Tephritidae bacterial symbionts: potentials for pest management.

Tephritidae is a large family that includes several fruit and vegetable pests. These organisms usually harbor a variegated bacterial community in their digestive systems. Symbiotic associations of bacteria and fruit flies have been well-studied in the genera Anastrepha, Bactrocera, Ceratitis, and Rhagoletis. Molecular and culture-based techniques indicate that many genera of the Enterobacteriaceae family, especially the genera of Klebsiella, Enterobacter, Pectobacterium, Citrobacter, Erwinia, and Providencia constitute the most prevalent populations in the gut of fruit flies. The function of symbiotic bacteria provides a promising strategy for the biological control of insect pests. Gut bacteria can be used for controlling fruit fly through many ways, including attracting as odors, enhancing the success of sterile insect technique, declining the pesticide resistance, mass rearing of parasitoids and so on. New technology and recent research improved our knowledge of the gut bacteria diversity and function, which increased their potential for pest management. In this review, we discussed the diversity of bacteria in the economically important fruit fly and the use of these bacteria for controlling fruit fly populations. All the information is important for strengthening the future research of new strategies developed for insect pest control by the understanding of symbiotic relationships and multitrophic interactions between host plant and insects.

The influence of antibiotics on gut bacteria diversity associated with laboratory-reared Bactrocera dorsalis.

The oriental fruit fly Bactrocera dorsalis (Hendel) is a destructive insect pest of a wide range of fruit crops. Commensal bacteria play a very important part in the development, reproduction, and fitness of their host fruit fly. Uncovering the function of gut bacteria has become a worldwide quest. Using antibiotics to remove gut bacteria is a common method to investigate gut bacteria function. In the present study, three types of antibiotics (tetracycline, ampicillin, and streptomycin), each with four different concentrations, were used to test their effect on the gut bacteria diversity of laboratory-reared B. dorsalis. Combined antibiotics can change bacteria diversity, including cultivable and uncultivable bacteria, for both male and female adult flies. Secondary bacteria became the dominant population in female and male adult flies with the decrease in normally predominant bacteria. However, in larvae, only the predominant bacteria decreased, the bacteria diversity did not change a lot, likely because of the short acting time of the antibiotics. The bacteria diversity did not differ among fruit fly treatments with antibiotics of different concentrations. This study showed the dynamic changes of gut bacterial diversity in antibiotics-treated flies, and provides a foundation for research on the function of gut bacteria of the oriental fruit fly.

The Most Serious Offenses and Penalties Concerning Unsafe Foods under the Food Safety Laws in Bangladesh, India, and Australia: A Critical Analysis.

The right to food is an internationally recognized human rignt, which inherently denotes the right to safe food simply because unsafe foods cause different diseases resulting in consumer's disability, organ failure, or even early demise. Food safety currently may not be an issue of public concern in Australia, but it has been a "silent killer" for decades in both Bangladesh and India contributing to deaths of thousands and injuries of millions of others. Unscrupulous businesses have been making money at the cost of immense human casualties with almost complete impunity in Bangladesh. The situation in Bangladesh is so intractable that the government has been making laws one after another; but food traders remain undeterred, and consequently consumers continue to die from adulterated foods. This paper examines the loopholes in the definitions of the most serious offenses under three major pieces of legislation in Bangladesh, India, and Australia. It finds that all three statutes seem flawed to some extent, though they all may mutually benefit from one another in defining and clarifying the most serious food safety offenses and penalties with a view to strengthening their effectiveness.

Food Safety Offenses in New South Wales, Australia: A Critical Appreciation of Their Complexities.

Food is essentially a primary need of all life to remain alive. Faults or carelessness of human beings renders foods unsafe, which may cause disease and death. This article examines selected food safety offenses of New South Wales aimed at assessing their definitional clarity and penal rationality looking through the lens of an offender's culpability. It carries out a critical analysis based on archival materials and concludes that the present offense provisions hold significant merits to regulate food safety; however, further clarity of their inherent complexities could enhance their efficacy.

Civil Liabilities for Unsafe Foods in Bangladesh and Australia: A Comparative Perspective on Consumer Protection.

