Fatty acids penetration into human skin ex vivo: A TOF-SIMS analysis approach.
Linoleic, oleic, palmitoleic, palmitic, and stearic fatty acids (FAs) are commonly used in dermatological formulations. They differ by their structure, presence in the skin, and mode of application in pharmaceuticals and cosmetics compounding. These FAs are also known as chemical penetration enhancers, but their mechanisms of penetration enhancement and effect on barrier characteristics of the skin require additional study. In this study, the authors conducted an ex vivo analysis of the distribution of lipid components in the epidermis and dermis of human skin after applying individual FAs. The goal was to elucidate possible mechanisms of penetration enhancement and FA effects on barrier characteristics of the skin. FA penetration studies were conducted ex vivo on human skin and time-of-flight secondary ion mass spectrometry (TOF-SIMS) bioimaging analysis was performed to visualize and analyze distribution of FAs in skin sections. The current study demonstrated that TOF-SIMS imaging was effective in visualizing the distribution of linoleic, oleic, palmitoleic, palmitic, and stearic acid in the human skin ex vivo after the skin penetration experiment of individual FAs. The integration of the obtained TOF-SIMS images allowed a semiquantitative comparison of the effects induced by individual FA applications on the human skin ex vivo. FAs showed varying abilities to penetrate the skin and disorder the FAs within the skin, based on their structures and physicochemical properties. Linoleic acid penetrated the skin and changed the distribution of all the analyzed FAs. Skin treatment with palmitoleic or oleic acid increased the amounts of singular FAs in the skin. Penetration of saturated FAs was low, but it increased the detected amounts of linoleic acid in both skin layers. The results indicate that application of FAs on the skin surface induce redistribution of native FAs not only in the stratum corneum layer of epidermis but also in the lipid content of full epidermis and dermis layers. The results indicate that topically applied pharmaceutical products should be evaluated for potential chemical penetration enhancement and lipid component redistribution effects during formulation.


The influence of defoamer on removal of PAHs in soil washing.
The use of surfactants during soil washing process can create massive foam, which has a negative impact on the effective use of equipment. A series of tests was conducted to evaluate the defoaming performance of three defoamers and to investigate the influence on removal of polycyclic aromatic hydrocarbons (PAHs) during enhanced soil washing by the addition of the defoamer. Results showed that polydimethylsiloxane oil, which is the most common biomaterial used in commercial antifoaming and defoaming agents, has the best defoaming performance. With the addition of 0.1% polydimethylsiloxane oil, the removal ratios of total 16 PAHs (SigmaPAHs) increased up to 53.48% and 75.92% when washing time was 5 min and 30 min, respectively, compared with the removal ratios of 44.12% and 67.28% with Triton X-100 solution only. This indicated that the proper selection of defoamer not only solves massive foaming problem but also brings out a positive influence on PAH removal during the soil washing process. Three kinds of defoamers (kieselguhr, dodecanol, and polydimethylsiloxane oil) were collected to destroy the foam produced by Triton X-100. Among those defoamers, the polydimethylsiloxane (PDMS) oil has the best defoaming performances. The surface tension of the Triton X-100 solution with the addition of PDMS was lower. The addition of PDMS could improve the removal ratio of SigmaPAHs during soil washing. That may be attributed to the addition of the nonionic surfactant Tergitol NP-10 as the emulsifier in the defoamer. After all, the results do not provide any indication of the influence on the solubilization micelles. It is thus questionable whether other components of PDMS oil could improve the PAH solubilization.


[Water quality evaluation of the Three Gorges Reservoir area].
One year water quality monitoring results of 16 sections alongside the Three Gorges Reservoir area were presented. From the evaluation carried out using the integrated polluted index (P value), some characteristics of the water quality were obtained. The results showed that water quality of the Three Gorges Reservoir area was slightly polluted in 1999 mainly because of the discharge of urban sewerage and industrial wastewater. Main polluted city sections were along the river banks of Chongqing, Changshou, Fuling and Wanzhou. Evaluation also showed that there were 4 indicators that, to different extent, affected the water quality: colon bacillus, TP, non-ionic ammonia and oils.


Heparin and heparan sulfate enhancement of the inhibitory activity of plasminogen activator inhibitor type 1 toward urokinase type plasminogen activator.
To study effects of glycosaminoglycan on the interaction between two chain urokinase type plasminogen activator (tcu-PA) (EC 184.108.40.206) and plasminogen activator inhibitor type 1 (PAI-1) the second order rate constant (k1) between high molecular weight tcu-PA and active recombinant prokaryotic PAI-1 (rpPAI-1) was determined employing a continuous method using chromogenic substrate S-2444 either in the presence or absence of various kinds of glycosaminoglycans. k1 was (5.9 +/- 1.6).10(6)/mol per s in the absence of effector molecule, and following addition of heparin (1.0 U/ml) k1 was enhanced to (3.22 +/- 0.73).10(7). A significant enhancement of k1 was also obtained by heparan sulfate (1.87 +/- 0.25).10(7). Dermatan sulfate or chondroitin sulfate did not show a significant effect on k1 although a slight decrease was obtained by mono-dextran sulfate (4.2 +/- 1.2).10(6). The intrinsic fluorescence of rpPAI-1 was shown to be slightly increased following addition of heparin (1.49 +/- 0.22%, n = 6), suggesting that heparin may enhance the inhibitory activity of PAI-1 toward tcu-PA both by a template mechanism and by a modification of PAI-1 structure.


Renal-protective effect of thalidomide in streptozotocin-induced diabetic rats through anti-inflammatory pathway.
Diabetic nephropathy (DN) is a major microvascular complication in diabetes. An increasing body of evidence has shown that DN is related to chronic inflammation, kidney hypertrophy, and fibrosis. While thalidomide has been shown to have anti-inflammatory and antifibrotic effects, the effects of thalidomide on the pathogenesis of DN are unclear. This study was undertaken to explore whether thalidomide has renal-protective effects in diabetic rats. Male Sprague Dawley rats were injected intraperitoneally with 50 mg/kg streptozotocin to induce diabetes. Diabetic rats were treated with thalidomide (200 mg/kg/d) for 8 weeks, and then blood and urine were collected for measurement of renal function-related parameters. Histopathology, immunohistochemistry, enzyme-linked immunosorbent assay, and Western blot analyses were performed to assess renal proinflammatory cytokines, fibrotic protein, and related signaling pathways. Diabetic rats exhibited obvious renal structural and functional abnormalities, as well as renal inflammation and fibrosis. Compared with diabetic control rats, those treated with thalidomide showed significantly improved histological alterations and biomarkers of renal function, as well as reduced expression of renal inflammatory cytokines, including NF-κB and MCP-1. Furthermore, renal fibrotic proteins, such as TGF-β1, TβRII, TβRI, smad3, collagen IV, and fibronectin were also remarkably suppressed. Treatment with thalidomide markedly stimulated the phosphorylation of AMPKα. In this study, thalidomide suppressed the inflammatory and fibrotic processes in DN. These effects were partly mediated by the activation of AMPKα, and inhibition of the NF-κB/MCP-1 and TGF-β1/Smad signaling pathways. These results suggest that thalidomide may have therapeutic potential in diabetic renal injury through the anti-inflammatory pathway.


