SIAMESE VERIFICATION FRAMEWORK FOR AUTISM IDENTIFICATION DURING INFANCY USING CORTICAL PATH SIGNATURE FEATURES.
Autism spectrum disorder (ASD) is a complex neurodevelopmental disability, which is lack of biologic diagnostic markers. Therefore, exploring the ASD Identification directly from brain imaging data has been an important topic. In this work, we propose the Siamese verification model to identify ASD using 6 and 12 months cortical features. Rather than directly classifying a testing subject is ASD or not, we determine whether it has the same or different label with the reference subject who has been successfully diagnosed. Then, based on the comparison to all the reference subjects, we can predict the label of the testing subject. The advantage of modeling the classification problem as a verification framework is that it can greatly enlarge the training data size and enable us to train a more accurate and reliable model in an end-to-end manner. In addition, to further improve the classification performance, we introduce the path signature (PS) features, which can capture the dynamic longitudinal information of the brain development for the ASD Identification. Experiments showed that our proposed method reaches the best result, i.e., 87% accuracy, 83% sensitivity and 90% specificity comparing to the state-of-the-art methods.


11. Breast cancer in young women.
Women under the age of 35 years comprise only 5% of cases of breast cancer but because of the unexpected nature of the diagnosis this may be associated with delay. In the clinic, the diagnosis may not be immediate because of the low sensitivity of the components of triple diagnosis. The disease tends to be more aggressive with a higher incidence of poorly differentiated (grade III) carcinomas and more hormone insensitive (ER/PR negative) tumours. Additionally, the tumours are often rapidly proliferating and express abnormal p53. Women under 35 have an increased risk of local failure following breast cancer therapy, but this does not affect their cancer-specific survival. Young women treated with cyclophosphamide, methotrexate and fluorouracil chemotherapy have a greater risk of relapse and death than older premenopausal patients, especially if their tumours express oestrogen receptors, so endocrine treatment should also be offered under these circumstances.


Epilepsy in India I: Epidemiology and public health.
Of the 70 million persons with epilepsy (PWE) worldwide, nearly 12 million PWE are expected to reside in India; which contributes to nearly one-sixth of the global burden. This paper (first of the two part series) provides an in-depth understanding of the epidemiological aspects of epilepsy in India for developing effective public health prevention and control programs. The overall prevalence (3.0-11.9 per 1,000 population) and incidence (0.2-0.6 per 1,000 population per year) data from recent studies in India on general population are comparable to the rates of high-income countries (HICs) despite marked variations in population characteristics and study methodologies. There is a differential distribution of epilepsy among various sociodemographic and economic groups with higher rates reported for the male gender, rural population, and low socioeconomic status. A changing pattern in the age-specific occurrence of epilepsy with preponderance towards the older age group is noticed due to sociodemographic and epidemiological transition. Neuroinfections, neurocysticercosis (NCC), and neurotrauma along with birth injuries have emerged as major risk factors for secondary epilepsy. Despite its varied etiology (unknown and known), majority of the epilepsy are manageable in nature. This paper emphasizes the need for focused and targeted programs based on a life-course perspective and calls for a stronger public health approach based on equity for prevention, control, and management of epilepsy in India.


The association between resilience resources, contextual factors and mental health status: a national population-based study.
Although a range of risk factors have been linked with poor mental health across the population, the underlying pathways leading to mental ill health remain unclear. There is a need to investigate the effects and interplay of both protective and risk factors. This population-based study aimed to explore the effects of individual and contextual factors on mental health status. Record-linkage was implemented between health and lifestyle data drawn from HealthWise Wales (HWW), a national population health survey of people > 16 years who live or access their healthcare in Wales, and treatment data from primary healthcare records. Mental health status was assessed using three different measures, including the self-reported MHI-5 and WEMWBS scales and mental health treatment in electronic healthcare records (EHR). Using cross-sectional data from 27,869 HWW participants aged over 16 years, lifestyle factors, resilience, social cohesion and neighbourhood attraction were associated with mental health across all measures. However, compared to contextual factors, the cluster of individual factors was more closely associated with poor mental health, explaining more of the variance across all measures used (MHI-5: 9.8% versus 5.4%; WEMWBS: 15.9% versus 10.3%; EHR: 5.5% versus 3.0%). Additional analysis on resilience sub-constructs indicated that personal skills were the most closely correlated with poorer mental health. Mental health status was more closely linked with individual factors across the population than contextual factors. Interventions focusing on improving individual resilience and coping skills could improve mental health outcomes and reduce the negative effect of contextual factors such as negative neighbourhood perceptions.


The late follow-up of chronic sarcoid patients previously treated with corticosteroids.
The aim of the study was to evaluate, in a white population with chronic sarcoidosis, the rate and pattern of relapses, the correlated factors, and the course of disease after prednisone withdrawal. We have retrospectively examined the charts of 702 consecutive patients with histologically proven sarcoidosis, first seen in the Milan Sarcoidosis Clinic in the period October 1978-October 1994. 239 patients required corticosteroid therapy; in 82 it was possible to discontinue prednisone therapy and to have a follow-up of at least 18 months after withdrawal. A relapse, requiring a new course of steroids, was observed in 30 (36.6%) of the 82 patients (R group). The other 52 patients (No-R group) did not relapse during a mean follow-up of 36.8 +/- 24.8 months (range 18-125). There were no relapses after 3 asymptomatic years of prednisone withdrawal. Extrapulmonary sarcoidosis was a reason for giving therapy in 46.6% of patients in the R group, vs 23.0% in the No-R group (P < 0.05). The first course of therapy lasted 22 months [median time; i.q. 11.5 to 34.5] in R group vs 26 months [i.q. 18 to 41] in No-R group (P > 0.05). The mean daily prednisone dose was higher in the R group: 17 mg [median value; i.q. 8.9 to 23.2] vs 10.6 mg [i.q. 8.1 to 13.8] in the No-R group (p < 0.05). Logistic regression confirmed the prognostic significance of mean daily prednisone dose and of extrapulmonary sarcoidosis at presentation (P < 0.01). A mild sarcoid activity at the time of withdrawal was still present in 51.9% of patients who did not relapse, and in 66.7% of patients who relapsed (p > 0.05). Relapse in the first year after withdrawal of prednisone therapy occurred in twenty-five of the 30 patients. The pattern of relapse was different from the initial manifestation in 5. Nine of the 30 patients could ultimately be weaned successfully from prednisone. Relapses occurred in 36.6% of cases, and their pattern was the same as the initial manifestation in the majority of cases. A mild sarcoid activity at the time of withdrawal is not a reason for continuing steroids when the disease is abating. In our white population severe irreversible pulmonary impairment is rare, and even patients requiring chronic therapy need low prednisone dosage, usually around 10 mg daily, to control the disease in the late course.


Absolute film separation of dyes/salts and emulsions with a superhigh water permeance through graded nanofluidic channels.
The development of multifunctional films with a high permeability has been of great concern for effective separation of complex aqueous contaminants, especially in the face of zero or near-zero release regulations. Inspired by the natural structure of sandy soils, polydopamine-wrapped/connected polypyrrole sub-micron spheres (PPSM) were closely packed onto a polypyrrole-coated bacterial cellulose (PBC) support, by which a new two-layered PBC/PPSM composite film formed with graded nanofluidic channels. Interestingly, after being soaked in complex water environments of ethanol, acids, bases, heat, cold and high salinity, or else bended/folded for more than 10 times, the structure and performance of this film still stayed the same, validating its high structural stability and flexibility. Even in a high salinity environment over seawater, this PBC/PPSM film exhibits a dye-separation capacity of almost 100% with a surprisingly superhigh water permeance over one thousand L h-1 m-2 bar-1, one or two magnitudes higher than that of the related films reported in the literature. Meanwhile, the ability for effective oil-water-separation was also validated. Besides the superhydrophilicity and underwater superoleophobicity, the synapse-like-structure-induced graded nanofluidic channels are also proposed to play a key role for rendering such an outstandingly comprehensive performance of the film by greatly overcoming fluid resistance and reducing permeation viscosity.


Causes of haze in the Columbia River Gorge.
Visibility impairment in the Columbia River Gorge National Scenic Area is an area of concern. A field study conducted from July 2003 to February 2005 was followed by data analysis and receptor modeling to better understand the temporal and spatial patterns of haze and the sources contributing to the haze in the Columbia River Gorge in the states of Washington and Oregon. The nephelometer light scattering and surface meteorological data at eight sites along the gorge showed five distinct wind patterns, each with its characteristic diurnal and spatial patterns in light scattering by particles (bsp). In summer, winds were nearly always from west to east (upgorge) and showed decreasing bsp with distance into the gorge and a pronounced effect of the Portland, OR, metropolitan area on haze, especially in the western portions of the gorge. Winter often had winds from the east with very high levels of bsp, especially at the eastern gorge sites, with sources east of the gorge responsible for much of the haze. The major chemical components responsible for haze were organic carbon, sulfate, and nitrate. Positive matrix factorization (PMF) using chemically speciated Interagency Monitoring of Protected Visual Environments data indicated seven source factors in the western gorge and five factors in the eastern gorge. Organic mass is a large contributor to haze in the gorge in all seasons, with a peak in fall. The PMF analysis suggests that approximately half of the organic mass is biomass smoke, with mobile sources as the second largest contributor. PMF analysis showed nitrates (important in fall and winter) mainly attributed to a generic secondary nitrate factor, with the next largest contributor being oil combustion at Mt. Zion, WA and mobile sources at Wishram, WA. Sulfate is a significant contributor in all seasons, with peak sulfate concentrations in summer.


Multicentric Castleman disease with secondary AA renal amyloidosis, nephrotic syndrome and chronic renal failure, remission after high-dose melphalan and autologous stem cell transplantation.
Multicentric Castleman disease is a systemic lymphoproliferative disease with incomplete understood etiology. The various renal complications of this disease may include minimal change disease, mesangial proliferative glomerulonephritis, membranous glomerulonephritis and nephrotic syndrome, caused by secondary amyloidosis. In several reported cases of localized Castleman disease associated with renal amyloidosis and nephrotic syndrome, resection of organs involved by lymphoid proliferation resulted in complete remission. However, therapy of multicentric Castleman disease with renal amyloidosis is not well-established. We treated a case of a 39-year-old woman with multicentric Castleman disease complicated by nephrotic syndrome caused by secondary AA amyloidosis. The patient underwent autologous peripheral blood stem cell transplantation (auto-PBSCT), achieving complete remission. Autologous stem cell transplantation may be an attractive choice in therapy for refractory multicentric Castleman disease.


