Retinal drusen counts are increased in inflammatory bowel disease, and with longer disease duration, more complications and associated IgA glomerulonephritis.

Retinal drusen are deposits of inflammatory proteins that are found in macular degeneration and glomerulonephritis and result, in part, from complement activation. This was a cross-sectional observational study of individuals with inflammatory bowel disease (IBD) recruited from a Gastroenterology clinic who underwent non-mydriatic retinal photography. Deidentified images were examined for drusen, and drusen counts and size were compared with matched controls, and examined for clinical associations. The cohort with IBD comprised 19 individuals with ulcerative colitis, 41 with Crohn's disease and three with indeterminate colitis, including 34 males (54%) and an overall median age of 48 (IQR 23) years. Their median IBD duration was 7 (IQR 10) years, median CRP level was 7 (IQR 14) mg/L, and 28 (44%) had complications (fistula, stricture, bowel resection etc.), while 28 with Crohn's disease (68%) had colonic involvement. Drusen counts were higher in IBD than controls (12 ± 34, 3 ± 8 respectively, p = 0.04). Counts ≥ 10 were also more common (14, 22%, and 4, 6%, p = 0.02, OR 4.21, 95%CI 1.30 to 13.63), and associated with longer disease duration (p = 0.01, OR 1.06, 95%CI 1.00 to 1.13), an increased likelihood of complications (p = 0.003, OR 6.90, 95%CI 1.69 to 28.15) and higher CRP levels at recruitment (p = 0.008, OR1.02, 95%CI 1.00 to 1.05). Increased retinal drusen were found in all four individuals with Crohn's disease and IgA glomerulonephritis. IBD and drusen may share pathogenetic mechanisms and underlying risk factors such as complement activation.

Prognostic implication of the neoadjuvant rectal score and other biomarkers of clinical outcome in Hong Kong Chinese patients with locally advanced rectal cancer undergoing neoadjuvant chemoradiotherapy.

BACKGROUND: Neoadjuvant chemoradiotherapy is a standard treatment for locally advanced rectal cancer, for which pathological complete response is typically used as a surrogate survival endpoint. Neoadjuvant rectal score is a new biomarker that has been shown to correlate with survival. The main objectives of this study were to investigate factors contributing to pathological complete response, to validate the prognostic significance of neoadjuvant rectal score, and to investigate factors associated with a lower neoadjuvant rectal score in a cohort of Hong Kong Chinese. METHODS: Data of patients with locally advanced rectal cancer who received neoadjuvant chemoradiotherapy from August 2006 to October 2018 were retrieved from hospital records and retrospectively analysed. RESULTS: Of 193 patients who had optimal response to neoadjuvant chemoradiotherapy and surgery, tumour down-staging was the only independent prognostic factor that predicted pathological complete response (P<0.0001). Neoadjuvant rectal score was associated with overall survival (hazard ratio [HR]=1.042, 95% confidence interval [CI]=1.021-1.064; P<0.0001), disease-free survival (HR=1.042, 95% CI=1.022-1.062; P<0.0001), locoregional recurrence-free survival (HR=1.070, 95% CI=1.039-1.102; P<0.0001) and distant recurrence-free survival (HR=1.034, 95% CI=1.012-1.056; P=0.002). Patients who had pathological complete response were associated with a lower neoadjuvant rectal score (P<0.0001), but pathological complete response was not associated with survival. For patients with intermediate neoadjuvant rectal scores, late recurrences beyond 72 months from diagnosis were observed. CONCLUSION: Neoadjuvant rectal score is an independent prognostic marker of survival and disease recurrence in a cohort of Hong Kong Chinese patients who received neoadjuvant chemoradiotherapy for locally advanced rectal cancer.

Clinical standards for the diagnosis, treatment and prevention of TB infection.

