Recurrent vesico-cervical fistula: our experience.
Vesico-cervical (VCxF) is an uncommon entity among the gamut of genitourinary fistulas. The common causes include prolonged labor, previous lower-segment cesarean sections (LSCS), difficult vaginal deliveries, and traumatic injuries. A 31-year-old woman presented with a history of LSCS for prolonged labor 4 years ago followed by a failed robotic repair for diagnosed VCxF and vesico-uterine fistula (VUtF) 1 year ago. The patient developed a recurrence 4 weeks after catheter removal. The patient underwent cystoscopic fulguration 6 months after the robotic surgery, but this failed after 2 weeks. Now, the patient presented with continuous urine leakage through the vagina for 6 months. On evaluation, she was diagnosed with recurrent VCxF and a repeat transabdominal repair was planned. On cystovaginoscopy, there was difficulty in negotiating the fistulous tract from either end. With great difficulty, we placed the guidewire from the vaginal end, which reached a false paracervical passage. Although in the false tract, the guidewire helped with localization of the intraoperative fistula site. After docking, port placement, and localization of the fistula site (tug on the guide wire), a mini cystostomy was performed. A plane was created between the bladder and cervicovaginal layer and dissected up to 1 cm beyond the fistula. The cervicovaginal layer was closed. An omental tissue interposition was followed by cystotomy closure and drain placement. The postoperative period was uneventful, and the patient was discharged on the 2nd day after drain removal. The catheter was removed after 3 weeks and the patient is doing fine under regular follow-up for 6 months. It is challenging to diagnose and repair VCxF. Transabdominal repair is better than transvaginal repair owing to its location. Patients can opt for open or minimally invasive (laparoscopic/robotic) surgery, with better postoperative outcomes in minimally invasive techniques.


Acute ethanol intoxication suppresses pentraxin 3 expression in a mouse sepsis model involving cecal ligation and puncture.
Acute ethanol intoxication impairs immunological reactions and increases the risk of sepsis; however, the underlying mechanism remains unclear. Pentraxin (PTX) 3 is a humoral pattern recognition receptor whose levels rapidly increase in response to inflammation. PTX3 production is triggered by tumor necrosis factor (TNF)-α and is mediated by c-Jun N-terminal kinase (JNK). As PTX3 exerts protective effects against sepsis as well as acute lung injury, we investigated whether acute ethanol exposure exacerbates sepsis by altering PTX3 expression. Sepsis was induced in C57/BL6 mice by cecal ligation and puncture (CLP) after ethanol/saline administration. Survival rates were significantly lower in ethanol-treated than in saline-treated mice. Increased vascular permeability and attenuation of PTX3 expression were observed in the lungs of ethanol-treated mice 4 h after CLP. Concomitant with a delayed increase of plasma TNF-α in ethanol-treated mice, plasma PTX3 was also suppressed in the early phase of sepsis. Although TNF-α level in ethanol-treated mice exceeded that in saline-treated mice 16 h after CLP, PTX3 levels were still suppressed in the former group. JNK phosphorylation in lung tissue was suppressed in both groups 4 and 16 h after CLP. Furthermore, JNK phosphorylation in ethanol-treated human umbilical vein endothelial cells was suppressed even in the presence of exogenous TNF-α, resulting in inhibition of PTX3 mRNA and protein expression. Our results suggest that ethanol suppresses de novo PTX3 synthesis via two mechanisms - i.e., suppression of TNF-α production and inhibition of JNK phosphorylation. PTX3 suppression may therefore contribute to exacerbation of sepsis in acute ethanol intoxication.


Cardiovascular responsiveness to norepinephrine in mild essential hypertension.
The responses of blood pressure, heart rate and forearm vascular resistance to exogenous norepinephrine (NE) were measured in 40 normotensive and 65 mildly hypertensive subjects (mean blood pressure 117/72 and 146/92 mm Hg, respectively). Both groups received low incremental doses of NE: 15, 30 and 60 ng/kg/min for 8 minutes each. In contrast to previous studies that compared the dose-response curves in normo- and hypertensive subjects, this study corrected the cardiovascular responses for the increment of plasma NE to account for differences in metabolic clearance of NE. Although age and sex appeared to play a role, the corrected cardiovascular responses did not differ significantly between normo- and hypertensive subjects. Thus, an increased cardiovascular sensitivity to exogenous NE was not demonstrated in mildly hypertensive subjects. This finding confirms some but not all previous studies of the dose-response relation.


Contribution of CXCR4 and SMAD4 in predicting disease progression pattern and benefit from adjuvant chemotherapy in resected pancreatic adenocarcinoma.
Prognosis of patients with pancreatic adenocarcinoma is poor. Many prognostic biomarkers have been tested, but most studies included heterogeneous patients. We aimed to investigate the prognostic and/or predictive values of four relevant biomarkers in a multicentric cohort of patients. A total of 471 patients who had resected pancreatic adenocarcinoma were included. Using tissue microarray, we assessed the relationship of biomarker expressions with the overall survival: Smad4, type II TGF-β receptor, CXCR4, and LKB1. High CXCR4 expression was found to be the only independent negative prognostic biomarker [hazard ratio (HR) = 1.74; P < 0.0001]. In addition, it was significantly associated with a distant relapse pattern (HR = 2.19; P < 0.0001) and was the strongest prognostic factor compared with clinicopathological factors. In patients who did not received adjuvant treatment, there was a trend toward decrease in the overall survival for negative Smad4 expression. Loss of Smad4 expression was not correlated with recurrence pattern but was shown to be predictive for adjuvant chemotherapy (CT) benefit (HR = 0.59; P = 0.002). CXCR4 is a strong independent prognostic biomarker associated with distant metastatic recurrence and appears as an attractive target to be evaluated in pancreatic adenocarcinoma. Negative SMAD4 expression should be considered as a potential predictor of adjuvant CT benefit.


The school behavior of Leucaspius delineatus (Heckel) in relation to ambient space and the presence of a pike (Esox lucius).
1. Tests were carried out to study school concentration in relation to quality of space and presence of a pike. 2. At a water depth of 60 cm (without pike) school concentration is very much lower than at 20 cm, both at 980 lux and at 0.02 lux. 3. At 0.02 lux in the absence of the predator, the shapes of the water space cannot be ascertained to have an influence. 4. At 980 lux (with and without pike) Shape IV has an intense effect on school concentration. 5. In the dark (0.02 lux) the effect of a pike in intensifying school formation is smaller, the larger the quantity of water.


Formation of large area closely packed carbon onions film by plasma-based ion implantation.
A substantial quantity of carbon onions in a durable film state is indispensable for its applications. In this study, large area fabrication of closely packed homogeneous carbon onion nanoparticle film using plasma-based ion implantation was demonstrated. Ag film deposited on a Si substrate was used as the implantation target for the hydrocarbon ions accelerated at 20 kV. Nanoparticles with the mean diameter of 7.5 nm were formed at the grain boundary of the Ag film. Carbon onions with the mean diameter of 17.4 nm were synthesized and arranged to a closely packed nanoparticle film with the thickness of around 200 nm by gradual thermal vaporization of the Ag. The closely packed configuration was achieved due to the isolated growth of carbon onion nanoparticle and high uniformity of the diameter. This process can be used in principle large area formation compered to typical ion implantation technique of carbon onion nanoparticle film, which can be applicable for the practical use in mechanical and electrochemical applications.


Bioaccumulation of microcystins in two freshwater gastropods from a cyanobacteria-bloom plateau lake, Lake Dianchi.
To investigate the bioaccumulation patterns of microcystins (MCs) in organs of two gastropods, samples were collected in Lake Dianchi monthly from May to October, 2008, when cyanobacteria typically bloom. The average MCs concentrations for Radix swinhoei (pulmonate) and Margarya melanioides (prosobranch) tended to be similar for the different organs: the highest values in the hepatopancreas (9.33 by 3.74 μg/g DW), followed by digestive tracts (1.66 by 3.03 μg/g DW), gonads (0.45 by 1.34 μg/g DW) and muscles (0.22 by 0.40 μg/g DW). Pulmonate had higher value than prosobranch because of the stronger bioaccumulation ability in hepatopancreas. The levels in organs of R. swinhoei were correlated with environmentally dissolved MCs, but influenced by intracellular MCs for M. melanioides. The estimated MCs concentrations in edible parts of M. melanioides were beyond the WHO's provisional tolerable daily intake (0.04 μg/kg), suggesting the risk of consumption of M. melanioides from the lake.


Knowledge, attitudes and practices in relation to antimicrobial resistance amongst Chinese public health undergraduates.
The aim of this study was to assess knowledge, attitudes and practices amongst public health undergraduates in relation to antimicrobial resistance (AMR) in China. A cross-sectional survey was conducted amongst all final-year public health undergraduates from 18 universities across China. A structured questionnaire was used to collect information on AMR-related knowledge, attitudes and practices, whilst multivariable linear and logistic regressions were employed to detect associations among these three aspects. A total of 1115 participants were included in this study. The mean ± standard deviation AMR knowledge score was 7.68 ± 2.56. Moreover, 75.2% of students had performed incorrect antimicrobial practice. Studying in a key university [slope = 1.49, 95% confidence interval (CI) 0.71-2.27], being male (slope = 0.36, 95% CI 0.02-0.70), having clinical experience (slope = 1.71, 95% CI 1.13-2.30) and having an affirmative attitude towards AMR were positively associated with knowledge score. Knowledge score was also positively associated with AMR practice (odds ratio = 1.07, 95% CI 1.00-1.13). A knowledge gap in relation to AMR was determined among Chinese public health students. This gap is associated with attitudes towards AMR and in turn influences antimicrobial use. It is clear that additional measures are needed in the curriculum, including additional AMR-specific clinical practices.


An in vitro bioengineered model of the human arterial neurovascular unit to study neurodegenerative diseases.
The neurovascular unit (NVU) - the interaction between the neurons and the cerebrovasculature - is increasingly important to interrogate through human-based experimental models. Although advanced models of cerebral capillaries have been developed in the last decade, there is currently no in vitro 3-dimensional (3D) perfusible model of the human cortical arterial NVU. We used a tissue-engineering technique to develop a scaffold-directed, perfusible, 3D human NVU that is cultured in native-like flow conditions that mimics the anatomy and physiology of cortical penetrating arteries. This system, composed of primary human vascular cells (endothelial cells, smooth muscle cells and astrocytes) and induced pluripotent stem cell (iPSC) derived neurons, demonstrates a physiological multilayer organization of the involved cell types. It reproduces key characteristics of cortical neurons and astrocytes and enables formation of a selective and functional endothelial barrier. We provide proof-of-principle data showing that this in vitro human arterial NVU may be suitable to study neurovascular components of neurodegenerative diseases such as Alzheimer's disease (AD), as endogenously produced phosphorylated tau and beta-amyloid accumulate in the model over time. Finally, neuronal and glial fluid biomarkers relevant to neurodegenerative diseases are measurable in our arterial NVU model. This model is a suitable research tool to investigate arterial NVU functions in healthy and disease states. Further, the design of the platform allows culture under native-like flow conditions for extended periods of time and yields sufficient tissue and media for downstream immunohistochemistry and biochemistry analyses.


