In Lebanon and many other countries where structures are vulnerable to impact loads caused by accidental rock falls due to landslides, specifically bridges with hollow core slab, it is mandatory to develop safe and efficient design procedures to design such types of structures to withstand extreme cases of loading. The structural response of concrete members subjected to low velocity high falling weight raised the interest of researchers in the previous years. The effect of impact due to landslide falling rocks on reinforced concrete (RC) slabs has been investigated by many researchers, while very few studied the effect of impact loading on pre-stressed structures, noting that a recent study was conducted at Beirut Arab University which compared the dynamic behavior of reinforced concrete and post-tensioned slabs under impact loading from a 605 kg impactor freely dropped from a height of 20 m. Hollow core slabs are widely used in bridges and precast structures. Thus, studying their behavior due to such hazards becomes inevitable. This study focuses on these types of slabs. For a better understanding of the behavior, a full scale experimental program consists of testing a single span hollow core slab. The specimen has 6000 mm × 1200 mm × 200 mm dimensions with a 100 mm cast in a place topping slab. Successive free fall drops cases from 14 m height will be investigated on the prescribed slab having a span of 6000 m. This series of impacts will be held by hitting the single span hollow core slab at three different locations: center, edge, and near the support. The data from the testing program were used to assess the structural response in terms of experimental observations, maximum impact and inertia forces, structural damage/failure: type and pattern, acceleration response, and structural design recommendations. This research showed that the hollow core slab has a different dynamic behavior compared to the post tensioned and reinforced concrete slabs mentioned in the literature review section. Lebanon is characterized by its varied terrain . With the increase in population, people moved to live in the mountain region, increasing the percentage of inhabitants there. Lebanon is one of the countries where many landslides are caused because of heavy rain falling in the winter, particularly in mountain areas, resulting in rock falls threatening lives and causing severe damage to the infrastructure and to the residential buildings. Considering the advantages of precast pre-stressed concrete structures, they were introduced in the industry for construction purposes such as covering large spans and speed of erection compared to conventional RC structures. Noting that the most commonly used bridge deck system used in Lebanon mountain areas are made up using precast hollow core units and because of the high probability of natural catastrophes that may highly cause failure for this structures, it is mandatory to study the behavior of hollow core slab under impact loading and finally provide design recommendations for manufactures and structural enhancement for a better performance under such extreme cases of loading. This complex phenomenon drew the attention of many researchers noting that structural engineers do not take into consideration such type of loading cases though the international design codes used.Numerous studies have been conducted, experimentally and numerically, on the behavior of reinforced concrete and pre-stressed structures when subjected to impact loads.Reference : The aimReference : This reReference  studied Reference  studied References ,6,7,8 nuThe current study intended to extend understanding and to get a deep insight into the structural response of pre-stressed slabs’ behavior, namely the hollow core slabs when subjected to low-velocity successive impacts.The hollow core slab unit was selected based on the thickness to span and characteristic service loads where a 200 mm hollow core slab with a 6 m long span can support 10.5 KPa according to the manufacturer.The experimental test in this paper is part of an ongoing doctoral program at the department of structural engineering in Beirut Arab University, studying the structural response of concrete structures under impact loading.-Tested SpecimenThe analyzed slab is a structure 6000 mm in length by 2400 mm (width) and 200 mm thickness as illustrated is The slab system consists of two precast hollow core units. As illustrated in The topping slab is made of concrete with a 45 MPa compressive strength and includes steel reinforcement bars as illustrated in Construction materials properties were grouped in The bars are of 12 mm diameter spaced at 200 mm in both directions with no use of shear connectors or any other type of shear reinforcement. They have an average modulus of elasticity and tensile strength of 200 GPA and 515 MPa, respectively.-Drop WeightThe mass of the drop-weight used in the experimental program is 600 kg . The droThe impact loads were generated by what was essentially a free-fall condition of the drop weight. The cable of the moving crane attached to the steel ball ran through the center of the drop-weight and was used to guide the weight during the fall.The hollow core slab was tested under successive impact loading at three different locations: Slab center, edge, and near the support as illustrated in The hollow core slab was mounted by four electronic accelerometer fixed at different positions as shown in The experimental analysis consists of simulating a slab subject to a series of successive impacts. The tests involve dropping a steel ball of 600 kg as illustrated in The drop weight is lifted to the dropping height by a crane as shown in The generated accelerations with respect to time were recorded and the data were saved through the data acquisition system. Then these values were used to derive the displacements and calculating the impact force, as discussed in the following section. The structural assessment of the specimen response to the impacts such as damaged zones, failure pattern, cracks detections, and propagation were registered after each impact, and results were then analyzed.Several measurements have been made on the analyzed slab. We present in this paper the results related to the (i) damage analysis, (ii) dynamic behavior in terms of acceleration response, and damping ratio, (iii) shear strength, inertia force, and impact force grouped in --Impact crater diameter 28 cm;-No cracks in the topping slab;-No punching with a 2 cm impact penetration through the slab thickness.Concrete topping slab damage assessment:-No global failure in the hollow core units;-Local damage directly beneath the impact represented by the spalling of the 25 mm concrete cover from the bottom side as illustrated in the figure below;-Overall damages were concentrated in the lower unreinforced flange of the hollow core unit;-No damage in the upper flange of the hollow core unit was assessed (Topping slab and hollow core unit worked compositely);-There is no separation between the concrete topping and the hollow core unit;-No de-bonding between the embedded strands and the concrete host.Hollow core slab damage assessment:First Impact Experimental Observations :Concrete--Concrete fracture at the impact location with damaged zone;-Transversal crack passing through the depth was initiated in the topping slab and the hollow core unit;Concrete topping slab damage assessment:-Severe shear damage normal to the slab caused a cut off for the first three cores of the hollow core unit;-Total concrete facture of the web, top, and bottom flanges of the hollow core unit;-Normal and transversal contact separation between the concrete topping and the hollow core units;-The first three tendons were de-bonded from the hollow core unit because of the concrete facture of the web, top, and bottom flanges of the hollow core;-The total stiffness of the hollow core unit was highly reduced by the loss of three of its cores with their strands;-The composite behavior between the concrete topping and the hollow core unit in terms of flexural rigidity was highly reduced because of the surface contact separation;-As expected, the edge impact caused a much higher damage in both the concrete topping and hollow core unit as compared to the one done by the first impact at the center.Hollow core slab damage assessment:Second Impact Experimental Observations :Concrete--Impact crater diameter 35 cm;-No cracks in the topping slab;-Concrete topping was punched through its depth (high shear force near the support);Concrete topping slab damage assessment:-Large damage distributed along the whole parts of the hollow core units;-Major concrete facture of the web, top and bottom flanges of the hollow core unit;-The brittle damage in the top and bottom thin flanges connecting the webs leads to a total loss of hollow core slab stiffness;-The brittle damage in the web connecting the two flanges leads to a total loss of hollow core slab stiffness mainly when the lower part where the pre-stressing strands are embedded separates from the gross the section of the slab;-The brittle failure of the top and bottom thin flanges governs the global behavior of the slab.Hollow core slab damage assessment:Third Impact Experimental Observations :ConcreteThe structural damage in the concrete topping and in the hollow core slab was assessed as following:Experimental results of the three impacts are summarized in Damping ratio was calculated by the use of the first two peak accelerations and according to the Equation (3):Equation (4) from the PCI code was used to calculated the shear strength of the composite slab and found to be equal to 121.27 KN.And Equations (5) and (6) were used to calculate the maximum impact force and the dynamic magnification factor respectively for each impact.This paper studied the behavior of single span hollow core slab under successive impact load at three different locations: center, edge, and near the support under a 600 kg free falling steel ball from a height of 14 m. The structural response of the slab in terms of damage assessment, acceleration response, damping, and impact force has been studied. The results thus obtained were mentioned and the following conclusions were drawn:-Structural damages in hollow core units cannot be repaired or strengthened.-Voids, thin web, and thin flanges are considered the weak points of the hollow core slab.-The presence of strands has no participation in the section load resistance if the continuity of the webs is lost by the facture of one or both flanges.-The slab system (HC + Topping) showed a lower capacity in terms of damage and acceleration response for impact at the edge compared to the impact at the slab center.--The severe damage in the slab body led to a vibration with a low acceleration amplitude directly after the impact;-The concrete topping as solid section and the hollow core units as voided section vibrate in a different manner under impact loading;-The concrete topping and the hollow core units vibrate independently from each other under vertical excitation because of the absence of any type of connectors enforcing the total thickness to work as one unit;-The reduction in slab capacity to resist impact can be demonstrated by the ratio of the maximum acceleration response between the first and the third impact The decaying function of the acceleration response represented by the accelerometers readings indicate an unconventional damped vibration. This response can be explained by the following reasons:-The reinforced concrete topping with high compressive strength (45 Mpa) helped the hollow core slab section to carry more impacts.-Concrete solid section behaves in a much better way than the hollow section in terms of structural damage and cracks generation.-Adding shear connectors can enhance the structural response of the slab system (Topping + HC unit) to avoid the contact separation specially in the case of impact at the slab edge.-Code limitations must be provided to select the minimum flange and web thicknesses in addition to the maximum void diameter in hollow core units.-Filling material such as foam can be used to absorb a part of the energy induced in the body of the hollow core unit to mitigate the brittle fracture of the thin flanges, therefore enhancing the structural performance of the slab system.-The presented damping ratio showed the vulnerability of the impact load location in the hollow core slab.-The reduction in slab impact capacity after successive impacts can be measured by the ratio of impact resistance factor = F1/(F2) = 13,868/1600 = 8.67.


