Atypical organisation of the auditory cortex in dyslexia as revealed by MEG

Neuroanatomical and -radiological studies have converged to suggest an atypical organisation in the temporal bank of the left-hemispheric Sylvian fissure for dyslexia. Against the background of this finding, we applied high temporal resolution magnetoencephalography (MEG) to investigate functional aspects of the left-hemispheric auditory cortex in 11 right-handed dyslexic children (aged 8–13 years) and nine matched normal subjects (aged 8–14 years). Event-related field components during a passive oddball paradigm with pure tones and consonant–vowel syllables were evaluated. The first major peak of the auditory evoked response, the M80, showed identical topographical distributions in both groups. In contrast, the generating brain structures of the later M210 component were located more anterior to the earlier response in children with dyslexia only. Control children exhibited the expected activation of more posterior source locations of the component that appeared later in the processing stream. Since the group difference in the relative location of the M210 source seemed to be independent of stimulus category, it is concluded that dyslexics and normally literate children differ as to the organisation of their left-hemispheric auditory cortex.     

Importance of studying the contributions of early adverse experience to neurobiological findings in depression.

Almost four decades of intensive research have sought to elucidate the neurobiological bases of depression. Epidemiological studies have revealed that both genetic and environmental factors contribute to the risk for depression. Adverse early-life experiences influence neurobiological systems within genetic limits, leading to the neurobiological and behavioral manifestations of depression. We summarize the burgeoning evidence concerning a pre-eminent role of early adverse experience in the pathogenesis of depression. The available data suggest that (1) early adverse experience contributes to the pathophysiology of depression, (2) there are neurobiologically different subtypes of depression depending on the presence or absence of early adverse experience, likely having confounded previous research on the neurobiology of depression, and (3) early adverse experience likely influences treatment response in depression. Classification of depression based on developmental and neurobiological features will likely considerably improve future research in the field of depression, and might lead to optimized treatment strategies that directly target different neurobiological pathways to depression.     

Fulminant Adenoviral-Induced Hepatitis in Immunosuppressed Patients

Human adenovirus (HAdV) can often lead to fulminant hepatitis in immunocompromised patients, mostly after reactivation of HAdV. Different risk factors, e.g., transplantation and chemotherapy, increase the risk of developing a HAdV hepatitis. We retrospectively analyzed three patients who showed the characteristics of a HAdV hepatitis observed in disseminated disease. In addition to PCR, diagnosis could be proven by pathology, CT scan, and markedly elevated transaminases. All patients had a hemato-oncologic underlying disease. Two had received a stem-cell transplant, and one was under chemotherapy including rituximab. Despite therapy with cidofovir, all patients died. As the incidence of HAdV hepatitis is low, diagnosis may be easily overlooked. No treatment approaches have yet been established. HAdV hepatitis should be considered as a differential diagnosis, especially when risk factors are present. To avoid dissemination, treatment should be initiated as soon as possible.     

Non-traumatic lower limb older amputees: a database survey from a geriatric centre

Purpose: The purpose of this survey was to examine the characteristic of a geriatric population admitted for amputation of a lower limb and to explore some of the factors that may affect the course of their hospital stay. Method: The study took place in the geriatric division of a tertiary general hospital and included a close geriatric-orthopaedic liaison. Two-hundred and forty-one patients were included in the final analysis. Results: Many above knee amputations were performed, which correlated with advanced age. Rates of in hospital mortality and systemic complications were 16% and 19%, respectively. Thirty-three percent of the patients were discharged back home, and only 6% were supplied with an artificial limb. The general condition of most patients remained poor. Conclusion: We conclude that despite a team approach to the care of the geriatric amputee a poor functional result was obtained. By encouraging earlier referrals from the community it is postulated that a reduction in the costly provision of antibiotics would be beneficial and that perhaps lower levels of amputation could be performed thereby enhancing the possibilities for ambulation.     