A Novel Hybrid Harris Hawk-Arithmetic Optimization Algorithm for Industrial Wireless Mesh Networks.
A novel hybrid Harris Hawk-Arithmetic Optimization Algorithm (HHAOA) for optimizing the Industrial Wireless Mesh Networks (WMNs) and real-time pressure process control was proposed in this research article. The proposed algorithm uses inspiration from Harris Hawk Optimization and the Arithmetic Optimization Algorithm to improve position relocation problems, premature convergence, and the poor accuracy the existing techniques face. The HHAOA algorithm was evaluated on various benchmark functions and compared with other optimization algorithms, namely Arithmetic Optimization Algorithm, Moth Flame Optimization, Sine Cosine Algorithm, Grey Wolf Optimization, and Harris Hawk Optimization. The proposed algorithm was also applied to a real-world industrial wireless mesh network simulation and experimentation on the real-time pressure process control system. All the results demonstrate that the HHAOA algorithm outperforms different algorithms regarding mean, standard deviation, convergence speed, accuracy, and robustness and improves client router connectivity and network congestion with a 31.7% reduction in Wireless Mesh Network routers. In the real-time pressure process, the HHAOA optimized Fractional-order Predictive PI (FOPPI) Controller produced a robust and smoother control signal leading to minimal peak overshoot and an average of a 53.244% faster settling. Based on the results, the algorithm enhanced the efficiency and reliability of industrial wireless networks and real-time pressure process control systems, which are critical for industrial automation and control applications.


Non-invasive lipid measurement in living insects using NMR microscopy.
Nuclear magnetic resonance (NMR) microscopy allows us to image and quantify the distribution of NMR-active nuclei in living specimens. Using high-field NMR microscopy at a magnetic field strength of 14.1 T and strong gradients up to 3 T m(-1), we show that separation of fat and water nuclear resonances in living insects can be achieved. In contrast to destructive conventional photometric and mass measurements, we demonstrate exemplarily in the European spruce bark beetle that NMR can be efficiently used to quantify absolute fat and water content in living insects. Additionally, anatomic images with a spatial in-plane resolution up to 10 μm and with high soft tissue contrast were acquired. We demonstrate that fat distribution and fat consumption of living insects can be obtained by magnetic resonance imaging (MRI). This enables future research to address questions where single individuals have to be measured several times, which is not possible with conventional destructive methods.


Blood sugar profile in diabetics receiving plain insulin.
Blood sugar profile was studied by checking multiple plasma venous samples at 1/2 hr interval after porcine plain insulin. Mean blood sugar was the highest (198.8 +/- 24.6 mg%) at 1 1/2 hrs and the lowest (86.3 +/- 18.4) at 4 1/2 hrs after breakfast. 52% of the patients had hypoglycemias between 4 and 5 hrs. It is recommended that pre-lunch blood sugar be checked in those receiving plain insulin.


Estrogen biosynthesis and action in ovarian cancer.
Ovarian cancer is still the deadliest of all gynecologic malignancies in women worldwide. This is attributed to two main features of these tumors, namely, (i) a diagnosis at an advanced tumor stage, and, (ii) the rapid onset of resistance to standard chemotherapy after an initial successful therapy with platin- and taxol-derivatives. Therefore, novel targets for an early diagnosis and better treatment options for these tumors are urgently needed. Epidemiological data show that induction and biology of ovarian cancer is related to life-time estrogen exposure. Also experimental data reveal that ovarian cancer cells share a number of estrogen regulated pathways with other hormone-dependent cancers, e.g., breast and endometrial cancer. However, ovarian cancer is a heterogeneous disease and the subtypes are quite different with respect to mutations, origins, behaviors, markers, and prognosis and respond differently to standard chemotherapy. Therefore, a characterization of ovarian cancer subtypes may lead to better treatment options for the various subtypes and in particular for the most frequently observed high-grade serous ovarian carcinoma. For this intention, further studies on estrogen-related pathways and estrogen formation in ovarian cancer cells are warranted. The review gives an overview on ovarian cancer subtypes and explains the role of estrogen in ovarian cancer. Furthermore, enzymes active to synthesize and metabolize estrogens are described and strategies to target these pathways are discussed.


Role of multiple, adjustable toes in distributed control shown by sideways wall-running in geckos.
Remarkable progress has been made characterizing one of nature's most integrated, hierarchical structures--the fibrillar adhesive system of geckos. Nonetheless, we lack an understanding of how multiple toes coordinate to facilitate geckos' acrobatic locomotion. Here, we tested the control function of gecko toes by running them on vertical substrates varying in orientation, friction and roughness. Sideways wall-running geckos realigned the toes of their top feet upward to resist gravity. Toe contact area was not compromised, but redistributed. Geckos aligned all toes upward to resist slipping when encountering low-friction patches during sideways wall-running. Negotiation of intermittent slippery strips showed an increased contribution of particular toes to compensate for toes that lost adhesion. Increasing substrate roughness using discrete rods perpendicular to sideways locomotion resulted in geckos bending and/or rotating toes to conform to and even grasp the rods, with potential forces more than five times body weight. Geckos increase their effectiveness of manoeuvrability in demanding environments by taking advantage of the distributed control afforded by multiple toes. Our findings provide insight on biological attachment and offer inspiration to advance gecko-inspired robotics and other biomimetic applications.


Single-layer transition metal dichalcogenide nanosheet-based nanosensors for rapid, sensitive, and multiplexed detection of DNA.
Single-layer transition metal dichalcogenide nanosheets, including MoS2, TiS2, and TaS2, are used as novel sensing platforms for sensitive and selective detection of DNA, based on their high fluorescence-quenching ability and different affinities toward single-stranded DNA and double-stranded DNA. Importantly, for the first time, a single-layer TaS2 nanosheet-based multiplexed DNA sensor is also developed.


Cortical morphology and early adverse birth events in men with first-episode psychosis.
Reduced cortical gray-matter volume is commonly observed in patients with psychosis. Cortical volume is a composite measure that includes surface area, thickness and gyrification. These three indices show distinct maturational patterns and may be differentially affected by early adverse events. The study goal was to determine the impact of two distinct obstetrical complications (OCs) on cortical morphology. A detailed birth history and MRI scans were obtained for 36 patients with first-episode psychosis and 16 healthy volunteers. Perinatal hypoxia and slow fetal growth were associated with cortical volume (Cohen's d = 0.76 and d = 0.89, respectively) in patients. However, the pattern of associations differed across the three components of cortical volume. Both hypoxia and fetal growth were associated with cortical surface area (d = 0.88 and d = 0.72, respectively), neither of these two OCs was related to cortical thickness, and hypoxia but not fetal growth was associated with gyrification (d = 0.85). No significant associations were found within the control sample. Cortical dysmorphology was associated with OCs. The use of a global measure of cortical morphology or a global measure of OCs obscured important relationships between these measures. Gyrification is complete before 2 years and its strong relationship with hypoxia suggests an early disruption to brain development. Cortical thickness matures later and, consistent with previous research, we found no association between thickness and OCs. Finally, cortical surface area is largely complete by puberty and the present results suggest that events during childhood do not fully compensate for the effects of early disruptive events.


Long-term memory contribution as applied to the motion of discrete dynamical systems.
We consider the evolution of logistic maps under long-term memory. The memory effects are characterized by one parameter, alpha. If it equals to zero, any memory is absent. This leads to the ordinary discrete dynamical systems. For alpha=1 the memory becomes full, and each subsequent state of the corresponding discrete system accumulates all past states with the same weight just as the ordinary integral of first order does in the continuous space. The case with 0<alpha<1 has the long-term memory effects. The characteristic features are also observed for the fractional integral depending on time, and the parameter alpha is equivalent to the order index of the fractional integral. We study the evolution of the bifurcation diagram among alpha=0 and alpha=0.15. The main result of this work is that the long-term memory effects make difficulties for developing the chaos motion in such logistic maps. The parameter alpha resembles a governing parameter for the bifurcation diagram. For alpha>0.15 the memory effects win over chaos.


Structures of oligonucleotides containing 5-(methoxymethyl)-2'-deoxyuridine determined by NMR spectroscopy.
Base pairing of 5-(methoxymethyl)-2'-deoxyuridine (MMdU) opposite either adenine or guanine in a seven base pair oligonucleotide duplex has been studied by NMR spectroscopy. When paired with A, we observe that the MMdU.A base pair adopts Watson-Crick geometry. The methoxymethyl substituent is not held in a fixed conformation and may rotate around the C5-CH2 and CH2-O bonds. Examination of the potential energy as a function of rotation around these bonds indicates the presence of four low energy conformations. No hydrogen bonding is indicated for the methoxymethyl substituent, and the four potential minima result from reduced steric clash. For the MMdU.G base pair, the two bases adopt a wobble geometry which does not change with increasing solvent pH. Similarly, we find four low energy conformations for the methoxymethyl substituent in the major groove of the DNA helix.


A practical entry to β-aryl-β-alkyl amino alcohols: application to the synthesis of a potent BACE1 inhibitor.
The 1,2-addition of alkyl Grignard reagents to readily available N-tert-butanesulfinyl ketimines, bearing an α-silyloxy substituent, proceeds in high yields and excellent diastereocontrol. The utility of the present method was demonstrated by the synthesis, in enantiomerically pure form, of one recently disclosed β-secretase (BACE1) inhibitor.


The discovery of Kv1.5 blockers as a case study for the application of virtual screening approaches.
Different virtual screening techniques are available as alternatives to high throughput screening. These different techniques have been rarely used together on the same target. We had the opportunity to do so in order to discover novel blockers of the voltage-dependent potassium channel Kv1.5, a potential target for the treatment of atrial fibrillation. Our corporate database was searched, using a protein-based pharmacophore, derived from a homology model, as query. As a result, 244 molecules were screened in vitro, 19 of them (7.8%) were found to be active. Five of them, belonging to five different chemical classes, exhibited IC50 values under 10 microM. The performance of this structure-based virtual screening protocol has been compared with those of similarity and ligand-based pharmacophore searches. The analysis of the results supports the conventional wisdom of using as many virtual screening techniques as possible in order to maximize the chance of finding as many chemotypes as possible.


