Search

Background: Malignant gliomas are the most prevalent primary malignant cerebral tumors. Preoperative imaging plays an important role, and the prognosis is closely related to surgical resection and histomolecular aspects. Our goal was to correlate Ki67 indexes with tumoral volumetry in semiautomatic segmentation on preoperative magnetic resonance images and residual fluorescence in a 5-ALA-assisted resection cohort., Methods: We included 86 IDH-wildtype glioblastoma patients with complete preoperative imaging submitted to 5-ALA assisted resections. Clinical, surgical, and histomolecular findings were also obtained. Preoperative magnetic resonance studies were preprocessed and segmented semiautomatically on Visualization and Analysis for whole tumor (WT) on 3D FLAIR, enhancing tumor (ET), and necrotic core on 3D postgadolinium T1. We performed a linear regression analysis for Ki67 and a multivariate analysis for surgical outcomes., Results: Higher Ki-67 indexes correlated positively with higher WT (P = 0.048) and ET (P = 0.002). Lower Ki67 correlated with 5-ALA free margins (P = 0.045). WT and ET volumes correlated with the extent of resection (EOR; P = 0.002 and 0.002, respectively). Eloquence did not impact EOR (P = 0.14)., Conclusions: There is a correlation between Ki67, the metabolically active tumoral volumes (WT and ET), and 5-ALA residual fluorescence. Methodological inconsistencies are probably responsible for contradictory literature findings, and further prospective studies are needed to validate and reproduce these findings., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Glioblastoma is a malignant and aggressive brain tumour that, although there have been improvements in the first line treatment, there is still no consensus regarding the best standard of care (SOC) upon its inevitable recurrence. There are novel adjuvant therapies that aim to improve local disease control. Nowadays, the association of intraoperative photodynamic therapy (PDT) immediately after a 5-aminolevulinic acid (5-ALA) fluorescence-guided resection (FGR) in malignant gliomas surgery has emerged as a potential and feasible strategy to increase the extent of safe resection and destroy residual tumour in the surgical cavity borders, respectively., Objectives: To assess the survival rates and safety of the association of intraoperative PDT with 5-ALA FGR, in comparison with a 5-ALA FGR alone, in patients with recurrent glioblastoma., Methods: This article describes a matched-pair cohort study with two groups of patients submitted to 5-ALA FGR for recurrent glioblastoma. Group 1 was a prospective series of 11 consecutive cases submitted to 5-ALA FGR plus intraoperative PDT; group 2 was a historical series of 11 consecutive cases submitted to 5-ALA FGR alone. Age, sex, Karnofsky performance scale (KPS), 5-ALA post-resection status, T1-contrast-enhanced extent of resection (EOR), previous and post pathology, IDH (Isocitrate dehydrogenase), Ki67, previous and post treatment, brain magnetic resonance imaging (MRI) controls and surgical complications were documented., Results: The Mantel-Cox test showed a significant difference between the survival rates (p = 0.008) of both groups. 4 postoperative complications occurred (36.6%) in each group. As of the last follow-up (January 2024), 7/11 patients in group 1, and 0/11 patients in group 2 were still alive. 6- and 12-months post-treatment, a survival proportion of 71,59% and 57,27% is expected in group 1, versus 45,45% and 9,09% in group 2, respectively. 6 months post-treatment, a progression free survival (PFS) of 61,36% and 18,18% is expected in group 1 and group 2, respectively., Conclusion: The association of PDT immediately after 5-ALA FGR for recurrent malignant glioma seems to be associated with better survival without additional or severe morbidity. Despite the need for larger, randomized series, the proposed treatment is a feasible and safe addition to the reoperation., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Competing Interests: The authors have no conflict of interest to declare.

Astroblastoma is a rare astrocytic glial neoplasm that affects mainly young girls, peaking between 10 and 30 years of age, with low- and high-grade manifestations. Imaging characteristics are well-described, but histopathologic and, more recently, molecular analysis is fundamental to establish the diagnosis, now based on MN1 alterations. We describe a case with typical imaging and histologic features of an MN1 -altered astroblastoma., (© 2023 by American Journal of Neuroradiology.)

We report a case of a 30-year-old previously higid female presenting with dorsal pain and persistent fever after COVID-19 vaccine booster dose. CT and MR revealed a prevertebral heterogeneous and infiltrating mass, with spontaneous regression in control imaging which biopsy confirmed an inflammatory myofibroblastic tumor., Competing Interests: Conflict of InterestNone., (© Association of Otolaryngologists of India 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Although machine learning (ML) has shown promise across disciplines, out-of-sample generalizability is concerning. This is currently addressed by sharing multi-site data, but such centralization is challenging/infeasible to scale due to various limitations. Federated ML (FL) provides an alternative paradigm for accurate and generalizable ML, by only sharing numerical model updates. Here we present the largest FL study to-date, involving data from 71 sites across 6 continents, to generate an automatic tumor boundary detector for the rare disease of glioblastoma, reporting the largest such dataset in the literature (n = 6, 314). We demonstrate a 33% delineation improvement for the surgically targetable tumor, and 23% for the complete tumor extent, over a publicly trained model. We anticipate our study to: 1) enable more healthcare studies informed by large diverse data, ensuring meaningful results for rare diseases and underrepresented populations, 2) facilitate further analyses for glioblastoma by releasing our consensus model, and 3) demonstrate the FL effectiveness at such scale and task-complexity as a paradigm shift for multi-site collaborations, alleviating the need for data-sharing., (© 2022. The Author(s).)