Quantitative proteomics and phosphoproteomics on serial tumor biopsies from a sorafenib-treated HCC patient

Compensatory signaling pathways in tumors confer resistance to targeted therapy, but the pathways and their mechanisms of activation remain largely unknown. We describe a procedure for quantitative proteomics and phosphoproteomics on snap-frozen biopsies of hepatocellular carcinoma (HCC) and matched nontumor liver tissue. We applied this procedure to monitor signaling pathways in serial biopsies taken from an HCC patient before and during treatment with the multikinase inhibitor sorafenib. At diagnosis, the patient had an advanced HCC. At the time of the second biopsy, abdominal imaging revealed progressive disease despite sorafenib treatment. Sorafenib was confirmed to inhibit MAPK signaling in the tumor, as measured by reduced ribosomal protein S6 kinase phosphorylation. Hierarchical clustering and enrichment analysis revealed pathways broadly implicated in tumor progression and resistance, such as epithelial-to-mesenchymal transition and cell adhesion pathways. Thus, we describe a protocol for quantitative analysis of oncogenic pathways in HCC biopsies and obtained first insights into the effect of sorafenib in vivo. This protocol will allow elucidation of mechanisms of resistance and enable precision medicine.Hepatocellular carcinoma (HCC) is a global health concern with an estimated 750,000 new cases per year (1). In more than 80% of cases, HCC arises in a setting of liver cirrhosis mainly of alcoholic or viral origin (2). The prognosis for HCC patients is poor, with less than 30% qualifying for curative treatments such as tumor resection or liver transplantation (2). Median survival time of patients that cannot be treated surgically is less than 1 y. Sorafenib is the only approved targeted therapy for HCC, prolonging median patient survival by ∼3 mo (3). Sorafenib is a multikinase inhibitor of Raf (B and C), vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptor (PDGFR) (4), which presumably inhibits not only tumor cells but also endothelial cells responsible for tumor vascularization.Resistance to a targeted cancer drug can be intrinsic or adaptive (5). Sorafenib is largely cytostatic (6), suggesting that intrinsic resistance is more common in tumors, although some reports describe tumor shrinkage upon sorafenib treatment (7). Studies involving HCC cell lines or immunohistochemical staining of tumor sections revealed that sorafenib resistance correlates with the up-regulation of several signaling pathways, including the mammalian target of rapamycin (mTOR) pathway as assayed by S6 S235/236 (8) and Akt S473 phosphorylation (9). Other potential resistance mechanisms involve epithelial-to-mesenchymal transition (EMT) and autophagy (10, 11). However, the molecular mechanisms of sorafenib resistance in patients are largely unknown. Understanding the pathways that confer intrinsic or adaptive resistance would allow precision medicine and increase treatment efficacy.Proteomic analysis allows the identification of drug targets for cancer treatment and biomarkers for cancer classification or recurrence. In particular, MS is a powerful tool for resolving the complexity of cancer signaling pathways. With regard to HCC, qualitative proteomics has been performed on resected tumor material (12), laser-capture microdissected material from tissue sections (13, 14), and primary hepatocytes or serum derived from patients (15, 16). These studies (17, 18) identified HCC biomarkers such as glutamine synthetase and heat shock protein 70 (Hsp70) that are currently in use for diagnosis (19, 20). Quantitative proteomics has been performed on HCC resected tissue and serum (21, 22). Recently, proteomics has been performed on tumor biopsies of renal cell carcinoma patients (23). Several studies also have described phosphoproteomic analyses of resected HCC or other cancer material (24–26), in some cases quantifying up to 8,000 phosphorylated sites (hereafter referred to as “phosphosites”) starting with 2 mg of protein (18, 27–30). However, to our knowledge, quantitative proteomics and phosphoproteomics, hereafter collectively referred to as “(phospho)proteomics,” have yet to be performed on tumor biopsies, possibly because biopsy material is nonrenewable and typically provides only a very small amount of protein. Importantly, quantitative (phospho)proteomics on serial biopsies taken before and during treatment has not been described. We note that although a biopsy procedure generates less material than a resection, it has the important advantage of capturing normally dynamic properties of a tumor, such as the phosphorylation status of signaling pathways. Biopsies are immediately snap-frozen upon removal from the patient and, unlike resected tissue, are obtained without causing ischemia or hypoglycemia in the collected tissue. Needle biopsies are taken routinely to diagnose and stage the disease. Another important consideration is a method to perform quantitative (phospho)proteomics, such as super-SILAC (“SILAC” is an acronym for “stable isotope labeling of amino acids in cell culture”), that allows direct comparison of biopsies obtained at different times or from different patients (31).We describe quantitative (phospho)proteomic analyses of needle biopsies of HCC and matched nontumor tissue from a human patient. These analyses provide a global snapshot of signaling pathways in the biopsy material. Analyzing serial biopsies taken from a patient before and during therapy, we measured differences in signaling pathways between tumor and matched nontumor control tissue and the changes in these signaling pathways upon sorafenib treatment. Our findings provide insight into mechanisms of tumor progression and resistance to cancer therapy.     

Recognition of a positive MLR within 4 hours using a carrier free electrophoresis system

Summary Indicator cells — tanned, surface stabilized sheep erythrocytes — were incubated for 1 h in supernatants of 3 h MLCs. Their electrophoretic mobility was measured by an analytical, carrier free electrophoresis system. The change in their mobility compared with an appropriate control was calculated in per cent and correlated with the conventional measured MLR-cpm. The correlation of the two quantities is statistically highly significant (p<0.01). Furthermore, the difference of the electrophoretic mobility values of the group of HLA-D-identical and the groups of HLA-D-haploidentical or -different donors is significant beyond the 1 level (p<0.0005). Our method enables, therefore recognition of a positive or negative MLC after only 4 h. Typing for HLA-D-determinants seems to be possible. This could be of great importance for histocompatibility testing and organ transplantation.     

Cytogenetics of secondary myelodysplasia (sMDS) and acute nonlymphocytic leukemia (sANLL)

76 cases of secondary myelodysplasia (sMDS) and acute non-lymphocytic leukemia (sANLL) were cytogenetically analyzed. Among the 36 sMDS patients, 13 (36%) had only normal karyotypes whereas 23 (64%) displayed clonal chromosomal abnormalities. The most common aberrations were -7, 5q-, -5, and +8. In 10 patients (43% of the cytogenetically aberrant cases), clones with only one anomaly, mostly 5q- or -7, were found. Of the 40 sANLL patients, normal karyotypes were detected in 10 (25%). Among the 30 (75%) abnormal cases, the most frequent aberrations were -7, -5, +8, 7q-, -17, and +21. 12 patients (40%) had clones with single abnormalities, most often -7. In 4 sANLL patients cytogenetically unrelated clones were detected. A survey of all previously published secondary hematologic neoplasias reveals that the most frequent abnormalities in sMDS are -7 (41%), 5q- (28%), and -5 (11%), followed by der(21q), +8, 7q-, der(12p), t(1;7), -12, -17, der(17p), der(3p), der(6p), and -18. Clones with single aberrations have been found in 45% of the cases and cytogenetically unrelated clones have been described in 6%. The most common abnormalities in sANLL are -7 (38%), 5q- (17%), -5 (15%), +8 (13%), and -17 (11%), followed by der(3q), der(11q), der(12p), -21, 7q-, -18, der(3p), der(17p), +21, der(21q), der(6p), and -16. 38% of the sANLL patients have had clones with only one aberration and 3% have had unrelated clones. The frequencies of these nonrandom abnormalities in sMDS and sANLL are thus remarkably similar - the only exception appears to be 5q-, which is more common in sMDS. Also the mean number of abnormalities per case is similar - 5.3 in sMDS and 5.6 in sANLL. When the incidences of characteristic cytogenetic abnormalities were correlated with the type of previous therapy, -7 was found to be more frequent in sMDS and sANLL patients who had been exposed to chemotherapy whereas 5q- was associated with previous exposure to ionizing radiation in sMDS patients.