A simple method has been developed which facilitates the detailed cytogenetic analysis of proliferating tumour cells within clusters and colonies arising from clonogenic tumour stem cells in biopsy samples of human cancers. The method uses a simple agar cloning technique for human tumours, which provides marked enhancement in the number of cases with observable mitotic activity and the number of mitotic figures available for detailed karyotypic assessment. The frequency of mitotic figures in cluster and colony samples is much greater than is attainable with standard chromosomal techniques. This novel approach should prove to be a powerful tool for the study of human tumour karyology.


Three outbreaks of Ebola hemorrhagic fever have recently occurred in Gabon. Virus has been isolated from clinical materials from all three outbreaks, and nucleotide sequence analysis of the glycoprotein gene of the isolates and virus present in clinical samples has been carried out. These data indicate that each of the three outbreaks should be considered an independent emergence of a different Ebola virus of the Zaire subtype. As in earlier Ebola virus outbreaks, no genetic variability was detected between virus samples taken during an individual outbreak.


Despite several years of implementation, prevention of mother-to-child transmission (PMTCT) programmes in many resource poor settings are failing to reach the majority of HIV positive women. We report on a data driven participatory quality improvement intervention implemented in a high HIV prevalence district in South Africa.A participatory quality improvement intervention was implemented consisting of an initial assessment undertaken by a team of district supervisors, workshops to assess results, identify weaknesses and set improvement targets and continuous monitoring to support changes.The assessment highlighted weaknesses in training and supervision. Routine data revealed poor coverage of all programme indicators except HIV testing. Monthly support to all facilities took place including an orientation to the PMTCT protocol, review of local data and identification of bottlenecks to optimal coverage using a continuous quality improvement approach. One year following the intervention large improvements in programme indicators were observed. Coverage of CD4 testing increased from 40 to 97%, uptake of maternal nevirapine from 57 to 96%, uptake of infant nevirapine from 15 to 68% and six week PCR testing from 24 to 68%.It is estimated that these improvements in coverage could avert 580 new infant infections per year in this district. This relatively simple participatory assessment and intervention process has enabled programme managers to use a data driven approach to improve the coverage of this important programme. UNAIDS estimates that approximately 370 000 children were infected with HIV in 2007. More thProgramme evaluations from a number of countries in Africa have found deficiencies in various components of PMTCT programmes including uptake of antenatal HIV testing,7, receiIntegrating PMTCT programmes into an already overburdened health system has been identified as a common reason for the sub-optimal performance of PMTCT programmes as they scale up to achieve national coverage. There is little documentation of how these challenges have been/are being addressed in routine (programmatic) settings where PMTCT programmes are taken to scale but evidence suggests that 'one size fits all' clinical guidelines are not leading to the desired changes. This paThe package of care for the PMTCT programme at the time of this intervention included routine offer of antenatal voluntary counselling and testing (VCT), infant feeding counselling, single dose nevirapine to mothers and infants, infant PCR testing at six weeks and six months of free formula milk to women choosing not to breastfeed. The PMTSouth Africa has a district health system in which comprehensive primary health care (PHC) clinics provide primary level care, referring patients to district and regional hospitals for secondary level care. PHC services are nurse driven. Clinic nurses are responsible for the diagnosis and management of infectious diseases such as tuberculosis, HIV and sexually transmitted infections, preventive care such as childhood immunisations and growth monitoring, antenatal care, as well as providing an acute curative service and attending to chronic conditions such as hypertension and diabetes.The intervention was carried out in one district in KwaZulu-Natal province, Amajuba. In 2006 the district was estimated to have a total population of 585 858 and a population under one year of 13 259. The antth year[Routine maternal and child health indicators for the district are good with an antenatal care coverage rate of 94%; 92% of deliveries undertaken by trained health professionals (midwives or doctors) and an immunisation coverage rate under one year of 83%. PMTCT wth year. Anthropth year has idenThe intervention consisted of a participatory assessment phase followed by a feedback and planning phase and then an implementation and monitoring phase. Each phase of the intervention had a focus on using routine data for problem identification, target setting and monitoring Table .During the participatory assessment phase a task team consisting of programme managers for HIV, PMTCT, maternal and child health (MCH), unit managers for hospital labour and postnatal wards and PHC clinic supervisors was formed to improve the performance of the PMTCT programme. The purpose of the participatory assessment phase was to build the capacity of local programme managers to conduct a simple assessment of maternal and child health services in their district. The process was introduced at a workshop held with this team in May 2007. During the workshop the team was oriented to the assessment framework, introduced to the assessment tools and supported in a short phase of piloting. An evaluation guide was developed to give step by step instructions about how to plan, prepare for and undertake the assessments.Three data collection tools were developed for the assessments; a structured interview tool for facility managers, an observation tool for PHC clinics and a structured interview tool for lay counsellors. These tools are described in Table Assessment teams consisted of three to four people (district and sub-district co ordinators and PHC supervisors) who visited facilities over a one week period. Each facility visit took approximately 3-4 hours. Assessment of the entire district took 7 days. Routine district PMTCT data from the district information officer was also collected in order to assess performance of key PMTCT indicators.The feedback and planning phase and the intervention and monitoring phase are described in the results section of the paper as these were developed following review of the findings of the participatory assessments.All eighteen comprehensive PHC clinics were visited in the assessment phase. At three facilities the facility manager was not present at the time of the assessment due to meetings or training resulting in a total of 15 facility manager interviews. Sampling of lay counsellors was determined by their availability but at least half of the total number assigned to each facility were included resulting in a total of 35 lay counsellor interviews.Interview and observation tools were submitted at the end of each day to the project facilitator who entered the data into excel. Epi-Info was used to generate basic frequencies for all tracer indicators as shown in Table Clinics had on average 7 full time clinical staff who were mainly nurses; only two clinics had doctors on site. Whilst there are no national norms for doctors in PHC it is expected that 10-15% of patients in clinics will be seen by a doctor and therefore clinics are expected to have a visiting doctor once a week. Coverage of PMTCT training was found to be sub-optimal with less than a third of clinical staff trained in PMTCT and HIV and infant feeding Table . InterviThe median number of clients seen per lay counsellor per day was 9 (range 2-30). This is slightly less than would be expected of a full time counsellor (10-12) but is dependent on the size of the facility and the number of nurses available to perform rapid HIV testing. Less than half of the lay counsellors reported having their own dedicated counselling room and 56% reported having to wait for a room to become available before they could counsel a client. 48% reported that this occurred on a daily basis.Management of drugs and supplies was good with only one clinic found to be out of stock of rapid HIV test kits and one facility did not have nevirapine tablets. Documentation and record keeping was generally found to be good with all clinics having an HIV testing register and a nevirapine drug register which were up to date. All clinics had guidelines for HIV testing, however, a quarter did not have a PMTCT manual on site.Supervision systems however were found to be poor. Forty seven percent of facilities had been visited by the district MCH supervisor in the previous six months and 33% had been visited by the district PMTCT supervisor in the previous six months. Supervision from the PHC clinic supervisors was better with a median of 3 visits per clinic (range 0-7) in the previous six months. These fall far short of the national norm of one visit per month to each facility.All of the clinics visited were open 5 days a week until 4 pm, however, a third of the clinics did not take first antenatal bookings every day of the week. Three clinics did not take blood for CD4 testing on site but referred clients to another facility. The South African PMTCT policy states that a CD4 cell count should be taken on the same day that the HIV positive status is established, and preferably at the first ANC visit therefore all clinics should be drawing blood for the CD4 test. The median turn around time for CD4 results was one week (range 1-5 weeks). This is better than the nationally recommended turn around time of two weeks. All of the clinics except one provided infant PCR testing and the median turn around time for PCR results was 6 weeks (range 1-24 weeks). National PMTCT guidelines state that all facilities should have the capacity to collect dried blood spots for PCR testing of infants. There is no South African norm for turn around time however WHO recommends a turn around time (from collection of sample to return of results) of no more than four weeks.The review of routine PMTCT data for the period January to June 2007  were receiving a PCR test.Assuming 4837 births to HIV positive women per year in the district and 12% A common complaint amongst programme managers is the large amount of data they have to collect and process. The development of a comprehensive health systems framework, key tracer indicators and relatively simple data collection tools in this intervention enabled middle level managers to feasibly collect relevant data rapidly and to identify possible bottle necks to optimal programme performance.The results of the assessment showed that the district is clearly performing well in terms of HIV testing within antenatal care and this has been achieved through adequate human resource provision in terms of lay counsellors and a philosophy of making HIV testing a routine component of antenatal care. Areas of weakness identified include inadequate coverage of training amongst clinical staff, inadequate infrastructure in terms of counselling rooms, infrequent supervision by district supervisors, low coverage of CD4 testing, nevirapine to mother and infant and infant PCR testing. These weaknesses are due to the complex interaction of client and health systems factors. Client factors include lack of information and fear of disclosing HIV status, health systems factors include lack of ownership of the PMTCT programme amongst nurses, unclear roles and responsibilities, lack of knowledge of the protocol, poor recording systems and continuity of care.The process of identifying weak areas and implementation of a participatory approach to problem solving together with regular, data driven, facility level support resulted in large increases in key programme indicators over the period of one year.An intervention in Zimbabwe to improThis intervention used a participatory approach which has both advantages and disadvantages. The disadvantages are that it relies on support and buy in from senior district management to allow mid level managers the time to participate in the workshops and to actually undertake the assessments. Without this support, the participatory approach would not succeed. It is also possible that there is some loss of data quality by utilising health workers to collect assessment data instead of trained research data collectors however the aim of the project was not to be a rigorous research study but rather to develop the skills of mid level managers to conduct assessments of their own programmes and to interpret and act on the findings. The advantages of a participatory approach are that the process of conducting the assessments enables mid level managers to see first hand how well their facilities are functioning and to take ownership of the findings since it is data that they themselves have collected.This operational research study has several limitations which deserve discussion. Firstly the assessment of the intervention relied on routinely collected primary health care data. Routine health system data for PMTCT in South Africa has been found to suffer from problems of completeness and accuracy and thisSecondly the operational research design did not include a control or comparison group hence the findings cannot be causally attributed to the intervention. However, the intervention was adopted and supported by the district management team as something that would be conducted across the entire district and during its implementation there were no other large scale efforts by NGOs or the district health department to address the quality of the PMTCT programme. The changes reported here were observed over a period of approximately 18 months prior to the introduction of the new PMTCT regimen when no media activities or health system changes were occurring. It is therefore plausible that the effects seen are due to this intervention.Improving PMTCT programmes is vital if the worsening under five mortality in high HIV burden countries such as South Africa is to be reversed. This is unlikely to be achieved through resource intensive generic health-system interventions (e.g. training courses and development of protocols and guidelines). The impact of these, in terms of programme functioning and health outcomes, has been disappointing; this has been attributed to their failure to link with specific programme activities. We propThis study was undertaken in one district with a relatively well functioning basic PHC system. The findings therefore cannot be generalised to every district in South Africa. All districts in the country do however have similar district management structures that would be applicable to this form of intervention. The addition of a facilitator for the duration of the intervention does add to the cost however it has been found to be essential at least in the initial stages of the intervention to encourage motivation and focus on the improvement targets. This approach of providing ongoing support through an external facilitator has recently been adopted as part of a national government accelerated plan for PMTCT. Several large NGOs have entered into performance contracts with the government which includes provision of external support for quality improvement.The development of a comprehensive programme evaluation framework, identification of key indicators and relatively simple data collection tools in this intervention enabled district and sub-district level managers to collect relevant data rapidly on the individual effectiveness of each programme component, as well as identifying possible efficiency gains and missed opportunities for improved programme performance. This approach could be scaled up as a model for participatory programme improvement.The authors declare that they have no competing interests.TD, MC and DN participated in the design of the study, conducted training and drafted the manuscript. TD and DN analysed the data. DM participated in the coordination and implementation of the study and helped to draft the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