BACKGROUND: Tuberculosis (TB) preventive therapy (TPT) decreases the risk of developing TB disease and its associated morbidity and mortality. The aim of these clinical standards is to guide the assessment, management of TB infection (TBI) and implementation of TPT.METHODS: A panel of global experts in the field of TB care was identified; 41 participated in a Delphi process. A 5-point Likert scale was used to score the initial standards. After rounds of revision, the document was approved with 100% agreement.RESULTS: Eight clinical standards were defined: Standard 1, all individuals belonging to at-risk groups for TB should undergo testing for TBI; Standard 2, all individual candidates for TPT (including caregivers of children) should undergo a counselling/health education session; Standard 3, testing for TBI: timing and test of choice should be optimised; Standard 4, TB disease should be excluded prior to initiation of TPT; Standard 5, all candidates for TPT should undergo a set of baseline examinations; Standard 6, all individuals initiating TPT should receive one of the recommended regimens; Standard 7, all individuals who have started TPT should be monitored; Standard 8, a TBI screening and testing register should be kept to inform the cascade of care.CONCLUSION: This is the first consensus-based set of Clinical Standards for TBI. This document guides clinicians, programme managers and public health officers in planning and implementing adequate measures to assess and manage TBI.

Percutaneous distal clavicle excision for acromioclavicular joint arthritis: our experience and early results of a novel surgical technique.

PURPOSE: Symptomatic acromioclavicular joint (ACJ) osteoarthritis causes pain and limitations in activities of daily living. Open and arthroscopic distal clavicle excision techniques have been described with good outcomes. However, both techniques have their own sets of advantages and disadvantages. This study describes a novel technique of percutaneous distal clavicle excision for symptomatic ACJ osteoarthritis and our two-year results. METHODS: Fifteen consecutive patients underwent percutaneous distal clavicle excision for ACJ arthritis. These patients had failed a trial of conservative treatment. The ACJ was confirmed as the pain generator with an intraarticular steroid/lignocaine injection, and shoulder MRI was used to exclude alternative pain generators in the shoulder. They had a minimum of two years of follow-up. RESULTS: At a mean of 26.8 months postoperatively, the mean VAS pain score was 0, and the mean Constant score for the shoulder was 87.3 points (range 50-94), which corresponded to 1 good, 1 very good and 13 excellent results. The mean SF-36 score was 94.9 points (range 65-100). There were statistically significant improvements in the VAS scores, Constant shoulder scores and SF-36 scores at one year and two years of follow-up (p < 0.05). Three unique complications, namely subcutaneous emphysema, "missing" of the distal clavicle and thermal skin injury, were encountered. Our surgical technique has since been modified to circumvent these complications. CONCLUSION: Our novel technique of percutaneous distal clavicle excision yields a 93.3% good-to-excellent results based on the Constant shoulder score and durable pain relief based on VAS at two years.

Anxiety and depression in patients with haematological neoplasms in Malaysia.

BACKGROUND: It is not uncommon that anxiety and depression occur in patients with cancers, and past researches have shown that the quality of life of patients is negatively affected. This study aims to determine the prevalence of anxiety and depression of patients with haematological cancers in Malaysia and to investigate the possible association of these psychological symptoms with their quality of life. METHODS: This is a cross-sectional study where patients with haematological cancers attending two major hospitals were recruited. Anxiety and depression symptoms were assessed using the Hospital Anxiety and Depression scale (HADS). Quality of life (QoL) of these patients was measured using the European Organisation for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ C30). An overall summary QoL score in combination with financial difficulty score and global health score were used for analysis. RESULTS: A total of 319 patients were recruited. Thirty-three percent of patients had anxiety symptoms, 23.5% had depression symptoms. In summary the overall score of QoL is significantly lower in patients with higher scores for depression and anxiety, (p<0.05). Patients who exhibit anxiety symptoms were more frequently female, still undergoing treatment whereas patients who had higher depression scores were older and had acute leukemias or myeloproliferative neoplasms. Patients who have depression are significantly associated with a higher financial difficulty score, p<0.05. CONCLUSION: The poor quality of life in patients who have anxiety and depression should raise awareness amongst the health professions treating them so that additional support can be provided.

