The projection-specific signals that establish functionally segregated dopaminergic synapses.

Dopaminergic projections regulate various brain functions and are implicated in many neuropsychiatric disorders. There are two anatomically and functionally distinct dopaminergic projections connecting the midbrain to striatum: nigrostriatal, which controls movement, and mesolimbic, which regulates motivation. However, how these discrete dopaminergic synaptic connections are established is unknown. Through an unbiased search, we identify that two groups of antagonistic TGF-ß family members, bone morphogenetic protein (BMP)6/BMP2 and transforming growth factor (TGF)-ß2, regulate dopaminergic synapse development of nigrostriatal and mesolimbic neurons, respectively. Projection-preferential expression of their receptors contributes to specific synapse development. Downstream, Smad1 and Smad2 are specifically activated and required for dopaminergic synapse development and function in nigrostriatal vs. mesolimbic projections. Remarkably, Smad1 mutant mice show motor defects, whereas Smad2 mutant mice show lack of motivation. These results uncover the molecular logic underlying the proper establishment of functionally segregated dopaminergic synapses and may provide strategies to treat relevant, projection-specific disease symptoms by targeting specific BMPs/TGF-ß and/or Smads.

Primary and secondary diseases of the perinephric space: an approach to imaging diagnosis with emphasis on MRI.

The perinephric space is the middle compartment of the retroperitoneum, containing the kidneys and adrenal glands. Differential considerations for diseases involving primarily the perinephric space differ from those arising from the kidney itself, show variant imaging features, and require identification and characterisation by interpreting radiologists-an imaging diagnosis can be suggested in many cases. Lymphangiomas are congenital cystic lesions that may contain lipid-laden chyle, which may be detectable on magnetic resonance imaging (MRI). Retroperitoneal fibrosis, Erdheim-Chester disease, and lymphoma may present as a perinephric soft tissue rind. Osseous findings favour Erdheim-Chester, ureteric obstruction favours retroperitoneal fibrosis, and associated lymphadenopathy with mass-effect, but without invasion of adjacent structures favours lymphoma. Extramedullary haematopoiesis and brown fat stimulation are both characterised by signal drop on opposed-phase T1-weighted (W) images, the former resulting from severe anaemia and the latter in the context of elevated serum catecholamines, especially in the setting of phaeochromocytoma. Liposarcoma is the most common primary sarcoma of the retroperitoneum. Metastases are uncommon; however, they can be seen in melanoma, among other primary malignancies. Increased T1W signal hyperintensity is typical of melanoma metastases and haematomas. Abscesses show non-enhancing fluid centrally with marked diffusion restriction. This article presents a review of the perinephric space, pathological conditions of the perinephric space, and an approach towards imaging and diagnosis using cross-sectional imaging, with emphasis on MRI. MRI provides better tissue characterisation, assessment of enhancement kinetics, and detection of intralesional fat in comparison to CT. Clinical and laboratory correlation or tissue sampling may be required for definitive diagnosis in some cases.

Making surgery safer in an increasingly digital world: the internet-friend or foe?

PURPOSE: The internet has resulted in huge efficiency gains in health care, the ability to deal with massive data accumulation and better manage patient data. However, potential and real pitfalls exist, including breeches in security of data and patient confidentiality, data storage issues, errors, and user interface issues. METHODS: A MEDLINE review was performed using MeSH terms "health care" and "information technology." Cross-referencing was used to explore the different opportunities and challenges the internet has to offer. RESULTS: As health professionals, we are fast adopting technologies at our fingertips, such as WhatsApp and video capabilities, into our clinical practice to increase productivity and improve patient care. However, the potential security breaches are significant for the health professional and health service. Further, electronic medical records have theoretical advantages to improve patient care, reduce medication errors, and expedite referrals. The downside is a less personalized approach to patient care, as well as the potential for these systems to be even more cumbersome. In regard to the acquisition of knowledge, there is no doubt the internet is our friend. Health care professionals as well as patients have unlimited resources for learning, including podcasts videos, apps, simulators, and wearable devices. Unfortunately, this comes with a risk of misinformation and poorly referenced data with little to no regulation of content. CONCLUSION: In this increasing digital world, it is our task as health care providers to embrace these new technologies but develop guidelines and control systems to minimize the pitfalls.