Competing Interests: The authors report no conflicts of interest.

Competing Interests: The authors have no conflict of interests to declare.

Delleman-Oorthuys or oculocerebrocutaneous syndrome (OCCS) is an extremely rare condition which relies on three pillars of manifestations: ophthalmological, neurological, and dermatological. It was first described by Delleman and Oorthuys in 1981, and since then, very few other cases have been reported. We report the case of a 13-month-old boy, referred to an ophthalmological tertiary service for investigation of a microglobe with a cystic retrobulbar mass on translucency test. MRI revealed a left microphthalmia, with extensive retrobulbar cystic lesions occupying the remaining orbit and protruding anteriorly the microglobe. Cerebral findings included polymicrogyria, subependymal nodular heterotopia at the level of the left occipital horn of the lateral ventricle, and an importantly enlarged mesencephalic tectum observed in association with an absent cerebellar vermis. The ensemble of malformations met the criteria for definite OCCS. Being a tremendously rare syndrome, OCCS will always represent a diagnostic challenge. However, its emblematic cutaneous manifestations might be an important part of the road map leading to its correct interpretation. Thus, when absent, diagnosis can be harder than usual, and, on these cases, neurologists, ophthalmologists, and radiologists play a crucial role., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Cutaneous myiasis is an endemic infestation in Latin America and Africa. Many unusual sites of larval infection can cause diagnostic confusion, especially if the patient is not from an endemic area. In the breast, the furuncular aspect suggests some differential diagnosis. We report a case of an 84-year-old patient with an ulcerated lesion on the right breast, who was referred to the reference service to exclude malignancy. Considering the clinical aspects and after further evaluation with imaging methods, she was diagnosed with myiasis. This study reinforces the importance of differential diagnosis of myiasis in patients that come from endemic areas., (© 2021 Wiley Periodicals LLC.)

Tau is a microtubule stabilizing protein that forms abnormal aggregates in many neurodegenerative disorders, including Alzheimer's disease. We have previously shown that co-expression of fragmented and full-length tau in P301SxTAU62on tau transgenic mice results in the formation of oligomeric tau species and causes severe paralysis. This paralysis is fully reversible once expression of the tau fragment is halted, even though P301S tau expression is maintained. Whereas various strategies to target tau aggregation have been developed, little is known about the long-term consequences of reverted tau toxicity. Therefore, we studied the long-term motor fitness of recovered, formerly paralysed P301SxTAU62on-off mice. To assess the seeding competence of oligomeric toxic tau species, we also inoculated ALZ17 mice with brainstem homogenates from paralysed P301SxTAU62on mice. Counter-intuitively, after recovery from paralysis due to oligomeric tau species expression, ageing P301SxTAU62on-off mice did not develop more motor impairment or tau pathology when compared to heterozygous P301S tau transgenic littermates. Thus, toxic tau species causing extensive neuronal dysfunction can be cleared without inducing seeding effects. Moreover, these toxic tau species also lack long-term tau seeding effects upon intrahippocampal inoculation into ALZ17 mice. In conclusion, tau species can be neurotoxic in the absence of seeding-competent tau aggregates, and mice can clear these tau forms permanently without tau seeding or spreading effects. These observations suggest that early targeting of non-fibrillar tau species may represent a therapeutically effective intervention in tauopathies. On the other hand, the absent seeding competence of early toxic tau species also warrants caution when using seeding-based tests for preclinical tauopathy diagnostics., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Terminal myelocystocele is a rare type of neural tube malformation, consisting of a skin-covered lumbosacral mass, highly associated with other complex abdominal malformations within the OIES complex (omphalocele, imperforate anus, exstrophy of the cloaca and spinal defects). We present a case of a premature female with an extensive lumbosacral mass at birth, as well as an omphalocele, cloacal exstrophy, renal abnormalities, and sacral agenesis. Lumbar magnetic resonance imaging revealed a meningocele sac herniating through the bone defects and containing a syringocele sac. Advanced imaging techniques showed turbulent cerebrospinal fluid flow. At control, 4 weeks later, the defect doubled in size. The myelocystocele sac was evacuated and closed, and the patient persisted with paraparesis. The role of cerebrospinal fluid flow analysis is well established in Chiari-type malformations, in which turbulent flow within the syrinx is related to a better outcome after surgery. It is possible that the same principle could be applied to other spinal malformations, as shown in this case of terminal myelocystocele., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Blunt abdominal organ injury is an abundant and relevant topic in forensic medicine, yet comparatively few experimental studies have been performed to quantify organ injury threshold parameters. The goal of this study was to relate an impact to a kidney injury determining an energy threshold while taking account of the influence of the overlaying soft tissue thickness. A model consisting of ballistic gelatin with an embedded filled porcine kidney was made such that a gelatin layer of 2 or 4 cm thickness covered the organ. An impactor was dropped on this model from different heights and the resulting organ damage was categorized according to the abbreviated injury scale (AIS). The 50% energy threshold for damage and the 50% energy threshold causing injuries ≥ AIS 3 were determined for the two protecting soft layers to be 22 J and 32 J and 27 J and 36 J, respectively. A finite element model was created to determine the strain energy densities at the depth of the organ's surface for these energies. The strain energy densities for the 50% damage thresholds were 88.9 mJ/cm 3 and 86.7 mJ/cm 3 for 2 and 4 cm and for the injuries ≥ AIS 3104.2 mJ/cm 3 and 98.7 mJ/cm 3 . For forensic cases, this means that the thickness of the abdominal layers must be taken into account when the severity of an injury is used to draw conclusions about the applied impact strength.

