Intensive critical care and management of asthmatic and smoker patients in COVID-19 infection.

This century's most serious catastrophe, COVID-19, has been dubbed "the most life-threatening disaster ever". Asthmatic persons are even more prone to COVID-19's complex interplay with the underlying inflammatory condition. In order to protect themselves against COVID-19, asthmatic patients must be very vigilant in their usage of therapeutic techniques and drugs (e.g., bronchodilators, 5-lipoxygenase inhibitors), which may be accessed to deal with mild, moderate, and severe COVID-19 indications. People with asthma may have more severe COVID-19 symptoms, which may lead to a worsening of their condition. Several cytokines were found to be elevated in the bronchial tracts of patients with acute instances of COVID-19, suggesting that this ailment may aggravate asthma episodes by increasing inflammation. The intensity of COVID-19 symptoms is lessened in patients with asthma who have superior levels of T-cells. Several antibiotics, antivirals, antipyretics, and anti-inflammatory drugs have been suggested to suppress COVID-19 symptoms in asthmatic persons. Furthermore, smokers are more likely to have aggravated repercussions in COVID-19 infection. Being hospitalized to critical care due to COVID-19, needing mechanical breathing, and suffering from serious health repercussions, are all possible outcomes for someone who has previously smoked. Smoking damages airways and alveoli, which significantly raises the risk of COVID-19-related health complications. Patients with a previous record of smoking are predisposed to severe COVID-19 disease symptoms that essentially require a combination of bronchodilators, mucolytics, antivirals, and antimuscarinic drugs, to cope with the situation. The present review discusses the care and management of asthmatic and smoker patients in COVID-19 infection.

Synthesis and Biological Evaluation of 2-(Halophenyl)benzoxazole-5-Carboxylic Acids as Potential Anti-Inflammatory and Cytotoxic Agent with Molecular Docking Studies.

2-Halogenatedphenyl benzoxazole-5-carboxylic acids with mono-halogen (chloro, bromo and fluoro) substituted at ortho-, meta- and para-positions on the phenyl ring were designed and synthesized based on significance of presence of halogen in increasing number of marketed halogenated drugs and importance of benzoxazoles. These 2-alogenatedphenylbenzoxazole-5-carboxylic acids and their methyl esters were screened for anti-inflammatory activity, and cytotoxicity. 2-(3-Chlorophenyl)benzoxaole-5-carboxylic acid (6b) exhibited significant anti-inflammatory activity with IC50 values of 0.103 mM almost equivalent to the standard drug ibuprofen (0.101 mM). 2-(4-Chlorophenyl)benzoxaole-5-carboxylic acid (6c) showed excellent cytotoxic activity against 22Rv1 cells (human prostate carcinoma epithelial cell lines) with IC50 value of 1.54 µM better than that of standard drug doxorubicin having IC50 value of 2.32 µM. More importantly, the selectivity index of this potential molecule was found to be 57.74. Molecular docking analysis resulted in good binding interactions of these compounds with their respective biochemical targets viz. Cyclooxygenase-2 and aldo-keto reductase IC3.

Synthesis, Biological Activity and Molecular Docking Studies of Heterocyclic Chalcones.

Nineteen heterocyclic chalcones were synthesized from 4-acetyl-5-methylquinolylpyrazole and heteroaryl (imidazole, pyrazole, thiophene, indole and triazole) aldehydes and were screened in vitro using four tumor cell lines for their cytotoxic capability and for antimicrobial activity. The chalcone 5b exhibited the highest activity with IC50 values 2.14 µM against colon (HCT-116) and 5.0 µM, against prostate (PC-3) cancer cell lines and also displayed good activity against fungal strain (A. niger) with MIC value 9.1 µM. The chalcones 5q and 5p displayed good activity against bacterial strains (S. aureus) having MIC value 2.6 µM and fungal strain (C. albicans) having MIC value 5.4 µM, respectively. The molecular docking outcome revealed that the synthesized heterocyclic chalcones demonstrated hydrogen bond, hydrophobic and electrostatic interactions with their respective biochemical targets.

