An Anti-C1s Monoclonal, TNT003, Inhibits Complement Activation Induced by Antibodies Against HLA.

Antibody-mediated rejection (AMR) of solid organ transplants (SOT) is characterized by damage triggered by donor-specific antibodies (DSA) binding donor Class I and II HLA (HLA-I and HLA-II) expressed on endothelial cells. While F(ab')2 portions of DSA cause cellular activation and proliferation, Fc regions activate the classical complement cascade, resulting in complement deposition and leukocyte recruitment, both hallmark features of AMR. We characterized the ability of an anti-C1s monoclonal antibody, TNT003, to inhibit HLA antibody (HLA-Ab)-induced complement activation. Complement deposition induced by HLA-Ab was evaluated using novel cell- and bead-based assays. Human aortic endothelial cells (HAEC) were cultured with HLA-Ab and human complement; production of activated complement proteins was measured by flow cytometry. Additionally, C3d deposition was measured on single antigen beads (SAB) mixed with HLA-Ab and human complement. TNT003 inhibited HLA-Ab mediated complement deposition on HAEC in a concentration-dependent manner; C3a, C4a and C5a anaphylatoxin production was also diminished by TNT003. Finally, TNT003 blocked C3d deposition induced by Class I (HLAI-Ab)- and Class II (HLAII-Ab)-specific antibodies on SAB. These data suggest TNT003 may be useful for modulating the effects of DSA, as TNT003 inhibits complement deposition and split product formation generated by HLA-I/II-Ab in vitro

How Does the dGEMRIC Index Change After Surgical Treatment for FAI? A Prospective Controlled Study: Preliminary Results.

BACKGROUND Delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) allows an objective, noninvasive, and longitudinal quantification of biochemical cartilage properties. Although dGEMRIC has been used to monitor the course of cartilage degeneration after periacetabular osteotomy (PAO) for correction of hip dysplasia, such longitudinal data are currently lacking for femoroacetabular impingement (FAI). QUESTIONS/PURPOSES (1) How does the mean acetabular and femoral dGEMRIC index change after surgery for FAI at 1-year followup compared with a similar group of patients with FAI treated without surgery? (2) Does the regional distribution of the acetabular and femoral dGEMRIC index change for the two groups over time? (3) Is there a correlation between the baseline dGEMRIC index and the change of patient-reported outcome measures (PROMs) at 1-year followup? (4) Among those treated surgically, can dGEMRIC indices distinguish between intact and degenerated cartilage? METHODS We performed a prospective, comparative, nonrandomized, longitudinal study. At the time of enrollment, the patients' decision whether to undergo surgery or choose nonoperative treatment was not made yet. Thirty-nine patients (40 hips) who underwent either joint-preserving surgery for FAI (20 hips) or nonoperative treatment (20 hips) were included. The two groups did not differ regarding Tönnis osteoarthritis score, preoperative PROMs, or baseline dGEMRIC indices. There were more women (60% versus 30%, p = 0.003) in the nonoperative group and patients were older (36 ± 8 years versus 30 ± 8 years, p = 0.026) and had lower alpha angles (65° ± 10° versus 73° ± 12°, p = 0.022) compared with the operative group. We used a 3.0-T scanner and a three-dimensional dual flip-angle gradient-echo technique for the dGEMRIC technique for the baseline and the 1-year followup measurements. dGEMRIC indices of femoral and acetabular cartilage were measured separately on the initial and followup radial dGEMRIC reformats in direct comparison with morphologic radial images. Regions of interest were placed manually peripherally and centrally within the cartilage based on anatomic landmarks at the clockface positions. The WOMAC, the Hip disability and Osteoarthritis Outcome Score, and the modified Harris hip score were used as PROMs. Among those treated surgically, the intraoperative damage according to the Beck grading was recorded and compared with the baseline dGEMRIC indices. RESULTS Although both the operative and the nonoperative groups experienced decreased dGEMRIC indices, the declines were more pronounced in the operative group (-96 ± 112 ms versus -16 ± 101 ms on the acetabular side and -96 ± 123 ms versus -21 ± 83 ms on the femoral side in the operative and nonoperative groups, respectively; p < 0.001 for both). Patients undergoing hip arthroscopy and surgical hip dislocation experienced decreased dGEMRIC indices; the decline in femoral dGEMRIC indices was more pronounced in hips after surgical hip dislocation (-120 ± 137 ms versus -61 ± 89 ms, p = 0.002). In the operative group a decline in dGEMRIC indices was observed in 43 of 44 regions over time. In the nonoperative group a decline in dGEMRIC indices was observed in four of 44 regions over time. The strongest correlation among patients treated surgically was found between the change in WOMAC and baseline dGEMRIC indices for the entire joint (R = 0.788, p < 0.001). Among those treated nonoperatively, no correlation between baseline dGEMRIC indices and change in PROMs was found. In the posterosuperior quadrant, the dGEMRIC index was higher for patients with intact cartilage compared with hips with chondral lesions (592 ± 203 ms versus 444 ± 205 ms, p < 0.001). CONCLUSIONS We found a decline in acetabular, femoral, and regional dGEMRIC indices for the surgically treated group at 1-year followup despite an improvement in all PROMs. We observed a similar but less pronounced decrease in the dGEMRIC index in symptomatic patients without surgical treatment indicating continuous cartilage degeneration. Although treatment of FAI is intended to alter the forces acting across the hip by eliminating impingement, its effects on cartilage biology are not clear. dGEMRIC provides a noninvasive method of assessing these effects. Longer term studies will be needed to determine whether the matrix changes of the bradytrophic cartilage seen here are permanent or clinically important. LEVEL OF EVIDENCE Level II, therapeutic study