A 16-year-old man presented to our Emergency hospital for a major traumatic scalp injury of pubic and scrotal region; this occurred as a consequence of an autonomous motorcycle accident. Early surgical esploration showed the bilateral section of spermatic cord in correspondence of the abdominal-pelvic tract; a conservative management was adopted and the patient underwent bilateral intratesticular sperm biopsy for cryopreservation. In the presence of extensive scalp injury of the pubic and scrotum skin a early surgical exploration should be performed and the multidisciplinary decision making should take in account comorbidity, age and impact on the quality of life. Male genital injuries are rare to occur relatively due to isolated location of the genitals and in most of the cases are caused by road traffic and machinery-related accidents; rarely, the peno-scrotal degloving injury with total amputation of the scrotum has been reported. Although injuries of genitalia are non-lethal, the lesions could be incapacitating and psychologically overwhelming to patients if not treated appropriately.4A case of bilateral spermatic cord section as a consequence of an autonomous motorcycle accident has been reported.A previously well, 16-year-old man presented after sustaining with a major traumatic injury to pubic and the scrotal region; this occurred as a consequence of an autonomous motorcycle accident during a motocross race occurred about 12 hours before hospital admission. Physical examination revealed extensive scalp injury of the pubic and scrotum skin involving bilateral testis and penis ; the pat,Genitourinary injury is present in approximately 10% of cases of abdominal traumaIn our case, the first to our knowledge reported in literature, an extensive scalp injury of the pubic and scrotum skin involving bilateral testis and penis only the bilateral spermatic cord section was reported. Although CDUIn the presence of extensive scalp injury of the scrotum skin involving bilateral testis and penis an early surgical exploration should be mandatory; in the presence of isolated bilateral spermatic cord section the multidisciplinary decision making should take in account comorbidity, age and impact on the quality of life for the patient.All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.Written informed consent was obtained from the patient for his anonymized information to be published in this article.The authors declare that they have no conflicts of interest.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.