Surgical Management of Crohn Disease in Children: Guidelines From the Paediatric IBD Porto Group of ESPGHAN.

The incidence of Crohn disease (CD) has been increasing and surgery needs to be contemplated in a substantial number of cases. The relevant advent of biological treatment has changed but not eliminated the need for surgery in many patients. Despite previous publications on the indications for surgery in CD, there was a need for a comprehensive review of existing evidence on the role of elective surgery and options in pediatric patients affected with CD. We present an expert opinion and critical review of the literature to provide evidence-based guidance to manage these patients. Indications, surgical options, risk factors, and medications in pre- and perioperative period are reviewed in the light of available evidence. Risks and benefits of surgical options are addressed. An algorithm is proposed for the management of postsurgery monitoring, timing for follow-up endoscopy, and treatment options.

Faecal calprotectin: factors affecting levels and its potential role as a surrogate marker for risk of development of Crohn's Disease.

BACKGROUND: Faecal calprotectin (FC) is one of the most widely used non-invasive tests for the diagnosis and assessment of Crohn's disease (CD) activity. Despite this, factors other than disease activity which affect levels have not been extensively reviewed. This is of importance when using FC in the diagnostic setting but also may be of utility in studying the aetiology of disease. OBJECTIVES: Our review outlines environmental risk factors that affect FC levels influencing diagnostic accuracy and how these may be associated with risk of developing CD. FC as a surrogate marker could be used to validate risk factors established in case control studies where prospective studies are not feasible. Proof of this concept is provided by our identification of obesity as being associated with elevated FC, our subsequent confirmation of obesity as risk factor for CD and the subsequent verification in prospective studies, as well as associations of lack of physical activity and dietary fibre intake with elevated FC levels and their subsequent confirmation as risk factors in prospective studies. CONCLUSION: We believe that FC is likely to prove a useful surrogate marker for risk of developing CD. This review has given a theoretical basis for considering the epidemiological determinants of CD which to date has been missing.

Treatment of Crohn's Disease with an IgG4-Guided Exclusion Diet: A Randomized Controlled Trial.

BACKGROUND AND AIM: We previously reported an improvement in symptoms in Crohn's disease following an IgG4-guided exclusion diet in an open-label study. We aimed to evaluate, in a double-blinded randomized sham-controlled setting, the efficacy of IgG4-guided diet in improving quality of life in patients with Crohn's disease. METHODS: Consecutive patients with Crohn's disease and a Crohn's disease activity index (CDAI) of 80-400 attending tertiary and secondary care centers were screened. All patients had IgG4 titers tested against 16 common food types using ELISA. The true diet group excluded four food types with the highest antibody titers for 4 weeks, and the sham group excluded four foods with the lowest antibody titers. Quality of life was assessed using the Short Inflammatory Bowel Disease Questionnaire (SIBDQ) at beginning and end of the trial. Secondary outcome measures were CDAI, Harvey Bradshaw index, serum C-reactive protein, and fecal calprotectin. RESULTS: One hundred and forty-five subjects were screened and 96 subjects had initial food antibody testing performed with 76 patients completing the study. Milk, beef, pork and egg were the most commonly excluded food types in the true diet group. There was a 3.05 (0.01-6.11) p < 0.05 improvement in SIBDQ and 41 (10.4-71.5) in CDAI p = 0.009. CONCLUSION: IgG4-guided exclusion diet, as an adjunct, can improve quality of life and symptoms in patients with CD.

The wisdom of crowds and the repurposing of artesunate as an anticancer drug.

