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Recessive mutations in diacylglycerol kinase epsilon (DGKE) display genetic pleiotropy, with pathological features reported as either thrombotic microangiopathy or membranoproliferative glomerulonephritis (MPGN), and clinical features of atypical hemolytic uremic syndrome (aHUS), nephrotic syndrome or both. Pathophysiological mechanisms and optimal management strategies have not yet been defined. In prospective and retrospective studies of aHUS referred to the United Kingdom National aHUS service and prospective studies of MPGN referred to the National Registry of Rare Kidney Diseases for MPGN we defined the incidence of DGKE aHUS as 0.009/million/year and so-called DGKE MPGN as 0.006/million/year, giving a combined incidence of 0.015/million/year. Here, we describe a cohort of sixteen individuals with DGKE nephropathy. One presented with isolated nephrotic syndrome. Analysis of pathological features reveals that DGKE mutations give an MPGN-like appearance to different extents, with but more often without changes in arterioles or arteries. In 15 patients presenting with aHUS, ten had concurrent substantial proteinuria. Identified triggering events were rare but coexistent developmental disorders were seen in six. Nine with aHUS experienced at least one relapse, although in only one did a relapse of aHUS occur after age five years. Persistent proteinuria was seen in the majority of cases. Only two individuals have reached end stage renal disease, 20 years after the initial presentation, and in one, renal transplantation was successfully undertaken without relapse. Six individuals received eculizumab. Relapses on treatment occurred in one individual. In four individuals eculizumab was withdrawn, with one spontaneously resolving aHUS relapse occurring. Thus we suggest that DGKE-mediated aHUS is eculizumab non-responsive and that in individuals who currently receive eculizumab therapy it can be safely withdrawn. This has important patient safety and economic implications., Graphical abstract

SUMMARY Chitin, a major component of fungal cell walls, has been associated with allergic disorders such as asthma. However, it is unclear how mammals recognize chitin and the principal receptor(s) on epithelial cells that sense chitin remain to be determined. In this study, we show that LYSMD3 is expressed on the surface of human airway epithelial cells and demonstrate that LYSMD3 is able to bind chitin, as well as β-glucan, on the cell walls of fungi. Knockdown or knockout of LYSMD3 also sharply blunts the production of inflammatory cytokines by epithelial cells in response to chitin and fungal spores. Competitive inhibition of the LYSMD3 ectodomain by soluble LYSMD3 protein, multiple ligands, or antibody against LYSMD3 also blocks chitin signaling. Our study reveals LYSMD3 as a mammalian pattern recognition receptor (PRR) for chitin and establishes its role in epithelial cell inflammatory responses to chitin and fungi., Graphical abstract, In brief Mammalian chitin recognition is poorly understood but significant because chitin is ubiquitous and linked to disease. Here, He et al. reveal that LYSMD3 on human lung epithelial cells binds to chitin and fungal spores and mediates production of cytokines. They find that LYSMD3 is also able to bind β-glucan.

Neo-Whorfians argue that the structures our language uses to encode spatial relations influence the way we conceptualise space. One explicit test of this link has been studies of how speakers of different languages configure arrays of objects in non-linguistic rotation tasks. Subjects perform these tasks differently depending on their dominant linguistic frame of reference: relative e.g. left/right terms, or absolute e.g. N/S/W/E terms. One prediction is that changes in the linguistic system should result in corresponding cognitive changes. Such a linguistic shift has occurred among Gurindji people (Australia). Traditionally Gurindji people used a system of cardinal directions, however many have now also been exposed to the English left/right system. This paper demonstrates that this language difference is reflected cognitively. The ‘Animals-in-a-row’ task was administered to 107 Gurindji people. The results show strong ‘viewpoint independent’ responses, nonetheless those with a Tertiary education gave significantly more ‘viewpoint dependent’ responses which we attribute to exposure to English, and perhaps associated literacy practices.

