Citrullinated human and murine MOG35-55 display distinct biophysical and biochemical behavior.

The peptide spanning residues 35 to 55 of the protein myelin oligodendrocyte glycoprotein (MOG) has been studied extensively in its role as a key autoantigen in the neuroinflammatory autoimmune disease multiple sclerosis. Rodents and nonhuman primate species immunized with this peptide develop a neuroinflammatory condition called experimental autoimmune encephalomyelitis, often used as a model for multiple sclerosis. Over the last decade, the role of citrullination of this antigen in the disease onset and progression has come under increased scrutiny. We recently reported on the ability of these citrullinated MOG35-55 peptides to aggregate in an amyloid-like fashion, suggesting a new potential pathogenic mechanism underlying this disease. The immunodominant region of MOG is highly conserved between species, with the only difference between the murine and human protein, a polymorphism on position 42, which is serine in mice and proline for humans. Here, we show that the biophysical and biochemical behavior we previously observed for citrullinated murine MOG35-55 is fundamentally different for human and mouse MOG35-55. The citrullinated human peptides do not show amyloid-like behavior under the conditions where the murine peptides do. Moreover, we tested the ability of these peptides to stimulate lymphocytes derived from MOG immunized marmoset monkeys. While the citrullinated murine peptides did not produce a proliferative response, one of the citrullinated human peptides did. We postulate that this unexpected difference is caused by disparate antigen processing. Taken together, our results suggest that further study on the role of citrullination in MOG-induced experimental autoimmune encephalomyelitis is necessary.

A unified call to action from Australian nursing and midwifery leaders: ensuring that Black lives matter.

Nurses and midwives of Australia now is the time for change! As powerfully placed, Indigenous and non-Indigenous nursing and midwifery professionals, together we can ensure an effective and robust Indigenous curriculum in our nursing and midwifery schools of education. Today, Australia finds itself in a shifting tide of social change, where the voices for better and safer health care ring out loud. Voices for justice, equity and equality reverberate across our cities, our streets, homes, and institutions of learning. It is a call for new songlines of reform. The need to embed meaningful Indigenous health curricula is stronger now than it ever was for Australian nursing and midwifery. It is essential that nursing and midwifery leadership continue to build an authentic collaborative environment for Indigenous curriculum development. Bipartisan alliance is imperative for all academic staff to be confident in their teaching and learning experiences with Indigenous health syllabus. This paper is a call out. Now is the time for Indigenous and non-Indigenous nurses and midwives to make a stand together, for justice and equity in our teaching, learning, and practice. Together we will dismantle systems, policy, and practices in health that oppress. The Black Lives Matter movement provides us with a 'now window' of accepted dialogue to build a better, culturally safe Australian nursing and midwifery workforce, ensuring that Black Lives Matter in all aspects of health care.

Advanced Ultrasound Screening for Temporomandibular Joint (TMJ) Internal Derangement.

PURPOSE: To present an advanced ultrasound (US) technique and propose its use as a screening diagnostic tool for temporomandibular joint (TMJ) internal derangement. MATERIALS AND METHODS: The technique is based on maintaining the US probe parallel to the articular disc, rather than traditional axial and coronal views, with the position described relative to a clock face. Validation was achieved by direct comparison with magnetic resonance imaging (MRI). A total of 61 patients, with age ranging from 13 to 67 years, were prescreened for TMJ pain and internal derangement, underwent US imaging for screening, and MRI evaluation for final diagnosis. RESULTS: 29 of the 61 patients had disc pathology on MRI. US screening produced no false positive results and only 6 false negative results, corresponding to a sensitivity of 79% and specificity of 100%. Half of the false negative cases involved disc pathology with a medial component to the disc displacement. CONCLUSION: US is both a sensitive and a specific screening tool for TMJ dysfunction when used by an appropriately trained operator, with the exception of medially displaced discs. If TMJ assessment is found to be abnormal, the patient should be referred for MRI, and any patient scheduled for surgery must have the diagnosis confirmed by MRI. If a component of medial disc displacement is suspected, MRI should be performed despite a normal screening US.