Atrophy of retinal inner layers is associated with poor vision after endophthalmitis: a spectral domain optical coherence tomography study.

PurposeTo investigate the retinal structural changes in endophthalmitis and their association with visual outcome.Patients and methodsForty-five eyes of 45 patients diagnosed with endophthalmitis were included. Spectral domain optical coherence tomography (SD-OCT) was performed after inflammation was controlled. The relationship between SD-OCT features and best-corrected visual acuity (BCVA) at the last follow-up was analyzed.ResultsThe structural changes included inner segment ellipsoid (ISe) disruption (49%), atrophy of retinal inner layers (24%), epimacular membrane (24%), and macular edema (24%). BCVA was worse in patients with ISe disruption (P=0.005) and retinal inner layers' atrophy (P=0.004) compared with those without. There was no significant difference of BCVA between the patients with and without epimacular membrane, or intraretinal cysts. Multivariate regression showed that atrophy of retinal inner layers (b=0.41±0.17, P=0.022) was the only independent factor associated with BCVA.ConclusionAtrophy of retinal inner layers is associated with visual impairment in endophthalmitis, despite successful management.

Intravenous lignocaine infusion facilitates acute rehabilitation after laparoscopic colectomy in the Chinese patients.

INTRODUCTION: Intravenous infusion of lignocaine has emerged in recent years as a feasible, cost-effective, and safe method to provide postoperative analgesia. There is, however, no literature about this perioperative pain control modality in Chinese patients. This study aimed to determine whether perioperative intravenous lignocaine safely reduces postoperative pain, shortens postoperative ileus, and reduces the length of hospital stay in laparoscopic colorectal surgery. METHODS: Between September 2012 and May 2015, 16 patients who underwent elective laparoscopic resection of colorectal cancer and received a 1% lignocaine infusion for 24 hours postoperatively were studied. After surgery, categorical pain scores were obtained immediately, followed by hourly pain scores at rest. Pain scores at rest and with mobilisation, and patient satisfaction score were documented on postoperative day 1. Return of bowel function was measured by time of first flatus and bowel opening. The patient's rehabilitation was assessed by time taken to tolerate diet, full mobilisation, and length of hospital stay. RESULTS: The median (interquartile range) self-reported pain scores at 2 hours and 6 hours after surgery were 1.5 (0-4) and 2 (0-3), respectively. The median pain scores at rest and mobilisation on postoperative day 1 were 1 (0-2.5) and 2 (2.5-5), respectively, with a median satisfaction score of 7.5 (7-9). The median times to first flatus and first bowel opening were 21 (18-35) hours and 3 (1-3) days, respectively. No patient had postoperative ileus. The median times to tolerating diet and mobilisation were 1 (1-1) day and 2 (2-3) days, respectively. The median postoperative stay was 6 (5-8) days. CONCLUSIONS: Intravenous lignocaine is a safe and effective postoperative analgesic in a Chinese population. It enhances the rehabilitation process for patients following laparoscopic resection of colorectal cancer.

Stathmin mediates neuroblastoma metastasis in a tubulin-independent manner via RhoA/ROCK signaling and enhanced transendothelial migration.

