Collagen Turnover in Relation to Risk Factors and Hemodynamics in Human Intracranial Aneurysms.

Background and Purpose- Determinants for molecular and structural instability, that is, impending growth or rupture, of intracranial aneurysms (IAs) remain uncertain. To elucidate this, we endeavored to estimate the actual turnover rates of the main molecular constituent in human IA (collagen) on the basis of radiocarbon (14C) birth dating in relation to IA hemodynamics. Methods- Collagen turnover rates in excised human IA samples were calculated using mathematical modeling of 14C birth dating data of collagen in relation to risk factors and histological markers for collagen maturity/turnover in selected IA. Hemodynamics were simulated using image-based computational fluid dynamics. Correlation, logistic regression, and receiver operating characteristic analyses were performed. Results- Collagen turnover rates were estimated in 46 IA (43 patients); computational fluid dynamics could be performed in 20 IA (20 patients). The mean collagen turnover rate (γ) constituted 126% (±1% error) per year. For patients with arterial hypertension, γ was greater than 2600% annually, whereas γ was distinctly lower with 32% (±1% error) per year for patients without risk factors, such as smoking and hypertension. There was a distinct association between histological presence of rather immature collagen in human IA and the presence of modifiable risk factors. Spatial-temporal averaged wall shear stress predicted rapid collagen turnover (odds ratio, 1.6 [95% CI, 1.0-2.7]). Receiver operating characteristic analysis demonstrated a good test accuracy (area under the curve, 0.798 [95% CI, 0.598-0.998]) for average wall shear stress with a threshold ≥4.9 Pa for rapid collagen turnover. Conclusions- Our data indicate that turnover rates and stability of collagen in human IA are strongly associated with the presence of modifiable risk factors and aneurysmal hemodynamics. These findings underline the importance of strict risk factor modification in patients with unruptured IA. Future should include more detailed risk factor data to establish a more causal understanding of hemodynamics and the rupture risk of individual IA.

Circulating monocytes and tumor-associated macrophages express recombined immunoglobulins in glioblastoma patients.

BACKGROUND: Glioblastoma is the most common and malignant brain tumor in adults. Glioblastoma is usually fatal 12-15 months after diagnosis and the current possibilities in therapy are mostly only palliative. Therefore, new forms of diagnosis and therapy are urgently needed. Since tumor-associated macrophages are key players in tumor progression and survival there is large potential in investigating their immunological characteristics in glioblastoma patients. Recent evidence shows the expression of variable immunoglobulins and TCRαß in subpopulations of monocytes, in vitro polarized macrophages and macrophages in the tumor microenvironment. We set out to investigate the immunoglobulin sequences of circulating monocytes and tumor-associated macrophages from glioblastoma patients to evaluate their potential as novel diagnostic or therapeutic targets. RESULTS: We routinely find consistent expression of immunoglobulins in tumor-associated macrophages (TAM) and circulating monocytes from all glioblastoma patients analyzed in this study. However, the immunoglobulin repertoires of circulating monocytes and TAM are generally more restricted compared to B cells. Furthermore, the immunoglobulin expression in the macrophage populations negatively correlates with the tumor volume. Interestingly, the comparison of somatic mutations, V-chain usage, CDR3-length and the distribution of used heavy chain genes on the locus of chromosome 14 of the immunoglobulins from myeloid to B cells revealed virtually no differences. CONCLUSIONS: The investigation of the immunoglobulin repertoires from TAM and circulating monocytes in glioblastoma-patients revealed a negative correlation to the tumor volume, which could not be detected in the immunoglobulin repertoires of the patients' B lymphocytes. Furthermore, the immunoglobulin repertoires of monocytes were more diverse than the repertoires of the macrophages in the tumor microenvironment from the same patients suggesting a tumor-specific immune response which could be advantageous for the use as diagnostic or therapeutic target.

Dual- versus Single-Energy CT-Angiography Imaging for Patients Undergoing Intracranial Aneurysm Repair.