Cardiovascular disease risk prediction in older people: a qualitative study.

BACKGROUND: Despite cardiovascular disease (CVD) risk prediction equations becoming more widely available for people aged ≥75 years, views of older people on CVD risk assessment are unknown. AIM: To explore older people's views on CVD risk prediction and its assessment. DESIGN AND SETTING: Qualitative study of community-dwelling older people in New Zealand. METHOD: A diverse group of older people was purposively recruited. Semi-structured interviews and focus groups were conducted, transcribed verbatim, and thematically analysed. RESULTS: Thirty-nine participants (mean age 74 years) of Māori, Pacific, South Asian, and European ethnicities participated in one of 26 interviews or one of three focus groups. Three key themes emerged: poor knowledge and understanding of CVD and its risk assessment; acceptability and perceived benefit of knowing and receiving advice on managing personal CVD risk; and distinguishing between CVD outcomes - stroke and heart attack are not the same. Most participants did not understand CVD terms, but were familiar with the terms 'heart attack' and 'stroke', and understood lifestyle risk factors for these events. Participants valued CVD outcomes differently, fearing stroke and disability - which might adversely affect independence and quality of life - but were less concerned about a heart attack, which was perceived as causing less disability or swifter death. These findings and preferences were similar across ethnic groups. All but two participants wanted to know their CVD risk, how to manage it, and distinguish between CVD outcomes. Those who did not wish to know perceived this as something only their God could decide. CONCLUSION: To inform clinical decision making for older people, consideration of an individual's wish to know their risk is important, and risk prediction tools should provide separate event types rather than just composite outcomes

Clinical and pathological kidney aspects of sickle cell anemia at Dakar: study of 11 cases of renal biopsies

Few studies are devoted to the practice of renal biopsy in sickle cell nephropathy; our objective was to determine the histological and evolutionary patterns of renal lesions in sickle cell patients who underwent renal biopsy in Dakar.Methods:This was a retrospective multicentric study (conducted from December 2009 to August 2011) on renal biopsies performed on sickle cell anaemic patients at the Nephrology Department of Teaching Hospital Aristide Le Dantec and the Albert Royer Childrens Hospital. The histological, therapeutic and evolutionary data were analysed.From the 292 total renal biopsies, 11 (3.80%) were performed on sickle cell patients (6SS, 1SBth + 4 AS) with a mean age of 23.1 [13-51 years]. Nephrotic syndrome was the indication of renal biopsy in all cases. Focal segmental glomerulosclerosis was the most frequent histological finding (five cases), followed by a combination of various specific lesions (hypertrophy of glomerular and peritubular capillaries), minimal glomerular lesions (three cases), membranoproliferative glomerulonephritis (two cases) and extra-membranous glomerulonephritis (one case). Complete remission after treatment was achieved in seven cases and one patient expired. Three patients did not continue with follow-up appointments.Conclusions:Renal biopsy is not very frequent in the course of sickle cell anaemia and in most cases it is performed because of nephrotic syndrome. The histological findings are diverse with a predominance of focal segmental glomerulosclerosis