Terbinafine has proved to treat numerous fungal infections, including onychomycosis, successfully. Due to its liver metabolization and dependency on the cytochrome P450 enzyme complex, undesirable drug interaction are highly probable. Additionally to drug interactions, the treatment is long, rising the chances of the appearance of side effects and abandonment. Pharmacokinetic data suggest that terbinafine maintains a fungicidal effect within the nail up to 30 weeks after its last administration, which has aroused the possibility of a pulse therapy to reduce the side effects while treating onychomycosis. This study's goal was to evaluate the effectiveness of three different oral terbinafine regimens in treating onychomycosis due to dermatophytes. Sixty-three patients with onychomycosis were sorted by convenience in three different groups. Patients from group 1 received the conventional terbinafine dose (250 mg per day for 3 months). Group 2 received a monthly week-long pulse-therapy dose (500 mg per day for 7 days a month, for 4 months) and group 3 received a 500 mg/day dose for 7 days every 3 months, totaling four treatments. There were no statistical differences regarding the effectiveness or side effects between the groups. Conclusion: A quarterly terbinafine pulse regimen can be a possible alternative for treating onychomycosis caused by dermatophytes.

Tau is a microtubule stabilizing protein that forms aggregates in Alzheimer's disease (AD). Tau derived from AD patients' brains induces tau aggregation in a prion-like manner when injected into susceptible mouse models.Here we investigated whether cerebrospinal fluid (CSF) collected from patients diagnosed with probable AD or mild cognitive impairment (MCI) likely due to AD harbors a prion-like tau seeding potential. CSF was injected intrahippocampally into young P301S tau transgenic mice. CSF obtained from AD or MCI patients increased hippocampal tau hyperphosphorylation and tau tangle formation in these mice at 4 months post-seeding. Tau pathology was also accentuated in the contralateral hippocampus, and in anterior and posterior directions, indicative of spreading.We provide first evidence for in vivo prion-like properties of AD patients' CSF, accelerating tau pathology in susceptible tau transgenic mice. This demonstrates that biologically active tau seeds reach the CSF compartment in AD. Further studies may help to evaluate strain specific properties of CSF derived tau bioseeds, and to assess their diagnostic potential.

The Snf2 proteins, comprising 53 different enzymes in humans, belong to the SF2 family. Many Snf2 enzymes possess chromatin-remodeling activity, requiring a functional ATPase domain consisting of conserved motifs named Q and I-VII. These motifs form two recA-like domains, creating an ATP-binding pocket. Little is known about the function of the conserved motifs in chromatin-remodeling enzymes. Here, we characterized the function of the Q and I (Walker I) motifs in hBRG1 (SMARCA4). The motifs are in close proximity to the bound ATP, suggesting a role in nucleotide binding and/or hydrolysis. Unexpectedly, when substituting the conserved residues Gln 758 (Q motif) or Lys 785 (I motif) of both motifs, all variants still bound ATP and exhibited basal ATPase activity similar to that of wildtype BRG1 (wtBRG1). However, all mutants lost the nucleosome-dependent stimulation of the ATPase domain. Their chromatin-remodeling rates were impaired accordingly, but nucleosome binding was retained and still comparable with that of wtBRG1. Interestingly, a cancer-relevant substitution, L754F (Q motif), displayed defects similar to the Gln 758 variant(s), arguing for a comparable loss of function. Because we excluded a mutual interference of ATP and nucleosome binding, we postulate that both motifs stimulate the ATPase and chromatin-remodeling activities upon binding of BRG1 to nucleosomes, probably via allosteric mechanisms. Furthermore, mutations of both motifs similarly affect the enzymatic functionality of BRG1 in vitro and in living cells. Of note, in BRG1-deficient H1299 cells, exogenously expressed wtBRG1, but not BRG1 Q758A and BRG1 K785R, exhibited a tumor suppressor-like function., (© 2019 Hoffmeister et al.)

Abundant tau inclusions are a defining hallmark of several human neurodegenerative diseases, including Alzheimer's disease. Protein fragmentation is a widely observed event in neurodegenerative proteinopathies. The relevance of tau fragmentation for the neurodegenerative process in tauopathies has yet remained unclear. Here we found that co-expression of truncated and full-length human tau in mice provoked the formation of soluble high-molecular-weight tau, the failure of axonal transport, clumping of mitochondria, disruption of the Golgi apparatus and missorting of synaptic proteins. This was associated with extensive nerve cell dysfunction and severe paralysis by the age of 3 weeks. When the expression of truncated tau was halted, most mice recovered behaviorally and functionally. In contrast, co-expression of full-length tau isoforms did not result in paralysis. Truncated tau thus induces extensive but reversible neurotoxicity in the presence of full-length tau through the formation of nonfilamentous high-molecular-weight tau aggregates, in the absence of tau filaments. Targeting tau fragmentation may provide a novel approach for the treatment of human tauopathies.