Artesunate, a semi-synthetic and water-soluble artemisinin-derivative used as an anti-malarial agent, has attracted the attention of cancer researchers due to a broad range of anti-cancer activity including anti-angiogenic, immunomodulatory and treatment-sensitisation effects. In addition to pre-clinical evidence in a range of cancers, a recently completed randomised blinded trial in colorectal cancer has provided a positive signal for further clinical investigation. Used perioperatively artesunate appears to reduce the rate of disease recurrence - and the Neo-Art trial, a larger Phase II RCT, is seeking to confirm this positive effect. However, artesunate is a generic medication, and as with other trials of repurposed drugs, the Neo-Art trial does not have commercial sponsorship. In an innovative move, the trial is seeking funds directly from members of the public via a crowd-funding strategy that may have resonance beyond this single trial.

What is known about the mechanisms of dietary influences in Crohn's disease?

Much has been written about the role of diet and risk for Crohn's disease (CD). However, the evidence is contradictory. Recent evidence has pointed to fiber playing an important role along with the possibility that dietary fat and overnutrition also have a role. Diet has a clearer place in disease modification, with some diets used in the treatment of CD. The lack of clarity stems from a poor understanding of the mechanisms underlying the relationship between diet and CD. Gut permeability is likely to play a key role in the risk for CD. Mechanisms whereby diet can affect gut permeability, including the effects of the gut microbiota, are reviewed. Modification of disease behavior is likely to be influenced by additional mechanisms, including recognition of complex food antigens. As with many other chronic diseases, a surrogate marker of CD risk would greatly aid evaluation of the dietary factors involved. Formal measures of gut permeability are too cumbersome for large-scale use, but fecal calprotectin may be a convenient measure of this. There are only preliminary data on the effect of diet and microbiota composition on fecal calprotectin and these require further investigation.

A Randomised, Double Blind, Placebo-Controlled Pilot Study of Oral Artesunate Therapy for Colorectal Cancer.

BACKGROUND: Artesunate is an antimalarial agent with broad anti-cancer activity in in vitro and animal experiments and case reports. Artesunate has not been studied in rigorous clinical trials for anticancer effects. AIM: To determine the anticancer effect and tolerability of oral artesunate in colorectal cancer (CRC). METHODS: This was a single centre, randomised, double-blind, placebo-controlled trial. Patients planned for curative resection of biopsy confirmed single primary site CRC were randomised (n = 23) by computer-generated code supplied in opaque envelopes to receive preoperatively either 14 daily doses of oral artesunate (200 mg; n = 12) or placebo (n = 11). The primary outcome measure was the proportion of tumour cells undergoing apoptosis (significant if > 7% showed Tunel staining). Secondary immunohistochemical outcomes assessed these tumour markers: VEGF, EGFR, c-MYC, CD31, Ki67 and p53, and clinical responses. FINDINGS: 20 patients (artesunate = 9, placebo = 11) completed the trial per protocol. Randomization groups were comparable clinically and for tumour characteristics. Apoptosis in > 7% of cells was seen in 67% and 55% of patients in artesunate and placebo groups, respectively. Using Bayesian analysis, the probabilities of an artesunate treatment effect reducing Ki67 and increasing CD31 expression were 0.89 and 0.79, respectively. During a median follow up of 42 months 1 patient in the artesunate and 6 patients in the placebo group developed recurrent CRC. INTERPRETATION: Artesunate has anti-proliferative properties in CRC and is generally well tolerated.

Resection leads to less recurrence than strictureplasty in a paediatric population with obstructive Crohn's disease.

