“New Jerusalem” in Seventeenth-Century Russia

Patriarch Nikon’s creation of the Resurrection “New Jerusalem” Monastery in cooperation with Tsar Aleksei Mikhailovich reflects Russia’s self‑image as a new Holy Land and its relations with the Orthodox East in the seventeenth century. This essay identifies the “Byzantine” paradigms guiding the patriarch’s visualization of Salvation history at Voskresenskii Monastery and demonstrates the extent to which the construction of and responses to the monastery were shaped by Greek hierarchs in Moscow. Nikon conceptualized the monastery as “image” or “icon” of the Holy Land on the authority of the Decree of the Seventh Ecumenical Council, Synodicon, Skrizhal´, and certain “historical” texts. The realization of the patriarch’s New Jerusalem involved both the replication of prototypes in Palestine and the Romanovs’ reenactment of the original construction of the Holy Land by Emperor Constantine and his mother Helen in the fourth century. Notions of the Russian New Jerusalem and the Romanovs’ claims to the Byzantine legacy were interdependent and mutually reinforcing. While embraced by dissenting Old Believers, the New Jerusalem‑related charges initiated in the 1660s by the Eastern hierarchs in order to disgrace and condemn the patriarch and his foundation were soon rejected by the Russian hierarchy and the Romanovs who resurrected the “New Jerusalem” idea and favored its namesake monastery for centuries.La création par le patriarche Nikon, et avec l’appui du tsar Aleksej Mihajlovič, du monastère de la Résurrection de la « Nouvelle Jérusalem » reflète l’image qu’avait de soi la Russie en tant qu’une nouvelle Terre sainte et ses relations avec l’Orient orthodoxe au xviiesiècle. Dans cet article, l’auteur identifie les paradigmes « byzantins » guidant la visualisation du patriarche de l’histoire du Salut au monastère de la Résurrection et montre dans quelle mesure la construction du monastère et les réactions qu’il a suscitées étaient influencées par les hiérarques grecs de Moscou. Nikon a conceptualisé le monastère comme une « image » ou une « icône » de la Terre sainte en se basant sur des textes faisant autorité, le décret du septième concile œcuménique, le Synodikon, le Skrizhal´ et certains textes « historiques ». La réalisation de la Nouvelle Jérusalem du patriarche impliquait à la fois de reproduire les prototypes de Palestine et, pour les Romanov, de rejouer la construction de la Terre sainte originale par l’empereur Constantin et sa mère Hélène au ivesiècle. Le concept de Nouvelle Jérusalem russe et les prétentions des Romanov à l’héritage byzantin étaient interdé­pen­dants et se confortaient mutuellement. Si les accusations contre la Nouvelle Jérusalem initiées dans les années1660 par les hiérarques orientaux dans le but d’obtenir la disgrâce et la condamnation du patriarche et de sa fondation furent adoptées par les vieux croyants dissidents, elles furent rapidement rejetées par la hiérarchie russe et par les Romanov, qui ressuscitèrent l’idée de la « Nouvelle Jérusalem » et accordèrent leur faveur au monastère éponyme pendant des siècles

Adjunctive therapy for severe malaria: a review and critical appraisal.

BACKGROUND: Despite recent efforts and successes in reducing the malaria burden globally, this infection still accounts for an estimated 212 million clinical cases, 2 million severe malaria cases, and approximately 429,000 deaths annually. Even with the routine use of effective anti-malarial drugs, the case fatality rate for severe malaria remains unacceptably high, with cerebral malaria being one of the most life-threatening complications. Up to one-third of cerebral malaria survivors are left with long-term cognitive and neurological deficits. From a population point of view, the decrease of malaria transmission may jeopardize the development of naturally acquired immunity against the infection, leading to fewer total cases, but potentially an increase in severe cases. The pathophysiology of severe and cerebral malaria is not completely understood, but both parasite and host determinants contribute to its onset and outcomes. Adjunctive therapy, based on modulating the host response to infection, could help to improve the outcomes achieved with specific anti-malarial therapy. RESULTS AND CONCLUSIONS: In the last decades, several interventions targeting different pathways have been tested. However, none of these strategies have demonstrated clear beneficial effects, and some have shown deleterious outcomes. This review aims to summarize evidence from clinical trials testing different adjunctive therapy for severe and cerebral malaria in humans. It also highlights some preclinical studies which have evaluated novel strategies and other candidate therapeutics that may be evaluated in future clinical trials