The statutory laws concerning food safety, which allow the consumers affected by unsafe foods to claim compensation for their loss or damage in Bangladesh, are flawed in several respects. These flaws are argued to have harmful impacts on consumer protection. The ineffective legislation in the absence of application of the common law principles of negligence has left the consumers virtually helpless in securing remedies for their injuries. This article endeavors to critically examine the ambiguities and shortcomings in the Consumer Rights Protection Act 2009 (Bangladesh) looking through the prisms of the Australian Consumer Law 2010 and relevant case law from major common law jurisdictions. It discovers a number of weaknesses in the legislation of Bangladesh and provides specific suggestions for strengthening the civil liability provisions from the perspective of consumer protection by preventing their contraventions and providing adequate compensation.

Chemically processed CdTe thin films for potential applications in solar cells - Effect of Cu doping.

Thin films of cadmium telluride (CdTe) have attained the attention of researchers due to the potential application in solar cells. However, cost-effective fabrication of solar cells based on thin films along with remarkable efficiency and control over optical properties is still a challenging task. This study presents an analysis of the structural, optical and electrical properties of undoped and Cu-doped CdTe thin films fabricated on ITO coated glass substrates using an electrodeposition process with a focus on practical applications. Electrolytes of cadmium (Cd), tellurium (Te) and copper (Cu) are prepared with a low molarity of 0.1 M. Thin films are deposited by keeping current density in the range of 0.12-0.3 mA/cm2. Copper doping is varied (2-10 wt%) for the optimized sample. X-ray diffraction crystallography indicates that both undoped CdTe and Cu-doped CdTe films crystallize into a dominant hexagonal lattice. Direct energy band gap is observed for both undoped and doped conditions. The study revealed a drop in the optical band gap energy to ∼1.46 eV with the increase in doping (Cu) concentration from 2 to 10 wt%. Increase in mobility and conductivity is observed with the increase in current density of the deposited undoped CdTe thin films. Whereas, Cu doping of 6 wt% produced thin films with acceptable mobility and conductivity for the doped samples. Furthermore, photoluminescence (PL) spectroscopy unveiled a multitude of emission peaks encompassing the visible spectrum, arising from the combination of electrons and holes through both direct and indirect recombination processes. Findings of this study suggest that chemically produced CdTe thin films would be suitable for use as low-cost applications pertaining to solar cells.

Octreotide for the treatment of diarrhoea in patients with ileal pouch anal anastomosis: a placebo-controlled crossover study.

AIM: Diarrhoea with urgency is a debilitating long-term complication of ileal pouch anal anastomosis (IPAA) after a proctocolectomy. Somatostatin analogues are used to control diarrhoea and high-output ostomies. Hence, we designed a prospective, double-blind, crossover trial to explore the efficacy and tolerability of octreotide to reduce diarrhoea in adult patients with IPAA. METHOD: Patients were randomized to octreotide subcutaneously (SC), 500 µg three times daily (t.i.d.), or matching placebo SC for 7 days. Responders (a reduction in stool frequency of three or more stools per 24-h period and with a reduction in stool frequency of at least 30% after 7 days of treatment compared with baseline; the primary end-point) remained in the same group and nonresponders could cross over to the alternative treatment for 7 days. Open-label octeotide LAR 30 mg was offered to all responders on day 14. Flexible pouchoscopy with biopsies was performed at baseline in all patients and was repeated on days 7 and 14 in patients with pouchitis. RESULTS: Fifteen patients (11 men, median age 52 years), all with ulcerative colitis, were randomized. Three patients were withdrawn for side effects during the blinded phase. Response was achieved by two of 12 and two of 11 patients treated with octreotide or placebo, respectively (including crossover, P = 0.9). The median stool frequency remained stable in both groups [Δoctreotide: 0 (IQR, -4 to 0), Δplacebo: -1 (IQR, -1 to 1), P = 0.45]. Octreotide had no effect on the modified pouch disease activity index (mPDAI), and pouchitis persisted in five of six subjects with pouchitis at onset. One subject received open-label octreotide LAR. CONCLUSION: Octreotide has no clear beneficial effect on the stool pattern or on pouchitis severity in patients with high stool frequency after IPAA.