Background: This study reports the baseline characteristics of diffusion tensor imaging data in Parkinson's disease (PD) patients and healthy control subjects from the Parkinson's Progression Markers Initiative. The main goals were to replicate previous findings of abnormal diffusion imaging values from the substantia nigra. in a large multicenter cohort and determine whether nigral diffusion alterations are associated with dopamine deficits., Methods: Two hundred twenty subjects (PD = 153; control = 67) from 10 imaging sites were included. All subjects had a full neurological exam, a ((123) I)ioflupane dopamine transporter (DAT) single-photon emission computer tomography scan, and diffusion tensor imaging. Fractional anisotropy as well as radial and axial diffusivity was computed within multiple regions across the substantia nigra., Results: A repeated-measures analysis of variance found a marginally nonsignificant interaction between regional fractional anisotropy of the substantia nigra and disease status (P = 0.08), conflicting with an earlier study. However, a linear mixed model that included control regions in addition to the nigral regions revealed a significant interaction between regions and disease status (P = 0.002), implying a characteristic distribution of reduced fractional anisotropy across the substantia nigra in PD. Reduced fractional anisotropy in PD was also associated with diminished DAT binding ratios. Both axial and radial diffusivity were also abnormal in PD., Conclusions: Although routine nigral measurements of fractional anisotropy are clinically not helpful, the findings in this study suggest that more-sophisticated diffusion imaging protocols should be used when exploring the clinical utility of this imaging modality., (© 2015 International Parkinson and Movement Disorder Society.)

Background and Methods: To investigate the possible efficacy of an elastic abdominal binder to control orthostatic hypotension (OH) associated with Parkinson's disease (PD), 15 patients with PD and OH were enrolled in a single-blind crossover study with elastic abdominal versus placebo binder on two different days, separated by a 1-day interval, followed by a 4-week open-label follow-up., Results: Intervention significantly reduced blood pressure fall upon tilting. The mean difference (standard deviation; 95% confidence intervals) between abdominal binder versus placebo was +10 mm Hg (10.2; +3.5, +16.5; P = 0.006). No significant effect on supine mean blood pressure values was observed compared to placebo ( P = 0.3). Symptoms of OH decreased significantly during follow-up ( P = 0.003), as assessed by means of the Orthostatic Hypotension Questionnaire., Conclusions: Our findings suggest that elastic abdominal binders may be a simple complementary tool to alleviate OH in PD.

Early diagnosis of Alzheimer`s disease (AD) is currently difficult and involves a complex approach including clinical assessment, neuroimaging, and measurement of amyloid-β (Aβ) and tau levels in cerebrospinal fluid (CSF). A better mechanistic understanding is needed to develop more accurate and even presymptomatic diagnostic tools. It has been shown that Aβ derived from amyloid-containing brain tissue has prion-like properties: it induces misfolding and aggregation of Aβ when injected into human amyloid precursor protein (APP) transgenic mice. In contrast, Aβ in the CSF has been less studied, and it is not clear whether it also exhibits prion-like characteristics, which might provide a sensitive diagnostic tool. Therefore, we collected CSF from APP transgenic mice carrying the Swedish mutation (APP23 mice), and injected it intracerebrally into young mice from the same transgenic line. We found that CSF derived Aβ did not induce increased β-amyloidosis, even after long incubation periods and additional concentration. This suggests that Aβ present in the CSF does not have the same prion-like properties as the Aβ species in the brain.

Eukaryotic organisms use conserved checkpoint mechanisms that regulate Cdk1 by inhibitory phosphorylation to prevent mitosis from interfering with DNA replication or repair. In metazoans, this checkpoint mechanism is also used for coordinating mitosis with dynamic developmental processes. Inhibitory phosphorylation of Cdk1 is catalyzed by Wee1 kinases that phosphorylate tyrosine 15 (Y15) and dual-specificity Myt1 kinases found only in metazoans that phosphorylate Y15 and the adjacent threonine (T14) residue. Despite partially redundant roles in Cdk1 inhibitory phosphorylation, Wee1 and Myt1 serve specialized developmental functions that are not well understood. Here, we expressed wild-type and phospho-acceptor mutant Cdk1 proteins to investigate how biochemical differences in Cdk1 inhibitory phosphorylation influence Drosophila imaginal development. Phosphorylation of Cdk1 on Y15 appeared to be crucial for developmental and DNA damage-induced G2-phase checkpoint arrest, consistent with other evidence that Myt1 is the major Y15-directed Cdk1 inhibitory kinase at this stage of development. Expression of non-inhibitable Cdk1 also caused chromosome defects in larval neuroblasts that were not observed with Cdk1(Y15F) mutant proteins that were phosphorylated on T14, implicating Myt1 in a novel mechanism promoting genome stability. Collectively, these results suggest that dual inhibitory phosphorylation of Cdk1 by Myt1 serves at least two functions during development. Phosphorylation of Y15 is essential for the premitotic checkpoint mechanism, whereas T14 phosphorylation facilitates accumulation of dually inhibited Cdk1-Cyclin B complexes that can be rapidly activated once checkpoint-arrested G2-phase cells are ready for mitosis.

There is pivotal evidence that tau pathology can be triggered by amyloid-β (Aβ) pathology in experimental systems. On the other side, studies on human brain specimen have elucidated that tau pathology may occur before amyloid pathology is present indicating that in principle tau pathology could also trigger Aβ aggregation. To address this question, we have crossed 5XFAD mice coexpressing human mutant APP695 with the Swedish, Florida, and London mutations and human mutant presenilin-1 (PS1) with the M146L and L286V mutations with the PS19 model overexpressing human mutant tau with the P301S mutation. The resulting triple transgenic model 5XFAD/PS19 has been characterized at 3 and 9 months of age. A dramatic aggravation of hyperphosphorylated tau pathology together with a dramatically increased inflammatory response and a loss of synapses and hippocampal CA1 neurons in aged 5XFAD/PS19 mice were observed. Extracellular amyloid deposits were unaltered. These data support the assumption of tau pathology being downstream of amyloid pathology, suggesting that both pathologies together trigger the severe neuron loss in the hippocampus in the 5XFAD/PS19 mouse model., (Copyright © 2013 Elsevier Inc. All rights reserved.)