Introduction. Resection and strictureplasty are used to treat patients with obstructive Crohn's disease. Strictureplasty is preferable in adults as it retains bowel length. This study aims to identify differences in outcomes of children undergoing strictureplasty and resection for obstructive Crohn's disease. Method. Patients under 20 years undergoing surgery over a nine-year period were included. Data was collected on procedures for stenotic Crohn's disease. Patients were divided into 2 groups: Group 1 treated with strictureplasties and Group 2 resections. Postoperative complications and recurrence rates were recorded. Kaplan-Meier method was used to analyze the data. Results. Twenty-six patients and 40 operations were identified. Mean age was 15.6 years (7.2-19.4) with equal numbers of males and females. Mean follow-up was 45.9 months (0.1-149.9). 20/40 procedures involved the terminal ileum; 9/40, the ileocolic junction; 8/40, the upper GI tract; and 3/40, the colon. Group 1 consisted of 19 strictureplasties and Group 2 consisted of 13 resections and 8 combined procedures. Significantly more patients in Group 1 required further surgery (11/19 versus 3/21; P = 0.008). Conclusion. Allowing for variations in disease duration, severity, and previous medical management, these data suggest that resection is preferable to strictureplasty in treating obstructive Crohn's disease in children and adolescents.

Design, regioselective synthesis and cytotoxic evaluation of 2-aminoimidazole-quinoline hybrids against cancer and primary endothelial cells.

In search of new selective anti-cancer agents, a series of sixteen novel 2-aminoimidazole-quinoline hybrid compounds (5a-5p) have been designed and synthesized regioselectively. We have characterized the compounds extensively using IR, 1D and 2D NMR Spectroscopy and mass spectrometry. The cytotoxicity studies against different cancer cell lines showed that the compound 5a (Imd-Ph) emerged as a potent cytotoxic scaffold. Imd-Ph (5a) exhibited a selective anticancer activity against human colon cancer cell line (HCT-116, DLD-1) and was found relatively non-toxic to breast cancer cells (MDA-MB-231) as well as to normal primary endothelial cells (HUVEC). Structure-activity relationship of imidazole-quinoline hybrid scaffolds revealed differential and selective toxicities exerted by the different derivatives against cancer and normal cells. Structural modification of the scaffold with library of a wide variety of substituents may lead to the development of novel selective anti-cancer agents in the future.

Stroke-induced immune depression-a randomized case control study in Kashmiri population of North India.

BACKGROUND: Stroke leads to transient immunedepression, which leads to increased incidence of poststroke infections. Because infection is one of the most common causes of increased mortality in patients with stroke, this study was undertaken to document immunedepression after stroke in our population. METHODS: A case-controlled study wherein 39 patients with acute ischemic stroke in the age group of 18 and 60 years without any evidence of previous immunedepression were included. Interleukin 6 (IL-6) and interleukin 10 (IL-10) levels were checked in plasma in both the groups on day 3 and day 45. Also Cortisol and epinephrine levels were checked in the urine samples collected on day 3 and day 8. RESULTS: No significant difference was seen between the IL-6 and the IL-10 levels in samples collected on day 3 between the controls and cases, whereas Cortisol and norepinephrine were significantly raised in samples collected on day 3 in cases who developed infection as compared with controls. CONCLUSIONS: The higher levels of urinary cortisol and norepinephrine were observed in patients with stroke who developed infections, which indirectly reflected increased amount of stroke related stress. Furthermore, the levels of plasma IL-6 and IL-10 were also elevated in the same group of patients, which means transformation of immunecompetence to immunedepression, which is responsible for higher mortality. Subsequently on recovery from infection the plasma levels of interleukins and urinary cortisol and norepinephrine did not show any difference, which indirectly means recovery of the immune system on recovery from acute stage of stroke. Mortality in the patients with infection was increased than controls.

Abdominal adiposity is the main determinant of the C-reactive response to injury in subjects undergoing inguinal hernia repair.

