A large number of classical and recently discovered plants are indicated in preventing and/or treating Alzheimer’s disease (AD).Name of plants with their anti-AD effects are important for their further use and investigation.A short overview of AD is given; anti-Alzheimer plants are given in a Table.Various medicinal plants are listed here as sources of popular medicines to be used in cases when patients are afraid of developing and/or suffer from AD. Some of these plants have been used for centuries. The major sources in the literature, over one hundred of references are given for plants that show beneficial effect on the progress of AD. Plant extracts are widely used addition to the synthetic drugs approved by various administrative authorities to stop/slow down the progress of symptoms of AD. Its etiAn increasing number of herbal extracts, poly-herbal and herbo-mineral preparations and phytochemicals obtained from herbs have been studied for their neuroprotective potential in AD for the past decade. These above mentioned studies have supplied us with utilizable new drug therapies based on medicinal plants.2in vitro and in vivo adaptation of various plant extracts in AD. The therapeutic potential and postulated ways of action of these agents have been thoroughly examined in multiple experiments in earlier reviews [This review gives an overview of beneficial  reviews , 9. Rece reviews . As neurin vitro and in vivo models of AD.Encouraged by the success of galantamine, several medicinal plants and phytochemicals have been evaluated for the inhibitory effect against acetylcholine esterase enzyme (AChE) in both A variety of plants reported to show inhibition of AChE, may be considered promising for the treatment of AD associated cognitive decline . Given tin vitro and in vivo models of AD. Naturally occurring dietary polyphenol compounds such as curcumin, resveratrol and green tea catechins have received considerable attention as attractive candidates for AD therapy. These polyphenolic compounds have been demonstrated to prevent AD due to their antioxidant, anti-inflammatory, antiamyloidogenic effects and activating cellular stress adaptive to responses called “neurohormesis” process [Ginkgo biloba extract Egb761 has been the most frequently studied. Huperzine A, a cholinesterase inhibitor from Huperzia serrata has also been demonstrated to be effective against AD. Based on the systemic review of clinical studies, herbal medicines are believed to be effective and safe medicines for AD treatment.Traditional medicines are being rediscovered for the fulfilment of a strategy aimed at the treatment. Recently, several targets including antioxidants, anti-inflammatory antiapoptotic, neurotrophic and antiamyloid/genesis drugs have been explored in the  process . The saf process . FifteenIn this view finding for new compounds effective enough to act on various biochemical targets having new action and low toxicity are requirements hard to meet for both scientists and the pharmaceutical industry. On the other hand, the need to find remedies for this crippling disease has resulted in the reviving interest in natural chemistry. Active constituents of plants, long-known herbs and their extracts may lead to the discovery of medicines successfully used for the treatment of AD. It is generally believed that research on natural product chemistry has a large number of unexploited values capable of providing new possibilities in the treatment of AD.In this paper, we treat mechanisms that might underlie the improvements in cognitive abilities, neurovascular functions and protection of nerve cells.31). A number of medicinal plants, used in Chinese, Ayurvedic, Tibetan, Oriental and Kampo medicines have a reputation enhancing cognitive functions.The complete scientific name of the medicinal plants, the possible mechanism(s) of action and relevant references can be found in Table , a serotonin neurotoxin (para-chloro-amphetamine), the amyloid β-peptide, the ethanol, the aluminum applied on animal models of AD have also proved used to impair cognitive functions. The cognitive or antidementia effects of herbal agents on behavioral pharmacological models, as soon as the passive avoidance test, the Morris water maze test, the T-maze, and both the radial maze paradigms were also checked. Although the mechanisms responsible for the cognition-enhancing effects of most herbal extracts and phytoconstituents are still not completely understood. One or more of the following factors are involved in the improvement of central ACh function; Inhibition of acetylcholinesterase (AChE) and facilitation of ACh synthesis or facilitation of the ACh receptor function; prevention of β-amyloidogenesis by antioxidant action; protection against neurotoxicity and death of nerve cells; facilitation of some neurotrophic effects, e.g., nerve growth factor (NGF). In the field of drug discovery, more attention has been focused on neuroprotection in AD utilizing traditional medicinal plants. Natural compounds with anti- oxidant, anti-inflammatory, anti-apoptotic, and neurofunctional regulational effects may exhibit preventive or therapeutic features against AD. Herbal drugs of traditional medicine which have been well characterized and studied for their behavioral effects and pharmacological properties, may be attractive candidates for furtherapproved for the treatment of patients with Alzheimer's disease, many herbal agents appeared to inhibit of AChE activity.The degeneration of acetylcholine (ACh) neurotransmission in the central nervous system due to neural degradation is considered to be a major neuropathological characteristic of AD . The aniin vitro results when protection from nerve cell death was induced by exposure to abundant free radicals, excitatory toxins, toxic derivatives of amyloid precursor protein, and other neurotoxins.Tacrine was discriminated in 2013 because of concerns of hepatotoxicity. At the same time, substantial number of herbal extracts and isolated constituents have antioxidant and neuroprotective effects. Antidementia effects are evidenced from Here we reiterate the fact that natural products represent sources of compounds having potential therapeutic implication in AD and other cognitive dysfunctions.Discovery of drugs from medicinal plants has traditionally been a long process and more cumbersome than other ways of development.Bioassay screening of extract libraries faces significant difficulties and finding of lead compound libraries is a crucial strategy for discovering drugs. Revealing the precise pathogenesis of AD will give a wider insight into new drug discovery and development and will rationalize drug design with better outcomes and therapeutic benefits. Considering the multitarget, multicomponent action strategy of natural products widely used in the traditional medicine in AD, they offer an unexploited source of new and effective therapy. The traditionally applied herbal preparations offer an adjunctive therapy to drugs acting on amyloidogenesis, AChE and cell death are intensively tested in order to offer better therapeutic prospects in the improvement of learning and memory functions of patients suffering from AD. Currently, very few plant-based medicines are accepted for clinical application. The reasons behind these very few approvals seem to be the complex nature of the chemical components in herbal preparations, difficulties in standardization. Identification of the active ingradient(s) of medical herbs would significantly increase acceptance of these medicinal plants in the clinical practice. The information provided in the present review on numerous plant extracts, formulations and phytoconstituents that have preventive and therapeutic effects on AD in animal models can be used to find new drug therapies for AD and related sequels.In view of detrimental actions of the agents for AD, in particular treatment refractoriness, high recurrence and side effects that occur in the course of long-term treatments, herbal drugs may offer an alternative possibility. In fact, some human studies have confirmed the beneficial effects of herbal medicines in the prevention and treatment of dementia -21. BaseThe therapeutic effects of most herbal agents reviewed in this paper are still to be confirmed in clinical settings .


We present a case of cardiac tamponade that was precipitated by thoracocentesis and discovered at autopsy. Cardiac or pericardial tamponade is a life-threatening condition characterized by the slow or rapid compression of the heart by fluid, pus, blood, clots, or gas, as a result of effusion, trauma, or rupture of the heart, which has accumulated between the visceral and parietal pericardia . Such coA 44-year-old woman was admitted into the ward on account of three months history of cough and one-week history of fever and difficulty with breathing. The cough was insidious in onset and productive of yellow sputum that is non-bloody and non-foul smelling. The fever was high grade with associated chills and rigor. There was associated history of progressive weight loss and drenching night sweats. There was no history of contact with person with chronic cough. Physical examination revealed a middle-aged woman who was in obvious respiratory distress. The pulse rate was 92 beats per minute (regular and good volume) with a blood pressure of 100/60mmHg and respiratory rate of 36 cycles per minute. Chest examination revealed dull percussion notes and absent breath sounds on the left lower lobes of the left lung. The apex beat was located in the fifth left intercostal space, mid clavicular line. An assessment of pulmonary tuberculosis was entertained to rule out metastatic lung disease. Chest x-ray that was done showed homogenous opacity with circumscribed nodular lesions of the left lower lung zones. Emergency in-patient thoracocentesis (with no imaging guidance) was performed for microbiological studies and cytology with 10mls of haemorrhagic fluid aspirated. However, some minutes after the procedure, patient complained of dizziness and went into coma. She was pronounced dead after failed resuscitation and autopsy was performed in our facility. Findings at autopsy revealed shrunken and partially fibrotic lower lobe of the left lung  with the presence of three areas of caseous necrosis located in both the upper and lower lobes . The enlThoracocentesis  describes a procedure whereby pleural fluid or air is aspirated via a system inserted temporarily into the pleural space . This maRisk of cardiac injury is high with non-image guided thoracocentesis especially in individuals with suspected chronic lung disease. Improvement and strict adherence to laid out guidelines should be implemented. Thoracocentesis should be performed in places where emergency support can be easily mobilized to remedy complications should they occur.The authors declare no competing interests.