Continuous Venovenous Hemodialysis Via Extracorporeal Membrane Oxygenation Pump for Treatment of Hyperammonemia Secondary to Propionic Acidemia in Monochorionic Diamniotic Twin Boys.
Late-preterm twins with propionic acidemia developed severe hyperammonemic encephalopathy at 5 days of age. Continuous venovenous hemodialysis was performed successfully for both infants via extracorporeal membrane oxygenation pump, and both rapidly improved. They were taken off continuous venovenous hemodialysis and extracorporeal membrane oxygenation and discharged with dietary therapy. At 3 years of age, neurodevelopment showed globally delayed milestones.


Accelerating Use of Self-measured Blood Pressure Monitoring (SMBP) Through Clinical-Community Care Models.
Self-measured blood pressure monitoring (SMBP), the regular measurement of blood pressure by a patient outside the clinical setting, plus additional support, is a proven, cost-effective but underutilized strategy to improve hypertension outcomes. To accelerate SMBP use, the Centers for Disease Control and Prevention (CDC) funded the National Association of Community Health Centers, the YMCA of the USA, and Association of State and Territorial Health Officials to develop cross-sector care models to offer SMBP to patients with hypertension. The project aimed to increase the use of SMBP through the coordinated action of health department leaders, community organizations and clinical providers. From 1/31/2017 to 6/30/2018, nine health centers in Kentucky, Missouri, and New York partnered with seven local Y associations (local Y) and their local health departments to design and implement care models that adapted existing primary care SMBP practices by leveraging capacities and resources in community and public health organizations. Nine collaborative care models emerged, shaped by available community assets, strategic priorities, and organizational culture. Overall, 1421 patients were recommended for SMBP; of those, 795 completed at least one cycle of SMBP (BP measurements morning and evening for at least three consecutive days). Of those recommended for SMBP, 308 patients were referred to a local Y to receive additional SMBP and healthy lifestyle support. Community and public health organizations can be brought into the health care delivery process and can play valuable roles in supporting patients in SMBP.


Cocaine and D-amphetamine induce changes in central beta-adrenoceptor sensitivity: effects of acute and chronic drug treatment.
The effects of acute and chronic treatment with psychomotor stimulants on specific binding of [3H]dihydroalprenolol to beta-adrenoceptors in rat brain were examined. At a dose of 10 mg/kg both acute and chronic treatment with cocaine and chronic treatment with D-amphetamine (10 mg/kg) caused increased binding of [3H]dihydroalprenolol. The molecular mechanism for this enhanced binding appears to be augmentation of the density of beta-adrenoceptors in rat brain. At a lower dose (5 mg/kg), however, chronic administration of D-amphetamine caused a decrease in the density of beta-adrenoceptors in rat brain. Chronic treatment with either D-amphetamine (10 mg/kg) or cocaine induced a marked increase in the magnitude of cyclic AMP accumulation in rat brain slices elicited by norepinephrine. Acute as well as chronic administration of D-amphetamine in vivo inhibited the temperature-dependent uptake of [3H]norepinephrine in rat brain synaptosomal homogenates, but no such inhibition was observed after chronic or acute treatment with cocaine. The results suggest that psychomotor stimulants induce beta-adrenoceptor supersensitivity which may be involved in the phenomenon of reverse tolerance and possibly psychosis in humans. The development of beta-adrenoceptor supersensitivity does not appear to be mediated through alterations in norepinephrine transport at the presynaptic sites.


The utilisation of peripherally-administered intravenous nutrient solutions.
The utilisation of three peripherally-administered intravenous nutritional regimens has been evaluated in 42 patients on the first four days following surgery for colorectal cancer. A standard dextrose-saline (DS) regimen (n = 16) has been compared with an amino-acid (AA) regimen (n = 12) and a regimen consisting of glucose, amino-acid and fat (GAF) (n = 14). Fat and carbohydrate oxidation was calculated pre- and post-operatively using indirect calorimetry. Patients receiving AA showed a fall in carbohydrate oxidation (p < 0.01) and a rise in fat oxidation (p < 0.05) post-operatively, whereas no significant changes in fat and carbohydrate oxidation occurred in the DS and GAF groups. Cumulative nitrogen balance (NB) for the first four post-operative days was significantly better (p < 0.01) in the AA group (-10.3 +/- 3.8 g; mean +/- s.e.m.) than in the DS group (-25.3 +/- 3.1 g), due to an improved NB in the AA group on the first and second days only. Cumulative NB in the GAF group (+7.7 +/- 2.3 g) was significantly better (p < 0.01) than in the other two groups. Where the provision of peripheral intravenous nutritional support is desired, the use of a combination of glucose, amino-acid and fat is recommended.


Impact of Frailty and Malnutrition on Outcomes After Surgical Fixation of Lower Extremity Fractures in Young Patients.
Evaluate the relationship of nutrition parameters and the modified frailty index (mFI) on postsurgical complications within a young patient population sustaining lower extremity orthopaedic trauma. Retrospective observational cohort study. Urban, American College of Surgeons-Verified, Level-1, Trauma Center. Seventeen-thousand one hundred nine adult patients under the age of 65 sustaining lower extremity fractures undergoing operative intervention from 2006 to 2018. On admission, mFI and albumin levels were obtained, as well as complication data. Statistical analysis was used to analyze the association between frailty, malnutrition, and postoperative complications. Patients were stratified, healthy (mFI ≤1, albumin ≥3.5 g/dL), malnourished (mFI ≤1, albumin <3.5 g/dL), frail (mFI ≥2, albumin ≥3.5 g/dL), and frail and malnourished (mFI ≥2, albumin <3.5 g/dL). 60.4% of patients were healthy, 18.8% were malnourished, 11.7% were frail, and 9.0% were frail and malnourished. Frailty and/or malnourishment on admission predicted significantly higher odds of postoperative complications and mortality when compared with healthy patients. Frailty and malnourishment in conjunction predicted a significantly higher odds ratio of 1.46 (1.22-1.75) for developing postoperative complications when compared with the only malnourished. This was also observed when compared with the only frail (odd ratio: 1.61, P < 0.001); however, there was also a 2.72 (P < 0.001) increased odds of mortality. Frailty and malnutrition in conjunction predicts a subset of patients with a higher risk of postoperative complications beyond that of frailty or malnutrition in isolation. Identification of these physiological states on admission allows for interventional opportunities during hospitalization. Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.


In vivo roles of Rad52, Rad54, and Rad55 proteins in Rad51-mediated recombination.
Repairing a double-strand break by homologous recombination requires binding of the strand exchange protein Rad51p to ssDNA, followed by synapsis with a homologous donor. Here we used chromatin immunoprecipitation to monitor the in vivo association of Saccharomyces cerevisiae Rad51p with both the cleaved MATa locus and the HML alpha donor. Localization of Rad51p to MAT precedes its association with HML, providing evidence of the time needed for the Rad51 filament to search the genome for a homologous sequence. Rad51p binding to ssDNA requires Rad52p. The absence of Rad55p delays Rad51p binding to ssDNA and prevents strand invasion and localization of Rad51p to HML alpha. Lack of Rad54p does not significantly impair Rad51p recruitment to MAT or its initial association with HML alpha; however, Rad54p is required at or before the initiation of DNA synthesis after synapsis has occurred at the 3' end of the invading strand.


Comparative pharmacokinetics of nalbuphine nasal spray and solution for injection in healthy volunteers.
Nalbuphine is a synthetic opioid with comparable analgesic activity to morphine but with a better safety profile. Nalbuphine is only available in injectable form due to low oral bioavailability. Nasal nalbuphine spray provides advantages in drug safety, avoids hepatic first-pass metabolism, is non-invasive and is convenient for patient-controlled analgesia by self-administration. This study aimed to evaluate the safety and pharmacokinetics (PK) of the newly developed nalbuphine nasal spray in comparison with a solution for injections. Twenty-four healthy Caucasian volunteers were enrolled in this randomized, open-label, cross-over study. Subjects were administered one of the drugs: nasal spray 7.0 mg/dose, nalbuphine hydrochloride solution for injection 10 mg/dose intravenously (IV) or intramuscularly (IM). High-performance liquid chromatography-tandem mass spectrometry was used to determine nalbuphine concentrations. A comparison of PK profiles for IV, IM and intranasal (IN) routes of nalbuphine administration revealed a close similarity of absorption phases for nasal spray and IM injection. Differences between the mean Tmax and dose-adjusted Cmax values for nasal spray and IM injection were statistically insignificant. The median values of the elimination rate constants and the terminal elimination half-life following IV, IM and IN nalbuphine administration were similar. The mean absolute bioavailability of the nasal spray equalled 65.04%. The similarity of PK parameters of IM-injected nalbuphine solution and the nasal spray allows us to assume the latter is a feasible alternative to intramuscular nalbuphine injections appropriate for self-administration and field environments for managing moderate and severe pain of various aetiologies.


