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Four-post buildings were found in the Outer Camp on a 1 in 6 slope, facing north-east. They had been rebuilt several times since their foundation c. 900 B.C. and were burnt c. 420 B.C. The village was then reduced to the Inner Camp but within a hundred years the Outer Camp was probably re-occupied. The hill fort was finally abandoned following afire at about the time of the Roman advance c. A.D. 50. [ABSTRACT FROM AUTHOR]

Computerized tomography (CT) of the brain has been available since 1973 and has changed neurological, neurosurgical and radiological practice beyond recognition. A rapid growth of literature has documented it role in the diagnosis of intracranial hematoma, cerebral atrophy, brain tumor, orbital lesions and postoperative tumor evaluation. This computerized method of image reconstruction is now also being applied to the rest of the body and to other diagnostic modalities such as isotopes and ultrasound. The initial impact of CT scanning in otolaryngology is largely in four areas: 1. Facial deformities either acquired or congenital as hypertelorism, fibrous dysplasia, ossifying fibroma and Crouzon's disease. 2. Tumors involving sinuses primarily or by secondary invasion. 3. Cerebello-pontine angle lesions as meningiomas, acoustic neuromas, and glomus jugulare tumors. The larger acoustic neuroma is well visualized by this technique rendering contrast myelography unnecessary. In CT scanning, subtle differences in position and an increase in density before contrast enhancement should allow a differentiation of angle meningiomas from acoustic neuromas; in addition, CT scanning has a very important role in the postoperative assessment of angle tumors. 4. Infections as cerebral abscess or cerebritis secondary to sinus or mastoid disease. The future holds changes that will allow much finer detail, re-orientation of the horizontal information into any plane, and much more accurate differentiation of tissue density. The principle of CT image reconstruction is being applied to both isotope and ultrasound scanning and should improve their accuracy and yield. If the rapid growth of the new technology over the past two years continues, even greater usefulness can be anticipated. [ABSTRACT FROM AUTHOR]

Deep skin wounds represent a serious condition and frequently require split-thickness skin grafts (STSG) to heal. The application of autologous human-skin-cell-suspension (hSCS) requires less donor skin than STSG without compromising the healing capacity. Impaired function and replicative ability of senescent cutaneous cells in the aging skin affects healing with autologous hSCS. Major determinants of senescence are telomere erosion and DNA damage. Human telomerase reverse transcriptase (hTERT) adds telomeric repeats to the DNA and can protect against DNA damage. Herein, hTERT mRNA lipid nanoparticles (LNP) are proposed and evaluated for enhancing cellular engraftment and proliferation of hSCS. Transfection with optimized hTERT mRNA LNP system enables delivery and expression of mRNA in vitro in keratinocytes, fibroblasts, and in hSCS prepared from donors' skin. Telomerase activity in hSCS is significantly increased. hTERT mRNA LNP enhance the generation of a partial-thickness human skin equivalent in the mouse model, increasing hSCS engraftment (Lamin) and proliferation (Ki67), while reducing cellular senescence (p21) and DNA damage (53BP1)., (© 2023 Wiley-VCH GmbH.)

