal development

The WNT/β-catenin signaling pathway is a critical regulator of chondrocyte and osteoblast differentiation during multiple phases of cartilage and bone development. Although the importance of β-catenin signaling during the process of endochondral bone development has been previously appreciated using a variety of genetic models that manipulate β-catenin in skeletal progenitors and osteoblasts, genetic evidence demonstrating a specific role for β-catenin in committed growth-plate chondrocytes has been less robust. To identify the specific role of cartilage-derived β-catenin in regulating cartilage and bone development, we studied chondrocyte-specific gain- and loss-of-function genetic mouse models using the tamoxifen-inducible Col2Cre(ERT2) transgene in combination with β-catenin(fx(exon3)/wt) or β-catenin(fx/fx) floxed alleles, respectively. From these genetic models and biochemical data, three significant and novel findings were uncovered. First, cartilage-specific β-catenin signaling promotes chondrocyte maturation, possibly involving a bone morphogenic protein 2 (BMP2)-mediated mechanism. Second, cartilage-specific β-catenin facilitates primary and secondary ossification center formation via the induction of chondrocyte hypertrophy, possibly through enhanced matrix metalloproteinase (MMP) expression at sites of cartilage degradation, and potentially by enhancing Indian hedgehog (IHH) signaling activity to recruit vascular tissues. Finally, cartilage-specific β-catenin signaling promotes perichondrial bone formation possibly via a mechanism in which BMP2 and IHH paracrine signals synergize to accelerate perichondrial osteoblastic differentiation. The work presented here supports the concept that the cartilage-derived β-catenin signal is a central mediator for major events during endochondral bone formation, including chondrocyte maturation, primary and secondary ossification center development, vascularization, and perichondrial bone formation.