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We examine the gap between the current and desired state of Doctor of Nursing Practice (DNP) education from the perspective of postdoctoral (DNP) teaching and education fellows.In the assessment of the DNP Essentials framework, command of scholarly and scientific writing, ability to demonstrate critical thought, and significant variation in clinical experience among DNP graduates are top concerns.These inconsistencies are problematic to the professional and public value of this terminal degree in nursing.

Background Retinoic acid signaling plays a critical role during embryogenesis and requires tight regulation. Exposure to exogenous retinoic acid during fetal development is known to have teratogenic effects, producing a recognizable embryopathy. Case We describe a case of retinoic acid embryopathy secondary to maternal isotretinoin use until the ninth week of gestation and expand the phenotype to include the rare features of parietal bone agenesis and athelia. Histology of the parietal region showed fibrous tissue with no intramembranous ossification. The fetus also had multiple craniofacial dysmorphisms, thymic agenesis, and transposition of the great arteries with double outlet right ventricle and subaortic perimembranous ventricular septal defect. Neuropathology revealed enlarged ventricles with agenesis of the cerebellar vermis, focal duplication of the central canal and scattered parenchymal ependymal rests, and possible cerebral heterotopias with associated abnormal neuronal lamination. A chromosomal microarray was normal. Conclusion Parietal bone agenesis and athelia are both rare congenital anomalies not previously reported in retinoic acid embryopathy. However, retinoic acid or its degrading enzyme has been demonstrated to exert effects in both of these developmental pathways, offering biological plausibility. We propose that this case may represent an expansion of the phenotype of retinoic embryopathy.

Background: Ofatumumab, an FDA-approved fully-human anti-CD20 monoclonal antibody with a 20 mg subcutaneous (s.c.) monthly dosing regimen, is indicated for the treatment of relapsing forms of multiple sclerosis (MS) in adults, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease. ARTIOS is a Phase 3b study exploring the treatment outcomes in relapsing MS (RMS) patients with disease activity that are switching from commonly used oral disease-modifying therapies. This patient population was relatively under-represented in the ASCLEPIOS I/II studies. Objectives: To present the innovative design of the ARTIOS study in RMS patients. Methods: ARTIOS is a single-arm, prospective, multicenter, open-label study in RMS patients aged 18-60 years with an Expanded Disability Status Scale score of 0-4 and breakthrough disease activity (defined as 1 relapse or 1 disease activity on MRI) after 6 months (m) of treatment with dimethyl fumarate or fingolimod. The study comprises of a screening and transition period (60 days), a treatment period (96 weeks) and a safety follow-up and/or extension period (9m). Ofatumumab 20 mg s.c. is self-administered monthly via an auto-injector. Treatment effectiveness (primary endpoint) will be evaluated as the annualized relapse rate over 96 weeks. Safety evaluations (secondary endpoint) include the proportion of patients with adverse events, laboratory/vital sign results meeting abnormal criteria, and treatment discontinuations. Exploratory endpoints include disability, MRI activity, no evidence of disease activity (NEDA-3) and patient-reported outcomes (MS impact, fatigue, treatment satisfaction and anxiety/depression). This innovative study design employs digital tools such as FloodlightTM (smartphone application), Actigraphy (activity-tracking watch), and an eCOA handheld for electronic diary to allow collection of data on the patient's activity (daily activity, sleep quality and injection reactions). Biomarkers of disease activity (neurofilament light chain [NfL] and glial fibrillary acidic protein [GFAP]) will also be evaluated. Results: The study plans to enroll ~550 patients across 25 countries. The first patient first visit was achieved on 14 July 2020 and study completion is expected in 2023. To account for COVID-19 associated restrictions, the original study was modified to provide more flexibility to patients visiting the clinic only to perform procedures which cannot be done at home with the support of home nurses (e.g., MRI and EDSS). An interim analysis is planned after completion of 1 year of treatment. Conclusions: The ARTIOS study will provide clinical data for the selected MS patient population that was not studied in the pivotal ofatumumab trials. ARTIOS leverages various digital technologies to collect unique and comprehensive data which may enrich treatment outcomes in this patient population.

Periventricular white matter hyperintensities (pvWMH) are neuroimaging abnormalities surrounding the lateral ventricles that are apparent on magnetic resonance imaging (MRI). They are associated with age, neurodegenerative disease, and cerebrovascular risk factors. While pvWMH ultimately represent a loss of white matter structural integrity, the pathological causes are heterogeneous in nature, and currently, cannot be distinguished using neuroimaging alone. pvWMH could occur because of a combination of small vessel disease (SVD), ependymal loss, blood–brain barrier dysfunction, and microgliosis. In this study we aimed to characterize microvascular stenosis, fibrinogen extravasation, and microgliosis within pvWMH with and without imaging evidence of periventricular infarction. Using postmortem neuroimaging of human brains (n = 20), we identified pvWMH with and without periventricular infarcts (PVI). We performed histological analysis of microvessel stenosis, perivascular spaces, microgliosis, and immunohistochemistry against fibrinogen as a measure of serum protein extravasation. Herein, we report distinctions between pvWMH with and without periventricular infarcts based on associations with microvessel stenosis, enlarged perivascular spaces, and fibrinogen IHC. Microvessel stenosis was significantly associated with PVI and with cellular deposition of fibrinogen in the white matter. The presence of fibrinogen was associated with PVI and increased number of microglia. These findings suggest that neuroimaging‐based detection of infarction within pvWMH may help distinguish more severe lesions, associated with underlying microvascular disease and BBB dysfunction, from milder pvWMH that are a highly frequent finding on MRI., White matter fibrinogen deposition is associated with post‐mortem MRI evidence of periventricular infarcts, arteriole stenosis and increases in microglia.

