The impact of sedation on the quality of initial skeletal surveys performed for suspected physical abuse in children: a comparative two-centre audit.

BACKGROUND: The impact of sedation on the quality of initial skeletal surveys performed for suspected physical abuse in children is not known. OBJECTIVE: To assess whether sedation influenced the number of, reason for and effective dose of repeat radiographs obtained as part of initial skeletal surveys, and their mean examination times. MATERIALS AND METHODS: One hundred consecutive antemortem initial skeletal survey examinations performed for suspected physical abuse in children <2 years were retrieved from two tertiary paediatric hospitals: Centre 1, where sedation is not used for initial skeletal survey imaging; and Centre 2, where sedation is used routinely. RESULTS: In total, 4055 radiographic projections were performed, of which 93 (2.3%) were repeats. Comparing centres, there was a significant difference in the total number of repeats (P=0.001) and the number of repeats in children aged <12 months (P=0.008). Mean examination times were significantly shorter in unsedated children (P=0.005), even after outliers were excluded (P=0.002). There was no significant difference between the number of routine projections (P=0.587), incompletely imaged body parts (P=0.254), rotation/suboptimal positioning (P=0.527), repeats in children aged >12 months (P=0.089), routine projections in children aged <12 months (P=0.642) or >12 months (P=0.979) or the effective doses of repeats (P=0.286). CONCLUSION: There were fewer repeat projections in sedated children and those aged <12 months but examination times were significantly longer. There was no difference in the effective doses of repeated projections. The routine use of sedation is not supported when performing skeletal survey imaging if the primary considerations are reducing radiation dose and examination time.

Ingested (oral) adrenocorticotropic hormone (ACTH) inhibits interleukin-17 in the central nervous system after adoptive transfer of T helper (Th)1/Th17 T cells in the mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis.

BACKGROUND: Experimental autoimmune encephalomyelitis (EAE) is an inflammatory autoimmune disease of the central nervous system (CNS) that resembles multiple sclerosis (MS) and provides a useful animal model for the evaluation of mechanisms of action for potential immunomodulatory therapies. We have previously shown that oral adrenocorticotropic hormone (ACTH) decreased either interleukin (IL)-17 and/or interferon (IFN)γ in the CNS during EAE. OBJECTIVE: We wanted to examine whether oral ACTH showed a preferential effect on Th17 as opposed to Th1 phenotypes. DESIGN/METHODS: We therefore examined whether oral ACTH could inhibit EAE in the C57BL/6 (B6) mouse strain after adoptive transfer of equal quantities of Th17 (CD4+IL-17+) and Th1 (CD4+IFN-γ+) T cells generated after in vitro skewing. B6 mice were injected with a 1:1 ratio of Th1:Th17 T cells and were gavaged daily with control scrambled peptide (s-MSH) or 10 µg ACTH. RESULTS: Ingested (oral) ACTH attenuated ongoing clinical EAE disease and decreased the frequencies of Th17 cells in the spleen and in the CNS, but not Th1. CONCLUSIONS: These findings suggest that there was preferential regulation of Th17 cells by oral ACTH compared to Th1 T cells in the CNS.

The genealogy, methodology, similarities and differences of immune reconstitution therapies for multiple sclerosis and neuromyelitis optica.

Immune reconstitution therapies (IRTs) are a type of short course procedure or pharmaceutical agent within the MS pharmacopeia. They emanate from oncology and induce transient incomplete lympho-ablation with or without myelo-ablation, resulting in potential prolonged immunomodulation. Thus, they provide significant prophylaxis from disease activity without retreatment. Modern IRT for autoimmunity encompasses a heterogeneous group of pulsed lympho- and non-myelo-ablative treatments designed to re-boot the adaptive immune system in a quasi-permanent manner - a re-induction of ontogeny. IRT is the extensive debulking of an auto-aggressive immune system to attempt to reach the Holy Grail of immune tolerance. This incomplete yet significant lympho-ablation induces lymphoproliferation, reduces pathogenic clonal cells, causes thymopoiesis and results in the induction of immune tolerance. Lympho-ablation with immune reconstitution can result in minimal residual autoimmunity. There is a resetting of the immune thermostat - i.e., the immunostat. IRTs have the potential to provide prolonged periods of disease inactivity without retreatment in part through the immunological results of their pulsatile lymphocyte depletion. It is vital to increase our understanding of how IRTs alter a patient's immune response to the antigenic target of the disease so that we can devise newer, more durable and safer forms of such agents. What common features do extant IRTs (i.e., stem cell transplant, alemtuzumab and oral cladribine) have to produce the durable therapeutic response without long term treatment in neuroimmunological diseases such as MS (multiple sclerosis) and NMOSD (neuromyelitis optica spectrum disorders)? Can we learn from these critical features to predict what other maneuvers or agents might effect similar clinical results with equal or greater efficacy and safety?

