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Deep vein thrombosis (DVT) and post-thrombotic syndrome (PTS) remain highly prevalent despite modern medical therapy. Contact activation is a promising target for safe antithrombotic anticoagulation. The anti-factor XI (FXI) monoclonal antibody 14E11 reduces circulating levels of FXI without compromising hemostasis. The human recombinant analog, AB023, is in clinical development. The role of FXI in mediation of inflammation during DVT resolution is unknown.Investigate the effects of pharmacological targeting of FXI with 14E11 in an experimental model of venous thrombosis.Adult wild-type CD1 mice were treated with subcutaneous anti-FXI antibody (14E11, 5 mg/kg) versus saline prior to undergoing surgical constriction of the inferior vena cava (IVC). Mice were evaluated at various time points to assess thrombus weight and volume, as well as histology analysis, ferumoxytol enhanced magnetic resonance imaging (Fe-MRI), and whole blood flow cytometry.14E11-treated mice had reduced thrombus weights and volumes after IVC constriction on day 7 compared to saline-treated mice. 14E11 treatment reduced circulating monocytes by flow cytometry and macrophage content within thrombi as evaluated by histologic staining and Fe-MRI. Collagen deposition was increased at day 3 while CD31 and smooth muscle cell actin expression was increased at day 7 in the thrombi of 14E11-treated mice compared to saline-treated mice.Pharmacologic targeting of FXI enhances the early stages of experimental venous thrombus resolution in wild-type CD1 mice, and may be of interest for future clinical evaluation of the antibody in DVT and PTS.

Chemotherapeutics play a significant role in the management of most brain tumors. First pass effect, systemic toxicity, and more importantly, the blood-brain barrier pose significant challenges to the success of chemotherapy. Over the last 80 years, different techniques of intraarterial chemotherapy delivery have been performed in many studies but failed to become standard of care. The purpose of this article is to review the history of intraarterial drug delivery and osmotic blood-brain barrier disruption, identify the challenges for clinical translation, and identify future directions for these approaches.

Ferumoxytol, an FDA-approved superparamagnetic iron oxide nanoparticle (SPION) preparation used for the treatment of iron deficiency anemia, is also known to be taken up by macrophages in areas of infection or inflammation, where it produces negative contrast changes on T2-weighted MR images.We sought to compare Ferumoxytol-induced MRI contrast changes with those observed using standard-of-care Gadolinium in patients presenting with symptoms suggestive of osteomyelitis.Out of eighteen enrolled patients, 15 had MR imaging with both ferumoxytol and gadolinium. Based on clinical and/or pathologic criteria, 7 patients were diagnosed with osteomyelitis, 5 patients had osteomyelitis ruled out, and in 3 patients a definitive diagnosis could not be made.1.5 Tesla.Used included STIR, T1-weighted and T2-weighted spin echo.The mean contrast changes upon ferumoxytol and gadolinium administration were measured from lesion regions of interest and compared with control regions.Student's t-test, propagation of errors. Data are reported as means ± S.E.The mean contrast changes, ΔC, associated with a diagnosis of osteomyelitis were found to be ΔCFe = -2.7 ± 0.7 when Ferumoxytol and T2w imaging sequences were used and ΔCGd = +3.1 ± 1.1 (P 0.001) when Gadolinium and a T1w imaging sequence was used. The MRI contrast changes for both agents correlated with systemic markers of inflammation, such as the erythrocyte sedimentation rate. In patients without osteomyelitis, no significant contrast changes were observed in T2-weighted, Ferumoxytol-contrasted MRI. The macrophages in osteomyelitic lesions were found to take up at least 16 times as much iron as benign bone marrow.We conclude that in terms of its MRI diagnostic accuracy for osteomyelitis Ferumoxytol-contrasted MRI is a promising approach for diagnosing osteomyelitis that merits further study.