Temporomandibular arthropathies: A retrospective study with histopathological characteristics.

BACKGROUND: To investigate the incidence of temporomandibular arthropathies diagnosed in a university center and to describe their histopathological characteristics. MATERIAL AND METHODS: Temporomandibular arthropathy cases with corresponding slides were selected from an oral and maxillofacial surgical pathology service. Cases of exclusively articular disc disease were not included. RESULTS: The mean age was 31.3 years with a predominance of females (69.7%). Of these diagnoses, 53.6% were unilateral condylar hyperplasia, 17.8% were bony ankylosis, 14.3% were degenerative joint disease, 10.7% were osteochondroma, and 3.6% were synovial chondromatosis. Condylar hyperplasia presented as thick fibrocartilage and cartilage nests in the cancellous bone. Bony ankylosis exhibited lamellar bone and nests of chondrocytes. Degenerative joint disease presented as an irregular layer of fibrocartilage with areas of clustered chondrocytes and calcified cartilage. Osteochondroma of the condyle exhibited hyaline cartilage and areas of new bone formation. Synovial chondromatosis presented as immature cartilaginous tissue and randomly arranged chondrocytes. CONCLUSIONS: The pathological alterations verified in these arthropathies involved diseases that were predominantly proliferative, i.e., unilateral condylar hyperplasia, osteochondroma and synovial chondromatosis of the tumor or pseudotumor type and bony ankylosis associated with callus formation of the reparative type, and less frequent degenerative changes for which the disease is so named.

Associations of osteoprotegerin with coronary artery calcification among women with systemic lupus erythematosus and healthy controls.

Objective We tested the hypothesis that higher circulating levels of osteoprotegerin (OPG) are related to higher levels of coronary artery calcification (CAC) among women with systemic lupus erythematosus (SLE) compared with healthy controls (HCs). Methods Among 611 women in two age- and race-matched SLE case-control studies, OPG was assayed in stored blood samples (HEARTS: plasma, n cases/controls = 122/124, and SOLVABLE: serum, n cases/controls = 185/180) and CAC was measured by electron beam computed tomography. Results In both studies, SLE patients had higher OPG and CAC levels than HCs. Higher OPG was associated with high CAC (>100 vs.100) among SLE, and with any CAC (>0 vs. 0) among HCs. Multivariable-adjusted OR (95% CI) for OPG tertile 3 vs. 1 was 3.58 (1.19, 10.76), p trend = 0.01 for SLE, and 2.28 (1.06, 4.89), p trend = 0.04 for HCs. Associations were attenuated when age-adjusted, but remained significant for HC women aged ≥ 40 and SLE women aged ≥ 50. ROC analyses identified 4.60 pmol/l as the optimal OPG cutpoint for predicting high CAC (>100) among SLE patients with sensitivity = 0.74 and specificity = 0.61, overall, but 0.92 and 0.52, respectively, for SLE patients aged ≥ 50. Conclusion Our cross-sectional results suggest that higher OPG levels are related to higher CAC levels among women with SLE vs. healthy controls.

Improving medication safety and diabetes management in Hong Kong: a multidisciplinary approach.