Alterations of microsatellites have been found at relatively high frequency in hereditary and sporadic colorectal cancer and gastric and pancreatic cancers and at lower frequency in some other cancers. We determined the frequency of instability at 39 poly-CA microsatellite loci in 20 squamous cell carcinomas and 26 Barrett's adenocarcinomas of the oesophagus. None of the tumours presented instability for a high percentage of the tested loci. Four squamous cell carcinomas and six Barrett's adenocarcinomas showed microsatellite instability at one locus, and three Barrett's adenocarcinomas showed microsatellite instability at two loci. The presence of few loci showing microsatellite instability could be due to an instability background. We conclude that genetic defects in the DNA mismatch repair system do not play an important role in oesophageal cancers.


We used a link between cancer  and AIDS  registries in the United States to study whether nasopharyngeal carcinoma (NPC) was increased in the population with AIDS. There was no indication of a significantly increased risk up to or after the AIDS diagnosis, which argues against progressively failing immunity being important in the development of this malignancy.


The distribution of iron and iron binding proteins (IBP) have been compared with control spleen tissue in an attempt to establish a pattern of staining restricted to Hodgkin's disease (HD). All but one of the HD spleens examined stained for ferritin, which was largely present in red pulp dendritic macrophages (DM). In spleens histologically involved with HD heavy deposits of ferritin were seen around tumour nodules. Staining for ferritin increased with involvement of the spleen in HD but DM still represented the bulk of positive cells. However, ferritin positive DM were frequently seen in control spleens, and often in large numbers. Staining of ferric iron by Perls technique was less prominent than ferritin but this observation was also true of the non-HD spleens studied. Patterns of staining with transferrin were equivalent in both groups of spleens with DM being the most frequently positive cell type. Polymorphous macrophages showing erythrophagocytosis were present in the red pulp sinuses of all groups of spleens and although these cells have been considered as precursors of the Reed-Sternberg cell their presence seemed related to total splenic ferritin regardless of the disease process. These cells marked as macrophages and their presence was not restricted to HD. The results show that there is no particular appearance of iron or IBP distribution which is restricted to HD spleens. However, staining for ferritin and iron increased in HD spleens with tumour involvement and could contribute to circulatory abnormalities in this disease.


DNA flow cytometry was performed on formalin fixed, paraffin embedded melanocytic naevi. DNA aneuploidy was detected in all three types of naevus but was significantly more frequent in those naevi accepted as precursors of malignancy: that is, dysplastic and congenital pigmented hairy naevi. It may be that the presence of DNA aneuploidy has prognostic significance in these naevi. Technical problems were encountered in the analysis of data from melanocytic lesions so that caution is recommended in interpretation of studies using formalin fixed tissue.