Purpose High dose corticosteroids are an effective tool for rapidly alleviating neurologic symptoms caused by intracranial mass lesions. However, there is concern that preoperative corticosteroids limit the ability to obtain a definitive pathologic diagnosis, particularly if imaging features suggest primary central nervous system lymphoma (PCNSL). Methods To explore the impact of preoperative corticosteroids in newly diagnosed PCNSL patients, from 2009 to 2018 treated at our institution. Results We identified 54 patients; 18 had received corticosteroids prior to biopsy or resection. Only in one case did the patient have a prior non-diagnostic biopsy, requiring a second procedure. The cumulative doses of preoperative dexamethasone ranged from 4 mg to 120 mg (mean 32 mg, median 24 mg), given over 1–14 days (mean 2 days, median 1 day), and the majority had received corticosteroids for only 1–2 days. There was a trend for a larger diameter of lesional T1 contrast enhancement for patients who received steroids (39 mm vs. 34 mm, p = 0.11). In this series of cases with pathologically and clinically proven PCNSL, preoperative corticosteroids had been given in a third of cases, suggesting that they may be given for symptomatic relief without compromising pathologic diagnosis. Conclusions Despite the commonly held tenet that preoperative corticosteroids can obscure the pathologic diagnosis in PCNSL, this is likely not the case in the majority of patients who receive a short course preoperatively. Obtaining a second stereotactic scan to confirm continued presence of the lesion prior to tissue sampling may also mitigate these concerns.

Contrast-enhanced magnetic resonance imaging is a commonly used diagnostic tool. Compared with standard gadolinium-based contrast agents, ferumoxytol (Feraheme, AMAG Pharmaceuticals, Waltham, MA), used as an alternative contrast medium, is feasible in patients with impaired renal function. Other attractive imaging features of i.v. ferumoxytol include a prolonged blood pool phaseand delayed intracellular uptake. With its unique pharmacologic, metabolic, and imaging properties, ferumoxytol may play a crucial role in future magnetic resonance imaging of the central nervous system, various organs outside the central nervous system, and the cardiovascular system. Preclinical and clinical studies have demonstrated the overall safety and effectiveness of this novel contrast agent, with rarely occurring anaphylactoid reactions. The purpose of this review is to describe the general and organ-specific properties of ferumoxytol, as well as the advantages and potential pitfalls associated with its use in magnetic resonance imaging. To more fully demonstrate the applications of ferumoxytol throughout the body, an imaging atlas was created and is available online as supplementary material.

The mammalian brain is supplied with blood by specialized vasculature that is structurally and functionally distinct from that of the periphery. A defining feature of this vasculature is a physical blood-brain barrier (BBB). The BBB separates blood components from the brain microenvironment, regulating the entry and exit of ions, nutrients, macromolecules, and energy metabolites. Over the last two decades, physiological studies of cerebral blood flow dynamics have demonstrated that substantial intercellular communication occurs between cells of the vasculature and the neurons and glia that abut the vasculature. These findings suggest that the BBB does not function independently, but as a module within the greater context of a multicellular neurovascular unit (NVU) that includes neurons, astrocytes, pericytes, and microglia as well as the blood vessels themselves. Here, we describe the roles of these NVU components as well as how they act in concert to modify cerebrovascular function and permeability in health and in select diseases.

