A Thioether-Ligated Cupric Superoxide Model with Hydrogen Atom Abstraction Reactivity.

The central role of cupric superoxide intermediates proposed in hormone and neurotransmitter biosynthesis by noncoupled binuclear copper monooxygenases like dopamine-ß-monooxygenase has drawn significant attention to the unusual methionine ligation of the CuM ("CuB") active site characteristic of this class of enzymes. The copper-sulfur interaction has proven critical for turnover, raising still-unresolved questions concerning Nature's selection of an oxidizable Met residue to facilitate C-H oxygenation. We describe herein a model for CuM, [(TMGN3S)CuI]+ ([1]+), and its O2-bound analog [(TMGN3S)CuII(O2•-)]+ ([1·O2]+). The latter is the first reported cupric superoxide with an experimentally proven Cu-S bond which also possesses demonstrated hydrogen atom abstraction (HAA) reactivity. Introduction of O2 to a precooled solution of the cuprous precursor [1]B(C6F5)4 (-135 °C, 2-methyltetrahydrofuran (2-MeTHF)) reversibly forms [1·O2]B(C6F5)4 (UV/vis spectroscopy: λmax 442, 642, 742 nm). Resonance Raman studies (413 nm) using 16O2 [18O2] corroborated the identity of [1·O2]+ by revealing Cu-O (446 [425] cm-1) and O-O (1105 [1042] cm-1) stretches, and extended X-ray absorption fine structure (EXAFS) spectroscopy showed a Cu-S interatomic distance of 2.55 Å. HAA reactivity between [1·O2]+ and TEMPO-H proceeds rapidly (1.28 × 10-1 M-1 s-1, -135 °C, 2-MeTHF) with a primary kinetic isotope effect of kH/kD = 5.4. Comparisons of the O2-binding behavior and redox activity of [1]+ vs [2]+, the latter a close analog of [1]+ but with all N atom ligation (i.e., N3S vs N4), are presented.

Benign postoperative hepaticojejunostomy stricture: percutaneous recanalisation using the reverse end of a microwire.

AIM: To evaluate the technical feasibility and safety of percutaneous recanalisation of benign postoperative hepaticojejunostomy strictures using the reverse end of a microwire. MATERIALS AND METHODS: Twenty-one patients with benign postoperative hepaticojejunostomy strictures that had failed to recanalise following management with conventional percutaneous techniques from January 2012 to March 2019 were included in the study. The stricture was punctured by the reverse end of a microwire. Subsequently, serial balloon dilatation and covered stent placement was performed. Technical as well as clinical success, complications, and patency of the hepaticojejunostomy were evaluated. RESULTS: Technical success was achieved in 19 of 21 (90.5%) patients. The mean number of treatment sessions was 1.2 (range, 1-2). The obstructive symptoms were resolved within 3 days after the procedure in 19 patients (100%). There were no major complications. The 1-year and 3-year patency rates were 76.9% and 61.5%, respectively. CONCLUSION: Percutaneous recanalisation using the reverse end of a microwire is technically feasible and safe in the treatment of benign postoperative hepaticojejunostomy strictures. This technique is useful when the conventional percutaneous technique cannot be used to cross the stricture.

Misdiagnosis of community-acquired pneumonia in patients admitted to respiratory wards, Penang General Hospital.

INTRODUCTION: Pneumonia continues to be as one of the top causes of hospitalisations and deaths in Malaysia despite the advancement in prevention and treatment of pneumonia. One of the possible explanations is the frequent misdiagnosis of pneumonia which had been reported elsewhere but such data is not available locally. OBJECTIVES: This is an audit project aiming to evaluate the proportion of misdiagnosis among hospitalised communityacquired pneumonia (CAP) patients in the Respiratory wards of Penang General Hospital based on their initial presentation data, and their associated outcomes. METHODS: We reviewed the medical notes and initial chest radiographs of 188 CAP patients who were admitted to respiratory wards. Misdiagnosis was defined as cases which lack suggestive clinical features and/or chest radiograph changes. In-hospital mortality and length of stay (LOS) were the outcomes of interest. RESULTS: The study found that 38.8% (n=73) of the hospitalised CAP patients were misdiagnosed. The most common alternative diagnosis was upper respiratory tract infection (32.8%, n=24). There was no statistical difference between misdiagnosis and CAP patients in the demographic and clinical variables collected. In terms of outcomes, misdiagnosed patients were discharged earlier (mean LOS= 3.5±3.28 days vs. 7.7±15.29 days, p=0.03) but the in-hospital mortality difference was not statistically significant (p=0.07). CONCLUSIONS: One third of our CAP admissions were misdiagnosed. Although initial misdiagnosis of CAP in our study did not show any increase in mortality or morbidity, a proper diagnosis of CAP will be helpful in preventing inappropriate prescription of antibiotics and unnecessary admission.