Despite the 1991 reforms of the health system in Zambia, mental health is still given low priority. This is evident from the fragmented manner in which mental health services are provided in the country and the limited budget allocations, with mental health services receiving 0.4% of the total health budget. Most of the mental health services provided are curative in nature and based in tertiary health institutions. At primary health care level, there is either absence of, or fragmented health services.The aim of this paper was to explore health providers' views about mental health integration into primary health care.A mixed methods, structured survey was conducted of 111 health service providers in primary health care centres, drawn from one urban setting (Lusaka) and one rural setting (Mumbwa).There is strong support for integrating mental health into primary health care from care providers, as a way of facilitating early detection and intervention for mental health problems. Participants believed that this would contribute to the reduction of stigma and the promotion of human rights for people with mental health problems. However, health providers felt they require basic training in order to enhance their knowledge and skills in providing health care to people with mental health problems.It is recommended that health care providers should be provided with basic training in mental health in order to enhance their knowledge and skills to enable them provide mental health care to patients seeking help at primary health care level.Integrating mental health services into primary health care is critical to improving and promoting the mental health of the population in Zambia. Over the last decade, Zambia has embarked on a radical transformation process aimed at creating a well functioning, cost effective and equitable district-based health care system . Such reMental health was not amongst the ten priority areas for health services in the BHCP. In fact, none of Zambia's strategic health plans and policy documents have addressed and incorporated mental health . AlthougMental health services appear to have been inadequately incorporated into the primary health care in Zambia, a problem shared with many other low-income African countries -9. AlthoThere has been widespread recognition of the benefits of and need for low and middle income countries to better integrate mental health within primary health care ,14. InteThere is a dearth of research on mental health generally in Zambia ,13,5 witA survey was devised and conducted in order assess the knowledge, attitudes and practices (KAP) regarding mental health of general and mental health care providers' in Zambia. The main objective behind this survey was to guide and inform the training that would be carried out amongst general and mental health care practitioners to better identify and manage common mental illness.Data collection took the form of a questionnaire with both open and closed ended questions. The questionnaires were administered to selected health care providers who worked in Out-Patients departments. Seventy six questions were asked covering three topics namely: Knowledge, Attitudes and Practices. Knowledge and Practice included the following sub-headings; knowledge about causes of mental illness, knowledge about mental disorders and ability to treat, prescribe, and administer drugs while Attitudes involved; stereotypes, separatist and discriminatory attitudes, restrictiveness. The questions on which this paper is based formed part of the 'attitudes' component of the survey instrument which included questions on attitudes towards training, and attitudes towards integration. The guiding questions are shown in table 1The questionnaire was piloted on fifteen health workers in Kafue District that was not part of the survey sites. Based on the findings from this pilot, the questionnaire was adapted and revised.The data were collected from two purposively selected sites: Lusaka, representing an urban setting, and Mumbwa, representing a rural setting. These sites were selected as Ministry of Health pilot districts for integration of mental health into primary health care as well as for the purpose of representation of rural and urban scenarios. A total of 111 participants drawn from health facilities in the mentioned areas took part in the survey. Purposive sampling technique was used to select participants. Health workers from Out-Patients departments were selected because they see all incoming patients and refer them to respective departments depending on the patient's condition.Participants were recruited from more than half the number of health centres in Lusaka. In Mumbwa they were recruited from health centres that were accessible. However, the health centres and clinics that participated were typical of all clinics in the sense that they are government financed and supervised health centres, and being served through the same basic health care package. The clinics also recruit categories of staff with similar levels of qualifications and training. In addition, almost all the health centres in Lusaka are placed in low density areas catering for similar characteristics of the population. The same applies to the rural health centres. Therefore the sample was representative of the districts from which participants were drawn. The data were collected between March and April 2009.The quantitative data were entered into the excel data entry programme where numeric data were aggregated. Descriptive statistical analyses of relevant items were conducted.The qualitative data were analysed using thematic analysis informed by Braun and Clarke  in orderPermission to conduct this study was obtained from the Ministry of Health Directory of public health and research, and the District Directors of Health for the respective districts. Detailed information was provided to participants concerning participation and the consequence of the study. Participation was voluntary, and informed consent was obtained. For the purpose of anonymity, participants' names were omitted from the questionnaire.One hundred and one participants were took part in the survey. The age ranged between 19 and 65 years with the majority (41.4%) of them aged between 35 and 45 years. All participants were health care providers working in out-patients departments. Their work experience ranged from the newly graduated to those almost reached their retirement.Table The results revealed a high degree of favorable attitudes towards the proposed integration of mental health into primary health care. As indicated in table The reasons different respondents gave for why mental health should be integrated into primary health care can be categorized into three main themes: Better detection and management of mental health problems; stigma reduction; and human rights."early intervention", "early detection" and that "Early diagnosis of mental illness patients will be facilitated" .A key theme advanced by most of the participants that supported integration was that integration of mental health services into primary health care will facilitate early detection of mental health problems and prevent complications. Many respondents indicated that integration would aid It was indicated further by many health care providers that many people avoid or delay seeking care and treatment at Chainama, the main mental hospital, as the institution is a major source of stigma. It was indicated that people with mental disorders would be more willing to access care and treatment at primary health care clinics, which do not have the same negative connotations attached:'Mental illness will not be let to reach advanced stage since early detection and treatment will be effected by both health facility and community, since some family members fear/avoid being associated with Chainama Hospital and end up delaying seeking attention' .Similarly, another health care provider indicated:'People usually have a negative perception about Chainama and mostly people don't even go there if they are referred from health centres so by bringing this service nearer to their community and also being treated in the same facility just like any other patient, then people can be willing to get treatment from the centres without being stigmatized and discriminated against. Other problem can be identified apart from mental illness'.As alluded to in this last remark, integration of mental health with primary health care would also improve the general health care of persons with mental disorders.Many participants also indicated that integration would facilitate the detection and management of mental disorders as mental health care would be brought closer to the communities. Numerous health care providers highlighted that many people have to travel long distances, and incur great costs to seek care at Chainama mental hospital. This was particularly emphasized by health care providers in rural areas. It was argued that mental health care would be more accessible and available if it was integrated into primary health care:'It will enable the mentally ill to receive care within easy reach in our community and lessen the cost of transport to other institutions like Chainama'.In addition, it was indicated that mental health workers are in short supply in comparison with other types of health workers. It was thus suggested that integration would mean that there would be many more staff available for the management and treatment of mental disorders, as general health care workers would be able to attend to patients. This was most aptly revealed by the following two statements:'All health care providers would receive training and will be ready to handle mental illness cases in the community and at health centre level, so there would be many more staff available' and'Patients will be receiving professional case management from all health workers'.The rationale behind this was summarised by one participant as follows:'Primary health care system is the only health framework can bring health as close as possible to the communities'.less congestion at Chainama Hospital" as "'People with simple mental illness could be handled within the clinic instead of sending them to Chainama'.There was also widespread agreement that integration would aid better detection and management of mental health problems because less people would go to Chainama mental hospital, and Chainama would be less congested and overcrowded. This would ensure that those patients who are admitted to the main mental hospital, would receive better and more comprehensive care. Many respondents indicated that integration will create "once integrated they come out of stigma" and integration would "lessen stigma") and "reduce negative attitudes". It was suggested that stigma would be reduced because people would start to "regard mental illness as a disease like any other because they would be treated in the same facility just like any other patient". Furthermore, one respondent indicated:The issue of stigma and discrimination appeared to be prominent in many participants' responses around integration of mental health into primary health care. Numerous respondents who supported integration stated that stigma would be reduced if people with mental health problems were treated at primary health care units. It was not uncommon to hear statements such as "'The community attitude will gradually change as they see mental patients are cared for and recover, rather than being locked away'.Many respondents shared this view that stigma would be reduced as many people would be able to receive care within their communities, rather than being institutionalized far away in Chainama.Numerous participants stated that the government has made a clear commitment to providing health care to the population at the primary health care level. Some respondents said that over and above the benefits of integration, people with mental health problems possess an intrinsic right to treatment at this level of care, just like any other person seeking help for a health problem. They thought that integration of mental health at primary health care level would serve to uphold the human rights that people with mental health problems are thus equally entitled to. As one respondent indicated when stating that he supported integration:'Because mentally ill patients like any other patients deserve treatment and care from the primary health care system, in health centres'.This view was shared by another health care worker who stipulated:'The patients are all important and need equal rights and attention as early as primary care level'."right to receive care at the primary level", and the "right to care without segregation".Indeed, many respondents spoke about how people with mental disorders have the Although respondents who were against integration were not asked directly why they held such attitudes, some of the reasons could be hypothesized based on respondents responses to other questions such as the one asking about the importance participants attached to integrating mental health into primary health care. As such, it seems that fear and negative attitudes towards people with mental disorders may underlie some health care providers reservations regarding integration. Table It thus seems that such attitudes may be informing certain reservations around potential integration between mental health and primary health care.There was widespread agreement amongst respondents that better integration of mental health into primary health care required increased training in the identification and management of mental disorders. Responses are shown in Table It was indicated that a lot of mental health problems currently go undiagnosed at the primary health care level because of inadequate knowledge and skills to identify and treat mental health problems. As one respondent indicated:'Most cases go unidentified and undiagnosed, so training in mental health at the primary level is long overdue'.It was indicated that training would equip general health care workers with necessary skills to manage cases of mental illness appropriately. The rural population indicated that training in mental health would also prevent them from referring uncomplicated cases to Chainama hospital. As the following remark indicates:'Training will equip us to manage mental illness cases at clinic level and give adequate support'.This study explored integration of mental health into primary health care from the perspective of health care providers in two districts in Zambia. It documents their attitudes towards integrating mental health into primary health care, as well as some of the possible reasons for such attitudes. It also highlights health care providers' recommendations regarding integration. One of the key barriers around integrating mental health into primary health care that has been identified is that the views and concerns of health care providers around integration have not been fully taken into account . This stThe results revealed a general willingness amongst health workers to have mental health added to their list of care responsibilities, and integrated with primary health care. A multitude of reasons were highlighted as to why integration would be beneficial. These included improving the detection and management of mental health problems as people would be more willing to access care, care would be brought closer to the communities, there would be more human resources and Chainama would be less congested. Furthermore, it was indicated that integration would help reduce the stigma surrounding mental illness, as people would receive care in the same facilities as other patients, rather than being institutionalized. Finally, some respondents indicated that integration was a human right for people with mental disorders.Integrating mental health into primary health care has been shown to improve the diagnosis of mental disorders and uptake of treatment, as health care at the primary level is generally more accessible, available and less stigmatizing . FurtherHowever, while most respondents favoured integration, most also said that people with mental health problems should not be treated in the same health centre as general patients. Although it was not explored fully, it seems that resistance to integration may stem from the fear and negative attitudes some health care providers may have towards mentally ill persons. Indeed, fear and stigma, which are common amongst general health care providers -25, haveThe World Health Organisation has been encouraging nations to have a deliberate policy to integrate mental health into primary health care since the Alma Ata International Conference on Primary Health Care in 1978. Despite the numerous health sector reforms that have taken place in Zambia that have been situated within a primary health care philosophy, mental health has been largely overlooked in these reforms. Indeed, the Zambian health service's priority is placed on communicable diseases, at the expense of non-communicable diseases. Jenkins and Stratdee  emphasizIt is with the above background in mind that the present study suggests restructuring of mental health services through its integration into primary health care and involvement of the community in the management of mental health problems and promotion of mental health . ResearcBearing in mind the commitment by government contained in the Zambian mental health policy  that menThe recommendations of this study are consistent with Orley and Sartorius'  suggestiIn this way, the health system would be upholding the holistic concept and person centred approach to care that WHO has recommended in its mental health programmes. Given the current inadequacy in human resource in Zambia in general and at primary health care level in particular, it is appropriate to build capacity so that people with mental health problems can be seen and cared for by health care providers who are not specialised in mental health but have basic knowledge and skills.It is thus clear that in principle, primary health care workers in Zambia appear to support integration of mental health into primary health care, but many still have stigmatising attitudes towards the mentally ill. Consequently, further work is needed, not only in the provision of clinical skills, but also in providing education to change attitudes and beliefs. Integrating mental health into primary health care is however ultimately going to require increased consensus, commitment and political will within government to place mental health on the national agenda and secure funding for the sector. This is essential if the country is to realize the many of the ideals enshrined in the progressive health reforms undertaken over the last decade. As indicated by the World Health Organization, ultimately, there is "no health without mental health" .The authors declare that they have no competing interests.AF and CL conceived of the study, and participated in its design and coordination and helped to draft the manuscript. LW and SC drafted the manuscript. AS, AK and AS were involved in revising the manuscript critically for important intellectual content. All authors read and approved the final manuscript.