Neuroblastoma, the most common solid tumor of young children, frequently presents with aggressive metastatic disease and for these children the 5-year survival rates are dismal. Metastasis, the movement of cancer cells from one site to another, involves remodeling of the cytoskeleton including altered microtubule dynamics. The microtubule-destabilizing protein, stathmin, has recently been shown to mediate neuroblastoma metastasis although precise functions remain poorly defined. In this study we investigated stathmin's contribution to the metastatic process and potential mechanism(s) by which it exerts these effects. Stathmin suppression significantly reduced neuroblastoma cell invasion of 3D tumor spheroids into an extracellular matrix. Moreover, inhibiting stathmin expression significantly reduced transendothelial migration in two different neuroblastoma cell lines in vitro. Inhibition of ROCK, a key regulator of cell migration, in neuroblastoma cells highlighted that stathmin regulates transendothelial migration through ROCK signaling. Reduced stathmin expression in neuroblastoma cells significantly increased the activation of the RhoA small GTPase. Notably, re-expression of either wild type or a phospho-mimetic stathmin mutant (4E) made defective in tubulin binding returned cell migration and transendothelial migration back to control levels, indicating that stathmin may influence these processes in neuroblastoma cells independent of tubulin binding. Finally, stathmin suppression in neuroblastoma cells significantly reduced whole body, lung, kidney and liver metastases in an experimental metastases mouse model. In conclusion, stathmin suppression interferes with the metastatic process via RhoA/ROCK signaling in neuroblastoma cells. These findings highlight the importance of stathmin to the metastatic process and its potential as a therapeutic target for the treatment of neuroblastoma.

Self-assembling oligothiophene-bolaamphiphiles for loading and controlled release of doxorubicin into living cells.

Design and synthesis of symmetric mannose-functionalized oligothiophenes is reported. Self-organization of these bolaamphiphiles in solution and in the solid state was investigated by optical and AFM experiments. Fluorescence measurements revealed efficient loading and pH-dependent release of the anti-cancer drug doxorubicin. Delivery and release of the active drug into viable A549 cells as well as chirality-dependent cellular toxicity of the bolaamphiphilic transporter were evident from in vitro experiments.

Minimal incision posterior approach levator plication for aponeurotic ptosis.

PURPOSE: To assess the efficacy and predictability of a minimal incision posterior approach levator plication technique for correction of involutional ptosis. METHOD: Retrospective chart review of patients with involutional aponeurotic ptosis underwent minimal incision posterior approach levator plication technique between August 2013 and June 2014 by a single surgeon. The upper lid was double everted, and the conjunctiva and Muller's muscle layers were incised vertically until the levator aponeurosis could be identified. The incision(s) was similar to performing incision and curettage of chalazion, except that the site was above the tarsal plate and extended towards the fornix. Then insertion of aponeurosis was dissected away from the anterior tarsal surface, and the more superiorly located levator was plicated on it with double arm suture(s). No tissue was excised in this procedure. Surgical success was defined as a postoperative margin reflex distance (MRD)>2 mm and<4.5 mm, interlid height<1 mm and satisfactory contour. RESULTS: Forty-four lids of 27 patients were included. Preoperative mean MRD was 0.48 +/- 0.56 mm. Severe ptosis of MRD<1 mm was present in 34/44 patients (77.3%). The postoperative mean MRD was 2.49 +/- 0.53 mm, and mean improvement was 2.02 +/- 0.61 mm, which was statistically significant (P<0.001). The overall success rate was 38/44 (86.4%). CONCLUSIONS: Minimal incision posterior approach to levator plication was effective for the correction of aponeurotic ptosis with moderate to good levator function.

A unique role for p53 in the regulation of M2 macrophage polarization.

P53 is critically important in preventing oncogenesis but its role in inflammation in general and in the function of inflammatory macrophages in particular is not clear. Here, we show that bone marrow-derived macrophages exhibit endogenous p53 activity, which is increased when macrophages are polarized to the M2 (alternatively activated macrophage) subtype. This leads to reduced expression of M2 genes. Nutlin-3a, which destabilizes the p53/MDM2 (mouse double minute 2 homolog) complex, promotes p53 activation and further downregulates M2 gene expression. In contrast, increased expression of M2 genes was apparent in M2-polarized macrophages from p53-deficient and p53 mutant mice. Furthermore, we show, in mice, that p53 also regulates M2 polarization in peritoneal macrophages from interleukin-4-challenged animals and that nutlin-3a retards the development of tolerance to Escherichia coli lipopolysaccharide. P53 acts via transcriptional repression of expression of c-Myc (v-myc avian myelocytomatosis viral oncogene homolog) gene by directly associating with its promoter. These data establish a role for the p53/MDM2/c-MYC axis as a physiological 'brake' to the M2 polarization process. This work reveals a hitherto unknown role for p53 in macrophages, provides further insight into the complexities of macrophage plasticity and raises the possibility that p53-activating drugs, many of which are currently being trialled clinically, may have unforeseen effects on macrophage function.