Primary Thrombosis Prophylaxis in Persistently Antiphospholipid Antibody-Positive Individuals: Where Do We Stand in 2018?
To update our previous literature review and management recommendations on risk stratification and primary thrombosis prophylaxis in persistently antiphospholipid antibody (aPL)-positive individuals. The estimated annual thrombosis incident rate (ATIR) among aPL-positive individuals with or without systemic autoimmune disease (SAIDx) is 0 to 5.3%, probably very low (< 1%/year) in those with no other SAIDx and thrombosis risk factors. Risk stratification based on aPL profile, age, additional SAIDx, and traditional cardiovascular disease (CVD) or venous thrombosis risk factors is crucial to determine the risk of first thrombosis in aPL-positive patients. The protective effect of low-dose aspirin for primary thrombosis prophylaxis prevention is not supported by randomized controlled data. Hydroxychloroquine is protective against thrombosis in aPL-positive SLE patients; however, its role in aPL-positive individuals with other SAIDx remains uncertain. Statins downregulate proinflammatory and prothrombotic biomarkers among antiphospholipid syndrome (APS) patients and may have a role in aPL-positive individuals with high CVD risk. The optimal primary thrombosis prevention strategy in patients with clinically significant aPL profiles should include (a) regular screening and elimination of non-aPL thrombosis risk factors, (b) optimal management of concomitant SAIDx,


Genetic Evidence for Causal Association Between Atrial Fibrillation and Dementia: A Mendelian Randomization Study.
Background The knowledge gap regarding whether the correlation between atrial fibrillation (AF) and dementia in observational studies is causation or driven by other shared risk factors remains substantially unfilled. Methods and Results We performed a comprehensive 2-sample Mendelian randomization study to evaluate the causal effect of AF on overall dementia and its subtypes, including vascular dementia, Alzheimer dementia, Lewy body dementia, and frontotemporal dementia. The primary results in inverse variance-weighted analyses were further validated by various Mendelian randomization sensitivity analyses. Additionally, we conducted multivariable Mendelian randomization to examine 10 candidate mediators of the causal association of AF and dementia. Genetic predisposition to AF was modestly associated with an increased risk of overall dementia (odds ratio, 1.140 [95% CI, 1.023-1.271]; P=0.018) and strongly associated with vascular dementia (odds ratio, 1.350 [95% CI, 1.076-1.695]; P=0.010). Genetically predicted AF indicated neutral effects on Alzheimer dementia, Lewy body dementia, and frontotemporal dementia. In multivariable Mendelian randomization analysis, the total effect of AF on overall dementia was remarkably attenuated by adjusting for genetic effect for ischemic stroke (odds ratio, 1.068 [95% CI, 0.953-1.197]; P=0.259) and low cardiac output (odds ratio, 1.046 [95% CI, 0.926-1.181]; P=0.475), indicating that the causal association of genetically predicted AF with dementia was potentially mediated by ischemic stroke and low cardiac output. The causal effect of genetically predicted AF on dementia was independent of cerebral small-vessel disease and brain volume phenotypes. Conclusions Our findings provided novel evidence supporting the causal effect of genetically predicted AF on dementia mediated by ischemic stroke and low cardiac output. Future clinical trials are warranted to evaluate the potential role of appropriate AF management in dementia prevention.


Ciliary block (malignant) glaucoma.
A review of the history, recognition, mechanisms, and therapy of ciliary block glaucoma has been given. Cycloplegic therapy is stressed in the susceptible eye.


Further study of nebulisation chemotherapy, a new chemotherapeutic method in the treatment of lung carcinomas: fundamental and clinical.
Nebulisation chemotherapy, a chemotherapeutic method for the treatment of lung cancer that involves the administration of anticancer agents through the inhalation of nebulised aerosols, has been found to be highly effective (Tatsumura et al., 1983a,b). We confirmed that 5-FU administered by this method accumulates in the trachea, bronchi and regional lymph nodes of patients treated before surgery, along with 5-FU metabolites, FUR and FUdR, indicating that 5-FU is directly incorporated and metabolised in the respiratory tract. Parallel result were obtained using mongrel dogs. The 5-FU levels in other organs, such as the heart and liver, were found to be extremely low. Only a trace of 5-FU was found in the serum of both the patients and the dogs. We further investigated the anti-tumour effect of this therapy in ten selected patients and observed a satisfactory anti-tumour response of 60.0%. These results, along with our previous finding that the retention time of isotope tracers inhaled as aerosol is considerably longer in tumour tissues than in normal parts (Tatsumura et al., 1983a) explain the high antitumour action of this therapy and the absence of adverse effects of administered 5-FU.


Quantification of Intrafraction and Interfraction Tumor Motion Amplitude and Prediction Error for Different Liver Tumor Trajectories in Cyberknife Synchrony Tracking.
To research the fiducial-based, real-time tracking intrafraction (during the fraction [intra-]) and interfraction (between fractions [inter-]) tumor respiration amplitude, motion trajectory, and prediction error and quantify their relationships for different types of motion trajectories during Cyberknife-based stereotactic ablation radiotherapy. Twelve patients with liver tumors were treated using a Cyberknife system, and 58 fractions were involved in this study. Real-time target motion tracking data were extracted and transformed from the robot coordinate system into the patient coordinate system by the rotation matrix. Only the time sessions of the beam on were studied according to the data information generated from the Cyberknife motion tracking system. The motion correlation model between the external marker signal and internal fiducial position was built to present the type of motion trajectory. Using the correlation model as a function of external marker signal and internal fiducial position, we knew 4 motion trajectories mainly existed for liver cancer patients as follows: perfect linearity (group I), simple linearity (group II), hysteresis (group III), and area respiratory (group IV) patterns. More than half of the patients had a linear breathing trajectory. Analyzing all patients together, the intra-amplitudes were slightly less than those of the inter-amplitudes. The amplitude from large to small was in the superior-inferior, left-right and anterior-posterior directions, regardless of inter- and intra-amplitudes. Then, patients with a larger peak-to-peak have a larger standard deviation of amplitude and a larger amplitude in all fractions/sessions. The prediction errors of the linear motion trajectory were generally less than 1 mm. The prediction errors of the regular hysteresis breathing model were smaller than those of the irregular hysteresis model. Scattered breathing would result in a larger tracking error, such as the area respiratory trajectory. It was logical that prediction errors were larger for patients who showed much variation in their breathing amplitude. This paper showed that the liver motion trajectory model included perfect linearity, sample linearity, hysteresis, and area. The linear motion trajectory presented the minimum tracking error and the best stability, and the hysteresis and area trajectory were the worst. Therefore, breathing management, including respiration training, control, and evaluation of motion trajectory in all directions, was significantly necessary during liver SABR treatment.


Altruistic donation to improve survey responses: a global randomized trial.
Web-based platforms have revolutionized the ability for researchers to perform global survey research. Methods to incentivize participation have been singularly focused on European and North American participants with varied results. With an ever increasing proportion of biomedical research being performed in non-western countries, assessment of novel methods to improve global survey response is timely and necessary. To that end, we created a three-arm nested randomized control trial (RCT) within a prospective cohort study to assess the impact of incentives on survey responsiveness in a global audience of biomedical researchers. Email invitations were sent to authors and editors involved in online publishing totaling 2426 participants from 111 countries. Overall we observed a 13.0% response rate: 13.3% for the control group, 14.4% for a group entered to win a gift card, and 11.1% for a group whose participation lead to donation to charity (p = 0.17). Year of publication nor country impacted response rate. Within subgroups, editors were significantly less likely to respond to the survey as compared to authors (6.5% vs. 18.9%; p-value < 0.01). With power to detect a 4.8% difference among groups, we could not detect an impact of incentives on global survey response.


Diversity of function and higher-order structure within HWE sensor histidine kinases.
Integral to the protein structure/function paradigm, oligomeric state is typically conserved along with function across evolution. However, notable exceptions such as the hemoglobins show how evolution can alter oligomerization to enable new regulatory mechanisms. Here, we examine this linkage in histidine kinases (HKs), a large class of widely distributed prokaryotic environmental sensors. While the majority of HKs are transmembrane homodimers, members of the HWE/HisKA2 family can deviate from this architecture as exemplified by our finding of a monomeric soluble HWE/HisKA2 HK (EL346, a photosensing light-oxygen-voltage [LOV]-HK). To further explore the diversity of oligomerization states and regulation within this family, we biophysically and biochemically characterized multiple EL346 homologs and found a range of HK oligomeric states and functions. Three LOV-HK homologs are primarily dimeric with differing structural and functional responses to light, while two Per-ARNT-Sim-HKs interconvert between differentially active monomers and dimers, suggesting dimerization might control enzymatic activity for these proteins. Finally, we examined putative interfaces in a dimeric LOV-HK, finding that multiple regions contribute to dimerization. Our findings suggest the potential for novel regulatory modes and oligomeric states beyond those traditionally defined for this important family of environmental sensors.


Feasibility, Safety, and Technical Success of the Flying Intervention Team in Acute Ischemic Stroke : Comparison of Interventions in Different Primary Stroke Centers with those in a Comprehensive Stroke Center.
Prompt endovascular care of patients with ischemic stroke due to large vessel occlusion (LVO) remains a major challenge in rural regions as primary stroke centers (PSC) usually cannot provide neuro-interventional services. Objective The core content of the Flying Intervention Team (FIT) project is to perform thrombectomy on-site at a local PSC after the neuro-interventionalist has been transported via helicopter to the target hospital. An important and so far unanswered question is whether mechanical thrombectomy can be performed as safely and successfully on-site as in a specialized comprehensive stroke center (CSC). Comparison of 100 FIT thrombectomies on site in 14 different PSCs with 128 control thrombectomies at 1 CSC (79 drip-and-ship, 49 mothership) performed by a single interventionalist with respect to technical-procedural success parameters, procedural times, and complications. There were no significant differences between the two groups in terms of technical success (95.0% successful interventions in FIT group vs. 94.5% in control group, p = 0.60) and complications (3% major complications in FIT vs. 1.6% in control group, p = 0.47). Regarding time from onset to groin puncture, there was no difference between FIT and the entire control group (182 vs. 183 min, p = 0.28), but a trend in favor of FIT compared with the drip-and-ship control subgroup (182 vs. 210 min, p = 0.096). Airborne neuro-interventional thrombectomy service is a feasible approach for rural regions. If performed by experienced neuro-interventionalists, technical success and complication rates are comparable to treatment in a specialized neuro-interventional department.


The syndrome of inappropriate secretion of antidiuretic hormone in children with bacterial meningitis.
Plasma concentrations of arginine vasopressin were determined by radioimmunoassay in 13 normal children, 21 patients with febrile illnesses (not bacterial meningitis), and 17 patients with bacterial meningitis. The mean +/- 1 SD concentrations of AVP in the normal children and patients with various febrile illnesses were 0.7 +/- 0.6 and 1.0 +/- 1.2 muU/ml, respectively. The mean +/- 1 SD concentration of AVP in patients with bacterial meningitis was 3.3 +/- 2.3 muU/ml. The concentrations of AVP in the patients with bacterial meningitis were significantly greater (P less than 0.001) than those noted in the normal children or children with other febrile diseases.


Nonlinear and chaos characteristics of heart period time series: healthy aging and postural change.
In this study we investigated nonlinear and linear characteristics of heart period variability with aging in supine and standing posture. Sixty healthy subjects (8-61 years) divided in three age groups participated in the study. Heart period variability was assessed by measurement of short-term scaling exponent, sample entropy, largest Lyapunov exponent and spectral low-frequency and high-frequency power. In standing, there was significant increase in short-term scaling exponent and largest Lyapunov exponent in all subjects, and significant decrease in sample entropy in children (<15 years) and young adults (15-39 years). Increasing age is associated with reduction in sample entropy in supine posture. Mutual effect of aging and postural change was reflected on heart rate and sample entropy. Correlation between low-frequency-to-high-frequency power ratio and short-term scaling exponent was found in supine posture. In standing both low-frequency and high-frequency powers are correlated with short-term scaling exponent and sample entropy. These results show that posture, standing compared to supine, has significant effect on nonlinear properties of heart period variability in healthy subjects while the influence of healthy aging is less pronounced. The findings indicate that intrinsic properties of heart period dynamics, reflected on nonlinear measures, are altered only by robust changes of autonomic modulation of heart rate.