Comparison of legislation, regulations and national health strategies for palliative care in seven European countries (Results from the Europall Research Group): a descriptive study.
According to EU policy, anyone in need of palliative care should be able to have access to it. It is therefore important to investigate which palliative care topics are subject to legislation and regulations in Europe and how these are implemented in (national) health care plans. This paper aims to deliver a structured overview of the legislation, existing regulations and the different health care policies regarding palliative care in seven European countries. In 2008 an inventory of the organisation of palliative care was developed by the researchers of the Europall project. Included were two open questions about legislation, regulations, and health policy in palliative care. This questionnaire was completed using palliative care experts selected from Belgium, England, France, Germany, the Netherlands, Poland and Spain. Additionally, (grey) literature on palliative care health policy and regulations from the participating countries was collected to complete the inventory. Comparative analysis of country specific information was performed afterwards. In all countries palliative care regulations and policies existed (either in laws, royal decrees, or national policies). An explicit right to palliative care was mentioned in the Belgium, French and German law. In addition, access to palliative care was mentioned by all countries, varying from explicit regulations to policy intentions in national plans. Also, all countries had a national policy on palliative care, although sometimes mainly related to national cancer plans. Differences existed in policy regarding palliative care leave, advance directives, national funding, palliative care training, research, opioids and the role of volunteers. Although all included European countries have policies on palliative care, countries largely differ in the presence of legislation and regulations on palliative care as well as the included topics. European healthcare policy recommendations should support palliative care access across Europe.


Measuring the Delivery of Complex Interventions through Electronic Medical Records: Challenges and Lessons Learned.
Health services and implementation researchers often seek to capture the implementation process of complex interventions yet explicit guidance on how to capture this process is limited. Medical record review is a commonly used methodology, especially when used as a proxy for provider behavior, with recognized benefits and limitations. The purpose of this study was to test the feasibility of chart review to measure implementation and offer recommendations for future researchers using this method to capture the implementation process. Grounded in qualitative research methods, we measured the implementation of a transitional care intervention for older adults with dementia being discharged from the hospital. We adapted the operationalization of the intervention's components to suit chart review methods, sought input from hospital providers before and after data collection, and assessed the agreement between the results of our chart review and provider-report. We believe chart review can be used effectively as a method for capturing the implementation process and provide future researchers with a list of recommendations based on our experience including understanding the nuance between data extraction versus data abstraction, allowing for large amounts of data not pre-specified in the data collection instrument to be collected, and purposefully and iteratively engaging the providers who are entering data into the chart. Measuring the implementation of complex interventions is a cornerstone in health services research and with the relative convenience and low costs of using chart data, we believe with more use and refinement this methodology could emerge as a valuable and widely used method in the field.


Modern Innovative Solutions in Improving Outcomes in Chronic Obstructive Pulmonary Disease (MISSION COPD): A Comparison of Clinical Outcomes Before and After the MISSION Clinic.
Chronic obstructive pulmonary disorder (COPD) affects over 1 million people in the United Kingdom, and 1 person dies from COPD every 20 minutes. The cost to people with COPD and the National Health Service is huge - more than 24 million working days lost a year and the annual expenditure on COPD is £810 million and £930 million a year. We aim to identify patients with COPD who are at risk of exacerbations and hospital admissions as well as those who have not been formally diagnosed, yet remain at risk. This mixed-methods study will use both data and interviews from patients and health care professionals. The project Modern Innovative SolutionS in Improving Outcomes iN COPD (MISSION COPD) will hold multidisciplinary carousel style clinics to rapidly assess the patients' COPD and related comorbidities, and enhance patient knowledge and skills for self-management. This study is ongoing. This research will capture quantitative and qualitative outcomes to accompany a program of quality improvement through delivery of novel care models.


Algorithm for the diagnosis of HER-2/neu status in breast-infiltrating carcinomas.
Determination of HER-2/neu overexpression/amplification is becoming increasingly important. The aim of this study is to elaborate an algorithm for the diagnosis of Her-2/neu status in breast-infiltrating carcinomas. Three hundred five breast-infiltrating carcinomas were selected to determine HER-2/neu overexpression by immunohistochemistry with two different methods: the monoclonal antibody CB11 and the HercepTest. Fluorescence in situ hybridization (FISH) was performed in a subgroup of those cases. Time-consuming and reagent costs were calculated for each of the procedures. HER-2/neu overexpression was found in 16% and 33% of the tumors with the monoclonal antibody (mAb) CB11 and with the HercepTest, respectively. There were 50 cases with immunohistochemical discordant results; most of them were HercepTest score 2+/mAb CB11 negative (37/50). Of those cases, only 27% presented gene amplification. The algorithm consisted of testing all the specimens with the mAb CB11 for selection of positive cases, negative cases are confirmed with the HercepTest, and FISH is performed only in those cases with immunohistochemical discordant results. The algorithm rate of HER-2/neu positivity in our series was 22%. Time and costs are reduced by 60% and 41%, respectively, compared to FISH. The use of the algorithm is feasible, accurate, and cost-effective in relation to FISH.


Beyond injecting drug use: investigation of a Victorian cluster of hepatitis C among HIV-infected men who have sex with men.
To examine increased notifications of hepatitis C virus (HCV) in men who have sex with men (MSM) infected with HIV in Victoria, and evaluate HCV transmission risk factors other than injecting drug use. Case series through retrospective review of all HCV cases in Victoria from 1 April 2010 to 30 June 2011, with clinical and laboratory data examined in likely MSM to identify a co-infected cohort. Patients with newly acquired HCV with HIV co-infection were invited to complete a questionnaire exploring novel risk factors for HCV transmission (non-injecting drug use, sexual practices with increased likelihood of trauma, and presence of genital ulcers). Sequencing was performed to determine the local molecular epidemiology of HCV co-infection. Demographics of newly co-infected MSM, traditional versus novel risk factors for HCV acquisition, prior knowledge of potential for sexual transmission of HCV, and association between viral sequences. Thirty-one patients with HIV were identified from 3365 notifications of hepatitis C. The median age was 42 years, and median time from HIV to HCV diagnosis was 22 months. Most patients were asymptomatic, with abnormal liver function tests prompting HCV testing. Interviews with 14 patients identified a high prevalence of novel risk factors and limited knowledge of HCV risk. Two clusters of matching viral sequences were identified. Novel HCV transmission routes have emerged in Victoria. These data reinforce the need for targeted testing and prevention strategies among HIV-infected MSM.


Pulmonary arterial dilation by inhaled NO: arterial diameter, NO concentration relationship.
The objective of this study was to determine the nitric oxide (NO) concentration and vessel diameter dependence of the pulmonary arterial dilation induced by inhaled NO. Isolated dog lung lobes were situated between a microfocal X-ray source and X-ray detector and perfused with either blood or plasma. Boluses of radiopaque contrast medium were injected into the lobar artery under control conditions, when the pulmonary arteries were constricted by infusion of serotonin and when the serotonin infusion was accompanied by inhalation of from 30 to 960 parts/million NO. Arterial diameter measurements were obtained from X-ray images of vessels having control diameters in the 300- to 3,400-microm range. Serotonin constricted the vessels throughout the size range studied, with an average decrease in diameter of approximately 20%. The fractional reversal of the serotonin-induced constriction by inhaled NO was directly proportional to inhaled NO concentration, inversely proportional to vessel size, and greater with plasma than with blood perfusion in vessels as large as 3 mm in diameter. The latter indicates that intravascular hemoglobin affected the bronchoalveolar-to-arterial luminal NO concentration gradient in fairly large pulmonary arteries. The data provide information regarding pulmonary arterial smooth muscle accessibility to intrapulmonary gas that should be useful as part of the database for modeling the communication between intrapulmonary gas and pulmonary arterial smooth muscle cells in future studies.


Ambra1 spatially regulates Src activity and Src/FAK-mediated cancer cell invasion via trafficking networks.
Here, using mouse squamous cell carcinoma cells, we report a completely new function for the autophagy protein Ambra1 as the first described 'spatial rheostat' controlling the Src/FAK pathway. Ambra1 regulates the targeting of active phospho-Src away from focal adhesions into autophagic structures that cancer cells use to survive adhesion stress. Ambra1 binds to both FAK and Src in cancer cells. When FAK is present, Ambra1 is recruited to focal adhesions, promoting FAK-regulated cancer cell direction-sensing and invasion. However, when Ambra1 cannot bind to FAK, abnormally high levels of phospho-Src and phospho-FAK accumulate at focal adhesions, positively regulating adhesion and invasive migration. Spatial control of active Src requires the trafficking proteins Dynactin one and IFITM3, which we identified as Ambra1 binding partners by interaction proteomics. We conclude that Ambra1 is a core component of an intracellular trafficking network linked to tight spatial control of active Src and FAK levels, and so crucially regulates their cancer-associated biological outputs.


Preparation and characterization of CdSe/ZnS quantum dots encapsulated in poly(ethylene glycol)-b-poly(D,L-lactide) micelle nanoparticles.
The final goal of this study is to develop multi-functional organic/inorganic hybrid nanoparticles, which can be utilized as biomedical imaging probes and drug delivery carriers. As an initial step toward this goal, we encapsulated CdSe/ZnS quantum dots (QDs) into poly(ethylene glycol)-b-poly(D,L-lactide) (PEG-PLA) micelles using a solid dispersion method. The size and fluorescent intensity of QDs encapsulated in PEG-PLA micelles depended on the amount of incorporated QDs. For example, when the amount of QDs increased from 0.1 to 1.0 microg, the mean diameter increased from 24.2 +/- 6.0 to 211.2 +/- 6.5 nm and the fluorescent intensity changed from 10.2 +/- 1.0 to 469.9 +/- 15.6 (RFU). Stability studies showed that the size and zeta-potential (ZP) of QDs encapsulated in PEG-PLA micelles (QEMs) did not change significantly in response to a change in pH conditions or under a 10% serum condition. We also tested the cytotoxicity and cellular uptake of the QEMs. The viability of HeLa cells treated with micelles for 24 h was 80-100% in various concentration ranges of micelles. Confocal laser scanning microscopic images showed that the QEMs penetrated into the cells, particularly into the cytosolic compartments. Our results suggest that the QEMs may be a promising multi-functional nanocarrier for biomedical imaging and drug delivery.