We were very interested to read the article by The potential carcinogenic risk of nano-materials that are structurally similar to asbestos and have been used in many industrial fields in the last few years has been highlighted by In addition to mesothelioma  or lung cancer, asbestos can cause other types of cancer. On the basis of our clinical experience, we hypothesize that at least a portion of bile ducts cancers  are caused by exposure to this known carcinogenic agent.From 2002 to 2008 we treated 258 patients with cholangiocarcinoma at our institute. Over the previous year, we carefully interviewed 66 consecutive patients using a standardized questionnaire asking about their exposure to asbestos and other known risk factors linked to bile duct carcino genesis . We collAsbestos fibers cause cancer through chronic inflammation, amplifying the production of oxygen radicals, cytokines, growth factors, and proinflammatory factors responsible for both impaired antioxidant and control cell proliferation and apoptosis mechanisms in target cells . In contThe putative increased risk of bile duct cancer in subjects exposed to asbestos may be due to different mechanisms. The asbestos fibers cross the alveolar barrier by inhalation or penetrate the gastrointestinal mucosa by ingestion. They then reach the interstitial environment and circulatory system through lymphatic vessels and are finally delivered to all tissues, namely the liver and bile ducts , where tIn the near future we may have to consider asbestos as another factor accounting for the etiopathogenesis of cholangiocarcinomas that may explain the otherwise mysterious increasing incidence of intrahepatic cholangio carcinomas in Western countries.


Constuction of the obturator prostheses and providing the patient's comfort with them are very difficult. Primary and the most important stage for these prostheses is to perform a proper impression.A 55-year-old edentulous Turkish female patient with a congenitally maxillary defect was rehabilitated with an open hollow obturator prosthesis. After the preliminary impression was completed, a metal frame suitable with the maxillary defect was constructed manually and used for making the impression of the defect area. After the first part of the obturator was finished, second part which separates nasal cavity and oral cavity was constructed by the aid of the bulb.When constructing an obturator prosthesis, making a detailed impression from the defect area can be performed by the aid of a metal frame, and an intraorally shaped extension that separates oral cavity from nasal cavity might be more effective for adaptation of the prosthesis. Maxillary defects can be sourced by congenital malformations or the acquired defects resulting from surgeries . The maxThis clinical report describes the prosthetic rehabilitation of an edentulous patient with congenital maxillary defect with an obturator made by a modified technique to restore the defect and separate the oral and nasal cavities from each other.A 55-year-old edentulous Turkish female patient was referred to the Department of Prosthetic Dentistry in Karadeniz Technical University for examination and treatment. The patient had a history of congenital palatal defect with an opening between oral and nasal cavities. Detailed case history revealed that the oronasal opening was present since year of birth and the defect was not treated surgically. The patient's major complaint was being edentulous after looosing her natural teeth because of periodontal diseases. She had never had obturator prosthesis until she lost her last teeth. Construction of obturator prosthesis was decided for the rehabilitation of the patient after clinical examination.Local anesthetic spray  was used for the palatal and post palatal region before making the impression. A tampon covered with Vaseline and anesthetic solution was placed in the defect cavity to protect the area from the residual impression material Figure  It was tThe prosthetic rehabilitation of an edentulous patient with congenital maxillary defect with an obturator has some difficulties at the stages of impression and construction. Even the defect area is filled with a tampon before the impression, protecting the soft tissues from the residual impression materials and making a detailed impression is not easy. In this respect, recording the tissue borders with modeling wax around a metal frame intraorally may be more protective and still an effective method. Separating nasal and oral cavities from each other helps to form speech voices better and to protect nasal cavity from the food escape during chewing, and swallowing. Constructing a second part which extends to the palatal defect cavity on previously constructed bulb using an intraorally shaped modeling wax, helps the second part to cover the defect area without any damage to the soft tissues even during the functional movements. Fabricating method of this open hollow obturator provides better initial record base retention, which is also compatible with the oral tissues. And the design of this obturator prosthesis has also some advantages as: better phonation and protection of food escape to nasal cavity.Fabricating a successful obturator prosthesis used for the prosthetic rehabilitation of congenital or acquired defects in maxilla depends on making a detailed impression and constructing the prosthetic parts compatible with the oral tissues. This clinical report describes an intraoral technique for impression making and fabrication of open hollow obturator prosthesis.The authors declare that they have no competing interests.BB performed for the case and prepared the manuscript. EA helped at the some steps of constructing the prosthesis and to draft the manuscript. UH supervised the case and reviewed the manuscript. All authors read and approved the final manuscript.Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.


The report contrasts the ascertainment of cases by the regional cancer registry with a specially designed search for records and pathology material which was then submitted to critical review irrespective of the original diagnosis. Boundary changes over the intervening years were accounted for and the results contrasted between time periods and with the cancer registry records. A large proportion of cancer registry cases were never subjected to histopathological diagnosis and comparisons between the new data and records are not easy to undertake. The study describes a probable true rise in the incidence of follicular non-Hodgkin's lymphoma in certain parts of Yorkshire over the last 20 years; there is less evidence of a similar change in Hodgkin's disease incidence over the same period of time.


The recognition of genital chlamydial infection as an important public health problem was made first by the recognition of its role in acute clinical syndromes, as well as in serious reproductive and ocular complications, and secondly by our awareness of its prevalence when diagnostic tests became widely accessible. The recent availability of effective single dose oral antimicrobial therapy and sensitive molecular amplification tests that allow the use of noninvasive specimens for diagnosis and screening is expected to have a major impact in reducing the prevalence of disease in the next decade. Clinical manifestations associated with Chlamydia pneumoniae infection continue to emerge beyond respiratory illness. In particular, its association with atherosclerosis deserves further investigation. Chlamydia pecorum, a pathogen of ruminants, was recently recognized as a new species. The continued application of molecular techniques will likely elucidate an expanding role for chlamydiae in human and animal diseases, delineate the phylogenetic relationships among chlamydial species and within the eubacteria domain, and provide tools for detection and control of chlamydial infections.


