Upregulation of adenosine A2A receptor and downregulation of GLT1 is associated with neuronal cell death in Rasmussen's encephalitis

Rasmussen encephalitis (RE) is a severe pediatric inflammatory brain disease characterized by unilateral inflammation and atrophy of the cerebral cortex, drug‐resistant focal epilepsy and progressive neurological and cognitive deterioration. The etiology and pathogenesis of RE remain unclear. Our previous results demonstrated that the adenosine A1 receptor (A1R) and the major adenosine‐removing enzyme adenosine kinase play an important role in the etiology of RE. Because the downstream pathways of inhibitory A1R signaling are modulated by stimulatory A2AR signaling, which by itself controls neuro‐inflammation, glial activation and glial glutamate homeostasis through interaction with glutamate transporter GLT‐1, we hypothesized that maladaptive changes in adenosine A2A receptor (A2AR) expression are associated with RE. We used immunohistochemistry and Western blot analysis to examine the expression of A2ARs, glutamate transporter‐I (GLT‐1) and the apoptotic marker Bcl‐2 in surgically resected cortical specimens from RE patients (n = 18) in comparison with control cortical tissue. In lesions of the RE specimen we found upregulation of A2ARs, downregulation of GLT‐1 and increased apoptosis of both neurons and astroglia. Double staining revealed colocalization of A2ARs and Bcl‐2 in RE lesions. These results suggest that maladaptive changes in A2AR expression are associated with a decrease in GLT‐I expression as a possible precipitator for apoptotic cell loss in RE. Because A2AR antagonists are already under clinical evaluation for Parkinson's disease, the A2AR might likewise be a tractable target for the treatment of RE.     

Detection of possible spillover of a novel hantavirus in a Natal mastomys from Guinea

Virus Genes - To date, only two rodent-borne hantaviruses have been detected in sub-Saharan Africa. Here, we report the detection of a yet unknown hantavirus in a Natal mastomys (Mastomys...     

Position of polyaxial versus monoaxial screws in locked plating for proximal humeral fractures: analysis of a prospective randomized study

Background

Aim of the study was to compare the chosen position of polyaxial locking screws with the position of monoaxial screws in the humeral head of proximal humeral fractures treated by locked plating.

Methods

In a prospective randomized observational study, 124 consecutive patients (mean age 70.9 ± 14.8 years) sustaining a displaced proximal humeral fracture were treated with either monoaxial or polyaxial screw-inserted locking plate fixation. The chosen positions of locking screws were identified from standardized postoperative radiographs in anteroposterior and outlet-view, with regard to a regional mapping of the humeral head.

Results

In monoaxial locking technique, a mean of 6 screws purchased the humeral head (95 % CI 5.1–6.2), and in polyaxial locking technique, a mean of 4 screws (95 % CI 3.3–4.5), respectively. Screws were placed in the regions superolateral: monoaxial 24.8 %, polyaxial 20.7 % (p = 0.49); superomedial: monoaxial 21.9 %, polyaxial 20.0 % (p = 0.433); inferolateral: monoaxial 32.5 %, polyaxial 35.0 % (p = 0.354); inferomedial: monoaxial 20.8 %, polyaxial 24.2 % (p = 0.07), superoposterior: monoaxial 45.5 %, polyaxial 30.8 % (p = 0.57); superoanterior: monoaxial 4.4 %, polyaxial 8.3 % (p = 0.33); inferoposterior: monoaxial 22.5 %, polyaxial 29.8 % (p = 0.49) and inferoanterior: monoaxial 27.5 %, polyaxial: 31.2 % (p = 0.09).

Conclusion

The chosen screws’ position in monoaxial and polyaxial locking plate fixation of displaced proximal humeral fractures do not differ significantly. However, loss of fixation is observed more frequently if the fixation did not include at least one screw within the superoposterior region of the humeral head, suggesting that a screw purchasing the superoposterior region is beneficial in locked plating of proximal humeral fractures.

Level of evidence

Treatment Study, Level II.     