Quantitative mRNA expression analysis of co-stimulatory molecules in sequential biopsies from heart allografts.
Allograft-specific T-cell activation requires two signals, "signal one" via the T-cell receptor and "signal two" via costimulatory pathways. Animal models provide promising data that blockade of costimulatory signals can lead to T-cell anergy and tolerance. We analyzed 72 formalin-fixed and paraffin-embedded sequential heart allograft biopsies from 22 patients by quantitative real-time reverse transcriptase-polymerase chain reaction for the mRNA expression of the costimulatory molecules CD28, CD80, CD86, CD40, and CD154. mRNA expression levels were correlated to histological grade and time-point of rejection. mRNA expression of costimulatory molecules predominantly expressed by antigen-presenting cells (CD80, CD86, CD40), correlated with histological grade of cell-mediated acute rejection. Costimulatory molecules were up-regulated not only during rejection episodes early after transplantation, but also at late occurring rejection. The present results suggest a simultaneous and long-term therapeutical blockade of more than one costimulatory pathway for the prevention of repetitive T-cell mediated acute rejection episodes after heart transplantation.


Direct Trifluoromethylation of Alcohols Using a Hypervalent Iodosulfoximine Reagent.
The direct trifluoromethylation of a variety of aliphatic alcohols using a hypervalent iodosulfoximine reagent afforded the corresponding ethers in moderate to good yields (14-72 %). Primary, secondary, and even tertiary alcohols, including examples derived from natural products, underwent this transformation in the presence of catalytic amounts of zinc bis(triflimide). Typical reaction conditions involved a neat mixture of 6.0 equivalents of the alcohol with 1.0 equivalent of the reagent, with the majority of reactions complete within 2 h with 2.5 mol % of the Lewis acid catalyst. Furthermore, experimental evidence was provided that the C-O bond-forming process occurred via the coordination of the alcohol to the iodine atom and subsequent reductive elimination.


Supraphysiologic Vaginal Estrogen Therapy in Aged Mice Mitigates Age-Associated Bladder Inflammatory Response to Urinary Tract Infections.
Bladder diseases characterized by chronic inflammation are highly prevalent in older women, as are recurrent urinary tract infections (rUTIs). Recurrent urinary tract infections lead to chronic inflammation of the bladder mucosa and cause lower urinary tract symptoms that persist even after the infection is cleared. Vaginal estrogen therapy (VET) has long been used for the treatment of rUTIs; however, its mechanism of action remains unclear. The objective of this study was to examine the mechanism(s) by which VET affects bladder inflammation and response to rUTIs. Here, we induced surgical menopause in aged (18 months old) mice followed by VET. Mice were then infected with uropathogenic Escherichia coli , and course of infection was investigated. Inflammatory cytokine response was assessed before and during infection using enzyme-linked immunosorbent assay. RNA sequencing analysis was used to compare the inflammatory status of the young versus aged bladder and principal changes confirmed via quantitative reverse transcriptase-polymerase chain reaction to determine the effects of VET on bladder inflammation. Impact on age-associated bladder tertiary lymphoid tissue formation was evaluated histologically. In the ovariectomized aged model, VET not only mitigated uterine atrophy but was also associated with reduced rUTIs, number of bacterial reservoirs, dampened immune response, and promotion of terminal differentiation of urothelial cells. Bladder tertiary lymphoid tissue lesions were also reduced with VET, with an associated decrease in signals important for bladder tertiary lymphoid tissue formation. Finally, we determined that VET reverses age-associated upregulation of inflammatory genes and pathways. Our data suggest that VET is effective by reducing age-associated hyperinflammatory conditions in bladder mucosa and in enhancing the host response to infection.


Induction of heat shock proteins and the proteasome system by casein-N epsilon-(carboxymethyl)lysine and N epsilon-(carboxymethyl)lysine in Caco-2 cells.
Repeated mild heat shock treatment has been shown to have anti-aging effects on cellular mechanisms in vitro. Among these, the age-associated accumulation of advanced glycation end products (AGEs), such as N(epsilon)-(carboxymethyl)lysine (CML), has been demonstrated to be effectively prevented in glyoxal-exposed human skin fibroblasts following mild heat shock treatment. The biochemical mechanism responsible for this inhibition is not yet known. However, the involvement of heat shock proteins (HSPs) and the misfolded proteins degrading the ubiquitin-proteasome system have been hypothesized. As AGE-modified proteins are likely to be conformationally modified, we investigated whether treatment of human intestinal cells with casein-linked CML or nonprotein-linked CML affects the expression of HSPs and the ubiquitin-proteasome system by using matrix-assisted laser desorption/ionization-time-of-flight tandem mass spectroscopy (after protein separation by two-dimensional gel electrophoresis) and by Western blotting. Compared to nontreated control cells, expression of HSP90, HSP60, HSP70 chaperones, and the proteasome S26 ATPase subunit 2 were significantly upregulated in casein-CML and in CML-treated cells. Exposure of Caco-2 cells to beta-amyloid, a nonglycation product, revealed similar results. In conclusion, the results indicate that CML and casein-linked CML activate the expression of HSPs as well as the proteasome system, which are involved in the degradation of misfolded and possibly glycated proteins. Whether this mechanism is based on binding to cell surface receptors, such as the receptor for AGE, has to be clarified in future studies.


Associations between obstructive sleep apnea and dental pain and chewing discomfort in Korean adults: a nationwide cross-sectional study.
Obstructive sleep apnea (OSA) may be linked with oral health issues. This study evaluated the associations between OSA, dental pain, and chewing discomfort. Big data from a nationwide survey involving 6984 participants aged ≥ 40 years were analyzed. The STOP-Bang questionnaire was used to assess the OSA risk, categorizing the participants into low-, intermediate-, and high-risk groups. The associations of OSA risk with dental pain and chewing discomfort were evaluated using multivariate logistic regression analyses (α = 0.05). Results revealed that 50.33%, 37.50%, and 12.17% of the population belonged to the low-, intermediate-, and high-risk groups, respectively. After adjusting for covariates, a significant association emerged between OSA risk and dental pain, with adjusted odds ratios (95% confidence intervals) of 1 (reference), 1.208 (1.003-1.455), and 1.472 (1.131-1.916) for the low-, intermediate-, and high-risk groups, respectively (p = 0.0156). The adjusted odds ratio for chewing discomfort in the high-risk OSA group was 1.307 (0.977-1.748), although not significantly different from that of the low-risk group (p > 0.05). A high risk of OSA was associated with 1.472-fold increased risk of dental pain compared to those at low risk, implicating OSA as a potential risk indicator of poor oral health.


Promoting population health with public-private partnerships: Where's the evidence?
Although public-private partnerships have become common in the health sector, the evidence supporting their effectiveness is limited, and when the products or services provided by the private partner are harmful to health inherent conflicts of interest may be difficult to overcome. The objective of this study is to appraise the evidence describing process or effectiveness of public-private partnerships (PPPs) that aim to promote population health, and analyse how characteristics such as independence or competing interests influence the results of their evaluation. We carried out a systematic search of Medline and Web of Science to identify scientific reports evaluating the process or effectiveness of PPPs that aim to promote population health. Two reviewers applied inclusion criteria, extracted and evaluated study quality. We classified PPPs according to the health problem tackled, the independence of the evaluation, and the potential for competition between business interests of the private partner and health promotion activity undertaken. We classified the conclusions of the evaluation as positive (supportive/tentatively supportive) or negative (semi-critical/critical). We identified 36 studies evaluating 25 PPPs. Evaluations that were favourable to the use of PPPs in health promotion were more frequently classed as "not independent" and of poor quality. On the other hand, negative evaluations were more common when the PPP involved a private partner with a high potential for competition between the health promotion activity undertaken and their financial interests. PPPs that sought to prevent non-communicable diseases were more frequently negatively evaluated compared to PPPs tackling infectious disease or other types of health problem. Almost all of the evaluations evaluated process, with only 2 papers reporting quantitative health related outcomes. There is still a lack of sound evidence supporting the effectiveness of public-private partnerships in health promotion, and the evidence base is skewed by non-independent evaluations. Public health actors should abstain from engaging in agreements with industries whose business interests have a high potential for competition with the health promotion activity undertaken.


Evaluation of antero-posterior instability of the hip using modified Lequesne's false profile view.
Accurate evaluation of hip instability is critical for the diagnosis and successful treatment of developmental dysplasia of the hip (DDH). However, dynamic evaluation of hip instability is not well established. This study aimed to use the lateral view from a radiograph to evaluate dynamic antero-posterior hip instability in patients with DDH. Seventy-four patients (92 hips) with DDH (DDH group) and 46 patients (59 hips) without hip pain and DDH (Control group) were examined. A false profile view (FPV) according to Lequesne was taken at standard and 90° flexion with the hip of interest defined as functional FPV; the translation of the center of the femoral head (CFH) obtained from the functional FPV was measured. As a validation test, we measured the anterior translation of the CFH using ultrasonography (US). There was a significant difference between the two groups in the translation of the CFH (p < 0.01). The degree of CFH translation depended on the severity of DDH (lateral center edge angle, r = -0.56, p < 0.01; vertical center anterior margin angle, r = -0.57, p<0.01) and lateralization of the femoral head (head lateralization index, r = 0.54, p < 0.01). There was a significant correlation between functional FPV and US measurements (r = 0.71, p < 0.01). The present study confirmed that antero-posterior hip instability in DDH patients can be detected using functional FPV. Our novel measurement, as a new method for assessing hip instability, may be useful for evaluating hip dynamic instability in diagnosing the etiology, and determining and evaluating the treatment for DDH at lower cost and improved accessibility.


[Medical engineering computer technologies of testing cognitive functions in children].
Studies of higher mental functions in children are shown to present great difficulties in many parameters. Analysis has provided a number of requirements for medical devices and complexes and principles of their construction. Based on these data, the authors have developed and put computer test systems into practice, their advantages being shown. The studies of cognitive functions in children by using computer test systems are dealt with.


Medial prefrontal cortical innervation of the intercalated nuclear region of the amygdala.
The projections of the infralimbic area (IL) of the medial prefrontal cortex to the intercalated nuclei (ICNs) of the amygdala are thought to form a critical component of the forebrain circuitry for fear extinction. Despite the importance of these projections, there have been no focussed anatomical studies that have investigated the extent of IL inputs to different portions of the ICN complex. The present investigation used anterograde tract tracing in the rat to study the projections of the ventromedial PFC, including the IL, to the ICNs and surrounding amygdalar regions. Immunohistochemistry for the μ-opioid receptor (MOR) was used to identify the ICNs. At rostral levels of the amygdala there was a very dense projection to a far lateral portion of the capsular subdivision of the central nucleus (CLC) located between the main and medial ICNs, but only very light projections to these ICNs and the lateral ICNs. This distinct portion of the CLC receiving strong IL inputs was termed the capsular infralimbic target zone (CITZ), and was MOR-negative. Likewise, at more caudal levels of the amygdala, IL projections to the medial, lateral, and dorsal ICNs were light to moderate compared with projections to adjacent portions of the basolateral amygdala and amygdalostriatal transitional area. These findings suggest that the putative role of the IL-to-ICN connection in fear inhibition may be mediated by light to moderate projections from the IL to the medial ICN, and that the CITZ may be an equally important amygdalar target for this function.