Development and validation of a staging system for gastric adenocarcinoma after neoadjuvant chemotherapy and gastrectomy with D2 lymphadenectomy.

BACKGROUND: Neoadjuvant chemotherapy followed by gastrectomy with D2 lymphadenectomy is commonly used for patients with locally advanced gastric adenocarcinoma. The eighth AJCC ypTNM staging system was validated based on patients undergoing more limited lymphadenectomy (less than D2). The aim of this study was to develop a system for accurate staging of patients with locally advanced gastric adenocarcinoma who receive neoadjuvant chemotherapy followed by gastrectomy with D2 lymphadenectomy. METHODS: A modified system of ypTNM was developed, based on overall survival (OS) of patients receiving neoadjuvant chemotherapy followed by gastrectomy with D2 lymphadenectomy at Memorial Sloan Kettering Cancer Center, and validated using data from an international cohort of patients who had similar treatment. RESULTS: Of 325 patients in the derivation cohort, 33 (10·2 per cent) had ypT0 N0/+ tumours, which are not classifiable under the AJCC system. The 5-year OS rate for modified ypTNM stages I, II, IIIA and IIIB was 89, 71, 42·3 and 10 per cent respectively, compared with 82, 65·2 and 24·1 for AJCC stages I, II and III respectively. The concordance index (0·730 versus 0·709), estimated area under the curve (0·765 versus 0·740) and time-dependent receiver operating characteristic (ROC) curve throughout the observation period were all superior for modified ypTNM staging. For the validation cohort of 186 patients, the modified system was again better at separating patients into prognostic groups for OS. CONCLUSION: The modified ypTNM staging system improves the accuracy of OS prediction for patients treated with neoadjuvant chemotherapy followed by gastrectomy with D2 lymphadenectomy.

Intramolecular Hydrogen Bonding Enhances Stability and Reactivity of Mononuclear Cupric Superoxide Complexes.

[(L)CuII(O2•-)]+ (i.e., cupric-superoxo) complexes, as the first and/or key reactive intermediates in (bio)chemical Cu-oxidative processes, including in the monooxygenases PHM and DßM, have been systematically stabilized by intramolecular hydrogen bonding within a TMPA ligand-based framework. Also, gradual strengthening of ligand-derived H-bonding dramatically enhances the [(L)CuII(O2•-)]+ reactivity toward hydrogen-atom abstraction (HAA) of phenolic O-H bonds. Spectroscopic properties of the superoxo complexes and their azido analogues, [(L)CuII(N3-)]+, also systematically change as a function of ligand H-bonding capability.

Percutaneous stent placement for malignant hilar biliary obstruction: a comparison between criss-cross and T-configuration techniques.

AIM: To compare the clinical effectiveness of percutaneous stent placement between T and criss-cross configuration techniques in patients with advanced malignant hilar biliary obstruction. MATERIALS AND METHODS: Between January 2009 and December 2014, 59 patients who underwent percutaneous stent placement for malignant hilar obstruction were included in this retrospective study. T-configured stent placement (T group) was performed in 33 patients and criss-cross configured stent placement (criss-cross group) in 26 patients. Technical and clinical success, complications, patient survival, and stent patency were compared between the two groups. RESULTS: Stent placement was technically successful in all patients of the two groups. Clinical success was achieved in 30 (90.9%) patients of T group and 25 (96.9%) of criss-cross group (p=0.62). Two patients in the T group (6.1%) required additional stent placement for internal drainage of undrained sector. There were no major complications. Median survival was not statistically different between the two groups (128 days in the T group versus 183 days in the criss-cross group; p=0.33). Stent occlusion occurred in 15 patients in the T group and seven patients in the criss-cross group. The stent patency of the criss-cross group (median 330 days) was longer than that of the T group (median 132 days; p=0.0007). CONCLUSIONS: Early clinical effectiveness is comparable between the two techniques; however, additional intervention is occasionally required for drainage of an undrained sector after T-configured stent placement. Stent placement with criss-cross configuration provides longer stent patency than T-configuration technique.

