Nearly 10% of the population of Turkey lives in the Southeast Anatolian Project (SEAP) region. The population growth rate and the rate of unintended pregnancies are high and family planning services are insufficient in this region. Lifetime induced abortion rate is also high in this region.Public health problems of the SEAP region were investigated in the "SEAP Public Health Project" in 2001 and 2002. As it is one of the most important health problems of the women living in this region; induced abortion was also investigated in this project.An optimumsample size representing the rural and urban area of the region (n = 1150) was chosen by the State Institute of Statistics by a sampling method proportional to size. 1126 of the area's 1150 houses have been visited and data about induced abortions have been obtained by applying a questionnaire to 1491 ever married women who live in the region.It has been found that 9.0% of these women who had at least one pregnancy in their life had at least one induced abortion. The lifetime induced abortion per 100 pregnancies was found to be 2.45. The primary reason given for induced abortions was "wanting no more children" (64.6%). Lifetime induced abortions were 5.3 times greater with women using a family planning method than women not using family planning methods. Lifetime induced abortions were 4.1 times greater with unemployed women than working women. Most of the women have used private doctors in order to have an induced abortion.Although 32.29% have not yet begun to use a contraceptive method after their last induced abortion, 43.75% of the women have since started to use an effective contraceptive method. 23.96% of them have begun to use an ineffective contraceptive method.Induced abortion is still an important problem at the SEAP region. The results of the study remind us that unemployed women and women who have more than four children is our target group in the campaign against induced abortions. Most of the women use private doctors in order to have an induced abortion. Thus, priority must be given to educate private gynecologists with respect to induced abortion. After induced abortions, a qualified family planning consultant can be given to women and they can be secured to use a suitable contraceptive method. Abortions are divided into two groups as 1) induced abortion and 2) spontaneous abortion. The spontaneous abortion rate increases when the maternal and natal care is insufficient. Induced abortions occur at the desire of the couple and an increase in induced abortion rate is a good indicator of insufficient family planning services. The aim of the family planning services is the prevention of unwanted pregnancies. Inadequate access to contraceptive methods, method failure caused by misuse of the methods and non-use of effective methods are the reasons of unwanted pregnancies, which lead women to induced abortion [Abortion is defined by World Health Organization (WHO) as a pregnancy that ends before 28Induced abortions have been used as a family planning method for many years and become an important problem in women's health especially in developing countries. It is one of the main causes of death of women of reproductive age . InducedIn Turkey, the Population Planning Law legalized the provision of safe abortion services within ten weeks in May 1983. As a result, the facility to terminate unwanted pregnancies in safe conditions has been provided . But indNearly 10% of the population of Turkey lives in the Southeast Anatolian Project (SEAP) region. The population growth rate and the rate of unintended pregnancies are high and family planning services are insufficient in this region.Public health problems of the SEAP region were investigated in the "SEAP Public Health Project" in 2001 and 2002. Induced abortion was one of the health problems investigated in this project.The Southeast Anatolian Project (SEAP) region has a population of approximately 6 million people and nearly 10% of the population of Turkey lives in this region. The population growth rate and the rate of unintended pregnancies are high and family planning services are insufficient in this region.Public health problems of the SEAP region was investigated in the "SEAP Public Health Project" and this project was supported by the SEAP Regional Development Management of Prime Ministry Republic of Turkey and conducted by a consortium constituted by the Turkish Parasitology Association, Gaziantep University, Dicle University (in Diyarbakır province) and Harran University (in Şanlıurfa province). Induced abortion – an important problem for women – was investigated in this project in 2001 and 2002.The population of the nine provinces in the region is 6,128,973. In order to investigate the public health problems of the region such as abortion, an optimumsample size which represents the rural and urban area of the region was determined as 6900 (d = 0.03, p = 0.04, α = 0.01). This number (6900) was divided to the average number of households (approximately 6 people live in each house in the SEAP region) and the number of houses in the sample was found to be 1150. An optimum sample size representing the rural and urban area of the region was chosen by the State Institute of Statistics by a sampling method proportional to size.Questionnaires were prepared by the academic staff of public health departments of medical faculties of the two universities (Gaziantep and Dicle Universities). Three of the questionnaires were for individuals (the questionnaire of 5 year and older girls and women, the questionnaire of 5 year and older boys and men, and the questionnaire of 0–59 month's old children) and one of the questionnaires was about the house conditions. Before the study, the questionnaires were applied to houses that were not in the study sample as a pilot study and then checked.A team for questionnaire application was constituted in every province and the teams were educated about the questionnaires. These teams visited all of the houses in the sample with a public health specialist (the head) and applied the questionnaires by face-to-face interview. Data about the people living in the house were obtained by the house questionnaire. Data about the demographic features of women, fertility, and features about abortion were obtained by the questionnaire from 5 year and older girls and women. Educated nurses  applied the questionnaire to women by face-to-face interview in a separate room.1126 households of the area's 1150 houses participated to the survey. Households of the 24 houses were not found at home during the study. There were 1491 ever married (married, divorced or widow) women in the 1126 houses that participated in the survey.The data were evaluated using the SPSS 5.0 and Excel programs. Chi-square, Student's t test and logistic regression analysis were used for the statistical analysis.There were 1491 ever married (married, divorced or widow) women in the 1126 houses that participated in the survey. 1266 (84.9%) of these women had at least one pregnancy in their life.9.0% of the women who were ever married and who had at least one pregnancy in their life have had at least one induced abortion in the past. The rate of the women who have had two or more induced abortions was found to be 3.63%. The lifetime induced abortion rates of the women who were ever married and who had at least one pregnancy in their life according to some basic factors are shown in Table The percentage of women who have made at least one lifetime induced abortion was higher in women living in urban areas 10.39%) than women living in rural areas (6.85%, p < 0.05). The percentage of lifetime induced abortion was higher in 35–49 age group  than the other age groups (p < 0.01). Lifetime induced abortion rate was 7.15% in illiterate women and 10.53% in literate women and was higher among women who graduated from a primary school or higher (%12.77, p < 0.05). The percentage of women who have had at least one induced abortion was found to be higher in unemployed women and Turkish women than the other groups (p < 0.0001, Table 0.39% thaThe lifetime induced abortion rates of the women who were ever married and who had at least one pregnancy in their life according to some fertility characteristics are shown in Table Lifetime induced abortion was found to be significantly higher in women who had got pregnant with their last child without the desire of both of the couples, who wanted no more children and who were using a family planning method (13.31%, 11.95% and 15.21% respectively)  (Table "Wanting no more children" is the primary reason given for lifetime induced abortion 64.58%). In 63.54% of the lifetime induced abortions both of the couples have decided to the induced abortion together. Most of the lifetime induced abortions take place at the private doctors' consultant room (46.88%)  (52.38%) took the first and condom (26.19%) took the second place among the effective family planning methods. Withdrawal, with a rate of 87%, took the first sequence among the ineffective family planning methods . Lifting heavy things (35.4%) took the second place. Women who live in rural areas preferred to lift heavy things (64.3%) while women in urban areas preferred to take drugs (50.0%).The percentage of having at least one induced abortion among ever married women who had at least one pregnancy in their life in the SEAP region was 9.0% (lifetime induced abortion rate). Approximately one out of ten ever married women has made at least one induced abortion in their life. Also, 2.45 induced abortion per 100 lifetime pregnancies occurred at the region. When we evaluated the results of the Turkish Demographic and Health Survey 1998; (TDHS 1998)  the percentage of lifetime induced abortion among ever married women was reported as 18.2% and induced abortion per 100 pregnancies during the five-year period before the survey was 7.6 for the East Anatolian region . The SEAP rates were lower than the TDHS 1998 [There is a decrease in the lifetime induced abortion rate in the course of time compared with the TDHS 1998. Also, there is a decrease in the lifetime induced abortion rate in the same region (in the East Anatolian provinces) when the data of the TDHS 1993 is compared with the data of the TDHS 1998. Induced abortion rate per 100 pregnancies during the five-year period before the survey has decreased to 7.6 from 8.7 in the course of time . A similHowever, this low lifetime induced abortion rates do not show a success because unintended pregnancies end with births in the region. As a matter of fact, 30.1% of the latest births of the women during the last five year period were not desired by both of the couples in the Southeast Anatolian region . Also, tThe rate of induced abortion was higher in urban