Neoadjuvant Immune Checkpoint Inhibitors in hepatocellular carcinoma: a meta-analysis and systematic review.

Background: Neoadjuvant immunotherapy has demonstrated beneficial outcomes in various cancer types; however, standardized protocols for neoadjuvant immunotherapy in hepatocellular carcinoma (HCC) are currently lacking. This systematic review and meta-analysis aims to investigate the reliability of neoadjuvant immunotherapy's efficacy and safety in the context of HCC. Methods: A systematic search was conducted across PubMed (MEDLINE), EMBASE, the Web of Science, the Cochrane Library, and conference proceedings to identify clinical trials involving resectable HCC and neoadjuvant immunotherapy. Single-arm meta-analyses were employed to compute odds ratios and 95% confidence intervals (CIs). Heterogeneity analysis, data quality assessment, and subgroup analyses based on the type of immunotherapy drugs and combination therapies were performed. This meta-analysis is registered in PROSPERO (identifier CRD42023474276). Results: This meta-analysis included 255 patients from 11 studies. Among resectable HCC patients, neoadjuvant immunotherapy exhibited an overall major pathological response (MPR) rate of 0.47 (95% CI 0.31-0.70) and a pathological complete response (pCR) rate of 0.22 (95% CI 0.14-0.36). The overall objective response rate (ORR) was 0.37 (95% CI 0.20-0.69), with a grade 3-4 treatment-related adverse event (TRAE) incidence rate of 0.35 (95% CI 0.24-0.51). Furthermore, the combined surgical resection rate was 3.08 (95% CI 1.66-5.72). Subgroup analysis shows no significant differences in the efficacy and safety of different single-agent immunotherapies; the efficacy of dual ICIs (Immune Checkpoint Inhibitors) combination therapy is superior to targeted combined immunotherapy and monotherapy, while the reverse is observed in terms of safety. Discussion: Neoadjuvant immunotherapy presents beneficial outcomes in the treatment of resectable HCC. However, large-scale, high-quality experiments are warranted in the future to provide robust data support.

Network Pharmacology Studies on the Molecular Mechanism of Hashimoto's Thyroiditis Treated with Shutiao Qiji Decoction.

BACKGROUND: In recent years, the number of patients with Hashimoto's thyroiditis has been increasing, and traditional Chinese medicine ingredients and combinations have been applied to treat Hashimoto's thyroiditis to increase efficacy and reduce side effects during the treatment process. OBJECTIVE: Shutiao Qiji Decoction is one of the Chinese traditional medicine prescriptions, which is commonly used to treat cancer, tumor, etc. It is also used for thyroid-related diseases in the clinic. Hashimoto's thyroiditis is an autoimmune disease. In this study, the mechanism of Shutiao Qiji Decoction in treating Hashimoto's thyroiditis was studied through network pharmacology and molecular docking verification. METHOD: Each Chinese medicine ingredient of Shutiao Qiji Decoction was retrieved from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. The related genes of HT were searched from the UniProt and GeneCards databases. Meanwhile, we used Cytoscape to construct the protein-protein interaction (PPI) visual network analysis, and used the search tool to search the database of Interacting Genes (STRING) to build a PPI network. These key proteins were enriched and analyzed by molecular docking validation, Gene Ontology (GO), and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Hashimoto's thyroiditis disease model was established in SD rats, and SQD was administered by gavage after the successful establishment of the model. After 6 weeks of continuous administration of the drug by gavage, tissue samples were collected and the thyroid and spleen tissues were visualized by HE staining to verify the therapeutic effect. RESULTS: The results showed that there were 287 TCM active ingredients, 1920 HT-related disease targets, and 176 drug and disease targets in SQD. Through PPI analysis, GP analysis, and KEGG analysis of the common targets of drugs and diseases, we found their pathways of action to be mainly cancer action pathway, PI3K-AKT signaling pathway, and T-cell action pathway. The active ingredients of the drugs in SQD, malvidin, stigmasterol, porin-5-en-3bta-ol, and chrysanthemum stigmasterol, were docked with the related target proteins, MAPK, GSK3ß, TSHR, and NOTCH molecules. The best binding energies obtained from docking were mairin with TSHR, stigmasterol with TSHR, poriferast-5-en-3beta-ol with MAPK, and chryseriol with GSK3ß, with binding energies of -6.84 kcal/mol, -6.53 kcal/mol, -5.03 kcal/mol, and -5.05 kcal/mol, respectively. HE staining sections of rat thyroid and spleen tissues showed that SQD had a therapeutic effect on Hashimoto's thyroiditis and restored its immune function. CONCLUSION: It is verified by molecular docking results that Shutiao Qiji Decoction has a potential therapeutic effect on Hashimoto's thyroiditis in the MAPK/TSHR/NOTCH signal pathway, and that the main components, mairin, stigmasterol, poriferast-5-en-3beta-ol, and chryseriol play a role in it. SQD has been shown to have a good therapeutic effect on Hashimoto's thyroiditis.