This commentary describes the need for a birth dose monovalent hepatitis B virus (HBV) vaccine and an effective programme for the prevention of mother-to-child-transmission (MTCT) of HBV in Africa. Current World Health Organization guidelines recommend routine maternal screening for HBV followed by treatment of highly infectious HBV-infected mothers, and HBV birth dose vaccination and the administration of hepatitis B immunoglobulin for HBV-exposed infants as an effective strategy for the prevention of HBV MTCT. None of these practices are currently in place in most parts of Africa. To date, fewer than 10 African countries vaccinate children at birth against HBV. Despite the hurdles associated with implementing this practice, its expansion to the rest of Africa is feasible and crucial to reducing the global number of new HBV infections by 90% by 2030, as targeted by the current Global Health Strategy for the elimination of viral hepatitis. Hepatitis B virus (HBV) infection remains an important co-morbidity in the global HIV pandemic. The 2013 Global Disease Burden study showed that the total number of yearly deaths attributable to the complications of this infection was estimated at 686,000 and the number of life years lost was higher than for HIV [After East Asia, sub-Saharan Africa (SSA) carries the highest proportion of chronic hepatitis B (CHB) carriers, the majority of whom are unaware of their HBV status. The long-term sequelae of CHB infection include liver cirrhosis and hepatocellular carcinoma. The latter is reported as the third most common cause of cancer deaths worldwide in the 2012 GLOBOCAN report [CHB is usually a consequence of acquisition of the virus during early childhood. The proportion of infected individuals who develop CHB decreases with age: from about 90% of children infected perinatally, to 30%-50% of those infected as toddlers to less than 5% in adulthood . TherefoElimination of HBV is achievable more quickly if we can step up efforts to prevent HBV MTCT. In May 2016, the World Health Assembly announced the first ever Global Health Strategy for the elimination of viral hepatitis as a public health threat globally by reducing mortality due to viral hepatitis by 65% and the number of new infections by 90% by 2030. To reduce new infections, the strategy seeks to increase the global coverage of the hepatitis B birth dose vaccine, from the current 38% to 90%. World Health Organization (WHO)/United Nations International Children´s Fund (UNICEF) coverage estimates for 2015 suggest that HBV birth dose vaccine coverage in Africa is the lowest globally, at only 10% [Despite improved immunization coverage rates achieved through combination vaccines, the risk of vertically-transmitted HBV infection is significant for infants who are born to highly-infectious HBV-infected mothers. Infants remain vulnerable to infection from vertically transmitted virus during the six weeks before they receive the first dose of the HBV vaccine. Vaccination at six weeks will reduce the risk of horizontal transmission but may be too late to halt the cycle of infection from mother to child.Current HBV vaccination schedules in Africa are based on data generated from early HBV studies, where horizontal transmission was identified as the predominant route of transmission of this virus, causing around 90% of chronic infections while the remaining 10% was attributed to MTCT. Rates of vertical transmission were considered low because of the low prevalence of hepatitis B e antigen (HBeAg) among African pregnant women and therefore lower hepatitis B viral loads and risk of vertical transmission. However, data from Africa have emerged showing that the prevalence of HBeAg among HBV-infected pregnant women may not be as low as previously thought, with around 10% of all HBV-infected pregnant women being HBeAg seropositive, regardless of HIV status . In the Despite these troubling data and current WHO guidelines strongly recommending antenatal routine screening in countries with a HBsAg seroprevalence ≥2% in the general population , most AfHBV MTCT prevention services can be incorporated into the existing and extensive HIV MTCT prevention infrastructure that is already in place in most of SSA, thus reducing costs of introducing a new screening test. Combination rapid tests that are able to detect HIV, syphilis, and HBsAg in pregnant women are desirable for the integration of MTCT prevention services. Also appealing are combination rapid tests that are able to detect both HBsAg and HBeAg, which is a marker of high infectivity and active viral replication. Therefore, these tests would be able to identify those women at high risk of transmitting HBV to their infants. Affordable, Sensitive, Specific, User-friendly, Rapid and Robust, Equipment-free, and Deliverable to end-users (ASSURED) combination tests will present a significant step forward towards efforts to control maternally transmitted infections.Identifying HBV-infected pregnant women early in their pregnancy would allow their linkage to care, where those women at high risk of transmission could access efficacious antiviral therapy. The use of antivirals such as tenofovir in the third trimester, together with vaccination of infants at the time of birth has been shown to prevent HBV MTCT , 14. HowHigh-level political commitment is required in order to have functional and effective HBV MTCT prevention - a key component missing in much of SSA. This calls for a prevention strategy that includes bringing HBV vaccination closer to the time of birth. Although costs and the limited availability of resources may be important issues to consider, vaccinating children at birth is feasible and cost-effective in SSA , 16. LarImplementation of the HBV monovalent birth dose vaccine has been impeded by a number of barriers, exhaustively detailed in the Practices to improve coverage of the hepatitis B birth dose vaccine document of the WHO . PoliticData from Lao People´s Democratic Republic, a resource-limited country, shows that the HBV birth dose vaccine can indeed be stored outside the cold chain whilst maintaining stability for up to 28 days . MoreoveAfrica needs the HBV birth dose vaccine if we are to achieve the goal of eliminating HBV MTCT. Although there are still hurdles to overcome for its successful implementation, with concerted efforts from all stakeholders, it is achievable. Screening pregnant women for HBV and treating those with high viral loads would further reduce the risk of vertical transmission. The combined use of these practices would serve to effectively break the HBV transmission cycle, bringing us closer to eliminating HBV in Africa, with considerable medical and socioeconomic benefits.The authors declare no competing interests.


A National Immunization Program Review (NIP Review) is a comprehensive external assessment of the performance of a country’s immunization programme. The number of recommended special-topic NIP assessments, such as those for vaccine introduction or vaccine management, has increased. These assessments often have substantial overlap with NIP reviews, raising concern about duplication. Innovative technical and management approaches, including integrating several assessments into one, were applied in the United Republic of Tanzania’s 2015 NIP Review. These approaches and processes were documented and a post-Review survey and group discussion. The Tanzania Review found that integrating assessments so they can be conducted at one time was feasible and efficient. There are concrete approaches for successfully managing a Review that can be shared and practiced including having a well-planned desk review and nominating topic-leads. The use of tablets for data entry has the potential to improve Review data quality and timely analysis; however, careful team training is needed. A key area to improve was to better coordinate and link findings from the national-level and field teams. National immunization program (NIP) Reviews are the core of a country’s monitoring and evaluation activities; they guide implementation of immunization services nationwide and help track progress towards goals of the national programme and of the Global Vaccine Action Plan 2016-2020 [The World Health Organization (WHO) recommends that Member States conduct a comprehensive NIP Review every five years to guide the development of a new comprehensive multiyear plan for immunization (cMYP) . NIP RevThe WHO Regions have developed Review guidelines ,4; howevHaemophilus influenza type b (DTP-HepB-Hib) vaccine during 2010-2014. The country continues to strive to improve the program, especially to reach high coverage in all districts (12% of districts had <80% coverage with three doses of DTP-HepB-Hibvaccine in 2014) and to increase measles 2nd dose coverage (29% in 2014). A NIP Review was planned for 2015 in preparation for developing the cMYP for 2016-2020.Tanzania’s immunization program is one of the best performing in Africa with >90% of children completing three doses of Diphtheria-Tetanus-Pertussis-Hepatitis B- This report outlines lessons learned from applying innovative strategies to the 2015 NIP Review in Tanzania.To improve the quality and efficiency of the NIP Review, Tanzania MoHSW and WHO Tanzania implemented innovative Review strategies and assessed their feasibility and acceptability. Five such strategies used were:Extensive integration of assessments: this Review integrated the measles-rubella (MR) PIE, an assessment of the human papillomavirus (HPV) vaccine demonstration project, and assessments of data systems and quality, VPD surveillance and immunization financing.Modified desk review: new timing and tasks of the desk review were tested. It is generally recommended [ommended  to conduSelection of topic-leads: this Review nominated topic-leads responsible for facilitating discussion and drafting conclusions and recommendations for their respective topic areas. Topic-leads were identified before field deployment by reviewing the expertise of all external Review members and making the best match of skill sets with topic areas.Interactive review team training: the training included practical sessions on using hand-held tablets and mock interviews to familiarize the teams with the data collection tools and country context. A trainer initially guided each team through the data collection tools and use of the handheld tablets. Afterwards, each individuals within each team conducted mock interviews with one another to familiarize themselves with each question in the data collection tool and with use of the handheld tablets. Feedback was immediately collected from each team to identify any problems encountered with either the tablet or the data collection tool.Streamlined data collection tools and use of hand-held tablets: as part of a regional effort to develop a standardized methodology for conducting Reviews in the African region, A team of experts from global agencies  reviewed tools from previous reviews to identify core variables. The core variables were provided to the team Topic Leads conducting the Tanzania Review and these variables were enhanced based on the desk review findings and objectives of the other assessments being integrated. Topic leads reviewed the respective segment of the questionnaires to ensure desk review findings and local context were taken into account. Field teams used a tablet containing the data collection tools programmed with Zegeba software [software .Evaluation of review strategies: the following methods were used to evaluate the review strategies.Post-review survey: to assess the acceptability and feasibility of strategies, all reviewers were asked to complete a standard post-review evaluation form.Post-review group