Myrica salicifolia Hochst. ex A. Rich. suppress acetic acid-induced ulcerative colitis in rats by reducing TNF-alpha and interleukin-6, oxidative stress parameters and improving mucosal protection.

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) with rising prevalence in developing countries, and limited success of current therapies, natural products have immense potential for therapy due to their "disease modifying and side-effect neutralizing" potential. Myrica salicifolia is traditionally used for gastrointestinal diseases and have reported antiinflammatory activities, but its use in IBD has not yet been studied. Therefore, in the present study, the effects of the root extract of M. salicifolia (Ms.Cr) were investigated using the acetic acid-induced UC model in rats. For 6 days, the rats were given either vehicle (10 mL/kg), lower (200 mg/kg), and higher (400 mg/kg) doses of Ms.Cr, or the positive control drug (prednisolone; 2 mg/kg) orally. A single dosage of 5% acetic acid (1.0 mL) was administered intrarectally to rats on day 6 to induce UC. Disease activity index (DAI), histological observations, the biochemical parameters related to oxidative stress, and specific cytokines such as interleukin-6 (IL-6) and the tumor necrosis factor-α (TNF-α) were determined to assess the effect of Ms.Cr. In comparison to the AA-induced colitis rats, Ms.Cr's pretreatment significantly decreased DAI, colonic ulceration, and inflammatory score. Total glutathione levels and catalase activity were considerably recovered in the colitis group treated with Ms.Cr, whereas enhanced lipid peroxidation in colon tissues was significantly decreased. Moreover, Ms.Cr pretreatment also caused inhibition of the activation of IL-6 and TNF-α in the colonic tissues of respective groups. Based on these findings, Ms.Cr might be developed to treat UC in the future.

Reported effects of the COVID-19 pandemic on the psychological status of emergency healthcare workers: A scoping review.

BACKGROUND: While literature on psychological consequences among frontline healthcare workers (HCWs) flourishes, understanding the psychological burden on this group is particularly crucial, as their exposure to COVID-19 makes them especially at high risk. We explored what is known about psychological effects of the COVID-19 pandemic on emergency HCWs. METHODS: We used a scoping review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews. RESULTS: The search identified 5432 articles, from which a total of 21 were included in the final review. Anxiety, burnout, depression, inadequate sleep, post-traumatic stress disorder (PTSD) symptoms, distress/stress and secondary trauma, were all reportedly experienced by emergency HCWs. Anxiety, burnout, depression and stress levels were higher among physicians and nurses compared to others. Post-traumatic stress disorder symptoms were higher among reserve medics, while Red Cross volunteers developed similar reactions of psychological stress and secondary trauma to other healthcare workers. Male HCWs reported more post-traumatic stress disorder symptoms than females, while stress was higher among females than male HCWs. CONCLUSIONS: Emergency HCWs providing care during the COVID-19 pandemic are at risk from specific psychological impacts, including anxiety, burnout, depression, inadequate sleep, PTSD symptoms, psychological distress/stress and secondary trauma, and stress TWEETABLE ABSTRACT: Emergency healthcare workers are at direct risk of psychological impacts from the COVID-19 pandemic.

A caution for oncologists: chemotherapy can cause chaotic dynamics.

BACKGROUND AND OBJECTIVE: The effect of chemotherapy in cancer models is mostly handled by using a separate equation for chemotherapeutic agent. In this study, we do not consider a separate equation for drug but rather introduce its effect in terms of a parameter m representing the fraction of tumor cells killed by chemotherapeutic drug module. The main objective of this study is to provide conditions on model parameters which when fulfilled the grave consequences of cancer can be avoided. This study also shows that chemotherapy at times can produce unexpected results. METHODS: Linearization method to study the stability of model equilibria. RESULTS: The results obtained in this study are governed by the trichotomy law on the number 1-a12-d1, where a12 represents the negative effect on the growth of cancer cells due to their competition with host cells for resources and d1 is rate of annihilation of cancer cells due to chemotherapy. It is seen that in case of under-dose drug module when d1<1-a12, the complete eradication of cancer is not possible. When d1=1-a12, the model suggests occurrence of chaotic dynamics. When the drug dose is properly adjusted so that d1>1-a12, the complete eradication of cancer is guaranteed. CONCLUSION: The results of the model of this paper given for the post vascular stages of tumor suggest criteria to select a particular drug module (a single drug or a combination of drugs) that the chemotherapy procedure should adapt to eradicate cancer. This study injects a note of caution for oncologists that chemotherapy as cancer treatment can also cause chaotic dynamics in certain situations. This study also presents a plausible explanation to the question why sometimes a tumor grows in the body and then gets cured without any medical intervention.