Steering and control of miniaturized untethered soft magnetic grippers with haptic assistance.

Untethered miniature robotics have recently shown promising results in several scenarios at the microscale, such as targeted drug delivery, microassembly, and biopsy procedures. However, the vast majority of these small-scale robots have very limited manipulation capabilities, and none of the steering systems currently available enable humans to intuitively and effectively control dexterous miniaturized robots in a remote environment. In this paper, we present an innovative micro teleoperation system with haptic assistance for the intuitive steering and control of miniaturized self-folding soft magnetic grippers in 2-D space. The soft grippers can be wirelessly positioned using weak magnetic fields and opened/closed by changing their temperature. An image-guided algorithm tracks the position of the controlled miniaturized gripper in the remote environment. A haptic interface provides the human operator with compelling haptic sensations about the interaction between the gripper and the environment, as well as enables the operator to intuitively control the target position and grasping configuration of the gripper. Finally, magnetic and thermal control systems regulate the position and grasping configuration of the gripper. The viability of the proposed approach is demonstrated through two experiments involving 26 human subjects. Providing haptic stimuli elicited statistically significant improvements in the performance of the considered navigation and micromanipulation tasks. Note to Practitioners-The ability to accurately and intuitively control the motion of miniaturized grippers in remote environments can open new exciting possibilities in the fields of minimally-invasive surgery, micromanipulation, biopsy, and drug delivery. This paper presents a micro teleoperation system with haptic assistance through which a clinician can easily control the motion and open/close capability of miniaturized wireless soft grippers. It introduces the underlying autonomous magnetic and thermal control systems, their interconnection with the master haptic interface, and an extensive evaluation in two real-world scenarios: following of a predetermined trajectory, and pick-and-place of a microscopic object.

Presentation of available CTL epitopes that induction of cell-mediated immune response against HIV-1 Koran clade B strain using computational technology.

OBJECTIVE: Theoretical predicting cytotoxic T lymphocyte (CTL) epitopes are an important tool in vaccine design and CTL therapy for enhancing our understanding of the cellular immune system. We would like to identify available CTL epitopes against HIV-1 Korean clade B. CTL activity was assessed in freshly isolated peripheral blood mononuclear cells from Korean HIV patients in order to assess whether these CTL epitopes induce a cell-mediated immune response (CMI). METHODS: NetCTLpan1.1 software, which is the most popular prediction computer software package, and full atom-based simulation (FABS), which is a 3D modelling system for binding activity between epitopes and human leucocyte antigen (HLA) molecules, were used to predict the peptide-spanning Env region binding to HLA-A*24:02, HLA-A*02:01 and HLA-B*15:01, which are frequently found in the Korean population. Granzyme B and interferon-γ ELISPOT assays were used to determine whether identified CTL epitopes induce CMI. RESULTS: Three HIV-1 Korean clade B-specific Env CTL epitopes were identified: Gp41-RYL and Gp41-RQG are localized within gp41, and Gp120-LLQ within gp120. In in vitro assays using granzyme B ELISPOT, Gp120-LLQ and Gp41-RQG induced epitope-specific CTL responses in HLA-restricted cells. In ex vivo assay using IFN-γ ELISPOT, cell-mediated immune responses to Gp41-RYL were present in 50% of HLA-matched patients, and responses to Gp120-LLQ and Gp41-RQG were found in 33% of HLA-matched patients. CONCLUSION: In this study, we found that a prediction pipeline for CTL epitopes might be based on the most popular computer prediction software and FABS methods. Our results suggest that these CTL epitopes may provide useful tools and information for the development of a therapeutic vaccine against HIV-1 Korean clade B.

Hypoxia-activated chemotherapeutic TH-302 enhances the effects of VEGF-A inhibition and radiation on sarcomas.