areas than rural areas. This was similar with the TDHS 1998 .Lifetime induced abortion rate was 7.15% among illiterate women, 10.53% among literate women and was higher among women graduated from primary school or higher (% 12.77, p < 0.05). In a study conducted by Akın et al. similar results have been found [In the logistic regression analysis the total number of pregnancies of the women, the family planning method usage status of the women and the employment of the women have been evaluated as the independent factors affecting lifetime induced abortion. As the total number of pregnancies increases, lifetime induced abortion risk increases (odds ratio is 1.7). Women who have more than four children may be the target group of the studies planned on this subject. In a study conducted by Akın et al. a similar odds ratio (1.1) have been found .Lifetime induced abortions were 4.1 times greater with unemployed women than working women. This was due to the fact that these women have lower family planning usage rates but their pregnancy rate was high.These results remind us that unemployed women and women who have more than four children must be our target group in the campaign against induced abortions as a family planning method.Lifetime induced abortions were 5.3 times greater with women using a family planning method than women not using family planning methods. I.e. the usage of family planning methods are 5.3 times higher among the women who have had an induced abortion in the past. In a study conducted by Akın et al. similar results were reported during the five-year period before the survey (odds ratio is 2.9) [Lifetime induced abortions have usually taken place at a health facility and with the assistance of health personnel. After these lifetime induced abortions, a qualified family planning consultant can be appointed to these women and they can be encouraged to use a suitable contraceptive method. The rate of effective family planning method usage after induced abortion was 43.7% in our study. The same rate was 34.2% in the TDHS 1998 during the five-year period before the survey . There iAfter lifetime induced abortion, 32.3% of the women were not using a family planning method in the study and this was nearly the same with the percentage evaluated in the TDHS 1998 during the five-year period before the survey (32.1%) . There wAfter lifetime induced abortion, 67.71% of the women have begun to use a family planning method in our study.The primary reason given for the last induced abortion was "wanting no more children" 64.5%) and this is similar with the data of the TDHS 1998 % and thi.Although the rate of lifetime induced abortions are decreasing in the course of time it is still an important health problem in the SEAP region. Unintended pregnancy and total fertility rates of the region is still higher than the other regions of Turkey. Thus, family planning services, the educational level of women and the status of women need improvement.Although 9.0% of the ever married women who had at least one pregnancy in their life have made at least one induced abortion and 2.45 induced abortion per 100 lifetime pregnancies occurred at the SEAP region, these rates are lower than the whole rate of Turkey. But, the high fertility rate shows us that family planning services are insufficient in the region. Also 32.29% have not begun to use a contraceptive method after their last induced abortion and 23.96% of them have begun to use an ineffective contraceptive method. This shows an important lack on this subject. After these lifetime induced abortions a qualified family planning consultant can be appointed to these women and they can be encouraged to use a suitable contraceptive method. Also to decrease lifetime induced abortions; women who have more than four children and unemployed women may be the target group of studies planned on this subject.The author(s) declare that they have no competing interests.AİB participated in the conception and design, provision of study materials, analysis of the data, statistical expertise, drafting the article and revision of the article. BÖ participated in the conception and design, collection and assembly of data, provision of study materials, analysis of the data, statistical expertise, drafting the article, revision of the article and final approval of the article. SÖ participated in the conception and design, collection and assembly of data, provision of study materials, analysis of the data, statistical expertise, drafting the article, revision of the article and final approval of the article. SŞ participated in the conception and design, collection and assembly of data, provision of study materials, analysis of the data, statistical expertise, drafting the article, revision of the article and final approval of the article. TŞ participated in the collection and assembly of data, provision of study materials, analysis of the data and statistical expertise. GS participated in the conception and design, collection and assembly of data, provision of study materials, analysis of the data and statistical expertise. AC participated in the conception and design, collection and assembly of data, provision of study materials, analysis of the data and statistical expertise. Eİ participated in the conception and design, collection and assembly of data, provision of study materials, analysis of the data, statistical expertise, drafting the article, revision of the article and final approval of the article. HA participated in the collection and assembly of data, provision of study materials, analysis of the data and statistical expertise. YP participated in the collection and assembly of data, provision of study materials, analysis of the data and statistical expertise. FA participated in the conception and design, collection and assembly of data, provision of study materials. MA participated in the conception and design, collection and assembly of data, provision of study materials.The pre-publication history for this paper can be accessed here:


An organism's ability to sense and respond to potentially harmful pathogens is key to its survival. To fight off disease and infection, organisms must detect pathogens, activate immune cell signaling pathways, and produce molecules able to thwart a pathogenic attack. So fundamental is this need that molecules and protein domains related to innate immunity are evident in organisms as diverse as plants, flies, and humans, highlighting the ancient origins of defense mechanisms. Once detected, the pathogen's presence triggers a cascade of signaling events that generate a rapid response tailored to specific classes of pathogens.Drosophila fruitfly, they elicit a range of defensive reactions in the fly, including the production of antimicrobial proteins, phagocytes (which engulf the pathogen), and toxic metabolites. A microbe sets off one of these responses by interacting with a receptor, triggering a pathway that activates a special class of transcription factors, which in turn activate genes needed to make antimicrobial peptides, say, or toxins. Drosophila attacked by fungi and a certain class of bacteria activate these transcription factors through a pathway (the Toll pathway) that also operates in mammals.When pathogens attack the A second pathway is activated when a different class of bacteria attack. While the general steps of this pathway, called the Immune deficiency (Imd) pathway, are known—Dredd-mediated activation of the Relish transcription factor, for example, is central to this antibacterial response—the details and mechanisms remain unclear. Signaling pathways are notoriously complex and the Imd pathway is no different. In the current model, bacterial pathogens stimulate a transmembrane receptor, which activates the Imd protein, which then transmits the signal through intermediary proteins, which ultimately activate Dredd, sending Relish into the nucleus to activate genes required for an immune response.PLoS Biology, Edan Foley and Patrick O'Farrell use a genome-wide approach to characterize the Imd pathway, with an eye toward understanding what regulates the Dredd-Relish interaction. To identify pertinent genes and their roles, Foley and O'Farrell took advantage of a technique, called RNA interference (RNAi), that can selectively target and “silence,” or inhibit, nearly any gene. After silencing a gene, researchers can then track how a cell responds and infer the gene's function. The technique uses double-stranded RNA (dsRNA) molecules with nucleic acid sequences that match a gene of interest (RNA can bind to DNA through complementary base pairing). The dsRNAs precipitate a series of steps that ultimately degrade the messenger RNA associated with the gene, preventing messenger RNA translation, thereby silencing the gene.In this issue of Drosophila genes with counterparts in mammals or the worm C. elegans (that is, conserved genes), then developed a cell culture model to analyze the components of the Imd pathway. Since the cells in these cultures respond to the presence of bacterial proteins by generating antimicrobial peptides, they provide a good testbed for identifying genes involved in the pathway. Foley and O'Farrell's RNAi screen identified many molecules involved in signaling, including both signal inhibitors and activators. Among these signaling components, they discovered two new genes: one, which they named sickie, is required to activate Relish; the second, called defense repressor 1 (dnr1), appears to inhibit Dredd activity and thus inhibit the pathway. Based on molecular analysis of these genes—which involved exposing cells to bacterial proteins—the authors propose a model of Imd signaling in which Dredd and the protein produced by dnr1, called Dnr1, operate through a negative feedback loop: Dredd activity appears to promote the accumulation of its own inhibitor, Dnr1. Since suppression of Dnr1 through RNAi can trigger an immune response, the authors explain, it appears that interruption of this feedback loop activates the signaling pathway. Without the inhibitory action of Dnr1, Dredd can activate Relish, which dissociates from Dredd, enters the nucleus, and activates the transcription of antimicrobial genes.The authors produced over 7,000 dsRNAs corresponding to most of the It's likely that the two genes described here play a key role in activating Relish, the authors conclude, and that others identified in this screen will also prove significant. Since many of these components are conserved in mammals, the pathway may likewise operate in humans. Future experiments will be the test of these assumptions, but until then, Foley and O'Farrell have demonstrated the soundness of using RNAi screens on a large scale to dissect the elements of a complex signaling pathway.