Fifteen-year experience in managing obturator hernia: from open to laparoscopic approach.

PURPOSE: Obturator hernia is a rare disease and preoperative diagnosis is always difficult. There are increasing reports employing laparoscopic approach in the recent literature. Our aim was to review and compare the open and laparoscopic approach in repairing obturator hernia. METHODS: All patients with obturator hernia from 1997 to 2011 were recruited. Patient's demographics, presentation, operative details, morbidity, and mortality were retrospectively collected and reviewed. RESULTS: There were 36 patients during the 15-year period. All of them were elderly ladies (median 83). Nineteen underwent open surgery while 16 received laparoscopic surgery. Both age and ASA were comparable. The median operative time was 68 and 65 min for laparoscopic and open group, respectively (p = 0.690). The median hospital stay was significantly longer in the open group (19 vs 5 days, p = 0.007). There were less major complications (p = 0.004) and mortality (p = 0.049) in the laparoscopic group. Two recurrences were reported in the laparoscopic group, although statistically not significant (p = 0.202). CONCLUSIONS: Laparoscopic repair can achieve a shorter hospital stay and has lesser major complications and mortality in selected patients.

Andrographolide protects against cigarette smoke-induced oxidative lung injury via augmentation of Nrf2 activity.

BACKGROUND AND PURPOSE: Cigarette smoke is a major cause for chronic obstructive pulmonary disease (COPD). Andrographolide is an active biomolecule isolated from the plant Andrographis paniculata. Andrographolide has been shown to activate nuclear factor erythroid-2-related factor 2 (Nrf2), a redox-sensitive antioxidant transcription factor. As Nrf2 activity is reduced in COPD, we hypothesize that andrographolide may have therapeutic value for COPD. EXPERIMENTAL APPROACH: Andrographolide was given i.p. to BALB/c mice daily 2h before 4% cigarette smoke exposure for 1h over five consecutive days. Bronchoalveolar lavage fluid and lungs were collected for analyses of cytokines, oxidative damage markers and antioxidant activities. BEAS-2B bronchial epithelial cells were exposed to cigarette smoke extract (CSE) and used to study the antioxidant mechanism of action of andrographolide. KEY RESULTS: Andrographolide suppressed cigarette smoke-induced increases in lavage fluid cell counts; levels of IL-1ß, MCP-1, IP-10 and KC; and levels of oxidative biomarkers 8-isoprostane, 8-OHdG and 3-nitrotyrosine in a dose-dependent manner. Andrographolide promoted inductions of glutathione peroxidase (GPx) and glutathione reductase (GR) activities in lungs from cigarette smoke-exposed mice. In BEAS-2B cells, andrographolide markedly increased nuclear Nrf2 accumulation, promoted binding to antioxidant response element (ARE) and total cellular glutathione level in response to CSE. Andrographolide up-regulated ARE-regulated gene targets including glutamate-cysteine ligase catalytic (GCLC) subunit, GCL modifier (GCLM) subunit, GPx, GR and heme oxygenase-1 in BEAS-2B cells in response to CSE. CONCLUSIONS: Andrographolide possesses antioxidative properties against cigarette smoke-induced lung injury probably via augmentation of Nrf2 activity and may have therapeutic potential for treating COPD.

Replication of 13 obesity loci among Singaporean Chinese, Malay and Asian-Indian populations.