Objective: To observe and describe the development and underlying structure of the spinal manifestations of individuals osteologically diagnosed with DISH (Diffuse Idiopathic Skeletal Hyperostosis), using micro-XCT imaging., Materials: A total of 72 individuals with DISH were identified in two modern skeletal collections in South Africa., Methods: Vertebral columns affected by DISH were scanned at the micro-focus x-ray computed tomography facility at the Nuclear Energy Corporation of South Africa. Four features were macroscopically examined: (1) the origin of the new bone growth; (2) retention of the original vertebral cortex at the site of the new bone formation associated with DISH; (3) evidence of trabecular bone with or without sclerosis on the anterolateral surface of affected vertebrae; and (4) abnormal areas of osteosclerosis beyond features associated with DISH., Results: Considerable variation across and between the four recorded features was found. Of note, 81% (n = 58) of individuals had both developed trabecular bone within the flowing new bone formation (feature 3), without retention of the original vertebral cortex (feature 2)., Conclusions: Possible localised erosive/inflammatory processes destroyed the original cortex of the vertebral body and resulted in the expansion of trabeculae with new bone formation., Significance: Micro-XCT imaging shed new light on the development of DISH, adding to literature suggesting that it could be an inflammatory disease., Limitations: Clinical histories of the individuals were not known., Suggestions for Further Research: The role of chronic inflammatory disease in the development of DISH should be further explored including both the extra-spinal and spinal manifestations., Competing Interests: Declarations of conflicts of interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Metastasis to the brain is a major challenge with poor prognosis. The blood-brain barrier (BBB) is a significant impediment to effective treatment, being intact during the early stages of tumor development and heterogeneously permeable at later stages. Intravenous injection of tumor necrosis factor (TNF) selectively induces BBB permeabilization at sites of brain micrometastasis, in a TNF type 1 receptor (TNFR1)-dependent manner. Here, to enable clinical translation, we have developed a TNFR1-selective agonist variant of human TNF that induces BBB permeabilization, while minimizing potential toxicity., Methods: A library of human TNF muteins (mutTNF) was generated and assessed for binding specificity to mouse and human TNFR1/2, endothelial permeabilizing activity in vitro, potential immunogenicity, and circulatory half-life. The permeabilizing ability of the most promising variant was assessed in vivo in a model of brain metastasis., Results: The primary mutTNF variant showed similar affinity for human TNFR1 than wild-type human TNF, similar affinity for mouse TNFR1 as wild-type mouse TNF, undetectable binding to human/mouse TNFR2, low potential immunogenicity, and permeabilization of an endothelial monolayer. Circulatory half-life was similar to mouse/human TNF and BBB permeabilization was induced selectively at sites of micrometastases in vivo, with a time window of ≥24 hours and enabling delivery of agents within a therapeutically relevant range (0.5-150 kDa), including the clinically approved therapy, trastuzumab., Conclusions: We have developed a clinically translatable mutTNF that selectively opens the BBB at micrometastatic sites, while leaving the rest of the cerebrovasculature intact. This approach will open a window for brain metastasis treatment that currently does not exist., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Aims: Hutchinson-Gilford progeria syndrome (HGPS) is an accelerated ageing syndrome associated with premature vascular disease and death due to heart attack and stroke. In HGPS a mutation in lamin A (progerin) alters nuclear morphology and gene expression. Current therapy increases the lifespan of these children only modestly. Thus, greater understanding of the underlying mechanisms of HGPS is required to improve therapy. Endothelial cells (ECs) differentiated from induced pluripotent stem cells (iPSCs) derived from these patients exhibit hallmarks of senescence including replication arrest, increased expression of inflammatory markers, DNA damage, and telomere erosion. We hypothesized that correction of shortened telomeres may reverse these measures of vascular ageing., Methods and Results: We generated ECs from iPSCs belonging to children with HGPS and their unaffected parents. Telomerase mRNA (hTERT) was used to treat HGPS ECs. Endothelial morphology and functions were assessed, as well as proteomic and transcriptional profiles with attention to inflammatory markers, DNA damage, and EC identity genes. In a mouse model of HGPS, we assessed the effects of lentiviral transfection of mTERT on measures of senescence, focusing on the EC phenotype in various organs. hTERT treatment of human HGPS ECs improved replicative capacity; restored endothelial functions such as nitric oxide generation, acetylated low-density lipoprotein uptake and angiogenesis; and reduced the elaboration of inflammatory cytokines. In addition, hTERT treatment improved cellular and nuclear morphology, in association with a normalization of the transcriptional profile, effects that may be mediated in part by a reduction in progerin expression and an increase in sirtuin 1 (SIRT1). Progeria mice treated with mTERT lentivirus manifested similar improvements, with a reduction in inflammatory and DNA damage markers and increased SIRT1 in their vasculature and other organs. Furthermore, mTERT therapy increased the lifespan of HGPS mice., Conclusion: Vascular rejuvenation using telomerase mRNA is a promising approach for progeria and other age-related diseases., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Acetaminophen ( N -acetyl- p -aminophenol; APAP) toxicity is a common cause of liver damage. In the mouse model of APAP-induced liver injury (AILI), interleukin 11 (IL11) is highly up-regulated and administration of recombinant human IL11 (rhIL11) has been shown to be protective. Here, we demonstrate that the beneficial effect of rhIL11 in the mouse model of AILI is due to its inhibition of endogenous mouse IL11 activity. Our results show that species-matched IL11 behaves like a hepatotoxin. IL11 secreted from APAP-damaged human and mouse hepatocytes triggered an autocrine loop of NADPH oxidase 4 (NOX4)-dependent cell death, which occurred downstream of APAP-initiated mitochondrial dysfunction. Hepatocyte-specific deletion of Il11 receptor subunit alpha chain 1 ( Il11ra1 ) in adult mice protected against AILI despite normal APAP metabolism and glutathione (GSH) depletion. Mice with germline deletion of Il11 were also protected from AILI, and deletion of Il1ra1 or Il11 was associated with reduced c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) activation and quickly restored GSH concentrations. Administration of a neutralizing IL11RA antibody reduced AILI in mice across genetic backgrounds and promoted survival when administered up to 10 hours after APAP. Inhibition of IL11 signaling was associated with the up-regulation of markers of liver regenerations: cyclins and proliferating cell nuclear antigen (PCNA) as well as with phosphorylation of retinoblastoma protein (RB) 24 hours after AILI. Our data suggest that species-matched IL11 is a hepatotoxin and that IL11 signaling might be an effective therapeutic target for APAP-induced liver damage., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: Activation of the classical and lectin pathway of complement may contribute to tissue damage and organ dysfunction of antibody-mediated diseases and ischemia-reperfusion conditions. Complement factors are being considered as targets for therapeutic intervention., Objective: We sought to characterize ARGX-117, a humanized inhibitory monoclonal antibody against complement C2., Methods: The mode-of-action and binding characteristics of ARGX-117 were investigated in detail. Furthermore, its efficacy was analyzed in in vitro complement cytotoxicity assays. Finally, a pharmacokinetic/pharmacodynamic study was conducted in cynomolgus monkeys., Results: Through binding to the Sushi-2 domain of C2, ARGX-117 prevents the formation of the C3 proconvertase and inhibits classical and lectin pathway activation upstream of C3 activation. As ARGX-117 does not inhibit the alternative pathway, it is expected not to affect the antimicrobial activity of this complement pathway. ARGX-117 prevents complement-mediated cytotoxicity in in vitro models for autoimmune hemolytic anemia and antibody-mediated rejection of organ transplants. ARGX-117 exhibits pH- and calcium-dependent target binding and is Fc-engineered to increase affinity at acidic pH to the neonatal Fc receptor, and to reduce effector functions. In cynomolgus monkeys, ARGX-117 dose-dependently reduces free C2 levels and classical pathway activity. A 2-dose regimen of 80 and 20 mg/kg separated by a week, resulted in profound reduction of classical pathway activity lasting for at least 7 weeks., Conclusions: ARGX-117 is a promising new complement inhibitor that is uniquely positioned to target both the classical and lectin pathways while leaving the alternative pathway intact., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Current prosthetic ankle joints are designed either for walking or for running. In order to mimic the capabilities of an able-bodied, a powered prosthetic ankle for walking and running was designed. A powered system has the potential to reduce the limitations in range of motion and positive work output of passive walking and running feet., Methods: To perform the experiments a controller capable of transitions between standing, walking, and running with speed adaptations was developed. In the first case study the system was mounted on an ankle bypass in parallel with the foot of a non-amputee subject. By this method the functionality of hardware and controller was proven., Results: The Walk-Run ankle was capable of mimicking desired torque and angle trajectories in walking and running up to 2.6 m/s. At 4 m/s running, ankle angle could be matched while ankle torque could not. Limited ankle output power resulting from a suboptimal spring stiffness value was identified as a main reason., Conclusions: Further studies have to show to what extent the findings can be transferred to amputees.

