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Stroke is a leading cause of death and a major cause of permanent disability. Its management is demanding because of variety of protocols, imaging modalities, pulse sequences, hemodynamic maps, criteria for treatment, and time constraints to promptly evaluate and treat. To cope with some of these issues, we propose novel, patented solutions in stroke management by employing multiple brain atlases for diagnosis, treatment, and prediction. Numerous and diverse CT and MRI scans are used: ARIC cohort, ischemic and hemorrhagic stroke CT cases, MRI cases with multiple pulse sequences, and 128 stroke CT patients, each with 170 variables and one year follow-up. The method employs brain atlases of anatomy, blood supply territories, and probabilistic stroke atlas. It rapidly maps an atlas to scan and provides atlas-assisted scan processing. Atlas-to-scan mapping is application-dependent and handles three types of regions of interest (ROIs): atlas-defined ROIs, atlas-quantified ROIs, and ROIs creating an atlas. An ROI is defined by atlas-guided anatomy or scan-derived pathology. The atlas defines ROI or quantifies it. A brain atlas potential has been illustrated in four atlas-assisted applications for stroke occurrence prediction and screening, rapid and automatic stroke diagnosis in emergency room, quantitative decision support in thrombolysis in ischemic stroke, and stroke outcome prediction and treatment assessment. The use of brain atlases in stroke has many potential advantages, including rapid processing, automated and robust handling, wide range of applications, and quantitative assessment. Further work is needed to enhance the developed prototypes, clinically validate proposed solutions, and introduce them to clinical practice.

Background and ObjectivesLate neuropathologies of repetitive head impacts from contact sports can include chronic traumatic encephalopathy (CTE) and white matter degeneration. White matter hyperintensities (WMH) on fluid-attenuated inversion recovery (FLAIR) MRI scans are often viewed as microvascular disease from vascular risk, but might have unique underlying pathologies and risk factors in the setting of repetitive head impacts. We investigated the neuropathologic correlates of antemortem WMH in brain donors exposed to repetitive head impacts. The association between WMH and repetitive head impact exposure and informant-reported cognitive and daily function were tested.MethodsThis imaging–pathologic correlation study included symptomatic male decedents exposed to repetitive head impacts. Donors had antemortem FLAIR scans from medical records and were without evidence of CNS neoplasm, large vessel infarcts, hemorrhage, or encephalomalacia. WMH were quantified using log-transformed values for total lesion volume (TLV), calculated using the lesion prediction algorithm from the Lesion Segmentation Toolbox. Neuropathologic assessments included semiquantitative ratings of white matter rarefaction, cerebrovascular disease, hyperphosphorylated tau (p-tau) severity (CTE stage, dorsolateral frontal cortex), and β-amyloid (Aβ). Among football players, years of play was a proxy for repetitive head impact exposure. Retrospective informant-reported cognitive and daily function were assessed using the Cognitive Difficulties Scale (CDS) and Functional Activities Questionnaire (FAQ). Regression models controlled for demographics, diabetes, hypertension, and MRI resolution. Statistical significance was defined as p ≤ 0.05.ResultsThe sample included 75 donors: 67 football players and 8 nonfootball contact sport athletes or military veterans. Dementia was the most common MRI indication (64%). Fifty-three (70.7%) had CTE at autopsy. Log TLV was associated with white matter rarefaction (odds ratio [OR] 2.32, 95% confidence interval [CI] 1.03, 5.24; p = 0.04), arteriolosclerosis (OR 2.38, 95% CI 1.02, 5.52; p = 0.04), CTE stage (OR 2.58, 95% CI 1.17, 5.71; p = 0.02), and dorsolateral frontal p-tau severity (OR 3.03, 95% CI 1.32, 6.97; p = 0.01). There was no association with Aβ. More years of football play was associated with log TLV (unstandardized β 0.04, 95% CI 0.01, 0.06; p = 0.01). Greater log TLV correlated with higher FAQ (unstandardized β 4.94, 95% CI 0.42, 8.57; p = 0.03) and CDS scores (unstandardized β 15.35, 95% CI −0.27, 30.97; p = 0.05).DiscussionWMH might capture long-term white matter pathologies from repetitive head impacts, including those from white matter rarefaction and p-tau, in addition to microvascular disease. Prospective imaging–pathologic correlation studies are needed.Classification of EvidenceThis study provides Class IV evidence of associations between FLAIR white matter hyperintensities and neuropathologic changes (white matter rarefaction, arteriolosclerosis, p-tau accumulation), years of American football play, and reported cognitive symptoms in symptomatic brain donors exposed to repetitive head impacts.

Chronic obstructive pulmonary disease (COPD) is induced by cigarette smoking and characterized by inflammation of airway tissue. Since smokers with COPD have a higher risk of developing lung cancer than those without, we hypothesized that they carry more mutations in affected tissue. We called somatic mutations in airway brush samples from medium-coverage whole genome sequencing data from healthy never and ex-smokers (n = 8), as well as from ex-smokers with variable degrees of COPD (n = 4). Owing to the limited concordance of resulting calls between the applied tools we built a consensus, a strategy that was validated with high accuracy for cancer data. However, consensus calls showed little promise of representing true positives due to low mappability of corresponding sequence reads and high overlap with positions harbouring known genetic polymorphisms. A targeted re-sequencing approach suggested that only few mutations would survive stringent verification testing and that our data did not allow the inference of any difference in the mutational load of bronchial brush samples between former smoking COPD cases and controls. High polyclonality in airway brush samples renders medium-depth sequencing insufficient to provide the resolution to detect somatic mutations. Deep sequencing data of airway biopsies are needed to tackle the question.

Background: Biologic augmentation via extracellular matrix (ECM) scaffolds has been utilized to address rotator cuff tears with poor-quality tissue. Purpose: To evaluate the cellular changes in graft explants taken from patients treated with porcine dermal grafts for rotator cuff tears. Study Design: Case series; Level of evidence, 4 Methods: Four graft biopsy specimens were obtained from patients treated with porcine dermal grafts in an interposition technique for rotator cuff tears and compared with a nonimplanted graft and a normal rotator cuff specimen. Biopsy of the graft site was performed at 18 days, 3 months, 7 months, and 10.5 months after implantation. Hematoxylin and eosin staining was used to evaluate for cellular and vascular changes. Picrosirius red (PSR) stain with 90° polarized light was performed to evaluate collagen fibril size and orientation. All biopsy specimens were analyzed by a pathologist. Results: There was evidence of progressive remodeling of the porcine dermal grafts. The most mature grafts demonstrated vessel infiltration and extensive remodeling without evidence of inflammation, foreign body reaction, or tissue rejection. PSR demonstrated increased organization of collagen domains, resembling normal tendon by 10.5 months postoperatively. Conclusion: This series suggests that ECM grafts may serve as an effective scaffold for host cell infiltration, collagen reorganization, and vascularization as a result of histologic changes demonstrated with retrieval of specimens from patients with rotator cuff tears that were augmented with porcine dermal grafts.

Background Various surgical methods are used for early treatment of nonsyndromic sagittal craniosynostosis. The craniofacial centers in Uppsala and Helsinki fundamentally both use the H-Craniectomy: Renier's technique. However, the Helsinki group systematically adds coronal suturectomies to prevent secondary coronal synostosis and posterior barrel staves to address posterior bulleting. The effects of these additions in early treatment of sagittal craniosynostosis are currently unknown. Methods Thirty-six patients from Uppsala and 27 patients from Helsinki were included in the study. Clinical data and computed tomography scans were retrieved for all patients. Results The Helsinki patients had a smaller preoperative Cranial index (CI) (65 vs 72) and a smaller preoperative width (10.1 vs 11.2). There was no difference in postoperative CI, corresponding to a difference in change in CI. Regression analysis indicated that the larger change in CI in the Helsinki group was mainly due to a lower preoperative CI allowing for a larger normalization. The Helsinki patients had less growth in length (1.5 vs 2.1 cm) and more growth in width (2.3 vs 1.9 cm). There were no differences in head circumference or surgical complications. Secondary coronal synostosis was present in 43% of the Uppsala group at 3 years of age, while calvarial defects located at sites of previous coronal suturectomies and posterior barrel staving were seen in the Helsinki group 1 year postoperatively. Conclusions Lower preoperative CI appears to be the main factor in determining the amount of normalization in CI. Prophylactic coronal suturectomies do not seem to benefit preservation of coronal growth function since the modification correlates to less sagittal growth and more growth in width.