Nemaline myopathies (NEM) are heterogeneous congenital muscle disorders that cause skeletal muscle weakness and in the most severe cases, death.We describe a neonatal patient presenting with hypotonia and muscle biopsy showing nemaline myopathy. Genetic testing identified a de novo variant c.43G>C (p.Asp15His) in theTPM3 gene not previously described

Background Carotid endarterectomy (CEA) is a safe and effective procedure, with a low risk of complications when performed by experienced surgeons. Postoperative infections are particularly rare, reportedly affecting less than 1% of cases. Incisional metastases have not been described. Objective To describe a previously unreported complication, the incisional seeding of metastatic squamous cell carcinoma (SCC) during neck dissection, which presented and was treated as a presumed postoperative neck abscess. Methods Clinical records were reviewed regarding a 73-yr-old female who underwent routine CEA and presented 2 mo postoperatively with neck induration and erythema. Tissue submitted during the initial CEA was reexamined given the updated clinical history. Results Postoperatively, a complex, multi-cystic fluid collection beneath the incision was identified and percutaneously drained. Although cultures were negative, an infection was favored and antibiotic therapy initiated. The patient's symptoms worsened prompting surgical exploration, and tissue sent for pathological examination was consistent with metastatic SCC. Retrospective analysis of a lymph node excised during the initial dissection also revealed tumor deposits, indicating that the surgical site had been seeded during exposure. A primary origin was not identified. Conclusion The time from initial presentation of postoperative complications to a final diagnosis of metastatic SCC was 2 mo, during which time the patient was treated as having a postoperative infection. Further investigations were consistent with diffuse and incurable metastatic disease. This report highlights the diagnostic challenges and potential avoidance strategies when dealing with rare complications following CEA.

Background: Malignant peripheral nerve sheath tumors (MPNSTs) are uncommon but aggressive neoplasms associated with radiation exposure and neurofibromatosis Type I (NF1). Their incidence is low compared to other nervous system cancers, and intramedullary spinal lesions are exceedingly rare. Only a few case reports have described intramedullary spinal cord MPNST. Case Description: We describe the clinical findings, management, and outcome of a young patient with NF1 who developed aggressive cranial nerve and spinal MPNST tumors. This 35-year-old patient had familial NF1 and a history of optic glioma treated with radiation therapy (RT). She developed a trigeminal MPNST that was resected and treated with RT. Four years later, she developed bilateral lower extremity deficits related to an intramedullary cervical spine tumor, treated surgically, and found to be a second MPNST. Conclusion: To the best of our knowledge, this is the first report of cranial nerve and intramedullary spinal MPNSTs manifesting in a single patient, and only the third report of a confined intramedullary spinal MPNST. This unusual case is discussed in the context of a contemporary literature review.

Highlights • Ultra high-field post mortem MRI is a valid tool for the study of white matter hyperintensities. • Demyelination and parenchymal rarefaction are associated with FLAIR and T2 changes on 7 Tesla MRI. • Age, length of fixation and pathological diagnosis are all significant predictors of white matter FLAIR voxel intensity., White matter hyperintensities (WMH) occur in normal aging and across diagnostic categories of neurodegeneration. Ultra-high field imaging (UHF) MRI machines offer the potential to improve our understanding of WMH. Post-mortem imaging using UHF magnetic resonance imaging (MRI) is a useful way of assessing WMH, however, the responsiveness of UHF-MRI to pathological changes within the white matter has not been characterized. In this study we report post-mortem MRI sequences of white matter hyperintensities in normal aging, Alzheimer’s disease, and cerebrovascular disease. Seven Tesla post-mortem MRI reliably detected periventricular WMH using both FLAIR and T2 sequences and reflects underlying pathology of myelin and axon density despite prolonged fixation time. Co-registration of histological images to MRI allowed for direct voxel- wise comparison of imaging findings and pathological changes. Myelin content and cerebrovascular pathology were the most significant predictors of MRI white matter intensity as revealed by linear mixed models. Future work investigating the utility of UHF- MRI in studying cell-specific changes within WMH is required to better understand radio-pathologic correlations.

International audience; The aim of this study was to investigate how body thermal resistance between sexes evolves over time in the recovery period after a WBC session and to show how this parameter should be considered as a key parameter in WBC protocols. Eighteen healthy participants volunteered for the study (10 males and 8 females). Temperature (core and skin) were recorded pre- and post (immediately and every 5 min until 35 min post) exposure to a single bout of WBC (30 s at -60 °C, 150 s at -110 °C). From both core and skin temperatures a bio-heat transfer model was applied which led to the analytical formulation of the body thermal resistance. An unsteady behavior presenting a similar time-evolution trend in the body insulative response is shown for both females and males, possibly due to the vasodilatation process following an intense peripheral vasoconstriction during the extreme cold. Females present a 37% higher inner thermal resistance than males when reaching an asymptotical thermal state at rest due to a higher concentration of body fat percentage. Adiposity of tissues inherent in fat mass percentage appears to be a key parameter in the body thermal resistance to be taken into account in the definition of appropriate protocols for males and females. The conclusions of this preliminary study suggest that in order to achieve the same skin effects on temperature and consequently to cool efficiency tissues in the same way, the duration of cryotherapy protocols should be shorter when considering female compared to male.

A previously healthy 21-year-old male presented with acute urinary retention on a background of subacute back pain, progressive bilateral upper and lower extremity weakness, and night sweats. His f...