interview: an interactive group session was held at the end of the Review to obtain feedback on process and practical experiences from the Review.Written feedback: the review process was documented through reports written by the desk review consultant and the review-lead.These evaluation findings are presented according to the five NIP Review phases: 1) concept development, 2) preparation, 3) implementation, 4) synthesis of conclusions and recommendations, and 5) translating recommendations to action [th to 24thJuly 2015 and included 22 national and 10 international participants. The post-Review survey was completed by 22(66%) participants. Of these, over half (55%) had previously participated in at least one NIP Review. The post-Review interactive group session was attended by 25 persons, of whom over 90% participated as field team reviewers.The Tanzania Review was conducted from 8Phase 1: concept developmentThe concept note was developed six months prior to the review and was used to secure national participation and help partner agencies nominate external reviewers with the required expertise as topic leads.Phase 2: preparationAn international consultant was hired for four weeks to conduct the desk review and assist with tool development and team training. A second international consultant was hired as the overall Review-lead, responsible for Review team training, oversight, debriefing and report writing. Additionally, eight external expert reviewers served as topic-leads on: NIP management and financing, vaccine management, service delivery, monitoring and data quality, surveillance, community demand, measles-rubella and HPV vaccine introduction.The desk review summarized the status of recommendations from six large assessments during 2010-2014 including the 2010 NIP Review, three PIEs, a VPD surveillance review and a vaccine management assessment. Immunization stakeholders were interviewed to help assess status of recommendations from these previous assessments and identify priority areas for the Review.Phase 3: review implementationThe NIP Review questionnaires were shortened by at least 30% (based on number of questions) compared to questionnaires used in other recent NIP Reviews. Ten of 30 regions in Tanzania were purposefully selected to be representative of the geographic variations in the country; within each region, one high-performing district and one low-performing district were randomly selected from a high-performing and low-performing sampling frame (performance based on DTP3 vaccination coverage) . Within Among the surveyed Review participants, 60% found integration of multiple assessments acceptable and 65% found the length of the tools acceptable . ParticiPhases 4 & 5: synthesis of conclusions and recommendations and translation into actionField teams reconvened and presented findings from the region they visited, while topic-leads consolidated the respective topic-area findings from all teams into a topic-area report and presentation. Immediately afterwards, topic-leads led breakout groups to discuss and draft cross-teamconclusions and recommendations. Back in plenary, topic-specific conclusions and recommendations were presented to ensure agreement. Linking findings from the national and field teams was limited due to intense focus on the field team findings. Of the surveyed reviewers, 86% reported having sufficient time to synthesize findings. The Review concluded with a presentation to MOHSW and key NIP partners; Review findings and recommendations that were endorsed by MOHSW and NIP partners were used to develop the 2016-2020 cMYP.Tanzania was able to successfully implement a high quality integrated NIP Review. The findings and recommendations of the Review were summarized and translated into action plans during a subsequent workshop to develop the 2016-2020 cMYP. Although a number of these innovations may have been utilized on an ad-hoc basis in prior reviews, this Review is among the first to use a systematic approach to implementing multiple innovations together as a single package with the goal of streamlining the Review while also ensuring this Review provides sufficient information to answer questions that would normally be answered through conducting several separate reviews. Additionally, the Tanzania Review provided an opportunity to document lessons learned that were later incorporated into new integrated NIP review guidelines which are designed to ensure countries need only conduct a single activity to answer the many questions which originally had to be answered through the conduct of several separate activities. These lessons are summarized in The approach to conducting an integrated review as a means to efficiently address several different objectives simultaneously  has gained traction in recent years, with examples of countries where the Review leads choose a more integrated approach, including in Ghana and Rwanda. In these latter two reviews, the general aim was to incorporate a traditional NIP review with a post-vaccine introduction evaluation (PIE) rather than conducting two separate activities. In contrast, for Tanzania, our regional team of immunization experts aimed to design this integrated review to address the needs of a traditional NIP review, PIE, financial records review, supply chain management review, and surveillance systems review. Additionally, the integrated review leads shared this aim through the review concept note with all immunization program stakeholders to ensure that their needs would be met by the single review and that they would not mandate an additional separate review. Additionally, we incorporated a framework of efficiency measures, including using topic leads to consolidate the field review findings by topic, and using electronic data collection to accelerate data management and analysis. Lastly, we documented the feedback of all review participants in regards to both the integrated design of the review and the success of the efficiency measures as a means to feed into a draft set of best practices for conducting integrated NIP reviews. This best practices document will be disseminated soon on the WHO website for all countries to incorporate into their future NIP reviews.Here we document lessons for future NIP Reviews which may also be relevant for other nationwide program evaluations. First, adetailed NIP Review concept note developed six months prior to the field review helped secure both national and international participation. Second, timely engagement of an experienced desk review consultant helped tailor the Review to meet country needs. Third, the majority of surveyed participants found that integrating multiple assessments was feasible and NIP management found it highly desirable for efficiency reasons. Fourth, reviewers recommended tablet use for future reviews with a major benefit being that quantitative data were available in time to support conclusions and recommendations. However, a staff member with specialized technical knowledge was required to support tablet use. Lastly, identifying experienced topic-leads allowed for highly technical and focused discussions on various topics to take place concurrently during the field teams’ debriefing sessions. In future Reviews, linking of national and field findings may be improved by engaging topic-leads earlier in the process and having explicit guidance for them to synthesize the two levels of findings.Limitations and challenges exist in the innovations used in the Tanzania Review. Although we used electronic data collection to great success per the feedback provided by participants, the ability of sharing data rapidly with all participants requires cellular or wireless network availability which could be limited in a number of rural settings globally. Additionally, a specialized skillset is required to manage and troubleshoot computing devices; this skillset may not be available in all reviews, which could hamper use of electronic data collection. Another challenge is ensuring that topic leads with sufficient applicable experience are recruited to a review; generally a key aspect of these reviews is inclusion of an external reviewer who is likely to provide a less-biased perspective on the performance of the program, but sufficiently experienced external participants may not always be available for all reviews.Many reviews have been conducted in the WHO African Region and it is common for reviewers to report that topics are not fully assessed even when the long version of the tools are used. This is the nature of a comprehensive evaluation covering a broad range of technical areas. The finding that the majority of participants found integration of multiple assessments and streamlined data collection tools acceptable was considered a favorable outcome, especially given that data collection queries were reduced by at least 30%. This approach was made successful by having a thorough desk review and training that provided the rationale for eliminating or expanding certain topics.National Immunization Program (NIP) Reviews are routinely conducted in low and middle income countries;Multiple other types of immunization program reviews are also conducted on an annual basis and may heavily overlap with NIP Review objectives.Aligning and conducting multiple assessments at one time is feasible with appropriate planning;Using the desk review findings to develop tailored data collection tools and training improves the relevance of the Review;Nominating Review members to be topic-leads based on their topic-specific expertise can significantly improve the quality and relevance of conclusions and recommendations.The authors declare no competing interests.


Congenital long QT syndrome (LQTS) is an inherited ion channel disorder caused by gene mutations that encode for cardiac ion channels. The incidence of inherited LQTS in the general population is estimated to be 1:2000 0.05%) [% [5]. SuOver the last decade, advances in fetal magnetocardiography (MCG) have significantly enhanced our ability to diagnose fetal rhythm abnormalities, including LQTS. MCG is the magnetic analog of ECG. Unlike the fetal ECG, which is strongly attenuated by the electrical resistance of the fetal skin and vernix, the fetal MCG shows relatively high signal quality. The efficacy of fetal MCG is supported by a substantial literature, including several review articles ,9. It haAssessment of repolarization using MCG is considerably more difficult in the fetus than in the neonate or adult due to the lower amplitude of the signal and the presence of large interference, primarily from the maternal MCG. Signal processing techniques are required to remove the interference and facilitate detection of abnormalities such as QTc prolongation and T-wave alternans (TWA), i.e. beat-to-beat variation in the amplitude of shape of the T-wave –19. TWA In a recent fetal MCG study, the electrophysiology of LQTS in utero was characterized for the first time in a sizeable cohort, consisting of 30 fetuses at risk of LQTS . Heart rWhile the efficacy of fetal MCG has become more widely recognized, the high cost of the technology, which is based on superconducting sensors known as SQUID magnetometers, has limited its widespread use. This situation will likely change in the near future due to a recent breakthrough in atomic magnetometry, leading to the development of the so-called SERF (spin exchange relaxation free) magnetometer ,22. The Fetal MCG is an enabling technology for the in utero detection and management of LQTS. Due to the ability to effectively treat TdP in utero, these capabilities can be lifesaving. We foresee a promising future for in utero diagnosis of LQTS and other life-threatening fetal rhythm disorders.