Background Whether the clinical or pathophysiologic significance of the “treatable trait” high blood eosinophil count in COPD is the same as for asthma remains controversial. We sought to determine the relationship between the blood eosinophil count, clinical characteristics and gene expression from bronchial brushings in COPD and asthma. Methods Subjects were recruited into a COPD (emphysema versus airway disease [EvA]) or asthma cohort (Unbiased BIOmarkers in PREDiction of respiratory disease outcomes, U‐BIOPRED). We determined gene expression using RNAseq in EvA (n = 283) and Affymetrix microarrays in U‐BIOPRED (n = 85). We ran linear regression analysis of the bronchial brushings transcriptional signal versus blood eosinophil counts as well as differential expression using a blood eosinophil > 200 cells/μL as a cut‐off. The false discovery rate was controlled at 1% (with continuous values) and 5% (with dichotomized values). Results There were no differences in age, gender, lung function, exercise capacity and quantitative computed tomography between eosinophilic versus noneosinophilic COPD cases. Total serum IgE was increased in eosinophilic asthma and COPD. In EvA, there were 12 genes with a statistically significant positive association with the linear blood eosinophil count, whereas in U‐BIOPRED, 1197 genes showed significant associations (266 positive and 931 negative). The transcriptome showed little overlap between genes and pathways associated with blood eosinophil counts in asthma versus COPD. Only CST1 was common to eosinophilic asthma and COPD and was replicated in independent cohorts. Conclusion Despite shared “treatable traits” between asthma and COPD, the molecular mechanisms underlying these clinical entities are predominately different., In a chronic obstructive pulmonary disease (COPD) cohort (EvA, n = 283), 12 genes, whereas in asthma cohort (UBIOPRED, n = 85), 1197 genes in bronchial epithelial brushes were correlated with a blood eosinophil count. The gene CST1 was common to eosinophilic asthma and COPD and was replicated in independent cohorts. Despite shared “treatable traits” between asthma and COPD, the molecular mechanisms underlying these clinical entities are predominately different.

Background: Chronic obstructive pulmonary disease (COPD) is associated with airway inflammation and bacterial dysbiosis. The relationship between the airway microbiome and bronchial gene expression in COPD is poorly understood. We aimed to identify differences in the airway microbiome from bronchial brushings in patients with COPD and healthy individuals and to investigate whether any distinguishing bacteria are related to bronchial gene expression. Methods: For this 16S rRNA gene sequencing and host transcriptomic analysis, individuals aged 45–75 years with mild-to-moderate COPD either receiving or not receiving inhaled corticosteroids and healthy individuals in the same age group were recruited as part of the Emphysema versus Airways Disease (EvA) consortium from nine centres in the UK, Germany, Italy, Poland, and Hungary. Individuals underwent clinical characterisation, spirometry, CT scans, and bronchoscopy. From bronchoscopic bronchial brush samples, we obtained the microbial profiles using 16S rRNA gene sequencing and gene expression using the RNA-Seq technique. We analysed bacterial genera relative abundance and the associations between genus abundance and clinical characteristics or between genus abundance and host lung transcriptional signals in patients with COPD versus healthy individuals, and in patients with COPD with versus without inhaled corticosteroids treatment. Findings Between February, 2009, and March, 2012, we obtained brush samples from 574 individuals. We used 546 of 574 samples for analysis, including 207 from healthy individuals and 339 from patients with COPD (192 with inhaled corticosteroids and 147 without). The bacterial genera that most strongly distinguished patients with COPD from healthy individuals were Prevotella (median relative abundance 33·5%, IQR 14·5–49·4, in patients with COPD vs 47·7%, 31·1–60·7, in healthy individuals; p

Secondary Coronal Synostosis (SCS) in patients operated for non-syndromic Sagittal Craniosynostosis is a postoperative phenomenon with unclear implications. The aim of this study was to investigate whether SCS is a negative or a benign occurrence in the postoperative course. The authors hypothesized that SCS is related to reduced cranial growth and intracranial hypertension. Thirty-one patients operated for SC at an early age with the H-craniectomy technique were included in the study. Associations between SCS and cranial shape, growth, and signs of intracranial hypertension were analyzed. Intracranial volume distribution was assessed by measuring partial intracranial volumes defined by skull base landmarks. A total of 12/31 patients developed SCS during the postoperative course. The presence of SCS was associated with a higher prevalence of gyral impressions and a larger normalization of Cranial Index due to less growth in the anteroposterior plane. The SCS group had a smaller postoperative intracranial volume due to less posterior intracranial volume as well as less growth in head circumference. Whether this is a growth restriction caused by the SCS or a secondary effect of less primary brain growth remains to be determined. However, the correlation between SCS, less cranial growth and gyral impressions does imply that SCS should be taken into consideration during clinical follow-up as a potentially adverse event.

Objective We evaluated the usefulness of a three-dimensional (3D) interactive atlas to illustrate and teach surgical skull base anatomy in a clinical setting. Study Design A highly detailed atlas of the adult human skull base was created from multiple high-resolution magnetic resonance imaging (MRI) and computed tomography (CT) scans of a healthy Caucasian male. It includes the parcellated and labeled bony skull base, intra- and extracranial vasculature, cranial nerves, cerebrum, cerebellum, and brainstem. We are reporting retrospectively on our experiences with employing the atlas for the simulation and teaching of neurosurgical approaches and concepts in a clinical setting. Setting The study was conducted at the University Hospital Mainz, Germany, and Hirslanden Hospital, Zürich, Switzerland. Participants Medical students and neurosurgical residents participated in this study. Results Handling the layered graphical user interface of the atlas requires some training; however, navigating the detailed 3D content from intraoperative perspectives led to quick comprehension of anatomical relationships that are otherwise difficult to perceive. Students and residents appreciated the collaborative learning effect when working with the atlas on large projected screens and markedly improved their anatomical knowledge after interacting with the software. Conclusion The skull base atlas provides an effective way to study essential surgical anatomy and to teach operative strategies in this complex region. Interactive 3D computer graphical environments are highly suitable for conveying complex anatomy and to train and review surgical concepts. They remain underutilized in clinical practice.

Noncontrast Computed Tomography (NCCT) of the brain has been the first-line diagnosis for emergency evaluation of acute stroke, so a rapid and automated detection, localization, and/or segmentation of ischemic lesions is of great importance. We provide the state-of-the-art review of methods for automated detection, localization, and/or segmentation of ischemic lesions on NCCT in human brain scans along with their comparison, evaluation, and classification. Twenty-two methods are (1) reviewed and evaluated; (2) grouped into image processing and analysis-based methods (11 methods), brain atlas-based methods (two methods), intensity template-based methods (1 method), Stroke Imaging Marker-based methods (two methods), and Artificial Intelligence-based methods (six methods); and (3) properties of these groups of methods are characterized. A new method classification scheme is proposed as a 2 × 2 matrix with local versus global processing and analysis, and density versus spatial sampling. Future studies are necessary to develop more efficient methods directed toward deep learning methods as well as combining the global methods with a high sampling both in space and density for the merged radiologic and neurologic data.

After craniotomy, the monitoring of the skull healing progression is strongly needed to take a proper medical intervention. The CT scans is however currently used for follow-up after craniotomy res ...