BACKGROUND: Human sarcomas with a poor response to vascular endothelial growth factor-A (VEGF-A) inhibition and radiation therapy (RT) have upregulation of hypoxia-inducible factor 1α (HIF-1α) and HIF-1α target genes. This study examines the addition of the hypoxia-activated chemotherapy TH-302 to VEGF-A inhibition and RT (a.k.a. trimodality therapy). METHODS: Trimodality therapy was examined in two xenograft models and in vitro in tumour endothelial cells and sarcoma cell lines. RESULTS: In both mouse models, VEGF-A inhibition and radiation showed greater efficacy than either therapy alone in slowing sarcoma growth. When TH-302 was added, this trimodality therapy completely blocked tumour growth with tumours remaining dormant for over 3 months after cessation of therapy. Trimodality therapy caused 2.6- to 6.2-fold more endothelial cell-specific apoptosis than bimodality therapies, and microvessel density and HIF-1α activity were reduced to 11-13% and 13-20% of control, respectively. When trimodality therapy was examined in vitro, increases in DNA damage and apoptosis were much more pronounced in tumour endothelial cells compared with that in sarcoma cells, especially under hypoxia. CONCLUSIONS: The combination of TH-302, VEGF-A inhibition, and RT is highly effective in preclinical models of sarcoma and is associated with increased DNA damage and apoptosis in endothelial cells and decreased HIF-1α activity.

Identification of a new HLA-A*24 allele, A*24:313.

The new allele, A*24:313, showed one nucleotide difference with A*24:02:01 (595G>A).

A new HLA-B*15 allele, HLA-B*15:263, identified in a Korean individual.

HLA-B*15:263 differs from HLA-B*15:18:01 by a single nucleotide exchange at position 824, C>G (codon 251 TCT>TGT).

Identification of a novel HLA-B*15 variant, B*15:367, using sequence-based typing in a Korean woman.

New allele, B*15:367, differs from B*15:11:01 by a single nucleotide exchange at codon 222 (GAG→AAG).

Identification of the novel allele, HLA-C*15:02:01:03, by full-length genomic sequencing.

The HLA-C*15:02:01:03 allele differs from the HLA-C*15:02:01:01 allele by a single-nucleotide substitution in the 5' untranslated region (-42 C>A).

Fluoroscopy-guided radiofrequency ablation for small hepatocellular carcinoma: a retrospective comparison with ultrasound-guided ablation.

AIM: To compare the therapeutic efficacy of fluoroscopy-guided radiofrequency ablation (F-RFA) and ultrasound-guided RFA (US-RFA) in treatment of small hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Between January 2006 and January 2012, 93 patients with small HCCs underwent percutaneous RFA. In 42 patients with 46 HCCs invisible on US, F-RFA was performed following intra-arterial iodised oil injection (group A). The remaining 51 patients with 58 HCCs received US-RFA (group B). Technical effectiveness, complications, local tumour progression, and patient survival were retrospectively compared between the two groups. RESULTS: Technical effectiveness was achieved in 45 HCCs of group A (97.8%) and 64 HCCs of group B (96.6%; p=0.65). There was no major complication in either group. The 1-, 3-, and 5-year local tumour progression rates were lower in group A than those of group B with marginal significance (0%, 3.7% and 3.7% in group A, and 13%, 13%, and 13% in group B; p=0.05). The 1-, 3-, and 5-year patient survival rates were 100%, 58.3%, and 51.2% (group A), and 82.4%, 54.9%, and 46.1% (group B; p=0.26). CONCLUSIONS: F-RFA is a feasible and safe treatment for small HCC invisible on US. Its therapeutic efficacy was comparable with that of US-RFA.

A new HLA-A*30 allele, A*30:81, identified by sequence-based typing.

The new allele, HLA-A*30:81, differs from A*30:01:01 by one nucleotide substitution at codon 272 (CTG→ATG).

A new HLA-C allele, C*06:99, identified by sequence-based typing in a Korean individual.

The C*06:99 allele substitutes one nucleotide of C*06:02:01:01 at codon 50 (CCG→CTG), Pro to Leu.

Spatial propagation of protein polymerization.

We consider the spatial dependence of filamentous protein self-assembly. Through studying the cases where the spreading of aggregated material is dominated either by diffusion or by growth, we derive analytical results for the spatial evolution of filamentous protein aggregation, which we validate against Monte Carlo simulations. Moreover, we compare the predictions of our theory with experimental measurements of two systems for which we identify the propagation as either growth or diffusion controlled. Our results connect the macroscopic observables that characterize the spatial propagation of protein self-assembly with the underlying microscopic processes and provide physical limits on spatial propagation and prionlike behavior associated with protein aggregation.

Comparison of cortical thickness in patients with early-stage versus late-stage amnestic mild cognitive impairment.