We have developed a compact microbeam radiation therapy device using carbon nanotube cathodes to create a linear array of narrow focal line segments on a tungsten anode and a custom collimator assembly to select a slice of the resulting wedge-shaped radiation pattern. Effective focal line width was measured to be 131 μ m, resulting in a microbeam width of ∼300 μ m. The instantaneous dose rate was projected to be 2 Gy/s at full-power. Peak to valley dose ratio was measured to be >17 when a 1.4 mm microbeam separation was employed. Finally, multiple microbeams were delivered to a mouse with beam paths verified through histology.

Centromeres are specified epigenetically in animal cells. Therefore, faithful chromosome inheritance requires accurate maintenance of epigenetic centromere marks during progression through the cell cycle. Clarification of the mechanisms that control centromere protein behavior during the cell cycle should profit from the relatively simple protein composition of Drosophila centromeres. Thus we have analyzed the dynamics of the three key players Cid/Cenp-A, Cenp-C and Cal1 in S2R+ cells using quantitative microscopy and fluorescence recovery after photobleaching, in combination with novel fluorescent cell cycle markers. As revealed by the observed protein abundances and mobilities, centromeres proceed through at least five distinct states during the cell cycle, distinguished in part by unexpected Cid behavior. In addition to the predominant Cid loading onto centromeres during G1, a considerable but transient increase was detected during early mitosis. A low level of Cid loading was detected in late S and G2, starting at the reported time of centromere DNA replication. Our results reveal the complexities of Drosophila centromere protein dynamics and its intricate coordination with cell cycle progression.

N-truncated Aβ4-42 is highly abundant in Alzheimer disease (AD) brain and was the first Aβ peptide discovered in AD plaques. However, a possible role in AD aetiology has largely been neglected. In the present report, we demonstrate that Aβ4-42 rapidly forms aggregates possessing a high aggregation propensity in terms of monomer consumption and oligomer formation. Short-term treatment of primary cortical neurons indicated that Aβ4-42 is as toxic as pyroglutamate Aβ3-42 and Aβ1-42. In line with these findings, treatment of wildtype mice using intraventricular Aβ injection induced significant working memory deficits with Aβ4-42, pyroglutamate Aβ3-42 and Aβ1-42. Transgenic mice expressing Aβ4-42 (Tg4-42 transgenic line) developed a massive CA1 pyramidal neuron loss in the hippocampus. The hippocampus-specific expression of Aβ4-42 correlates well with age-dependent spatial reference memory deficits assessed by the Morris water maze test. Our findings indicate that N-truncated Aβ4-42 triggers acute and long-lasting behavioral deficits comparable to AD typical memory dysfunction.

Parkinson's disease (PD) is the second most common neurodegenerative disorder that affects approximately 1 % of people over the age of 60 years. Accurate diagnosis and individualized assessment of the risks and benefits of available antiparkinsonian medications as well as specific clinical features and the phase of disease should guide treatment for patients with PD. Levodopa still remains the gold standard for the treatment of motor symptoms of PD but dopamine agonists (DAs), catechol-O-methyltransferase (COMT) inhibitors and monoamine oxidase B (MAO-B) inhibitors have also been developed to provide more continuous oral delivery of dopaminergic stimulation in order to improve motor outcomes and decrease the risk of levodopa-induced motor complications. Deep-brain stimulation as well as other invasive therapies can be used for the treatment of drug-refractory levodopa-induced motor complications. Despite all of the therapeutic advances achieved within the last 20 years, PD continues to be a progressive disorder leading to severe disability caused by motor and non-motor symptoms. To date, neuroprotective interventions able to modify PD progression are not available. This review focuses on medical and invasive treatment strategies for early and advanced stages of PD as well as on the treatment of PD non-motor symptoms such as mood and behavioural disorders, cognitive and autonomic dysfunction, and sleep disorders, which can antedate PD motor symptoms for years.

Background: Microarray technology may offer a new opportunity to gain insight into disease-specific global protein expression profiles. The present study was performed to apply a serum antibody microarray to screen for differentially regulated cytokines in Parkinson's disease (PD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS)., Results: Serum samples were obtained from patients with clinical diagnoses of PD (n = 117), MSA (n = 31) and PSP/CBS (n = 38) and 99 controls. Cytokine profiles of sera from patients and controls were analyzed with a semiquantitative human antibody array for 174 cytokines and the expression of 12 cytokines was found to be significantly altered. In a next step, results from the microarray experiment were individually validated by different immunoassays. Immunoassay validation confirmed a significant increase of median PDGF-BB levels in patients with PSP/CBS, MSA and PD and a decrease of median prolactin levels in PD. However, neither PDGF-BB nor prolactin were specific biomarkers to discriminate PSP/CBS, MSA, PD and controls., Conclusions: In our unbiased cytokine array based screening approach and validation by a different immunoassay only two of 174 cytokines were significantly altered between patients and controls.