Background: Ethanol is a potent teratogen. Its adverse neural effects are partly mediated by disrupting fetal neurogenesis. The teratogenic process is poorly understood, and vulnerable neurogenic stages have not been identified. Identifying these is a prerequisite for therapeutic interventions to mitigate effects of teratogen exposures., Methods: We used flow cytometry and qRT-PCR to screen fetal mouse-derived neurosphere cultures for ethanol-sensitive neural stem cell (NSC) subpopulations, to study NSC renewal and differentiation. The identity of vulnerable NSC populations was validated in vivo, using a maternal ethanol exposure model. Finally, the effect of ethanol exposure on the ability of vulnerable NSC subpopulations to integrate into the fetal neurogenic environment was assessed following ultrasound guided, adoptive transfer., Results: Ethanol decreased NSC mRNAs for c-kit, Musashi-1and GFAP. The CD24(+) NSC population, specifically the CD24(+)CD15(+) double-positive subpopulation, was selectively decreased by ethanol. Maternal ethanol exposure also resulted in decreased fetal forebrain CD24 expression. Ethanol pre-exposed CD24(+) cells exhibited increased proliferation, and deficits in cell-autonomous and cue-directed neuronal differentiation, and following orthotopic transplantation into naïve fetuses, were unable to integrate into neurogenic niches. CD24(depleted) cells retained neurosphere regeneration capacity, but following ethanol exposure, generated increased numbers of CD24(+) cells relative to controls., Conclusions: Neuronal lineage committed CD24(+) cells exhibit specific vulnerability, and ethanol exposure persistently impairs this population's cell-autonomous differentiation capacity. CD24(+) cells may additionally serve as quorum sensors within neurogenic niches; their loss, leading to compensatory NSC activation, perhaps depleting renewal capacity. These data collectively advance a mechanistic hypothesis for teratogenesis leading to microencephaly.