SummarySkeletal muscle mitochondrial fatty acid (FA) overload in response to chronic overnutrition is a prominent pathophysiological mechanism in obesity-induced metabolic disease. Increased disposal of FAs is therefore an attractive strategy for intervening in obesity and related disorders. Skeletal muscle uncoupling protein 3 (UCP3) activity is associated with increased FA oxidation and antagonizes weight gain in mice on obesogenic diets, but the mechanisms involved are not clear. Here, we show that UCP3 forms a direct, FA-stimulated, mitochondrial matrix-localized complex with the auxiliary unsaturated FA-metabolizing enzyme, Δ3,5-Δ2,4dienoyl-CoA-isomerase (ECH1). Expression studies in C2C12 myoblasts that functionally augments state 4 (uncoupled) respiration and FA oxidation in skeletal myocytes.Mechanistic studies indicate that ECH1:UCP3 complex formation is likely stimulated by FA import into the mitochondria to enhance uncoupled respiration and unsaturated FA oxidation in mouse skeletal myocytes. In order to characterize the contribution of ECH1-dependent FA metabolism in NST, we generated an ECH1 knockout mouse and found that these mice were severely cold intolerant, despite an up-regulation of UCP3 expression in SKM. These findings illuminate a novel mechanism that links unsaturated FA metabolism with mitochondrial uncoupling and non-shivering thermogenesis in SKM.

Despite the human brain being considered the most complex living organ, our objective is to make the presentation and understanding of brain anatomy easy and quick. To achieve this, we use a 3D electronic brain atlas created from multiple 3 and 7 Tesla in vivo scans of the same brain specimen to assure spatial consistency.

Key points Both uncoupling protein 1 (UCP1) and UCP3 are important for mammalian thermoregulation. UCP1 and UCP3 in brown adipose tissue mediate early and late phases of sympathomimetic thermogenesis, respectively. Lipopolysaccharide thermogenesis requires skeletal muscle UCP3 but not UCP1. Acute noradrenaline-induced hyperthermia requires UCP1 but not UCP3. Loss of both UCP1 and UCP3 accelerate the loss of body temperature compared to UCP1KO alone during acute cold exposure. Abstract Uncoupling protein 1 (UCP1) is the established mediator of brown adipose tissue-dependent thermogenesis. In contrast, the role of UCP3, expressed in both skeletal muscle and brown adipose tissue, in thermoregulatory physiology is less well understood. Here, we show that mice lacking UCP3 (UCP3KO) have impaired sympathomimetic (methamphetamine) and completely abrogated lipopolysaccharide (LPS) thermogenesis, but a normal response to noradrenaline. By comparison, UCP1 knockout (UCP1KO) mice exhibit blunted methamphetamine and fully inhibited noradrenaline thermogenesis, but an increased febrile response to LPS. We further establish that mice lacking both UCP1 and 3 (UCPDK) fail to show methamphetamine-induced hyperthermia, and have a markedly accelerated loss of body temperature and survival after cold exposure compared to UCP1KO mice. Finally, we show that skeletal muscle-specific human UCP3 expression is able to significantly rescue LPS, but not sympathomimetic thermogenesis blunted in UCP3KO mice. These studies identify UCP3 as an important mediator of physiological thermogenesis and support a renewed focus on targeting UCP3 in metabolic physiology.

Fatal hyperthermia as a result of 3,4-methylenedioxymethamphetamine (MDMA) use involves non-esterified free fatty acids (NEFA) and the activation of mitochondrial uncoupling proteins (UCP). NEFA gain access into skeletal muscle via specific transport proteins, including fatty acid translocase (FAT/CD36). FAT/CD36 expression is known to increase following chronic exercise. Previous studies have demonstrated the essential role of NEFA and UCP3 in MDMA-induced hyperthermia. The aims of the present study were to use a chronic exercise model (swimming for two consecutive hours per day, five days per wk for six wk) to increase FAT/CD36 expression in order to: 1) determine the contribution of FAT/CD36 in MDMA (20 mg/kg, s.c.)-mediated hyperthermia; and 2) examine the effects of the FAT/CD36 inhibitor, SSO (sulfo-N-succinimidyl oleate), on MDMA-induced hyperthermia in chronic exercise and sedentary control rats. MDMA administration resulted in hyperthermia in both sedentary and chronic exercise animals. However, MDMA-induced hyperthermia was significantly potentiated in the chronic exercise animals compared to sedentary animals. Additionally, chronic exercise significantly reduced body weight, increased FAT/CD36 protein expression levels and reduced plasma NEFA levels. The FAT/CD36 inhibitor, SSO (40 mg/kg, ip), significantly attenuated the hyperthermia mediated by MDMA in chronic exercised but not sedentary animals. Plasma NEFA levels were elevated in sedentary and exercised animals treated with SSO prior to MDMA suggesting attenuation of NEFA uptake into skeletal muscle. Chronic exercise did not alter skeletal muscle UCP3 protein expression levels. In conclusion, chronic exercise potentiates MDMA-mediated hyperthermia in a FAT/CD36 dependent fashion.

Intra cranial pressure (ICP) monitoring is used in treating severe traumatic brain injury (TBI) patients. All current clinical available measurement methods are invasive presenting considerable social costs. This paper presents a preliminary investigation of the feasibility of ICP monitoring using an innovative microwave-based non-invasive approach. A phantom mimicking the dielectric characteristics of human tissues of the upper part of the head at low microwave frequencies is employed together to a proof-of-concept prototype based on the proposed approach consisting in a readout system and a sub-dermally implanted passive device, both based in split ring resonator techniques. This study shows the potential of our approach to detect two opposite pressure variation stages inside the skull. The employed phantom model needs to be improved to support finer variations in the pressure and better phantom parts, principally for the skull mimic and the loss tangent of all mimics.

Background The skull base region is anatomically complex and poses surgical challenges. Although many textbooks describe this region illustrated well with drawings, scans and photographs, a complete, 3D, electronic, interactive, realistic, fully segmented and labeled, and stereotactic atlas of the skull base has not yet been built. Our goal is to create a 3D electronic atlas of the adult human skull base along with interactive tools for structure manipulation, exploration, and quantification. Methods Multiple in vivo 3/7 T MRI and high-resolution CT scans of the same normal, male head specimen have been acquired. From the scans, by employing dedicated tools and modeling techniques, 3D digital virtual models of the skull, brain, cranial nerves, intra- and extracranial vasculature have earlier been constructed. Integrating these models and developing a browser with dedicated interaction, the skull base atlas has been built. Results This is the first, to our best knowledge, truly 3D atlas of the adult human skull base that has been created, which includes a fully parcellated and labeled brain, skull, cranial nerves, and intra- and extracranial vasculature. Conclusion This atlas is a useful aid in understanding and teaching spatial relationships of the skull base anatomy, a helpful tool to generate teaching materials, and a component of any skull base surgical simulator.

Lack of Information about how bone mineralization progress over time in the cranial vault of newborns makes it difficult to quantitatively assess the recovery after the surgical intervention. Available technologies are considerably risky to reduce this gap and new solutions are nowadays being researched. Sensors operating at low microwave frequencies could be devised to read some changes in the composition of the superficial layers of the head of which skull are a substantial part. These changes could be associated to different stages of bone mineralization. This hypothetical solution is being studied in a pilot clinical campaign executed in the frame of the Indo-Swedish Vinnova - DST funded BDAS project (www.bdas.se). In this work we present a part of the current progress of this project. A preliminary statistical data analysis is performed and the observations and conclusions made from it will direct the future research with a special focus on the earlier stages of bone mineralization (up to 1 month after surgery).