BACKGROUND: Obesity and serum C-reactive protein (CRP) (a sensitive marker of inflammatory activity) are associated with most chronic diseases. Abdominal adiposity along with age is the strongest determinant of baseline CRP levels in healthy subjects. The mechanism of the association of serum CRP with disease is uncertain. We hypothesized that baseline serum CRP is a marker of inflammatory responsiveness to injury and that abdominal adiposity is the main determinant of this responsiveness. We studied the effect of abdominal adiposity, age and other environmental risk factors for chronic disease on the CRP response to a standardised surgical insult, unilateral hernia repair to not only test this hypothesis but to inform the factors which must be taken into account when assessing systemic inflammatory responses to surgery. METHODS: 102 male subjects aged 24-94 underwent unilateral hernia repair by a single operator. CRP was measured at 0, 6, 24 and 48 hrs. Response was defined as the peak CRP adjusted for baseline CRP. RESULTS: Age and waist:hip ratio (WHR) were associated both with basal CRP and CRP response with similar effect sizes after adjustment for a wide-range of covariates. The adjusted proportional difference in CRP response per 10% increase in WHR was 1.50 (1.17-1.91) p = 0.0014 and 1.15(1.00-1.31) p = 0.05 per decade increase in age. There was no evidence of important effects of other environmental cardiovascular risk factors on CRP response. CONCLUSION: Waist:hip ratio and age need to be considered when studying the inflammatory response to surgery. The finding that age and waist:hip ratio influence baseline and post-operative CRP levels to a similar extent suggests that baseline CRP is a measure of inflammatory responsiveness to casual stimuli and that higher age and obesity modulate the generic excitability of the inflammatory system leading to both higher baseline CRP and higher CRP response to surgery. The mechanism for the association of baseline CRP and waist:hip ratio to chronic disease outcomes could be through this increase in inflammatory system excitability.

A rare cause of rectal bleeding masquerading as proctitis.

BACKGROUND AND AIMS: Diffuse cavernous haemangioma of the rectum (DCHR) is a rare benign vascular neoplasm that affects mainly young adults and can present with rectal bleeding or massive haemorrhage. We report a case of DCHR masquerading as proctitis which was diagnosed many years ago following colonoscopy. This is the first case where the DCHR was resected with subsequent formation of a colonic J pouch versus conventional colo-anal anastomosis in order to maintain good bowel function. METHOD: Clinical case report including a review of current literature regarding DCHR. RESULTS: This is one of few cases of DCHR reported that was initially misdiagnosed as proctitis. CONCLUSIONS: Awareness of this rare condition is important when investigating patients presenting with rectal bleeding to prevent unnecessary treatment and delay surgery. Prompt intervention is necessary to prevent severe rectal haemorrhage.

Synthesis, antimicrobial and cytotoxicity study of 1,3-disubstituted-1H-naphtho[1,2-e][1,3]oxazines.

A series of new 1,3-disubstituted-1H-naphtho[1,2-e][1,3]oxazines (3 and 7) was synthesized in good yields and the structure was determined with the help of NMR, 2D-NMR, HRMS studies and X-ray crystallography. These compounds were tested in vitro for their antibacterial activity against Gram-positive and Gram-negative bacteria and as well as for antifungal activity. The compounds 3c, 3e, 7a, 7d and 7k showed significant antibacterial activity and 7l showed moderate antifungal activity. The cytotoxicity of 1,3-disubstituted-1H-naphtho[1,2-e][1,3]oxazines showed that 3e and 7e are more effective against breast, lung and colon cell proliferation.

Current concepts in the non-operative management of rectal cancer after neoadjuvant chemoradiation.

BACKGROUND: Neoadjuvant chemoradiation (CRT) is used to downstage locally advanced rectal cancer prior to surgery. This is an established paradigm of treatment in the West. Some patients who undergo chemoradiotherapy achieve a complete clinical response, where no evidence of tumour can be found on clinical assessment prior to surgery. Recent studies have suggested a 'watch and wait policy' for patients who achieve a complete clinical response with close clinical follow-up, and to only intervene surgically if local recurrence manifests. This notion differs from established regimes of treatment, but by virtue of its positive implications for patients, deserves further consideration and scrutiny. This article reviews the evidence for the non-operative 'watch and wait' management of rectal cancer in patients with complete clinical response after chemoradiation, and discusses the limitations in applying a policy of this nature. METHODS: The evidence in the literature for non-operative treatment of. Only a few studies have examined this issue. Results have been variable, with only one study supporting non-operative management, where low local recurrence rates were shown on intermediate follow-up (<3%), with excellent overall and disease-free survival rates (100% and 86% respectively). Another two studies found high local recurrence rates (approximately 80%) and poor survival on short-term follow-up (around 20%). Differences in selection of patients were found between studies, as well as other aspects that might explain some of the disparity in results found. CONCLUSION: There is not enough evidence to justify a non-operative approach to treating rectal cancer after chemoradiation in complete clinical responders at present. Better designed studies are required to clarify some of the issues involved.

