Paradigm shift towards emergency cholecystectomy: one site experience of the Chole-QuiC process.

INTRODUCTION: Substantial evidence exists for the superiority of emergency over delayed cholecystectomy for gallstone disease during primary admission. Despite this, emergency surgery rates in the UK remain low compared with other developed countries, with great variation in care across the nation. We aimed to describe the local paradigm shift towards emergency surgery and investigate outcomes. METHODS: This is a prospective observational study examining patients enrolled onto an emergency cholecystectomy pathway, following the hospital's subscription to the Royal College of Surgeons of England's Cholecystectomy Quality Improvement Collaborative (Chole-QuIC), between 1 December 2021 and 31 January 2023. Multivariate logistical regression models were used to identify patient and hospital factors associated with postoperative outcomes. RESULTS: Of the 307 suitable acute admissions, 261 (85%) had an emergency cholecystectomy, compared with 5% preceding the Chole-QuIC interventions. Waiting time dropped from 67 to 5 days. A total of 208 (79.7%) patients were primary presentations, 92 (35.2%) were classed Tokyo grade 2 and 142 (54.4%) were obese. A total of 23 (8.8%) patients underwent preoperative endoscopic retrograde cholangiopancreatography, and 26 (10%) patients had a subtotal cholecystectomy. Favourable outcomes (Clavien Dindo ≥3) were observed in first presentations (odds ratio (OR) 0.35; p=0.042) and for operation times within 7 days (OR 0.32; p=0.037), with worse outcomes in BMI ≥35 (OR 3.32; p=0.005) and operation time >7 days (OR 3.11; p=0.037). CONCLUSION: A paradigm shift towards emergency cholecystectomy benefits both the patient and the service. Positive outcomes are apparent for early operation in patients presenting for the first time and recurrent attendees, with early operation (<7 days) providing the most favourable outcome in a select patient group.

Replica symmetry broken states of some glass models.

We have studied in detail the M-p balanced spin-glass model, especially the case p=4. These types of model have relevance to structural glasses. The models possess two kinds of broken replica states; those with one-step replica symmetry breaking (1RSB) and those with full replica symmetry breaking (FRSB). To determine which arises requires studying the Landau expansion to quintic order. There are nine quintic-order coefficients, and five quartic-order coefficients, whose values we determine for this model. We show that it is only for 2≤M<2.4714⋯ that the transition at mean-field level is to a state with FRSB, while for larger M values there is either a continuous transition to a state with 1RSB (when M≤3) or a discontinuous transition for M>3. The Gardner transition from a 1RSB state at low temperatures to a state with FRSB also requires the Landau expansion to be taken to quintic order. Our result for the form of FRSB in the Gardner phase is similar to that found when 2≤M<2.4714⋯, but differs from that given in the early paper of Gross et al. [Phys. Rev. Lett. 55, 304 (1985)0031-900710.1103/PhysRevLett.55.304]. Finally we discuss the effects of fluctuations on our mean-field solutions using the scheme of Höller and Read [Phys. Rev. E 101, 042114 (2020)2470-004510.1103/PhysRevE.101.042114] and argue that such fluctuations will remove both the continuous 1RSB transition and discontinuous 1RSB transitions when 8>d≥6 leaving just the FRSB continuous transition. We suggest values for M and p which might be used in simulations to confirm whether fluctuation corrections do indeed remove the 1RSB transitions.

Neoadjuvant tyrosine kinase inhibitor therapy in locally advanced differentiated thyroid cancer: a single centre case series.

OBJECTIVE: Primary surgical resection remains the mainstay of management in locally advanced differentiated thyroid cancer. Tyrosine kinase inhibitors have recently shown promising results in patients with recurrent locally advanced differentiated thyroid cancer. This study discussed four patients with locally advanced differentiated thyroid cancer managed with tyrosine kinase inhibitors used prior to surgery in the 'neoadjuvant' setting. METHOD: Prospective data collection through a local thyroid database from February 2016 identified four patients with locally advanced differentiated thyroid cancer unsuitable for primary surgical resection commenced on neoadjuvant tyrosine kinase inhibitor therapy. RESULTS: All cases had T4a disease at presentation. Three cases tolerated tyrosine kinase inhibitor therapy for more than 14 months while the last case failed to tolerate treatment at 1 month. All patients subsequently underwent total thyroidectomy to facilitate adjuvant radioactive iodine treatment. Disease-specific survival remains at 100 per cent currently (range, 29-75 months). CONCLUSION: Neoadjuvant tyrosine kinase inhibitors in locally advanced differentiated thyroid cancer can be effective in reducing primary tumour extent to potentially facilitate a more limited surgical resection for local disease control.