Ingested (Oral) Adrenocorticotropic Hormone Inhibits IL-17 in the Central Nervous System in the Mouse Model of Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) is an inflammatory autoimmune disease of the CNS that resembles multiple sclerosis and provides a useful animal model for the evaluation of mechanisms of action for potential immunomodulatory therapies. We have previously shown that oral adrenocorticotropic hormone (ACTH) decreased IL-17 in the gut lamina propria and the spleen and increased CD4+ Foxp3+ T regulatory cells and IL-10 in the spleen during EAE in the C57BL/6 mouse. However, we did not investigate the specific cellular alterations of proinflammatory and anti-inflammatory factors in the CNS. The aim was to determine if oral ACTH would have a similar clinical effect on inflammatory cytokines in the gut and define specific cellular effects in the CNS in an alternative strain of mice. SJL/J mice were immunized with proteolipid protein peptide 138-151 and gavaged with scrambled ACTH (scrambled α-melanocyte-stimulating hormone) or ACTH 1-39 during ongoing disease. Ingested (oral) ACTH attenuated ongoing clinical EAE disease, decreased IL-6 production, and increased T regulatory cells in the lamina propria and decreased CD4+ and γδ IL-17 production in the CNS. Ingested ACTH attenuated EAE clinical disease by decreasing IL-6 in the gut-associated lymphoid tissue and decreasing IL-17 in the CNS.

Anti-Inflammatory Agents: An Approach to Prevent Cognitive Decline in Alzheimer's Disease.

Systemic inflammation is an organism's response to an assault by the non-self. However, that inflammation may predispose humans to illnesses targeted to organs, including Alzheimer's disease (AD). Lesions in AD have pro-inflammatory cytokines and activated microglial/monocyte/macrophage cells. Up to this point, clinical trials using anti-amyloid monoclonal antibodies have not shown success. Maybe it is time to look elsewhere by combating inflammation. Neuroinflammation with CNS cellular activation and excessive expression of immune cytokines is suspected as the "principal culprit" in the higher risk for sporadic AD. Microglia, the resident immune cell of the CNS, perivascular myeloid cells, and activated macrophages produce IL-1, IL-6 at higher levels in patients with AD. Anti-inflammatory measures that target cellular/cytokine-mediated damage provide a rational therapeutic strategy. We propose a clinical trial using oral type 1 IFNs to act as such an agent; one that decreases IL-1 and IL-6 secretion by activating lamina propria lymphocytes in the gut associated lymphoid tissue with subsequent migration to the brain undergoing inflammatory responses. A clinical trial would be double-blind, parallel 1-year clinical trial randomized 1 : 1 oral active type 1 IFN versus best medical therapy to determine whether ingested type I IFN would decrease the rate of cognitive decline in mild cognitive impairment or mild AD. Using cognitive psychometrics, imaging, and fluid biomarkers (MxA for effective type I IFN activity beyond the gut), we can determine if oral type I IFN can prevent cognitive decline in AD.

A proposal: How to study pro-myelinating proteins in MS.

Multiple sclerosis (MS) is an inflammatory and degenerative disease of the CNS. An unmet need in MS is repair i.e.,promoting endogenous regeneration and remyelination after demyelinating inflammatory injury. Remyelination is critical in neuronal preservation and the prevention of clinical progression. There is a good deal of evidence for histological repair and remyelination in MS patients. Repair is driven by several prominent endogenous pro-myelinating proteinsincluding neural cellular adhesion molecule (N-CAM) and brain derived neurotrophic factor (BDNF) among others. To follow changes during acute re-myelination in vivo in MS subjects, non conventional MRI techniques are necessary such as quantitative susceptibility mapping (QSM) that detects the release of Fe from dying oligodendroglial cells and myelin water imaging (MWI) that detects water captured within newly formed myelin. The best time to monitor changes in pro-myelinating proteins and link those changes to imaging evolution is immediately after the acute inflammatory response in MS lesions (gadolinium enhancement [Gd+]) during an intense period of remyelination. We can monitor MS subjects with new Gd + lesions with periodic imaging along with sampling of blood and CSF and determine if myelin formation is linked with increases in pro-myelinating proteins. This would lead to potential therapeutic manipulation with directly administered proteins to promote CNS re-myelination in animal models and in early clinical trials.

