Two novel AIRE mutations in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) among Indians

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare recessive disorder resulting from mutations in the autoimmune regulator ( AIRE ) gene. There is no information on AIRE mutations in Indians. In a cross-sectional study, nine patients (eight families), from four referral hospitals in India, were studied for AIRE mutations by direct sequencing. We screened for new mutations in 150 controls by allele-specific PCR. The patients had 1–7 known components of APECED. Three patients had unusual manifestations: presentation with type 1 diabetes; chronic sinusitis and otitis media; and facial dysmorphism. All patients carried homozygous, probably recessive, AIRE mutations. Two unrelated patients from a small in-bred community (Vanika Vaisya) in south India carried an unreported missense mutation, p.V80G, in the N-terminal caspase recruitment domain. Another unique mutation, p.C302X, resulting in a truncated protein with deletion of both zinc-finger domains, was detected in a patient from Gujarat. Neither mutation was detected in controls. Other mutations, previously described in Caucasians, were: 13 base pair deletion (p.C322fsX372) in 4 (38%), and Finn-major (p.R257X) and p.R139X (Sardinian) mutation in one subject each. In conclusion, in this first series of APECED in Indians, we detected AIRE mutations previously reported in Caucasians, as well as unique mutations. Of these, p.V80G is possibly an ancestral mutation in an in-bred community.     

Extracellular functions of glycolytic enzymes of parasites: Unpredicted use of ancient proteins

In addition of their usual intracellular localization where they are involved in catalyzing reactions of carbohydrate and energy metabolism by glycolysis, multiple studies have shown that glycolytic enzymes of many organisms, but notably pathogens, can also be present extracellularly. In the case of parasitic protists and helminths, they can be found either secreted or attached to the surface of the parasites. At these extracellular localizations, these enzymes have been shown to perform additional, very different so-called “moonlighting” functions, such as acting as ligands for a variety of components of the host. Due to this recognition, different extracellular glycolytic enzymes participate in various important parasite–host interactions such as adherence and invasion of parasites, modulation of the host's immune and haemostatic systems, promotion of angiogenesis, and acquisition of specific nutrients by the parasites. Accordingly, extracellular glycolytic enzymes are important for the invasion of the parasites and their establishment in the host, and in determining their virulence.     

Antigen‐specific TIL therapy for melanoma: A flexible platform for personalized cancer immunotherapy

Tumor infiltrating lymphocyte (TIL) therapy has shown objective clinical response rates of 50% in stage IV melanoma patients in a number of clinical trials. Nevertheless, the majority of patients progress either directly upon therapy or after an initial period of tumor control. Recent data have shown that most TIL products that are used for therapy contain only low frequencies of T cells reactive against known melanoma‐associated epitopes. Because of this, the development of a technology to create T‐cell products that are enriched for reactivity against defined melanoma‐associated antigens would seem valuable, both to evaluate the tumoricidal potential of T cells directed against different antigen classes and to potentially increase response rates. Here, we developed and validated a conditional MHC streptamer‐based platform for the creation of TIL products with defined antigen reactivities. We have used this platform to successfully enrich both high‐frequency (≥1%) and low‐frequency (<1%) tumor‐specific CD8⁺ T‐cell populations, and thereby created T‐cell products with enhanced tumor recognition potential. Collectively, these data demonstrate that selection of antigen‐specific T‐cell populations can be used to create defined T‐cell products for clinical use. This strategy thus forms a highly flexible platform for the development of antigen‐specific cell products for personalized cancer immunotherapy.     

Similar biological activity in skin prick test for Oralair® (8200 BAU) and Grazax® (6200 BAU) reinforces effective SLIT dosing level

In Europe, allergen extracts are standardized based on skin prick wheal size in 20–30 allergic subjects. To understand the biological activity of clinically effective Sublingual immunotherapy, we used this method to determine the biological activity of solution and tablet Timothy grass pollen (TIM) extracts, compared to an FDA‐approved extract (Reference) of 10 000 BAU/ml. Blinded, quadruplicate skin prick tests with concentrate and three serial half‐log dilutions allowed the construction of a semilogarithmic regression line per extract. Bioequivalent allergy units (BAU) values were obtained from the comparison with reference. Extracts and dilutions showed a neat linear dose response (all: R² > 0.98) in 33 rhinitis patients. Relative potencies: Staloral^® 12 000 BAU/ml, Soluprick^® 10 300 BAU/ml, Oralair^® 8200 BAU, and Grazax^® 6200 BAU. Even though all extract concentrates differed in wheal size (P = 0.01–0.001), Grazax^® producing a 25% smaller wheal size than Oralair^®, and the biological activity of these clinically effective TIM tablets led in the same range (6200–8200 BAU; 0.92–1.23 cm²). SLIT dose‐finding studies for other pollens might start with allergen extracts producing 1.1 cm² wheal surface.     