Revised legislation and bans on imports of waste electrical and electronic equipment (WEEE) into many Asian countries for treatment are driving the need for more efficient WEEE fractionation in Europe by expanding the capacity of treatment plants and improving the percentage recovery of materials of economic value. Data from a key stakeholder survey and consultation are combined with the results of a detailed literature survey to provide weighted matrix input into multi-criteria decision analysis calculations to carry out the following tasks: (a) assess the relative importance of 12 process options against the 6 industry-derived in-process economic potential criteria, that is, increase in product quality, increase in recycling rate, increase in process capacity, decrease in labour costs, decrease in energy costs and decrease in disposal costs; and (b) rank 25 key technologies that have been selected as being the most likely to benefit the efficient sorting of WEEE. The results indicate that the first stage in the development of any total system to achieve maximum economic recovery of materials from WEEE has to be the selection and application of appropriate fractionation process technologies to concentrate valuable components such as critical metals into the smallest possible fractions to achieve their recovery while minimising the disposal costs of low-value products. The stakeholder-based study has determined the priority for viable technical process developments for efficient WEEE fractionation and highlighted the economic and technical improvements that have to be made in the treatment of WEEE. Waste electrical and electronic equipment (WEEE) is a large and increasingly diverse type of waste with an estimated global yield of approximately 45 million tonnes per annum . ParticuReport on Critical Raw Materials for the EU  triboelectrostatic separation  under apSeveral sorting technologies have been applied to the removal of metals from WEEE , 2006. TA number of remote sensing technologies that are sufficiently fast in detecting and removing target particles have been validated for the sorting of WEEE. When these technologies are used, high levels of differentiation that can enhance the separation and value of recovered material can be achieved . Sensor-Hydrometallurgical methods have been used in the recovery of metals from WEEE  but haveWith increasing tonnages of WEEE requiring treatment, and recent import bans on wastes by Asian and Far Eastern countries, there is a need within the EU to develop process technologies for efficient WEEE fractionation and separation that take into account technical and legislative requirements in the EU, including the safe removal of any hazardous materials. We now report on the analysis of stakeholder-based survey data combined with a detailed literature survey to prioritise viable WEEE process development options and rank technologies that concentrate valuable materials in the smallest possible fractions to permit maximum economic recovery and separation of commercially viable materials.The methodology used to obtain stakeholder data to enable the evaluation of viable WEEE process development options, particularly for e-waste, consisted of four parts: (a) a detailed literature analysis of both technologies that have already been developed and those under development that can be applied to separating the components of WEEE; (b) selection of key stakeholder participants; (c) design of a questionnaire to collect stakeholder data on process development options for WEEE; and (d) data handling and analysis.A detailed review of the primary and secondary literature and technical documents using critical citation keyword searches was carried out to determine what relevant fractionation technologies are available to the WEEE treatment industries. The aim of the review was to identify technologies that were likely to achieve the efficient fractionation of WEEE, particularly e-waste, within the constraints of the WEEE Directive to maximise material recovery and value. The technologies and methods identified were classified into four main groups: comminution; direct sorting; sensor-based sorting; and hydrometallurgical and chemical methods. The results from the literature review were analysed in detail to produce a subset of 25 current and emerging technologies identified as being of particular relevance to the separation and fractionation of WEEE in terms of achieving selective recovery of economically viable materials. Consultation with the 33 key stakeholders led to a classification of these technologies in terms of the key process options (chosen for their function) likely to effect the successful separation and fractionation of high-value materials from WEEE: metals, engineered plastics, glass and composite materials of value. A set of key process options was then identified through a combination of the literature survey and detailed discussions with relevant industry stakeholders: removal of specific molecules; separation of component materials of composites; comminution; sizing; removal of ferromagnetic metals; removal of non-ferromagnetic metals; removal of plastics; removal of glass and ceramics; sorting ferromagnetic metals; sorting non-ferromagnetic metals; sorting plastics; and sorting glass and ceramics.The 33 stakeholders were selected from the network of the authors’ contacts within the European WEEE management sector, and all of them held senior management positions (as directors or operations managers) with responsibility for managing automated WEEE sorting processes in Europe within their organisations. All the stakeholders were users of relevant technologies for the separation of target materials from WEEE, had a sound understanding of the relevant economic and technical aspects of such processes and had responsibility for key decisions with regard to investment in the company’s technology portfolio.Engagement with the stakeholders included discussions on (a) the findings from the literature survey to assess their opinion on the selection of the technologies most likely to be successful in separation of materials, (b) the relevant key process options for WEEE fractionation and (c) the economic process criteria that should be used in the data analysis. Each stakeholder was invited to participate in the survey, which was designed to determine the practitioner’s point of view with regard to the relative importance of technologies available to the WEEE treatment industries. Direct input from the 33 stakeholders obtained in this part of the research resulted in endorsement of the concept of the research, the selection of technologies and process options to be used and the measures against which the options should be judged. The 33 stakeholders also decided on what cost priorities they regarded as important in the technology survey, expressed in A questionnaire was designed to obtain meaningful and unbiased data from the key stakeholders who had responsibility for managing automated WEEE sorting processes in Europe. To eliminate bias, the stakeholders selected for inclusion in the survey represented the different activities and priorities that exist across the electrical and electronics recycling industries, for example, companies that focus on specialist processes such as plastics recovery or sorting of non-ferrous metals, and those that treat and recycle all fractions and components of WEEE. The questionnaire consisted of two parts and it was supplied to relevant stakeholders in German or English, as appropriate, for completion either by means of an interview or email response, and the survey was conducted over a period of four months.Of the 33 stakeholders, 21 confirmed their agreement to participate in the survey, and the surveys were sent by email  to each stakeholder for completion either by email or via a telephone or face-to-face interview. Of the 21 stakeholders, 10 responded in full, matching their weightings against the agreed criteria. The remaining 11 stakeholders provided partial responses that added to the information provided in the full responses.The first part of the questionnaire was designed to gain an understanding of the nature of the activities of the stakeholder and an insight into the WEEE collection streams and the separated fractions of secondary raw materials derived from WEEE by individual stakeholder organisations. The following set of open-ended questions was used:What collection streams of WEEE do you accept?What module/component fractions of WEEE do you accept?What material fractions of WEEE do you accept?Which of the material streams that you produce incur disposal costs?Which of the material streams that you produce generate revenue?In your answers to questions 1–5, which of the materials  mentioned do you expect to have relatively high potential for economic improvement?In the second part of the questionnaire, stakeholders were required to complete two data input sheets providing relative numerical scores between 1 and 10 for (a) the 12 key process options, chosen to represent the methods used in the separation of WEEE fractions to optimise total value recovery, matched against a set of 6 criteria  that describe economic potential , and (b)Questions 1 to 6 in the first part of the questionnaire are evaluated by ranking the most common keywords  found in the stakeholder responses on the basis of the number of times they appear. Identified keywords are counted only if they occur more than once throughout all stakeholder responses, and repetition of any keyword by the same stakeholder in answer to the same question is counted only once. Because questionnaires were answered by stakeholders from different European countries, in selecting keywords the differences in definitions of WEEE collection streams in individual national member state countries were taken into account.The weighted matrix information supplied by individual stakeholders in the second part of the questionnaire provides data that can be analysed mathematically to aid management decisions. Examples of this type of approach in waste management decision-making include use of a weighted matrix analysis to develop a hierarchy of waste management options for the treatment of the organic waste fraction of municipal waste , benchmaThe numerical data obtained from stakeholders were analysed using multi-criteria decision analysis (MCDA), an analytical approach designed to deal with the difficulties that human decision-makers have in handling large amounts of complex information in a consistent way to identify best options . The guiin which each option has to be judged individually against each criterion Each criterion is also assigned a weighting In this work, the MCDA was carried out by normalising the data supplied by stakeholders for both the economic potential criteria and the weightings they attributed to the relative importance of each criterion using equations (1) and (2).The normalised economic potential is given bywhere The normalised weightings of the economic potential for the criteria where A dimensionless priority ranking score for each key process option For each option in set 125) identified as most likely to be successful for use in one or more of the 12 key process options  are given in Data obtained from a detailed relevant literature survey and key stakeholder consultations have been combined with those from a stakeholder questionnaire and constitute the input into MCDA calculations  and 2 toThe MCDA calculations involved (a) ranking of the 12 key process options against a set of stakeholder industry-derived process economic criteria, which were chosen for their potential importance in achieving optimum fractionation success, and (b) ranking of the 25 technologies most likely to benefit one or more of the 12 key process options. The numerical input data required in the evaluation of the rankings were provided by stakeholders in the form of weighted matrix information on two parameters, first, as illustrated in The data obtained from the stakeholder survey have been combined with the findings from a detailed literature review and stakeholder consultation exercise using the analysis described in decrease in disposal costs > increase in product quality = increase recycling rate > increase in process capacity > decrease in labour costs > decrease in energy costs. Although the criteria may not be totally independent, for example, the three criteria increase in product quality, increase in recycling rate and decrease in disposal costs may have mutual dependency, it is clear that in any process, the cost of disposal of low-quality materials has a major effect on the economics of efficient recycling of WEEE, leading to decrease in disposal costs having the highest ranking. Achieving a reduction in disposal costs is seen as the most desirable of the economic factors affecting recovery of value from WEEE, but there will always be a conflict between the disposal and process costs involved, for example, automated removal of black plastics on an industrial scale, which would reduce the disposal costs of low-grade plastics created as a by-product from separation processes designed to recover high-value engineering plastics, is not currently carried out.The results of a normalised analysis  of the aThe information from stakeholder numerical data input into an MCDA calculation is shown in Although the results of the study of the technologies most likely to achieve optimal fractionation of WEEE to achieve maximum material recovery for recycling are specific to the European situation, the methodology developed is general, and with appropriate stakeholder input can be applied to any region, country or recovery operation.The treatment of large tonnages of the heterogeneous waste streams from end-of-life electrical and electronic goods has become an increasing problem for the recovery and recycling industries. Recovery of value from these wastes, however, is complicated both by their complexity and by national and international legislation applied to the treatment processes used and to any materials derived from these. In Europe, there is now a requirement to expand the capacity of treatment plants and improve the percentage recovery of materials with economic value. The need to concentrate valuable materials in WEEE into the smallest possible fractions to maximise recovery potential is now an important issue; for example, this will ensure that treatment after fractionation makes it possible to remove hazardous flame-retardant components from plastics, and also that specific components such as critical metals are concentrated into very small fractions to achieve maximum recovery potential. For reasons such as these, efficient separation of components containing metal from plastics has to be a crucial stage in any WEEE recovery process.increase in product quality, increase in recycling rate, increase in process capacity, decrease in labour costs, decrease in energy costs and decrease in disposal costs), which were selected by the key stakeholders as being the most relevant in-process cost considerations that would lead to the optimal fractionation of WEEE. The results of this normalised analysis of the assessment of the relative importance that stakeholders attach to the economic criteria show that these are ranked as follows: decrease in disposal costs > increase in product quality = increase recycling rate > increase in process capacity > decrease in labour costs > decrease in energy costs. Although the criteria may not be totally independent it is clear that in any process, the cost of disposal of low-quality materials will have a major effect on the economics of efficient recycling of WEEE, and that any fractionation processes developed must take account of this. The 25 technologies were also ranked using a combination of the results of the process option rankings and a stakeholder-determined relevance indicator.The initial stage in the development of total systems to achieve maximum economic recovery of materials from WEEE has to be the selection and application of appropriate fractionation process technologies. A combination of stakeholder-based survey data with a detailed literature survey has been used in this study to provide weighted matrix input data into MCDA calculations to prioritise and rank both process options and technologies available that could achieve optimal fractionation of WEEE with the aim of maximising material recovery for recycling. The literature review and stakeholder consultation survey permitted the ranking of 12 key process options and 25 technologies against the following six in-process economic criteria (This stakeholder-based study has (a) determined the priorities for viable technical process developments for efficient WEEE fractionation for maximum recovery of high-quality material, and (b) highlighted the economic and technical improvements in WEEE treatment that will have to be made at a time when European electronics recyclers will be required to expand their facilities because of increased volumes of WEEE and new import bans on wastes by Asian countries. Although it is important that fractionation processes have the ability to recover metal content  from the smallest fractions possible to achieve maximum economic recovery, it is also important as far as the European situation is concerned that the processes are capable of recovering high-quality economically recyclable plastic fractions that are free from hazardous flame-retardant materials.The results of the study of the technologies most likely to achieve optimal fractionation of WEEE to achieve maximum material recovery for recycling are specific to the European situation, but the methodology developed is general, and with appropriate stakeholder input it can be applied to any region, country or recovery operation.


