Accurate assessment of suicidality is of major importance in both clinical and research settings. The Scale for Suicidal Ideation (SSI) is a well-established clinician-rating scale but its suitability to adolescents has not been studied. The aim of this study was to evaluate the reliability and validity, and to test an appropriate cutoff threshold for the SSI in a depressed adolescent outpatient population and controls.218 adolescent psychiatric outpatient clinic patients suffering from depressive disorders and 200 age- and sex-matched school-attending controls were evaluated by the SSI for presence and severity of suicidal ideation. Internal consistency, discriminative-, concurrent-, and construct validity as well as the screening properties of the SSI were evaluated.Cronbach's α for the whole SSI was 0.95. The SSI total score differentiated patients and controls, and increased statistically significantly in classes with increasing severity of suicidality derived from the suicidality items of the K-SADS-PL diagnostic interview. Varimax-rotated principal component analysis of the SSI items yielded three theoretically coherent factors suggesting construct validity. Area under the receiver operating characteristic (ROC) curve was 0.84 for the whole sample and 0.80 for the patient sample. The optimal cutoff threshold for the SSI total score was 3/4 yielding sensitivity of 75% and specificity of 88.9% in this population.SSI appears to be a reliable and a valid measure of suicidal ideation for depressed adolescents. Accurate assessment of suicidality is of major importance in both clinical and research settings. Adolescent suicide occurs usually in the context of an active, often treatable, but unrecognized or untreated mental illness -3. The iSuicide attempts are complex acts for which no single set of clinical features can be expected to be a good predictor . SuicidaThe Scale for Suicidal Ideation (SSI)  was desiThe psychometric properties of the SSI have been evaluated in adult population and in inpatient children. Both in a sample of adult psychiatric inpatients and in a sample of inpatient children the internal consistency of the scale was good ,13. SSI The predictive validity of the SSI has been studied in a sample of hospitalised patients, where the SSI scores of those who committed suicide were not significantly higher than the scores of inpatients that did not . In a saSome instruments have evolved from the SSI, for example the Modified scale for suicidal ideation (MSSI)  that wasThe SSI has been used widely in adult psychiatric populations e.g. ,21], but, but21]]The study population consisted of two samples; a psychiatric outpatient sample of 218, and an age- and sex-matched control sample of 200 school-attending adolescents. The outpatients suffered from depressive mood disorder, were of ages 13 through 19, and took part in the Adolescent Depression Study (ADS). They were recruited between 1.2.1998 and 31.12.2001 from a consecutive sample of patients attending the outpatient clinics of the Department of Adolescent Psychiatry of Peijas Medical Health Care District covering approximately 210,000 inhabitants and comprising the cities of Vantaa and Kerava in the Helsinki metropolitan area, southern Finland.Of the eligible  660 outpatients, 624 (94.5%) were screened during their first consultation visit by the Beck Depression Inventory (BDI)  and the The control sample was drawn from the enrollment lists in four schools in the corresponding geographical area. It was a random sample of age- and sex-matched students equating the distribution of the educational level of the outpatients.1) The Scale for Suicide Ideation (SSI) is a clinician-rating scale and is presented in a semi-structured interview format . It cons2) The Schedule for Affective Disorders and Schizophrenia for School-Aged Children-Present and Lifetime (K-SADS-PL)  is a widThe K-SADS-PL is considered internationally reliable and valid diagnostic instrument for adolescent population . It has 3) Clinical suicidality assessment (CSA): A three-point mutually exclusive grouping of suicidality  is a simplified version of the 5-item "Spectrum of Suicidal Behavior Scale" . It has After a description of the study, a written informed consent was obtained from the subjects. For subjects less than 18 years consent was also asked from the parents or other legal guardians. For the community sample the K-SADS-PL and the SSI were performed at the same day by an expert clinician. For the outpatient sample the K-SADS-PL was performed within variable time from the SSI rating. The CSA was performed for the patient sample by clinicians during the beginning of the treatment.Central tendencies of some data were reported using medians and quartiles because of non-normal distribution. Mann-Whitney U test was used to assess the significance of differences between the two samples.Internal consistency of the SSI was evaluated by calculation of Cronbach's α for the whole scale.Concurrent validity of the instrument was examined by comparing it with the K-SADS-PL with the CSA classifications. SSI total scores were first assessed in 5 classes of increasing suicidality derived from the K-SADS-PL responses in the following way: 1-no suicidal ideation or acts, 2-mild suicidal ideation (score 2 on item-1), 3-severe suicidal ideation (score 3 on item-1), 4-mild suicidal acts (score 2 on any of items 2–4 regardless of ideation), 5-severe suicidal acts (score of 3 on any of items 2–4 regardless of ideation).Then the SSI total scores were measured in 3 classes of increasing suicidal ideation severity, regardless of possible suicidal acts, derived from the K-SADS-PL responses on item 1: 1-no ideation, 2-mild ideation, and 3-severe ideation. Severe ideation (score 3) in this item was considered as "clinically significant suicidal ideation".Finally the SSI total score was assessed in the three classes of the CSA: 1-no suicidality, 2-suicidal ideation, 3-suicidal or self-harming acts.The statistical significance of the between-class differences was evaluated by Kruskal-Wallis test. For the analyses of concurrent validity only SSI-measurements in a range of 30 days from the K-SADS-PL and the CSA were included.Construct validity was measured by performing a principal component analysis (PCA) with varimax rotation in the outpatient sample. The internal consistencies (Cronbach's α) of the extracted components as well as the originally reported factors  were calROC-analysis was performed to evaluate the screening properties of the SSI, and the cutoff threshold for the instrument was defined by optimal trade-off between sensitivity and specificity (Youden's index ). The K-SPSS 11.0  was used for the statistical analysis.Eighteen percent (n = 40) of the outpatient sample were boys and 82% (n = 178) girls, in the community sample the percentages were 18.6% (n = 37) and 81.4% (n = 162), respectively. The subjects' mean age was 16.4 (SD 1.6) in the outpatient sample and 16.5 (SD 1.6) in the community sample. The median SSI total score for the patient sample was 0 (Q1–3 = 0–6) and for the community sample 0 (Q1–3 = 0-0) . The median SSI total score for subjects aged 13–15 was 0 (Q1–3 = 0–1) and those aged 16–19 0 (Q1–3 = 0–1) . The median time distance between SSI and K-SADS-PL was 21.5 days (Q1–3 = 9–36) for the patient sample and 0 days (Q1–3 = 0-0) for the control sample . The median time distance between SSI and the CSA was 6 days (range 0–35).Forty-seven (21.6%) outpatients and one  control subject had current clinically significant suicidal ideation (p = 0.000) according to the K-SADS-PL.Cronbach's α was 0.95 for the whole sample, 0.81 for the community sample and 0.95 for the outpatient sample.146 (67%) of the outpatients and 199 (99.5%) of the controls were included in the analyses for concurrent validity, as their measurements were within the required range of 30 days.2 = 111.6, df 4, p = 0.000).The median SSI sum scores in the five suicidality classes derived from the K-SADS-PL were class-1 = 0 (Q1–3 = 0-0); class-2 = 5.5 (Q1–3 = 0–8); class-3 = 13 (Q1–3 = 0–18.5); class-4 = 4 (Q1–3 = 0–17.3); class-5 = 8 (Q1–3 = 0–13). The differences were significant .The median SSI sum scores in the three classes of suicidal ideation derived from the K-SADS-PL were class-1 = 0 (Q1–3 = 0-0); class-2 = 4 (Q1–3 = 0–8); class-3 = 13 (Q1–3 = 4–18). The differences were significant .The median SSI sum scores in the three clinical suicidality evaluation classes (only the outpatient sample) were class-1 = 0 (Q1–3 = 0–1); class-2 = 10 (Q1–3 = 5–18); and class.3 = 15 (Q1–3 = 13.3–16.6). The differences were significant  and the sample of patients was large compared to earlier similar studies in adult populations, and probably representative of adolescent psychiatric outpatients with depressive disorders. The main finding was that the SSI appeared to be a reliable and valid instrument for evaluation of suicidal ideation in a depressed adolescent population. Its internal consistency and different aspects of validity were good and similar to what has been reported among adults.The construct validity of the SSI was checked by Principal Component Analysis, which yielded 3 theoretically meaningful and coherent factors, only slightly different from the original ones, with good internal consistencies. This suggests good construct validity. The first factor  was nearly identical to Beck's original one . The secThe SSI converged theoretically meaningfully with both the three-class K-SADS-PL suicidal ideation-item and the clinical suicidality assessment (CSA); growing SSI scores were found within categories with increasing severity of suicidality. As to the convergence with the 5-class K-SADS-PL suicidality instrument, the results were more complex. The Kruskal-Wallis test yielded significant differences between the SSI scores in the different categories as expected, but the SSI-scores in the K-SADS-PL classes 4 and 5, with the supposedly most severe suicidality were not higher than in class 3. Classes 4 and 5 inquire about suicidal acts, and may represent a partly