Summary Background Sodium thiosulfate is an antioxidant shown in preclinical studies in animals to prevent cisplatin-induced hearing loss with timed administration after cisplatin without compromising the antitumour efficacy of cisplatin. The primary aim of this study was to assess sodium thiosulfate for prevention of cisplatin-induced hearing loss in children and adolescents. Methods ACCL0431 was a multicentre, randomised, open-label, phase 3 trial that enrolled participants at 38 participating Children's Oncology Group hospitals in the USA and Canada. Eligible participants aged 1–18 years with newly diagnosed cancer and normal audiometry were randomly assigned (1:1) to receive sodium thiosulfate or observation (control group) in addition to their planned cisplatin-containing chemotherapy regimen, using permuted blocks of four. Randomisation was initially stratified by age and duration of cisplatin infusion. Stratification by previous cranial irradiation was added later as a protocol amendment. The allocation sequence was computer-generated centrally and concealed to all personnel. Participants received sodium thiosulfate 16 g/m 2 intravenously 6 h after each cisplatin dose or observation. The primary endpoint was incidence of hearing loss 4 weeks after final cisplatin dose. Hearing was measured using standard audiometry and reviewed centrally by audiologists masked to allocation using American Speech-Language-Hearing Association criteria but treatment was not masked for participants or clinicians. Analysis of the primary endpoint was by modified intention to treat, which included all randomly assigned patients irrespective of treatment received but restricted to those assessable for hearing loss. Enrolment is complete and this report represents the final analysis. This trial is registered with ClinicalTrials.gov, number NCT00716976. Findings Between June 23, 2008, and Sept 28, 2012, 125 eligible participants were randomly assigned to either sodium thiosulfate (n=61) or observation (n=64). Of these, 104 participants were assessable for the primary endpoint (sodium thiosulfate, n=49; control, n=55). Hearing loss was identified in 14 (28·6%; 95% CI 16·6–43·3) participants in the sodium thiosulfate group compared with 31 (56·4%; 42·3–69·7) in the control group (p=0·00022). Adjusted for stratification variables, the likelihood of hearing loss was significantly lower in the sodium thiosulfate group compared with the control group (odds ratio 0·31, 95% CI 0·13–0·73; p=0·0036). The most common grade 3–4 haematological adverse events reported, irrespective of attribution, were neutropenia (117 [66%] of 178 participant cycles in the sodium thiosulfate group vs 145 [65%] of 224 in the control group), whereas the most common non-haematological adverse event was hypokalaemia (25 [17%] of 149 vs 22 [12%] of 187). Of 194 serious adverse events reported in 26 participants who had received sodium thiosulfate, none were deemed probably or definitely related to sodium thiosulfate; the most common serious adverse event was decreased neutrophil count: 26 episodes in 14 participants. Interpretation Sodium thiosulfate protects against cisplatin-induced hearing loss in children and is not associated with serious adverse events attributed to its use. Further research is needed to define the appropriate role for sodium thiosulfate among emerging otoprotection strategies. Funding US National Cancer Institute.

Ferumoxytol ultrasmall superparamagnetic iron oxide nanoparticles can enhance contrast between neuroinflamed and normal-appearing brain tissue when used as a contrast agent for high-sensitivity magnetic resonance imaging (MRI). Here we used an anti-dextran antibody (Dx1) that binds the nanoparticle's carboxymethyldextran coating to differentiate ferumoxytol from endogenous iron and localize it unequivocally in brain tissue. Intravenous injection of ferumoxytol into immune-competent rats that harbored human tumor xenograft-induced inflammatory brain lesions resulted in heterogeneous and lesion-specific signal enhancement on MRI scans in vivo. We used Dx1 immunolocalization and electron microscopy to identify ferumoxytol in affected tissue post-MRI. We found that ferumoxytol nanoparticles were taken up by astrocyte endfeet surrounding cerebral vessels, astrocyte processes, and CD163(+)/CD68(+) macrophages, but not by tumor cells. These results provide a biological basis for the delayed imaging changes seen with ferumoxytol and indicate that ferumoxytol-MRI can be used to assess the inflammatory component of brain lesions in the clinic.

While informality has long been studied as a feature of governance in the global South, a growing range of accounts examine informal governing arrangements as endemic to cities and nations of the global North. This paper contributes to such scholarship by drawing attention to informal practices and mechanisms involved in the spatial management of sex work in the global North. Existing literature on the spatial management of sex work has long emphasised how informality shapes local sex work practices and mediates formal state-based regulation. We synthesise these studies to suggest three modes of informal governance: as component, catalyst and alternative to formal regulation. Through a case study of street-based sex work management in Christchurch, Aotearoa New Zealand, we discuss how informal governance emerged as a de facto component of formal regulation at the national scale and an alternative to formal regulation at the local scale. Specifically, we detail how an ambiguous regulatory environment, combined with highly localised understandings of spatial appropriateness, led to and influenced the informal management of sex work through a community-level partnership between local authorities, residents and sex worker advocates. In doing so, the paper advocates for more attention to the multi-modal and multi-scalar aspects of informal governance.