High Prevalence of Spinal Cord Cavernous Malformations in the Familial Cerebral Cavernous Malformations Type 1 Cohort.

BACKGROUND AND PURPOSE: Cavernous malformations occur most often in the brain but can occur in the spinal cord. Small studies of patients with familial cerebral cavernous malformations suggested a prevalence of spinal cord cavernous malformations of 20%-42%. We aimed to review our familial cohort and prospectively estimate the prevalence of spinal cord cavernous malformations. MATERIALS AND METHODS: We initially reviewed our familial cerebral cavernous malformations cohort for spinal cord cavernous malformations and reviewed clinical spine MR imaging examinations for sequence sensitivity. We then prospectively performed research MR imaging of the spinal cord in 29 patients from the familial cohort to estimate the prevalence. RESULTS: Gradient-based sequences identified the most spinal cord cavernous malformations on clinical MR images, forming the basis for developing our screening MR imaging. Screening spinal cord MR imaging demonstrated a prevalence of 72.4%, and a positive correlation with patient age and number of cerebral cavernous malformations. CONCLUSIONS: Spinal cord cavernous malformations occur commonly in the familial cerebral cavernous malformation population. Gradient-based sequences are the most sensitive and should be used when spinal cord cavernous malformations are suspected. This study establishes the prevalence in the familial population at around 70% and supports the idea that this condition is a progressive systemic disease that affects the entire central nervous system.

Temporal tendinosis: A cause of chronic orofacial pain.

PURPOSE OF REVIEW: Diverse musculoskeletal disorders and neuropathic symptoms of the face pose significant diagnostic challenges. In particular, temporal tendinosis is generally overlooked in the medical and dental literature and is therefore a poorly understood topic and often problematic cause of chronic orofacial pain. In this article, we explore temporal tendinosis as a cause of unresolved orofacial pain by reviewing the complex anatomy of the temporalis muscle, common presentations of temporal tendinosis, possible etiologies for injury and place a strong emphasis on required diagnostic evaluation and clinical management. RECENT FINDINGS: Temporal tendinosis remains under diagnosed due to a combination of anatomical complexity and incomplete description in the majority of general anatomy medical textbooks. The two main presentations are unilateral facial pain with or without temporal headache and pain radiating from the distal temporalis tendon to the temporalis muscle. Diagnosis should be made with a combination of focused history, physical examination and specialised imaging, preferably with ultrasound but with MRI an alternate option. While many management options are available, optimal treatment remains unclear. Temporal tendinosis is an under-recognised and under-treated condition. Despite the fact that orofacial pain is one of the single most common complaints of patients presenting to physicians or dentists, it is widely acknowledged that training for diagnosis and manage of temporal tendinopathy among primary care physicians in both medical and dental professions is inadequate. This may result in extensive workups, leading to suboptimal management and chronic pain syndromes.

Ultrasound-Guided Injection of the Temporalis Tendon: A Novel Technique.

A novel technique, ultrasound-guided injection of the temporalis tendon in adults, is described. Ultrasound-guided injection of the temporalis tendon is based on visualization of the temporalis muscle, temporalis tendon, and coronoid process. A practical step-by-step guide to doing the procedure is given. This technique is effective and reproducible. Two patients successfully treated with this technique will be briefly discussed. The anatomic location and size of the temporalis tendon make it mandatory to use ultrasound to ensure precision.

Proposed Diagnostic Criteria for Chronic Antibody-Mediated Rejection in Liver Allografts.