Central and North West London's Clinical Ethics Committee (CEC) offers a non-judgmental space to discuss ethical concerns and challenges and provide ethical guidance. This project aims to publicise these ethical dilemmas and guidance to inform decision making trust-wide.A Clinical Ethics Committee (CEC) encompasses a diverse range of figures, from psychiatrists and general practitioners to members of the clergy and experts by experience. The CEC in Central and North West London have been meeting regularly since 2003 to provide ethical assistance to a wide range of medical, surgical and psychiatric teams. Complex ethical cases are presented by the treating team, allowing a subsequent discussion of the ethical theories and frameworks within the case with the committee members. This synthesis of information can then assist the treating team in the shaping of ethical based solutions to their dilemmas.The committee wished to encourage ethical based clinical thinking within the trust and enable others to learn from the valuable insights already provided by the CEC over the years.Case notes, recorded from the last 17 years of meetings of the Clinical Ethics Committee were reviewed. 98 cases were identified between 2003-2019. The contemporaneous case reports were then anonymised and indexed into one easy to use file. This file was published on the local intranet and publicised to staff.The cases were compiled into a PDF document which is available for all staff members within the trust on the intranet. This resource is open to all clinical staff, and serves the dual purpose of encouraging ethical-based thinking and also promoting the ethics committee to those who might be in need of assistance.Clinical decisions can be complex and nuanced, often complicated by multiple viewpoints and ways of thinking. The database demonstrates the use of ethical dimensions by the ethics committee to inform decision making in a series of varied clinical and management dilemmas. The project required careful consideration around preservation of confidentiality as well as overcoming the logistical barriers of trust-wide dissemination. The result is a document that will allow ethical based decision-making to be embedded into everyday practice.


Gene amplification is a mechanism whereby cultured animal cells and human tumours become resistant to cancer chemotherapeutic agents. This review of studies from the authors' laboratory describes properties of the acquisition of resistance to methotrexate in cultured mammalian cells by virtue of amplification of the dihydrofolate reductase gene. These properties result in a heterogeneous cell population with respect to many cell properties, including the number and stability of the amplified genes. Gene amplification results from overreplication of DNA in a single cell cycle as a result of inhibition of DNA synthesis. The cells surviving such overreplication constitute a heterogeneous population with multiple chromosomal changes, including partial or complete endoreduplication of chromosomes, as well as a variety of chromosomal rearrangements. A similar phenomenon may underlie the generation of aneuploidy in tumours, their malignant progression, and the generation of heterogeneity in the tumour cell population.


Data in a regional cancer registry covering a population of 5 million and with an efficiency of registration of over 95% have been used to examine incidence trends in oesophageal and gastric carcinoma. In the West Midlands Region of the UK, during the period 1962 to 1981 the age standardised incidence of gastric carcinoma decreased by 20%. However, an analysis by both histological type and detailed site reveals that while the incidence of distal lesions is diminishing, the incidence of adenocarcinoma of the oesophagus and cardia is increasing. The proximal and distal lesions also exhibit marked differences in social class distribution and sex ratio. The results strongly suggest that the aetiological factors involved for cardia and adjoining sites are different from those for pyloric antrum.


Investigators with complementary expertise on the application of microarray technology in clinical oncology presented their recent findings and debated critical aspects regarding diagnostic and prognostic applications and current trends in the use of this technology for monitoring and predicting clinical response to treatment of cancer patients. This meeting report summarizes the main contributions and underlines some critical issues, which need to be addressed to enhance the effectiveness of this potential powerful new technology in clinical oncology.The completion of the human genome project together with the development and implementation of microarray technologies have opened new opportunities for progress in cancer research. For instance, an increasing number of molecular markers with prognostic and diagnostic potential have been identified in a broad range of human cancers by cDNA microarray analysis . Thus, tMicroarray technologies have been extensively used to evaluate genetic markers and changes in gene expression associated with cancer onset and progression for certain types of solid tumors . Ulrich Microarray technology has provided the opportunity to begin a comprehensive molecular and genetic profiling of human breast cancer . AlthougIn the hematological field, cDNA microarrays have contributed to an increasingly well-defined molecular taxonomy of leukemias and lymphomas. This has led to the segregation of morphologically identical tumors according to molecular patterns predictive of distinct clinical outcomes -8. MoreoThe increasing use of microarray technology for characterizing the transcriptional profile of tumors opened the opportunity to develop potent tools for prediction of response to treatment and for the identification of novel therapeutic targets. The genome-wide perspective offered by microarrays has allowed the focus of drug development to shift towards targeted therapeutics acting on specific molecular targets. For instance, it has been reported that growth factor signals are mutated in a number of cancers including colorectal cancer . Advancein vitro exposure to GM-CSF and IFN-α as compared to cells treated with GM-CSF alone. This study could also provide insights into the mechanisms contributing to the in vivo anti-tumor activity of IFN-α through the enhancement of monocyte and dendritic cell functions [Although there is circumstantial evidence that the activation of the anti-tumor immune response may be critical in affecting the natural or treatment-induced history of cancer, the complex interactions underling this phenomenon remains largely unknown . For insunctions ,20. The The influence of the genetic background of patients on treatment outcome was discussed by Marincola  and Panelli . Short oligonucleotide (18 to 22 oligonucleotide) microarrays represent a powerful tool for genome-wide screening of genetic variations such as single nucleotide polymorphisms (SNPs), which can be used to identify genetic differences potentially responsible for divergent responses to therapy . They boThe workshop concluded with a roundtable discussion of critical issues associated with the introduction of microarray technology to the practice of clinical oncology. There was general agreement that a series of scientific, ethical and legal concerns must be resolved before these genomic tools can become part of the armamentarium of clinical practitioners . The forThe use of microarrays in clinical oncology raises another critical issue: the management of the tremendous volume of data generated in the context of different types of analyses. It was highlighted that this could be turned into an advantage since it may be that complex relationships in gene expression patterns can be resolved only when very large data sets are available for analyses. However, in order to achieve this goal, more efficient data management systems are required. For instance, James F. Reid  pointed out that in building predictive models from gene expression profiling experiments, it is also important to report proper estimates of classification accuracies and validate promising classifiers on independent data to further evaluate their clinical utility . MoreoveMicroarray Technologies in Clinical Oncology: Potential and Perspectives" will have contributed to a better understanding of the "state of the art" of this promising field of cancer research. In addition, we have hopefully provided a clearer definition of some critical issues that need to be addressed in order to translate the great expectations of the scientific community into realities for the better management of cancer patients.The expectations for what might be gained from high throughput microarray technology in clinical oncology are high as its utilization in clinical practice could markedly improve our current strategies for the diagnosis of cancer and prediction of the clinical outcome. This in turn may lead to the identification of treatments optimized according to the genetic background of individual patients and the biological characteristics of their tumors. However, many concerns about microarray-based experimentation need to be resolved regarding sample handling and data interpretation in order to fulfill these expectations. This can only be achieved by establishing a close cooperation between experts in microarray technologies, "trialists" and clinicians. A strategic international cooperation involving public and private institutions is also needed in order to exploit the potentialities of these new, continuously changing, microarray technologies in clinical oncology. Indeed, the true potential of this powerful tool will be fully exploited only when networks of excellence capable of correctly performing large validation studies and of directing data into new translational studies are established. In addition, the routine application of microarray technologies in clinical oncology would raise some relevant legal, ethical, social and regulatory issues, which have been poorly addressed so far. Therefore, efforts should be undertaken to achieve maximal technical consistency and standardization and to define specific and comprehensive regulatory frameworks for addressing the many unresolved issues. The authors hope that that the Workshop "