Aim The aim of this study was to identify the frequency and prevalence of comorbidities in sarcoid patients and to assess their influence on overall mortality in the cohort of patients with sarcoidosis. Materials and methods A cohort of 557 patients with histologically confirmed sarcoidosis diagnosed between 2007 and 2011 and a group of non-sarcoid controls were observed. All patients were carefully observed for comorbidities and mortality. Results 291 males (52.2%) and 266 females (47.8%) with mean age 48.4 ± 12.0 years in sarcoidosis group and a group of 100 controls with mean age (49.25 ± 10.3) were observed. The mean number of comorbidities in both groups was similar (0.9 ± 0.99 vs 0.81 ± 0.84 NS). The frequency of thyroid disease was significantly higher in sarcoidosis group comparing to controls at the time of diagnosis (OR = 3.62 P = 0.0144). During the observation period (median 58.0 months), 16 patients died (2.9%). The mean number of comorbidities was significantly higher in the groups of non-survivors as compared to survivors (2.8 ± 1.0, vs 0.8 ± 0.9), P

Summary Background The aim of this study was to evaluate the contribution of a single unilateral facial vein in the venous outflow of total-face allograft using three-dimensional computed tomographic imaging techniques to further elucidate the mechanisms of venous complications following total-face transplant. Methods Full-face soft-tissue flaps were harvested from fresh adult human cadavers. A single facial vein was identified and injected distally to the submandibular gland with a radiopaque contrast (barium sulfate/gelatin mixture) in every specimen. Following vascular injections, three-dimensional computed tomographic venographies of the faces were performed. Images were viewed using TeraRecon Software (Teracon, Inc., San Mateo, CA, USA) allowing analysis of the venous anatomy and perfusion in different facial subunits by observing radiopaque filling venous patterns. Results Three-dimensional computed tomographic venographies demonstrated a venous network with different degrees of perfusion in subunits of the face in relation to the facial vein injection side: 100% of ipsilateral and contralateral forehead units, 100% of ipsilateral and 75% of contralateral periorbital units, 100% of ipsilateral and 25% of contralateral cheek units, 100% of ipsilateral and 75% of contralateral nose units, 100% of ipsilateral and 75% of contralateral upper lip units, 100% of ipsilateral and 25% of contralateral lower lip units, and 50% of ipsilateral and 25% of contralateral chin units. Conclusion Venographies of the full-face grafts revealed better perfusion in the ipsilateral hemifaces from the facial vein in comparison with the contralateral hemifaces. Reduced perfusion was observed mostly in the contralateral cheek unit and contralateral lower face including the lower lip and chin units.

Objective To evaluate the importance of dental status for long-term outcome after alveolar bone grafting in patients with unilateral cleft lip and palate. Design Retrospective longitudinal study. Setting Cleft lip and palate-craniofacial center, Uppsala University Hospital, Sweden. Patients A total of 67 consecutive patients with unilateral complete cleft lip and palate. Interventions Secondary alveolar bone grafting, prior to the eruption of the permanent canine, was performed at the average age of 10.0 years (range, 8.5 to 12.0 years). Main Outcome Measures Alveolar bone height was evaluated with the modified Bergland index at 1 and 10 years after surgery. Results Of the patients, 97% had modified Bergland index grade I and the remaining 3% had modified Bergland index grade II at 1 year after surgery. At 10 years' follow-up, 43% showed modified Bergland index grade I; 55%, modified Bergland index grade II; and 2% (one patient), modified Bergland index grade III. The degree of dental anomalies in the cleft area, such as enamel hypoplasia, incisor rotation, incisor inclination, canine inclination, and oral hygiene registered preoperatively, all correlated negatively to the modified Bergland index at 10 years after surgery. Enamel hypoplasia (ρ = 0.70195, P < .0001), followed by canine inclination (ρ = 0.55429, P < .0001), showed the strongest correlation to reduced bone height in the cleft area. Conclusions In patients with unilateral cleft lip and palate, excellent results from secondary alveolar bone grafting in terms of bone height in the alveolar cleft tend to decrease with time. This seems to be correlated with factors that might to some extent be treated preoperatively through adequate planning and execution of the orthodontic treatment.

Despite numerous efforts, a fairly complete (holistic) anatomical model of the whole, normal, adult human brain, which is required as the reference in brain studies and clinical applications, has not yet been constructed. Our ultimate objective is to build this kind of atlas from advanced in vivo imaging. This work presents the taxonomy of our currently developed brain atlases and addresses the design, content, functionality, and current results in the holistic atlas development as well as atlas usefulness and future directions. We have developed to date 35 commercial brain atlases (along with numerous research prototypes), licensed to 63 companies and institutions, and made available to medical societies, organizations, medical schools, and individuals. These atlases have been applied in education, research, and clinical applications. Hundreds of thousands of patients have been treated by using our atlases. Based on this experience, the first version of the holistic and reference atlas of the brain, head, and neck has been developed and made available. The atlas has been created from multispectral 3 and 7 Tesla and high-resolution CT in vivo scans. It is fully 3D, scalable, interactive, and highly detailed with about 3,000 labeled components. This atlas forms a foundation for the development of a multi-level molecular, cellular, anatomical, physiological, and behavioral brain atlas platform. Electronic supplementary material The online version of this article (doi:10.1007/s40708-015-0012-4) contains supplementary material, which is available to authorized users.

We have recently witnessed an explosion of large-scale initiatives and projects addressing mapping, modeling, simulation and atlasing of the human brain, including the BRAIN Initiative, the Human Brain Project, the Human Connectome Project (HCP), the Big Brain, the Blue Brain Project, the Allen Brain Atlas, the Brainnetome, among others. Besides these large and international initiatives, there are numerous mid-size and small brain atlas-related projects. My contribution to these global efforts has been to create adult human brain atlases in health and disease, and to develop atlas-based applications. For over two decades with my R&D lab I developed 35 brain atlases, licensed to 67 companies and made available in about 100 countries.This paper has two objectives. First, it provides an overview of the state of the art in brain atlasing. Second, as it is already 20 years from the release of our first brain atlas, I summarise my past and present efforts, share my experience in atlas creation, validation and commercialisation, compare with the state of the art, and propose future directions.

Smoking is accepted as the cause of respiratory bronchiolitis-associated ILD (RB-ILD), desquamative interstitial pneumonia(DIP), pulmonary Langerhans cell histiocytosis(PLCH).It is also a risk factor for idiopathic pulmonary fibrosis(IPF). Aim: The aim of the study was to assess the smoking status (ever-smokers/never-smokers)(ES/NS) among ILDs(not sarcoidosis) patients(pts). Methods: The group of 131 consecutive ILDs pts admitted to our hospital were asked about smoking. Questionnaire was designed, data was recorded. Results: Among recruited pts (52±7y); 57 were male and 74 were female. There were 22(20ES/2NS)pts diagnosed as PLCH, 27(13ES/14NS) as hypersensitivity pneumonitis(HP),22(11ES/11NS) as connective tissue disease(ILD-CTD),17(9ES/8NS) as unclassifiable idiopathic interstitial pneumonia(UIIP),10(8ES/2NS) as granulomatosis with polyangiitis(GPA),7(6ES/1NS) as IPF, 10(4ES/6NS) as cryptogenic organising pneumonia(COP),3(2ES/1NS) idiopathic nonspecific interstitial pneumonia(NSIP), 2(2ES/0NS) as DIP, 2(1ES/1NS) as chronic eosinophilic pneumonia(CEP),1(0ES/1NS) as RBILD, 8(0ES/8NS) as lymphangioleiomyomatosis(LAM).In ES group 8 pts continue to smoke. Women smoked fewer cigarettes per day compared to men(14.6vs 17.7)p Conclusions: There were more smokers among pts with some ILDs. Passive smoking exposure in infancy could be a risk factor for some ILDs.

