This because the income distribution received and paid for by each institutional sector required for a financial SAM is not available, i.e. the INE does not break down the data by institutional destination and source. In this sense, our contribution rely on estimating a complete series of from-whom-to-whom matrices of Property Income for the Spanish economy between 1999 and 2016, in which we have devoted special attention to staying in line with the Data Gaps Initiative (DGI-2) recommendation released by the Financial Stability Board (FSB) and the International Monetary Fund (IMF), claiming that more focus is needed on data sets that support the monitoring of risks in the financial sector in response to regulatory and macro-financial emerging policy needs).A common problem in compiling and updating Social Accounting Matrices (SAM) or Input-Output tables is that of incomplete information. In the case of the submatrix ‘Property Income of the Account Allocation of Primary Income’, the information published by the National Bureau of Statistics of Spain (INE) is limited because it is not possible to build the set of  Specifications TableValue of the data•from-whom-to-whom matrix scheme. This representation allows the question ‘who’ is financing ‘whom’ to be answered, which allows a more detailed and complex analysis of the financial flows between sectors and their role in the economy.The dataset provides accurate estimates of the allocation of primary income account – property income – in a •from-whom-to-whom framework by financial instruments turns out to be very useful for analyzing the real-financial interconnectedness of the Spanish economy.The novel approach to provide the stocks of Asset and Liabilities Matrices in a •The dataset provides the necessary elements to estimate the breakout of the total income return, resulting in an outstanding sources of information for investment analysis and impact analysis of public policies.•The set of submatrices results in a consistent accounting framework useful for improving and extending Social Accounting Matrices, sectorial-financial linkage analysis, macroeconomic forecasting and improve and enrich the scope of real-financial computable general equilibrium (CGE) models.1from-whom-to-whom basis, and the compilation guides suggested by Tsujimura and Mizoshita The real side information concerning the allocation of primary income account – property income – was obtained from the statistics of the Integrated Economic Accounts (IEA) provided by the National Bureau of Statistics of Spain (INE). The financial side information was retrieved from the financial statistics of the Flow of Funds (FoF) provided by the Bank of Spain (BdE). Both INE and BdE data sets correspond to the yearly series 1999 to 2016 due to the constraints to using the more recent official data set available to build a Property Incomes matrix for Spain. Given that both the real statistics of the INE and the financial statistics of the BdE shape the entire System of National Accounts (SNA93) The statistical information from the INE is available in integrated structured tables separated by years, while the database from the BdE is expressed in quarterly time series. Since the data from the BdE are in quarterly series, different treatments among figures expressed in flows from those expressed in balances were required, adding the former to form flows for the year and considering the figures of the last quarter as the closing balances of the respective year.2In the wake of the 2008 financial and economic crisis, the Group of Twenty economies (G-20) asked the Financial Stability Board (FSB) and the International Monetary Fund (IMF) “to explore gaps and provide appropriate proposals for strengthening data collection before the next meeting of the G-20 Finance Ministers and Central Bank Governors.” In its Spring Meeting in April 2009, the FSB-IMF came up with 20 recommendations 2.1from-whom-to-whom (or debtor/creditor) framework, correspond to the matrix form representation that allow the analysis of the financial connections among institutional sectors in a national economy and abroad. As have been pointed out by Shrestha et al. from-whom-to-whom representation of statistical information allows answering questions like “Who is financing whom, in what amount, and with which type of financial instrument?”. As regards of property income, it also permits tracing who is paying/receiving income  to/from whom. The from-whom-to-whom compilation approach also enhances the quality and consistency of data by providing more cross-checking and balancing opportunities.The integrated system of sector accounts in a from-whom-to-whom matrices as three dimensional tables where the flows from one sector to another sector for each type of financial instruments are showed. In this regard, to estimate the matrix Property Income, we based our approach on the definition provided by the SNA2008 manual, which states:The System of National Accounts 2008 (SNA2008) “7.107 Property income accrues when the owners of financial assets and natural resources put them at the disposal of other institutional units. The income payable for the use of financial assets is called investment income while that payable for the use of a natural resource is called rent. Property income is the sum of investment income and rent.7.108 Investment income is the income receivable by the owner of a financial asset in return for providing funds to another institutional unit…”.Hence, we can use the balances account of the financial account relating to financial assets and liabilities across the institutional sectors as estimators of the shares of income received and paid by each institutional sector. Intuition suggests that the property income received and/or paid for each institutional sector should be directly proportional to its levels of assets and/or liabilities. Thus, we used the balance account of the financial account relating to financial assets and liabilities across the institutional sectors as estimators of the shares of income received and paid by each of them.2.2from-whom-to-whom matrix show how the income is received by the owner of a financial asset in return for providing funds to another institutional sector. The income payable for the use of financial assets is called investment income while that payable for the use of a natural resource is called rent The property income led rent PImxmxp= to/from whom, in what amount, and with which type of transaction?”. Also, as have been pointed out by Shrestha et al. In this sense, the integrated framework on a 2.3from-whom-to-whom representation of the net worth of this economy in terms of stocks:from-whom-to-whom matrices in expression Financial instruments include the full range of financial contracts made between institutional sectors. These contracts are the basis of creditor/debtor relationships through which asset owners acquire unconditional claims on economic resources of other institutional sectors 2.4Like Leung and Secrieru Under the GRAS algorithm Eq. In this sense, we are capable to derive the breakdown of the Property Income by types of financial transactions for the Spanish economy, in which we have devoted special attention to staying in line with DGI-2 recommendation II.8, referring to the compilation of sectorial account flows and balance sheet data, based on from-whom-to-whom matrices expressed in transactions and stocks to support balance sheet analysis, and recommendation II.9, which encourages the development and dissemination of distributional information on income allocation.


The development of artificial organelles is a new, fast-growing field in which a variety of techniques have been employed. This article gives a brief overview of the history of artificial organelles, and describes the development of an artificial endoplasmic reticulum and Golgi organelle on a digital microfluidic platform. This device should be useful in high-throughput combinatorial proteoglycan/glycoprotein synthesis, providing critical information about the control of biosynthetic pathways for these important signaling molecules.


Clinical and TranslationalMedicine are issuing an editorial expression of concern to alertreaders that concerns have been raised regarding the ethics of this study [The Editors-in-Chief of is study . Appropr


Such a law is relevant for the global oncology community because few low- or middle-income countries have enacted similar legislation.2 It may pave the way for enactment of similar legal directives in other developing countries, thereby resulting in a greater impact around the globe.The Government of India recently published a draft version of the Medical Treatment of Terminally-Ill Patients Bill for comments and feedback from the public.The legislation provides clarity to several facets of end-of-life care. Competent patients can decline introduction of life-sustaining medical treatment, a decision with which their physicians will be bound to comply. The legislation seeks to protect both the patient and the physician from legal complications that may arise from such a decision. It also emphasizes the importance of appropriate documentation and record keeping.3 Families of terminally ill patients have also reported less stress and greater satisfaction with care after such discussions.4 If the principle of patient autonomy is to be respected, the proposed bill should consider upholding advance directives as an integral part of end-of-life care of terminally ill patients.Although the Government of India must be applauded for moving ahead with this legislation, we believe that the current version may be a misstep for two reasons. First, the proposed bill prohibits the use of advance medical directives—living wills or medical powers of attorney—in India. Therefore, any advance medical directive prepared by a patient with a terminal illness for his or her health care providers and family in the event he or she becomes unable to take a decision about life-sustaining treatment will not be legally binding. This will result in increased use of life-sustaining treatment and intensive care unit admissions among terminally ill patients for whom death is an inevitable event. We fear this violates the autonomy of the patient. End-of-life discussions can reduce the rates of intensive care unit admissions and life-sustaining treatment use, such as the use of a ventilator, at the end of life.Second, it is unreasonable to expect the court to take decisions on withholding or withdrawing life-sustaining care from terminally ill patients who are unable to make informed decisions. The Indian legal system is already burdened by backlogged cases, and such an expectation could potentially harm the care of terminally ill patients by causing unnecessary delays. Instead, the bill should consider providing guidance to the formation of hospital-based ethics committees comprising physicians from various specialties, including palliative care, nurses, and representatives from the community, who could decide on the ethical aspects of withholding or withdrawing life-sustaining medical care.In summary, we congratulate the Government of India on its noble intention of creating legislation defining appropriate end-of-life care. We hope to bring attention to the potential negative impact of the proposed bill on patient autonomy with regard to advance medical directives.


It must be included in the differential diagnosis of posterior mediastinal and retroperitoneal mass. We report a case of retroperitoneal ganglioneuroma involving the celiac axis and superior mesenteric arteries in a 40-year-old female.Ganglioneuroma is a rare neoplasm arising from the sympathoadrenal neuroendocrine system and has anatomic distribution paralleling the sympathetic chain ganglia and the adrenal medulla. In some cases, ganglioneuroma is the end stage maturation of less-differentiated neoplasms such as neuroblastoma or ganglioneuroblastoma, but based on age at diagnosis (over 10 years of age) and anatomic location, many of these tumors appear to arise


The authors of the paper “Characteristics of Articles About Human Papillomavirus Vaccination in Japanese Newspapers: Time-Series Analysis Study” :e97) omitted information in the caption of The corrected article will appear in the online version of the paper on the JMIR website on March 16, 2018, together with the publication of this correction notice. Because this was made after submission to PubMed or Pubmed Central and other full-text repositories, the corrected article also has been re-submitted to those repositories.Please see the figure with the corrected caption here.