Most research focuses on overt stroke caused by blockage of major blood vessels. Less attention has been paid to small vessel disease which gives rise to covert stroke that often leads to vascular cognitive impairment (VCI). One reason for this may be the relative lack of relevant animal models. Herein, we describe, a model of VCI induced in middle-aged Sprague-Dawley rats exposed to a diet high in saturated fats, salt and refined sugar (HFSS). In Experiment 1, rats were fed HFSS and subjected to a small mediodorsal (MD) thalamic stroke with or without concomitant permanent bilateral carotid artery occlusion. MD lesions produce significant executive dysfunction in an attention set-shift task ( p = 0.012). In Experiment 2, rats were exposed to either HFSS or control diet and functional effects assessed. We found significant hypertension ( p = 0.013), blockage of brain microvessels ( p = 0.018) and white matter atrophy ( p = 0.039) in HFSS diet animals. As in Experiment 1, profound, specific set-shifting executive dysfunction was noted ( p = 0.003) following both small MD infarcts (0.332 mm3) and the HFSS diet. In summary, these data describe a middle-aged animal model of VCI that includes clinically relevant metabolic disturbances and small vessel disease and as such may be helpful in developing new cognitive therapies.

DIAGNOSTIC INVESTIGATIONS Imaging techniques, including computed tomography-guided biopsy and FDG-PET Stephen Connor Ultrasound imaging, including ultrasound-guided biopsy Rachel Oeppen and Rhodri Evans Surgical and other investigations Julia Woolgar Fine needle aspiration biopsy Matthias AW Merkx Three-dimensional imaging Ashraf F Ayoub ORAL SURGERY Tooth extraction Cathy Bryant Removal of unerupted teeth James Swift Nerve injuries and repair John Zuniga and Andrew Tay Surgical endodontics Helen Spencer Benign cysts of the face and jaws Joseph Helman Basic implantology: An American perspective Jaime Brahim Adjunctive office-based techniques for bone augmentation in oral implantology: An American perspective Gary Warburton Basic and advanced implantology: A European perspective John Cawood Major preprosthetic surgery, incorporating implants Eugene Keller Craniofacial implantology Greg Boyes-Varley and Dale Howes Tissue engineering Miller H Smith, Kenji Izumi and Stephen E Feinberg SURGICAL TECHNIQUES Emergency procedures David Macpherson and Clive Pratt Intraoral flaps and skin grafting John Carter Pectoralis major Andrew Lyons Reconstructive surgery : harvesting, skin mucosa and cartilage Peter Ward Booth Microvascular surgery : principles Cyrus Kerawala Radial forearm flap Andrew E Brown and Christopher M Avery Scapular and parascapular flap (with or without bone) Xin Peng, Chi Mao and Guang-yan Yu Rectus abdominis Xin Peng, Chi Mao and Guang-yan Yu Latissimus dorsi Andrew Baker Anterolateral thigh flap Andrew Lyons Gracilis flap Henning Schliephake Fibular flap Peter Brennan and Andre Eckardt Vascularized iliac crest grafts Andrew Lyons Facial Reanimation Henning Schliephake The use of lasers: general principles Madanogopalan Ethunandan The use of lasers: photodynamic therapy Colin Hopper MALIGNANT DISEASE OF THE MOUTH AND JAW Assessment and principles of management Peter A Brennan Percutaneous endoscopic gastrostomy Susannah Green and Pradeep Bhandran Oral and oropharyngeal squamous cell carcinoma: Pathological assessment of resection specimens and neck dissections Julia Woolgar Access surgery Barrie Evans and Dorothy Lang Excision of skin lesions and orbital and nasal reconstruction Bruce B Horswell Local resection and reconstruction of oral carcinomas and lip cancer Robert A Ord Jaw resection James S Brown Orbital resection and reconstruction Alexander D Rapidis Neck dissection Peter A Brennan Sentinel node biopsy Moni Abraham Kuriakose and Nirav Pravin Trivedi Tumours of the skull base Dorothy A Lang and Barrie T Evans SALIVARY AND THYROID SURGERY Submandibular, sublingual and minor salivary gland surgery John D Langdon Management of stones and strictures and interventional sialography Michael P Escudier and Jacqui E Brown Parotid surgery John D Langdon Extracapsular dissection Mark McGurk and Luke Cascarini Thyroidectomy, cysts of the thyroglossal duct tract and ectopic thyroid Eric J Dierks VASCULAR LESIONS Treatment techniques, surgery and sclerosants Maria E Papadaki and Leonard B Kaban Interventional radiology of the head and neck John S Millar TRAUMA Assessment and initial management Mohan F Patel Contemporary maxillofacial fixation techniques Domenick P Coletti Soft tissue injuries Suhail K Mithani and Eduardo D Rodriguez Dentoalveolar trauma Bernard J Costello and Brian Marin Mandibular fractures Michael Perry Management of condylar fractures, including endoscopic reduction Roger Currie Middle third fractures Joe McManners, Jeremy McMahon and Ian Holland Orbital trauma Michael Williams Craniofacial trauma, including management of frontal sinus and nasoethmoidal injuries Robert P Bentley Zygomatic fractures Michael Perry TEMPOROMANDIBULAR JOINT Temporomandibular joint arthroscopy Joseph McCain and King Kim Surgery to the temporomandibular joint George Dimitroulis Treatment of temporomandibular joint ankylosis Andrew J Sidebottom and Robert Hensher Total prosthetic replacement of the temporomandibular joint Andrew J Sidebottom and Robert Hensher CLEFT LIP AND PALATE Primary closure of unilateral cleft lip Chris Penfold Primary closure of bilateral clefts Krishna Shama Rao Primary closure of cleft palate Christoph Huppa Secondary cleft procedures John Caccamese Alveolar bone grafting Tim Flood Cleft rhinoplasty V Ilankovan CRANIOFACIAL SURGERY Segmental surgery of the jaws Paul JW Stoelinga Orthognathic surgery of the mandible Paul A Johnson Orthognathic surgery: maxilla (Le Fort I, II and III) George Obeid Surgical management of craniosynostosis GE Ghali and David M Montes Hemifacial microsomia Janice Lee Sleep apnoea and snoring, including non-surgical techniques Joe Deatherage and Peter Waite FACIAL AESTHETIC SURGERY Nonsurgical techniques: botox, fillers N Ravindranathan Hair transplantation N Ravindranathan and E Antonio Mangubat Brow lift and face lift including endoscopic surgery Tirbod Fattahi Blepharoplasty Leo Stassen Otoplasty Leo Stassen Rhinoplasty and septoplasty: Closed and open techniques and the Oriental no