OBJECTIVE Recent genomewide association studies have implicated the calcium channel, voltage-dependent, L type, alpha 1C subunit (CACNA1C) genetic variant in schizophrenia, which is associated with functional brain changes and cognitive deficits in healthy individuals. However, the impact of CACNA1C on brain white matter integrity in schizophrenia remains unclear. On the basis of prior evidence of CACNA1C-mediated changes involving cortical brain regions, we hypothesize that CACNA1C risk variant rs1006737 is associated with reductions of white matter integrity in the frontal, parietal, and temporal regions and cingulate gyrus. METHOD A total of 160 Chinese participants (96 DSM-IV-diagnosed patients with schizophrenia and 64 healthy controls) were genotyped by using blood samples and underwent structural magnetic resonance imaging and diffusion tensor imaging scans from 2008 to 2012. Two-way analysis of covariance was employed to examine CACNA1C-related genotype effects, diagnosis effects, and genotype × diagnosis interaction effects on fractional anisotropy (FA) of relevant brain regions. RESULTS Significant diagnosis-genotype interactions were observed (left frontal lobe mean FA: F₁,₁₅₆ = 6.22, P = .014; left parietal lobe mean FA: F₁,₁₅₆ = 7.14, P = .008; left temporal lobe mean FA: F₁,₁₅₆ = 8.37, P = .004). Compared with patients who were A carriers, patients who were G homozygotes had lower mean FA in the left frontal lobe (F₁,₉₃ = 2.504, P = .014), left parietal lobe (F₁,₉₃ = 2.37, P = .020), and left temporal lobe (F₁,₉₃ = 3.01, P = .003), with standardized effect sizes of -1.43, -1.3, and -1.0, respectively. CONCLUSIONS CACNA1C risk variant rs1006737 affects cortical white matter integrity in schizophrenia. Further imaging genetic investigations on the mediating effect of CACNA1C in schizophrenia can uncover brain circuitries involved in schizophrenia and suggest potential novel targets for intervention.

To maintain core body temperature in cold conditions, mammals activate a complex multi-organ metabolic response for heat production. White adipose tissue (WAT) primarily functions as an energy reservoir, while brown adipose tissue (BAT) is activated during cold exposure to generate heat from nutrients. Both BAT and WAT undergo specific metabolic changes during acute cold exposure. Here, we use an untargeted metabolomics approach to characterize the initial metabolic response to cold exposure in multiple adipose tissue depots in mice. Results demonstrate dramatically distinct metabolic responses during cold exposure in BAT and WAT. Amino acids, nucleotide pathways, and metabolites involved in redox regulation were greatly affected 4 hours post-exposure in BAT, while no polar metabolites were observed to significantly change in WAT depots up to 6 hours post exposure. Lipid metabolism was activated early (2 hours) in both BAT and the subcutaneous WAT depots, with the most striking change being observed in the modulation of diglyceride and monoglyceride levels in BAT. Overall, these data provide a timeline of global thermogenic metabolism in adipose depots during acute cold exposure. We have highlighted differences in visceral and subcutaneous WAT thermogenic metabolism and demonstrate the distinct metabolism of BAT during cold exposure.

CCN2 (previously known as connective tissue growth factor) is a multifunctional matricellular protein that has numerous effects on cell life and cell interactions with the connective tissue. Although the importance of CCN2 for the fibrotic process in wound healing has been well studied, the involvement of CCN2 in keratinocyte function has not yet been explored. Therefore, the aim of the present study was to investigate the role of CCN2 in the epidermis during wound healing.Immunohistochemistry was done on sections from full-thickness porcine wounds. The effect of CCN2 on the migration of cultured human keratinocytes exposed to scratch wounds, the effect on phosphorylation of extracellular signal-related kinases (ERK), and the effect of adding inhibitors to the ERK/mitogen-activated protein kinase pathway to human keratinocytes were studied.The CCN2 protein was transiently expressed in vivo at the leading keratinocyte edge during re-epithelialization of full-thickness porcine wounds. In vitro, exogenous addition of CCN2 to human keratinocyte cultures regulated keratinocyte migration and resulted in phosphorylation of ERK. The addition of inhibitors of ERK/mitogen-activated protein kinase counteracted the effect of CCN2 on migration.CCN2 was transiently expressed at the leading keratinocyte edge in vivo. The biologic importance of this was supported in vitro, because CCN2 regulated human keratinocyte migration through activation of the Ras-mitogen-activated protein kinase kinase-ERK signal transduction pathway.

Update The print version of this article has an error that has been corrected. The doi number for the paper, which was given as “doi:10.2106/JBJS.L.00005,” has been corrected and is now given as “doi:10.2106/JBJS.L.10005.” Background: Reverse shoulder arthroplasty (RSA) is an accepted treatment that provides reproducible results in the treatment of shoulder arthritis and rotator cuff deficiency. Concerns over the longevity of the prosthesis have resulted in this procedure being reserved for the elderly. There are limited data in the literature with regard to outcomes in younger patients. We report on the early outcomes of RSA in a group of patients who were sixty years or younger and who were followed for a minimum of two years. Methods: A retrospective multicenter review of sixty-six patients (sixty-seven RSAs) with a mean age of 52.2 years was performed. The indications included rotator cuff insufficiency (twenty-nine), massive rotator cuff disorder with osteoarthritis (eleven), failed primary shoulder arthroplasty (nine), rheumatoid arthritis (six), posttraumatic arthritis (four), and other diagnoses (eight). Forty-five shoulders (67%) had at least one prior surgical intervention, and thirty-one shoulders (46%) had multiple prior surgical procedures. Results: At a mean follow-up time of 36.5 months, mean active forward elevation of the arm as measured at the shoulder improved from 54.6° to 134.0° and average active external rotation improved from 10.0° to 19.6°. A total of 81% of patients were either very satisfied or satisfied. The mean American Shoulder and Elbow Surgeons (ASES) score and visual analog scale (VAS) score for pain improved from 40.0 to 72.4 and 7.5 to 3.0, respectively. The ability to achieve postoperative forward arm elevation of at least 100° was the only significant predictor of overall patient satisfaction (p < 0.05) that was identified in this group. There was a 15% complication rate postoperatively, and twenty-nine shoulders (43%) had evidence of scapular notching at the time of the latest follow-up. Conclusions: RSA as a reconstructive procedure improved function at the time of short-term follow-up in our young patients with glenohumeral arthritis and rotator cuff deficiency. Objective outcomes in our patient cohort were similar to those in previously reported studies. However, overall satisfaction was much lower in this patient population (81%) compared with that in the older patient population as reported in the literature (90% to 96%). Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Mucopolysaccharidosis type IIIA (MPSIIIA) is a lysosomal storage disorder caused by mutations in N-sulfoglucosamine sulfohydrolase (SGSH), resulting in heparan sulfate (HS) accumulation and progressive neurodegeneration. There are no treatments. We previously demonstrated improved neuropathology in MPSIIIA mice using lentiviral vectors (LVs) overexpressing SGSH in wild-type (WT) hematopoietic stem cell (HSC) transplants (HSCTs), achieved via donor monocyte/microglial engraftment in the brain. However, neurological disease was not corrected using LVs in autologous MPSIIIA HSCTs. To improve brain expression via monocyte/microglial specificity, LVs expressing enhanced green fluorescent protein (eGFP) under ubiquitous phosphoglycerate kinase (PGK) or myeloid-specific promoters were compared in transplanted HSCs. LV-CD11b-GFP gave significantly higher monocyte/B-cell eGFP expression than LV-PGK-GFP or LV-CD18-GFP after 6 months. Subsequently, autologous MPSIIIA HSCs were transduced with either LV-PGK-coSGSH or LV-CD11b-coSGSH vectors expressing codon-optimized SGSH and transplanted into MPSIIIA mice. Eight months after HSCT, LV-PGK-coSGSH vectors produced bone marrow SGSH (576% normal activity) similar to LV-CD11b-coSGSH (473%), but LV-CD11b-coSGSH had significantly higher brain expression (11 versus 7%), demonstrating improved brain specificity. LV-CD11b-coSGSH normalized MPSIIIA behavior, brain HS, GM2 ganglioside, and neuroinflammation to WT levels, whereas LV-PGK-coSGSH partly corrected neuropathology but not behavior. We demonstrate compelling evidence of neurological disease correction using autologous myeloid driven lentiviral-HSC gene therapy in MPSIIIA mice. © The American Society of Gene & Cell Therapy.

