Expression of human cathepsin L or human cathepsin V in mouse thymus mediates positive selection of T helper cells in cathepsin L knock-out mice

A genetic deficiency of the cysteine protease cathepsin L (Ctsl) in mice results in impaired positive selection of conventional CD4+ T helper cells as a result of an incomplete processing of the MHC class II associated invariant chain or incomplete proteolytic generation of positively selecting peptide ligands. The human genome encodes, in contrast to the mouse genome, for two cathepsin L proteases, namely cathepsin L (CTSL) and cathepsin V (CTSV; alternatively cathepsin L2). In the human thymic cortex, CTSV is the predominately expressed protease as compared to CTSL or other cysteine cathepsins. In order to analyze the functions of CTSL and CTSV in the positive selection of CD4+ T cells we employed Ctsl knock-out mice crossed either with transgenic mice expressing CTSL under the control of its genuine human promoter or with transgenic mice expressing CTSV under the control of the keratin 14 (K14) promoter, which drives expression to the cortical epithelium. Both human proteases are expressed in the thymus of the transgenic mice, and independent expression of both CTSL and CTSV rescues the reduced frequency of CD4+ T cells in Ctsl-deficient mice. Moreover, the expression of the human cathepsins does not change the number of CD4+CD25+Foxp3+ regulatory T cells, but the normalization of the frequency of conventional CD4+ T cell in the transgenic mice results in a rebalancing of conventional T cells and regulatory T cells. We conclude that the functional differences of CTSL and CTSV in vivo are not mainly determined by their inherent biochemical properties, but rather by their tissue specific expression pattern.

Treatment of hemispatial neglect by means of rTMS--a review

Hemispatial neglect - defined as the failure to attend, explore, and act upon the contralesional side of space - is a frequent and disabling neurological syndrome. Interhemispheric rivalry is considered as a major pathophysiological mechanism underlying hemispatial neglect. According to this account, the contralesional, intact hemisphere undergoes a pathological hyperactivity due to a deficient transcallosal inhibition from the damaged hemisphere. This model offers a framework for possible therapeutic interventions with repetitive transcranial magnetic stimulation (rTMS), i.e. a reduction of the pathological hyperactivity with a rTMS protocol that has lasting inhibitory effects. In the present work, we will first review evidence for the interhemispheric rivalry account coming from animals and humans. We will then describe studies showing the possibility to perturb and to restore interhemispheric balance in healthy subjects as a proof of concept for therapeutic rTMS application. Finally, we will consider studies applying rTMS as a therapeutic approach in hemispatial neglect. We conclude that rTMS is a promising approach to reduce the interhemispheric imbalance in neglect patients and to ameliorate symptoms. Newly developed protocols such as Theta Burst Stimulation (TBS) - with short stimulation times and long offline effects - seem to be particularly convenient. However, future studies should assess stimulation effects not only in clinical testing, but also on disability, considering combination with traditional therapies as well.

Comparison of periapical radiography and limited cone-beam computed tomography in mandibular molars for analysis of anatomical landmarks before apical surgery

The purpose of the present study was to evaluate the detectability and dimensions of periapical lesions, the relationship of the mandibular canal to the roots of the respective teeth, and the dimension of the buccal bone by using limited cone-beam computed tomography (CBCT) in comparison to conventional periapical (PA) radiographs for evaluation of mandibular molars before apical surgery.

Activation of the unfolded protein response in human acute myeloid leukemia

There is accumulating evidence for the involvement of the unfolded protein response (UPR) in the pathogenesis of many tumor types in humans. This is particularly the case in rapidly growing solid tumors in which the demand for oxygen and nutrients can exceed the supply until new tumor-initiated blood vessels are formed. In contrast, the role of the UPR during leukemogenesis remains largely unknown. Acute myeloid leukemia (AML) is a genetically heterogeneous clonal disorder characterized by the accumulation of somatic mutations in hematopoietic progenitor cells that alter the physiological regulation of self-renewal, survival, proliferation, or differentiation. The CCAAT/enhancer-binding protein alpha (CEBPA) gene is a key myeloid transcription factor and a frequent target for disruption in AML. In particular, translation of CEBPA mRNA can be specifically blocked by binding of the chaperone calreticulin (CALR), a well-established effector of the UPR, to a stem loop structure within the 5' region of the CEBPA mRNA. The relevance of this mechanism was first elucidated in certain AML subtypes carrying the gene rearrangements t(3;21) or inv(16). In our recent work, we could demonstrate the induction of key effectors of the UPR in leukemic cells of AML patients comprising all subtypes (according to the French-American-British (FAB) classification for human AML). The formation of the spliced variant of the X-box binding protein (XBP1s) was detectable in 17.4% (17 of 105) of AML patients. Consistent with an activated UPR, this group had significantly increased expression of the UPR target genes CALR, the 78 kDa glucose-regulated protein (GRP78), and the CCAAT/enhancer-binding protein homologous protein (CHOP). Consistently, in vitro studies confirmed that calreticulin expression was upregulated via activation of the ATF6 pathway in myeloid leukemic cells. As a consequence, CEBPA protein expression was inhibited in vitro as well as in leukemic cells from patients with activated UPR. We therefore propose a model of the UPR being involved in leukemogenesis through induction of calreticulin along the ATF6 pathway, thereby ultimately suppressing CEBPA translation and contributing to the block in myeloid differentiation and cell-cycle deregulation which represent key features of the leukemic phenotype. From a more clinical point of view, the presence of activated UPR in AML patient samples was found to be associated with a favorable disease course.

Overview of literature and information on "khat-related" mortality: a call for recognition of the issue and further research

During the past 20 years or so, more has become known about the properties of khat, its pharmacology, physiological and psychological effects on humans. However, at the same time its reputation of social and recreational use in traditional contexts has hindered the dissemination of knowledge about its detrimental effects in terms of mortality. This paper focuses on this particular deficit and adds to the knowledge-base by reviewing the scant literature that does exist on mortality associated with the trade and use of khat. We sought all peer-reviewed papers relating to deaths associated with khat. From an initial list of 111, we identified 15 items meeting our selection criteria. Examination of these revealed 61 further relevant items. These were supplemented with published reports, newspaper and other media reports. A conceptual framework was then developed for classifying mortality associated with each stage of the plant's journey from its cultivation, transportation, consumption, to its effects on the human body. The model is demonstrated with concrete examples drawn from the above sources. These highlight a number of issues for which more substantive statistical data are needed, including population-based studies of the physiological and psychological determinants of khat-related fatalities. Khat-consuming communities, and health professionals charged with their care should be more aware of the physiological and psychological effects of khat, together with the risks for morbidity and mortality associated with its use. There is also a need for information to be collected at international and national levels on other causes of death associated with khat cultivation, transportation, and trade. Both these dimensions need to be understood.