Emergence of novel coronavirus and progress toward treatment and vaccine

In late December 2019, a group of patients was observed with pneumonia‐like symptoms that were linked with a wet market in Wuhan, China. The patients were found to have a novel coronavirus genetically related to a bat coronavirus that was termed SARS‐CoV‐2. The virus gradually spread worldwide and was declared a pandemic by WHO. Scientists have started trials on potential preventive and treatment options. Currently, there is no specific approved treatment for SARS‐CoV‐2, and various clinical trials are underway to explore better treatments. Some previously approved antiviral and other drugs have shown some in vitro activity. Here we summarize the fight against this novel coronavirus with particular focus on the different treatment options and clinical trials exploring treatment as well as work done toward development of vaccines.     

伯氏疟原虫氯喹抗性株和敏感株基因组DNA比较研究

目的　比较伯氏疟原虫敏感株 (N株 )和抗性株 (RC株 )基因组DNA差异。　方法　应用基因组DNA随机多态性扩增 (RAPD)和锚定引物扩增DNA(APAD) ,分别对抽提的伯氏疟原虫N株和RC株基因组DNA进行PCR扩增 ,并对扩增的产物进行电泳 ,对结果进行统计分析。　结果　 3 7条随机引物RAPD方法扩增出 44 0条DNA条带 ,其中RC株和N株的共有条带是 196条 ,差异带 43条。 84条锚定多聚A引物APAD方法扩增出 95 2条DNA条带 ,其中RC株和N株的共有条带是 43 6条 ,差异带 5 3条。两种方法得到N株和RC株基因组DNA的同源性分别为 0 .89和0 .91;距离系数分别为 0 .197和 0 .15 5。　结论　伯氏疟原虫N株和RC株基因组DNA具有高度同源性。     

Tumorigenesis in tuberous sclerosis complex is autophagy and p62/sequestosome 1 (SQSTM1)-dependent

Tuberous sclerosis complex (TSC) is a tumor suppressor syndrome characterized by benign tumors in multiple organs, including the brain and kidney. TSC-associated tumors exhibit hyperactivation of mammalian target of rapamycin complex 1 (mTORC1), a direct inhibitor of autophagy. Autophagy can either promote or inhibit tumorigenesis, depending on the cellular context. The role of autophagy in the pathogenesis and treatment of the multisystem manifestations of TSC is unknown. We found that the combination of mTORC1 and autophagy inhibition was more effective than either treatment alone in inhibiting the survival of tuberin (TSC2)-null cells, growth of TSC2-null xenograft tumors, and development of spontaneous renal tumors in Tsc2(+/-) mice. Down-regulation of Atg5 induced extensive central necrosis in TSC2-null xenograft tumors, and loss of one allele of Beclin1 almost completely blocked macroscopic renal tumor formation in Tsc2(+/-) mice. Surprisingly, given the finding that lowering autophagy blocks TSC tumorigenesis, genetic down-regulation of p62/sequestosome 1 (SQSTM1), the autophagy substrate that accumulates in TSC tumors as a consequence of low autophagy levels, strongly inhibited the growth of TSC2-null xenograft tumors. These data demonstrate that autophagy is a critical component of TSC tumorigenesis, suggest that mTORC1 inhibitors may have autophagy-dependent prosurvival effects in TSC, and reveal two distinct therapeutic targets for TSC: autophagy and the autophagy target p62/SQSTM1.     

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口腔扁平苔藓(oral lichen planus,OLP)是一种常见的口腔黏膜病,好发于女性,尤以30~60岁中年女性最为常见。目前对OLP的治疗尚无特效方法。本研究采用局部微波热凝技术联合小剂量氯喹口服治疗OLP,经过临床观察、随访,取得比较满意疗效。报道如下。     

Molecular assessment of drug resistance in Plasmodium falciparum from Bahr El Gazal province, Sudan

AIMS: To assess resistance to chloroquine (CQ) and sulphadoxine/pyrimethamine (SP) in a Sudanese parasite population. METHODS: Recurrent security problems in Akuem, Sudan, prevented us from conducting a classical in vivo treatment efficacy study. Instead we genotyped key mutations in the chloroquine resistance transporter (pfcrt), the multidrug resistance gene (pfmdr1), dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps). We genotyped the K76T mutation in pfcrt and the N86Y mutation in (pfmdr) by restriction digestion of fluorescent end-labelled polymerase chain reaction (PCR) products, while we genotyped codons 16, 51, 59, 108 and 164 in dhfr and codons 436, 437, 540, 581 and 613 in dhps by primer extension in 100 blood samples. RESULTS: Sixty-three percent of parasites carried the 76T mutation at pfcrt critical for CQ resistance, while 31% carried the 86Y mutation at pfmdr that is associated with, although not essential, for CQ resistance. We found five dhfr alleles: 60% of infections contained wild-type dhfr alleles, 3% had one mutation, 34% had two mutations, while 3% had three mutations. We found three dhps alleles: 47% were wild type, 44% had one mutation, while 9% had two mutations. CONCLUSIONS: We expect high levels of treatment failure (RI-RIII) with CQ (20-40%) and predict efficient treatment with SP. However, dhfr alleles with three mutations (51I, 59R, 108N) are present as are dhps alleles with two mutations (437G, 540E). Successful treatment with SP is therefore likely to be short-lived.     

Malaria morbidity,treatment-seeking behaviour,and mortality in a cohort of young children in rural Burkina Faso

OBJECTIVE: To describe the pattern of fever-associated morbidity, treatment-seeking behaviour for fever episodes, and cause-specific mortality in young children of a malaria-holoendemic area in rural Burkina Faso. METHODS: In a longitudinal community-based intervention study, 709 representative children aged 6-31 months were followed daily over 6 months (including the main malaria transmission period) through village-based field staff. RESULTS: Of 1848 disease episodes, 1640 (89%) were fever episodes, and of those, 894 (55%) were attributed to malaria (fever + > or =5000 parasites/microl). Eighty-five percent of fever episodes were treated, mainly with chloroquine and paracetamol, 69% of treatments took place in households, 16% in local health centres, 13% in villages, and 1% in hospitals. Treatment-seeking in a health centre or hospital was associated with accessibility and disease severity. Cerebral malaria and malnutrition-associated diarrhoea were the most frequently diagnosed causes of death. While most children with a post-mortem diagnosis of diarrhoea had not received any treatment, children who died of malaria had often received insufficient treatment. In particular, there was a lack of an appropriate second-line treatment at formal health services after chloroquine treatment had failed to resolve symptoms. CONCLUSIONS: These findings call for more effective prevention and treatment of malaria, malnutrition and diarrhoea in rural African communities, as well as for better supervision of existing malaria treatment guidelines in formal health services.     

Quantitation of platelet antigens after chloroquine treatment

The effect of chloroquine treatment on the expression of various platelet antigens was studied. For this purpose, the binding of several human platelet-reactive antibodies (polyspecific HLA antibodies; platelet-specific PlA1, PlA2, Baka antibodies; platelet autoantibodies) and of murine monoclonal antibodies specific for epitopes on the glycoprotein (Gp) complexes IIb/IIIa or Ib/IX were quantitated by means of a competitive enzyme-linked immunoassay (CELIA) using fresh and stored chloroquine-treated platelets. We found that HLA antigens were substantially removed from platelets following chloroquine treatment (confirming earlier results) while platelet-specific antigens on the Gp complex IIb/IIIa were but little affected. Epitopes on the Gp complex Ib/IX did not show any alteration. Storage of chloroquine-treated panel platelets known to interfere with immunofluorescence had no effect on quantitative IgG determinations by CELIA. We conclude that chloroquine treatment of platelets is practicable for platelet antibody analysis, but exerts its effect unspecifically and requires cautious interpretation.     

Malaria epidemic and drug resistance, Djibouti

Analysis of Plasmodium falciparum isolates collected before, during, and after a 1999 malaria epidemic in Djibouti shows that, despite a high prevalence of resistance to chloroquine, the epidemic cannot be attributed to a sudden increase in drug resistance of local parasite populations.     

No benefits from combining chloroquine with artesunate for three days for treatment of Plasmodium falciparum in Guinea-Bissau

The use of a combination of chloroquine and artesunate has been suggested for treatment of malaria in Africa. We used concomitant as well as sequential medication with these 2 drugs in relation to each drug separately for children infected with Plasmodium falciparum in Guinea-Bissau from March 2000 to November 2001. By block-randomization, 474 children with symptomatic malaria were divided into 4 groups and given either a total of 8 mg artesunate per kg bodyweight for 3 d, a total of 25 mg chloroquine base per kg bodyweight for 3 d, both drugs concomitantly for 3 d, or both drugs in sequence. All children were followed weekly for 5 weeks. On day 28, parasites had been detected in 40% of the children who were treated with artesunate only compared with 21% treated with chloroquine, 20% treated with artesunate in combination with chloroquine, and 16% treated with artesunate and chloroquine in sequence; on day 35 the corresponding percentages were 48%, 29%, 27%, and 24%, respectively. The outcome of the combination of chloroquine and artesunate in the doses studied was similar to the outcome of chloroquine monotherapy regardless of whether the 2 drugs are given concomitantly (relative risk [RR] = 0.93, 95% CI 0.56-1.53, P = 0.76) or in sequence (RR = 0.78, 95% CI 0.47-1.28, P = 0.32). Thus, neither an antagonistic, an additive, or a synergistic effect of the 2 drugs was indicated.     

Cell Handling,Membrane-Binding Properties and Membrane-Penetration Modeling Approaches of Pivampicillin and Phthalimidomethylampicillin,Two Basic Esters of Ampicillin,in Comparison with Chloroquine and Azithromycin

Purpose. The purpose of this work was to examine and understand the cellular pharmacokinetics of two basic esters of ampicillin, pivaloyloxymethyl (PIVA) and phthalimidomethyl (PIMA), in comparison with lysosomotropic drugs (chloroquine, azithromycin). Methods. Cell culture studies (J774 macrophages) were undertaken to study uptake and release kinetics and to assess the influence of concentration, pH, proton ionophore (monensin), and MRP and P-gp inhibitors (probenecid, gemfibrozil, cyclosporin A, GF 120918). Equilibrium dialysis with liposomes were performed to directly asses the extent of drug binding to bilayers. Conformational analysis modeling of the drug penetration in bilayers was conducted to rationalize the experimental observations. Results. PIVA and PIMA showed properties in almost complete contrast with those of chloroquine and azithromycin, i.e., fast apparent accumulation and fast release at 4°C as well as at 37°C, saturation of uptake (apparent K _d 40 M), no influence of monensin, MRP, or P-gp inhibitors; tight binding to liposomes (K _d approx. 40 M); and sharp increase in calculated free energy when forced in the hydrophobic domain. Conclusions. Although they are weak organic bases, PIVA and PIMA show none of the properties of lysosomotropic agents. We hypothesize that they remain locked onto the pericellular membrane and may never penetrate cells as such in significant amounts.