Immune reconstitution therapy in NMOSD.

IMPORTANCE: NMO spectrum disorders [NMOSD] is a relapsing autoimmune disorder with attacks of optic neuritis (ON) and transverse myelitis (TM). A large proportion of NMOSD patients have no or a partial recovery after relapse. OBSERVATIONS: The neuro-immunological community now has a number of indicated agents for NMOSD therapy including eculizumab [Soliris®], inebilizumab (Uplizna®) and satralizumab (Enspryng®) with different mechanisms of action (MOA), rapidity of the onset of action (OOA) and issues of long-term safety. Autologous hematopoietic stem cell transplantation (AHSCT) may be another therapeutic option. CONCLUSIONS AND RELEVANCE: The advantages of eculizumab are preservation of immunosurveillance, immediate onset of action and persistent efficacy but frequent IV administration and cost are important drawbacks. Inebilizumab allows a slight decrease in relapse free subjects over time but decreases B and plasmablast cell disease-inducing pathogenic antibody production. However, inebilizumab may cause immunosuppression. Satralizumab is immunomodulatory and self-administration but has delayed onset of action. AHSCT may be the best therapeutic option for the prevention and therefore the progression of NMO. In NMO, control the complement (eculizumab), reconstitute the immune system (AHSCT), transition to immunomodulation (satralizumab) and reserve immunosuppression (inebilizumab) as 4th line. AHSCT might also be used as rescue therapy for severe breakthrough disease after NMO-DMTs.

Review of approved NMO therapies based on mechanism of action, efficacy and long-term effects.

IMPORTANCE: Neuromyelitis optica (NMO - including NMO spectrum disorders [NMOSD]) is a devastating disease. Eighty-three percent of patients with transverse myelitic (TM) attacks and 67% of patients with optic neuritis (ON) attacks have no or a partial recovery. OBSERVATIONS: Up until recently, there was no proven agent to treat to prevent relapses. The neuro-immunological community had a dearth of indicated agents for NMOSD. We now have three agents indicated for the treatment of NMO including (eculizumab [Soliris®]), an anti-C5 complement inhibitor, satralizumab (ENSRYNG®), a monoclonal antibody against the IL-6 receptor (IL-6R) that blocks B cell antibody production and inebilizumab (Uplinza®), a monoclonal antibody that binds to the B-cell surface antigen CD19 with subsequent B and plasmablast cell lymphocytolysis with decreasing antibody production. Autologous hematopoietic stem cell bone marrow transplantation (AHSCBMT) has also been used. How do we sequence NMO therapies with the understanding of the acuteness and severity of the disease, the individual mechanism of action (MOA) and rapidity of onset of action, onset of efficacy and long-term safety of each agent? CONCLUSIONS AND RELEVANCE: We might suggest the following sequence - 1st line using eculizumab for rapid efficacy and stabilization without effect on the acquired immune system followed by satrilizumab (long term immunomodulation). Reserve inebilizumab (immunosuppressant) for breakthrough disease and salvage the severe with AHSCBMT. In NMO, control the complement, transition to modulation, and reserve suppression - and salvage the severe with AHSCBMT.

Pathologic and clinical tumor size discordance in early-stage cervical cancer: Does it matter?