Ribosome display was applied to the Fc region of human immunoglobulin G (IgG1) to select for improved binding to human FcγRIIIa, the receptor expressed on human natural killer cells that mediates antibody-dependent cellular cytotoxicity (ADCC). A library of human Fcγ1 variants was generated using error-prone polymerase chain reaction, and subjected to multiple rounds of ribosome display selection against progressively decreasing concentrations of soluble human FcγRIIIa, to enrich for improved binders. Radioimmunoassay and alphascreen analyses of the aglycosylated IgG-Fc output revealed variants with improved binding to FcγRIIIa relative to wild-type IgG-Fc. Subsequent expression in human (HEK-EBNA) cells generated glycosylated IgGs with modified activity in ADCC assays. One particular variant, 125_B01 triggered enhanced ADCC (EC(50) up to four-fold reduced with increased maximal lysis) relative to wild-type antibody, having more equal levels of ADCC for each allotype (V158/F158) of FcγRIIIa. Deconvolution of individual replacements within the variant showed that improved function arose from the Phe243Leu replacement within the CH2 domain, rather than the CH3 domain replacements Thr393Ala or His433Pro. Surprisingly, the oligosaccharide profiles of 125_B01 indicated more oligosaccharide chains lacking fucose, or with bisecting N-acetylglucosamine relative to wild-type IgG1, which correlates with improved function and the replacement Phe243Leu that is a carbohydrate contact residue within the C(H)2 domain.

We describe a method for high-throughput, parallel purification of secreted proteins to analyse large numbers of protein samples in cell-based assays for the discovery of protein therapeutics. The procedure is generic and capable of 96 parallel purifications and compatible, in both yield and purity, with a wide assay range. By optimising expression and purification steps as well as using novel hardware, in particular a chromatography press capable to purify target proteins from viscous media, we exemplify the process for the generation of single-chain Fv antibody fragments (scFv) and the purification of full-length IgG. The described process can operate robustly with a throughput of over 2,000 samples per month., ((c) 2006 Wiley Periodicals, Inc.)

The tumour suppressor p53 is a multifunctional protein important for the maintenance of genomic integrity. It is able to form molecular complexes with different DNA targets and also with cellular proteins involved in DNA transcription and DNA repair. In mammalian cells the biochemical processing of DNA occurs on a nuclear sub-structure termed the nuclear matrix. Previously Deppert and co-workers have identified p53 in association with the nuclear matrix in viral- and non-viral transformed cell lines. In the present study we demonstrate, for the first time, that p53 is bound to the nuclear matrix in primary cultures of normal mammalian cells and that this binding increases following DNA damage. Analysis of cell lines expressing structural mutants of p53 revealed that association with the nuclear matrix is independent of the tertiary and quaternary structure of p53. However, the proline-rich domain towards the N-terminus of p53 (residues 67 to 98) appeared important for binding to the nuclear matrix. This was demonstrated by TET-ON regulated expression of p53-derived constructs in p53(-/-) murine embryonic fibroblasts (MEF p53(-/-)). The proline-rich domain of p53 has potential for SH3 protein-protein interaction, and has a role in p53-mediated apoptosis and possibly base excision repair of DNA damage. We discuss our observations in relation to the ability of p53 to facilitate DNA repair and also review evidence indicating that matrix-bound p53 in SV40-transformed cells may facilitate the transforming potential of SV40 large T antigen.