Rapid characterization of anti-CRISPR proteins and optogenetically engineered variants using a versatile plasmid interference system.

Anti-CRISPR (Acr) proteins are encoded by mobile genetic elements to overcome the CRISPR immunity of prokaryotes, displaying promises as controllable tools for modulating CRISPR-based applications. However, characterizing novel anti-CRISPR proteins and exploiting Acr-related technologies is a rather long and tedious process. Here, we established a versatile plasmid interference with CRISPR interference (PICI) system in Escherichia coli for rapidly characterizing Acrs and developing Acr-based technologies. Utilizing the PICI system, we discovered two novel type II-A Acrs (AcrIIA33 and AcrIIA34), which can inhibit the activity of SpyCas9 by affecting DNA recognition of Cas9. We further constructed a circularly permuted AcrIIA4 (cpA4) protein and developed optogenetically engineered, robust AcrIIA4 (OPERA4) variants by combining cpA4 with the light-oxygen-voltage 2 (LOV2) blue light sensory domain. OPERA4 variants are robust light-dependent tools for controlling the activity of SpyCas9 by approximately 1000-fold change under switching dark-light conditions in prokaryotes. OPERA4 variants can achieve potent light-controllable genome editing in human cells as well. Together, our work provides a versatile screening system for characterizing Acrs and developing the Acr-based controllable tools.

Exploring the pathogenesis of colorectal carcinoma complicated with hepatocellular carcinoma via microarray data analysis.

Background: Despite the increasing number of research endeavors dedicated to investigating the relationship between colorectal carcinoma (CRC) and hepatocellular carcinoma (HCC), the underlying pathogenic mechanism remains largely elusive. The aim of this study is to shed light on the molecular mechanism involved in the development of this comorbidity. Methods: The gene expression profiles of CRC (GSE90627) and HCC (GSE45267) were downloaded from the Gene Expression Omnibus (GEO) database. After identifying the common differentially expressed genes (DEGs) of psoriasis and atherosclerosis, three kinds of analyses were performed, namely, functional annotation, protein-protein interaction (PPI) network and module construction, and hub gene identification, survival analysis and co-expression analysis. Results: A total of 150 common downregulated differentially expressed genes and 148 upregulated differentially expressed genes were selected for subsequent analyses. The significance of chemokines and cytokines in the pathogenesis of these two ailments is underscored by functional analysis. Seven gene modules that were closely connected were identified. Moreover, the lipopolysaccharide-mediated signaling pathway is intricately linked to the development of both diseases. Finally, 10 important hub genes were identified using cytoHubba, including CDK1, KIF11, CDC20, CCNA2, TOP2A, CCNB1, NUSAP1, BUB1B, ASPM, and MAD2L1. Conclusion: Our study reveals the common pathogenesis of colorectal carcinoma and hepatocellular carcinoma. These common pathways and hub genes may provide new ideas for further mechanism research.

Discovery of potent and versatile CRISPR-Cas9 inhibitors engineered for chemically controllable genome editing.

Anti-CRISPR (Acr) proteins are encoded by many mobile genetic elements (MGEs) such as phages and plasmids to combat CRISPR-Cas adaptive immune systems employed by prokaryotes, which provide powerful tools for CRISPR-Cas-based applications. Here, we discovered nine distinct type II-A anti-CRISPR (AcrIIA24-32) families from Streptococcus MGEs and found that most Acrs can potently inhibit type II-A Cas9 orthologs from Streptococcus (SpyCas9, St1Cas9 or St3Cas9) in bacterial and human cells. Among these Acrs, AcrIIA26, AcrIIA27, AcrIIA30 and AcrIIA31 are able to block Cas9 binding to DNA, while AcrIIA24 abrogates DNA cleavage by Cas9. Notably, AcrIIA25.1 and AcrIIA32.1 can inhibit both DNA binding and DNA cleavage activities of SpyCas9, exhibiting unique anti-CRISPR characteristics. Importantly, we developed several chemically inducible anti-CRISPR variants based on AcrIIA25.1 and AcrIIA32.1 by comprising hybrids of Acr protein and the 4-hydroxytamoxifen-responsive intein, which enabled post-translational control of CRISPR-Cas9-mediated genome editing in human cells. Taken together, our work expands the diversity of type II-A anti-CRISPR families and the toolbox of Acr proteins for the chemically inducible control of Cas9-based applications.