Carpal tunnel syndrome (CTS) results from median nerve entrapment during increased intra-tunnel pressure that is often a product of swelling of the digital flexor tendon sheaths consequent to repetitive movements of the hand and wrist or by direct compression on the wrist. Individuals with CTS may experience pain, tingling, numbness and weakness in the palmar surface of the first three digits, small thumb and lateral two lumbrical muscles . OccupatMeasurements of the cross sectional area (CSA) of the proximal tunnel are effective in predicting CTS. In individuals presenting with CTS, the CSA of the median nerve is significantly larger than in unaffected individuals. Further, the nerve tunnel index (CSA median nerve/CSA tunnel) in affected individuals is much higher than in non-affected individuals. .CTS may arise exclusively in humans as a consequence of adopting bipedalism; the loss of forelimb usage during locomotion may have resulted in anatomical changes in the hand, including a reduction in the size and functional orientation of the pisiform bone. The proximal transverse carpal ligament attaches to the pisiform bone, forming the ‘roof’ of the carpal tunnel. The elongated, rod-shaped pisiform bone in apes serves as the medio-proximal border of the CT and increases the CSA  4, 5]. , 5. 4, 5Comparison of the pisiform bone length and development between humans and primates may shed light on the increased risk of CTS in humans. Unlike humans, apes retain a growth plate and secondary center of ossification in the pisiform, resulting in long pisiform bones  that funCommon treatments for CTS include immobilization, corticoid injections, and surgery. Surgical incision of the flexor retinaculum is one of a few treatments known to permanently alleviate symptoms. Thus, there is a desire to explore more favorable strategies to alleviate CTS pathology.Further research is needed to trace the exact function by which the biomechanical lever of the pisiform serves to increase the CSA of the carpal tunnel in non-human primates. Additional allometric analysis of the articular surface of the triquetrum in proportion to body size in other primate species would be necessary to better understand the anatomical factors that can increase risk in humans.


An ensemble of four regional climate model realizations using different global circulation models at the boundary and different emission scenarios are used to force a single ocean model for the Mediterranean Sea. Freshwater flow is modified according to the simulated changes in the precipitation rates for the different rivers’ catchment regions. To isolate the effect resulting from a change in freshwater flow, model results are evaluated against a ‘baseline’ simulation realized assuming a constant inflow equivalent to climatologic values. Our model results indicate that sea surface salinity could be significantly altered by freshwater flow modification in specific regions and that the affected area and the sign of the anomaly are highly dependent on the used climate model and emission scenario. Sea surface temperature and phytoplankton biomass, on the contrary, show no coherent spatial pattern but a rather widespread scattered response. We found in open-water regions a significant negative relationship between sea surface temperature anomalies and phytoplankton biomass anomalies. This indicates that freshwater flow modification could alter the vertical stability of the water column throughout the Mediterranean Sea, by changing the strength of vertical mixing and consequently upper water fertilization. In coastal regions, however, the correlation between sea temperature anomalies and phytoplankton biomass is positive, indicating a larger importance of the physiological control of growth rates by temperature.We evaluate the changes on the hydrological  and biogeochemical (phytoplankton biomass) characteristics of the Mediterranean Sea induced by freshwater flow modifications under two different scenarios for the end of the 21 The Mediterranean Sea has been described as a hot-spot for climate change  as it isThe combined effect of natural and anthropogenic forcings will potentially create a wide range of pressures for the Mediterranean Sea ecosystems. Such pressures could undermine its environmental status putting at risk the ecosystems’ services provided by this European regional sea. Thus, being able to anticipate potential changes and having the opportunity to propose measures to avoid deleterious effects is a fundamental tool for EU regulations and, more specific, for the Marine Strategy Framework Directive (MSFD)  in orderOne of the tools used to look at potential changes in future conditions in this region is the Regional Climate System model . NumericAll these previous works considered the combined effect of expected future changes in atmospheric forcing, boundary conditions and land-sea interactions . However, integrated modelling systems could also provide a quantitative assessment of the relative importance of each changing element for different scenarios. For example  performeWith the present contribution we expand this previous work by evaluating the effects on the Mediterranean basin of a change in the quantity of the freshwater flow associated to expected alterations of the precipitation rate in the different rivers’ catchment areas. The same ocean model that has already shown to provide a reasonable representation of past and present hydrodynamic and biogeochemical conditions of the Mediterranean basin , 14 is uHenceforth, the main aim of the present contribution is to quantitatively evaluate the effects of a change in the freshwater flow for the Mediterranean Sea ecosystem under different climate scenarios. Changes in the hydrodynamic  and biogeochemical  conditions will be evaluated by comparing the ecosystems’ conditions simulated for the future assuming no change in freshwater flow and those simulated imposing alterations of freshwater inputs from rivers.http://www.getm.eu.We applied the 3-D General Estuarine Transport Model (GETM) simulate the hydrodynamics in the Mediterranean Sea. GETM solves the three-dimensional hydrostatic equations of motion applying the Boussinesq approximation and the eddy viscosity assumption  as detaiThe configuration of the Mediterranean Sea  presentshttp://www.ngdc.noaa.gov/mgg/global/) database was used to build the bathymetric grid by averaging depth levels to the corresponding horizontal resolution of the model grid. The salinity and temperature climatologies used as initial conditions at the start of the model integration were obtained from the Mediterranean Data Archeology and Rescue-MEDAR/MEDATLAS database (http://www.ifremer.fr/medar/) while biogeochemical initial and boundary conditions were computed from the World Ocean Atlas database (www.nodc.noaa.gov/OC5/indprod.html). All model runs described below started with exactly the same initial conditions.The ETOPO1  while the rest of the water column temperature was not changed. No horizontal currents were imposed at the open boundary. With this boundary configuration the circulation through the Strait is established by the internally-adjusted baroclinic balance provoked mainly by the deep-water formation within the basin .The present configuration of the ocean model includes 37 rivers discharging along the Mediterranean coast (red stars in The GETM configuration for the Mediterranean Sea is forced at surface every 6 hours by the following atmospheric variables: wind velocity at 10 meters (U10 and V10), air temperature at 2 m (t2), specific humidity (sh), cloud cover (tcc) and sea level pressure (SLP) provided by the different realizations of the atmospheric model described in the next section. Bulk formulae are used to calculate the corresponding relevant heat, mass and momentum fluxes between atmosphere and ocean . No tidahttps://sourceforge.net/projects/fabm/)[GETM is coupled online to the MedERGOM biogeochemical model , 19 by uts/fabm/). MedERGOts/fabm/) specificts/fabm/) and fututs/fabm/) biogeochTo explore changes on vertical stratification of the water column in the different model runs the integrated value of the thermal expansion coefficient (α) and of the salinity contraction coefficient (β) where calculated. α represents how much the seawater increases its volume (hence reducing density) for each increment of temperature while β represents the seawater loss in volume (increase in density) with the increasing salinity value . Hencefohttp://www.clm-community.eu/), in the framework of the EURO-CORDEX initiative (http://www.euro-cordex.net/). The RCM is forced by two GCMs, namely EC-Earth and MPI-ESM-MR included in the CMIP5  database while nutrient loads (nitrate and phosphate) of freshwater runoff were obtained from . We, the changes .http://www.eea.europa.eu/data-and-maps/data/wise-river-basin-districts-rbds-1) but grouping together sets of rivers sharing a common basin area. This way, 8 different ‘provinces’ have been defined as indicated in To estimate potential changes in freshwater flow in the different climate scenarios a proxy was created by evaluating the relative change on precipitation over the different rivers’ basins for the end of the century in a similar way as done by . First oFor the rest of the basins/rivers it is possible to compute relative changes of precipitation (P) between the first five years of the forecasting period (2014–2019) and the last five years of the simulations (2094–2099) for each combination of GCM/RCP. The monthly coefficients of relative P changes for each model/emission scenario  are usedbaseline simulations [baseline simulation).We then use the initial conditions corresponding to January 2090 in the ulations  to startThe used model configuration is, thus, exactly the same as in  but we aThe annual average changes in P values for each model/emission scenario and for each basin are shown in In order to consider also the seasonality of the potential changes, the climatological P cycles for the first 5 years of the RCM realization (2014–2019) are compared to the climatological P cycles during the last 5 years of the runs (2094–2099). The percentage of change for each river’s basins are shown in Adriatic and Aegean provinces show the lower decreases, especially under RCP8.5.In No clear seasonal pattern could be identified on the EC-Earth forced scenarios  as they The effect of changing freshwater flow in the Mediterranean ecosystems is investigated by comparing the simulations results obtained with the climatological rivers  with thoFor sea surface salinity (SSS), relative mean differences  are arouSea surface temperature (SST) anomalies maps  do not sWe can also examine the anomaly maps for the phytoplankton biomass in terms of chlorophyll (Chla) concentration . In gene, although a large dispersion is observed in all scatter plots. This general relationship is more evident using phytoplankton biomass anomaly than PPR (not shown) and for MPI rather than for EC-Earth simulations .To understand better the mechanisms behind the relationships shown in For all model forcings there is a clear pattern, during the blooming season the total area of the basin where a significant (either positive or negative) correlation between SST and Chla anomalies is found, is rather small  as for MPI the region will became drier while for EC-Earth it will be wetter. This difference is more acute in RCP4.5 than in RCP8.5 where the different models point to similar P anomalies. It is, however, important to mention that the proposed P and freshwater flow changes are not crucial to the main purpose of this manuscript. We do not aim to create plausible freshwater flow scenarios for the future Mediterranean Sea but only to evaluate how a change in this flow will affect the properties of this marine ecosystem. In this sense, the variety of P changes simulated by the different GCMs is particularly appropriate for our aim as we can test the impacts of a wide range of freshwater flow modifications.Relative changes in P (and hence in freshwater flow) varies between emission scenarios and between used GCM. As shown in Alpine region  [SSS changes in other regions of the Mediterranean as, for example, the Balearic Sea under MPI-RCP4.5 are more difficult to interpret. In this particular case, P decreases both in the France and Iberian regions  so the Sulation) .On the other hand, no clear structures could be detected for both SST and phytoplankton biomass anomalies . Also, tA suitable mechanism that could explain the observed SST anomalies could be the alteration of the vertical water stratification and, hence, of the vertical mixing intensity. The effect of rivers’ outflow on seawater vertical stratification has been described in previous works  as it cri.e., summer, stratified period) indicates that, indeed, the modification of water column vertical stability is a very probably cause for this relationship.Our results indicate that altering the amount of freshwater flow, even if relatively low in absolute terms as described above, could change the baroclinic balance of the whole basin, provoking changes in the vertical mixing intensity throughout the entire Mediterranean Sea. Places with enhanced vertical mixing will present lower SST than in the baseline run and those with decreased mixing will appear warmer. At the same time, more intense mixing will provoke larger fertilization of the upper water column and, hence, increased phytoplankton biomass. This might be the reason of the negative, significant correlation between SST anomalies and phytoplankton biomass anomalies in open water regions (blue regions in Figs On the contrary, in coastal regions, the water depth is not large enough to allow a successful fertilization of the surface by vertical mixing. Henceforth, the positive correlation between SST anomalies and phytoplankton biomass anomalies in such places could be a mere consequence of the physiological reaction of growth rates to warmer temperatures . The facIn order to further explore if stratification changes could be responsible for the observed phytoplankton anomalies, the AONB anomalies see  were comIn conclusion, our set of simulations has indicated that a change in the amount of freshwater flow into the Mediterranean Sea, albeit small in comparison with total volume of the basin, could provoke widespread changes in its physical and biogeochemical properties. Salinity changes are more regionally located while temperature and phytoplankton biomass show anomalies in regions quite far away from any freshwater source. The reason behind these last modifications seems to be an alteration of the vertical stratification properties of the water column that changes the vertical mixing intensity and, hence, new surface production triggered by deep nutrients supply.