The inability to assess the extent of tumour damage immediately following treatment is a major clinical obstacle to improving the management of cancer patients. Normally, the effectiveness of chemotherapy or radiation therapy cannot be determined for at least several weeks after treatment. We studied the increase in mRNA of the growth arrest and DNA damage-inducible gene GADD153 in human 2008 ovarian carcinoma cells in vitro and in vivo to determine whether treatment-induced increases in the level of GADD153 mRNA could be used as a marker of the extent of tumour damage. GADD153 mRNA was increased in a transient, dose-dependent manner by cisplatin (DDP) when the tumour cells were grown both in vitro and as tumour xenografts in nude mice. The magnitude of induction of GADD153 mRNA did not vary significantly between different 2008 xenografts treated with equal doses of DDP, and GADD153 mRNA induction correlated with the degree of in vitro cytotoxicity for two different schedules of drug exposure. DDP increased GADD153 mRNA levels in melanoma and head and neck xenograft models as well. We conclude that the increase in GADD153 mRNA can be used to detect tumour injury at time points as short as 24 h after administration of DDP.


This issue of the MEAJO journal mainly containing original and educational articles on uveitis is compiled from the uveitis course and symposium organised during the last MEACO meeting in Bahrain in March 2009 by the Society for Ophthalmo-Immunoinfectiology in Europe (SOIE). Although the course was held on the last day of the meeting and consisted of a full day course, sustained attendance indicated that considerable interest exists in the Middle-East for uveitis. Together with Ahmed Abu El Asrar, the local organiser of the SOIE course and Deepak P. Edward, the Chief-Editor of MEAJO, we decided to publish a theme based issue on uveitis.SOIE is an association oriented towards educational activities in the field of uveitis in Europe but is also organising activities beyond Europe, especially in the Middle East and North Africa. The society has organized educational courses in Saudi Arabia in 2005 and 2008 and in Bahrain in 2009. SOIE symposia were held in Krakau, Poland in 2007, in Ancona, Italy in 2008, in Cappadoccia, Turkey in 2008 as well as in Tunisia in November 2009, with significant attendance at each venue. Our group is willing to collaborate with any local partner to organise courses or symposia on uveitis. We are interested in working interactively and exchange information with the local organisers and ophthalmologists and provide educational content on the practical aspects of uveitis taking into account local specificities. We are open to all viable propositions to promote the recognition and management of uveitis and ophthalmic infectious disease.For this MEAJO issue, the instructors of the SOIE Bahrain course were asked to contribute articles either on original ongoing uveitis research or to summarize their course presentations for didactic and educational purposes in a manuscript. A significant number of instructors made contributions so that an attractive theme oriented issue on uveitis could be produced.In his tutorial article on the differential diagnosis of anterior uveitis Carl P. Herbort gives a practical method for the appraisal and work-up of anterior uveitis based on clinical examination. He emphasizes the simplicity of the diagnostic steps of uveitis cases as long as investigations are based on clinical signs and not on random endless lists that are published in uveitis textbooks.The article on angiography in uveitis puts forward a comprehensive approach of angiographic investigation indicating the need for dual fluorescein and indocyanine green angiography (ICGA) in most cases where performing angiography is deemed necessary. By demonstrating lesions not shown by any other means, ICGA shows its pre-eminence over fluorescein angiography that merely gives more precision on superficial fundus lesions and RPE changes usually already identified by fundus observation, optical coherence tomography or other means.The two articles by Professor Ahmed Abu El Asrar and his group from Riyadh touch upon two important topics in uveitis. The first article has the merit to reassess the role of tuberculosis in present day uveitis. The second article is gives an excellent summary on the difficult clinical question of retinal vasculitis. The article includes a practical approach to the diagnosis of retinal vasculitis and provides precious information for the clinician.Who better than Professor Ilknur Tugal-Tutkun from Istanbul University could write a review article on Behçet's uveitis? This reknowned specialist who is recognized globally for her expertise in ocular Behçet's disease has put all her experience and expertise to give an overview on what the clinician should know about Behçet's uveitis. In this article the author also presents the latest developments in the management of Behçet's uveitis including laser flare photometry which has become an essential tool for non invasive follow-up of intraocular inflammation in most uveitis entities.We have the opportunity to publish a very important and interesting review article on emergent causes of infectious uveitis; thanks to Professor Khairallah from Monastir University in Tunisia who has been at the origin of several reports on emerging agents causing uveitis. He certainly is the most appropriate person to write this report on rare and unknown etiologies of uveitis which should nevertheless be known by all practicing ophthalmologists in this era of increased travel and migration.The last review article relates to inflammatory choroidal neovascularization, a complication of uveitis which is of rare occurence but that however has devastating consequences on visual function. Piergiorgio Neri, being both a specialist in medical retina as well as in uveitis, the review he and his team are presenting here is based on a very longstanding experience in the management of this feared complication of uveitis. So far treatment has been unsatisfactory but the availability of intra-vitreal anti-VEGF therapies seems to have drastically changed the outcome of inflammatory CNV although this statement still relies on an accumulation of cases as the authors indicate. In such rare diseases however, where controlled studies are impossible, medical treatment should be based on common sense which in this case points to the use of anti-VEGF treatment.The theme based part of this issue is completed by an original article on Fuch's uveitis, the publication of which is especially appropriate in the MEAJO journal, as the readership mainly comes from areas where irises are predominantly brown. This article indicates that heterochromia should not be considered as a preponderant feature. Indeed in brown iris geographical areas heterochromia will rarely be seen and iris texture changes should be evaluated instead. The authors therefore recommend abandoning the term Fuch's heterochromic cyclitis and to resort to the simple eponym of Fuchs' uveitis. The main message of this article however is the importance and relevance of posterior segment involvement that has been scotomized in the last decades although it was clearly described in Ernst Fuchs' initial reports. The failure to associate posterior signs such as vitritis with Fuchs' uveitis was identified as the single most important reason for misdiagnosis or delay in the diagnosis of Fuchs' uveitis.It is always a great pleasure for the SOIE to collaborate with our colleagues from the Middle-East where several successful projects have been conducted so far. We hope that the present project resulting in this theme based issue will be appreciated and are looking forward to future collaborations and projects.


The following information was omitted from the funding statement: This study was supported by NIH grants NS39089 and NS35962 to NS and MSMT CR grants LC06044 and 002162080 to JP and DV.


The intensifying pressure on reducing the development time for new pharmaceutical products is resulting in an increasing need for laboratory automation. A key element for the successful implementationof robotics for drug product analysis is the establishment of a reliable process for interaction of the automation team with its various customers, for example development product team and manufacturing group. The reduction of cycle time for product development appears to be resulting in more stability studies to support NDA/MAA filings for several reasons. Key clinical information may not be available before initiation of the stability studies and simultaneous world-wide development may result in an increase in the number of product strength and pack options.


Percutaneous Transvenous Mitral Annuloplasty for mitral regurgitation is in early stages of development and involves a complex intervention which can not be done in patients with left ventricular leads. Since functional mitral regurgitation is common in low ejection fraction states, we propose a device which can serve for annuloplasty in addition to cardiac resynchronization therapy and simplifying the intervention. Treatment of dilated cardiomyopathy has evolved considerably over years leading to marked improvement in quality of life and survival. This has been possible by intervening at the various biochemical, hemodynamic and electrical abnormalities by drugs and  use of  various devices. The role of cardiac resynchronization therapy (CRT) is an established one resulting in improvement in quality of life and survival and lately studies have shown  its benefit even in patients with  moderate fall in ejection fraction.One important accompaniment of dilated heart is functional mitral regurgitation secondary to mitral annular dilatation, apical displacement of papillary muscles and reduced transmitral closure force  secondary to LV systolic dysfunction.Cardiac resynchronization therapy helps by synchronizing the contractions of the postero-lateral wall and the interventricular septum and thereby improving the ejection fraction and by decreasing the functional mitral regurgitation by its presumed effect of synchronizing the motion of two papillary muscles and increasing transmitral closure force.Percutaneous  transvenous mitral  annuloplasty (PTMA) for ischemic or functional mitral regurgitation is in its evolution. The procedure involves cannulation of coronary sinus via subclavian or internal jugular  vein and delivering  a hemispherical  structure from coronary sinus ostium posteriorly to the anerior interventricular branch of the  great cardiac vein anteriorly. As the coronary sinus  forms  the lateral half of the mitral annulus, the device alters  the geometry of the mitral annulus  thereby causing better apposition of two valve cusps  and decreasing mitral regurgitation. Three such devices under investigation include Viacor PTMA device, CARILLON contour system and MONARC (previously VIKING) PTMA system all utilizing the various modifications of the same principle. These PTMA devices cannot be placed in patients who have coronary sinus leads of CRT devices. Since low ejection fraction states are usually associated with functional mitral regurgitation hence to produce a device which can address both issues seems compelling.Although the left ventricular leads of CRT devices are soft and may not significantly bring about conformational changes in the mitral annulus, part of reduction of mitral regurgitation can be expected by left ventricular lead especially once the lead is distally nicely fixed and under some tension. However  left ventricular lead is placed in the  lateral most  vein  which may include  only one fourth of the mitral annulus. If  left ventricular lead is modified in such a way that it is rendered  stiff in its distal part and part of the stiff end projects anteriorly upto anterior interventricular groove  it can serve as well for annuloplasty in addition to CRT. Otherwise a stiff  annuloplasty hemisphere can be delivered over the left ventricular lead hence simplifying the procedure and simultaneously addressing both issues.