Services to meet adequate rehabilitation needs of elderly stroke survivors are not always provided. Indeed, since 1995, in the wake of the Quebec shift to ambulatory care, home care services, mainly those related to rehabilitation of the elderly, are either unavailable or incomplete. The aim of this study was to examine the rehabilitation needs of this clientele from their hospitalization to their reintegration into the community.The "Handicap Production Process" conceptual approach was chosen to help identify the rehabilitation needs of persons affected by physical or cognitive disabilities due to the interactions between personal and environmental factors, and . This qualitative exploratory study was performed in 2003. Data were collected among four groups of experts: patients, caregivers, health care providers and administrators. Data triangulation was used to ensure a rigorous analysis and validity of the results.Unfulfilled needs could be found in the categories of pertaining to residence, community living, psychological and emotional needs. Indeed, it appears that a psychological follow-up to discuss acceptance and consequences of non-acceptance would facilitate mid-to long-term rehabilitation.Improving accessibility to healthcare services, respecting priority parking spaces for the disabled as well as promoting public awareness would enable a better social reintegration and recovery of social roles, thus limiting the onset of handicap situations. After a stroke, a good proportion of the elderly rapidly re-enter the community without having benefited from rehabilitation services to help reduce their impairments and disabilities. Indeed, in Canada, only about 10% of stroke sufferers have access to intensive rehabilitation services  and be aThe World Health Organization  defines The HPP (handicap production process) ensues from the works of the International Network of the Handicap Production Process Figure  – formerPersonal factors relate to the person's basic characteristics like age, sex, socio-cultural identity, body systems (integrity vs. impairment) and the aptitudes (capacities vs. disabilities). Body systems identify components of the whole body. Integrity of these systems is based on the human biological norms while an impairment relates to a degree of anatomical, or physiological damage. Aptitudes are associated with a person's capacity for physical or mental activity such as walking or understanding. The value of an aptitude is measured on a scale ranging from optimal capacity to total disability. In the HPP, ensure the survival and thriving of an individual within society, during his/her entire life. They are arranged in twelve categories, the first six referring to activities of daily living and the last six relating to social roles valued by the person or his/her socio-cultural context. These categories are: nutrition, body condition, personal care, speech, habitation, mobility, responsibilities, interpersonal relationships, community living, leisure activities as well as education and work. The environmental factors are the constituents of a person's surroundings than can affect the realization of a living habit. Interactions between personal and environmental factors create needs that impact a person in the execution of his/her activities of daily living, thus limiting his/her social participation. A positive interaction between personal and environmental factors supports social participation while a negative interaction produces the development of handicap situations.Les besoins de santé des individus. Unpublished manuscript). It could be a need for a resource to provide adequate and ample services. Bradshaw's taxonomy [Needs are subjective, since they are felt by the person , the aim of this research was to investigate the expressed and normative rehabilitation needs of post-stroke elderly living in the community.As proposed by Morgan and Krueger , an induIn order to achieve experimental diversification, participants were identified by purposive selection. The patients (n = 4) and the caregivers (n = 5) were recruited through social workers from the local community service centers, daycare centers and also chosen from a data bank of participants to previous studies. Health care providers (n = 9) were solicited through directors of professional services and coordinators of rehabilitation or home-based services. They worked in different fields of healthcare and services, in rural and urban areas. Administrators (n = 7) were recruited through hospital managers who would identify which one was more familiar with the study clientele and worked in various rural and urban areas. All participants were recruited because of their critical abilities and their experience with needs related to the stroke process from onset to reintegration into the community. The area were the research took place is known as rural and semi-rural with a population of 150,000.Each of the four meetings lasted approximately two hours and was recorded on audiotape. A interview guide (Appendix 1 ) was buiIn order to ensure the validity of results, data was triangulated as described hereafter. During the last minutes of the meetings, the assistant-moderator would ask the participants to clarify some statements she had jotted down during the encounter. She would then sum up the meeting to validate its content with the participants, at which time they could complement, rectify or add to the information already given. This information along with the notes of the observer would help summarize the focus after each of the meetings. Later, a member of the team listened to the audiotape, allowing further analysis of the data. In the following weeks, each participant was sent a brief report of his/her focus group meeting. One week later, each participant was contacted to corroborate the content of the report. During these interviews, the comments of the participants testified to their understanding and approval of each report and allowed to add some details. Verbal and written summarized reports on the four groups were presented to the research team.Normative and expressed needs were grouped according to the twelve categories of the HPP model. After analysis of the focus groups, two categories were added in order to include psychological-emotional needs as well as psychological-cognitive needs and the education and work categories were abandoned. The participants from the four groups identified their needs as: a) needs already fulfilled or not mentioned, b) needs partially fulfilled c) unfilled needs.Characteristics of the participants of the four focus groups are presented in Table Eight out of nine health care providers had a fairly good knowledge of stroke and seven of them had more than nine years of experience with a stroke clientele. They were from different professional fields: special education (1), occupational therapy (1), social work (2), neuropsychology (1), speech therapy (1), physiotherapy or physical rehabilitation therapy (3). These professionals practiced in an active care hospital (2), a CLSC (4), a daycare center (2), a day hospital (1) and a community organization (1). The administrators came from the same kinds of facilities with the addition of an intensive functional rehabilitation unit and a rehabilitation center. Four of the administrators had a restricted knowledge of stroke and had other customers aside from stroke patients. Two out of seven took care only of persons over 65 years old or with neurological problems. Education fields of the administrators were either management or health related disciplines.patients were acceptance of their health problem (stroke) and accessibility to physiotherapy and occupational therapy services on an outpatient basis. Then subsequently followed the needs relating to adapted means of transportation, medical follow-up, home visit from healthcare personnel, and stimulus and motivation provided by a caregiver. Domestic help and encouragement from the healthcare personnel were also important needs that have been expressed. Patients were more communicative about their needs relating to community, their psychological and emotional needs, and house alteration requirements. Unfulfilled needs mainly included the occasional home visit from a health professional, domestic help, coaching by the CLSC and medical follow-up.The most important expressed needs of the caregivers was that the patient be loved, surrounded, and that he felt secure. These were followed by the necessity to make home adaptations, the need to inform the stroke patient and to provide him with physical and mental stimuli. Finally, the needs relating to tactile sensation problems, supportive care and attention, and acceptance of the situation were also important. It is worth noting that participating caregivers looked after individuals much more severely impaired than our group of patients. These caregivers mentioned the same categories of needs but in a different order of priority. For them, the psychological needs were the top priority; then came the need to adapt the home followed by community living needs. Notice that the beneficiaries had not resumed many of their social roles in the community. According to the caregivers, the less fulfilled needs were mainly related to psychological needs and associated with community living. Specifically, they concerned medication and its side effects, adaptation to this new situation for the caregiver and acceptance by the beneficiary. Respite, emergency help, supportive care and attention, training of family members were also needs partially fulfilled in these categories.The foremost rehabilitation need identified by the health care providers, the needs that were less fulfilled mainly concerned related to community living, psychological needs and speech impairment. More precisely, they included: leisure activities, awareness, long-term family support, bond between spouses, respect of the person's pace, delivery of timely and simplified medical information to the patient and his/her spouse, adaptation of the home and respite, because in rural areas, for instance, there is no specialized transportation.For the Re-education for basic activities like eating or getting dressed and psychological assistance for acceptance, self-esteem and dignity were the most important. Followed the capacity to communicate and the family's need to be supported in understanding the health problem. Finally, long-term follow-up, simplification of the information given and home alterations also constituted essential needs, again according to the health care providers. For the most part, the health care providers worked with severely disabled persons. In their view, the interventions having to do with personal care held a priority over those concerning psychological needs and communication needs. As also identified by the caregivers, needs related to community living and the home followed.administrators' view, a psychological support intervention made by the case manager, for instance, was more necessary in rural areas. They mentioned more "partially fulfilled" needs in the areas of speech, mobility and community living. They underlined the necessity to become sensitive to this clientele with cognitive problems and their needs for spirituality, means of transportation, financial support, the need to maintain and improve speech re-education.In the Administrators emphasized their wish to ensure the complete