Linearized stability analysis of gravastars in noncommutative geometry

In this work, we find exact gravastar solutions in the context of noncommutative geometry, and explore their physical properties and characteristics. The energy density of these geometries is a smeared and particle-like gravitational source, where the mass is diffused throughout a region of linear dimension $\sqrt{(\alpha)}$ due to the intrinsic uncertainty encoded in the coordinate commutator. These solutions are then matched to an exterior Schwarzschild spacetime. We further explore the dynamical stability of the transition layer of these gravastars, for the specific case of $\beta=M^2/\alpha<1.9$, where M is the black hole mass, to linearized spherically symmetric radial perturbations about static equilibrium solutions. It is found that large stability regions exist and, in particular, located sufficiently close to where the event horizon is expected to form.Comment: 6 pages, 3 figure

Barriers to enrollment in a randomized controlled trial of hydrocortisone for cardiovascular insufficiency in term and late preterm newborn infants.

ObjectiveTo analyze reasons for low enrollment in a randomized controlled trial (RCT) of the effect of hydrocortisone for cardiovascular insufficiency on survival without neurodevelopmental impairment (NDI) in term/late preterm newborns.Study designThe original study was a multicenter RCT. Eligibility: ⩾34 weeks' gestation, &lt;72 h old, mechanically ventilated, receiving inotrope. Primary outcome was NDI at 2 years; infants with diagnoses at high risk for NDI were excluded. This paper presents an analysis of reasons for low patient enrollment.ResultsTwo hundred and fifty-seven of the 932 otherwise eligible infants received inotropes; however, 207 (81%) had exclusionary diagnoses. Only 12 infants were randomized over 10 months; therefore, the study was terminated. Contributing factors included few eligible infants after exclusions, open-label steroid therapy and a narrow enrollment window.ConclusionDespite an observational study to estimate the population, very few infants were enrolled. Successful RCTs of emergent therapy may require fewer exclusions, a short-term primary outcome, waiver of consent and/or other alternatives

Modularity of gene-regulatory networks revealed in sea-star development

Evidence that conserved developmental gene-regulatory networks can change as a unit during deutersostome evolution emerges from a study published in BMC Biology. This shows that genes consistently expressed in anterior brain patterning in hemichordates and chordates are expressed in a similar spatial pattern in another deuterostome, an asteroid echinoderm (sea star), but in a completely different developmental context (the animal-vegetal axis). This observation has implications for hypotheses on the type of development present in the deuterostome common ancestor

HPV type-specific prevalence using a urine assay in unvaccinated male and female 11- to 18-year olds in Scotland

We conducted a baseline prevalence survey of unvaccinated 11- to 18-year olds to inform effectiveness studies for the new human papillomavirus (HPV) immunisation programme in Scotland

Psychological principles of successful aging technologies: A mini-review

Based on resource-oriented conceptions of successful life-span development, we propose three principles for evaluating assistive technology: (a) net resource release; (b) person specificity, and (c) proximal versus distal frames of evaluation. We discuss how these general principles can aid the design and evaluation of assistive technology in adulthood and old age, and propose two technological strategies, one targeting sensorimotor and the other cognitive functioning. The sensorimotor strategy aims at releasing cognitive resources such as attention and working memory by reducing the cognitive demands of sensory or sensorimotor aspects of performance. The cognitive strategy attempts to provide adaptive and individualized cuing structures orienting the individual in time and space by providing prompts that connect properties of the environment to the individual's action goals. We argue that intelligent assistive technology continuously adjusts the balance between `environmental support' and `self-initiated processing' in person-specific and aging-sensitive ways, leading to enhanced allocation of cognitive resources. Furthermore, intelligent assistive technology may foster the generation of formerly latent cognitive resources by activating developmental reserves (plasticity). We conclude that `lifespan technology', if co-constructed by behavioral scientists, engineers, and aging individuals, offers great promise for improving both the transition from middle adulthood to old age and the degree of autonomy in old age in present and future generations. Copyright (C) 2008 S. Karger AG, Basel