At the point of entry to the health care system sit general practice receptionists (GPRs), a seldom studied employment group. The place of the receptionist involves both a location within the internal geography of the clinic and a position within the primary care team. Receptionists literally ‘receive’ those who phone or enter the clinic, and are a critical influence in their transformation from a ‘person’ to a ‘patient’. This process occurs in a particular space: the ‘waiting room’. We explore the waiting room and its dynamics in terms of ‘acceptability’, an under-examined aspect of access to primary care. We ask ‘How do GPRs see their role with regard to patients with complex health and social needs, in light of the spatio-temporal constraints of their working environments?’ We engaged receptionists as participants to explore perceptions of their roles and their workspaces, deriving narrative data from three focus groups involving 14 GPRs from 11 practices in the Northland region of New Zealand. The study employed an adapted form of grounded theory. Our findings indicate that GPRs are on the edge of the practice team, yet carry a complex role at the frontline, in the waiting space. They are de facto managers of this space; however, they have limited agency within general practice settings, due to the constraints imposed upon them by physical and organisational structures. The agency of GPRs is most evident in their ability to shape the social dynamics of the waiting space, and to frame the health care experience as positive for people whose usual experience is marginalisation. We conclude that, if well supported, receptionists have the potential to positively influence health care acceptability, and patients' access to care.

Background/Aims: Acetaminophen overdose causes hepatotoxicity mediated by toxic metabolites generated through the cytochrome P450 enzyme. The objective of this study was to investigate whether acetaminophen (AAP) can enhance cisplatin (CDDP) cytotoxicity against human hepatocarcinoma and hepatoblastoma cells in vitro and whether this effect can be prevented by N-acetylcysteine (NAC). Methods: In vitro studies (glutathione [GSH] level, cell viability, and immunoblot assays) were performed using human hepatocarcinoma and hepatoblastoma cells cultured in AAP, CDDP, and the combination of both with or without delayed NAC administration. The pharmacology and toxicology of high-dose AAP in rats were also examined. Results: Acetaminophen decreased GSH levels in liver cancer cells in a dose- and time-dependent manner. Acetaminophen combined with CDDP had enhanced cytotoxicity over CDDP alone. The cytotoxicity caused by AAP plus CDDP was decreased by NAC, with the effectiveness being time-dependent. The GSH level was lowered in the liver but not in the blood or the brain in rats treated with a high dose of AAP (1000 mg/kg). The expression of CYP2E1 protein, a key cytochrome P450 enzyme, varies among species but is not correlated to AAP sensitivity in liver cancer cells. Conclusions: Our results suggest that a chemotherapeutic regimen containing both AAP and CDDP with delayed NAC rescue has the potential to enhance chemotherapeutic efficacy while decreasing adverse effects. This would be a promising approach particularly for hepatoblastomas regardless of cellular CYP2E1 protein level but could also be beneficial in other malignancies.

The effect of the immunomodulatory chemotherapeutic agent cyclophosphamide (CTX) on tumor growth was investigated in primary and metastatic intracerebral and subcutaneous rat xenograft models. Nude rats were treated with CTX (100 mg/kg, intraperitoneally) 24 hours before human ovarian carcinoma (SKOV3), small cell lung carcinoma (LX-1 SCLC), and glioma (UW28, U87MG, and U251) tumor cells were inoculated subcutaneously, intraperitoneally, or in the right cerebral hemisphere or were infused into the right internal carotid artery. Tumor development was monitored and recorded. Potential mechanisms were further investigated. Only animals that received both CTX and Matrigel showed consistent growth of subcutaneous tumors. Cyclophosphamide pretreatment increased the percentage (83.3% vs 0%) of animals showing intraperitoneal tumors. In intracerebral implantation tumor models, CTX pretreatment increased the tumor volume and the percentage of animals showing tumors. Cyclophosphamide increased lung carcinoma bone and facial metastases after intra-arterial injection, and 20% of animals showed brain metastases. Cyclophosphamide transiently decreased nude rat white blood cell counts and glutathione concentration, whereas serum vascular endothelial growth factor was significantly elevated. Cyclophosphamide also increased CD31 reactivity, a marker of vascular endothelium, and macrophage (CD68-positive) infiltration into glioma cell-inoculated rat brains. Cyclophosphamide may enhance primary and metastatic tumor growth through multiple mechanisms, including immune modulation, decreased response to oxidative stress, increased tumor vascularization, and increased macrophage infiltration. These findings may be clinically relevant because chemotherapy may predispose human cancer subjects to tumor growth in the brain or other tissues.