BackgroundObesity is increasingly prevalent in bipolar disorder (BD) but data about the impact of elevated body mass index (BMI) on brain white-matter integrity in BD are sparse. Based on extant literature largely from structural magnetic resonance imaging (MRI) studies, we hypothesize that increased BMI is associated with decreased fractional anisotropy (FA) in the frontal, temporal, parietal and occipital brain regions early in the course of BD.MethodA total of 26 euthymic adults (12 normal weight and 14 overweight/obese) with remitted first-episode mania (FEM) and 28 controls (13 normal weight and 15 overweight/obese) matched for age, handedness and years of education underwent structural MRI and diffusion tensor imaging scans.ResultsThere are significant effects of diagnosis by BMI interactions observed especially in the right parietal lobe (adjusted F1,48 = 5.02, p = 0.030), occipital lobe (adjusted F1,48 = 10.30, p = 0.002) and temporal lobe (adjusted F1,48 = 7.92, p = 0.007). Specifically, decreased FA is found in the right parietal (F1,23 = 5.864, p = 0.023) and occipital lobes (F1,23 = 4.397, p = 0.047) within overweight/obese patients compared with normal-weight patients with FEM. Compared with overweight/obese controls, decreased FA is observed in right parietal (F1,25 = 6.708, p = 0.015), temporal (F1,25 = 10.751, p = 0.003) and occipital (F1,25 = 9.531, p = 0.005) regions in overweight/obese patients with FEM.ConclusionsOur findings suggest that increased BMI affects temporo-parietal-occipital brain white-matter integrity in FEM. This highlights the need to further elucidate the relationship between obesity and other neural substrates (including subcortical changes) in BD which may clarify brain circuits subserving the association between obesity and clinical outcomes in BD.

Abnormalities in glutamate signaling and glutamate toxicity are thought to be important in the pathophysiology of bipolar disorder (BD). Whilst previous studies have found brain white matter changes in BD, there is paucity of data about how glutamatergic genes affect brain white matter integrity in BD. Based on extant neuroimaging data, we hypothesized that GRIN2B risk allele is associated with reductions of brain white matter integrity in the frontal, parietal, temporal, and occipital regions and cingulate gyrus in BD. Fourteen patients with BD and 22 healthy controls matched in terms of age, gender and handedness were genotyped using blood samples and underwent diffusion tensor imaging. Compared to G allele, brain FA values were significantly lower in BD patients with risk T allele in left frontal region (P=0.001), right frontal region (P=0.002), left parietal region (P=0.001), left occipital region (P=0.001), right occipital region (P<0.001), and left cingulate gyrus (P=0.001). Further elucidation of the interactions between different glutamate genes and their relationships with such structural, functional brain substrates will enhance our understanding of the link between dysregulated glutamatergic neurotransmission and neuroimaging endophenotypes in BD.

As the field of face transplantation develops, it may be possible to transplant segments of facial skin to replace facial aesthetic subunits in selected cases. The aim of this study was to identify the more reliable vascular pedicles of each facial aesthetic subunit for its use in transplantation METHODS:: Six full facial soft-tissue flaps were harvested, and the external carotid artery was identified and cannulated proximal to the facial artery. Next, radiopaque contrast was injected through the facial artery into three of the facial flaps and through the superficial temporal artery in the other three facial flaps. After vascular injections, three-dimensional computed tomographic arteriographs of the faces were obtained, allowing analysis of the arterial anatomy and perfusion in different facial aesthetic subunits.The chin, lower lip, upper lip, medial cheek, nose, and periorbital units were perfused in all facial flaps where the facial artery was injected and in none of those where the superficial temporal artery was injected. The lateral cheek was perfused in 100 percent of the superficial temporal artery flaps and in 67 percent of the facial artery flaps. The lateral forehead contained contrast in 100 percent of the superficial temporal artery-injected flaps and in none of the facial artery-injected flaps, and the medial foreheads contained contrast in 67 percent of the facial artery-injected flaps and in 67 percent of the superficial temporal artery-injected flaps.The majority of the facial subunits can be harvested based on the facial artery pedicle, with the exception of the lateral forehead, which is based on the superficial temporal artery.

BACKGROUND: Unilateral cleft lip and palate (UCLP) affects nasal function and appearance. There is a lack of objective measurements to evaluate these features. This study analyzes whether objective measurements on photographs correlate with nasal function and/or appearance among adults treated for UCLP. METHODS: All patients with UCLP born from 1960 to 1987 treated at the Uppsala University Hospital were invited (n = 109). Participation rate was 68% (n = 74); mean follow-up was 35 years. An age-matched control group (n = 61) underwent the same tests. Nostril area, nasal tip deviation angle, and width of the nostril were measured on photographs and were compared with functional tests and with appearance as assessed by self-assessment questionnaire, professional panel, or laymen panel. RESULTS: The photographically measured nostril area correlated with nasal volume (acoustic rhinometry) among UCLP patients, both cleft side and noncleft side, and controls (0.331, P = 0.005; 0.338, P = 0.004; and 0.420, P < 0.001, respectively). For the patients' noncleft side and controls, the area correlated inversely with airflow resistance at inspiration (noncleft side: -0.245, P = 0.043; controls: -0.226, P = 0.013). Laymen assessment of nasal appearance correlated with width ratio of the patients (0.27, P = 0.022) and with nasal tip deviation angle and area ratio of the controls (0.26, P = 0.041, and 0.31, P = 0.015, respectively). CONCLUSIONS: Photographic measurements correlate partially with both functional tests of the nose and panel ratings of appearance. No correlation was found with self-assessment of appearance. Evaluation of photographs needs to be combined with patient-reported outcome measures to be a valuable endpoint of nasal appearance.

This article presents a treatment strategy for early release of interalveolar synechiae, aiming to facilitate early oral feeding and prevent temporomandibular joint ankylosis.The treatment results of 2 patients with van der Woude syndrome were retrospectively studied. Both patients underwent early surgical release of interalveolar synechiae under general anesthesia through fiberscopic nasal intubation. The 2 patients were treated at the ages of 6 and 14 days, respectively. The interincisival distances increased from 5 and 6 mm preoperatively to 11 and 10 mm immediately after surgery. This was increased further to 25 and 20 mm at long-term follow-up (6 and 24 months).In conclusion, synechiae between the upper and lower jaws can be safely treated at a very early age under general anesthesia with fiberscopic nasotracheal intubation. The purpose of early intervention in these cases is to facilitate oral feeding and prevent temporomandibular joint ankylosis.

Knowledge of the cranial nerves and their nuclei is critical in clinical practice, medical research and education. However to our best knowledge, a comprehensive source capturing full three-dimensional (3D) relationships of the cranial nerves along with surrounding neuroanatomy is not yet available. This work addresses the construction and validation of an atlas of the cranial nerves with their nuclei, correlated with surface neuroanatomy, vasculature, and magnetic resonance imaging. The atlas is interactive, stereotactic, 3D, detailed, fully parcellated, completely labeled, consistent in 3D, electronically dissectible, and scalable. A 3D geometrical model of the 12 pairs of cranial nerves with nuclei was created from an in vivo magnetic resonance scan exploiting in-house developed tools and methods, including tubular and iso-surface modeling, interactive editing, and mesh compression. This virtual model contains 439 objects with 121 different names, labeled based on Terminologia Anatomica. The model was integrated with a 3D atlas of structure, vasculature and tracts developed earlier, and correlated with sectional magnetic resonance anatomy. The whole model or its components can be interactively rotated, zoomed, panned, and add or removed with a simple few clicks. The studied material can be adaptively selected in an in-depth manner by using controls available in the user interface. This atlas is potentially useful for anatomy browsing, user self-testing, automatic student assessment, preparing materials, and localization in clinical neurology.