Sodium phosphate is superior to polyethylene glycol in constipated patients undergoing colonoscopy: a systematic review and meta-analysis.

BACKGROUND: Constipation is an important and highly prevalent predictor of inadequate bowel preparation during colonoscopy. In North America, between 2 and 28% of the general population suffer from constipation. Despite the high prevalence of constipation, to our knowledge, no meta-analysis on the optimal bowel preparation for constipated patients has been performed. We aimed to systematically review the literature to determine the ideal bowel preparation regiment for patients with chronic constipation. METHODS: A comprehensive search of electronic databases (MEDLINE, EMBASE, SCOPUS, and Web of Science) was performed. We included studies that assessed the quality of bowel preparation in constipated patients receiving different agents prior to colonoscopy. The primary outcome was colon cleanliness. Secondary outcomes included tolerability of the bowel preparation and serious adverse events. RESULTS: Preliminary database search yielded 1581 articles after duplicates were removed. After screening of the titles and abstracts using the exclusion criteria, 358 full-text articles were retained. Full-text articles were reviewed and eight studies meeting the inclusion criteria were included for qualitative synthesis. Three randomized controlled trials identified a total of 1636 constipated patients, of whom 225 were eligible for meta-analysis. Of those, 107 (47.6%) received NaP and 118 (52.4%) received PEG. Patients receiving NaP before colonoscopy had a higher chance of a successful bowel preparation than patients receiving PEG (OR 1.87, CI 1.06 to 3.32, P = 0.003). In the studies comparing PEG to NaP, two found that NaP resulted in greater tolerability of the bowel preparation and one study found that PEG resulted in superior tolerability. CONCLUSIONS: In chronically constipated patients undergoing colonoscopy, the use of NaP may result in superior colonic cleanliness when compared to PEG, however, quality of evidence was low. Further high-quality studies are required to delineate the optimal bowel preparation in patients with constipation.

Predictive factors for diabetes remission after bariatric surgery

Background: Bariatric surgery has been shown to induce type 2 diabetes mellitus (T2DM) remission in severely obese patients. After laparoscopic Roux-en-Y gastric bypass (LRYGB), diabetes remission occurs early and independently of weight loss. Previous research has identified preoperative factors for remission, such as duration of diabetes and HbA1c. Understanding factors that predict diabetes remission can help to select patients who will benefit most from bariatric surgery. Methods: We retrospectively reviewed all T2DM patients who underwent laparoscopic sleeve gastrectomy (LSG) or LRYGB between January 2008 and July 2014. The primary outcome was diabetes remission, defined as the absence of hypoglycemic medications, fasting blood glucose < 7.0 mmol/L and HbA1c < 6.5%. Data were analyzed using multivariable logistic regression analysis to identify predictive factors of diabetes remission. Results: We included 207 patients in this analysis; 84 (40.6%) had LSG and 123 (59.4%) had LRYGB. Half of the patients (49.8%) achieved diabetes remission at 1 year. Multivariable logistic analysis showed that LRYGB had higher odds of diabetes remission than LSG (odds ratio [OR] 6.58, 95% confidence interval [CI] 2.79­15.50, p < 0.001). Shorter duration of diabetes (OR 0.91, 95% CI 0.83­0.99, p = 0.032) and the absence of long-acting insulin (OR 0.0011, 95% CI < 0.000­0.236, p = 0.013) predicted remission. Conclusion: Type of bariatric procedure (LRYGB v. LSG), shorter duration of diabetes and the absence of long-acting insulin were independent predictors of diabetes remission after bariatric surgery.