Rocaglates as dual-targeting agents for experimental cerebral malaria

Cerebral malaria (CM) is a severe and rapidly progressing complication of infection by Plasmodium parasites that is associated with high rates of mortality and morbidity. Treatment options are currently few, and intervention with artemisinin (Art) has limited efficacy, a problem that is compounded by the emergence of resistance to Art in Plasmodium parasites. Rocaglates are a class of natural products derived from plants of the Aglaia genus that have been shown to interfere with eukaryotic initiation factor 4A (eIF4A), ultimately blocking initiation of protein synthesis. Here, we show that the rocaglate CR-1-31B perturbs association of Plasmodium falciparum eIF4A (PfeIF4A) with RNA. CR-1-31B shows potent prophylactic and therapeutic antiplasmodial activity in vivo in mouse models of infection with Plasmodium berghei (CM) and Plasmodium chabaudi (blood-stage malaria), and can also block replication of different clinical isolates of P. falciparum in human erythrocytes infected ex vivo, including drug-resistant P. falciparum isolates. In vivo, a single dosing of CR-1-31B in P. berghei-infected animals is sufficient to provide protection against lethality. CR-1-31B is shown to dampen expression of the early proinflammatory response in myeloid cells in vitro and dampens the inflammatory response in vivo in P. berghei-infected mice. The dual activity of CR-1-31B as an antiplasmodial and as an inhibitor of the inflammatory response in myeloid cells should prove extremely valuable for therapeutic intervention in human cases of CM.We thank Susan Gauthier, Genevieve Perreault, and Patrick Senechal for technical assistance. This work was supported by a research grant (to P.G.) from the Canadian Institutes of Health Research (CIHR) (Foundation Grant). J.P. and P.G. are supported by a James McGill Professorship salary award. D.L. is supported by fellowships from the Fonds de recherche sante Quebec, the CIHR Neuroinflammation training program. J.P. is supported by CIHR Research Grant FDN-148366. M.S. is supported by a CIHR Foundation grant. J.A.P. is supported by NIH Grant R35 GM118173. Work at the Boston University Center for Molecular Discovery is supported by Grant R24 GM111625. K.C.K. was supported by a CIHR Foundation Grant and the Canada Research Chair program. (Canadian Institutes of Health Research (CIHR); James McGill Professorship salary award; Fonds de recherche sante Quebec; CIHR Neuroinflammation training program; FDN-148366 - CIHR Research Grant; CIHR Foundation grant; R35 GM118173 - NIH; Canada Research Chair program; R24 GM111625

Altered high-energy phosphate and membrane metabolism in Pelizaeus-Merzbacher disease using phosphorus magnetic resonance spectroscopy

Pelizaeus-Merzbacher disease is an X-linked recessive leucodystrophy of the central nervous system caused by mutations affecting the major myelin protein, proteolipid protein 1. The extent of the altered in vivo neurochemistry of protein, proteolipid protein 1 duplications, the most common form of Pelizaeus-Merzbacher disease, is, however, poorly understood. Phosphorus magnetic resonance spectroscopy is the only in vivo technique that can assess the biochemistry associated with high-energy phosphate and membrane phospholipid metabolism across different cortical, subcortical and white matter areas. In this cross-sectional study, whole-brain, multi-voxel phosphorus magnetic resonance spectroscopy was acquired at 3 T on 14 patients with Pelizaeus-Merzbacher disease with protein, proteolipid protein 1 duplications and 23 healthy controls (all males). Anabolic and catabolic levels of membrane phospholipids (phosphocholine and phosphoethanolamine, and glycerophosphoethanolamine and glycerophosphocholine, respectively), as well as phosphocreatine, inorganic orthophosphate and adenosine triphosphate levels relative to the total phosphorus magnetic resonance spectroscopy signal from 12 different cortical and subcortical areas were compared between the two groups. Independent of brain area, phosphocholine, glycerophosphoethanolamine and inorganic orthophosphate levels were significantly lower (P = 0.0025, P \u3c 0.0001 and P = 0.0002) and phosphocreatine levels were significantly higher (P \u3c 0.0001) in Pelizaeus-Merzbacher disease patients compared with controls. Additionally, there was a significant group-by-brain area interaction for phosphocreatine with post-hoc analyses demonstrating significantly higher phosphocreatine levels in patients with Pelizaeus-Merzbacher disease compared with controls across multiple brain areas (anterior and posterior white matter, superior parietal lobe, posterior cingulate cortex, hippocampus, occipital cortex, striatum and thalamus; all P ≤ 0.0042). Phosphoethanolamine, glycerophosphoethanolamine and adenosine triphosphate levels were not significantly different between groups. For the first-time, widespread alterations in phosphorus magnetic resonance spectroscopy metabolite levels of Pelizaeus-Merzbacher disease patients are being reported. Specifically, increased high-energy phosphate storage levels of phosphocreatine concomitant with decreased inorganic orthophosphate across multiple areas suggest a widespread reduction in the high-energy phosphate utilization in Pelizaeus-Merzbacher disease, and the membrane phospholipid metabolite deficits suggest a widespread degradation in the neuropil content/maintenance of patients with Pelizaeus-Merzbacher disease which includes axons, dendrites and astrocytes within cortex and the myelin microstructure and oligodendrocytes within white matter. These results provide greater insight into the neuropathology of Pelizaeus-Merzbacher disease both in terms of energy expenditure and membrane phospholipid metabolites. Future longitudinal studies are warranted to investigate the utility of phosphorus magnetic resonance spectroscopy as surrogate biomarkers in monitoring treatment intervention for Pelizaeus-Merzbacher disease

Vitamin A and zinc supplementation among pregnant women to prevent placental malaria: a randomized, double-blind, placebo-controlled trial in Tanzania

BACKGROUND: Malaria causes nearly 200 million clinical cases and approximately half a million deaths each year, primarily in sub-Saharan Africa.1 The risk of malaria increases during pregnancy,2 a period during which its prevention is especially important. Not only do pregnant women experience greater severity of illness compared with nonpregnant women,2 but studies have shown strong associations between prenatal malaria and maternal anemia,2 fetal loss, low birthweight, and infant mortality.2 Improving preventive measures that specifically target malaria in pregnancy is a global health priority.3 METHODS: Study design and participants. This randomized, doubleblind, placebo-controlled trial was implemented at 8 antenatal care clinics in the urban Temeke and Ilala districts of Dar es Salaam, Tanzania. The trial was registered RESULTS: A total of 2,500 screened participants were enrolled in the trial. The trial profile is shown in Figure 1. It was not possible to collect placentas from 875 participants for the following reasons: miscarriages (fetal loss before 28 weeks of gestation) (N = 234), delivery outside of Dar es Salaam or at a non-study hospital (N = 577), or withdrawal from the study (N = 34). Of the remaining 1,589 women, 1,404 placental samples were obtained (88%); histology results were available for 1,361 participants. PCR results were available for 1,158 participants, and 1,404 participants had either histology or PCR results available. CONCLUSION: This study is the first to examine the impact of vitamin A and zinc supplementation starting in early pregnancy on placental malaria. We observed that supplementation with 25 mg zinc per day from the first trimester until delivery was associated with a 36% (95% CI = 9–56%) reduced risk of histopathology-positive placental infection, but not PCRpositive infection. Vitamin A supplementation had no impact on placental malaria, but was associated with an increased risk for severe anemia