Donor-specific alloantibodies (DSA) can cause acute antibody-mediated rejection (AMR) in all solid organ allografts. However, long-term outcome in patients with posttransplant DSA needs further study. We retrospectively evaluated prospectively collected paired serum, tissue, and data on 45 matched DSA- positive [DSA+; mean florescence intensity (MFI) ≥10,000] and -negative (DSA-) recipients of a primary liver-only allograft from January 2000 to April 2009. Blinded histopathologic evaluation demonstrated that DSA+ versus DSA- patients were more likely to have subtle inflammation and unique patterns of fibrosis, despite normal or near-normal liver function tests. Stepwise multivariable modeling developed a score (putatively named the chronic AMR [cAMR] score) that included interface activity, lobular inflammation, portal tract collagenization, portal venopathy, sinusoidal fibrosis, and hepatitis C virus status. The score was developed (c = 0.811) and cross-validated (c = 0.704) to predict allograft failure. Two cutoffs were employed to optimize sensitivity and specificity (80% each); a value >27.5 predicted 50% 10-year allograft failure. We propose chronic AMR as a potential new entity defined by (1) a high cAMR score, (2) DSA, and (3) elimination of other potential causes of a similar injury pattern. In conclusion, cAMR score calculation identified liver allograft recipients with DSA at highest risk for allograft loss, although independent validation is needed.

Clinical efficacy of a new CD28-targeting antagonist of T cell co-stimulation in a non-human primate model of collagen-induced arthritis.

T cells have a central pathogenic role in the aetiopathogenesis of rheumatoid arthritis (RA), and are therefore a favoured target of immunotherapy aiming at physical or functional elimination. Here we report an efficacy test of FR104, a new co-stimulation inhibitor directly targeting CD28 on T cells, in a translationally relevant model, the rhesus monkey model of collagen-induced arthritis (CIA). As a relevant comparator we used abatacept [cytotoxic T lymphocyte antigen immunoglobulin (CTLA Ig)], an antagonist of CTLA-4 binding to CD80/86 clinically approved for treatment of RA. Treatment with either compound was started at the day of CIA induction. Although FR104 previously demonstrated a higher control of T cell responses in vitro than abatacept, both compounds were equally potent in the suppression of CIA symptoms and biomarkers, such as the production of C-reactive protein (CRP) and interleukin (IL)-6 and anti-collagen type II (CII) serum antibody (IgM/IgG). However, in contrast to abatacept, FR104 showed effective suppression of CII-induced peripheral blood mononuclear cell (PBMC) proliferation. The current study demonstrates a strong potential of the new selective CD28 antagonist FR104 for treatment of RA.

Increased number of white matter lesions in patients with familial cerebral cavernous malformations.

BACKGROUND AND PURPOSE: Familial cerebral cavernous malformations, an autosomal dominant disorder, result in excess morbidity and mortality in affected patients. The disorder is most prevalent in the Southwest United States, where the affected families are most often carriers of the CCM1-KRIT1 Common Hispanic Mutation. The brain and spinal cord parenchyma in these individuals is usually affected by multiple cavernous malformations. Previous studies have shown abnormalities of endothelial cell junctions and the blood-brain barrier in cerebral cavernous malformations. Endothelial cell abnormalities have also been described in pathologic studies of white matter hyperintensities. We compared the prevalence of white matter hyperintensities in a population with known familial cerebral cavernous malformations. MATERIALS AND METHODS: We examined 191 subjects with familial cerebral cavernous malformations who were enrolled into an institutional review board-approved study. All carry the same Common Hispanic Mutation in the CCM1 gene. Each subject underwent 3T MR imaging, including gradient recalled-echo, SWI, and FLAIR sequences. The number of cavernous malformations and the number of nonhemorrhagic white matter hyperintensities were counted. Subjects older than 60 years of age were excluded due to the high prevalence of white matter lesions in this population, and children younger than 6 were excluded due to potential sedation requirements. Logistic regression analysis was performed to determine the prevalence of abnormal white matter hyperintensities in those with familial cerebral cavernous malformations compared with healthy controls or those with sporadic cerebral cavernous malformation within the familial cerebral cavernous malformations group; it was also performed to evaluate the associations between abnormal white matter hyperintensities and age, sex, headaches, thyroid disease, diabetes, hypertension, hyperlipidemia, seizure history, or modified Rankin Scale score. RESULTS: Familial CCM1 carriers have a higher prevalence of abnormal white matter hyperintensities (15.4%) compared with both control populations (2.1% and 2.5%, respectively) (P < .05). Logistic regression showed no statistical association with sex, headaches, hyperlipidemia, hypertension, thyroid disease, seizure history, number of cerebral cavernous malformations, or modified Rankin Scale score among those with familial cerebral cavernous malformation. An expected correlation with age was shown. CONCLUSIONS: Familial CCM1 carriers have not only an increased number of cerebral cavernous malformations but also an increased number of white matter T2 hyperintensities, spatially distinct from cerebral cavernous malformations, which exceeded that of a healthy population. Clinical findings did not explain the association with abnormal white matter hyperintensities in the familial cerebral cavernous malformation population. To our knowledge, these relationships have not been previously reported. This finding suggests an additional manifestation of endothelial abnormalities in this population.