Immune surveillance of human cancer: if the cytotoxic T-lymphocytes play the music, does the tumoral system call the tune?

Accumulating evidence indicates that the innate and adaptive immune systems participate in the recognition and destruction of cancer cells by a process known as cancer immunosurveillance. Tumor antigen-specific cytotoxic T-lymphocytes (CTL) are the major effectors in the immune response against tumor cells. The identification of tumor-associated antigen (TAA) recognized primarily by CD 8(+) T-lymphocytes has led to the development of several vaccination strategies that induce or potentiate specific immune responses. However, large established tumors, which are associated with the acquisition of tumor resistance to specific lysis, are usually not fully controlled by the immune system. Recently, it has become clear that the immune system not only protects the host against tumor development but also sculpts the immunogenic phenotype of a developing tumor and can favor the emergence of resistant tumor cell variants. Moreover, it has become obvious that the evasion of immunosurveillance by tumor cells is under the control of the tumor microenvironment complexity and plasticity. In this review, we will focus on some new mechanisms associated with the acquisition of tumor resistance to specific lysis during tumor progression, involving genetic instability, structural changes in cytoskeleton, and hypoxic stress. We will also discuss the interaction between CTLs and tumor endothelial cells, a major component of tumor stroma.

Long-term safety of infliximab for the treatment of inflammatory bowel disease: a single-centre cohort study.

BACKGROUND AND AIMS: This study evaluates the long-term safety of infliximab in patients with inflammatory bowel disease (IBD) treated with the drug over a 14-year period. METHODS: The medical records of 734 patients with IBD treated with infliximab and 666 control patients not treated with infliximab were reviewed for adverse events. The time of onset and outcome, severity and concomitant medication were recorded. RESULTS: Patients and controls were followed up for serious adverse events for a median time of 58 months (IQR 33-88) and 144 months (IQR 83-163), respectively. 112 severe adverse events occurred in 93 patients (13%) treated with infliximab and 157 occurred in 126 (19%) control patients (OR 1.33 (95% CI 0.56 to 3.00, p = 0.45). There was no difference between the two groups in mortality, malignancies and infection rate. Tuberculosis was diagnosed in two patients receiving infliximab who had negative skin tests at baseline whereas none of 16 patients with positive skin tests who received prophylaxis developed tuberculosis. Concomitant treatment with steroids was the only independent risk factor for infections in patients treated with infliximab (OR 2.69 (95% CI 1.18 to 6.12), p = 0.018). The most commonly observed systemic side effects were skin eruptions including psoriasiform eruptions in 150 patients (20%). CONCLUSIONS: Long-term infliximab treatment had a good overall safety profile in the patient cohort studied.

Long-term outcome of treatment with infliximab in 614 patients with Crohn's disease: results from a single-centre cohort.

BACKGROUND AND AIMS: This observational study assessed the long-term clinical benefit of infliximab (IFX) in 614 consecutive patients with Crohn's disease (CD) from a single centre during a median follow-up of 55 months (interquartile range (IQR) 27-83). METHODS: The primary analysis looked at the proportion of patients with initial response to IFX who had sustained clinical benefit at the end of follow-up. The long-term effects of IFX on the course of CD as reflected by the rate of surgery and hospitalisations and need for corticosteroids were also analysed. RESULTS: 10.9% of patients were primary non-responders to IFX. Sustained benefit was observed in 347 of the 547 patients (63.4%) receiving long-term treatment. In 68.3% of these, treatment with IFX was ongoing and in 31.7% IFX was stopped, with the patient being in remission. Seventy patients (12.8%) had to stop IFX due to side effects and 118 (21.6%) due to loss of response. Although the yearly drop-out rates of IFX in patients with episodic (10.7%) and scheduled treatment (7.1%) were similar, the need for hospitalisations and surgery decreased less in the episodic than in the scheduled group. Steroid discontinuation also occurred in a higher proportion of patients in the scheduled group than in the episodic group. CONCLUSIONS: In this large real-life cohort of patients with CD, long-term treatment with IFX was very efficacious to maintain improvement during a median follow-up of almost 5 years and changed disease outcome by decreasing the rate of hospitalisations and surgery.