The role, techniques and tools of interventional neuroradiology are growing rapidly because of the number of active investigators. Training programs are being certified by the American Society of Neuroradiology. Recommendations are that Interventional Neuroradiologists be fully qualified in neuroradiology (two years) and have a one or two-year additional fellowship in interventional. The ideal interventionalist would also have some clinical neuroscience training. While these training requirements seem excessive on the surface one must recognize that with the overall drop in routine angiography that a longer exposure is necessary to acquire the prerequisite knowledge, skill and experience easily obtained in one year ten years ago. In fact there has been some pressure to place all of diagnostic neuroangiography in the hands of interventionalists. Endovascular approaches are the treatment of choice for: (1) cerebral vasospasm, (2) carotid cavernous fistulae, (3) vertebral artery origin stenosis, (4) subclavian artery stenosis, (5) innominate and left carotid origin stenosis, and (6) giant intracranial aneurysms. Endovascular treatment is developmental and should be restricted to centers performing formal trials in the treatment of: (1) cerebral arteriovenous malformations and (2) internal carotid artery and intracranial stenosis.

Magnetic resonance imaging (MRI) brain scans were performed on 12 patients with obsessive-compulsive disorder and 12 healthy controls. Measurements of the area of the head of the caudate nucleus, cingulate gyrus thickness, intracaudate/frontal horn ratio, and area of the corpus callosum did not differ between the two groups. These limited data do not support the presence of a consistent gross brain structural abnormality in obsessive-compulsive disorder. Further studies using other anatomic measurements and other brain structural imaging techniques are warranted.

Vascular anomalies of the middle ear are extremely rare. The most common anomaly is a persistent stapedial artery. This artery is important clinically because of the risk of profuse bleeding during middle ear surgery. We describe a 26-year-old woman with a glomus tympanicum tumor. The blood supply to the tumor was from a persistent stapedial artery. A preoperative angiogram supported this finding by demonstrating a small vessel originating from the anterior branch of the middle meningeal artery as the major vascular supply to the tumor. To our knowledge, this is the first case report of a glomus tympanicum tumor vascularized by a persistent stapedial artery that was suggested by angiography and confirmed intraoperatively. To better understand this anomaly, we review the embryological development of the stapedial artery and discuss its clinical significance.

Angioplasty of the proximal portions of major cerebral arteries at the base of the brain has shown promise as a therapy for symptomatic vasospasm after subarachnoid hemorrhage. The blind-ended, single-lumen balloon-dilatation catheter most widely used to date lacks steerability, limiting its application to unbranched stems and single branches at bi- or trifurcation points. To extend the capabilities of cerebral angioplasty, we describe two modifications of the basic technique that have allowed increased selectivity and successful angioplasty of multiple branches, both proximal and distal, involved by vasospasm. Of four patients treated, three showed early improvement in their clinical condition, likely attributable to the angioplasty procedure. Our modifications to the basic angioplasty technique enhanced its success. Further refinement of this technique in the treatment of vasospasm will make it safer in treating this serious and widespread disorder.

We treated a 5-year-old girl and a 6-year-old boy with acquired Brown's syndrome associated with pansinusitis. In both patients, the diagnosis was established roentgenographically, and the patients were treated with oral antibiotics. Systemic corticosteroids were used in one case, although their clinical value was uncertain. Patients presenting with acute-onset Brown's syndrome of undetermined cause should undergo computed imaging of the orbits and paranasal sinuses.

A woman with secondary amenorrhea was found to have hyperprolactinemia without clinical galactorrhea. Radiological findings of an enlarged sella turcica with displacement of the pituitary stalk were considered consistent with a prolactin macroadenoma. Treatment with bromocriptine corrected the amenorrhea and hyperprolactinemia, and the patient inadvertently became pregnant. However, no complications to the mother or fetus occurred during pregnancy or postpartum. On transsphenoidal surgery three months postpartum, the unexpected presence of a large Rathke's pouch cyst with a microadenomatous or nodular hyperplasia type of prolactin-secreting tumor was observed to account for the preoperative clinical and radiological findings.

Conventional radiology and selective complex-motion tomography suffice for the diagnosis of isolated facial fractures. Complex facial fractures, however, require a more directed diagnostic approach, utilizing the imaging potential of computed tomography (CT). In the acutely injured but stable patient, unenhanced axial CT (preview-monitored under clinical orientation) provides the most effective, safe, reasonably rapid diagnostic examination. Direct coronal CT can also be utilized. The brain is studied by contiguous 10 mm slices; the facial skeleton is studied with contiguous 5 mm slices, which permits coronal and sagittal reformations. In suspected cervical spine injury (where direct coronal CT is contraindicated), the axial CT format above will provide essential diagnostic information and allow image reconstruction. The late complications of brain abscess and CSF leak are well imaged by CT; the latter is best assessed (during activity) by preview-controlled CT after intrathecal injection of metrizamide.