Cognitive dysfunction, as a consequence of dementia, is a significant cause of morbidity lacking efficacious treatment. Females comprise at least half of this demographic but have been vastly underrepresented in preclinical studies. The current study addressed this gap by assessing the protective efficacy of physical exercise and cognitive activity on learning and memory outcomes in a rat model of vascular dementia. Forty ovariectomized Sprague-Dawley rats (~6 months old) were exposed to either a diet high in saturated fats and refined sugars or standard laboratory chow and underwent either chronic bilateral carotid occlusion or Sham surgery. Learning and memory abilities were evaluated using standard cognitive outcomes over the ensuing 6 months, followed by histologic analyses of hippocampal CA1 neurons. In Experiment 1, we confirmed hypoperfusion-induced cognitive dysfunction using a 2 × 2 (Surgery × Diet) experimental design, without alterations in hippocampal architecture. In Experiment 2, hypoperfused animals were either exposed to alternating days of physical (wheel running) and cognitive activity (modified Hebb–Williams maze) or sedentary housing. In contrast to males, this combination rehabilitation paradigm did not improve cognition or histopathologic outcomes in hypoperfused animals. These findings, highlighting differences between female and male animals, show the necessity of including both sexes in preclinical experimentation.

Most basic science research has focused on overt stroke caused by blockage of major blood vessels. Less attention has been paid to small vessel disease giving rise to covert stroke that often leads to vascular cognitive impairment (VCI). One reason for this may be the relative lack of relevant animal models. This talk will describe a model of VCI induced in middle-aged Sprague-Dawley rats exposed to a diet high in saturated fats, salt and refined sugar (HFSS). In Experiment 1, rats fed HFSS and subjected to a small mediodorsal (MD) thalamic stroke with or without concomitant cerebral hypoperfusion experienced significant executive dysfunction. In Experiment 2, dietary influences on functional, physiological and anatomical parameters were assessed. We found significant hypertension, blockage of brain microvessels (2-photon microscopy) and white matter atrophy in HFSS diet animals. As in Experiment 1, profound, specific set-shifting executive dysfunction was noted following both small MD infarcts (0.332 mm3) and the HFSS diet. In summary, these data describe a middle-aged animal model of VCI that includes clinically-relevant metabolic disturbances and small vessel disease and as such may be helpful in developing new cognitive therapies.

Early poststroke rehabilitation effectively improves recovery of function, likely by engaging multiple plasticity processes through use-dependent activation of neural circuits. The loci of such neuroplastic reorganization have not been examined during the initial phase of behavioral recovery. In the current study, we sought to evaluate sub-components of rehabilitation and to identify brain sites first engaged by early rehabilitation. Rats were subjected to endothelin-1 ischemia and placed in either enriched environment (EE), daily reach training (RT), combination of enriched environment and reach training (ER), or standard housing (ST) starting 7 days post ischemia. Functional and histopathological assessments were made after 2, 5, and 10 days of treatment. Animals exposed to 10 days of ER treatment exhibited significantly more use-dependent neuronal activity (FosB/ΔFosB expression) in perilesional cortex than those exposed to EE, RT, or ST treatments. Similar trends were observed in both perilesional striatum and contralesional forelimb motor cortex. This use-dependent plasticity was not explained by differences in neuronal death, inflammation, or lesion volume. The increased activity likely contributes to the neuroplastic changes and functional recovery observed after extended periods of rehabilitation. Importantly, EE or RT alone did not lead to enhanced activity suggesting that combination therapy is necessary to promote maximum recovery.

Background. After hemiplegic stroke, people often rely on their unaffected limb to complete activities of daily living. A component of residual motor dysfunction involves learned suppression of movement, termed learned nonuse. Objective. To date, no rodent stroke model of persistent learned nonuse has been described that can facilitate understanding of this phenomenon and test interventions to overcome it. Methods. Rats were trained in the staircase skilled-reaching and limb use asymmetry (cylinder) tasks. Endothelin-1 was injected into the cortex and striatum to create focal ischemia. Starting 7 days poststroke, half of the rats (ipsilateral training; n = 15) were trained to reach for food reward pellets in the tray-reaching task with the ipsilateral forelimb. Training lasted 20 days. Rats in the control group (control; n = 15) did not receive training. All rats then remained in their home cages for an additional 30 days. Performance on the cylinder and staircase tasks was assessed ~2 months poststroke. Results. Ischemia caused significant functional impairments in all rats. Significant contralateral forelimb skilled-reaching recovery was evident in the control group at 2 months but not the ipsilateral training group. There was no difference in performance in the cylinder task. Similarly, the volume of brain injury (~66 mm3) was similar between groups. Ipsilateral forelimb training reduced poststroke motor recovery. Conclusion. This rodent model of persistent nonuse after stroke may be used to further understand mechanisms of learned nonuse as well as to evaluate pharmacological and rehabilitation treatments to overcome it.

