Hematopoietic stem cell gene therapy for IFNγR1 deficiency protects mice from mycobacterial infections.

Mendelian susceptibility to mycobacterial disease is a rare primary immunodeficiency characterized by severe infections caused by weakly virulent mycobacteria. Biallelic null mutations in genes encoding interferon gamma receptor 1 or 2 (IFNGR1 or IFNGR2) result in a life-threatening disease phenotype in early childhood. Recombinant interferon γ (IFN-γ) therapy is inefficient, and hematopoietic stem cell transplantation has a poor prognosis. Thus, we developed a hematopoietic stem cell (HSC) gene therapy approach using lentiviral vectors that express Ifnγr1 either constitutively or myeloid specifically. Transduction of mouse Ifnγr1-/- HSCs led to stable IFNγR1 expression on macrophages, which rescued their cellular responses to IFN-γ. As a consequence, genetically corrected HSC-derived macrophages were able to suppress T-cell activation and showed restored antimycobacterial activity against Mycobacterium avium and Mycobacterium bovis Bacille Calmette-Guérin (BCG) in vitro. Transplantation of genetically corrected HSCs into Ifnγr1-/- mice before BCG infection prevented manifestations of severe BCG disease and maintained lung and spleen organ integrity, which was accompanied by a reduced mycobacterial burden in lung and spleen and a prolonged overall survival in animals that received a transplant. In summary, we demonstrate an HSC-based gene therapy approach for IFNγR1 deficiency, which protects mice from severe mycobacterial infections, thereby laying the foundation for a new therapeutic intervention in corresponding human patients.

Quantification of stato-kinetic dissociation by semi-automated perimetry.

The difference in threshold sensitivities that are found when examining the visual field (VF) with static versus kinetic perimetric methods is called stato-kinetic dissociation (SKD). In this pilot study, we describe a semi-automated procedure for quantifying SKD. Fifteen patients with VF defects were examined with kinetic and static perimetry. SKD values were defined as positive when the static scotoma was larger than the kinetic one. We found significant local variations of SKD along scotoma borders with the individual reaction time as an important criterion when determining kinetic thresholds. There was a verifiable SKD in all patients with locally negative values in eight subjects.

Distribution of scotoma pattern related to chiasmal lesions with special reference to anterior junction syndrome.

PURPOSE: To evaluate pathogenetic mechanisms and frequency distribution of visual field defects (VFDs) in patients with chiasmal lesions. Secondly, to reconsider the existence of "Wilbrand's knee" as far as referable to the anterior junction syndrome. METHODS: Consecutive visual field records related to chiasmal lesions were retrieved from the Tuebingen Perimetric Database. In all cases, at least one eye was examined with the Tuebingen Automated Perimeter using a standardized grid of 191 static targets within the central 30 degrees visual field, and a threshold-related, slightly supraliminal strategy. VFDs were classified according to standard neuro-ophthalmological categories. RESULTS: Results from 153 consecutive patients (65 male, 88 female) were evaluable. The majority (65%) of chiasmal lesions was due to pituitary adenoma, followed by craniopharyngioma (12%), astrocytoma (9%), and meningioma (8%). Vascular lesions in this region occurred rarely (2%). Three per cent of all patients had no final diagnosis. The majority (22%) of scotomas was attributable to involvement of the temporal hemifield in both eyes, with true bitemporal hemianopia being a very rare event (1%). Anterior junction syndrome, characterized by advanced visual field loss affecting the visual field centre in one eye and (possibly subtle) defects respecting the vertical midline in the fellow eye, was the second most frequent classifiable VFD (13%). Homonymous hemianopic VFDs occurred in 11% of all cases. Nine per cent of all patients exhibited monocular VFDs which did not respect the vertical midline, whereas in 3% of the subjects the monocular VFDs did not cross the vertical meridian. Binasal defects and posterior junction syndrome also occurred seldom (< 1%). Nineteen per cent of all visual field records of patients with chiasmal lesions had results, which could not be classified unequivocally, and an identical portion was rated normal. CONCLUSION: In patients with chiasmal lesions, incomplete involvement of the temporal hemifields in both eyes was the most frequent event (22%), followed by anterior junction syndrome (13%). The latter entity at least clinically indicates the proximity of the pre-chiasmal ipsilateral optic nerve and decussating fibres emanating from the inferior nasal hemiretina of the fellow eye. However, this cannot provide conclusive evidence for the existence of anterior Wilbrand's knee.

[Tuebingen Education System (TES)--An interactive case demonstration software]. / Tuebingen Education System (TES) - eine interaktive Falldemonstrationssoftware.

BACKGROUND: Presentations based on slides, videos and/or computer presentations are usually sequentially structured, resulting in an inflexible order of the demonstrated information and examination results. However, in (medical) education such a system only inadequately reflects the real physician-patient situation. MATERIALS AND METHODS: The software solution presented here is based on the widespread computer programme Microsoft PowerPoint(R) (PPT) which offers an opportunity to present information via text boxes, figures, illustrations, video sequences and/or audio files in an user-friendly way. However, PPT's capabilities of simulating realistic decision processes (e. g. by "interactive keys" and "hyperlinks") are still restricted as far as adapting the order of the information/slides to the individual demand is concerned. The Tuebingen Education System (TES) uses an additional user interface based on Visual Basic. By means of this, every examination result or information can be chosen via five additional pull-up menus in an arbitrary order. Furthermore, the pathway - i. e. the examinations used to arrive at a diagnosis - as well as the costs incurred are documented in parallel and are finally compared to the costs incurred using an optimum pathway. RESULTS: TES has been used routinely in the education of the students and residents of the University Eye Hospital Tuebingen for three (half-)terms. Meanwhile, an adapted version of TES is used to educate students in the department of paediatric surgery. TES was judged in extensive evaluations of both subjects very positively. CONCLUSIONS: TES is an easy to use tool suitable for lecturers and students, a further step towards realistic, practice-oriented and interactive education.