separate domain from suicidal ideation, which may be related to the presence of comorbid personality traits or conduct disorders. The SSI was designed to tap suicidal ideation and it may not satisfactorily tap features related with suicidal acts. In accordance with the theory of multidimensional nature of suicidality , severe The authors are not aware of previous empirical estimations of clinically relevant cutoff for the SSI in adolescents. In this study ROC analysis of the whole sample yielded a reasonable result, but the validity coefficients for the different cutoffs of the SSI were somewhat difficult to interpret. In the community sample, there was only one subject with K-SADS-PL-diagnosed clinically significant suicidal ideation, which may have biased the analyses made with the whole sample. The results for both the whole sample and the patient sample suggest that a cutoff threshold score of four or more might be optimal for adolescents. Depending on the purpose the SSI is used, however, the emphasis between sensitivity and specificity may change, and a different threshold may be useful. For example, if the purpose is to detect the maximum number of potential suicides the cutoff threshold should be lowered to minimize the number of false negatives.Several methodological limitations should be noted, some suggesting caution in interpreting the findings. Inter-rater and test-retest reliabilities, which would have given a complete picture of the reliability of the SSI, could not be evaluated in our setting; they would have required repeated SSI measurements for each subject. However, the alpha-coefficients are a marker of internal consistency, which is one indicator of reliability.Although large and representative, the sample was a pure outpatient sample with age- and sex-matched controls, and females were over-represented. The absence of inpatients may have caused us to see the spectrum of suicidal ideation narrower than in real clinical situations. The sample was limited to an urban area in southern Finland, the generalizability of our findings to rural areas, or to other countries, is not known.The use of K-SADS-PL as a standard for clinically significant suicidal ideation and behavior may be criticized, as the authors are not aware of a data on its validity. It is used, however, as one of the best available standards in adolescent mood disorder diagnostics, and taps suicidality with 4 relevant items.The same rater rated the K-SADS-PL and the SSI, which is a weaker test of concurrent validity than correlating measures rated by separate raters.The SSI can safely be used to evaluate suicidal ideation in adolescents where it seems to perform as well as in adults, where it is considered to be well established. When screening clinically significant suicidality in adolescents, a total score threshold of 3/4 may be useful.Suicidal acts may occur among adolescents with only "mild" suicidal ideation. Thus, prevention of suicidal acts cannot rely solely on the SSI, which does not seem to tap them accurately. Furthermore, questionnaires should be only an adjunct to the clinical evaluation of suicidality.SSI appears to be a reliable and a valid measure of suicidal ideation at depressed adolescents, with a cutoff threshold value of four or more of total SSI score being an appropriate for detecting significant suicidal ideation.The author(s) declare that they have no competing interests.MMH analyzed the data and wrote the paper. MP interviewed patients, participated in planning the study and analyses, and writing the paper. LK, TR, HH and VT participated in planning the study, interviewed patients, and commented on the manuscript. OK participated in planning the study and the analyses, and commented on the manuscript. MM supervised the study, interviewed patients and participated in planning of the study and analyses, and writing the paper. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


The mammalian retina is a valuable model system to study neuronal biology in health and disease. To obtain insight into intrinsic processes of the retina, great efforts are directed towards the identification and characterization of transcripts with functional relevance to this tissue.With the goal to assemble a first genome-wide reference transcriptome of the adult mammalian retina, referred to as the retinome, we have extracted 13,037 non-redundant annotated genes from nearly 500,000 published datasets on redundant retina/retinal pigment epithelium (RPE) transcripts. The data were generated from 27 independent studies employing a wide range of molecular and biocomputational approaches. Comparison to known retina-/RPE-specific pathways and established retinal gene networks suggest that the reference retinome may represent up to 90% of the retinal transcripts. We show that the distribution of retinal genes along the chromosomes is not random but exhibits a higher order organization closely following the previously observed clustering of genes with increased expression.The genome wide retinome map offers a rational basis for selecting suggestive candidate genes for hereditary as well as complex retinal diseases facilitating elaborate studies into normal and pathological pathways. To make this unique resource freely available we have built a database providing a query interface to the reference retinome . The mammalian retina is a highly structured tissue developmentally originating from neuroectodermal evagination of the diencephalon and subsequent invagination processes resulting in the formation of two cellular layers which ultimately give rise to the inner neural retina and the outer retinal pigment epithelium (RPE) monolayer . In the Recent progress in retinal research has greatly enhanced our current understanding of basic functional processes in the adult retina e.g. ,5). A gr. A gr5])Despite these advances, a remaining challenge is to obtain a reference genome-wide expression map of the retina/RPE transcriptome, further facilitating the identification of retinal susceptibility genes, but most importantly, offering an invaluable resource for functional genomics studies. Initial analyses of human ,10 and mIn recent years, a number of approaches and technologies were adopted to identify genes expressed in the retina/RPE of human, cow, dog and mouse including data-mining and assembly of publically available expressed sequence tag (EST) information -23, sequBased on a comprehensive survey of data available from 27 independent studies applying a wide spectrum of gene identification approaches we have now assembled a first genome-wide reference transcriptome of the adult mammalian retina/RPE. This reference transcriptome comprises 13,037 non-redundant transcripts and likely reflects up to 90% of the mammalian retinome.A total of 481,137 primary datasets on gene transcripts from the adult mammalian retina/RPE tissues have been generated in 27 independent studies  to be specifically expressed in the retina/RPE  , liver  and prostate . A total of 2,330 genes are expressed in all tissues and represent putative "housekeeping" genes  versus the number of human non-redundant syntenic gene predictions (SGPs)   along 61RP29 locus contains 28 SGPs of which 5 are present in the reference retinome including GPM6A, WDR17, FLJ22649, VEGFC, AGA). The number of possible candidates is further reduced in the "retinome-enriched" transcript category to GPM6A and VEGFC. To make the information on the reference retinome available, we have created the interactive RetinaCentral database, a research portal which collects and stores information on genes and proteins functionally relevant to the retinal tissues [To provide positional candidates for syndromic and non-syndromic hereditary retinopathies, the 13K reference retinome as well as the "retinome-enriched" transcripts  were superimposed onto the disease intervals of 42 thus far uncloned retinal disorders  not included in the 13K retinome. Similarly, an additional three genes  involved in the vitamin A/phototransduction pathway are part of the 15K but not the 13K retinome. With additional transcription data on the retina/RPE becoming available, a second generation retinome map will need to address this issue.The present meta-analysis has integrated information from 27 studies employing diverse technologies to identify retinal/RPE transcrips. Among these, SAGE represents a sensitive tool to detect low level transcription  while thThe estimation of transcriptome size represents one of the fundamental questions in molecular biology. Early studies using reassociation kinetics have calculated the number of distinct mRNA transcripts present in various mouse tissues to be between 11,500 and 12,500 . Initialany of the partial transcriptomes revealed overlapping gene profiles between 92 % and 95 %. This would suggest that only a minor proportion of retinome transcripts is indeed unique to the retina/RPE. Thus far, we have identified a group of so called "retinome-enriched" genes comprising 5,051 transcripts which are not present in the partial transcriptomes of heart, liver and prostate. This group most likely contains additional "housekeeping" or tissue-restricted transcripts and needs further adjustment by more refined in-silico normalization to comprehensive reference transcriptomes of other tissues.Another point of interest concerns the proportion of retinome transcripts which is uniquely expressed in this tissue. Brentani et al.  estimateHighly expressed genes including those with a ubiquitous or a tissue-specific transcription profile, have been shown to cluster in chromosomal regions of increased gene expression (termed RIDGEs) ,56. FuncRP28 or VRNI, we have similarly integrated the "retinome-enriched" transcripts. This also accommodates for the fact that approximately 50% of retinal disease genes are retina/RPE-specific [AIED, COD4, CORD8, CRV, LCA5, RP28, and USH2B, the number of candidates may still exceed capacities of most laboratories for direct analysis. For other disease loci , a restricted number of candidates are now available  