Abnormal Acoustic Features Following Pharyngeal Flap Surgery in Patients Aged Six Years and Older.
In our study, older velopharyngeal insufficiency (posterior velopharyngeal insufficiency) patients were defined as those older than 6 years of age. This study aimed to evaluate the abnormal acoustic features of older velopharyngeal insufficiency patients before and after posterior pharyngeal flap surgery. A retrospective medical record review was conducted for patients aged 6 years and older, who underwent posterior pharyngeal flap surgery between November 2011 and March 2015. The audio records of patients were evaluated before and after surgery. Spectral analysis was conducted by the Computer Speech Lab (CSL)-4150B acoustic system with the following input data: The vowel /i/, unaspirated plosive /b/, aspirated plosives /p/, aspirated fricatives /s/ and /x/, unaspirated affricates /j/ and /z/, and aspirated affricates /c/ and /q/. The patients were followed up for 3 months. Speech outcome was evaluated by comparing the postoperatively phonetic data with preoperative data. Subjective and objective analyses showed significant differences in the sonogram, formant, and speech articulation before and after the posterior pharyngeal flap surgery. However, the sampled patients could not be considered to have a high speech articulation (<85%) as the normal value was above or equal to 96%. Our results showed that pharyngeal flap surgery could correct the speech function of older patients with posterior velopharyngeal insufficiency to some extent. Owing to the original errors in pronunciation patterns, pathological speech articulation still existed, and speech treatment is required in the future.


Effectiveness of grasping and duration of clamping using laparoscopic graspers.
Manipulating tissue with laparoscopic forceps is more difficult than using the hands. This study investigates the effectiveness of grasping and the duration of tissue-clamping using laparoscopic forceps. Video recordings of 10 laparoscopic colectomies and 15 cholecystectomies were analyzed using time-action analysis. The results indicated that 62% of the grasping actions were successful: the tissue was clamped sufficiently to perform an action. Of all the clamping actions on the colon, 10% were repeated actions. On the gallbladder 7% were repeated actions. The bowel slipped out of the grasper in 7% of the clamping actions, whereas the gallbladder slipped in 17%. In 89%, the colon was clamped less than 1 min. The maximum clamping time for colon clamps was 7 min for the colon, and 55 min for the gallbladder. The low percentage of successful grasping actions indicates that the design of laparoscopic graspers is not optimal.


Microbiological method for the determination of L-tryptophan.
Sebek, Oldrich K. (The Upjohn Company, Kalamazoo, Mich.). Microbiological method for the determination of l-tryptophan. J. Bacteriol. 90:1026-1031. 1965.-The ability of Chrombacterium violaceum to utilize l-tryptophan for the synthesis of a purple pigment, violacein, served as a basis for the development of a quantitative estimation of this amino acid. The method consists of suspending washed colorless cells of the organism in an agar layer, placing a paper disc impregnated with a tryptophan solution on top of the layer, and allowing the system to incubate. As tryptophan diffuses into the agar, it is converted into violacein, and appears as a zone of striking purple color. Since the diameter of the zone is a function of the amount of tryptophan applied, the amino acid can be quantitatively estimated within the range of 10 to 320 mug per sample with 5.6% standard deviation. The method is fairly specific for free tryptophan, since only indole, indole-3-pyruvic acid, and, to a small degree, anthranilic acid interfere. Other amino acids, tissue homogenates, tryptophan in peptide linkage, or compounds related to this amino acid do not affect its determination. The bacterium does not utilize tryptophan for the synthesis of cellular material unless its growth has been initiated by another substrate.


Endoscopic vacuum assisted closure (E-VAC) of upper gastrointestinal leakages.
Endoscopic vacuum-assisted closure (E-VAC) of leaks of the upper gastrointestinal tract is an increasingly applied endoscopic technique. Data on indication, clinical success, complications and prognostic factors are still sparse. Patients treated with E-VAC between 2012 and 2019 at a tertiary referral center have been retrospectively analyzed. Overall, 116 patients treated with E-VAC were identified. Indication for E-VAC placement was postoperative leakage in 94/116 (81%), iatrogenic perforations 7/116 (6%) and others 15/116 (13%). In 92/116 (79%) of the patients E-VAC therapy showed successful wound closure. The first E-VAC after detection of insufficiency was significantly more often placed intracavitary in patients with E-VAC failure (p = .031). There was a trend for longer intensive care unit treatment for patients with E-VAC failure (p = .069). Complications occurred significantly more often in patients with E-VAC failure (p = .009). Platelet count was significantly higher in patients with E-VAC success at day of insufficiency detection (257/Thsd/µL (interquartile range [IQR], 185-362) vs. 195 (IQR, 117-309); p = .039). Platelet count (375 Thsd/µL (IQR, 256-484) vs. 190 (IQR, 129-292)), hemoglobin (9.5 g/dL (IQR, 8.8-10.1) vs. 8.7 g/dL (IQR, 8.15-9.35)) and C-reactive protein level (79 mg/L (IQR, 39.7-121.9) vs. 152 mg/L (IQR, 73.7-231)) at day 14 differed significantly. The 30 days mortality rate was 33.3% (8/24) in E-VAC failure compared with 2.2% in patients with E-VAC success (p = .001). E-VAC is an emerging highly effective interventional endoscopic technique for gastrointestinal wound closure even in highly selected patients.


Tumor necrosis factor as a potent inhibitor of adrenocorticotropin-induced cortisol production and steroidogenic P450 enzyme gene expression in cultured human fetal adrenal cells.
We have previously demonstrated that tumor necrosis factor alpha (TNF-alpha), a multifunctional cytokine mainly produced by activated monocytes, inhibits the ACTH-induced production of cortisol in cultures of human fetal adrenals. To clarify the molecular basis of this suppression, we investigated the effect of recombinant TNF-alpha (rTNF-alpha) on the messenger RNAs (mRNAs) for adrenal cytochrome P450 oxidases, P450scc (cholesterol side-chain cleavage enzyme/20.22-desmolase), P450c11 (11 beta-hydroxylase/18-hydroxylase/18-methyl oxidase), P450c17 (17 alpha-hydroxylase/17,20-lyase), and P450c21 (21-hydroxylase). Northern and dot blot experiments showed that 36 h incubation of primary cultures of human fetal adrenals with ACTH (200 ng/ml) increased the levels of all P450 enzymes severalfold. Preincubation of the cultures with rTNF-alpha at concentrations ranging from 0.1-100 ng/ml produced a dose-dependent inhibition of the ACTH-induced accumulation of all P450 mRNAs. The decrease in the expression of genes for steroidogenic enzymes was accompanied by a similar decrease in the production of cortisol but not in that of dehydroepiandrosterone sulphate nor androstenedione. Neither the basal expression of P450 enzymes nor the basal secretion of the steroids was significantly altered by 10 ng/ml of rTNF-alpha. rTNF-alpha did not affect the level of actin mRNA, the cell viability, nor the cell number. All the effects brought about by rTNF-alpha could be neutralized by addition of monoclonal anti-TNF-alpha antibody. These results show that TNF-alpha suppresses the synthesis of cortisol and shifts the steroid secretory pattern towards androgen production at least partly by suppressing the accumulation of mRNAs for adrenal cytochrome P450 oxidases.


Changes to postgraduate medical education in the 21st century.
Medicine is a constantly evolving profession, especially with the advent of rapid advances in the scientific base that underpins this vocation. In order to ensure that training in medicine is contemporary with the continuous evolution of the profession, there has been a multitude of changes to postgraduate medical education, particularly in the UK. This article aims to provide an overview of relevant key changes to postgraduate medical education in the UK during the 21st century, including changes to the structure, governance and commissioning of medical education, effects of European Working Time Directive on training, recent recommendations in the Future Hospital Commission report and Shape of training report, and recent requirements for accreditation of medical education trainers. Many of these recommendations will require complex discussions often at organisational levels, hopefully with some realistic and pragmatic solutions for implementation.


Heparin-induced thrombocytopenia and arterial thrombosis: alternative therapies.
There are three distinct syndromes of heparin-induced thrombocytopenia: an acute reversible from seen immediately after intravenous bolus injection, a delayed-onset antibody-mediated form seen several days after the initiation of therapy, and an intermediate type characterized by mild thrombocytopenia developing just a few days after starting therapy. Delayed-onset heparin-induced thrombocytopenia, clinically the most important form, results from the formation of heparin-dependent antibodies that are directed against the platelet membrane. In the presence of heparin, these antibodies may induce in vitro or in vivo platelet aggregation. Consequently, the course may be complicated by arterial thromboses. Treatment of this syndrome includes the prompt cessation of heparin. Since continued or future anticoagulation is usually necessary, alternative means of anticoagulation have been explored. Oral anticoagulation is often started but requires several days to take effect. Other options include low-molecular-weight heparins, antiplatelet agents, prostacyclin analogues, and low-molecular-weight dextran. In vitro laboratory tests may be helpful in guiding alternative therapy in some, but not all cases. Unfortunately, none of these agents have proved to be uniformly effective and additional agents and clinical investigation are needed before a definitive option becomes available.


Safe Completion of Laparoscopic Anterior Resection in a Patient With a Solitary Pelvic Kidney: A Case Report.
Pelvic kidney, an ectopic renal mass caused by developmental failure, is a rare condition. Here, we report a case of laparoscopic anterior resection in a patient with a solitary pelvic kidney. A 76-year-old man was diagnosed as having rectosigmoid colon cancer. Preoperative computed tomography revealed a left ectopic kidney in his pelvis. Computed tomographic angiography and retrograde pyelography were performed preoperatively to identify the renal vessels and the ureter. To keep the surgical plane intact for complete mesocolic excision, a complete laparoscopic anterior resection was safely performed without open conversion, and there was no injury to the pelvic kidney. The patient was discharged on postoperative day eight without any complication. No deterioration of renal function was observed after surgery. This report describes a case of laparoscopic anterior resection that was safely performed without conversion to open surgery in a patient with a pelvic ectopic kidney.