The impact of impulsivity on weight loss after bariatric surgery: a systematic review.

BACKGROUND: Impulsivity has been shown to be associated with obesity through links to pathological eating behavior such as binge eating. The recent literature suggests that impulsivity is linked to poorer outcomes post-bariatric surgery. Impulsivity can be measured in various ways and comprises of three broad domains: impulsive choice, impulsive action, and impulsive personality traits. The aim of this systematic review is to synthesize the current evidence on the impact of impulsivity on post-bariatric surgery weight loss. METHODS: A literature review was performed in February 2020. Original studies investigating the relationship between impulsivity and weight loss post-bariatric surgery were evaluated. RESULTS: Ten studies with a total of 1246 patients were analyzed. There were four case-control, four prospective observational and two retrospective observational studies. The postoperative follow-up ranged from 0.5 to 12 years. Eight studies measuring trait impulsivity did not show any association with weight loss post-bariatric surgery, although two studies reported an indirect effect of impulsivity on weight loss mediated via pathological eating behavior. Assessment of impulsive action by two studies showed that post-bariatric surgery weight loss is affected by impulsive action. CONCLUSION: Impulsivity may adversely affect postoperative outcomes after bariatric surgery. However, this may be specific to state impulsivity or impulsive action rather than trait impulsivity. Patients with a higher state impulsivity may benefit from closer follow-up post-bariatric surgery, as well as cognitive behavioral therapies targeting cognitive control over food. LEVEL OF EVIDENCE: Level I, systematic review.

Possible instability of one-step replica symmetry breaking in p-spin Ising models outside mean-field theory.

The fully connected Ising p-spin model has for p>2 a discontinuous phase transition from the paramagnetic phase to a stable state with one-step replica symmetry breaking (1RSB). However, simulations in three dimension do not look like these mean-field results and have features more like those which would arise with full replica symmetry breaking (FRSB). To help understand how this might come about we have studied in the fully connected p-spin model the state of two-step replica symmetry breaking (2RSB). It has a free energy degenerate with that of 1RSB, but the weight of the additional peak in P(q) vanishes. We expect that the state with full replica symmetry breaking (FRSB) is also degenerate with that of 1RSB. We suggest that finite-size effects will give a nonvanishing weight to the FRSB features, as also will fluctuations about the mean-field solution. Our conclusion is that outside the fully connected model in the thermodynamic limit, FRSB is to be expected rather than 1RSB.

Role of oral flora in chemotherapy-induced oral mucositis in vivo.

OBJECTIVE: To determine if commensal oral microflora impacts the severity of chemotherapy-induced oral mucositis (OM). DESIGN: Specific-pathogen-free (SPF) and germ-free Swiss Webster mice in the experimental groups were dosed with 5-fluorouracil (5-FU) to induce OM. Mice in the control group received phosphate buffered saline. Comparative analyses of the epithelial thickness and cell proliferation/turnover rates, as well as the expression levels of metalloproteinases and pro-inflammatory mediators in the oral mucosa between the control and experimental groups were determined by histopathological and immunohistochemical analyses. RESULTS: 5-FU-treated SPF and germ-free mice showed characteristic features of OM with reduced oral epithelial thickness, presence of inflammatory cells in the connective tissues, and increased levels of expression of metalloproteinases and pro-inflammatory cytokines compared to the respective control groups. When 5-FU-treated SPF and germ-free mice were compared, 5-FU-treated germ-free mice exhibited less severe epithelial destruction with higher expression of the cell proliferation marker Ki67, coupled with lower expression levels of metalloproteinases and pro-inflammatory cytokine in the oral mucosa. CONCLUSION: This study provides the first histopathological evidence that oral flora has a detrimental effect on chemotherapy-induced OM in vivo.

The impact of completion thyroidectomy.