A mixed therapy minimal model: Some strategies for eradication or minimization of cancer.

BACKGROUND AND OBJECTIVE: In most of the cancer therapeutic models separate equations for consumption of drugs are used, we however use parameters m and s to see the effect of chemotherapy and immunotherapy respectively. The main objective of this theoretical study is to develop strategies for eradication or minimization of cancer. METHODS: Linearization method to study the local stability of model equilibria. RESULTS: The results obtained in this study provide thresholds on m-fraction of cancer cells killed by chemotherapy and s-fraction of immune cells stimulated by immunotherapy. CONCLUSION: The model considered relates to immune-cancer-normal cell interactions in post vascularization process. The study aims to develop strategies for complete eradication or minimization of cancer in terms of model parameters. This paper presents a minimal immuno-chemotherapeutic cancer model by describing interacting dynamics of cancer, immune and normal cells in a system of three ordinary differential equations. The source of the immune cells is considered outside the sytem given by a constant influx rate, s. The minimality of the model lies in not considering a separate equation for the dynamics of the drug but its overall killing effect on the cancer cells represented by a parameter, m. Thus the parameter m relates to chemotherapy and s to immunotherapy. The analysis of the model yields thresholds on these parameters for therapeutic strategies which guarantee either eradication or minimization of cancer from a patient's body.

Quality of care in an inflammatory bowel disease clinical trial center : a prospective study evaluating patients' satisfaction.

BACKGROUND AND STUDY AIMS: Quality of care is a very timely topic in medicine. We designed a questionnaire to measure perceived quality of care and to explore areas of improvement. PATIENTS AND METHODS: In this prospective study a questionnaire was developed and administered to all patients with inflammatory bowel disease participating in a randomized clinical trial. The questionnaire was based on validated surveys and supplemented with novel, relevant questions. Factors associated with (poor) quality of care were identified. RESULTS: Between October 2016 and January 2017, all 107 patients participating in a randomized controlled trial completed the questionnaire (63% male, 76% ulcerative colitis, median age of 47 years). The median satisfaction score was 9 out of 10. Areas of improvement were that too little attention was paid to the disease impact on family and work, dietary and exercise pattern, daily activities and quality of life. Multivariate analysis showed that clinical remission [5.77 (2.03-16.39), p=0.001] was a predictor of good quality of care. CONCLUSIONS: In this large IBD trial bureau, inflammatory bowel disease patients were very satisfied with the quality of care. Domains for quality improvement, such as attention to the impact of IBD on family and work, were identified.

JC viral loads in patients with Crohn's disease treated with immunosuppression: can we screen for elevated risk of progressive multifocal leukoencephalopathy?

BACKGROUND AND AIMS: Anti-alpha4 integrin therapy with natalizumab is efficacious in refractory Crohn's disease and in multiple sclerosis, but carries an estimated 1/1000 risk of progressive multifocal leukoencephalopathy (PML) caused by reactivation of latent JC virus infection. Although anti-alpha4 integrin therapies are likely to be introduced in the clinic, screening for the risk of PML has not been developed. METHODS: We prospectively collected urine, serum, plasma and buffy coats from 125 patients with Crohn's disease, 100 control subjects with gastrointestinal (GI) disease, and 106 healthy volunteers. Four to eight weeks after this first sample collection, we additionally collected a set of urine, serum, plasma and buffy coat samples from the 125 patients with Crohn's disease, and a next set of samples was collected 12-16 weeks after the first collection. JC viral loads were determined with quantitative real-time polymerase chain reaction (PCR), and JC virus seroprevalence with a specific enzyme-linked immunosorbant assay (ELISA). RESULTS: The overall JC virus seroprevalence was 65%. JC virus DNA copies were detected in the urine from 29-44% of subjects, both those with Crohn's disease and controls. Median viral loads were significantly higher in patients with Crohn's disease who were immunosuppressed (7.36x10(6) copies/ml) compared to healthy volunteers (2.77x10(5) copies/ml) and compared to GI controls (1.8x10(6) copies/ml). Clearance at any time point occurred in 4/107 (3.7%) subjects only. JC viraemia was found in two patients with Crohn's disease. CONCLUSIONS: The natural history of JC virus in patients with Crohn's disease is still unknown. Our study results show that JC virus latency and urine viral shedding is frequent in immunosuppressed patients with Crohn's disease. More prospective studies are needed in order to agree on possible recommendations concerning the exclusion of patients with JCV viraemia from anti-alpha4 integrin treatment.