Building an embryo is like building a house: everything has to be done at the right time and the right place if the plans are to be translated faithfully. On the building site, if the roofer comes along before the bricklayer has finished, the result may be a bungalow instead of a two-story residence. In the embryo, if the neurons, for example, start to make connections prematurely, the resultant animal may lack feeling in its skin.On the building site, the project manager passes messages to the subcontractors, and they tell the laborers what to do and where. In the embryo, the expression of specific transcription factors (molecules that tell the cell which DNA sequences to convert into proteins) at different stages of development and in different places controls the orderly construction of the body.Silvia Arber and her colleagues are studying the protracted process of neuronal differentiation in mice. Early in development, neurons are generated from dividing progenitor cells. Cell division stops soon after, and long extensions called axons grow out of the neurons in specific directions. When these axons reach their targets—peripheral tissues like the skin at one end, in the case of sensory neurons, and the spinal cord at the other—they form characteristic terminal branches. Finally, the nerves form contacts with other neurons so that they can pass messages on to the brain.Many aspects of neuronal character are acquired through the expression of transcription factors in the progenitor cells or immediately after cell division stops. But Arber and her colleagues have been investigating whether an even later wave of transcription programs is needed for neuronal differentiation and circuit assembly in the sensory neurons of the dorsal root ganglia (DRG), structures containing the cell bodies of the sensory neurons. Previous work indicates that the release of molecules called neurotrophic factors by the neuron's target tissues directs the late expression of Er81 and Pea3. These ETS transcription factors  control late aspects of the differentiation of DRG neurons. What would happen, the researchers asked, if ETS proteins were expressed earlier? Would precocious ETS expression in DRG neurons also direct the appropriate neuronal developmental programs?Arber's team made genetically engineered mice in which ETS signaling occurred either at the correct time or earlier, and examined the development of the proprioceptive sensory neurons, which are involved in the coordination of body balance. In vivo, they found that early initiation of ETS signaling disrupts the axonal growth of the DRG neurons, both to their peripheral targets and into the spinal cord, and perturbs the acquisition of terminal differentiation markers. In vitro, premature ETS signaling allows the DRG neurons to survive and grow in the absence of the neurotrophins normally required for these processes.Arber and her coworkers conclude that the late onset of expression of ETS transcription factors induced by target-derived signals is essential for many of the later aspects of neuronal differentiation and circuit formation. During their differentiation, the researchers suggest, DRG neurons undergo a temporal switch in their ability to respond to ETS signaling. Further analysis of the mechanisms by which responses to transcription factor programs are altered over time during development will advance our understanding not only of neuronal differentiation but of other aspects of embryogenesis.


We have produced human CEA transgenic mice which were found to express CEA mRNA in all tissues. By immunoblot analysis using anti-CEA polyclonal antibody, we also detected CEA protein in all tissues. However, the molecular size of CEA in the brain was different from that in other tissues, although the mRNA size was same and no deletion nor rearrangement was detected at the DNA level. Immunohistochemical analysis of the lung and the colon showed that the expression sites were the bronchial epithelial cells of the lung and the columnar epithelial cells of the colon. Interestingly, the expression of CEA protein in the transgenic mice was polarised to the luminal side of epithelial cells similar to the normal CEA expression in human tissues. We also detected cell surface expression of human CEA on thymocytes and spleen cells and CEA expression was greatly reduced by the phosphatidylinositol-specific phospholipase C (PI-PLC) treatment.


The skin is a composite structure composed of a superficial epidermis and an underlying dermis. Wounding of this structure with resultant functional and anatomical disintegration leads to a cascade of events directed at the restoration of these features. However, maintenance of anatomical integrity has a higher priority from the standpoint of preservation of homeostatic equilibrium. The uncoupling of anatomical and functional renovation due to accelerated wound closure without proper regeneration and spatial organization of the underlying cellular/extracellular assembly leads to scarring and loss of function. Epithelialization and contraction are the major mechanisms acting to minimize the exposed wound surface.Fibroblasts and epithelial cells are major regulatory elements of wound contraction and epithelialization, respectively. Fibroblasts contribute to contraction directly by producing contractile forcesThis prospective modality may be useful for wounds where excessive contraction and fibrosis is probable, for example, extensive burns. Future research may be directed toward testing the hypothesis via EMT markers and also developing therapeutic strategies for regulation of the TGF/EGF ratio.


The results of the Swedish two-county study are analysed with respect to tumour size, nodal status and malignancy grade, and the relationship of these prognostic factors to screening and to survival. It is shown that these factors can account for much of the differences in survival between incidence screen detected, interval and control group cancers but to a lesser extent for cancers detected at the prevalence screen where length bias is greatest. Furthermore, examination of the relationships among the prognostic factors and mode of detection indicates that malignancy grade, as a measure of inherent malignant capacity, evolves as a tumour grows. The proportion of cancers with poor malignancy grade is several fold lower for cancers of diameter less than 15 cm than for cancers greater than 30 cm, independent of the length bias of screening. The implications of these findings for screening frequency are briefly discussed.


Virology Journal will reflect the excitement of the "New Phage Biology."Bacteriophage research continues to break new ground in our understanding of the basic molecular mechanisms of gene action and biological structure. The abundance of bacteriophages in nature and the diversity of their genomes are two reasons why phage research brims with excitement. The pages of  Virology Journal comes at a time of resurgence of interest in the basic biology of the bacteriophages and the impact that these viruses have on earth's ecology, evolution of microbial diversity and the control of infectious disease. Since playing an important part in the birth of Molecular Biology more than 50 years ago [The launching of ears ago , phage rears ago . This trears ago , the pro30 or ~10 million per cubic centimeter of any environmental niche where bacteria or archaea reside [Aeromonas, Vibrio, Acinetobacter, marine and other bacterial species. The genomes of a few T4-like phages have been sequenced and found to indeed share homologies with T4, but to also differ from one another in size, organization of the T4-like genes and content of other putative genes and DNA mobile elements . It appears that phage families like the T4-related phages have learned to cross bacterial species barriers and possess plastic genomes that can acquire and lose genetic cassettes through their travels in the microbial world. In essence, genomes of the dsDNA phages may be repositories of the genetic diversity of all microorganisms in nature.Two reasons why the new era of phage research brims with excitement are the abundance of bacteriophages in nature and the diversity of their genomes. Phage is probably the most widely distributed biological entity in the biosphere, with an estimated population of >10a reside . At one In addition to evolving by serving as traffickers of microbial genes, phage genomes evolve through the accumulation of mutations in both acquired and core genes. Sequence divergence among homologues of the essential genes for phage propagation within a phage family can be used as a source of information about the determinants of specificity of the protein-protein and protein-nucleic-acid interactions that underlie biological function. Phages are excellent sources of many enzymes and biochemical transactions that are broadly represented in all divisions of life. The large numbers of phylogenetic variants of biologically interesting proteins and nucleic acids that one can derive from sequenced phage genomes are treasure troves for studies of biological structure in relation to function. Interest in phage and phage gene products as potential therapeutic agents is also increasing rapidly and is likely to have profound impact on the pharmaceutical industry and biotechnology in general over the coming years. There is a general sense that the best is yet to come out of phage research.Virology Journal will reflect the excitement of the "New Phage Biology" by publishing reports in the areas of Ecology and Taxonomy, Genomics and Molecular Evolution, Regulation of Gene Expression, Genome Replication and Maintenance, Protein and Nucleic Acid Structure, Virus assembly, Biotechnology, Pathogenesis, Therapeutics and more. It would be especially interesting to see submissions of phage genome sequence briefs and their biological implications.We anticipate that the pages of The author(s) declare that they have no competing interests.