OBJECTIVE: The objective of this study was to assess the rate of discordance between clinical and pathologic tumor size for women with stage IB1 cervical cancer (FIGO 2009 criteria), assess risk factors for discordance, and determine the impact of discordance on oncologic outcomes. METHODS: This was a secondary analysis of a prior multi-institutional retrospective review of patients diagnosed with stage IB1 (FIGO 2009 staging) cervical cancer undergoing radical hysterectomy between 2010 and 2017. Demographic, clinicopathologic, and oncologic data were collected. Pathologic upstaging was defined as having a preoperative diagnosis of stage IB1 cervical cancer with pathology demonstrating a tumor size >4 cm. Demographic and clinicopathologic data was compared using chi-square, fisher exact or 2-sided t-test. Survival was estimated using the Kaplan-Meier method. RESULTS: Of the 630 patients, 77 (12%) were upstaged. Patients who were upstaged had lower rates of preoperative conization (p < .001) or preoperative tumor sizes ≤2 cm (p < .001). Upstaged patients had increased odds of deep stromal invasion, lymphovascular space invasion, positive margins and positive lymph nodes. Almost 88% of upstaged patients received adjuvant therapy compared to 29% of patients with tumors ≤4 cm (odds 18.49, 95% CI 8.99-37.94). Finally, pathologic upstaging was associated with an increased hazard of recurrence (hazard ratio [HR] 1.95, 95% CI 1.03-3.67) and all-cause death (HR 2.31, 95% CI 1.04-5.11). CONCLUSIONS: Pathologic upstaging in stage IB1 cervical cancer is relatively common. Upstaging is associated with an 18-fold increased risk of receipt of adjuvant therapy. Patients undergoing preoperative conization and those with tumors <2 cm had lower risks of upstaging. Improvement in preoperative assessment of tumor size may better inform primary treatment decisions.

In MS: Immunosuppression is passé.

IMPORTANCE: Prolonged and significant alterations of the immune system by immunosuppression makes multiple sclerosis (MS) patients susceptible to opportunistic infections and malignancies over long periods of treatment. OBSERVATIONS: A reasonable clinical and practical definition of immunosuppression is a temporary or permanent alteration of the body's immune system and subsequent lack of ability to fight infections and malignancies. Immunosurveillance is the sine qua non of the immune system. Immunosurveillance is the constant process by which the immune system looks for and recognizes foreign pathogens such as bacteria and viruses or pre-cancerous or cancerous cells in the body. Immunomodulation (a decrease or increase in pitch or tone - in this case a decrease) maintains immunosurveillance. Immunosuppression (quashing, stamping out) impedes immunosurveillance by one mechanism or another. Immunosuppressive agents need to be administered continually in order to maintain effectiveness. In contrast, immune reconstitution therapies (IRTs) are short course agents that are initially immunosuppressive but ultimately immunomodulatory and can provide significant decreased disease activity over time without retreatment. CONCLUSIONS AND RELEVANCE: The goal of disease modifying therapies in MS is effectiveness over long periods of time with minimal risk. The preservation, reduction or elimination of immunosurveillance should be an important consideration in deciding on the optimal disease modifying treatments (DMT) for an individual MS patient. IRTs have the advantage of providing long term control of disease activity with short term immunosuppression followed by long term immunomodulation without retreatment. For most MS patients with mild or modest disease activity, initial immunomodulation followed by IRT for breakthrough disease may be the best option. In MS, immunosuppression may be passé.

Ingested ACTH blocks Th17 production by inhibiting GALT IL-6.

BACKGROUND: EAE is an inflammatory autoimmune process of the CNS that resembles multiple sclerosis (MS) and provides a useful animal model for the evaluation of mechanisms of action for potential immunomodulatory therapies. Oral ACTH (adrenocorticotropic hormone) can decrease clinical disease, IL-17 and Th1-like encephalitogenic IFN-γ secretion and increase Treg frequency. The mechanism by which oral ACTH decreases inflammatory proteins and increases Treg cell frequencies is unknown. OBJECTIVE: IL-6 is a pivotal cytokine in the gut that determines the relative frequencies of Th17 vs Treg cells. We examined whether oral ACTH inhibited IL-6 in the gut associated lymphoid tissue (GALT) in EAE. DESIGN/METHODS: B6 mice were immunized with MOG peptide 35-55 and gavaged with scrambled ACTH (scrambled melanocyte stimulating hormone [scrambled α-MSH]) or ACTH 1-39 during ongoing disease. RESULTS: Ingested (oral) ACTH inhibited ongoing clinical disease. In the lamina propria (LP) immune compartment, there were significantly less CD11b + IL-6 and IL-17 producing lymphocytes from ACTH fed mice compared to s-MSH fed mice. There was also a decrease in the frequency of IL-17 and IFN-γ producing spleen cells and an increase in CD4 + FoxP3+ Treg cell frequency in ACTH fed mice compared to s-MSH fed control spleens. There were less IFN-γ producing CNS lymphocytes in ACTH fed mice compared to s-MSH fed control CNS. CONCLUSIONS: Ingested ACTH inhibits EAE clinical disease by inhibiting IL-6 in the GALT.