Dementia is a major cause of morbidity in the western society. Pharmacological therapies to delay the progression of cognitive impairments are modestly successful. Consequently, new therapies are urgently required to improve cognitive deficits associated with dementia. We evaluated the effects of physical and cognitive activity on learning and memory in a rat model of vascular dementia (VasD). Male Sprague-Dawley rats (6 months old) were exposed to either regular chow or a diet rich in saturated fats and sucrose and chronic bilateral common carotid artery occlusion or sham surgery. First, this model of VasD was validated using a 2 × 2 experimental design (surgery × diet) and standard cognitive outcomes. Next, using identical surgical procedures, we exposed animals to a paradigm of cognitive rehabilitation or a sedentary condition. At 16 weeks post surgery, VasD animals demonstrated significant learning and memory deficits in the Morris water maze, independent of diet. Rehabilitation significantly attenuated these cognitive deficits at this time point as well as at 24 weeks. Further, rehabilitation normalized hippocampal CA1 soma size (area and volume) to that of control animals, independent of cell number. Importantly, these findings demonstrate beneficial neuroplasticity in early middle-aged rats that promoted cognitive recovery, an area rarely explored in preclinical studies.

Preclinical studies must rigorously assess whether putative therapies improve motor and cognitive function following brain injury. Intracerebral hemorrhage (ICH) causes significant sensory-motor and cognitive deficits in humans. However, no study has evaluated cognition in rodent ICH models. Thus, we used a battery of tests to comprehensively examine whether a striatal ICH causes cognitive impairments in rats. Bacterial collagenase (or sterile saline for SHAM surgery) was injected into the striatum to create an ICH. Two days later, functional deficits were assessed using a neurological deficit scale (NDS), which is most sensitive to ICH injury. Sensory and/or motor deficits may confound cognitive testing; thus, we waited until these had resolved before testing learning and memory. Testing was conducted 1-7 months after ICH and included spontaneous alternation, elevated plus maze, open-field, Morris water maze, T-maze (win-shift and win-stay paradigms), and the radial arm maze (eight and four arms baited protocols). Significant motor deficits at 2 days completely resolved by 1 month, at which time cognitive testing began. In contrast to persistent cognitive deficits that occur after ICH in humans, we did not detect significant learning or memory deficits after ICH in rats. Our results suggest that these tests will not likely be useful for assessing outcome in experimental ICH studies. In conclusion, animal models that better mimic clinical ICH (both motor and cognitive deficits) must be developed. This may include increasing ICH severity or injuring other functional subdivisions within the striatum that may lead to more profound cognitive deficits.

Cognitive deficits associated with cardiac arrest have been well documented; however, the corresponding deficits in animal models of global ischemia have not been comprehensively assessed, particularly after long-term, clinically relevant survival times. We exposed male Sprague-Dawley rats to 10 min of bilateral carotid artery occlusion + systemic hypotension (40-45 mmHg) or sham surgery, and used histopathological assessments for short-term survival animals (16 days) and both behavioral and histopathological assessments for long-term survival animals (270 days). Analyses revealed significant long-term deficits in ischemic animals' learning, memory (T-maze, radial arm maze), working memory (radial arm maze), and reference memory (Morris water maze, radial arm maze) abilities that were not associated with a general cognitive decline. Histological results showed significant increases in glial fibrillary acidic protein, neuron glia 2, OX-42 and ED-1 staining, as well as significant decreases in microtubule-associated protein 2 staining and cornu ammonis area 1 (CA1) cell counts 16 days post-ischemia. The pattern at 270 days was similar, but notably there was a persistent elevation of ED-1 staining, suggesting recent cell death as well as significant atrophy of CA1. Whereas previous work has primarily reported transient changes in behavior after global ischemia, this study describes disturbances in several different functional domains following CA1 cell loss at clinically relevant survival times. Moreover, the histopathological outcome is suggestive of a spontaneous repopulation of CA1, but this was not sufficient to offset the behavioral impairments arising from the ischemic insult.

Developing new therapeutants for stroke requires animal models in which typical stroke outcomes can be detected. In rats, temporary occlusion of the middle cerebral artery (MCAo) closely resembles reversible human ischemic stroke, but most neuroprotection studies have used limited, short-term (1-2 weeks) behavioural and histological endpoints in this model. Further, the use of this model for assessing long-term recovery has been questioned. Long-term deficits may be difficult to detect because testing may not reflect the diversity of functional outcomes in clinical stroke, and/or high mortality rates mean that only the least severely affected rats remain to be tested. We believe that enhanced survival through intensive post-operative husbandry practices, and extensive behavioural testing that reflects multiple clinically relevant behavioural endpoints, will permit the detection of long-term functional deficits. In the present study, male SD rats (280-320 g) received transient (90 min) MCAo (n = 19) or sham surgery (n = 13). An intense post-operative care protocol was maintained, and assessments included various physical and sensorimotor parameters, tests of emotionality and tests of learning and memory. We report 0% mortality, and statistically significant deficits on all aspects of this battery, including learning and memory deficits up to 2 months post-MCAo. The current study demonstrates that with adequate post-operative care and extensive behavioural testing, assessing the potential of new therapeutants for promoting long-term functional neuroprotection following MCAo in the rat is feasible.

Critically ill patients with a preexisting diagnosis of diabetes mellitus are very common and they have several inherent disorders that make their ICU care challenging. There is increasing evidence that hyperglycemia is all too common in the critically ill and that improved glucose control at presentation and during an ICU stay improves mortality. Glucose control after acute myocardial infarction and coronary artery bypass grafting in particular affects patient outcome and mortality. Diabetic patients are more prone to several medical problems that can predispose them to critical illness, prolong hospitalization, and increase mortality. Delayed gastric emptying and altered metabolism that affect medication dosing, absorption, and efficacy are common in this population. In addition, many patients with diabetes have renal dysfunction that can cause difficulties with drug excretion and glucose monitoring. Finally, patients with diabetes have an increased rate and severity of life-threatening infections and venous thromboembolism than do patients with normal glucose metabolism. There are many treatment options for patients with diabetes, and hyperglycemia in the ICU should be corrected in order to avoid adverse outcomes.