There is a paucity of therapies for most neurological disorders--from rare lysosomal storage diseases to major public health concerns such as stroke and Alzheimer's disease. Advances in the targeting of drugs to the CNS are essential for the future success of neurotherapeutics; however, the delivery of many potentially therapeutic and diagnostic compounds to specific areas of the brain is restricted by the blood-brain barrier, the blood-CSF barrier, or other specialised CNS barriers. These brain barriers are now recognised as a major obstacle to the treatment of most brain disorders. The challenge to deliver therapies to the CNS is formidable, and the solution will require concerted international efforts among academia, government, and industry. At a recent meeting of expert panels, essential and high-priority recommendations to propel brain barrier research forward in six topical areas were developed and these recommendations are presented here.

Background: Primary intraocular lymphoma (PIOL) is an uncommon subset of primary central nervous system lymphoma. Because it is rare and difficult to diagnose, the natural history and optimal management are unknown. Patients and methods: A retrospective study of 83 HIV negative, immunocompetent PIOL patients was assembled from 16 centers in seven countries. Results: Median age at diagnosis was 65. Median ECOG performance status was 0. Presenting symptoms included blurred vision, decreased visual acuity, and floaters. Median time to diagnosis was 6 months. Diagnosis was made by vitrectomy (74), choroidal/retinal biopsy (6) and ophthalmic exam (3). Eleven percent had positive CSF cytology. Initial treatment was categorized as focal in 23 (intra-ocular methotrexate, ocular radiotherapy) or extensive in 53 (systemic chemotherapy, whole brain radiotherapy). Six received none; details are unknown in one. Forty-seven relapsed: brain 47%, eyes 30%, brain and eyes 15%, and systemic 8%. Median time to relapse was 19 months. Focal therapy alone did not increase risk of brain relapse. Median progression free (PFS) and overall survival (OS) were 29.6 and 58 months, respectively, and unaffected by treatment type. Conclusion: Treatment type did not affect relapse pattern, median PFS or OS. Focal therapy may minimize treatment toxicity without compromising disease control.

Purpose To evaluate the safety and efficacy of intravitreal methotrexate in the management of primary central nervous system lymphoma (PCNSL) involving the eye. Design Retrospective noncomparative interventional case series. Participants Sixteen human immunodeficiency virus-negative white patients (5 males and 11 females, aged 30–76 years) with intraocular B cell lymphoma treated with intravitreal methotrexate at Oregon Health & Science University or Hadassah University Hospital between August 1995 and September 2000. Intervention Patients were treated with intravitreal methotrexate (400 μg/0.1 ml) according to a standard induction-consolidation-maintenance regimen and monitored by serial examinations, including measurement of visual acuity, slit-lamp biomicroscopy, and dilated funduscopy. Main outcome measures Clinical response to intravitreal chemotherapy, number of injections for clinical remission, visual acuity, complications during study period, length of survival from diagnosis, and cause of death. Results Time of follow-up from commencement of the methotrexate injections was 6 to 35 months (median, 18.5 months). Twenty-six of 26 eyes (100%) were cleared clinically of malignant cells after a maximum of 12 methotrexate injections. A second remission was induced in three patients, who were treated with a further course of intravitreal chemotherapy after their tumor recurred within the eye. Complications that occurred during the period of treatment and follow-up included cataract (73% of 26 eyes), corneal epitheliopathy (58% of 26 eyes), maculopathy (42% of 26 eyes), vitreous hemorrhage (8% of 26 eyes), optic atrophy (4% of 26 eyes), and sterile endophthalmitis (4% of 26 eyes). No patient had irreversible loss of vision that could be definitely attributed to the intravitreal injection of methotrexate. Conclusions Intravitreal chemotherapy with methotrexate is effective in inducing clinical remission of intraocular tumor in PCNSL with acceptable morbidity. Further study is indicated to determine whether this approach extends life expectancy.

