Gamma-D crystallin gene (CRYGD) mutation causes autosomal dominant congenital cerulean cataracts

Congenital cataracts are a major cause of bilateral visual impairment in childhood. We mapped the gene responsible for autosomal congenital cerulean cataracts to chromosome 2q33-35 in a four generation family of Moroccan descent. The maximum lod score (7.19 at recombination fraction theta=0) was obtained for marker D2S2208 near the g-crystallin gene (CRYG) cluster. Sequencing of the coding regions of the CRYGA, B, C, and D genes showed the presence of a heterozygous C>A transversion in exon 2 of CRYGD that is associated with cataracts in this family. This mutation resulted in a proline to threonine substitution at amino acid 23 of the protein in the first of the four Greek key motifs that characterise this protein. We show that although the x ray crystallography modelling does not indicate any change of the backbone conformation, the mutation affects a region of the Greek key motif that is important for determining the topology of this protein fold. Our data suggest strongly that the proline to threonine substitution may alter the protein folding or decrease the thermodynamic stability or solubility of the protein. Furthermore, this is the first report of a mutation in this gene resulting in autosomal dominant congenital cerulean cataracts

PERFORMANCE ANALYSIS OF OPTICAL CDMA SYSTEM USING VC CODE FAMILY UNDER VARIOUS OPTICAL PARAMETERS

The intent of this paper is to study the performance of spectral-amplitude coding optical code-division multiple-access (OCDMA) systems using Vector Combinatorial (VC) code under various optical parameters. This code can be constructed by an algebraic way based on Euclidian vectors for any positive integer number. One of the important properties of this code is that the maximum cross-correlation is always one which means that multi-user interference (MUI) and phase induced intensity noise are reduced. Transmitter and receiver structures based on unchirped fiber Bragg grating (FBGs) using VC code and taking into account effects of the intensity, shot and thermal noise sources is demonstrated. The impact of the fiber distance effects on bit error rate (BER) is reported using a commercial optical systems simulator, virtual photonic instrument, VPITM. The VC code is compared mathematically with reported codes which use similar techniques. We analyzed and characterized the fiber link, received power, BER and channel spacing. The performance and optimization of VC code in SAC-OCDMA system is reported. By comparing the theoretical and simulation results taken from VPITM, we have demonstrated that, for a high number of users, even if data rate is higher, the effective power source is adequate when the VC is used. Also it is found that as the channel spacing width goes from very narrow to wider, the BER decreases, best performance occurs at a spacing bandwidth between 0.8 and 1 nm. We have shown that the SAC system utilizing VC code significantly improves the performance compared with the reported codes

Laser Doppler Electrophoresis and electro-osmotic flow mapping: A novel methodology for the determination of membrane surface zeta potential

A novel technique employing an Uzigirs dip cell arrangement is used in conjunction with Laser Doppler Electrophoresis for the determination of the surface zeta potential for a UF, NF, and RO membrane. To the authors best knowledge this is the first study employing Laser Doppler Electrophoresis and Electro-osmotic Flow Mapping for membrane surface charge determination. High correlation of the regression fit (R2>0.95) for a carboxylated polystyrene latex particle electrophoretic mobility was achieved at low electrolyte concentrations (1mM and 10mM NaCl), but the reliability and accuracy of the extrapolated zeta potential values were problematic at higher concentration due to high measurement uncertainty (>10% in some cases). Changes in the applied electric field increased the phase resolution of 50mM NaCl electrolyte solutions between 0.5-2.0V. However, the effects of Joule heating at higher voltages compromised 50mM NaCl sample integrity. When compared with the established Tangential Streaming Potential method, Laser Doppler Electrophoresis measurements provided similar zeta potential values and trends indicating that this new methodology can indeed be employed for membrane characterization purposes; however, further research needs to be conducted in order to optimize this new technique and set appropriate operating limits

Laparoscopic radical 'no-touch' left pancreatosplenectomy for pancreatic ductal adenocarcinoma: technique and results