Does letter-form constrain errors in peripheral dyslexia? In Hebrew, 5 of the 22 letters have two different letter forms, one is used only when the letter occurs in word-final position, the other form is used in initial and middle positions. Is the information on final-forms encoded in the letter identity information and used for word identification, or is it discarded? The current research explored this question through the effect of final vs. non final letter form on the error pattern in neglect dyslexia (neglexia) and letter position dyslexia (LPD). Left word-based neglexia results in errors of omission, substitution and addition of letters in the left side of words, which in Hebrew is the end of the word. We examined whether final letter form blocks the addition of letters to the end of the word and whether omissions of letters after letters in non-final form are avoided. The predominant error type in LPD is migration of letters within words. We tested whether migrations also occur when they cause form change of either final-form letters that move to middle position or middle-form letters that move to final position. These questions were assessed in both acquired and developmental neglexia and LPD. The results indicated a strong effect of final letter-form on acquired neglexia and on acquired and developmental LPD, which almost completely prevented form-changing errors. This effect was not found in developmental neglexia, where words that end in final-form letters were actually more impaired than other words, probably because final-form letters appear only on the neglected side of the word for Hebrew-reading children with left developmental neglexia. These data show that early visuo-orthographic analysis is sensitive to final letter form and that final letter form constrains errors in peripheral dyslexia.


The case of a 67-year-old right-handed Chinese man with Central Pontine Myelinolysis [CPM] is described to illustrate the resulting cognitive and emotional disturbances. A comparison of the data in this report with that in published studies suggests that ethnicity does not seem to have much effect on the symptoms of CPM. Possible underlying neural-pathological mechanisms are discussed. This case further substantiates the speculation that the brainstem plays a role in higher cognitive processes and emotional regulation.


The renin-angiotensin-aldosterone system is now considered to be far more complex than previously thought when the vasoconstrictor and other physiological effects of the octapeptide angiotensin II in the circulating blood were emphasized. The reasons for this altered viewpoint, involving angiotensins other than the octapeptide in the regulation of blood pressure, water and electrolyte homeostasis, are briefly advanced and discussed.