Regulation of cognition and symptoms of psychosis: focus on GABA(A) receptors and glycine transporter 1

Adaptive purposeful behaviour depends on appropriate modifications of synaptic connectivity that incorporate an organism's past experience. At least some forms of such synaptic plasticity are believed to be mediated by NMDA receptors (NMDARs). Complementary interaction with inhibitory neurotransmission mediated by GABA(A) receptors, and upstream control of the excitability of NMDARs by glycine availability can greatly influence the efficacy of NMDAR mediated neuroplasticity, and thereby exert significant effects on cognition. Memory, selective attention or sensorimotor gating functions can be modified in mice with a reduction of alpha(5)GABA(A) receptors in the hippocampus or a selective deletion of glycine transporter 1 (GlyT1) in the forebrain. Both genetic manipulations altered the formation or persistence of associative links leading to distinct phenotypes on trace conditioning, extinction learning, latent inhibition, working memory, and object recognition. Behavioural assays of latent inhibition, prepulse inhibition, working memory, and sensitivity to psychostimulants in particular suggest that alpha(3) and alpha(5) subunit-containing GABA(A) receptors as well as GlyT1 are potential sites for ameliorating psychotic-like behaviour. Taken together, these results qualify distinct GABA-A receptor subtypes and GlyT1 as molecular targets for the development of a new pharmacology in the treatment of cognitive decline and psychotic symptoms.     

Prevention of cardiac remodeling after myocardial infarction in transgenic rats deficient in brain angiotensinogen

The brain renin-angiotensin-aldosterone system (RAAS) plays a major role in cardiac remodeling after myocardial infarction (MI). To assess the contribution of the brain RAAS in the activation of the cardiac RAAS post-MI, transgenic (TG) rats deficient in brain angiotensinogen and Wistar rats with intracerebroventricular (ICV) infusion of spironolactone were studied. An MI was induced by acute coronary artery ligation. TG and control Sprague-Dawley (SD) rats were followed for 8 weeks and Wistar rats for 6 weeks. Infarct sizes, % of left ventricle (LV) area, were in the 30-33% range. In SD rats at 8 weeks post-MI, internal circumference, interstitial and perivascular fibrosis, cardiomyocyte diameter in the LV and right ventricle (RV), laminin and fibronectin in the LV, and lung weights were increased. Aldosterone was increased markedly in both the LV and RV at 8 weeks post-MI. In TG rats, the MI-induced increases of RV internal circumference and weight were prevented and increases of lung weight and LV internal circumference were significantly inhibited. In TG rats, the post-MI increases of interstitial fibrosis and cardiomyocyte diameter were prevented in septum and RV and significantly inhibited in the peri-infarct zone of the LV. The increases in perivascular fibrosis, laminin and fibronectin were prevented in the LV. In TG rats, cardiac aldosterone did not increase. In Wistar rats at 6 weeks post-MI, aldosterone was markedly increased in the LV, but not in the RV. This increase was prevented by ICV infusion of spironolactone. These findings support the pivotal role of locally produced angiotensin II in the brain in cardiac remodeling post-MI. The brain RAAS appears to activate a cascade of events, among others an increase in cardiac aldosterone, which play a major role in cardiac remodeling post-MI.     

Conserved synteny in rat and mouse for a blood pressure QTL on human chromosome 17

Evidence for blood pressure quantitative trait loci (QTLs) on rat chromosome 10 has been found in multiple independent studies. Analysis of the homologous region on human chromosome 17 revealed significant linkage to blood pressure. The critical segment on human chromosome 17 spans a large interval containing the genes Itga2b, Gfap, and Itgb3. Therefore, findings in the rat may help to refine the position of blood pressure-regulating loci, assuming a common molecular cause across species. However, it has recently been suggested that the gene order in human, rat, and mouse is not conserved in this region, leaving uncertainty about the overlap of the blood pressure- regulating region between human chromosome 17 and rat chromosome 10. We have performed a detailed comparative analysis among human, mouse, and rat, defining the segment in question, by obtaining gene structure information in silico and by radiation hybrid mapping. It is of interest that this region also contains Wnk4, a gene previously identified to cause pseudohypoaldosteronism type II and human hypertension. Our results definitively show that the conserved synteny extends among human chromosome 17, rat chromosome 10, and mouse chromosome 11, demonstrating an overlap between previously localized blood pressure QTLs in humans and rats.     