sources  were retrieved (as of December 2003) and chromosomally mapped to the reference sequence of the human genome (July 2003) utilizing the USCS Genome Table Browser . Based oCORD1, CORD4 and RCD1) are insufficiently mapped on the respective human chromosomes and were therefore not included in the analysis.Mapped loci of retinal dystrophies with unknown genetic basis (n = 45) were taken from RetNet, January 2004  and placTo determine if either of the two datasets, the 43,109 human non-redundant SGPs and the 13K retinome transcripts, is distributed in a non-parametric and distribution free manner over the genome, the Kolmogorov-Smirnov Goodness-of-Fit Test was used . StatistHLS participated in the design of the study, collected and processed the information from the published reports related to the retina and RPE genes. TG conceptually developed the RetinaCentral database and is involved in the curation of the site. JK carried out the statistical analyses and helped with the computational handling of data. BHFW was involved in all aspects of data assembly and prepared the manuscript. All authors read and approved the final manuscript.Retina/RPE genes reported only in a single study List of genes expressed in the retina or RPE reported only in one studyClick here for fileGene list of the reference retina / RPE transcriptome List of 13,037 genes expressed in the retina/RPEClick here for fileList of genes identified exclusively in retina studiesClick here for fileList of genes identified exclusively in RPE studiesClick here for filePartial list of genes known to be expressed specifically in the retina and/or RPEClick here for filePartial list of genes known to be involved in the vitamin A cycle and phototranduction pathwayClick here for filePartial list of genes known to encode retina / RPE proteinsClick here for fileList of known genes involved in retinal diseasesClick here for filePartial gene list of the heart transcriptomeClick here for filePartial gene list of the liver transcriptomeClick here for filePartial gene list of the prostate transcriptomeClick here for fileList of genes present in the reference retinome and partial transcriptomes of heart, liver, prostateClick here for fileList of genes present in partial transcriptomes of heart, liver, and prostate but not in reference retinomeClick here for fileList of retinome transcripts mapping to retinal disease intervals.Click here for fileData sources used to compile the retina / RPE transcriptomeClick here for fileData sources used to compile partial transcriptomes of heart, liver, and prostateClick here for file


To evaluate the validity (study 1) and the reproducibility (study 2) of an interviewer-administered food frequency questionnaire (FFQ).Study 1: The FFQ was compared against a 3-day food record (2 week-days and 1 weekend-day), at week 0, 6 and 12 of a nutritional intervention. Study 2: In order to evaluate the reproducibility of the FFQ, 2 registered dietitians administered the FFQ 4-weeks apart among subjects who were not part of the nutritional intervention.The FFQ was designed at Laval University and contains 91 items and 33 subquestions. Study 1: Mean values for intake of most nutrients assessed by the FFQ and by the 3-day food record were not statistically different. Energy-adjusted correlation coefficients for major macronutrients ranged from 0.36 for proteins to 0.60 for carbohydrates (p ≤ 0.01). Agreement analysis revealed that on average, 35% of the subjects were classified in the same quartile when nutrients were assessed by either the 3-day food record or the FFQ. Study 2: Significant associations were observed between dietary measurements derived from the two FFQs administered 4 weeks apart. Correlation coefficients for the reproducibility of macronutrients ranged from 0.66 for carbohydrates to 0.83 for lipids after energy adjustment. On average, 46% of the subjects were classified in the same quartile when nutrient intakes were assessed by either FFQ.These data indicated that the FFQ developed has a good validity and is reproducible. There is increasing evidence that nutrients may be important in the development of chronic diseases such as coronary heart disease (CHD) and type 2 diabetes. In the late 60s, the Mediterranean diet became a topic of interest primarily because of results of the Seven Countries Study, which demonstrated that the 15-y mortality rate from CHD in Southern Europe, was two to threefold lower than in Northern Europe or United States . ReliablAccurate assessment of dietary intakes, when based on self-report in free-living populations poses significant scientific challenges. All standard dietary assessment methods including food records, dietary recalls and list-type methods such as food frequency questionnaires (FFQ), are subjected to considerable error and bias, and none of these can be considered as a 'gold standard' measure . FFQ hasIn Québec, no validated FFQ was adapted for the needs of our nutritional intervention design. In fact, in the context of our nutritional intervention we wanted to use a FFQ to evaluate a Mediterranean food pattern in a North-American context that would contain foods available in Québec and also foods characteristic of the Mediterranean diet. In order to improve the precision in quantifying reported intakes we decided to use and interviewer-administered FFQ to facilitate the determination of portion size using food models. Thus, we decided to design an interviewer-administered FFQ to assess the dietary changes among a French-Canadian population in a nutritional intervention promoting the Mediterranean food pattern. The first purpose of the present study was therefore to test the validity of this interviewer-administered FFQ. In order to reach this objective, nutrient intakes derived from the FFQ were compared to intakes obtained by the 3-day food record. Comparisons were performed for baseline as well as for post-intervention values. This allowed us to determine whether our FFQ would permit to identify similar changes in nutrient intake in response to the intervention as the ones measured by the 3-day food record. As a second objective, we also wanted to estimate the short-term reproducibility of this FFQ in a control group who did not receive the nutritional intervention.This paper reports results of two studies: 1) a study on validity of the FFQ tested against a 3-day food record during a nutritional intervention program promoting the Mediterranean food pattern and 2) a study on reproducibility of the FFQ in a control population.For the validation study, women from the Québec City metropolitan area were recruited through the Laval University newspaper during the summer of 2001. Women included in the study were aged between 30 to 65 years . To be eFor the reproducibility study, 20 men and 19 women from the Québec City metropolitan area were also recruited through the Laval University newspaper during the summer of 2002. Men and women included in the study were aged between 25 to 70 years. Three men and 4 women did not complete the second FFQ for personal reasons. Therefore, 17 men and 15 women were included for the reproducibility analyses. The study was approved by the Ethics Committees of Laval University.The interviewer-administered FFQ developed inquired on the food habits during the last month and is based on typical food items, which are available in Québec. It contains 91 items among which 27 had between 1 and 3 subquestions. The FFQ was structured to reflect Quebecers' food habits and food items were listed in food groups . Because of the nature of our nutritional intervention, our FFQ was designed to make sure to document with enough details consumption of typical items of the Mediterranean diet such as type of oils, whole grain products and legumes. The 30-minutes FFQ was administered face-to-face by one of the 3 registered dietitians involved in the study. During the interview, the dietitians used food models for a better estimation of the real portion consumed by the subject. Participants were questioned about frequency of intake for different foods during the last month and were asked to report the frequency of these intakes in terms of day, week or month. The subquestions allowed a better definition of the food items consumed. For example, following the question "How often do you eat yogurt?" subjects were asked about the fat percentage and brand of the yogurt consumed. An open question at the end of the FFQ allowed individuals to report any other frequency eaten foods not listed in the FFQ and provide details about usual recipes used in order to quantify better intakes of individual food items.Estimates of basal metabolic rate (BMR) were calculated from the Harris-Benedict formulas based on height, weight, age and sex . Energy st, the 6th and 12th weeks of the intervention in order to evaluate the changes and to select further objectives for increasing the adherence to the Mediterranean food pattern. Three registered dietitians were trained to provide a standardized intervention.The methodology of the nutritional intervention has been described previously . BrieflyEach participant completed a 3-day food record, 2-week days and 1-weekend day, at week 0, 6 and 12. At screening of the nutritional intervention, a dietitian provided 15 minutes of instructions to each participant on how to complete the food records. Written copies of record examples were provided to each subject. Also, participants were encouraged to consume usual amounts of typical foods and drinks for the completion of the food record. Participants were not required to weight foods but were asked to measure the volume of foods consumed with household measurements  or to indicate the weight of commercial products when it was possible to assess portion sizes. The food record included a section for recording information recipes. After completing the food record, participants met with the dietitian to review all the information for record accuracy and completeness and portion size of individual items on the food record were reviewed when needed