PNPLA3 rs738409C/G polymorphism in cirrhosis: relationship with the aetiology of liver disease and hepatocellular carcinoma occurrence.
The PNPLA3 rs738409 C>G polymorphism has been found to be strongly associated with non-alcoholic fatty liver disease and with alcoholic liver disease. Whether the PNPLA3 rs738409 polymorphism could be a risk factor for the development of hepatocellular carcinoma (HCC) in cirrhosis patients is unknown. This study included 483 (344 males) consecutive Italian patients of Caucasian ethnicity affected by cirrhosis, of whom 279 had undergone transplantation for end-stage liver disease while 204 had been referred to our liver and transplant unit for the diagnosis of cirrhosis. The aetiologies were hepatitis C virus=209, hepatitis B virus=76, alcohol=166, metabolic=32. Ile148Met rs738409 transversion was genotyped using an restriction fragment length polymorphism-based assay. The genotype frequencies of the rs738409 polymorphism were distributed differently in patients with cirrhosis C/C=168, C/G=220, G/G=95 vs controls C/C=218, C/G=175, G/G=35 (P<0.0001). Among cirrhotics, the G allele was over-represented in alcoholic/metabolic (0.505) vs viral (0.368, P<0.001) liver disease. Patients with cirrhosis complicated by HCC were more likely to be G/G homozygotes (38/141) than the remaining patients (57/342, P<0.02). At multivariate analysis, the PNPLA3 rs738409 polymorphism was confirmed to be an independent predictor of HCC occurrence (odds ratio 1.76, 95% confidence interval 1.06-2.92, P<0.05). HCC rates increased from 13/116 (11.2%; female C/(*) carriers), to 97/295 (32.9%; male C/(*) carriers and female G/G homozygotes), to 31/72 (43.1%; male G/G homozygotes) (P<0.0001). The PNPLA3 rs738409 C>G polymorphism is associated with cirrhosis. In synergy with gender, this polymorphism is a strong predictor of HCC occurrence among patients with cirrhosis.


How can we exploit the brain's ability to repair itself?
The notion of our brain having a limited repertoire of cells to be used throughout our life has been refuted multiples times, showing systems by which new neurons are generated on demand, accounting for crucial aspects of brain function in a process known as neurogenesis. The potential of neurogenesis to replace lost neurons is enormous and has direct implications on how we understand the brain's response to pathology. But replacing functional neurons is not trivial: an orchestrated sequence of steps is needed to ensure the timed generation of new cells, their migration to the sites of injury and their correct differentiation and integration into the pre-existing circuitry. However, there is evidence of this sequence being effective in replacing certain neuronal populations in brain disease. The perspective of understanding, manipulating and directing the brain's self-repairing responses opens a vast avenue to explore novel therapeutic approaches to replace neuronal loss in neurodegenerative diseases.


Hybrid SPECT/CT evaluation of Marine-Lenhart syndrome.
Marine-Lenhart syndrome has been described as a variant of Graves disease with the following criteria: (1) the thyroid scan shows an enlarged gland and 1 or 2 poorly functioning nodules; (2) the nodule is TSH dependent and the paranodular tissue is TSH independent; (3) after endogenous or exogenous TSH stimulation, the return of function in the nodule can be demonstrated; and (4) the nodule is histologically benign. We report a 57-year-old woman with Marine-Lenhart syndrome evaluated with technetium scanning and hybrid SPECT/CT.


Occupational exposures to potentially hazardous agents in the petroleum industry.
This chapter has been created to acquaint the reader with occupational exposures that are more common in, and somewhat unique to, the petroleum industry. Both highly toxic materials capable of causing acute illness or even death following short-term exposure, and chemical and physical agents that pose risk of chronic and irreversible damage to health during prolonged exposure are addressed.


Effect of interventional embolotherapy on FHIT and p16 expression in hepatocellular carcinoma patients.
Effects of interventional embolotherapy on the expression of fragile histidine triad (FHIT) and p16 in hepatocellular carcinoma (HCC) patients were investigated. Patients with primary HCC who were definitely diagnosed and treated in the Department of Gastroenterology in Qingdao Central Hospital from March 2014 to March 2016 were selected, and they underwent interventional embolotherapy. HCC and cancer-adjacent tissues of the patients were harvested for immunohistochemical staining. The correlation between the expression levels of FHIT and p16 was analyzed at the gene and protein level. Clinical data were collected, and whether they were correlated with the expression of FHIT and p16 was investigated. The expression levels of FHIT and p16 in primary HCC tissues were remarkably lower than that in cancer-adjacent tissues (P<0.05). In HCC tissues, FHIT expression was obviously positively correlated with p16 expression (Spearman's correlation coefficient, r=0.308; P=0.025). FHIT was related to HCC tumor-node-metastasis (TNM) staging, the differentiation degree in Edmondson-Steiner grading, lymph node metastasis and portal vein thrombosis (P<0.05 in all comparisons), whereas, p16 was associated with tumor size and the differentiation degree in Edmondson-Steiner grading (P<0.05 in all comparisons). The expression of FHIT and p16 genes and proteins in HCC tissues were obviously lower than those in cancer-adjacent tissues (P<0.05 in all comparisons). FHIT and p16 genes, as tumor suppressor genes, inhibit the proliferation of HCC, and there is a positive correlation between them. The proteins of the FHIT and p16 can be used as new indicators for clinical detection, thus providing a new method for clinical diagnosis.


MiR-18a-5p aggravates homocysteine-induced myocardial injury via autophagy.
Hyperhomocysteinaemia (Hcy) is an independent risk factor for cardiovascular and cerebrovascular diseases. MicroRNA (miR)-18a-5p is closely related to cardiovascular diseases. This study aims to investigate the effects of miR-18a-5p on homocysteine (Hcy)-induced myocardial cells injury. H9c2 cells were transfected with miR-18a-5p mimic/miR-18a-5p mimic negative control (NC) or combined with Hcy for intervention, and untreated cells were set as a control group. The transfection efficiency was verified by real-time RT-PCR, and cell counting kit-8 (CCK-8) assay was used to determine cell viability. Flow cytometry was used to detect apoptosis and reactive oxygen species (ROS) levels. Western blotting was performed to measure the protein levels of microtubule-associated protein 1 light chain 3 (LC3)-I, LC3-II, Beclin1, p62, Bax, Bcl-2, and Notch2. Dual luciferase reporter assay was used to detect the interaction of miR-18a-5p with Notch2. Compared with the control, treatment with Hcy or transfection with miR-18a-5p mimic alone, or combined treatment with Hcy and miR-18a-5p mimic/miR-18a-5p mimic NC significantly reduced the H9c2 cell viability, promoted apoptosis and ROS production, up-regulated the expressions of Bax and Beclin, down-regulated the expressions of Bcl-2, p62, and Notch2, and increased the ratio of LC3-II/LC3-I (all P<0.05). Compared with the combined intervention of miR-18a-5p mimic NC and Hcy group, the above indexes were more significantly changed in the combined intervention of miR-18a-5p mimic and Hcy group, and the difference between the 2 groups was statistically significant (all P<0.05). There is a targeted binding between Notch2 and miR-18a-5p. MiR-18a-5p could induce autophagy and apoptosis via increasing ROS production in cardiomyocytes, and aggravate Hcy-induced myocardial injury. Notch2 is a target of miR-18a-5p.


Contingent negative variation and schizophrenia: a long-term follow-up study.
The CNVs of three disorganized schizophrenics and three paranoid schizophrenics were studied longitudinally over a 5-year period. The CNV of the disorganized-type schizophrenics reached its maximum decrease within 3 years of disease onset. A more gradual and less accentuated decrease was noted in the paranoid group within a span of 5 years.


High shear stress induces atherosclerotic vulnerable plaque formation through angiogenesis.
Rupture of atherosclerotic plaques causing thrombosis is the main cause of acute coronary syndrome and ischemic strokes. Inhibition of thrombosis is one of the important tasks developing biomedical materials such as intravascular stents and vascular grafts. Shear stress (SS) influences the formation and development of atherosclerosis. The current review focuses on the vulnerable plaques observed in the high shear stress (HSS) regions, which localizes at the proximal region of the plaque intruding into the lumen. The vascular outward remodelling occurs in the HSS region for vascular compensation and that angiogenesis is a critical factor for HSS which induces atherosclerotic vulnerable plaque formation. These results greatly challenge the established belief that low shear stress is important for expansive remodelling, which provides a new perspective for preventing the transition of stable plaques to high-risk atherosclerotic lesions.


Generation of site-specific mutant mice using the CRISPR/Cas9 system.
The CRISPR/Cas9 system is a recently developed important technology for genome editing in cellular and animal models. Here we established a CRISPR/Cas9-based system of generating site-specific mutant mice using DNA double-strand breaks (DSBs) induced homologous recombination (HR)-dependent or independent repair mechanism. Through co-microinjection of Cas9 mRNA and single-guide RNA (sgRNA) targeting genomic DNA sequence corresponding to enzyme activity of lysine (K)-specific demethylase 2b (Kdm2b), both a frame-shifted Kdm2b null mutant and a Kdm2b enzyme activity disrupted mouse strain were obtained simultaneously. Moreover, sgRNA targeting flavin containing monooxygenases3 (Fmo3) gene and the corresponding single strand oligonucleotides (ssODN) donor template with point mutation were co-injected into the male pronucleus of one-cell mouse embryos stimulated HR-mediated repair mechanism. Genomic sequence analysis of F0 mice showed that frame-shifted Fmo3 knockout mouse and site-specific Fmo3 knock-in mouse with single base substitution were successfully generated, and these mutations could be stably transmitted to the next generation. Therefore, we successfully generated mouse strains containing site-specific mutations through HR-dependent and -independent DSB repair using the CRISPR/Cas9 system.


Breast Cancer Awareness among Middle Class Urban Women--a Community-Based Study from Mumbai, India.
Targeting breast cancer awareness along with comprehensive cancer care is appropriate in low and middle income countries like India, where there are no organized and affordable screening services. It is essential to identify the existing awareness about breast cancer in the community prior to launching an organized effort. This study assessed the existing awareness about breast cancer amongst women and their health seeking practices in an urban community in Mumbai, India. A postal survey was undertaken with low or no cost options for returning the completed questionnaires. The majority of the women were aware about cancer but awareness about symptoms and signs was poor. Women were willing to accept more information about cancer and those with higher awareness scores were more likely to seek medical help. They were also more likely to have undergone breast examination in the past and less likely to use alternative medicines. High income was associated with better awareness but this did not translate into better health seeking behaviour. Organized programmes giving detailed information about breast cancer and its symptoms are needed and women from all income categories need to be encouraged for positive change towards health seeking. Further detailed studies regarding barriers to health seeking in India are necessary.


