Circulating alloreactive T cells correlate with graft function in longstanding renal transplant recipients

Monitoring for alloreactive memory T cells after organ transplantation may allow individualization of immunosuppression. Two pathways of T cell allorecognition have been implicated in chronic graft dysfunction: Direct (recipient T cells respond to donor peptides presented by donor antigen-presenting cells) and indirect (donor peptides are processed and presented by recipient antigen-presenting cells). Previous studies have assessed these alloresponses only during the first 2 yr after kidney transplantation,so this study correlated the presence of circulating donor-reactive memory/effector T cells, primed by both pathways, in 34 longstanding living-donor renal transplant recipients using the highly sensitive IFN-gamma Elispot assay. Remarkably, 59% of patients had directly primed donor-reactive T cells, and their presence correlated directly with serum creatinine (P = 0.001) and inversely with estimated GFR (P = 0.042). Multivariate analysis revealed that hyporesponsiveness of direct, donor-specific T cells was the only variable that significantly correlated with graft function and that antidonor indirect alloreactivity was the only variable that significantly correlated with proteinuria. Interestingly, when both allorecognition pathways were considered together, patients with undetectable direct alloreactivity had better longterm graft function, independent of allosensitization by the indirect pathway. In conclusion, circulating donor-specific alloreactive T cells primed by both pathways are detectable long after transplantation and are associated with graft injury. Assessment of alloreactive memory/effector T cells might be helpful to tailor individual immunosuppression regimens for transplant recipients in the future.     

Dopaminergic modulation of auditory cortex-dependent memory consolidation through mTOR

Previous studies in the auditory cortex of Mongolian gerbils on discrimination learning of the direction of frequency-modulated tones (FMs) revealed that long-term memory formation involves activation of the dopaminergic system, activity of the protein kinase mammalian target of rapamycin (mTOR), and protein synthesis. This led to the hypothesis that the dopaminergic system might modulate memory formation via regulation of mTOR, which is implicated in translational control. Here, we report that the D1/D5 dopamine receptor agonist SKF-38393 substantially improved gerbils' FM discrimination learning when administered systemically or locally into the auditory cortex shortly before, shortly after, or 1 day before conditioning. Although acquisition performance during initial training was normal, the discrimination of FMs was enhanced during retraining performed hours or days after agonist injection compared with vehicle-injected controls. The D1/D5 receptor antagonist SCH-23390, the mTOR inhibitor rapamycin, and the protein synthesis blocker anisomycin suppressed this effect. By immunohistochemistry, D1 dopamine receptors were identified in the gerbil auditory cortex predominantly in the infragranular layers. Together, these findings suggest that in the gerbil auditory cortex dopaminergic inputs regulate mTOR-mediated, protein synthesis-dependent mechanisms, thus controlling for hours or days the consolidation of memory required for the discrimination of complex auditory stimuli.     

Polytetrafluoroethylene in the surgery of cases with severe limitation of abduction Long-term results

Background: In cases of severe palsy or paralysis of eye muscles, it is sometimes necessary to extensively weaken the homolateral antagonist. Large recessions reduce the ocular motility by shortening the arc of contact between muscle and sclera. The lengthening of the muscle tendon with Fascia lata, Lyo-Dura®, or the free transplantation of an excided piece of autologous eye muscle tendon does not ensure predictable precise results. We used polytetrafluoroethylene (PTFE, Gore-Tex®) for seven years and report on our results. Method: A new technique is introduced in which the muscle is lengthened by PTFE. Ten patients (7 sixth nerve palsies, 1 strabismus fixus, 2 Duane’s retraction syndromes) underwent lengthening of the medial rectus muscle with a Gore-Tex® soft tissue patch between 8 and 14mm in size. The two patients with the Duane's retraction syndrome were not operated on the rectus externus muscle. All other patients had a resection of the paralytic muscle. Results: In most cases, good results were obtained: binocular single vision in primary head position within a small field of fusion. Histological examination of a specimen of Gore-Tex® four years after surgery showed an excellent integration of the graft into the tissue. Fibrous connective tissue wrapped the Gore-Tex® like a capsule. There were no signs of inflammation or graft reaction. Conclusions: PTFE (Gore-Tex® Soft Tissue Patch) is a suitable material for complicated strabismus surgery. Main advantages: availability at any time in the operation theater; high biocompatibility; form stability; and no diminution of operative results.     