INTRODUCTION: Patients with diabetes often require complex medication regimens. The positive impact of pharmacists on improving diabetes management or its co-morbidities has been recognised worldwide. This study aimed to characterise drug-related problems among diabetic patients in Hong Kong and their clinical significance, and to explore the role of pharmacists in the multidisciplinary diabetes management team by evaluating the outcome of their clinical interventions. METHODS: An observational study was conducted at the Diabetes Clinic of a public hospital in Hong Kong from October 2012 to March 2014. Following weekly screening, and prior to the doctor's consultation, selected high-risk patients were interviewed by a pharmacist for medication reconciliation and review. Drug-related problems were identified and documented by the pharmacist who presented clinical recommendations to doctors to optimise a patient's drug regimen and resolve or prevent potential drug-related problems. RESULTS: A total of 522 patients were analysed and 417 drug-related problems were identified. The incidence of patients with drug-related problems was 62.8% with a mean of 0.9 (standard deviation, 0.6) drug-related problems per patient. The most common categories of drug-related problems were associated with dosing (43.9%), drug choice (17.3%), and non-allergic adverse reactions (15.6%). Drugs most frequently involved targeted the endocrine or cardiovascular system. The majority (71.9%) of drug-related problems were of moderate clinical significance and 28.1% were considered minor problems. Drug-related problems were totally solved (50.1%) and partially solved (11.0%) by doctors' acceptance of pharmacist recommendations, or received acknowledgement from doctors (5.5%). CONCLUSIONS: Pharmacists, in collaboration with the multidisciplinary team, demonstrated a positive impact by identifying, resolving, and preventing drug-related problems in patients with diabetes. Further plans for sustaining pharmacy service in the Diabetes Clinic would enable further studies to explore the long-term impact of pharmacists in improving patients' clinical outcomes in diabetes management.

Characterising brain network topologies: A dynamic analysis approach using heat kernels.

Network theory provides a principled abstraction of the human brain: reducing a complex system into a simpler representation from which to investigate brain organisation. Recent advancement in the neuroimaging field is towards representing brain connectivity as a dynamic process in order to gain a deeper understanding of how the brain is organised for information transport. In this paper we propose a network modelling approach based on the heat kernel to capture the process of heat diffusion in complex networks. By applying the heat kernel to structural brain networks, we define new features which quantify change in heat propagation. Identifying suitable features which can classify networks between cohorts is useful towards understanding the effect of disease on brain architecture. We demonstrate the discriminative power of heat kernel features in both synthetic and clinical preterm data. By generating an extensive range of synthetic networks with varying density and randomisation, we investigate heat diffusion in relation to changes in network topology. We demonstrate that our proposed features provide a metric of network efficiency and may be indicative of organisational principles commonly associated with, for example, small-world architecture. In addition, we show the potential of these features to characterise and classify between network topologies. We further demonstrate our methodology in a clinical setting by applying it to a large cohort of preterm babies scanned at term equivalent age from which diffusion networks were computed. We show that our heat kernel features are able to successfully predict motor function measured at two years of age (sensitivity, specificity, F-score, accuracy = 75.0, 82.5, 78.6, and 82.3%, respectively).

Laparoscopic gastrojejunostomy for superior mesenteric artery syndrome in a patient with Parkinson's disease.

INTRODUCTION: Superior mesenteric artery syndrome is rare cause of intestinal obstruction. We report an unusual case of a patient with Parkinson's disease who developed superior mesenteric artery syndrome and discuss her management including laparoscopic gastrojejunostomy and Roux-en-Y anastomosis. CASE PRESENTATION: A 78-year-old patient with advanced Parkinson's disease presented with significant malnutrition, vomiting and post-prandial abdominal pain. Computed tomography confirmed duodenal compression by the superior mesenteric artery. We hypothesised this was likely triggered by extreme weight loss associated with advanced Parkinson's disease. As the patient failed to improve with conservative measures, laparoscopic gastrojejunostomy and Roux-en-Y anastomosis was successfully performed without complications and the patient discharged on day 7. CONCLUSION: Successful treatment was achieved due to early recognition of the consequences of chronic illness and addressing malnutrition. From this experience, we propose that laparoscopic gastric bypass is a safe and minimally invasive effective treatment option for superior mesenteric artery syndrome.

Subversion of cytokine networks by virally encoded decoy receptors.