INTRODUCTION: The oncological benefit of completion thyroidectomy (CT) following thyroid lobectomy (TL) is presumed to be similar to that of upfront total thyroidectomy(TT), from a patient's perspective the risk and inconvenience of further surgery adds significantly to the impact of the overall treatment. The aim of this study is to assess the impact of CT in terms of the duration of admission and associated complications. METHODS: A study of consecutive patients with DTC identified from prospective MDT records of South-East Scotland from 2009 to 2015. Surgical data was extracted from electronic medical record. RESULTS: Of 361 patients diagnosed with DTC, 161 (45%) had CT. The median postoperative stay was 1 day (range 1-5days). In total 22 patients (14%)suffered complications. Four patients (3%) developed postoperative haematoma. Two (1%) had an identified permanent nerve palsy on the completion side. 13 patients (8%) remained on calcium supplementation for more than 6 months postoperatively and three patients (2%) developed wound complications. CONCLUSIONS: Our study confirms that CT is regularly performed (45%). Recent changes in international guidelines recognize increasing number of patients as eligible for a conservative approach but recommend CT based on whether upfront TT would have been recommended if the TL pathology were known from the outset. Such an approach fails to consider the additional risk and inconvenience of CT on the overall patient experience. Due to a relatively high rate of complications, only those patients who are most likely to benefit from further surgery to facilitate adjuvant radioactive iodine should be offered additional surgery.

Hypoxia improves hair inductivity of dermal papilla cells via nuclear NADPH oxidase 4-mediated reactive oxygen species generation'.

BACKGROUND: Dermal papilla cells (DPCs) play a key role in hair regeneration and morphogenesis. Therefore, tremendous efforts have been made to promote DPC hair inductivity. OBJECTIVES: The aim of this study was to investigate the mitogenic and hair inductive effects of hypoxia on DPCs and examine the underlying mechanism of hypoxia-induced stimulation of DPCs. METHODS: DPCs' hair inductivity was examined under normoxia (20% O2 ) and hypoxia (2% O2 ). RESULTS: Hypoxia significantly increased the proliferation and delayed senescence of DPCs via Akt phosphorylation and downstream pathways. Hypoxia upregulated growth factor secretion of DPCs through the mitogen-activated protein kinase pathway. Hypoxia-preconditioned DPCs induced the telogen-to-anagen transition in C3 H mice, and also enhanced hair neogenesis in a hair reconstitution assay. Injected green fluorescent protein-labelled DPCs migrated to the outer root sheath of the hair follicle, and hypoxia-preconditioning increased survival and migration of DPCs in vivo. Conditioned medium obtained from hypoxia increased the hair length of mouse vibrissa follicles via upregulation of alkaline phosphatase, vascular endothelial growth factor, and glial cell line-derived neurotrophic factor. We examined the mechanism of this hypoxia-induced stimulation, and found that reactive oxygen species (ROS) play a key role. For example, inhibition of ROS generation by N-acetylcysteine or diphenyleneiodonium treatment attenuated DPCs' hypoxia-induced stimulation, but treatment with ROS donors induced mitogenic effects and anagen transition. NADPH oxidase 4 is highly expressed in the DPC nuclear region, and NOX4 knockout by CRISPR-Cas9 attenuated the hypoxia-induced stimulation of DPCs. CONCLUSIONS: Our results suggest that DPC culture under hypoxia has great advantages over normoxia, and is a novel solution for producing DPCs for cell therapy. What's already known about this topic? Dermal papilla cells (DPCs) play a key role in hair regeneration and morphogenesis, but they are difficult to isolate and expand for use in cell therapy. Tremendous efforts have been made to increase proliferation of DPCs and promote their hair formation ability. What does this study add? Hypoxia (2% O2 ) culture of DPCs increases proliferation, delays senescence and enhances hair inductivity of DPCs. Reactive oxygen species play a key role in hypoxia-induced stimulation of DPC. What is the translational message? Preconditioning DPCs under hypoxia improves their hair regenerative potential, and is a novel solution for producing DPCs for cell therapy to treat hair loss.

Antimicrobial activities of an oxygenated cyclohexanone derivative isolated from Amphirosellinia nigrospora JS-1675 against various plant pathogenic bacteria and fungi.

