Seroma formation is the most frequent postoperative complication after breast cancer surgery. We carried out a study to investigate the effect of various demographic, clinical and therapeutic variables on seroma formation.A retrospective cross sectional study of patients who underwent surgical therapy for breast cancer with either modified radical mastectomy (MRM) or breast preservation (BP) was carried out. The demographic data and clinical information were extracted from case records. Seroma formation was studied in relation to age, type of surgery, tumor size, nodal involvement, preoperative chemotherapy, surgical instrument , use of pressure garment, and duration of drainage. The multiple logistic regression analysis was performed to estimate odds ratios.A total of 158 patients with breast cancer were studied. The mean age of the patients was 46.3 years (SD ± 11.9). Seventy-three percent underwent modified radical mastectomy and the remaining 27% received breast preservation surgery. Seroma occurred in 35% of patients. In multivariate logistic regression analysis an association of postoperative seroma formation was noted with modified radical mastectomy . No other factor studied was found to significantly effect the seroma formation after breast cancer surgery.The findings suggest that the type of surgery is a predicting factor for seroma formation in breast cancer patients. Breast cancer is the second leading cause of cancer death among women. The surgical treatment of choice for these patients is either modified radical mastectomy or breast preservation depending upon stage of the disease. Seroma formation is the most frequent postoperative complication after breast cancer surgery. It occurs in most patients after mastectomy and is now increasingly being considered side effect of surgery rather than a complication however, all patients are not clinically symptomatic . Seroma A cross sectional study of a consecutive sample of 158 patients attending the breast cancer clinic between January 2000 to October 2002 in Tehran, Iran, was carried out. All patients undergoing surgical therapy [modified radical mastectomy (MRM) or breast preservation (BP)] were included. Level II axillary lymph node dissection was performed for both groups. None of the patients underwent immediate reconstruction. The demographic data and clinical information were extracted from case records. Axillary seroma was defined as any clinically apparent fluid collection in the axilla or under the skin flaps and was treated with multiple needle aspirations. Seroma formation was studied in relation to age, type of surgery, tumor size, nodal involvement, preoperative chemotherapy, surgical instrument , use of pressure garment, and duration of drainage. To analyze data univariate odds ratio (or relative risk) was calculated using Chi-square tests or regression analysis and this was followed by the multivariate logistic regression analysis to evaluate independent risk factors related to seroma formation. The variables of interest were selected in a single step (enter method), classification cut off was  set at 0.5, probably of step for entry into the model was set at 0.05 and  removal at 0.1, and the model was set to converge in maximum of 20  iterations. All variables under study were considered as independent predicting factors and seroma formation was considered as dependent variable for multivariate analysis. The study was approved by the institutional ethics committee.2 = 4.52, df = 1, P = 0.03) indicating that those who underwent MRM had higher rate of positive axillary nodes compared to those who received BP (78% vs. 21% respectively). Thirty-one mastectomies were performed by scalpel dissection of the skin flap (20%) and 127 by cautery dissection (80%). Two closed suction drains were placed in all patients undergoing surgery. Sixty-six percent of patients (n = 104) were node positive and the remaining 34% (n = 54) were node negative. The patients' characteristics and univariate odds ratios are shown in Table In all, 158 breast cancer patients were recruited into the study and 55 patients developed seroma, giving an overall incidence of 35% for seroma formation after breast surgery. The mean age of patients was 46.3 years (SD ± 11.9). One hundred and fifteen patients (73%) underwent MRM and BP was performed in 43 patients (27%). The axillary node involvement was significantly different between MRM and BP patients . Of patients with BP, 10 of 43 (23%) developed seroma, while those who underwent MRM 45 of 115 (39%) developed seroma. The seroma formation did not show any significant association with any other variables studied. The results of maultivariate analysis are shown in Table Breast cancer is the most common malignancy in women. Surgery is the mainstay of treatment. Modified radical mastectomy with or without reconstruction or breast preservation in addition to axillary lymph node dissection are common surgical procedures in breast cancer. Surgery of the axilla is associated with numerous complications, including infection, lymphedema of the ipsilateral upper extremity and collection of fluid in surgical site (seroma). Most common complication after breast cancer surgery is wound seroma. The exact etiology of seroma formation remains controversial. Several interventions have been reported with the aim of reducing seroma formation including the use of ultrasound scissors in performing lymphadenectomy , buttreset al reported that the use of electrocautery to create skin flaps in mastectomy reduces blood lose but increased the rate of seroma formation [Several studies have been performed to investigate factors related to post-surgical seroma. These studies have observed that the early removal of drains might led to increased incidence of seroma , whereasormation . In addiormation . Compresormation . Howeverormation  and evenormation .et al, demonstrated that patients who underwent modified radical mastectomy had a greater incidence of seroma formation than patients who underwent breast preservation surgery [et al indicated that the tumor size and total amount of drainage represented the principal factors of seroma formation following axillary dissection in patients underwent surgery for breast cancer [In the present study no relationship was observed between the incidence of seroma and the patients' age, tumor size, and lymph node status. However, the study found that the MRM was associated with higher rate of postoperative seroma formation . Similarly, Gonzalez  surgery . They al surgery . A recent cancer .The results of our study suggest that seroma formation after breast cancer surgery is independent of duration of drainage, compression dressing and other known prognostic factors in breast cancer patients except the type of surgery, i.e there is a 2.5 times higher risk of seroma formation in patients undergoing MRM compared to BP. The small sample size of present study is a limitation and hence the power of the study is low. A number of questions remain unanswered and more research is needed to answer these.The authors declare that they have no competing interests.NoneEH designed the study, collected the data and wrote the first draft of the manuscript.AK, MN, ME and HH all contributed to patient recruitment and the preparation of first draft of the manuscript.AM contributed to the study design, data analysis, and edited the final version.All authors read and approved of the manuscript.


The contribution of low-penetrant susceptibility variants to cancer is not clear. With the aim of searching for genetic factors that contribute to cancer at one or more sites in the body, we have analyzed familial aggregation of cancer in extended families based on all cancer cases diagnosed in Iceland over almost half a century.We have estimated risk ratios (RRs) of cancer for first- and up to fifth-degree relatives both within and between all types of cancers diagnosed in Iceland from 1955 to 2002 by linking patient information from the Icelandic Cancer Registry to an extensive genealogical database, containing all living Icelanders and most of their ancestors since the settlement of Iceland.We evaluated the significance of the familial clustering for each relationship separately, all relationships combined (first- to fifth-degree relatives) and for close (first- and second-degree) and distant (third- to fifth-degree) relatives. Most cancer sites demonstrate a significantly increased RR for the same cancer, beyond the nuclear family. Significantly increased familial clustering between different cancer sites is also documented in both close and distant relatives. Some of these associations have been suggested previously but others not.We conclude that genetic factors are involved in the etiology of many cancers and that these factors are in some cases shared by different cancer sites. However, a significantly increased RR conferred upon mates of patients with cancer at some sites indicates that shared environment or nonrandom mating for certain risk factors also play a role in the familial clustering of cancer. Our results indicate that cancer is a complex, often non-site-specific disease for which increased risk extends beyond the nuclear family. It's not often that an entire nation's genealogy and cancer records are available. But they are in Iceland, and have been used to determine how often cancers occur in families BRCA1 and BRCA2 genes account for around 2%–3% of all breast cancer cases [Highly penetrant susceptibility variants explain only a small fraction of the genetics of all cancer cases. As an example, mutations in the er cases ,5,6,7. HFamily studies have given insight into the contribution of genetic and environmental factors to the etiology of cancer. Case-control, registry- and population-based studies have evaluated familial clustering using either risk ratio (RR) estimations for relatives of cancer patients, or kinship coefficient (KC) estimations for cancer patients. The largest of these studies, utilizing either the Utah Population and Cancer Registry Database or the Swedish Family-Cancer Database, have demonstrated excess familial clustering at practically all cancer sites in the body ,10,11,12Twin studies have also evaluated the role of genes versus environment in cancer susceptibility. The largest study involved close to 45,000 twins from Denmark, Sweden, and Finland where the RR of same type of cancer was calculated for individuals with affected twins and compared to those without an affected twin . The autIn addition to well documented familial clustering for the majority of individual cancers, aggregation of different types of cancers in families has also been observed. Reports have been published on the results of systematic analysis of the aggregation of different cancers using the Utah Population and Cancer Registry Database ,25. In aWe have studied a registry of all cancer cases diagnosed in Iceland from 1 January 1955 to 31 December 2002, with the aim of searching for evidence of genetic factors both at individual cancer sites and those shared by different sites. By cross-referencing cancer prevalence in relatives of cases with the aid of a comprehensive nationwide genealogy database, we have estimated RR separately for first- to fifth-degree relatives of all cancer patients diagnosed in Iceland over 48 y. We demonstrate here an increased cancer risk in relatives outside the nuclear family (third- to fifth-degree relatives) for many cancer sites. These relatives share significant genetic makeup but are less likely to share environmental factors beyond those shared by the general population, indicating that genetic factors may be involved. By applying the analysis across different cancer sites we also demonstrate shared familiality between certain cancer sites both in close and distant relatives. These results suggest that cancer can be considered a broad phenotype with shared genetic factors crossing different cancer sites. That is, the difference between cancers at various sites may in part be the consequence of variable expressivity of the same cancer-predisposing genes.This study was approved by the National Bioethics Committee of Iceland, the Data Protection Authority of Iceland, and the Icelandic Cancer Society. All names of patients listed in the Icelandic Cancer Registry (ICR) and the genealogic database were encrypted through a process approved by the National Bioethics Committee and the Data Protection Authority before being analyzed .The ICR of the Icelandic Cancer Society is a carefully constructed database containing practically complete records of all cancer cases diagnosed in Iceland after 1 January 1955 . RecordsdeCODE Genetics has built a computerized genealogy database of more than 687,500 individuals ,30. The Mates are defined as individuals of the opposite sex who have one or more children in common, regardless of marital status.The RR for relatives is a measure of the risk of disease for a relative of an affected person compared to the risk in the population as a whole. More precisely, for a given relationship the RR for disease B in the relatives of probands with disease A is defined asAP denotes the event that the proband is affected with disease A, and BR denotes the event that the relative is affected with disease B. Note that disease A and disease B can be the same in this definition which applies when estimating RR at individual cancer sites. Using Bayes' rule it can be shown that for symmetric relationships, RR is the same if the roles of A and B are switched, i.e., the RR for disease A in the relatives of probands with disease B is the same as the described above. In this study we always chose the less common phenotype as the proband when estimating RR.where RBO and PAO are the events that the relative and proband are observed with diseases A and B, respectively):A basic underlying assumption in our estimation of RR is that of conditional independence of ascertainment, or censoring, , let n be the size of the population, and finally let x be the number of affected individuals in the population. If P(BR) and P(B | PAR) can reasonably be assumed to be constant in the population, then x/n and a/r, respectively, are estimates of these probabilities. Given these estimates, RR is consistently estimated byThe approach chosen here is to estimate the RR for a number of subpopulations, where prevalence is reasonably constant, and combine them into a single estimate of RR for the full population. Let probands , let a bN subpopulations, such that within each subpopulation P(BR) and P(B | PAR) can be assumed to be constant, although they may vary between subpopulations, and assuming furthermore that RR is the same in all the subpopulations, then the RR is consistently estimated by a convex combination of the estimates for the subpopulations. We selected weights for the combination such that the efficiency of the estimator was at maximum for RR equal to one. Making the simplifying assumption that the relatives are independent , the optimal weight for group j isAssuming the population can be split into j), where a, r, x, and n are defined as above, restricted to the subpopulation j. Note that probands are not restricted to the subpopulation. Given these weights, our estimate of RR is(this is the inverse of the variance of the estimate for RR in subpopulation P(BR) and P(B | PAR) stem from time-dependent censoring of affected status and sex-specific differences. Hence, we have stratified the population so that j runs over groups of people of the same sex and born in the same 5-y periods. For a fixed year-of-birth stratum, there is censoring of affected status (missing data) based on year of onset because of the fact that records cover only the period 1955–2002. Our approach is designed to address this type of missing data. As an example of the stratification, the breast cancer patients in our analysis were born in the years 1865 to 1970 (5-y strata), yielding 35 subpopulations, 22 for female patients, but only 13 for male, as this cancer is rare for males.In this study, the most relevant variations in p values can be calculated using the control groups; thus, a p value of 0.05 for the RR would indicate that 5% of the matched control groups had values as large as or larger than that for the patient's relatives or mates. The number of control groups required to obtain a fixed accuracy of the empirical p values is inversely proportional to the p value. We therefore selected the number of control groups generated adaptively up to a maximum of 100,000. When none of the values computed for the maximum number of control groups were larger than the observed value for the patient's relatives and mates, we report the p value as being less than 0.00001. Using a variance-stabilizing square-root transform, an approximate confidence interval may be constructed based on the distribution of RR for control groups [To assess the significance of the RR obtained for a given group of patients, we compared their observed values with the RR computed for up to 100,000 independently drawn and matched groups of control individuals. Each patient was matched to a single control individual in each control group. The control individuals were drawn at random from the genealogic database with the conditions that they had the same year of birth, the same sex, and the same number of ancestors recorded in the database at five generations back as the matched patients. Empirical l groups .dRR is the RR for relatives of degree d, then dRR – 1 is known to decrease proportional to 2-d as d increases for a monogenetic single variant or additive disease models, and faster for more complex disease models [dRR denoted by As another test for significance of RR between cancer sites, we used combined estimators for risk in relatives of degree 1 and 2 together, degrees 3, 4, and 5 together, and degrees 1 through 5 together. If e models . With thd summed over the relevant degrees. For dRR close to one, the variance of the estimate d for the proband. Based on the Icelandic genealogy for the cancers being studied here, the number of relatives is proportional to γd, where the value of γ quantifies how the number of relatives grows with each degree of relatedness to the proband. This factor γ varies only slightly between cancers and is on average 2.46. Minimizing the variance of the test statistic in equation 6 with respect to the weights yields the statisticwith As above, the choice of weights and the form of the statistic affects only power, not validity. To assess significance, the observed value of the statistic was compared to its value for multiple matched control groups as described above.Although our evaluations of familial clustering, for both close and distant relatives, are based on RR, an alternative approach based on comparing KCs among patients and among controls exists ,24,25. TWe have studied the familial clustering of cancer by estimating RR for first- and up to fifth-degree relatives both within and between all cancer sites. Here we present results for 27 sites that contain 200 or more cancer cases each, based on International Classification of Disease version 10 codes. These 27 sites represent 89% of all cancer cases in the ICR.A significantly increased RR to first-degree relatives of patients with cancer was seen for 22 of the 27 cancer sites . Among tThe medians of the estimated RR values for the 27 sites in first- to fifth-degree relatives were 2.00, 1.32, 1.21, 1.10, and 1.04, respectively.p-values incorporating the increased risk for first- to fifth-degree relatives identified 21 sites being significant at a nominal level of 0.05. Sixteen of those sites remained significant after Bonferroni adjustment for the 27 individual tests   . To discher hand . FourteeThe RR for developing cancer at the same site was also estimated for mates of cancer patients at 22 out of the 27 individual sites. The remaining five sites are sex-specific and calculations thus not applicable. For seven rare cancer sites, affected mates were not observed, corresponding to a RR of zero. Only lung, stomach, and colon cancer were characterized by significantly increased RR values in mates .p values were calculated for all (first- to fifth-degree), close (first- and second-degree), and distant (third- to fifth-degree) relationships. p value, significant at a level of 1 × 10-4, for first- to fifth-degree relationships. This level was significant at the 0.05 level after Bonferroni adjustment for the 351 tests (number of unique pairs of cancers). The strength of the distant familiality  between these pairs of cancers is represented by the thickness of the lines joining sites in We calculated RR between all cancer sites for first- and up to fifth-degree relatives and mates  for distant relationships, of which nine were significant at the 0.001 level. In the latter group, prostate, rectum, stomach, and cervical cancers each appeared in two pairs, and colon cancer in three.All of the 20 pairs shown in In this study we have comprehensively analyzed familial aggregation of cancer cases in a whole nation, both within and between pairs of cancer sites. The completeness of our genealogy database allows us to accurately trace distant relationships, which we believe is unique to this study. Linking the ICR to our nationwide genealogy database thus has made it possible to uncover distant familial connections between cancer cases, and reach beyond shared environmental factors to identify individual and combined cancer sites with the strongest genetic influences. Furthermore, even though the genetic effect decreases with more distant relationships, the sample sizes used to estimate familiality are dramatically larger for the distant relationships than for the closer ones. This compensates to some extent for the lower effect and adds considerable statistical power to the study.In this paper we restrict the presentation and discussion to the most significant findings. However, we provide results for all pairs of 27 cancer sites in The largest population-based studies reported to date, evaluating familial clustering within the same cancer site, are from Utah and Sweden ,9,10. ThAs seen in Utah and Sweden, high RR values were found in this study for multiple myeloma, lymphoid leukemia, and thyroid, testicular, and laryngeal cancer. The RR for thyroid cancer in first-degree relatives was much higher in Utah and Sweden (8.48 and 9.51) than in Iceland (3.02). One possible explanation of the lower RR may be the high incidence of thyroid cancer in Iceland, due to an excess of the papillary subtype ,37, whicThe cancer sites showing the highest RR for first-degree relatives tend to be among the rarer sites. There are two potential reasons why rare tumors tend to show higher RRs than common cancers. Being common, the baseline frequency is not low and that creates a bound on how large the RR can be. Also, common cancers are expected to be genetically complex, whereas it is more likely for a rare tumor to be closer to a Mendelian trait, caused by rare alleles with high penetrances.p values (after adjustment for multiple testing) for the combined group of first- to fifth-degree relatives. Furthermore, eight of these 16 sites remained significant even after exclusion of the first- and second-degree relatives (after adjustment for multiple testing). The majority of the 16 significant cancer sites are among the sites of the most prevalent cancers, indicating that we may lack power to detect extended familiality for the less prevalent cancer sites. Indeed the median number of cases per cancer site was 943 for the 16 significant sites compared to 342 for the non-significant sites. Nevertheless, significant familial clustering (first- to fifth-degree relatives) is seen for some of the less prevalent sites, i.e., lymphoid leukemia and esophagus and meningeal cancer.Most individual cancer sites, or 16 out of the 27 studied here, showed familiality as evidenced by significant The largest cancer twin study reported to date  documentA significantly increased risk of the same cancer was seen in mates only for individuals diagnosed with stomach, lung, or colon cancer. These results are in accordance with previous reports, including Swedish population-based studies, except for colon cancer ,39,40,41p values corresponding to the increased risk for first- to fifth-degree relationships. With this method, we detected 17 cancers that linked into 20 pairs of sites that were significant after adjustment for multiple testing. Stomach and prostate cancer appeared more frequently in the pairs than other cancer types, followed by colon, ovarian, and cervical cancer. We emphasize again, as with the same-cancer calculations, that we might lack power to connect rare cancers to other cancer sites. This possibility is highlighted by the fact that the 17 cancers in the significant pairs are the most prevalent cancer sites in Iceland.We also assessed the significance of familial clustering between cancer sites by calculating combined BRCA1 and BRCA2 may explain in part the cluster seen between prostate, breast, ovarian, and possibly pancreatic cancer [Some connections seen here between cancer sites may be partly explained by known high-risk genes involved in heritable syndromes. Thus, mutations in genes associated with hereditary nonpolyposis colorectal cancers could explain a part of the risk shared between stomach, colon, rectal, and endometrial cancer, and possibly brain and ovarian cancer ,43. In ac cancer ,44,45,46Undiscovered genetic factors could contribute to some connections seen here to a much greater extent than the known susceptibility factors. Although these could include unknown high-risk susceptibility genes, they are more likely multiple genetic variants, each conferring small to moderate risk.Familial clusters were identified between cancer sites, both in close and distant relatives, that do not correspond to known cancer syndromes. These include lung, esophageal, cervical, and stomach cancer, which, interestingly, have been associated with environmental rather than genetic factors. One explanation for this excess familiality between these cancer sites is an interaction of genetic susceptibility factors with environmental carcinogens  or infectious agents. Thus, the same environmental factor could interact with the same genetic susceptibility factor or factors to induce different cancers . Alternatively, different environmental factors could interact with the same genetic susceptibility factor or factors to increase the risk for different cancers .BRCA1 and BRCA2 mutations [Hormone-related cancers form another risk cluster. Thus, shared genetic susceptibility factors could directly influence the hormonal metabolism to induce breast, prostate, thyroid, or ovarian cancer in carriers. Alternatively, shared genetic factors could interact with dietary factors to induce aggregation of cancers at these sites in related individuals. A significantly increased risk of breast, prostate, cervical, and non-melanoma skin cancer was recently reported in first-degree relatives of early-onset breast cancer patients from Sweden that tested negative for utations . Our datTwo more groups of cancers with shared risk were identified that each include sites that share the same developmental progenitors: the prostate, kidney, and bladder are sites derived from the nephrogenic ridge while colon, rectum, and stomach are derived from the primitive gut tube. Therefore, the sites in each group may share risk alleles that regulate embryonic development, which can later play a role in oncogenesis.Interestingly, three cancer sites/types, non-melanoma skin, brain, and melanoma, that do not have significant same-cancer familial clustering demonstrate significant cross-cancer familial clustering with more prevalent cancer sites, i.e., rectum, stomach, and kidney cancers, respectively.Previous reports systematically evaluating the significance of co-clustering of cancer pairs in families have utilized the Utah Population Database. In these studies lip and prostate cancers appear to associate most frequently with other cancer sites. The same is true for prostate cancer in our study, whereas lip cancer does not significantly associate with any other cancer sites. This can at least in part be explained by the difference in age-standardized incidence rates for lip cancer in Iceland and Utah (Iceland 1.1 and Utah 2.4) . In contBecause the increased cross-site RR extends beyond the nuclear family, shared genetic factors may contribute to the risk of more than one cancer type. This suggests that cancer could be considered a broad phenotype with shared genetic factors across cancer sites. Therefore cancer should in certain cases be studied in a broader context than previously done. Combining multiple cancers that show increased cross-site RR may serve to increase the power of linkage and case-control studies. Our results also have implications for genetic counseling and imply that the focus of attention should broaden to the history of multiple cancer types in relatives within and outside the nuclear family. These results also suggest the utility of comparing expression profiles and in vitro biological processes across the cancers that we have identified as sharing genetic risk. The isolation of cancer predisposition genes with broad effects may define new rate-limiting pathways that can be used to search for drug targets for a more focused treatment with fewer side effects but with utility across multiple cancers.Table S1(1.9 MB DOC).Click here for additional data file.http://www.ncbi.nlm.nih.gov/projects/LocusLink/) accession numbers for the genes discussed in this paper are BRCA1(LocusLink ID 672) and BRCA2 (LocusLink ID 675).The LocusLink (Although a few cancers have a fairly simple genetic cause, most, especially the most common cancers, do not, and what makes one person rather than another develop cancer is not clear. One way of trying to work out how much genes rather than environment contribute to disease is to study large populations. One such population is the Icelandic nation: not only is detailed health information about individuals available, including information on cancer, but also very good genealogical information and a substantial amount of genetic data.Researchers examined all cancer records dating back to 1955 and then analyzed the chances of relatives and mates of these patients having cancer. They found that some cancers, especially rare ones, had a higher than baseline chance of occurring in relatives, but so did many common cancers, and for some cancers, the higher chances extended to quite distant relatives. In addition, the risk sometimes involved different cancer types.Even for the highest risk cancers, the absolute increased risk for relatives remains very small. In addition, despite the large numbers of patients studied, the numbers of cancer cases are still not large enough to be completely certain of the results, apart from very common cancers, which had the lowest chance of occurring in relatives. So these results will not help doctors much at the present time in telling an individual patient what their risk is of getting cancer if a relative has it—but they will be useful for other researchers in knowing how to plan future studies to look at the underlying causes of cancer.http://www.krabb.is/cancer/Icelandic Cancer Society: http://cis.nci.nih.gov/The United States National Cancer Institute's Cancer Information Service: http://www.cancerhelp.org.uk/CancerHelp UK, a free information service about cancer and cancer care: http://www.decode.comdeCODE Genetics:


Many primary malignancies spread via lymphatic dissemination, and accurate staging therefore still relies on surgical exploration. The purpose of this study was to explore the possibility of semiautomated noninvasive nodal cancer staging using a nanoparticle-enhanced lymphotropic magnetic resonance imaging (LMRI) technique.We measured magnetic tissue parameters of cancer metastases and normal unmatched lymph nodes by noninvasive LMRI using a learning dataset consisting of 97 histologically proven nodes. We then prospectively tested the accuracy of these parameters against 216 histologically validated lymph nodes from 34 patients with primary cancers, in semiautomated fashion. We found unique magnetic tissue parameters that accurately distinguished metastatic from normal nodes with an overall sensitivity of 98% and specificity of 92%. The parameters could be applied to datasets in a semiautomated fashion and be used for three-dimensional reconstruction of complete nodal anatomy for different primary cancers.These results suggest for the first time the feasibility of semiautomated nodal cancer staging by noninvasive imaging. Injection of targeted nanoparticles, combined with magnetic resonance imaging, allows identification and detailed three dimensional placement of malignant lymph nodes Most primary malignancies spread systemically via lymphatic dissemination . For exaNoninvasive imaging studies are commonly used during the workup of primary malignancies. Typically, lymph nodes are diagnosed by tomographic techniques  as malignant when their short axis is >10 mm in size . Such siDespite the advances of LMRI for cancer staging, image analysis has been challenging and occasionally controversial. Traditional analysis has been based on a reader's identification of certain structural abnormalities that can be variable, given differences in acquisition parameters and interpretation criteria ,20,21. FThe goal of the current study was to develop and test technologies that would vastly improve the accuracy of current LMRI nodal staging. Specifically we set out to (a) determine whether unique magnetic parameters existed and could be used for semiautomated image analysis and (b) whether the technique could be applied to different primary cancers. Here we provide the first comprehensive analysis of tissue parameters validated against histopathology as an end point.n = 97 lymph nodes with known histopathology) and a test dataset  and/or nodal biopsy (n = 10). The investigated nodes had a mean short axis diameter of 10.5 mm (range 3–39 mm).The Institutional Review Board approved the current study and all patients signed informed consent. The study was divided into a learning (n = 18), breast (n = 7), penile (n = 4), bladder (n = 2), testes (n = 2), and colon (n = 1). Seventy-nine percent of the nodes were benign and 21% of the nodes were malignant. The nodes in the test dataset had a mean short axis diameter of 10.0 mm (range 3–39 mm). Both datasets included the full spectrum of normal nodes to completely replaced nodes.The test dataset was obtained from 34 patients  with histologically proven malignancies from different primaries , includin = 56) extended from the pubic symphysis to just above the level of aortic bifurcation. In patients with primary testicular cancers (n = 7) imaging was extended superiorly to include the renal hilum and retroperitoneum. In patients with breast cancer (n = 7) we obtained MR images of the bilateral axillae, including the internal mammary and supraclavicular regions. All patients were imaged with identical pulse sequences and timing parameters. Imaging was performed before and 24 h after intravenous ferumoxtran-10 administration .MRI was performed at 1.5 T  using phased-array coils. All images were archived on DICOM PACS servers  for subsequent analysis. Images of the pelvis (The acquired pulse sequences included (a) axial T2-weighted fast spin-echo ; (b) a T1-weighted two-dimensional gradient-echo sequence obtained in different anatomical planes ; (c) an axial T2-weighted dual TE gradient-echo ; and (d) a three-dimensional (3D) T1-weighted gradient echo sequence; TR/TE 4.5–5.5/1.4; flip angle, 15°; field of view, 24–28 cm; slice thickness, 1.4 mm; matrix, 256 × 256; in-plane resolution, 1.0 mm).The above listed imaging sequences and parameters had previously been optimized to reduce motion artifacts, maximize signal-to-noise ratio (SNR), and provide diagnostically useful images of the pelvis, abdomen, and chest within clinically acceptable time limits. The T2-weighted fast spin-echo sequence, in (a) above, was primarily used for qualitative nodal detection, and hence a square pixel with more than one acquisition was obtained. The two-dimensional axial T1-weighted gradient-echo sequence, in (b) above, was chosen to achieve adequate anatomical coverage within a short imaging time. The axial dual-echo gradient-echo sequence, in (c) above, was developed specifically for this project to provide artifact-free datasets for quantitative image analysis. A matrix size of 160 × 256 was chosen for this sequence to achieve a balance between the upper limits for imaging time while reducing image noise. Finally, a 3D T1-weighted sequence was obtained, in (d) above to provide a dataset for vascular maximum intensity projection (MIP) reconstructions.All image analysis was performed on archived DICOM images using different software packages . Lymph nodes were identified by readers who manually placed kernels onto each node for automated boundary detection and calculation of nodal dimensions and volumes. The thus identified regions of interest (ROIs) encompassed the entire lymph node (not only portions of it) and were used for quantitative signal-intensity (SI) measurements see . Serial noise. The T2* was calculated in nodal ROIs on dual TE images using CMIR-Image. T2* maps were constructed by performing fits of a standard exponential relaxation model (S = Ke–TE/T2*) to the data on a pixel-by-pixel basis. Only pixels with intensity greater than a threshold level (2X of noise) were considered during the fitting process. Pixel variance was obtained from post-MR images. Comparative visual analysis included short axis measurements, and identification of heterogeneity, large focal defects, and central hyperintensity, according to criteria previously established [A number of quantitative tissue parameters were calculated either as differences between pre- and postcontrast scans (δ) or as single-value analysis on postcontrast scans see . The lymablished ,17.To determine the diagnostic accuracy of the different tissue parameters in the learning dataset, we determined sensitivity, specificity, and predictive values for each parameter alone and in combination . The mosIn the final set of semiautomated image analysis, 3D reconstructions were obtained for nodal mapping onto vascular anatomy using MIP projections. While the MIP projections do not aid in the differentiation between malignant and benign lymph nodes, they are invaluable in providing anatomic content to the dozens of lymph nodes identified. In particular, MIP images were generated interactively from postcontrast, fat-saturated, volumetric interpolated breath-hold images to outline vascular anatomy. The evaluated lymph nodes characterized as benign or malignant  were then superimposed on the volumetric 3D images, using customized software .t-test , and values are summarized in Data were expressed as mean ± standard deviations (SD) and medians. All statistical testing was performed using GraphPad Prism . The significance between two individual groups was determined using the nonpaired Student's n = 55; both benign and malignant nodes) or in fine needle aspirates and core biopsies , implementing careful mapping procedures to correlate nodes. Surgically excised nodes were sectioned at 10–20 μm intervals after bihalving and were stained with hematoxylin-eosin.All lymph nodes were sampled histologically within 2 wk of the MRI . The analysis was done in surgically resected lymph nodes  and specificity  in the learning dataset E. Using To determine whether feature extraction would be accurate for prospective nodal staging, we utilized the above criteria against a larger test dataset encompassing 216 validated lymph nodes from 34 patients, including different primaries see . The senUsing the dual-value analysis, there were two malignant outliers in the benign dataset  and three benign outliers in the malignant dataset . More important, all the misclassified nodes occurred in individual patients rather than in the same patient and, hence, did not affect the overall nodal staging on a patient-by-patient basis in this dataset.Utilizing semiautomated feature extraction to identify lymph nodes and image analysis (based on T2* and pixel variance), we subsequently proceeded to map individual lymph nodes onto vascular anatomy in the different anatomic drainage patterns. We show that it is feasible to extract various quantitative tissue parameters to predict the likelihood of nodal metastases in vivo. These results are highly relevant in cancer staging because they provide evidence that (a) quantitative tissue parameters enable diagnosis of lymph node metastases while reducing interobserver variability and (b) that semiautomated reconstructions allow spatially more extensive mapping than is currently possible.Metastases to lymph nodes occur during growth of most primary malignancies, and their presence mandates the need for more extensive and systemic therapy. Nodal cancer staging currently relies on invasive procedures  with significant morbidity and cost ,23, or iThe significance of the above findings is 3-fold. First, the ability to directly and noninvasively monitor nodal tumor involvement represents a powerful diagnostic tool for cancer. Accurate staging represents the cornerstone for triaging patients to either localized or to more aggressive and systemic therapies. Second, the method described here was sensitive for the limited subsets of primary cancers tested. It is reasonable to hypothesize that such analysis could be applied to staging of other common primaries. In particular, lung, colorectal, genitourinary, and head and neck cancers could benefit from this staging procedure. In addition to nodal staging, the nanoparticle-enhanced MRI can also be used to measure microvascularity in primary tumors  and to iThe LMRI staging technique is believed to be clinically relevant in several key areas. First, LMRI may play a significant role in avoiding unnecessary surgeries, that is, those in node-positive patients. Second, since LMRI can detect lymph nodes outside traditional surgical fields, this information may influence surgical approaches. In colorectal cancer, LMRI may provide a “sentinel-node-like” guide to staging. Third, it is likely that LMRI would be useful to identify appropriate patients to receive neoadjuvant chemotherapy prior to surgery. Currently, neoadjuvant therapy is often reserved for postoperative patients, once the nodal status has been determined. Fourth, LMRI may be particularly useful to guide radiation therapy by mapping the complete nodal status onto bony and vascular landmarks. Finally, LMRI could be used to avoid invasive diagnostic procedures, which are not part of therapy. For example, LMRI could replace lymphangiography, mediastinoscopy, or endoscopic ultrasound for nodal staging.Our findings have a number of direct implications for technology development and in clinical care. Accurate measurements of T2* relies on motion artifact-free multiecho pulse sequences that are not routinely available on clinical scanners at spatial resolutions required for nodal staging. Such sequences will have to be implemented and combined with postprocessing tools to simplify and semiautomate analysis. Similar software approaches are already used routinely in lung nodule characterization  or screeWhen deciding on treatment for patients with cancer, it is very important to assess whether the cancer has spread to lymph nodes—both to help decide what treatment a patient should have and what the eventual outcome might be. Previous ways of finding involved lymph nodes included taking out the nodes by surgery, ultrasound, and CT and MRI scans.A solution of magnetic nanoparticles that tend to go to lymphoid organs was injected and then tracked by MRI. The pattern of the particles was abnormal when there was metastasis in the nodes, and it was possible to train a computer to recognize this abnormality. The authors developed the program in one group of patients and then tested it in another group, in which they were able to correctly predict whether the nodes were involved in about nine of ten nodes. In addition, they could use the information to display a virtual picture of the involved nodes.The technique will need to be validated in a larger group of patients, and by other investigators. However, it means that it is potentially possible to work out much more precisely, and with less chance of error, whether lymph nodes are involved in cancer. Hence, treatment can be better planned, and if surgery is needed to remove nodes for analysis, then this technique could ensure that the surgery is as minimal as possible.http://www.radiologyinfo.org/RadiologyInfo, a public information site developed by the American College of Radiology and the Radiological Society of North America: http://www.nlm.nih.gov/medlineplus/cancer.htmlMedline Plus, which has health information from the National Library of Medicine:


In older adults, depression has been associated with increased fall risk, but the reasons for this link are not fully clear. Given parallels between major depression and Parkinson's disease, we hypothesized that major depression and related affective disorders would be associated with impairment in the ability to regulate the stride-to-stride fluctuations in gait cycle timing.We measured stride-to-stride fluctuations of patients with two forms of mood disorders, unipolar major depressive disorder (MDD) and bipolar disorder, and compared their gait to that of a healthy control group. The primary outcomes were two measures of gait unsteadiness that have been associated with fall risk: stride time variability and swing time variability.Compared to the control group, the two patient groups tended to walk more slowly and with decreased swing time and increased stride time. However, none of these differences was statistically significant. Compared to the control group, swing time variability was significantly larger in the subjects with bipolar disorder (p < 0.0001) and in the subjects with MDD (p < 0.0004).Patients with MDD and patients with bipolar disorder display gait unsteadiness. This perturbation in gait may provide a mechanistic link connecting depression and falls. The present findings also suggest the possibility that measurement of variability of gait may provide a readily quantifiable objective approach to monitoring depression and related affective disorders. In older adults, depression has been associated with increased fall risk ,2. EpideParallels between Parkinson's disease and depression also support the possibility of gait unsteadiness in the latter. Psychomotor studies have revealed deficits in the motor performance of persons with major depression similar to some of the motor disturbances observed in Parkinson's disease ,15. In bGiven the associations between fall risk and depression and the parallels between major depression and Parkinson's disease, we hypothesized that major depression and related affective disorders would be associated with gait unsteadiness and impairment in the ability to regulate the dynamics of gait stability. To this end, we measured the stride-to-stride fluctuations in the gait cycle timing of patients with two forms of mood disorders, unipolar major depressive disorder (MDD) and bipolar disorder, and compared their gait to that of a healthy control group. The primary outcomes were two measures of gait unsteadiness: stride time variability and swing time variability ,19,20. WPatients with a clinically defined major affective disorder were recruited from the clinics of McLean Hospital, a psychiatric teaching center in Belmont, MA. Specifically, patients were invited to participate if they were being treated for either bipolar disorder or unipolar MDD, as defined by DSM-IV criteria . PatientSubjects were instructed to walk at their normal pace on level ground for 35 meters, to turn and to walk the same route back, and to continue walking for a total of six minutes. Study subjects were not aware of the specific questions addressed in this investigation.Previously described methods were used to evaluate gait dynamics and analyze the stride-to-stride fluctuations of gait timing ,19,20. BTo focus on the assessment of the intrinsic dynamics of continuous, usual walking and gait unsteadiness and to insure that the analysis was not influenced by outlier data points, previously described analysis methods were used ,19,20. BResults are reported as means ± standard deviation. For continuous data, the Wilcoxon Rank Sum test  was used to compare each patient group to the control group . Subgroup analyses were performed to evaluate the effects of subject characteristics such as age and use of certain drugs. A p-value less than or equal to 0.01 was considered statistically significant (Bonferroni-like adjustment for the five measures of gait). Statistical analysis was performed using SPSS for Windows (version 10.1).Fifty subjects (17 women) were studied. Subjects were 36.3 ± 14.7 years old. Twenty-three of the subjects had bipolar disorder (mean age: 43.4 ± 14.2 yrs), nine subjects had MDD (mean age: 40.9 ± 16.9 yrs), and eighteen of the subjects were healthy controls (mean age: 24.9 ± 3.5 yrs). Scores on the Clinical Global Impression (CGI) scale were 0.2 ± 0.4, 3.8 ± 0.9, and 3.2 ± 0.7 for the control, bipolar and MDD groups, respectively. As expected, the mean CGI scores were significantly higher in both patient groups compared to the control group (p < 0.001 for both groups).Table All but one of the subjects with MDD was being treated for acute illness, as were nineteen of the subjects with bipolar disorder. Among the subjects with bipolar disorder, the subjects whose disease was stable tended to walk more normally  compared to those subjects with bipolar disorder being treated acutely. Swing time variability tended to be larger (p = 0.044) in the subjects with bipolar disorder who were being treated acutely (3.2 ± 1.5 %) compared to those who were more clinically stable (2.2 ± 0.3 %).Among the subjects with MDD, swing time variability tended to be higher in subjects on antidepressants (n = 5) compared to subjects not taking antidepressants (p = 0.027). Other measures of gait and the CGI were similar in the MDD subjects who were on or off antidepressants (p > 0.41). One patient with MDD was taking a neuroleptic and none was taking mood stabilizers. Among bipolar patients, there were no significant differences in any of the gait measures in patients who were taking antidepressants (n = 15), neuroleptics (n = 14) or mood stabilizers (n = 12) compared to those who were not. Compared to controls, swing time CV was significantly increased among bipolar patients who were not taking antidepressants (p < 0.001), not taking neuroleptics (p < 0.002) or not taking mood stabilizers (p < 0.001). Stride time CV tended (p = 0.068) to be increased among bipolar patients who were taking antidepressants, neuroleptics, or mood stabilizers (n = 17), compared to those who were not (n = 6). Compared to the controls, swing time CV was significantly increased among the six bipolar patients who were not taking antidepressants, neuroleptics or mood stabilizers (p < 0.007).Subjects in the two patient groups were generally older than the subjects in the control groups. To evaluate if the group effects were only a result of these age differences, we analyzed the subset of all the subjects who were less than forty years of age. In this subgroup (n = 32), mean ages of all three groups were similar (p > 0.32) and CGI scores remained significantly higher in the two patient groups compared to the control group p < 0.0001). The results of this subset analysis are consistent with those shown in Table . The resPrevious studies reported that patients with clinical depression walk more slowly and with less time spent in the swing phase of the gait cycle ,7. The pAlthough not necessarily apparent to the clinical observer, the present quantitative study suggests that severe clinical depression and related major affective disorders may be associated with an unsteady gait, with certain features reminiscent of impairments in Parkinson's disease. There are, however, subtle but important differences. In advanced Parkinson's disease ,19, gaitIn some previous studies that have examined both stride time variability and swing time variability, an increase in one measure was accompanied by an increase in the other measure ,19. ThisAnother related explanation for the discrepancy been stride time variability and swing time variability has been suggested by Gabell and Nayack . They prIn older adults, depression is associated with an increase in the risk of falls and hip fractures ,3. The mA previous study of gait in depression did not find any significant differences in the gait of subjects who were taking medications compared to those who were not . SpecifiThis preliminary study has a number of limitations. As noted, subjects in the control group were generally younger than the two patient groups (mean differences of 4 and 7 years). However, a number of considerations suggest that the observed increase in swing time variability in the patient groups was not simply a function of aging. 1) Subgroup analysis demonstrates that the differences between the groups persist even when only the relatively young subjects (< 40 years of age) are studied. 2) Like the variability of gait speed and stride length, previous work has shown that the variability of stride time and swing time is similar in healthy young and healthy older adults, and that increases in older adults are a sign of pathology -26,30-32The present study has other limitations and raises additional questions that should be addressed in future studies. Among subjects with MDD, we could not evaluate if there were differences between subjects treated for acute illness and those with more chronic symptoms. Further, among patient with bipolar disorder, we did not control for the patients' acute mood status. The present study may have also been underpowered to detect small differences between the patients with bipolar disorder and MDD. A prospective study of a larger number of patients, perhaps in different age groups before and after they undergo different types of therapy, including pharmacologic interventions, should be helpful in leading to a more complete understanding of the relationships among stride variability, fall risk, and medication usage. Such studies may also be helpful in determining the mechanisms whereby depression and related mood disorders influence stride variability, in assessing how this relationship changes over time and with respect to disease state , and in evaluating if stride variability measures may prove clinically useful as an objective measure of major affective disorders. Stride variability is less affected by a conscious effort to alter gait and more closely reflects intrinsic underlying impairment . Additiovariability in major mood disorders may be more sensitive to certain subtle neuropsychiatric influences than measures based only on the mean value of a given parameter. Our findings also demonstrate that measurement of variability of gait may provide a readily quantifiable approach to monitoring depression and other affective disorders. Moreover, these results suggest that this perturbation in gait dynamics may provide a mechanistic link connecting depression and falls in older adults.Despite the limitations of this study, the present findings in a relatively small sample size indicate that patients with MDD and patients with bipolar disorder display gait unsteadiness evidenced by increased swing time variability, even while other measures of gait are not markedly changed. This apparent disparity between measures of stride variability, on the one hand, and gait speed and other features of gait, on the other, raises the possibility that stride-to-stride CV: coefficient of variationThe author(s) declare that they have no competing interests.JMH, ALG and ALS conceived of the study, and participated in its design and coordination. JMH drafted the manuscript. JMH and CKP carried out the time series and statistical analyses. All authors helped to revise the manuscript and read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


If you've ever hit a patch of ice on the road that sent your car swerving left while you resolutely—and futilely—steered right to get back in your lane, you've experienced what neuroscientists call a “visuomotor rotation task.” On a dry road, your response would have been appropriate. But under icy conditions, the same sensory cue produces a decidedly negative result: a car fishtailing out of control. While you're figuring out what movements will straighten out the car, the neurons in your primary motor cortex—the region of the brain responsible for movement—are taking notes. Chances are, your next icy encounter was less dramatic. But how does your brain learn to produce a different movement in response to the same visual cue?Neuroscientists investigate such questions by recording and analyzing the electrical activity of neurons during learning and performance of new sensory-motor transformations. Such studies, for example, show that populations of neurons in different brain areas map sensory cues and desired arm motion by creating an internal representation of the corresponding sensory and motor coordinates in a way that allows flexible responses to changing conditions. In previous studies, Rony Paz and Eilon Vaadia, of The Hebrew University in Israel, found that neurons in the primary motor cortex that fire before monkeys move their arm in a particular direction have higher firing rates after the monkey learns to dissociate the arm direction from the cursor direction . Interestingly, changes in activity preferentially occurred in a subset of neurons that were already tuned  to the direction experienced while learning.While many studies indicate that learning new tasks can generate specific changes in brain activity, it had not been clear how or if such changes improve the internal representation inside the brain. Specifically, is the neuronal code any “better” after learning? Now Paz and Vaadia show that while these neurons are firing at higher rates they are also transmitting more information about specific task parameters.Paz and Vaadia trained two rhesus monkeys to learn various visual-motor tasks—which involved operating a joystick to move a cursor on a screen—and then changed the relationship between the visual feedback (the cursor) and hand movement. Using information-theory analysis—which measures the amount of information that single neurons can tell about the movement—they were able to correlate neuron activity with direction of movement and, conversely, distinguish differences between directions based on neuron activity. Their analysis revealed that the neurons transmit more information about the direction of movement after the monkeys learn a task. To figure out what aspect of neuron activity conveys this improved information, Paz and Vaadia examined two features of neuron signaling—response variability and directional sensitivity—which they reasoned might plausibly accomplish this. Increased information content after learning a task, they found, corresponded to sensitivity to a single direction, and neurons attuned to that direction contributed to the increase.These findings suggest that subsets of directionally sensitive neurons increase their firing rates to more finely tune their sensitivity to that direction. By successfully reconstructing the movement direction from the neuron signals captured after learning a task, Paz and Vaadia also demonstrate that the observed learning improvement can be extracted to predict behavior. The authors argue that their results suggest a close association between properties of neurons—such as directional tuning of cells—and learning a skill that is focused on the same parameter—in this case, direction. Together with results from visual and auditory areas, they propose that similar mechanisms may control the interplay between neurons and learning throughout the central nervous system.


Low and high body mass index (BMI) have been recently shown to be associated with increased and decreased mortality after ICU admission, respectively. The objective of this study was to determine the impact of BMI on mortality and length of stay in patients admitted to the intensive care unit (ICU).2. A multiple logistic regression analysis was used to determine the independent impact of BMI on hospital mortality. The ICU length of stay ratio was defined as the ratio of the observed to the predicted LOS. P-value < 0.05 was considered significant. The 95% confidence interval (CI) was calculated for the odds ratio (OR).In this retrospective cohort study, the Acute Physiology and Chronic Health Evaluation (APACHE) III database of patients admitted to the ICUs of a tertiary academic medical center, from January 1997 to September 2002, was crossed with a Hospital Rule-based Systems database to obtain the height and weight of the patients on admission to the ICU. The cohort was divided in post-operative and non-operative groups. We created the following five subgroups based on the BMI: <18.5, 18.5 to 24.9, 25 to 29.9, 30.0 to 39.9, ≥ 40.0 Kg/mBMI was available in 19,669 of the 21,790 patients in the APACHE III database; 11,215 (57%) of the patients were admitted post-operatively. BMI < 18.5 was associated with increased mortality in both post-operative  and non-operative  patients. Post-operative patients with a BMI between 30.0 to 39.9 had a lower mortality rate . Post-operative patients with BMI <18.5 or BMI ≥ 40 had an ICU length of stay ratio significantly higher than patients with BMI between 18.5 to 24.9. The addition of BMI < 18.5 did not improve significantly the accuracy of our prognostic model in predicting hospital mortality.Low BMI is associated with higher mortality in both post- and non-operative patients admitted to the ICU. LOS is increased in post-operative patients with low and high BMIs. The rel patients. In the mortality.Previous studies did not analyze the data from post-operative and non-operative patients separately when they looked at the impact of BMI on the outcome of critically ill patients. We undertook this study to determine the influence of BMI on mortality in post-operative and non-operative patients admitted to the ICU, in a single tertiary academic medical center. Based on the association of low BMI with increased mortality, a recent publication has highlighted the importance of looking at whether adding BMI would improve the predictive accuracy of the ICU prognostic models. In the In this retrospective, cohort study, we crossed the prospectively collected Acute Physiology and Chronic Health Evaluation (APACHE) III database of adult patients consecutively admitted to the intensive care units of Mayo Medical Center, Rochester, Minnesota, between January 1997 and September 2002, with a Hospital Rule-based Systems database that records the height and weight on admission to the ICU. Patients were admitted to one medical, two surgical and one multi-specialty ICU. Those patients admitted to the neurological, cardiovascular surgery, and coronary care units were not included since they were not part of the APACHE III database. Only first admissions were included in this study. The Mayo Foundation Institutional Review Board approved the study, and a waiver of informed consent was granted. Patients who did not authorize their medical records to be reviewed for research, and those whose weight or height values were missing were excluded.Mayo Medical Center includes two hospitals with a total of approximately 1900 beds. The medical ICU is a 15-bed closed unit in Saint Mary's Hospital. The surgical ICUs consist of a general surgical/trauma 24-bed unit and a 20-bed surgical unit mainly for thoracic and vascular surgery patients, both located at Saint Mary's Hospital. The 12-bed (increased to 17 beds in March 2000) multi-specialty ICU is located in Rochester Methodist Hospital. The patient population in the multi-specialty ICU included liver, kidney, pancreas and bone marrow transplant recipients; and hematology, oncology, general surgery and orthopedic patients.Data were obtained from the APACHE III database using the software provided by Cerner Corporation . Data collected included age, ethnicity, gender, ICU admission source, admission type (postoperative or non-operative), intensity of treatment , ICU admission diagnosis group, ICU length of stay (LOS), APACHE III score, APACHE III-predicted hospital mortality, APACHE III predicted-ICU LOS and hospital discharge status. The admission source was classified as operating room/recovery room (OR/RR), emergency room/direct admission from outpatient clinic (ER/direct), transfer from other floors of the same hospital and transfer from other institutions. All ICU admissions were categorized into three groups based on the intensity of treatment: "active treatment" if a patient received one or more of 33 items of the Therapeutic Intervention Scoring System (TISS) defined as ICU specific therapy on the first ICU day; "high-risk monitor" if a patient who did not receive active treatment on the first ICU day had greater than 10% probability of receiving active treatment during the ICU stay; and "low-risk monitor" if a patient who did not receive active treatment on the first ICU day had less than 10% probability of receiving active treatment during the ICU stay . The ICU2. Four BMI subgroups were created using the cut-off points of the World Health Organization (WHO): 18.5 to 24.9 , 25.0 to 29.9 (grade 1 overweight), 30.0 to 39.9 (grade 2 overweight), ≥ 40 (grade 3 overweight)[The body mass index for each patient (BMI) was calculated as the weight (in kilograms) divided by the square of the height (in meters). All BMIs are presented in Kg/merweight). A fifthP-values.Descriptive data were summarized as mean (standard deviation), median (interquartile range) (IQR) or percentages. The cohort was divided into post-operative and non-operative patients. The primary analysis consisted of a comparison of hospital mortality for each BMI subgroup. A multiple logistic regression model consisting of hospital mortality as a dependent variable, BMI subgroup, APACHE III predicted mortality, admission source, and intensity of treatment as independent variables was created to adjust for potentially confounding variables that could affect hospital mortality. In the post-operative group the admission source was not included in the model since the source in all the patients was either the recovery room or the operating room. This logistic regression model was based on a previous analysis that identified the variables independently associated with hospital mortality. We perfThe ICU LOS ratio was defined as the ratio of the observed to the predicted LOS. LOS ratios less than one indicate stays shorter than predicted. In compP-value < 0.05 was considered statistically significant.StatView 5.0  and MedCalc 7.3  computer softwares were used for statistical analyses. Patients with missing data were excluded from analysis involving the missing elements. A Of the 21,790 patients with first ICU admissions during the study period, 19,669 had height and weight data. Their baseline characteristics are listed in Table P < 0.0001). Among the ICU admission diagnoses, BMI < 18.5 was associated with increased adjusted mortality in cardiovascular, genitourinary and musculoskeletal groups . Compared to the normal BMI subgroup, the ICU LOS ratio was higher in the BMI < 18.5 (P = 0.0411 by Mann-Whitney U test) and BMI ≥ 40 (P < 0.0001 by Mann-Whitney U test).For post-operative patients, the crude hospital mortality rate was 3.3 %, and the median (IQR) ICU LOS and ICU LOS ratio were 1.04 0.82–2.15) and 0.42 (0.25–0.77) days, respectively. After adjusting for confounding variables, postoperative patients with a BMI < 18.5 had a higher hospital mortality, and those with BMI of 30.0–39.9 had a lower hospital mortality rate (Table  and 0.42P = 0.3414)  ICU LOS and ICU LOS ratio were 1.68 (0.89–3.69) and 0.45 (0.25–0.89) days, respectively. After adjusting for confounding variables, the patients with a BMI < 18.5 had a higher hospital mortality rate (Table ) Tables .P = 0.102).In discriminating hospital survivors from non-survivors, the AUC (95% CI) of the model with BMI < 18.5 was 0.859 (0.854 to 0.864) and the AUC of the model without BMI < 18.5 was 0.858 (0.853 to 0.863) (The results of our retrospective study suggest that a BMI <18.5 is independently associated with higher mortality in post- and non-operative patients admitted to the ICU. We found no difference in the ICU LOS among the BMI subgroups in non-operative patients. In post-operative patients, the LOS was longer in patients with a BMI <18.5 or BMI ≥ 40. We also noted that the addition of BMI does not improve significantly the predictive accuracy of the prognostic model.In this study, we wanted to determine the impact of BMI on mortality in post- and non-operative patients separately since patients admitted to the ICUs from hospital wards have higher mortality than patients admitted from the operating room, independent of disease severity,18. In oOur study has several limitations. It has been speculated that a low BMI is simply the consequence of a serious illness before the hospitalization that it is ultimately fatal,6. We haThis study shows that a BMI < 18.5 is independently associated with increased mortality in post- and non-operative patients admitted to the ICU; and in post-operative patients, the LOS was longer in patients with a BMI < 18.5 or BMI ≥ 40. We also found that the inclusion of BMI < 18.5 in a prognostic model does not improve the accuracy of mortality prediction.The authors declare that they have no competing interests.JDF participated in conception, design, acquisition of the data, analysis of the data, and drafting of the manuscript.OG participated in analysis of the data, and critical revision of the manuscript.BA participated in conception, design, analysis of the data, statistical analysis, critical revision of the manuscript, and supervision.The pre-publication history for this paper can be accessed here:


The practice of Evidence-based Medicine requires that clinicians assess the validity of published research and then apply the results to patient care. We wanted to assess whether our soon-to-graduate medical students could appraise and apply research about a diagnostic test within a clinical context and to compare our students with peers trained at other institutions.th year medical students who previously had demonstrated competency at probability revision and just starting first-year Internal Medicine residents were used for this research. Following an encounter with a simulated patient, subjects critically appraised a paper about an applicable diagnostic test and revised the patient's pretest probability given the test result.4The medical students and residents demonstrated similar skills at critical appraisal, correctly answering 4.7 and 4.9, respectively, of 6 questions (p = 0.67). Only one out of 28 (3%) medical students and none of the 15 residents were able to correctly complete the probability revision task (p = 1.00).This study found that most students completing medical school are able to appraise an article about a diagnostic test but few are able to apply the information from the article to a patient. These findings raise questions about the clinical usefulness of the EBM skills possessed by graduating medical students within the area of diagnostic testing. Evidence-based medicine (EBM) has been described as the "conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients" . Thus, tNearly all medical schools now provide their students with instruction on EBM . StudentIn undertaking this research, we wanted to assess the critical appraisal and probability revision skills of our medical students shortly before graduation within the domain of diagnostic testing. We specifically wanted to evaluate medical students who had previously demonstrated competency at probability revision in a classroom setting. Because EBM is designed to support the delivery of clinical care, transfer of these skills from the classroom to the exam room seemed an appropriate measure of instructional success. We were also interested in comparing the skills of our students nearing graduation to physicians just entering the Internal Medicine residency at our medical center with the intention of comparing the skills of our students to those of students who had trained at other medical schools.The data were collected during a performance-based assessment utilizing standardized patients (SPs). During this assessment, subjects had a series of 15 minute encounters with SPs followed by a 10 minute post-encounter activity, thus making each station 25 minutes in length. A 25 minute non-SP based station was integrated into this assessment during which subjects were asked to read and appraise an article about a diagnostic test and apply the information to a preceding SP encounter.Two different groups of subjects participated in this research. The first group was composed of medical students who were assigned to the Psychiatry clerkship in the late winter and spring of 2003. The second group was composed of all incoming first-year Internal Medicine residents who were in the process of orienting to the residency in June 2003 in preparation for their clinical duties.Subjects were asked to critically appraise a research study about a diagnostic test using a worksheet derived from the article about diagnostic tests published in Users' Guides to EBM series . They weThe fourth year medical students, who were participating in their Psychiatry clerkship, were asked to assess an article about a questionnaire to aid in the diagnosis of Major Depression and Panic Disorder . The IntFor this study, the calculated posttest probability was considered correct if it was ±5% of the correct answer derived from Bayes' Theorem. The performances of the medical students and the Internal Medicine residents were compared using Fisher's Exact Test for dichotomous outcomes and t-test for continuous outcomes. Cronbach's alpha was used to calculate the internal reliability of the 6-item critical appraisal worksheet for each group of subjects. The analyses were undertaken using NCSS 2004 . An alpha of 0.05 was used and all tests were 2-tailed. Approval from the institutional review board was obtained for this project.th year medical students who had demonstrated mastery of Bayesian probability revision during a preceding Laboratory Medicine clerkship. The data from these students were analyzed for this report. The other 10 students were dropped from the analysis because they were either M3s or M4s who had not yet completed their Laboratory Medicine clerkship.Thirty-eight medical students on the Psychiatry clerkship completed the critical appraisal exercise. Twenty-eight of these students were 4Twenty-two first year Internal Medicine residents participated in this performance-based assessment and completed the EBM appraisal task and Bayesian inference exercises during their clinical skills assessment. For this report we used the data from the 15 residents who were recent graduates of US medical schools. The data from the 7 non-US graduates were dropped from the analysis.Twenty-six of the 28 medical students (93%) correctly identified whether there was an independent, blind comparison of the test with a reference standard Table . SeventeAll 15 residents (100%) correctly identified whether there was an independent, blind comparison of the test with a reference standard. Eight (53%) correctly identified the reference standard. Eleven (73%) correctly assessed whether referral bias was present, and fourteen (93%) were able to comment on the generalizability of the study. Thirteen (87%) of the Internal Medicine residents were able to identify the sensitivity and specificity of the test for congestive heart failure. The internal reliability of the 6-item appraisal work sheet was 0.66 for this group of subjects. On average, a resident, who had just recently graduated from a US medical school, correctly answered 81% of the questions related to critical appraisal but none of the 15 residents (0%) were able to revise the pretest probability given a test result.Overall, the performances of the two groups of subjects were very similar. We did not find any significant differences in their ability to critically appraise an article about a diagnostic test. Medical students, on average, correctly answered 4.7 of the 6 questions related to appraisal while residents correctly answered 4.9 of these questions (p = 0.67). The two groups also showed similar performance on each of the 6 items on the worksheet as shown in Table Over the past decade, EBM has become a major driving force world wide, impacting medical education, policymaking, and research. The teaching of evidence-based medicine has been increasingly integrated into curricula at all levels of medical education as advocated by the Medical School Objectives Program developed by the Association of American Medical Colleges (AAMC) . Like moOur finding that incoming residents demonstrate similar levels of skill at critically appraisal and also are unable to revise a pretest probability implies that our medical students' skill deficit is not solely due to a local curricular problem. Because the residents had only just graduated from 12 different US medical schools, this finding suggests that many medical school graduates are able to critically appraise articles on diagnostic testing but few are able to take the next step- that of revising the probability of disease given a test result.rd year medical students demonstrated good performance at critically appraisal [There are few other assessments of the EBM skills of graduating medical students using simulated clinical encounters. In an earlier study, 3ppraisal , a findippraisal . To our ppraisal .Our study has a number of limitations. The first is the very small sample size. However, it is unlikely that a larger sample size would change our conclusion that by the end of medical school students have largely mastered critical appraisal of an article on diagnostic testing but are unable to use this information to revise a patient's probability of disease. A second limitation is that these data were collected at only one medical school. However, as we find the same pattern of competencies in the recently graduated students who are entering our Internal Medicine program it is likely that our findings apply to many other medical schools. A third limitation is that we had our two groups of subjects critically appraise two different articles although they were very similar from this perspective. A final limitation is that it is possible that our subjects would have demonstrated competency in probability revision if we had provided them with a Bayes nomogram or computer spreadsheet. But we wanted to assess whether our students could apply EBM skills to a clinical encounter without any other external supports except for a simple calculator. In the same way, we do not allow our students to take handbooks or other work aids into their 15 minute OSCE encounters with standardize patients.The poor performance of our students and residents at probability revision is worrisome although previous studies have shown that many clinicians do not master Bayesian inference. Nearly 25 years ago, Casscells documented that few students or faculty at Harvard Medical School were able to correctly complete a probability revision problem . Eddy duCurrently, most of our medical students are able to critically appraise research articles about diagnostic testing but few are able to apply this information at the patient level using Bayesian inference. Because we are able to document the same pattern of skills in entering Internal Medicine residents, we expect this lack of competence with probability revision to be wide spread amongst medical learners. This raises concerns about the clinical utility of the EBM training many students are currently receiving within the domain of diagnostic testing.The authors declare that they have no competing interests.GB conceived of the study. GB, SV, JT, EF participated in study design. GB, EF, RF participated in data collection. GB performed the data analysis. GB, SV, ST, EF, RF participated in drafting the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


Escherichia coli and Bacillus subtilis. Computer modeling of chemotaxis in these species now reveals some important differences in the network architecture that controls this complex behavior.When we think of foraging for food, we usually imagine animals wandering in the woods, poking behind bushes and trees, trying to find something tasty. Amazingly, even single-cell bacteria display a simplified version of this behavior. Many species of bacteria can respond to chemical or nutritional cues (chemoattractants) in the environment by moving toward locations with more favorable conditions, a process known as chemotaxis. The bacteria adjust their movements by rotating threadlike projections called flagella either clockwise or counterclockwise; these adjustments are made by a network of proteins in response to chemoattractants. Chemotaxis has been identified in many bacterial species, but two of the best-studied examples are in E. coli and B. subtilis have been identified and well studied, but much remains to be learned about this biological process. As scientists have begun to understand how the proteins work together, they're discovering a network of interactions that operates a bit like an electronic circuit. Researchers have found that using the circuit as a model for protein networks has helped them to understand how complex system properties arise from seemingly simple interactions between proteins. These properties can be explored with the aid of computer simulations, whereby researchers can rapidly test a given system under many different situations and can tweak the properties of the proteins and their connections.Most of the proteins involved in chemotaxis in E. coli and B. subtilis. Not surprisingly, the proteins involved in the signaling pathway are conserved—that is, they have changed very little since they first evolved—even though these species are evolutionarily very distant. In many cases, a gene from one species can even substitute for the ortholog (a conserved gene that retains the same function even though two species have diverged) in the other. Despite these similarities, however, disrupting the function of orthologous genes in these two species often has different, even opposite, effects. This is surprising, especially given that the chemotactic behaviors of E. coli and B. subtilis are almost identical. In order to understand this puzzling observation, the researchers constructed a network model of the chemotaxis system in B. subtilis and used simulations to understand how the network properties differ from those of existing models of E. coli chemotaxis.The team, led by Adam Arkin of the University of California at Berkeley, has compared the system level properties of chemotaxis in the two bacterial species The group found that despite the similarities in proteins and the nearly identical behavior between the two species, the mechanisms underlying the behavior are quite distinctive. When comparing the system properties of these two bacterial systems, the researchers also made an unusual observation. Though the two “circuits” have different wiring, the system properties underlying the behavior, called the control strategy, are very similar. The two species of bacteria therefore achieve the same chemotaxis behavior by using similar proteins, but in different ways.Arkin and colleagues draw two important conclusions from these results. First, these two systems have conserved proteins, but the proteins are wired together differently. This means that wiring of signaling networks cannot be inferred simply by identifying the conserved proteins in the network. Second, in these systems, conserved proteins use different mechanisms to accomplish the same overall control strategy. This raises the question of how such systems evolve. The authors suggest that the control strategy itself may be an evolutionarily conserved property. These conclusions will be important to keep in mind as researchers examine these systems in more detail and begin to examine more complex systems as well.


Omega-3 fatty acids play a critical role in the development and function of the central nervous system. Emerging research is establishing an association between omega-3 fatty acids  and major depressive disorder. Evidence from epidemiological, laboratory and clinical studies suggest that dietary lipids and other associated nutritional factors may influence vulnerability and outcome in depressive disorders. Research in this area is growing at a rapid pace. The goal of this report is to integrate various branches of research in order to update mental health professionals. Major depressive disorder (MDD) is a recurrent, debilitating, and potentially life threatening illness. Over the last 100 years, the age of onset of major depression has decreased, and its overall incidence has increased in Western countries. The increases in depression, up to 20-fold higher post 1945, cannot be fully explained by changes in attitudes of health professionals or society, diagnostic criteria, reporting bias, institutional or other artifacts .Depression is undoubtedly an extremely complex and heterogeneous condition. This is reflected by the non-universal results obtained using cognitive-behavior and antidepressant medications. As research continues to mount, it is becoming clear that neurobiology/physiology, genetics, life stressors, and environmental factors can all contribute to vulnerability to depression. While much attention has been given to genetics and life stressors, only a small group of international researchers have focused on nutritional influences on depressive symptoms. Collectively, the results of this relatively small body of research indicate that nutritional influences on MDD are currently underestimated . Omega-3Omega-3 fatty acids are long-chain, polyunsaturated fatty acids (PUFA) of plant and marine origin. Because these essential fatty acids cannot be synthesized by the human body, they must be derived from dietary sources. Flaxseed, hemp, canola and walnut oils are all generally rich sources of the parent omega-3, alpha linolenic acid (ALA). Dietary ALA can be metabolized in the liver to the longer-chain omega-3 eicosapentaenoic (EPA) and docosahexaenoic acid (DHA). This conversion is limited in human beings, it is estimated that only 5–15% of ALA is ultimately converted to DHA . Aging, The dietary intake of omega-3 fatty acids has dramatically declined in Western countries over the last century, the North American diet currently has omega-6 fats outnumbering omega-3 by a ratio of up to 20:1. There are a number of reasons for this skewed ratio, most notably the mass introduction of the aforementioned omega-6 rich oils into the food supply, either directly or through animal rearing practices . The ideA number of epidemiological studies support a connection between dietary fish/seafood consumption and a lower prevalence of depression. Significant negative correlations have been reported between worldwide fish consumption and rates of depression . ExaminaNot all studies support a connection between omega-3 intake and mood. A recent cross-sectional study of male smokers, using data collected between 1985 and 1988, indicated that subjects reporting anxiety or depressed mood had higher intakes of both omega-3 and omega-6 fatty acids . In a laThe epidemiological studies which support a connection between dietary fish and depression clearly do not prove causation. There are a number of cultural, economic and social factors which may confound the results. Most significantly, those who do consume more fish may generally have healthier lifestyle habits, including exercise and stress management. Despite the limitations, the epidemiological data certainly justify a closer examination of omega-3 fatty acids in those actually with depression.There are a number of methods used to determine EFA status in the human body, notably the plasma and red blood cell (RBC) phospholipids. These are a reflection of dietary fatty acid intake within the preceding few weeks. While not identical, significant correlations exist between blood and brain phospholipids. A number of studies have found decreased omega-3 content in the blood of depressed patients -21. FurtMore recently, investigators have been utilizing adipose tissue as a longer term measurement of EFA intake (1–3 years). In a study of 150 elderly males from Crete, the parent omega-3 ALA adipose tissue stores were negatively correlated with depression . A separRelationships between omega-3 status and post-partum depression have also been investigated. In a cohort of 380 Australian women, plasma DHA was investigated at 6 months post-partum. Logistic regression analysis indicated that a 1% increase in plasma DHA was associated with a 59% reduction in the reporting of depressive symptoms . It is wSuicide attempts have also been associated with low levels of RBC EPA. In a study involving 100 suicide attempt cases in China compared to 100 hospital admission controls, there was an eightfold difference in suicide attempt risk between the lowest and highest RBC EPA level quartiles . The seaThe overlap between cardiovascular disease and depression has also been noted, with omega-3 status emerging as a common thread. Indeed, major depression in acute coronary syndrome patients is associated with significantly lower plasma levels of omega-3 fatty acids, particularly DHA . In addiIt is important to note that not every study supports an association between lowered omega-3 status and depression. Two studies have actually shown significant increases in plasma and RBC omega-3 status among depressed patients ,33. A reDetailed reviews of the possible neurobehavioral mechanisms of omega-3 fatty acids have been previously published and are beyond the scope of this review ,36. The The second area where omega-3 fatty acids may exert significant influence in major depression is via cytokine modulation. A growing body of research has documented an association between depression and the production these proinflammatory immune chemicals. These cytokines, including interleukin-1 beta (IL-1β), -2 and -6, interferon-gamma, and tumor necrosis factor alpha (TNFα), can have direct and indirect effects on the CNS. Some of the documented activities of these cytokines include lowered neurotransmitter precursor availability, activation of the hypothalamic-pituitary axis, and alterations of the metabolism of neurotransmitters and neurotransmitter mRNA . ResearcOmega-3 fatty acids, and EPA in particular, are well documented inhibitors of proinflammatory cytokines such as IL-1 β and TNFα. In addition, it has recently been suggested that the anti-inflammatory role of omega-3 fatty acids may influence brain derived neurotrophic factor (BDNF) in depression . BDNF isThe epidemiological and laboratory studies, along with the research which shows depressed patients appear to have lowered omega-3 status, have naturally led to clinical investigations. A number of case reports have appeared in the literature, the first of which was over 20 years ago. In this initial series of case reports, flaxseed oil (source of the parent omega-3 ALA) at various dosages, was reported to improve the symptoms of bipolar depression and agoraphobia . An addiDespite the interesting results, there are major scientific problems with case reports, most notably the placebo response. A recently published case report published took advantage of modern brain imaging to corroborate clinical improvements. In this case a patient with treatment resistant depression was placed on a daily dose of 4 g pure EPA, and after one month there were significant improvements, including a co-morbid social phobia. After nine months the patient was reportedly symptom free. It was found that over the course of the nine months of treatment, there was a 53 percent increase in cerebral phosphomonoesters and the ratio of cerebral phosphomonoesters to phosphodiesters increased 79 percent, indicating reduced neuronal phospholipid turnover. Utilizing MRI technology, the researchers found that the EPA treatment was associated with structural brain changes, including a reduction in lateral ventricular volume. This is likely to be a result of increased phospholipid biosynthesis and reduced phospholipid breakdown . Given tA series of case reports also suggest that 1 – 4 g of pure EPA may be helpful in anorexia nervosa, a condition with the highest risk of morbidity and mortality among psychiatric disorders . In all An interesting study examined fish oil vs.marine oil extracted from Antarctic krill in premenstrual syndrome. Krill is similar to fish oil, with the exception that it contains naturally-occurring phospholipids, and contains more EPA per gram than standard fish oil capsules (240 mg/g EPA in krill vs.180 mg/g in standard fish oil). In the 3-month trial, patients (n = 70) received 2 g of krill oil or 2 g fish oil daily for one month, then for eight days prior to, and two days during, menstruation for the following two months. Evaluation at 45 days and three months showed that krill oil significantly improved depressive symptoms of premenstrual syndrome. The absence of significant effects of fish oil on mood suggests that the presence of the phospholipids and/or higher amounts of EPA may be responsible for the therapeutic effect of krill oil .There have been some controlled studies that have examined omega-3 fatty acids and a placebo intervention in depression. The first small clinical study (n = 30) showed that four months of treatment with 9.6 g of omega-3 fatty acids (6.2 g EPA/3.4 g DHA) was of therapeutic value in bipolar disorder. Specifically, this study showed a highly significant effect in treating depression (p < 0.001 HRSD scores) . In a seIn a small pilot study (n = 30), Harvard researchers found that just 1 g of EPA could reduce aggression  and depressive symptom scores  among borderline personality disorder patients. The results of this 2-month, placebo-controlled study are encouraging, given the difficulty in treating borderline personality disorder. It is also of note that 90 percent of participants remained in the study and no clinically relevant side effects were noticed with EPA .In a double-blind, placebo-controlled trial over two months, high dose fish oil (9.6 g/day) was added to standard antidepressant therapy in 28 patients with MDD. In this study the patients who received the omega-3 fish oil capsules had a significantly decreased score on the HRSD compared to those taking the placebo. Once again, the fish oil, even at this high dose, was well tolerated with no adverse events reported .Various doses of pure EPA have also been investigated in depression. In a 12-week, randomized, double-blind, placebo-controlled study, patients (n = 70) were given ethyl-EPA at doses of 1 g, 2 g or 4 g. The patients in this case had experienced persistent depression, despite ongoing standard antidepressant pharmacotherapy at adequate does. Interestingly, in this study, "less was more." Those in the 1 g per day group had the best outcome. The patients who received 1 g per day of EPA were the only group to show statistically significant improvements. Among the 1 g/day group, 53 percent achieved a 50 percent reduction in HRSD scores. The 1 g EPA led to improvements in depression, anxiety, sleep, lassitude, libido, and suicidal ideation. These findings suggest that omega-3 fatty acids can augment antidepressant pharmacotherapy and/or alleviate depression by entirely different means than standard medications [th – 36th week of pregnancy and was assessed through 12 weeks post-partum. In these women the fish oil combination did not reduce the risk of relapse [To date, the published data on supplementation with pure EPA on MDD or depressive symptoms have been positive. With regard to DHA or a combination of EPA and DHA, there have been three negative reports. A trial on DHA alone as monotherapy in the treatment of MDD was recently reported. In this study, 2 g pure DHA or placebo was administered to 36 patients with depression for six weeks. The response differences between the groups, as measured by scores on the Montgomery-Asberg Depression Rating Scale did not reach statistical significance . In an o relapse . Finally relapse .It is important to consider the nutrients which can ultimately influence omega-3 status. Among them, four important dietary factors also relate to MDD: zinc, selenium, folic acid and dietary antioxidants. A number of studies have shown that zinc levels are lower among patients with depression and a recent study found that 25 mg zinc supplementation may improve depressive symptoms . InteresRegarding folic acid, a growing body of research has documented the low levels of folic acid among patients with depression . In addiIn patients with MDD there are in fact signs of oxidative stress and lipid peroxidation, and antidepressant medications may reverse the severity of oxidative stress in depressed patients . A recenWhile far from robust, there is enough epidemiological, laboratory and clinical evidence to suggest that omega-3 fatty acids may play a role in certain cases of depression. Fish oil supplements are well tolerated, and have been shown to be without significant side effects over large scale, 3-year research . GeneralThe research reviewed here shows that the data is far from unequivocal. Large trials are warranted to truly determine efficacy, appropriate dosing and the potentially active components – EPA, DHA, or both. It is also clear that omega-3 intake occurs in dietary context, one that includes other important nutrients. Future research should consider the influence of zinc, selenium, folic acid and dietary antioxidant status to determine who may be a successful candidate for omega-3 supplementation.In the meantime, given the current excess intake of omega-6 rich oils, and the emerging research on omega-3 fatty acids and MDD, all mental health professionals should at least ensure adequate intake of omega-3 fatty acids among patients with MDD. The current average North American intake of EPA and DHA is approximately 130 mg per day, well short of the minimum 650 mg recommended by the international panel of lipid experts [