Oral Diseases (2012) 18, 417–419 The use of eponyms has long been contentious, but many remain in common use, as discussed elsewhere (Editorial: Oral Diseases. 2009: 15; 185). The use of eponyms in diseases of the head and neck is found mainly in specialties dealing with medically compromised individuals (paediatric dentistry, special care dentistry, oral and maxillofacial medicine, oral and maxillofacial pathology, oral and maxillofacial radiology and oral and maxillofacial surgery) and particularly by hospital-centred practitioners. This series has selected some of the more recognised relevant eponymous conditions and presents them alphabetically. The information is based largely on data available from MEDLINE and a number of internet websites as noted below: the authors would welcome any corrections. This document summarises data about Yersiniosis.

Oral Diseases (2012) 18, 214–216 The use of eponyms has long been contentious, but many remain in common use, as discussed elsewhere (Editorial: Oral Diseases. 2009: 15; 185). The use of eponyms in diseases of the head and neck is found mainly in specialties dealing with medically compromised individuals (paediatric dentistry, special care dentistry, oral and maxillofacial medicine, oral and maxillofacial pathology and oral, oral and maxillofacial radiology and maxillofacial surgery) and particularly by hospital-centred practitioners. This series has selected some of the more recognized relevant eponymous conditions and presents them alphabetically. The information is based largely on data available from MEDLINE and a number of internet websites as noted below: the authors would welcome any corrections. This document summarizes data about Wegener granulomatosis.

Although the pathogenesis of Warthin's tumour is not fully understood, it is generally thought that the tumour arises from heterotopic salivary ducts within pre-existing lymphoid tissue. Prolonged nitric oxide (NO) production by the enzyme type 2 nitric oxide synthase (NOS2) has been implicated in the pathogenesis of many solid tumours, but not in Warthin's tumour. Since NO and NOS2 are known to be associated with p53, the immunohistochemical expression of both NOS2 and p53 was investigated in 23 cases of Warthin's tumour. Widespread diffuse cytoplasmic immunostaining for NOS2 was found in tumour epithelial cells of all 23 cases studied, and it was additionally expressed in normal salivary duct epithelium. p53 staining was localised to the nuclei of tumour epithelium in 16 cases, with a similar pattern of distribution to tumour NOS2 expression. A significant correlation was found between NOS2 and p53 staining in the tumours (P < 0.001). In contrast to NOS2, p53 was not expressed by normal salivary ductal cells in any of the cases studied. NOS2 is widely expressed by the tumour epithelium of Warthin's, and its association with p53 expression is discussed. The role of NO in the pathogenesis of Warthin's tumour remains to be established.

Oral Diseases (2011) 17, 538–540 The use of eponyms has long been contentious, but many remain in common use, as discussed elsewhere (Editorial: Oral Diseases. 2009: 15; 185). The use of eponyms in diseases of the head and neck is found mainly in specialties dealing with medically compromised individuals (paediatric dentistry, special care dentistry, oral and maxillofacial medicine, oral and maxillofacial pathology, oral and maxillofacial radiology and oral and maxillofacial surgery) and particularly by hospital-centred practitioners. This series has selected some of the more recognized relevant eponymous conditions and presents them alphabetically. The information is based largely on data available from MEDLINE and a number of internet websites as noted below: the authors would welcome any corrections. This document summarizes data about Sjogren syndrome.

Oral Diseases (2011) 17, 342–344 The use of eponyms has long been contentious, but many remain in common use, as discussed elsewhere (Editorial: Oral Diseases. 2009: 15; 185). The use of eponyms in diseases of the head and neck is found mainly in specialties dealing with medically compromised individuals (paediatric dentistry, special care dentistry, oral and maxillofacial medicine, oral and maxillofacial pathology, oral and maxillofacial radiology and oral and maxillofacial surgery) and particularly by hospital-centred practitioners. This series has selected some of the more recognized relevant eponymous conditions and presents them alphabetically. The information is based largely on data available from MEDLINE and a number of internet websites as noted below: the authors would welcome any corrections. This document summarizes data about Quincke’s oedema.

Oral Diseases (2011) 17, 238–240 The use of eponyms has long been contentious, but many remain in common use, as discussed elsewhere (Editorial: Oral Diseases. 2009: 15; 185). The use of eponyms in diseases of the head and neck is found mainly in specialties dealing with medically compromised individuals (paediatric dentistry, special care dentistry, oral and maxillofacial medicine, oral and maxillofacial pathology, oral and maxillofacial radiology and oral and maxillofacial surgery) and particularly by hospital-centred practitioners. This series has selected some of the more recognised relevant eponymous conditions and presents them alphabetically. The information is based largely on data available from MEDLINE and a number of internet websites as noted below: the authors would welcome any corrections. This document summarises data about Paget disease of bone.

Background Nitric oxide (NO) has been implicated both in tumor progression and inhibition. This study investigated whether type II nitric oxide synthase (NOS2) expression correlated with cell proliferation in oral squamous cell carcinoma (OSCC) and dysplasia. Methods Paraffin-embedded tissue samples of normal oral mucosa, OSCC, and dysplasia were assessed immunohistochemically using monoclonal antibodies to NOS2 and Ki-67 antigen. We used Western blotting to confirm NOS2 antibody specificity and protein expression in select cases. Results NOS2 staining was increased in OSCC relative to normal oral mucosa, in which no expression was found. Both NOS2 expression and Ki-67 indices independently correlated with grade of dysplasia (p < .001) but not with the degree of tumor differentiation. A positive correlation was found between NOS2 expression and Ki-67 in cases of mild and moderate dysplasia (p < .001), but not in severe dysplasia and OSCC. Conclusions No correlation exists between Ki-67 and NOS2 expression in severe dysplasia and OSCC. The findings suggest that the level of NO produced by NOS2 is insufficient to affect cellular proliferation in these conditions. The mechanism of NOS2 activation and the consequences of its expression remain to be fully explained. © 2001 John Wiley & Sons, Inc. Head Neck 23: 217–222, 2001.