Decreased mitochondrial oxidative metabolism is a hallmark bioenergetic characteristic of malignancy that may have an adaptive role in carcinogenesis. By stimulating proton leak, mitochondrial uncoupling proteins (UCP1-3) increase mitochondrial respiration and may thereby oppose cancer development. To test this idea, we generated a mouse model that expresses an epidermal-targeted keratin-5-UCP3 (K5-UCP3) transgene and exhibits significantly increased cutaneous mitochondrial respiration compared with wild type (FVB/N). Remarkably, we observed that mitochondrial uncoupling drove keratinocyte/epidermal differentiation both in vitro and in vivo. This increase in epidermal differentiation corresponded to the loss of markers of the quiescent bulge stem cell population, and an increase in epidermal turnover measured using a bromodeoxyuridine (BrdU)-based transit assay. Interestingly, these changes in K5-UCP3 skin were associated with a nearly complete resistance to chemically-mediated multistage skin carcinogenesis. These data suggest that targeting mitochondrial respiration is a promising novel avenue for cancer prevention and treatment.

The ideal fixation technique for the treatment of proximal humeral fractures remains unclear. In the present study, we evaluated the experience of three surgeons with the treatment of two-part surgical neck fractures with angular-stable intramedullary fixation.Forty-eight patients with forty-eight Neer two-part surgical neck proximal humeral fractures were managed with locked angular-stable intramedullary nail fixation by three surgeons. Shoulder pain and outcomes were quantified with Constant scores and standard radiographs.Thirty-eight patients (including twenty-eight female patients and ten male patients) with a mean age of sixty-five years were followed for at least twelve months (mean, twenty months; range, twelve to thirty-six months). All fractures healed primarily. The mean follow-up Constant score (and standard deviation) was 71 ± 12 points (range, 37 to 88 points), with a mean age-adjusted Constant score of 97% (range, 58% to 119%). The mean Constant pain score was 13 ± 2.2 (possible range, 0 to 15 points, with 15 points representing no pain). The mean forward flexion was 132° ± 22°. All fractures but one healed with a neck-shaft angle of ≥125°.Patients who were managed with locked angular-stable intramedullary nailing of two-part surgical neck proximal humeral fractures via an articular entry point had reliable fracture-healing, favorable clinical outcomes, and little residual shoulder pain.

Virtual surgical planning and computer-aided surgery were used to treat a mono-ostotic fibrous dysplasia of the right zygoma. Mirroring of the contralateral zygoma sets the target for the contouring of the affected zygomatic bone. An optical system for computer-guided surgery was used. Instruments were calibrated and visualized in real time on screen. Achievement of the virtually set target for the orbitozygomatic anatomy was assessed during surgery. Postoperative computed tomography and clinical follow-up confirmed an excellent result with regard to facial symmetry and eye bulb position. The volume of the orbit was increased from 24.2 to 26.0 mL compared with a contralateral orbital volume of 25.7 mL. Computer-guided surgery may be a useful tool in the surgical reduction of craniofacial fibrous dysplasia.

To investigate the mechanisms behind the antifibrotic effect associated with epidermal regeneration, the expression of 12 fibroblast genes important for the modulation of the extracellular matrix (ECM), as well as α-smooth muscle actin, was studied in a keratinocyte-fibroblast organotypic skin culture model. The study was performed over time during epidermal generation and in the presence or absence of the profibrotic factor transforming growth factor-β. the Presence of epidermal differentiation markers in the model was essentially coherent with that of native skin. Fibroblast gene expression was analyzed with real-time polymerase chain reaction after removal of the epidermal layer. After 2 days of air-exposed culture, 11 out of the 13 genes studied were significantly regulated by keratinocytes in the absence or presence of transforming growth factor-β. The regulation of connective tissue growth factor, collagen I and III, fibronectin, plasmin system regulators, matrix metalloproteinases and their inhibitors as well as α-smooth muscle actin was consistent with a suppression of ECM formation or contraction. Overall, the results support a view that keratinocytes regulate fibroblasts to act catabolically on the ECM in epithelialization processes. This provides possible mechanisms for the clinical observations that reepithelialization and epidermal wound coverage counteract excessive scar formation.

Reconstruction of the fractured orbit serves to prevent functional and aesthetic posttraumatic sequels. In 2004, the surgical protocol at our unit was modified with respect to techniques for surgical access, types, and materials for reconstruction. The modifications were as follows: (a) introduction of medial orbital wall reconstructions through a bicoronal approach, (b) transconjunctival approach instead of the subciliary approach, and (c) porous polyethylene or porous polyethylene-titanium instead of autologous bone grafts. To evaluate the different surgical techniques and materials used, orbital reconstructions performed at our unit from 2000 to 2007 were retrospectively studied. In total, 177 primary or first-time secondary reconstructions were performed in 176 patients. The overall rate of early complications requiring medical or surgical intervention was 6.4%, and the reoperation rate was 3.4%. There were no statistically significant differences in the frequency of cicatricial eyelid complications between the subciliary and the transconjunctival approaches. There was a reduction in operative time with the use of implants compared with the use of bone. The overall rate of infections was 2%; however, there were no infections in the group treated with implants. Seven patients had secondary surgery for persistent enophthalmos, 4 of them due to defects in the medial orbital wall that had not been corrected at the time of primary reconstruction of the orbital floor. In conclusion, porous polyethylene/porous polyethylene-titanium is a safe material for orbital reconstructions. Reconstruction of the medial orbital wall is important to prevent posttraumatic enophthalmos, particularly in combined medial wall-orbital floor fractures.

Chan W-Y, Yang G-L, Chia M-Y, Woon P-S, Lee J, Keefe R, Sitoh Y-Y, Nowinski WL, Sim K. Cortical and subcortical white matter abnormalities in adults with remitted first-episode mania revealed by Tract-Based Spatial Statistics. Bipolar Disord 2010: 12: 383–389. © 2010 The Authors. Journal compilation © 2010 John Wiley & Sons A/S. Objectives: Abnormalities of brain white matter have been noted in structural magnetic resonance imaging and diffusion tensor imaging (DTI) studies of bipolar disorder, but there are fewer investigations specifically examining white matter integrity early in the course of illness. In this study, we employed DTI to elucidate white matter changes in adult patients with remitted first-episode mania and hypothesized that first-episode mania was associated with decreased fractional anisotropy in cortical (frontal) and subcortical (thalamus, striatum) white matter as well as white matter tracts (cingulum, corpus callosum). Methods: Diffusion tensor images were acquired from 16 patients with remitted first-episode mania and 16 healthy controls matched for age, gender, handedness, and years of education. Fractional anisotropy and radial and axial diffusivities were analyzed using Tract-Based Spatial Statistics. Results: Patients had lower fractional anisotropy and higher radial diffusivity in the left anterior frontal white matter, right posterior thalamic radiation, left cingulum, and bilateral sagittal striatum. In addition, increased radial diffusivity was found in the left corpus callosum. Conclusion: Our findings highlighted that white matter abnormalities were present by the time of remission of first-episode mania. The widespread occurrence of these white matter abnormalities both in first-episode mania and chronic bipolar disorder suggested that disruption of white matter cortical-subcortical networks as well as projection, associative, and commissural tracts is a hallmark of the illness.