Descriptive Study of Nasopharyngeal Carcinoma and Treatment Outcomes: An Eight Years Experience in Hadhramout National Cancer Centre, Yemen.
To describe the histological patterns, and to evaluate the long-term outcomes of non surgical treatment of nasopharyngeal carcinoma (NPC) in patients registered at Hadhramout National Cancer Centre (HNCC) in Mukalla City, in Hadhramout Province, Yemen. Non-randomized descriptive cancer registrybased study of patients with different WHO types of nasopharyngeal cancer and different non surgical treatment modality. Data was obtained from the medical records of patients seen and followed-up at HNCC. Data was collected using Can-Reg 10 computerized program and statistical analysis done using SPSS version-17 software program. The study included 109 patients with NPC, males were 71(65.14%) and females were 38(34.86%), with a male to female ratio of 2:1. The mean age was 43 (range10-89 years). The majority of the patients were from Hadhramout 85(77.98%), while 24(22.2%) patients were from outside Hadhramout. The most common type of NPC seen according WHO classification was type III 82(75.24%) patients, followed by type II 15(13.76%) patients, and lastly type I 12(11%). The type III tumors of nasopharynx was the predominant type seen in younger patients. Cervical nodal metastasis was found in 86(78.9%) patients, N0 neck was observed in 23(21.1%) patients. The highest annual incidence was observed in 2011 and 2012; fourteen females and 31 males. Patients who underwent curative radiotherapy were 14(12.85%), chemotherapy were 33(30.28%), and concurrent chemoradiotherapy were 62 (56.88%) as initial cancer treatment. Deaths during follow-up period due to local recurrences of NPCs after radiotherapy, chemotherapy and chemoradiotherapy were 1(0.92%), 5(4.59%), 11(10%) respectively. The period of follow-up was 72 months. Two patients were lost from follow-up. Our results reveal that WHO-NPC type III is the most common type seen in patients, and the predominant type in young males who presented from Hadhramout regions. Treatment outcome was best in irradiated group followed by chemoradiotherapy and lastly chemotherapy.


Review paper: preclinical models of psoriasis.
Psoriasis is the most common autoimmune disease in man and is characterized by focal to coalescing raised cutaneous plaques with consistent scaling and variable erythema. The specific pathogenesis of psoriasis is not completely understood, but the underlying mechanisms involve a complex interplay between epidermal keratinocytes, T lymphocytes as well as other leukocytes (including dendritic cells and other antigen presenting cells [APCs]), and vascular endothelium. Mirroring the complexity of mechanisms that underlie psoriasis, there are a relatively large number of models of psoriasis. Each model is based on a slightly different pathogenic mechanism, and each has its similarities to psoriasis as well as its limitations. In general, psoriasis models can be very broadly divided on the basis of the pathogenic mechanisms that interplay to cause psoriasis, with the addition of several relatively poorly defined spontaneous murine mutant models. Other than the spontaneous mutant models, murine models of psoriasis can be divided into those that are genetically engineered (transgenic and knockout-with manipulation of either the epidermis, leukocytes, or the endothelium), and those that are induced (either by immune transfer or by xenotransplantation of skin from psoriatic patients). In addition to the murine models, in vitro human epidermal models have recently become more widely utilized. While no one single model of psoriasis is ideal, many have proven to be extremely valuable in investigating and better understanding the molecular mechanisms that underlie the complex interplay between epidermal keratinocytes, the innate and adaptive immune system, and the vascular endothelium in psoriasis.


Root tip morphology, anatomy, chemistry and potential hydraulic conductivity vary with soil depth in three temperate hardwood species.
Root traits in morphology, chemistry and anatomy are important to root physiological functions, but the differences between shallow and deep roots have rarely been studied in woody plants. Here, we selected three temperate hardwood species, Juglans mandshurica Maxim., Fraxinus mandschurica Rupr. and Phellodendron amurense Rupr., in plantations in northeastern China and measured morphological, anatomical and chemical traits of root tips (i.e., the first-order roots) at surface (0-10 cm) and subsurface (20-30 cm) soil layers. The objectives of this study were to identify how those traits changed with soil depth and to reveal potential functional differences. The results showed that root diameters in deep root tips were greater in J. mandshurica and F. mandschurica, but smaller in P. amurense. However, root stele diameter and the ratio of stele to root diameter in the subsurface layer were consistently greater in all three species, which may enhance their abilities to penetrate into soil. All deep roots exhibited lower tissue nitrogen concentration and respiration rate, which were possibly caused by lower nutrient availability in the subsurface soil layer. Significant differences between shallow and deep roots were observed in xylem structure, with deep roots having thicker stele, wider maximum conduit and greater number of conduits per stele. Compared with shallow roots, the theoretical hydraulic conductivities in deep roots were enhanced by 133% (J. mandshurica), 78% (F. mandschurica) and 217% (P. amurense), respectively, indicating higher efficiency of transportation. Our results suggest that trees' root tip anatomical structure and physiological activity vary substantially with soil environment.


Prevalence and severity of depression and anxiety in patients with systemic lupus erythematosus: An epidemiologic study in Iranian patients.
We aimed to evaluate the prevalence of depression and anxiety in patients with systemic lupus erythematosus (SLE) and explore their association with demographic and clinical features. In this cross-sectional study, 166 SLE patients in rheumatology center of Shariati hospital, Tehran University of Medical Sciences were enrolled. SLE disease activity index (SLEDAI) and Beck and Cattell inventories for evaluation of depression and anxiety were completed for each patient. The mean age of patients was 33.1 ± 11.1 years and 92.2% of them were female. Two patients (1.2%) had only depression (without anxiety), while 36 patients (21.6%) had only anxiety (without depression). Meanwhile, 105 patients (63.3%) had mixed depression-anxiety and 23 patients (13.8%) did not have either depression or anxiety. Mean daily dose of prednisolone and number of administered drugs did not show significant difference between different subgroups of patients. In assessment of clinical and therapeutic items, no significant correlation between severity of depression (P = 0.65) and anxiety (P = 0.36) with daily dose of prednisolone in SLE patients was observed. There was no significant association between SLEDAI and severity of depression or anxiety. Occupational status had significant correlation with severity of depression and anxiety (P = 0.005).On the contrary, no significant correlation between number of administered drugs and severity of depression and anxiety was present. This study indicated the high prevalence of depression and anxiety among SLE patients and reinforced the need of a comprehensive psychiatric work-up in SLE.


Photobleaching and photoactivation: following protein dynamics in living cells.
Cell biology is being transformed by the use of fluorescent proteins as fusion tags to track protein behaviour in living cells. Here, we discuss the techniques of photobleaching and photoactivation, which can reveal the location and movement of proteins. Widespread applications of these fluorescent-based methods are revealing new aspects of protein dynamics and the biological processes that they regulate.


Psychophysiological effects of an iTBS modulated virtual reality challenge including participants with spider phobia.
Preliminary evidence suggests beneficial effects of transcranial magnetic stimulation (TMS) on anxiety. The objective of this study was to investigate the effects of intermittent theta burst stimulation (iTBS) as a form of TMS on acute anxiety provoked by a virtual reality (VR) scenario. Participants with spider phobia (n=41) and healthy controls (n=42) were exposed to a spider scenario in VR after one session of iTBS over the prefrontal cortex or sham treatment. Participants with spider phobia reacted with more anxiety compared to healthy controls. Their heart rate and skin conductance increased compared to baseline. Contrary to expectations, iTBS did not influence these reactions, but modulated heart rate variability (HRV). Sympathetic influence on HRV showed an increase in the active iTBS group only. This study does not support the idea of beneficial effects of a single session of iTBS on anxiety, although other protocols or repeated sessions might be effective.


First-Line Unrelated Double-Unit Umbilical Cord Blood Transplantation for Acquired Severe Aplastic Anemia.
We analyzed the outcomes of 14 patients with severe aplastic anemia (SAA) who received first-line double-unit cord blood transplantation (dUCBT). Patients' median age was 24.5 years (range, 10-44 years). The median numbers of infused nucleated and CD34+ cells were 5.48 × 107/kg (range, 3.33-7.96 × 107/kg) and 2.30 × 105/kg (range, 0.86-3.97 × 105/kg), respectively. One patient died 5 days after transplantation. Three of the 13 patients acquired autologous myeloid recovery. Neutrophil engraftment was observed in 10 patients (76.29%), and the median time of neutrophil recovery was 19 days (range, 15-40 days). Platelet engraftment was observed in 7 cases (53.8%), and 3 patients experienced platelet graft failure. The median time of platelet recovery was 32 days (range, 22-80 days). The cumulative incidence of grade II-IV acute graft-vs-host disease (GVHD) was 38.5%. One patient demonstrated mild chronic GVHD. After a median follow-up of 61 months (range, 18-102 months), 6 patients were alive. The predicted 5-year overall survival and GVHD-free, failure-free survival rates were 42.9% ± 13.2% and 14.3% ± 9.4%, respectively. The first-line dUCBT for SAA is still primarily evaluated through multicenter prospective clinical trials by an optimal conditioning regimen, cell dose, and other graft and transplantation-related factors.


Mutation and virulence assessment of chromosomal genes of Rhodococcus equi 103.
Rhodococcus equi can cause severe or fatal pneumonia in foals as well as in immunocompromised animals and humans. Its ability to persist in macrophages is fundamental to how it causes disease, but the basis of this is poorly understood. To examine further the general application of a recently developed system of targeted gene mutation and to assess the importance of different genes in resistance to innate immune defenses, we disrupted the genes encoding high-temperature requirement A (htrA), nitrate reductase (narG), peptidase D (pepD), phosphoribosylaminoimidazole-succinocarboxamide synthase (purC), and superoxide dismutase (sodC) in strain 103 of R. equi using a double-crossover homologous recombination approach. Virulence testing by clearance after intravenous injection in mice showed that the htrA and narG mutants were fully attenuated, the purC and sodC mutants were unchanged, and the pepD mutant was slightly attenuated. Complementation with the pREM shuttle plasmid restored the virulence of the htrA and pepD mutants but not that of the narG mutant. A single-crossover mutation approach was simpler and faster than the double-crossover homologous recombination technique and was used to obtain mutations in 6 other genes potentially involved in virulence (clpB, fadD8, fbpB, glnA1, regX3, and sigF). These mutants were not attenuated in the mouse clearance assay. We were not able to obtain mutants for genesfurA, galE, and sigE using the single-crossover mutation approach. In summary, the targeted-mutation system had general applicability but was not always completely successful, perhaps because some genes are essential under the growth conditions used or because the success of mutation depends on the target genes.