Baby talk is an aspect of infant- or child-directed speech where caregivers imitate children's immature productions in stylized form. Within non-generativist approaches to language acquisition, children's language acquisition is often viewed an emergent response to a highly patterned linguistic environment, at least some of which is tailored by caregivers to children's cognitive and social needs. Some cross-cultural research, however, has disputed whether caregivers modify speech to children in all cultures, and whether or to what extent special infant- or child-directed speech is necessary for successful language acquisition. In this paper we present new cross-linguistic and cross-cultural data on baby talk or janyarrp among Gurindji people. Using a corpus of naturalistic family interactions and interviews with Gurindji people of northern Australia we describe the phonological modifications and specific lexicon of baby talk and investigate its possible functions. Several phonological reductions were found which are familiar from baby talk and child speech in other languages, including rhotic replacement and cluster reduction. More unusually, baby talk neutralizes the three-way coronal contrast in Gurindji Kriol, the language which Gurindji children learn at home. The functions of baby talk for Gurindji people likewise seem to comprise familiar baby talk functions like holding attention as well as less familiar functions, such facilitating children's imitations in production.

The goal of the present study was to investigate hepato-protective effects of growth factor (GF) arrays during alcohol injury. Hepatocyte growth factor (HGF) and bone morphogenetic protein (BMP)7 were mixed with collagen (I) and robotically printed onto standard glass slides to create arrays of 500 microm diameter spots. Primary rat hepatocytes were seeded on top of the arrays forming clusters corresponding in size to the underlying protein spots. Cell arrays were then injured in culture by exposure to 100 mm ethanol for 48 h. Hepatocytes residing on GF spots were found to have less apoptosis then cells cultured on collagen-only spots. Least apoptosis (0.3% as estimated by TUNEL assay) was observed on HGF/BMP7/collagen spots whereas most apoptosis (17.3%) was seen on collagen-only arrays. Interestingly, the extent of alcohol-induced apoptosis in hepatocytes varied based on the concentration of printed GF. In addition to preventing apoptosis, printed GFs contributed to maintenance of epithelial phenotype during alcohol injury as evidenced by higher levels of E-cadherin expression in HGF-protected hepatocytes. Importantly, GF microarrays could be used to investigate heterotypic interactions in the context of liver injury. To highlight this, stellate cells - nonparenchymal liver cells involved in fibrosis - were added to hepatocytes residing on arrays of either HGF/collagen or collagen-only spots. Exposure of these cocultures to ethanol followed by RT-PCR analysis revealed that stellate cells residing alongside HGF-protected hepatocytes were significantly less activated (less fibrotic) compared to controls. Overall, our results demonstrate that GF microarray format can be used to screen anti-fibrotic and anti-apoptotic effects of growth factors as well as to investigate how signals delivered to a specific cell type modulate heterotypic cellular interactions.

Growth factors are commonly present in soluble form during in vitro cell cultivation experiments in order to provide signals for cellular proliferation or differentiation. In contrast to these traditional experiments, we investigated solid-phase presentation of a hepatocyte growth factor (HGF), a protein important in liver development and regeneration, on microarrays of extracellular matrix (ECM) proteins. In our experiments, HGF was mixed in solution with ECM proteins (collagen (I), (IV) or laminin) and robotically printed onto silane-modified glass slides. Primary rat hepatocytes were seeded onto HGF/ECM protein microarrays and formed cellular clusters that corresponded in size to the dimensions of individual protein spots (500 microm diameter). Analysis of liver-specific products, albumin and alpha1-antitrypsin, revealed several fold higher levels of expression of these proteins in hepatocytes cultured on HGF/ECM microarrays compared to cells cultivated on ECM proteins alone. In addition, cultivation of hepatocytes on HGF/ECM protein spots led to spontaneous reorganization of cellular clusters from a monolayer into three-dimensional spheroids. We also investigated the effects of surface-tethered HGF on hepatocytes co-cultivated with stromal cells and observed a significantly higher level of albumin in co-cultures where hepatocytes were stimulated by HGF/ECM spots compared to co-cultures created on ECM protein islands without the growth factor. In summary, our study suggests that incorporation of HGF into ECM protein microarrays has a profound and long-lasting effect on the morphology and phenotype of primary hepatocytes. In the future, the number of growth factors printed on ECM microarrays will be expanded to enable multiplexed and combinatorial screening of inducers of cellular differentiation or proliferation.