Re-emergence of dog rabies in Mpumalanga province, South Africa.
Dog rabies has commonly been associated with the eastern and southern border areas in Mpumalanga province, and the Nkomazi district in the east has been most affected. In other parts of the province, canid rabies has been under control for many years; however, in 2008, dog rabies spread to other parts of the province and resulted in a widespread outbreak. The objective of this study was to genetically characterize rabies viruses in an attempt to determine the source of this recent outbreak. Fifty-five rabies viruses were recovered from domestic dogs between 2000 and 2008 from Mpumalanga province and bordering areas. The viruses were characterized through nucleotide sequencing of the cytoplasmic domain of the glycoprotein gene and the G-L intergenic region. Phylogenetic analysis of these viruses and those previously characterized from Mpumalanga province and neighboring countries and provinces clearly supported the placement of the viruses from the current outbreak and those from Nkomazi district in one lineage. This demonstrated that the recent emergence of rabies in Mpumalanga province resulted from the spread of rabies from Nkomazi district. A comparative analysis demonstrated close genetic relationships among rabies viruses from Mpumalanga and KwaZulu-Natal provinces, Swaziland, and Mozambique. Findings from this investigation have shown that rabies continues to pose a definite public health threat in South Africa, a situation similar to other African countries.


The public health response to the Chi-Chi earthquake in Taiwan, 1999.
On September 21, 1999, at 1:47 a.m., an earthquake measuring 7.3 on the Richter scale struck the middle Chi-Chi region of Taiwan. The present study examines the response of the public health sector to the earthquake. A community needs assessment using modified cluster sampling was performed in shelters of Nantou and Taichung Counties five days after the earthquake struck. Twenty-five temporary medical service systems (TMSSs) conducted surveillance for selected diseases and mortality within one week post-earthquake aided by a buddy system that allowed unaffected counties to provide support to affected counties. The number of cases of acute respiratory infections and acute gastroenteritis in the affected area was higher than that of neighboring unaffected counties in the post-earthquake phase (p<0.001). Earthquake-related deaths were estimated at 2,347 deaths (death rate 116 per 100,000 population); the mean age of the decedents was 49.7 years. No significant difference was observed between males (120/100,000) and females (110/100,000) (risk ratio [RR]=1.09; 95% confidence interval [CI] 0.84, 1.42; p>0.05). The age-adjusted mortality rate was significantly higher in 1999 (odds ratio [OR]=2.11; 95% CI 1.99, 2.24) than in a comparable period in 1998. Emergency preparedness must be based on carefully conceived priorities, information, and communications, and improved capabilities must be developed to rapidly implement an emergency public health network. The emergency response to this event-consisting of TMSSs, a buddy system, and a communication system-should be considered in planning for future disaster events in Taiwan.


Combined impact of high-pressure processing and slightly acidic electrolysed water on Listeria monocytogenes proteomes.
Slightly acidic electrolysed water (SAEW) and high-pressure processing (HPP) are well-established non-thermal preservation technologies. This study investigated the deactivation mechanisms of Listeria monocytogenes by label-free quantitative proteomics analysis. Samples were treated through HPP (300 MPa for 3 min), SAEW (20 ppm available chlorine concentration), and their combinations. The KEGG pathway analysis found SAEW + HPP induced differentially expressed proteins (DEPs) associated to biofunctions of ribosomes, secondary metabolite biosynthesis, microbial metabolism in diverse environments, carbon metabolism, and biosynthesis of amino acid and aminoacyl-transfer RNA. The results showed these non-thermal treatments were able to induce the shifting of ribosome biogenesis to initiate translation in L. monocytogenes. During protein translation, the initiation stage was upregulated. However, subsequent elongation, termination, and recycling of used ribosomes were retarded. Comparing various treatments, the combination of hurdles showed greater deactivation of L. monocytogenes than any single one. The approaches developed in this study provided crucial information for minimally processing in the food industries on the application of foodborne listeriosis prevention.


Conformation-dependent regulation of inward rectifier chloride channel gating by extracellular protons.
We have investigated the gating properties of the inward rectifier chloride channel (Cl(ir)) from mouse parotid acinar cells by external protons (H(+)(o)) using the whole-cell patch-clamp technique. Increasing the pH(o) from 7.4 to 8.0 decreased the magnitude of Cl(ir) current by shifting the open probability to more negative membrane potentials with little modification of the activation kinetics. The action of elevated pH was independent of the conformational state of the channel. The effects of low pH on Cl(ir) channels were dependent upon the conformational state of the channel. That is, application of pH 5.5 to closed channels essentially prevented channel opening. In contrast, application of pH 5.5 to open channels actually increased the current. These results are consistent with the existence of two independent protonatable sites: (1) a site with a pK near 7.3, the titration of which shifts the voltage dependence of channel gating; and (2) a site with pK = 6.0. External H(+) binds to this latter site (with a stoichiometry of two) only when the channels are closed and prevent channel opening. Finally, block of channels by Zn(2+) and Cd(2+) was inhibited by low pH media. We propose that mouse parotid Cl(ir) current has a bimodal dependence on the extracellular proton concentration with maximum activity near pH 6.5: high pH decreases channel current by shifting the open probability to more negative membrane potentials and low pH also decreases the current but through a proton-dependent stabilization of the channel closed state.


Antibiotic Resistance in the Neonatal Intensive Care Unit.
Antibiotic-resistant bacteria are an increasing problem in the NICU. Ineffective empiric antibiotic therapy is associated with increased risk for morbidity and mortality. Organisms that are resistant to multiple antimicrobial agents (multidrug-resistant organisms) are particularly problematic. These organisms may be transmitted to infants if infection control practices are not adhered to, or they may be created by antibiotic exposure. Therefore, meticulous infection prevention-including hand hygiene, surveillance cultures, contact precautions, and selective decolonization-and antibiotic stewardship are important strategies to minimize drug resistance in the NICU.


A Retrospective, Descriptive, Comparative Study to Identify Patient Variables That Contribute to the Development of Deep Tissue Injury Among Patients in Intensive Care Units.
Deep tissue injury (DTI) may develop in critically ill patients despite implementation of preventive interventions. A retrospective, descriptive study was conducted in a 620-bed, level 1 trauma, academic medical center with 7 adult intensive care units ([ICUs] cardiac surgery, trauma surgery, burn surgery, med-surgery, neurosurgery, medical, and transfer) among patients treated from January 1, 2010 to January 1, 2015. All patients 18 years of age or older that developed a sacral DTI that evolved into a Stage 3, Stage 4, or unstageable hospital-acquired pressure ulcers (HAPU) in the ICU were included. Control group data were obtained from a sample of ICU patients who did not develop a DTI during 1 random day during that time period. Data were extracted from electronic medical records to compare ICU patients that developed a DTI (n = 47; age 55 [range 28-93] years, 28 men) to those who did not develop a DTI (n = 72; age 58.9 [range 18-94] years, 46 men). Twenty-five (25) potential sociodemographic and clinical risk factors were identified from root cause analysis and measured for significance. Systolic and diastolic blood pressure, length of surgery, hematocrit levels, international ratio, dialysis treatments, history of shock or vasopressor use, and total Braden score were significantly (P <.05) different between the general and HAPU population. Braden scores were low for general ICU (15.0 ± 0.4) and HAPU patients (12.9 ± 0.3) (P = 0.03). Multivariate, univariate, and regression analysis showed patients with poor perfusion (low blood pressure) (OR 0.93; 95% CI 0.88-0.99), prolonged surgical procedures (time in surgery OR 1.20; 95% CI 1.07-1.33), or a history of dialysis (OR 4.0; 95% CI 0.060-0.99) and shock (OR 10.0; 95% CI 0.025-0.43) were at greatest risk for the development of DTI evolving into a Stage 3, Stage 4, or unstageable HAPU. For every mm Hg decrease in diastolic blood pressure, the odds of a DTI increased by approximately 7.5% (1/0.93 = 1.075). For every hour increase in surgery, the odds of developing a DTI increased by 20%. These data suggest when all modifiable (Braden Scale-identified) risk factors are addressed, as was the case in this population, patient-related risk factors may be more important for HAPU development in ICU patients than quality of nursing care variables. Future research should focus on the role of and methods to increase perfusion to prevent DTI development, especially during dialysis and surgical procedures.