Purpose: In conventional Digital Breast Tomosynthesis (DBT) systems a single x-ray source moves over a limited angle arc. This leads to motion blurring in the projection images associated with x-ray source motion and total scan times. We have developed a stationary DBT (s-DBT) system which forgoes a rotating source for an array of carbon nanotube (CNT) based x-ray sources. Here we report the results of evaluating the performance and the optimization of image acquisition parameters of the s-DBT system., Methods: The s-DBT system consists of a linear source array with 31 x-ray generating focal spots distributed over a 30 degree angular span. The source array has been retrofitted onto a Hologic Selenia Dimensions DBT system. An American College of Radiology accreditation phantom was imaged to assess the quality of the reconstruction images in different configurations. A line wire phantom is used to measure the modulation transfer function (MTF)., Results: For the standard imaging protocol, the system resolution along the scanning direction is increased from 3.0 cycles/mm in DBT to 4.2 cycles/mm in s-DBT at a magnification factor of 1.08. The MTF did not have a noticeable change between different configurations, whereas in DBT the MTF can be degraded for larger angular spans due to faster x-ray source motion. The overall image quality factor is found to be best for the configuration with a large angular span and intermittent number of projection views., Conclusions: We demonstrated successful construction and operation of the s-DBT system integrating a CNT x-ray source array with a Hologic DBT system. The spatial resolution of the s-DBT system is demonstrated to be substantially increased over the corresponding DBT system. It was found that a configuration with a large angular span, an intermittent number of projection views, and an even dose distribution resulted in the best overall image quality. Hologic INC has provided the Hologic Selenia Dimensions used in the research. The project is supported by the National Cancer Institute under grant number U54CA119343 and R01CA134598 and the UNC University Cancer Research Fund. Dr. Xin Qian is supported by a fellowship from the Department of Defense under grant number BC087505., (© 2012 American Association of Physicists in Medicine.)

Purpose: The purpose of this study is to investigate the feasibility of increasing the system spatial resolution and scanning speed of Hologic Selenia Dimensions digital breast tomosynthesis (DBT) scanner by replacing the rotating mammography x-ray tube with a specially designed carbon nanotube (CNT) x-ray source array, which generates all the projection images needed for tomosynthesis reconstruction by electronically activating individual x-ray sources without any mechanical motion. The stationary digital breast tomosynthesis (s-DBT) design aims to (i) increase the system spatial resolution by eliminating image blurring due to x-ray tube motion and (ii) reduce the scanning time. Low spatial resolution and long scanning time are the two main technical limitations of current DBT technology., Methods: A CNT x-ray source array was designed and evaluated against a set of targeted system performance parameters. Simulations were performed to determine the maximum anode heat load at the desired focal spot size and to design the electron focusing optics. Field emission current from CNT cathode was measured for an extended period of time to determine the stable life time of CNT cathode for an expected clinical operation scenario. The source array was manufactured, tested, and integrated with a Selenia scanner. An electronic control unit was developed to interface the source array with the detection system and to scan and regulate x-ray beams. The performance of the s-DBT system was evaluated using physical phantoms., Results: The spatially distributed CNT x-ray source array comprised 31 individually addressable x-ray sources covering a 30 angular span with 1 pitch and an isotropic focal spot size of 0.6 mm at full width at half-maximum. Stable operation at 28 kV(peak) anode voltage and 38 mA tube current was demonstrated with extended lifetime and good source-to-source consistency. For the standard imaging protocol of 15 views over 14, 100 mAs dose, and 2 × 2 detector binning, the projection resolution along the scanning direction increased from 4.0 cycles/mm [at 10% modulation-transfer-function (MTF)] in DBT to 5.1 cycles/mm in s-DBT at magnification factor of 1.08. The improvement is more pronounced for faster scanning speeds, wider angular coverage, and smaller detector pixel sizes. The scanning speed depends on the detector, the number of views, and the imaging dose. With 240 ms detector readout time, the s-DBT system scanning time is 6.3 s for a 15-view, 100 mAs scan regardless of the angular coverage. The scanning speed can be reduced to less than 4 s when detectors become faster. Initial phantom studies showed good quality reconstructed images., Conclusions: A prototype s-DBT scanner has been developed and evaluated by retrofitting the Selenia rotating gantry DBT scanner with a spatially distributed CNT x-ray source array. Preliminary results show that it improves system spatial resolution substantially by eliminating image blur due to x-ray focal spot motion. The scanner speed of s-DBT system is independent of angular coverage and can be increased with faster detector without image degration. The accelerated lifetime measurement demonstrated the long term stability of CNT x-ray source array with typical clinical operation lifetime over 3 years.

Studies have shown that digital breast tomosynthesis (DBT) can improve breast cancer diagnosis by reconstructing 3D images. However, DBT scanners based on rotation gantry prolong the imaging time and reduce spatial resolution due to motion comparing with the regular two-view mammography. To obtain three dimension reconstruction images and maintain the high image quality of conventional mammography, we proposed a prototype stationary digital breast tomosynthesis system (s-DBT). The proposed s-DBT system acquires projection images without mechanical movement. The core component of the s-DBT system is a specially designed spatially distributed multi-beam x-ray tube based on the carbon nanotube field emission x-ray technology. The multi-beam x-ray source array enables collection of all projection images from different viewing angles without mechanical motion. Preliminary results show the s-DBT system can achieve a scan time comparable to the regular two-view mammography, and improve the spatial resolution comparing with rotating gantry DBT.