AIMS: To evaluate the antimicrobial activities of an active compound isolated from the culture broth of Amphirosellinia nigrospora JS-1675 against various plant pathogenic bacteria and fungi. METHODS AND RESULTS: While screening for bioactive secondary metabolites from endophytic fungi, we found that A. nigrospora JS-1675 showed strong in vitro antibacterial activity against Ralstonia solanacearum. One compound (1) was isolated and identified as (4S, 5S, 6S)-5,6-epoxy-4-hydroxy-3-methoxy-5-methyl-cyclohex-2-en-1-one. Growth of most of the tested phytopathogenic bacteria was inhibited by compound 1 and the ethyl acetate (EtOAc) layer except Pseudomonas syringae pv. lachrymans. Compound 1 also inhibited the mycelial growth of several plant pathogenic fungi. Both compound 1 and the EtOAc layer reduced bacterial leaf spot disease in detached peach leaves. They also suppressed the development of bacterial wilt on tomato seedlings quite effectively. CONCLUSIONS: Amphirosellinia nigrospora JS-1675 showed antimicrobial activity against plant pathogenic bacteria and fungi by producing compound 1. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report on the occurrence of compound 1 in A. nigrospora JS-1675 and its efficacy against plant pathogenic bacteria and fungi. Their strong disease control efficacy against tomato bacterial wilt suggests that this fungus can be used as a microbial bactericide.

Design, Synthesis and Evaluation of Novel 3/4-((Substituted benzamidophenoxy) methyl)-N-hydroxybenzamides/propenamides as Histone Deacetylase Inhibitors and Antitumor Agents.

BACKGROUND: Histone Deacetylase (HDAC) inhibitors represent an extensive class of targeted anticancer agents. Among the most explored structure moieties, hydroxybenzamides and hydroxypropenamides have been demonstrated to have potential HDAC inhibitory effects. Several compounds of these structural classes have been approved for clinical uses to treat different types of cancer, such as givinostat (ITF2357) and belinostat (PXD-101). AIMS: This study aims at developing novel HDAC inhibitors bearing N-hydroxybenzamides and Nhydroxypropenamides scaffolds with potential cytotoxicity against different cancer cell lines. METHODS: Two new series of N-hydroxybenzamides and N-hydroxypropenamides analogues (4a-j, 6a-j) designed based on the structural features of nexturastat A, AR-42, and PXD-101, were synthesized and evaluated for HDAC inhibitory potency as well as cytotoxicity against three human cancer cell lines (SW620 (colorectal adenocarcinoma), PC3 (prostate adenocarcinoma), and NCI-H23 (adenocarcinoma, non-small cell lung cancer). Molecular simulations were finally carried out to gain more insight into the structure-activity relationships. RESULTS: It was found that the N-hydroxypropenamides (6a-e) displayed very good HDAC inhibitory potency and cytotoxicity. Various compounds, e.g. 6a-e, especially compound 6e, were up to 5-fold more potent than suberanilohydroxamic acid (SAHA) in terms of cytotoxicity. These compounds also comparably inhibited HDACs with IC50 values in the sub-micromolar range. Docking experiments showed that these compounds bound to HDAC2 at the enzyme active binding site with the same binding mode of SAHA, but with higher binding affinities. CONCLUSIONS: The two series of N-hydroxybenzamides and N-hydroxypropenamides designed and synthesized were potential HDAC inhibitors and antitumor agents. Further development of these compounds should be warranted.

Renal failure and progressive pancytopenia.

Hyperparathyroidism may be a precipitating factor to the development of myelofibrosis; however, this is extremely rare with only a few documented case reports of myelofibrosis caused by secondary hyperparathyroidism. We describe a case of a 24-year-old female who had a failed live donor renal transplant and secondary hyperparathyroidism. While on haemodialysis she became increasingly pancytopenic despite erythropoietin injections and adequate iron, vitamin B12 and folate replacement. Her secondary hyperparathyroidism evolved to tertiary hyperparathyroidism despite vitamin D supplementation and phosphate binders. In order to determine the cause of her pancytopenia, a bone marrow biopsy was performed that confirmed myelofibrosis due to her secondary hyperparathyroidism. Following a successful parathyroidectomy in a tertiary hospital, her pancytopenia resolved and she is now awaiting a second transplant.