A Drug to Prevent Pediatric Myopia-What Would it Take?
Because of the epidemic of myopia with both its short-term and long-term effects, we desperately need ways to slow myopic progression. In this study which was part of a myopia prevention symposium, the author answers the following question: Assuming that researchers did come up with a pharmacological treatment to slow myopic progression-what would it take to obtain regulatory approval from the United States Food and Drug Administration (FDA)? Previous publicly available information (a 2003 FDA advisory committee on this topic, International Conference on Harmonisation guidances on drug development, and published articles) as well as the author's experience is used. Development pathways including preclinical safety, chemistry, manufacturing and controls, and early- and late-stage clinical studies are presented. In particular, challenges for the conduct of multi-year controlled double-masked studies are presented. As any treatment would have to be chronic, prophylactic, and pediatric, there are a host of concerns as to efficacy, safety, and benefit/risk (therapeutic index). Although more challenging than some short-term indications in ophthalmology, nonetheless the pharmaceutical community is investing in seemingly equally challenging conditions such as retinal degeneration. The author looks forward to working with colleagues in academia and industry to evaluate and develop novel therapies to slow the development of myopia.


Body mass index and waist circumference in midchildhood and adverse cardiovascular disease risk clustering in adolescence.
Body mass index (BMI) may not indicate the level of central adiposity associated with the clustering of cardiovascular disease (CVD) risk factors. Hence, it has been recommended that waist circumference be used as an alternative measure. The objective was to investigate whether waist circumference in midchildhood is more effective at predicting cardiovascular disease risk clustering in adolescence than is BMI. Anthropometric measurements were made in 342 children aged 8 y. Seven years later, anthropometric measurements were made in 290 participants, and metabolic profiles were determined in 172 participants. At 15 y, between 9.4% and 11.0% of adolescents were defined as having CVD risk clustering. Children who were overweight or obese at 8 y of age were 7 times (odds ratio: 6.9; 95% CI: 2.5, 19.0; P < 0.001) as likely to have CVD risk clustering in adolescence than were their peers who were not overweight or obese. Those with an increased waist circumference at 8 y were 4 times (3.6; 1.0, 12.9; P = 0.061) as likely to have CVD risk clustering in adolescence than were children with a smaller waist circumference. Neither BMI nor waist circumference were predictive of CVD risk clustering if adiposity was not included as a risk factor. The association between measures of adiposity in midchildhood and later adverse CVD risk is a result of the tracking of adiposity status. Our results do not support the need to measure waist circumference in children, in addition to BMI, to identify those at increased risk of CVD risk factor clustering in adolescence.


Which of 51 Plate Designs Can Most Stably Fixate the Fragments in a Fracture of the Mandibular Condyle Base?
In the surgical treatment of the most common fracture of the mandible, which is a fracture of the condylar base, a great choice of different plate shapes is observed. The aim of this study was to determine which shape gives the greatest fixation stiffness. To ensure homogeneity in comparison, tests were performed on polyurethane models divided at the level of the condylar base fracture and each were fixed with 51 plates. The plates were cut from a 1 mm thick grade 23 titanium sheet. The models were then loaded and the force required for 1 mm of fracture displacement was recorded. It was noted that in addition to osteosynthesis from two simple plates, there were also two dedicated single plates with similar rigidity. Among the large number of described designs of plates, there is considerable variation in terms of the stability of the fixation performed with them. The proposed Mechanical Excellence Factor allows a pre-evaluation of the expected rigidity of fixation with a given plate shape without the need for a loading experiment. The authors expect this to be helpful for surgeons in the application of relevant plates, as well for inventors of new plates for the osteosynthesis of basal fractures in mandibular condyle.


Comparison Study of Two Differently Clicked 18F-Folates-Lipophilicity Plays a Key Role.
Within the last decade, several folate-based radiopharmaceuticals for Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) have been evaluated; however, there is still a lack of suitable 18F-folates for clinical PET imaging. Herein, we report the synthesis and evaluation of two novel 18F-folates employing strain-promoted and copper-catalyzed click chemistry. Furthermore, the influence of both click-methods on lipophilicity and pharmacokinetics of the 18F-folates was investigated. 18F-Ala-folate and 18F-DBCO-folate were both stable in human serum albumin. In vitro studies proved their high affinity to the folate receptor (FR). The lipophilic character of the strain-promoted clicked 18F-DBCO-folate (logD = 0.6) contributed to a higher non-specific binding in cell internalization studies. In the following in vivo PET imaging studies, FR-positive tumors could not be visualized in a maximum intensity projection images. Compared with 18F-DBCO-folate, 18F-Ala-folate (logD = -1.4), synthesized by the copper-catalyzed click reaction, exhibited reduced lipophilicity, and as a result an improved in vivo performance and a clear-cut visualization of FR-positive tumors. In view of high radiochemical yield, radiochemical purity and favorable pharmacokinetics, 18F-Ala-folate is expected to be a promising candidate for FR-PET imaging.


Five-year outcomes following a randomized trial of femorofemoral and femoropopliteal bypass grafting with heparin-bonded or standard polytetrafluoroethylene grafts.
Cohort studies suggest superior long-term patency of luminal heparin-bonded polytetrafluoroethylene (Hb-PTFE) bypass grafts compared with standard PTFE grafts. The aim of this study was to compare the outcomes of Hb-PTFE grafts with those of standard PTFE grafts 5 years after a randomized trial. Patients with intermittent claudication or critical limb ischaemia requiring femorofemoral or femoropopliteal bypass grafting were randomized in a clinical trial of Hb-PTFE versus standard PTFE in 11 Scandinavian centres between 2005 and 2009. Patients were followed up for 5 years with clinical assessment and surveillance Duplex ultrasound imaging. The primary endpoint of this study was primary patency. Secondary endpoints included major amputation and mortality. Overall, 569 patients were enrolled in the randomized trial. Some 552 had follow-up data available for analysis of the primary outcome. Use of Hb-PTFE significantly improved patency by 37 per cent at 2 years, but 5 years after randomization there was no difference in primary patency (adjusted hazard ratio (HR) 0·95, 95 per cent c.i. 0·71 to 1·28; P = 0·748). In patients with critical limb ischaemia the use of Hb-PTFE reduced the 5-year risk of loss of primary patency by 37 per cent (HR 0·63, 0·40 to 0·99; P = 0·049). In this study there was no difference in primary graft patency between Hb-PTFE and standard PTFE grafts. Patients receiving Hb-PTFE grafts for critical limb ischaemia were more likely to have a patent graft at 5 years than those with standard PTFE grafts.