by using food models.At weeks 0, 6 and 12, body weight and height were measured according to the procedures recommended at the Airlie Conference on the Standardization of anthropometric measurements  and bodyThe 32 participants of the reproducibility study were distributed into two groups. In the first group, dietitian #1 administered the FFQ and 4 weeks later dietitian #2 administered the FFQ for the second time. Inversely, in the second group of participants, dietitian #2 administered the first FFQ and 4 weeks later dietitian #1 administered the FFQ for the second time. An interval of one month was chosen to reduce any training effect and memory influence of the method. Both dietitians were taught to use the FFQ similarly, using the same examples of portion size, and asking similar questions.At the first visit, body weight and height were measured according to standard procedures  and BMI Evaluation of nutrient intakes derived from the FFQs and food records was performed using the Nutrition Data System for Research (NDS-R) software version 4.03, developed by the Nutrition Coordination Center, University of Minnesota, Minneapolis, MN, Food and Nutrient Database 31, released in November 2000 . This daIn the validation study, means and standard deviations for nutrient intakes were calculated from the FFQs and from the food records. Student t-tests were performed to determine the differences between nutrient intakes assessed by the FFQ and by the 3-day dietary record. Since many variables were not normally distributed, Spearman correlations were used to put into relationship nutrient intakes from FFQ with those from the food record. Student t-tests were also performed to determine the differences between changes in nutrient intakes in response to the nutritional intervention assessed by the FFQ and by the 3-day dietary record. Agreement analyses were performed to verify the concordance of different nutritional variables among quartiles of the distribution between FFQ and the 3-day food record. In the reproducibility study, Student t test was performed to assess the differences between both FFQs. Spearman correlations were used to put into relationship the nutrients reported in the first and the second FFQ. Agreement analyses were assessed to verify the degree of concordance in classifying subjects among quartiles of the distribution between both FFQs. For both studies, the dietary variables were log transformed when necessary to achieve a normal distribution, and the formula log(x + 1) was used for alcohol because some subjects had a value of 0 g for alcohol intake. In addition, to make the comparisons based on absolute nutrient intakes, correlations were also made using energy-adjusted variables. Adjustment for total energy intake was achieved by using the residual method proposed by Willett and Stampfer . Residua2 and a mean age of 46.8 ± 7.9 y. Average daily nutrient intakes derived from FFQ and the 3-day food records are shown in Table Women had a mean BMI of 25.8 ± 3.9 kg/mSpearman correlations between values of nutrient intakes measured by the 3-day food record and those assessed by the FFQ at week 0 of the nutritional intervention are shown in Table Table st tertile) and from 27.8% for CHO to 55.6% for alcohol for the highest intakes (4th tertile). When considering all nutrients studied, it was found that, on average, 35.1% of subjects were categorized exactly in the same quartile by the FFQ and by the 3-day food record and 5.1% of the subjects were misclassified in extreme quartiles i.e. subject in the first quartile according to one method and in the fourth quartile according to the other (not shown).Agreement between quartile classification of FFQ and 3-day food record is show in Table 2 for women and 27.6 ± 5.1 kg/m2 for men. The mean age was 42.5 ± 10.4 y for women and 41.2 ± 11.9 y for men.The 32 subjects in study 2 had a mean BMI of 23.9 ± 3.6 kg/mst FFQ) showed similar variation in nutrients intakes between FFQ1 and FFQ2 than subjects from the 2nd group (in which dietitian #2 administered the first FFQ).Table st FFQ. In addition, similar correlations were observed when analyses were computed within each gender separately (not shown).Table st quartile) and from 37.5% for SFA and MUFA to 75.0% for energy, proteins, CHO and alcohol for the highest intakes (4th quartile). When considering all the nutrients studied, it was found that on average, 45.7% of subjects were categorized exactly in the same quartile by both FFQs and 2.6% of the subjects were misclassified in extreme quartile (not shown).Table Accurate assessment of dietary intakes and dietary changes plays a central role in nutritional studies. Each tool used to evaluate dietary intakes has some strengths and limitations. Also, all standard dietary assessment methods are subjected to bias such as underreporting . In our In the validation study, coefficients of correlation between values derived from the FFQ and those obtained by the 3-day food record ranged from 0.30 to 0.60 for macronutrients and from 0.19 to 0.56 for micronutrients at week 0. It has been previously reported that correlation coefficients for validation studies ranged from 0.4 to 0.7, similar to our results after energy adjustment . Also, oDespite the fact that we obtained similar values for energy intake with both dietary methods, we can not exclude the possibility that both tools are subjected to underreporting and therefore underestimate usual dietary intakes. It has been previously suggested that subjects may tend to underreport actual food intake by as much as 20% when completing a weighted dietary record . It has In a nutritional intervention, interpretation of the study outcomes with regard to dietary changes will depend not only of the validity and the reproducibility of the method used but also of the sensibility of the method to detect dietary changes in response to the intervention. In our nutritional intervention study, conducted in a sample of healthy women, both diet assessment methods detected similar dietary changes over the duration of the intervention. These findings suggested that our FFQ is sensitive to dietary changes in response to our intervention and could be used to assess dietary changes during a nutritional intervention. Our results are in agreement with study that showed that in response to a nutritional intervention a FFQ measured similar dietary changes as compared to 24-hour recalls  or 4-dayThe major differences between the two methods in our study were noted for total lipids and MUFA intakes. Our FFQ was designed to assess precisely lipid intake and many questions were asked about types of fat used to spread or to cook. The more important differences between FFQ and 3-day food record for MUFA and lipids could therefore be explained by the fact that it was difficult for participants to report precisely their lipid consumption when completing the FFQ. It has also been reported in obese men that underreporting of food record is usually specific to lipid intake  and it iThe agreement in quartile classification was acceptable for selected nutrients with a mean of 35.1% of subjects who were in exact agreement and 5.1% who were misclassified in extreme quartiles. This finding is similar to previous observations ,19,32,33When analyses were performed at week 6 and 12 after the beginning of the nutritional intervention, coefficients of correlation were slightly higher than at week 0. We suggest that this finding be partly explained by the intervention effect. As previously reported  subjectsIn a nutritional intervention, it is important to use a reproducible method to insure that dietary changes observed are due to the intervention effects and not to the instrument error. Our study suggests that the FFQ presents a good degree of reproducibility. In fact, in reproducibility studies the coefficients of correlation generally ranged from 0.5 to 0.7 . In our In our reproducibility study, lower mean energy intake and nutrient intakes were found at the second administration of the FFQ as compared to the first FFQ (difference of approximately 10%). However, relatively high and uniform correlation coefficients for values derived from the two FFQs were observed. Riley et al  also repIn conclusion, the FFQ that we developed to estimate usual average daily energy and nutrient intakes in subjects from the Québec City metropolitan area is valid and reproducible. Mean energy and nutrient intakes were estimated accurately by our FFQ compared to the 3-day food record. The fact that our FFQ was administered by a dietitian trained to insure a standardized administration of FFQ was important to optimize the validity and reproducibility of the method. We also showed that both methods appeared to underestimate energy intake in a large proportion of subjects. Usually, food records are considered as the gold standard method to assess dietary intakes. It is however important to recognize that food records also have their own limitations. In nutritional studies, an interviewer-administered FFQ, as the one we used in the present study, can be used to assess energy and nutrient intakes and requires less time to compute dietary informations than food records. FFQ also decreases the possibility of interpretation by the coding person. Finally, there is still a need to develop other efficient methods to measure dietary intakes that will permit to more closely match habitual dietary intakes of individuals in their living environment.CHD: coronary heart diseaseFFQ: Food Frequency QuestionnaireBMR: basal metabolic rate (BMR)BMI: body mass indexNDS-R: Nutrition Data System for ResearchCHO: carbohydratesSFA: saturated fatty acidsMUFA: monounsaturated fatty acidsPUFA: polyunsaturated fatty acidsEPA: eicosapentaenoic acidDHA: docosahexaenoic acidNone declared.JG participated to data collection, performed data analysis and drafted the manuscript. GN and AL participated to data collection. BL and SL conceived the study, and participated in its design and coordination. All authors read and approved the final version of the manuscript.