OBJECTIVE: Recent genome-wide association studies (GWAS) have identified 38 obesity-associated loci among European populations. However, their contribution to obesity in other ethnicities is largely unknown. METHODS: We utilised five GWAS (N=10 482) from Chinese (three cohorts, including one with type 2 diabetes and another one of children), Malay and Indian ethnic groups from Singapore. Data sets were analysed individually and subsequently in combined meta-analysis for Z-score body-mass index (BMI) associations. RESULTS: Variants at the FTO locus showed the strongest associations with BMI Z-score after meta-analysis (P-values 1.16 × 10(-7)-7.95 × 10(-7)). We further detected associations with nine other index obesity variants close to the MC4R, GNPDA2, TMEM18, QPCTL/GIPR, BDNF, ETV5, MAP2K5/SKOR1, SEC16B and TNKS/MSRA loci (meta-analysis P-values ranging from 3.58 × 10(-4)-1.44 × 10(-2)). Three other single-nucleotide polymorphisms (SNPs) from CADM2, PTBP2 and FAIM2 were associated with BMI (P-value ≤ 0.0418) in at least one dataset. The neurotrophin/TRK pathway (P-value=0.029) was highlighted by pathway-based analysis of loci that had statistically significant associations among Singaporean populations. CONCLUSION: Our data confirm the role of FTO in obesity predisposition among Chinese, Malays and Indians, the three major Asian ethnic groups. We additionally detected associations for 12 obesity-associated SNPs among Singaporeans. Thus, it is likely that Europeans and Asians share some of the genetic predisposition to obesity. Furthermore, the neurotrophin/TRK signalling may have a central role for common obesity among Asians.

Proteomic divergence in Arabidopsis autopolyploids and allopolyploids and their progenitors.

Autopolyploidy and allopolyploidy are common in many plants and some animals. Rapid changes in genomic composition and gene expression have been observed in both autopolyploids and allopolyploids, but the effects of polyploidy on proteomic divergence are poorly understood. Here, we report quantitative analysis of protein changes in leaves of Arabidopsis autopolyploids and allotetraploids and their progenitors using isobaric tags for relative and absolute quantitation (iTRAQ) coupled with mass spectrometry. In more than 1000 proteins analyzed, the levels of protein divergence were relatively high (~18%) between Arabidopsis thaliana and Arabidopsis arenosa, relatively low (~6.8%) between an A. thaliana diploid and autotetraploid and intermediate (~8.3 and 8.2%) in F(1)- and F(8)-resynthesized allotetraploids relative to mid-parent values, respectively. This pattern of proteomic divergence was consistent with the previously reported gene expression data. In particular, many non-additively accumulated proteins (61-62%) in the F(1) and F(8) allotetraploids were also differentially expressed between the parents. The differentially accumulated proteins in functional categories of abiotic and biotic stresses were overrepresented between an A. thaliana autotetraploid and diploid and between two Arabidopsis species, but not significantly different between allotetraploids and their progenitors. Although the trend of changes is similar, the percentage of differentially accumulated proteins that matched previously reported differentially expressed genes was relatively low. Western blot analysis confirmed several selected proteins with isoforms the cumulative levels of which were differentially expressed. These data suggest high protein divergence between species and rapid changes in post-transcriptional regulation and translational modifications of proteins during polyploidization.

Differentiating osteoradionecrosis from nasopharyngeal carcinoma tumour recurrence using 99Tcm-sestamibi SPECT/CT.

Osteoradionecrosis (ORN) of the base of skull is a known complication of external beam radiotherapy in the treatment of nasopharyngeal carcinoma, and is widely believed to be sequelae of radiation-induced endarteritis, leading to cellular death and fibrosis. Differentiating ORN from tumour recurrence is challenging and has direct clinical implications. We present a case where (99)Tc(m)-sestamibi SPECT/CT was used to differentiate ORN from tumour recurrence and in which prior imaging using bone scintigraphy and fluorodeoxyglucose PET/CT were equivocal.