SWOG S1400C (NCT02154490)-A Phase II Study of Palbociclib for Previously Treated Cell Cycle Gene Alteration-Positive Patients with Stage IV Squamous Cell Lung Cancer (Lung-MAP Substudy).

OBJECTIVE: Lung-MAP (SWOG S1400) is a master platform trial assessing targeted therapies in squamous NSCLC. The objective of study C (S1400C) was to evaluate the response rate to palbociclib, a cyclin-dependent kinase 4 and cyclin-dependent kinase 6 inhibitor, in patients with cell cycle gene abnormalities. METHODS: Patients with squamous NSCLC, a performance status of 0 to 2, and normal organ function who had progressed after at least one prior platinum-based chemotherapy with cyclin-dependent kinase 4 gene (CDK4) or cyclin D1 gene (CCND1), cyclin D2 gene (CCND2), or cyclin D3 gene (CCND3) amplifications on tumor specimens were eligible. The study was originally designed as a phase II/III trial comparing palbociclib with docetaxel, but it was modified to a single-arm phase II trial with the primary end point of response when immunotherapy was approved. If two or fewer responses were seen in the first 20 patients, then the study would cease enrollment. RESULTS: A total of 88 patients (9% of patients screened) were assigned to S1400C, and 53 patients enrolled (including 17 to receive docetaxel). One patient who had been registered to receive docetaxel was re-registered to receive palbociclib after progression while taking docetaxel. The frequencies of cell cycle gene alterations in the eligible patients taking palbociclib (n = 32) were as follows: CCND1, 81% (n = 26); CCND2, 9% (n = 3); CCND3, 6% (n = 2); and CDK4, 3% (n = 1). In all, 32 eligible patients received palbociclib. There were two partial responses (response rate 6% [95% confidence interval (CI): 0%-15%]), both with CCND1 amplification. Twelve patients had stable disease (38% [95% CI: 21%-54%]). The median progression-free survival was 1.7 months (95% CI: 1.6-2.9 months) and the median overall survival was 7.1 months (95% CI: 4.2-12.5). CONCLUSION: Palbociclib as monotherapy failed to demonstrate the prespecified criteria for advancement to phase III testing.

Hypoxic stress: obstacles and opportunities for innovative immunotherapy of cancer.

Tumors use several strategies to evade the host immune response, including creation of an immune-suppressive and hostile tumor environment. Tissue hypoxia due to inadequate blood supply is reported to develop very early during tumor establishment. Hypoxic stress has a strong impact on tumor cell biology. In particular, tissue hypoxia contributes to therapeutic resistance, heterogeneity and progression. It also interferes with immune plasticity, promotes the differentiation and expansion of immune-suppressive stromal cells, and remodels the metabolic landscape to support immune privilege. Therefore, tissue hypoxia has been regarded as a central factor for tumor aggressiveness and metastasis. In this regard, manipulating host-tumor interactions in the context of the hypoxic tumor microenvironment may be important in preventing or reverting malignant conversion. We will discuss how tumor microenvironment-driven transient compositional tumor heterogeneity involves hypoxic stress. Tumor hypoxia is a therapeutic concern since it can reduce the effectiveness of conventional therapies as well as cancer immunotherapy. Thus, understanding how tumor and stromal cells respond to hypoxia will allow for the design of innovative cancer therapies that can overcome these barriers. A better understanding of hypoxia-dependent mechanisms involved in the regulation of immune tolerance could lead to new strategies to enhance antitumor immunity. Therefore, discovery and validation of therapeutic targets derived from the hypoxic tumor microenvironment is of major importance. In this context, critical hypoxia-associated pathways are attractive targets for immunotherapy of cancer. In this review, we summarize current knowledge regarding the molecular mechanisms induced by tumor cell hypoxia with a special emphasis on therapeutic resistance and immune suppression. We emphasize mechanisms of manipulating hypoxic stress and its associated pathways, which may support the development of more durable and successful cancer immunotherapy approaches in the future.