The disappearing exostosis? A report of an unusual case.
A girl aged 11 years was referred to us with a medial upper right tibial exostosis. As the lesion was asymptomatic, surgery was not undertaken. The patient defaulted from follow up, and, when reviewed 32 months later, there was no clinical or radiographic evidence of the exostosis. Spontaneous involution of an exostosis may occasionally occur in childhood.


Isolated hamstrings fatigue alters hip and knee joint coordination during a cutting maneuver.
The aim of this study was to determine the effects of hamstrings fatigue on lower extremity joint coordination variability during a sidestep cutting maneuver. Twenty female recreational athletes performed five successful trials of a sidestep cutting task pre- and postfatigue. Each participant completed an isolated hamstrings fatigue protocol consisting of isokinetic maximum effort knee flexion and passive extension contractions. Vector coding was used to examine hip and knee joint couplings (consisting of various planar motions) during the impact and weight acceptance phases of the sidestep cut stance phase. Paired t tests were used to analyze differences of each phase as an effect of fatigue, where alpha was set a priori at .05. The hip rotation/knee rotation coupling exhibited a significant decrease in coordination variability as a function of fatigue in both the impact (P = .015) and weight acceptance phases (P = .043). Similarly, the hip adduction-abduction/knee rotation coupling exhibited a significant decrease in coordination variability in the weight acceptance phase (P = .038). Hamstrings fatigue significantly decreased coordination variability within specific lower extremity joint couplings that included knee rotation. Future studies should be conducted to determine if this decrease in coordination variability is related to lower extremity injury mechanisms.


Exteroceptive stimuli override interoceptive state in reaction time control.
The processing of reaction time (RT) stimulus is modulated by its timing relative to the cardiac cycle. RT stimulus processing is also influenced by task-irrelevant stimuli: a sensory stimulus speeds RT when it accompanies a cue to react in another sensory modality. Different theories have been proposed to explain this accessory stimulus effect (ASE). However, it is unclear whether the ASE interacts with the cardiac timing effect. In the present study, the relationship of the ASE, cardiac timing, and stimulus valence was examined. Fifty-two subjects performed 400 trials of a simple RT task. Images of neutral and fear faces served as visual accessory stimuli; the RT stimulus was a 75 dB tone. Electrocardiography was recorded. Visual and auditory stimuli were presented at either cardiac systole or diastole. The stimulus onset asynchrony between visual and auditory stimuli was either 0 or 75 ms. Repeated measures ANOVAs showed that cardiac timing modulated RT, but only when accessory stimuli were absent. RT was shorter when the accessory stimulus preceded the imperative stimulus with respect to simultaneous presentation. The ASE was not influenced by visual stimulus valence or cardiac timing. Results indicate that the ASE overrides cardiac timing effects, suggesting a dynamic balance between exteroceptive stimuli and interoceptive states, and highlight the importance of embodied information processing.


Quantitative Profiling of Endogenous Fat-Soluble Vitamins and Carotenoids in Human Plasma Using an Improved UHPSFC-ESI-MS Interface.
Analytical solutions enabling the quantification of circulating levels of liposoluble micronutrients such as vitamins and carotenoids are currently limited to either single or a reduced panel of analytes. The requirement to use multiple approaches hampers the investigation of the biological variability on a large number of samples in a time and cost efficient manner. With the goal to develop high-throughput and robust quantitative methods for the profiling of micronutrients in human plasma, we introduce a novel, validated workflow for the determination of 14 fat-soluble vitamins and carotenoids in a single run. Automated supported liquid extraction was optimized and implemented to simultaneously parallelize 48 samples in 1 h, and the analytes were measured using ultrahigh-performance supercritical fluid chromatography coupled to tandem mass spectrometry in less than 8 min. An improved mass spectrometry interface hardware was built up to minimize the post-decompression volume and to allow better control of the chromatographic effluent density on its route toward and into the ion source. In addition, a specific make-up solvent condition was developed to ensure both analytes and matrix constituents solubility after mobile phase decompression. The optimized interface resulted in improved spray plume stability and conserved matrix compounds solubility leading to enhanced hyphenation robustness while ensuring both suitable analytical repeatability and improved the detection sensitivity. The overall developed methodology gives recoveries within 85-115%, as well as within and between-day coefficient of variation of 2 and 14%, respectively.


Compensatory growth, condition and food utilization in barbel Barbus barbus juveniles reared at different feeding periodicities with a dry diet.
In a 40 day experiment, barbel Barbus barbus juveniles were fed a dry diet continuously, or food was withheld for 2, 5 or 10 days, and then resumed feeding. Improved feed utilization efficiency allowed fish deprived of food for 2 or 5 days to fully compensate for body mass loss. Short-term food deprivation as a method of preventing negative effects of overfeeding in intensive rearing of juvenile B. barbus is proposed.


Preoperative Frailty Score for 30-Day Morbidity and Mortality After Cranial Neurosurgery.
Evaluating preoperative frailty is critical for guiding shared surgical decision-making. The purpose of this study was to develop a novel preoperative frailty index for classification of adverse outcomes following cranial neurosurgery procedures. The American College of Surgeons National Surgical Quality Improvement Program database was queried for all cranial neurosurgery cases from 2006 to 2014. Sequential univariate and multivariate testing was used to identify significant independent predictors of 30-day mortality. Frailty scores were computed by summating across weighted predictors. Receiver operating characteristic curve analysis quantified the discriminative capacity of the frailty score for classifying mortality and other major adverse outcomes. List-wise exclusion of patients with incomplete datasets yielded a final sample of 27,098 patients (mortality rate = 3.9%). Multivariate regression testing identified 19 independent predictors of 30-day mortality. Receiver operating characteristic curve analysis revealed impressive outcome discrimination (area under the curve = 0.87, P < 0.001, optimal classification accuracy = 83.0%). Patients in the "high-risk" group (score ≥4, n = 5155) had significantly increased risk for mortality (15.4%) and major adverse outcomes (32.0%) compared with patients in the "low-risk" group (n = 21,943, mortality = 1.2%, major adverse outcomes = 4.0%). The frailty score remained highly discriminative across all age groups examined. Neurosurgical patients undergo extensive preoperative evaluation, but the field currently lacks a robust bedside scoring system for quantifying patient frailty. In this study, we introduced a novel preoperative frailty index capable of classifying 30-day morbidity and mortality outcomes following cranial neurosurgeries.


Misclassification of genetic susceptibility biomarkers: implications for case-control studies and cross-population comparisons.
Phenotype and genotype markers of genetic susceptibility are of increasing interest in case-control studies of cancer. It is well established that bias to the odds ratio is caused by less-than-perfect assay sensitivity and specificity and varies with risk factor prevalence. As such, the observed variation in odds ratio between studies of genetic markers and cancer risk may be real, or may be attributed, in part, to variation in assay accuracy or in risk factor prevalence (e.g., prevalence differences between racial groups). The latter can be a particular concern when the prevalence of the "at risk" polymorphism in one or more populations is either very high (e.g., > 85%) or very low (e.g., < 15%). For example, even very high sensitivity (e.g., 98%) can produce substantial bias to the odds ratio when the risk factor prevalence is high. Under some prevalence conditions, however, assays with only moderate accuracy are sufficient and result in minimal bias to the odds ratio. Understanding misclassification in the context of marker prevalence may help to explain disparate findings in the literature and should assist investigators in selecting markers that are appropriate for future studies.


