Thalamic integrity underlies executive dysfunction in traumatic brain injury.

OBJECTIVE: To quantify the effects of traumatic brain injury on integrity of thalamocortical projection fibers and to evaluate whether damage to these fibers accounts for impairments in executive function in chronic traumatic brain injury. METHODS: High-resolution (voxel size: 0.78 mm x 0.78 mm x 3 mm(3)) diffusion tensor MRI of the thalamus was conducted on 24 patients with a history of single, closed-head traumatic brain injury (TBI) (12 each of mild TBI and moderate to severe TBI) and 12 age- and education-matched controls. Detailed neuropsychological testing with an emphasis on executive function was also conducted. Fractional anisotropy was extracted from 12 regions of interest in cortical and corpus callosum structures and 7 subcortical regions of interest (anterior, ventral anterior, ventral lateral, dorsomedial, ventral posterior lateral, ventral posterior medial, and pulvinar thalamic nuclei). RESULTS: Relative to controls, patients with a history of brain injury showed reductions in fractional anisotropy in both the anterior and posterior corona radiata, forceps major, the body of the corpus callosum, and fibers identified from seed voxels in the anterior and ventral anterior thalamic nuclei. Fractional anisotropy from cortico-cortico and corpus callosum regions of interest did not account for significant variance in neuropsychological function. However, fractional anisotropy from the thalamic seed voxels did account for variance in executive function, attention, and memory. CONCLUSIONS: The data provide preliminary evidence that traumatic brain injury and resulting diffuse axonal injury results in damage to the thalamic projection fibers and is of clinical relevance to cognition.

[Diagnosis and treatment of colorectal liver metastases - workflow]. / Diagnostik und Therapie von Lebermetastasen kolorektaler Karzinome - Workflow.

In this review, standards of diagnosis and treatment of colorectal liver metastases are described on the basis of a workshop discussion. Algorithms of care for patients with synchronous / metachronous colorectal liver metastases or locoregional recurrent tumour are presented. Surgical resection is the procedure of choice in the curative treatment of liver metastases. The decision about the resection of liver metastases should consider the following parameters: 1. General operability of the patient (comorbidity); 2. Achievability of an R 0 situation: i. if necessary, in combination with ablative methods, ii. if necessary, neoadjuvant chemotherapy, iii. the ability to eradicate extrahepatic tumour manifestations; 3. Sufficient volume of the liver remaining after resection ("future liver remnant = FLR): i. if necessary, in combination with portal vein embolisation or two-stage hepatectomy; 4. The feasibility to preserve two contiguous hepatic segments with adequate vascular inflow and outflow as well as biliary drainage; 5. Tumour biological aspects ("prognostic variables"); 6. Experience of the surgeon and centre! Extrahepatic disease does not contraindicate hepatectomy for colorectal liver metastases provided a complete resection of both intra- and extrahepatic disease is feasible. Even in bilobar colorectal metastases and 5 or more tumours in the liver, a complete tumour resection has been described. The type of resection (hepatic wedge resection or anatomic resection) does not influence the recurrence rate. Preoperative volumetry is indicated when major hepatic resection is planned. The FLR should be 25 % in patients with normal liver, 40 % in patients who have received intensive chemotherapy or in cases of fatty liver, liver fibrosis or diabetes, and 50-60 % in patients with cirrhosis. In patients with initially unresectable colorectal liver metastases, preoperative chemotherapy enables complete resection in 15-30 % of the cases, whereas the value of neoadjuvant chemotherapy in patients with resectable liver metastases has not been sufficiently supported. In situ ablative procedures (radiofrequency ablation = RFA and laser-induced interstitial thermotherapy = LITT) are local therapy options in selected patients who are not candidates for resection (central recurrent liver metastases, bilobar multiple metastases and high-risk resection or restricted patient operability). Patients with tumours larger than 3 cm have a high local recurrence rate after percutaneous RFA and are not optimal candidates for this procedure. The physician's experience influences the results significantly, both after hepatectomy and after in situ ablation. Therefore, patients with colorectal liver metastases should be treated in centres with experience in liver surgery.

Persistent increases in basal cerebral metabolic activity induced by morphine sensitization.