Improving the quality and efficiency of follow-up after curative treatment for breast cancer--rationale and study design of the MaCare trial.
After curative treatment for breast cancer women frequently attend scheduled follow-up examinations. Usually the follow-up is most frequent in the first 2-3 years (2-4 times a year); thereafter the frequency is reduced to once a year in most countries. Its main aim is to detect local disease recurrence, or a second primary breast cancer, but also to provide information and psychosocial support. However, the cost-effectiveness of these frequent visits is under much debate, leading to a search for less intensive and more cost-effective follow-up strategies. In this paper the design of the MaCare trial is described. This trial compares the cost-effectiveness of four follow-up strategies for curatively treated breast cancer patients. We investigate the costs and effects of nurse-led telephone follow-up and a short educational group programme. The MaCare trial is a multi centre randomised clinical trial in which 320 breast cancer patients are randomised into four follow-up strategies, focussed on the first 18 months after treatment: 1) standard follow-up; 2) nurse-led telephone follow-up; 3) arm 1 with the educational group programme; 4) arm 2 with the educational group programme. Data is collected at baseline and 3, 6, 12 and 18 months after treatment. The primary endpoint of the trial is cancer-specific quality of life as measured by the global health/QoL scale of the EORTC QLQ-C30. Secondary outcomes are perceived feelings of control, anxiety, patients' satisfaction with follow-up and costs. A cost-effectiveness analysis will be performed from a societal perspective. Reduced follow-up strategies for breast cancer have not yet been widely applied in clinical practice. Improvement of psychosocial support and information to patients could lead to a better acceptance of reduced follow-up. The MaCare trial combines a reduced follow-up strategy with additional psychosocial support. Less frequent follow-up can reduce the burden on medical specialists and costs. The educational group programme can improve QoL of patients, but also less frequent follow-up can improve QoL by reducing the anxiety experienced for each follow-up visit. Results of the trial will provide knowledge on both costs and psychosocial aspects regarding follow-up and are expected in 2009.


Employee well-being, early-retirement intentions, and company performance.
To explore the relationship between employee well-being and early-retirement intentions, and the extent to which early-retirement intentions are associated with company performance. This study is based on cross-sectional survey data on the ageing employees of the Finnish metal industry and retail trade, collected in 2007 (company-level n = 129, employee-level n = 1281). It was analyzed using multinomial logistic and multiple regression analysis. Poor work ability, frequent emotional exhaustion, low organizational commitment, and job control were associated with the prevalence of early-retirement intentions among aging employees in both industries. Metal industry employees' early-retirement intentions were associated with weaker company performance measured by the perceptions of the manager. By enhancing well-being, employees may stay at work for longer rather than retiring early. Early-retirement intentions can be counterproductive for companies.


[Construction of an activation tagging library of Arabidopsis and cloning for mutant genes].
Activation tagging is an important strategy in plant genomics by generating gain-of-function mutants. In this work, a library of Arabidopsis mutants was constructed by in planta transformation mediated by Agrobacterium tumefaciens containing an activation tagging vector pSKI015 with herbicide Basta as a selection marker (Fig. 1). Among 20000 independent transformants, 38 lines, i.e. about 0.2% of T(1) progeny, show visible morphological phenotypic variations (Fig. 2). Results of Southern blot analysis revealed that most of the transformants have more than three copies of T-DNA insertion (Fig. 3). Plasmid rescue and TAIL-PCR were used to recover the flanking genomic sequences of mutated target genes as the first step towards mutant gene cloning (Fig. 4, 5).


Association of tea consumption and the risk of oral cancer: a meta-analysis.
Epidemiological studies evaluating the association of tea consumption and the risk of oral cancer risk have produced inconsistent results. Thus, we conducted a meta-analysis to assess the relationship between tea consumption and oral cancer risk. Pertinent studies were identified by a search in PubMed, Web of Knowledge and Wan Fang Med Online. The fixed or random effect model was used based on heterogeneity test. Publication bias was estimated using Egger's regression asymmetry test. Finally, 14 articles with 19 studies comprising 4675 oral cancer cases were included in this meta-analysis. The relative risk (95% confidence interval) of oral cancer for the highest versus the lowest category of tea consumption was 0.853 (0.779-0.934), and the association was significant between oral cancer risk and green tea consumption [0.798 (0.673-0.947)] but not in the black tea consumption [0.953 (0.792-1.146)]. The associations were also significant in Asian and Caucasian. Our analysis indicated that tea consumption may have a protective effect on oral cancer, especially in green tea consumption.


[Interdisciplinary relationships of physiotherapy to psychology, psychotherapy, and psychiatry].
The relationship of physiotherapy to psychology, psychotherapy, and psychiatry is critically examined from the point of view of physiotherapy. The relations existing between these disciplines cannot, at present, be considered satisfactory from an overall therapy point of view. The paper also discusses tendencies toward interdisciplinary collaboration.


Polarization-dependent strong coupling between surface plasmon polaritons and excitons in an organic-dye-doped nanostructure.
In this work, we demonstrate polarization-dependent strong coupling between surface plasmon polaritons (SPPs) and excitons in the J-aggregates-attached aperture array. It is shown that the excitons strongly couple with the polarization-dependent SPPs, and Rabi splittings are consequently observed. As a result, the polarization-dependent polariton bands are generated in the system. Increasing the incident angle, the polaritons disperse to higher energies under transverse-electric illumination, while the polaritons disperse to lower energies under transverse-magnetic illumination. Therefore, at different polarization incidence, we experimentally achieve distinct polaritons with opposite dispersion directions. In this way, tuning the polarization of the incident light, we can excite different polaritons whose energy propagates to different directions. Furthermore, by retrieving the mixing fractions of the components in these polariton bands, we find that the dispersion properties of the polaritons are inherited from both the SPPs and the excitons. Our investigation may inspire related studies on tunable photon-exciton interactions and achieve some potential applications on active polariton devices.


Diversity of group A rotavirus genes detected in the Triângulo Mineiro region, Minas Gerais, Brazil.
Group A rotaviruses are the main causative agent of infantile gastroenteritis. The segmented nature of the viral genome allows reassortment of genome segments, which can generate genetic variants. In this study, we characterized the diversity of the VP7, VP4 (VP8*), VP6, NSP4, and NSP5 genes of the rotaviruses that circulated from 2005 to 2011 in the Triângulo Mineiro (TM) region of Brazil. Samples with genotypes G2 (sublineages IVa-1 and IVa-3), G1 (sublineage I-A), G9 (lineage III), G12 (lineages II and III), G8 (lineage II), G3 (lineage III), P[4] (sublineages IVa and IVb), P[8] (sublineages P[8]-3.6, P[8]-3.3, and P[8]-3.1), I2 (lineage VII), E2 (lineages VI, XII, and X), and H2 (lineage III) were identified. The associations found in the samples were G1, G9, or G12 with P[8]-I1-E1-H1; G2 or G8 with P[4]-I2-E2-H2; G12 with I3-E3-H6; and G3 with P[4]-I2-E3-H3 (previously unreported combination). Reassortment events in G2P[4] strains and an apparent pattern of temporal segregation within the lineages were observed. Five TM samples contained genes that exhibited high nucleotide and amino acid identities with strains of animal origin. The present study includes a period of pre- and post-introduction of rotavirus vaccination in all Brazilian territories, thereby serving as a basis for monitoring changes in the genetic constitution of rotaviruses. The results also contribute to the understanding of the diversity and evolution of rotaviruses in a global context.


Comparing outcomes of pediatric and adult external dacryocystorhinostomy in Nepal: Is age a prognostic factor?
We determine whether age is a prognostic factor for surgical outcomes of external dacryocystorhinostomy (Ex-DCR). This retrospective cohort study conducted at Tilganga Institute of Ophthalmology (Kathmandu, Nepal) compared pediatric Ex-DCR procedures (age ≤ 15 years) to adult Ex-DCR procedures (age > 15 years) and was performed between January 2013 and December 2013, with a minimum follow-up period of 6 months. Primary outcome measure was rate of success, defined as complete resolution of subjective symptom(s) of epiphora (subjective success), combined with patent lacrimal passage on syringing (anatomical success) at last follow-up visit. Other outcome measures included clinical presentation, diagnosis, intraoperative complications and post-operative complications. In total, 154 Ex-DCR procedures were included, with an age range of 8 months to 81 years (mean age 36.4 ± 21.0 years). In all, 38 pediatric Ex-DCR procedures were compared to 116 adult procedures. Success rates were 97% in the pediatric group and 95% in the adult group, with no clinically or statistically significant difference in success rate or complication rate between groups (p > 0.05). Our study yielded high success rates of Ex-DCR in both pediatric and adult age groups suggesting that Ex-DCR remains an optimal treatment choice for all age groups. With no difference in surgical outcomes between pediatric and adult patients, including complication rate, we conclude that age is not a prognostic factor for Ex-DCR failure. We do not recommend adjuvant therapy for pediatric patients.


Good Food, Bad Food, and White Rice: Understanding Child Feeding Using Visual-Narrative Elicitation.
Visual-narrative elicitation, a process combining photo elicitation and pile sorting in applied medical anthropology, sheds light on food consumption patterns in urban areas of Vanuatu where childhood malnutrition is a persistent problem. Groups of participants took photographs of the foods they feed their children, and the resources and barriers they encounter in accessing foodstuffs. This revealed how imported and local foods are assigned value as "good" or "bad" foods when contributing to dietary diversity and creating appropriate meals for children, particularly in the context of consuming white rice. The process of gathering and working with photographs illuminated the complex negotiations in which caregivers engaged when making food and nutritional choices for their children. At the nexus of visual and medical anthropology, the visual-narrative elicitation process yielded nuanced, comprehensive understandings of how caregivers value the various foods they feed their children.


Introducing treat-to-target strategies of autoimmune extrahepatic manifestations of chronic hepatitis C virus infection.
The hepatitis C virus (HCV) is recognized as one of the hepatic viruses most often associated with extrahepatic manifestations (EHMs). It is currently accepted that cryoglobulinemic vasculitis (CV) is the key autoimmune extrahepatic disease associated with HCV infection. Therapeutic approaches have mainly been based on the use of old antiviral interferon (IFN)-based regimens and immunosuppressive therapies, often with an inadequate balance between therapeutic benefits and excess side effects. Areas covered: Therapeutic management of HCV patients with EHMs, including both non-autoimmune (cardiovascular, hematological, general features) and autoimmune complications (organ-specific and systemic autoimmune diseases). Therapies included antiviral (IFN, ribavirin, direct-acting antivirals - DAAs-) and non-antiviral (immunosuppressive agents, rituximab, plasma exchanges) options. The review analyses the current evidence for proposing a treat-to-target (T2T) approach for HCV-related autoimmune EHMs based on an organ-by-organ strategy. Expert commentary: Eradication of HCV must be considered the key T2T in the therapeutic approach to HCV-related EHMs, as there has been a disruptive change due to the appearance of direct-acting antivirals (DAAs) as game-changers in HCV therapy, with an efficacy reaching nearly 100%. In this scenario, the central role played until now by IFN and ribavirin is not currently supported and they will not be used in the future.