Disparate effects of antibiotics on hypertension.

Gut microbiota are associated with a variety of complex polygenic diseases. The usage of broad-spectrum antibiotics by patients affected by such diseases is an important environmental factor to consider, because antibiotics, which are widely prescribed to curb pathological bacterial infections, also indiscriminately eliminate gut commensal microbiota. However, the extent to which antibiotics reshape gut microbiota and per se contribute to these complex diseases is understudied. Because genetics play an important role in predisposing individuals to these modern diseases, we hypothesize that the extent to which antibiotics influence complex diseases depends on the host genome and metagenome. The current study tests this hypothesis in the context of hypertension, which is a serious risk factor for cardiovascular diseases. A 3 × 2 factorial design was used to test the blood pressure (BP) and microbiotal effects of three different antibiotics, neomycin, minocycline, and vancomycin, on two well-known, preclinical, genetic models of hypertension, the Dahl salt-sensitive (S) rat and the spontaneously hypertensive rat (SHR), both of which develop hypertension, but for different genetic reasons. Regardless of the class, oral administration of antibiotics increased systolic blood pressure of the S rat, while minocycline and vancomycin, but not neomycin, lowered systolic blood pressure in the SHR. These disparate BP effects were accompanied by significant alterations in gut microbiota. Our study highlights the need to consider an individualized approach for the usage of antibiotics among hypertensives, as their BP could be affected differentially based on their individual genetic and microbiotal communities.

Gastric poorly cohesive carcinoma: a correlative study of mutational signatures and prognostic significance based on histopathological subtypes.

AIMS: Genome-wide next-generation sequencing has revealed several driver mutations and has allowed the establishment of a molecular taxonomy of gastric cancer. However, there are few detailed studies on the mutational spectrum of poorly cohesive gastric carcinoma. Thus, this study aim to investigate its mutation profile based on clinicopathological characteristics. METHODS AND RESULTS: Herein, we analysed the mutational pattern of 77 genes in a cohort of 91 patients with poorly cohesive carcinoma by using targeted sequencing, and evaluated the clinicopathological significance of the various mutations based on histological pattern, either signet ring cell (SRC) or other types of poorly cohesive carcinoma (not otherwise specified) (PCC-NOS). Panels of seven (PIK3CA, CDH1, PTEN, RHOA, HDCA9, KRAS, and ATM), three (PIK3CA, CTNNB1, and KRAS) and two (HDCA9 and IGF1R) genes were associated with a diffuse infiltrative growth pattern, lymphovascular invasion, and perineural invasion, respectively. Furthermore, PDGFRB mutations were associated with a favourable prognosis, whereas MET mutations were associated with a poor prognosis. The PCC-NOS-predominant type was associated with a greater depth of invasion, lymph node metastasis and poorer prognosis than the SRC-predominant type. Mutations in TP53, BRAF, PI3CA, SMAD4 and RHOA were associated with PCC-NOS. Interestingly, RHOA-mutated gastric cancers showed a distinct morphology, as they were characterised by a superficial SRC or tubular component and a deep invasive PCC-NOS component with desmoplasia. CONCLUSIONS: Taken together, our findings demonstrate that gastric poorly cohesive carcinomas show several mutational patterns associated with specific clinicopathological characteristics, and particularly show distinct morphological findings when associated with RHOA mutation.

Characteristics of CSF Velocity-Time Profile in Posttraumatic Syringomyelia.

BACKGROUND AND PURPOSE: The development of syringomyelia has been associated with changes in CSF flow dynamics in the spinal subarachnoid space. However, differences in CSF flow velocity between patients with posttraumatic syringomyelia and healthy participants remains unclear. The aim of this work was to define differences in CSF flow above and below a syrinx in participants with posttraumatic syringomyelia and compare the CSF flow with that in healthy controls. MATERIALS AND METHODS: Six participants with posttraumatic syringomyelia were recruited for this study. Phase-contrast MR imaging was used to measure CSF flow velocity at the base of the skull and above and below the syrinx. Velocity magnitudes and temporal features of the CSF velocity profile were compared with those in healthy controls. RESULTS: CSF flow velocity in the spinal subarachnoid space of participants with syringomyelia was similar at different locations despite differences in syrinx size and locations. Peak cranial and caudal velocities above and below the syrinx were not significantly different (peak cranial velocity, P = .9; peak caudal velocity, P = 1.0), but the peak velocities were significantly lower (P < .001, P = .007) in the participants with syringomyelia compared with matched controls. Most notably, the duration of caudal flow was significantly shorter (P = .003) in the participants with syringomyelia. CONCLUSIONS: CSF flow within the posttraumatic syringomyelia group was relatively uniform along the spinal canal, but there are differences in the timing of CSF flow compared with that in matched healthy controls. This finding supports the hypothesis that syrinx development may be associated with temporal changes in spinal CSF flow.