Tomosynthesis requires projection images from different viewing angles. Using a distributed x-ray source this can be achieved without mechanical motion of the source with the potential for faster image acquisition speed. A distributed x-ray tube has been designed and manufactured specifically for breast tomosynthesis. The x-ray tube consists of 31 field emission x-ray sources with an angular range of 30°. The total dose is up to 100mAs with an energy range between 27 and 45 kVp. We discuss the source geometry and results from the characterization of the first prototype. The x-ray tube uses field emission cathodes based on carbon nanotubes (CNT) as electron source. Prior to the manufacturing of the sealed x-ray tube extensive testing on the field emission cathodes has been performed to verify the requirements for commercial tomosynthesis systems in terms of emission current, focal spot size and tube lifetime.

The prosoma of spiders bears different gnathal (labrum, chelicerae, pedipalps) and locomotory appendages (legs). In most species these appendages are also used for additional functions, e.g. sensing, mating, and courtship. The opisthosoma is equipped with four pairs of highly specialized appendages. Two pairs of spinnerets are used for silk production and manipulation. The other two pairs of appendages are internalized during development and give rise to a complex respiratory system of book lungs and tracheae. Thus spiders have a number of different appendage types with radically different adult morphologies. Furthermore, all these appendage types display significant additional species specific diversity correlating with a large spectrum of functions of the appendages. Despite this importance of appendage diversity for the evolution of the spiders we know relatively little about the genetic patterning mechanisms producing this diversity of morphology. We review recent advances concerning the developmental genetics of spider appendage diversification, mainly concentrating on open questions and future directions of research. We conclude that the deeper understanding of appendage development and diversity in spiders can contribute significantly not only to evolutionary developmental biology, but also to behavioral biology, speciation research and population genetics, and the study of sexually dimorphic traits., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Tomosynthesis imaging requires projection images from different viewing angles. Conventional systems use a moving xray source to acquire the individual projections. Using a stationary distributed x-ray source with a number of sources that equals the number of required projections, this can be achieved without any mechanical motion. Advantages are a potentially faster image acquisition speed, higher spatial and temporal resolution and simple system design. We present distributed x-ray sources based on carbon nanotube (CNT) field emission cathodes. The field emission cathodes deliver the electrons required for x-ray production. CNT emitters feature a stable emission at high current density, a cold emission, excellent temporal control of the emitted electrons and good configurability. We discuss the use of stationary sources for two applications: (i) a linear tube for stationary digital breast tomosynthesis (sDBT), and (ii) a square tube for on-board tomosynthesis image-guided radiation therapy (IGRT). Results from high energy distributed sources up to 160kVp are also presented.

Caenorhabditis elegans is an excellent model to observe cell movements and shape changes during the morphogenesis of the egg-shaped embryo into an elongated tube-like larva. Although much is known about the structural determinants involved in epidermal morphogenesis, relatively little is known about the transcriptional and post-transcriptional regulatory networks involved. Here, we describe the identification and functional characterization of the novel nuclear protein VAB-23, which belongs to a conserved protein family found in all metazoans. C. elegans VAB-23 is essential for ventral closure and elongation of the embryo. Time-lapse analysis indicates that VAB-23 is required for the formation of proper cell contacts between contralateral pairs of ventral epidermal cells. Tissue-specific rescue experiments reveal a function of VAB-23 in ventral neuroblasts that control the enclosure of the embryo by the overlaying epidermal cells. Finally, we provide evidence suggesting a role of VAB-23 in post-transcriptional gene regulation. We thus propose that VAB-23 regulates the expression of multiple secreted guidance cues in ventral neuroblasts that direct the migration of the overlaying epidermal cells. Members of the VAB-23 family may perform similar functions during morphogenesis in other metazoans.

The authors present the design and simulation of an imaging system that employs a compact multiple source x-ray tube to produce a tomosynthesis image from a set of projections obtained at a single tube position. The electron sources within the tube are realized using cold cathode carbon nanotube technology. The primary intended application is tomosynthesis-based 3D image guidance during external beam radiation therapy. The tube, which is attached to the gantry of a medical linear accelerator (linac) immediately below the multileaf collimator, operates within the voltage range of 80-160 kVp and contains a total of 52 sources that are arranged in a rectilinear array. This configuration allows for the acquisition of tomographic projections from multiple angles without any need to rotate the linac gantry. The x-ray images are captured by the same amorphous silicon flat panel detector employed for portal imaging on contemporary linacs. The field of view (FOV) of the system corresponds to that part of the volume that is sampled by rays from all sources. The present tube and detector configuration provides an 8 x 8 cm2 FOV in the plane of the linac isocenter when the 40.96 x 40.96 cm2 imaging detector is placed 40 cm from the isocenter. Since this tomosynthesis application utilizes the extremities of the detector to record image detail relating to structures near the isocenter, simultaneous treatment and imaging is possible for most clinical cases, where the treated target is a small region close to the linac isocenter. The tomosynthesis images are reconstructed using the simultaneous iterative reconstruction technique, which is accelerated using a graphic processing unit. The authors present details of the system design as well as simulated performance of the imaging system based on reprojections of patient CT images.