Background Laparoscopic left pancreatectomy has been well described for benign pancreatic lesions, but its role in pancreatic adenocarcinoma remains open to debate. We report our results adopting a laparoscopic technique that obeys established oncologic principles of open distal pancreatosplenectomy. Methods This is a post hoc analysis of a prospectively kept database of 135 consecutive patients undergoing laparoscopic left pancreatectomy, performed across two sites in the UK and the Netherlands (07/2007–07/2015 Southampton and 10/2013–07/2015 Amsterdam). Primary outcomes were resection margin and lymph node retrieval. Secondary endpoints were other perioperative outcomes, including post-operative pancreatic fistula. Definition of radical resection was distance tumour to resection margin >1 mm. All patients underwent ‘laparoscopic radical left pancreatosplenectomy’ (LRLP) which involves ‘hanging’ the pancreas including Gerota’s fascia, followed by clockwise dissection, including formal lymphadenectomy. Results LRLP for pancreatic adenocarcinoma was performed in 25 patients. Seven of the 25 patients (28 %) had extended resections, including the adrenal gland (n = 3), duodenojejunal flexure (n = 2) or transverse mesocolon (n = 3). Mean age was 68 years (54–81). Conversion rate was 0 %, mean operative time 240 min and mean blood loss 340 ml. Median intensive/high care and hospital stay were 1 and 5 days, respectively. Clavien–Dindo score 3+ complication rate was 12 % and ISGPF grade B/C pancreatic fistula rate 28 %; 90-day (or in-hospital) mortality was 0 %. The pancreatic resection margin was clear in all patients, and the posterior margin was involved (<1 mm) in 6 patients, meaning an overall R0 resection rate of 76 %. No resection margin was microscopically involved. Median nodal sample was 15 nodes (3–26). With an average follow-up of 17.2 months, 1-year survival was 88 %. Conclusions A standardised laparoscopic approach to pancreatic adenocarcinoma in the left pancreas can be adopted safely. Our study shows that these results can be reproduced across multiple sites using the same technique

Robotic Pancreatoduodenectomy: Patient Selection, Volume Criteria, and Training Programs

INTRODUCTION: There has been a rapid development in minimally invasive pancreas surgery in recent years. The most recent innovation is robotic pancreatoduodenectomy. Several studies have suggested benefits as compared to the open or laparoscopic approach. This review provides an overview of studies concerning patient selection, volume criteria, and training programs for robotic pancreatoduodenectomy and identified knowledge gaps regarding barriers for safe implementation of robotic pancreatoduodenectomy. MATERIALS AND METHODS: A Pubmed search was conducted concerning patient selection, volume criteria, and training programs in robotic pancreatoduodenectomy. RESULTS: A total of 20 studies were included. No contraindications were found in patient selection for robotic pancreatoduodenectomy. The consensus and the Miami guidelines advice is a minimum annual volume of 20 robotic pancreatoduodenectomy procedures per center, per year. One training program was identified which describes superior outcomes after the training program and shortening of the learning curve in robotic pancreatoduodenectomy. CONCLUSION: Robotic pancreatoduodenectomy is safe and feasable for all indications when performed by specifically trained surgeons working in centers who can maintain a minimum volume of 20 robotic pancreatoduodenectomy procedures per year. Large proficiency-based training program for robotic pancreatoduodenectomy seem essential to facilitate a safe implementation and future research on robotic pancreatoduodenectomy

Impact of COVID-19 on the oncological outcomes of colorectal cancer surgery in northern Italy in 2019 and 2020: multicentre comparative cohort study

BACKGROUND: This study compared patients undergoing colorectal cancer surgery in 20 hospitals of northern Italy in 2019 versus 2020, in order to evaluate whether COVID-19-related delays of colorectal cancer screening resulted in more advanced cancers at diagnosis and worse clinical outcomes. METHOD: This was a retrospective multicentre cohort analysis of patients undergoing colorectal cancer surgery in March to December 2019 versus March to December 2020. Independent predictors of disease stage (oncological stage, associated symptoms, clinical T4 stage, metastasis) and outcome (surgical complications, palliative surgery, 30-day death) were evaluated using logistic regression. RESULTS: The sample consisted of 1755 patients operated in 2019, and 1481 in 2020 (both mean age 69.6 years). The proportion of cancers with symptoms, clinical T4 stage, liver and lung metastases in 2019 and 2020 were respectively: 80.8 versus 84.5 per cent; 6.2 versus 8.7 per cent; 10.2 versus 10.3 per cent; and 3.0 versus 4.4 per cent. The proportions of surgical complications, palliative surgery and death in 2019 and 2020 were, respectively: 34.4 versus 31.9 per cent; 5.0 versus 7.5 per cent; and 1.7 versus 2.4 per cent. Cancers in 2020 (versus 2019) were more likely to be symptomatic (odds ratio 1.36 (95 per cent c.i. 1.09 to 1.69)), clinical T4 stage (odds ratio 1.38 (95 per cent c.i. 1.03 to 1.85)) and have multiple liver metastases (odds ratio 2.21 (95 per cent c.i. 1.24 to 3.94)), but were not more likely to be associated with surgical complications (odds ratio 0.79 (95 per cent c.i. 0.68 to 0.93)). CONCLUSION: Colorectal cancer patients who had surgery between March and December 2020 had an increased risk of advanced disease in terms of associated symptoms, cancer location, clinical T4 stage and number of liver metastases