Trachoma accounts for 15% of blindness worldwide, affecting the world's poorest communities. How can the disease be controlled? Trachoma is almost exclusively a disease of poor families and communities living in developing countries. It accounts for 15% of blindness worldwide—around 6 million people .,12.11,12Herbert's pits  and Arlt's line  are two other classical features of the disease.WHO currently recommends the “SAFE” strategy for the management of trachoma: Surgery for trichiasis, Antibiotics for active disease, Facial hygiene, Environmental improvement to reduce the transmission of the disease ,14,15.People with trachomatous trichiasis are at risk of blindness, and so treating these people is the first priority for the SAFE strategy. An evidence-based review of the SAFE strategy found that trichiasis surgery can alleviate discomfort and improve vision, though the evidence is less clear on whether such surgery prevents corneal opacification . The revThere are different types of surgical procedures to correct trachomatous trichiasis . Their hIn addition to recurrence, there are other problems with the surgical approach to managing trachoma. It cannot correct all the complications, such as dry eyes. Even more important, and the main obstacle to preventing blindness from trachoma, is the low rate of uptake of surgery by communities with trachomatous trichiasis . BarrierOffering surgery at the community level, rather than in distant medical facilities, is one strategy that could reduce travel times and costs and increase uptake. A cluster randomized controlled trial of village-based surgery versus health-center-based surgery in Gambia found a significantly higher uptake rate with the village-based service .The use of antibiotics aims to treat active infection and eliminate the reservoir. WHO currently recommends two regimens for the treatment of trachoma in endemic regions. These are 1% topical tetracycline ointment (twice daily for six weeks) or a single dose of oral azithromycin (1 g in adults and 20 mg/kg in children) [Although antibiotics are a cornerstone of the SAFE strategy, clinical trials of antibiotics versus control  have produced conflicting results and are difficult to pool because of their heterogeneity. A recent Cochrane systematic review concluded “there is some evidence that antibiotics reduce active trachoma but results are not consistent and cannot be pooled” . The revSeveral questions remain about the use of antibiotics, such as who should receive them and how often. Lietman and colleagues have developed a mathematical model of frequency of treatment that uses available epidemiological data from a variety of countries . Based oGood facial hygiene aims to reduce transmission, the risk of autoinfection in a community, and the risk of attracting flies ,15. ManyA Cochrane systematic review found evidence that face washing combined with topical tetracycline can be effective in reducing severe active trachoma . HoweverInterventions aimed at promoting facial hygiene have not yielded expected results in all settings, as behavioral change is not always readily achievable.This component of the SAFE strategy also aims to reduce transmission of trachoma by eliminating or reducing its risk factors, some of which are ubiquitous while others are specific to a region. Improving access to water is a key element. Other measures, such as provision of latrines to reduce the fly population, have also been found effective in reducing transmission . Such enAs mentioned previously, there is an important association between water and trachoma—though the association is not a simple one. The distance to the water source constrains the amount of water used for hygiene practices. Improving access to water on its own, however, may not be enough. In the case-control study in Gambia, families with trachoma used less water per person per day for washing children than families without the disease, regardless of the amount of water available . In otheTrachoma is a disease of poor, underprivileged, and socioeconomically disadvantaged communities. It affects people who have little or no say in public decision making . InvestiStill, there is some room for optimism, given WHO's vision of the global elimination of trachoma by the year 2020 and the efforts of the International Trachoma Initiative and other non-governmental organizations. The implementation of the SAFE strategy to eliminate blinding trachoma has already proven effective in several countries . Many coAlthough the new initiatives in trachoma control are encouraging, trachoma elimination programs clearly need to be extended to many more countries. In addition, there are three crucial steps that still need to be undertaken if blindness from trachoma is to be eliminated.www.wsscc.org) in trachoma control efforts. Similar partnerships need to be strengthened [First, there needs to be more emphasis on the “F” and “E” components of the SAFE strategy. Antibiotics and surgery alone will not eliminate trachoma; work also needs to be done to eliminate the risk factors and decrease the transmission of the disease in affected communities. Such primary prevention is more likely to have a sustainable impact but requires a prolonged effort and investment ,24. Becangthened . Socioecngthened .Second, research into different aspects of the disease should continue. Work on a vaccine for trachoma, although not successful thus far, should receive more attention . Future Third, awareness about the disease and the SAFE strategy need to be promoted globally. At the same time, local, cost-effective solutions to trachoma need to be encouraged. Provision of pit latrines to reduce fly populations is just one such measure .Unless these steps are taken, trachoma will continue to be a major cause of blindness in communities in the developing world .