Tumor lysis syndrome in gynecologic cancers: An uncommon but important diagnosis to recognize.

OBJECTIVES: To describe the incidence, treatment and outcomes associated with tumor lysis syndrome (TLS) in women with gynecologic cancer (GOC). METHODS: A retrospective multi-institutional review of TLS associated with GOC. Women presenting with an elevated serum uric acid managed with intravenous (IV) rasburicase were included. Descriptive statistics of patient demographics, clinical findings, and outcome data was completed. RESULTS: From two large academic institutions N = 18 patients were found to meet inclusion criteria from 2008 to 2018, reflecting an approximate 5% incidence of clinically treated TLS associated with GOC in our cohort. Median age was 60 years, a majority were Caucasian (n = 11, 61.1%), median BMI was 36.2. TLS was associated with a high-grade GOC in n = 17 (94.4%) cases. TLS was commonly diagnosed with a new GOC (n = 12, 70.6%) and following receipt of chemotherapy in n = 9 (50.0%) cases. Six (66.7%) patients were treated with paclitaxel or combination, five (55.5%) with a platinum or combination, and two (22.2%) with a CD47 inhibitor. Chief complaints included electrolyte and renal abnormalities (n = 11, 73.3%). Peak serum uric acid, potassium, creatinine and phosphorus levels were 14.1 mg/dL, 5.7 mEq/L, 5.1 mg/dL, and 6.8 mg/dL, respectively. Nine patients received hospice during their admission with 3 (20%) deaths occurring as inpatients. There were 12 deaths with median OS of 16 d (range: 2-87 d). CONCLUSIONS: Though rare, TLS can be associated with GOC. Early recognition of presenting symptoms, laboratory findings and expedited treatment may help with electrolyte recovery; however, TLS associated with GOC may herald a rapidly deteriorating state with significant associated mortality.

Tumefactive demyelination: Clinical outcomes, lesion evolution and treatments.

OBJECTIVE: Large demyelinating lesions with possible mass effect (tumefactive multiple sclerosis or tumefactive demyelination) can be mistaken for tumour-like space-occupying lesions suggesting a malignant outcome. METHODS: We reviewed our own experience of multiple sclerosis subjects (n = 28) with tumefactive demyelination to determine the relationship between clinical outcomes and lesion evolution, clinical outcomes and their relationship to different therapies. Patients with central nervous system demyelinating disease were identified from our database over the last 10 years. RESULTS: No patient increased in extended disability status scale (EDSS). Overall, lesion regression was associated with improved EDSS. Lesion regression was also associated with therapy versus no therapy. No specific therapy or corticosteroid infusions improved EDSS over the long term. The absence of enhancement on follow up on magnetic resonance imaging portended lesion regression. CONCLUSION: Tumefactive demyelination may predict a more benign overall course and is susceptible to traditional immunomodulatory treatments.

Myelinating Proteins in MS Are Linked to Volumetric Brain MRI Changes.

BACKGROUND AND PURPOSE: There is evidence of a relationship between promyelinating proteins and clinical multiple sclerosis (MS) activity during clinical relapse or recovery from clinical relapses. We examined the linkage between promyelinating biomarkers and volumetric changes in MS subjects during serial magnetic resonance imaging (MRI). METHODS: We enrolled 13 MS subjects with active brain MRI scans not on disease modifying therapies. Subjects underwent baseline MRI, serum, and cerebrospinal fluid (CSF) sampling. Qualitative changes, new/resolving gadolinium, new/enlarging/diminishing T2 and T1 hypointense lesions, were compared to baseline in subsequent MRI scans, and volumetric analysis was calculated. Analysis of biomarkers on serial CSF samples was performed only in subjects with qualitative (and quantitative) changes on MRI. The study was performed at a MS Center of Excellence academic medical center. RESULTS: There was increased CSF neural cell adhesion molecule (N-CAM) during increased qualitative T1 activity. A positive correlation between CSF and serum N-CAM and T1 lesion volume was observed. A negative correlation between serum brain-derived neurotrophic factor (BDNF) and BPH (T1 vol/T2 vol + T1 vol) was observed. CONCLUSIONS: Increased N-CAM levels may be related to repair or remyelination following injury to the brain as shown by increased T1 volumes. Our data suggest an early kind of blood signaling that induces release of peripheral BDNF levels.