management of the patient. They were interested in the list of needs identified by the patients, since the needs of the affected individuals cannot be dissociated from those of their family. Needs identified as a priority by the administrators were a stabilized health condition, recovery of biological, psychological and social abilities, compensation mechanisms, integration into the community and support in finding a new sense to one's life. The chronology of those needs was unanimous because it set a continuum in the rehabilitation process. Priority needs identified by the administrators seemed closer to those listed by the patients. Administrators seemed to believe the patients had made a fairly good functional recovery and insisted on needs related to community living, personal care and psychological well-being. Finally, they were the only ones to clearly talk about spiritual needs.On the whole, unfulfilled needs were identified in the four groups as from categories relating to housing, community living, psychological and emotional needs. Table Although some of the categories were partially fulfilled for the health care providers and administrators, the gradient of the providers' opinion on each of the needs specifically mentioned, stood between "partially fulfilled" and "unfulfilled". Conversely, the gradient of the administrators' answers stood between "fulfilled" and "partially fulfilled". Interestingly, only the patients' group acknowledged nutrition needs.In Lewinter et al. , resultsThe perceived needs of the caregivers really stood out during focus groups and would be inseparable from those of the patients. Caregivers considered rehabilitation in terms of recovery and excluded compensation mechanisms. For instance, they were unable to imagine any possible means to compensate for poor vision, a need expressed by the patients. While patients referred to the psychological need of accepting the situation, caregivers mentioned the psychological need to face one's own limitations and the probability of complete rehabilitation. These results agreed with the study of Gauthier  who collFrom our results, it seems that supporting the caregiver at the time of the hospitalization would allow him to offer a better support to the stroke victim. That support would perhaps allow acceptance of the situation and an active implication in the rehabilitation. Long-term follow-up and respect of the person's pace were mentioned as being important. Caregivers felt useful and appreciated this phase of the rehabilitation where attendance, supportive care and attention as well as information were provided at the day hospital. All groups pointed out the need for a more aggressive early re-education and a continuing rehabilitation. None of the groups mentioned needs pertaining to responsibilities. Finally, needs associated with sexuality were acknowledged by all groups, but none offered any solution.Health care providers felt powerless, even frustrated, with so many needs to be fulfilled and so little human resources available. Health care providers proposed many possible avenues worth exploring in relation with community and some ways of addressing psychological problems.The health care providers identified most of the partially fulfilled needs, ranging the whole continuum of the rehabilitation process. They pointed out the necessity for health system administrators to acknowledge expressed and normative needs of stroke patients. Adding human resources would begin solving the problem. Patients who benefit from intensive rehabilitation (about 10% of the stroke clientele) are treated according to their impairments in order to diminish their disabilities and improve their functionality. Services to help the family and to modify to the physical environment are usually available. The only help rarely provided is that of fulfilling psychological or cognitive needs and supporting social integration. However for 90% of the stroke clientele who only benefits from rehabilitation services at the acute care hospital, little of their needs are fulfilled.This data concurs with that of Lewinter et al.  on the iIn general, the answers of the administrators were based on what the resources should offer instead of on the accessibility to services, which they were less aware of. It seems that most of the participating administrators were preoccupied by the needs of the patients throughout the whole process and not only when they were using their services. They proposed solutions focused on the needs of the patient and on the most adequate resource to fulfill those needs at this stage of the rehabilitation process. In fact, the need for specially trained personnel to help prevent contractures and dehydration, as well as spiritual needs, were reported by administrators from chronic care facilities. Spiritual needs had also been reported by McLean et al.  in theirRegarding prevention and treatment of secondary impairments, which is the second stage of the rehabilitation process described by Duncan, et al. , adminisMany strengths and limitations have to be mentioned. Methodologically speaking, holding the first meeting with the patients' focus group ensured a valid identification of their needs, as they were perceived. As for the other participants, recruitment was done in a rigorous manner in order to obtain a fairly equal number of representatives from rural and urban areas, from various professions, and from different types of rehabilitation resources, including representatives of community organizations. It should be mentioned that recruitment of the patients and caregivers was difficult; participants from these two groups were probably not typical of persons being dismissed to their home after a stroke. However, the fact that the severity of the stroke ranged from severe to mild in those two groups increases the external validity of the results.Recall bias is significant in this study as patients and caregivers had to recall events that took place few years ago.The implication of the four groups of participants ensures a better validity of the data as was suggested by Liu and Mackenzie . The rigAfter a stay in an active care hospital (ACH), before the patient is discharged, a meeting between family members and a stroke specialist  could allow discussions about a possible mental depression of the stroke patient and about upcoming difficulties. It would also be necessary at this time to give the caregivers information on their loved one's health status and to inform them of their future needs.After hospital discharge, a specially trained healthcare worker could remain available by telephone to counsel the caregivers. Finally, a psychological follow-up of the caregiver would allow him to better support his/her relative in his/her rehabilitation process. After discharge from the hospital or from the rehabilitation center, a better communication between healthcare facilities and increased availability of services at the CLSC – like twice a year home visits by a health care provider – are suggested by the patients. As concluded by Lewinter et al , it seemImproving accessibility to services, respecting priority parking spaces for the disabled and promoting public cooperation would allow for a better social integration and recovery of social roles. On the whole, a better distribution of financial resources between institutions having to deal with this clientele, would allow long-term support of the person and his/her family. Health care providers first suggest that full rehabilitation teams  be created (for example stroke team). They also propose the appointment of a case administrator or pivotal health care provider, based on the total system concept in healthcare, which would simplify communication between partners . Services would be more suited to the needs of the individual and available for the families. Intervention priorities would be centered on needs expressed by the person. Education programs on how to deal with different types of clienteles would be made available to the health care providers to help them adjust to the difficulties associated with all kinds of issues. For mid- to long-term needs, improving means of transportation, adding support groups in rural areas, improving long-term follow-up in urban areas, humanizing of care, making information accessible, educating the neighbours and demystifying stroke by informing the public, would help integration and recovery of social roles to counter handicap situations. Finally, it is imperative to consider the perceived and expressed needs of the patients and caregivers and to integrate those needs with the normative needs identified in planning rehabilitation programs.Appendix 1: Course of the group discussions for the patients, caregivers, health providers and administratorsClick here for file


Individuals with coronary artery disease are at high risk for adverse health outcomes. This risk can be diminished by aggressive lipid management, but adherence to lipid management guidelines is far from ideal and substantial racial disparities in care have been reported. Lipid treatment and goal attainment information is not readily available for large patient populations seen in the fee-for-service setting. As a result, national programs to improve lipid management in this setting may focus on lipid testing as an indicator of lipid management. We describe the detection, treatment, and control of dyslipdemia for African Americans and Caucasians with coronary artery disease to evaluate whether public health programs focusing on lipid testing can eliminate racial disparities in lipid management.Physicians and medical practices with high numbers of prescriptions for coronary artery disease medications were invited to participate in the Quality Assurance Program. Medical records were reviewed from a random sample of patients with coronary artery disease seen from 1995 through 1998. Data related to the detection, treatment, and control of dyslipidemia were abstracted from the medical record and evaluated in cross-sectional stratified and logistic regression analyses using generalized estimation equations.Data from the medical records of 1,046 African Americans and 22,077 Caucasians seen in outpatient medical practices in 23 states were analyzed. African-American patients were younger, more likely to be women and to have diabetes, heart failure, and hypertension. The low density lipoprotein cholesterol (LDL-C) testing rate for Caucasian men was over 1.4 times higher than that for African-American women and about 1.3 times higher than that for African-American men. Almost 60% of tested Caucasian men and less than half of tested African Americans were prescribed lipid-lowering drugs. Tested and treated Caucasian men had the highest LDL-C goal attainment (35%) and African-American men the lowest (21%).Although increased lipid testing is clearly needed for African Americans, improvements in treatment and control are also necessary to eliminate racial disparities in lipid management. Disparities in treatment and goal attainment must be better understood and reflected in policy to improve the health of underserved populations. Individuals with coronary disease (CAD) are at high risk for subsequent cardiovascular disease events and mortality. ClinicaImproved lipid management through the diagnosis of dyslipidemia has been a focus of quality improvement programs in the outpatient fee-for-service setting such as Medicare's