The use of eponyms has long been contentious, but many remain in common use, as discussed elsewhere (Editorial: Oral Diseases. 2009: 15; 185). The use of eponyms in diseases of the head and neck is found mainly in specialties dealing with medically compromised individuals (paediatric dentistry, special care dentistry, oral and maxillofacial medicine, oral and maxillofacial pathology, oral and maxillofacial radiology and oral and maxillofacial surgery) and particularly by hospital-centred practitioners. This series has selected some of the more recognised relevant eponymous conditions and presents them alphabetically. The information is based largely on data available from MEDLINE and a number of internet websites as noted below: the authors would welcome any corrections. This document summarises data about Osler–Rendu–Weber disease. Oral Diseases (2011) 17, 125–127

Nitric oxide (NO) has been implicated in a variety of diseases but has not been previously studied in oral lichen planus (OLP). Since OLP has a complex immunogenesis with abundant macrophage infiltration, this study determined by im- munohistochemistry whether or not the expression of the in- ducible form of nitric oxide synthase (iNOS) was increased in this condition relative to normal mucosa. Thirty cases of OLP and 10 normal buccal mucosa biopsies were studied utilising primary antibodies to iNOS and CD68, a myelomonocytic marker. iNOS activity was additionally assessed using a ( 14» C)- labelled arginine to citrulline assay. CD68 expression was sig- nificantly increased in the cellular infiltrate of all 30 cases of OLP compared with normal mucosa (P∞0.009). Although iNOS staining was seen in a minority of cells in nine cases, this was not statistically significant when compared with the absent staining in normal oral mucosa (P50.26). Furthermore, the minimal iNOS activity found in OLP was similar to that in normal mucosa. We conclude that expression of iNOS by macrophages is downregulated in OLP and discuss the possible reasons for this finding.

Normal expression of the human β-globin domain genes is dependent on at least three types of regulatory elements located within the β-globin domain: the locus control region (LCR), globin enhancer elements (3′β and 3′Aγ), and the individual globin gene promoter and upstream regions. It has been postulated that regulation occurs through physical interactions between factors bound to these elements, which are located at considerable distances from each other. To identify the elements required for promoter-enhancer interactions from a distance, we have investigated the expression of the wild-type, truncated, and mutated γ-globin promoters linked to the 5′HS2 enhancer. We show that in K562 cells, 5′HS2 increases activity approximately 20-fold from both a wild-type and truncated (-135 → +25) γ promoter and that truncation or site-directed mutagenesis of the tandem CCAAT boxes eliminated the enhancement by 5′HS2. Mutation of the γ-globin gene promoter GATA-1 binding sites did not decrease either promoter strength or enhancement of activity by 5′HS2. To determine if enhanced expression of γ-globin gene promoters carrying mutations associated with hereditary persistence of fetal hemoglobin (HPFH) was due to greater interactions with enhancers, we linked these HPFH γ-globin gene promoters to 5′HS2 and demonstrated a twofold to threefold higher expression than the corresponding wild-type promoter plus enhancer in MEL cells. Addition of the Aγ-globin gene 3′ enhancer to a plasmid containing the γ-globin gene promoter and 5′HS2 did not further enhance promoter strength. Furthermore, we have demonstrated that the previously identified core 5′HS2 enhancer (46-bp tandem AP-1/NF-E2 sites) increased expression only when located 5′, but not 3′, to the γ-globin-luciferase reporter gene, suggesting that its enhancer effect is not by DNA looping. Our results suggest that CCAAT boxes, but not GATA or CACCC binding sites, are required for interaction between the γ-globin promoter and the LCR/5′HS2 and that regulatory elements in addition to the core enhancer may be required for the enhancer to act from a distance.

Small (lacunar) infarcts frequently arise in frontal and midline thalamic regions in the absence of major stroke. Damage to these areas often leads to impairment of executive function likely as a result of interrupting connections of the prefrontal cortex. Thus, patients experience frontal-like symptoms such as impaired ability to shift ongoing behavior and attention. In contrast, executive dysfunction has not been demonstrated in rodent models of stroke, thereby limiting the development of potential therapies for human executive dysfunction. Male Sprague-Dawley rats (n=40) underwent either sham surgery or bilateral endothelin-1 injections in the mediodorsal nucleus of the thalamus or in the medial prefrontal cortex. Executive function was assessed using a rodent attention set shifting test that requires animals to shift attention to stimuli in different stimulus dimensions. Medial prefrontal cortex ischemia impaired attention shift performance between different stimulus dimensions while sparing stimulus discrimination and attention shifts within a stimulus dimension, indicating a selective attention set-shift deficit. Rats with mediodorsal thalamic lacunar damage did not exhibit a cognitive impairment relative to sham controls. The selective attention set shift impairment observed in this study is consistent with clinical data demonstrating selective executive disorders following stroke within specific sub-regions of frontal cortex. These data contribute to the development and validation of a preclinical animal model of executive dysfunction, that can be employed to identify potential therapies for ameliorating cognitive deficits following stroke.