During the course of evolution, viruses have captured or created a diverse array of open reading frames, which encode for proteins that serve to evade and sabotage the host innate and adaptive immune responses that would otherwise lead to their elimination. These viral genomes are some of the best textbooks of immunology ever written. The established arsenal of immunomodulatory proteins encoded by viruses is large and growing, and includes specificities for virtually all known inflammatory pathways and targets. The focus of this review is on herpes and poxvirus-encoded cytokine and chemokine-binding proteins that serve to undermine the coordination of host immune surveillance. Structural and mechanistic studies of these decoy receptors have provided a wealth of information, not only about viral pathogenesis but also about the inner workings of cytokine signaling networks.

Impact of Consensus Guidelines by the Society of Surgical Oncology and the American Society for Radiation Oncology on Margins for Breast-Conserving Surgery in Stages 1 and 2 Invasive Breast Cancer.

BACKGROUND: This study aimed to evaluate the impact that the release of consensus guidelines for margins in breast-conserving surgery (BCS) had on re-excision rates. METHODS: A retrospective review examined a prospectively maintained database of patients who had operable invasive breast cancer treated with BCS at the authors' institution. The patients were divided into two groups: (1) those with a diagnosis determined from 1 July 2011 to 31 July 2013 (before release of the guidelines) and (2) those with a diagnosis determined from 1 February 2014 to 31 July 2014 (after release of the guidelines). The groups were evaluated with respect to patient and tumor characteristics, re-excision rates, and reasons for re-excision. RESULTS: A total of 846 cases of BCS were managed: 597 in group 1 and 249 in group 2. Re-excision rates were significantly reduced after release of the consensus guidelines (p = 0.03). Re-excisions were performed for 115 (19 %) of 597 patients in group 1 and 32 (13 %) of 249 patients in group 2. After release of the guidelines, re-excisions were performed for positive margins, as defined by the consensus statement, in 25 (78 %) of 32 cases. The two groups did not differ significantly in terms of age, tumor size, grade, nodal status, estrogen receptor status, progesterone receptor status, or human epidermal growth factor receptor 2 status. Group 1 had more tumors of mixed ductal and lobular histology than group 2, and group 2 had more lobular tumors than group 1 (p = 0.02). CONCLUSIONS: The consensus guidelines on margins for BCS were applied for 78 % of the patients who underwent re-excision and resulted in a significant reduction in re-excision rates.

Defending the fort: a role for defensin-2 in limiting Rickettsia montanensis infection of Dermacentor variabilis.

The importance of tick defensins is evidenced by their expression in a wide variety of tick tissues and prevalence across many tick genera. To date, the functional and biological significance of defensin-2 as a rickettsiastatic or rickettsiacidal antimicrobial peptide has not been addressed. In a previous study, defensin-2 transcription was shown to increase in Dermacentor variabilis ticks challenged with Rickettsia montanensis. In the present study, the hypothesis that defensin-2 is functional as a rickettsiastatic and/or rickettsiacidal antimicrobial peptide is tested. We show that defensin-2 plays a role in reducing burden after acquisition of Rickettsia montanensis through capillary feeding. Moreover, defensin-2 is shown to associate with R. montanensis in vitro and in vivo, causing cytoplasmic leakiness.

Work-based assessment: qualitative perspectives of novice nutrition and dietetics educators.

BACKGROUND: The assessment of competence for health professionals including nutrition and dietetics professionals in work-based settings is challenging. The present study aimed to explore the experiences of educators involved in the assessment of nutrition and dietetics students in the practice setting and to identify barriers and enablers to effective assessment. METHODS: A qualitative research approach using in-depth interviews was employed with a convenience sample of inexperienced dietitian assessors. Interviews explored assessment practices and challenges. Data were analysed using a thematic approach within a phenomenological framework. Twelve relatively inexperienced practice educators were purposefully sampled to take part in the present study. RESULTS: Three themes emerged from these data. (i) Student learning and thus assessment is hindered by a number of barriers, including workload demands and case-mix. Some workplaces are challenged to provide appropriate learning opportunities and environment. Adequate support for placement educators from the university, managers and their peers and planning are enablers to effective assessment. (ii) The role of the assessor and their relationship with students impacts on competence assessment. (iii) There is a lack of clarity in the tasks and responsibilities of competency-based assessment. CONCLUSIONS: The present study provides perspectives on barriers and enablers to effective assessment. It highlights the importance of reflective practice and feedback in assessment practices that are synonymous with evidence from other disciplines, which can be used to better support a work-based competency assessment of student performance.