Editorial on the Research TopicRadiation and the Immune System: Current Knowledge and Future PerspectivesAt present, the opinions about the interaction between ionizing radiation and the immune system are largely controversial. For long, high-dose ionizing radiation was considered as net immune suppressing mainly due to the exquisite radiosensitivity of the lymphoid system. While this increased radiosensitivity cannot be contested, a rapidly growing number of scientific publications have demonstrated a very heterogeneous quantitative and functional response of the different components of the immune system to radiation –3. A majIt was additionally recognized that some of the radiation-induced late side effects are of immune and inflammatory nature. At present, one of the most studied fields of research in radiation biology is focused around the biological effects of low doses, where the observed pathophysiological endpoints are due to mechanisms other than radiation-induced direct cell killing. Such mechanisms are for example radiation-induced bystander effects or abscopal effects, which by sharing common mediators with various immunological signaling processes, are most probably immune-mediated.Schaue, who gives a comprehensive historical overview regarding the interaction between ionizing radiation in general and RT, in particular, and the immune system.The multitude of studies investigating the interactions between ionizing radiation and the immune system lead to the emergence of a new, highly interdisciplinary scientific field called radioimmunobiology, with the potential to induce a paradigm change in this area and to achieve direct clinical applications within a relatively short term. Scientific primary and overview papers collected in the present Research Topic aim to give an up-to-date state of the art of the complex interactions between the immune system and ionizing radiation while highlighting future perspectives as well. This paradigm change is nicely illustrated in the review by Wennerberg et al. summarize further immune suppressive properties of radiation on the cellular and molecular level besides the impact of radiation on expression of inhibitory immune checkpoint molecules such as PD-L1. The impact of RT and radiochemotherapy (RCT) on the latter on tumor cells of different tumor entities is the focus of the research article by Derer et al. They show that, in particular, RCT increases the expression of PD-L1 on melanoma and glioblastoma cells. This demands radioimmunotherapies (RIT) to counteract radiation-induced immune suppression. For the design of beneficial RIT, many additional parameters have to be taken into account. What is the best radiation dose and radiation quality? Ebner et al. review the unique biological and physical benefits of particle irradiation that may be superior in some aspects for the generation of systemic radiation-induced immune-mediated effects. Besides the radiation quality, the dose and the chronological sequence of immune cell infiltration into the tumor has to be kept in mind. Frey et al. present data on timely restricted immune cell infiltration following hypofractionated radiation. Cytotoxic T cells follow the antigen-presenting cells and are present for only 2 days. Here, re-irradiation of the tumor should be revisited to spare the immune cells, and boosting of the immune system at this time point could be particularly effective. Since the inflamed microenvironment of tumors impacts on growth and progression, several articles deal with modulation of inflammation by radiation. Rödel et al. review radiation-induced mechanisms contributing to a modulation of proliferative and inflammatory processes. They focus on summarizing innovative concepts of treating hyperproliferative diseases by low and moderate doses of ionizing radiation. Since inflammatory events and bone metabolism are interconnected, radiation also impacts on bone turnover. Cucu et al. demonstrate in serum samples of patients who were exposed to very low doses of alpha-irradiation in radon spa that collagen fragments (in particular CTX-I) are decreased after radiation exposure. This suggests a reduced bone resorption by osteoclasts. The interleukin IL-33 has been described as an intracellular alarmin being involved in many inflammatory processes. Kurow et al. revealed that the release of full length IL33 in the damaged tissue does exacerbate radiation-induced skin reactions.Although the cell autonomous effects of ionizing radiation are well established, there is nowadays growing evidence that intercellular communication plays a major role in the outcome of radiation exposure at the tissue level. This is especially true in cancer therapy. Radiation exposure aims at killing tumor cells, but efficient tumor control/eradication also requires the activation of the immune system. The tumor microenvironment indeed contains various subsets of immune cells, both myeloid cells and lymphocytes. Among the myeloid cells, myeloid-derived suppressor cells and tumor-associated macrophages provide a supportive environment for tumor growth, in part by suppressing the activity of cytotoxic T cells. Manning et al. monitored the expression of about 250 genes associated with the inflammation response over the course of the RT in blood of patients with endometrial or head and neck cancer. Some of these inflammation-related genes could be promising biomarkers of radiation exposure and susceptibility to radiation-induced toxicity. Radiation-induced inflammatory reactions are also heavily involved in the development of radiation-related side effects in various tissues. Several papers within this research topic specifically focus on this aspect. Wirsdörfer and Jendrossek summarize radiation-dependent mechanism of acute and chronic environmental lung changes following thoracic irradiation. Acheva et al. present new data regarding the mechanism of RT-induced skin side effects focusing on the role of NFκB and Cox-2 in the generation of pro-inflammatory signals. Morini et al. investigate the impact of ionizing radiation on the permeability of the intestinal barrier in the context of colorectal cancer and show that several of the involved mechanisms are immune- and inflammation-related. Lumniczky et al. review radiation-induced immune and inflammatory reactions in the brain, highlighting potential mechanisms how these interactions can lead to long-lasting functional alterations and the development of cognitive impairment. Amelioration of chronic inflammation, induction of acute damage , and counter-balancing the tumor- and radiation-derived immune suppression can in sum result not only in specific and long-lasting antitumor immunity but also in less frequent or less severe side effects and lead to an increased resistance toward radiation. This is highlighted in the paper by Singh et al. who show that the radioprotective effect of two well-characterized antioxidant compounds (podophyllin and rutin) is mainly immune-mediated.Thus, radiation acts and modulates immune reactions, including inflammation, at various levels and in all tissues. Immune cells and, in particular, lymphocytes are key players in the response against radiation-modified tumor cells. In order to highlight transcriptionally responsive genes, which play a role in the inflammation response, Therefore, one of the beneficial effects of RT is, in some instance, to shift the equilibrium toward immune activation. For this, additional immunotherapy is mostly needed.Wu et al., in addition to the direct effects of radiation on the different immune cell subsets, a key event in the (re)-activation of tumor-associated immune cells is the type of tumor cell death induced by radiation, as apoptosis, necrosis, autophagic cell death, and mitotic catastrophe differ in their ability to reverse immunosuppression and elicit these tumor-specific immune responses. As the release of metabolites such as inosine by dying or dead tumor cells can on the opposite stimulate the outgrowth of rare spared tumor cells , the net outcome of radiation-therapy will depend on the competition between immunogenic and pro-tumorigenic events. Vaupel and Multhoff in particularly focus in their commentary on the role of adenosine as a consequence of hypoxia as metabolic immune checkpoint in the tumor microenvironment. Furthermore, the outcome of radiation exposure depends not only on the type of tumor and its microenvironment but also on the dose and quality of radiation and the irradiation scheme used. Even if more studies are required, especially on the effects of protons and carbon ions exposure , it is clear that these parameters can modulate the different aspects of the intercellular communication in the irradiated tumor microenvironment (reviewed by Diegeler and Hellweg). In addition to their direct effects on mature lymphocytes and T lymphocyte response to irradiation-induced bystander signals, ionizing radiation also affects T lymphocyte development. This aspect of the interactions between radiation and the immune system is addressed by Calvo-Asensio et al. in a research article where they analyze the response of thymic epithelial cells (TECs) to radiation exposure in vitro and ex vivo. TEC represent less than 1% of the cells found in the thymus, but these highly specialized cells are essential for the generation of mature, functional T lymphocytes. Although they are quite radio-resistant, the expression of many genes essential for proper T lymphocyte development is de-regulated after exposure. These effects probably contribute to the profound T cell deficiency observed in patient exposed to radiation in the frame of the conditioning regime before bone-marrow transplantation.As discussed in their review by Szatmári et al. demonstrate in an in vivo experimental setup that extracellular vesicles are responsible for mediating certain radiation-induced bystander effects in the bone marrow. Erbeldinger et al. present a new method by which the effect of ionizing radiation on endothelial cells can be investigated in vitro where hemodynamical parameters are much closer to physiological conditions than using conventional cell cultures. In this system, they show that both low energy and heavily charged particles induce altered adhesion of peripheral blood lymphocytes and activation of the NFκB pathway. With the perspective of space travel and a Mars mission in a reasonably near future, the impact of cosmic radiation becomes a particularly important health problem, and the potential effects of charged heavy particles on the immune system and their long-lasting health consequences will need to be addressed. Since heavy particles are increasingly used in therapeutic radiation as well, their interaction with the immune system, in the view of a potential combination with immunotherapy should be carefully studied. These issues are dealt with in detail in the mini-review by Fernandez-Gonzalo et al.Last but not least, a special focus is placed on the investigation of low-dose radiation-induced immune mechanisms and inflammatory reactions. Thus, the editors of the Research Topic hope that this collection of articles is able to give a good overview of the complex and often contradictory nature of the interactions between ionizing radiation and the immune system. Our intention was also to draw the attention of the non-radiobiological scientific community on these complex interactions and to highlight the fact that ionizing radiation is by far more than purely an immune suppressing agent. The increasing penetrance of low-dose ionizing radiation both through medical diagnostic or environmental sources or during cosmic travel in the population is becoming a major epidemiological concern world-wide and the mechanisms how low-dose radiation act and the potential long-term health consequences need to be thoroughly investigated.All authors contributed in the editing of the Radiation and the Immune System Research Topic.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Self-awareness is believed to be limited in human and great apes  and genital-unrelated (UR) behaviors than naïve monkeys when facing the mirror wall. Data collected supported the hypothesis: trained rhesus monkeys are capable to recognize themselves via mirror image.In the visual-somatosensory training, heat-induced high-power spots were projected to monkeys' face, which is controversial that after training, the mark touching response in monkey is a conditioned behavior not spontaneous MSR.The improved study perfected training devices to help monkeys precisely learn the association between the face mark position and the image by simply using a mirror. Then, the new study approved the transition from the mirror use to mirror-induced self-recognition performance in the trained monkey and demonstrated the ability to use a mirror and MSR are distinguishing cognitive abilities.Previous studies suggested that monkey species could not exhibit self-recognition behaviors and failed the MSR test (Roma et al., The underlying mechanism of MSR is unknown. Along with human, chimpanzees are inherent of MSR without training, but monkeys not, which possibly means enhance sensory integration to a certain degree that required for MSR. It's possible that mirror neurons, which are discovered in the monkeys and considered the neural mechanism of imitation behaviors, are the reason of generating self-consciousness in rhesus monkey (Chang et al., There are still some limitations in the present study. Tooling use is an evident indicator of high intelligence in human and high-rank primate and can be transferred within the group (Bayart and Anderson, XL and TL completed the first version of the paper and XH presented suggestions to revise the paper. The workload of the three authors was equal.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Proteolysis by the ubiquitin-proteasome pathway (UPP) is now widely recognized as a major molecular mechanism playing a role in numerous normal functions of the nervous system as well as in malfunctions of the brain in several neurodegenerative diseases. In the UPP, attachment of a small protein, ubiquitin, tags the substrates for degradation by a multi-subunit complex called the proteasome. Linkage of ubiquitin to protein substrates is highly specific and occurs through a series of well-orchestrated enzymatic steps. Protein degradation has key functions in the nervous system including fine-tuning of synaptic connections during development and synaptic plasticity in the adult organism Hegde, . In neurMany questions pertaining to the UPP in the nervous system remain unanswered. How is the UPP-mediated degradation regulated spatially and temporally in neurons? What is the role of local protein degradation? How does the interplay between proteolysis and protein synthesis affect synaptic plasticity and memory? Do perturbations in the UPP have a role in the pathology of neurodegenerative diseases?Frontiers in Molecular Neuroscience Research Topic-Special Issue on Ubiquitin and the Brain: Roles of Proteolysis in the Normal and Abnormal Nervous System cover a wide range of topics from development of methods and primary research studies to reviews. These articles from researchers working on yeast, neuronal and glial cell culture and mouse models, often validated in postmortem human brain tissue, cover a wide array of topics such as receptor endocytosis and synaptic plasticity in the normal nervous system to abnormalities of the nervous system such as AD and Huntington's disease.The papers in this Pinto et al. reports the results of studies on visualizing a specific type of ubiquitin linkage to substrate proteins in which ubiquitin molecules are linked to each other through a covalent linkage to Lysine-48 (K48) in the ubiquitin sequence. The K-48 linkage targets substrate proteins for degradation. Pinto et al. study adapted a technique to monitor K-48-liked ubiquitin molecules in cultured rat hippocampal neurons. In this technique, a yellow fluorescent protein called Venus is split into non-fluorescent N- and C- termini and fused to sequences containing ubiquitin-interacting-motifs (UIMs). These parts come together when they bind to closely spaced ubiquitin molecules in a polyubiquitin chain assembled through K-48 linkage. Using this technique, the authors show that proteins tagged with K-48-linked ubiquitin chains accumulate in presynaptic terminals when synapses newly form.The paper by Vaden et al.) builds on their previous work on the role of a deubiquitinating (DUB) enzyme called USP14 in the mammalian neuromuscular junction (NMJ). Their studies suggest that the role of USP14 in maintaining the free ubiquitin levels is critical for NMJ structure but the function of NMJ (such as muscle coordination) is likely to be regulated by USP14 through a separate pathway. Apart of USP14, many other DUBs play a role in the nervous system. Ristic et al. argue in their review that looking at the UPP from the point of view of DUBs can provide novel insights into the exquisite regulation of proteolysis in the nervous system and might be helpful in devising therapeutic approaches.The studies by Scott Wilson and colleagues  protein. Tagging of mHtt by ubiquitin plays a role in clearance by the proteasome as well as through autophagy. The authors present strategies to study local clearance and accumulation in neuronal sub-compartments.Jarome and Helmstetter review the evidence for the roles of protein degradation in long-term memory (LTM) storage. They discuss the interplay between protein degradation and protein synthesis in the hippocampus and amygdala and other cortical areas during formation and consolidation of LTM.Massaly et al. review the evidence for role of the UPP in mediating the effects of drug abuse on the nervous system. They details the role of the UPP in regulating molecules that mediate drug-abuse-related neuroplasticity. In addition, they present evidence from the literature regarding how drugs of abuse regulate amounts and function of the various components of the UPP. The review by Figueiredo et al. discusses the role in neuroinflammation of a specific class of prostaglandins called J2 which are the toxic products of cyclooxygenases. Among the pleiotropic effects of J2 prostaglandins is perturbation of UPP. The authors suggest that the targeting neuroinflammatory pathways stimulated by J2 prostaglandins might be beneficial in treating several neurodegenerative diseases such as AD, Parkinson's and amyotrophic lateral sclerosis. Gong et al. discuss the role of components of the UPP such as the deubiquitinating enzyme Uch-L1, F-Box protein Fbx2, and the proteasome in development of AD and spinal cord injury. They suggest pharmacological manipulations of these components could be developed as a therapeutic strategy. In addition, the role of UPP is highlighted in neurodegenerative diseases such as AD, Parkinson's disease and Huntington's disease .The coverage of the role of proteolysis by the UPP in abnormalities of the nervous system ranges from drug abuse to neuroinflammation and neurodegenerative diseases. Jansen et al. tackles this issue and discusses among other things the differences between neurons and glia in how the two cell types react to impaired proteolysis by the UPP.Until recently, the investigation with regard to the role of proteolysis in neurodegenerative diseases largely focused on neurons and role of the UPP in glia was largely ignored. This has been true also of other diseases with protein conformational abnormalities such as Amyotrophic Lateral Sclerosis and Parkinson's disease. The review by Brau), which can be subsequently validated using mammalian model systems. The group of Dantuma has developed many tools to detect proteasomal activity  in vitro as well as in vivo. The authors (Dantuma and Bott) discuss “the paradigm shift that has repositioned the UPS from being a prime suspect in the pathophysiology of neurodegeneration to an attractive therapeutic target that can be harnessed to accelerate the clearance of disease-linked proteins” (review by Dantuma and Bott). For example, downregulation misframed ubiquitin (UBB+1) that interacts in AD with γ-secretase (Gentier and van Leeuwen, The studies on the role of the UPP in neurodegenerative diseases can be greatly benefited by work on simple model systems such as yeast. This model system provides an easy readout of perturbations in the UPP and allows quick analysis of action of numerous chemicals on the UPP (see review by The research articles and reviews in this research topic now collected as an e-book highlight the complex role of ubiquitin-proteasome-mediated proteolysis in the neuronal and glial physiology and pathology. In spite of the considerable progress made over the last two decades, many challenges remain. For example, with respect to normal roles of the UPP in the nervous system, the roles of the UPP in memory formation especially in relation to the role of protein synthesis need to be better understood. The exact contributions and the interplay of the UPP with other protein-clearance systems such as autophagy in various neurodegenerative diseases also need to be delineated. As many new technological developments such as CRISPR/Cas9, allow precise testing of hypotheses, we may expect to see many additional interesting discoveries on both these fronts.Both authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Parkinson’s disease (PD) is a progressive neurodegenerative disorder causing movement disabilities and several non-motor symptoms in afflicted patients. Recent studies in animal models of PD and analyses of brain specimen from PD patients revealed an increase in the level and activity of the non-receptor tyrosine kinase Abelson (c-Abl) in dopaminergic neurons with phosphorylation of protein substrates, such as α-synuclein and the E3 ubiquitin ligase, Parkin. Most significantly inhibition of c-Abl kinase activity by small molecular compounds used in the clinic to treat human leukemia have shown promising neuroprotective effects in cell and animal models of PD. This has raised hope that similar beneficial outcome may also be observed in the treatment of PD patients by using c-Abl inhibitors. Here we highlight the background for the current optimism, reviewing c-Abl and its relationship to pathophysiological pathways prevailing in PD, as well as discussing issues related to the pharmacology and safety of current c-Abl inhibitors. Clearly more rigorously controlled and well-designed trials are needed before the c-Abl inhibitors can be used in the neuroclinic to possibly benefit an increasing number of PD patients. Age is a major risk factor for Parkinson’s disease (PD), but the precise molecular mechanisms underlying the disease are not fully understood. Recent advances in genetics and pathophysiology of PD have increased our understanding about the fundamental processes contributing to disease pathogenesis but in the majority of cases the precise etiology is unknown. However, evidence suggests that protein aggregation, mitochondrial dysfunctions, ER stress, neuroinflammation and reduced growth factor levels contribute to neurodegeneration and play key roles in PD , so that novel protein targets for the kinase should be experimentally verified under actual physiological conditions.c-Abl ABL1) is the cellular homolog of the Abelson murine leukemia virus oncogene and belongs to the Abl family of tyrosine kinase present in the cytoplasm and nucleus of the cell. c-Abl is expressed in most cells and is part of an intricate network of protein interactions and phosphorylation events in the cell  neurotoxin model of PD  was the first c-Abl tyrosine kinase inhibitor identified and has been used in the treatment of CML now for several years  is a second-generation c-Abl tyrosine kinase inhibitor that is used in CML in a daily dose of 300 mg to over 1000 mg per patient  c-Abl in the cerebrospinal fluid of treated PD patients  FS-ZONE Investigators ). FutureAll authors contributed to the writing of the manuscript that was finalized by DL.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The function of the reticulo-endothelial system in mice bearing Lewis lung carcinomas has been measured by(1) the rate of clearance of carbon particles from the circulation in vivo and calculation of the phagocytic index K; (2) chemotactic locomotion of macrophages in vitro in the presence or absence of serum or tumour supernate. The ability of the bone marrow to develop macrophage colonies in vitro in the presence or absence of sera from tumour-bearing mice has also been tested. A clear depression of macrophage locomotion and macrophage colony formation in vitro was found in the presence of sera or tumour supernates from tumour-bearing mice as early as 24 to 72 h after tumour inoculation. Similarly, tumour-bearing mice showed marked depression of carbon clearance in tests repeated throughout the first 72 h after tumour inoculation. This early depression of macrophage function may be an important step in allowing escape of tumour cells from host resistance.