Long-term effects of reproductive-age menstrual cycle patterns on peri- and postmenopausal fracture risk.
The authors examined the association between age at menarche, menstrual cycle characteristics between ages 28 and 32 years, and peri- and postmenopausal fracture risk in a cohort of 874 women who prospectively recorded menstrual cycle data for at least 5 years from their early 20s through their menopause. Fracture history was obtained with a self-administered questionnaire. The mean age of respondents at the time the questionnaire was completed was 73 years. Wrist fracture (n = 62) risk increased with increasing age at menarche (odds ratio 3.3, 95% confidence interval 1.7-6.2) for menarche age > or = 14 years compared with 12-13 years) and increasing mean cycle length at age 28-32 (odds ratio 2.2, 95% confidence interval 1.0-4.9) for > 30.5 days compared with 26.6-30.5 days). Similar results were seen in analyses of the combined wrist, hip, or vertebral fracture group (n = 92). These prospectively recorded menstrual diary data indicate that age at menarche and menstrual cycle patterns may have a long-term association with fracture risk, with effects lasting into the postmenopausal years.


Dam parity structure and body condition during lactation influence piglet growth and gilt sexual maturation through pre-finishing.
Energy demands during lactation greatly influence sow body condition and piglet performance. We hypothesized that primiparous sows or sows with reduced body condition would produce piglets with reduced growth and delayed sexual maturation. Eight weekly farrowing seasons were used to evaluate sow body condition (post-farrowing, PF and weaning, WN) and piglet growth from 157 dams. Body condition was measured at PF and WN using sow calipers (last rib and hip) and 10th rib ultrasound. Sows were categorized as thin, moderate, or fat by caliper (PF or WN). Individual pig weights were recorded on approximately 1, 10, WN, 45, 100, and 145 d of age. At 100 and 145 d of age, 10th-rib backfat and loin eye area were measured on 567 pigs and first estrus was monitored in 176 gilts reserved for breeding selection beginning at approximately 170 d of age. Sows had similar (P > 0.10) PF last rib caliper measurements but at WN, first parity sows had the smallest caliper measurements compared to other parities (P < 0.05). Parities 1, 2, and 3 sows had similar (P > 0.10) loin eye area at PF; however, at WN first parity sows had the smallest loin eye area (P < 0.05; 38.2 ± 0.63 cm2). Parity 1 sows had the greatest (P < 0.05) reduction of backfat and loin eye area over the lactation period (-2.9 ± 0.31 mm and -2.6 ± 0.49 cm2, respectively). At 1 d of age and WN, piglets from first parity sows weighed the least (P < 0.05) but were the heaviest (P < 0.05) at 100 and 145 d of age. Pigs from first parity litters had larger (P < 0.05) loin eye area at 100 and 145 d of age and greater backfat (P < 0.05) at 145 d of age. Fat sows at WN (last rib or hip) had the lightest (P < 0.05) piglets at 10 d of age and WN. However, at 45 d of age, piglets from fat sows (last rib or hip) were heavier (P < 0.05) than piglets from moderate and thin sows. Tenth rib backfat at 100 and 145 d of age tended (P < 0.10) to be less in pigs reared by thin sows (PF and WN hip). Tenth rib loin eye area was similar among pigs reared by fat, moderate, or thin sows. Gilts developed in litters from fourth parity sows had (P < 0.05) delayed age at puberty in contrast to gilts from first or third parity sows (200.9 ± 4.96 d vs. 189.0 ± 2.29 d and 187.5 ± 2.84 d, respectively). Although progeny body weights were typically less from first parity dams through 45 d of age, these progeny were similar or heavier at 100 and 145 d of age in contrast to progeny from other parities. Furthermore, gilt progeny from first parity dams did not have delayed pubertal attainment.


The development and resolution of glomerular basement membrane changes associated with subepithelial immune deposits.
The morphogenesis of glomerular basement membrane changes associated with subepithelial immune deposits was studied in kidney biopsies from patients with gold-induced membranous glomerulonephoritis. Serial biopsies showed focal accumulations of additional basement membrane material around the deposits, suggesting that the deposited material stimulated the epithelium to increased synthesis. Moreover, the deposits were gradually displaced towards the inner (endothelia) side of the basement membrane during the course of the disease, suggesting that this layer undergoes a slow continuous turnover, with removal at its endothelial aspect. The two processes--increased epithelial synthesis and turnover--are suggested to constitute the basis of a natural healing process resulting in elimination of the deposits and structural restoration of the basement membrane. The epithelial slit membranes were dislocated externally by the deposits or the excessive basement membrane material, indicating that their barrier function is preserved even in this pathologic condition.


Pharmacologic treatments for rosacea.
Rosacea represents a common and chronic inflammatory skin disorder. Clinical features include transient and permanent erythema, inflammatory papules and pustules, phymatous changes, and ocular signs and symptoms. Rosacea is generally classified into four subtypes and one variant. Subtype 1, erythematotelangiectatic rosacea, includes clinical features of flushing and persistent central facial erythema with or without telangiectasia. Subtype 2, papulopustular rosacea, is characterized by persistent central facial erythema with transient papules or pustules or both on the central face. Subtype 3, phymatous rosacea, includes thickening of the skin with irregular surface nodularities and enlargement. Subtype 4, ocular rosacea, includes inflammation of different parts of the eye and eyelid. A variant, granulomatous rosacea, is noninflammatory and is characterized by hard, brown, yellow, or red cutaneous papules or nodules of uniform size. Patients may present with more than one subtype, and each individual characteristic may fluctuate. There is debate whether rosacea progresses from one subtype over time or subtypes represent discreet entities. Defining clinical presentation and improved understanding of pathophysiology has resulted in identification of novel treatment approaches. This contribution outlines a rationale for treatment, highlights an evidence-based approach with approved treatments, and considers novel developments and off-license therapy available.


[Primary large-cell neuro-endocrine carcinoma of the bladder].
Primary large-cell neuro-endocrine carcinoma of the bladder is a rare aggressive tumour with a very poor prognosis. The authors report the case of 78-year-old male patient with primary large-cell neuro-endocrine carcinoma of the bladder and discuss the pathological and therapeutic aspects of this tumour in the light of a review of the literature.


The Neuroinflammatory Response in ALS: The Roles of Microglia and T Cells.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by upper and lower motoneuron death. Mutations in the gene for superoxide dismutase 1 (SOD1) cause a familial form of ALS and have been used to develop transgenic mice which overexpress human mutant SOD1 (mSOD) and these mice exhibit a motoneuron disease which is pathologically and phenotypically similar to ALS. Neuroinflammation is a pathological hallmark of many neurodegenerative diseases including ALS and is typified by the activation and proliferation of microglia and the infiltration of T cells into the brain and spinal cord. Although the neuroinflammatory response has been considered a consequence of neuronal dysfunction and death, evidence indicates that manipulation of this response can alter disease progression. Previously viewed as deleterious to neuronal survival, recent reports suggest a trophic role for activated microglia in the mSOD mouse during the early stages of disease that is dependent on instructive signals from infiltrating T cells. However, at advanced stages of disease, activated microglia acquire increased neurotoxic potential, warranting further investigation into factors capable of skewing microglial activation towards a neurotrophic phenotype as a means of therapeutic intervention in ALS.


Increasing Obesity in Treated Female HIV Patients from Sub-Saharan Africa: Potential Causes and Possible Targets for Intervention.
To investigate changing nutritional demographics of treated HIV-1-infected patients and explore causes of obesity, particularly in women of African origin. We prospectively reviewed nutritional demographics of clinic attenders at an urban European HIV clinic during four one-month periods at three-yearly intervals (2001, 2004, 2007, and 2010) and in two consecutive whole-year reviews (2010-2011 and 2011-2012). Risk-factors for obesity were assessed by multiple linear regression. A sub-study of 50 HIV-positive African female patients investigated body-size/shape perception using numerical, verbal, and pictorial cues. We found a dramatic rise in the prevalence of obesity (BMI > 30 kg/m(2)), from 8.5 (2001) to 28% (2011-2012) for all clinic attenders, of whom 86% were on antiretroviral treatment. Women of African origin were most affected, 49% being obese, with a further 32% overweight (BMI 25-30 kg/m(2)) in 2012. Clinical factors strongly associated with obesity included female gender, black African ethnicity, non-smoking, age, and CD4 count (all P < 0.001); greater duration of cART did not predict obesity. Individual weight-time trends mostly showed slow long-term progressive weight gain. Investigating body-weight perception, we found that weight and adiposity were underestimated by obese subjects, who showed a greater disparity between perceived and actual adiposity (P < 0.001). Obese subjects targeted more obese target "ideal" body shapes (P < 0.01), but were less satisfied with their body shape overall (P = 0.02). Seropositive African women on antiretroviral treatment are at heightened risk of obesity. Although multifactorial, body-weight perception represents a potential target for intervention.


Diagnosis and Treatment Strategies for Arachnoiditis Ossificans Following Subarachnoid Hemorrhage: A Case Report.
Arachnoiditis ossificans (AO) is a rare disease, wherein ossified lesions in the subarachnoid space obstruct the flow of spinal fluid or compress the spinal cord, thereby causing myelopathy. Here we describe a rare case of AO and discuss the diagnosis and treatment strategies for this disease. A 66-year-old man with a history of subarachnoid hemorrhage presented with gait disturbance and dysuria for 7 months. Spinal magnetic resonance imaging and computed tomography (CT) myelography showed syringomyelia at the T5-T8 level and dorsally tethered spinal cord at the T8-T10 level. Preoperative noncontrast CT was not performed. The patient was diagnosed with adhesive arachnoiditis and underwent arachnoidolysis. However, intraoperative findings showed the presence of ossification lesions on the dorsal surface of the spinal cord, and intraoperative ultrasound (IOU) showed a hyperintense lesion with acoustic shadowing on the dorsal surface of the spinal cord, with limited visibility of the spinal cord. After removal of the lesions, IOU showed untethered and well-decompressed spinal cord and restoration of cerebrospinal fluid pulsation. Based on these findings, the patient was finally diagnosed with AO, which is an extremely rare disease, with an unknown frequency of occurrence. Therefore, all patients with adhesive spinal arachnoiditis require a preoperative noncontrast CT scan to evaluate for ossification lesions. In this case, we were fortunate to be able to treat AO with IOU, which demonstrated specific findings.