Health Care Quality Improvement Program. Lipid tThis study describes outpatient lipid management for African Americans and Caucasians with CAD seen in medical practices throughout the United States. Data from medical records were examined for indicators of lipid management including lipid testing, lipid-lowering drug prescription, and goal attainment. Our objectives were to characterize lipid management across race-sex groups and evaluate the extent of disparities for the three components of lipid management: detection, treatment, and control. We then discuss the implications of our findings with respect to possible underlying causes and health policies for closing the gap in race-sex lipid management disparities.The Quality Assurance Program (QAP) is a national program sponsored by Merck & Company conducted during the late 1990's to identify physician practice patterns and to promote evidence-based best practices for the medical management of patients with cardiovascular disease seen in the outpatient setting . The QAPMedical records were reviewed by Access Medical Ltd (Arlington, VA) using a standardized electronic abstraction tool developed specifically for QAP-II. The QAP database contains data obtained from the medical record including race, sex, date of birth, medical history, and medical procedures. The most recent serum lipid testing results and the most recently recorded prescriptions for lipid-lowering drugs were also determined from the medical record. The medical record of each patient was reviewed only once. Patients were not followed over time. Patient and physician identifying information were not included in the QAP-II database to ensure confidentiality.Physicians and medical practices throughout the United States with high numbers of prescriptions for medications used in the treatment of cardiovascular disease were invited to participate in the QAP. The specialties of participating physicians included cardiology, internal medicine, family medicine, and endocrinology. Patients with cardiovascular disease were randomly selected within each participating medical practice.Patients included in the QAP study were at least 21 years of age with CAD and/or heart failure and were seen at least twice in two years by the participating physician. Patients were excluded if the medical record indicated a terminal illness, history of a transplant or awaiting transplant, or deceased.International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes (410–414), and cardiac procedures consistent with CAD (i.e., coronary artery bypass graft, angioplasty, and stent).Patients without medical record documentation of CAD were excluded from analysis. The presence of CAD was ascertained during analysis from abstracted medical record data based on medical history, Only patients with medical record documentation of African-American or Caucasian race were included. To reduce the influence of between-state variation in lipid management from states that contribute little information about African American populations, medical practices were excluded if they were located in states with fewer than 10 African-American patients in QAP-IIMeasures of detection (lipid testing), treatment (lipid-lowering drug prescription), and control  were the indicators of lipid management considered in this study. Low density lipoprotein cholesterol (LDL-C) testing was measured as the percentage of patients with at least one serum LDL-C value documented in the medical record. The use of lipid-lowering drugs (i.e., "treated" patients) was measured as the percentage of patients with medical record documentation of at least one prescription for a statin (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor) or non-statin lipid drug (e.g., gemfibrozil). Goal attainment among those with documented LDL-C values was based on recommended guidelines for patients with coronary artery disease (LDL-C < 100 mg/dL).We conducted a cross-sectional analysis of abstracted medical record data obtained from QAP-II. Indicators of lipid management  and potential confounding or explanatory variables were examined within strata of race and sex. Co-morbid conditions including diabetes mellitus, myocardial infarction, heart failure, and hypertension were identified from medical history and diagnosis codes.Logistic regression analyses were performed to evaluate the associations of race and sex with each of three dichotomous lipid management indicators while controlling for multiple confounding and explanatory variables. We accounted for correlations within medical practices using the generalized estimation equation (GEE) method. This meThe independent variables included in the regression models in addition to race and sex were age, medical history , and geographic region of medical practice. Logistic models predicting lipid-lowering drug prescriptions included a term for serum LDL-C concentration in addition to the above variables. LDL-C concentration was included to control for the severity of hyperlipidemia as a factor in the physician's decision to treat with lipid-lowering drugs.A total of 23,123 CAD patients with documented race and sex seen by 1,171 physicians at 238 medical practices in 23 states were included in the study. Of these patients, 1,046 were African American and 22,077 were Caucasian. African-American compared to Caucasian patients were more likely to be women (53% versus 36%). The average age for the study population was 69 years and ranged from 22 to 97 years.Within each race group, women were older than men on average and within each sex group Caucasians were older than African Americans Table . The preWithin sex strata, the percent of patients with LDL-C tests was lower for African-Americans compared to Caucasians Figure . Within Almost 60% of Caucasian men with LDL-C testing were prescribed lipid-lowering drugs Figure . The proIncluding those prescribed and not prescribed lipid-lowering drugs Table , a quartAmong patients tested and treated with lipid-lowering drugs about two-thirds or more failed to achieve goal Figure . Tested Results from GEE logistic regression analyses controlling for age, co-morbid conditions, and geographic region Table  were conConsistent with previous reports, our findings demonstrate that outpatient lipid management for CAD patients in the late 1990's had much room for improvement and that substantial race-sex disparities existed,16,21-26Much of the information needed to assess lipid management can be found only in the medical record. This information is generally not available to national and local public health programs attempting to implement policies promoting quality improvement in the many and diverse medical practices treating large patient populations. The most readily available data for patients seen in the fee-for-service setting is derived from administrative insurance claims for the reimbursement of costs associated with drugs and services. Insurance coverage for lipid-lowering drugs varies across plans. In contrast, lipid testing for CAD patients is a widely covered service that can be identified using electronic billing data without the need to review patient records in medical practices. For this reason, lipid testing is a focus of national efforts in the Medicare population to improve outpatient lipid management in the fee-for-service setting. Our finUnderlying causes of inadequate lipid management among CAD patients are multiple and likely vary by race and process of care (i.e., detection, treatment, and control). Factors that limit patient-physician encounters and continuity of care may partially account for racial disparities in lipid management. For example, African-American Medicare consumers with diabetes were more likely to receive outpatient care from emergency departments and had fewer physician visits per year than their Caucasian counterparts,27. The A report regarding racial disparities in the use of prescription drugs from the Center for Studying Health System Change provides evidence of other factors explaining racial disparities in lipid management. In thisBarriers to lipid management due to affordability may result in racial disparities if affordability differs by race. Patients who can not afford treatment may be less likely to aggressively pursue it with their physicians and may be less likely to comply with physician recommendations for testing and treatment. Secondary prevention of cardiovascular diseases among CAD patients with pharmacologic agents such as statins has been shown to be cost effective. But druThe fact that African Americans are more likely to be of low income has greater implications than simply the inability to afford medications. Income is one of several indicators of socioeconomic status correlated with factors related to health including education. Low eduAchieving LDL-C goal is challenging for all races, but African Americans may require especially aggressive lipid management accompanied by an enhanced understanding of reasons for failure to achieve goal. A recent report concerning patients with CAD and/or diabetes seen at a Veterans Affairs Medical Center found that African Americans were less likely to achieve lipid goal than Caucasians when prescribed identical doses of the same lipid-lowering drug even though African Americans had more clinic visits and lipid tests. The autPhysicians have indicated that oversight is a common reason for failure to adhere to lipid testing guidelines. WhetherPhysician-patient interactions are influenced by race and cultural factors related to race. African-American and Caucasian patients may differ with respect to cultural perceptions of health and disease and the ability of patients to influence or control their health outcomes. AfricanThe relatively poorer lipid management for African Americans compared to Caucasians may be partially explained by racial differences in the prevalence of co-morbid conditions. African Americans in the QAP were more likely than Caucasians to suffer from multiple chronic conditions including diabetes and heart failure. It has been shown that patients with diabetes compared to those without diabetes receive poorer lipid management and are less likely to be at goal. An earlThere are a number of limitations in the QAP study design and its population that potentially pose a threat to internal and external validity. These limitations suggest that our findings may not reflect the experiences of the general population. The medical practices included in the QAP were restricted to those writing large numbers of prescriptions for cardiovascular disease drugs. It is difficult to evaluate the impact of this selection bias, but we suspect that medical practices included in the QAP represent the larger and more sophisticated providers of care. Thus, lipid management among QAP participants may be better than that found in the general population. Another limitation to our study is the lack of information characterizing medical practices, physicians, and patients with respect to factors related to race, sex, and lipid management. Because of the unavailability of this information, we could not identify underlying factors potentially explaining our findings. Lipid management data for the QAP patients seeing multiple physicians were unavailable from physicians not participating in QAP and this may have influenced results in an unpredictable manner.Considering the relatively small proportion of the study population identified