Association study of six candidate genes with major depressive disorder in the North-Western population of Pakistan.
People around the world are currently affected by Major Depressive Disorder (MDD). Despite its many aspects, symptoms, manifestations and impacts, efforts have been made to identify the root causes of the disorder. In particular, genetic studies have concentrated on identifying candidate genes for MDD and exploring associations between these genes and some specific group of individuals. The aim of this research was to find out the association between single nucleotide polymorphisms in 6 candidate genes linked to the neurobiology of major depressive disorder in the North-Western population of Pakistan. We performed a case-control analysis, with 400 MDD and 232 controls. A trained psychiatrist or clinical psychologists evaluated the patients. Six polymorphisms were genotyped and tested for allele and genotype association with MDD. There were no statistical variations between MDD patients and healthy controls for genotypic and allelic distribution of all the polymorphisms observed. Thus, our analysis does not support the major role of these polymorphisms in contributing to MDD susceptibility, although it does not preclude minor impact. The statistically significant correlation between six polymorphisms and major depressive disorder in the studied population was not observed. There are inconsistencies in investigations around the world. Future research, including GWAS and association analysis on larger scale should be addressed for further validation and replication of the present findings.


The functional assessment Berg Balance Scale is better capable of estimating fall risk in the elderly than the posturographic Balance Stability System.
The purpose of this study was to verify which instrument better identifies recurrent falls in the elderly. Ninety-eight old people, with an average age of 80 ± 4 years, were submitted to an assessment of balance and fall risk by means of the Berg Balance Scale (BBS) and the posturographic Balance Stability System (BSS). The BBS was correlated with the BSS (r=-0.27; p=0.008), age (r=-0.38; p<0.001) and number of falls (r=-0.25; p=0.013) and the analysis of logistical regression showed that the elderly classified with fall risk on the BBS presented 2.5 (95%CI 1.08-5.78) more chance of identifying who had two falls or more over the last year. The BBS identified that the greater the age the worse the functional balance and demonstrated a greater capacity to identify falls risk suffered over the last year when compared with the BSS.


[Efficacy of Human Immunodeficiency Virus (HIV) Antigen-Antibody Combination Assay as a Screening Test and Factors Causing False-Positivity].
We aimed to evaluate the performance of an HIV antigen-antibody combination assay (fourth-generation) by comparing it with second generation assays that detect anti-HIV. A total of 105,439 HIV screening tests were performed from January 2004 to March 2015; the second - and fourth generation assays were used for 75,302 and 30,137 samples, respectively. Samples positive on a screening test were confirmed by anti-HIV-1 western blotting (WB) and nucleic acid amplification. By the results of confirmation tests, the efficacies of the second and fourth generation assays were estimated. The clinical backgrounds with false-positive samples were examined. Of 75,302 samples, 136(0.18%) were positive by the second-generation assay; 14 were confirmed positives, and 122 were false positives. Of 30,137 samples, 18(0.06%) were positive by the fourth-generation assay; 6 were confirmed positives, and 12 were false positives. The reliability of the positives by fourth-generation assay was significantly improved (p=0.006) Samples form individuals with malignant neoplasms were frequently false positive by both the second and fourth-generation assays. Of 67 samples performed by WB, 10 samples, including 6 from patients with a malignancy, showed indeterminate results. All indeterminate samples were found to have antibodies responding to HIV core protein. The fourth-generation assay had satisfactory reliability of the positives for HIV screening. Antibodies responding to HIV core protein may result in false positive HIV screening tests. [Original]


[Ocular complications of local anaesthesia in dentistry].
An estimated 1 in 1,000 local anaesthetic injections in the maxilla or the mandible lead to unwanted effects on the ipsilateral eye. We have seen a case with diplopia and lateral rectus palsy following bimaxillary anaesthesia. A systematic literature review of reports on this type of complication resulted in a total of 144 documented cases published between 1936 and 2016. The most frequently reported symptoms included diplopia (72%), partial or full ophthalmoplegia (26%), ptosis (22%), mydriasis (18%), amaurosis (13%) and orbital pain (12%). This type of complication is best understood by pathophysiological hypotheses that include intra-arterial injection, intravenous injection, autonomic dysregulation, or deep injection and diffusion. If ocular symptoms appear after local intraoral anaesthesia, the patient should be reassured. In the case of diplopia, the eye should be covered with a gauze dressing, and the patient should be instructed about associated safety risks. If symptoms persist or when vision deteriorates, referral to an ophthalmologist is advisable.


New pieces to the lanthanide puzzle.
Recently, rare-earth elements lanthanides (Ln3+ ) have emerged as enzyme cofactors of methanol dehydrogenases of the XoxF type. It is now understood that XoxF enzymes can functionally replace the alternative, calcium-dependent, MxaFI-type methanol dehydrogenases, when Ln3+ are available. These rare-earth metals are not only essential for XoxF activity, but they also regulate gene expression, in a reverse fashion, activating the expression of XoxF and repressing the expression of MxaFI. This type of regulation has created multiple conundrums, including the details of the solubility, transport, sensing and selection mechanisms for Ln3+ by the bacterial cells, as well as the questions relevant to the evolution of the alternative enzymes and their potentially different redox properties. Overall, the newly discovered biological activity of Ln3+ presents a big puzzle. Ochsner et al. add several pieces to this puzzle, utilizing a model phyllosphere colonizer Methylobacterium extorquens PA1. They determine that Ln3+ sensing by this organism can take place via both XoxF-dependent and XoxF-independent mechanisms. They also identify genes for a TonB-dependent transporter and an ABC-type transporter and demonstrate that both are essential for Ln3+ -dependent methanol metabolism. The puzzle still requires multiple additional pieces for completion, but great strides have been made toward the goal of solving it.


Widely tunable telecom MEMS-VCSEL for terahertz photomixing.
We report frequency-tunable terahertz (THz) generation with a photomixer driven by an ultra-broadband tunable micro-electro-mechanical system vertical-cavity surface-emitting laser (MEMS-VCSEL) and a fixed-wavelength VCSEL, as well as a tunable MEMS-VCSEL mixed with a distributed feedback (DFB) diode. A total frequency span of 3.4 THz is covered in direct detection mode and 3.23 THz in the homodyne mode. The tuning range is solely limited by the dynamic range of the photomixers and the Schottky diode/photoconductor used in the experiment.