Sir,We thank Dr Chaouachi for his interest in our study. Dr Chaouachi suggests that the association of hookah and oesophageal cancer observed in our study (


Growth curve measurements on the EMT6 tumour following treatment with cyclophosphamide indicate a growth delay of about 3 days for each 100 mg/kg of the drug. Tumours treated whilst still microscopic show a rather longer delay for the same dose. Data for the surviving fraction of cells in the tumours measured by in vitro plating at 2 h after cyclophosphamide are not compatible with the measured growth delay and realistic values for the doubling times of surviving clonogenic cells; It is concluded that there is considerable "repair of potentially lethal damage", and that there is probably no single time after cyclophosphamide treatment at which the surviving fraction of cells can be correctly measured by the in vitro plating technique. Cell loss from cyclophosphamide-treated tumours is increased only slightly over that from untreated tumours, and the regeneration of surviving cells is very rapid. In this situation, only marginal regressions in tumour volume are caused by the highest doses of the drug.


The recurrent synaptic activity may arise in a negative feedback loop between a bipolar cell and an amacrine cell that exhibits resonant behavior and oscillations in membrane potential when the normal balance between excitation and inhibition is disrupted by the absence of photoreceptor input.Here we review evidence that loss of photoreceptors due to degenerative retinal disease causes an increase in the rate of spontaneous ganglion spike discharge. Information about persistent spike activity is important since it is expected to add noise to the communication between the eye and the brain and thus impact the design and effective use of retinal prosthetics for restoring visual function in patients blinded by disease. Patch-clamp recordings from identified types of ON and OFF retinal ganglion cells in the adult (36–210 d old)  Retinitis pigmentosa (RP) refers to a number of related diseases that result in the death of rod and cone photoreceptors causing blindness in about one in 3,500 people, nearly 2 million people worldwide. Not surprisingly, PubMed lists more than 7,000 papers on RP that provide an abundant source of information about the genetic, biochemical, physiological, and therapeutic characteristics of the disease. The goal of much recent work on RP has been to develop methods to restore vision by resuscitating the retina using gene therapy to repair the mutation that gives rise to the dystrophy  or by drrd1 mice that was not present in normal animals. The patterned spike activity was reversibly abolished by temporarily occluding blood flow to the eye, providing evidence of its retinal origin. The frequency of the persistent discharge was dependent on the anesthetic and ranged between 9–14 Hz. These findings were confirmed subsequently using autocorrelgrams to demonstrate the rhythmicity of maintained spike activity in units recorded from the SC in dystrophic but not nondystrophic Royal College of Surgeons (RCS) rats [c-fos-like immunoreactivity in the superior colliculus and lateral geniculate nucleus in rd1 mice and RCS rats that is eliminated by intraocular injection of TTX or optic nerve transection [c-fos expression was attributed to the generation of rhythmic input from retinal ganglion cells. Out of the several thousand publications on RP, less than a dozen have addressed questions about the effects of retinal degeneration on RGC firing properties. The responses of individual cells cannot be evaluated using the electroretinogram (ERG), which is the widely employed standard method for assessing the functional changes in the retina resulting from loss of photoreceptor input. An early study by Drager and Hubel  based onCS) rats . There ansection , 19. Therd1 mouse [The changes in RGC spike activity during the progression of photoreceptor degeneration has been documented more directly using extracellular single RGC recording in the RCS rat  as well d1 mouse  and the d1 mouse . In agred1 mouse , 21 in ad1 mouse . Taken tIt is important to understand the properties of the ongoing spike activity that is present in RP because it represents an undesirable noise source that degrades the communication between the eye and the brain that the aforementioned strategies to restore vision in patients blinded by degenerative disease depend upon. Here we review experiments designed to investigate the cellular mechanisms responsible for the increase in maintained spike activity and explore the retinal circuitry that may give rise to it.rd1 retina [μm)—which, by virtue of their large size, are referred to here as alpha cells [To determine whether RGC hyperactivity was caused by changes in the intrinsic properties of RGCs, such as ion channel function or distribution, or by altered synaptic input, intracellular recording was used to study the effect of photoreceptor loss on the electrophysiological properties of selected types of ganglion cells in 1 retina . RGCs wiha cells —were tarha cells  were useha cells . The useha cells , 26.rd1 alpha RGS retained the characteristic differences in the weights of excitatory and inhibitory synaptic inputs that ON and OFF cell types receive. They also continued to generate rebound excitation in OFF cells and gave rise to voltage-evoked dendrite calcium signals that were similar to those recorded from the dendrites of RGCs in non-dystrophic retina [rd1 alpha RGC activity are triggered by oscillatory synaptic inputs as shown by the fact that they persist under voltage clamp recording conditions and are eliminated by CNQX, a glutamatergic blocker (Unlike ganglion cells from normal animals, which generate resting spike activity with no obvious temporal periodicity, the rate of spontaneous spike discharge in alpha RGCs from animals blinded by degeneration is increased and consists of continuous rhythmic bursts of spikes  with a bc retina . The rhy blocker .rd1 ON and OFF RGCs retain their normal distinguishing differences in the strengths of the excitatory and inhibitory inputs they receive, in spite of the ongoing oscillations in maintained synaptic activation, suggests that the organization and distribution of RGC contacts with presynaptic neurons have not been remodeled. The extensive changes in retina morphology that have been reported in this and other models of RP [rd1 animals where it appears that functional changes have occurred but massive remodeling of the inner retina has not taken place.The presynaptic source of the synaptic inputs that give rise to rhythmic firing is not known. That ls of RP , 29 emerls of RP . While trd1 retina show no evidence of having intrinsic pacemaker activity that gives rise to spontaneous fluctuations in membrane potential [Single cell recordings from bipolar cells isolated from dissociated otential . This inotential . This isotential , wide fiotential  and dopaotential , 35 amacrd1 retina, it might be expected that oscillations in spike discharge would not be confined to local spatial areas, but would instead be rather widespread. Stasheff [μm spacing of the electrode array that the study made use of.This hypothesized mechanism for oscillatory spike discharge could be tested by recording from bipolar cells in an intact dystrophic retina to determine if rhythmic changes in membrane voltage are present and sensitive to inhibitory synaptic blockade. Note that the proposed circuit cannot be rejected solely on the basis of finding no evidence of periodic fluctuations in baseline voltage in recordings from bipolar cells in retinal slices . In suchStasheff , howeverIn the proposed circuit the oscillations that give rise to rhythmic RGC spike discharge originate in an unidentified amacrine cell as a result of photoreceptor death and deafferentation. In this scenario, it is the loss of photoreceptor synaptic input that unbalances the circuitry of the normal retina and in so doing exposes the resonant membrane properties of an amacrine cell that is normally held in check in the functionally intact retina. Resonance is a consequence of the interactions between the active and passive membrane properties of a cell  that effrd1 mice were also present in single unit recordings in the visual cortex. Thus it is likely that the increased level of spontaneous activity that has been described in animals models of RP is also be present in patients with degenerative retinal disease and may participate in the generation of the phantom visual images that are reported by some RP patients [rd1-modified CNS circuitry gives rise to discontinuous visual sensations. In any case uncontrolled spontaneous spike activity would be expected to degrade the action potential encoded messages RGCs send to the brain and thus hinder attempts to restore vision using electrical or optical prosthetics designed to directly evoke RGC spike trains that the brain can interpret as meaningful visual information. The RP retina retains functional connections with the brain as shown originally by Drager and Hubel  who founpatients –41. ThesResearch designed to evaluate the treatment of RP using electronic or optical retinal prosthetics has not considered the influence that increased spontaneous RGC spike discharge might have on the successful use of prosthetics. While electrical stimulation of the retina in blind subjects can evoke the sensation of light and provide a rudimentary means of detecting motion, it has not been possible to use this approach to elicit the complex pattern percepts that are associated with more robust visual function . Whether


Dear Sir,et al.,[I read with interest the recent case report submitted by Bhartia et al., which deet al., While thet al.,With their report, the authors added to the growing number of reports of patients with right paraduodenal hernia managed safely and effectively using a laparoscopic technique and reminded the astute surgeon to expedite diagnosis and possibly shorten length of stay in the hospital by entertaining the diagnosis of paraduodenal hernia. This is particularly true in adults who present with acute symptoms associated with small-bowel obstruction. For surgeons with significant experience in minimally invasive techniques, physical examination and abdominal radiographs followed by diagnostic laparoscopy and definitive laparoscopic repair is a viable option for patients with acute and chronic presentation of right paraduodenal hernia.