as African American (<5%), it is likely that African Americans in this study do not represent the national population. We have no specific information about QAP medical practices or their patient populations, but we speculate that African Americans in the QAP were likely receiving better care on average than their counterparts in the general population, especially those with little or no access to outpatient care. If this is true, then racial disparities in lipid management in the general population may be even greater that those suggested by our findings.The time frame for this study includes years 1995 through 1998. Despite changes in guidelines and therapies since that time, our findings remain relevant to current practices. They provide historic context and baseline measures of lipid management disparities necessary to evaluate trends. In addition, they direct attention to the persistent need to provide aggressive treatment to high risk populations with CAD, especially African Americans and women who continue to be underserved. Finally, they highlight the growing view that public health strategies in lipid management must shift focus from testing to treatment and goal attainment.Clearly, a multi-pronged approach including all three elements of the process of care (i.e., detection, treatment, and control) is needed to improve lipid management for all race-sex groups, and particularly for African Americans. Although beyond the scope of this report, the application of conceptual models to the process of care may be useful in understanding how racial disparities arise at each step of the process. Furthermore, policies addressing health promotion and non-medical determinants of health such as socioeconomic status, community environment, and lifestyle choices need also be considered in confronting these disparities,45.Successful lipid management likely depends on a variety of processes that determine the provision of medical services including their availability, accessibility, and acceptability. The substantial racial disparities in lipid management among patients in contact with medical providers suggest that the effectiveness of medical services and patient characteristics play a prominent role in lipid management. Policies promoting appropriate delivery of care through system change as well as those ensuring equal access to care are required to eliminate lipid management disparities in the population of high-risk CAD patients,46.Our results suggest that policies and programs focusing solely on the elimination of lipid testing disparities can have only limited benefit in reducing the major disparity in lipid management. The elimination of lipid management disparities will require policies that view untested, untreated, and under-treated individuals as separate populations with unique challenges and solutions.Disparities in testing are just one element in explaining overall disparities in lipid management and ultimately, in cardiovascular outcomes. Future research should address patient, physician, and health system factors that lead to lower rates of testing, treatment and goal attainment for African Americans. Disparities in treatment and goal attainment must be better understood and reflected in policy in order to improve the health of underserved populations through optimal lipid management.CAD Coronary Artery DiseaseLDL-C Low-density lipoprotein cholesterolQAP Quality Assurance ProgramGEE Generalized Estimation EquationAnalyses were funded by an unrestricted grant from Merck & Co., Inc. No other competing interests are declared.MM conceived of the study, provided analytic and statistical support, and was the leading contributing author. KF participated in the design of the study and provided analytic support and interpretation of findings. LCE provided critical technical review and major contributions to the discussion section. CS provided conceptual guidance, assistance with QAP project database, and interpretation of analytic findings. CA provided critical review, QAP project experience, and contributions to the presentation and interpretation of findings. RS provided critical review, QAP project experience, and contributions to discussion and interpretation of findings. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


Crocus sativus L. is used to treat depression. Many medicinal plants textbooks refer to this indication whereas there is no evidence-based document. Our objective was to compare the efficacy of stigmas of Crocus sativus (saffron) with imipramine in the treatment of mild to moderate depression in a 6-week pilot double-blind randomized trial.The morbidity and mortality associated with depression are considerable and continue to increase. Depression currently ranks fourth among the major causes of disability worldwide, after lower respiratory infections, prenatal conditions, and HIV/AIDS. th edition for major depression based on the structured clinical interview for DSM IV participated in the trial. Patients have a baseline Hamilton Rating Scale for Depression score of at least 18. In this double-blind, single-center trial, patients were randomly assigned to receive capsule of saffron 30 mg/day (TDS) (Group 1) and capsule of imipramine 100 mg/day (TDS) (Group 2) for a 6-week study.Thirty adult outpatients who met the Diagnostic and Statistical Manual of Mental Disorders, 4Saffron at this dose was found to be effective similar to imipramine in the treatment of mild to moderate depression (F = 2.91, d.f. = 1, P = 0.09). In the imipramine group anticholinergic effects such as dry mouth and also sedation were observed more often that was predictable.The main overall finding from this study is that saffron may be of therapeutic benefit in the treatment of mild to moderate depression. To the best of our knowledge this is the first clinical trial that supports this indication for saffron. A large-scale trial with placebo control is warranted. Depressive disorders are very common in clinical practice, with approximately 11.3% of all adults afflicted during any one year ,3. The aCrocus sativus blossom, genuine saffron is worth its weight in gold. This plant belongs to the Iridaceae family. Although once considered a remedy for digestive problems, saffron is no longer used medicinally in the West [Crocus sativus is also used to treat depression [Crocus sativus with imipramine in the treatment of mild to moderate depression in a 6-week double blind randomized trial.Saffron is produced from the tiny, dried stigma of lily-like the West . In Asiathe West -10. Recethe West ,12. Althpression . Many PeThis was a 6-week randomized and double blind clinical trial. The investigation was conducted in the outpatient clinic of Roozbeh Psychiatric Hospital between January 2002 and February 2004.th edition (DSM IV) [Thirty adult outpatients who met the Diagnostic and Statistical Manual of Mental Disorders, 4(DSM IV)  for majo(DSM IV)  score ofThe saffron was used in this study was dedicated by Novin Zaferan Co (Mashhad, Iran) and was identified by the Department of Cultivation and Development of Institute of Medicinal Plants, Tehran, Iran. The stigma's extract was prepared as follow: 120 g of dried and milled stigmas was extracted with 1800 ml ethanol (80%) by percolation procedure in three steps then the ethanolic extract was dried by evaporation in temperature between 35–40°C. Each capsule had dried extract of saffron (10 mg), lactose (filler), magnesium stearate (lubricant), and sodium starch glycolate (disintegrant).Patients underwent a standard clinical assessment comprising a psychiatric evaluation, a structured diagnostic interview and a medical history. Patients were randomized to receive capsule of saffron or capsule of imipramine in a 1: 1 ratio using a computer-generated code. The investigation preparations were administrated in red capsules whole indistinguishable in color, size, form and taste. The assignments were kept in sealed, opaque envelopes until the point of allocation. The randomization and allocation process was done by the pharmacist of the Roozbeh Hospital. In this double-blind, single-center trial, patients were randomly assigned to receive capsule saffron 30 mg/day (TDS)(Group A) or capsule imipramine 100 mg/day (TDS) for a 6-week study. The dose of saffron was calculated according to a recent published animal study . All patSide effects were systematically recorded throughout the study and were assessed using a checklist administered by a resident of psychiatry on day 3, 7, 14, 21, 28 and 42  was used. The two groups as a between-subjects factor (group) and the six weekly measurements during treatment as the within-subjects factor (time) were considered. This was done for HAM-D total scores. In addition, a one-way repeated measures analysis of variance with a two-tailed post hoc Tukey mean comparison test were performed in the change from baseline for HAM-D scores in each group. To compare the two groups at baseline and the outcome of two groups at the end of the trial, an unpaired Student's t-test with a two-sided P value was used. Results are presented as mean ± S.E.M. Differences were considered significant with P < 0.05. To compare the demographic data and frequency of side effects between the protocols, Fisher's exact test (two sided) was performed. To consider, a = 0.05, β = 0.2, the final difference between the two groups at least score of 5 on the HAM-D total scores that is clinically detectable, S = 5 and power = 80%, the sample size was calculated at least 15 in each group.No significant differences were identified between patients randomly assigned to the group 1 or 2 conditions with regard to basic demographic data including age and gender (Table The mean ± SEM scores of groups 1 and 2 are shown in Fig. A number of probable side effects were studied Table . Dry mouThe current therapeutic goal in the treatment of major depression is to improve the quality of life by normalizing mood, increasing awareness of personal pleasures and interests, and reversing the functional and social disabilities associated with depression, as well as to reduce suicide rates . SaffronCrocus sativus extracts showed antidepressant effect [In this small preliminary double-blind and randomized comparison of saffron and imipramine in the treatment of mild to moderate depression, saffron at this dose was found to be effective similar to imipramine. Our results are in the line with a recent published animal study that t effect . In addit effect . In addit effect . The limNone declared.SA was the principal investigator and performed statistical analysis. HF and KA were the trialist. AHJ and FKC were the pharmacognosists of this study. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