Ebolavirus and currently there are no licensed therapeutics or vaccines to treat EVD. Due to its high mortality rates and potential as a bioterrorist weapon, a better understanding of the disease is of high priority. Multiparametric analysis techniques allow for a more complete understanding of a disease and the host response. Analysis of RNA species present in a sample can lead to a greater understanding of activation or suppression of different states of the immune response. Transcriptomic analyses such as microarrays and RNA-Sequencing (RNA-Seq) have been important tools to better understand the global gene expression response to EVD. In this review, we outline the current knowledge gained by transcriptomic analysis of EVD.Ebola virus disease (EVD) is a serious illness that causes severe disease in humans and non-human primates (NHPs) and has mortality rates up to 90%. EVD is caused by the  Ebolavirus is a member of the Filoviridae family of negative-sense single-stranded RNA viruses. Ebolaviruses are the causative agents of Ebola virus disease (EVD), which is a serious illness that can cause up to 90% case fatalities in humans and non-human primates (NHPs) [Ebolavirus: Zaire (EBOV), Sudan (SUDV), Bundibugyo (BDBV), Tai Forest (TAFV), and Reston (RESTV). Four of the five Ebolavirus species are known to cause disease in humans  with three of them linked to sporadic outbreaks in Central and Western Africa  [s (NHPs) . Currentnd BDBV) . The recnd BDBV) , emphasiEbolavirus infection can be initiated by virus entry into the body through mucosal sites or by direct contact (through open wounds). Once inside the body, the primary target cells for Ebolavirus are thought to be dendritic cells and macrophages which become actively infected [infected ,5. Theseinfected . Here, tEbolavirus can progress to a hemorrhagic fever, eventually presenting with disseminated intravascular coagulation (DIC), multi-system organ failure, and death. The presentation of DIC is often coupled with increased liver enzymes such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST), signifying poor liver health and which are associated with poor disease outcome [Symptoms of EVD usually start with a prodromal period of general malaise and fever. This can initiate 2–21 days after initial exposure to the virus. As the disease progresses, additional symptoms such as nausea and vomiting, loss of appetite, and severe diarrhea leading to dehydration develop [ outcome .Ebolavirus and human macrophages have been shown to produce many innate immune signals such as interferons [EVD pathogenesis is linked to the overactivation of innate inflammatory signaling and the absence of dendritic cell activation. The mechanism in which this excessively exuberant response is triggered is unknown. Macrophages, but not dendritic cells , are acterferons . The lacerferons  on the serferons  and non-erferons  models oSignificant focus has been put on understanding the innate immune response to EVD. The innate immune response to EVD contains two main areas of study: the antagonism of the interferon response and the cytokine response. Many pro-inflammatory cytokines have been shown to be associated with EVD. IL-10 and IL-8 levels have been shown to increase in human fatal infections of SUDV  and EBOVEbolavirus infections is the antagonism of the type I interferon (IFN) response. IFN antagonism is achieved through the inhibition of intracellular recognition of pathogen-associated molecular patterns (PAMPs) by the Ebolavirus protein VP35 [Ebolavirus protein, VP24, has also been implicated in antagonizing the IFN response. Interferon antagonism by VP24 occurs by inhibiting phosphorylation of STAT1/2 into pSTAT1/2 and thus preventing its nuclear translocation [Another aspect of the innate immune response that is of focus with regards to ein VP35 ,19. Howeein VP35 . Anotherlocation . The antMany aspects of virus–host interaction can lead to different responses in infected cells and therefore lead to the initiation of different extracellular signaling events. How innate (IFN and cytokine) responses are influenced by virus infection is a challenging question to answer using a few selected genes of interest. Therefore, multiplexed technologies such as transcriptomics are attractive way to interrogate the host response to EBOV infection. Over the past decade, this approach has been used with increasing sophistication to study how EBOV infection alters the host transcriptome at the cellular and organismal level. This review addresses the current state of the field, with a focus on noting the important findings and challenging questions highlighted by this line of experimentation.Understanding the impact of EBOV infection on the host transcriptional response can be carried out with multiple approaches. The most direct is the use of immortalized cells or purified populations of primary cells that are infected in vitro. Infection of these cells can be done under tightly controlled conditions and the virus titer can be accurately determined.The use of immortalized cell lines to study the host response to EBOV infections provides ease of access to cells and allows for large number of replicates to be analyzed with minimal increase to cost. The transcriptional response to EBOV infection has often been studied in immortalized human liver carcinoma cell lines (HepG2 and Huh7 cells). The liver is an initial organ of EBOV replication. Thus, the liver likely plays an important role in EBOV pathogenesis, making the host liver response a key question in understanding viral dysregulation of host signaling . FollowiEbolavirus, RESTV, that has yet to be associated with severe disease in humans. In RESTV-infected cells, the authors observed an induction of host antiviral genes such as interferon stimulated genes (ISGs) and inflammatory cytokines. These results are consistent with the conclusion that EBOV dominantly suppresses host signaling through the action of antiviral proteins VP35 and VP24, while non-pathogenic viruses fail to suppress these antiviral responses. This negative correlation of pathogenicity versus induction of ISGs has also been observed in other viral infections, particularly influenza [The earliest transcriptomic studies supported an existing hypothesis of the EBOV–host interaction, namely that EBOV is a strong suppressor of innate immune responses ,23,24. Influenza ,27.The lack of a strong innate immune response following EBOV infection was also seen following infection of HepG2 cells. The transcriptional profiles of cells infected with EBOV show little induction of an innate immune response ,29,30. IThe suppression of innate immune signaling following EBOV infection is outlined in Another finding that has been validated across multiple transcriptomic analyses is the decrease in the transcription of genes associated with coagulation and acute phase response in cell line infections with EBOV ,28,32. TBats are a hypothesized reservoir for EBOV, based both on serosurveillance studies that identified anti-EBOV antibodies in adult bats  and on tThe transcriptional response following EBOV-infection has also been studied in primary cells. Studies with primary cells are somewhat limited, as the isolation of primary cells from primary tissue targets such as the spleen and liver is challenging. This has led to a focus on cells that can be present in the circulating immune system, and on dendritic cells and macrophages, which are thought to be the initial targets of productive EBOV infection  and haveIn contrast, primary macrophages show a robust host response following EBOV infection . StudiesEbolavirus in vivo provides an opportunity to better understand how the multitude of cell types and organ systems interact and respond to the virus as a whole. The main animal models that are used for studying the transcriptional host response to EBOV to date have been rodents and non-human primates (NHPs).Studying the transcriptional response to Ebolavirus infection [Mice have been used to study EVD pathogenesis for more than two decades. Since standard inbred mouse strains are not susceptible to nfection , three dnfection . Studiesnfection ,43. A monfection ,45. Of tnfection . The latma/VP24ma, which are pathogenic in mice and wtEBOV, EBOV-NPma, or EBOV-VP24ma which are non-pathogenic in mice [Infection of mice with both pathogenic and non-pathogenic EBOV has indicated that there are strong transcriptional responses to EBOV infection in tissues and blood. Studies of the transcriptional response in the spleen of EBOV-infected mice have most effectively demonstrated that there are two distinct responses to infection based on pathogenicity. One study compared five different virus infections: EBOV-MA and EBOV-NP in mice . Followi in mice . Followi in mice . Upregul in mice  and maca in mice .Similar results have been seen in experiments using genetically diverse strains of mice derived from the collaborative cross (CC) ,52. ThroThe existence of a robust antiviral host response centered on IFN is also supported by experiments using wtEBOV infection in mice lacking intact antiviral signaling molecules ,55. ConsMouse models, such as humanized mice, which show promise to better parse out the dynamics of the host response to infection, have not had transcriptional analysis performed as of yet. Humanized mice display clinical signs that more closely relate to human disease ,45 and aMacaca mulatta) and cynomolgus (Macaca fascicularis) monkeys, supported by the annotation of the rhesus and cynomolgus transcriptomes [The most widely-accepted animal model of EVD for the study of countermeasures such as vaccines and therapies is the non-human primate (NHP) model . NHPs diriptomes ,63,64. AAs a first-order approximation, the NHP circulating immune response to EBOV challenge can be separated into four separate transcriptional phases . FollowiEbolavirus infections leading to an overactivation of proinflammatory cytokines which contributes to disease pathogenesis [The early phase of infection is closely followed by the up-regulation of many cytokine genes ,65. Thesogenesis . This upThe later stages of infection (5–11 days post-infection) are characterized by extreme changes in gene expression in NHPs exposed to EBOV. Around 2000–3000 genes are usually found to be differentially regulated during the late stages of disease, depending on the fold-change cutoffs used ,66,67,74Further work in NHPs has been done to fully understand the mechanism of the rVSV-EBOV vaccine ,78,79. TThere are fewer transcriptomic analyses of tissues response to EBOV in NHPs compared to the mouse models. However, one study suggests