Debt and suicidal behaviour in the Finnish general population.
We studied the significance of debt as a risk factor for suicidal ideation and suicide attempts in a nation-wide sample (n = 4868) of the Finnish general population. Those experiencing difficulties in repaying their debts more often than others (37 vs. 16%, P<0.001) had a probable minor mental disorder (GHQ-12 score > or =3). Nevertheless, difficulties in repaying debts were found to be a factor independently associated with suicidal ideation (OR, 2.8; 95% CI, 1.9-4.2). The clinical implication of these findings is that individuals experiencing difficulties in repaying their debts may require psychiatric evaluation as well as socio-economic counselling.


Bis(L-cysteinato)gold(I): chemical characterization and identification in renal cortical cytoplasm.
L-Cysteinatogold(I) was prepared by the reaction of L-cysteine with KAuBr4 in acidic media and its solubility determined from pH 4 to 10. The solubility at pH 7.4 and 37 degrees C is 1 microM. In the presence of excess cysteine, the solubility increases because of formation of bis(L-cysteinato)gold(I). The equilibrium-constant for formation of the bis complex is 2.1 +/- 0.4 X 10(-3), which at pH 7.4 CORRESPONDs to an apparant formation constant of 4.4 X10(4). The formation of the bis adduct was confirmed by chromatographic separation of the products of the reaction between [35S]-L-cysteine and Na2AuTM. This complex elutes with Kav = 1.15 which allows it to be distinguished from other gold thiolates that might form in vivo. The bis(cysteinato)gold(I) complex is shown to be present in kidney cytosol isolated from rats given Na2AuTM in vivo. When additional cysteine is added to the cytosol in vitro, the peak at 1.15 is increased, but if glutathione is added, the low molecular weight gold elutes at Kav = 1.00, which is taken as evidence for the existence of bis(cysteinato)gold(I) in the cytosol preparation. The amount of gold present as bis(cysteinato)gold(I) after 4 different dose schedules has been measured and found to increase with the total cytosol gold concentration. L-Cysteinatogold(I) does not dissolve in the presence of bovine serum albumin to form an adduct.


Comparative in vitro activity of cefoxitin, cefotaxime alone, and in combination with desacetylcefotaxime against the Bacteroides species.
The agar dilution method was used to determine the inhibitory activity of cefotaxime (CTX) alone, desacetylcefotaxime (dCTX) alone, CTX plus dCTX, and cefoxitin against 74 clinical isolates of the Bacteroides species recovered from diabetic patients with foot ulcers. The study concluded that the addition of dCTX to CTX increased the inhibitory activity from 45% to 73% for all strains tested and from 50% to 81% among the 32 strains of Bacteroides fragilis. This synergistic interaction against B. fragilis resulted in a four- to nine-fold reduction in the MIC of seven strains (64-128 micrograms/ml, resistant category MICs). While the lowest CTX MIC for B. fragilis was 2 micrograms/ml (four strains), the addition of dCTX also produced a remarkable reduction in susceptible range CTX MICs to 0.05-2 micrograms/ml in 16 strains (50%). The overall susceptibility to cefoxitin and CTX plus dCTX was as follows: 100% and 100% for Bacteroides vulgatus, 50% and 66% for Bacteroides thetaiotaomicron, 100% and 33% for Bacteroides ovatus, and 83% and 82% for Bacteroides species other than the B. fragilis group.


Genetic Alterations of Melanoma Brain Metastases: A Systematic Review and Meta-Analysis.
Data on molecular alterations harbored by melanoma brain metastases (MBMs) are limited, and this has hampered the development of more effective therapeutic strategies. We conducted a systematic review and meta-analysis of all the studies reporting DNA sequencing data of MBMs, in order to identify recurrently mutated genes and molecular pathways significantly enriched for genetic alterations. We searched PubMed, Embase and Scopus for articles published from the inception of each database to June 30, 2021. We included in the analysis all the studies that reported individual patient data on DNA sequencing of MBMs, assessing single nucleotide variants (SNVs) and/or gene copy number variations (CNVs) in at least five tumor samples. Meta-analysis was performed for genes evaluated for SNVs and/or CNVs in at least two studies. Pooled proportions of samples with SNVs and/or CNVs was calculated by applying random-effect models based on the DerSimonian-Laird method. Gene-set enrichment analysis (GSEA) was performed to identify molecular pathways significantly enriched for mutated genes. Ten studies fulfilled the inclusion criteria and were included in the analysis, for a total of 531 samples of MBMs evaluated. Twenty-seven genes were found recurrently mutated with a meta-analytic rate of SNVs higher than 5%. GSEA conducted on the list of these 27 recurrently mutated genes revealed vascular endothelial growth factor-activated receptor activity and transmembrane receptor protein tyrosine kinase activity to be among the top 10 gene ontology (GO) molecular functions significantly enriched for mutated genes, while regulation of apoptosis and cell proliferation were among the top 10 significantly enriched GO biological processes. Notably, a high meta-analytic rate of SNVs was found in several actionable cancer-associated genes, such as all the vascular endothelial growth factor (VEGF) receptor isoforms (i.e., Flt1 and Flt2 genes, for both SNV rate: 0.22, 95% CI 0.04-0.49; KDR gene, SNV rate: 0.1, 95% CI 0.05-0.16). Finally, two tumor suppressor genes were characterized by a high meta-analytic rate of CNVs: CDKN2A/B (CNV rate: 0.59, 95% CI 0.23-0.90) and PTEN (CNV rate: 0.31, 95% CI 0.02-0.95). MBMs harbored actionable molecular alterations that could be exploited as therapeutic targets to improve the poor prognosis of patients.


The medial hypothalamic defensive system: hodological organization and functional implications.
The hypothalamus is a relatively small division of the vertebrate forebrain that plays especially important roles in neural mechanisms assuring homeostasis, defense, and reproduction. Previous studies from our laboratory have suggested a distinct circuit in the medial hypothalamic zone as critically involved in the organization of innate defensive behavior. Thus, after exposure to a natural predator known to elicit innate defensive responses, increased Fos levels in the medial zone of the hypothalamus have been found restricted to the anterior hypothalamic nucleus, dorsomedial part of the ventromedial nucleus, and dorsal premammillary nucleus (PMd). Previous anatomical studies have shown that these Fos-responsive cell groups in the medial hypothalamus are interconnected in a distinct neural system, in which the PMd appears to be a critical element for the expression of defensive responses elicited by the presence of a predator. The purpose of this review is to provide an overview of what is currently known about the functional and hodological organization of this hypothalamic circuit subserving defensive responses.


The wealth→life history→innovation account of the Industrial Revolution is largely inconsistent with empirical time series data.
Baumard proposes a model to explain the dramatic rise in innovation that occurred during the Industrial Revolution, whereby rising living standards led to slower life history strategies, which, in turn, fostered innovation. We test his model explicitly using time series data, finding limited support for these proposed linkages. Instead, we find evidence that rising living standards appear to have a time-lagged bidirectional relationship with increasing innovation.


Selective bilateral lesion to caudate nucleus modulates the acute and chronic methylphenidate effects.
The psychostimulant methylphenidate (MPD) is currently the most prescribed drug therapy for attention deficit hyperactivity disorder (ADHD) and is used by students as a cognitive enhancer. The caudate nucleus (CN) is a structure within the motive circuit where MPD exerts its effects, it is known to contain high levels of dopaminergic cells and directly influence motor activity. The objective of this study was to understand the role of CN in response to acute and chronic administration of MPD. Specific and non-specific bilateral ablations were created in the CN using electrolytic lesion and 6-Hydoxydopamine (6-OHDA). Four groups of rats were used: control (n=4), sham (n=4), CN electrolytic lesion group (n=8) and CN 6-OHDA injected group (n=8). On experimental day one (ED 1) all rats received a saline injection and baseline locomotive activity was recorded. On ED 2 and ED 3 CN sham, electrolytic lesion and/or 6-OHDA injected groups were made followed by four to five days recovery (ED 3-7), followed by six daily 2.5 mg/kg MPD injections (ED 9-14), three days of washout (ED 15-17) and an MPD re-challenge of drug proceeding the washout days (ED 18). Locomotor activity was obtained at ED 1, 8, 9, and 18 using an open field assay. The results show that the CN electrolytic lesion group responded to the acute and chronic MPD administration similar to the control and sham group, while the CN 6-OHDA injected group prevented the acute and the chronic effects of MPD administration. One possible interpretation why nonspecific electroyltic lesioning of the CN failed to prevent acute and chronic effects of MPD administration is due to destruction of both the direct and the indirect CN pathways which act as an inhibitory/excitatory balance, electroylticelectroyltic. The selective dopaminergic lesioning prevented the effects of MPD administration suggesting that dopaminergic pathways in CN play a significant role in the effects of MPD.


Hyponatremia in acute brain disease: the cerebral salt wasting syndrome.
Hyponatremia in acute brain disease is a common occurrence, especially after an aneurysmal subarachnoid hemorrhage. Originally, excessive natriuresis, called cerebral salt wasting, and later the syndrome of inappropriate antidiuretic hormone secretion (SIADH), were considered to be the causes of hyponatremia. In recent years, it has become clear that most of these patients are volume-depleted and have a negative sodium balance, consistent with the original description of cerebral salt wasting. Elevated plasma concentrations of atrial or brain natriuretic peptide have been identified as the putative natriuretic factor. Hyponatremia and volume depletion may aggravate neurological symptoms, and timely treatment with adequate replacement of water and NaCl is essential. The use of fludrocortisone to increase sodium reabsorption by the renal tubules may be an alternative approach.


Canine Perianal Fistulas: Clinical Presentation, Pathogenesis, and Management.
Canine perianal fistulas are painful sinus tracts and ulcers that spontaneously develop in the skin around the anus. Middle-aged German shepherd dogs are most commonly affected and may have a genetic susceptibility. Although the disease was once believed related to conformational factors and primarily managed surgically, an immune-mediated pathogenesis is now recognized. Long-term medical management with immunomodulatory agents has become standard of care for canine perianal fistulas. Perianal fistulas can be debilitating and have a negative impact on quality of life of dogs and owners. Accurate diagnosis and aggressive medical therapy are key to successful management of canine perianal fistulas.