This experiment assessed the effect of variation in speech rate on comprehension and persuasiveness of a message presented in text-to-speech (TTS) synthesis to native and non-native listeners. Eighty non-native speakers of English and 80 native speakers of Australian English were randomly assigned to listen to eight banking product descriptions under one of four conditions: normal rate (155 words per minute) with no background noise, normal rate with multi-talker background noise (+6dB SNR), fast-normal (178 words per minute) with no background noise, and fast-normal with multi-talker background noise. Participants completed comprehension tests and rated each product's usefulness. A faster rate lowers comprehension for both native and non-native listeners but does not influence the persuasiveness of the message. The findings have implications for the selection of speech rates for persuasive messages delivered to native and non-native listeners using TTS.

Outcome after surgical treatment for nonunion and malunion of midshaft displaced clavicle fractures has generally been described as favorable and equal to results of acute repair. This assumption has been based on subjective criteria, however, and no direct comparison is available in the literature. This study used objective measurements of limb function to compare outcome in patients who underwent delayed operative intervention for nonunion and malunion with the outcome of patients who underwent immediate open reduction and internal fixation after displaced clavicle fracture. All patients had sustained completely displaced, closed, isolated midshaft clavicle fractures, of whom 15 had undergone acute open reduction and internal fixation with a compression plate at a mean of 0.6 months after injury (acute group). Another 15 patients had undergone delayed reconstruction with open reduction, bone grafting, and compression plate fixation for nonunion or malunion a mean of 63 months after injury (delayed group). The 2 groups were similar in age, gender, original fracture characteristics, and mechanism of injury. Complete assessment included standard history and physical examination, the Disabilities of the Arm, Shoulder and Hand (DASH) score and Constant Shoulder Score, subjective rating of outcome satisfaction, and objective muscle strength testing using a previously validated and published protocol on the Baltimore Therapeutic Equipment (BTE) work simulator. There were no significant differences between acute fixation and delayed reconstruction groups with regard to strength of shoulder flexion (acute, 94%; delayed, 93%; P = .82), shoulder abduction (acute, 97%; delayed, 97%; P = .92), external rotation (acute, 97%; delayed, 90%; P = .11), or internal rotation (acute, 98%; delayed, 96%; P = .55). Constant scores in the acute group were superior (acute, 95; delayed, 89; P = .02), but differences in DASH scores were not significant (acute, 3.0; delayed, 7.2; P = .15). Shoulder flexion muscle endurance was significantly decreased in the delayed group (acute, 109%; delayed, 80%; P = .05). Differences in muscle endurance in other planes were not significantly different (abduction endurance: acute, 107%; delayed, 81%; P = .24). Both groups rated their satisfaction with the procedure as excellent. Late reconstruction of nonunion and malunion after displaced midshaft fractures of the clavicle is a reliable and reproducible procedure that results in restoration of objective muscle strength similar to that seen with immediate fixation; however, there are subtle decreases in endurance strength and outcome compared with acute fracture repair. This information should not be used to justify primary operative repair in isolation but is useful in decision-making when counseling patients with displaced midshaft fractures of the clavicle.