A review of the use of human factors classification frameworks that identify causal factors for adverse events in the hospital setting.

Various human factors classification frameworks have been used to identified causal factors for clinical adverse events. A systematic review was conducted to identify human factors classification frameworks that identified the causal factors (including human error) of adverse events in a hospital setting. Six electronic databases were searched, identifying 1997 articles and 38 of these met inclusion criteria. Most studies included causal contributing factors as well as error and error type, but the nature of coding varied considerably between studies. The ability of human factors classification frameworks to provide information on specific causal factors for an adverse event enables the focus of preventive attention on areas where improvements are most needed. This review highlighted some areas needing considerable improvement in order to meet this need, including better definition of terms, more emphasis on assessing reliability of coding and greater sophistication in analysis of results of the classification. Practitioner Summary: Human factors classification frameworks can be used to identify causal factors of clinical adverse events. However, this review suggests that existing frameworks are diverse, limited in their identification of the context of human error and have poor reliability when used by different individuals.

Organization of an ascending circuit that conveys flight motor state in Drosophila.

Natural behaviors are a coordinated symphony of motor acts that drive reafferent (self-induced) sensory activation. Individual sensors cannot disambiguate exafferent (externally induced) from reafferent sources. Nevertheless, animals readily differentiate between these sources of sensory signals to carry out adaptive behaviors through corollary discharge circuits (CDCs), which provide predictive motor signals from motor pathways to sensory processing and other motor pathways. Yet, how CDCs comprehensively integrate into the nervous system remains unexplored. Here, we use connectomics, neuroanatomical, physiological, and behavioral approaches to resolve the network architecture of two pairs of ascending histaminergic neurons (AHNs) in Drosophila, which function as a predictive CDC in other insects. Both AHN pairs receive input primarily from a partially overlapping population of descending neurons, especially from DNg02, which controls wing motor output. Using Ca2+ imaging and behavioral recordings, we show that AHN activation is correlated to flight behavior and precedes wing motion. Optogenetic activation of DNg02 is sufficient to activate AHNs, indicating that AHNs are activated by descending commands in advance of behavior and not as a consequence of sensory input. Downstream, each AHN pair targets predominantly non-overlapping networks, including those that process visual, auditory, and mechanosensory information, as well as networks controlling wing, haltere, and leg sensorimotor control. These results support the conclusion that the AHNs provide a predictive motor signal about wing motor state to mostly non-overlapping sensory and motor networks. Future work will determine how AHN signaling is driven by other descending neurons and interpreted by AHN downstream targets to maintain adaptive sensorimotor performance.

Comparative connectomics of the descending and ascending neurons of the Drosophila nervous system: stereotypy and sexual dimorphism.

In most complex nervous systems there is a clear anatomical separation between the nerve cord, which contains most of the final motor outputs necessary for behaviour, and the brain. In insects, the neck connective is both a physical and information bottleneck connecting the brain and the ventral nerve cord (VNC, spinal cord analogue) and comprises diverse populations of descending (DN), ascending (AN) and sensory ascending neurons, which are crucial for sensorimotor signalling and control. Integrating three separate EM datasets, we now provide a complete connectomic description of the ascending and descending neurons of the female nervous system of Drosophila and compare them with neurons of the male nerve cord. Proofread neuronal reconstructions have been matched across hemispheres, datasets and sexes. Crucially, we have also matched 51% of DN cell types to light level data defining specific driver lines as well as classifying all ascending populations. We use these results to reveal the general architecture, tracts, neuropil innervation and connectivity of neck connective neurons. We observe connected chains of descending and ascending neurons spanning the neck, which may subserve motor sequences. We provide a complete description of sexually dimorphic DN and AN populations, with detailed analysis of circuits implicated in sex-related behaviours, including female ovipositor extrusion (DNp13), male courtship (DNa12/aSP22) and song production (AN hemilineage 08B). Our work represents the first EM-level circuit analyses spanning the entire central nervous system of an adult animal.