Prognosis for intracerebral hemorrhage during ongoing oral anticoagulant treatment.
Intracerebral hemorrhage (ICH) is the most serious adverse effect of treatment with oral anticoagulants. Prognostic data after ICH associated with non-vitamin K antagonist oral anticoagulants (NOAC) compared to vitamin K antagonists (VKA) are sparse. We compared 90-day survival and functional outcome following NOAC-ICH versus VKA-ICH using data from the Swedish Stroke Register (Riksstroke). Using data from Riksstroke and the Swedish Causes of Death Register between 2012 and 2016, we compared all-cause 90-day mortality for patients with NOAC-ICH versus VKA-ICH using Kaplan-Meier survival analysis and Log-rank test. Cox regression, with adjustment for age, sex, previous stroke, and level of consciousness (LOC) on admission, was used to estimate hazard ratios (HR) for 90-day mortality. Estimated functional outcome at 90 days, based on the modified Rankin Scale (mRS), was compared between VKA- and NOAC-associated ICH using chi-squared test. We included 2483 patients; 300 with NOAC-ICH and 2183 with VKA-ICH. In both groups, mean age was 79 years, and 58% were male. No significant difference between NOAC-ICH and VKA-ICH was found for all-cause 90-day mortality (44.3% NOAC-ICH versus 42.6% VKA-ICH; P = 0.54, HR = 0.93; 95% confidence interval (CI): 0.78-1.12) or 90-day estimated functional outcome (mRS 0-2:13.7% and 15.3%; mRS 3-5:27.3% and 28.9%, respectively (P = 0.52)). Factors predicting death were increased age (HR = 1.03; 95%CI: 1.02-1.04) and reduced LOC (drowsy: HR = 3.48; 95%CI: 2.86-4.23; comatose: HR = 12.27; 95%CI: 10.13-14.87). In this large study on anticoagulant-associated ICH, we found no significant difference in mortality and functional outcome at 90 days between NOAC-ICH versus VKA-ICH.


Rotational ankle instability: A current concept review.
Ankle sprains are extremely common. It is important to have a clear insight of the course of recovery after such injury to evaluate the effective strategies to guide management decisions, and understand the potential risk factors involved in the development of chronic problems and recurrent ankle sprains. When a prompt diagnosis is not formulated, ligament tears can remain untreated, and chronic ankle instability can result after acute lateral or medial ankle sprain. When the medial ligament complex (MLC), in particular the anterior fascicle of the deltoid ligament, is involved, rotational ankle instability (RAI) can develop. Generally, a tear of the anterior fibres of the MCL accompanied by anterior talofibular ligament (ATFL) insufficiency has been associated with RAI, while injury of the intermediate fibres of the MLC has been associated with medial ankle instability (MAI). Conservative management is the first line of treatment, with surgery reserved for special cases or if rehabilitation has failed. Regarding surgery, several options are available, including anatomic repair, anatomic reconstruction, and tenodesis procedures. Ankle arthroscopy is increasingly used to address ligament insufficiency and to identify and treat intra-articular pathologies. Repair of MLC tears by an arthroscopic all-inside procedure is effective in both MAI and RAI.


Repeatability and reproducibility of optic nerve head perfusion measurements using optical coherence tomography angiography.
Optical coherence tomography angiography (OCTA) has increasingly become a clinically useful technique in ophthalmic imaging. We evaluate the repeatability and reproducibility of blood perfusion in the optic nerve head (ONH) measured using optical microangiography (OMAG)-based OCTA. Ten eyes from 10 healthy volunteers are recruited and scanned three times with a 68-kHz Cirrus HD-OCT 5000-based OMAG prototype system (Carl Zeiss Meditec Inc., Dublin, California) centered at the ONH involving two separate visits within six weeks. Vascular images are generated with OMAG processing by detecting the differences in OCT signals between consecutive B-scans acquired at the same retina location. ONH perfusion is quantified as flux, vessel area density, and normalized flux within the ONH for the prelaminar, lamina cribrosa, and the full ONH. Coefficient of variation (CV) and intraclass correlation coefficient (ICC) are used to evaluate intravisit and intervisit repeatability, and interobserver reproducibility. ONH perfusion measurements show high repeatability [CV≤3.7% (intravisit) and ≤5.2% (intervisit)] and interobserver reproducibility (ICC≤0.966) in all three layers by three metrics. OCTA provides a noninvasive method to visualize and quantify ONH perfusion in human eyes with excellent repeatability and reproducibility, which may add additional insight into ONH perfusion in clinical practice.


A Comparative Study of Vasorelaxant Effects of ATP, ADP, and Adenosine on the Superior Mesenteric Artery of SHR.
We investigated superior mesenteric arteries from spontaneously hypertensive rats (SHR) to determine the relaxation responses induced by ATP, ADP, and adenosine and the relationship between the relaxant effects of these compounds and nitric oxide (NO) or cyclooxygenase (COX)-derived prostanoids. In rat superior mesenteric artery, relaxation induced by ATP and ADP but not by adenosine was completely eliminated by endothelial denudation. In the superior mesenteric arteries isolated from SHR [vs. age-matched control Wistar Kyoto rats (WKY)], a) ATP- and ADP-induced relaxations were weaker, whereas adenosine-induced relaxation was similar in both groups, b) ATP- and ADP-induced relaxations were substantially and partly reduced by N(G)-nitro-L-arginine [a NO synthase (NOS) inhibitor], respectively, c) indomethacin, an inhibitor of COX, increased ATP- and ADP-induced relaxations, d) ADP-induced relaxation was weaker under combined inhibition by NOS and COX, and e) adenosine-induced relaxation was not altered by treatment with these inhibitors. These data indicate that levels of responsiveness to these nucleotides/adenosine vary in the superior mesenteric arteries from SHR and WKY and are differentially modulated by NO and COX-derived prostanoids.


Unexpected presentation of ischemic colitis: a case report and review of the literature.
Ischemic colitis accounts for many cases of bowel infarction. Usually, it has various manifestations, such as vomiting, abdominal pain, hematochezia and many other symptoms. Risk factors might include age, medications, hypercoagulable state and chronic illnesses. However, it can still occur in healthy young patients. This might make it difficult for physicians to establish a correct diagnosis and generate the appropriate treatment plan for patients suffering from ischemic colitis. In this case we report a previously healthy 37-year-old female who had a sudden onset of lower abdominal pain associated with hematochezia. This patient was treated for upper respiratory tract infection by amoxicillin-clavulanate 2 weeks prior to her symptoms. The computed tomography abdomen findings along with the exploratory laparotomy confirmed the diagnosis of ischemic colitis. Ischemic colitis is a serious condition with high mortality and morbidity rate. Therefore, prompt investigation, and if indicated, surgical intervention should be calculated in sick patients complaining of abdominal pain and lower gastrointestinal bleeding.


Effect of butylphthalide intervention on experimental autoimmune myositis in guinea pigs.
Idiopathic inflammatory myopathies are a group of rare muscular diseases that are characterized by acute, subacute or chronic proximal and symmetric muscle weakness, muscle fiber necrosis and infiltration of inflammatory cells, particularly activated CD8+ cytotoxic T cells and phagocytes. 3-n-butylphthalide (NBP) protects mitochondria and reduces the inflammatory response in multiple disease models. In myositis, it has remained elusive whether NBP can protect muscle cells from muscle fiber injury. Experimental autoimmune myositis (EAM) was induced in a total of 40 guinea pigs by myosin immunization. After 4 weeks, low- or high-dose NBP solution was intraperitoneally injected. Saline solution was used as a negative control. After 10 days, the clinical manifestations were assessed by determining rodent grasping power, histopathological changes, Ca2+-adenosinetriphosphatase (ATPase) activity by an ATPase kit, and mRNA expression of interferon (IFN)-γ, retinoic acid receptor-related orphan nuclear receptor (ROR)γt and forkhead box (Fox) p3 in muscle tissue by reverse-transcription quantitative polymerase chain reaction analysis. It was demonstrated that NBP improved the myodynamia of guinea pigs with EAM and reduced the pathological inflammatory cell infiltration in a dose-dependent manner. NBP improved the Ca2+-ATPase activity of the muscle mitochondrial membrane and muscle plasma membrane in animals with EAM. It also reduced the mRNA expression of IFN-γ and RORγt, and significantly increased the mRNA expression of Foxp3 in muscle tissue. These results provided a basis for the consideration of NBP as a novel agent for the treatment of myositis and other muscular diseases associated with autoimmunity and inflammation.