that infected tissues have a robust host response to EBOV infection. The host transcriptional response in tissues is similar to the transcriptional response identified in PBMCs, with early expression appearing in the spleen, liver, and pancreas, concurrent expression in the adrenal gland, and delayed expression in the lymph nodes. Expression in the brain was barely detectable and was only observed in late stages of disease . AdditioThe analysis of the host transcriptional response to EBOV infection in NHPs has served as an important bridge for comparing and understanding the host transcriptional response of humans infected with EBOV in the 2013–2016 West African outbreak. Two recent studies have analyzed the global transcriptional response in the peripheral blood of infected patients in Guinea  and a loThe first of these two studies involved a patient cohort from Guinea during the outbreak that were taken at the European Mobil Lab (EMLab) . The focThe findings of this large patient cohort study are in general agreement with a second study of a single patient treated at the NIH Clinical Center , whose tIn addition to studies focusing on the mRNA coding transcriptome, there have also been studies that have focused the non-coding transcripts present in blood following EBOV infection. A study looking at patient samples from Sierra Leone identified microRNAs (miRNAs) whose regulation is altered in relation to viral load and selected a set of miRNAs that have potential to be used as a biomarker for survival . Many ofAcross the various platforms used to study EVD, there are gene sets that show agreement in their general pattern of regulation across many different models of EVD . Most no in NHPs  and a sm in NHPs .The limited data from human infections has identified important differences between the human transcriptional response and transcriptional response seen in animal models. One large difference is that the transcriptome from EBOV-infected patients in Guinea were found to have very high levels of acute phase genes circulating in the peripheral blood . The NHPAnalysis of survival factors in animal models can possibly help inform treatments in humans. Though most NHP survivors have either been vaccinated for the virus or received therapeutics, and the mouse model requires attenuation of the virus to create mouse-adapted forms, many factors found in either of these models agree with what was found in humans. Most notable is the association of natural killer cells and survival in both mice  and humaγ)  which isTranscriptional analysis of the host response to EBOV infection has greatly increased our understanding of the disease progression and pathogenesis. An important finding highlighted through transcriptomics is the strong induction of an IFN-like response following infection in vivo ,65,66. TTranscriptional analysis has also led to an appreciation of the entire scope of the immune response to infection. The discovery approach enabled by microarray and next generation sequencing (NGS) have allowed the identification of cytokine induction events that had not been previously associated with disease . ImportaThe new knowledge gained from these studies has several potential applications. One exciting opportunity is that the host response could be used as a biomarker. Work has already been performed in human samples to develop potential biomarkers for prognosis ,85. The To date, there is only one available dataset with transcriptional analysis of tissues . Through


Despite the need for sophisticated instrumentation, breath figure assembly (BFA) methods are restricted to produce macroporous films on a tiny scale so far. The current study narrates the fabrication of macroporous films in hollow fiber geometry which extends to adopt the method for continuous production of isoporous surfaces from commercially available low-priced polymer materials. The fabrication of the films in the hollow fiber geometry is carried out by a co-centric quadruple orifice spinneret through which four different liquids are co-extruded simultaneously: bore fluid (to fill the lumen of the fiber), support layer solution, glycerol, and an isoporous film forming solution through the outer most orifice. The extruded entities plunge into a coagulation bath after passing a definite air gap. The implementation of the concept of diffuse-in, droplet formation, and then condense-out behavior of glycerol in a co-extrusion method of hollow fiber spinning makes macroporous film formation possible in an interminable way sidestepping the use of breath figure assembly method. Moreover, the continuous film formation by the proposed mechanism is also authenticated in flat sheet geometry by employing two casting blades in a casting machine. The structure of the films is analyzed by scanning electron microscopy (SEM). Fabrication of many functional nanoporous materials are guided by nanoarchitectonics which spans its field from soft templating to hard templating. Monolayer or multilayer self-assembled lipids or the assembly of polymeric micelles to direct the porous inorganic structures, metal-organic frameworks (MOFs) have been of high research interest as well in recent years for the foreseeable utilization of the produced porous structures in fuel cells, separation technologies, catalysis and many more in near future14.Porous polymeric films have earned an enormous attention in research because of their significant potential in many fields. This type of films extends their adoption as supporting media in tissue engineering, inorganic growth templates, optical materials, antireflection coating, catalysis, bio or gas sensoring, dielectric materials for electronic devices, stamps for soft lithography, etching masks, etc. Many techniques are available nowadays to create surfaces with ordered uniform pores of nanometer to micrometer sizes. Foremost conceivable techniques are lithography, electron beam sculpting, colloidal templates, emulsion, breath figure assembly (BFA), block copolymer self-assembly, track etching, non-solvent induced phase separation of self-assembled block copolymers, etc18. Research on isoporous structure formation from both homopolymers and block copolymers had been clutched on this method for the last two and half decades after this nature inspired phenomenon first got recognized in the work of Widawski et al. in 199419. By the BFA method regular arrangements of micrometer sized pores are created by templating the droplets of water formed on cold surfaces. Even though this method does not require any sophisticated equipment, it requires steady state humidity all over the film on which the macroporous structure of high regularity can be built up on. However, the mode of processing does not promise yet a large scale production of films with uniformity in the pore sizes. A continuous process of making honeycomb structures in flat sheet geometry from commercially available polymers was first disclosed by FUJIFILM Corporation which includes the requirement of control over humidity around the production line as well and the final film was obtained after going through several steps20. Moreover, the ordered hexagonal structure formation in a dry environment reported before involved the spin coating of the water containing solution. But the spin coating method is limited by the range of area of the porous film it can produce in a single shot4.Among all the methods for formulating ordered macroporous films, BFA is a captivating root because of its simplicity and cost effectiveness21, transfer of the colloidal monolayer on a curved surface23, casting of a film forming solution on TEM grids, sugar crystal, or patterned silicon wafer26, combining the breath figure assembly with eletrospinning27, and etc. But all these approaches also face the challenge to produce isoporous structures on more than a square centimeter scale in one step.Along with the flat sheet geometry porous films need to be framed on substrates with cylindrical, spherical, or concave surfaces for many applications, too. Contriving macroporous structure on a non-planar surface is still a challenge even in a small scale and the strategy of transferring porous film on curved surface requires sophisticated arrangement. Some attempts to fabricate porous structures on non-planar substrates by the BFA method involved macro-patterned thin films on a bas-relief patternet al. introduced a method for creating an isoporous surface by spin coating of the pore forming material on a porous substrate filled with glycerol and the pores of a micrometer range formed by templating the droplets of glycerol28. However, large surfaces of isoporous films cannot be obtained by the spin coating. Widening this pore formation approach to processing methods different from spin coating would allow porous film formation in different geometries in a continuous manner beyond the BFA method.Recently Wang In this study we report on the formation of macroporous films in hollow fiber geometry from commercially available polymers in a continuous process. For doing so we combined the knowledge of hollow fiber spinning by non-solvent induced phase separation (NIPS) with the pore formation mechanism by diffuse-in and condense-out behavior of glycerol. The means applied to this work are comprised of some essential points: the spinning procedure requires a quadruple orifice spinneret where four different die gaps are designated to four different entities which are co-extruded by the dry-jet wet spinning method, the macroporous film in hollow fiber geometry is fabricated by the concept of diffuse-in condense-out behavior of glycerol, the macroporous film contains a support layer in the spinning stream to give mechanical integrity to the film for its handling afterwards.30 or, several solutions (for multiple layer hollow fiber)31 and the bore fluid are extruded synchronously through the different annular gaps of a spinneret. The bore fluid used in such method usually is a precipitant for the spinning solution/s but miscible with the solvent or solvents used in the spinning solution/s. After exiting from the spinneret the bore fluid gets into contact with the spinning solution and starts to solidify the spinning solution from the lumen side of the fiber. The partially solidified fiber enters into the coagulation bath after passing a definite distance in the air. The coagulant used in the coagulation bath is a precipitant for the spinning solution/s and miscible with the solvent/s of the spinning solution/s. After complete precipitation and solidification, the fibers are taken out of the bath and dried in air. The compositions