During the period 1957-1984 the annual age-adjusted incidence rate of cutaneous malignant melanoma (CMM) increased by 350% for men and 440% for women in Norway. The annual exposure to carcinogenic sunlight in Norway, calculated by use of measured ozone levels, showed no increasing trend during the same period. Thus, ozone depletion is not a cause of the increasing trend of the incidence rates of skin cancers. The incidence rates of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) increase with decreasing latitude in Norway. The same is true for CMM in Norway, Sweden, and Finland. Our data were used to estimate the implications of a future ozone depletion for the incidence rates of skin cancer: a 10% ozone depletion was found to give rise to a 16-18% increase in the incidence rate of SCC (men and women), a 19% increase in the incidence rate of CMM for men and a 32% increase in the incidence rate of CMM for women. The difference between the numbers for men and women is almost significant and may be related to a different intermittent exposure pattern to sunlight of the two sexes. The increasing trend in the incidence rates of CMM is strongest for the trunk and lower extremities of women, followed by that for the trunk of men. The increasing incidence rates of skin cancers as well as the changing pattern of incidence on different parts of the body is most likely due to changing habits of sun exposure. Comparisons of relative densities of CMM, SCC, LMM and SCC falling per unit area of skin at different parts of the body indicate that sun exposure is the main cause of these cancer forms although other unknown factors may play significant roles as well. For the population as a whole sun exposure during vacations to sunny countries has so far been of minor importance in skin cancer induction.


The main risk factors for oesophageal cancer previously identified in western Europe are tobacco smoking and alcohol drinking. However, a study of the time trend from 1951 to 1985 of the mortality from oesophageal cancer in 17 European countries shows that, except among the younger age groups in men, oesophageal cancer had either decreased or increased only slightly in most countries. This trend differed from that of lung cancer, cirrhosis and alcohol consumption which had in general increased substantially during the period. The results strongly suggest that population-wide changes in certain undetermined risk/protective factor(s), one possibility of which is the consumption of fruit, had overridden the effect of tobacco and alcohol and resulted in a reduction of oesophageal cancer risk. Apart from further efforts to reduce smoking and drinking, studies to identify the factor(s) will be of great public health importance to the prevention of oesophageal cancer.


The use of apical suction devices has been well described for maintaining satisfactory haemodynamics during off-pump surgical coronary revascularization. Its expanded use has been described in a few other situations. We describe here a case of recurrent coarctation where an extra-anatomic ascending to descending thoracic aorta bypass graft was constructed using cardiopulmonary bypass without arresting the heart, and access and exposure were facilitated by the use of an apical suction device. A 49 year old gentleman presented to cardiology with lower limb claudication pain and breathlessness of three years duration. Clinical examination revealed upper limb hypertension, with similar blood pressures in both arms (180/100 mm Hg). His past history included repair of coarctation of aorta about 30 years ago. The medical records and operative details from the previous operation were unavailable. The operation had been performed through a left thoracotomy. An MRI scan revealed a 2 cm long narrowing of the aorta just distal to the origin of an aberrant right subclavian artery, which was the last of four branches from the aortic arch  for venous outflow. Once the apex and the posterior surface of the heart were free of adhesions, an apical suction device  was placed in position and the beating heart was lifted superiorly. This allowed further dissection in the posterior pericardium and allowing freeing up of adhesions between the left lung and the descending thoracic aorta, and allowed visualization of and access to the descending thoracic aorta just above the diaphragm in spite of a deep thoracic cavity  to avoid cross clamping the heart for a prolonged period of time for an extra-cardiac operation 2) to make the elevation and retraction of the empty beating heart technically easier, and less traumatic on the epicardium and myocardium compared to retracting and elevating with the use of the assistant's hand. We could accomplish both these objectives safely and successfully, with adequate exposure to clamp the descending thoracic aorta and perform the anastomosis.This report describes another expanded use for the apical suction device.


The interaction between tumour and bone with respect to the proliferative activity of transplanted tumour cells was studied using five transplantable human urogenital tumours in nude mice. Cells from those tumours were injected subcutaneously over the calvaria of nude mice following disruption of the periosteum. The extent of tumour-bone interaction varied with the type of implanted tumour as shown on X-ray and by histologic examinations of the calvaria. The classic histologic pattern of bone remodelling including the destruction of bone with proliferation of osteoclasts and reactive new bone formation was seen with all five tumours. Tumour proliferative activity determined from the tumour doubling time and the S-phase fraction using bromodeoxyuridine labelling showed that the rate of reactive bone formation appeared to be inversely proportional to the rate of tumour cell proliferation.


Dysplasia in the upper gastrointestinal tract carries a risk of invasive malignant change. Surgical excision of the affected organ is the only treatment available. Photodynamic therapy has been shown to be promising in the treatment of early and superficial tumours and may be useful for the ablation of dysplastic mucosa. Because of the diffuse nature of the disease, such treatment would necessarily involve destruction of large areas of mucosa and it is desirable to confine its effect to the mucosa in order that safe healing can take place. By means of photometric fluorescence microscopy, we have studied the pattern of photosensitisation in the normal rat stomach using di-sulphonated aluminium phthalocyanine (AlS2Pc) and 5-aminolaevulinic acid (ALA) as photosensitisizers. AlS2Pc resulted in a panmural photosensitisation of the gastric wall with the highest level encountered in the submucosa. The mucosa and muscularis propria were sensitised to equal extent. Following light exposure, a full thickness damage resulted. ALA is a natural porphyrin precursor and exogenous administration gave rise to accumulation of protoporphyrin IX (PPIX) in the cells. The resultant pattern of photosensitisation was predominantly mucosal and its photodynamic effect was essentially confined to the mucosa. ALA produced a selective photosensitisation of the gastric mucosa for its photodynamic ablation with sparing the underlying tissue layers.