Derivatization of steroids in biological samples for GC-MS and LC-MS analyses.
The determination of steroids in biological samples is essential in different areas of knowledge. MS combined with either GC or LC is considered the best analytical technique for specific and sensitive determinations. However, due to the physicochemical properties of some steroids, and the low concentrations found in biological samples, the formation of a derivative prior to their analysis is required. In GC-MS determinations, derivatization is needed for generating volatile and thermally stable compounds. The improvement in terms of stability and chromatographic retention are the main reasons for selecting the derivatization agent. On the other hand, derivatization is not compulsory in LC-MS analyses and the derivatization is typically used for improving the ionization and therefore the overall sensitivity achieved.


Comparison of visual outcomes for aspheric and spherical toric intraocular lens implantation in cataract patients with pre-existing corneal astigmatism: a randomized control trial.
With spherical intraocular lens (IOL) implantation, unaided vision of cataract patients with pre-existing corneal astigmatism is unsatisfactory because astigmatic spectacles will always be needed for clear vision. Toric IOL has been proven to be a major improvement in cataract surgery for spectacle independence. Aspheric property, reported to improve visual quality in a non-toric IOL, has now been added to toric IOL for even better unaided vision. To compare visual and aberrometric outcomes of 2 toric IOL, spherical and aspheric, at 3 months after implantation. Cataract surgery was performed in cataract patients with pre-existing corneal astigmatism using 2 types of toric IOLs, a spherical toric IOL, Acrys of SN60T (Group A) and a aspheric toric IOL, Acrts of SN6AT, (Group B) as a randomized control trial. The uncorrected distance (UDVA) and corrected (CDVA) distance visual acuities, residual astigmatism, spherical equivalent (SE) and spherical aberration were evaluated 3 months after implantation. The present study included 44 eyes. No statistically significant difference was found in UDVA, CDVA and residual astigmatism between both groups. The UDVA of 0.1 logMAR or better was found in 78.26% in Group A and 85.71% in Group B. In Group A, 78.26% of eyes and in Group B, 76.19% had a refractive astigmatism value within 0.50 diopter at KP90 (polar value along the 90-degree meridian). The spherical equivalent (SE) was within ±0.5 diopter of emmetropia in 91.30% in Group A and in 80.95% in Group B. Group B had significantly lower spherical aberration Z (4, 0) than Group A. Both groups had similar clinical effectiveness for unaided visual acuity, aided visual acuity and astigmatism correction. Group B had significantly less spherical aberration induction when compared with Group A.


Doctors' assistants and what they do in The Netherlands.
In the Netherlands the title "doctor's assistant" is used by variously qualified, or even unqualified, people who perform a range of duties in support of general practitioners. The working day of the author, a qualified assistant, is outlined below.


Approach to cardiovascular disease prevention in patients with chronic kidney disease.
Chronic kidney disease (CKD) is associated with a large burden of cardiovascular risk factors ultimately leading to increased cardiovascular events and mortality. Prevention of cardiovascular disease (CVD) in CKD involves early identification of individuals at high-risk of renal disease. In fact, substantial evidence points to a complex bidirectional relationship between CKD and CVD. Therefore, most interventions directed at CKD prevention should include multiple risk factor interventions with the goal of preventing CVD events while slowing progression of CKD. Clearly, prevention of CVD in CKD is a complex task and requires a multidisciplinary team approach, with a well-defined program, rational targets for each risk factor, and implementation of the most effective intervention strategies. Although several interventions to prevent CVD have proven effective in the general population and in individuals at high risk for CVD, a true benefit in patients with CKD remains to be demonstrated for several of them. A few rational targets of intervention should be optimal blood pressure control, reduction of proteinuria, treatment of dyslipidemia, good control of diabetes, smoking cessation, dietary salt restriction, achievement of normal body mass index, partial correction of anemia, and management of mineral metabolism abnormalities. Lifestyle modification and pharmacological therapy with renin-angiotensin blockers, β-blockers, diuretics, statins, and aspirin should be encouraged in the early stages of CKD.


[Are SPA therapy and pulsed electromagnetic field therapy effective for chronic neck pain? Randomised clinical trial. Second part: medicoeconomic approach].
We report the results of a cost-effectiveness evaluation of pulsed electromagnetic field (PEMF) therapy and spa therapy (ST) versus usual care (control) for chronic neck pain. Inclusion criteria were age 18 to 80 years with pain in the neck area of more than 3 months' duration and no contraindications for PEMF therapy and ST. Randomization to the ST (n=25) and PEMF groups (n=26) was blinded, as was collection of data. Non-included subjects (n=29) underwent usual care. The trial respected the Helsinki declaration, and informed consent was obtained from subjects. The analysis was intent to treat; the main outcome measure was increase in health dimension scores on the MOS SF-36 in terms of increase in French health care costs from 6 months preceding to 6 months after the start of the study. The increase in health care costs was less for the PEMF group (+68 euro+/-539 [95% confidence interval (CI)]: -145.0+281) than the ST and control groups. The increase tended to be less, but not significantly, for the ST group (+373+/-938 euro [95% CI, -14.0+76.0]) than for controls (+618+/-2715 euro [95% CI, -434.0+167.0]). The gain of one physical MOS SF-36 unit during one year cost 3400 euro [95% CI, -6759+13 100] for the PEMF group, 29,000 euro [95% CI, -1093+59 375] for the ST group and 95076 euro [95% CI, -66 769+256 923] for the control group, but the differences were not significant. These results suggest a potential cost-effectiveness for ST and particularly PEMF as compared to usual care in chronic cervical pain. Our results perhaps lack significance probably because of lack of statistical power and do not distinguish costs related or not to chronic cervical pain.


Microflow-Based Device for In Vitro and Ex Vivo Drug Permeability Studies.
This paper presents a novel microflow-based concept for studying the permeability of in vitro cell models or ex vivo tissues. Using the proposed concept, we demonstrate how to maintain physiologically relevant test conditions and produce highly reproducible permeability values for a range (31) of drug compounds. The apparent permeability coefficients (Papp) showed excellent correlation (0.89) with the values from experiments performed with a conventional Ussing chamber. Additionally, the microflow-based concept produces notably more concentrated samples than the conventional Ussing chamber-based approach, despite the fact that more than 10 times smaller quantities of test compounds and biological membranes are needed in the microflow-based concept.


