Sphingosine 1 phosphate induces the chemotaxis of human natural killer cells. Role for heterotrimeric G proteins and phosphoinositide 3 kinases

We have examined the effect of sphingolipids on the chemotaxis of human natural killer (NK) cells. Messenger RNA for Edg-1, Edg-6 and Edg-8 but not Edg-3, are expressed in these cells. Sphingosine 1 phosphate (SPP), dihydro SPP (DHSPP) or the CC chemokine RANTES (CCL5), but not sphingosine induces the chemotaxis of these cells. Pertussis toxin inhibits the chemotaxis induced by these ligands. Permeabilization of NK cells with streptolysin O (SLO) and introduction of blocking antibodies to the heterotrimeric G proteins, showed that Galpha(i2), Galpha(s), Galpha(q/11) or Galpha(13) mediate the chemotaxis of SPP, whereas Galpha(i2), Galpha(o) or Galpha(q/11) mediate the chemotaxis of DHSPP. Galpha(i2), Galpha(o), Galpha(s), Galpha(q/11), Galpha(z) or Galpha(12 )mediates RANTES-induced NK cell chemotaxis. Further analysis showed that phosphoinositide 3 kinase (PI3K) inhibitors wortmannin and LY294002 inhibit NK cell chemotaxis induced by SPP, DHSPP or RANTES. Blocking antibody to PI3Kgamma inhibits the chemotaxis induced by the three ligands, whereas anti-PI3Kbeta was without effect. In contrast, SPP and DHSPP recruit PI3Kbeta isozyme into NK cell membranes, suggesting that although this isoform is not involved in chemotaxis, it is activated by these phospholipids.     

Immunosuppression in Kenyan visceral leishmaniasis

Cell-mediated immune responses were evaluated in 15 patients with active visceral leishmaniasis from Masinga location in eastern Kenya where the disease is endemic. Age and sex matched controls were selected from a village school in the same area. In vivo studies were carried out by skin testing with leishmanin, tuberculin, streptococcal and candida antigens. Lymphocyte blastogenic transformation to the mitogens phytohaemagglutinin (PHA) and concanavalin A (Con A) and the antigens purified protein derivative (PPD), streptokinase-streptodornase (SKSD) and leishmanial antigen (LA) was studied in vitro. The results showed that immunosuppression in visceral leishmaniasis in Kenya was both specific and non-specific. In the majority of patients there was complete anergy to all antigens in vivo and in vitro. The suppression of responses to mitogens was less marked. Recovery of non-specific responses preceded the development of specific immunity. In a small number of patients (23%) immune unresponsiveness to leishmanial antigens persisted 1 year after parasitological cure.     

Visceral leishmaniasis: current status of control,diagnosis, and treatment,and a proposed research and development agenda

Visceral leishmaniasis is common in less developed countries, with an estimated 500000 new cases each year. Because of the diversity of epidemiological situations, no single diagnosis, treatment, or control will be suitable for all. Control measures through case finding, treatment, and vector control are seldom used, even where they could be useful. There is a place for a vaccine, and new imaginative approaches are needed. HIV co-infection is changing the epidemiology and presents problems for diagnosis and case management. Field diagnosis is difficult; simpler, less invasive tests are needed. Current treatments require long courses and parenteral administration, and most are expensive. Resistance is making the mainstay of treatment, agents based on pentavalent antimony, useless in northeastern India, where disease incidence is highest. Second-line drugs (pentamidine and amphotericin B) are limited by toxicity and availability, and newer formulations of amphotericin B are not affordable. The first effective oral drug, miltefosine, has been licensed in India, but the development of other drugs in clinical phases (paromomycin and sitamaquine) is slow. No novel compound is in the pipeline. Drug combinations must be developed to prevent drug resistance. Despite these urgent needs, research and development has been neglected, because a disease that mainly affects the poor ranks as a low priority in the private sector, and the public sector currently struggles to undertake the development of drugs and diagnostics in the absence of adequate funds and infrastructure. This article reviews the current situation and perspectives for diagnosis, treatment, and control of visceral leishmaniasis, and lists some priorities for research and development.     