A case-control study was performed to determine the role of rural factors including occupation and previous malaria exposure in the development of classic Kaposi's sarcoma (CKS) in a high incidence area of Europe. The occurrence of CKS association with other malignancies was also examined. The results showed that the risk of having CKS was significantly increased in subjects farming cereals, while a previous history of malaria did not influence the risk of developing CKS. A near-significant increase in associated tumours was found.


Fifteen published randomised trials comparing adjuvant chemotherapy with no chemotherapy in soft-tissue sarcoma (STS) were identified (1546 patients). A qualitative review and a meta-analysis of this published literature were performed. With the qualitative review it was not possible to synthesise the apparently conflicting results of individual trials. The meta-analysis of the published data suggests an improvement in survival at 2 years  and at 5 years  in favour of chemotherapy. However, the assumptions and approximations required to conduct this quantitative summary demand that the results are interpreted with caution. The only reliable means of assessing the current evidence on whether adjuvant chemotherapy has a role in the treatment of patients with STS, is to collect, check and reanalyse individual patients data (IPD) from each trial centrally, and formally combine the results in a stratified time-to-event analysis. Such an IPD analysis is currently being undertaken by an international collaborative group.


Prostate-specific membrane antigen (PSM) is a glycoprotein recognised by the prostate-specific monoclonal antibody 7E11-C5, which was raised against the human prostatic carcinoma cell line LNCaP. A cDNA clone for PSM has been described. PSM is of clinical importance for a number of reasons. Radiolabelled antibody is being evaluated both as an imaging agent and as an immunotherapeutic in prostate cancer. Use of the PSM promoter has been advocated for gene therapy applications to drive prostate-specific gene expression. Although PSM is expressed in normal prostate as well as in primary and secondary prostatic carcinoma, different splice variants in malignant tissue afford the prospect of developing reverse transcription-polymerase chain reaction (RT-PCR)-based diagnostic screens for the presence of prostatic carcinoma cells in the circulation. We have undertaken characterisation of the gene for PSM in view of the protein's interesting characteristics. Unexpectedly, we have found that there are other sequences apparently related to PSM in the human genome and that PSM genomic clones map to two separate and distinct loci on human chromosome 11. Investigation of the function of putative PSM-related genes will be necessary to enable us to define fully the role of PSM itself in the development of prostatic carcinoma and in the clinical management of this malignancy.


A study has been made of the relationship between socio-economic factors and the incidence of acute lymphoblastic leukaemia (ALL) of childhood. It was found that the incidence of childhood ALL in 12 areas of Queensland. Australia, correlated well with some indicators of above-average socio-economic status for these areas. A similar result was found when Brisbane City was studied separately. Social class was determined from the fathers' occupations at the time of diagnosis. There was found to be a higher than expected number of ALL cases in each of the upper 5 social classes and a lower than expected number in the remaining 2 lower classes. Factors associated with differences in lifestyle amongst the various social classes may increase or decrease the risk of development of ALL.


Dear Editor,et al.[We read with great interest the article titled “Pneumatic displacement and intravitreal bevacizumab: A new approach for management of submacular hemorrhage in choroidal neovascular membrane” by Chawla S et al.We would like to share our experience of a 52-year-old male patient who presented with blurring of vision in the right eye for the last one month and a sudden drop of vision with a central black spot of two days duration. The best corrected visual acuity (BCVA) was counting fingers close to face in the right eye and counting fingers at 4 meters in the left eye. Intraocular pressure and slit-lamp examination were within normal limits. Fundus examination of the right eye showed submacular hemorrhage with breakthrough vitreous hemorrhage  and the Fundus examination of the right eye after one week showed displacement of the submacular hemorrhage inferiorly . FFA of At nine months follow-up the BCVA in the right eye was 20/120P, N36. Fundus examination showed old sub-retinal hemorrhage displaced to the lower macular area. FFA of the right eye showed a scarred CNVM with blocked fluorescence in the inferior macular area corresponding to the persistent old hemorrhage. Optical coherence tomography of the right eye showed a normal foveal contour and the scarred extrafoveal CNVM.et al.,[Management of the cases with submacular hemorrhage secondary to CNVM are often challenging. Various treatment options are available for the submacular hemorrhage such as pneumatic displacement with or without TPA or vitrectomy with evacuation of the blood. Chawla et al., in theirAs mentioned in the literature, the visual prognosis in cases with submacular hemorrhage depends on a number of factors such as location of the CNVM , duration of the submacular hemorrhage - longer the duration worse is the prognosis due to photoreceptor damage, level of the hemorrhage -sub-retinal or sub-retinal pigment epithelial (RPE), the size and the thickness of the hemorrhage and lastly the underlying disease process.The combination of gas tamponade with an anti-vascular endothelial growth factor (VEGF) such as bevacizumab without using TPA does provide an inexpensive treatment option to our patients, however, the visual recovery may not always be predictable.