Contexte: Il a été démontré que la chirurgie bariatrique provoque une rémission du diabète de type 2 chez les patients gravement obèses. Après la dérivation gastrique Roux-en-Y (DGRY) par laparoscopie, la rémission du diabète se produit tôt et indépendamment de la perte de poids. Des recherches antérieures ont identifié des facteurs préopératoires de rémission, notamment la durée du diabète et l'HbA1c. Comprendre les facteurs prédictifs de la rémission du diabète peut aider à sélectionner les patients qui bénéficieront le plus de la chirurgie bariatrique. Méthodes: Nous avons examiné rétrospectivement les dossiers de tous les patients atteints de diabète de type 2 qui ont subi par laparoscopie une gastrectomie en manchon (GM) ou une DGRY entre janvier 2008 et juillet 2014. Le principal résultat a été la rémission du diabète, définie comme l'absence de médicaments hypoglycémiques, la glycémie à jeun < 7,0 mmol/L et l'HbA1c < 6,5 %. Les données ont été soumises à une analyse de régression logistique multiple pour déterminer les facteurs prédictifs de la rémission du diabète. Résultats: Nous avons inclus 207 patients dans cette analyse; 84 (40,6 %) ont subi une GM et 123 (59,4 %), une DGRY. La moitié des patients (49,8 %) ont obtenu une rémission du diabète à 1 an. L'analyse logistique multiple a montré que la DGRY s'accompagnait de probabilités plus élevées de rémission du diabète que la GM (rapport de cotes [RC] 6,58; intervalle de confiance [IC] de 95 %, 2,79­15,50, p < 0,001). La durée plus courte du diabète (RC 0,91; IC de 95 %, 0,83­0,99, p = 0,032) et absence d'insuline à action prolongée (RC 0,0011; IC de 95 % < 0,000­0,236, p = 0,013) étaient prédicteurs de rémission. Conclusion: Le type d'intervention bariatrique (DGRY c. MG), la durée plus courte du diabète et l'absence d'insuline à action prolongée étaient des prédicteurs indépendants de la rémission du diabète après une chirurgie bariatrique.

Simethicone decreases bloating and improves bowel preparation effectiveness: a systematic review and meta-analysis.

BACKGROUND: Simethicone is an adjunct frequently used during bowel preparation before colonoscopy and currently there is no consensus on whether it should be recommended in standard bowel preparation. We performed a systematic review and meta-analysis to determine the effect simethicone has on bowel cleanliness, adenoma detection rate (ADR), and tolerability. METHODS: We searched the literature for studies that compared colon cleansing of patients that received standard bowel preparation alone and in combination with simethicone prior to colonoscopy. The primary outcomes were colon cleanliness, ADR, and tolerability. RESULTS: Sixteen randomized controlled trials with 5630 patients were included in meta-analysis. Overall, polyethylene glycol (PEG) with simethicone improves colon cleansing compared with PEG alone (odds ratio [OR] 1.48, CI 1.11 to 1.97, P = 0.008). This improvement was seen for single dosing (OR 1.83, CI 1.20 to 2.79, P = 0.005) but not for split dosing (OR 1.32, CI 0.72 to 2.43, P = 0.38). Overall, simethicone had no effect on ADR (OR 1.22, CI 0.81 to 1.83, P = 0.33), but in patients receiving single dosing, simethicone significantly increased ADR (OR 1.96, CI 1.22 to 3.16, P = 0.005). The rates of nausea (OR 0.96, CI 0.75 to 1.24, P = 0.75), vomiting (OR 1.00, CI 0.69 to 1.44, P = 0.99), and abdominal pain (OR 0.69, CI 0.40 to 1.18, P = 0.17) were not significantly different between PEG and PEG + simethicone cohorts. For abdominal bloating, the PEG cohort had greater odds of experiencing bloating than the PEG + simethicone cohort (OR 2.33, CI 1.70 to 3.20, P < 0.00001). CONCLUSIONS: Simethicone improves colon cleanliness and ADR; however, this improvement is not seen in patients receiving split-dose PEG. Furthermore, simethicone decreases abdominal bloating but has no effect on nausea, vomiting, and abdominal pain. Simethicone may be a useful bowel preparation adjunct in patients unable to receive split-dose PEG.

Antibiotic use in prevention of anal fistulas following incision and drainage of anorectal abscesses: A systematic review and meta-analysis.