BACKGROUND: The invasiveness and risk of thromboembolic complications of catheter angiography underline the need for alternative imaging modalities in patients following intracranial aneurysm (IA) repair. However, the overall image quality of existing noninvasive imaging modalities, such as single-energy CT angiography (SE-CTA), compromises its value in this respect. OBJECTIVE: We prospectively investigated the value of a novel dual-energy CTA (DE-CTA) scanner and algorithm for assessing the degree of occlusion and parent vessel patency in patients following IA repair. METHODS: A prospective cohort of 17 patients underwent DE-CTA imaging following surgical or endovascular IA repair. This dataset was matched with an identical historical cohort of 17 patients, who underwent IA repair and SE-CTA imaging. Beam-hardening artifacts, as a measure for objective imaging quality were analyzed based on the volume of a prolate ellipsoid, whereas subjective imaging quality at the IA site and corresponding parent vessels was rated by 2 independent neuroradiologists on a scale from 4 (excellent, no artifacts) to 1 (poor, severe artifacts). RESULTS: Objective DE-CTA image quality was markedly higher, compared to SE-CTA in patients undergoing surgical (0.77 ± 0.23 vs. 10.91 ± 1.88 mL, respectively; p < 0.001) or endovascular (32.36 ± 10.62 vs. 107.63 ± 24.51 mL, respectively; p = 0.026) IA repair. Subjective image quality for DE-CTA was significantly improved compared to SE-CTA in the surgical group but not in the endovascular group. The calculated dose values for DE-CTA in our study remain markedly below the legally required radiation dose limits. CONCLUSION: The imaging quality of DE-CTA, especially for patients undergoing surgical IA repair, is distinctly superior, compared to SE-CTA imaging. Therefore, DE-CTA may serve as a noninvasive alternative for assessing the IA occlusion rate and parent vessel patency.

Intraoperative neurophysiological monitoring during resection of infratentorial lesions: the surgeon's view.

OBJECTIVE Methods of choice for neurophysiological intraoperative monitoring (IOM) within the infratentorial compartment mostly include early brainstem auditory evoked potentials, free-running electromyography, and direct cranial nerve (CN) stimulation. Long-tract monitoring with somatosensory evoked potentials (SEPs) and motor evoked potentials (MEPs) is rarely used. This study investigated the incidence of IOM alterations during posterior fossa surgery stratified for lesion location. METHODS Standardized CN and SEP/MEP IOM was performed in 305 patients being treated for various posterior fossa pathologies. The IOM data were correlated with lesion locations and histopathological types as well as other possible confounding factors. RESULTS Alterations in IOM were observed in 158 of 305 cases (51.8%) (CN IOM alterations in 130 of 305 [42.6%], SEP/MEP IOM alterations in 43 of 305 [14.0%]). In 15 cases (4.9%), simultaneous changes in long tracts and CNs were observed. The IOM alterations were followed by neurological sequelae in 98 of 305 cases (32.1%); 62% of IOM alterations resulted in neurological deficits. Sensitivity and specificity for detection of CN deficits were 98% and 77%, respectively, and 95% and 85%, respectively, for long-tract deficits. Regarding location, brainstem and petroclival lesions were closely associated with concurrent CN IOM and SEP/MEP alterations. CONCLUSIONS The incidence of IOM alterations during surgery in the posterior fossa varied widely between different lesion locations and histopathological types. This analysis provides crucial information on the necessity of IOM in different surgical settings. Because MEP/SEP and CN IOM alterations were commonly observed during posterior fossa surgery, the authors recommend the simultaneous use of both modalities based on lesion location.

Bisphosphonates and connexin 43: a critical review of evidence.