The sensitivity to melphalan of clones derived from individual lung colonies produced by i.v. injection of cells of the MT murine mammary carcinoma (caMT) and its melphalan-resistant sub-line (MTME16) has been examined. A degree of clonal heterogeneity was observed which was greater than could be explained by experimental variation. The distribution of melphalan sensitivities in both wild-type caMT and MTME16 raises questions as to the validity of a two-compartment model of drug-resistance development in tumours. A more complex model, possibly involving a continuous spectrum of drug sensitivity, is required. Differences in the sensitivity of the clonal lines of wild-type caMT in various passages were observed and this would appear to be due to phenotypic instability in these lines. This suggests that to use survival data from clones which have been passaged many times for predicting the response of the parent tumour may be misleading.


A rare case of lymphoepithelial cyst formed in the piriform sinus of the hypopharynx is reported. Histopathological examination revealed a lymphoepithelial cyst. It was removed by laryngomicrosurgical technique using a side-opened direct laryngoscope. Because this cyst was wide-based on the antero-medial region in the right piriform sinus of the hypopharynx, the mucous membrane around the cyst was incised electrosurgically and then detached to facilitate removal. In this paper, we describe our surgical procedure for removing the cyst in this case and discuss the possible causes of the disease.


The pharmacological interest in lonidamine is related to its ability to enhance the cytotoxic effects of several DNA-damaging anti-tumour agents. This study was undertaken to better understand the in vivo interaction between lonidamine and cisplatin in the treatment of human tumour xenografts, including three carcinoma models characterized by a different responsiveness to cisplatin, in spite of the presence of a wild-type p53 gene in all tumours. The drug combination was more effective in tumour growth inhibition than cisplatin alone against MX-1 breast carcinoma and A2780 ovarian carcinoma, both highly responsive to cisplatin, whereas no influence of ionidamine was observed on anti-tumour activity of cisplatin in the treatment of the relatively resistant IGROV-1 ovarian carcinoma. As cisplatin activity is related to induction of apoptosis, the modulation of drug-induced apoptosis by lonidamine was investigated. Under conditions in which lonidamine itself had negligible effects on tumour growth and apoptosis, the modulating agent stimulated the apoptotic response induced by cisplatin in the responsive but not in the resistant tumours. Tumour response was dependent not only on the drug activation of apoptosis, but mainly on the persistence over time of the event. In the breast carcinoma MX-1, hypersensitive to cisplatin and to the lonidamine+cisplatin combination, the efficacy of drug treatment was associated with phosphorylation of bcl-2 followed by down-regulation of the protein. Lonidamine itself caused a delayed phosphorylation of bcl-2. These results are consistent with the interpretation that lonidamine is effective in modulating biochemical factors involved in regulation of apoptosis.


The reactivity of alpha-1-antitrypsin (AAT) with Lens culinaris agglutinin (LCA) was studied by crossed immuno-affinity electrophoresis of the sera of 246 subjects from 6 groups , carcinoma metastatic to the liver and normal controls). Two species of AAT (LCA-reactive and -nonreactive species) were detected on crossed immuno-affinity electrophoresis in a gel containing LCA. The percentages of LCA-reactive species of AAT in neoplastic diseases of the liver were significantly higher than those in benign liver diseases and normal controls. There was no correlation between the percentage of LCA-reactive species of AAT and serum AAT concentration in any group. Furthermore, in studying 15 pairs of serum samples before and after the subsequent development of HCC, the percentage of LCA-reactive species of AAT after HCC occurrence was significantly higher than that before, although there was no statistically significant difference between the serum AAT concentration before and after development of the disease. The latter 15 patients were all of the normal protease inhibitor phenotype (PiMM) and no change in phenotype was observed before and after the development of HCC. The results indicate that measurement of the reactivity of AAT with LCA can be a useful marker for the diagnosis of HCC and carcinoma metastatic to the liver, especially when serum concentrations of alpha-foetoprotein or other tumour markers are within the normal ranges.


Skeletal lesions in multiple myeloma are predominantly lytic and when non-union of pathological fractures occur it is typically atrophic. We report a lady of 61 years of age with myeloma who presented with a pathological fracture through an ulnar myeloma deposit. The fracture was immobilised initially then irradiated. Nine months later she re-presented with marked forearm pain particularly on rotation. Radiographs demonstrated a hypertrophic non-union of a pathological fracture with a typical elephant's hoof appearance. The fracture was immobilised using an ulnar nail. Whilst non-unions in metastatic malignancy are typically atrophic, just occasionally hypertrophic non-unions can occur. Management principles remain the same with stabilisation of the entire bone and early mobilisation being appropriate. Multiple myeloma (MM) is an incurable disease that is characterised by the accumulation of clonal plasmocytes in the bone marrow . It accoThe characteristic bone lesion seen in myeloma is a sharply defined small lytic area with no reactive bone formation arising in the medulla; the absence of bone sclerosis is due to an inhibition of osteoblastic activity . InvolveRadiotherapy often forms an important part of management and can lead to resolution of bone lesions . We repoA 61 year old lady with multiple myeloma, diagnosed nine years previously presented to our fracture service with pain in her right forearm. On examination it was painful over the mid-aspect of her forearm with no superficial erythema or swelling. She was neurovascularly intact. Radiographs revealed an undisplaced pathological fracture of the ulna  of her pain was 9 out of 10. Radiographs demonstrated that she had gone on to develop hypertrophic non-union  of her pathological ulna fracture Figure . The oriThe fracture was stabilised with a reamed Foresight ulnar nail  especially in the lower thoracic or lumbar vertebral bodies .Radiation therapy for the treatment of bone tumours and soft-tissue sarcomas may deliver damaging doses of radiation to skeletal bone . It is kFailure of bone healing or non-union results from an arrest of the healing process. A non-union that occurs despite the formation of a large volume of callus around the fracture site is commonly referred to as a hypertrophic non-union whilst in an atrophic non-union, little or no callus forms and bone resorption occurs at the fracture site . FracturWhilst non-unions in metastatic malignancy are typically atrophic, just occasionally hypertrophic non-unions can occur. This is a rare occurrence and the management principles remain the same with stabilisation of the entire bone and early mobilisation being appropriate.Written informed consent was obtained from the patient for publication of this case and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.TO assessed the patient, participated at surgery and was responsible for drafting the article and collating all relevant images; RUA conceived the idea for the case report, performed the surgery and was involved in review of the manuscript. All authors read and approved the final manuscript.


The carcinogenic effects of radium and X-rays on the rat uterus have been investigated. Malignant endometrial tumours, usually adenocarcinomas, were produced in a small proportion of treated rats. One rat treated with X-rays developed an adeno-sarcoma (possibly carcino-sarcoma) of the endometrium. Benign mixed polypoidal endometrial tumours occurred also in radium and X-ray treated rats and in non-radiated controls; radiation increased the incidence of these tumours and may have induced malignant transformation in some. The incidence of lymphosarcomas and mammary tumours in the strain of rat used appeared to be influenced by radiation treatment.Review of the literature of human cases of mixed uterine tumours showed that in women over 40 years, more than one-fifth of the reported cases had a history of previous pelvic radiation; with other kinds of uterine malignancy a history of prior radiation treatment was considerably less. The results of our experiments enhance the suspicion that radiations are one factor in the causation of uterine cancer, especially mixed tumours.


Sir,We would like to thank Gianluigi Ferreti and his colleagues for their interest in our systematic review.et al. interrogated on the prognostic role of Ras in NSCLC. They cited seven studies with apparent conflicting results. Some comments have to be made. First, we discussed in our articles the controversial results of the literature relative to biological prognostic factors, justifying the need for meta-analyses, as we reported with K-Ras (In their letter, Ferreti et al. Some of these articles were not included in our systematic review for the following reasons:no prognostic analysis (no survival prognostic analysis but assessment of the predictive role of K-Ras for response to chemotherapy (assessment of K-Ras mutation on resected tumours after induction chemotherapy (publication after the deadline for the selection of the studies to be included in the meta-analysis (Secondly, we have some concerns with the studies cited by Ferreti et al commented (The last two studies that Ferreti In conclusion, our systematic review showed that K-Ras is a potential prognostic factor for survival in lung cancer according to the literature published on this topic till end of 2003. The predictive role of K-Ras for response to chemotherapy and the impact of K-Ras mutation on survival in patients receiving induction chemotherapy before surgery were not the subjects of our meta-analysis and need further investigations.


Purpose.  Conservative treatment in the form of limited surgery and post-operative            radiotherapy is controversial in hand and foot sarcomas, both due to poor radiation            tolerance of the palm and sole, and due to technical difficulties in achieving adequate            margins.This paper describes the local control and survival of 41 patients with soft tissue            sarcoma of the hand or foot treated with conservative surgery and radiotherapy.            The acute and late toxicity of megavoltage radiotherapy to the hand and foot are described.            The technical issues and details of treatment delivery are discussed.            The factors influencing local control after radiotherapy are analysed.            Subjects .  Eighteen patients had sarcomas of the hand and 23 of the foot.            All patients received post-operative radiotherapy, the majority receiving a dose of 60            Gy in 2-Gy daily fractions using a two-phase treatment.            Results .  The acute and late toxicity of treatment were within acceptable limits.            The actuarial 5-year overall survival of the whole patient group was 67.6% and the            local relapse-free survival was 44%.The local control was similar in tumours of hand            and foot, and in patients treated at first presentation or relapse.            Discussion.  Post-operative radiotherapy to the hand or foot appears to be a well            tolerated treatment resulting in long-term local control in a significant proportion of patients.            The increased frequency of recurrence within the high-dose volume           suggests the need for the use of higher total doses of radiotherapy.