Female and male partner age and menotrophin requirements influence pregnancy rates with human menopausal gonadotrophin therapy in combination with intrauterine insemination

This study analyses the influence of female and male patient age and human menopausal gonadotrophin (HMG) requirements on clinical pregnancy rates and live birth rates with ovulation stimulation using HMG in combination with intrauterine insemination (IUI). In this study, 363 consecutive HMG/IUI treatment cycles in 184 patients carried out at a university fertility centre were analysed in a retrospective fashion. The main outcomes measured were clinical pregnancy rates and live birth rates. Increased female partner age (> or = 35) and male partner age (> or = 40) were found to negatively influence pregnancy rates with HMG/ IUI therapy. In addition, this study demonstrated a critical threshold of HMG requirements beyond which pregnancy did not occur. No pregnancies occurred in treatment cycles requiring > 25 ampoules (1875 IU) of menotrophins to achieve follicular maturity, irrespective of patient age. In conclusion, female partner age, male partner age, and HMG requirements all significantly influence pregnancy rates with HMG/IUI therapy.      

社交性应激反应问卷中文版在大学生中应用的信效度初步评价

目的：建立社交性应激反应问卷（RSQ-SSV）中文版，并分析其信、效度。方法：按量表翻译程序将RSQ—SSV翻译成中文，整群分层选取409名大学生进行RSQ—SSV中文版的测量。随机抽取90名学生于初评后一个月进行重测，并与美国样本进行比较。结果：RSQ-SSV中文版整个问卷的Cronbach α系数为0．88，各因子仅系数在0．73～0．81之间；重测信度为0．70；全量表的条目间平均相关系数为0．11，5因子的条目间平均相关系数在0．19～0．29之间，因子间相关系数在0．12～0．76之间；条目对因子负荷系数在0．38—0．86之间，复相关系数在0．14—0．74之间；验证性因子分析的指标：IFI为0．93，CFI为0．93，TLI为0．92，RMSEA为0．06。中国大学生样本的不随意的逃避反应因子得分高于美国大学生样本[（0．97&#177;0．41）vs．（0．91&#177;0．48），P=0．002]，而初级亲近控制应对反应、次级亲近控制应对反应、不随意的亲近反应得分均低于美国大学生样本[（1．75&#177;0．49）vs．（2．12&#177;0．50）、（1．51&#177;0．43）vs．（1．80&#177;0．48）、（1．17&#177;0．44）vs．（1．36&#177;0．56），均P〈0．001]。结论：RSQ-SSV中文版具有良好的信、效度，可以试用于我国大学生社交性应激反应的测评。     

Evidence and consensus based GKJR guidelines for the treatment of juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children and adolescents. Immunomodulatory drugs are used frequently in its treatment. Using the nominal group technique (NGT) and Delphi method, we created a multidisciplinary, evidence- and consensus-based treatment guideline for JIA based on a systematic literature analysis and three consensus conferences. Conferences were headed by a professional moderator and were attended by representatives who had been nominated by their scientific societies or organizations. 15 statements regarding drug therapy, symptomatic and surgical management were generated. It is recommended that initially JIA is treated with NSAID followed by local glucocorticoids and/or methotrexate if unresponsive. Complementing literature evidence with long-standing experience of caregivers allows creating guidelines that may potentially improve the quality of care for children and adolescents with JIA.     

Glucose-6-phosphate dehydrogenase is the target for the trypanocidal action of human steroids

Steroids such as dehydroepiandrosterone (DHEA) and epiandrosterone (EA) exert multiple effects in mammals including the inhibition of glucose-6-phosphate dehydrogenase (G6PDH). Initially, the inhibition was considered specific for the mammalian enzyme. The beneficial effect of these steroids on infections by protists and nematodes was attributed to stimulation of the immune system. However, we showed previously that DHEA and EA also inhibit Trypanosoma brucei and T. cruzi G6PDH, with low micromolar K(i)' values, but not the enzyme from Leishmania species, and kill in vitro cultured trypanosomes. We report here that, contrary to wild-type trypanosomes, mutant bloodstream-form T. brucei cells expressing L. mexicana G6PDH are not susceptible to the steroids, proving that G6PDH is the in situ target. Moreover, bromo-derivatives of the steroids show 50-100 fold lower K(i)' values for the enzyme and display an increased potency to kill the parasites. Therefore, the compounds offer promise for use in development of parasite-selective drugs.