It would be interesting to be able to quantify the extent of ROS formation. We investigated if histamine which is present at the inflammation site can serve as an endogenous marker for the formation of OH.. We found that histamine after incubation with OH. gave two distinct products in our HPLC system. One of the products gave the same characteristics as the synthesized 2-imidazolone derivative of histamine. This suggests that this derivative will be formed when histamine is incubated with OH..During inflammation an influx of neutrophils and release of mediators from mast cells (such as histamine) take place. The stimulated neutrophils can produce reactive oxygen species (ROS). One of these ROS is the highly reactive hydroxyl radical (OH


Intensity Modulated Radiation Therapy (IMRT) is a means of delivering radiation therapy where the intensity of the beam is varied within the treatment field. This is done by dividing a large beam into many small beamlets. Dose constraints are assigned to both the target and sensitive structures and computerised inverse optimization is performed to find the individual weights of this large number of beamlets. The computer adjusts the intensities of these beamlets according to the required planning dose objectives. The optimized intensity patterns are then decomposed into a series of deliverable multi leaf collimator (MLC) shapes in the sequencing step.One of the main problems of IMRT, which becomes even more apparent as the complexity of the IMRT plan increases, is the dramatic increase in the number of Monitor Units (MU) required to deliver a fractionated treatment. The difficulty with this increase in MU is its association with increased treatment times and a greater leakage of radiation from the MLCs increasing the total body dose and the risk of secondary cancers in patients. Therefore one attempts to find ways of reducing these MU without compromising plan quality.The design of inverse planning systems where the beam is divided into small beamlets to produce the required intensity map automatically introduces complexity into IMRT treatment planning. Plan complexity is associated with many negative factors such as dosimetric uncertainty and delivery issues A large search space is required necessitating much computing power. However, the limitations of the delivery technology are not taken into consideration when designing the ideal intensity map therefore a further step termed the sequencing step is required to convert the ideal intensity map into a deliverable one.Many approaches have been taken to reduce the complexity. These include setting intensity limits, putting penalties on the cost function and using smoothing filters Direct Aperture optimization (DAO) incorporates the limitations of the delivery technology at the initial design of the intensity map thereby eliminating the sequencing step. It also gives control over the number of segments and hence control over the complexity of the plan although the design of the segments is independent of the person preparing the plan. Intensity Modulated Radiation Therapy (IMRT) is an advanced form of 3D radiotherapy. The non-intuitive nature of IMRT planning can sometimes lead to very complex plans. This review highlights the difficulties of overly complex plans and evaluates Direct Aperture Optimization (DAO) as a potential means of reducing this complexity.Intensity Modulated Radiation therapy (IMRT) is a means of delivering radiation therapy where the intensity of the beam is varied within the treatment field. It is an advanced form of 3D conformal radiotherapy (3DCRT) which allows for more precise shaping of dose to the target and reduced dose to normal tissues. For example, in a study of 57 nasopharyngeal patients. IMRT sta3D conformal radiotherapy is forward planned requiring the expertise of the planner to decide on the weights, beam orientation, use of wedges or compensators to achieve the desired dose distribution. IMRT, in contrast, is inverse planned in that the planner inputs the desired tumour dose and dose limits and the computer adjusts the beam intensities to achieve as close as possible to this desired outcome. With inverse planning, the dose distribution is broken up into different beamlets, with the computer tracing each beamlet through the patient producing the initial dose distribution. By altering the weights of individual beamlets the computer can accept these changes if it results in an improved distribution. This process is repeated for all beamlets during a single cycle. This is repeated until no further improvements are seen. At present this computerised process is very lengthy as the adjustments required to produce an acceptable plan are not intuitive as with forward planning.IMRT can be delivered in many different ways; segmental, dynamic, arc or tomotherapy. Segmental IMRT (sIMRT) is where modulated field intensity is achieved by summing all the segments. The radiation is only turned on when the segment is in position, and is often known as step and shoot delivery. Dynamic MLC-IMRT is where the leaves are in continuous motion during each field. Although this method produces a more conformal dose distribution, a larger number of MU are required and there is more leaf transmission increasing the integral dose to normal tissue. As the The complexity of a plan is linked to the rate at which the fluence varies across each field. It is important however to avoid overly complex plans for several reasons.First, IMRT requires more treatment fields than conventional radiotherapy and therefore a larger volume of normal tissue is exposed to low doses of radiation. Second, IMRT treatments are inefficient with respect to the number of MU which are necessary to deliver daily fractional dose leading to an increased leakage exposure. The more complex the intensity patterns, the higher the number of MU will be required to deliver the prescribed dose. It has The increase in the number of monitor units relative to 3DCRT has led to concern about secondary malignancies with IMRT. Depending on the treatment energy IMRT treatments require 3.5–4.9 times as many MU to deliver a specified dose as compared to conventional treatments. From thHowever there is much uncertainty in these calculations of risk of secondary malignancies from the increase in MU. In factThe average number of MU per segment becomes very small for complex plans. This maTreatment planning algorithms are less accurate in more complex IMRT treatments. Treatment fields which contain highly modulated intensity regions will be affected by low resolution pencil beam kernels. This was apparent in a study which compared two commercial planning systems. One of the systems not only underestimated the dose of the high intensity peaks by over 13% but it also overestimated the horizontal spread of the dose at the sides of the peak. This inadequacy of this treatment planning system was only relevant in highly modulated fields.High dose rate, multiple beam segments, and low dose per segment have also been associated with the overshoot effect which generally occurs in the first and last beam segments due to the dose servo control system and causes an over and under dosage respectively. It occuIMRT plans can result in hot spots distant from the tumour, from crossing high intensity beamlets. This can be counteracted by drawing 'help structures' at the area of the crossing but this may result in the hot spot appearing elsewhere. A positive side effect of controlling the intensity variation may be that these distal spots are less prevalent.Decreasing the number of cycles in the optimization process has been shown to reduce dose dumping and MU. This maThe intensity distribution for each field is non-intuitive in highly complex plans and the complexity in general may increase the likelihood of human error. For example the verification of anatomical position through traditional imaging becomes difficult for multiple static segments of small size and varying intensity encompassing very little distinctive anatomy. This wilIn addition to the dosimetric uncertainty and less intuitive nature of complex plans there is also increased machine and resource allocation required which may increase treatment times  and thusA limitation in planning IMRT treatments is the time the optimization process takes. This can be reduced by decreasing the search space or number of variables. A common procedure would be to input set gantry angles for this reason. As computing power improves this will be less of an issue, but an important consideration is to use the computer power and time available appropriately. For example it may be more productive to use a more accurate dose calculation algorithm than using computer power calculating very complex plans, which may lead to inaccuracies.IMRT can be forward planned or inverse planned. With forward planned IMRT the beams are first of all shaped to the target volume. Additional beam segments are then added and weightings are distributed between the larger beams and the segments in order to shape the isodose distribution. Forward planning IMRT has been shown to be superior to conventional forward planned tangential techniques in intact breast cancer although it is inferior to inverse planning techniques Aperture-based inverse planning IMRT adopts some of the features of forward planning and incorporates inverse planning into the process. Apertures are designed from the anatomical shape of the targets and conformal apertures are also designed that exclude critical structures. An inverse optimization is then performed to optimise the weights of the apertures within the provided dose constraints. This method therefore is a development of forward planning by using inverse planning software to optimise the weights of individual segments.Direct Aperture optimisation (DAO), sometimes termed Direct Machine Parameter Optimisation, is another IMRT optimisation technique where similarly to aperture based inverse planning the apertures are identified during the planning process. However with this technique the apertures are not selected by considering the anatomical relationship between the target and critical structures. The planner inputs the dose constraints, beam angles, energies and number of apertures. With DAO the planner can also put a constraint on