Endoreplicating cells undergo multiple rounds of DNA replication leading to polyploidy or polyteny. Oscillation of Cyclin E (CycE)-dependent kinase activity is the main driving force in Drosophila endocycles. High levels of CycE-Cdk2 activity trigger S phase, while down-regulation of CycE-Cdk2 activity is crucial to allow licensing of replication origins. In mitotic cells relicensing in S phase is prevented by Geminin. Here we show that Geminin protein oscillates in endoreplicating salivary glands of Drosophila. Geminin levels are high in S phase, but drop once DNA replication has been completed. DNA licensing is coupled to mitosis through the action of the anaphase-promoting complex/cyclosome (APC/C). We demonstrate that, even though endoreplicating cells never enter mitosis, APC/C activity is required in endoreplicating cells to mediate Geminin oscillation. Down-regulation of APC/C activity results in stabilization of Geminin protein and blocks endocycle progression. Geminin is only abundant in cells with high CycE-Cdk2 activity, suggesting that APC/C-Fzr activity is periodically inhibited by CycE-Cdk2, to prevent relicensing in S-phase cells.

Term energies for dielectronic-recombination Rydberg resonances below 0.07 eV are determined for Sc18+ with absolute accuracies below 0.0002 eV by electron collision spectroscopy in an ion storage ring, using the twin-electron-beam technique and a cryogenic photocathode. The lithiumlike 2s_{1/2}-2p_{3/2} transition energy for Z=21 is determined to 4.6 ppm, less than 1% of the few-body effects on radiative corrections. Features from the hyperfine structure of the 2s state could be resolved in the dielectronic-recombination spectrum.

Cyclin A is targeted for mitotic destruction by the anaphase promoting complex/cyclosome (APC/C) and degradation proceeds even when proteolysis of other APC/C substrates are blocked by the spindle assembly checkpoint. Instead of a simple destruction box, a complex N-terminal destruction signal has been implicated in Cyclin A. We show here that Drosophila Cyclin A destruction employs both N- and C-terminal residues, which emphasize that a synergistic action by different parts of the protein facilitates recognition and degradation. The first KEN box, first D-box and an aspartic acid at position 70 are required at the N-terminus and they make additive contributions when the spindle checkpoint is active. From the C-terminal region, the cyclin box contributes. Single point mutations in these four elements abolish mitotic destruction. Additionally, eight lysines in the neighborhood of the N-terminal signals, which could serve as potential ubiquitin acceptor sites, are preferentially used for proteolysis. Mutations in these lysines and the N-terminal signals cause mitotic stability. However, mutating the lysines alone, only delays mitotic progression. Thus, presumably, lysines elsewhere in the protein are used when the preferred ones are absent and this requires the N-terminal signals. Furthermore, our results suggest that some function of the cyclin box other than Cdk1 binding promotes spindle checkpoint-independent recognition of Cyclin A by the APC/C.

Rca1 (regulator of Cyclin A)/Emi (early mitotic inhibitor) proteins are essential inhibitors of the anaphase-promoting complex/cyclosome (APC/C). In Drosophila, Rca1 is required during G2 to prevent premature cyclin degradation by the Fizzy-related (Fzr)-dependent APC/C activity. Here, we present a structure and function analysis of Rca1 showing that a carboxy-terminal fragment is sufficient for APC/C inhibition. Rca1/Emi proteins contain a conserved F-box and interact with components of the Skp-Cullin-F-box (SCF) complex. So far, no function has been ascribed to this domain. We find that the F-box of Rca1 is dispensable for APC/C-Fzr inhibition during G2. Nevertheless, we show that Rca1 has an additional function at the G1-S transition, which requires the F-box. Overexpression of Rca1 accelerates the G1-S transition in an F-box-dependent manner. Conversely, S-phase entry is delayed in cells in which endogenous Rca1 is replaced by a transgene lacking the F-box. We propose that Rca1 acts as an F-box protein in an as yet uncharacterized SCF complex, which promotes S-phase entry.

The energy-resolved rate coefficient for the dissociative recombination (DR) of H(3)(+) with slow electrons has been measured by the storage-ring method using an ion beam produced from a radiofrequency multipole ion trap, employing buffer-gas cooling at 13 K. The electron energy spread of the merged-beams measurement is reduced to 500 microeV by using a cryogenic GaAs photocathode. This and a previous cold- measurement jointly confirm the capability of ion storage rings, with suitable ion sources, to store and investigate H(3)(+) in the two lowest, (J,G) = (1,1) and (1,0) rotational states prevailing also in cold interstellar matter. The use of para-H(2) in the ion source, expected to enhance para-H(3)(+) in the stored ion beam, is found to increase the DR rate coefficient at meV electron energies.

Cyclin A (CycA), the only essential mitotic cyclin in Drosophila, is cytoplasmic during interphase and accumulates in the nucleus during prophase. We show that interphase localization is mediated by Leptomycin B (LMB)-sensitive nuclear export. This is a feature shared with human CyclinB1, and it is assumed that nuclear accumulation is necessary for mitotic entry. Here, we tested if the unique mitotic function of CycA requires nuclear accumulation. We fused subcellular localization signals to CycA and tested their mitotic capability. Surprisingly, nuclear accumulation was not required, and even a membrane-tethered form of CycA was able to induce mitosis. We noted that Cyclin B (CycB) protein disappears prematurely in CycA mutants, reminiscent of rca1 mutants. Rca1 is an inhibitor of Fizzy-related-APC/C activity, and in rca1 mutants, mitotic cyclins are degraded in G2 of the 16(th) embryonic cell cycle. Overexpression of Rca1 can restore mitosis in CycA mutants, indicating that the mitotic failure of CycA mutants is caused by premature activation of the APC/C. The essential mitotic function of CycA is therefore not the activation of numerous mitotic substrates by Cdk1-dependent phosphorylation. Rather, CycA-dependent kinase activity is required to inhibit one inhibitor of mitosis, the Fzr protein.