[Species composition and ecological peculiarities of the blood-sucking mosquito genus Ochlerotatus (communis species group) (Diptera: Culicidae) of the Novgorod Province].
Eleven mosquito species of the communis species group (genus Ochlerotatus, family Culicidae) were found in the Novgorod Province as a result of nine-year investigations (1996-2004). Ochlerotatus impiger, O. nigrinus, and O. sticticus are recorded in the Novgorod Province for the first time.


Iris transillumination and variable expression in ectopia lentis et pupillae.
Six children in three families showed variations of the rare genetic syndrome, ectopia lentis et pupillae. The siblings in two affected families demonstrated intermingling of simple lens ectopia with ectopia lentis et pupillae, suggesting that some types of simple ectopia lentis represent an incompletely expressed form of the full ectopia lentis et pupillae syndrome. Those patients with simple lens ectopia as well as those with ectopic lenses and pupils had striking transillumination of the iris periphery. Microphakia, cataract, and other anterior segment abnormalities were also observed.


Effects of transcutaneous electrical nervous stimulation on electromyographic and kinesiographic activity of patients with temporomandibular disorders: a placebo-controlled study.
The purpose of this study was to assess the effect of a single 60 min TENS application on sEMG and kinesiographic activity in TMD patients in remission, and to assess the sEMG and kinesiographic effect of TENS in placebo and untreated groups. Sixty female subjects, selected according to the inclusion/exclusion criteria, suffering from unilateral TMD in remission were assigned to one of the following group: Group TENS, that received a single session of 60 min of TENS; Group Placebo that received a single session of 60 min of sham TENS; Group Control, that received no treatment. Pre- and post-treatment differences in sEMG of TA, MM, SCM, and DA and interocclusal distance values within groups were tested using the Wilcoxon test. Differences in sEMG and kinesiographic data, among the three groups, were assessed by Kruskal-Wallis test. Significant differences were only observed in the TENS group, for masticatory muscles of both sides; one-way analysis of variance revealed that sEMG values of masticatory muscles of both sides in the TENS group were significantly reduced, in comparison with placebo and control groups. Kinesiographic results showed that the vertical component of the interocclusal distance was significantly increased after TENS only in the TENS group. TENS could be effective to reduce the sEMG activity of masticatory muscles and to improve the interocclusal distance of TMD patients in remission; the placebo effect seems not present in the TENS application.


Clinical and Therapeutic Factors Vary by Prognosis in Patients with Pathological Complete Response After Neoadjuvant Therapy for Breast Cancer.
To determine clinical predictors of recurrence and metastasis in patients with pathological complete response (pCR) after neoadjuvant chemotherapy (NCT). Patients treated with NCT who achieved pCR (n=285) were classified into three groups according to pre-NCT clinical stage (cStage): group I (IIa-IIb), group II (IIIa), and group III (IIIb-IIIc). Survival was analysed using the Kaplan-Meier method. The relationships between clinicopathological factors and recurrence were determined using Cox regression analysis. The median follow-up was 31 months. The 3-year disease-free survival and overall survival rates in groups I, II, and III were 92.7%, 87.8%, and 66.7% (P < 0.01) and 98.6%, 98.3%, and 90.6% (P=0.370), respectively. Lymph node status and tumour size were independent risk factors for recurrence and metastasis after NCT. In the human epidermal growth factor receptor 2-positive subgroup, advanced cStage and lymph node metastasis were associated with recurrence (P < 0.01). In the hormone receptor-positive subgroup, disease-free survival rates differed for cStages I-II compared to cStage III (P=0.049) and clinical node status 0-2 compared to clinical node status 3 (P=0.037). Pre-NCT cStage predicted the prognosis of pCR for different breast cancer subtypes. Patients with advanced cStage, lymph node metastasis, and large tumour sizes had a higher risk of recurrence or metastasis.


Lichenoid uvula mass as a rare cause of hot potato voice and progressive dysphagia.
Lichenoid uvula mass is an unusual entity and the clinicopathologic entities are important for the diagnosis. In this case report, we report an elderly lady presented with dysphagia and "hot potato voice" due to a lichenoid uvula mass. Apart from muffled voice, the other associated symptoms are dysphagia, sore throat, globus pharyngeus and snoring. She was a non-smoker, and not on any medications except for hypertension and dyslipidaemia. Apart from the enlarged uvula, other parts of the oral cavity, oropharynx and larynx were normal. She has no other signs such as cutaneous lesions. The mass was excised under general anaesthesia followed by resolution of symptoms. Awareness of this entity, the clinical and histopathological features should be highlighted to differentiate it from other diagnosis.


The immunopharmacologic potential of Semaxanib and new generation directed therapeutic drugs: Receptor tyrosine kinase regulation with anti-tumorigenensis/angiogenesis properties.
Molecular signaling of messages emanating from cellular membranes through receptor tyrosine kinases (RTKs) is a major mechanism for intercellular communication and transduction during development and metabolism, as well as in disease-associated processes. The phosphorylation status and signaling activity of RTKs are determined by a dynamic equilibrium of the activity of both RTKs and protein tyrosine phosphatases (PTPs). RTKs are essentially a class of cell-surface receptors for growth factors and other extracellular ligands, the most conspicuous perhaps are members of the vascular endothelial growth factor (VEGF) gene family, which plays a fundamental role in the growth and differentiation of vascular, as well as lymphatic endothelial cells. In particular, VEGF is a major regulator of normal (physiologic) and abnormal (cancerous) angiogenesis, including that associated with tumors and cancer. Blockers/inhibitors and regulators of RTKs are indeed promising cancer interventions, their specific mechanisms are yet to be unraveled. In this cutting-edge synopsis, I elaborate on breakthroughs/advances and current concepts of RTK regulation, further shedding light on exploring the role of potential regulators, particularly the RTK inhibitor Semaxanib, and the mechanisms associated with tumorigenesis in an effort to understand a potentially alleviating pharmacologic therapeutic intervention. This survey also tackles the loopholes and shortcomings of the aforementioned inhibitory role of Semaxanib, especially its inefficacy and ultimate discontinuation of relevant clinical trials.


Detection of HIV antibody and antigen (p24) in residual blood on needles and glass.
There is a significant rate of percutaneous injury with needles during the care of patients with acquired immunodeficiency syndrome (AIDS). Following puncture injury, it is recommended that the source of the contaminating blood be checked, and if human immunodeficiency virus-type 1- (HIV-1)-seropositive, zidovudine prophylaxis be considered. As the source of contaminating blood may be unknown, we studied the detectability of HIV-1 antibody and circulating antigen (p24) in the residual blood from needles and pieces of glass at various intervals following exposure to blood. The residual volume of blood remaining in needles varied from 183 +/- 50 microliters for a 20 G needle to 7.8 +/- 1 microliter for a 27 G needle, and the residual blood on small pieces of glass varied from 23 microliters for a piece weighing 558 mg to 2 microliters for a piece weighing 21 mg. Analysis of washed samples of residual blood from all 20 G through 26 G needles and from broken pieces of glass larger than 0.41 g that had been exposed to HIV-1-seropositive blood and left at room temperature for one hour, one day and one week resulted in positive tests for HIV-1 antibody by enzyme-linked immunosorbent assay (ELISA), immunofluorescence and Western blot assays. The circulating antigen was detected in residual blood of 20 G through 26 G needles, but not from contaminated pieces of glass. This technique could be applied to situations where a healthcare worker pricked him- or herself with a needle or with a piece of glass that had been contaminated with blood of unknown seroreactivity.(ABSTRACT TRUNCATED AT 250 WORDS)


Oxygen-sensitive 19F NMR imaging of the vascular system in vivo.
The fluorine nuclear magnetic resonance spin-lattice relaxation rate (1/T1) of the perfluorochemical blood substitute perfluorotripropylamine (FTPA) is very sensitive to oxygen tension. This presents the possibility of measuring blood oxygen tension by 19F MR imaging. We obtained oxygen-sensitive 19F NMR images of the circulatory system of rats infused with emulsified FTPA. Blood oxygenation was assessed under conditions of both air- and 100% O2-breathing. T1 relaxation times were derived from MR images using a partial saturation pulse sequence. The T1 times were compared with a phantom calibration curve to calculate average blood pO2 values in the lung, liver, and spleen. The results showed marked, organ-specific increases in blood oxygen tension when the rat breathed 100% O2 instead of air.


Eosinophil activation by lymphokines and T cell clone products in the rat.
T cell lines and T cell clones derived from inbred Fischer rats and specific for Schistosoma mansoni antigens were established. Cell-free supernatants from the T cell lines demonstrated a marked capacity to enhance IgE- and IgG2a-dependent eosinophil-mediated killing of S. mansoni larvae in vitro. In addition, supernatants from cloned T cells stimulated with concanavalin A or specific antigen, or unstimulated, enhanced IgE-dependent eosinophil-mediated helminthotoxicity. The enhancing activity in both cases was very heat-stable (100 degrees C, 10 min). We also found that clone-derived supernatants enhance eosinophil peroxidase release upon stimulation with homologous IgE and anti-IgE as well as inducing a more delayed spontaneous release of peroxidase. In view of the established thymus dependency for the development of immunity to schistosomiasis in the rat, the availability of these S. mansoni-specific cloned T cells has enabled the relationship between eosinophils, lymphocytes and anaphylactic antibodies to be examined more closely.


Ectopic Third Molar: A Hidden Cause For Maxillary Sinusitis-A Rare Case Report.
Odontogenic sinusitis (OS) accounts for about 10-20% of all the sinusitis occurring in maxillary sinus. OS may result due to periapical pathology, severe periodontitis, peri-implantitis, or oroantral communication due to displacement of tooth root into the sinus. Very rarely OS can be due to an impacted tooth in the maxillary sinus for which very few case reports are found in literature. The author presents a case report of 24 years female suffering from unilateral chronic sinusitis since 1 year caused due to impacted third molar tooth in left maxillary sinus associated with odontogenic keratocyst that was managed both medically and surgically. One year follow-up revealed that she was free from previous symptoms.


Endogenous Clostridium panophthalmitis.
Acute visual loss, pain, and redness in the left eye developed in a 61-year-old diabetic man. Results of ophthalmologic examination showed 4+ conjunctival hyperemia and chemosis, no light perception, and restricted ocular motility. Through a hazy cornea, a gas bubble was visualized filling about 50% of the anterior chamber. A vitreous tap disclosed myriad gram-positive rods with terminal and subterminal spores. Cultures of the vitreous grew Clostridium septicum, a gas-forming organism. Exploratory abdominal laparotomy showed a ruptured diverticulum of the sigmoid colon with acute peritonitis. In spite of intensive antibiotic therapy, the patient died approximately 24 hours after admission. Results of histopathologic examination of the postmortem left eye demonstrated massive necrosis of the intraocular structures with numerous gram-positive rods confined mainly to the retinal pigment epithelium (RPE), detached retina, and vitreous. To the best of the authors' knowledge, this is the second reported case of C. septicum panophthalmitis. Only 69 cases of clostridial infections with ocular involvement have been recorded previously in the literature.