BACKGROUND: Treatment of anorectal abscesses continues to revolve around early surgical drainage and control of perianal sepsis. Yet even with prompt drainage, abscess recurrence and postoperative fistula formation rates are as high as 40% within 12 months. These complications are thought to be associated with inadequate drainage, elevated bacterial load, or a noncryptoglandular etiology of disease. Postoperative antibiotics have been used to account for these limitations, but their use is controversial and only weakly supported by current guidelines due to low-quality evidences. The aim of the present study was to perform a systematic review and meta-analysis of the current literature to determine the role of antibiotics in prevention of anal fistula following incision and drainage of anorectal abscesses. METHODS: Literature search was conducted using Medline, EMBASE, Scopus, the Cochrane Library, and Web of Science databases from 1946 to April 2018. Search terms were "perianal OR anal OR fistula-in-ano OR ischiorectal OR anorectal AND abscess AND antibiotics" and was limited to human studies in the English language. Literature review and data extraction were completed using PRISMA guidelines. A total of six studies with 817 patients were included for systematic review. The weighted mean age was 37.8 years, 20.4% of patients were female, and the follow up ranged from one to 30 months. Antibiotic courses varied by study, and duration ranged from five to 10 days. Of included patients, 358 (43.8%) underwent management without antibiotics while 459 (56.2%) patients were treated with antibiotics. Fistula rate in subjects receiving antibiotics was 16% versus 24% in those not receiving postoperative antibiotics. Meta-analysis revealed a statistically significant protective effect for antibiotic treatment (3 studies, OR 0.64; CI 0.43-0.96; P = 0.03). CONCLUSIONS: Antibiotic therapy following incision and drainage of anorectal abscesses is associated with a 36% lower odds of fistula formation. An empiric 5-10-day course of antibiotics following operative drainage may avoid the morbidity of fistula formation in otherwise healthy patients, although quality of evidence is low. Further randomized trials are needed to fully clarify the role, duration, and type of antibiotics best suited for postoperative prevention of fistula following drainage of anorectal abscesses.

Impact of Bariatric Surgery on Male Sex Hormones and Sperm Quality: a Systematic Review and Meta-Analysis.

This systematic review and meta-analysis aims to establish the effects of bariatric surgery on male sex hormones, sperm parameters, and sexual function. We searched MEDLINE, EMBASE, Web of Science, and Scopus from database inception through June 2018. Articles were eligible for inclusion if they examined the effect of bariatric surgery on male sex hormones and sperm parameters in patients with obesity. Primary outcomes of interest were sex hormones and sperm quality. Secondary outcome was sexual function (International Index of Erectile Function (IIEF) score). Pooled estimates were calculated using random effects meta-analysis. A total of 28 cohort studies with 1022 patients were identified from 3896 potentially relevant citations. Both free and calculated testosterone levels were significantly increased after bariatric surgery (mean difference (MD) - 7.47 nM, 95% CI - 8.62 to - 6.31, p < 0.001 and MD - 0.05 nM, 95% CI - 0.07 to - 0.02, p < 0.001, respectively). Consistent with the increase in testosterone, LH, FSH, and SHBG levels were also significantly increased after surgery. In contrast, free and total estradiol and prolactin levels were significantly decreased after bariatric surgery. From studies that reported the IIEF score, bariatric surgery led to a significant increase in erectile function after surgery (MD - 0.46, 95% CI - 0.89 to - 0.02, p = 0.04). However, bariatric surgery did not affect sperm quality, DHEA, androstenedione, and inhibin B levels. Sustained weight-loss induced by bariatric surgery had a significant effect on increasing male sex hormones and decreasing female sex hormones in male patients with obesity. However, sperm quality and function were not improved after surgery.

Indocyanine green for the prevention of anastomotic leaks following esophagectomy: a meta-analysis.