of the bore fluid, the spinning solutions, and the coagulation bath determine the phase separation path of the spinning solution/s which brings about different morphologies in the hollow fiber but this discussion is out of the focus of our present study. Supplementary Fig. 34. Here the quadruple orifice spinneret serves the purpose of co-extruding bore fluid, support layer forming solution, glycerol, and macroporous film forming layer solution The macroporous structure formation in hollow fiber geometry by templating the glycerol droplets is illustrated in Fig. b-polybutadiene-b-polystyrene (PS-b-PB-b-PS) (StyroClear® GH 62 from BASF). Since the support layer solution is employed only as a guide in the spinning line for the macroporous film forming layer, there is a broad variety of the bore fluid and the support layer solution which can be chosen by considering the phase separation behavior of the support layer solution. Depending on the intended application of the macroporous film this layer can be removed later on. In principle also ceramic materials can be used as a support layer, but for the ease of extrusion with our existing spinning facilities we have applied only a polymer solution for this purpose. The experiments are divided into three groups according to the combination of solutions chosen for the spinning. They are listed in Table Two different commercial polymers are chosen to validate our process for macroporous film formation. One is cellulose acetate (CA 398–30 Eastman) and another one is a star block copolymer of polystyrene-In spite of using the same solvent higher concentration of polymer decreases the surface tension of the solution which means that the difference in surface energy of glycerol and the film forming solution is higher when 12% of CA solution is used compared to 8% CA solution  and in tetrahydrofuran (THF)35 (used for Styro Clear® GH 62 solution). In the present work, from the spinneret exit to the coagulation bath these highly volatile solvents evaporate from the film forming solution while diffused glycerol forms droplets in the film forming solution at lower concentrations of glycerol than in pure 1,4-dioxane or THF. Because of the continuous evaporation of the solvent from the macroporous film forming layer, the temperature drops down at the solution-air interface and the glycerol droplets condense out at the surface. If the glycerol droplets are stabilized at the surface then they act as template for the pore formation. The stabilization of glycerol droplets in the surface is also governed by the spinning parameters and this supposition is supported by comparing the surface structures obtained at different air-gaps.Glycerol has limited solubility in 1,4-dioxaneIn Fig. As seen, the surface of the fiber spun with 10 cm air gap distance carries pores Fig. . With th36. Moreover, the effect of increased air gap distance for pore formation is expelled when it is coupled with higher flow rate of polymer solution/s, i.e. having shorter time span of the fiber strand in the air. Furthermore, the surface of the fiber which is spun with longer distance between spinneret and coagulation bath might come up against pore shape stability because of higher elongational stretching of the thin film originated by gravity. That might result in elongated pores . Because of its inherent nano-scale heterogeneity this copolymer appears transparent. StyroClear® GH 62 (BASF) is an asymmetric star block copolymer with polybutadiene core and polystyrene external blocks37. Such star-shaped block copolymers self-assemble in a variety of ordered structure because of the intramolecular phase separation of the blocks39.The consequence of using polymers of different structures and behavior is substantiated by choosing a commercially available star block copolymer of polystyrene and polybutadiene  or casting parameters (for flat sheet geometry) may lead to uniform pore sizes with their ordered arrangement on the film surface by the described approach in large scale in a single step. The presented method of pore formation can be applied to create ordered assembly of inorganic nanoparticles in nonplanar and planar geometry by using nanoparticle precursors in the film forming solution. Accordingly, the method is expected to offer a continuous process to create micropatterned surfaces which may find their way to applications in catalysis, sensing, templating, cell culture or in microelectronics.Supplementary Information


Urinary incontinence and neurogenic bladder are common in children, and can be difficult to treat. This themed issue includes contributions by experts in the management of these disorders. Dr. John Kryger discusses the nonsurgical management of neurogenic bladder in children with spina bifida. Drs. Lori Dyer and Israel Franco summarize the literature and their experience with the use of botulinum toxin in neurogenic and non-neurogenic incontinence in children. Dr. Paul Austin summarizes the use of alpha-adrenergic blockers. These drugs are primarily used to treat bladder outlet obstruction due to prostatic hyperplasia, but show great promise in the treatment of dysfunctional voiding in children.


Here we report a unique case of bilateral ganglion cysts originating from the ligamentum flavum in the cervical spine. Degenerative cysts of the ligamentum flavum are rare lesions, and most had been reported in the lumbar spine. Its occurrence in the cervical spine is extremely rare: only eight have been reported. A 66-year-old male patient presented with progressive paraparesis, pain, and paresthesia in his bilateral T1 dermatomes that had lasted for three weeks. Magnetic resonance imaging of the cervical spine demonstrated a well-demarcated cystic lesion in the bilateral dorsolateral aspects of the C7/T1 segment and significant compression of the cervical cord. All case reports of ganglion cysts of the cervical ligamentum flavum including the present one showed characteristic symptoms and signs of myelopathy such as paraparesis or quadriparesis associated with varying degrees of paresthesia or pain in the upper extremities. Ganglion cysts of the cervical ligamentum flavum are considered a cause of cervical radiculomyelopathy due to cervical intraspinal cystic lesions. Bilateral occurrence and associated subluxation of the involved cervical segments again support the degenerative pathogenesis of ganglion cysts of the ligamentum flavum in the cervical spine. Ganglion cysts of the ligamentum flavum are uncommon degenerative spinal lesions that are mostly encountered in the lumbar spine –6. CerviA 66-year-old male patient, usually in good health, presented progressive paraparesis of three weeks' duration. Three months prior to admission, he had worked hard for four to five hours a day for three months. He developed posterior neck pain and was treated several times with acupuncture. Three weeks earlier, the left leg had lost strength, and his right leg began to flex within a week. Eventually, he could not stand by himself due to the gradual progression of the paraparesis; he also felt paresthesia and pain on his bilateral medial upper arm. No urinary incontinence developed. He was admitted to a hospital and had magnetic resonance imaging (MRI) of the cervical spine and was referred for further evaluation.Neurologic examination showed paraparesis and ataxia. Decreased motor strength, mainly of the quadriceps and adductors, was noted in his lower extremities, 4/5 on his right side and 3/5 on the left. He had more pronounced deep tendon reflex in his left patellar than in his right one. His upper extremities showed no weakness, but he had pain associated with paresthesia and hypesthesia in bilateral C8 dermatomes. We observed no urinary difficulty. MRI of the cervical spine revealed bilateral extradural cystic masses that compromised the dural sac at the level of C7/T1 . The lesAfter a laminectomy of C7 and small medial facetectomy of C7/T1, we removed a hypertrophied ligamentum flavum and exposed the underlying dura. We found a fibrotic, extradural cyst on the internal aspect of the ligamentum flavum  that wasThe postoperative course was uneventful. Immediately after the operation, the patient's severe pain and paresthesia of the bilateral medial upper arm corresponding to the T1 dermatome were alleviated. Although he experienced immediate functional improvement in both legs, the weakness in both legs improved only slowly over the six months following the operation. There was no weakness or sensory deficit in his arms and legs at the one-year postoperative follow-up and no neck pain or radiological instability.Intraspinal degenerative cysts are rare and usually located in the lumbar spine –6. BecauIt has been suggested that ganglion cysts are caused by myxoid degeneration and cystic softening of the connective tissue of the joint capsule or tendon sheath as a result of degenerative process or trauma . The patSymptoms and signs of myelopathy with or without cervical radiculopathy association are the most common presenting symptoms in symptomatic ganglion cysts of the ligamentum flavum in the cervical spine. In our review of the literature regarding theses cysts, six of seven reported cases (86%), including the current case, showed paraparesis or quadriparesis owing to their location within the narrow cervical spinal canal. Most symptoms and signs of myelopathy are gradual and insidious . HoweverMRI is the imaging study of choice in the diagnosis of ganglion cysts in the cervical spine, although histopathologic examination is needed for definitive diagnosis . The MRISurgical excision of ganglion cysts of the cervical spine with posterior laminectomy appears to be a straightforward for decompressing the spinal cord, removing the ganglion cysts, addressing the connection to the facet joint, and taking histologic specimens for definitive diagnosis. All case reports regarding symptomatic ganglion cysts of the cervical ligamentum flavum adopted surgical excision via laminectomy, and the prognosis of surgical treatment is favorable. Although some degree of adhesion between the dura and the ganglion cyst was always mentioned, no surgical morbidity or neurologic compromise was reported. Gradual recovery of the symptoms and signs of radiculomyelopathy appear to occur within 6 to 12 months postoperatively.We here report a very rare case of bilateral ganglion cysts of the cervical ligamentum flavum that presented with progressive myelopathy and radiculopathy. The characteristic bilateral occurrence and associated cervical subluxation at the involved segment supported the degenerative pathophysiology in the cyst.