Interaction of Mucosal Microbiota with the Innate Immune System

Organisms live in continuos interaction with their environment; this interaction is of vital importance but at the same time can be life threatening. The largest and most important interface between the organism and its environment is represented by surfaces covered with epithelial cells. Of these surfaces, mucosae comprise in humans approximately 300 m², and the skin covers approximately 1.8 m² surface of the human body. Mucosal tissues contain two effector arms of the immune system, innate and adaptive, which operate in synergy. Interaction with commensal bacteria, which outnumber the nucleated cells of our body, occurs physiologically on epithelial surfaces; this interaction could pose the risk of inflammation. The mucosal immune system has developed a complex network of regulatory signalling cascades that is a prerequisite for proper activation but also for a timely inactivation of the pathway. As demonstrated in gnotobiotic animal models of human diseases, impaired regulation of mucosal responses to commensal bacteria plays an important role in the development of several inflammatory and autoimmune diseases.     

Isolation of Lautropia mirabilis from Oral Cavities of Human Immunodeficiency Virus-Infected Children

Lautropia mirabilis, a pleomorphic, motile, gram-negative coccus, has been isolated from the oral cavities of 32 of 60 (53.3%) children infected with human immunodeficiency virus (HIV) and 3 of 25 (12.0%) HIV-uninfected controls; the association of L. mirabilis isolation with HIV infection is significant (P < 0.001). All children in the study, both HIV-infected children and controls, were born to HIV-infected mothers. The presence of this bacterium was not associated with clinical disease in these children. The HIV-infected children with L. mirabilis did not differ from the HIV-infected children without L. mirabilis in immunological status, clinical status, or systemic medications. The role of HIV infection itself or concomitant factors in the establishment of L. mirabilis in the oral cavity remains to be elucidated.     

Towards mapping phenotypical traits in 18p- syndrome by array-based comparative genomic hybridisation and fluorescent in situ hybridisation

Molecular karyotyping holds the promise of improving genotype-phenotype correlations for frequent chromosome conditions such as the 18p- syndrome. In spite of more than 150 reported cases with deletions in 18p, no reliable phenotype map for the characteristic clinical findings such as mental retardation, post-natal growth retardation and typical facial features has been established yet. Here, we report on four patients with partial monosomy 18p of different sizes owing to unbalanced translocations that were thoroughly characterised clinically and by molecular karyotyping. One patient had a terminal deletion of 1.6 Mb in 18p and a trisomy of 8q24.23-qter as determined by array-based comparative genomic hybridisation and large insert clone fluorescent in situ hybridisation. In two sibs and a fourth patient, cytogenetic and molecular-cytogenetic analyses showed the terminal deletions in 18p (8.0 and 13.84 Mb, respectively) to be accompanied by partial trisomies of 20p. Literature analyses of typical phenotypic features of 18p-, 8q+ and 20p+ syndromes allowed the attribution of clinical findings in our patients to the respective chromosomal aberration. Based on these data, we propose a phenotype map for several clinical features of the 18p- syndrome: Round face was tentatively mapped to the distal 1.6 Mb of 18p; post-natal growth retardation and seizures to the distal 8 Mb and ptosis and short neck to the proximal half of 18p.     

Classification and characterization of postural transitions using instrumented shoes

The frequency and quality of sit-to-stand and stand-to-sit postural transitions decrease with age and are highly relevant for fall risk assessment. Accurate classification and characterization of these transitions in daily life of older adults are therefore needed. In this study, we propose to use instrumented shoes for postural transition classification as well as transition duration estimation from insole force signals. In the first part, data were collected with 10 older adults and 10 young participants performing transitions in the laboratory while wearing the instrumented shoes, without arm assistance. A wavelet approach was used to transform the insole force data, and candidate events were selected for transition duration estimation. Transition durations were then validated against a model based on force plate reference. Vertical force estimation was also compared to force plate measurement. In the second part, postural transitions were classified in daily life using the instrumented shoes and validated against a highly accurate wearable system. Transition duration was estimated with an error ranging from 10 to 20% while the error for vertical force estimation was 7%. Postural transition classification was achieved with excellent sensitivity and precision exceeding 90%. In conclusion, the instrumented shoes are suitable for classifying and characterizing postural transitions in daily life conditions of healthy older adults.

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Graphical abstract “Experimental setup showing instrumented shoes, reference force plate, as well as IMUs used for postural transition classification and duration estimation comparison”