The reduced number of hospital beds and an ageing population have resulted in growing demands for home nursing. We know very little about the comprehensive care of these patients. The objectives were to identify the care, in addition to primary health care, of patients with primary-care home nursing to give a comprehensive view of their care and to investigate how personal, social and functional factors influence the use of specialised medical care.One-third (158) of all patients receiving primary-care home nursing in an area were sampled, and 73 % (116) were included. Their care from October 1995 until October 1996 was investigated by sending questionnaires to district nurses and home-help providers and by collecting retrospective data from primary-care records and official statistics. We used non-parametric statistical methods, i.e. medians and minimum – maximum, χ2, and the Mann-Whitney test, since the data were not normally distributed. Conditional logistic regression was used to study whether personal, social or functional factors influenced the chance (expressed as odds ratio) that study patients had made visits to or had received inpatient care from specialised medical care during the study year.56 % of the patients had been hospitalised. 73 % had made outpatient visits to specialised medical care. The care took place at 14 different hospitals, and more than 22 specialities were involved, but local care predominated. Almost all patients visited doctors, usually in both primary and specialised medical care. Patients who saw doctors in specialised care had more help from all other categories of care. Patients who received help from their families made more visits to specialised medical care and patients with severe ADL dependence made fewer visits.The care of patients with primary-care home nursing is complex. Apart from home nursing, all patients also made outpatient visits to doctors, usually in both primary and specialised medical care. Many different caregivers and professions were involved. Reduced functional capacity decreased and help from family members increased the chance of having received outpatient specialised medical care. This raises questions concerning the medical care for patients with both medical and functional problems. This article describes the situation in a suburban area in Sweden, and concerns the comprehensive medical care of patients with primary-care home nursing, i.e. patients who require regular assistance from nurses in their homes in order to maintain their health and manage their health problems. This does not include hospital-at-home care, where a multiprofessional team is responsible for the medical care.The use of inpatient hospital care in Sweden as in many other Western countries has diminished in recent decades. In combination with an ageing population with greater needs for medical care, this has resulted in an increase in different forms of home care. The overall situation is similar in many countries, although local conditions may vary considerably -4.The shift of care from the hospital to the home "has had an enormous impact on care recipients, their families and friends, and in-home service providers."  and "is Much is known about the medical care, especially inpatient and outpatient hospital care of older persons, and that factors like age, health problems and socio-economic conditions influence the utilisation of inpatient hospital care ,7. HospiIn a previous paper  we have In view of the lack of knowledge in this expanding field, we considered it important to investigate and describe the comprehensive care of patients with home nursing as a starting point for further research and development.The objectives of the present paper are as follows:To identify the specialised medical care of patients who were receiving primary-care home nursing.To give a comprehensive view of the care of these patients.To investigate how personal, social and functional factors and help by relatives influenced the use of specialised medical care by these patients.The study was performed in a suburban area of Stockholm with 40 000 inhabitants, 18 percent of whom were 70 years of age or older. The care of patients, with primary-care home nursing, who lived in ordinary houses or flats was studied. Patients in the study area who received regular nursing care at home for a period of more than two weeks from the district nurses in primary health care were registered as primary-care home nursing patients  or outpatient departments in the city. Two emergency hospitals, two geriatric hospitals and two wards for psychiatric inpatient care were located in or close to the study area.During the registration week (21 to 27 October 1996), 486 patients in the study area had primary-care home nursing. Using a random table, we selected one-third of the patients of each district nurse for the study.The study was designed as a retrospective study of the comprehensive medical care of patients with primary-care home nursing, including the medical care they received both in their homes and in other places. It was also designed to study whether non medical factors that are common among patients with home nursing may have influenced the care. The data were not obtained from the patients, but from records and from the family physicians and district nurses responsible for the patients' primary health care, i.e. professionals dealing with the patients' medical problems. Data were also obtained from the official statistics of the Swedish County Councils, a source that is generally considered by researchers to be of high quality and well suited for scientific purposes. A description of the patients and the care performed by family physicians, district nurses and assistant nurses was given in a previous article .The hypotheses were- that care outside the home comprises a substantial part of the total care of patients with home nursing.- that personal, social and functional factors may influence the use of medical care outside the homeInformation concerning the situation during the registration week was obtained from questionnaires distributed the week following the registration week. Retrospective data from the study year (28 October 1995 to 27 October 1996) were obtained from the official statistics, and the family physician (21 family physicians) and nursing (20 district nurses) primary health care records.The official statistics were used to identify and describe inpatient care and outpatient visits in specialised medical care, and the number of home and practice visits to/by the nurses in primary health care. Notes in the family physician records were used to describe the family physician care  as well as the diagnoses of the patients . Notes iGroup 1 were either without functional deficiencies or dependent only regarding cleaning, shopping and/or transport, patient in Group 2 were, in additions, dependent with respect to cooking, bathing and/or dressing, but not eating, and patients in Group 3 were in addition dependent concerning eating. The factor mobility was excluded from the ADL groups, as this was assessed separately using data from other questions. The factors toileting and continence were excluded, as the answers were not consistent when compared with answers to questions concerning the same functions in other parts of the questionnaire.Personal, social and functional data concerning the situation during registration week, as well as patients' symptoms, and help from relatives at that time, were obtained from the questionnaires. When possible, validated questions that had been tested in other studies were used, but some were modified to suit the situation in home nursing. These revisions were made by the Stockholm Gerontology Research Centre in cooperation with a group of district nurses . PersonaSymptoms were registered in a 23-item protocol originally used in studies of nursing homes, but modified to suit the situation in home nursing. The questionnaires also included questions about how long the patient had had home nursing, and whether the patient had had contact with any private doctor in specialised medical care.The questions were thus chosen so that the district nurses responsible for the care could answer them without additional patients assessments, either because the information would be well known to them since they were responsible for the nursing care or because the answers were based on assessment tools used in the regular care, such as that used for ADL.Questionnaires sent to the home-help providers focused on whether the patient had home help Table .From the randomised one-third of selected patients (n = 158), we excluded 42, . Information about all patients from one district nurse was excluded (12 patients), since it was obvious that she had not understood the questions, leaving 116 patients (73%).Information could not be obtained from all sources for all patients. Visits to private doctors in specialised medical care and to private physiotherapists are not included, as they were not included in the official statistics. According to questionnaire responses from the district nurses, 11 patients saw private doctors in specialised medical care on a regular basis. We have no information about private physiotherapists.As the number of visits and care periods did not have a normal distribution, we used non-parametric statistical methods, i.e. medians and minimum – maximum. The Mann-Whitney test and χ2 were used to compare differences between groups. Conditional logistic regression was used to study whether personal, social or functional factors influenced the chance (expressed as odds ratio) that study patients had made visits to or had had inpatient specialised medical care during the study year. We used a case control design where patients with specialised care were cases and patients without this care were controls. The different factors were first tested by univariate logistic regression. The factors that showed significant influences were included in a multiple logistic regression model. One of these factors (home help) showed no significant influence when included in the model, and it was therefore excluded from the main effect model . The facThe study was approved by the Research Ethics Committee at Huddinge University Hospital. This approval included the design of the study as well as the way informed consent was obtained from the individual patients.Eighty-nine of the 116 study patients (77%) lived alone, 86 patients (74%) were women and 41 (35%) received substantial assistance from family members according to the district nurses. Sixty-eight patients (65%) had home help. Patients who lived alone were less likely to have assistance from family members than those who lived with a relative , but on the other hand they were more likely to have home help . Patients who got help from family members were less likely to have home help .More than half of the patients had been admitted to hospital during the study year Table . Among tThe median values for all study patients were one care period