New class of inhibitors of amyloid-beta fibril formation. Implications for the mechanism of pathogenesis in Alzheimer's disease

The amyloid hypothesis suggests that the process of amyloid-beta protein (Abeta) fibrillogenesis is responsible for triggering a cascade of physiological events that contribute directly to the initiation and progression of Alzheimer's disease. Consequently, preventing this process might provide a viable therapeutic strategy for slowing and/or preventing the progression of this devastating disease. A promising strategy to achieve prevention of this disease is to discover compounds that inhibit Abeta polymerization and deposition. Herein, we describe a new class of small molecules that inhibit Abeta aggregation, which is based on the chemical structure of apomorphine. These molecules were found to interfere with Abeta1-40 fibrillization as determined by transmission electron microscopy, Thioflavin T fluorescence and velocity sedimentation analytical ultracentrifugation studies. Using electron microscopy, time-dependent studies demonstrate that apomorphine and its derivatives promote the oligomerization of Abeta but inhibit its fibrillization. Preliminary structural activity studies demonstrate that the 10,11-dihydroxy substitutions of the D-ring of apomorphine are required for the inhibitory effectiveness of these aporphines, and methylation of these hydroxyl groups reduces their inhibitory potency. The ability of these small molecules to inhibit Abeta amyloid fibril formation appears to be linked to their tendency to undergo rapid autoxidation, suggesting that autoxidation product(s) acts directly or indirectly on Abeta and inhibits its fibrillization. The inhibitory properties of the compounds presented suggest a new class of small molecules that could serve as a scaffold for the design of more efficient inhibitors of Abeta amyloidogenesis in vivo

Gemcitabine-Based Neoadjuvant Treatment in Borderline Resectable Pancreatic Ductal Adenocarcinoma: A Meta-Analysis of Individual Patient Data

Background: Non-randomized studies have investigated multi-agent gemcitabinebased neo-adjuvant therapies (GEM-NAT) in borderline resectable pancreatic ductal adenocarcinoma (BR-PDAC). Treatment sequencing and specific elements of neoadjuvant treatment are still under investigation. The present meta-analysis aims to assess the effectiveness of GEM-NAT on overall survival (OS) in BR-PDAC. Patients and Methods: A meta-analysis of individual participant data (IPD) on GEMNAT for BR-PDAC were performed. The primary outcome was OS after treatment with GEM-based chemotherapy. In the Individual Patient Data analysis data were reappraised and confirmed as BR-PDAC on provided radiological data. Results: Six studies investigating GEM-NAT were included in the IPD metanalysis. The IPD metanalysis was conducted on 271 patients who received GEM-NAT. Pooled median patient-level OS was 22.2 months (95%CI 19.1–25.2). R0 rates ranged between 81 and 95% (I 2 = 0%, p = 0.64), respectively. Median OS was 27.8 months (95%CI 23.9–31.6) in the patients who received NAT-GEM followed by resection compared to 15.4 months (95%CI 12.3–18.4) for NAT-GEM without resection and 13.0 months (95%CI 7.4–18.5) in the group of patients who received upfront surgery (p < 0.0001). R0 rates ranged between 81 and 95% (I 2 = 0%, p = 0.64), respectively. Overall survival in the R0 group was 29.3 months (95% CI 24.3–34.2) vs. 16.2 months (95% CI 7·9–24.5) in the R1 group (p = 0·001). Conclusions: The present study is the first meta-analysis combining IPD from a number of international centers with BR-PDAC in a cohort that underwent multi-agent gemcitabine neoadjuvant therapy (GEM-NAT) before surgery. GEM-NAT followed by surgical resection improve sur