Breast US in patients with breast cancer presenting as only microcalcifications on mammography: can US differentiate ductal carcinoma in situ from invasive cancer?
To retrospectively review sonographic findings of breast cancers presenting as only microcalcifications on mammography and to evaluate factors essential for differentiating ductal carcinoma in situ (DCIS) from invasive cancers. We retrospectively reviewed the medical records of 620 consecutive patients with confirmed breast cancer according to surgery performed between March 2008 and October 2011 at our institution. Of these, 53 lesions from 52 patients who had only microcalcifications without a mass or other associated findings on mammography were selected. Sonographic findings of microcalcification areas were analyzed and correlated with the histopathological findings. Of the 53 lesions, 26 (49.18 %) were classified as invasive cancer and 27 (50.9 %) as DCIS. Ultrasonography (US) showed only echogenic calcifications in five (9.4 %), calcifications within hypoechoic parenchymal thickening in 14 (26.4 %), calcifications within ductal changes in three (5.7 %), and calcifications within a mass in 14 (26.4 %). Seventeen (32.1 %) lesions were not visible on US. Negative findings in US were more frequently observed for DCIS (n = 15, 55.6 %) than for invasive cancers (n = 2, 7.7 %) (p < 0.001). Masses (n = 11, 42.3 % of invasive cancer; n = 3, 11.1 % of DCIS; p = 0.01) were more frequently observed in invasive cancers than in DCIS. US findings of breast cancers presenting as only mammographic microcalcifications were significantly different between DCIS and invasive cancers. Targeted US of microcalcifications might be helpful for predicting invasive cancers and for determining the clinical preoperative work-up, including axillary staging.


Integrating environmental health into medical education.
Although environmental factors contribute to more than 25% of all global disease, and toxic agents ranked fifth in underlying causes of U.S. deaths in 2000, environmental medicine education is largely omitted in the continuum of U.S. medical education. The paucity of specialists trained in environmental medicine (i.e., occupational medicine and other preventive medicine specialties and subspecialties), coupled with the lack of adequate general medical education on how to prevent, diagnose, refer, or treat patients exposed to hazardous substances in the environment, contributes to lost opportunities for primary prevention or early intervention to mitigate or minimize environmentally related disease burden. Survey findings of graduating medical students over the past few years have identified environmental health as a medical school topic area that can be improved. This article reflects a panel presentation on the challenge of including environmental health in general medical education. It was given at the 2010 "Patients and Populations: Public Health in Medical Education" conference cosponsored by the CDC and the American Association of Medical Colleges. A variety of educational strategies, models, and educational resources are presented that illustrate how recommended competency-based environmental health content can be integrated into medical education to better prepare medical students and physicians without specialized expertise in environmental medicine to provide or facilitate environmental preventive or curative patient care.


Successfully treated advanced esophageal cancer with left axillary lymph node metastasis and synchronous right breast cancer: a case report.
The incidence of double cancer of the esophagus and breast is rare, and axillary lymph node metastasis (ALM) in esophageal cancer is also very rare. We report a case of advanced esophageal cancer with left ALM and synchronous right breast cancer. A 64-year-old woman was admitted to our hospital with dysphagia. The clinical diagnosis was esophageal cancer (T3N0M1 stage IV) and right breast cancer (T1cN0M0 stage I). She was initially treated with triple chemotherapy with docetaxel, cisplatin, and 5-fluorouracil. The primary lesion in the esophagus achieved almost complete response as assessed by esophageal endoscopy. A computed tomography scan showed that the left ALM reduced in size and that stable disease was achieved for the right breast cancer. She underwent partial mastectomy of the right breast and bilateral axillary lymph node dissection. The histopathological diagnosis of the breast cancer was T1cN1M0 stage IIA. The lymph nodes from the left axilla contained metastatic cells from the squamous cell carcinoma of the esophagus. Complete response was achieved for the primary lesion in the esophagus following chemoradiotherapy (CRT), and the patient has been relapse free 2 years after treatment. Thus, we report the successful treatment of synchronous double cancers of the esophagus with left ALM and right breast by combination therapy with chemotherapy, CRT, and surgery.


A Novel Application of Ultrasound-Guided Interscalene Anesthesia for Proximal Humeral Fractures.
Proximal humeral fractures are commonly encountered in the emergency department (ED). These injuries are often associated with significant pain, with patients often receiving multiple doses of opiate medications while awaiting definitive management. The interscalene nerve block has been efficacious as perioperative analgesia for patients undergoing operative shoulder repair. The utilization of the interscalene nerve block in the ED for proximal humeral fractures is largely unexplored. We report the use of an ultrasound-guided interscalene nerve block in the ED for a patient presenting with significant pain from a proximal humerus fracture. The procedure provided excellent regional anesthesia with no additional need for intravenous or oral opiates during the rest of her ED course. With the significant risks associated with pain medication, particularly opiates, regional anesthesia may be an excellent option for the appropriate patient in the ED. As documented in this report, the ultrasound-guided interscalene block, in particular, may be utilized as a means to provide adequate pain control for patients with proximal humerus fractures in the ED.


Drug-induced acute pancreatitis: results from the hospital-based Berlin case-control surveillance study of 102 cases.
Drug toxicity is a well-known cause of acute pancreatitis (AP). Although many drugs have been associated with AP, the magnitude of the risk of most of them remains largely unknown. To determine the pancreatotoxic risk of a wide range of drugs. The hospital-based Berlin case-control surveillance study, including all 51 Berlin hospitals in a hospital network, ascertained 102 cases with idiopathic AP (IAP) and 750 controls between 2002 and 2011. Patients with IAP were thoroughly validated using anamnestic, clinical or laboratory data. Drug exposure was obtained in a face-to-face interview. Possible drug aetiology was assessed in individual patients through a standardised causality assessment applying the criteria of the World Health Organization. Drug risks were further quantified [odds ratios (OR) with 95% confidence intervals (CI)] in a case-control design with unconditional logistic regression analysis. The pancreatotoxic risk of several drugs, including azathioprine (OR 5.1; 95% CI 1.9-13.5), fenofibrate (OR 12.2; 95% CI 2.3-69.1), mesalazine (OR 3.3; 95% CI 1.1-9.5) or angiotensin-converting enzyme inhibitors, was corroborated by case-control analysis and causality assessment. Causality assessment suggested a pancreatotoxic potential, among others, for mercaptopurine or the seldom reported leflunomide, and alluded to a novel risk for tocilizumab. Case-control analysis showed an increased risk for two phytotherapeutics: harpagophytum and valerian radix. Our study quantified the pancreatotoxic risk of different drugs and phytotherapeutics. The findings corroborate previous results from the literature but also indicate risks for substances not previously reported, highlighting the need for further controlled studies on pancreatic toxicity.


Associating dose-volume characteristics with theoretical radiobiological metrics for rapid Gamma Knife stereotactic radiosurgery plan evaluation.
To examine general dose-volume characteristics in Gamma Knife (GK) plans which may be associated with higher tumor control probability (TCP) and equivalent uniform dose (EUD) using characteristic curve sets. Two sets of dose-volume histograms (DVHs) were exported alongside an analytical purpose-generated DVH: (a) single-shot large collimator (8 or 16 mm) emulated with multiple shots of 4 mm collimator. (b) shot-within-shot (SWS) technique with isodose lines (IDLs) of 40-75%. TCP, average dose, EUD in single-fraction (EUDT ) and 2 Gy fractionated regimens (EUDR ) were examined for trends with cumulative DVH (cDVH) shape as calculated using a linear-quadratic cell survival model (α/β = 10.0 Gy, N0 = 1 × 106 ) with both α = 0.20 Gy-1 and α = 0.23 Gy-1 . Using α = 0.20 Gy-1 (α = 0.23 Gy-1 ), plans in the analytical set with higher shoulder regions had TCP, EUDT , EUDR increased by 180%, 5.9%, 10.7% (11.2%, 6.3%, 10.0%), respectively. With α = 0.20 Gy-1 (α = 0.23 Gy-1 ), plans with higher heels had TCP, EUDT , EUDR increased by 4.0%, <1%, <1% (0.6%, <1%, <1%), respectively. In emulating a 16 (8) mm collimator, 64 (12) shots of the small collimators were used. Plans based on small collimators had higher shoulder regions and, with α = 0.20 Gy-1 (α = 0.23 Gy-1 ), TCP, EUDT , EUDR was increased up to 351.4%, 5.0%, 8.8% (270.4%, 5.0%, 6.8%) compared with the single-shot large collimator. Delivery times ranged from 10.2 to 130.3 min. The SWS technique used 16:8 mm collimator weightings ranging from 1:2 to 9.2:1 for 40-75% IDL. With α = 0.20 Gy-1 (α = 0.23 Gy-1 ), the 40% IDL plan had the highest shoulder with increased TCP, EUDT , EUDR by 130.7%, 9.6%, 17.1% (12.9%, 9.1%, 16.4%) over the 75% IDL plan. Delivery times ranged 6.9-13.8 min. The magnitude of the shoulder region characteristic to GK cDVHs may be used to rapidly identify superior plan among candidates. Practical issues such as delivery time may require further consideration.


Sodium-glucose cotransporter 2 inhibitors versus dipeptidyl peptidase 4 inhibitors on new-onset overall cancer in Type 2 diabetes mellitus: A population-based study.
Cancer is currently the second leading cause of death globally. There is much uncertainty regarding the comparative risks of new-onset overall cancer and pre-specified cancer for Type 2 diabetes mellitus (T2DM) patients on sodium-glucose cotransporter 2 inhibitors (SGLT2I) versus DPP4I. This population-based cohort study patients included patients who were diagnosed with T2DM and administered either SGLT2 or DPP4 inhibitors between 1 January 2015 and 31 December 2020 in public hospitals of Hong Kong. This study included 60,112 T2DM patients (mean baseline age: 62.1 ± 12.4 years, male: 56.36%), of which 18,167 patients were SGLT2I users and 41,945 patients were dipeptidyl peptidase 4 inhibitor (DPP4I) users. Multivariable Cox regression found that SGLT2I use was associated with lower risks of all-cause mortality (HR: 0.92; 95% CI: 0.84-0.99; p= 0.04), cancer-related mortality (HR: 0.58; 95% CI: 0.42-0.80; p ≤ 0.001) and new diagnoses of any cancer (HR: 0.70; 95% CI: 0.59-0.84; p ≤ 0.001). SGLT2I use was associated with a lower risk of new-onset breast cancer (HR: 0.51; 95% CI: 0.32-0.80; p ≤ 0.001), but not of other malignancies. Subgroup analysis on the type of SGLT2I, dapagliflozin (HR: 0.78; 95% CI: 0.64-0.95; p = 0.01) and ertugliflozin (HR: 0.65; 95% CI: 0.43-0.98; p = 0.04) use was associated with lower risks of new cancer diagnosis. Dapagliflozin use was also linked to lower risks of breast cancer (HR: 0.48; 95% CI: 0.27-0.83; p = 0.001). Sodium-glucose cotransporter 2 inhibitor use was associated with lower risks of all-cause mortality, cancer-related mortality and new-onset overall cancer compared to DPP4I use after propensity score matching and multivariable adjustment.