A Drug Repurposing Approach Reveals Targetable Epigenetic Pathways in Plasmodium vivax Hypnozoites.

Radical cure of Plasmodium vivax malaria must include elimination of quiescent 'hypnozoite' forms in the liver; however, the only FDA-approved treatments are contraindicated in many vulnerable populations. To identify new drugs and drug targets for hypnozoites, we screened the Repurposing, Focused Rescue, and Accelerated Medchem (ReFRAME) library and a collection of epigenetic inhibitors against P. vivax liver stages. From both libraries, we identified inhibitors targeting epigenetics pathways as selectively active against P. vivax and P. cynomolgi hypnozoites. These include DNA methyltransferase (DNMT) inhibitors as well as several inhibitors targeting histone post-translational modifications. Immunofluorescence staining of Plasmodium liver forms showed strong nuclear 5-methylcystosine signal, indicating liver stage parasite DNA is methylated. Using bisulfite sequencing, we mapped genomic DNA methylation in sporozoites, revealing DNA methylation signals in most coding genes. We also demonstrated that methylation level in proximal promoter regions as well as in the first exon of the genes may affect, at least partially, gene expression in P. vivax. The importance of selective inhibitors targeting epigenetic features on hypnozoites was validated using MMV019721, an acetyl-CoA synthetase inhibitor that affects histone acetylation and was previously reported as active against P. falciparum blood stages. In summary, our data indicate that several epigenetic mechanisms are likely modulating hypnozoite formation or persistence and provide an avenue for the discovery and development of improved radical cure antimalarials.

miR-21 is a key therapeutic target for renal injury in a mouse model of type 2 diabetes.

AIMS/HYPOTHESIS: As microRNA-21 (miR-21) plays a pathological role in fibrosis, we hypothesised that it may be a therapeutic target for diabetic nephropathy. METHODS: Abundance of miR-21 was examined in diabetic kidneys from db/db mice. The therapeutic potential of miR-21 in diabetic kidney injury was examined in db/db mice by an ultrasound-microbubble-mediated miR-21 small hairpin RNA transfer. In addition, the role and mechanisms of miR-21 in diabetic renal injury were examined in vitro under diabetic conditions in rat mesangial and tubular epithelial cell lines by overexpressing or downregulating miR-21. RESULTS: In db/db mice, a mouse model of type 2 diabetes, renal miR-21 at age 20 weeks was increased twofold compared with db/m (+) mice at the same age, and this increase was associated with the development of microalbuminuria and renal fibrosis and inflammation. More importantly, gene transfer of miR-21 knockdown plasmids into the diabetic kidneys of db/db mice at age 10 weeks significantly ameliorated microalbuminuria and renal fibrosis and inflammation at age 20 weeks, revealing a therapeutic potential for diabetic nephropathy by targeting miR-21. Overexpression of miR-21 in kidney cells enhanced, but knockdown of miR-21 suppressed, high-glucose-induced production of fibrotic and inflammatory markers. Targeting Smad7 may be a mechanism by which miR-21 regulates renal injury because knockdown of renal miR-21 restored Smad7 levels and suppressed activation of the TGF-ß and NF-κB signalling pathways. CONCLUSIONS/INTERPRETATION: Inhibition of miR-21 might be an effective therapy for diabetic nephropathy.

medpie: an information extraction package for medical message board posts.

SUMMARY: We have developed medpie, a software package for preparing medical message board corpora and extracting patient mentions and statistics for drugs, herbs and adverse effects experienced from them. The package is divided into web-crawling, HTML-cleaning, de-identification and information extraction modules. It also includes a sample controlled vocabulary of drugs, herbs and adverse effect terms. AVAILABILITY: http://www.cis.upenn.edu/~ungar/medpie.zip. DEPENDENCIES: Python 2.6 or 2.7.