Electroporation is currently receiving much attention as a way to increase drug and DNA delivery. Recent studies demonstrated the feasibility of electrogene therapy using a range of therapeutic genes for the treatment of experimental tumors. However, the transfection efficiency of electroporation-assisted DNA delivery is still low compared to viral methods and there is a clear need to optimize this approach. In order to optimize treatment, knowledge about spatial and time dependency of gene expression following delivery is of utmost importance in order to improve gene delivery. Intravital microscopy of tumors growing in dorsal skin fold window chambers is a useful method for monitoring gene transfection, since it allows non-invasive dynamic monitoring of gene expression in tumors in a live animal.Intravital microscopy was used to monitor real time spatial distribution of the green fluorescent protein (GFP) and time dependence of transfection efficiency in syngeneic P22 rat tumor model. DNA alone, liposome-DNA complexes and electroporation-assisted DNA delivery using two different sets of electric pulse parameters were compared.Electroporation-assisted DNA delivery using 8 pulses, 600 V/cm, 5 ms, 1 Hz was superior to other methods and resulted in 22% increase in fluorescence intensity in the tumors up to 6 days post-transfection, compared to the non-transfected area in granulation tissue. Functional GFP was detected within 5 h after transfection. Cells expressing GFP were detected throughout the tumor, but not in the surrounding tissue that was not exposed to electric pulses.Intravital microscopy was demonstrated to be a suitable method for monitoring time and spatial distribution of gene expression in experimental tumors and provided evidence that electroporation-assisted gene delivery using 8 pulses, 600 V/cm, 5 ms, 1 Hz is an effective method, resulting in early onset and homogenous distribution of gene expression in the syngeneic P22 rat tumor model. The maiin vitro gene delivery system in both prokaryotes and eukaryotic cells. Electroporation is a physical means of importing small molecules and macromolecules into cells via increased cell membrane permeability. Electroporation combined with chemotherapeutic drugs bleomycin and cisplatin (electrochemotherapy) has shown to be very promising antitumor therapy. It was tested on many different tumor types on the preclinical level demonstrating high antitumor effectiveness resulting in tumor cures at very low chemotherapeutic doses. It was also tested in clinical trials for the treatment of accessible cutaneous tumors of different histological types in cancer patients resulting in up to 100% objective responses [Electroporation is currently receiving much attention as a way to increase drug and DNA delivery -5. Electesponses ,6,7. Recesponses ,8-14. Hoesponses . In studesponses , making In order to optimize treatment, knowledge about spatial and time dependency of gene expression following delivery is of utmost importance in order to improve gene delivery. This information is also important for the timing of gene therapy with other cancer treatment modalities. Intravital microscopy of tumors growing in dorsal skin fold window chambers is a useful method for monitoring gene transfection, since it allows non-invasive dynamic monitoring of gene expression in tumors in a live animal ,17. So fAll animal experiments were carried out in accordance with the UK animals (Scientific Procedures) Act 1986, following the UKCCCR guidelines and with approval from the local Ethical Review Committee of the Gray Cancer Institute.Early generations of the P22 transplanted rat carcinosarcoma were used in experiments. Donor tumors were grown subcutaneously in the left flank of 8–10 week old male BD9 rats .Surgery was carried out under general anesthesia using intraperitoneal injection of fluanisone (10 mg/kg), fentanyl citrate (0.315 mg/kg)  and midazolam (2 mg/kg) ('Hypnovel', Roche Products Ltd., UK) as described previously . BrieflyEP1 – amplitude 180 V (voltage/distance ratio 600 V/cm); pulse length 5 ms; repetition frequency 1 Hz and EP2 – amplitude 390 V (voltage/distance ratio 1300 V/cm); pulse length 0.1 ms; repetition frequency 1 Hz. Immediately after the procedure, the glass window was replaced and GFP fluorescence monitored at selected time points for 6 days.Transfection was carried out 7 to 14 days following surgery, when tumors measured 3–4 mm in diameter, using a plasmid encoding the green fluorescent protein . Animals were anaesthetized with Hypnorm and midazolam. The window on the tumor side was removed and 40 μg of DNA alone or encapsulated in lipofectin  vesicles was carefully placed on the tumor surface in a total volume of 75 μl in phosphate buffered solution [Intravital microscopy was carried out using an inverted Nikon Diaphot 200 fluorescence microscope, with a stage modified in-house for holding rats. Animals were anaesthetized with Hypnorm and midazolam and placed on the stage, in such a way that the window chamber was located centrally above the objectives using location screws. Rectal temperature was maintained between 34–37°C throughout the experiment, using a thermostatically controlled heating pad beneath the rat and an infrared overhead lamp for maintenance of tumor temperature.Tumor preparations were alternatively viewed at each time point under transmitted visible light for measurement of tumor diameter and under fluorescence epi-illumination using a 100 W mercury arc lamp, for visualization of GFP fluorescence (excitation filter of 450–490 nm, emission filter of 520 nm) using x1.6, x4, x10 and x20 objective. Prior to transfection, two different regions of interest (ROI) using x10 objective were selected, one in the center of the tumor and one in the tumor periphery. Tumor preparations were monitored at each time point for 15 s using transmitted or epi-illumination.Observations were recorded in digital format, using a Sony DSR-30P digital videocassette recorder, for off-line analysis. Multiple frames  were captured onto computer and the images averaged for the analysis of the fluorescence intensity using the Visilog Image Processing package (Noesis, France). Increase in fluorescence intensity in the tumors was determined by subtracting the values of fluorescence intensity of non-transfected granulation tissue from the values of tumors and normalizing them to the values of non-transfected tissue. The calculations were performed for each animal at all time points.Statistical analysis was carried out using SigmaStat Statistical software (Systat Software GmbH, Erkrath, Germany). Data were tested for normality using Kolmogorov-Smirnov test and differences between the groups were tested for significance using Holm-Sidak method, after one-way repeated measures analysis of variance was performed. A value of p < 0.05 for the comparisons was considered to represent a significant difference between groups.Three different types of non-viral transfection methods were compared: DNA alone, liposome-DNA complex and electroporation-assisted DNA delivery, using two different sets of electric pulse parameters. Transfection of GFP was monitored using intravital microscopy on syngeneic P22 rat carcinosarcoma tumors growing in the dorsal skin flap window chamber of BD9 rats Figure . The train vivo appeared to be obtained only in the vicinity of the electrodes, whereas in the case of EP1 a larger area of the tumor was prone to DNA transfer. Effectiveness of electroporation-assisted gene delivery was also evident by lack of transfection efficiency in the granular tissue surrounding the tumor that was not exposed to electric pulses, but to DNA only , plasmid DNA appeared to be present in the progeny cells. In addition, intravital microscopy demonstrated that application of electric pulses to the tumors did not induce major cell damage as no effect on the tumor growth was observed compared to untreated controls. Six days post transfection there was no difference in increase in tumor diameter between the tumors that were transfected with DNA alone (2.2 fold), liposome-DNA complexes (2.3 fold), and electroporation-assisted DNA delivery using EP1 (2.4 fold) or EP2 (2.2 fold).In conclusion, this study showed that intravital microscopy is useful for monitoring the spatial and temporal efficacy of electroporation methods for gene transfection in animal tumor models. As such, it will be valuable for the evaluation of new methods of optimizing gene delivery. Electroporation-assisted gene delivery using EP1 was found to result in early onset and homogenous distribution of gene expression in the P22 tumor model. Further improvement in transfection efficiency may be gained by optimizing electric pulse parameters.The author(s) declare that they have no competing interests.MC conceived the study, participated in its design and experiments, and drafted the manuscript. IW participated in design of the study and experiments. GUD participated in design of the study and critically revised the draft. GMT participated in design of the study and coordination, and critically revised the draft. GS helped to draft the manuscript and participated in analysis and interpretation of the data.The pre-publication history for this paper can be accessed here:


Major issues in surgery for advanced ovarian cancer remain unresolved. Existing treatment guidelines are supported by a few published reports and fewer prospective randomized clinical trials.We reviewed published reports on primary surgical treatment, surgical expertise, inadequate primary surgery/quality assurance, neoadjuvant chemotherapy, interval debulking, and surgical prognostic factors in advanced ovarian cancer to help resolve outstanding issues.The aim of primary surgery is a well-planned and complete intervention with optimal staging and surgery. Surgical debulking is worthwhile as there are further effective treatments available to control unresectable residual disease. Patients of gynecologic oncology specialist surgeons have better survival rates. This may reflect a working 'culture' rather than better technical skills. One major problem though, is that despite pleas to restrict surgery to experienced surgeons, specialist centers are often left to cope with the results of inadequate primary surgical resections. Patients with primary chemotherapy or those who have had suboptimal debulking may benefit from interval debulking. A proposal for a better classification of residual tumor is given.Optimal surgical interventions have definite role to play in advanced ovarian cancers. Improvements in surgical treatment in the general population will probably improve patients' survival when coupled with improvements in current chemotherapeutic approaches. The Fédération Internationale de Gynécologie et d'Obstétrigue (FIGO) classifies ovarian carcinoma in stage I to IV ,2. StageTumors in stages I and II are generally considered to represent early disease, while stages III and IV evince late or advanced disease ,4. The sUnfortunately, most ovarian carcinomas are detected only when they are advanced. Results of studies evaluating screening by tumor markers  and/or ultrasonography to detect early disease are not clear ,7. Ultraet al., [Though controversial till 70s, surgery is now recognized an integral part of the treatment armamentarium in advanced ovarian carcinoma. Aure et al.,  presenteet al., . Subsequet al., ,16. It wet al., -19. Theset al., .Ongoing discussions about quality assurance and guideline-based therapy had helped to foster the impression that the main issues in treating ovarian cancer have been resolved and that the value of each procedure involved has been supported by high levels of scientific evidence -23. ClosThus, in this article we will concentrate on looking more closely at several issues in surgical treatment, their effects and importance in relation to outcome in advance ovarian cancer.The utility of primary surgery for advanced ovarian cancer is well established. Its aim should be a well-planned, extensive and complete intervention. Thus, no facility should offer surgery for patients with ovarian cancer if adequate standards of care cannot be met.The