A novel tissue inhibitor of metalloproteinases-3 mutation reveals a common molecular phenotype in sorsby's fundus dystrophy

Sorsby’s fundus dystrophy (SFD) is a dominantly inherited degenerative disease of the retina that leads to loss of vision in middle age. It has been shown to be caused by mutations in the gene for tissue inhibitor of metalloproteinases-3 (TIMP-3). Five different mutations have previously been identified, all introducing an extra cysteine residue into exon 5 (which forms part of the C-terminal domain) of the TIMP-3 molecule; however, the significance of these mutations to the disease phenotype was unknown. In this report, we describe the expression of several of these mutated genes, together with a previously unreported novel TIMP-3 mutation from a family with SFD that results in truncation of most of the C-terminal domain of the molecule. Despite these differences, all of these molecules are expressed and exhibit characteristics of the normal protein, including inhibition of metalloproteinases and binding to the extracellular matrix. However, unlike wild-type TIMP-3, they all form dimers. These observations, together with the recent finding that expression of TIMP-3 is increased, rather than decreased, in eyes from patients with SFD, provides compelling evidence that dimerized TIMP-3 plays an active role in the disease process by accumulating in the eye. Increased expression of TIMP-3 is also observed in other degenerative retinal diseases, including the more severe forms of agerelated macular degeneration, the most common cause of blindness in the elderly in developed countries. We hypothesize that overexpression of TIMP-3 may prove to be a critical step in the progression of a variety of degenerative retinopathies

Clinical features of a novel TIMP-3 mutation causing Sorsby's fundus dystrophy: implications for disease mechanism

AIMS: To describe the phenotype in three family members affected by a novel mutation in the gene coding for the enzyme tissue inhibitor of metalloproteinase-3 (TIMP-3). METHODS: Three members of the same family were seen with a history of nyctalopia and visual loss due to maculopathy. Clinical features were consistent with Sorsby's fundus dystrophy. Exon 5 of the gene coding for TIMP-3 was amplified by the polymerase chain reaction, single strand conformation polymorphism analysis undertaken and exon 5 amplicons were directly sequenced. RESULTS: Onset of symptoms was in the third to fourth decade. Five of six eyes had geographic macular atrophy rather than neovascularisation as a cause for central visual loss. Peripheral retinal pigmentary disturbances were present. Scotopic ERGs were abnormal in all three. Mutation analysis showed a GT transversion in all three resulting in a premature termination codon, E139X, deleting most of the carboxy terminal domain of TIMP-3. CONCLUSIONS: The patients described had a form of Sorsby's fundus dystrophy which fell at the severe end of the spectrum of this disease. Postulated disease mechanisms include deposition of dimerised TIMP-3 protein

X-ray diffraction from shock-loaded polycrystals

X-ray diffraction was demonstrated from shock-compressed polycrystalline metal on nanosecond time scales. Laser ablation was used to induce shock waves in polycrystalline foils of Be, 25 to 125 microns thick. A second laser pulse was used to generate a plasma x-ray source by irradiation of a Ti foil. The x-ray source was collimated to produce a beam of controllable diameter, and the beam was directed at the Be sample. X-rays were diffracted from the sample, and detected using films and x-ray streak cameras. The diffraction angle was observed to change with shock pressure. The diffraction angles were consistent with the uniaxial (elastic) and isotropic (plastic) compressions expected for the loading conditions used. Polycrystalline diffraction will be used to measure the response of the crystal lattice to high shock pressures and through phase changes

Threshold concepts: Impacts on teaching and learning at tertiary level

This project explored teaching and learning of hard-to-learn threshold concepts in first-year English, an electrical engineering course, leadership courses, and in doctoral writing. The project was envisioned to produce disciplinary case studies that lecturers could use to reflect on and refine their curriculum and pedagogy, thereby contributing to discussion about the relationship between theory and methodology in higher education research (Shay, Ashwin, & Case, 2009). A team of seven academics investigated lecturers’ awareness and emergent knowledge of threshold concepts and associated pedagogies and how such pedagogies can afford opportunities for learning. As part of this examination the lecturers also explored the role of threshold concept theory in designing curricula and sought to find the commonalities in threshold concepts and their teaching and learning across the four disciplines. The research highlights new ways of teaching threshold concepts to help students learn concepts that are fundamental to the disciplines they are studying and expand their educational experiences. Given that much of the international research in this field focuses on the identification of threshold concepts and debates their characteristics (Barradell, 2013; Flanagan, 2014; Knight, Callaghan, Baldock, & Meyer, 2013), our exploration of what happens when lecturers use threshold concept theory to re-envision their curriculum and teaching helps to address a gap within the field. By addressing an important theoretical and practical approach the project makes a considerable contribution to teaching and learning at the tertiary level in general and to each discipline in particular

Developmental hematology of SS and SC disease in association with α-thalassemia-2

The nuber and organization of the α, ζ and γ globin genes have been determined on the DNA of 400 patients attending the Pediatric Sickle Cell Clinics of our Center. The patients were participating in long-term prospective studies on possible effects of α-thal on the hecatological changes accompanying postnatal development. CBC and Hb composition were obtained in the steady state on patients of different ages and correlated with the number of α globin genes.peer-reviewe

Evaluating Accomplished Teaching: Report of a Pilot Study into Means of Investigating the Impact of Accomplished Teaching on Pupils’ Learning in the Context of the Chartered Teacher Initiative in Scotland

No abstract available

Identifying experiences of supportive care of children and young people affected by kidney failure: a qualitative systematic review.

Children and young people affected by kidney failure experience complexities in their care. Little is known about the unique needs of this young patient population group living with a long-term condition. A meta-aggregation of all qualitative studies was conducted to identify experiences of supportive care among children and young people living with kidney failure. A systematic review of qualitative studies was conducted following the Joanna Briggs Institute meta-aggregation method. This review has been reported according to the PRISMA statement guidelines. Six electronic databases (CINAHL, Cochrane Library, MEDLINE, Proquest, PsycINFO, and Scopus) were comprehensively searched by an expert systematic review librarian using keywords and subject headings, from inception to September 2022. All studies were accessed using a predetermined inclusion and exclusion criteria. Methodological quality assessment and data extraction performed. Qualitative findings accompanied by illustrative quotes from included studies were extracted and grouped into categories which created the overall synthesised findings. A total of 34 studies were included in this review representing a total of 613 children and young people affected by kidney failure. There was a total of 190 findings which created 13 categories representing experiences of supportive care. The meta-aggregation developed five synthesised findings namely: 'physical needs', 'information and technology', 'treatment and healthcare', 'social needs' and 'psychological impacts'. This systematic review identified that children and young people affected by kidney failure can experience a range of unmet supportive care needs in routine clinical services. Kidney failure impacted children and young people's self-identify, social and peer networks, introduced daily practical needs because of inherent physical and psychological burden due to the failure and associated treatments. Despite improvements in the medical management of kidney failure in children and young people, further attention is needed to optimise supported self-management in this young patient group

A Human Atrial Natriuretic Peptide Gene Mutation Reveals a Novel Peptide With Enhanced Blood Pressure-Lowering, Renal-Enhancing, and Aldosterone-Suppressing Actions

ObjectivesWe sought to determine the physiologic actions and potential therapeutic applications of mutant atrial natriuretic peptide (mANP).BackgroundThe cardiac hormone atrial natriuretic peptide (ANP) is a 28-amino acid (AA) peptide that consists of a 17-AA ring structure together with a 6-AA N-terminus and a 5-AA C-terminus. In a targeted scan for sequence variants within the human ANP gene, a mutation was identified that results in a 40-AA peptide consisting of native ANP(1-28)and a C-terminal extension of 12 AA. We have termed this peptide mutant ANP.MethodsIn vitro 3′,5′-cyclic guanosine monophosphate (cGMP) activation in response to mANP was studied in cultured human cardiac fibroblasts known to express natriuretic peptide receptor A. The cardiorenal and neurohumoral properties of mANP compared with ANP were assessed in vivo in normal dogs.ResultsWe observed an incremental in vitro cGMP dose response with increasing concentrations of mANP. In vivo with high-dose mANP (33 pmol/kg/min), we observed significantly greater plasma cGMP activation, diuretic, natriuretic, glomerular filtration rate enhancing, renin-angiotensin-aldosterone system inhibiting, cardiac unloading, and blood pressure lowering properties when compared with native ANP. Low-dose mANP (2 pmol/kg/min) has natriuretic and diuretic properties without altering systemic hemodynamics compared with no natriuretic or diuretic response with low-dose native ANP.ConclusionsThese studies establish that mANP activates cGMP in vitro and exerts greater and more sustained natriuretic, diuretic, glomerular filtration rate, and renal blood flow enhancing actions than native ANP in vivo

Lipid Thermotropic Transitions in Human Stratum Corneum

The techniques of differential scanning calorimetry (DSC) and thermal perturbation infrared (IR) spectrometry were used to investigate thermal transitions in intact, fractionated, and lipid-extracted human stratum corneum. The DSC results show 3 major and one minor thermal transition in the range of 30-120°C. Of particular interest to this study are 2 transitions seen near 65° and 75°C in intact stratum corneum and a stratum corneum membrane preparation, but absent from lipid-extracted samples. Results of IR spectrometry show that thermally induced spectral changes related to enhanced motion of the lipid acyl chains also occur in the region of about 60-80°C. The combined DSC and IR results show that the thermal transitions near 65° and 75°C depend on water concentration in a manner identical to that seen for a variety of lipid-water systems. Taken together, these results suggest that thermal transitions occurring near 65° and 85°C involve increased acyl chain motion of stratum corneum lipids