While the majority of patients with cancer treated with chemotherapy initially respond to treatment, a sub-group of patients either do not respond or eventually stop responding to the therapy in a phenomenon known as tumor cell resistance. Evidence of many different mechanisms of resistance have been reported in the literature, and it remains a great challenge to delineate the pathways involved, and subsequently develop therapies to combat and overcome chemotherapy resistance. It is only in the understanding of the mechanisms of tumor cell resistance to cytotoxic drug-induced apoptosis at the molecular and biochemical levels that will allow the development of drugs that target the resistance factors.Dr. Benjamin Bonavida is well-qualified to edit this book given his expertise as he has years of investigation, and well over 100 publications devoted to understanding tumor cell resistance. Dr. Bonavida has assembled a stellar cast of contributing authors that are clearly leaders in this field of study. The book, while quite comprehensive, is not designed to, nor does it attempt to cover the entire field of drug resistance. The focus of the book is to highlight specific mechanisms of cancer drug resistance and review or propose new treatments targeting each of these mechanisms. The contributing authors of the 12 chapters provide reviews of widely studied aspects of cancer drug resistance, present the latest findings, and offer speculative targets for novel drug development. Both tissue specific mechanisms/interventions and targets common to many cancers are included. The practice of single agent administration and the use of sensitizing drugs synergized with other therapies are also discussed. A brief overview of some of the chapters contained in the book follows.The first chapter may be the most important one for readers that are not already familiar with cancer drug resistance. It gives an excellent overview of the phenomenon of multidrug resistance (MDR) by the overexpression of the ATP-binding Cassette (ABC) drug transporters. The chapter details the structure and function, substrate specificity, and the polymorphic effects on the three most important ABC genes. Small molecule targeted therapies and natural products as modulators (enhanced by well-referenced tables) are reviewed. This chapter is followed by a review that provides details on the role of pH changes that alter physical properties of the cell membrane and MDR functions. The remaining chapters each review important mechanisms and pathways that contribute to chemotherapy resistance and the treatment strategies to overcome this phenomenon.An interesting chapter worth mentioning reviews what is currently understood about “collateral sensitivity,” or hypersensitivity to otherwise drug-resistant cells. This is a lesser-known multiple mechanism process in drug resistance, and a possible novel treatment strategy. The challenges of optimizing combination therapies, cross-resistance and hypersensitivity in multidrug-resistant cells are reviewed in detail. This chapter contains an especially helpful table describing collateral sensitivity in drug-resistant tumors broken down by currently used cell lines.The Raf/MEK/ERK signaling pathways are often aberrantly activated in cancer and the description of the mechanisms of Raf inhibitor resistance and therapies to target this are discussed in two comprehensive chapters. The need for, and application of, combination therapies designed to co-target multiple aspects of signaling pathways is presented with an emphasis on personalized medicine. B-Raf as a target for anti-cancer agents and novel therapeutic strategies are reviewed.In one of several chapters that focuses on a tissue specific cancer, the role of β 1 integrins and resistance to lung cancer is discussed. This chapter highlights the importance of the β 1 integrin-extracellular matrix signaling in tumorigenesis and subsequent drug resistance. The authors describe ongoing efforts to target the β 1 integrin as a potential breakthrough in the successful treatment of lung cancers. The aldo-keto reductase (AKR) genes as targets for chemoresistance in colon cancer are discussed in a separate chapter. Current literature focusing on expression profiles is reviewed and the accompanying figures of the important metabolic pathways are excellent.Many anticancer agents induce Reactive Oxygen Species (ROS) that triggers apoptosis resulting in cancer cell death. A thorough chapter reviews the ROS molecular mechanism. The treatment approach to identify targets for elevating ROS levels as way of sensitizing drug-resistant cells is also discussed in detail. Well-written and referenced chapters that review the role of apoptosis, DNA repair and signal transduction pathways, TRAIL-apoptotic pathway, and cancer stem cells in resistance to cytotoxic drugs are also included in the book.Overcoming cancer drug resistance has become a priority in the treatment of many types of cancer with drug-resistant cells becoming harder to kill even with the arrival of new cytotoxic drugs. The field is complicated due to the wide array of pathways and mechanisms involved. In conclusion, this well-organized book provides the reader with an excellent overview of the field of cancer drug resistance. The test is informative and comprehensive complemented by extensive references and helpful schema that make this book a valuable resource for students, those new to the field, and veteran investigators.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Damage to the articular cartilage is an important, prevalent, and unsolved clinical issue for the orthopaedic surgeon. This review summarizes innovative basic research approaches that may improve the current understanding of cartilage repair processes and lead to novel therapeutic options. In this regard, new aspects of cartilage tissue engineering with a focus on the choice of the best-suited cell source are presented. The importance of non-destructive cartilage imaging is highlighted with the recent availability of adapted experimental tools such as Second Harmonic Generation (SHG) imaging. Novel insights into cartilage pathophysiology based on the involvement of the infrapatellar fat pad in osteoarthritis are also described. Also, recombinant adeno-associated viral vectors are discussed as clinically adapted, efficient tools for potential gene-based medicines in a variety of articular cartilage disorders. Taken as a whole, such advances in basic research in diverse fields of articular cartilage repair may lead to the development of improved therapies in the clinics for an improved, effective treatment of cartilage lesions in a close future. Articular cartilage damage is an important, prevalent, and unsolved clinical issue following joint trauma or during osteoarthritis (OA). In the absence of vascularity, the cartilage does not have access to progenitor cells that may support and participate in regenerative processes. Clinical interventions such as marrow stimulation techniques that support cell invasion from the bone marrow do not restore the original cartilage structure and function in the lesions. Instead, these options lead to the formation of a poorly organized, mechanically inadapted fibrocartilage made of type-I collagen instead of type-II collagen with proteoglycans that are normally found in the hyaline cartilage  lesions. The three-dimensional (3D) environment of a scaffold is crucial in cartilage engineering strategies for cell entrapment, proliferation, and chondrogenic differentiation. A scaffold must display the several, following features: they must be biocompatible, must allow for cell adhesion and proliferation, and preferably be biodegradable. Various biodegradable scaffolds based on natural or synthetic polymers have been developed for cartilage tissue engineering , adipose tissue, umbilical cord, Wharton’s jelly, and the synovial membrane. BMSCs are currently the most studied and best characterized progenitor cells for cartilage engineering. Recently, a new, promising strategy for cartilage regeneration has been identified by isolating MSCs from the synovial fluid, with