Colorectal cancer in the young: trends, characteristics and outcome.

BACKGROUND: Colorectal cancer (CRC) in young patients is associated with a poor outcome due to advanced stage at diagnosis and poor differentiation. AIM: The aim of this study is to compare clinicopathological characteristics, overall survival (OS) and disease-free survival (DFS) of young (≤40 years) and older patients with CRC. METHODS: A total of 2,538 patients including 59 young patients (age ≤40 years) with CRC were identified over 20 years. The clinicopathological variables of young patients were compared with a group of consecutive older patients (n = 416) spanning both decades. Survival analysis was done using Kaplan-Meier, log-rank and Cox regression models. RESULTS: The frequency in young patients increased from 1.4% to 3.0% from first to second decade (overall -2.3%, p = 0.006). There was a higher frequency of tumours with poor differentiation (43% vs. 16%, p = < 0.001), T4 stage (47% vs. 30%, p = 0.005) and vascular invasion (VI; 38% vs. 29%, p = 0.13) in younger group. There was no significant difference in OS (p = 0.116) and DFS (p = 0.261) between the two groups. Node-negative young patients had a significantly better OS (p = 0.046). Young patients with VI had significantly reduced OS (p = 0.043), whereas young patients without VI had significantly better OS (p = 0.012). Multivariate analysis showed T4 status (p = 0.001) and vascular invasion (p = 0.002) as independent prognostic factors for OS and T4 status (p = 0.004) as independent factor influencing DFS. CONCLUSION: The frequency of CRC in young patients increased significantly. Vascular invasion is the single most important prognostic factor in young CRC. Along with vascular invasion, high proportion of T4 status in young patients increases the chances of recurrence and negates any survival advantage in young patients.

Is obesity a risk factor for Crohn's disease?

BACKGROUND: Obesity is associated with a proinflammatory state. AIM: To determine whether obesity at diagnosis is a risk factor for Crohn's disease vs. ulcerative colitis and also vs. community controls and whether there is a U-shaped relationship between body mass index at diagnosis and risk of Crohn's disease versus ulcerative colitis. METHODS: A total of 524 consecutive inflammatory bowel disease patients attending gastroenterology clinics were administered a questionnaire inquiring about weight at diagnosis and height as well as other risk factors for inflammatory bowel disease. An opportunistic control group of 480 community controls aged 50-70 were randomly selected from the registers of four local general practices as part of another study. RESULTS: Obesity at diagnosis was more common in subjects with Crohn's disease versus ulcerative colitis odds ratio 2.02 (1.18-3.43) p = 0.0096 and also Crohn's disease versus community controls in the 50-70 year age group (odds ratio 3.22 (1.59-6.52) p = 0.001). There was evidence of a 'dose response' with increasing degrees of obesity associated with increased risk. Low BMI at diagnosis was also associated with risk of Crohn's disease versus ulcerative colitis. A U-shaped relationship between BMI and risk of Crohn's was supported by the strong inverse association of BMI at diagnosis (p = 0.0001) and positive association of BMI at diagnosis squared (p = 0.0002) when they were fitted together into the model. CONCLUSIONS: Obesity may play a role in the pathogenesis of Crohn's disease and it may be that obesity-related enteropathy is a distinct entity or a sub-type of Crohn's disease.