Comparative study of sulfadoxine-pyrimethamine and amodiaquine + sulfadoxine-pyrimethamine for the treatment of malaria caused by chloroquine-resistant Plasmodium falciparum in Maputo, Mozambique

To compare the efficacy and side-effects of two therapeutic regimens for chloroquine-resistant falciparum malaria, a randomized study was carried out in 69 patients in Maputo Central Hospital in 1986-1987. The two treatments were sulfadoxine 25 mg/kg + pyrimethamine 1.25 mg/kg as a single dose (S + P) and amodiaquine 10 + 10 + 5 mg/kg over three days with sulfadoxine + pyrimethamine on the third day (A + S + P). The cure rate was 25/29 (86%) with S + P and 27/30 (90%) with A + S + P. No serious side-effects were observed. The probably slightly higher cure rate with the triple combination is hardly of clinical importance in semi-immune patients, but may theoretically help retard the development of resistance to sulfadoxine-pyrimethamine. This point and the question of the incidence of side-effects with the two regimens should be made the object of an epidemiological study.     

In vitro and in vivo antimalarial activity of ferrochloroquine, a ferrocenyl analogue of chloroquine against chloroquine-resistant malaria parasites

Previous studies have shown that ferrochloroquine (FQ) exhibited an antimalarial activity against Plasmodium spp. The present work confirmed this activity, described the curative effect on P. vinckei and investigated the FQ toxicity in vitro and in vivo. The in vitro and in vivo growth inhibition of P. falciparum and P. berghei N, respectively, showed that FQ antimalarial activity was 1.5–10 times more potent than chloroquine. FQ completely inhibited the in vivo development of both chloroquine-susceptible and resistant P. vinckei strains and protected mice from lethal infection at a dose of 8.4 mg kg⁻¹ day⁻¹ given for 4 days subcutaneously or orally. This curative effect was 5–20 times more potent than chloroquine, according to the strains' resistance to chloroquine. At this curative dose, no clinical changes were observed in mice up to 14 days after the last administration. Nevertheless, the acute toxicity and lethality of ferrochloroquine seemed to be dependent on gastric surfeit. The FQ security index determined in vitro confirmed that it might be a promising compound. Received: 12 August 2000 / Accepted: 16 August 2000     

慢性病所致的慢性创面的防治

慢性创面是慢性病、创伤、感染等疾病常见的并发症.近年来,慢性病所致的慢性创面发生率呈逐渐增加趋势,且大部分慢性创面得不到规范治疗,创面长期不愈合,给患者带来巨大痛苦,给社会带来很大负担.此类慢性创面的愈合是一个从凝血、炎症反应、肉芽组织形成(增殖)到塑性的有序过程,任何破坏该过程的因素都会导致创面难以愈合.慢性创面主要...     

Induction of regulatory cells by helminth parasites: exploitation for the treatment of inflammatory diseases

Helminth parasites are highly successful pathogens, chronically infecting a quarter of the world's population, causing significant morbidity but rarely causing death. Protective immunity and expulsion of helminths is mediated by T-helper 2 (Th2) cells, type 2 (M2) macrophages, type 2 innate lymphoid cells, and eosinophils. Failure to mount these type 2 immune responses can result in immunopathology mediated by Th1 or Th17 cells. Helminths have evolved a wide variety of approaches for immune suppression, especially the generation of regulatory T cells and anti-inflammatory cytokines interleukin-10 and transforming growth factor-β. This is a very effective strategy for subverting protective immune responses to prolong their survival in the host but has the bystander effect of modulating immune responses to unrelated antigens. Epidemiological studies in humans have shown that infection with helminth parasites is associated with a low incidence of allergy/asthma and autoimmunity in developing countries. Experimental studies in mice have demonstrated that regulatory immune responses induced by helminth can suppress Th2 and Th1/Th17 responses that mediate allergy and autoimmunity, respectively. This has provided a rational explanation of the ‘hygiene hypothesis’ and has also led to the exploitation of helminths or their immunomodulatory products in the development of new immunosuppressive therapies for inflammatory diseases in humans.     

Normalization of the vasculature for treatment of cancer and other diseases

New vessel formation (angiogenesis) is an essential physiological process for embryologic development, normal growth, and tissue repair. Angiogenesis is tightly regulated at the molecular level. Dysregulation of angiogenesis occurs in various pathologies and is one of the hallmarks of cancer. The imbalance of pro- and anti-angiogenic signaling within tumors creates an abnormal vascular network that is characterized by dilated, tortuous, and hyperpermeable vessels. The physiological consequences of these vascular abnormalities include temporal and spatial heterogeneity in tumor blood flow and oxygenation and increased tumor interstitial fluid pressure. These abnormalities and the resultant microenvironment fuel tumor progression, and also lead to a reduction in the efficacy of chemotherapy, radiotherapy, and immunotherapy. With the discovery of vascular endothelial growth factor (VEGF) as a major driver of tumor angiogenesis, efforts have focused on novel therapeutics aimed at inhibiting VEGF activity, with the goal of regressing tumors by starvation. Unfortunately, clinical trials of anti-VEGF monotherapy in patients with solid tumors have been largely negative. Intriguingly, the combination of anti-VEGF therapy with conventional chemotherapy has improved survival in cancer patients compared with chemotherapy alone. These seemingly paradoxical results could be explained by a "normalization" of the tumor vasculature by anti-VEGF therapy. Preclinical studies have shown that anti-VEGF therapy changes tumor vasculature towards a more "mature" or "normal" phenotype. This "vascular normalization" is characterized by attenuation of hyperpermeability, increased vascular pericyte coverage, a more normal basement membrane, and a resultant reduction in tumor hypoxia and interstitial fluid pressure. These in turn can lead to an improvement in the metabolic profile of the tumor microenvironment, the delivery and efficacy of exogenously administered therapeutics, the efficacy of radiotherapy and of effector immune cells, and a reduction in number of metastatic cells shed by tumors into circulation in mice. These findings are consistent with data from clinical trials of anti-VEGF agents in patients with various solid tumors. More recently, genetic and pharmacological approaches have begun to unravel some other key regulators of vascular normalization such as proteins that regulate tissue oxygen sensing (PHD2) and vessel maturation (PDGFRβ, RGS5, Ang1/2, TGF-β). Here, we review the pathophysiology of tumor angiogenesis, the molecular underpinnings and functional consequences of vascular normalization, and the implications for treatment of cancer and nonmalignant diseases.     

细胞自噬机制开启疾病治疗新途径

自噬是指细胞内细胞器和蛋白质等在溶酶体被降解及其降解产物被重新利用的过程。日本科学家大隅良典(Yoshinori Ohsumi)发现了15个自噬相关基因并阐述了自噬机制,获得2016年诺贝尔生理学与医学奖。他的开创性研究成果为探讨细胞自噬的生理和病理作用奠定了重要基础,并为通过调节细胞自噬治疗疾病开辟了新途径。自噬是一种普遍性细胞反应,正常情况下细胞自噬水平很低,受生理或病理性刺激后自噬水平显著升高。自噬相关基因缺失或自噬功能障碍时可导致某些疾病的发生。近来,人们试图通过激活或抑制细胞自噬预防和治疗自噬障碍相关性疾病。     

Free-flow electrophoresis for the separation of malaria infected and uninfected mouse erythrocytes and for the isolation of free parasites (Plasmodium vinckei): A new rapid technique for the liberation of malaria parasites from their host cells

Summary After aggregation of erythrocytes from malaria infected mice, the parasites (Plasmodium vinckei) could be set free using gentle mechanical forces. The mixture of freed parasites, infected and non-infected erythrocytes, and membraneous material was separated by free-flow electrophoresis. The free parasites produced were very pure and infectious. Morphological and enzymatic data on the separated fractions are presented. Free-flow electrophoresis also allowed the separation of infected and uninfected erythrocytes.     

The respiratory burst is not required for killing of intracellular and extracellular parasites by a lymphokine-activated macrophage cell line

The macrophage cell line, IC-21, was found to be incapable of producing the oxygen products associated with the respiratory burst. However, IC-21 cells were activated by lymphokine (LK) to kill intracellular (Leishmania donovani amastigotes) and extracellular (Schistosoma mansoni larvae) parasites, as well as tumor cells. In each case, the cytotoxicity exhibited by activated IC-21 cells and activated peritoneal macrophages was indistinguishable. However, nonactivated IC-21 cells were unable to kill L. donovani log-growth phase promastigotes, while nonactivated peritoneal macrophages destroyed greater than 90% of the initial infection. These results indicate that amastigotes and schistosome larvae are susceptible to killing by nonoxidative cytotoxic mechanism induced by lymphokine activation but, on the other hand, support the concept that the killing of log-growth phase promastigotes by nonactivated cells is dependent upon the respiratory burst. We propose that the IC-21 cell line may be a useful model for studying nonoxidative killing functions of activated macrophages.     

Possibilities for prevention and treatment of blindness and impaired vision in children caused by congenital eye diseases

Blindness, disability, and impaired vision present important medicosocial problems. According to the WHO, there are 1.5 million blind children in the world. The prevalence of child blindness in Russia is 1.6, and that of impaired vision is 3.5 per 10000 children. It is considered that child blindness can be prevented in 40 to 50% of children. According to data collected during ophthalmological examinations in specialized school, blindness in 88 to 92% of cases is caused by. Presently, significant achievements have been made in treatment of congenital eye diseases. Application of modem surgical techniques in patients with cataract, aphakia, or amblyopia makes it possible to increase visual acuity to 0.3 or higher in 35% of children, and to 0.005 to 0.25 in 45% of children. Modem pathogenetically directed surgery together with timely treatment allows for the normalization of intraocular pressure and visual stabilization in 76.4 to 86.4% of children with congenital glaucoma. In this connection, the achievements of scientific research should be introduced into practice. Realization of the 1999 WHO program on liquidation of eliminable blindness include three key directions: treatment and prevention of blindness; consolidation of the infrastructure and technology of ophthalmological aid; training of specialists.     

Evaluation of treatment effects in Alzheimer's and other neurodegenerative diseases by MRI and MRS

Neurodegeneration refers to a large clinically and pathologically heterogeneous disease entity associated with slowly progressive neuronal loss in different anatomical and functional systems of the brain. Neurodegenerative diseases often affect cognition, e.g. Alzheimer's disease (AD), dementia with Lewy bodies and vascular dementia, or different aspects of the motor system, e.g., amyotrophic lateral sclerosis, Parkinson's disease and ataxic disorders. Owing to increasing knowledge about the mechanisms leading to neurodegeneration, the development of treatments able to modify the neurodegenerative process becomes possible for the first time. Currently, clinical outcome measures are used to assess the efficacy of such treatments. However, most clinical outcome measures have a low test-retest reliability and thus considerable measurement variance. Therefore, large patient populations and long observation times are needed to detect treatment effects. Furthermore, clinical outcome measures cannot distinguish between symptomatic and disease-modifying treatment effects. Therefore, alternative biomarkers including neuroimaging may take on a more important role in this process. Because MR scanners are widely available and allow for non-invasive detection and quantification of changes in brain structure and metabolism, there is increasing interest in the use of MRI/MRS to monitor objectively treatment effects in clinical trials of neurodegenerative diseases. Particularly volumetric MRI has been used to measure atrophy rates in treatment trials of AD because the relationship between atrophic changes and neuron loss is well established and correlates well with clinical measures. More research is needed to determine the value of other MR modalities, i.e. diffusion, perfusion and functional MRI and MR spectroscopy, for clinical trials with neuroprotective drugs.     

Detection and species determination of malaria parasites by PCR: comparison with microscopy and with ParaSight-F and ICT malaria Pf tests in a clinical environment

A rapid procedure for the diagnosis of malaria infections directly from dried blood spots by PCR amplification was evaluated with samples from 52 patients. Plasmodium infections were identified with a genus-specific primer set, and species differentiation between Plasmodium falciparum and Plasmodium vivax was analyzed by multiplex PCR. The PCR test with any of the three primer sets was able to detect as few as four parasites per microliter by gel electrophoresis or by nonisotopic paper hybridization chromatography. The diagnoses obtained by PCR correlated closely with those obtained by Giemsa staining except for two samples observed to have mixed P. falciparum-P. vivax infections. These were initially missed by microscopic analysis. In comparison with antigen-capture assays for P. falciparum, the PCR assays were able to detect three infections that were missed by the ParaSight-F test. The PCR test was negative for nine ParaSight-F-positive samples and one ICT Malaria Pf-positive sample, and these were confirmed to be false-positive results. The PCR thus gave no false-negative or false-positive results. Patients undergoing antimalarial therapy were also monitored by the PCR assay. Four of seven patients who were PCR positive for P. vivax at the time of discharge were later readmitted to the hospital with a recurrence of P. vivax infection. We would like to propose that PCR is a sensitive and easy method that can serve as a useful addition to microscopy for the diagnosis and the clinical monitoring of treatment of malaria.