HoxD cluster are expressed in two spatiotemporally distinct phases. In the first phase, Hoxd9-13 are activated sequentially and form nested domains along the anteroposterior axis of the limb. This initial phase patterns the limb from its proximal limit to the middle of the forearm. Later in development, a second wave of transcription results in 5′ HoxD gene expression along the distal end of the limb bud, which regulates formation of digits. Studies of zebrafish fins showed that the second phase of Hox expression does not occur, leading to the idea that the origin of digits was driven by addition of the distal Hox expression domain in the earliest tetrapods. Here we test this hypothesis by investigating Hoxd gene expression during paired fin development in the shark Scyliorhinus canicula, a member of the most basal lineage of jawed vertebrates. We report that at early stages, 5′Hoxd genes are expressed in anteroposteriorly nested patterns, consistent with the initial wave of Hoxd transcription in teleost and tetrapod paired appendages. Unexpectedly, a second phase of expression occurs at later stages of shark fin development, in which Hoxd12 and Hoxd13 are re-expressed along the distal margin of the fin buds. This second phase is similar to that observed in tetrapod limbs. The results indicate that a second, distal phase of Hoxd gene expression is not uniquely associated with tetrapod digit development, but is more likely a plesiomorphic condition present the common ancestor of chondrichthyans and osteichthyans. We propose that a temporal extension, rather than de novo activation, of Hoxd expression in the distal part of the fin may have led to the evolution of digits.The evolutionary transition of fins to limbs involved development of a new suite of distal skeletal structures, the digits. During tetrapod limb development, genes at the 5′ end of the  Tulerpeton), seven (in Ichthyostega) and eight or more (in Acanthostega) short digits, with comparatively simple or poorly defined wrists and ankles The origin of limbs was a defining event in the evolution of tetrapods. Important new discoveries in developmental genetics and vertebrate paleontology have enhanced our understanding of limb development and evolution Comparative developmental studies have demonstrated that the mechanisms controlling initiation, position, outgrowth and pattern are remarkably conserved between teleost fins and tetrapod limbs Hoxd genes regulate the anteroposterior pattern of both fins and limbs by establishing an early map of cell identity that is important for specification of the ZPA Hoxd genes are expressed in highly dynamic patterns during limb development. Early work suggested that there are three phases of Hox expression in tetrapod limbs Hoxd9, is expressed in lateral plate mesoderm up to the pectoral level Hoxd9 expression is maintained and the neighboring Hoxd10-Hoxd13 genes are activated sequentially. This produces a spatially and temporally collinear pattern of nested expression domains along the anteroposterior axis of fins and limbs, with the Hoxd13 domain being the most posteriorly restricted Hoxd genes being re-expressed along the distal margin of the limb buds, in the area of the prospective digits Hoxd13 is expressed in all of the developing digits whereas Hoxd12 and Hoxd11 are expressed in all but the anteriormost digit. By contrast, this late phase of Hox expression was not observed during zebrafish fin development Hoxd genes for digit development and the emerging picture of early tetrapod digit evolution, and an elegant new hypothesis proposed that digits are neomorphic structures that resulted from acquisition of the late distal domain of Hoxd gene expression during tetrapod evolution HoxD gene regulation in mice have shown that the two phases of expression within the limb buds result from two independent waves of transcriptional activation. The first wave involves the action of opposite regulatory modules located outside of the cluster, which leads to sequential transcription of HoxD genes from the 3′ to the 5′ end of the complex HoxD genes in the distal region of the limb HoxD gene expression during mouse limb development is consistent with the proposal that proximal and distal parts of the limb have distinct evolutionary histories Hoxd cluster and resulted in distal activation of Hoxd expression, or that the preexisting regulatory modules were co-opted to perform this function during the transition from fins to limbs Hoxd expression in the distal aspect of the limb is unique to tetrapods and contributed to the evolutionary origin of digits.Genetic analyses of Hoxd genes observed in zebrafish fin buds is representative of the primitive condition for gnathostome (jawed vertebrate) fins. Zebrafish fin morphology is highly derived relative to other actinopterygians, sarcopterygians and chondrichthyans. A tribasal fin skeleton, containing a propterygium anteriorly, a mesopterygium in the middle and a metapterygium posteriorly, is widely considered to be the primitive pattern for gnathostomes Here we investigate whether the monophasic expression of Scyliorhinus canicula), and find, at both cellular and molecular levels, striking similarities to tetrapod patterns of skeletogenesis as well as differences relative to the zebrafish pattern. In order to identify the primitive role of 5′Hoxd genes in fin evolution, we analyze the expression pattern of these genes during catshark paired fin development. At early stages of fin development, 5′Hoxd genes are expressed in collinear, nested patterns along the anteroposterior axis of the fins, which resemble the initial wave of Hoxd transcription that occurs in the paired appendages of other gnathostomes. We also describe an unexpected second wave of expression at later stages of shark fin development, in which Hoxd12 and Hoxd13 are re-expressed along the distal margin of the paired fin buds. The results indicate that biphasic, distal expression of Hoxd genes is not uniquely associated with tetrapod digit development, but is more likely a plesiomorphic condition that was present the common ancestor of chondrichthyans and osteichthyans.In this report, we first examine skeletal development in the fins of the catshark  and the associated radials  and the adjacent radials  mesoderm and endoderm at the cloacal level between stages 25 and 28  those examined in previous reports. Our analysis of skeletal development in shark fins shows a process with greater similarity to the tetrapod limb than to the teleost fin. The latter undergoes differentiation of the fin bud mesenchyme into a chondrogenic plate, which it then segments to form the individual bones of the fin, whereas shark and tetrapod appendicular skeletons develop by polarized condensation of separate prechondrogenic elements that then differentiate into cartilage. The teleost pectoral fin skeleton is also stunted relative to the elaborate distal endoskeleton of sharks and basal actinopterygians Hoxd gene expression may underlie the developmental truncation of their fin skeletons. Our results indicate that biphasic, distal expression of Hoxd genes is not uniquely associated with tetrapod digit development, but is more likely a plesiomorphic condition for gnathostomes.More surprising is the discovery that the initial phase of collinear Hoxd gene expression is that proximal and distal domains are separated by a zone of non-expressing cells at late stages of development, and late expression appears to be regionalized along the proximodistal axis. In tetrapod limbs, the appearance of collinear Hoxd expression along the proximodistal axis of the limb has been termed “virtual collinearity”, which arises as an artifact of the two independently-regulated waves of collinear activation, the early/proximal phase controlled by the ELCR and the late/distal phase controlled by GCR/Prox Hoxd expression domains, which later appear proximodistally subdivided, suggests that the proximal and distal limb may have been under modular developmental control from an early point in gnathostome fin evolution. This also raises the possibility that factors from the AER may be involved in maintaining expression at the distal tip of the fin bud (perhaps by keeping these cells in a proliferative state). It is therefore interesting that the shark AER expresses Fgf8 Another striking similarity between the shark and tetrapod patterns of Sox8 data demonstrate that catshark fin bud mesenchyme does not undergo chondrogenic differentiation prior to the condensation of individual radials, which contrasts with patterns described for actinopterygians and some species of shark, which undergo early formation of a chondrogenic plate that later perforates to separate the radials Sox8 expression also revealed that chondrogenesis in catshark pectoral fins follows an anterior to posterior progression, starting in the prospective pectoral girdle. Similar directionality occurs in urodele amphibian limbs, whereas in amniotes the polarity of chondrogenesis generally is from posterior to anterior Hoxd expression occurs distal to the region of differentiated cartilage is consistent with idea that the second phase governs cell proliferation in the distal limb bud Sharks develop paired fins as localized outgrowths of the lateral plate mesoderm at discrete positions along the body axis, and these fin buds then develop an AER that later becomes an AEF Hoxd genes are expressed in cloacal mesoderm and endoderm. Similar patterns were observed in zebrafish Hoxd13 is required for anorectal and external genital development, and its expression in the genital tubercle and digits is under shared genomic regulation Hoxd gene expression in these tissues led to the hypothesis that the evolution of terapod digits and external genitalia may have been coordinated by a shared mechanism. Our results suggest a more ancient origin for Hoxd expression in the distal aspect of the fin buds and in the cloaca. Interestingly, Shh, which is expressed in the cloaca-derived urethral plate of the mouse genital tubercle and is required for outgrowth of the phallus During development of the shark gut, 5′ Hoxd genes was associated with the origin of digits. Based on evidence that the second wave of transcriptional activity in the mouse autopod is controlled by its own regulatory modules and is required for digit development, and that this phase is absent in zebrafish (which lack digits), this domain of expression has been considered a character of the autopod. It is therefore tempting to speculate that the distal domain of Hoxd expression in sharks may define a population of cells with an autopodial identity, as was suggested recently for paddlefish Hox genes function to specify two developmental modules, proximal and distal, and these modules are not linked to specific anatomical landmarks This study allows reconsideration of the idea that the distal expression of Hoxd gene expression at the distal tip of paired appendages can be extended to the chondrichthyan lineage allows us to exclude the hypothesis that a novel domain of distal Hoxd expression first appeared in stem-group tetrapods. Secondly, distal Hoxd expression does not itself lead to development of an autopod. The third point relates to the demonstration by Duboule and co-workers that 5′ HoxD and HoxA genes are required for proliferation of skeletogenic precursors cells in the limb Hoxd domain in shark fins may regulate cell proliferation beneath the AER. As such, its presence at late stages of shark fin and tetrapod limb development, and its absence from zebrafish, would fit with elaboration of the distal skeleton in the former and its truncation in the latter. It is therefore intriguing that the size of the distal expression domain in sharks is extremely narrow relative to that of tetrapods. The pivotal event with respect to the origin of digits may have been a temporal extension of the second transcriptional wave, which would have led to a sustained period of cell proliferation, thereby increasing the size of the distal Hoxd domain, at the terminus of the limb . Embryos were isolated from the eggshells, dissected from the yolk sac in ice-cold phosphate buffered saline solution (PBS) and staged according to Ballard et al For alcian green staining, embryos were washed in PBS, fixed overnight in 5% trichloroacetic acid (TCA) and transferred to 0.1% alcian green in acid ethanol. Stained specimens were differentiated in acid ethanol, dehydrated in ethanol and cleared in benzyl alcohol:benzyl benzoate (BABB). Hatchling specimens were fixed in 80% ethanol and eviscerated before being stained with alcian blue and alizarin red as described previously Acridine orange (AO) was used to identify apoptotic cells, following the method of Abrams et al 5′Hoxd genes and Sox8 were used to generate digoxigenin-labelled riboprobes as described previously In situ hybridization of catshark embryos were carried out using our published modification in situ hybridization, embryos were equilibrated in graded sucrose (15% and 30%) at 4°C, incubated overnight in 20% gelatine in 30% sucrose at 50°C and embedded in 20% gelatin at 50°C. The blocks were frozen on dry ice, mounted in TissueTek OCT and cryosectioned at a thickness of 35 µm.Fragments of