Intra-medullary nailing is a standard form of treatment for diaphyseal tibial fractures. Insertion of the nail requires threading of the nail over a smooth guide-wire. Inadvertent complications during this stage have been reported. We report a case of inadvertent penetration of the tibio-talar joint by the smooth guide wire caused by incarceration of a fracture fragment between the nail and the guide wire at the time of insertion. This was noted intra-operatively. The guide-wire and the nail were removed followed by insertion of a new nail and completion of the procedure. The patient did not have any symptoms attributable to this at the time of healing of her fracture. A 54 year old Sri Lankan woman was admitted for management of a grade 1 open fracture of both bones of her right leg. She also had a proximal humerus fracture on the left shoulder. After preliminary care in the emergency room, she was taken up for definitive surgical treatment of her fractures. The wound in her right leg was excised and primarily closed. This was followed by intra-medullary nailing of the tibia. A knobbed guide-wire was inserted through a patellar tendon-splitting approach through the tibial tubercle. This was followed by reaming of the medullary canal. The knobbed guide-wire was exchanged for a smooth guide wire followed by insertion of the nail. As the nail was hammered inside, a prominence was felt on the skin of the sole. Checking under image intensifier revealed that the guide-wire had penetrated the ankle and the sub-talar joint . The naiAt the time of the last follow up, the patient did not have any residual ankle problems attributable to the complication.Complications related to guide-wires have been reported during intra-medullary nailing . Guide-wet al.We have had a similar complication in our patient who underwent closed reamed intramedullary nailing of fracture of her tibia. However, our case was considerably different from the previous report. The penetration of the wire was detected intra-operatively when the assistant felt the guide wire in the sole of the patient’s foot. This had happened at the time of insertion of the nail over a straight guide-wire without any ball-tip . The nai


The development of monoclonal antibodies (mAb) reactive with the thymicmicroenvironment has identified distinct subpopulations within the stromal component,but the function of these subregions in intrathymic T-cell differentiation remainsessentially an enigma. In this study, we have used such a panel of mAb to examine thechicken thymus during ontogenic development to gain insight into the contributions ofthese thymic regions to the distinct phases of T-cell development and to furthercharacterize the development of this organ. Our reagents have demonstrated thecomplex differentiation of the primitive endodermal epithelium into more specializedstructures and the development of other thymic stromal components frommesectodermal cells. We also describe molecules localized to the subcapsular andperivascular regions, which have an ontogenic expression corresponding to the earlylocalization and stimulation of thymic precursors and another molecule on themedullary vasculature expressed corresponding to the exit of mature cells from thethymus. In addition, two markers of distinct medullary epithelial clusters are initiallyexpressed corresponding to the appearance of T-cell receptor-1 (TcR-1) and TcR-2positive cells in the medulla, respectively. These mAb potentially represent excellentreagents for further definition of the thymic modulation of T-cell differentiation.


A 17-year-old patient with a small paratesticular embryonic sarcoma presented with symptoms of renal failure, polyuria and widespread bone metastases. Investigation revealed hypercalcaemia and uraemia without any evidence of hyperparathyroidism. The hypercalcaemia responded over a period of weeks to administration of mithramycin with initial improvement in the symptoms and metabolic derangements. Control was lost with the necrosis of intra-abdominal tumour deposits and haemorrhagic polypoid deposits in the alimentary tract. The value and hazards of mithramycin are well demonstrated by these rare complications of this type of tumour.


There may be need to assess intelligent quotient (IQ) scores in sub-Saharan African children with intellectual disability, either for the purpose of educational needs assessment or research. However, modern intelligence scales developed in the western parts of the world suffer limitation of widespread use because of the influence of socio-cultural variations across the world. This study examined the agreement between IQ scores estimation among Nigerian children with intellectual disability using clinicians' judgment based on International Classification of Diseases, tenth Edition(ICD - 10) criteria for mental retardation and caregivers judgment based on 'ratio IQ' scores calculated from estimated mental age in the context of socio-cultural milieu of the children. It proposed a viable option of IQ score assessment among sub-Saharan African children with intellectual disability, using a ratio of culture-specific estimated mental age and chronological age of the child in the absence of standardized alternatives, borne out of great diversity in socio-cultural context of sub-Saharan Africa.Clinicians and care-givers independently assessed the children in relation to their socio-cultural background. Clinicians assessed the IQ scores of the children based on the ICD - 10 diagnostic criteria for mental retardation. 'Ratio IQ' scores were calculated from the ratio of estimated mental age and chronological age of each child. The IQ scores as assessed by the clinicians were then compared with the 'ratio IQ' scores using correlation statistics.A total of forty-four (44) children with intellectual disability were assessed. There was a significant correlation between clinicians' assessed IQ scores and the 'ratio IQ' scores employing zero order correlation without controlling for the chronological age of the children . First order correlation controlling for the chronological age of the children showed higher correlation score between clinicians' assessed IQ scores and 'ratio IQ' scores .Agreement between clinicians' assessed IQ scores and 'ratio IQ' scores was good. 'Ratio IQ' test would provide a viable option of assessing IQ scores in sub-Saharan African children with intellectual disability in the absence of culture-appropriate standardized intelligence scales, which is often the case because of great diversity in socio-cultural structures of sub-Saharan Africa. One of the earliest objectives of developing scales to assess intelligence among children was to determine those children that would require special attention and instructions in educational systems. Alfred Binet, the French psychologist published the first modern intelligence test called Binet-Simon intelligence scale in 1904 .William Stern, the German Psychologist coined the abbreviation, 'IQ (intelligence quotient)' in 1912, with a proposition that individual's intelligence level can be measured as a quotient of mental age and chronological age. This proposition was adapted into the revised Binet-Simon scale which became the Stanford-Binet scale which was published in 1916 by Lewis Terman from Stanford University. The Stanford-Binet intelligence scale led to a mental age score and IQ was calculated as a percentage of mental age and chronological age ratio .Subsequently over the years, standardized intelligence scales that based IQ scoring on normal distribution curve rather than age-based quotient had been developed . The newThe modern standardized intelligence scales like Wechsler Intelligence Scales for Children  had been known to be influenced by socio-cultural variations in different environments that impact on child rearing practices and cultural expectations of a child in a particular society -6.It is well established that both genes and environments have influence on cognitive abilities ,8. FactoThe great diverse multi-ethnic and multi-culture nature of sub-Saharan African regions are often impediments to developing comparable standardized IQ assessment scales among children that would cut across sub-cultures as obtained in the Western region of the world. Nigeria for example, which is a country in sub-Saharan Africa has well over three hundred major and minor ethnic tribes and sub-cultures ,16 that The attendant influence of socio-cultural variations across regions on cognitive ability and social competence of children, necessitated the provision of a general guide by Diagnostic Criteria for Research of International Classification of Diseases, tenth Edition (ICD - 10)  for asseThis study assessed the agreement between 'ratio IQ' scores calculated from ratio of mental age and chronological age of children with intellectual disability as assessed by nursing staff and teacher (care givers) and clinicians' assessed IQ scores, based on the categories specified in the Diagnostic Research Criteria of ICD - 10 for mental retardation .The location of the study was the Therapeutic Care Center (TCC), Abakpa, Enugu, Nigeria. This privately owned center provides special educational instructions, and behavioral modification to children with intellectual disabilities in south eastern Nigeria. The participants are children with intellectual disability admitted into the boarding facility of the TCC, Abakpa, Enugu, Nigeria. All children with suspected learning disability admitted into the center were studied. The children have associated co-morbid medical conditions ranging from Pervasive developmental disorders (PDD), Down syndrome and Cerebral palsy.Ethical approval for this study was obtained from the Institutional Review Board (IRB) of Federal Neuro-Psychiatric Hospital, New Haven, Enugu, Enugu State, Nigeria. Informed consent was obtained from the parents of the children studied and from the authority of Therapeutic Care Center (TCC), Abakpa, Enugu, Nigeria.This questionnaire was designed to obtain socio-demographic information of the children, which included their chronological or actual age and mental age as estimated by the consensus agreement of the nursing staff and teacher (care givers) who are of the same socio-cultural background with the children and responsible for the care of each child studied at the TCC, Abakpa, Enugu, Nigeria. From the information obtained about the estimated mental age and chronological age of the children, 'ratio IQ' score was calculated for each child using a ratio of culture-specific estimated mental age and chronological age multiply by a factor of 100.The diagnostic criteria stated that depending upon the cultural norms and expectations of the individuals being studied; research workers must make their own judgments as to how best to estimate intelligence quotient (IQ) or mental age according to the bands given in Table Two clinicians that are of the same socio-cultural background with the children independently assessed each child with the diagnostic criteria in Table The socio-demographic questionnaire was used to obtain information from which 'ratio IQ' score was calculated for each child. Each child was also assigned IQ scores based on the clinicians' assessment and placement of the child in specific diagnostic categories as spelt out in ICD - 10 diagnostic criteria  shown inTwo major specific areas were assessed to estimate the mental age of the children which are:i. Cognitive ability - This was assessed based on age appropriate;Verbal test.• Ability of the child to communicate, being able to pronounce words, phrases and sentences that are comprehensible and appropriate for age - Performance test.• Ability of the child to copy and draw shaped objects such as circles, squares and triangles - ii. Social competence - This was assessed based on the age appropriate;Adaptive self care.• Ability of the child to care for self, which includes cleaning up self and dressing for classes in the morning. This was rated in the range of, Need hundred percent help in caring for self; Need substantial help in caring for self and, Need minimal help in caring for self - Adaptive social skills.• Ability of the assessed children to relate with other pupils and teachers in the areas of expressing their needs and wants - The criteria followed by the clinicians in assigning the assessed children to specific diagnostic category of ICD-10 criteria for mental retardation were essentially the same as that followed by the teachers and nursing staffs in estimating the mental age, with the exemption that assessment of social competence by the clinicians were based on observation of the children's ability to relate with other pupils and the teachers to express their needs and wants.The clinicians involved in assessment of the children are psychiatrist trainees at Senior Registrar level of their training and had been working with children with learning disabilities for a minimum of six months period. All assessment by the clinicians, teachers and the nursing staffs were based on the same specific socio-cultural milieu with the children assessed.The major difference between the care givers' and clinicians' assessment is that the clinicians had access to categories of ICD-10 diagnostic criteria for mental retardation and based their assessment on this, but the care givers did not. The IQ of each child was assessed by the care givers from a ratio of estimated mental age and the chronological age of the child.Data were analyzed using the Statistical Package for Social Sciences (SPSS), version 15.The frequency and percentage distribution of the children in different diagnostic categories of mental retardation as specified by ICD - 10  based onA total of forty four (44) children with intellectual disability were independently assessed by the care-givers and the clinicians for estimation of mental age and classification under different categories of ICD - 10 diagnostic criteria for mental retardation . There wThe actual or chronological age range of the children was from 4 to 18 years. The mean chronological age of the children was 13.16 ± 3.58 years. The mean mental age as assessed by the care-givers was 4.82 ± 1.90 years. The mean mental age as assessed by the clinicians using ICD - 10  diagnostFour (9.1%), 27 (61.4%), 11 (25.0%) and 2 (4.5%) of the children with intellectual disability were classified under the ICD - 10 categories of F 70, F 71, F 72, and F 73 respectively as assessed by both the clinicians' IQ scores and calculated 'ratio IQ' scores.2 = 0.00, df = 3, p = 1.000).Table Correlations between mean IQ scores as assessed by the clinicians, using the median IQ scores in each diagnostic category and mean 'ratio IQ' scores as calculated from ratio of estimated mental age and chronological age of each child.When the chronological/actual ages of the children were not controlled for, the correlation between clinicians' assessed IQ scores and 'ratio IQ' scores was statistically significant . The zero order correlation co-efficient is shown in Table When the chronological/actual ages of the children are controlled for, the correlation between clinicians' assessed IQ scores and 'ratio IQ' scores showed a much higher level of statistical significance .Figure Both the clinicians' assessment of IQ scores and 'ratio IQ' scores calculation based on mental age as estimated by the care-givers showed agreement in classification of the children into different diagnostic categories of mental retardation as specified by ICD - 10 . The corThe observation that cultural background could influence neural activity that underlies both high and low level cognitive function  indicateSpecial educators providing educational instructions to children with intellectual disability may need a quick assessment of a child IQ score in sub-Saharan African sub-cultures, where there is wide variation in cultural practices and societal structures. Employing a ratio of culture-specific estimated mental age and chronological age of the child would provide a viable option in the absence of culture appropriate standardized 'deviance IQ' tests like Wechsler Intelligence Scales for Children  used widely among children in the western parts of the world.Both the clinicians' assessment of IQ scores and estimation of mental age of the children by the care-givers from which the 'ratio IQ' scores were derived were subjective. However, the effect of this subjectivity had been cushioned by allowing two independent assessors with the same socio-cultural background with the children in each case of the clinicians and care-givers to reach a consensus on a particular child following the criteria highlighted in the procedure section. The 'ratio IQ' scores produced for each child from the estimation of mental age would serve an approximate guide in educational needs assessment of these children and for purpose of research.Another limitation of mental age estimation in children as proposed by this study is that, lack of background knowledge of normal child development by the care-givers may constitute an impediment in estimation of mental age. It is therefore recommended that people in position of caregivers willing to estimate mental age of children with intellectual disability according to the procedure highlighted in this study have some background knowledge of normal child development.In view of the confounding cultural and environmental influence on human intelligence -14, therTherefore, for the purpose of educational needs assessment and research in sub-Saharan African children with intellectual disability, consensus estimation of mental age in relative to peculiar socio-cultural milieu of the child would provide a viable option of estimating IQ score through the ratio of estimated mental age and chronological age of the child, in the absence of culture appropriate standardized 'deviance IQ' tests.The authors declare that they have no competing interests.All authors contributed to the conception of the study. MOB was involved in writing the initial draft of the manuscript. MOB, VNU, INO, CMA and POE were involved in revising the manuscript. All authors read and approved the final draft of the manuscript.


Ten cell lines of human squamous carcinomas of the tongue and larynx have been established from surgical specimens removed from 36 unselected patients, in order to provide systems for investigating the invasive and tissue-destructive capacity of squamous carcinomas of the head and neck. The morphology, ultrastructure and growth characteristics of the 10 lines are described. Detailed cytogenetic analysis of the first 4 lines indicates that each is karyotypically unique, with no evidence of cross-contamination. Nine of the 10 cell lines secrete immunoreactive beta human chorionic gonadotrophin (beta-hCG) in the culture medium. No correlation was demonstrated between the ability of the cell lines to secrete plasminogen activator and their capacity to grow in soft agar or as xenografts in immune-deficient mice.


A total of 165 adult patients with Hodgkin's disease (HD) were questioned following treatment to examine their perceptions of actual and desired involvement and provision of information in the treatment decision-making process. Irrespective of the degree to which patients felt they had been involved in the decision-making process and of the outcome of their particular treatment, patients who felt satisfied with the adequacy of information given were significantly more likely to feel happy with their level of participation in the overall process of decision-making (P < 0.001). As part of a strategy investigating patient priorities, patients were asked to rank a series of possible acute and late treatment-related morbidities. Counter-intuitively, the majority of long-term survivors felt early short-term side-effects were more, or equally, as important as late morbidity with respect to influencing choice of therapy. Unpredictable importance was placed by patients on side-effects such as weight gain and fatigue in relation to other complications such as infertility and risk of relapse. Patients do not necessarily share doctors' priorities in decision-making or place the same emphasis on different types of morbidity. Experienced surrogates may assist us in understanding patients' perspectives and priorities.


Gorham's (vanishing bone) disease is an extremely rare condition of the bone. The diagnosis is usually made on the basis of the characteristic history of osteolysis and failure of bone healing in conjunction with the histological findings of marrow fibrosis and increased vascularity. When the disease is established, an X-ray and magnetic resonance imaging show complete loss of affected bone. There are very few reports found in literature on bone scan appearance of the disease. A bone scan of a 24-year-old female patient with known Gorham's disease revealed absence of tracer uptake in the right iliac bone, right sacroiliac joint, and part of the right ischial pubic rami, which matched the radiographic abnormalities. Consequently this disease should be added to the gamut of cold defects seen on bone scan. Gorham's (vanishing bone) disease is an extremely rare condition of the bone. The diagnosis is usually made on the basis of the characteristic history of osteolysis and failure of bone healing in conjunction with the histological findings of marrow fibrosis and increased vascularity. When the disease is established an X-ray and MRI show complete loss of affected bone. Very few reports are found in literature on bone scan appearance of the disease.A bone scan was performed on a 24-year-old female patient with known Gorham's disease. This was correlated with a pelvic radiograph and corresponding MRI.Images showed absence of tracer uptake in the right iliac bone, right sacroiliac joint, and part of the right ischial pubic rami, indicating absence of bone in the mentioned regions, which matched the absent bone tissue on the pelvic X-ray  and 2.Cold defects on bone scan have been reported in many disease conditions. Gorham's


Aprotinin was bound and endocytosed by Landschütz ascites carcinoma (LAC) cells in vitro. Addition of the antiprotease to cultures of these cells led to a dose-dependent growth-inhibitory and cytotoxic effect. In mice inoculated with LAC cells and treated with aprotinin there was a transient reduction in both the number and concentration of recovered ascites cells during the early phase of tumour growth. This was accompanied by a temporary increase in the proportion of peritoneal phagocytes (mononuclear phagocytes and polymorphonuclear leucocytes) relative to carcinoma cells. However, the number and concentration of ascites cells eventually achieved was comparable in saline and aprotinin-treated animals.