This study examined white matter volume change and integrity jointly in patients with first-episode schizophrenia using an empirically derived region of interest approach and novel Diffusion Tensor Imaging (DTI) geometric indices. Structural images from 103 individuals comprising of 39 patients with first-episode schizophrenia and 64 healthy controls were examined for regions of white matter volume change using voxel-based morphometry (VBM). These regions were then further interrogated for group differences employing geometric indices in addition to fractional anisotropy (FA).VBM analyses revealed that patients with first-episode schizophrenia had lower white matter volume in the right temporal-occipital region (p

Since the 1920s, it has been known that the repetitive brain trauma associated with boxing may produce a progressive neurological deterioration, originally termed dementia pugilistica, and more recently, chronic traumatic encephalopathy (CTE). We review 48 cases of neuropathologically verified CTE recorded in the literature and document the detailed findings of CTE in 3 profession althletes, 1 football player and 2 boxers. Clinically, CTE is associated with memory disturbances, behavioral and personality changes, parkinsonism, and speech and gait abnormalities. Neuropathologically, CTE is characterized by atrophy of the cerebral hemispheres, medial temporal lobe, thalamus, mammillary bodies, and brainstem, with ventricular dilatation and a fenestrated cavum septum pellucidum. Microscopically, there are extensive tau-immunoreactive neurofibrillary tangles, astrocytic tangles, and spindle-shaped and threadlike neurites throughout the brain. The neurofibrillary degeneration of CTE is distinguished from other tauopathies by preferential involvement of the superficial cortical layers, irregular patchy distribution in the frontal and temporal cortices, propensity for sulcal depths, prominent perivascular, periventricular, and subpial distribution, and marked accumulation of tau-immunoreactive astrocytes. Deposition of beta-amyloid, most commonly as diffuse plaques, occurs in fewer than half the cases. Chronic traumatic encephalopathy is a neuropathologically distinct slowly progressive tauopathy with a clear environmental etiology.

The Talairach-Tournoux (TT) atlas is one of the most prevalent brain atlases. Although its spatial inconsistencies were reported earlier, there has been no systematic quantification of them across the entire atlas, which is addressed here. The consistency of the TT atlas, defined as uniformity of labeling across all three orthogonal atlas orientations, is calculated and presented as maps. It is analyzed in function of discrepancy measuring spatial offset in labeling. The TT atlas has 27.4% consistency and 37.7% inconsistency. The most consistent structure is the thalamus (85.7% consistency, 5.4% inconsistency). The consistency of the basal ganglia is good. For 3-mm discrepancy, the inconsistency of major subcortical gray matter structures is very low: 0% (globus pallidus medial and putamen), 0.7% (thalamus), 2.2% (globus pallidus lateral), 4.8% (hippocampus) and 4.9% (caudate nucleus). The inconsistency of all subcortical structures is relatively high (16.8%), caused by a very high inconsistency of white matter tracts. The consistency of stereotactic targets is 69.2% (GPi), 50.0% (STN) and 42.9% (VPL). The overall TT consistency increases by 20% for 1-mm discrepancy, constantly grows by 10% for 2–4-mm discrepancy and slows down to 3% for 5–6-mm discrepancy. This work enhances our understanding of the TT atlas and its variable spatial consistency. It is helpful in using multiple atlas orientations simultaneously. It also may be useful in atlas interpolation and construction of a fully consistent 3D atlas. As the consistency of the main stereotactic targets is medium, the use of the TT atlas in stereotactic procedures requires a great deal of care and understanding of its limitations.

We describe a process aiming to construct a 3-D geometric model of the human normal intracranial venous system from MRA data. An analysis of geometric properties of the intracranial veins and sinuses results in proposing three models: circular, elliptic, and free-shape. We formulate a rule based on which a suitable geometric venous model can be selected. The cross-sectional shape of different parts of dural venous sinuses is found to be better approximated by ellipses and free shapes, while for veins the circular and elliptic models are comparable. An analysis of using splines for radii smoothing is also provided. The approach is useful for building venous models in education and clinical applications.

Registration of brain atlases to MR images is important in both anatomic and functional studies of human brains. Existing intensity-based methods are confronted with the translation of image-similarity functions to desired anatomic correspondences; while feature-based methods are challenged with the automated extraction of required features. In this paper, we propose a non-rigid registration method, in which, a block matching method is first used to calculate boundary displacement of all structures in a brain atlas, and a topology preserving front propagation method is then used to deform the atlas by warping the structures according to their boundary displacements. The novelty of our method is that the registration procedure is automated and anatomically driven while there is no need to extract particular structures. Experiments on the registration of the Talairach---Tournoux brain atlas to phantom brain MR images and real data show that our method is robust to noise and intensity inhomogeneity, more accurate than the commonly used Talairach stereotaxic spatial normalization, and thus promising to open new applications for brain atlases.

BACKGROUND: Biologic glenoid resurfacing was developed in 1988 as an alternative to total shoulder arthroplasty in selected (usually younger) patients with primary, posttraumatic, or postreconstructive glenohumeral arthritis. A variety of biologic surfaces, including anterior capsule, autogenous fascia lata, and Achilles tendon allograft, have been combined with a humeral hemiarthroplasty. METHODS: From November 1988 to November 2003, thirty-four patients (thirty-six shoulders) who were managed with biologic glenoid resurfacing and humeral head replacement either with cement (ten shoulders) or without cement (twenty-six shoulders) were followed prospectively. The study group included thirty men and four women with an average age of fifty-one years. The diagnoses included primary glenohumeral osteoarthritis (eighteen shoulders), postreconstructive arthritis (twelve), posttraumatic arthritis (five), and osteonecrosis (one). Anterior capsule was used for seven shoulders, autogenous fascia lata for eleven, and Achilles tendon allograft for eighteen. All shoulders were assessed clinically and with serial radiographs. RESULTS: The mean American Shoulder and Elbow Surgeons score was 39 points preoperatively and 91 points at the time of the most recent follow-up. According to Neer's criteria, the result was excellent for eighteen shoulders, satisfactory for thirteen, and unsatisfactory for five. Glenoid erosion averaged 7.2 mm and appeared to stabilize at five years. There were no revisions for humeral component loosening. Complications included infection (two patients), instability (three patients), brachial plexitis (one patient), and deep-vein thrombosis (one patient). Factors that appeared to be associated with unsatisfactory results were the use of capsular tissue as the resurfacing material and infection. CONCLUSIONS: Biologic resurfacing of the glenoid can provide pain relief similar to total shoulder arthroplasty. It allows selected younger patients to maintain an active lifestyle, including weight-lifting and manual work, without the risk of polyethylene wear. On the basis of this and previous reviews, we currently recommend Achilles tendon allograft as the preferred resurfacing material when this option is chosen. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions to Authors for a complete description of levels of evidence. ORIGINAL ABSTRACT CITATION: “Humeral Hemiarthroplasty with Biologic Resurfacing of the Glenoid for Glenohumeral Arthritis. Two to Fifteen-Year Outcomes” (2007;89:727-34).

Background: The external intercostal muscles are chronically exposed to increased inspiratory loading and to continuous hypoxia-reoxygenation cycles in patients with obstructive sleep apnoea syndrome (OSAS). It was therefore hypothesised that oxidative stress levels would be increased in these muscles, and that treatment with continuous positive airway pressure (CPAP) would modify the oxidative stress levels and improve muscle dysfunction. Methods: A case-control study and a case-case study were conducted on the external intercostal muscles of 12 patients with severe OSAS (before and after 6 months of treatment with CPAP) and 6 control subjects. Reactive carbonyl groups, malondialdehyde (MDA)-protein and hydroxynonenal (HNE)-protein adducts, antioxidant enzyme levels, 3-nitrotyrosine and fibre type proportions were measured using immunoblotting and immunohistochemistry. Results: Compared with controls, the intercostal muscles of patients with OSAS had higher levels of protein carbonylation (median values 3.06 and 2.45, respectively, p = 0.042), nitration (median values 1.64 and 1.05, respectively, p = 0.019) and proportions of type I fibres (median values 57% and 48%, respectively, p = 0.035) and reduced respiratory muscle endurance (median values 3.2 and 9.5 min, respectively, p = 0.001). Positive correlations were found between MDA-protein and HNE-protein adducts ( r = 0.641, p = 0.02 and r = 0.594, p = 0.05, respectively) and 3-nitrotyrosine ( r = 0.625, p = 0.03) and the apnoea-hypopnoea index (AHI) in all the patients with OSAS. Although treatment with CPAP significantly improved the AHI and oxygen desaturation, muscle oxidative stress levels and respiratory muscle endurance were not affected. Conclusions: This study suggests that inspiratory muscle performance is not completely restored after long-term treatment with CPAP.