Adjunctive therapy for severe malaria: a review and critical appraisal

BACKGROUND: Despite recent efforts and successes in reducing the malaria burden globally, this infection still accounts for an estimated 212 million clinical cases, 2 million severe malaria cases, and approximately 429,000 deaths annually. Even with the routine use of effective anti-malarial drugs, the case fatality rate for severe malaria remains unacceptably high, with cerebral malaria being one of the most life-threatening complications. Up to one-third of cerebral malaria survivors are left with long-term cognitive and neurological deficits. From a population point of view, the decrease of malaria transmission may jeopardize the development of naturally acquired immunity against the infection, leading to fewer total cases, but potentially an increase in severe cases. The pathophysiology of severe and cerebral malaria is not completely understood, but both parasite and host determinants contribute to its onset and outcomes. Adjunctive therapy, based on modulating the host response to infection, could help to improve the outcomes achieved with specific anti-malarial therapy. RESULTS AND CONCLUSIONS: In the last decades, several interventions targeting different pathways have been tested. However, none of these strategies have demonstrated clear beneficial effects, and some have shown deleterious outcomes. This review aims to summarize evidence from clinical trials testing different adjunctive therapy for severe and cerebral malaria in humans. It also highlights some preclinical studies which have evaluated novel strategies and other candidate therapeutics that may be evaluated in future clinical trials

Safety and tolerability of adjunctive rosiglitazone treatment for children with uncomplicated malaria.

BACKGROUND: Despite the widespread use and availability of rapidly acting anti-malarials, the fatality rate of severe malaria in sub-Saharan Africa remains high. Adjunctive therapies that target the host response to malaria infection may further decrease mortality over that of anti-malarial agents alone. Peroxisome proliferator-activated receptor-gamma agonists (e.g. rosiglitazone) have been shown to act on several pathways implicated in the pathogenesis of severe malaria and may improve clinical outcome as an adjunctive intervention. METHODS: In this study, the safety and tolerability of adjunctive rosiglitazone in paediatric uncomplicated malaria infection was evaluated in Mozambique, as a prelude to its evaluation in a randomized controlled trial in paediatric severe malaria. The study was a prospective, randomized, double-blind, placebo-controlled, phase IIa trial of rosiglitazone (0.045 mg/kg/dose) twice daily for 4 days versus placebo as adjunctive treatment in addition to Mozambican standard of care (artemisinin combination therapy Coartem®) in children with uncomplicated malaria. The primary outcomes were tolerability and safety, including clinical, haematological, biochemical, and electrocardiographic evaluations. RESULTS: Thirty children were enrolled: 20 were assigned to rosiglitazone and 10 to placebo. Rosiglitazone treatment did not induce hypoglycaemia nor significantly alter clinical, biochemical, haematological, or electrocardiographic parameters. CONCLUSIONS: Adjunctive rosiglitazone was safe and well-tolerated in children with uncomplicated malaria, permitting the extension of its evaluation as adjunctive therapy for severe malaria. The trial is registered with Clinicaltrials.gov, NCT02694874

Severe Acute Respiratory Syndrome–associated Coronavirus in Lung Tissue

Efforts to contain severe acute respiratory syndrome (SARS) have been limited by the lack of a standardized, sensitive, and specific test for SARS-associated coronavirus (CoV). We used a standardized reverse transcription-polymerase chain reaction assay to detect SARS-CoV in lung samples obtained from well-characterized patients who died of SARS and from those who died of other reasons. SARS-CoV was detected in all 22 postmortem lung tissues (to 109 viral copies/g) from 11 patients with probable SARS but was not detected in any of the 23 lung control samples (sample analysis was blinded). The sensitivity and specificity (95% confidence interval) were 100% (84.6% to 100%) and 100% (85.1% to 100%), respectively. Viral loads were significantly associated with a shorter course of illness but not with the use of ribavirin or steroids. CoV was consistently identified in the lungs of all patients who died of SARS but not in control patients, supporting a primary role for CoV in deaths