Synthesis of (arylimido)vanadium complexes and their application for oxidative coupling reactions of silyl enol ether derivatives.
(Arylimido)vanadium(v) complexes, V(NAr)(OEt)Cl(2) [Ar = C(6)H(5), p-BrC(6)H(4), p-(MeO)C(6)H(4)] or V(NAr)Cl(3) [Ar = o-BrC(6)H(4), o-(MeO)C(6)H(4)] were synthesized by the reaction of VO(OEt)Cl(2) or VOCl(3), respectively, with the corresponding aryl isocyanates. X-Ray crystal structure determination for V(NAr)(OEt)Cl(2) (Ar = C(6)H(5) and p-BrC(6)H(4)) elucidates the alkoxido-bridged dimeric building blocks [V(NAr)(OEt)Cl(2)](2), wherein the substituent on the benzene ring was found to affect the character of the imido nitrogen. The (51)V NMR spectroscopic measurements indicated that the electronic state of the vanadium metal centre depends on the ligands connecting to the vanadium and the substituents on the benzene ring. The selective oxidative cross-coupling reaction of silyl ketene acetal with silyl enol ether was achieved using V(Np-BrC(6)H(4))Cl(3) or V(No-BrC(6)H(4))Cl(3).


Spatially dependent H-bond dynamics at interfaces of water/biomimetic self-assembled lattice materials.
Understanding hydrogen-bond interactions in self-assembled lattice materials is crucial for preparing such materials, but the role of hydrogen bonds (H bonds) remains unclear. To gain insight into H-bond interactions at the materials' intrinsic spatial scale, we investigated ultrafast H-bond dynamics between water and biomimetic self-assembled lattice materials (composed of sodium dodecyl sulfate and β-cyclodextrin) in a spatially resolved manner. To accomplish this, we developed an infrared pump, vibrational sum-frequency generation (VSFG) probe hyperspectral microscope. With this hyperspectral imaging method, we were able to observe that the primary and secondary OH groups of β-cyclodextrin exhibit markedly different dynamics, suggesting distinct H-bond environments, despite being separated by only a few angstroms. We also observed another ultrafast dynamic reflecting a weakening and restoring of H bonds between bound water and the secondary OH of β-cyclodextrin, which exhibited spatial uniformity within self-assembled domains, but heterogeneity between domains. The restoration dynamics further suggest heterogeneous hydration among the self-assembly domains. The ultrafast nature and meso- and microscopic ordering of H-bond dynamics could contribute to the flexibility and crystallinity of the material--two critically important factors for crystalline lattice self-assemblies--shedding light on engineering intermolecular interactions for self-assembled lattice materials.


Biological stabilization of natural pigment-phytochemical from poppy-pollen (Papaver bracteatum) extract: Functional food formulation.
In this study, poppy-pollen extract (as a novel source of pigment and natural phytochemical) was microencapsulated. The spray-drying process maintained the encapsulation efficiency (EE) of phenolic (84-93%), anthocyanins (71-83%), and also antioxidant activity of extract in inhibiting DPPH (68-80%), ABTS (74-95%), OH (63-74%) radicals and reducing power (84-95%). The results of the Photo- and thermal (40-70˚C) stability of the bioactive compounds (TPC and TAC) indicated the thermal degradation and decomposition of particles' surface compounds during storage. The chemical (FTIR) and morphological analyses respectively revealed the insertion of extract compounds in the carrier matrix and the production of healthy particles with wrinkled structures. An increase in the carrier concentration elevated physical-stability, maintained structural properties, reduced hygroscopicity, and formed liquid/solid bridges or deliquescence phenomenon. The evaluation of the color histogram of the fortified gummy-candies indicated the usability of the spray-dried PP extract in producing an attractive red color with high sensory perception.


Saethre–Chotzen syndrome with an atypical phenotype: identification of TWIST microdeletion by array CGH.
Saethre–Chotzen syndrome is a very rare autosomal dominant congenital disorder characterized by craniosynostosis and acrocephalosyndactyly. It is caused by a mutation in TWIST1, located on chromosome 7p21. A shortage of functional TWIST1 protein affects the development and maturation of cells in the skull, face, and limbs. The patient described in this report displayed craniofacial features classic for Saethre–Chotzen syndrome, including craniosynostosis, low-set ears, small pinna with prominent crura, a high-arched palate, and a simian crease on the left hand. He did not have the limb anomalies commonly seen in patients with Saethre–Chotzen syndrome, and the results of conventional chromosome analysis were normal. However, results of a microarray-based comparative genomic hybridization (array CGH) study confirmed the karyotype of46,XY.7p21.1p15.3(15,957,375-20,331,837)x1, a region that includes TWIST1. Subsequent fluorescent in situ hybridization analysis confirmed this result. No other chromosome was involved in the rearrangement. This case illustrates the important contribution of array CGH to the identification of TWIST microdeletions, even in a patient not showing the phenotype typical of Saethre–Chotzen syndrome.


MIL-100(Fe)/Ti3C2 MXene as a Schottky Catalyst with Enhanced Photocatalytic Oxidation for Nitrogen Fixation Activities.
A new microporous MIL-100(Fe)/Ti3C2 MXene composite was constructed as a non-noble metal-based Schottky junction photocatalyst with improved nitrogen fixation ability. Ti3C2 MXene nanosheets exhibited excellent metal conductivity and were employed as two-dimensional support to optimize the composite's energy band structure. MIL-100(Fe) with a large specific surface area was used as an adsorbent and a photocatalytic oxidation center. The MIL-100(Fe)/Ti3C2 MXene composite not only exhibited higher thermal stability but also showed significantly increased nitrogen fixation activity under visible light. The NO conversion rate of the composite catalyst was about four and three times higher than that of the pure Ti3C2 MXene and the pure MIL-100(Fe) samples, respectively. Although adsorption plays an important role in the nitrogen fixation process, the synergistic effects of the Schottky junctions are the main cause of the enhanced photocatalytic activity. The built-in electric field can be generated to form charge-transfer channels, which help to achieve a desirable photocatalytic activity.


Comparisons of Clinical Features in Japanese Patients with Behçet's Uveitis Treated in the 1990s and the 2000s.
Purpose: We investigated clinical characteristics of ocular Behçet's disease (BD) patients treated in the 1990s and the 2000s.Methods: We retrospectively examined records of 68 newly arrived patients with ocular BD followed for more than 4 months during the 2000s and compared to those of 107 patients during the 1990s. Patient profiles, ocular and systemic symptoms, frequency of ocular attacks, BD ocular attack score 24-6 months (BOS24-6M), best-corrected visual acuity (BCVA), and immunomodulatory treatment were noted.Results: Clinical characteristics in the 2000s showed increases in iridocyclitis type, intestinal-, vasculo-, and neuro-BD cases, oral corticosteroid, methotrexate, and infliximab therapy usage, cataract and glaucoma surgery, and pseudophakia, and decreases in BOS24-6M and cyclophosphamide usage. BCVA of 20/30 or better at the final visit was slightly increased in the 2000s.Conclusions: Milder ocular BD tendency was seen in cases in the 2000s, whereas the incidence of special type of BD might be increasing.


Electrocardiographic localization of peripherally inserted central catheter tip position in critically ill patients with advanced cancer: An application study.
We compared the methods of electrocardiogram (ECG) and X-ray localization of the peripherally inserted central catheter (PICC) tip position, in order to find a more convenient, practical, and safe method. To investigate the value of applying electrocardiographic localization of the PICC tip position in critically ill patients with advanced cancer in Hebei Province, China. Enrolled 137 advanced cancers requiring PICC placement. The position of the catheter tip was localized with the bedside electrocardiogram in real time. Then, the localization was performed using a chest X-ray (the gold standard). The accuracy of electrocardiographic location was checked. Specific P waves were observed in 130 patients. No change in the P waves was observed for the remaining seven patients. The age of the latter group of patients was more advanced (87.29 [5.15] years), a significant difference to that of the 130 patients with specific P waves (71.58 [14.84] years) (t = -6.704, p < .001). Specific P waves not only involve ascendance in P waves but also ascendance in QRS waves. The use of an ECG to localize the PICC tip in critically ill patients with advanced cancer may replace the unnecessary use of chest X-rays. Specific P waves not only involve an increase in P waves but also an increase in QRS waves. If there is no change in the P wave, a chest X-ray film must be obtained. In elderly patients, because there is a possibility of catheter tip malposition, a comprehensive evaluation should be performed before surgery.


Kinetic characterization and identification of a novel inhibitor of hypoxia-inducible factor prolyl hydroxylase 2 using a time-resolved fluorescence resonance energy transfer-based assay technology.
The human hypoxia-inducible factor prolyl hydroxylases 1, 2, and 3 (HIF-PHD1, -2, and -3) are thought to act as proximal sensors of cellular hypoxia by virtue of their mechanism-based dependence on molecular oxygen. These 2-oxoglutarate (2-OG) and non-heme iron-dependent oxygenases constitutively hydroxylate HIF, resulting in high-affinity binding to Von Hippel-Lindau protein (pVHL). Some reported affinities for the HIF-PHDs for 2-OG and iron approach the estimated physiological concentrations for these cofactors, suggesting that the system as described is not catalytically optimal. Here we report the enzymatic characterization of full-length recombinant human HIF-PHD2 using a novel and sensitive catalytic assay. We demonstrated submicromolar affinities for 2-OG and ferrous iron and HIF-PHD2 Km values for oxygen that are greater than atmospheric oxygen levels, suggesting that molecular oxygen is indeed the key regulator of this pathway. In addition, we observed enhancement of HIF-PHD2 catalytic activity in the presence of ascorbic acid with only minor modifications of HIF-PHD2 requirements for 2-OG, and a detailed pH study demonstrated optimal HIF-PHD2 catalytic activity at pH 6.0. Lastly, we used this sensitive and facile assay to rapidly perform a large high-throughput screen of a chemical library to successfully identify and characterize novel 2-OG competitive inhibitors of HIF-PHD2.