Biotherapy of cancer

Prospects for a new biologically based strategy of cancer treatment are being discussed. While physically and chemically based therapies, such as radio- and chemotherapy, are not directed against cancer tissue only and have a suppressive effect on the immune system, immunotherapy and gene therapy, which are discussed here, try to be more selective and to stimulate rather than suppress antitumor immune mechanisms. On the basis of personal experience with these new technologies, good future prospects are predicted for the application of cancer vaccines and immune T lymphocytes for active specific immunization (ASI) and adoptive immunotherapy (ADI) respectively. While ASI strategies aim at micrometastases being affected by activated host immune T cells, and might find a place for postoperative adjuvant treatment in high-risk cancer patients, cellular therapies such as ADI do not require an intact host immune system and could therefore also find application in advanced stages of disease. In spite of the exciting new perspectives of immuno- and gene therapy for the cancer patient, this therapy is not yet a defined discipline and requires years of further research.Abbreviations ASI active specific immunization - ADI adoptive immunotherapy - TA tumor-associated antigen - APC antigen-presenting cells - CAM cell-adhesion molecule - TNF tumor necrosis factor - TIL tumor-infiltrating lymphocytes - IFN interferon - IL interleukin - GM-CSF granulocyte/macrophage-colony-stimulating factor - NDV Newcastle disease virus - CTL cytotoxic T lymphocytes TheJournal of Cancer Research and Clinical Oncology occasionally publishes Editorials and Guest Editorials on current and controversial problems in experimental and clinical oncology. These papers reflect the personal opinions of the authors. Readers should send any comments directly to the authorsIn honour of Prof. G. Schwenker, Heidelberg, on the occasion of his 70. birthday     

Transdermal fentanyl and initial dose-finding with patient-controlled analgesia in cancer pain. A pilot study with 20 terminally ill cancer patients

This pilot study evaluated the efficacy and side effects of a combination of initial patient-controlled analgesia (PCA) for dose-finding with transdermal fentanyl administration. Twenty inpatients, requiring strong opioids for severe cancer pain, received intravenous fentanyl on an on-demand basis over a 24-h period. The amount of fentanyl administered was then used as a guideline for selecting a suitable transdermal therapeutic system (TTS) on the 2nd day, which remained in place for 3 days. The size of 2nd TTS, being used from day 5 to 7, was adjusted according to the amount of supplementary intravenous fentanyl doses on day 3. From day 4 to 7 intravenous fentanyl was stopped, and subcutaneous morphine was made available as a rescue medication. A standardized adjuvant medication was allowed. Pain intensity, pain relief, quality of sleep, mood, general state of health, activity, mobility, rescue morphine consumption and side effects were assessed using a diary after baseline pain and symptoms were recorded. Vital functions were monitored and fentanyl plasma levels were measured daily in 15 patients.

The use of TTS fentanyl in combination with initial dose titration using PCA gave rapid and statistically significant pain relief. Patient compliance and acceptance were excellent. In the absence of severe side effects the main complaints were dryness of the mouth and constipation.

Increasing pain intensity and increasing supplementary morphine requirements as well as decreasing plasma fentanyl levels on day 7 may indicate that conversion ratios from intravenous to transdermal administration should be increased or that TTS should be changed earlier. Special indications for this combination may be in patients with dysphagia or vomiting, where pain management could be facilitated.     

Multiple juvenile xanthogranulomas successfully treated with CO2 laser

Juvenile xanthogranulomas are a rare disease entity within the spectrum of cutaneous non‐Langerhans cell histiocytoses characterized by single or multiple cutaneous xanthogranulomas without further organ involvement. A 16‐year‐old girl developed multiple xanthogranulomas in various skin regions, especially the trunk and the flexural areas, over a period of 6 months. The clinical diagnosis was confirmed by H&E histology, showing a histiocytic infiltrate admixed with foam cells and Touton giant cells, and by immunohistochemistry using anti‐bodies to stabilin‐1 whose expression is highly specific for cutaneous non‐Langerhans cell histiocytoses. No diabetes insipidus, pituitary hyperplasia or paraproteinemia were observed. Skin lesions were treated with a CO₂ laser and did not reappear during a 5 years follow‐up period.     

Infantile fibrosarcoma with TPM3-NTRK1 fusion in a boy with Bloom syndrome

Familial Cancer - Bloom syndrome (BS) is a genomic and chromosomal instability disorder with prodigious cancer predisposition caused by pathogenic variants in BLM. We report the clinical and...