Bronchomalacia in adults is rare. A case is reported here of a 65-year-old man with severe cough and mucostasis, caused by a benign bronchomalacia of the ventral wall of the left main bronchus. Thiswas treated successfully with the insertion of a silicone Dumon stent as an alternative to surgicalbronchoplasty.


The effects of doxorubicin on the cellular biochemistry of the HeLa cell using 1H spin echo nuclear magnetic resonance spectroscopy (NMR) of the intact and viable cell in conjunction with dual wavelength HPLC of cell lysates is reported. Directly dose-related changes were observed in lactate and reduced glutathione concentration. Doxorubicin induces a time-dependent depletion of the cytosolic pool of glutathione and a change in the glycolytic pattern of the cell. The glutathione depletion could be partially reversed by controlled pre-treatment of the cells with N-acetylcysteine and cysteine, the protection being linked to the intracellular concentration of the thiol.


The formulae for calculation of carry-over and sample interactionare derived for the first time in this study. A scheme proposed by Thiers et al. (two samples of low concentration followed by a high concentration sample and low concentration sample) is verified and recommended for the determination of the carry-over coeffcient.The derivation demonstrates that both widely used schemes of a high concentration sample followed by two low concentration samples, and a low concentration sample followed by two high concentration samples actually measure the sum of the carry-overcoeffcient and sample interaction coefficient. A scheme of three low concentration samples followed by a high concentration sample is proposed and verified for determination of the sample interaction coeffcient. Experimental results indicate that carry-over is a strongfunction of cycle time and a weak function of ratio of sample time to wash time. Sample dispersion is found to be a function of sample time. Fitted equations can be used to predict the carry-over, absorbance and dispersion given sample times, and wash timesfor an analytical system. Results clearly show the important role of intersample air segmentation in reducing carry-over, sample interaction and dispersion.


Data on self-reported cancer by a sample of 3349 elderly persons in the south-west of France were validated against registry data in the same region: only 21% of the persons on the cancer registry reported occurrence of cancer. Breast cancer was found to be most frequently accurately reported.


Anorectal malformation, one of the most common congenital defects, may present with a wide spectrum of defects. Almost all male patients present within first few days of life.A five-month-old baby boy of Indian origin and nationality presented with anal atresia and associated rectourethral prostatic fistula. The anatomy of the malformation and our patient's good condition permitted a primary definitive repair of the anomaly. A brief review of the relevant literature is included.Delayed presentation of a patient with high anorectal malformation is rare. The appropriate treatment can be rewarding. Anorectal malformation (ARM) is one of the most common congenital defects having an incidence of between one per 1500 and one per 5000 live births . This anARM may present with a wide spectrum of defects, ranging from relatively low malformations to very complex high defects . ARMs arA five-month-old baby boy of Indian origin and nationality presented to the department of Pediatric Surgery at the Institute of Medical Sciences, Banaras Hindu University with absent anal opening, along with passage of flatus and feces through the urethra since birth without any problem Figures  and 2. OOur patient was planned for the primary posterosagittal anorectoplasty (PSARP). Intra-operatively, a large rectourethral prostatic fistula was found and closed. The post-operative period was uneventful Figure  and the The bad financial conditions of the family led to the delayed presentation of the child to a specialist.The most unusual fact of this case is the age of presentation. As mentioned previously, male patients with ARM usually present within the first four or five days of life. This is due to the presence of a narrow fistulous communication between the rectum and the urinary tract, which does not allow the bowel to decompress.Although the diagnosis of ARM is made at birth , the sitA (long-term) study noticed  that allThis case has a few peculiarities. First, it is probably the oldest ever reported case of high ARM presenting at five months of age; the previous case presented at 45 days of life . Second,This is an extremely uncommon case of a patient with high ARM in respect of the anatomy of malformation and the time of presentation. A primary repair without colostomy is unusual in such patients, but proved to be appropriate and successful in this child having a large fistula and a non-distended rectum.The authors declare that they have no competing interests.ANG, SPS and AP operated upon the patient. AP, ANG and VK carried out the literature review. All authors read and approved the final manuscript.Written informed consent was obtained from the parents of the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the journal's Editor-in-Chief.


It has been shown that thin metal-based films can at certain frequencies act as planar near-field lenses for certain polarization components. A desirable property of such “lenses” is that they can also enhance and focus some large transverse spatial frequency components which contain sub-diffraction limit details. Over the last decade there has been much work in optimizing designs to reduce effects  that are detrimental to image reconstruction. One design that can reduce some of these undesirable effects, and which has received a fair amount of attention recently, is the stacked metal-dielectric superlens. Here we theoretically explore the imaging ability of such a design for the specific purpose of imaging a fluorescent dye (the common bio-marker GFP) in the vicinity of the superlens surface. Our calculations take into consideration the interaction (damping) of an oscillating electric dipole with the metallic layers in the superlens. We also assume a Gaussian frequency distribution spectrum for the dipole. We treat the metallic-alloy and dielectric-alloy layers separately using an appropriate effective medium theory. The transmission properties are evaluated via Transfer matrix ( In conventional far-field fluorescence microscopy the spatial resolution is severely restricted by the diffraction-limit The use of superlenses for fluorescent imaging purposes is additionally complicated by the interactions between the fluorescent dyes and the metal film(s), which will distort the local field The electric field of GFP can as a first approximation be taken as that of an oscillating electric dipole with a finite frequency spectrum, and described by a Gaussian with its peak at The superlens we consider consists of a stack of The interactions of electric dipoles with metallic surfaces and tips has been studied theoretically Changes in the emission spectra and lifetime of a dipole due to near-field interactions with very thin  and propagation matrices (P). For a stacked superlens with M is:We write the electric fields with the position dependent modified frequency on the sample side of the superlens as P for a layer T for the interface between layers The indexes The Optical Transfer Function (OTF) is determined by the ratio of the total emerging and incident field. For a range of superlens-source distances we find the largest OTF is obtained when Reconstructed images of oscillating electric-dipoles with their axis perpendicular and parallel to the superlens surface are studied as a function of distance from the superlens. We find that the transmitted intensity increases by a factor of not adjusted but fixed at We find that, for negligible absorption in both the source medium (water) and dielectric layer, the superlens is characterized by very high transmission in and around the The results of a similar self consistent calculation for the change in a In this manuscript we have theoretically studied a double-layer planar superlens for fluorescence imaging applications. We have found that when the parameters  are tuned the superlens is characterized by a high transmission at desirable wavelengths. Whilst the maximum theoretical resolution of the proposed superlens may be very high see e.g.  & Fig. 3A fluorophores brightness will depend in detail on numerous factors, such as the fluorophore's local environment In the far-field the maximum resolution is often estimated using the Rayleigh Criterion. In the near-field however a definition of resolution is somewhat more arbitrary, and will depend a greater deal on the photon statistics irection , we findIn One interesting question is whether the change in the fluorescence decay-rate with fluorophore-superlens distance can be used for obtaining 1) The complicated interactions of the sample with the dynamic SNOM probe 2) The superlens-SNOM approach would allow for the study of processes in viscous or inhomogenious media and at (cell) surfaces in which direct SNOM scanning is either very complicated or not possible. In the SNOM-superlens setup the superlens may be fabricated on an ultra-thin silicon based membrane, which could in itself be part of the superlens structure - e.g. the middle dielectric layer (see A promising method of image acquisition would be to fabricate a sub-wavelength grating on the image side of the superlens. It is then possible to reconstruct the sub-diffraction limit details by measuring the scattered propagating negative diffraction orders in the far-field ayer see .In conclusion we have presented calculations that suggest the feasibility of imaging a GFP-like fluorescent source through a stacked superlens. We have proposed a design based on a double layer metal-alloy/dielectric stack that operates slightly off resonance. Experimental realization of the introduced superlens will rely on overcoming the undesirable effects of surface roughness and the challenges associated with image acquisition discussed above. However, recent advances in nanofabrication technologies give a bright outlook for the use of stacked superlenses, such as the one discussed in this manuscript, in fluorescence imaging applications.


Docetaxel is a new taxoid with clinical activity in breast and lung cancer. Using docetaxel-sensitive and -refractory mammary and pancreatic murine tumours, as well as human-derived neoplasms, we investigated if a determinant of docetaxel sensitivity could be found at the level of its mechanism of action. Because microtubules represent the cellular targets of the drug, we studied their heterogeneity in the tumour models to try to explain the differences in drug sensitivity. Reverse transcription-polymerase chain reaction (RT-PCR) analysis of the expression of microtubular components showed that levels of Mbeta4-tubulin and Tau mRNAs were higher in the murine sensitive neoplasms than in the refractory ones. It was also found that Tau protein levels differed markedly among the tumours. In the human-derived sensitive neoplasm, beta-tubulins and some Tau isoforms were found to be more abundant than in the resistant one. Western blot analysis of MAP2 revealed the presence of several immunoreactive species. Some of these polypeptides were also found in higher amounts in the docetaxel-sensitive tumours. The possible meaning of these correlations is discussed in connection with the regulation of microtubule dynamics.