expansion over a short period of time, leading to the successful differentiation of the cells in chondrocytes  and the synthesis of cartilage-specific matrix molecules  while downregulating the expression of genes associated with terminal differentiation (type-X collagen) , contributing to the maintenance of the chondrocyte phenotype and to a tight control of the chondrogenic commitment and differentiation of various types of MSCs. MSC isolation and expansion under hypoxic conditions (3%) increases the ability of the cells to undergo a more robust chondrogenesis. Studies also suggest that hypoxia, like growth factors, may be a potential tool to control hypertrophic MSC differentiation  the presence of growth or soluble factors, 2) the effects of mechanical loading, and 3) the stimulation by environmental factors such as hypoxia. The presence of growth or soluble factors (e.g. vitamins) in the culture medium is known to modulate the conditions of chondrocyte culture and chondrogenic differentiation. Members of the transforming growth factor beta (TGF-β) superfamily are good candidates to promote chondrogenesis Figure . Additioversus resident-matrix type-I collagen is a crucial step for non-destructive, preclinical implantation validation. The goal of our work was to develop a novel, non-invasive procedure that permits to characterize the collagen network in 3D constructs by Second Harmonic Generation (SHG) imaging . To achieve a purpose-made biofunctionality, engineered cartilage needs to exhibit biochemical and physical properties similar to those of the native, hyaline cartilage. Additionally, early analysis of the amount of type-II collagen produced To integrate the notion of multiscale imaging in real “clinical” live  analyses, a two-photon excitation laser was adapted to a macroscope optical way. To combine multidimensional fluorescence data , a new multimodality imaging (SHG-TCSPC) based on the SHG method was considered to detect especially collagen matrix and Time Correlated Single Photon Counting (TCSPC) method to contrast signal   evaluation (5-μm thick sections). Similar increases in type-II collagen expression produced by the cells seeded in the constructs were noted after 28 days of culture with TGF-β1 using either microscopic or macroscopic tests. The levels achieved were always higher than in the absence of growth factor, regardless of the technique applied .The technique was validated using human BMSCs (hBMSCs) as a population of cells capable of chondrogenic differentiation when subjected to appropriate culture conditions (Kuroda & Dezawa ex vivo cartilage degeneration (density and homogeneity of the collagen matrix). This technique may be used for the convenient and rapid screening of a large number of biomaterials simultaneously, noninvasively, and nondestructively, as a means to optimize the implant before grafting in a cartilage lesion  due to the rapid clearance from the host. Approaches based on the transfer of genetic coding sequences have the advantage of allowing for the sustained production of a candidate agent in a desired location like in a cartilage lesion (Cucchiarini & Madry Recombinant adeno-associated virus (rAAV) vectors are currently the best suited, clinically relevant gene delivery systems for human gene therapy and regenerative medicine as they are based on the non-pathogenic, replication defective adeno-associated virus (AAV) and have been reported for both their elevated gene transfer efficiencies and higher safety compared with other more classical classes of vectors   to successfully modify normal and OA human adult articular chondrocytes in primary culture in vitro, in cartilage explant tissue in situ, and in sites of articular damage in vivo  and transcription (SOX9) factors in cartilage lesions in clinically relevant animal models of focal defects and of OA were next documented, allowing to improve the capacities of this tissue for stable repair for at least 4 months Altogether, rAAV vectors appear as particularly advantageous gene vehicles capable of promoting the effective, durable, and safe healing and remodelling of injured articular cartilage. The recent example of the market authorization of Glybera®   the well-established link between OA and obesity and 2) the changes in the whole OA joint, including synovium, bone, muscle, ligaments, joint capsule, and cartilage  is an important candidate to become the focus of investigations that aim at further understanding the pathophysiology of OA  were isolated after sequential enzymatic digestion of the corresponding tissues. The data showed that the IFP released elevated amounts of leptin and adiponectin. Interestingly, the IFP from male OA patients exhibited similar secretory activity than the scAT, but the production of both adipokines differed between both adipose tissues for female OA patients. The IFP was the major source of adiponectin while the scAT released elevated levels of leptin. Besides, the conditioned media from IFP strongly induced the expression of microsomal prostaglandin E synthase-1 (mPGES-1) and cyclooxygenase-2 (COX-2) both in chondrocytes and synoviocytes. The mRNA level for inducible nitric oxide (NO) synthase (iNOS) was markedly increased in chondrocytes but not in synoviocytes. The expression of the genes encoding degradative enzymes  and to a lesser extent that of IGF-I was upregulated in the chondrocytes. In contrast, the conditioned media from the IFP did not stimulate the expression of TGF-β, aggrecan, or type-II collagen. Conditioned media from the IFP increased the production of PGE2 and NO and the activity of MMP13 in chondrocytes, stimulating also the release of PGE2 in culture supernatants from synoviocytes (Table The data indicated that IFP is a particularly active organ with a major endocrine function, releasing notably leptin and adiponectin. The IFP and scAT exhibited different secretory patterns for adipokines in female OA patients. More importantly, the IFP may also be an important source of inflammation for chondrocytes and synoviocytes, thus contributing to articular changes associated with OA. Future studies on the identification of IFP-derived inflammatory mediators and on the characterization of infiltrating immune cells will be critical to understand the biology of this tissue.in vivo. In the field of gene therapy, the recent example of the market authorization of an rAAV vector-based gene medicine raises strong hopes for a clinical translation of this potent technology for musculoskeletal applications. Finally, the IFP has been identified as another particularly active organ involved in OA. It remains to be seen whether apart from its roles in OA, the IFP and in particular its associated mediators might be of value as targets for therapeutic interventions to enhance cartilage repair. Such advances in basic scientific and translational research in diverse fields of articular cartilage repair may have strong value to further develop improved clinical therapies (Madry Despite the availability of various options in the clinics, lesions to the articular cartilage remain a major unsolved problem due to the poor healing properties inherent to this avascular tissue. The development of new, effective therapeutic regimens is therefore critical to stimulate the intrinsic repair capacities of the cartilage. The use of basic science tools including cells, genes, and biomaterials that might be implanted in sites of cartilage lesions may open new avenues of clinically adapted research in orthopaedic surgery. Challenges that remain to advance the field of cartilage engineering include the choice of the best suited source of cells to undergo optimal chondrocyte differentiation without undesirable, premature chondrocyte hypertrophy and osseous metaplasia in dedicated scaffolds (Johnstone et al. es Madry .In light of the new advancements in basic and applied experimental cartilage research, establishing a constant exchange of knowledge between scientists and clinicians appears to be the most adapted method to generate new, effective therapeutic options for an optimal treatment of articular cartilage lesions in patients.


This practice guideline was developed to provide recommendations to clinicians in Ontario on the preferred standard radiotherapy fractionation schedule for the treatment of painful bone metastases.A systematic review and meta-analysis was performed and published elsewhere. The Supportive Care Guidelines Group, a multidisciplinary guideline development panel, formulated clinical recommendations based on their interpretation of the evidence. In addition to evidence from clinical trials, the panel also considered patient convenience and ease of administration of palliative radiotherapy. External review of the draft report by Ontario practitioners was obtained through a mailed survey, and final approval was obtained from the Practice Guidelines Coordinating Committee.Meta-analysis did not detect a significant difference in complete or overall pain relief between single treatment and multifraction palliative radiotherapy for bone metastases. Fifty-nine Ontario practitioners responded to the mailed survey (return rate 62%). Forty-two percent also returned written comments. Eighty-three percent of respondents agreed with the interpretation of the evidence and 75% agreed that the report should be approved as a practice guideline. Minor revisions were made based on feedback from the external reviewers and the Practice Guidelines Coordinating Committee. The Practice Guidelines Coordinating Committee approved the final practice guideline report.For adult patients with single or multiple radiographically confirmed bone metastases of any histology corresponding to painful areas in previously non-irradiated areas without pathologic fractures or spinal cord/cauda equine compression, we conclude that:Where the treatment objective is pain relief, a single 8 Gy treatment, prescribed to the appropriate target volume, is recommended as the standard dose-fractionation schedule for the treatment of symptomatic and uncomplicated bone metastases.• Several factors frequently considered in clinical practice when applying this evidence such as the effect of primary histology, anatomical site of treatment, risk of pathological fracture, soft tissue disease and cord compression, use of antiemetics, and the role of retreatment are discussed as qualifying statements.Our systematic review and meta-analysis provided high quality evidence for the key recommendation in this clinical practice guideline. Qualifying statements addressing factors that should be considered when applying this recommendation in clinical practice facilitate its clinical application. The rigorous development and approval process result in a final document that is strongly endorsed by practitioners as a practice guideline. Radiotherapy is a well-recognized, effective modality in the palliative treatment of painful bone metastases. Bone metastases are a common manifestation of distant relapse from many types of malignant tumours, especially from cancers of the lung, breast, and prostate. With the advent of effective systemic therapies and improvements in supportive care, cancer patients are expected to live longer and may suffer from metastatic disease for a considerable length of time. Many patients with bone metastases suffer from compromised mobility and performance status.optimal" with different treatment goals, one could recommend that a "preferred" dose-fractionation is one that provides pain relief without undue toxicity and is least onerous to the patient.The optimal dose-fractionation schedule for the treatment of bone metastases is unclear. Two surveys of Canadian patterns of practice found that various fractionation schedules are employed by radiation oncologists, ranging from a single large-dose fraction  to a more prolonged course of 30 Gy/10 fractions over 2 weeks . While dDuring the past decade, significant clinical trial efforts have been devoted to comparing single large-dose radiation 8 Gy to 10 Gy) with multifraction regimens (five to ten fractions) . The two Gy with This provincial guideline was initiated to summarize the evidence and to provide recommendations on the preferred standard radiotherapy fractionation schedule for the treatment of painful bone metastases.This practice guideline was developed by Cancer Care Ontario's Practice Guidelines Initiative (PGI), using the methods of the Practice Guidelines Development Cycle . The praEvidence was selected and summarized by four members of the Supportive Care Guidelines Group (SCGG) and methodologists. Members of the SCGG disclosed potential conflict of interest information, reviewed the analysis of the evidence, and prepared draft recommendations. The SCGG includes palliative care physicians, medical and radiation oncologists, psychiatrists, nurses, psychologists, a chaplain, an anesthetist, a surgeon, methodologists, and administrators. After reviewing the evidence and considering issues of patient convenience and resource utilization, the SCGG reached consensus on draft recommendations. The systematic review and meta-analysis, conducted as the initial step in formulating this practice guideline, has been described elsewhere .External review by Ontario practitioners was obtained through a mailed survey consisting of items that address the quality of the draft practice guideline report and recommendations and whether the recommendations should serve as a practice guideline. The efficacy of the practitioner feedback survey process has been previously described . Final aPractitioner feedback was obtained through a mailed survey of 95 radiation oncologists across Ontario. The survey consisted of items evaluating the methods, results, and interpretive summary used to inform the draft recommendation and whether the draft recommendation should be approved as a practice guideline. Written comments were invited. Follow-up reminders were sent at two weeks (post card) and four weeks (complete package mailed again). The SCGG reviewed the results of the survey.Fifty-nine of the 95 surveys were returned (62% return rate). Key results of the practitioner feedback survey are summarized in Table The practice guideline report was circulated to PGCC members for review and approval. Eleven of the fourteen PGCC members completed and returned ballots. Ten PGCC members approved the practice guideline report as written, and one member approved the guideline and provided suggestions for consideration by the SCGG. Suggestions made were to reword the Target Population section and to clarify the second qualifying statement. The SCGG agreed with the suggestions and modified the guideline accordingly.Standard" refers to what is applicable to the majority of patients, with a preference for patient convenience and ease of administration without compromising treatment efficacy or morbidity. Our meta-analysis of all published randomized trials found no difference in pain relief between single fraction and multifraction treatments . Antiemetic agents should be considered as a prophylaxis, given that 30% or more of patients experienced vomiting following single or multifraction treatment in the two studies that specifically collected patient-assessed nausea/vomiting data ,10.For patients where the treatment objective is pain relief, a single 8 Gy treatment, prescribed to the appropriate target volume, is recommended as the standard dose-fractionation schedule for the treatment of symptomatic and uncomplicated bone metastases. This recommendation applies to adult patients with single or multiple radiographically confirmed bone metastases of any histology corresponding to painful areas in previously non-irradiated areas without pathologic fractures or spinal cord/cauda equina compression. It does not apply to the management of malignant primary bone tumour. The following qualifying statements are provided to support the application of the recommendation in clinical practice:Standard" refers to what is applicable to the majority of patients, with a preference for patient convenience and ease of administration and without compromising treatment efficacy or morbidity.• "• The recommendation does not apply to lesions previously irradiated, or lesions causing cord compression or pathologic fractures, because such patients were mostly excluded from clinical trials examining fractionation schedules.• Prophylactic antiemetic agents should be considered when a significant proportion of the gastrointestinal tract is in the irradiated volume.• Patients and referring physicians should be advised that repeat irradiation to the treated area may be possible.• There is insufficient evidence at this time to make a dose-fractionation recommendation for other treatment indications, such as long-term disease control for patients with solitary bone metastasis, prevention/treatment of cord compression, prevention/treatment of pathologic fractures, and treatment of soft tissue masses associated with bony disease.This practice guideline incorporates recommendations based on a systematic review, comprehensive consideration of how the evidence may be applied to clinical practice, feedback from Ontario practitioners, and input from the Practice Guidelines Coordinating Committee prior to final approval. It is strongly endorsed by practitioners for whom it was developed.ASTRO, American Society for Therapeutic Radiology and Oncology; CARO, Canadian Association of Radiation Oncologists; CT, computed tomography; Gy, gray(s); met, metastasis(es); MRI, magnetic resonance imaging; NCIC, National Cancer Institute of Canada; PGCC, Practice Guidelines Coordinating Committee; PGI, Practice Guidelines Initiative; RTOG, Radiation Therapy Oncology Group; SCGG, Supportive Care Guidelines Group.The authors declare that they have no competing interests.JW was the lead author responsible for designing and conducting the systematic review of the literature and the meta-analysis that informed the practice guideline, and for drafting and modifying the practice guideline report. JW was a member of the Supportive Care Guidelines Group and a Radiation Oncologist at the Juravinski Cancer Centre during the development of this guideline. RW reviewed all drafts of the guideline report and made major contributions to performing the meta-analysis that informed the practice guideline, and provided extensive input to the guideline as a radiation oncologist and methodologist. RW is co-Chair of the Supportive Care Guidelines Group. NL and MJ coordinated input from members of the SCGG, conducted literature searches, and drafted and edited the guideline report. MJ conducted duplicate data extraction and meta-analysis. NL updated the literature search, incorporated new data, conducted the practitioner feedback survey, and coordinated approval of the guideline by the Practice Guidelines Coordinating Committee. As members of the Supportive Care Guidelines Group, AB and TW provided substantial feedback on the guideline report at several points during its development, from both a radiation oncology and methodology perspective. Members of the SCGG provided feedback on all draft guideline reports.The pre-publication history for this paper can be accessed here:


The pancreas is a rare but occasionally favored target for metastasis. Metastatic lesions in the pancreas have been described for various primary cancers, such as carcinomas of the lung, the breast, renal cell carcinoma and sarcomas.We report the case of a 60-year old female with a mass in the pancreatic head four years after partial gastrectomy for gastric adenocarcinoma. The patient underwent a pancreatoduodenectomy. Pathological examination revealed metastases of the primary gastric carcinoma within the pancreatic head and in regional lymph nodes.Pancreatic tumors in patients with a history of non-pancreatic malignancy should always be considered to be a putative metastatic lesion at an unusual site. If the pancreas can be identified as the only site of spread, radical resection may prolong survival. The pancreas is an uncommon location for solitary metastasis from other primary cancers . DespiteA 60-year-old woman presented with elevated blood levels of the tumor markers CEA  and CA 19-9 . Four years before being referred to our institution, the patient had undergone gastric resection (Billroth II gastrectomy) for an adenocarcinoma of the stomach. The tumor was located at the lesser curvature of the gastric antrum, measuring 3 cm in the largest diameter. Pathologic examination revealed a gastric carcinoma of low differentiation, which infiltrated the gastric wall into the subserosal layer without penetrating the serosa. Microscopically, the carcinoma was mainly composed of tubular formations of mitotically active, atypical epithelial cells Figure . The tumFour years after gastric resection, however, ultrasound examination, computed tomography and magnetic resonance imaging revealed an inhomogeneous mass of the pancreatic head, measuring 4 cm in largest diameter Figure . RadiogrThe patient was discharged from the hospital without any perioperative morbidity on the ninth postoperative day. The postoperative blood levels of the tumor markers declined to normal values . Due to the complete surgical resection and the lack of risk factors for recurrence, the patient received no further adjuvant therapy. Under regular follow-up for one year with determination of the tumor markers and computed tomography, the patient revealed no signs or symptoms of local or systemic recurrence.Death from recurrence of gastric adenocarcinoma occurs in 70–75% of patients during the first two years after surgical intervention, however, reports of recurrences more than 10 years after primary diagnosis have been reported as well . The moset al [Adenocarcinomas of the pancreas and of other primary sites frequently display a large histomorphological and immunohistochemical overlap. Thus the differential diagnosis of primary pancreatic cancer versus solitary metastases of other adenocarcinomas may be very difficult – if not impossible – using common pathological and immunohistochemical techniques. According to Robbins et al , solitarPancreatic resections can nowadays be performed with low morbidity and mortality rates, in particular in high-volume centers ,12. ResuThe authors declare that they have no competing interests.MNW collated the information, searched the literature and wrote the manuscript.FB and PS contributed to the pathological aspects of the manuscript and helped in preparing the manuscript.BEF assisted in literature search and writing of the manuscript.MWB and HF managed the patient and helped in preparing the manuscript and edited the final version with PS.All authors read and approved the final version of the manuscript.


In randomized, controlled trials, antidepressant medications have been shown to reduce the duration of major depressive episodes and to reduce the frequency of relapse during long-term treatment. The epidemiological impact of antidepressant use on episode duration and relapse frequency, however, has not been described.Data from two Canadian general health surveys were used in this analysis: the National Population Health Survey (NPHS) and the Canadian Community Health Survey (CCHS). The NPHS is a longitudinal study that collected data between 1994 and 2000. These longitudinal data allowed an approximation of episode incidence to be calculated. The cross-sectional CCHS allowed estimation of episode duration. The surveys used the same sampling frame and both incorporated a Short Form version of the Composite International Diagnostic Interview.Episodes occurring in antidepressant users lasted longer than those in non-users. The apparent incidence of major depressive episodes among those taking antidepressants was higher than that among respondents not taking antidepressants. Changes in duration and incidence over the data collection interval were not observed.The most probable explanation for these results is confounding by indication and/or severity: members of the general population who are taking antidepressants probably have more highly recurrent and more severe mood disorders. In part, this may have been due to the use of a brief predictive diagnostic interview, which may be prone to detection of sub-clinical cases. Whereas antidepressant use increased considerably over the data-collection period, differences in episode incidence and duration over time were not observed. This suggests that the impact of antidepressant medications on population health may have been less than expected. While primary prevention for this condition has remained an elusive goal, provision of treatment has been viewed as having the capacity to reduce its impact on population health. Randomized, controlled clinical trials confirm that treatment with antidepressant medications can favorably impact the course of major depressive disorder. Clinical practice guidelines recommend acute treatment to reduce episode duration, continuation treatment to prevent relapse and maintenance treatment for those at high risk of recurrence [Depressive disorders are among the most important contributors to disease burden at the population level currence .Direct generalization of clinical trial data to the general population results in an expectation that depressive episode frequency and episode duration should be reduced in those receiving antidepressant treatment. However, outcomes reported in clinical trials are not necessarily reflected in "real world" outcome data. Since treatments are not assigned randomly in clinical settings, those treated are likely to have more severe illness (both in terms of episode duration and recurrence risk) than those who do not seek or receive treatment. In such circumstances, the effect of treatment may become confounded with the effect of the underlying disorder itself, and/or its severity .Despite the plausible occurrence of confounding by indication and confounding by severity, population-based studies examining outcomes in relation to treatment status in the general population have not been reported. The objective of the current study was to estimate the incidence and duration of major depressive episodes in members of the general population who are receiving or not receiving antidepressant treatment. The NPHS sample consists of 17,262 subjects selected in 1994 and 1995 (hereafter denoted 1994/95) who have been followed prospectively with interviews every two years since. Data has been released for the first four cycles (1994/95 to 2000/01). The Canadian Community Health Survey (CCHS) is another general health survey conducted by Statistics Canada. The CCHS has a very large sample size  and employed a cross-sectional study design. Data collection for the CCHS occurred in 2000.The National Population Health Survey (NPHS) is a longitudinal general health survey conducted by the Canadian government's statistical agency, Statistics Canada Both the NPHS and the CCHS utilized probability samples, based on the same sampling frame, from the Canadian general population. The sampling procedures incorporated both clustering and unequal selection probabilities. Valid inference therefore requires the use of sampling weights and statistical procedures accounting for non-independence within clusters. In order to deal with these methodological issues, a bootstrap procedure for variance estimation developed by Statistics Canada was employed in this analysis. This procedure accounts for the design effects.Both the NPHS and the CCHS recorded medication use with a series of self-report items. The item relevant to this analysis asked whether the respondent had taken antidepressant medications during the month preceding the interview. Each interview also included the Composite International Diagnostic Interview Short Form for Major Depression (CIDI-SFMD), which was developed and validated by Kessler et al. . This isIn calculating incidence, pairs of observations across NPHS longitudinal data collection cycles were used. There were three suitable intervals covered by the four data collection rounds: 1994/95 to 1996/97, 1996/97 to 1998/99 and 1998/99 to 2000/01.Attrition rates have generally been modest in the NPHS, with 76.6% of subjects having been successfully followed over the first four cycles [Estimates of the number of weeks depressed in the past year derived from the CCHS were computed from 126,715 subjects who provided valid responses both to the CIDI-SFMD (including the duration item) and the antidepressant use survey item. There were 9729 subjects with an episode of major depression in the year preceding the interview and 9508 (97.7%) of these provided valid duration data. Figure Figure Table Direct generalization of clinical trial data to the general population would lead to an expectation that subjects in the general population who report antidepressant treatment should have briefer episodes of major depression than those who do not receive such treatment. Similarly, one might hypothesize that subjects reporting antidepressant treatment should have a reduced incidence of episodes. In the current analysis of national survey data, neither expectation was found to hold true. Subjects reporting an episode of major depression and reporting receipt of antidepressant treatment reported more, rather than fewer, weeks depressed in the preceding year. Similarly, subjects who did not have an episode of major depression in the year preceding an interview but who nevertheless reported using antidepressant medications had a higher risk of having an incident episode than similar subjects who did not report taking antidepressants. The most obvious explanation for these findings is that of confounding by indication or severity.Some of these results may have been due to inadequacies involving the data sources. One of these is the brief, and therefore somewhat crude  nature oItems evaluating antidepressant use in each survey referred to use of the medications during the past month, whereas probable major depressive episodes occurring during the past year are detected by the CIDI-SFMD. Therefore, even though subjects who reported taking antidepressants were found to be more likely to have a subsequent episode of major depression, the data did not allow a determination of whether some of these subjects may have stopped or started antidepressants at some time during the follow-up interval.Another limitation of the data sources used in this project was the lack of comorbidity data. Many of the subjects taking antidepressants may have been doing so for indications such as the prophylaxis of migraine headaches or for treatment of anxiety disorders. Both migraine headaches ,10 and aWhile confounding by indication and severity offer, perhaps, the most appealing explanation for these results it is important to emphasize that the attractiveness of these explanations is based on a set of assumptions: that antidepressants are efficacious in reducing episode duration and the risk of relapse and recurrence. An altered set of initial assumptions leads to other possible interpretations. For example, some authors have hypothesized that antidepressant treatment may lead to a deterioration in the long-term course of mood disorders . This hyGenerally, the public health challenges associated with major depression have been conceptualized in "common sense" terms, and in a way that does not depend on underlying etiological features of the disorder. For example, the idea that preventing relapse (episode incidence) should translate into reduced prevalence and reduced disease burden seems on the surface to be a common-sense belief. However, it has been hypothesized that depression can assume an adaptive role . If an aMost of the literature concerned with major depression and public health has emphasized that the disorder is under-treated, although more recent studies have begun to move beyond the frequency of treatment to address the issue of treatment adequacy . There iCIDI-SFMD Composite International Diagnostic Interview Short Form for Major DepressionDSM-IV Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.MDE Major Depressive EpisodeNPHS National Population Health SurveyCCHS Canadian Community Health Survey (iteration 1.1)The author(s) declare that they have no competing interests.


Bacterial signal transduction mechanism referred to as a "two component regulatory systems" contributes to the overall adaptability of the bacteria by regulating the gene expression. Osmoregulation is one of the well-studied two component regulatory systems comprising of the sensor, EnvZ and the cognate response regulator, OmpR, which together control the expression of OmpC and OmpF porins in response to the osmolyte concentration.Escherichia coli was constructed by integrating the enzyme rate equations using E-CELL system. Using the substance reactor logic of the E-CELL system, a total of 28 reactions were defined from the injection of osmolyte till the regulated expression of porins by employing the experimental kinetic constants as reported in literature. In the case of low osmolarity, steady state production of OmpF and repression of OmpC was significant. In this model we show that the steady state – production of OmpF is dramatically reduced in the high osmolarity medium. The rate of OmpC production increased after sucrose addition, which is comparable with literature results. The relative porin production seems to be unaltered with changes in cell volume changes, ATP, EnvZ and OmpR at low and high osmolarity conditions. But the reach of saturation was rapid at high and low osmolarity with altered levels of the above components.A quantitative model of the osmoregulatory switch operative in ompF and ompC regulatory regions. The preliminary simulation experiment indicates that both reaching steady state expression and saturation is delayed in the case of OmpC compared to OmpF. Experimental analysis will help improve the model. The model captures the basic features of the generally accepted view of EnvZ-OmpR signaling and is a reasonable starting point for building sophisticated models and explaining quantitative features of the system.The E-CELL system allows us to perform virtual experiments on the bacterial osmoregulation model. This model does not take into account interaction with other networks in the cell. It suggests that the regulation of OmpF and OmpC is a direct consequence of the level of OmpRP in the cell and is dependent on the way in which OmpRP interacts with  Among prokaryotes, a remarkable number of cellular functions are controlled by two component regulatory systems . DedicatTwo component systems interact with each other and also with other regulatory systems mediating specific gene expression or cellular locomotion. Such complexes should be analysed quantitatively. Although quantitative data on cellular processes other than metabolism are still relatively sparse, scientists have modeled some systems with considerable success . For exaTwo-component regulatory systems  are widely used signaling machinery of bacterial adaptive responses. The system constitutes of sensor kinases and response regulators that can be phosphorylated and dephosphorylated by sensor kinases  Figure .4) is transferred to a specific Histidine (His) residue in the protein. The transmitter domain possesses a kinase activity that enables it to transfer the phosphate group to the receiver-regulator, when the environmental signal is detected [4) from the transmitter domain. The second domain is the regulator that in response to phosphorylation can bind to specific DNA sequences near specific promoters to activate gene expression. These two domains are linked together by a flexible linker [The first component sensor-transmitter that spans the cytoplasmic membrane has two domains a sensory domain and a transmitter domain. The two domains are anchored in the cytoplasmic membrane by two membrane-spanning regions. The transmitter domain is capable of autophosphorylation utilizing ATP. During this reaction a phosphate group  regulated by the osmotic signal and modulates the ratio of the kinase to phosphatase activity of EnvZ [ompF gene triggering OmpF expression. In case of high osmolyte concentration the kinase activity of EnvZ is triggered resulting in the binding of the phosphorylated regulator to the low affinity promoters of ompC gene favouring OmpC expression [The sensor kinase is triggered by the osmolyte concentration of the environment and controls the production of phosphorylated regulator OmpR. This leads to the expression of outer membrane proteins OmpC or OmpF . Phosphoromoters ,17. OmpRromoters  and reguhia coli . The osmhia coli . First,  of EnvZ ,22. Undepression .ompC and ompF genes. As the number of phosphorylated OmpR protein molecules increases, two events occur: OmpR binds not only to the high affinity binding sites upstream of the ompF promoter but also to the one low affinity-binding site. Binding to this low affinity site results in repression of ompF gene expression. So OmpF porin protein production is stopped. When OmpR binds to the three low affinity sites upstream of the OmpC promoters ompC gene expression is stimulated, more OmpC porin protein is made and appears in the outer membrane of the cell [In the high osmolarity state, EnvZ actively undergoes autophosphorylation at histidine residue-243 in the C-terminal kinase domain, and then efficiently transfers its phosphoryl group to the N-terminal receiver domain of OmpR at aspartate residue-55 through EnvZOmpR complex formation . Upon phthe cell . The sumi.e., high phosphatase activity) towards OmpR. Such osmotic modulation of the kinase/phosphatase activity of EnvZ results in the relative amounts of the phosphorylated form of OmpR in cells varying in response to the medium osmolarity. When the medium osmolarity is low, the relative amount of the phosphorylated form of OmpR in cells is relatively small. In this particular situation, the ompF gene is first triggered, because the ompF promoter has relatively high-affinity OmpR-binding sites [ompC gene with low affinity OmpRP binding sites [In the low osmolarity state Figure , howeverng sites . As the ng sites .In summary, the relative amount of phosphorylated OmpR protein in the cell determines whether OmpF or OmpC is the predominantly expressed outer membrane porin. The relative amount of phosphorylated OmpR is determined by the perception of osmotic pressure by EnvZ .Escherichia coli cells are grown in normal nutrient medium. The first event of start of simulation is the activation of phosphatase activity of EnvZ followed by autophosphorylation of EnvZp by ATP dissociation. Later EnvZpp-OmpR complex formation occurs . OmpF synthesis seen to be triggered at the start of simulation. The entire trend of OmpF synthesis, gradual increase, steady state (at 50 seconds after the start of simulation with about a constant increase of 10 molecules for every 10 seconds) and final saturation  are represented graphically. Figure . A similEscherichia coli cells are grown in nutrient broth with 20% additional concentration of sucrose  [For high osmolarity conditions, the model generated incorporates the concentration of sucrose with the assumption that ivalent) . With thompF promoters and ompC promoters. OmpC molecules start accumulating. In the course of time there is complete dissociation of EnvZkOmpR complex, thereby both sensor and response protein are brought back to the pool  and saturation reaches by 100 seconds. OmpF repression shows steady state increase of 6 molecules for every 10 seconds and finally at saturation takes up a constant value by 90 seconds  in silicos Figure  but stils Figure . Here 10Escherichia coli is associated with osmotic change [-15 Litres was incorporated into the simulation model at low and high osmolarity conditions. In both cases the decrease in volume did not affect the relative porin production. Although the reach of saturation was rapid, the levels of porin and their relative ratios were found to be maintained with the same trend. This agrees with the data by Wood [Escherichia coli K-12. The simulation model presented is at the first phase of physiological and structural responses triggered by osmotic shift where there is decreased cytoplasmic streaming. Our simulation time also corresponds with the time period of this first phase of the responses in the above literature. Table Shrinkage of c change . The eff by Wood  with regEscherichia coli cells [To address the issue whether ATP levels has any effect over relative porin levels, simulation run was done at high and low levels of ATP. ATP level of 3 and 5 mM has been reported in exponentially growing li cells ,36. Simuli cells . This doEscherichia coli in the absence of sensor, EnvZ has been studied [in vitro, EnvZ is required for the maximal OmpC production and for efficient induction of OmpC at high osmolarity. This is established in the in silico model. Also the lack of EnvZ in the simulation did not affect the OmpF at low osmolyte condition and incomplete OmpF repression could be noticed after osmolyte shift as reported by in vitro studies. The relative levels of porins without EnvZ is cross verified with the data reported by Frost et al. [Regulation of OmpC and OmpF expression in  studied . We havet et al. , over stWithin the context of the EnvZ/OmpR two component system, the mathematical model predicts the OmpF/OmpC transcription to be insensitive to variations in the level of EnvZ and OmpR. By increasing levels of EnvZ upto 10 fold (1000 molecules), the relative porin ratio was found to be constant during simulation, evidently agreeing with the robust nature of the switch as per the mathematical model .in silico model the OmpC/OmpF transcription was found to be independent of the OmpR levels upto 10-fold increase (20000 molecules). In either case both at high and low osmolarity, porins levels were found to be insensitive to elevated or decrease levels of response regulator, OmpR corresponding to the results of mathematical model . The simulation models are constructed with three fundamental object classes, Substance, Reactor and System. Substances represent state variables, Reactors represent operations on the state variables, and Systems represent logical and/or physical compartments containing other objects. The distributed package of version employed for carrying out simulation has 18 different classes of standard Reactors, such as for Michaelis-Menten formula and generalized chemical equilibrium . In the in vivo condition considering Escherichia coli cells grown in mid-log phase. Accordingly the levels of OmpR and EnvZ are reported to be 3500 and 100 molecules in cell respectively. OmpR and EnvZ levels were almost the same from cells grown in L-broth medium or in a high osmolarity medium (NB (Nutrient Broth) +20% sucrose) [-15 liters [The present model is built on the assumption of the sucrose) . The rat5 liters . At low 5 liters Table 1)in vivo c5 liters . The lis5 liters . As the KVS was responsible for data collection and analysis. SK conceived of the study, and participated in its design and analysis. Two referees and an advisor of the journal helped to bring this information into the biological context.


It aims to reduce the intra-operative dissemination of colorectal cancer cells. Recently, the detection of circulating tumour cells has been enhanced by molecular biology techniques. This paper reviews the evidence for the no-touch isolation technique in light of the recent developments in circulating tumour cell detection.Lymphovascular ligation before tumour manipulation during colorectal cancer resection is termed the 'Studies investigating the effect of colorectal cancer surgery on circulating tumour cells were identified by a Medline search using the subject headings colorectal neoplasms and neoplasm circulating cells together with the map term 'no-touch isolation technique'. Further references were obtained from key articles.Molecular biological techniques have improved the detection of circulating colorectal cancer cells. There is a trend towards reduced tumour cell dissemination with the no-touch technique compared with the conventional method. However the benefit in terms of improved patient survival remains unproven.The no-touch isolation technique reduces circulating tumour cell dissemination but further work is needed to determine the significance of this with regards to patient survival. This was proposed by Barnes [Of the patients with colorectal cancer (CRC) undergoing surgery for resectable disease, 30–50% will subsequently develop metastases . Dissemiy Barnes  as a wayy Barnes .Animal studies suggest tumour cells are shed into the circulation during resection of a primary tumour, increasing the likelihood of metastases . However7 normal cells [In recent years, the question of tumour cell dissemination during surgical resection has been re-examined following the introduction of molecular biology techniques to detect CTC. These are much more sensitive, and it is now possible to detect one tumour cell in a sample of 10This paper reviews the evidence for the no-touch isolation technique for the resection of a CRC in light of the recent developments in molecular biological techniques for CTC detection.In performing this review, the studies looking at the effect of CRC surgery on CTC were identified by a Medline search using the subject headings colorectal neoplasms and neoplasm circulating cells together with the map term 'no-touch isolation technique' -16. FurtWe decided to review this topic by addressing three areas of uncertainty. Firstly, does the surgical manipulation of a CRC increase the level of tumour cells within the blood? Secondly, what is the biological significance of CTC in CRC? Thirdly, is the no-touch isolation technique of CRC resection associated with an improved patient survival?To investigate the effect of tumour manipulation on CTC, we have reported the conversion, for each reviewed article, of a negative preoperative blood sample (for CTC) to a positive intra- or post-operative sample within the same patient. We have only noted conversions within the same sample source (systemic venous (SV) or portal venous (PV) blood). Where conversion rates cannot be determined, as data for individual patients are not provided, a comparison between overall preoperative and intra/post-operative positivity for CTC is given. Unless otherwise stated in the reviewed article, we have presumed the conventional method was utilised (tumour manipulation before lymphovascular ligation).A number of experimental models have been used to investigate the effect of surgical manipulation on CTC. Nishitaki et al  studied Romsdahl et al  measuredIn order for the no-touch technique to be effective in humans, early ligation of the main pedicle must eliminate passage of liberated tumour cells into the portal and systemic circulations. However, Salsbury et al  found thOn theoretical grounds, the no-touch technique would appear unsuitable for low rectal cancers, as it is necessary to mobilise tumours in the rectum before all the draining veins are controlled. In addition, a large proportion of the venous drainage occurs into the iliac system, thereby negating the effect of mesenteric pedicle ligation.There have been numerous studies investigating the effect of tumour manipulation on CTC in human tumours. This review focuses on studies involving CRC. The overall conversion rates for each study  are listed in Additional Files The only study to compare directly the conventional and no-touch techniques for the resection of a CRC involved the non-random assignment of 27 patients into conventional and no-touch groups . The tecThe other studies involving CRC have used either the conventional or no-touch surgical techniques, but have not directly compared both. Weitz et al  and SaleStudies employing the conventional technique of CRC resection have found overall conversion rates of 0 – 80% in SV samples -15,18,19As a number of patients were positive for CTC before surgery, a more direct assessment of the effect of tumour manipulation might be to analyse the conversion rates only for those patients negative for CTC preoperatively. This reveals a much greater conversion rate for most studies  involves detection and amplification of certain DNA mutations. A copy of the DNA containing the target sequence is made and the process is repeated many times, producing multiple copies and thereby increasing the sensitivity of detection. Mutations in the k-ras gene have often been used for detection of CTC in CRC.However, the detection of these sequences within the blood does not necessarily imply there are circulating tumour cells, as DNA is relatively stable and may represent fragments of tumour DNA released by cell necrosis or apoptosis and persisting in the blood for some time . Also, t7 normal cells [An alternative technique, now more commonly employed, is reverse transcriptase-PCR (RT-PCR). This detects messenger RNA (mRNA), which is used as an indicator of tissue-specific gene transcription. The technique is rapid, more easily automated than immunocytochemistry, and is capable of detecting one tumour cell in 10al cells . RNA is al cells .in-vitro sensitivity reported in the reviewed articles will be higher than the true in-vivo sensitivity, as the cell lines used to determine the sensitivity are known to express strongly the marker of interest and are not affected by the presence of in-vivo PCR inhibitors.However, there is a lack of standardisation of RT-PCR techniques, resulting in different sensitivities and specificities between centres . IllegitMost of the reviewed articles that state the specificity of their technique claim a rate of 100%, indicating all the tumour samples were positive for the marker of interest, whereas none of the control blood samples  were positive. However, Patel et al  examinedThere are no tumour-specific genes for CRC, and it is known malignant cells continue to express markers that are characteristic of their tissue of origin. Therefore, a range of epithelial cell markers, which are normally absent from the blood, have been used as RT-PCR targets for cancer cells derived from epithelial tissues.a and sialyl Lex, are associated with CRC formation and progression [The cytokeratin (CK) polypeptides are found within the cytoplasm of epithelial cells, and several CK markers have been used to detect CTC. The most common of these is CK 20, which is expressed in gastrointestinal epithelia, urothelium, Merkel cells, and tumours derived from these tissues . Carcinogression , and havConcerns regarding marker specificity have been raised. CK 8, 18 and 19 have all been shown to be expressed in normal blood . CK 20 aThe source of blood for analysis appears to be important. Most studies have investigated systemic venous samples for the presence of CTC. Animal studies suggest tumour cells become trapped in the capillary bed of the first organ encountered ,40, and Due to the discrepancy in sample sources, we have only noted patients who converted within the same venous compartment. Several studies detected CTC in draining vein blood intra-operatively, and compared it against a reference SV sample taken before manipulation. It is difficult to be certain of conversion in these patients, however, as it is possible the PV samples were positive preoperatively. It is important for subsequent studies to measure CTC in both systemic venous and draining vein blood, before, during and after tumour manipulation to investigate further the discrepancy in CTC detection between the venous compartments.The importance of multiple sampling should be considered. Glaves et al  suggestsWeitz et al  suggest The detachment of malignant cells from the primary tumour is an early step in the formation of metastases . The relEarly studies suggested fewer than 0.1% of circulating tumour cells survive in the circulation , and onlThe metastatic process may be enhanced by the surgical procedure itself. It is known the entrapment of tumour cells in the microcirculation of a target organ is facilitated by the presence of fibrin and platelets ,49. The The prognostic value of CTC in CRC has yet to be fully determined. Fujita et al  found paThere are few studies directly comparing the outcomes following conventional and no-touch techniques. Turnbull et al  retrospeWiggers et al  randomlyThe largest series was reported recently by Slanetz , who retAnother component of the no-touch isolation technique investigated by Slanetz is the control of intraluminal spread of malignant cells by applying bowel clamps or ligatures before tumour manipulation. He reviewed the results of 599 CRC resections in which bowel ligation prior to tumour mobilisation was used, and compared the data against 1416 resections in which bowel ligation was not performed. He found the application of bowel ligatures before tumour mobilisation significantly improved the 5-year cancer-related death rate for colon cancer , but not for rectal cancer. When considering colon and rectal cancer combined, bowel ligation prior to mobilisation significantly reduced the local  and distant  recurrence rates compared to resection without prior bowel ligation. These findings support the earlier work by Cole et al , who shoIt is difficult to draw any firm conclusions from the articles studied due to the lack of standardisation of sample source, CTC detection method and the small sample sizes. However, the only study directly comparing conventional and no-touch surgical techniques found a conversion rate of 73% for conventional surgery and 14% for the no-touch technique, suggesting a benefit of vascular clamping before tumour mobilisation. The overall conversion rates for the other studies employing the no-touch technique were 0–16% see , compareDue to the lack of consensus regarding the best technique for detection, the biological importance of CTC has not been fully determined. With the introduction of molecular biological techniques, the sensitivity for detection has improved considerably. The hope is that accurate detection of occult circulating malignant cells would help to stage the disease and predict prognosis, as well as monitor the response to therapy and highlight early the possibility of recurrence. However due to the differences in methodology and conclusions of studies investigating this area, the detection of CTC cannot, at present, be used to dictate therapeutic strategy.Despite the methodological heterogeneity of the articles reviewed, we believe the introduction of highly sensitive methods of CTC detection has forced a re-analysis of the role of the no-touch isolation technique in CRC surgery, and the stages of CRC resection using the no-touch technique would appear to offer a sensible, systematic approach to the surgical management of large bowel tumours. However, further work needs to be done to investigate the remaining areas of uncertainty. In particular, future developments in CTC detection must ensure more automation and greater standardisation of techniques between centres. RT-PCR appears to offer the greatest sensitivity, and techniques detecting multiple markers that are more tumour-specific should be investigated ,58. The The author(s) declare that they have no competing interests.GA researched the topic and prepared the manuscript, IM conceived the article and AC critically analysed and formatted the manuscript.Conversion rates for studies employing the no-touch isolation technique of CRC resectionClick here for fileConversion rates for studies employing the conventional technique of CRC resectionClick here for file


The objective of this study was to examine the Minimum Data Set (MDS) and Geriatric Depression Scale (GDS) as measures of depression among nursing home residents.The data for this study were baseline, pre-intervention assessment data from a research study involving nine nursing homes and 704 residents in Massachusetts. Trained research nurses assessed residents using the MDS and the GDS 15-item version. Demographic, psychiatric, and cognitive data were obtained using the MDS. Level of depression was operationalized as: (1) a sum of the MDS Depression items; (2) the MDS Depression Rating Scale; (3) the 15-item GDS; and (4) the five-item GDS. We compared missing data, floor effects, means, internal consistency reliability, scale score correlation, and ability to identify residents with conspicuous depression (chart diagnosis or use of antidepressant) across cognitive impairment strata.The GDS and MDS Depression scales were uncorrelated. Nevertheless, both MDS and GDS measures demonstrated adequate internal consistency reliability. The MDS suggested greater depression among those with cognitive impairment, whereas the GDS suggested a more severe depression among those with better cognitive functioning. The GDS was limited by missing data; the DRS by a larger floor effect. The DRS was more strongly correlated with conspicuous depression, but only among those with cognitive impairment.The MDS Depression items and GDS identify different elements of depression. This may be due to differences in the manifest symptom content and/or the self-report nature of the GDS versus the observer-rated MDS. Our findings suggest that the GDS and the MDS are not interchangeable measures of depression. Depression is common among residents of nursing homes . Of the The Minimum Data Set (MDS), created in response to the US Omnibus Budget Reconciliation Act of 1987, aims to provide a uniform, standardized, and comprehensive assessment of residents in nursing homes . The MDSThis study compares the measurement properties of two measures of geriatric depression: the GDS and the MDS. The GDS is evaluated via a 15 and five item form. The MDS is evaluated by the items located in Section E in total and as a subset included in the Depression Rating Scale.Participants were nursing home residents living in nine Massachusetts nursing facilities participating in a research study between July 1994 and March 1998. Details of the study are described elsewhere [Residents were evaluated with the Minimum Data Set (MDS) Resident Assessment Instrument version 2.0  as well We also examined the depression symptom scales with regard to indicators of clinically recognized depression: chart diagnoses of depression and recent use of antidepressant medication. These data were also obtained by research nurses using structured chart review forms keyed to data elements collected with the MDS. MDS assessors are instructed to note the presence of a disorder related to the resident's current functional, cognitive, and behavioural status, medical treatments, and risk of death . Among tWe stratified the sample into two groups based on the severity of cognitive impairment. The impaired group comprised residents who were comatose (MDS 2.0 item B1 = 1), and/or with a short-term memory problem (B2a = 1) and those who only rarely/never make themselves understood (C4 = 3). All other residents were assigned to the "cognitively intact" group. This decision rule matches a screening rule for the MDS versus GDS depression symptom assessment proposed in the US Centers for Medicare & Medicaid Services' (CMS) working draft of the MDS version 3.0 .We compared sample statistics and psychometric properties for each of the four depression scales across strata defined by cognitive impairment. We evaluated missing data by examining the proportion of residents with complete data on all assessment items, and also by the proportion of residents with complete data on a majority of items in the scale. For all other analyses we substituted missing values with the mean of the resident's non-missing items if a majority of the scale items were not missing. We examined means, standard deviations (SD), proportion of residents scoring at the floor, the internal consistency reliability  and areThe very high frequency of missing data for the GDS encouraged us to examine the frequency of missing data at the item level. We present this information in Table The means for the GDS- and MDS-derived scales were different between the cognitively intact and impaired groups Table . Of noteFigure The GDS-15 had the highest internal consistency reliability coefficient, and the lowest was observed for the DRS. However, this difference does not substantially exceed that expected due to the greater scale length of the GDS-15. Using the Spearman-Brown prophecy formula , the relThe correlation between the GDS- and DRS- derived measures were not statistically different from zero. All of the differences in correlation coefficients are similar among the cognitively impaired and cognitively intact and not statistically different, except for the correlation of the E1SUM and DRS (P < .001).The comparison of mean depression symptom scale scores among residents that received antidepressants and/or had a chart diagnosis of depression, within and across cognitive impairment strata, is reported in Table For the MDS-derived depression scales, the differences in means associated with antidepressant use and depression diagnoses are much more dramatic than for the GDS-derived scales, but only among the cognitively impaired. For both the E1SUM and DRS, the marginal differences for depression diagnoses and antidepressant use describe moderate to large effect sizes. These differences are statistically significant (both P < .001). On the other hand, among those residents not identified as cognitively impaired, the marginal differences associated with antidepressant use and a depression diagnosis were trivial to small and not statistically significant.In this study, we found that MDS- and GDS-derived depression measures were not correlated with one another, but were apparently adequately reliable measures of their intended construct. Thus, we infer that the MDS and the GDS measure different aspects of nursing home residents' depression. Each scale has specific strengths and limitations. The practical utility of the GDS is undermined by a very high frequency of missing data. The proportion of GDS responses missing differs greatly by level of cognitive functioning. The floor effect limits both instruments. While the internal consistency reliability is apparently greater for the GDS, this may simply be due to the greater number of items on the GDS. We observed a weak relationship between GDS-5 scale scores and clinical indicators of depression , but the strong association between MDS-derived scales and clinical indicators was only seen among cognitively impaired residents.Other investigators have found a low correlation between the DRS and the GDS and other instruments for assessing depression, but these findings vary according to data collection strategies. For example, Anderson et al found a low correlation between the MDS DRS abstracted from residents' charts and symptom data collected with the GDS (r = .13) and the Hamilton Depression Rating Scale  using research interviewers . SimilarIn our study, the assessment methods followed more closely how they were designed to be used. The GDS was used as a direct interview, and the MDS was used as instructed in the MDS manual , and incThe fact that the MDS- and GDS-derived scales do not correlate implies that the two scales evaluate different aspects of a resident's depression. For positive MDS depression symptom ratings, residents must visibly act by making negative statements, be easily angered, and display unrealistic fears to trigger MDS symptoms. The GDS asks residents if they are satisfied with their life, feel helpless or worthless, and are often bored. It is conceivable that GDS-derived measures capture a brooding mental set, reflective of a dysphoric personality trait or adjustment disorder (for example in response to a recent change in living situation) rather than the presence of major depression.RAI include a provision for self-assessment of depression [The lack of correlation between MDS depression measures has implications for proposed revisions to the MDS. Until more is known about the phenomenology and clinical validity of syndromes measured by these and other depression measures used in long-term care settings, adding self-report of symptoms of depression to the MDS is supported by our findings. We note that both CMS's draft revision of the MDS and new pression . HoweverThe Geriatric Depression Scale and Minimum Data Set mood items measure different aspects of the depression syndrome among nursing home residents. The two measures cannot be treated as exchangeable or equivalent, and each has it's own strengths and limitations. The GDS uses self-report, but as a consequence suffers from a high frequency of missing data. The MDS relies upon informant ratings and therefore provides information about most residents. Although the GDS has higher internal consistency reliability than MDS, this is not beyond that expected due to greater scale length. The MDS measures were more strongly related to antidepressant use and record of a diagnosis of depression than were GDS measures. These results highlight the fact that more psychometric research is needed to better understand and improve the measurement of depression among frail nursing home residents.GDS Geriatric Depression ScaleMDS Minimum Data SetDRS Depression Rating ScaleCSDD Cornell Scale for Depression in DementiaHDRS Hamilton Depression Rating Scale.No financial competing interests. TR, JH, GIC, BEF and JNM are fellows of InterRAI, a non-profit group dedicated to improving the health care for persons who are elderly, frail or disabled. InterRAI owns the copyright to the MDS for nursing homes and many other care settings. InterRAI offers free licenses for the use of assessment forms of which it owns the copyright to. Therefore, there are no financial competing interests for members of the writing group. For more information please visit MK and RNJ conceived of the study. MK drafted the manuscript. RNJ performed the analyses and provided critical review of and completed the manuscript. JNM obtained the data, participated in the analysis and provided critical review of the manuscript. JH, MS, GIC and BEF provided critical review of the analyses and manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here: