Similar sensitivity of regulatory T cells towards CD95L-mediated apoptosis in patients with multiple sclerosis and healthy individuals

Impaired suppressive function of CD4(+)CD25(high) regulatory T cells (T(reg)) has been reported as a novel pathogenetic mechanism in Multiple sclerosis (MS). We addressed if high apoptosis sensitivity of MS-T(reg) could explain this functional T(reg) defect. T(reg) from treatment-na?ve MS patients showed high sensitivity towards CD95Ligand-mediated apoptosis and exhibited enhanced cell death to IL-2 and TCR-signal deprivation. Since susceptibility of T(reg) to cell death was similar in MS patients and healthy controls, this cannot explain the inhibitory dysfunction of T(reg) associated with MS. Furthermore, as cell death is not enhanced, therapeutic expansion of MS-T(reg)in vitro should be a reasonable and novel therapeutic option.     

Evaluation of body position in upper airway stimulation for obstructive sleep apnea—is continuous voltage sufficient enough?

Purpose

The definition of positional obstructive sleep apnea (POSA) is widely accepted as a difference of 50% or more in AHI between supine and non-supine position. Upper airway stimulation (UAS) is an effective treatment for OSA but the implant delivers a single voltage over sleep period without consideration of body position. Clinical practice suggests different outcomes for OSA in supine position under UAS treatment.

Methods

Outcomes of 44 patients were analyzed 12 months after implantation in a two-center, prospective consecutive trial in a university hospital setting. Total night and supine AHI were evaluated and the ratio of time spent in supine was considered. Correlation between the classic and the modified definition of POSA and treatment response were evaluated.

Results

The time ratio spent in supine position did not differ before implantation and after 12 months. Total and supine AHI were reduced with the use of UAS therapy (p?<?0.001) but both the baseline and final supine AHI were higher than total night AHI. Considering POSA definition as a ratio of supine to non-supine AHI, there was no clear cutoff for defining responders neither with nor without the additional component of time in supine position.

Conclusions

The OSA reduction is strong for the total AHI and supine AHI. Nonetheless, here, there is no cutoff for defining POSA as critical for UAS therapy response. Therefore, there is no evidence for excluding POSA patients from UAS in general. Future technology improvement should take body position and adaptive voltage into account.

     

Spatial packing, cranial base angulation, and craniofacial shape variation in the mammalian skull: testing a new model using mice

The hypothesis that variation in craniofacial shape within and among species is influenced by spatial packing has a long history in comparative anatomy, particularly in terms of primates. This study develops and tests three alternative models of spatial packing to address how and to what extent the cranial base angle is influenced by variation in brain and facial size. The models are tested using mouse strains with different mutations affecting craniofacial growth. Although mice have distinctive crania with small brains, long faces, and retroflexed cranial bases, the results of the study indicate that the mouse cranial base flexes to accommodate larger brain size relative to cranial base length. In addition, the mouse cranial base also extends, but to a lesser degree, to accommodate larger face size relative to cranial base length. In addition, interactions between brain size, face size, and the widths and lengths of the components of the cranial base account for a large percentage of variation in cranial base angle. The results illustrate the degree to which the cranial base is centrally embedded within the covariation structure of the craniofacial complex as a whole.     

Clinicopathological analysis of the homozygous p.W1327X AGL mutation in glycogen storage disease type 3

We report on clinicopathological and whole body MRI analyses of the index patient of a large nonconsanguineous German-Ukraine family with homozygous and heterozygous AGL gene mutations at position p.W1327X (c.3980G > A). There are only limited reports on this phenotype with a homozygous genotype. The index patient, a 49-year-old woman presented with hepatomegaly, cardiomyopathy and moderate progressive proximal limb myopathy. Skeletal muscle showed severe vacuolar myopathy with storage of PAS-positive non-membrane-limited glycogen. An increase in glycogen content and completely decrease of debranching enzyme activity was measured in erythrocytes. Mutational analysis of the AGL gene showed a homozygous p.W1327X mutation. In the family, two brothers had been affected by severe infantile onset hepatomegaly and died within their first years of life by fatal liver cirrhosis. Furthermore, another sister severely affected by hepatomegaly, cardiomyopathy and proximal skeletal myopathy died at age 33. Three younger heterozygous sisters and a brother noticed exercise-induced myalgia and weakness since their teens. In sum, a homozygous p.W1327X mutation leads to a severe generalized glycogenosis types 3a and 3b within the same family. Even heterozygous p.W1327X mutation carriers may present with mild non-progressive neuromuscular symptoms, such as exercise-induced myalgia and fatigue.     

Oncogene complementation in fetal brain transplants.

Using a neural transplantation model and retrovirus-mediated gene transfer, we have introduced the oncogenes v-Ha-ras and v-myc into the developing rat brain. Upon insertion of a construct encoding v-Ha-ras and the Escherichia coli beta-galactosidase marker gene, the retroviral vector was found to be expressed in neurons, astrocytes, and endothelial cells of the graft. After latency periods of several months, fascicular neoplasms with expression of S-100 protein were observed in 50% of the transplants. The foreign genes were shown to be highly expressed in the tumors and in intact donor cells, by 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside histochemistry, indicating that an activated Ha-ras oncogene has the potential to initiate neoplastic transformation of glial cells. Introduction of the v-myc oncogene into 15 grafts resulted in only a single primitive neuroectodermal tumor. However, simultaneous expression of the v-Ha-ras and v-myc genes yielded highly malignant, polyclonal neoplasms in all recipient animals, as early as 13 days after transplantation, from which cell lines could be easily derived. In addition, neoplastic transformation was also observed in vitro following introduction of ras and myc into embryonic forebrain cultures and into newborn cerebellar cultures. These data indicate a powerful complementary transforming effect of ras and myc on neural progenitors in vivo and in vitro. Coexpression of ras and myc may, therefore, provide a highly efficient tool for transforming neural precursor cells in distinct segments of the central nervous system at different stages of development.     

HIV Encephalopathy: Incidence, Definition and Pathogenesis

The incidence of HIV encephalopathies was determined in an ongoing consecutive autopsy study. Among 345 patients who died from AIDS in Switzerland during 1981–1990, 68 (19%) showed morphological evidence of HIV encephalopathy. Two major histopathological manifestations were observed. Progressive diffuse leukoencephalo-pathy (PDL) was present in 33 cases and is characterized by a diffuse loss of myelin staining in the deep white matter of the cerebral and cerebellar hemispheres, with scattered multinucleated giant cells but little or no inflammatory reaction. Multinucleated giant cell encephalitis (MGCE) was diagnosed in 32 cases; it's hallmarks are accumulations of multinucleated giant cells with prominent inflammatory reaction and focal necroses. In 3 patients both types of lesions overlapped. Brain tissue from 27 patients was analyzed for the presence of HIV gag sequences using the polymerase chain reaction (PCR) with primers encoding a 109 base pair segment of the viral gene. Amplification succeeded in all patients with clinical and histopathological evidence for HIV encephalopathy but was absent in AIDS patients with opportunistic bacterial, parasitic and/or viral infections. Potential mechanisms by which HIV exerts it's adverse effects on the human CNS are discussed.