Changes of cortical activation in swallowing following high frequency repetitive transcranial magnetic stimulation in older adults.

BACKGROUND: This study explored whether high-frequency repetitive transcranial magnetic stimulation (rTMS) can induce positive changes in the cortical areas of older adults who do not have functional difficulties in swallowing. METHODS: Ten healthy, right-handed, elderly volunteers were subjected to 18F-labeled fluorodeoxyglucose positron emission tomography(FDG-PET) scans when at rest, swallowing before rTMS, and swallowing after rTMS. During the swallowing study, water was infused orally via a catheter at a rate of 600 mL/h. Subjects swallowed water every 20 seconds following a light flash for 30 minutes. During rest, the light source was active, but subjects were requested not to swallow. The rTMS consisted of 5 Hz applied to a pharyngeal motor hot spot in the right hemisphere for 10 minutes every weekday for 2 weeks. The intensity of the stimulation was set at 90% of the thenar motor threshold of the same hemisphere. The differences between each patient's active image and the control images (P<.05) on a voxel-by-voxel basis were examined to find significant increases in metabolism using statistical parametric mapping software. KEY RESULTS: The cortical areas activated by swallowing before rTMS included the bilateral sensorimotor cortex (Brodmann's areas 3 and 4) and showed symmetry. The cortical areas activated by swallowing after rTMS were the same as the areas before rTMS. There was no statistical difference between the two swallowing activation areas. CONCLUSIONS AND INFERENCES: Older adults displayed the symmetry of cortical control of swallowing function. High frequency rTMS did not affect the activation in the swallowing sensorimotor cortices of elderly people.

Comparison of digital tomosynthesis and chest radiography for the detection of pulmonary nodules: systematic review and meta-analysis.

OBJECTIVE: To compare the diagnostic accuracy of digital tomosynthesis (DTS) with that of chest radiography for the detection of pulmonary nodules by meta-analysis. METHODS: A systematic literature search was performed to identify relevant original studies from 1 January 1 1976 to 31 August 31 2016. The quality of included studies was assessed by quality assessment of diagnostic accuracy studies-2. Per-patient data were used to calculate the sensitivity and specificity and per-lesion data were used to calculate the detection rate. Summary receiver-operating characteristic curves were drawn for pulmonary nodule detection. RESULTS: 16 studies met the inclusion criteria. 1017 patients on a per-patient basis and 2159 lesions on a per-lesion basis from 16 eligible studies were evaluated. The pooled patient-based sensitivity of DTS was 0.85 [95% confidence interval (CI) 0.83-0.88] and the specificity was 0.95 (0.93-0.96). The pooled sensitivity and specificity of chest radiography were 0.47 (0.44-0.51) and 0.37 (0.34-0.40), respectively. The per-lesion detection rate was 2.90 (95% CI 2.63-3.19). CONCLUSION: DTS has higher diagnostic accuracy than chest radiography for detection of pulmonary nodules. Chest radiography has low sensitivity but similar specificity, comparable with that of DTS. Advances in knowledge: DTS has higher diagnostic accuracy than chest radiography for the detection of pulmonary nodules.

Proteolytic inactivation of nuclear alarmin high-mobility group box 1 by complement protease C1s during apoptosis.