Bisphosphonates (BPs) are drugs commonly used in the treatment of various disease arising or affecting bone tissue. There is a standard use in bone neoplasia and metastasis, hormonal and developmental disorders as well as for compensation of adverse effects in several medical therapies. Many in-vivo and in-vitro studies have assessed the efficacy of this drug and its function in cellular scale. In this concern, BPs are described to inhibit the resorptive function of osteoclasts and to prevent apoptosis of osteoblasts and osteocytes. They can preserve the osteocytic network, reduce fracture rate, and increase the bone mineral content, which is therapeutically used. Connexin 43 (Cx43) is a crucial molecule for basal regulation of bone homeostasis, development, and differentiation. It is described for signal transduction in many physiological and pathological stimuli and recently to be involved in BP action.

Postcraniotomy function of the temporal muscle in skull base surgery: technical note based on a preliminary study.

PURPOSE: Patients undergoing craniotomies necessitating preparation of the temporal muscle (TM) may experience postoperative functional impairment of the temporomandibular joint. This topic has not been thoroughly discussed in the literature so far. In the present study, the authors propose a questionnaire as an evaluation tool to assess to what degree different TM preparation techniques correlate with postoperative temporomandibular joint dysfunction. MATERIALS AND METHODS: Between 2004 and 2006, 286 patients underwent either pterional or temporal craniotomies in the department of craniotomies at the University of Münster in Germany. Intraoperatively the TM was prepared either interfascial, submuscular, or subfascial. A patient-based questionnaire was designed and validated (Kendalls-τ = +1) in order to evaluate the patients' postoperative temporomandibular functional outcome. Based on strict inclusion/exclusion criteria, 69 patients were eligible for the application of the questionnaire in this preliminary study. RESULTS: Seventeen percent of the patients complained of either temporomandibular joint pain (3%) or restricted mouth opening (13%) postoperatively in a follow-up period between 3 and 12 months. In 92% postoperative complaints were reported within the first 3 months and in 58% of the patients with complaints the pain eased off. In 34% a therapy was required for the pain to be controlled. In one patient (8%) a postoperative arthroscopy has been necessary. Of the patients who experienced postoperative complaints, 67% had undergone temporal and 33% pterional craniotomy. In the group where postoperatively there were issues of temporomandibular pain/dysfunction, 42% had had the TM dissected, in 25% incised, and in 8% transected. For 25% of the patients, the type of intraoperative manipulation remained unknown. CONCLUSION: For postoperative quality control, the questionnaire showed to be a suitable evaluation tool. Concerning the different preparation techniques, subfascial preparation of the TM tends to result in less postoperative complaints and is thus recommended.

Pannexin1 stabilizes synaptic plasticity and is needed for learning.

Pannexin 1 (Panx1) represents a class of vertebrate membrane channels, bearing significant sequence homology with the invertebrate gap junction proteins, the innexins and more distant similarities in the membrane topologies and pharmacological sensitivities with gap junction proteins of the connexin family. In the nervous system, cooperation among pannexin channels, adenosine receptors, and K(ATP) channels modulating neuronal excitability via ATP and adenosine has been recognized, but little is known about the significance in vivo. However, the localization of Panx1 at postsynaptic sites in hippocampal neurons and astrocytes in close proximity together with the fundamental role of ATP and adenosine for CNS metabolism and cell signaling underscore the potential relevance of this channel to synaptic plasticity and higher brain functions. Here, we report increased excitability and potently enhanced early and persistent LTP responses in the CA1 region of acute slice preparations from adult Panx1(-/-) mice. Adenosine application and N-methyl-D-aspartate receptor (NMDAR)-blocking normalized this phenotype, suggesting that absence of Panx1 causes chronic extracellular ATP/adenosine depletion, thus facilitating postsynaptic NMDAR activation. Compensatory transcriptional up-regulation of metabotropic glutamate receptor 4 (grm4) accompanies these adaptive changes. The physiological modification, promoted by loss of Panx1, led to distinct behavioral alterations, enhancing anxiety and impairing object recognition and spatial learning in Panx1(-/-) mice. We conclude that ATP release through Panx1 channels plays a critical role in maintaining synaptic strength and plasticity in CA1 neurons of the adult hippocampus. This result provides the rationale for in-depth analysis of Panx1 function and adenosine based therapies in CNS disorders.