Immune modulation by a tolerogenic myelin oligodendrocyte glycoprotein (MOG)10-60 containing fusion protein in the marmoset experimental autoimmune encephalomyelitis model.

Current therapies for multiple sclerosis (MS), a chronic autoimmune neuroinflammatory disease, mostly target general cell populations or immune molecules, which may lead to a compromised immune system. A more directed strategy would be to re-enforce tolerance of the autoaggressive T cells that drive tissue inflammation and injury. In this study, we have investigated whether the course of experimental autoimmune encephalomyelitis (EAE) in mice and marmosets can be altered by a potent tolerizing fusion protein. In addition, a multi-parameter immunological analysis was performed in marmosets to assess whether the treatment induces modulation of EAE-associated cellular and humoral immune reactions. The fusion protein, CTA1R9K-hMOG10-60-DD, contains a mutated cholera toxin A1 subunit (CTA1R9K), a dimer of the Ig binding D region of Staphylococcus aureus protein A (DD), and the human myelin oligodendrocyte glycoprotein (hMOG) sequence 10-60. We observed that intranasal application of CTA1R9K-hMOG10-60-DD seems to skew the immune response against myelin oligodendrocyte glycoprotein (MOG) towards a regulatory function. We show a reduced number of circulating macrophages, reduced MOG-induced expansion of mononuclear cells in peripheral blood, reduced MOG-induced production of interleukin (IL)-17A in spleen, increased MOG-induced production of IL-4 and IL-10 and an increased percentage of cells expressing programmed cell death-1 (PD-1) and CC chemokine receptor 4 (CCR4). Nevertheless, the treatment did not detectably change the EAE course and pathology. Thus, despite a detectable effect on relevant immune parameters, the fusion protein failed to influence the clinical and pathological outcome of disease. This result warrants further development and improvement of this specifically targeted tolerance inducing therapy.

Armies of pestilence: CNS infections as potential weapons of mass destruction.

Infectious agents have been investigated, developed, and used by both governments and terrorist groups as weapons of mass destruction. CNS infections, though traditionally considered less often than respiratory diseases in this scenario, may be very important. Viruses responsible for encephalitides can be highly infectious in aerosol form. CNS involvement in anthrax is ominous but should change treatment. Brucellosis, plague, Q fever, and other bacteria can uncommonly manifest with meningoencephalitis and other findings. Emerging diseases may also pose threats. We review infectious agents of particular concern for purposes of biowarfare with respect to CNS manifestations and imaging features.

CNS myelin induces regulatory functions of DC-SIGN-expressing, antigen-presenting cells via cognate interaction with MOG.