BACKGROUND: Intraoperative evaluation with fluorescence angiography using indocyanine green (ICG) offers a dynamic assessment of gastric conduit perfusion and can guide anastomotic site selection during an esophagectomy. This study aims to evaluate the predictive value of ICG for the prevention of anastomotic leak following esophagectomy. METHODS: A comprehensive search of electronic databases using the search terms "indocyanine/fluorescence" AND esophagectomy was completed to include all English articles published between January 1946 and 2018. Articles were selected by two independent reviewers. The quality of included studies was assessed using the Methodological Index for Non-Randomized Studies (MINORS) instrument. RESULTS: Seventeen studies were included for meta-analysis after screening and exclusions. The pooled anastomotic leak rate when ICG was used was found to be 10%. When limited to studies without intraoperative modifications, the pooled sensitivity, specificity, and diagnostic odds ratio were 0.78 (95% CI 0.52-0.94; p = 0.089), 0.74 (95% CI 0.61-0.84; p = 0.012), and 8.94 (95% CI 1.24-64.21; p = 0.184), respectively. Six trials compared ICG with an intraoperative intervention to improve perfusion to no ICG. ICG with intervention was found to have a risk reduction of 69% (OR 0.31, 95% CI 0.15-0.63). CONCLUSIONS: In non-randomized trials, the use of ICG as an intraoperative tool for visualizing microvascular perfusion and conduit site selection to decrease anastomotic leaks is promising. However, poor data quality and heterogeneity in reported variables limits generalizability of findings. Randomized, multi-center trials are needed to account for independent risk factors for leak rates and to better elucidate the impact of ICG in predicting and preventing anastomotic leaks.

Diagnostic evaluation of sentinel lymph node biopsy using indocyanine green and infrared or fluorescent imaging in gastric cancer: a systematic review and meta-analysis.

BACKGROUND: Sentinel node navigation surgery (SNNS) for gastric cancer using infrared visualization of indocyanine green (ICG) is intriguing because it may limit operative morbidity. We are the first to systematically review and perform meta-analysis on the diagnostic utility of ICG and infrared electronic endoscopy (IREE) or near infrared fluorescent imaging (NIFI) for SNNS exclusively in gastric cancer. METHODS: A search of electronic databases MEDLINE, EMBASE, SCOPUS, Web of Science, and the Cochrane Library using search terms "gastric/stomach" AND "tumor/carcinoma/cancer/neoplasm/adenocarcinoma/malignancy" AND "indocyanine green" was completed in May 2017. Articles were selected by two independent reviewers based on the following major inclusion criteria: (1) diagnostic accuracy study design; (2) indocyanine green was injected at tumor site; (3) IREE or NIFI was used for intraoperative visualization. 327 titles or abstracts were screened. The quality of included studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2. RESULTS: Ten full text studies were selected. 643 patients were identified with the majority of patients possessing T1 tumors (79.8%). Pooled identification rate, diagnostic odds ratio, sensitivity, and specificity were 0.99 (0.97-1.0), 380.0 (68.71-2101), 0.87 (0.80-0.93), and 1.00 (0.99-1.00), respectively. The summary receiver operator characteristic for ICG + IREE/NIFI demonstrated a test accuracy of 98.3%. Subgroup analysis found improved test performance for studies with low-risk QUADAS-2 scores, studies published after 2010 and submucosal ICG injection. IREE had improved diagnostic odds ratio, sensitivity, and identification rate compared to NIFI. Heterogeneity among studies ranged from low (I2 < 25%) to high (I2 > 75%). CONCLUSIONS: We found encouraging results regarding the accuracy, diagnostic odds ratio, and specificity of the test. The sensitivity was not optimal but may be improved by a strict protocol to augment the technique. Given the number and heterogeneity of studies, our results must be viewed with caution.

The role of antibiotics in acute uncomplicated diverticulitis: A systematic review and meta-analysis.

BACKGROUND: Antibiotics use in acute uncomplicated diverticulitis (AUD) remains debated despite recent studies suggesting no difference in outcomes for patients treated without antibiotics. DATA SOURCES: Systematic review and meta-analysis were performed to determine the role of antibiotics in managing AUD. Literature search was conducted using Medline, EMBASE, Scopus, the Cochrane Library, and Web of Science databases from 1946 to June 2017. Eight studies with 2469 patients were included for review. Overall complication rates were not statistically significant between groups (OR 0.72; CI 0.45 to 1.16; P = 0.18), but antibiotic use was associated with a longer length of stay in hospital. Subgroup analysis revealed no difference in readmission rates, treatment failure rates, progression to complicated diverticulitis, or increased need for elective or emergent surgery between study groups. CONCLUSIONS: Antibiotic use in patients with AUD increases length of hospital stay but is not associated with a reduction in overall or individual complication rates.

Trapping of BMP receptors in distinct membrane domains inhibits their function in pulmonary arterial hypertension.