In a search for aetiological processes which might explain the association of stomach cancer with poverty, we have related mortality from the disease in the local authority areas of England and Wales during 1968-78 to indices of living standards derived from the 1971, 1951 and 1931 censuses. We have also analysed recently released data from a national survey of overcrowding carried out in 1936. Geographical differences in stomach cancer were most closely related to occupationally derived indices of socio-economic structure from the 1971 census, and to measures of domestic crowding from the 1931 census and 1936 survey. Unlike other indices of poor living standards, levels of past domestic crowding in north-west Wales were consistent with its previously unexplained high death rates from stomach cancer. We conclude that overcrowding in the home during childhood may be a major determinant of stomach cancer, and might act by promoting the transmission of causative organisms.


Immunocytochemical localisation of follicle stimulating hormone (FSH) was carried out in normal, benign and malignant human prostates by indirect immunoperoxidase technique. Positive staining was observed in the epithelial cells of all the three categories, while the stromal cells showed a weakly positive reaction in a few specimens. The brown reaction product was dispersed in the cytoplasm of the epithelial cells. These observations demonstrate the presence of immunoreactive FSH-like peptide in human prostate. The significance of FSH in the aetiopathology of prostatic disorders is discussed.


Promoting best gynecologic oncology practice is the subject of a manuscript from the Society of Gynecologic Oncologists of Canada. This manuscript is a descriptive report from a meeting that took place in Montreal involving members of various Canadians societies interested in the management of patients with gynecologic malignancies. Although this manuscript only partly deals with the objectives of the meeting and does not provide a clinical practice guideline report (to be reported later), this important paper may lead and stimulate other oncologic societies to embark on similar exercises.This month’s issue also contains the second part of a manuscript discussing the merits of naturally occurring anti-angiogenetic herbal compounds and their potential relevance to clinical practice. Encouragement is offered to explore the potential (and highly complex) effects in humans through clinical research. These agents have multiple effects and, presumably, a potential for multiple benefits.The Genitourinary Disease Site Group of the Cancer Care Ontario Program in Evidence-based Care undertook a tricky review of the value of maximal androgen blockade in the treatment of meta-static prostate cancer. In this issue, the authors note that many meta-analyses have been published and yet the magnitude of any benefit remains unclear. The reported benefits of these agents  is discussed—together with the their potentially negative impact on quality of life.imrt) treatment of head-and-neck cancers, Ballivy and colleagues address the subject of variation in target volumes and normal tissues during this form of radiation therapy delivery. The issue is not only important and relevant for head-and neck imrt, but also for all of radiotherapy as image guidance becomes the norm.In discussing the impact of the geometric uncertainties associated with intensity modulated radiotherapy (


Estimations of the incidence of hepatocellular carcinoma (HCC) for the period 1968-74 in the Province of Inhambane, Mozambique, have been calculated and together with rates observed in South Africa among mineworkers from the same Province indicate very high levels of incidence in certain districts of Inhambane. Exceptionally high incidence levels in adolescents and young adults are not sustained at older ages and suggest the existence of a subgroup of highly susceptible individuals. A sharp decline in incidence occurred during the period of study. Concurrently with the studies of incidence, 2183 samples of prepared food were randomly collected from 6 districts of Inhambane as well as from Manhica-Magude, a region of lower HCC incidence to the south. A further 623 samples were taken during 1976-77 in Transkei, much further south, where an even lower incidence had been recorded. The mean aflatoxin dietary intake values for the regions studied were significantly related to HCC rates. Furthermore, data on aflatoxin B1 contamination of prepared food from 5 different countries showed overall a highly significant relationship with crude HCC rates. In view of the evidence that chronic hepatitis B virus (HBV) infection may be a prerequisite for the development of virtually all cases of HCC and given the merely moderate prevalence of carrier status that has been observed in some high incidence regions, it is likely that an interaction between HBV and aflatoxin is responsible for the exceptionally high rates evident in parts of Africa and Asia. Various indications from Mozambique suggest that aflatoxin may have a late stage effect on the development of HCC. This points to avenues for intervention that could be more rapidly implemented than with vaccination alone.


Crimean-Congo haemorrhagic fever (CCHF) is an often fatal viral infection described in about 30 countries around the world. The authors report a fatal case of Crimean-Congo hemorrhagic fever (CCHF) observed in a patient from Kosova. The diagnosis of CCHF was confirmed by reverse transcription-PCR. Late diagnosis decreased the efficacy of treatment and patient died due to severe complications of infection. Nairovirus of the Family Bunyaviridae. Infection is transmitted to humans by Hyalomma ticks or by direct contact with the blood or tissues of infected humans or viraemic livestock . Phylogenetic studies have shown that the Kosovan strain is grouped together in the clade with the Southwest Russian and Turkish strains and is phylogenetically most closely related to Drosdov strain of CCHFV [Complete S segment of the Kosovo Hoti strain was confirmed in Slovenia . It was of CCHFV .From this report, the most important lesson to be derived is that late diagnosis decreases the efficacy of treatment and aggravates the outcome of the disease. Diagnosis of CCHF is important to prevent the spread of CCHF virus among the health-care workers and relatives of patients. Treatment with ribavirin may be useful if given within the early stage of disease . The preThe author(s) declare that they have no competing interestsSA participated in acquisition, analysis and interpretation of data. LR participated in the design of the study and drafted the manuscript. Both authors read and approved the final manuscript.


Activation of the ras gene family by point mutation at codons 12, 13 and 61 has been demonstrated in up to 20% of unselected series of human tumours. The present study was carried out to assess the incidence of ras activation in 37 squamous cell carcinomas of the head and neck, seven squamous cell carcinomas of the skin and eight squamous carcinoma cell lines. Oligonucleotide probes and the polymerase chain reaction were used on DNA extracted from achival paraffin embedded material. Mutations in codon 12 of the Harvey ras gene was found in a carcinoma of the larynx and a carcinoma of the lip, both of which had received prior irradiation. A cell line (LICR-LON-HN8) established from the same laryngeal cancer showed the same mutation. This study indicates that there is a low incidence of ras mutation in human squamous cell carcinomas and that activation of this family of genes is probably not a common factor in the development of this group of tumours.