Acute Hepatitis Induced by Lyprinol, the Lipid Extract of the Green-Lipped Mussel (Perna canaliculus), in a Patient with Polyarthrosis.

Lyprinol, the lipid extract of the green-lipped mussel (Perna canaliculus), is a readily and freely available agent with a putative anti-inflammatory impact. It has already found application as a complementary and supplementary treatment of osteoarthritis, rheumatoid arthritis, asthma, and cancer. So far no major side effects for Lyprinol have been reported, yet. Here, we present the case of a 76-year-old woman with acutely exacerbating abdominal pain and highly elevated liver transaminases while taking Lyprinol as a complementary treatment of polyarthrosis.

Intramedullary spinal cord metastasis and multiple brain metastases from urothelial carcinoma.

Intramedullary spinal cord metastases (ISCM) are rare spinal cord neoplasms associated with severe neurological deterioration and poor life expectancy. However, their incidence is expected to increase as a result of advances in diagnostic techniques and longer survival of patients with cancer due to improvements in cancer therapy. Reports on ISCM from primary urothelial carcinoma are virtually non existent. We report a 74-year-old male patient with a significant history of a high-grade urothelial carcinoma who presented with progressive back pain and concomitant weakness, grade 3-4/5 proximally and 0-1/5 distally, and distal hyperesthesia and hyperalgesia, particularly of the left lower limb. MRI revealed a contrast-enhancing intramedullary lesion at Th11/Th12. Laminectomies of Th11/Th12 and lesion resection were performed. Postoperative histopathological examinations confirmed the metastatic nature of the lesion. Subsequently the patient developed multiple brain metastases. Radiation therapy was refused by the patient. We conclude that ISCM are devastating complications of systemic cancer. Early and thorough diagnosis, as well as carefully considered and prompt therapy, is important for minimizing the patient's functional deficit, thus improving quality of life.

Unified patch clamp protocol for the characterization of Pannexin 1 channels in isolated cells and acute brain slices.

In the central nervous system, Pannexin 1 (Panx1) channels are implicated in a variety of physiological and pathological conditions. One of the prerequisites to enlighten the role of Panx1 is the development and standardization of reliable methods. Here, we address the applicability of voltage clamp protocols to identify Panx1 channel mediated currents in neurons of acutely dissected brain slices. We improved an established protocol and report on a modified paradigm that robustly evokes Panx1 channel currents. Crucial advances are the use of physiologic ion gradient conditions and a preconditioning step of depolarizing membrane potential ramps of long duration. This new paradigm provides significant impact on membrane current generation at hypo- and depolarized holding potential steps post voltage ramp preconditioning in heterologous expression systems and primary hippocampal CA1 neurons of mouse brain slices in vitro. Finally, we demonstrate that under these conditions the analysis of tail currents elicited by repolarization of the cells from preconditioning holding potential depolarization permits an independent method to isolate Panx1 mediated channel activity. In summary, this study provides a comprehensive methodological improvement in the biophysical analysis of Panx1 channels with a particular focus on investigations under physiological conditions in complex tissues.

Primary carcinoid tumor of the filum terminale--a case report.

Carcinoid tumors with a primary site in the central nervous system have not been reported in literature yet. We report here about a 41-year-old patient with recurrent and progressive low back pain and bilateral S1 radiculopathy on admission. The patient underwent hemi-laminectomies of the vertebral bodies L5 and S1 and an en bloc resection of the tumor. Postoperative histopathological examination resulted in a well-differentiated intrathecal neuroendocrine tumor (carcinoid) of the terminal filum. Postoperative staging showed no pathological abnormalities and no tumor recurrence after 6 months. Even though rare, carcinoids should be considered as differential diagnosis of tumors occurring in the CNS.