Background. In humans, retrospective studies suggest that habitual physical activity (PA) or cognitive activity (CA) can help maintain or improve cognitive function. Similar findings have been reported using physical exercise in animal studies; however, the exercise paradigms differ markedly in duration and frequency, making extrapolation difficult. Here, the authors present a novel PA and CA paradigm that combines voluntary wheel running with Hebb-Williams and radial arm maze (RAM) training. Methods. A total of 57 male Sprague-Dawley rats were divided into 4 treatment groups: the PA, CA, and combined PA and CA groups and sedentary controls. PA (voluntary wheel running) and CA (Hebb-Williams mazes) consisted of a moderate 2 h/d, 5 d/wk treatment paradigm. Results. Animals exposed to a combination of PA and CA made significantly fewer working memory errors and exhibited superior choice accuracy when compared with animals exposed to either PA or CA alone in the 8-arm baited configuration of the RAM. Additional analyses revealed that the cognitive improvements were independent of exercise intensity/duration. Assessment of brain-derived neurotrophic factor (BDNF) levels revealed a significant increase in hippocampal BDNF only in the PA-alone group. Conclusion. A novel combination of PA and CA improves learning and memory abilities independent of activity intensity, BDNF, or phosphorylated cyclic AMP response element binding protein levels. This is the first report of significant changes in cognitive ability using a paradigm involving moderate levels of PA plus cognitive stimulation. An adaptation of this paradigm may be particularly beneficial in slowing the development of mild cognitive impairment and subsequent dementia in elderly people.

A diet consisting of high levels of saturated fat has been linked to a dramatic rise in obesity, type II diabetes, and metabolic syndrome. The effect of these co-morbidities on stroke outcome has not been examined in detail in human or animal studies. In this study we hypothesized that maintaining animals on a high fat, "Western diet" (WD), for an extended period would have a detrimental effect on ischemic outcome. Forty-eight male Sprague-Dawley rats were exposed to 1 month of either WD or control diets initiated at 6 weeks of age (Experiment 1) or 3 months of either WD or control diets initiated at 4 weeks of age (Experiment 2) prior to endothelin-1-induced ischemia. Following ischemia, animals were assessed in the staircase reaching and beam-traversing tests at 2 and 4 weeks post-ischemia and infarct volumes were calculated at 4 weeks post-ischemia. Analysis revealed no difference between animals exposed to either WD or control diets for 1 month in behavioral or histological assessments. In contrast, 3 months of WD diet exposure significantly increased functional impairments in both the staircase and beam-traversing tests as well as increasing the volume of infarction, primarily in the cortex. The results of this study demonstrate that long-term exposure to WD diets are detrimental to ischemic outcome. Consequently, it is important to incorporate disease co-morbidities and/or risk factors in pre-clinical evaluation of neuroprotective or restorative interventions if therapies are to be translated into the clinic.

International audience; Background: Evidence for efficacy of disease-modifying drugs in multiple sclerosis (MS) comes from trials of short duration. We report results from a 16-year, retrospective follow-up of the pivotal interferon beta-1b (IFNB-1b) study. Methods: The 372 trial patients had been randomly assigned to placebo (n = 123), IFNB-1b 50 ìg (n = 125), or IFNB-1b 250 ìg (n = 124) subcutaneously every other day for at least 2 years. Some remained randomised for up to 5 years, but subsequently patients received therapy according to physician discretion. Patients were re-contacted and asked to participate. Efficacy-related measures included magnetic resonance imaging (MRI) parameters, relapse rate, the Expanded Disability Status Scale, the Multiple Sclerosis Functional Composite Measure, and conversion to secondary progressive MS. Results: Of the 88.2% (328/372) of patients who were identified, 69.9% (260/372) had available case report forms. No differences in outcome between original randomisation groups could be discerned using standard disability and MRI measures. However, mortality rates among patients originally treated with IFNB-1b were lower than in the original placebo group (18.3% [20/109] for placebo vs 8.3% [9/108] for IFNB-1b 50 ìg and 5.4% [6/111] for IFNB-1b 250 ìg). Conclusions: The original treatment assignment could not be shown to influence standard assessments of long-term efficacy. On-study behaviour of patients was influenced by factors that could not be controlled with the sacrifice of randomisation and blinding. Mortality was higher in patients originally assigned to placebo than those who had received IFNB-1b 50 ìg or 250 ìg. The dataset provides important resources to explore early predictors of long-term outcome.

OBJECTIVE: The 16-Year Long-Term Follow-Up (LTF) to the pivotal interferon-beta-1b (IFNbeta-1b) trial explored clinical, MRI, cognitive, and patient-reported outcomes. Here, we report the safety assessments. METHODS: In the pivotal study, 372 patients were randomized to placebo (n = 123), IFNbeta-1b 50 microg (n = 125), or IFNbeta-1b 250 microg (n = 124) subcutaneously every other day for up to 5 years. Sixteen years later, patients were asked to participate in this cross-sectional follow-up study. No particular therapy was stipulated during follow-up. Adverse events experienced since the pivotal trial were recorded. Neutralizing antibodies (NAbs) to IFNbeta-1b were measured using the myxovirus protein A induction assay. Statistical analyses were descriptive. RESULTS: In total, 88.2% of patients (328/372) were identified. Some centers achieved 100% ascertainment, obviating selection bias. Treatment-related adverse events (e.g., leukopenia and liver and thyroid dysfunction) reported by LTF participants were in keeping with those previously established. Based on a follow-up period that includes 2,000 patient-years of IFNbeta-1b treatment, no new adverse events were observed that were associated with long-term IFNbeta-1b exposure. By LTF, NAbs to IFNbeta-1b disappeared in the majority (76%) of NAb-positive patients. NAb status during the pivotal study appeared to have no impact on long-term clinical and MRI outcomes. There were more deaths among patients assigned to placebo in the pivotal study (20/109 [18.3%]) compared with patients who received IFNbeta-1b 50 microg (9/108 [8.3%]) or IFNbeta-1b 250 microg (6/111 [5.4%]). CONCLUSION: The results from the 16-Year Long-Term Follow-Up study support the long-term safety of interferon-beta-1b therapy in multiple sclerosis. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that patients with relapsing-remitting MS taking IFNbeta-1b 50 microg or 250 microg subcutaneously every other day for up to 5 years, with subsequent unspecified treatment, have fewer deaths after 16 years of follow-up than similar patients on placebo for up to 5 years, with subsequent unspecified treatment (risk difference 11.5%, 95% confidence interval 4-19).