The impact of major depressive disorder on the short- and long-term outcome of Crohn's disease treatment with infliximab.

BACKGROUND: Major depressive disorder is the most common psychiatric diagnosis in Crohn's disease. In other chronic diseases, evidence suggests that depression influences the course of the disease. Strong evidence of such a mediating role of major depressive disorder in Crohn's disease has never been found. AIM: To assess the relationship between major depressive disorder and outcome of treatment of luminal Crohn's disease with infliximab. METHODS: In this prospective study, 100 consecutive unselected patients underwent assessment of psychosocial, demographical disease-related biological and clinical parameters at baseline and at 4 weeks after infliximab. Major depressive disorder was diagnosed using the Patient Health Questionnaire. Subsequently, the patients were followed up clinically until the next flare or during 9 months. RESULTS: The Crohn's disease responded in 75% of the patients, and remission was achieved in 60%. The presence of major depressive disorder at baseline predicted a lower remission rate (OR = 0.166, 95% CI = 0.049-0.567, P = 0.004). At follow-up, 88% of the patients needed retreatment. At univariate regression analysis, major depressive disorder significantly decreased time to retreatment (P = 0.001). Multivariate Cox regression confirmed major depressive disorder as an independent determinant of active disease both at baseline and at re-evaluation (hazard ratio = 2.271, 95% CI: 1.36-3.79, P = 0.002). CONCLUSION: Major depressive disorder is a risk factor for failure to achieve remission with infliximab and for earlier retreatment in patients with active luminal Crohn's disease. Assessment and management of major depressive disorder should be part of the clinical approach to patients with Crohn's disease.

Polymorphisms in apoptosis genes predict response to infliximab therapy in luminal and fistulizing Crohn's disease.

BACKGROUND: Infliximab treatment is effective in 70-80% of patients with refractory luminal and fistulizing Crohn's disease. The effect of infliximab is ascribed to induction of apoptosis. AIM: To study whether polymorphisms in apoptosis genes predict the response to infliximab and whether they interact with clinical predictors. METHODS: Cohort of 287 consecutive patients treated with infliximab for refractory luminal (n = 204) or fistulizing (n = 83) Crohn's disease was genotyped for 21 polymorphisms in apoptosis genes. Short-term clinical response was assessed at week 4 (luminal Crohn's disease) or 10 (fistulizing Crohn's disease) after the first infliximab infusion. RESULTS: The response rate was 69% in luminal and 80% in fistulizing Crohn's disease. In luminal Crohn's disease, two genetic predictors were identified: (i) patients with the Fas ligand -843 CC/CT genotype (n = 135) responded in 75%, with the TT genotype (n = 21) in 38% only (P = 0.002; OR = 0.11; 95% CI: 0.08-0.56). (ii) Patients with the caspase-9 93 TT (n = 9) genotype all responded, in contrast with 67% (n = 147) with the CC and CT genotype (P = 0.04; OR = 1.50; 95% CI: 1.34-1.68). Concomitant azathioprine/mercaptopurine therapy overcame the effect of unfavourable genotypes. In the fistulizing Crohn's disease cohort, the same Fas ligand -843 CC/CT genotype was the only predictor of response (P = 0.002; OR = 1.66; 95% CI: 1.21-2.29), interacting with caspase-9 93 polymorphism but not with azathioprine/mercaptopurine. CONCLUSION: We observed that polymorphisms in FasL/Fas system and caspase-9 influence the response to infliximab in luminal and fistulizing Crohn's disease. The strongest association was seen between the Fas ligand -843 TT genotype and non-response. Concomitant mercaptopurine/azathioprine therapy, however, was able to overcome the effect of unfavourable genotypes in luminal disease.