Myelin oligodendrocyte glycoprotein (MOG), a constituent of central nervous system myelin, is an important autoantigen in the neuroinflammatory disease multiple sclerosis (MS). However, its function remains unknown. Here, we show that, in healthy human myelin, MOG is decorated with fucosylated N-glycans that support recognition by the C-type lectin receptor (CLR) DC-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) on microglia and DCs. The interaction of MOG with DC-SIGN in the context of simultaneous TLR4 activation resulted in enhanced IL-10 secretion and decreased T cell proliferation in a DC-SIGN-, glycosylation-, and Raf1-dependent manner. Exposure of oligodendrocytes to proinflammatory factors resulted in the down-regulation of fucosyltransferase expression, reflected by altered glycosylation at the MS lesion site. Indeed, removal of fucose on myelin reduced DC-SIGN-dependent homeostatic control, and resulted in inflammasome activation, increased T cell proliferation, and differentiation toward a Th17-prone phenotype. These data demonstrate a new role for myelin glycosylation in the control of immune homeostasis in the healthy human brain through the MOG-DC-SIGN homeostatic regulatory axis, which is comprised by inflammatory insults that affect glycosylation. This phenomenon should be considered as a basis to restore immune tolerance in MS.

Whole blood stimulation with Toll-like receptor (TLR)-7/8 and TLR-9 agonists induces interleukin-12p40 expression in plasmacytoid dendritic cells in rhesus macaques but not in humans.

Macaques provide important animal models in biomedical research into infectious and chronic inflammatory disease. Therefore, a proper understanding of the similarities and differences in immune function between macaques and humans is needed for adequate interpretation of the data and translation to the human situation. Dendritic cells are important as key regulators of innate and adaptive immune responses. Using a new whole blood assay we investigated functional characteristics of blood plasmacytoid dendritic cells (pDC), myeloid dendritic cells (mDC) and monocytes in rhesus macaques by studying induction of activation markers and cytokine expression upon Toll-like receptor (TLR) stimulation. In a head-to-head comparison we observed that rhesus macaque venous blood contained relatively lower numbers of pDC than human venous blood, while mDC and monocytes were present at similar percentages. In contrast to humans, pDC in rhesus macaques expressed the interleukin (IL)-12p40 subunit in response to TLR-7/8 as well as TLR-9 stimulation. Expression of IL-12p40 was confirmed by using different monoclonal antibodies and by reverse transcription-polymerase chain reaction (RT-PCR). Both in humans and rhesus macaques, TLR-4 stimulation induced IL-12p40 expression in mDC and monocytes, but not in pDC. The data show that, in contrast to humans, pDC in macaques are able to express IL-12p40, which could have consequences for evaluation of human vaccine candidates and viral infection.

Dematiaceous fungi mimicking a conjunctival melanoma.

An 85-year-old, immunocompetent man was referred to the authors due to the presence of an enlarging, pigmented mass of the conjunctiva concerning for a conjunctival melanoma. Wide excision of the mass revealed a pigmented or "dematiaceous" fungus. He was treated with topical natamycin, and the lesion healed well without any evidence of recurrence. Dematiaceous fungi should be considered in the differential for pigmented conjunctival lesions.

Ganciclovir-resistant cytomegalovirus (CMV) retinitis in a patient with wild-type CMV in her plasma.

A patient with systemic cytomegalovirus (CMV), including chorioretinitis, received localized and systemic ganciclovir, systemic cidofovir analog, and localized foscarnet. Mutations conferring ganciclovir and cidofovir resistance were detected in CMV from the aqueous fluid but not in CMV from plasma. Quantifying CMV from aqueous fluid was valuable for monitoring the clinical response and predicting resistance.

Epithelioid hemangioma responsive to oral propranolol.

An 11-year-old boy presented with progressive right-sided proptosis and an orbital mass on neuroimaging. Incisional biopsy revealed an epithelioid hemangioma. The patient underwent an orbitotomy with subtotal excision of the mass. However, the tumor recurred and progressed to the cavernous sinus, despite oral steroids, tacrolimus, and a second subtotal excision. Because of encouraging results reported with beta-blockers in the treatment of pediatric capillary hemangiomas, the patient was subsequently started on oral propranolol, 2 mg/kg/day, with discontinuation of steroids and tacrolimus. A rapid and impressive interval decrease in tumor size was observed, with improvement in proptosis and exposure keratopathy. The patient remains without recurrence approximately 9 months after initiation of propranolol. Our results suggest that oral propranolol may be a potential alternative therapy when complete excision of an epithelioid hemangioma is not practical.

Utilization of health care services by pregnant mothers during delivery: a community based study in Nigeria.

OBJECTIVE: Poor utilization of health facilities during delivery by pregnant mothers is still a major cause of maternal and childhood morbidity and mortality in Nigeria. The aim of this study was to determine the level of utilization of health care services by pregnant women during delivery in Gokana Local Government Area of River State, Nigeria. MATERIALS AND METHODS: This was a cross-sectional, questionnaire; based study involving 112 mothers aged 15 years to 49 years from Gokana Local Government Area of Rivers State, Nigeria. The local Government Area has 12 health centres and 6 health centres were selected by multistage sampling. 112 were then selected by simple random sampling. RESULTS: Of the 112 mothers interviewed 91 (81.3%) were married, 13 (11.6%) were single, 5 (4.5%) were widows, 2 (1.8%) divorced and 1 (0.9%) separated. Ninety seven (86.6%) of these mothers (n = 112) had formal education while 15 (13.4%) had no formal education. Most 42 (37.5%) of the mothers were between 25-29 years. Sixty four (57.1%) of the 112 mothers in their recent delivery used a health facility while 48 (42.9%) did not. Factors responsible for non utilization of health facility for delivery include: Long distance to health facility 33 (68.7%), onset of labour at night 40 (83.3%), unavailability of means of transportation 37 (77.1%), Lack of money for transportation 26 (54.2%), unsatisfactory services at health facility 26 (54.2%), unfriendly attitude of staff of the health facility 34 (70.8%), unavailability of staff at health facility 32 (64.0%), lack of urgency at health facility 36 (75.0%), previous uneventful delivery at the health facility 32 (66.7%). CONCLUSION: Utilization of health care services during delivery in Nigeria is still poor. Concerted efforts should be made both at community and Government levels to improve utilization of health facility during delivery. This will go a long way in reducing maternal and child mortality.

Insecticide - treated bednet ownership and utilization in Rivers State, Nigeria before a state-wide net distribution campaign.

BACKGROUND & OBJECTIVES: Malaria presents a huge health and economic burden to families living in malaria endemic areas. The use of insecticide-treated nets (ITNs) is one of the global strategies in decreasing the malaria burden on vulnerable populations. The use of ITNs reduces clinical malaria by over 50% and all cause mortality in children by 15-30% when the overall population coverage is >70%. This study was aimed at establishing the level of household insecticide -treated bednet ownership and utilization in Rivers State, Nigeria before a statewide scale -up distribution campaign. STUDY DESIGN: A descriptive, cross - sectional study was carried out in the Rivers State in November 2008 among household heads or their proxies to serve as a pre -intervention baseline for the scale -up distribution of insecticide treated bednets in the state. The households were selected by a multi -staged sampling technique: first stage being the selection of Local Government Areas (LGAs) from Senatorial districts, second stage the selection of communities from LGAs and final stage the selection of households. Data were collected using a questionnaire adapted from the WHO/FMoH and analyzed using the Epi -Info version 6.04d statistical software package. Hypothesis tests were conducted to compare summary statistics at 95% significance level. RESULTS: A total of 811 household heads or their proxies were interviewed. Their age ranged between 20 and 70 yr, with a mean of 47.96 ± 4.39 yr. The study showed that although 552 (68.1%) of the households owned bednets, only 245 (30.2%, 95% CI=27.1-33.5) of them owned long -lasting insecticidal nets (LLINs). Similarly, only 37.2% of those who owned ITNs slept under them the night preceding the survey. CONCLUSION: Household ITN ownership and utilization were low in the state. Incorporating behavour change communication package as part of the ITN distribution intervention is advocated to increase ITNs utilization in the state.