Ingested (oral) rituximab inhibits EAE.

BACKGROUND: Blocking CD20 can inhibit autoimmune diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA). OBJECTIVE: We examined whether an antibody against CD20, rituximab (RTX) (Rituxan®), used clinically in oncology, MS and RA would have similar anti-inflammatory effects in EAE after oral administration. DESIGN/METHODS: B6 mice were immunized with MOG peptide 35-55 and gavaged with control saline or RTX during ongoing disease. Splenocytes or CD4(+) T cells from control fed or RTX fed mice were adoptively transferred into active MOG peptide 35-55 immunized recipient mice during ongoing disease. Actively fed and recipient mice were examined for disease inhibition, inflammation, and cytokine responses. RESULTS: Ingested (oral) RTX inhibited ongoing disease and decreased inflammation. Adoptively transferred cells from RTX fed donors protected against actively induced disease and decreased inflammation. There was a decrease in Th1-like cytokines IFN-γ and IL-12, IL-17 and TNF-α in active fed and adoptively treated recipients without upregulation of counter-regulatory cytokines. CONCLUSIONS: Ingested (orally administered) RTX can inhibit disease, CNS inflammation, decrease pro-inflammatory IL-17 and Th1-like cytokines without increases in Th2-like anti-inflammatory cytokines.

Ingested (oral) anti-IL-12/23 inhibits EAE.

BACKGROUND: Blocking the activity of IL-12/23 can inhibit autoimmune diseases such as psoriasis. OBJECTIVE: We examined whether an antibody against IL-12/23, ustekinumab (UTZ) (Stelera®), used clinically in psoriasis would have similar anti-inflammatory effects in EAE after oral administration. DESIGN/METHODS: B6 mice were immunized with MOG peptide 35-55 and gavaged with isotype IgG control or UTZ during ongoing disease. Splenocytes, CD4(+) T cells or macrophages/monocyte lineage cells (CD11b(+)) from control fed or UTZ fed mice were adoptively transferred into active MOG peptide 35-55 immunized recipient mice during ongoing disease. Actively fed and recipient mice were examined for disease inhibition, inflammation, and cytokine responses. RESULTS: Ingested (oral) UTZ inhibited ongoing disease and decreased inflammation. Adoptively transferred cells from UTZ fed donors protected against actively induced disease and decreased inflammation. Oral UTZ decreased pro-inflammatory cytokines Th1-like cytokines IL-2, IL-12, IFN-γ, IL-17 (Teff) and TNF-α in UTZ fed mice and increased counter-regulatory cytokines IL-4, IL-10 and IL-13 in recipients of donor cells from UTZ fed mice. CONCLUSIONS: Ingested (orally administered) UTZ can inhibit disease, CNS inflammation, decrease pro-inflammatory Th1-like and Th17 cytokines and increase Th2-like anti-inflammatory cytokines.

High precision optical cavity length and width measurements using double modulation.

We use doubly phase modulated light to measure both the length and the linewidth of an optical resonator with high precision. The first modulation is at RF frequencies and is set near a multiple of the free spectral range, whereas the second modulation is at audio frequencies to eliminate offset errors at DC. The light in transmission or in reflection of the optical resonator is demodulated while sweeping the RF frequency over the optical resonance. We derive expressions for the demodulated power in transmission, and show that the zero crossings of the demodulated signal in transmission serve as a precise measure of the cavity linewidth at half maximum intensity. We demonstrate the technique on two resonant cavities, with lengths 16 m and a 4 km, and achieve an absolute length accuracy as low as 70 ppb. The cavity width for the 16 m cavity was determined with an accuracy of approximately 6000 ppm. Through an analysis of the systematic errors we show that this result could be substantially improved with the reduction of technical sources of uncertainty.

Ingested (oral) tocilizumab inhibits EAE.