Effective clearance of apoptotic cells by phagocytes prevents the release of intracellular alarmins and manifestation of autoimmunity. This prompt efferocytosis is complemented by intracellular proteolytic degradation that occurs within the apoptotic cells and in the efferosome of the phagocytes. Although the role of extracellular proteases in apoptotic cells clearance is unknown, the strong association of congenital C1s deficiency with Systemic Lupus Erythematosus highlights the protective nature that this extracellular protease has against autoimmunity. The archetypical role of serine protease C1s as the catalytic arm of C1 complex (C1qC1r2C1s2) involve in the propagation of the classical complement pathway could not provide the biological basis for this association. However, a recent observation of the ability of C1 complex to cleave a spectrum of intracellular cryptic targets exposed during apoptosis provides a valuable insight to the underlying protective mechanism. High-mobility group box 1 (HMGB1), an intracellular alarmin that is capable of inducing the formation of antinuclear autoantibodies and causes lupus-like conditions in mice, is identified as a novel potential target by bioinformatics analysis. This is verified experimentally with C1s, both in its purified and physiological form as C1 complex, cleaving HMGB1 into defined fragments of 19 and 12 kDa. This cleavage diminishes HMGB1 ability to enhance lipopolysaccharide mediated pro-inflammatory cytokines production from monocytes, macrophages and dendritic cells. Further mass spectrometric analysis of the C1 complex treated apoptotic cellular proteins demonstrated additional C1s substrates and revealed the complementary role of C1s in apoptotic cells clearance through the proteolytic cleavage of intracellular alarmins and autoantigens. C1 complex may have evolved as, besides the bacteriolytic arm of antibodies in which it activates the complement cascade, a tissue renewal mechanism that reduces the immunogenicity of apoptotic tissue debris and decreases the likelihood of autoimmunity.

Clinical outcomes of adenoid cystic carcinoma of the head and neck: a single institution 20-year experience.

BACKGROUND: This study reports the clinical outcomes of head and neck adenoid cystic carcinoma treatment over a 20-year period. METHODS: The treatment outcome of 51 head and neck adenoid cystic carcinoma patients treated between 1992 and 2013 were analysed. Patients were stratified into radical treatment and disease control groups. RESULTS: A total of 40 patients underwent surgery and post-operative radiotherapy. The 10-year disease-specific survival rate was 93 per cent. Eleven patients had tumour recurrence: of these, nine were pulmonary metastases. The 11 patients in the disease control group had a median follow up of 21 months (range, 2-172 months); 5 underwent radical radiotherapy with palliative intent. CONCLUSION: There was late tumour recurrence in over 25 per cent of patients. Adenoid cystic carcinoma has a high tendency to relapse even after radical excision and adjuvant therapy. However, definitive radiotherapy should still be considered on an individual basis because it may provide local control and prolong patient survival.

Antibacterial activities of penicillic acid isolated from Aspergillus persii against various plant pathogenic bacteria.

UNLABELLED: The emergence of pathogenic bacterial strains resistant to agrochemicals and the increasing demand for organic foods have led to the discovery of new antibacterial metabolites that can be used either directly or as a lead molecule for development of synthetic bactericides. During the screening of antibacterial fungal cultures, we found that one fungal strain, Aspergillus persii EML-HPB1-11, showed strong in vitro antibacterial activity against Xanthomonas arboricola pv. pruni (Xap) with a minimum inhibitory concentration (MIC) of 10% of fermentation broth filtrate. The active compound was identified as penicillic acid (PA: 3-methoxy-5-methyl-4-oxo-2,5-hexadienoic acid) by mass and NMR spectroscopy. The in vitro antibacterial activity of PA was tested against 12 phytopathogenic bacteria. All of the bacterial pathogens tested were highly inhibited by PA with MIC values of 12·3-111·1 µg ml(-1) . It also effectively suppressed the development of bacterial spot disease in detached peach leaves, showing control values of 82·4 and 94·1% at concentrations of 111·1 and 333·3 µg ml(-1) respectively. This is the first report on the production of PA by A. persii. This study suggests that PA can be used as a lead molecule for development of synthetic bactericides for control of various plant diseases. SIGNIFICANCE AND IMPACT OF THE STUDY: Penicillic acid (PA) produced by the seed-borne fungus Aspergillus persii EML-HPB1-11 showed antibacterial activity against various plant pathogenic bacteria. The compound effectively inhibited the growth of 12 plant pathogenic bacteria and successfully controlled bacterial spot disease on peach leaf. These results suggest that PA can be used as a lead molecule for development of synthetic agrochemicals to control plant bacterial diseases.