Glomus deserticola, and leaf mulch from Gliricidia sepium and Senna siamea on the yield of cassava (Manihot esculenta) in a degraded alfisol of southwestern Nigeria was investigated. Inoculation in conjunction with mulching increased cassava tuber yield by 40–278% over the control. The highest yield was obtained with G. sepium and S. siamea mulch applied together in equal proportions. The results are explained in the light of the growth-enhancing effects of AMF, encouraged by the ameliorating effects of mulch on the soil structure and nutrient contents.The influence of arbuscular mycorrhizal fungus (AMF),


Epigallocatechin-3-gallate (EGCG) is a major ingredient of green tea (GT) and silibinin (SB), the active component of Silymarin presumably hold a potential to prevent pathogenomics. Prostate cancer exacerbation is triggered by fusion transcripts formed because of genomic instability induced by juxtapositioning of two genes. This chimeric transcript is implicated in androgen dependent and independent prostate cancer. Tremendous work is done on the characterization of the mediators involved in the disease refractoriness, yet no study has addressed clinical management of these prostate fusion transcripts impressively.An abolished ATM dynamics challenges integrity of DNA. In agreement with this assumption, ATM and DNA-PK were impaired in LNCaP cell line to confirm a tight interaction of these mediators with the expression profile of TMPRSS2-ERG. Abolished ATM enhanced the expression of the fusion transcript. Similarly blunting of DNA-PK downregulated the expression of the fusion transcript giving a notion that DNA-PK is involved in the chromosomal translocation. LNCaP cell lines were analyzed for the effect of EGCG and SB on the expression profile of TMPRSS2-ERG.In this particular unprecedented study, treatment of the LNCaP cell line with EGCG and Silibilin recapitulated ATM expression and activity and downregulated the fusion transcript appearance.These results underscore the therapeutic effect of EGCG and SB in mitigating the exacerbation of the disease with reference to the fusion transcripts. Prostate cancer is modulated by fusion transcripts. These chimeric transcripts were most common in hematological malignancies. However, few years back, these were reported in prostate epithelium. The generation of these transcripts is a result of genome rearrangements. These alterations or rearrangements disturb the individuality of the gene and there is a partial sharing between two incomplete genes to carry on the illegitimate dynamics of the neoplastic cell. The chromosomal translocation or genomic rearrangements are generated because of unfaithful repair of the genome after DNA damage. The demolition of genomic stability leads to oncogenesis. TMPRSS2-ERG is a fusion transcript that is a well documented example of genomics instability outcomes in prostate epithelium , 2. TomlThe prostate cancer cell line LNCaP was obtained from the American Type Culture Collection. Human PrECs was maintained in PrEGM media. Transfection of LNCaP and PrECs cells with siRNA was performed with Lipofectamine2000 (Invitrogen). For induction of chromosomal translocation, LNCaP cells or PrECs were grown in charcoal-stripped serum containing media for 48 h followed by mock, DHT (10–7 M), g-irradiation (50 Gy) treatment, or both. After treatment, the cells were reincubated for 24 h before being harvested for appropriate assays. Cells were then treated with 100 µM EGCG for indicated times. Cell viability in cultures before and after irradiation was assessed by trypan blue exclusion.The ATM siRNA (sc-29761) and siRNA DNA PK (sc-35200) target sequences generally consisted of pools of three to five target-specific 19-25 nt siRNAs designed to knockdown gene expression and were purchased from Santa Cruz biotechnology.LNCaP cells were treated with designated concentrations of SM or SB in the presence of 1 nM Mib for 24 h. Then cells were harvested and whole cell lysate and nuclear extract were prepared and Western blotting analysis was performed as described previously by Wen et al, 2001 . The suiSince the discovery of the fusion transcripts in prostate cancer, tremendous work has been done on the characterization of novel chimeric transcripts and the underlying mechanism. In most cases, the disease progresses to castration resistant prostate cancer (CRPC). However, therapeutic interventions are ignored in this time span. Only recently two studies were conducted by Palanisamy et al, 2010 and Pfeiffer et al, 2010 respectively. Palanisamy et al  worked oPfeiffer et al  used an We have explored the role of DNA repair genes in the induction of chromosomal translocation in this particular study. Any damage done to DNA drastically compromises the activities of the cell. To resume these activities there must be a repair of the DNA. Normally homologous recombination is mediating the repair, yet any hampering of the mediators of HR results in switching to NHEJ mode. This mode facilitates the genomic rearrangements. Androgen receptor is a key player in the stimulation of chromosomal rearrangements. In prostate cancer, the activity of ATM is compromised, and repair activities are carried out by DNA-PK. This protein triggered the appearance of the fusion transcripts in prostate cancer line. Nutraceuticals are 'natural' substances isolated or purified from food substances and used in a medicinal fashion. EGCG efficiently stabilized ATM activation and that was evident from the phosphorylation of ATM. The restoration of compromised ATM dynamics in our experiments is consistent with the study conducted by Amin et al  who docuAccording to our interpretations, DNA-PK is actively engaged in the induction of genomic rearrangement. Furthermore, we were able to downregulate the expression of TMPRSS2-ERG in the LNCaP cell line. To date, there is no study that specifically encompasses the expression pattern of fusion genes after treatment with nutraceuticals. Our particular study demonstrates that ablation of DNA-PK and recapitulation of ATM activities are indispensable for the suppression of gene fusions. The data in this study unmasked this tight correlation of push and pull between DNA repair genes in suppression or promotion of genomic instability. Still, the pro-apoptotic potential of these two compounds remains to be investigated. Various studies have been conducted in terms of exploring the role of DNA-PK in induction of apoptosis.One body of evidence suggests that phosphorylation of IGFBP-3 by DNA-dependent protein kinase (DNA-PK) at Ser(156) is functionally critical in its apoptosis-inducing actions. In the absence of DNA-PK activity, IGFBP-3 has reduced nuclear accumulation . On the It is believed that numerous of these 'natural' compounds have therapeutic potential and surely studies consisting of well-designed clinical trials assessing combinations of compounds concurrently will enable us to get a step closer to rational drug design. Yet a closer look into the crosstalks between proteins must be given utmost significance while trying to get a step closer in the standardization of therapy.


We present a rare case of a femoral shaft fracture in a 74-year-old woman with a preexisting untreated bilateral congenital hip dislocation and with concomitant leg length discrepancy. Because of the marked deformity of the upper femur, a derivative of the congenital hip disease, an open reduction and internal fixation was performed, with the use of an anatomic femur plate originally designed for the treatment of periprosthetic fractures. The patient was treated successfully and returned to her previous status of activity. The management of a femoral fracture in the presence of ipsilateral hip disease is a challenging issue. The surgical treatment choice in such cases has to be individualized, taking into consideration several anatomic and medical parameters. Congenital hip disease (CHD) is relatively common in Greek people . The incWe present here a case of a femoral shaft fracture in a female patient with untreated bilateral congenital hip dislocation. A good final outcome was achieved with internal fixation of the fracture using a periprosthetic fracture plate.A 74-year-old woman was admitted to the emergency department of our hospital after a closed injury of her left femur due to a fall. Plain X-rays showed a spiral shaft fracture of the proximal third of the femur. The radiographs of the pelvis and the patient's history as well revealed that she was also suffering from bilateral congenital hip disease Figures  and 2. TTaking into consideration the “personality” of the fracture, the patient's needs, and the surgical options, we performed an open reduction and internal fixation (ORIF) using the NCB periprosthetic femur polyaxial locking plate system . The operation was performed two days after the fracture, under spinal anaesthesia. The patient was placed in the right lateral decubitus position, and the middle and proximal thirds of the femur were accessed through a lateral approach. The subtrochanteric area of the femur was exposed with anterior retraction of vastus lateralis after an L-shaped detachment of its origin. The fracture was anatomically reduced, and two lag screws were placed initially. Then, the NCB periprosthetic femur plate was placed as a neutralization plate . Image iThe patient was mobilized on the first postoperative day (POD), and she stood upright using crutches, without weight bearing on the fourth POD. The postoperative period was uneventful, and she was discharged on the 6th POD. Because of the leg length discrepancy, she was protected from weight bearing for six weeks when she was reviewed in our outpatient clinic. At that time, the patient was free of pain, and the subsequent X-ray images showed signs of fracture healing Figures  and 5. FThe combination of a femoral fracture in the presence of preexisting hip pathology is extremely rare. Most of the published reports refer to the cases of either the upper femur or femoral shaft fracture under an arthrodesed hip –10. To tIn our case, it was a noncomminuted spiral fracture of the femoral shaft, caused by rotational forces after a simple fall. The gold standard for those fractures is closed intramedullary nailing (IMN) . HoweverBy contrast, open internal fixation using this specially designed periprosthetic femur plate proved to be a successful method of stabilization after open anatomical reduction. The specific plate fits anatomically to the lateral wall of the femur, extends to the greater trochanter, and facilitates the placement of multiple bicortical locking screws of various diameter sizes in different directions proximally and distally, adding stability to the fixation.