To characterize the underlying neuroanatomic substrate of morphine (MS) sensitization, changes in the local cerebral metabolic rate for glucose (LCMRglu) were examined in 95 brain regions of male F-344 rats using the 2-deoxy-D-[1-14C]glucose method. The results of these experiments demonstrate that MS-induced sensitization is manifested by increases in basal metabolic activity that last for at least 6 days. Although changes in basal metabolic rate were found to be more extensive in the presence of conditioned cues, the increases in LCMRglu in nonconditioned sensitized rats indicate a basic underlying pharmacologic effect of MS sensitization on basal brain activity. Regions in which MS sensitization had a lasting pharmacologic effect include the shell of the nucleus accumbens, the prelimbic area of the prefrontal cortex, and the dorsolateral prefrontal cortex. Interestingly, the core of the nucleus accumbens and regions of the caudate were found to have an increased LCMRglu only in the presence of conditioned cues, indicating conditioned brain activity without observable changes in behavior. The previous administration of an MS-sensitizing treatment was also found to alter the cerebral metabolic response to a subsequent acute MS challenge (0.5 mg/kg, subcutaneously), most notably in forebrain systems. The more widespread activation of brain structures in the basal state in the presence of conditioned cues suggests that these MS-sensitized rats may model an altered brain state related to craving in the abstinent opiate addict.

[Microsensor-controlled feedback bioactuators as a semi-integrated basis for biophysical cancer treatment]. / Mikrosensor-gesteuerte Rükkopplungs-Bioaktuatoren auf Halbleiterbasis zur biophysikalischen Krebsbehandlung.

Acidic microenvironmental conditions combined with large hypoxic areas are ubiquitous hallmarks of most solid tumors. They result from a poorly organized vascularization and a deviant energy metabolism. There is convincing evidence supporting the hypothesis that such physico-chemical conditions promote the microevolution of malignant cells, inhibit the cellular immune response, and favor tumor cell invasion. In agreement with published data, our cell biological analyses and computer simulations indicate that treatment schemes which restore a tumor microenvironment reflecting that one found in normal tissues might improve the efficiency of immunotherapies and classical methods for cancer treatment. We suggest that the tumor microenvironment could be effectively monitored and manipulated by means of silicon-based feedback bioactuators which are controlled by integrated microsensors. In principle, miniaturized bioactuators can be implanted directly at the sites of inoperable tumors and metastases where they function as a "pH clamp" and thereby can reconstitute normal physicochemical conditions. Drug application could be precisely controlled by an integrated microprocessor. Our paper summarizes the current state of development of microsensor-based feedback bioactuators and outlines possible applications in biophysical cancer treatment.

Drug targeting and metabolic investigations of cryoprepared tumor cells with analytical electron energy loss spectroscopy.

Analytical electron microscopy is an ideal tool for holistic data acquisition on biological systems. The use of analytical electron microscopy for both, the investigation of micropharmacokinetic problems and metabolic studies, is becoming more and more important. Depending on the mode of investigation, it is possible to localize drugs and xenobiotics precisely in situ under optical control or to quantify their uptake and distribution in the corresponding target cells without disintegrating the cell or tissue material. In this paper, we present instructive examples for the application of analytical electron energy loss spectroscopy in transmission electron microscopy in order to investigate the cellular uptake and distribution of cisplatin and cyclophosphamide and the metabolic changes induced by an alteration in the extracellular calcium concentration in a holistic manner.

The human eps15 gene, encoding a tyrosine kinase substrate, is conserved in evolution and maps to 1p31-p32.

Employing an expression cloning approach for tyrosine kinase substrates, we have previously isolated the coding sequence for a novel putative EGFR substrate, eps15, from NIH3T3 fibroblasts. Eps15 displayed a receptor-specific pattern of tyrosine phosphorylation in vivo and was able to transform NIH3T3 cells upon overexpression. To gain understanding of eps15 function as well as its role in normal and neoplastic proliferation, we cloned the human eps15 coding sequence and studied expression of the human RNA and protein, evolutionary conservation, and chromosomal location. The close structural similarity of human eps15 with the murine homologue is indicated by 89% and 90% identity of nucleotide and predicted amino acid sequences, respectively. Using the human eps15 coding sequence as probe, we demonstrate that eps15 is member of a gene family that is highly conserved during evolution. An essential function of eps15 in cell growth regulation is underscored by our observation of ubiquitous expression at the transcript and the protein level in normal and malignant human cells. The human EPS15 locus maps to chromosome 1p31-p32, a region involved in deletion in neuroblastoma, translocations in acute lymphoblastic leukemia, and exhibiting a fragile site.