Nebulised amiloride in respiratory exacerbations of cystic fibrosis: a randomised controlled trial

OBJECTIVE: To assess the benefit of nebulised amiloride added to the standard inpatient treatment of a respiratory exacerbation in cystic fibrosis. DESIGN: Prospective, randomised, double blind, placebo controlled trial. SUBJECTS: 27 cystic fibrosis patients (mean age 12.8 years). SETTING: Two hospitals in Leeds, UK. RESULTS: Both forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) showed improvements over the course of treatment, although there was no difference in respiratory function between the two groups at any of three time periods during the study. The time to reach peak FVC was significantly reduced in the amiloride group (4.2 v 7.6 days; 95% CI 0.4 to 6.4 days), but not in the time to reach peak FEV1 (5.7 v 7.9 days; 95% CI -1.2 to 5.6 days). CONCLUSIONS: Amiloride did not result in a greater overall improvement in respiratory function. There was a suggestion that it may have an effect on the rate of improvement, and thus may possibly influence the duration of treatment. This hypothesis deserves further evaluation.     

藻酸盐/PEI/DNA复合载体作为一种新型基因递送系统

目的克服多聚乙烯亚胺(PEI，polyethlenimine)/DNA载体对细胞的毒性以及在含血清培养基里对癌细胞基因的转移率低的问题。方法利用具有水溶性、可生物降解的、并带有负电的藻酸盐(alginate)对PEI/DNA载体进行包衣，制备出复合载体，并在体外含50%血清培养基里，与PEI/DNA载体比较对C3癌细胞转染率。结果 在含50%血清的培养基里，藻酸盐包衣制备的复合体载体［alginate:DNA，0.15 (w/w);PEI:DNA，N:P=10］与PEI/DNA载体相比，对C3癌细胞基因转染率高出10～30倍，而且其表面正电荷数比PEI/DNA载体减少了一半，颗粒较小，并降低对细胞毒性和红血球集聚反应。结论作为新型的藻酸盐包衣制备的复合载体能提高在体外含高浓度血清培养基里对C3癌细胞的转染率，并能减少其对细胞毒性。     

Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantar keratoderma [published erratum appears in Hum Mol Genet 1999 May;8(5):943]

Desmosomes are highly organized intercellular adhesive junctions that are particularly prominent in epidermis and other tissues experiencing mechanical stress. Desmoplakin, a constitutive component of the desmosomal plaque, is the most abundant protein present in such junctions and plays a critical role in linking the intermediate filament network to the plasma membrane in these tissues. Here we report the first mutation in the gene encoding desmoplakin. The identified mutation, resulting in a null allele and haploinsufficiency, was observed in genomic DNA from a kindred with the dominantly inherited skin disorder, striate palmoplantar keratoderma. Affected individuals had a linear pattern of skin thickening on the fingers and palms and circumscribed areas of skin thickening on the soles. Affected skin demonstrated loosening of intercellular connections, disruption of desmosome-keratin intermediate filament interactions and a proportion of rudimentary desmosomal structures. The disorder mapped to chromosome 6p21 with a maximum lod score of 10.67. The mutation was a heterozygous C-->T transition in exon 4 of the desmoplakin gene and predicted a premature termination codon in the N-terminal region of the peptide. This is the first reported mutation of desmo-plakin and also the first inherited skin disorder in which haploinsufficiency of a structural component has been implicated. It identifies dosage of desmoplakin as critical in maintaining epidermal integrity.      

Orthopaedic assessment unit: a service model for the delivery of orthopaedic trauma care in a major trauma centre during the global pandemic (COVID-19)

IntroductionWe describe a new service model, the Orthopaedic Assessment Unit (OAU), designed to provide care for trauma patients during the COVID-19 pandemic. Patients without COVID-19 symptoms and isolated musculoskeletal injuries were redirected to the OAU.MethodsWe prospectively reviewed patients throughput during the peak of the global pandemic (7 May 2020 to 7 June 2020) and compared with our historic service provision (7 May 2019 to 7 June 2019). The Mann–Whitney and Fisher Exact tests were used to test the statistical significance of data.ResultsA total of 1,147 patients were seen, with peak attendances between 11am and 2pm; 96% of all referrals were seen within 4h. The majority of patients were seen by orthopaedic registrars (52%) and nurse practitioners (44%). The majority of patients suffered from sprains and strains (39%), followed by fractures (22%) and wounds (20%); 73% of patients were discharged on the same day, 15% given follow up, 8% underwent surgery and 3% were admitted but did not undergo surgery. Our volume of trauma admissions and theatre cases decreased by 22% and 17%, respectively (p=0.058; 0.139). There was a significant reduction of virtual fracture clinic referrals after reconfiguration of services (p<0.001).ConclusionsRapid implementation of a specialist OAU during a pandemic can provide early definitive trauma care while exceeding national waiting time standards. The fall in trauma attendances was lower than anticipated. The retention of orthopaedic staff in the department to staff the unit and maintain a high standard of care is imperative.     

男性迟发性性腺功能减退症的检查、治疗和监测:国际男科学会(ISA)、国际老年男性研究会(ISSAM)、欧洲泌尿外科学会(EAU)、欧洲泌尿外科学院(EAA)和美国男科学会(ASA)联合推荐

简介 人口学资料明确显示:老年人口占总人口的百分率正逐年增加.当前,有关老年男性雄激素缺乏的问题逐渐成为令人感兴趣、但又充满争议的世界性话题.已经有横向和纵向的研究资料表明,随着年龄增大,成年男子的雄激素水平逐渐降低,且相当一部分年龄超过60岁男性的血清睾酮水平已降到正常年轻成年男性(20～30岁)的低限值以下.     

Inhibition of CXCR3-mediated chemotaxis by the human chemokine receptor-like protein CCX-CKR

Background and Purpose

Induction of cellular migration is the primary effect of chemokine receptor activation. However, several chemokine receptor-like proteins bind chemokines without subsequent induction of intracellular signalling and chemotaxis. It has been suggested that they act as chemokine scavengers, which may control local chemokine levels and contribute to the function of chemokines during inflammation. This has been verified for the chemokine-like receptor proteins D6 and DARC as well as CCX-CKR. Here, we provide evidence for an additional biological function of human (h)CCX-CKR.

Experimental Approach

We used transfection strategies in HEK293 and human T cells.

Key Results

Co-expression of hCCX-CKR completely inhibits hCXCR3-induced chemotaxis. We found that hCCX-CKR forms complexes with hCXCR3, suggesting a relationship between CCX-CKR heteromerization and inhibition of chemotaxis. Moreover, negative binding cooperativity induced by ligands both for hCXCR3 and hCCX-CKR was observed in cells expressing both receptors. This negative cooperativity may also explain the hCCX-CKR-induced inhibition of chemotaxis.

Conclusions and Implications

These findings suggest that hCCX-CKR prevents hCXCR3-induced chemotaxis by heteromerization thus representing a novel mechanism of regulation of immune cell migration.