BACKGROUND: Blocking the activity of IL-6 can inhibit autoimmune diseases such as rheumatoid arthritis and Crohn's disease. OBJECTIVE: We examined whether an antibody against IL-6, tocilizumab (TCZ) (Actemra®), used clinically in rheumatoid arthritis (RA) would have similar anti-inflammatory effects in EAE after oral administration. DESIGN/METHOD: B6 mice were immunized with MOG peptide 35-55 and gavaged with control saline or TCZ during ongoing disease. Splenocytes, CD4(+) T cells or macrophages/monocyte lineage cells (CD11b(+)) from control fed or TCZ fed mice were adoptively transferred into active MOG peptide 35-55 immunized recipient mice during ongoing disease. Actively fed and recipient mice were examined for disease inhibition, inflammation, and cytokine responses. RESULTS: Ingested (oral) TCZ inhibited ongoing disease and decreased inflammation. Adoptively transferred cells from TCZ fed donors protected against actively induced disease and decreased inflammation. There was a decrease in IL-6 in actively treated spleen, decrease in TNF-α, Th1-like cytokine IL-12 and increase in Th2-like cytokine IL-10 in active fed and adoptively treated recipients. CONCLUSIONS: Ingested (orally administered) TCZ can inhibit disease, CNS inflammation, decrease pro-inflammatory Th1-like cytokines and increase Th2-like anti-inflammatory cytokines.

Contrast enhanced MR venography with gadofosveset trisodium: evaluation of the intracranial and extracranial venous system.

PURPOSE: To demonstrate the efficacy of contrast enhanced magnetic resonance venography (CEMRV) using gadofosveset trisodium in the comprehensive evaluation of the intracranial and extracranial venous system. MATERIALS AND METHODS: Temporal signal decay, in-plane saturation and flow artifacts were assessed in an institutional review board approved, HIPAA compliant CEMRV study of 99 subjects. In a 39 subject subset, percent diameter narrowing of the internal jugular (IJ), brachiocephalic and azygous veins were coded according to the following ordinal grades for both catheter venography (CV) and CEMRV: grade 0 ≤ 50%, grade 1 >50% and ≤ 75%, grade 2 >75% and <100% and grade 3 = 100% and compared with pressure gradient measurements obtained during CV. RESULTS: There was no significant signal decay, in-plane saturation or flow artifacts identified on CEMRV or hemodynamically significant pressure gradients identified on CV. All brachiocephalic and azygous veins had matched grade 0 narrowing on both modalities. Discrepancy between modalities occurred in the IJ veins at the level of thyroid gland where 15% of IJ veins had CEMRV grade ≥ 1 narrowing compared with 4% for CV or below the thyroid gland where 5% of IJ veins had CEMRV grade ≥ 1 narrowing compared with 20% for CV. There was fair agreement (κ = 0.24) between modalities for grade of narrowing in the combined data set of all coded veins. CONCLUSION: CEMRV using gadofosveset trisodium is accurate in the evaluation of the venous system.

Chronic cerebrospinal venous insufficiency: masked multimodal imaging assessment.

BACKGROUND: Chronic cerebrospinal venous insufficiency (CCSVI) was implicated in the pathophysiology of multiple sclerosis (MS). OBJECTIVE: We evaluated neurosonography (NS), magnetic resonance venography (MRV), and transluminal venography (TLV) in subsets of MS patients drawn from a single-center, prospective, case-control study of 206 MS and 70 non-MS volunteers. METHODS: As previously reported, findings on high-resolution B-mode NS imaging with color and spectral Doppler of the extracranial and intracranial venous drainage consistent with CCSVI were similar among MS and non-MS volunteers (3.88% vs 7.14%; p = 0.266). Ninety-nine MS participants consented to intravascular contrast-enhanced 3D MRV to assess their major systemic and intracranial venous circulation, and 40 advanced to TLV that included pressure measurements of the superior vena cava, internal jugular, brachiocephalic, and azygous veins. RESULTS: NS findings and MRV patterns were discrepant for 26/98 evaluable subjects, including four with abnormal findings on NS that had normal venous anatomy by MRV. In no instance were TLV pressure gradients indicative of clinically significant functional stenosis encountered. The three imaging approaches provided generally consistent data with discrepancies referable to inherent technique properties. CONCLUSIONS: Our findings lend no support for altered venous outflow dynamics as common among MS patients, nor do they likely contribute to the disease process.