In 1996, Social Science & Medicine published a review of treatment seeking for malaria (McCombie, 1996). Since that time, a significant amount of socio-behavioral research on the home management of malaria has been undertaken. In addition, recent initiatives such as Roll Back Malaria have emphasized the importance of social science inputs to malaria research and control. However, there has been a growing feeling that the potential contributions that social science could and should be making to malaria research and control have yet to be fully realized. To address these issues, this paper critically reviews and synthesizes the literature (published, unpublished and technical reports) pertaining to the home management of illness episodes of malaria in sub-Saharan Africa from 1996 to the end of 2000, and draws conclusions about the use of social science in malaria research and control. The results suggest that while we have amassed increasing quantities of descriptive data on treatment seeking behavior, we still have little understanding of the rationale of drug use from the patient perspective and, perhaps more importantly, barely any information on the rationale of provider behaviors. However, the results underline the dynamic and iterative nature of treatment seeking with multiple sources of care frequently being employed during a single illness episode; and highlight the importance in decision making of gender, socio-economic and cultural position of individuals within households and communities. Furthermore, the impact of political, structural and environmental factors on treatment seeking behaviors is starting to be recognised. Programs to address these issues may be beyond single sector (malaria control programme) interventions, but social science practice in malaria control needs to reflect a realistic appraisal of the complexities that govern human behavior and include critical appraisal and proposals for practical action. Major concerns arising from the review were the lack of evidence of 'social scientist' involvement (particularly few from endemic countries) in much of the published research; and concerns with methodological rigor. To increase the effective use of social science, we should focus on a new orientation for field research (including increased methodological rigor), address the gaps in research knowledge, strengthen the relationship between research, policy and practice; and concentrate on capacity strengthening and advocacy.

The repressor element 1-silencing transcription factor (REST) has been proposed to restrict expression of repressor element 1 (RE1) bearing genes to differentiated neurons by silencing their expression in non-neural tissue. Here, we have examined the interaction of REST with the M 4 muscarinic acetylcholine receptor gene. We show that REST binds to the RE1 of the M 4 gene in those cell lines and brain regions where the M 4 gene is expressed but not in those where the M 4 is not expressed. Furthermore, in cells that express M 4 , the presence of REST represses but is insufficient to silence transcription of M 4 . In non-neural cells REST is absent from the RE1 of the silent M 4 gene and perturbation of REST function fails to induce M 4 expression. We propose that REST acts to regulate expression levels of some RE1-bearing genes in neural cells, thereby playing an important role in defining neuronal activity.

In WI-38 human fibroblasts, interleukin-1 beta and tumour necrosis factor-alpha (TNF-alpha) increased bradykinin B(1) receptor mRNA, which peaked between 2 and 4 h, remaining elevated for 20 h. Binding of the bradykinin B(1) receptor selective ligand [3H]des-Arg(10)-kallidin, also increased, peaking at 4 h and remaining elevated for 20 h. The B(max) value for [3H]des-Arg(10)-kallidin rose from 280+/-102 fmol/mg (n=3) to 701+/-147 fmol/mg (n=3), but the K(D) value remained unaltered (control, 1.04+/-0.33 nM (n=3); interleukin-1 beta, 0.88+/-0.41 nM (n=3)). The interleukin-1 beta-induced [3H]des-Arg(10)-kallidin binding sites were functional receptors, as bradykinin B(1) receptor agonist-induced responses increased in treated cells. Bradykinin B(2) receptor mRNA and [3H]bradykinin binding were upregulated by interleukin-1 beta, but not TNF-alpha. The effect of interleukin-1 beta on bradykinin B(2) receptors was smaller than for bradykinin B(1) receptors. Cycloheximide prevented interleukin-1 beta-mediated increases in B(1) and B(2) binding, but not mRNA suggesting that de novo synthesis of a transcriptional activator was unnecessary.

The second annual meeting of the Partnership for Social Sciences in Malaria Control was held at the London School of Hygiene and Tropical Medicine, UK, from 8 to 10 January 2002.

A new procedure for amplification of prion proteins has been described by researchers from Geneva, Switzerland. Reporting in the June 14 issue of Nature, Soto and colleagues present a technique analogous to PCR cycling that involves cyclic amplification of protein misfolding. This allows rapid conversion of a large excess of PrPc (the normal cell surface protein) into a proteasome-resistant, PrPSc-like form in the presence of minute quantities of PrPSc template (the abnormal protein and principal component of prions). Currently available methods of PrPSc detection are limited by the low amounts of abnormal protein. Therefore, this new method could lead to a diagnostic test for the presence of prions in tissue and biological fluids. CJ