optimal preparation of patients for surgery is very important. Patients must be in a position to give fully informed consent to any additional surgical procedures found necessary during the operation. They should also undergo colonic lavage, which will provide the surgeon with better access to the lymph nodes and reduce risks in cases where intestinal surgery is undertaken. Where cytological evaluation of peritoneal fluid aspired preoperatively, a raised concentration of serum CA125, or ultrasound results indicate advanced malignancy, the patient should be transferred to a specialist surgeon (see below).Many cases where the staging is not clear, laparoscopy appears to be good tool for obtaining a definitive histological diagnosis in advanced ovarian cancer and helps in planning the best surgical approach. Laparoscopic staging, in particular, can give a clear view of the extent of surgery required and the difficulties that may be expected, and it may be helpful in selecting patients for primary (neoadjuvant) chemotherapy . Video rHowever, laparoscopic surgery of any suspicious adnexal mass is not encouraged unless the risk of capsular rupture and tumor spill is minimized by the use of endobags . No cystin-vitro and animal studies that showed carbon dioxide pneumoperitoneum has adverse effects on outcomes is probably unfounded, as a recent analysis from second-look laparoscopies showed no influence of pneumoperitoneum on overall survival [The fear due to some survival . CertainSince laparoscopy may increase tumor growth rates, delays between laparoscopy and definitive surgery should be avoided . AlthougTumor stage is one of the primary prognostic factors. Appropriate staging is vitally important for effective postoperative therapeutic decision-making. Patients who have been accurately staged as stage I may not require adjuvant chemotherapy ,33.Requirements for appropriate staging after total abdominal hysterectomy and bilateral salpingo-oophorectomy include multiple cytological washings, random biopsies from the peritoneum and the diaphragm, omentectomy and lymphadenectomy. The value of peritoneal cytology is supported by prospective studies . There aIn addition to the staging procedures mentioned earlier, optimal surgical treatment for ovarian cancer comprises tumor removal; removal of remaining ovaries, uterus, and fallopian tubes, omentectomy, and radical para aortic and pelvic lymphadenctomy ,37. The Although the reasoning behind performing these measures seems convincing, only lymphadenectomy has been partly evaluated in a prospective, randomized trial. The previously held belief that mere palpation of lymph nodes is sufficient to gauge nodal status was refuted in this study .Lymphadenectomy plays a triple role in the treatment of ovarian cancer. First, it is of diagnostic value since tumors of apparently early stage show nodal involvement in about 20% to 40% of the cases -43. The To the best of our knowledge, there has been no study testing the benefit of hysterectomy or omentectomy. However, the concurrent incidence of endometrial carcinoma in 10% to 25 % of patients, or its precursors in about 30% to 50% of all ovarian cancers justifies this procedure ,49.Ovarian cancer is one of the tumors where surgical debulking is considered worthwhile. This is due to availability of further effective treatments that are available to control the unresectable residual disease. As early as 1934, Meigs suggested that maximum cytoreductive surgery was beneficial . Many yeThe results of an earlier meta analysis on cytoreductive surgery might have been flawed not only due to absence of clear definitions but also due to the combined effects of subsequent chemotherapy . In thisBased on available evidence it is generally accepted that the experience and technical expertise of a surgeon are important prognostic factors. Comparisons of overall survival in patients treated by gynecological oncology, gynecologists and general surgeons have shown that patients treated by surgeons trained in gynecology  have a significantly better prognosis ,58. ThisSurgical treatment of advanced ovarian cancer is one of the most demanding procedures in gynecological surgery. Despite repeated requests to restrict surgery to experienced surgeons, considerable numbers of patients are still operated by others. A population based study from Germany showed that omentectomies were performed in about 50% of all cases of ovarian cancer and lymphadenectomy were carried out only in 30% . AnotherThe situation with regard to specialism depends strongly on the medical infrastructure, and varies from country to country and region to region. However, the problem of inadequate primary surgery is real, and coping with it is a frequent task in specialist centers even in developed countries. The question is what should be done for the patient concerned? Interestingly, this is something that cannot be found in textbooks ,69,70. SIn general, one of two situations occurs. First patients present with no evidence of macroscopic tumor residuals but staging procedures and/or operative measures were omitted. Computed tomography (CT) or Magnetic resonance imaging (MRI) to identify enlarged lymph nodes or possible residual tumors in these situations may help to decide on the need for second surgery. The belief that tumor cells in retroperitoneal lymph nodes are better able to survive chemotherapy is supported by low cytotoxic drug concentrations in these . TherefoPatients with residual tumor mass have to be evaluated to determine if it is possible to achieve no residual tumor or microscopic residual tumor by immediate secondary surgery. Although immediate laparotomy seems to be a good idea, the limited capacity for surgery at specialist departments and delays in having the surgery are to be considered. The peritoneum shows inflammation shortly after surgery reaching a high about 7 to 14 days afterwards . SurgeryDisease spread >2 cm to the spleen, diaphragm, liver surface, mesentery, or gallbladder is generally believed to be inoperable. However, even these patients may often undergo effective debulking procedures ,77. As mAn analysis of several retrospective studies on neoadjuvant chemotherapy showed that there are no good reasons to assume that this approach is associated with a poorer prognosis . The EurInterval debulking, is another approach to reduce tumor burden between the cycles of chemotherapy. It has been evaluated in two prospective randomized trials ,81. The Although there seem to be only minor differences in the design of both trials, a closer look shows that in the GOG-152 study, the number of stage IV patients was lower (6%) compared with the EORTC (21%) study, the performance status was better, and there was less residual tumor. This was due to the eligibility criteria for GOG 152 which stated that patients should have had surgery with maximal effort to resect the uterus, tubes, ovaries, omentum, and all gross residual ovarian cancer at the time of primary surgery.The questions about the benefit of interval debulking surgery remain unresolved. However, it appears that patients who have had neoadjuvant chemotherapy or suboptimal debulking may profit from this treatment, while those who have undergone primary, maximum effort surgery by a gynecological oncologist are less likely to profit from it .Size of the residual tumor, volume of the residual disease and experience of the surgeon are important prognostic factors ,77. AmonAs mentioned above, the frequently used definition of <2 cm for optimal debulking is arbitrary since every further reduction in the size of residual tumor improves the prognosis . Thus, eIt is difficult to assess the future role of surgery in advanced ovarian cancer. Neoadjuvant chemotherapy may become more important. However, as the tumor debulking surgery works, except in stage IV patients with solid distant metastasis, it may be worth trying combined ultrasound-guided laser interstitial thermotherapy for non-resectable liver metastasis with conventional debulking surgery . Apart fNumerous studies have analyzed the effects of various kind of chemotherapy in ovarian cancer. In contrast, only a few prospective randomized studies have focused on surgical issues in this type of tumor ,80,81. TIn future, we must aim to ensure that all patients are treated along the generally accepted guidelines and receive optimal debulking surgery which leaves only microscopically detectable residual tumor as shown in number of studies; it is certainly unethical at present to evaluate this procedure in randomized clinical trials (see Introduction). Other then this, there are many other relevant issues which need to be resolved or clarified with special reference to neoadjuvant chemotherapy, interval debulking, the surgeon's training, and inadequate primary treatment. It would certainly be very helpful to demonstrate clearly the consequences of what is supposed to be an inadequate treatment.The simple dichotomization of FIGO stages to early or late does not correspond to any diagnostic, biological or therapeutic advantage. We believe that it is far more reasonable to consider stage I alone as early disease (perhaps even only stage Ia and b), stages II and III  as intermediate disease, and stage IV with organ metastasis as advanced disease. Such a classification would follow current views on treatment, since early ovarian carcinomas are treated primarily by surgery  and adjuvant chemotherapy in cases of increased risk, intermediate ones by surgery and routine chemotherapy, and advanced disease by chemotherapy only. Thus far, results of studies on stage IV patients with organ metastases are inconsistent regarding the benefit of surgery. This is another issue to be resolved . In thisDisappointingly, the Tumor-Nodes-Metastasis (TNM) classification follows the FIGO system and violates its own principles by not accepting distant peritoneal metastasis as a natural indicator of primary tumor size but also by summarizing a nodal-positive disease stage as T3c (corresponding to FIGO IIIC) regardless of intra-abdominal findings. This inconsistency has already created curious confusions in current research. Nodal involvement has been shown to impair prognosis, however, smaller intra-abdominal tumors with nodal involvement  show a significantly better prognosis than extensive intra-abdominal tumor masses (again stage IIIC) .Furthermore, residual disease should be properly defined. The most rational approach is to regard microscopic residuals as optimal. Case series claim that experienced gynecologic-oncologic surgeons can clear up to 85% of patients in the unfavorable subgroups (FIGO stage IIIc and IV) of all visible tumor, leading to an extraordinarily high five year survival rate of about 50% . As discIn summary, more attention need be paid to surgery for advanced ovarian cancer. These include necessary improvements in treatment in the general population, uniform definitions and terminology, and increasing number of surgical clinical trials. Extrapolating from the results of truly optimal ovarian cancer surgery, we believe that improvements in surgery will lead to better patient survival than improvements in current chemotherapeutic approaches ,90,91.The authors declare that they have no competing interests.KM and FEF both participated equally in literature search, conceptualization and preparation of the manuscript. Both authors have read the manuscript and approve it for publication.