A comparison of three dosage regimens of sodium stibogluconate in the treatment of visceral leishmaniasis in Kenya

A prospective randomized trial of three dosage regimens of sodium stibogluconate (Pentostam; Wellcome Foundation, London) to treat visceral leishmaniasis was conducted. Previously untreated patients were randomized to receive 31 doses of sodium stibogluconate (10 mg Sb/kg of body weight per dose) administered once daily for 31 days (group A), every 12 hr for 15 days (group B), or every 8 hr for 10 days (group C). Of the 29 patients who completed treatment, seven of 10 in group B and all of the patients in groups A and C responded to treatment and remained well for one year. One patient in group B failed to respond to treatment, and two others in group B initially responded to treatment but relapsed six weeks after discharge. None of the treatment regimens was toxic. Parasites disappeared from splenic aspirates most quickly and hemoglobin levels rose most rapidly in patients receiving sodium stibogluconate every 8 hr. Treatment of visceral leishmaniasis in Kenya with sodium stibogluconate at a dose of 10 mg Sb/kg every 8 hr for 10 days appears to be a safe alternative to conventional treatment. Its efficacy should be confirmed in a larger number of patients.     

基于PEAKING队列探讨慢性肾脏病患者运动的促进与阻碍因素

背景　运动有利于改善慢性肾脏病（CKD）患者的预后,但运动在CKD患者的普及程度仍较低。目的　探索CKD患者进行运动的意愿、动机、促进与障碍等行为改变因素,为未来的运动干预提供基础。方法　于2019年3-6月,采用目的抽样法从PEAKING队列中选取不同体力活动水平、不同规律运动情况的CKD患者（n=10）进行半结构式定性访谈。访谈内容主要包括：患者对CKD的认识,日常活动安排,对运动与疾病关系的认识,进行规律运动的促进与阻碍因素等。最后利用内容分析法进行访谈资料分析归纳,按照国际公认的定性研究报告标准（COREQ）进行报告。结果　促进CKD患者运动的因素包括：意识到运动可能有益于身心理健康（启动因素）;体验到运动带来的益处、自律（坚持运动的内在因素）;来自家庭、运动专业人员及社会水平的支持（保持运动的外部因素）。阻碍CKD患者运动的因素有：年老、心肺肾等相关合并症及疲劳感（身体状况因素）;担心骨骼及肾脏损伤（运动相关损伤潜在风险的担忧）;时间、地方、设施和陪伴不足（缺乏体育锻炼条件）。结论　在CKD患者中开展运动干预,需要增加运动获益宣传、增强自我效能及增加外部支持等促进因素,注意预防运动相关损伤和创造锻炼条件以减少阻碍因素。     

Diagnostic challenges for a novel SH2D1A mutation associated with X‐linked lymphoproliferative disease

Mutations in SH2D1A, encoding the intracellular adaptor signaling lymphocyte activation molecule associated protein (SAP), are associated with X‐linked lymphoproliferative disease type 1 (XLP1). We identified a novel hemizygous SH2D1A c.49G > A (p.E17K) variant in a 21‐year‐old patient with fatal Epstein‐Barr virus infection–associated hemophagocytic lymphohistiocytosis. Cellular and biochemical assays revealed normal expression of the SAP variant protein, yet binding to phosphorylated CD244 receptor was reduced by >95%. Three healthy brothers carried the SH2D1A c.49G > A variant. Thus, data suggest that this variant represents a pathogenic mutation, but with variable expressivity. Importantly, our results highlight challenges in the clinical interpretation of SH2D1A variants and caution in using functional flow cytometry assays for the diagnosis of XLP1.     

A combined medical and surgical approach to hydatid disease: 12 years' experience at the Hospital for Tropical Diseases, London

BACKGROUND: There is no consensus as to the most appropriate treatment for the varied and often complicated presentations of hydatid disease in Britain. We looked at our own results over a 12-year period to see if a consistent and logical plan had emerged. PATIENTS AND METHODS: 70 patients presenting between 1986 and 1998 were analysed retrospectively, with regard to their presentation, diagnosis, treatment and outcome, with particular reference to the use of chemotherapy, and to the difficulties of post-treatment assessment by serology and imaging. RESULTS: 37 patients had been treated previously. 35 had hepatic cysts and 26 multiple cysts. 4 patients were treated by surgery alone, 44 by chemotherapy and surgery, and 14 by chemotherapy alone. The combined use of albendazole and praziquantel pre-operatively reduced significantly the number of cysts that contained viable protoscolices: 1/25 versus 5/8 that received albendazole alone (P = 0.00013). During the 12-year period, it became our policy to aim for 3 months drug treatment (albendazole throughout with praziquantel for 2 weeks), re-assess and proceed either to surgery or to continue with chemotherapy. CONCLUSIONS: It is possible to construct an algorithm for the management of patients with hydatid disease by chemotherapy and surgery, but the assessment of results by indirect techniques remains difficult.