Bone morphogenetic proteins (BMPs) are pleiotrophic growth factors that influence diverse processes such as skeletal development, hematopoiesis, and neurogenesis. They play crucial roles in diseases such as pulmonary arterial hypertension (PAH). In PAH, mutants of the BMP type II receptors (BMPR2) were detected, and their functions were impaired during BMP signaling. It is thought that expression levels of these receptors determine the fate of BMP signaling, with low levels of expression leading to decreased Smad activation in PAH. However, our studies demonstrate, for the first time, that the localization of receptors on the plasma membrane, in this case BMPR2, was misdirected. Three BMPR2 mutants, D485G, N519K, and R899X, which are known to be involved in PAH, were chosen as our model system. Our results show that all three BMPR2 mutants decreased BMP-dependent Smad phosphorylation and Smad signaling. Although the three mutants reached the cell membrane and their expression was lower than that of BMPR2, they formed smaller clusters and associated differently with membrane domains, such as caveolae and clathrin-coated pits. The disruption of these domains restored the Smad signaling of D485G and N519K to the level of wild-type BMPR2, showing that these mutants were trapped in the domains, rather than just expressed at a lower level on the surface. Therefore, new treatment options for PAH should also target receptor localization, rather than just expression level.

Fungal surface remodelling visualized by atomic force microscopy.

Most fungal growth is localized to the tips of hyphae, however, early stages of spore germination and the growth of certain morphological mutant strains exhibit non-polarized expansion. We used atomic force microscopy (AFM) to document changes in Aspergillus nidulans wall surfaces during non-polarized growth: spore germination, and growth in a strain containing the hypA1 temperature sensitive morphogenesis defect. We compared wall surface structures of both wild-type and mutant A. nidulans following growth at 28 degrees and 42 degrees C, the latter being the restrictive temperature for hypA1. There was no appreciable difference in surface ultrastructure between wild-type and hypA1 spores, or hyphal walls grown at 28 degrees C. When dry mature A. nidulans conidia were wetted they lost their hydrophobin coat, indicating an intermediate stage between dormancy and swelling. The surface structure of hypA1 germlings grown at 42 degrees C was less organized than wild-type hyphae grown under the same conditions, and had a larger range of subunit sizes. AFM images of hyphal wall surface changes following a shift in growth temperature from restrictive (42 degrees C) to permissive (28 degrees C), showed a gradient of sizes for wall surface features similar to the trend observed for wild-type cells at branch points. Changes associated with the hyphal wall structure for A. nidulans hypA1 offer insight into the events associated with fungal germination, and wall remodelling.

Electrostatic interactions of colicin E1 with the surface of Escherichia coli total lipid.

The surface properties of colicin E1, a 522-amino acid protein, and its interaction with monolayers of Escherichia coli (E. coli) total lipid and 1,2-Dimyristoyl-sn-Glycero-3-Phosphocholine (DOPC) were studied using the Langmuir-Blodgett (LB) technique. Colicin E1 is amphiphilic, forming a protein monolayer at the air/buffer interface. The protein is thought to interact with the E. coli total lipid head groups through electrostatic interactions, followed by its insertion into the lipid monolayers. Supported lipid bilayers (SLBs) of E. coli total lipid and DOPC, deposited onto mica at the cell membrane equivalence pressure for E. coli and incubated with colicin E1, were imaged by contact mode atomic force microscopy (CM-AFM). Colicin E1 formed protein aggregates on DOPC SLBs, while E. coli total lipid SLB was deformed following its incubation with colicin E1. Corresponding lateral force images, along with electrostatic surface potentials for colicin E1 P190, imply a direct interaction of colicin E1 with lipid head groups facilitating their charge neutralization.

Mesoscopic organization of two-dimensional J-aggregates of thiacyanine in Langmuir-Schaefer films.

When dioctadecyl dimethylammonium bromide (DODAB) is compressed on a subphase containing 3,3'-disulfopropyl-5,5'-dichlorothiacyanine (THIAMS), adsorption of the dye to the DODAB monolayer results in the formation of J-aggregates which spontaneously organize into polygonal domains of micron size. The features of the domains depend on the surface pressure. The fluorescence of the individual domains is polarized. The shapes of the domains determined by fluorescence microscopy and atomic force microscopy (AFM) are identical. The domains differ however significantly from those observed after injection of a 3,3'-disulfopropyl-5,5'-dichloro-9-ethylthiacarbocyanine (THIATS) or THIAMS solution below a precompressed DODAB film, as well as from the domains observed upon compression of a DODAB monolayer on a subphase containing 10(-6) M THIATS.