and four days in care. The average number of care periods and days in inpatient care in Stockholm for the persons 75 to 84 years of age, and 85 years of age or older, were 0.6 of a care period and five days in inpatient care and 0.8 of a care period and seven days in inpatient care, respectively .During the study year a majority of the patients made outpatient visits to hospitals and outpatient departments Table . In all,The median value for visits to doctors in specialised care for all study patients was one visit. The average numbers of outpatient visits to doctors outside primary health care (excluding doctors in private practice) in Stockholm for persons 75–84 years of age and 85 years of age or older were 1.7 and 0.8, respectively .In the 104 cases where a family physician record was found, a visit to either their family physician or a doctor in outpatient specialised care, or both, was found for 95 patients (91%) median 3 visits). Approximately one third (32 %) of the patients saw doctors from two or more specialities, GP care not included. Thirty-eight study patients (33%) had visited a physiotherapist or an occupational therapist . Of these, 141 visits (49%) took place in primary health care and comprised 23 (20%) of the study patients  as the participants but might have had more severe conditions, as patients who had died or were admitted to hospital during the registration week were excluded. These patients probably did not receive less medical care than those who were included. Information about a few patients was missing from some sources. All practices had roughly the same proportion of drop-outs and missing data, and the reasons can be considered to be random. The results should then be valid for all patients with primary-care home nursing, in the study area. As the patients are similar to those with home nursing described in other studies, this study may serve as a reference for further investigation of the care of patients with home nursing.These patients who had primary-care home nursing also had many instances of specialised inpatient and outpatient medical care. However, their care did not differ substantially from that of the average population of comparable age in Stockholm County during 1996 . This isThere was one group with significantly more medical care than the others, i.e. those patients who made outpatient visits to doctors in specialised care. The probable reason is that they had more severe medical conditions, but this is not possible to confirm in the present study.Inpatient care seemed to be strongly associated with more outpatient contacts in specialised care, but not with more contacts in primary health care. It is not possible to say whether this was the result of a greater need for specialised care, or the result of a tendency to keep the patients in specialised care .Patients with no visits from a family physician received neither more nor less medical or nursing care elsewhere. The rest of the care was apparently not influenced by the low priority this was given by the family physicians.The care of an individual patient often included several caregivers from different organisations. For the individual patient who meets many different persons and goes to many different places, this means a lack of continuity. For this group of elderly patients with complicated medical problems, reduced mobility, reduced cognitive ability and reduced ADL-capacity, the risk that the individual caregiver does not have the proper information when decisions are made must be extremely great, especially taking into account the problems involved in the exchange of information between primary care and specialised care . On an oIn Sweden, the share of health care expenditures allocated to primary health care is often low (12 – 21 %) compared to other parts of Western Europe, where it is frequently 20 percent or more . FurtherWe found that functional and social factors influenced the chance of a patient having made outpatient visits to specialised medical care. Severe ADL dependence reduced the chance and receiving help from family members increased the chance. The fact that patients with severe ADL dependence do not make many outpatient visits is not surprising as reduced function limits the possibility to get to locations outside the home. The findings that help from family members increased the chance of having made outpatient visits to specialised medical care is not surprising either, in view of the age and functional problems of the patients. Relatives might be more observant concerning new symptoms, might easier establish contact and assist in transportation of the patients, than professional caregivers. Is the care organised so that old patients with multiple diseases and reduced functions need the help of a relative in order to get outpatient specialised medical care? Or do patients who get help from family members have more severe medical problems, even though there are no differences in primary-health-care diagnoses? Further studies are needed in this area.The picture that evolves from our study is that the care of patients with home nursing is more complex than has previously been assumed. In parallel with their primary-care home nursing, all patients had contact with doctors, often from both primary and specialised medical care. The situation resembles that in a hospital ward, where many different caregivers and many different professions are involved in the care of the same patient, but without the ward's geographical and temporal unity. This renders it almost impossible for the individual patient to get continuity in all aspects of care, and the possibility of cost effective care of good quality is diminished.Patients with home nursing have complicated medical problems and both nurses and doctors are involved in their care, contrary to the previous belief that some patients are cared for by nurses alone. Instead, there seems to be one group of patients with home nursing who also need both primary and specialised care, and who have greater care needs than other patients with home nursing.That reduced function decreases and help from family members increases the chance of getting outpatient, specialised medical care raises questions concerning the medical care for patients with both medical and functional problems.Our conclusions are based on a study in one suburban area, and further studies are needed in order to confirm them.ADL Activities of Daily LivingENT Ear Nose and ThroatNone declared.SM designed and carried out the study, performed the statistical analysis, participated in the interpretation of results, wrote the initial draft of the manuscript and made subsequent revisions. AKF participated in the interpretation of results and made critical revisions of the manuscript. Both authors have read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


The eyes may be the window to the soul for poets, but for neuroscientists, they serve a more practical purpose. Of the 100 trillion or so cells that make up the human body, over 100 billion are dedicated to the structure and operation of the brain alone. Given the molecular and functional complexity inherent in such numbers, neuroscientists have historically focused on a more tractable system, the vertebrate retina, to study central nervous system development and physiology. Cells in the retina are packaged into highly ordered anatomical layers, based on their specialized functions. This organizational structure is characteristic of other regions of the central nervous system, and allows the brain to take in and integrate sensory information simultaneously, using discrete computational units. Creating such functional microprocessors depends on making the right cell at the right place and time.During development, cells undergo periods of proliferation and increasing specialization (differentiation), generating seven types of retinal cells  in a precise order at specific times. Mature, specialized cells arise from a pool of proliferating progenitors—cells that have already committed to becoming a retinal cell but haven't yet settled on a particular cell type. But progenitors are not all alike; they display intrinsic differences in their “competence” to produce a particular subset of retinal cells at a particular stage of development. These differences may help ensure that ganglion cells, for example, are established before photoreceptors, since photoreceptors rely on ganglion cells to transmit their signals to the brain.Which path a cell ultimately chooses stems from a combination of both intrinsic competence factors—likely determined by a cell's gene expression program—and external signals from the cell's environment. Progenitors give rise to “postmitotic” cells (cells that have exited the cell cycle and ceased proliferating), which go on to express characteristics associated with a specific cell type.Beyond this framework, the molecular underpinnings of retinal development remain obscure. Differentiated cells exhibit a gene expression program unique to their cell type, but it's not clear what accounts for underlying differences among progenitors, for example, or what factors usher retinal cells into their respective specialties. To map the genetic landscape of retinal development, Constance Cepko and colleagues looked for genes expressed in retinal cells passing through various competence levels and making cell fate choices. They determined gene expression profiles by collecting bits of gene transcripts from the retinal tissue of developing mice at two-day intervals, starting with mice entering neurogenesis and ending with mice about six and a half days old. They also collected gene expression data from postnatal day 10 and from adult mice.The authors then examined the cellular expression patterns of 1,051 of the genes that showed dynamic patterns by genomic expression profiling. Cepko and colleagues then pegged these genes to specific cell types to create a “molecular atlas of gene expression in the developing retina.”  Nearly every gene known to direct retinal cell differentiation was detected in this analysis and showed high levels of expression. Genes required for cell fate choices showed peak expression near or after cells exited the cell cycle, supporting the idea that similar controls operate to put the brakes on cell proliferation and to determine cell fate. Many uncharacterized genes were expressed only in certain progenitor subsets, making them good candidates as cell fate determinants for different subtypes of retinal cells. A promising list of candidate genes for retinal development and function appear in this molecular atlas, along with candidates for retinal disease. Since many degenerative retinal diseases stem from defects in development, these genes will help researchers focus their search for therapies. And if the eye truly is the window of the nervous system, these findings may suggest general principles of cell fate determination for the developing brain, spinal cord, and other regions of the vertebrate nervous system.