the minimum size of each aperture and place a lower bound on the weight . The ape2. Dose constraints are assigned to the targets and sensitive structures. Computerised inverse optimization must be performed to find the individual weights of this large number of beamlets. The computer adjusts the intensities of these beamlets according to the required planning dose objectives. Plans frequently fail to achieve the desired dose constraints and so clinical decisions have to be made as to which are most important and which can be relaxed. Once the optimal fluence map is decided upon there is a further leaf sequencing step. The optimized intensity patterns are decomposed into a series of deliverable MLC shapes made up of a number of basic beamlets with mathematically related weights/intensities. This typically results in a total number of leaf segments ranging from 60–100 in prostate only IMRT plans[Beamlet based optimization divides a large beam into many small beamlets of about 1 cmMRT plans.In converting the plan from the computer generated solution to deliverable segments, the dose distribution will degrade from that originally decided upon. In comparing beamlet based sIMRT for three commercial inverse planning similar performance was found in all three systems and IMRT plans tended to converge. The main differences in the IMRT plans concerned dose gradients outside the target, MU and segment number; demonstrating the impact of the sequencing step. In anotDAO differs from beamlet based optimization in that it does not rely on the use of a segmentation routine (sequencing step) to select the initial leaf sequence as this step is incorporated into the original optimisation. Therefore with DAO the planner has direct control over the complexity of the IMRT plan. With DAO the treatment plan is optimized using a deliverable treatment solution. This avoids the plan degradation which can occur during the conversion of the ideal intensity map into a deliverable one at the end of optimization. The main purpose of direct aperture optimisation is to reduce the number of segments and MU required to treat a complex arrangement of targets and surrounding structures. The problems with large numbers of segments and high total MU have been discussed earlier.Many of the dosimetric concerns associated with IMRT such as low MU per segment, high overall MU, and dosimetric uncertainties can be improved by controlling plan complexity. Direct aperture optimization is a method of controlling complexity that provides a significant reduction in the number of beam segments and MU required. However it also has the advantage over other methods of complexity reduction in that it eliminates the sequencing step which is associated with plan degradation. Studies which evaluated the use of DAO in the clinical setting are illustrated in table When DAO was compared to 3D conformal radiotherapy, and beamlet based IMRT in 15 breast cancer patients it was found that DAO plans were equal to or better than those generated with 3D-CRT and standard beamlet IMRT. DAO IMRIn another study which compared DAO and beamlet based IMRT plans of 12 breast cancer patients  the doseJones at al. comparedIn a study of 10 hypopharyngeal patients, acting as their own control, no statistically significant difference was found for compliance to the dose volume constraints although the mean dose to the parotid was lower with the beamlet based plans compared to the DAO plans. Dose homogeneity within the PTV was superior for the DAO plans and they also required significantly less MU to deliver .Ludlub et al. comparedThe use of pencil beam algorithms when calculating IMRT treatments can lead to inaccuracies in difficult to calculate treatment geometries. To address this problem, Monte Carlo (MC) simulated dose data can be used with DAO in the optimization step. The optimized plan then undergoes a final dose calculation using MC. This is referred to as a MC DAO plan. This technique would be useful for planning small field IMRT cases for PTVs located within or adjacent to tissue inhomogenities. The optimized DVHs generated by the MC_DAO software are already a faithful representation of the final MC forward calculated doses as there is no leaf sequencing step required.DAO can also be applied with collimator rotation, termed rotating aperture optimisation (RAO). Plans generated with RAO were found to be as good as or better than DAO, while maintaining a smaller number of apertures and MU than beamlet based optimization. RAO is less sensitive to tongue and groove effects than DAO. However delivery time is increased due to the collimator rotation speed.Reducing the complexity of IMRT has been the focus of this review, but it has to be noted that there is a limit to the degree which the complexity of the plan can be reduced before severely affecting plan quality. This was demonstrated in prostate patients where it was found that for DAO plans with 20 segments the conformal indices values dropped drastically when compared to plans with 40 or greater segments confirming the indication for a threshold for the minimum number of segments. It was The smallest width of any aperture is the width of an MLC leaf and the minimum length of any aperture is determined by the minimum step size along the direction of travel of the MLC leaves. The quality of an IMRT plan can be improved by increasing the number of degrees of freedom. Therefore increasing the number of apertures per beam should improve plan quality. Reducing the step size from 10 mm to 1 mm demonstrated continuous improvements in the objective function value and led to steeper dose gradients between the target and critical structures. HoweverOther methods have been suggested to increase delivery efficiency and reduce MU without significantly affecting plan quality. In a study of 9 patients (including head and neck prostate and brain) it was found that by using intensity limits during inverse planning it was possible to reduce the total MU without compromising the clinical acceptability of the plan. MU reductions up to 38% were observed.Matuszak et al. looked aSmoothing parameters as either part of the optimization process or post optimization have been used to reduce the complexity in IMRT. Although those applied post optimization usually result in degradation of the plan quality, it has been shown that a smoother fluence can result in a reduction in dose to the healthy tissue and again that a reduction in fluence complexity is strictly correlated with a reduction in MU. Increasing the smoothing parameter has been shown to have an impact on the accuracy of delivery,30.It is important to reduce the complexity of IMRT plans as much as possible as overly complex plans deliver unnecessarily high MU and excessive radiation leakage. There is also more dosimetric uncertainty associated with highly complex plans as well as increased pressure on resources. Therefore a balance needs to be found between plan complexity and optimal dosimetry. Forward planning provides better dosimetry than 3D but is inferior in general to inverse planning approaches. Aperture based planning takes on some of the elements of forward and inverse planning. DAO differs from aperture based planning in that it is an entirely inverse planned approach which incorporates the restrictions of the treatment machine into the optimisation process. Many approaches have been taken to reducing the complexity of IMRT plans such as setting intensity limits, putting penalties on the cost function and using smoothing filters. DAO incorporates the treatment machine restrictions into the optimisation process thereby eliminating the sequencing step which has been associated with plan degradation. DAO has been associated with a reduction in MU in a number of clinical situations but further research needs to be conducted to establish the optimum number of segments for targets and OARs of varying geometry as it may not be possible to reduce segment number and MUs in the more difficult geometries.Due to increased pressure on resources, dosimetric uncertainties and leakage of radiation, treatment plans with very small fields, low MU per segment and high overall MU are not optimal. It is necessary therefore to look at ways of reducing the complexity of beamlet based IMRT treatment plans. It is also desirable to reduce the discrepancy between the optimal treatment solution and the deliverable treatment solution following segmentation. Many approaches have been taken to addressing these issues. This review discusses the potential role of DAO in attempting to reduce the number of field segments while achieving a similar dose distribution.IMRT: Intensity Modulated Radiation Therapy; MLC: Multi leaf collimator; MU: Monitor Units; DAO: Direct Aperture optimization; 3DCRT: 3D conformal radiation therapy; sIMRT: segmental IMRT; sMLC: static MLC; TLD: thermo luminescent dosimeters; MC: Monte Carlo; RAO: Rotating Aperture optinization; OAR: Organ at riskThe authors declare that they have no competing interests.MB conceived and drafted the manuscript. ML critically reviewed/revised the article. MC drafted the abstract. All authors read and approved the final manuscript.


The occurrence of organ-specific antigens on the surface of cells freshly isolated from normal adult rat liver and from liver cell lines cultured as monolayers for up to 6 months is demonstrated. Enzyme treatment used to disaggregate parenchymal cells from liver tissue did not result in appreciable changes in the antigen profile of the cell surface membrane.


Incompleteness of ascertainment of new cases of any disease leads to underestimation of its incidence rate and may result in false assumptions about incidence trends if incompleteness varies over the course of time . We report an attempt to assess the completeness of ascertainment in a cancer registry in the North-Western Region of England using a method based on independent comparison with accurate morbidity data. A total of 1955 verified cases of cancer from 5 independent sources covering 11 sites were used in the study. The corrected mean level of overall registration completeness was found to be 94% but this varied appreciably with site and source of data. Independent comparison is recommended as an effective method for estimating the completeness of cancer registration.