The objective of this study was to evaluate the efficacy of sequencing radiation therapy (RT) and antibody targeted chemotherapy (BR96-DOX) in nude rats bearing human lung cancer (B.5 LX-1) intracerebral (i.c.) xenografts.Our approach was to administer RT using 20 Gy single-fraction cranial irradiation either before, concurrent with, or after BR96-DOX treatment via osmotic blood-brain barrier disruption to enhance immunoconjugate delivery. All rats were inoculated with i.c. B.5 LX-1 tumors and were randomly assigned to treatment groups.BR96-DOX alone on Day 6 or Day 12 significantly increased survival compared to negative control rats receiving no treatment (25.9 +/- 2.1 and 23.3 +/- 2.5 days vs. 14.8 +/- 1.9 days, p0.05). Rats that received chemotherapy before radiation (34.0 +/- 2.0 days) lived the longest compared to the other sequences (RT prior, 29.5 +/- 1.9; RT concurrent, 27.1 +/- 2.1). Histopathology of 39 rat brains did not reveal any neuropathology.Enhanced delivery of immunoconjugates is more effective in combination with RT for the treatment of experimental metastatic brain tumors. Moreover, BR96-DOX administration prior to RT significantly increased survival compared to those receiving RT and chemotherapy concurrently (p0.05).

PURPOSE: To report severe ocular and orbital toxicity after administration of intracarotid etoposide phosphate and carboplatin. METHOD: Case report. RESULTS: A 52-year-old man with glioblastoma multiforme underwent left intracarotid administration of etoposide phosphate and carboplatin inferior to the ophthalmic artery. Within 7 hours, a nonpupillary block angle-closure glaucoma developed secondary to uveal effusion in the ipsilateral eye, which was relieved by cycloplegia. Four days later, severe orbital inflammation resulted in a visual acuity of counting fingers, proptosis, optic neuropathy, and total external ophthalmoplegia in the eye. The patient’s condition improved after a lateral cantholysis and administration of high-dose intravenous corticosteroids. Two weeks later, an anterior uveitis occurred in the left eye, which responded to topical corticosteroids. During a 2-month period, the patient recovered to a visual acuity of 20/70, near normal motility, and normal intraocular pressure, and the ocular and orbital inflammation resolved. Preexisting ipsilateral chemotherapy-induced maculopathy became more pronounced. CONCLUSION: Ocular and orbital toxicity after intracarotid etoposide phosphate and carboplatin therapy is infrequently reported.

A variety of iron oxide preparations with long blood half-lives have been synthesized for MR imaging. Potential applications of these agents include MR angiography, RES imaging, target specific imaging and neuronal transport imaging. This chapter reviews types of iron oxide and mechanisms that are responsible for a prolonged plasma half-life.

The rat brain abscess model provides a substrate for the modeling of delivery of therapeutic agents to intracerebral mass lesions. We now report refinement of the Escherichia coli brain abscess model in rat. A K1 surface antigen-negative E. coli isolated from human blood culture was stereotaxically inoculated into deep brain sites. Histopathologic analyses and quantitative cultures demonstrated the consistent production of lesions. No animal in this consecutive series developed meningitis, ventriculitis or sepsis. By contrast, prior experience with E. coli abscess production resulted in 25% failure rate of abscess production or death from sepsis. This improvement in the model may be attributable to specific characteristics of the bacteria used, modification of the inoculation method or the intracerebral placement technique. The present work suggests a reliable and consistent brain abscess model, which may be further used to study brain suppuration.

This paper compares total outpatient health care utilization of residents of the Labrador community of Sheshatshit, a predominantly native Innu settlement, with those for the adjacent and predominantly caucasian community of Northwest River for 1986. In lieu of a community survey, these data provide an approximation of the morbidity patterns within the populations. Findings indicate that the native population experiences proportionately more infectious diseases (39.3% of all visits compared to 12.5% of all visits for the non-native community). While residents of the Innu community utilize health services primarily for curative care, residents of Northwest River sought services for both curative and preventive care. It is concluded that inequalities in material wellbeing may underlie the morbidity in Sheshatshit. While desirable in light of the WHO Ottawa Charter, any modification of the health services on account of these morbidity patterns will have only modest effect until policy-based initiatives to reduce material inequalities are implemented.

A monoclonal antibody (mAb L6) to a carcinoma surface antigen has previously been shown to recognize neurophysins (NP), proteins associated with oxytocin and vasopressin14. L6-reactivity in rat hypothalamus was confined to magnocellular neuronal systems. No staining was detected in parvicellular syprachiasmatic or paraventricular systems. mAb L6 immunoprecipitated vasopressin-neurophysin only under reducing conditions, and detected it in Western blots only after gel-renaturation and electroblotting in basic buffer. These findings suggest L6-reactivity to NP is conformation-sensitive, and imply NP expression in a unique configurational form in hypothalamic parvicellular systems.