BACKGROUND AND PURPOSE: Disappointing outcomes from clinical trials involving amyloid-modifying therapies for Alzheimer's disease (AD) have prompted more focus on the concept of early-stage (E) amnestic mild cognitive impairment (E-aMCI). However, limited evidence suggests that E-aMCI may represent aMCI at a very early stage of AD. Furthermore, the nature of the progression of E-aMCI to late-stage aMCI (L-aMCI) remains unclear. Therefore, the aim of the present study was to characterize patterns of cortical thinning in both E-aMCI and L-aMCI patients. METHODS: Cortical thicknesses were measured in 190 patients with aMCI and 147 subjects with normal cognition. In accordance with memory test scores involving delayed recall items, aMCI patients were divided into two subgroups, containing 73 E-aMCI subjects with milder memory impairment [scores between -1.5 standard deviation (SD) and -1.0 SD compared with age- and education-matched norms] and 117 L-aMCI subjects with more severe memory impairment (scores lower than -1.5 SD). RESULTS: Compared with controls, the E-aMCI group exhibited cortical thinning in the left medial temporal and insular regions, whereas the L-aMCI group showed cortical thinning in widespread regions, including the bilateral dorsolateral prefrontal, anterior and medial temporal, and temporo-parietal association cortices, and the precuneus. When the two aMCI groups were directly compared, the L-aMCI group showed greater cortical thinning in the right superior prefrontal, medial temporal, posterior cingulate and lateral parietal cortices. CONCLUSION: Our findings suggest that E-aMCI might represent an early symptomatic stage of AD. Furthermore, L-aMCI might resemble AD more closely than E-aMCI, in terms of the topography of cortical thinning.

Higher C-peptide levels are associated with regional cortical thinning in 1093 cognitively normal subjects.

BACKGROUND AND PURPOSE: Recent studies have demonstrated an association between increased insulin secretion and cognitive impairment. However, there is no previous study that directly evaluates the association between increased insulin secretion and cortical thickness to our knowledge. Therefore, our aim was to evaluate the effect of hyperinsulinemia, as measured by C-peptide level, on cortical thickness in a large sample of cognitively normal individuals. METHODS: Cortical thickness was measured in 1093 patients who visited the Samsung Medical Health Promotion Center and underwent brain magnetic resonance imaging (MRI) and a blood test to measure C-peptide concentration. Automated surface-based analyses of the MRI data were used to measure cortical thickness. C-peptide levels were divided into quartiles for comparison. Patients in the first to third quartiles were used as the reference category. RESULTS: Patients in the highest quartile group (Q4) of C-peptide levels showed cortical thinning, predominantly in both medial temporal lobes, the right inferior temporal gyrus, both medial prefrontal lobes and the right superior parietal lobule, compared with the lower quartile groups (Q1-Q3) after controlling for age, gender, body mass index, history of hypertension, hyperlipidemia, previous stroke, cardiovascular disease and fasting glucose level. CONCLUSIONS: A higher C-peptide level is associated with regional cortical thinning, even in cognitively normal individuals.

Cortical thickness and hippocampal shape in pure vascular mild cognitive impairment and dementia of subcortical type.

BACKGROUND AND PURPOSE: The progression pattern of brain structural changes in patients with isolated cerebrovascular disease (CVD) remains unclear. To investigate the role of isolated CVD in cognitive impairment patients, patterns of cortical thinning and hippocampal atrophy in pure subcortical vascular mild cognitive impairment (svMCI) and pure subcortical vascular dementia (SVaD) patients were characterized. METHODS: Forty-five patients with svMCI and 46 patients with SVaD who were negative on Pittsburgh compound B (PiB) positron emission tomography imaging and 75 individuals with normal cognition (NC) were recruited. RESULTS: Compared with NC, patients with PiB(-) svMCI exhibited frontal, language and retrieval type memory dysfunctions, which in patients with PiB(-) SVaD were further impaired and accompanied by visuospatial and recognition memory dysfunctions. Compared with NC, patients with PiB(-) svMCI exhibited cortical thinning in the frontal, perisylvian, basal temporal and posterior cingulate regions. This atrophy was more prominent and extended further toward the lateral parietal and medial temporal regions in patients with PiB(-) SVaD. Compared with NC subjects, patients with PiB(-) svMCI exhibited hippocampal shape deformities in the lateral body, whilst patients with PiB(-) SVaD exhibited additional deformities within the lateral head and inferior body. CONCLUSIONS: Our findings suggest that patients with CVD in the absence of Alzheimer's disease pathology can be demented, showing cognitive impairment in multiple domains, which is consistent with the topography of cortical thinning and hippocampal shape deformity.