Patients with metastatic breast cancer (MBC) are frequently exposed to high cumulative doses of anthracyclines and are at risk of resistance and cardiotoxicity. This phase II trial evaluated the efficacy and toxicity of docetaxel plus cisplatin, as salvage chemotherapy in patients with MBC resistant to prior anthracyclines.2 followed by cisplatin 60 mg/m2 every 3 weeks for a maximum of 6 cycles or until disease progression.Patients with MBC that had progressed after at least one prior chemotherapy regimen containing anthracyclines received docetaxel 75 mg/mBetween Jan 2000 and May 2002, 24 patients with tumors primary resistant and 15 with secondary resistant disease were accrued. All 39 patients were evaluable for safety and 36 for efficacy. The objective response rate was 31%  with 3 complete responses. The median time to disease progression was 7 months, and the median overall survival was 23 months (median follow-up of 41 months). Neutropenia was the most frequently observed severe hematologic toxicity (39% of patients), whereas asthenia and nausea were the most common non-hematologic toxicities. No treatment-related death was observed.In conclusion, we found docetaxel plus cisplatin to be an active and safe chemotherapy regimen for patients with MBC resistant to anthracyclines. In the management of breast cancer, anthracycline-based chemotherapy regimens remain standard adjuvant or first-line palliative treatment. Furthermore, some patients cannot be treated with anthracyclines due to impaired cardiac function. It is thus important to identify active, well-tolerated, not anthracycline cross-resistant, salvage regimens .Taxanes (docetaxel and paclitaxel) are currently the most extensively studied new chemotherapeutic agents for metastatic breast cancer (MBC). Single-agent docetaxel has demonstrated significant survival advantages over other recognized regimens in 2 large randomized trials in patients with anthracycline-pretreated MBC . Phase ICisplatin monotherapy has shown response rate of 9% in salvage settings, and 50% as first-line therapy . BecauseEligible patients had measurable or assessable histologically confirmed breast cancer that had progressed after at least one prior chemotherapy regimen containing anthracyclines. All patients had Eastern Cooperative Oncology Group performance status of 2 or lower and adequate bone marrow, hepatic, and renal function, defined as white blood cells ≥4000/μL, absolute neutrophil count ≥1500/μL, platelets ≥100,000/μL, total bilirubin ≤2.0 mg/dL, transaminases ≤3 times the upper normal limit, and serum creatinine ≤1.5 mg/dL. Concurrent radiation or hormonal therapy was not allowed; however, patients with clinically stable metastases of the brain or other sites who had completed radiation therapy were permitted. Patients were eligible regardless of the nature of prior therapy, including high-dose therapy with stem cell support and prior exposure to paclitaxel. Any prior antitumor treatment had been completed at least 1 month before entering this study. Patients were excluded if they had severe comorbid illness, symptomatic peripheral neuropathy of any origin, or a history of anaphylaxis of any type. All patients were provided a thorough explanation of the study, and they signed informed consent prior to enrollment into the study.Patients were classified as primary and secondary anthracycline-resistant. Primary anthracycline-resistance was defined as relapse during or within 12 months after anthracycline-based adjuvant therapy, or disease progression with no intervening response during anthracycline-containing chemotherapy for MBC. Secondary resistance was defined as relapse more than 12 months after receiving adjuvant anthracycline chemotherapy, or disease progression at some time after a documented clinical response to anthracycline-based chemotherapy for MBC.Pretreatment evaluation included a complete medical history and physical examination, a computed tomographic (CT) scan of the chest and abdomen, magnetic resonance imaging (MRI) of the brain, and a bone scintigraphy to assess the extent of disease. Follow-up consisted of physical examination, monitoring of toxic effects, a complete blood count, liver function tests, chest radiography, and CT scan as clinically indicated.Tumor response and toxicity were recorded in accordance with the World Health Organization (WHO) criteria. Responses were assessed every 2 cycles of chemotherapy, and patients were evaluated before each new treatment cycle for toxicities.®, Aventis, Bridgewater, NJ) 75 mg/m2 given by a 1-hour intravenous infusion immediately followed by cisplatin 60 mg/m2 in a 2-hour infusion. Cycles were repeated every 3 weeks if the patient's blood count had returned to normal and non-hematologic toxicities had resolved. Dosage of subsequent cycles was adjusted according to the observed toxicities that developed during the preceding cycle. The treatment continued for a maximum of 6 cycles or until disease progression. All patients received standard supportive care regimen consisting of adequate hydration, dexamethasone, and antiemetic therapy according to the guidelines of the American Society of Clinical Oncology [The treatment consisted of docetaxel . Comparisons were performed using chi-square test and survival curves were generated using Kaplan-Meier method. Results were considered significant at the P = .05.Between Jan 2000 and May 2002, 24 patients with tumors primary resistant and 15 with secondary resistant disease were accrued. Among 39 patients assessable for safety, 3 were not evaluable for response due to early discontinuation of treatment.Baseline characteristics of the eligible patients are listed in Table According to the "intent-to-treat" analysis, the objective response rate was 31% . There were 3 complete responses, 12 partial responses and 15 patients had stable disease. The three patients who obtained a complete response had non-visceral metastatic pattern (neck lymph nodes and/or soft tissue lesions). Most patients who achieved a response did so at the end of the third cycle .At a median follow-up of 40.5 months , the median time to progression was 6.6 months  and the median overall survival was 22.9 months . The time to progression in responders were 16.7 months (P < 0.0001). The Kaplan-Meier method was used to estimate overall survival and time to progression, as shown in Figure We observed no significant differences in overall response rate or survival between primary and secondary anthracycline-resistant groups. The overall survival and time to progression were higher in patients with objective response .Patients received a median of 6 cycles  of docetaxel plus cisplatin. Relative dose intensities were 84%  and 86%  for docetaxel and cisplatin, respectively. Twenty-four patients (62%) completed 6 cycles of chemotherapy as planned; Nine patients had progression of disease while receiving treatment and 6 patients discontinued treatment because of toxicity. Treatment delay was occurred in 54 cycles (29%).Toxicity was evaluable in all 39 patients and 189 chemotherapy cycles. Even if the most frequent hematological toxicity was neutropenia (grade 3/4 in 22% of treatment cycles), only 12 episodes of non-fatal febrile neutropenia were observed. The most commonly encountered non-hematologic toxicities were asthenia and nausea. Other toxicities are reported per patient and per cycle in Table et al. also reported, in a similar patient population, 36% response rate and 69 weeks median survival with docetaxel 75 mg/m2 every 3 weeks[Single-agent docetaxel has been considered a standard treatment for patients with anthracycline-pretreated MBC for several years. Docetaxel monotherapy often demonstrated response rates of 50% or more in this setting ,18. Ahn y 3 weeks.Platinum-based combinations also have significant activity in previously treated as well as previously untreated patients. In several small clinical trials testing the cisplatin-based regimens, response rates of 50%-83% were reported . The Noret al. evaluated docetaxel 75 mg/m2 plus cisplatin 80 mg/m2 every 3 weeks in 38 patients with anthracycline-resistant MBC, giving an objective response rate of 36% [2 and cisplatin 80 mg/m2 in patients with anthracycline-pretreated MBC [et al. combined biweekly paclitaxel with cisplatin and achieved a response rate of 85% with few septic events [There are relatively few completed clinical studies involving platinum-based combination chemotherapy for anthracycline-resistant MBC. Spielmann e of 36% . Japanesated MBC . They reated MBC . Gelmon c events .et al. suggested that the status of anthracycline-resistance is important for the prediction of response to second-line treatment with docetaxel [We classified "anthracycline-resistant" into primary and secondary. Ando ocetaxel . However2 every 3 weeks, rather than 75 mg/m2 cited in a phase I study [This study demonstrated that a combination of docetaxel plus cisplatin in a 3-week cycle was an effective and well-tolerated regimen for patients with anthracycline-resistant MBC. In this study, the use of docetaxel plus cisplatin resulted in an overall response rate of 31% and the median time to progression was 7 months. Significant improvements in the actuarial survival rate and time to progression were observed in the group of patients who achieved objective responses. The main toxicities, gastrointestinal, hematological and asthenia, were manageable with dose adjustment and supportive care. Dose intensities of more than 80% were delivered and 61% of patients completed 6 cycles of chemotherapy, which is considered acceptable and expected. We used the planned dose of cisplatin 60 mg/m I study , becauseWith the increasing use of anthracycline-based chemotherapy as adjuvant treatment, as well as first-line chemotherapy against MBC, patients are frequently exposed to high cumulative doses of anthracyclines and are therefore at risk of resistance and cardiotoxicity . This coIn summary, the combination of docetaxel plus cisplatin is active and safe in patients with anthracycline-resistant MBC. The activity observed in anthracycline-resistant and heavily-pretreated patients suggests relative non-cross-resistance with other drug combinations. Therefore, we hope that this study could result in a prospective trial to determine whether this activity translates into actual improvement in survival and quality of life in patients with anthracycline-resistant MBC.The author(s) declare that they have no competing interests.SHP collected the data, performed the statistical analysis and drafted the manuscript. EKC, SB, JHL, YDL followed the patients. DBS designed the study, followed the patients and helped with the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here: