Avulsion fracture or progressive radiolucency of lesser trochanter is considered a pathognomic finding in patients with malignancies. Although surgical release of the iliopsoas tendon may be required during a total hip arthroplasty (THA), there is no literature on spontaneous rupture of the ilio-psoas tendon after a THA causing significant functional impairment. We report here such a case, which developed progressive radiolucency of the lesser trochanter over six years after a THA, simulating a malignancy. The diagnosis was confirmed by MRI. Because of the chronic nature of the lesion, gross retraction of the tendon into the pelvis, and low demand of our patient, he was treated by physiotherapy and gait training. Injury to the ilio-psoas tendon can occur in various steps of the THA and extreme care should be taken to avoid this injury. Prevention during surgery is better, although there are no reports of repair in the THA setting. This condition should be considered in patients who present with progressive radioluceny of the lesser trochanter, especially in the setting of a hip/pelvic surgery. Awareness and earlier recognition of the signs and symptoms of this condition will aid in diagnosis and will direct appropriate management. Avulsion fracture of lesser trochanter of the femur is a well known entity in children and adolescents . HoweverA 77-year old, otherwise healthy, sedentary male was referred to the orthopedic oncology service for a progressive radiolucency of the lesser trochanter on radiographs Fig. . He had On examination, he ambulated with a single crutch. Active straight leg raise was not sustainable. Seated hip flexion was graded as 3/5. There was no tenderness or palpable mass in the groin. Distal neuro-vascular status was intact. The previous surgeons did not recall any intraoperative complication or surgical release of ilio-psoas tendon. Radiographs were not suggestive of implant loosening, malpositioning, osteolysis or wear. Although radiolucency is common in Gruen Zones 7 and 14 after cemented THA [Because of the chronic nature of the lesion, gross retraction of the tendon into the pelvis, and low demand of our patient, he was treated by physiotherapy and gait training. At four years follow-up and almost 10 years after his THA, he still uses a cane for outdoor ambulation. Otherwise his medical history has been uneventful with no evidence of any malignancy.The differential diagnosis of groin pain after a THA includes sepsis, aseptic loosening of components, wear and osteolysis, heterotopic ossification, fracture, neurologic, vascular or abdominal pathology, referred pain from the spine or knee, as well soft tissue irritation such as ilio-psoas tendonitis and synovitis -8. AlthoPain specific to ilio-psoas irritation include activities like straight leg raise and resisted hip flexion, passive hyperextension and manifest in day to day life as ascending stairs, lifting the operative leg into the bed, lifting the leg in and out of the car (requiring use of a hand for support) and walking on uneven surface -8. This An acute rupture of the tendon may manifest as pain in the groin with exacerbation with both flexion and extension of the hip. A palpable mass along with ecchymosis may be present . In earlAlthough no CT was obtained in our case, radiographs did not show any component malpositioning. Ilio-psoas tendonitis has been shown even in the absence of impingement . HoweverThere is only one more report of spontaneous atraumatic rupture of distal ilio-psoas tendon in two patients (without arthroplasty); however their medical history was complicated by rheumatoid arthritis, diffuse non-myelinating polyneuropathy, Parkinsonism, Vitamin B-12 deficiency, osteoporosis and Alzheimer's disease . IliacusIn conclusion, we report a rare instance of rupture of the ilio-psoas tendon after a THA. This condition should be considered in patients who present with progressive radioluceny of the lesser trochanter, especially in the setting of a hip/pelvic surgery. Although weakness of hip flexion has not been reported after tenotomy for ilio-psoas impingement ,6, our pWritten informed consent was obtained from the patient for publication of this case report and the accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.JDP was the surgeon in charge of the patient described with in this report. AVM, DK and RM conducted the literature review and analysed the gathered reports for the described case. AVM, DK and RM composed and wrote the manuscript. All authors read and approved the final manuscript.


Campylobacter. The only form of campylobacteriosis of major public health importance is Campylobacter enteritis due to C. jejuni and C. coli. Research and control efforts on the disease have been conducted more often in developed countries than developing countries. However, because of the increasing incidence, expanding spectrum of infections, potential of HIV-related deaths due to Campylobacter, and the availability of the complete genome sequence of C. jejuni NCTC 11168, interest in campylobacteriosis research and control in developing countries is growing. We present the distinguishing epidemiologic and clinical features of Campylobacter enteritis in developing countries relative to developed countries. National surveillance programs and international collaborations are needed to address the substantial gaps in the knowledge about the epidemiology of campylobacteriosis in developing countries.Campylobacteriosis is a collective description for infectious diseases caused by members of the bacterial genus  Campylobacter. The only form of campylobacteriosis of major public health importance is Campylobacter enteritis due to C. jejuni and C. coliCampylobacter infections worldwide has been increasing, with the number of cases often exceeding those of salmonellosis and shigellosis Campylobacteriosis is a collective description for infectious diseases caused by members of the bacterial genus Surveillance and control of diseases of public health importance in developing countries have focused on diseases such as malaria, tuberculosis, trypanosomiasis, onchocerciasis, and schistosomiasis Campylobacter is one of the most frequently isolated bacteria from stools of infants with diarrhea in developing countries—a result of contaminated food or water —may also be of pathogenic importance; however, diagnostic capacities to determine their distribution are lacking in developing countries Campylobacter species constitute over 50% of campylobacters isolated at the Red Cross Children’s Hospital, Cape Town, South Africa, for example.  is an autoimmune disorder of the peripheral nervous system, which is characterized by acute flaccid paralysis. Campylobacter-associated diarrhea and bacteremia occur in HIV/AIDS patients worldwide. The species isolated include C. jejuni, C. coli, C. upsaliensis, Arcobacter butzleri, Helicobacter fennelliae, and H. cinaedii , immunoglobulin (Ig) A, IgG, and IgM levels in response to C. jejuni-induced diarrhea. It decreases the number of episodes and the duration of diarrhea Campylobacter infections than infants who were both breast-fed and bottle-fed Breast-feeding has been reported to play a role in Campylobacter after primary infection may prevent bloody diarrhea from developing and subsequently prevent any disease from manifesting Results of experimental observations among Mexican children have also shown that immunity to Campylobacter infection is hyperendemic in developing countries. The major sources of human infections are environmental contamination and foods. Human-to-human transmission as a result of prolonged convalescent-phase excretion and high population density have also been suggested  is the basic unit used in Burden of Disease (BoD) methodology to quantify the impact of disease on a population http://www1.oecd.org/agr/prog/sum-copenhagen00.htm). Ssubstantial gaps in knowledge about the epidemiology of campylobacteriosis in developing countries still exist. Present reported estimates of incidence are based on isolation rates from laboratory- and community-based studies conducted from 1980 to 1995. When various socioeconomic and health changes in developing countries are taken into account, these values may have changed considerably. Thus, public health awareness about the problem is needed, as are strengthened diagnostic facilities for campylobacteriosis, with a view towards setting up national surveillance programs. Such programs would determine the incidence rates, epidemiologic risk factors, interaction of HIV/AIDS and campylobacteriosis, seasonal variation, current state of resistance to antimicrobial agents, role of species other than C. jejuni and C. coli, and the role of campylobacteriosis in GBS. Collaboration among researchers in developed and developing countries needs to be strengthened, leading to development of regional centers of excellence. Funding organizations should provide incentives for North-South collaborations in Campylobacter research, as is done in other diseases such as malaria and trypanosomiasis that are endemic in some developing countries. All these should contribute to understanding of the global epidemiology of human campylobacteriosis.The incidence of human campylobacteriosis is increasing worldwide and has attracted the attention of WHO (


Comorbidity of Major Depressive Disorder (depression) and Alcohol Use Disorders (AUD) is well documented. Depression, AUD, and the comorbidity of depression with AUD show evidence of genetic and environmental influences on susceptibility. We used an integrated bioinformatics approach, mining available data in multiple databases, to develop and refine a model of gene-by-environment interaction consistent with this comorbidity.We established the validity of a genetic model via queries against NCBI databases, identifying and validating TNF (Tumor Necrosis Factor) and MTHFR (Methylenetetrahydrofolate Reductase) as candidate genes. We used the PDG-ACE algorithm  to show that TNF and MTHFR share significant commonality and that this commonality is consistent with a response to environmental exposure to ethanol. Finally, we used MetaCore from GeneGo, Inc. to model a gene-by-environment interaction consistent with the data.TNF Alpha Converting Enzyme (TACE) activity is suppressed by ethanol exposure, resulting in reduced TNF signaling. TNF binds to TNF receptors, initiating signal transduction pathways that activate MTHFR expression. MTHFR is an essential enzyme in folate metabolism and reduced folate levels are associated with both AUD and depression. Integrating these pieces of information our model shows how excessive alcohol use would be expected to lead to reduced TNF signaling, reduced MTHFR expression, and increased susceptibility to depression.The proposed model provides a novel hypothesis on the genetic etiology of comorbid depression with AUD, consistent with established clinical and biochemical data. This analysis also provides an example of how an integrated bioinformatics approach can maximize the use of available biomedical data to improve our understanding of complex disease. Comorbidity of Major Depressive Disorder (depression) with Alcohol Use Disorders (AUD) is well documented . FurtherDepression, AUD, and the comorbidity of depression with AUD are complex traits, demonstrating both genetic and environmental influences on susceptibility. Depression is familial, with estimates of heritability as high as 54% . ComorbiIn this analysis, we used available data in NCBI databases, plus three software suites . To identify potential candidate genes, we queried the Entrez Gene database  for "depThe Entrez Gene database provides reliable information about most genes, but the Entrez Gene record is a summary, so the information it provides is necessarily limited. Therefore, we queried a second NCBI database, PubMed , for morThere are, however, limitations to the use of MeSH annotation in querying publications. First, while MeSH contains thousands of Medical Subject Headings, it is not an exhaustive annotation of all potential biomedical contexts. Second, there may be missing annotation or ambiguity in the annotation for some publications. For example, as mentioned in the PPV analysis, not all of the 171 papers that we counted as True Positives were specifically about comorbid AUD with depression. The earlier papers tended to refer to AUD and depression as co-occurring phenotypes, while the later papers focused on evaluating the comorbidity. There also may be ambiguity in the user's choice of MeSH terms queried, and some publications may report negative associations, though the bias against publication of negative results minimizes the number of these papers. And finally, a lack of citations is not evidence of a lack of association. While co-occurrence of queried terms is not proof of association, co-occurrence does provide a quantitative measure of peer reviewed research on the association of these specific terms and complements other forms of data that can be mined. In future analyses, Natural Language Processing will help to improve these queries by mining the full text of publications for a wide variety of concepts, and provide additional evidence of association among terms. Given believable candidate genes, derived from queries of available data at Entrez Gene and PubMed, we continued the analysis using DAVID, PDG-ACE, and MetaCore  to understand how these candidate genes may be related to the etiology of AUD, depression, and comorbid AUD with depression.DAVID software, the PDG-ACE algorithm, and the GeneGo suite perform related tasks. The essential assumption in the use of all three tools is that, in complex diseases, multiple genetic influences converge on a single phenotype. The three tools use different approaches to identify how multiple genes may influence the phenotype of interest and assess the statistical significance of the results seen.DAVID  uses a dHowever, since much gene annotation remains incomplete, PDG-ACE  see Add serves abkeller@emich.edu.The PDG-ACE algorithm uses a controlled vocabulary of biomedical keywords to limit the search to concepts likely to be useful in understanding disease etiology and show statistically significant over-representation. For a given locus pair, PDG-ACE mines the Entrez Gene text to find keywords from the controlled vocabulary that are common across the locus pair. For keywords that are common across the locus pair, significance of over-representation is established by permutation testing. Keywords that are common and significantly over-represented across the locus pair highlight rare combinations of genes that share the biomedical concepts associated with the keywords. Testing of the PDG-ACE algorithm, using both positive controls (documented gene-gene interactions in complex disease) and negative controls (randomly selected gene pairs), demonstrates that PDG-ACE provides insight into the etiology of true genetic interactions, while excluding loci where the data is insufficient to identify interactions . As withThe GeneGo suite  uses theBased on prior evidence consistent with genetic and environmental influences on susceptibility to comorbid depression with AUD, we started the analysis with the hypothesis that genetic influences participate in depression and AUD. Figure TNF superfamily, member 2, GeneID 7124), Methylenetetrahydrofolate Reductase , GeneID 4524) ". This query returned exactly three genes: Tumor Necrosis Factor (ID 4524) , and APOTNF and MTHFR in depression, AUD, and comorbid depression with AUD. In searching PubMed, we found evidence that both TNF and MTHFR have been associated with depression and with ethanol in the literature, but not with the comorbidity of depression with AUD  , leadingSignal transduction, leading to transcriptional regulation of both TNF and MTHFR, is an essential assumption of this model. In addition to building networks, GeneGo analyzes networks for over-representation of genes that participate in Gene Ontology (GO) processes , then ranks the GO processes by p-value. Table Apolipoprotein E (APOE) was excluded from the formal analysis because the annotation in Entrez Gene was inferred, rather than curated. In pursuing the hypothesis that APOE is involved in comorbid depression with AUD, we re-started the analysis including APOE. We queried PubMed for citations consistent with this hypothesis Table  and founComorbid depression with AUD shows evidence of both genetic and environmental influences on susceptibility. In three phases of hypothesis generation and testing  we established and tested a model of gene-by-environment interaction that shows evidence of influencing the comorbidity and is consistent with established knowledge about AUD and depression . We firsMason and Choi  review oBased on the relationship between folate metabolism and one-carbon metabolism, we searched for evidence that the one-carbon metabolic process influences depression, AUD, and the comorbidity. Table Notably, while the evidence assembled in this analysis is consistent with our hypothesized model of gene-by-environment interaction of comorbid depression with AUD, much data remains missing. For example, we emphasize the environmental influence of alcohol consumption, though we have little information on how alcohol dosage or the duration of alcohol exposure might affect genetic influences in our model. Equally, while we have identified a network of genes that may influence the comorbidity, we have limited information on heritable variation that would be expected to increase or decrease susceptibility. To date, the C677T variant of MTHFR is associated with both susceptibility to depression ,45,46 anImplications of this model are consistent with dietary guidance recommending monitoring and appropriate supplementation of folate for patients in treatment for depression -50, AUD,The model developed in this analysis represents one mechanism whereby, for genetically susceptible individuals, alcohol intake could lead to altered folate metabolism and increased susceptibility to depression. The effect of excessive alcohol consumption on folate levels is not new  but thisCandidate gene approaches offer a necessarily limited view of gene-disease association because so much data is missing on virtually all genes. In addition, data mining approaches, if not carefully controlled, can lead to false positive associations. However, by starting with the most reliable data available to select candidate genes, using multiple lines of evidence to test the validity of candidates, then putting the candidates into context, we believe we have developed one valid model of gene-by-environment interaction influencing comorbid depression with AUD. The proposed gene-by-environment interaction model provides a biologically plausible and testable hypothesis on the genetic etiology of comorbid depression with AUD.With appropriate caveats, this approach to complex disease analysis could be applied to understanding many diseases. Both publication bias towards positive results and bias towards genes that are commonly studied will tend to steer text based evidence in the direction of a relatively limited set of genes. This bias will be countered by the large volumes of data currently being generated without prior hypotheses. In particular, WGA and microarray data are being deposited in publicly available datasets. These data will complement text based approaches by allowing for unbiased tests of the reduced number of hypotheses posed. Indeed, as the volume of data available in databases increases, this type of analysis will become more valuable.The authors declare that they have no competing interests.RCM initially conceived of the work, conducted the database queries as well as the PDG-ACE and GeneGo analyses, and wrote the first draft of the manuscript. BJK developed the PDG-ACE algorithm and helped in subsequent drafting of the manuscript. EFHS put the initial results in the context of one-carbon metabolism and helped with subsequent drafting of the manuscript. MGM participated in the design and coordination of the study and helped draft the final manuscript. All authors read and approved the final manuscript.Detailed PubMed database queries.Click here for fileManuscript describing the PDG-ACE algorithm.Click here for fileList of 2,531 keywords used in PDG-ACE analysis.Click here for file


There is a need for services that effectively and comprehensively address the complex needs of women with substance use issues and their children. A growing body of literature supports the relevance of integrated treatment programs that offer a wide range of services in centralized settings. Quantitative studies suggest that these programs are associated with positive outcomes. A qualitative meta-synthesis was conducted to provide insight into the processes that contribute to recovery in integrated programs and women's perceptions of benefits for themselves and their children.A comprehensive search of published and unpublished literature to August 2009 was carried out for narrative reports of women's experiences and perceptions of integrated treatment programs. Eligibility for inclusion in the meta-synthesis was determined using defined criteria. Quality assessment was then conducted. Qualitative data and interpretations were extracted from studies of adequate quality, and were synthesized using a systematic and iterative process to create themes and overarching concepts.A total of 15 documents were included in the meta-synthesis. Women experienced a number of psychosocial processes during treatment that played a role in their recovery and contributed to favourable outcomes. These included: development of a sense of self; development of personal agency; giving and receiving of social support; engagement with program staff; self-disclosure of challenges, feelings, and past experiences; recognizing patterns of destructive behaviour; and goal setting. A final process, the motivating presence of children, sustained women in their recovery journeys. Perceived outcomes included benefits for maternal and child well-being, and enhanced parenting capacity.A number of distinct but interconnected processes emerged as being important to women's addiction recovery. Women experienced individual growth and transformative learning that led to a higher quality of life and improved interactions with their children. The findings support the need for programs to adopt practices that focus on improving maternal health and social functioning in an environment characterized by empowerment, safety, and connections. Women's relationships with their children require particular attention as positive parenting practices and family relationships can alter predispositions toward substance use later in life, thereby impacting favourably on the cycle of addiction and dysfunctional parenting. The human and economic costs of substance use are considerable ,2. AlthoThere is a need for services that effectively and comprehensively address the complex needs of women with substance use issues and their children. In addition to experiencing physical and mental health problems, these women often have personal histories of exposure to physical and sexual abuse and other relationship problems, negative or inadequate social support systems, inadequate income, unemployment, unstable housing, and involvement with the criminal justice system -14. ConnHistorically there have been separate delivery systems to meet the diverse needs of women with substance use issues and their children. However, there is a growing body of literature reporting on integrated treatment programs that offer a wide range of services  in centralized settings for both women and children. These programs have primarily taken two forms: residential and outpatient. Intended treatment length can vary but generally ranges from 12 to 18 months in both types of programs.Studies that have examined the effectiveness of integrated intervention programs suggest positive outcomes for women and children, including reduced substance use and improved mental health, parenting, and child development outcomes ,19. HoweIn a systematic review of 38 studies on substance abuse treatment for women, Ashley, Marsden, and Brady  examinedWhile many quantitative studies have examined the effectiveness of integrated treatment programs, there also is a developing body of qualitative and mixed methods literature that encompasses studies conducted to describe the experiences and perceptions of pregnant women and mothers with young children who participate in such programs. As it is important to develop a better-informed understanding of the experiences of participating in integrated treatment programs from women's perspectives, a synthesis of these qualitative data is required.Meta-analyses of quantitative data and qualitative meta-syntheses share many similar characteristics including: asking of a focused question; establishment of strict inclusion criteria to guide a comprehensive search of the available evidence; and critical appraisal of the located evidence. The two types of reviews are most distinct in the processes for synthesizing findings across included studies, with quantitative meta-analyses utilizing statistical methods to aggregate data and qualitative meta-syntheses characterized by the integration of common findings into narrative themes and the identification of overarching abstract concepts . While qThe purpose of the qualitative meta-synthesis was to bring individual, high-quality qualitative studies together through a process of comparison, translation, and synthesis of original findings . The speA comprehensive and systematic literature search for studies of outcomes and processes associated with integrated intervention programs for women with substance use issues and their children was conducted simultaneously for a quantitative meta-analysis and the qualitative meta-synthesis. The initial search captured literature published up to August 2007. We used three main strategies to identify outcome studies of intervention programs for women with substance abuse issues and their children: online bibliographic database searches; checking printed sources; and requests to researchers ,25. FirsSecondly, we examined reference lists of retrieved articles for potentially relevant documents. In addition, we manually searched relevant journals in the area . Documents that appeared to be relevant on the basis of titles or abstracts were retrieved.Finally, we searched for fugitive data . All researchers identified through these searches, as well as researchers presenting at relevant conferences identified using Google and Cross Currents (Upcoming Events), were contacted by email to request any relevant published or unpublished data. Of the 200 researchers identified and emailed, 48% responded and 28 additional studies were identified. In total, 327 studies were retrieved (319 from literature searches and 28 through other forms of searching) and coded for eligibility. A hand-review of all retrieved studies resulted in the identification of 42 papers that included a report of narrative findings from a single qualitative or mixed methods study. The search was updated to capture any research published between the time of the initial search and August 2009, which yielded another three studies with narrative findings.Inclusion and exclusion criteria were developed specifically for the purposes of the meta-analysis and meta-synthesis. Studies had to have explicitly and appropriately defined the study design, the population being served, the intervention and its components, and outcomes or, in the case of qualitative research, processes that contributed to outcomes. Table Qualitative research is an inquiry process of understanding based on distinct methodological traditions of inquiry that explore a social or human problem. The researcher builds a complex, holistic picture, analyzes word, reports detailed views of informants, and conducts the study in a natural setting (p. 15).Two of the authors  with experience in qualitative research independently reviewed each research report for inclusion in the meta-synthesis. They then met to discuss their individual assessments; when a discrepancy occurred, discussion continued until consensus was met. In the end, 17 of the 45 documents were determined to have met the inclusion criteria. These 17 reports represented 14 distinct qualitative studies, with three reports discussing findings of one study -29 and tGiven the lack of a gold standard for assessing the quality of qualitative research , we searThe two authors who determined inclusion appropriateness also independently reviewed and rated each document for study quality. There was agreement that 7 of the 17 documents met all or most of the criteria (++), 8 met some criteria (+), and 2 met few or no criteria (-). There was disagreement on only one document in that one reviewer rated it ++ and the other reviewer +. As such, 15 reports (representing 12 studies) were deemed to be of adequate quality for inclusion in the meta-synthesis.We focused on data that pertained to psychosocial process that contributed to recovery and, secondly, to perceived outcomes for women and their children. Textual data that represented authors' findings and interpretations as well as verbatim data from study participants were extracted. These data were copied into Word documents, which were then imported into QSR International's NVivo7 program.Thematic analysis of data was conducted using the approach suggested by Atkins et al. . We firsThe lead author independently analyzed the data from all documents while the second author analyzed the data from half the documents, specifically, alternate documents from the chronological list. Themes became increasingly refined through reciprocal translation, that is, the translation of studies into one another by comparing the themes and concepts in one account with those in others . The conThe two lead authors met to discuss their findings part way through the analysis to discuss themes arising from the reciprocal translation. Much of the discussion focused on comparing and contrasting the more abstract analytical themes related to processes. After another period of independent coding of remaining documents, these authors met a second time to reach consensus on themes, which had become more refined and interpretive in nature. A higher order or synthesized translation was achieved.The characteristics of the studies included in the meta-synthesis are presented in Table Women experienced a number of psychosocial processes during treatment that played a role in their recovery and contributed to favourable outcomes. These processes included: development of a sense of self; development of personal agency; giving and receiving of social support; engagement with program staff; self-disclosure of challenges, feelings and past experiences; recognizing patterns of destructive behaviour; and goal setting. A final process, the motivating presence of children, sustained women in their journey to recovery. The sources of these process themes are shown in Table development of a sense of self. This included development of a sense of self-worth, self-identity, and self as a partner in a relationship.One commonly identified process that emerged as part of addiction recovery and was first reported by Nardi -29 was dNardi's -29 reseaAs women moved through the recovery process, Nardi  remarkedAnother transformation that impacted self-identity was that women developed greater awareness of their children and their maternal roles -29. WongNardi -29 notedWomen also developed a capacity for healthy relationships and a sense of self as a partner in relationships with friends, partners, family members, program staff, and other program participants -30. BaldGroup interaction and discussion were instrumental to self-development. Interactions with other mothers facilitated maternal self-awareness through role modeling, discussion, and positive feedback -29. Groudevelopment of personal agency during program involvement. As defined by Smith and colleagues [Women experienced lleagues , personalleagues ,31 and blleagues . Recognilleagues ,44.Development of personal agency fostered capacity for change. Women developed a willingness to accept personal responsibility for change, recognizing that they were the only ones who could regain control over their lives ,42,44. Wgiving and receiving of social support as being instrumental to women's recovery. Nardi [Many of the studies highlighted the y. Nardi  describey. Nardi ,38,43,44y. Nardi  commentey. Nardi -29. Morey. Nardi ,31,43.Through interaction, women were afforded the opportunity to understand and work through their problems while being provided support and encouragement ,31,46. PThe importance of social support being provided by others with a shared past is noteworthy. Within the group programs women felt safe and were able to talk with others who had similar experiences without being judged or manipulated ,39,42,43Listening to the stories of women who were improving their lives gave women encouragement and a sense of hope . MotivatEngagement with staff emerged as a process that was central to women's participation in the programs and behaviour change. The non-judgmental approach of staff and attributes such as compassion, honesty, empathy, and respect facilitated the development of therapeutic relationships [ionships ,38-40,42ionships ,39,43. Aionships .A non-directing approach by staff was important. Women valued being assisted to understand their problems and what contributed to them, and to identify strategies to address them ,46. TheyMotz and colleagues  and WongTwo studies reported on children's engagement with staff. Sword and colleagues  noted thself-disclosure, which was an important component of the recovery process [The nature of the relationship with group participants and staff facilitated  process . As repo process , "women  process  and Pola process  similarl process ,38.Through self-disclosure, women were able to confront the past. Often this revolved around women's relationships with their mothers and the painful experiences of abandonment, neglect, and abuse ,39,41,44recognizing destructiveness patterns. Women were enabled to examine their lives and choices [Another process fundamental to change and recovery was  choices -29, and  choices ,42. They choices -29,43,44 choices -29,38,40 choices ,31,38.Given the negative influence of others who use substances, it was important that women had the opportunity to develop and maintain relationships with sober peers . Such ingoal setting. It was important that women's goals were realistic, and staff played a role in determining the appropriateness of goals in relation to the program's resources, time frame, and purpose as well as in relation to women's specific needs [An activity undertaken with the support of program staff that contributed to treatment success was ic needs . Goal seic needs . Both thic needs . Reviewiic needs .While personal goals were variable, women often entered treatment wanting to become better parents and to establish their parental role ,31,37,38A major finding of Schretzman's study was the importance of having children present during treatment in that it helped sustain women's motivation in their recovery process . Other rWomen reflected on the value of learning to parent with their children by having them in the program ,37,38. CPerceived outcomes of participating in an integrated intervention program included: a maintained sense of personal agency; improvements in personal well-being; sustained sobriety or decreased substance use; establishment of positive social support networks; greater insight into self, others, and relationships; increased access to community services; and a more positive approach to professional relationships. Women also perceived that their capacity for parenting was enhanced in that they reported increased knowledge, skills, and confidence. They also identified improved maternal-child communication and relationships. Studies included in this meta-analysis did not explore women's perceptions of child health outcomes, with the exception of the study by Sword and colleagues in which women reported that program involvement had a positive impact on their children's behaviour and development . The souA sense of personal agency reportedly was maintained post-treatment. Women commented on their increased sense of control and confidence , and howWomen experienced improved personal well-being and a readjustment of priorities in that they were more content with self and life, and had learned to relax and enjoy life and their successes . Sword aThe study by Sword and colleagues  was the A number of studies reported enhanced capacity for parenting as an outcome of program involvement. Women gained increased knowledge about parenting and learned new parenting skills, which they willingly applied at home with their children ,42. TheyThrough involvement in treatment programs, women developed increased understanding of children, their behaviour, and their needs ,40,42. SFinally, women developed increased confidence in parenting and a positive identification with their parenting role . As one Many distinct but interconnected processes emerged as being important to women's addiction recovery. For the purposes of this discussion and consistent with the findings of the meta-synthesis, recovery is not simply a process of reducing use of drugs and alcohol or attaining abstinence from drugs and alcohol. Rather, recovery is regarded as a process of "re-covering" oneself, that is, as a process of personal and individualized growth that unfolds along a continuum, leading to a higher quality of life ,48.Through involvement in programs, women developed an enhanced sense of self. Development of a sense of self-worth is notable as women with substance use issues tend to have low levels of self-esteem  and pregAs part of the recovery process, and related to the development of a non-addict identify, women also developed a capacity for relationships with their children and with others internal and external to the treatment program. This is an important aspect of recovery because women who use substances often have histories of physical, sexual or emotional abuse as children ,55. ThesAnother finding of the meta-sythesis was that women developed personal agency through integrated treatment program involvement. Other first person accounts similarly describe people in recovery as active agents of change in their lives rather than passive recipients of services . This coThe finding that women experienced the giving and receiving of social support within integrated treatment programs is noteworthy as women who use substances often experience social isolation and limited social support ,60. SociGetting women to engage and participate in recovery activities is a first step to treatment retention and longer-term outcomes ,65. BecaTherapeutic engagement with staff and the support of women with shared experiences facilitated self-disclosure of histories of neglect and abuse and substance use-related issues. In a study of women in recovery, "breaking the silence" by discussing abuse experiences assisted them in reshaping their sense of self and connecting to others . AlterinRecognizing destructiveness patterns was a theme revealed by the meta-synthesis. It is consistent with the concept of "truthful self-nurturing" that was identified by Kearney  as the bGoal setting was another theme that emerged from the meta-synthesis. The ability to engage in future-oriented, goal-directed behaviour is central to the recovery process in substance use treatment . ProgramThe qualitative meta-synthesis highlighted the motivating presence of children for women to remain in integrated treatment programs. The meta-analysis of quantitative studies of integrated treatment programs we conducted (unpublished data) revealed that, relative to non-integrated programs, having children present increases client engagement, possibly because pregnancy-, parenting-, and child-related services increase maternal motivation to actively engage and remain in treatment . CreamerThe findings regarding outcomes are consistent with previous reviews and meta-analyses of quantitative studies in supporting the effectiveness of integrated programs in improving maternal engagement, substance use, and well-being. This qualitative meta-synthesis also identified positive outcomes of integrated programs for parenting knowledge, skills, and confidence, as well as child development and behaviour and the parent-child relationship. The lack of attention to child outcomes is an important omission of the qualitative studies conducted to date, especially given that integrated programs are designed to meet the needs of women and their children.Strengths of this meta-synthesis include the use of: a systematic and comprehensive search strategy; criteria that were congruent with the defined purposes of the synthesis to make inclusion decisions; and a quality assessment checklist developed by the National Institute for Health and Clinical Excellence (NICE) . SeveralThe main limitation of this meta-synthesis is that it relied on data derived predominantly from simple qualitative descriptive studies. Within the hierarchy of qualitative evidence , descripThe process findings of the meta-synthesis support the need for programs to adopt "wellness-oriented practices" that improve personal health and social functioning ,73. GiveRelational models of treatment take into account past and current family relationships, relationships with friends and partners, relationships with children, and relationships developed within the treatment context ,51. GiveThe phases of transformative learning are congruent with many of the process findings of the qualitative meta-synthesis. An initial step of transformative learning is self-reflection during which an individual tries to make meaning of one's life and experiences . InvolveWomen's relationships with their children need particular attention. Programs should provide support for the parenting role through a number of strategies, including: providing assistance in gaining insight into personal experiences with dysfunctional parenting and their influences on current parenting ; educatiThe authors declare that they have no competing interests.All authors contributed to the original study design. WS and SJ conducted the relevance and quality assessment, extracted data, carried out the thematic analysis, and prepared the draft of the manuscript. All authors read and approved the final manuscript.


We previously reported that a primitive vertebrate, the Mexican axolotl  synthesizes two classes of immunoglobulins. IgM are present in serum early inthe development, and represent the bulk of specific antibody synthesis after an antigenicchallenge. IgY occur in the serum later during the development, and are relativelyinsensitive to immunization.We demonstrate in the present work, using immunofluorescence with specific Mabs,that IgY are expressed in the gut epithelium, as secretory molecules. Secretory IgY arewell expressed in the stomach and intestinal mucosae of young animals from 1 monthafter hatching to the seventh month. Thereafter, IgY progressively disappear from thegut and become readily detectable in the serum of 9-month-old preadultimmunologically mature animals.Axolotl IgY are closely associated in the gut to secretory component-like (SC)molecules that are well-recognized by antisera to the SC of different mammalian species.This is the first description, in a primitive tetrapode, of an immunoglobulin class thatcould be the physiological counterpart of mammalian IgA.


A contributory role of endoscopic retrograde cholangiopancreatography(ERCP) in this schema has not been a consideration. An ERCP is rarely employed for therapy(or  diagnosis) when cholecystitis is suspected but it might assume a more significant role if it is consideredan efficacious alternative in specific conditions. We have had the unusual experience of managing11 patients with cholecystitis employing ERCP and its therapeutic modalities, i.e.,sphincterotomy, selective cannulation of the cystic duct, and relieving obstruction of that structureby catheter displacement of an obstructing stone. Endoscopic techniques providing decompressionof the gallbladder are described, and the feasibility of utilizing endoscopic procedures for treatmentof cholecystitis will be given consideration.Classically, until now, the management of cholecystitis has consisted of immediate and judiciousclinical assessment of the affected patient, interpolating into the assessment of the physical findingsand results from appropriate laboratory, x-ray, and scanning techniques (sonography and scintigraphy)to formulate a clinical impression. Usually, after the diagnosis has been established, the patientis subjected to a cholecystectomy, although the timing of the surgery may vary depending on theclinical condition of the patient. Alternatives to this management scheme have been suggested, but these are dependent upon the clinical condition ofthe patientand considerations of risks. Percutaneous drainage of the gallbladder or cholecystostomy issufficient enough to provide drainage, relieve obstruction, and the consequences of infection,


Cigarette smoking, one of the most pervasive habits in society, presents many well established health risks. While lung cancer is probably the most common and well documented disease associated with tobacco exposure, it is becoming clear from recent research that many other diseases are causally related to smoking. Whether from direct smoking or inhaling environmental tobacco smoke (ETS), termed secondhand smoke, the cells of the respiratory tissues and the lining pulmonary surfactant are the first body tissues to be directly exposed to the many thousands of toxic chemicals in tobacco. Considering the vast surface area of the lung and the extreme attenuation of the blood-air barrier, it is not surprising that this organ is the primary route for exposure, not just to smoke but to most environmental contaminants. Recent research has shown that the pulmonary surfactant, a complex mixture of phospholipids and proteins, is the first site of defense against particulates or gas components of smoke. However, it is not clear what effect smoke has on the surfactant. Most studies have demonstrated that smoking reduces bronchoalveolar lavage phospholipid levels. Some components of smoke also appear to have a direct detergent-like effect on the surfactant while others appear to alter cycling or secretion. Ultimately these effects are reflected in changes in the dynamics of the surfactant system and, clinically in changes in lung mechanics. Similarly, exposure of the developing fetal lung through maternal smoking results in postnatal alterations in lung mechanics and higher incidents of wheezing and coughing. Direct exposure of developing lung to nicotine induces changes suggestive of fetal stress. Furthermore, identification of nicotinic receptors in fetal lung airways and corresponding increases in airway connective tissue support a possible involvement of nicotine in postnatal asthma development. Finally, at the level of the alveoli of the lung, colocalization of nicotinic receptors and surfactant-specific protein in alveolar cells is suggestive of a role in surfactant metabolism. Further research is needed to determine the mechanistic effects of smoke and its components on surfactant function and, importantly, the effects of smoke components on the developing pulmonary system. Tobacco in various forms, as well as tobacco-related compounds such as marijuana, represent agents that present serious and insidious health risks to the general population. Both of these drugs have long and interesting histories. As this review is focused primarily on tobacco, marijuana use will be discussed only as it reflects on health effects resulting from both tobacco and marijuana. Tobacco use passed into Europe in the late sixteenth century after initial encounters between Europeans and native North and South Americans . TobaccoThe long history of both tobacco and marijuana as addictive drugs, their common routes of exposure, and their many common components make for an interesting dilemma in the health care field for both common and different reasons. On the one hand, the detrimental effects of cigarette smoking through both primary and secondary routes of exposure have become clear over the past few years . The lis2 by recent estimates [The pulmonary system which encompasses not only the lungs but the conducting airways, the nasal cavities, nasopharynx, oropharynx and larynx, is probably the most complex system in the body. This is due to the fact that the pulmonary system provides the most intimate interface with the external environment of any region of the body. The surface area of the lung tissue, approximately 120 mstimates -13, reprstimates . Some 40stimates . Their fstimates -17. Indestimates . Thus inBefore turning to a discussion of the interaction of tobacco smoke and related agents with the pulmonary surfactant system, it is important to have a conceptual knowledge of exactly what composes the lung surfactant. Therefore, we will begin our discussion in the form of a short review of what our latest concepts are concerning the surfactant, its composition and function. It should be noted, however, that this short review is not intended to be exhaustive as extensive reviews are available by acknowledged experts on pulmonary surfactant .Within the lung, an aqueous lining layer exists to varying degrees within the alveoli and intrapulmonary duct system . The comExcellent recent reviews of the biosynthesis, composition and functional contributions of the lipid components of the pulmonary surfactant are available ,24 and tThe pulmonary surfactant is composed of approximately 90% lipids ,26 with The defining characteristic of lung surfactant is its ability to generate very low surface tension at minimum expansion. Surface tension may be thought of as the force that resists expansion of a liquid . This isThe other surfactant phospholipid of particular note is phosphatidylglycerol (PG). This phospholipid is present at undetectable to very low levels in cells and is predominantly involved in synthesis of cardiolipin (di-phosphatidylglycerol) associated with the inner mitochondrial membrane . During Other minor phospholipids and neutral lipids exist in the pulmonary surfactant and while it is too early to dismiss their contributions as negligible, relatively few investigations into their functions have appeared. The reader is referred to recent reviews for more details ,55.+2-dependent proteins, both of which appear to originate from the surfactant-producing type II alveolar cell (see next section) and possibly the non-ciliated (Clara) cells of the bronchial epithelium [Four major proteins exist in the pulmonary surfactant. While they were recognized some years ago, it is only within the last few years that their functions have begun to be elucidated. Initially the proteins were thought to be derived in part from serum and there was considerable disagreement as to their number and function . Today iithelium . SP-A isithelium . It dispithelium . In lungithelium  while thithelium  dependinithelium ,62. The ithelium . Howeverithelium , restoreithelium  and mediithelium . Furtherithelium ,68, suggithelium ,69.SP-D, a collagenous 43 kDa glycoprotein secreted by type II alveolar cells , has alsThe remaining two surfactant proteins, SP-B and SP-C, are generally considered to be hydrophobic in nature and thus associate readily with the phospholipids of the surfactant. SP-B is expressed by both type II alveolar cells and the nonciliated bronchiolar epithelial Clara cells ,82. Its SP-C exists as a very non-polar α-helical protein of approximately 4.2 kDa composed of a mixture of isoforms (see review by Johansson ). It appSome 40 or more pulmonary cell types have been identified , making DPPC, as the primary phospholipid of the surfactant, is generally considered to display the surface tension characteristics required to withstand the high surface pressures that occur during the exhalation phase of the respiratory cycle . HoweverFrom the foregoing brief description of the pulmonary surfactant system, it is clear that the surfactant and its microenvironment present an extremely complex face, both in terms of composition and function, to any materials reaching the respiratory tissues. At the level of the air exchange tissue, the pulmonary surfactant presents the first interface encountered by inhaled smoke, whether from tobacco, marijuana or any other inhaled aerosolized material, for example fungal spores, mites or other allergens. Tobacco use and the potential for exposure to environmental tobacco smoke (ETS) has become an extremely important issue over the last several decades as it has become apparent that smoking carries with it a major and also preventable risk for the development of lung cancer. Lung cancer accounts for about 30% of all cancer deaths in men and 20% of all cancer deaths in women . In the Tobacco smoke contains between 2,000 and 4,000 agents  that mayStudies of the direct effects of tobacco smoke on pulmonary surfactant have been few. Several older studies ,140 suggSmoking appears to reduce the overall recovery by endobronchial lavage of surface active material and phosphatidylcholine in particular , althougSome changes have also been documented in other phospholipids. Specifically increases in phosphatidylethanolamine and sphingomyelin levels have been noted ,154 poss2 gas exposure, surfactant may improve mucociliary clearance from the bronchial tree [In addition to elevated numbers of alveolar macrophages , smokersial tree . Howeverial tree . This maial tree ,170. Altial tree . In any ial tree , the ultial tree , therebyial tree . What ovAt the molecular level, little is known about how smoke components interact with the surfactant either in the alveolus or at higher levels in the bronchial tree. Subramaniam and colleagues (1996) observed elevated levels of albumin in rat bronchoalveolar lavage following chronic cigarette smoke exposure  which haIn a limited series of experiments, freshly isolated rat alveolar type II cells appeared to undergo cell lysis after exposure to tobacco smoke . The impIn addition to the effects described above, some preliminary studies suggest cigarette smoke or smoke by-products affect the proteins of the pulmonary surfactant. Bronchoalveolar lavage samples from smokers and non-smokers showed reduced levels of SP-A and SP-D, standardized to lavage phospholipid levels  by ELISAMany other constituents of tobacco smoke may potentially alter or harm the pulmonary surfactant or type II cells. Of particular note, nitrogen dioxide, another constituent of tobacco smoke and a major environmental urban pollutant , has beeIt is generally accepted that surfactant deficiency, due to the immature nature of the surfactant-producing type II alveolar cells, is the main causative factor in the development of respiratory distress in prematurely delivered infants . However2, suggesting the pulmonary effects may vary according to the type and composition of the inhaled smoke [2 may have different effects as this compound appears to increase both the incorporation of precursors into surfactant phospholipids through enzyme activation, particularly CTP:cholinephosphate cytidylyltransferase, which regulates phosphatidylcholine synthesis [As noted above there is good evidence that smoking is associated with reduced surfactant phospholipids in the bronchoalveolar lavage . This maed smoke . Furtherynthesis ,201 and ynthesis ,202. In in utero to smoke [in utero and the postnatal period on the pulmonary surfactant is, however, not clear. In rat pups from smoke-exposed mothers and following postnatal sidestream exposure changes in dynamic compliance, reactivity to methacholine [Despite early observations that smoke exposure during pregnancy actually hastens pulmonary maturation ,204 whicto smoke . In factto smoke . These pto smoke , indicatto smoke . The ultacholine , and bioacholine . Howeverin utero [in utero induces altered lung mechanics in the fetus. However as they note, multiple binding sites for nicotine in developing lung, including the neuroendocrine cells, probably signifies a complex, multidimensional effect on the lung including such complex mechanisms as regulation of dichotomous branching, connection tissue interactions and muscle induction [While many agents in smoke may be detrimental to fetal development, some evidence supports a direct effect of nicotine on lung development suggesting that nicotine is capable of altering lung maturation. Nicotine crosses the human placenta with only minimal biotransformation to cotinine . It accuin utero . Changesin utero . Quantifin utero  suggestsin utero . Nicotinin utero ,240. Thenduction . Indeed nduction ,242.in vitro exposure of embryonic lung explants induced morphogenetic branching and enhanced expression of surfactant proteins A and C and the Clara cell-specific marker CC10 [While these studies overwhelming support the detrimental role for tobacco smoke exposure on prenatal and postnatal lung development and the overall well-being of the fetus, paradoxical evidence alluded to at the first of this section suggests that smoke-exposed fetuses display a state of advanced lung maturity ,204. Sucker CC10 . This acker CC10 . NeverthTobacco smoking, primarily through the use of cigarettes, was at one time a pervasive and accepted social habit. While use has declined to some extent in selected areas and the "acceptedness" of smoking, particularly in indoor environments, has similarly declined, exposure to tobacco smoke still remains a major health risk particularly in developing countries . Inhalatin vitro models will be necessary to establish smoke effects on lung function. This will enable characterization of the mechanisms by which agents in smoke potentially alter lung maturation, the developing respiratory tissues, and particularly the pulmonary surfactant.With regard to the developing fetus and fetal lung where the critical nature of the developmental process is underscored by the mortality levels due to respiratory distress, little question remains that smoking during pregnancy is detrimental. Altered fetal intracellular enzyme levels, receptor binding proteins and surfactant proteins are among some of the initial findings. Furthermore these changes are reflected in altered lung mechanics in the newborn which may extend into later periods of development and may compromise normal expansion and compliance during childhood. Clearly more research and application of markedly more sophisticated techniques as well as development of The authors declare that they have no competing interests.


Biomedical informatics involves a core set of methodologies that can provide a foundation for crossing the "translational barriers" associated with translational medicine. To this end, the fundamental aspects of biomedical informatics  may be essential in helping improve the ability to bring basic research findings to the bedside, evaluate the efficacy of interventions across communities, and enable the assessment of the eventual impact of translational medicine innovations on health policies. Here, a brief description is provided for a selection of key biomedical informatics topics  and their relevance to translational medicine. Based on contributions and advancements in each of these topic areas, the article proposes that biomedical informatics practitioners  can be essential members of translational medicine teams. Biomedical informatics, by definition-8, incorwhat interventions might be worthy to consider[why a proposed intervention works[how it can be appropriately scaled and applied to an entire population[translational barriers are comprised of the challenges associated with the translation of innovations developed through bench-based experiments to their clinical validation in bedside clinical trials, ultimately leading to their adoption by communities and potentially leading to the establishment of policies. The crossing of each translational barrier  Decision Support; (2) Natural Language Processing; (3) Standards; (4) Information Retrieval; and, (5) Electronic Health Records. For each topic, progress and activities in bio-, imaging, clinical and public health informatics are described. The article then concludes with a consideration of the role of biomedical informaticians in translational medicine teams.facilitate the application of basic research discoveries towards the betterment of human health or treatment of disease[Biomedical informatics is an over-arching discipline that includes sub-disciplines such as bioinformatics, imaging informatics, clinical informatics, and public health informatics; the relationships between the sub-disciplines have been previously well characterized,14,15, af disease.Bioinformatics approaches are needed to identify molecular and cellular regions that can be targeted with specific clinical interventions or studied to provide better insights to the molecular and cellular basis of disease[Imaging informatics techniques are needed for the development and analysis of visualization approaches for understanding pathogenesis and identification of putative treatments from the molecular, cellular, tissue or organ level[Clinical informatics innovations are needed to improve patient care through the availability and integration of relevant information at the point of care[public health informatics solutions are required to meet population based needs, whether focused on the tracking of emergent infectious diseases[Clinical informatics has historically been described as a field that meets two related, but distinct needs: patientf disease-25. Imaggan level-29. Clint of care-35. Fina diseases-39, the  diseases-44 or th diseases-47.translational bioinformatics is rapidly evolving with the enhancement and specialization of existing bioinformatics techniques and biological databases to enable identification of specific bench-based insights[clinical research informatics[At the T1 translational barrier crossing,  insights. Similarformatics emphasizTranslational bioinformatics and clinical research informatics are built on foundational knowledge-centric  approaches that are designed to meet the myriad of research and information needs of basic science, clinical, and public health researchers. The future of biomedical informatics depends on the ability to leverage common frameworks that enable the translation of research hypotheses into practical and proven treatments [eatments . Progreseatments  and neureatments ). It is eatments . Towardsknowledge acquisition - the gathering of relevant information from knowledge sources ; (2) knowledge representation - representing the gathered knowledge in a systematic and computable way ; (3)ule based or probaule based); and, , often resulting in encoded and structured forms that can be incorporated into subsequent applications[natural language generation systems that generate human understandable language from machine representations [Natural Language Processing (NLP) systems fall into two general categories: (1) lications,85; and,al rules). NLP hasal rules).The development and application of NLP approaches has been a significant focus of research across the entire spectrum of biomedical informatics. Biological knowledge extraction has also been a major area of focus in NLP systems,89, inclPeer-reviewed literature, such as indexed by MEDLINE, has been shown to be a source of previously unknown inferences across domains,102 as wrepresentation of data in a form that can be readily exchanged with other systems.The task of transmitting or linking data across multiple biomedical data sources is often difficult because of the multitude of different formats and systems that are available for storing data. Standard methods are thus needed for both representing and exchanging information across disparate data sources to link potentially related data across the spectrum of translational medicine - from laThe development of standards to represent and exchange data has been a major area of emphasis in biomedical informatics since the 1980's-113. MucThe re-use of data in the development and testing of research hypotheses is a regular area of interest in biomedical informatics,135. HowStandards that have been developed and are implemented by the biomedical informatics community will be an essential component towards the goal of integrating relevant data across the translational barriers . Additionally, standards can facilitate the access and integration of information associated with a particular individual in light of available biological, imaging, clinical, and public health data , ultimately enabling the development and testing the utility of "personalized medicine." Consequently, translational medicine will depend on biomedical informatics approaches to leverage existing standards  and resources like the UMLS, in addition to developing new standards for specialized domains  that satisfy the request. The quaAcross the field of biomedical informatics, various efforts have focused on the need to bring together information across a range of data sources to enable information retrieval queries,146. PerThe need to identify relevant information from multiple heterogeneous data sources is inherent in translational medicine, especially in light of the exponential growth of data from a range of data sources across the spectrum of translational medicine. Within the context of translational medicine, information retrieval systems could be built on existing and emerging approaches from within the biomedical informatics community, including those that make use of contemporary "Semantic Web" technologies-159. TheMedical charts contain the sum of information associated with an individual's encounters with the health care system. In addition to data recorded by direct care providers , medical charts typically include data from ancillary services such as radiology, laboratory, and pharmacy. With the increasing electronic availability of data across the health care enterprise, paper-based medical charts have evolved to become computerized as Electronic Health Records (EHRs). EHRs can capture a variety of information  and have electronic interfaces to individual services . Many EHRs can enable Computerized Provider Order Entry (CPOE), which allows clinicians to electronically order services and may also enable real-time clinical decision support . ClinicFrom the earliest propositions of electronic health records,165, it The increased availability of electronic health data, which are largely available and organized within EHRs, may have a significant impact on translational medicine. For example, the emergence of "personal health" projects  and conTranslational medicine is a trans-disciplinary endeavor that aims to accelerate the process of bringing innovations into practice through the linking of practitioners and researchers across the spectrum of biomedicine. As evidenced by major funding initiatives , thThe distinctions between multi-disciplinary, inter-disciplinary, and trans-disciplinary goals have been described as the difference between additive, interactive, and holistic approaches-198. UnlFormally trained biomedical informaticians have a unique education-205, oftThe success of translational medicine will depend not only on the addition of biomedical informaticians to translational medicine teams, but also on the acceptance and understanding of what biomedical informatics consists of by other members in the team. To this end, the importance of biomedical informatics training has been underscored as a key area of required competency across the spectrum of translational medicine, from biologists to cliniSince its beginnings, biomedical informatics innovations have been developed to support the needs of various stakeholders including biologists, clinicians/clinical researchers, epidemiologists, and health services researchers. A range of biomedical informatics topics, such as those described in this paper, form a suite of elements that can transform data across the translational medicine spectrum. The inclusion of biomedical informaticians in the translational medicine team may thus help enable a trans-disciplinary paradigm shift towards the development of the next generation of groundbreaking therapies and interventions.The author declares that they have no competing interests.INS conceived of and drafted the manuscript as written.


Nanotechnology is increasingly using both materials and nano-objects synthesized by living beings, most of them produced by microbial cells. Emerging technologies and highly integrative approaches (such as 'omics and systems biology), that have been largely proven successful for the production of proteins and secondary metabolites are now expected to become fully adapted for the improved biological production of nanostructured materials with tailored properties. The so far underestimated potential of microbial cell factories in nanotechnology and nanomedicine is expected to emerge, in the next years, in the context of novel needs envisaged in the nanoscience universe. This should prompt a careful revisiting of the microbial cell factories as the most versatile biological platforms to supply functional materials for nanotechnological applications. Generally speaking, Nanotechnology refers to the fabrication, manipulation and utilization of submicron objects, particularly those between 1 and 100 nm. Physical and chemical sciences have developed tools and procedures to fabricate nanoscale entities with intriguing applications in electronics, material sciences and medicine. In the biomedical context, the relevance of Nanotechnology relies on the particular biophysical properties of nanoscale objects and their particular interaction with living beings such as high diffusion in organs and tissues, high surface-volume ratio, efficient uptake by mammalian cells and high biological impact in biological interfaces through mecano-transduction signaling . The extBionanotechnology (as well as Nanobiotechnolgy) are rather fuzzy terms whose overlapping meanings are under continuous refining, as their associated technologies and applications keep evolving. They are often understood as the generation of hybrid materials , or bio-inspired materials . In a diIn summary, microbial cells are natural producers of (or they can be easily adapted to synthesize) nano-sized entities with relevant biomedical applications, being the cell factories themselves promising tools for the emerging technologies and biomedical applications related with the use of nanosized entities. Microbial Call Factories, the journal, has addressed some of these relevant topics through primary research papers and reviews. For instance, Chen and coauthors  have recMoreover, cell surface display technologies ,11 as weHowever, the number of submissions dealing with Nanotechnological applications or instruments deriving from microbial cells and the spectrum of coverage of Nanoscience-related topics are still low. Therefore, the editorial board of Microbial Cell Factories is pleased to encourage all the authors working in microbiology, biomedicine and biomaterial sciences to consider the potential of the Cell Factory platforms and to submit their primary research data and reviews to the journal. As a fully settled but highly dynamic journal, Microbial Cell Factories is committed to fully cover emerging technologies and scientific areas of hot interest from which microbial products are relevant, provided the biological aspects of the production (the Cell Factory concept) of the model particles, structures or materials are conveniently stressed.


To review studies on the cost consequences of compliance and/or persistence in cardiovascular disease (CVD) and related conditions  published since 1995, and to evaluate the effects of noncompliance on healthcare expenditure and the cost-effectiveness of pharmaceutical interventions.English language papers published between January 1995 and February 2007 that examined compliance/persistence with medication for CVD or related conditions, provided an economic evaluation of pharmacological interventions or cost analysis, and quantified the cost consequences of noncompliance, were identified through database searches. The cost consequences of noncompliance were compared across studies descriptively.Of the 23 studies identified, 10 focused on hypertension, seven on diabetes, one on dyslipidaemia, one on coronary heart disease, one on heart failure and three covered multiple diseases. In studies assessing drug costs only, increased compliance/persistence led to increased drug costs. However, increased compliance/persistence increased the effectiveness of treatment, leading to a decrease in medical events and non-drug costs. This offset the higher drug costs, leading to savings in overall treatment costs. In studies evaluating the effect of compliance/persistence on the cost-effectiveness of pharmacological interventions, increased compliance/persistence appeared to reduce cost-effectiveness ratios, but the extent of this effect was not quantified.Noncompliance with cardiovascular and antidiabetic medication is a significant problem. Increased compliance/persistence leads to increased drug costs, but these are offset by reduced non-drug costs, leading to overall cost savings. The effect of noncompliance on the cost-effectiveness of pharmacological interventions is inconclusive and further research is needed to resolve the issue. Studies quantifying the cost consequences of noncompliance with medication for CVD and related conditions were identified through searches of the MEDLINE, EMBASE and NHS Economic Evaluation databases. A manual search of reference lists from retrieved papers was also performed. Qualitative  and quantitative (medication possession ratio) data were extracted from the study reports.A review of 23 studies quantifying the cost consequences of noncompliance with medication for CVD and related conditions showed that increased compliance/persistence leads to an increase in the effectiveness of treatment and a decrease in medical events. This results in savings in the overall costs of treating CVD and related conditions. Increased compliance/persistence also appears to reduce cost-effectiveness ratios, but this effect requires further investigation.Cardiovascular disease (CVD) is responsible for more deaths worldwide than any other condition, and a large proportion of healthcare budgets are spent on its treatment and prevention . In the The preventative treatment of CVD aims to control related conditions, such as hypertension, hypercholesterolaemia and diabetes. The worldwide prevalence of hypertension was estimated to be 26% in 2000, and this is predicted to rise to 29% by 2025 . The figYet, for hypercholesterolaemia, for example, < 50% of those qualifying for lipid-modifying treatment actually receive it . Of thosThe pharmacological treatment of hypertension, hypercholesterolaemia and diabetes reduces the morbidity and mortality of associated CVD ,10,11. TThis review explores the cost consequences of noncompliance with pharmaceutical interventions in hypertension, diabetes, dyslipidaemia and heart failure. The aim is to evaluate the effects of noncompliance on the different types of expenditure, such as drug costs, overall healthcare expenditure and productivity costs, and to investigate the effect it has on the cost-effectiveness of pharmaceutical interventions for CVD and related conditions.Two common measures of compliance are adherence (sometimes used as a synonym for compliance) and persistence. Numerous definitions have been used to describe and measure these parameters. In this review, the definitions of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) were used, whereby compliance is defined as taking medication as prescribed, on time and at the correct dose, and persistence is defined as the continuing use (in time) of the prescribed therapy .Searches for relevant studies were conducted using the MEDLINE and EMBASE databases, and the NHS Economic Evaluation Database (NHSEED). The search terms used were: cardiovascular, hypertens*, hyperlipid*, dyslipid*, blood pressure, diabet*, cost*, economic*, compliance (adherence) and persistence. A manual search of the reference lists from retrieved papers was also performed to identify further relevant studies.Studies were deemed relevant if they were English language, human studies published before February 2007; if they involved patients with CVD or related conditions ; if they examined compliance (adherence) and/or persistence to pharmaceutical interventions (even if the primary objective was not to measure compliance/persistence); and if they provided an economic evaluation or cost analysis and quantified the cost consequences of compliance/persistence. Studies published before 1995 were excluded as results from these earlier studies could not be compared with those from more recent studies because of changes in treatment patterns , study methodology and the price of healthcare resources, including drug prices.Studies were also excluded from analysis if the economic consequence of compliance/persistence was not quantified; if they examined noncompliance with antiplatelets, aspirin, digoxin, insulin, non-pharmaceutical therapies or treatment guidelines; or if they were reviews of earlier (pre 1995) research papers, letters to the editor, commentaries or conference abstracts.Studies were divided into cost studies and economic evaluations. Cost studies examined the effect of compliance/persistence or compliance-enhancing interventions on the cost of treatment or on productivity costs, while economic evaluations examined changes in the cost-effectiveness of an intervention with different compliance/persistence rates using sensitivity analyses. For the latter, only studies that used a univariate sensitivity analysis of compliance/persistence were selected. When both compliance/persistence rates and costs were examined, but the cost consequences of noncompliance were not studied, the study was excluded.Qualitative data extracted from the studies included the country where the study was performed, the type of study , the type of evaluation , the disease area, the type of study population, the study setting, the study length, the definitions and methods of quantifying compliance and/or persistence, and the source of compliance/persistence data.Quantitative data extracted from the studies included the medication possession ratio (MPR), which is the most commonly used measure of compliance, and the rate of persistence. The MPR is defined as the days’ supply of a dispensed prescription divided by the number of days between prescription refills . For exaQuantitative analysis was not possible because of the different methodology used in the different studies, and difficulties in collating cost data from different countries, where treatment patterns and unit costs vary. Results from the different studies were, therefore, compared descriptively.Twenty-three studies that analysed the effect of compliance and/or persistence on the cost or cost-effectiveness of treatment were identified. Of these, 10 focused on hypertension, seven on diabetes, one on dyslipidaemia, one on CHD, one on heart failure and three on multiple diseases, including diabetes, hypertension, hypercholesterolaemia, general heart disease and heart failure . SeventeThree studies in hypertensive patients and one in diabetic patients gave no compliance/persistence rates ,35–37 anThe rate of compliance or persistence varied according to the type of study, the patient population, the method of data collection and the technique used to measure compliance/persistence. In studies assessing the cost-consequences of noncompliance, compliance rates were 45–80% in diabetes, 15–35% in hypertension, 51–59% in hypercholesterolaemia and 60–96% in other diseases, such as heart failure and CHD. In CHD, 88% of statins were taken in the prescribed time interval. Persistence rates were measured only in hypertension, and ranged from 63% to 81%.Overall healthcare costs may be divided into direct and indirect costs. Direct costs are those relating to goods, services and other resources that are consumed in the provision of an intervention or in dealing with the side effects or other current and future consequences. The resources used can be either medical or non-medical. Thus, direct costs include drug costs, but the major proportion of direct costs is non-drug-related. Indirect costs refer to productivity gains or losses relating to illness or death . To calcMost studies in this review examined only direct costs and four studies considered only medication costs ,33,34,39The three Italian studies investigated the drug costs associated with different patterns of compliance and persistence with antihypertensives ,34,39. TIn the later Italian study , averageIn another study , data frEstimating drug costs only gives an indication of the effect of noncompliance with the use of different drug types and acquisition prices; it does not provide data on the consequences of noncompliance on other healthcare costs, such as hospitalisation. As a result, even if a given drug or class of drug is associated with a low compliance rate (e.g. diuretics), the increase in drug costs as a result of switching can be offset by a high proportion of generics and thus relatively low drug costs.When other, non-drug costs are taken into account, the results obtained are quite different. The disease-related and all-cause direct healthcare costs in relation to compliance were investigated in a multiple disease study . All-cauFor all-cause costs, a high level (80–100%) of compliance with treatment for diabetes, hypertension and hypercholesterolaemia was associated with significantly lower non-drug medical costs than for lower levels (1–79%) of compliance . As these represent the major proportion of costs, higher levels of compliance with treatment were associated with lower overall healthcare costs, despite high drug costs. In diabetes, overall healthcare costs decreased with increasing compliance, and similar, although nonmonotonic, decreasing trends were seen in hypertension and hypercholesterolaemia. The decrease in healthcare costs with increasing compliance was attributed mainly to a decrease in the risk of hospitalisation, which led to a decrease in non-drug medical costs . SimilarIn the above study, no noticeable trends in overall costs were observed for congestive heart failure (CHF) . A numbeSimilarly, a study of compliance with statin monotherapy in patients at high risk of CHD showed that the level of compliance over a 6-month period had no significant effect on direct healthcare costs . In thisThe findings in diabetes are supported by the results of other studies in diabetic patients. In one study , MPR wasConcern over the rising prevalence and costs of diabetes to a large  company in the USA led the company to redesign its drug benefit scheme, such that diabetic employees (and their dependants) were required to pay only 10% of the cost for both brand-name and generic antidiabetic medications, rather than 30–50% as before . The ratIn a retrospective study of hypertensive Medicaid patients , the higAnother study in hypertensive patients compared a fixed-dose tablet, consisting of a combination of an angiotensin converting enzyme (ACE) inhibitor and calcium-channel blocker, with an ACE inhibitor and a calcium-channel blocker taken separately . The MPRA study of healthcare costs in heart failure  found thOnly one of the cost studies investigated both direct and indirect costs . BesidesOf the six economic evaluations, two assessed the cost-effectiveness of drug coverage using the assumption that high drug costs are a major barrier to compliance/persistence and that higher coverage would increase compliance and persistence with therapy; two analysed health promotion programmes and two assessed the economic effects of compliance and persistence in sensitivity analyses. All of the studies apart from two ,37 were A Canadian study  evaluateThe above study had many limitations. Namely, compliance and its effect on efficacy were based on assumptions; survival was calculated for all diabetes patients (type I and II disease); dialysis costs were probably underestimated and the life span of compliant patients was assumed to be similar to that of noncompliant patients. However, similar conclusions were reached in a study of Medicare diabetic patients . In thisThe economic effects of compliance were evaluated in sensitivity analyses of data from a clinical trial investigating the prevention of type 2 diabetes in patients with impaired glucose tolerance . The DiaA controlled trial evaluated a Canadian pharmacy-based health promotion programme in hypertension . The proA Spanish study evaluated the different parameters influencing the cost-effectiveness of antihypertensives in patients with stage I and II arterial hypertension . Direct Smaller effects were reported in another Spanish study investigating the primary prevention of CHD . In thisNoncompliance in CVD and related conditions is an important issue because of the chronic and often asymptomatic nature of such disease, resulting in poor disease control and long-term adverse consequences. This review confirms that noncompliance also has a significant effect on costs. However, the effect differs depending on the type and the range of costs taken into account. This effect, in turn, influences the cost-effectiveness of pharmaceutical interventions for CVD and related conditions.Noncompliance appears to have a significant effect on the costs of treatment. High compliance and persistence lead to an increase in drug costs ,33,34,39While the correlation between compliance/persistence and inpatient costs seems to be clear, the relationship between physician visits and compliance/persistence is two-sided. For hypertension, controlled blood pressure reduces the number of physician visits and hence medical costs. However, physician visits can also increase compliance/persistence by encouraging patients to comply with their treatment .Higher compliance/persistence rates appear to lower the cost-effectiveness ratio in diabetes ,25,40 anAlthough some of the economic evaluations incorporated noncompliance into the cost-effectiveness calculations, they did not report the numerical effects of changing the compliance/persistence rate. Rather, they simply reported whether or not it had an important effect. Thus, the results of these studies were inconclusive. For example, in a study to determine the cost-effectiveness of statins in the prevention of CHD, improved compliance did not change the order of treatments in terms of cost-effectiveness, but only changed the overall cost-effectiveness of statin therapy . AnotherFixed-dose combinations of different drugs may help to increase patient compliance/persistence in cases where more than one type of drug is being taken. In hypertension, such combinations have the potential to improve disease control and avoid adverse medical events, thus increasing effectiveness and lowering non-drug medical costs . The impIn most of the studies reviewed, the time interval analysed was 2 years or less. This may have influenced the results, since the time frame influences the effect of noncompliance. In the short term, good compliance/persistence is associated with an increase in the amount of medication taken, thus leading to an increase in drug costs. In the long term, however, medical events are avoided. The point where the savings from the non-drug costs offset the extra drug costs (i.e. where increasing compliance/persistence further would be cost-saving) depends on the drug costs, the avoided events and their costs, and how far into the future these events take place. The latter is determined by the course, nature and severity of the disease.In addition to the time interval, the type of healthcare system and reimbursement scheme can also influence the results. In healthcare systems involving significant patient co-payment, better compliance/persistence increases out-of-pocket payments. Hence, patients bear the higher financial burden, while savings are realised by the third-party payer (e.g. NHS or insurance company). This could reduce the patient incentive to be compliant, particularly in diseases where the consequences of noncompliance are realised in the very distant future, such as hypertension . HoweverRetrospective measurement with the aid of claims or pharmacy databases is a comparatively easy, precise and quick way of measuring compliance/persistence. However, possession of medication does not necessarily indicate consumption: hoarding and skipping of medication can occur and the timing of doses cannot be examined. It is also difficult to know which drug is responsible for the observed effects because of the high number of add-on therapies and because of switching between different drugs. In addition, retrospective collection of data does not allow for the selection of patients, so different treatment groups could differ significantly in their characteristics. Prospective collection of data  allows greater flexibility in the selection of patients, control groups and compliance/persistence measures. However, regular meetings with study investigators, the greater attention devoted to compliance/persistence and the selection of specific patients could bias the results, producing higher compliance/persistence rates than those observed in real life. If feasible, a prospective, real-world, observational study could represent a more realistic picture of what happens in a real-world, usual-care setting.Most of the studies included in this review used retrospective data. Accordingly, the most common measure of compliance used in the different studies was the MPR. However, compliance rates could not be compared across studies because of the different patient populations. As most of the retrospective studies used the claims databases of managed care organisations, such as Medicare and Medicaid, the applicability of the results may be limited to settings where third party payers are responsible for distributing health care. Further research is needed to confirm that increased compliance and persistence are associated with cost savings. Today, payers may relate increased compliance and persistence to increased short-term costs because of the impact on their budget. However, although drug costs alone may slightly increase, these costs are often off-set by reduced non-drug costs, which lead to overall cost savings.The association between patient compliance/persistence with medication and disease outcomes, such as cardiovascular or all-cause morbidity and mortality, has rarely been evaluated outside of the clinical trial setting. A recent publication from investigators at Colorado's Kaiser Permanente showed higher risks for all-cause hospitalisation and mortality in patients with diabetes who were non-optimally compliant with statins, antihypertensives and oral hypoglycaemic agents . SimilarFuture research should focus on long-term, real-world, longitudinal studies to measure the actual costs and savings associated with increased compliance and persistence, and the impact on positive health outcomes, such as improved blood pressure, lipid levels or glycosylated haemoglobin levels. The most significant limitation of retrospective analyses of administrative claims databases is that the impact of compliance on clinical outcomes across the different drug classes is not obtainable. These limitations can be overcome using a retrospective electronic medical record database. However, as drug use is recorded by prescription order, compliance data is lacking. Another alternative is to conduct such research using databases with access to both prescription refill information and information on outcomes, such as blood pressure. The Veterans Health Administration (VHA) health information system may serve such a purpose. Results from these studies would provide physicians and decision makers with additional insights into the various factors that impact on treatment effectiveness, and may lead to a paradigm shift with increased focus on the benefits of compliance and persistence rather than on drug costs alone.An ongoing study in the VHA is addressing the question of whether poor compliance with antihypertensive therapies is associated with an increase in hospitalisation and mortality rates or failure to improve clinical disease measures, such as blood pressure outcomes. Data from electronic health records and pharmacy records will be collected from the date of the first prescription for an antihypertensive. The study timeline will include a 1-year compliance assessment period and a 12- to 18-month outcomes assessment period. The primary outcome of the analysis will be a composite end-point of all-cause hospitalisation or death occurring during the outcomes assessment period. Secondary outcomes will include cardiovascular hospitalisation, cardiovascular death, and achievement of blood pressure goals based on recommended levels for patients with and without diabetes, during the outcomes assessment period. It is anticipated that the outcomes of this study will lend support to the outcomes obtained from the current review of retrospective studies that are largely dependent on administrative claims databases and lack clinical outcomes data.Noncompliance and non-persistence are significant problems in the management of CVD and related conditions, such as diabetes. The increased drug use associated with higher compliance and persistence is associated with an increase in drug costs. These costs are particularly high for patients switching therapies. However, better compliance/persistence increases the effectiveness of treatment, leading to a decrease in future adverse medical events. Fewer medical events results in lower non-drug costs and, as the majority of healthcare costs are non-drug costs, these offset the higher drug expenditures in the long term, such that a 10% increase in compliance results in a 2–9% decrease in total annual healthcare costs.Higher compliance/persistence rates also appear to reduce cost-effectiveness ratios, one study showing that a 20% decrease in compliance increased the ICER by $6700/QALY. However, most studies included in this review failed to investigate the extent of the effect, partly because of a lack of understanding about the relationship between compliance/persistence and effectiveness. Thus, the effect of compliance/persistence on cost-effectiveness is currently inconclusive. Further research into the relationship between effectiveness, compliance/persistence and cost-effectiveness is required to resolve the issue.