First-in-human evaluation of genetically attenuated Plasmodium falciparum sporozoites administered by bite of Anopheles mosquitoes to adult volunteers

Background

Immunization with genetically engineered, attenuated malaria parasites (GAP) that arrest during liver infection confers sterile protection in mouse malaria models. A first generation Plasmodium falciparum GAP (Pf p52⁻/p36⁻ GAP) was previously generated by deletion of two pre-erythrocytic stage-expressed genes (P52 and P36) in the NF54 strain.

Methods

A first-in-human, proof-of-concept, safety and immunogenicity clinical trial in six human volunteers was conducted. Exposure consisted of delivery of Pf p52⁻/p36⁻ GAP sporozoites via infected Anopheles mosquito bite with a five-bite/volunteer exposure followed by an approximately 200-bite exposure/volunteer one month later.

Results

The exposures were well tolerated with mild to moderate local and systemic reactions. All volunteers remained blood stage negative after low dose exposure. Five volunteers remained blood stage negative after high dose exposure. One volunteer developed peripheral parasitemia twelve days after high dose exposure. Together the findings indicate that Pf p52⁻/p36⁻ GAP was severely but not completely attenuated. All six volunteers developed antibodies to CSP. Furthermore, IFN-γ responses to whole sporozoites and multiple antigens were elicited in 5 of 6 volunteers, with both CD4 and CD8 cell cytokine production detected.

Conclusion

Severe attenuation and favorable immune responses following administration of a first generation Pf p52⁻/p36⁻ GAP suggests that further development of live-attenuated strains using genetic engineering should be pursued.     

云南省独龙族小学生肠道寄生虫感染调查

目的了解独龙族小学生肠道寄生虫感染情况,为防治工作提供依据。方法采用改良加藤厚涂片法查肠道蠕虫卵;直接涂片法查肠道原虫;透明胶纸肛拭法查蛲虫;改良抗酸染色法查稀便中的隐孢子虫卵囊。结果共检查239人,感染211人,总感染率为88.28%,共查到9种寄生虫,各种寄生虫感染率分别为:鞭虫71.55%,蛔虫66.95%,钩虫9.21%,微小内蜒阿米巴3.77%,蓝氏贾第鞭毛虫2.51%,哈氏内阿米巴1.67%,溶组织阿米巴、结肠阿米巴和布氏嗜碘阿米巴均为0.42%。钩虫虫种为美洲钩虫,蛲虫和隐孢子虫均未检出。蛔虫、钩虫和鞭虫的感染度均以轻度感染为主。性别、年级和民族构成比无统计学差异(P均0.05);来源于龙元村委会的学生感染率最高,为95.45%(21/22),马库学生的肠道感染率最低,为30.00%(3/10),各地学生肠道寄生虫感染率差异有统计学意义(P0.01)。结论独龙族小学生肠道寄生虫感染率较高,当地卫生环境差、不良的卫生习惯和学校的肠道寄生虫病防治工作缺乏是主要原因。     

Cancer: A reproductive strategy of "ultra-selfish" genes?

A hypothesis is presented in which the process of "malignant transformation" which ultimately results in the rapidly dividing tumor(s)(cells) causing "cancer", is regarded as an evolved reproductive strategy of "ultra-selfish" (proto-)(onco-)genes, already present in the genome, or introduced by a virus.     

新疆喀什市周边地区驴体内滞留寄生虫的检查报告

为了解新疆喀什市周边地区驴体内携带寄生虫种类和感染率、危害等情况,采用常规寄生虫病原学检查方法,对喀什市周边的疏勒县104份驴的粪样和疏附县的50份驴粪样进行了检查．其结果显示马圆线虫的感染率可达50％～82．7％,且该两个采样区域驴所感染的马圆线虫和毛细线虫混合感染情况较严重,其感染可达42％～48％。     

浙江省蜚蠊种群、地理分布特点及防制技术研究

目的;查清全省蜚蠊种群地理分布特点,进行防制对策研究。方法：在全省按地理分布建立监测点,根据对本省蜚蠊种群、分布、季节消长、药敏程度等特点制定防制规范在全省实施。结果：查清蜚蠊种群、数量、优势种及栖息场所特点,查清蜚蠊寄生蜂种群、数量、分布及生态习性等,采用防制规范技术,已有28个城市申报全部通过灭蜚蠊成果考核。结论：通过多年的基地研究,掌握本省蜚蠊特点,制定出切实可行的防制技术,提高了防制工作的科学性。     

Plasmodium falciparum pfhrp2 and pfhrp3 Gene Deletions and Relatedness to Other Global Isolates,Djibouti, 2019–2020

Deletions of pfhrp2 and paralogue pfhrp3 (pfhrp2/3) genes threaten Plasmodium falciparum diagnosis by rapid diagnostic test. We examined 1,002 samples from suspected malaria patients in Djibouti City, Djibouti, to investigate pfhrp2/3 deletions. We performed assays for Plasmodium antigen carriage, pfhrp2/3 genotyping, and sequencing for 7 neutral microsatellites to assess relatedness. By PCR assay, 311 (31.0%) samples tested positive for P. falciparum infection, and 296 (95.2%) were successfully genotyped; 37 (12.5%) samples were pfhrp2+/pfhrp3+, 51 (17.2%) were pfhrp2+/pfhrp3–, 5 (1.7%) were pfhrp2–/pfhrp3+, and 203 (68.6%) were pfhrp2–/pfhrp3–. Histidine-rich protein 2/3 antigen concentrations were reduced with corresponding gene deletions. Djibouti P. falciparum is closely related to Ethiopia and Eritrea parasites (pairwise G_ST 0.68 [Ethiopia] and 0.77 [Eritrea]). P. falciparum with deletions in pfhrp2/3 genes were highly prevalent in Djibouti City in 2019–2020; they appear to have arisen de novo within the Horn of Africa and have not been imported.     

Endoscopic removal of foreign bodies:A retrospective study in Japan

BACKGROUND The ingestion of foreign bodies(FBs) and food bolus impaction(FBI) in the digestive tract are commonly encountered clinical problems.Methods to handle such problems continue to evolve offering advantages,such as the avoidance of surgery,reduced cost,improved visualization,reduced morbidity,and high removal success rate.However,to date,no studies have evaluated the endoscopic management of FBs in Japan.AIM To elucidate level of safety and efficacy in the endoscopic management of FBs and FBI.METHODS A total of 215 procedures were performed at Keio University Hospital between November 2007 and August 2018.Data were collected from medical charts,and endoscopic details were collected from an endoscopic reporting system.Procedures performed with a flexible gastrointestinal endoscope were only taken into account.Patients who underwent a technique involving FB or FBI from the digestive tract were only included.Data on patient sex,patient age,outpatient,inpatient,FB type,FB location,procedure time,procedure type,removal device type,success,and technical complications were reviewed and analyzed retrospectively.RESULTS Among the 215 procedures,136(63.3%) were performed in old adults(≥ 60 years),180(83.7%) procedures were performed in outpatients.The most common type of FBs were press-through-pack(PTP) medications [72(33.5%) cases],FBI[47(21.9%)],Anisakis parasite(AP) [41(19.1%) cases].Most FBs were located in the esophagus [130(60.5%) cases] followed by the stomach [68(31.6%) cases].AP was commonly found in the stomach [39(57.4%) cases],and it was removed using biopsy forceps in 97.5% of the cases.The most common FBs according to anatomical location were PTP medications(40%) and dental prostheses(DP)(40%) in the laryngopharynx,PTP(48.5%) in the esophagus,AP(57.4%) in the stomach,DP(37.5%) in the small intestine and video capsule endoscopy device(75%) in the colon.A transparent cap with grasping forceps was the most commonly used device [82(38.1%) cases].The success rate of the procedure was100%,and complication were observed in only one case(0.5%).CONCLUSION Endoscopic management of FBs and FBI in our Hospital is extremely safe and effective.     

Infectious diseases of the upper gastrointestinal tract

A broad spectrum of pathogens produce gastrointestinal disease. The ongoing spread of human immunodeficiency virus/acquired immune deficiency syndrome, the increased use of immunosuppressive therapy and the persistence of overcrowding and suboptimal sanitation in underdeveloped areas facilitate both disease transmission from environmental and foodborne sources and person‐to‐person transmission. Clinicians increasingly rely on endoscopic biopsy sample interpretation to diagnose gastrointestinal infections. Thus, pathologists must be aware of diagnostic features of a variety of microbial pathogens. Detection with molecular techniques also allows for correlation between infectious agents and their histopathological features, which has expanded our knowledge of the inflammatory changes produced by infectious agents. This review covers infectious disorders of the upper gastrointestinal tract encountered in surgical pathology. Clinical, endoscopic and pathological features are presented. The review emphasises morphological features of viruses, bacteria, fungi and parasites that may be found in tissue samples, and the inflammatory patterns that they produce. Differential diagnoses and useful ancillary techniques are discussed.     

Treatment of cystic echinococcosis (Echinococcus granulosus) with mebendazole: Assessment of bound and free drug levels in cyst fluid and of parasite vitality in operative specimens

Summary Chemotherapy of the larval stage of Echinococcus granulosus in man with high oral doses of mebendazole has only been partly successful. In order to improve effective pharmacotherapy of this disease with mebendazole, the optimal time for blood sampling has been assessed and the mebendazole concentrations acting on the parasite have been compared with their viability. The optimal time for blood sampling was analysed in 14 patients during longterm treatment with mebendazole. The plasma level 4 h after the morning dose exhibited the best correlation with the average 24-h concentration, suggesting that the plasma level should be monitored 4 h after the morning dose. In 22 patients undergoing surgery for hydatid disease, the mebendazole concentration in cyst fluid was significantly correlated with its plasma level 4 h after the morning dose. In 13 of them the free drug concentration was determined by equilibrium dialysis and it was almost identical with the free mebendazole concentration in plasma. Results of viability tests in 12 cases revealed viable cysts in 6 cases and possibly viable cysts in 6 other cases. Even patients treated for more than 12 months still had viable cysts.     

新疆北部大沙鼠的生存环境以及鼠间的利什曼原虫和媒介的调查

在新疆天山北部的荒漠内，很多大沙鼠Ｒｈｏｍｂｏｍｙｓ ｏｐｉｍｕｓ的耳皮下组织内有利什曼原虫的感染。有的地方，鼠的感染率可达１００％（ＮＮＮ基培养法），已鉴定的原虫有都兰利什曼Ｌｅｉｓｈｍａ－ｎｉａ ｔｕｒａｎｉｃａ和沙鼠利什曼Ｌ．ｇｅｒｂｉｌｌｉ两种。大沙鼠洞是多种白蛉的栖息和吸血的场所，洞内的优势蛉种为蒙古白蛉Ｐｈｌｅｂｏｔｏｍｕｓ ｍｏｎｇｏｌｅｎｓｉｓ和安氏白蛉Ｐｈ．ａｎｄｒｅｊｅｕｉ。调