Periprocedural anticoagulation of patients undergoing pericardiocentesis for cardiac tamponade complicating catheter ablation of atrial fibrillation.
Anticoagulation of patients with cardiac tamponade (CT) complicating catheter ablation of atrial fibrillation (AF) is an ongoing problem. The aim of this study was to survey the clinical practice of periprocedural anticoagulation in such patients. This study analyzed the periprocedural anticoagulation of 17 patients with CT complicating AF ablation. Emergent pericardiocentesis was performed once CT was confirmed. The mean drained volume was 410.0 ± 194.1 mL. Protamine sulfate was administered to neutralize heparin (1 mg neutralizes 100 units heparin) in 11 patients with persistent pericardial bleeding and vitamin K1 (10 mg) was given to reverse warfarin in 3 patients with supratherapeutic INR (INR > 2.1). Drainage catheters were removed 12 hours after echocardiography confirmed absence of intrapericardial bleeding and anticoagulation therapy was restored 12 hours after removing the catheter. Fifteen patients took oral warfarin and 10 of them were given subcutaneous injection of LMWH (1 mg/kg, twice daily) as a bridge to resumption of systemic anticoagulation with warfarin. Two patients with a small amount of persistent pericardial effusion were given LMWH on days 5 and 13, and warfarin on days 6 and 24. The dosage of warfarin was adjusted to keep the INR within 2-3 in all patients. After 12 months of follow-up, all patients had no neurological events and no occurrence of delayed CT. The results showed that it was effective and safe to resume anticoagulation therapy 12 hours after removal of the drainage catheter. This may help to prevent thromboembolic events following catheter ablation of AF.


Applications of bilateral vascularized femoral bone marrow transplantation for chimerism induction across the major histocompatibility (MHC) barrier: part II.
Bilateral vascularized bone marrow transplant (VBMT) model was designed to induce chimerism across the major histocompatibility (MHC) barrier under combined alphabeta T-cell receptor monoclonal antibody and cyclosporine A (alphabeta-TCRmAb/CsA) protocol. Seventeen transplants were performed between BN(RT1) donors and Lewis(RTI) recipients. Group I, isograft controls; Group II, allografts rejection controls; Group III, allografts under 7-day protocol of alphabeta-TCRmAb/CsA. Donor bilateral femoral bones were bilaterally anastomosed to the abdominal aorta and inferior vena cava of recipient. At day 7 posttransplantation, all bone flaps were viable. Groups I and III survived without signs of rejection. In Group III, peak level of chimerism in peripheral blood was evaluated at day 21 (24.2%), at day 63 declined to 1.5%, and was maintained at this level thereafter. Donor-derived cells were present in the bone marrow of recipients at 28.2% at day 21 posttransplant. Histology confirmed viability of bone marrow cells in isograft during the entire follow-up and up to 35 days in treatment Group III. Bilateral VBMT induced donor-specific chimerism across the MHC barrier under the immunomodulatory protocol of alphabeta-TCRmAb/CsA.


Overview and proposed terminology for the reverse controlled antegrade and retrograde tracking (reverse CART) techniques.
During recent years, equipment and techniques for percutaneous coronary intervention (PCI) of chronic total occlusions (CTO) have improved significantly. The retrograde approach remains critical to the improved success of CTO PCI. Currently, the reverse controlled antegrade and retrograde tracking (CART) technique has become the dominant retrograde wire crossing technique. In this article, we propose a standardised terminology and classification for this technique divided into three subtypes: a) conventional reverse CART, usually involving the use of large balloons on the antegrade wire to achieve re-entry within the CTO segment; b) "directed" reverse CART, which is characterised by small antegrade balloon size and more active, intentional vessel tracking and penetration with a controllable retrograde wire, still within the CTO segment; and c) "extended" reverse CART, in which the intimal/subintimal dissection is extended proximal or distal to the CTO segment, achieving re-entry outside the CTO segment. The proposed standardised terminology will facilitate the communication, teaching and adoption of the reverse CART techniques.


Expression of human PKR protein kinase in transgenic mice.
There is a large amount of evidence describing the expression, interaction, and mode of activation of the human interferon (IFN)-mediated double-stranded RNA-activated protein kinase (PKR) gene. Studies from Pkr-null mice have defined the kinase as a transducer of dsRNA signals that converge on transcription, translation, and apoptotic programs involved in the innate resistance to viral infection. In vitro studies also suggest that PKR may possess important cell growth regulatory and tumor suppressor properties. However, the study of Pkr-null mice has not fully elucidated the role that the kinase plays in these processes, in part because of apparent redundancies in PKR-dependent and PKR-independent regulatory pathways. To overcome such limitations and to begin to examine the role of PKR in a complex biologic system, we have generated transgenic mice overexpressing wild-type human (Hu) PKR. HuPKR was expressed and active in various tissues and associated with a small body phenotype. Spleen cells from transgenic mice were resistant to apoptosis when treated with the genotoxic agent actinomycin D and showed a decrease in proliferation in response to concanavalin A (ConA) compared with spleen cells from wild-type control mice. The initial characterization of this transgenic mouse line suggests it may be useful as a model for investigating biology and diseases relative to a number of scientific disciplines.


Patterns of recruitment and injury in a heterogeneous airway network model.
In respiratory distress, lung airways become flooded with liquid and may collapse due to surface-tension forces acting on air-liquid interfaces, inhibiting gas exchange. This paper proposes a mathematical multiscale model for the mechanical ventilation of a network of occluded airways, where air is forced into the network at a fixed tidal volume, allowing investigation of optimal recruitment strategies. The temporal response is derived from mechanistic models of individual airway reopening, incorporating feedback on the airway pressure due to recruitment. The model accounts for stochastic variability in airway diameter and stiffness across and between generations. For weak heterogeneity, the network is completely ventilated via one or more avalanches of recruitment (with airways recruited in quick succession), each characterized by a transient decrease in the airway pressure; avalanches become more erratic for airways that are initially more flooded. However, the time taken for complete ventilation of the network increases significantly as the network becomes more heterogeneous, leading to increased stresses on airway walls. The model predicts that the most peripheral airways are most at risk of ventilation-induced damage. A positive-end-expiratory pressure reduces the total recruitment time but at the cost of larger stresses exerted on airway walls.


[Technique of transjugular intrahepatic portosystemic shunt: color Doppler US-guided paraumbilical vein puncture method].
The transjugular intrahepatic portosystemic shunt (TIPS) procedure is a percutaneous method for treating patients with symptomatic portal hypertension. One of the major technical difficulties of this procedure is the safe passage of a needle from the hepatic venous system into a major portal venous radical. The color US-guided paraumbilical vein puncture method involves percutaneous catheterization of a paraumbilical portosystemic collateral vein under sonographic guidance. We describe a method for portal venous localization that, while clearly not applicable in all candidates for TIPS, is easily and safely performed and should be considered a routine adjunct to the TIPS procedure when feasible.


Long-Term Use and Perceived Benefits of Goal-Oriented Attentional Self-Regulation Training in Chronic Brain Injury.
Primary Objective. To investigate the long-term use and perceived benefit(s) of strategies included in Goal-Oriented Attentional Self-Regulation (GOALS) training (Novakovic-Agopian et al., 2011) by individuals with acquired brain injury (ABI) and chronic executive dysfunction. Research Design. Longitudinal follow-up of training. Methods and Procedures. Sixteen participants with chronic ABI participated in structured telephone interviews 20 months (range 11 to 31 months) following completion of GOALS training. Participants responded to questions regarding the range of strategies they continued to utilize, perceived benefit(s) of strategy use, situations in which strategy use was found helpful, and functional changes attributed to training. Results. Nearly all participants (94%) reported continued use of at least one trained strategy in their daily lives, with 75% of participants also reporting improved functioning resulting from training. However, there was considerable variability with respect to the specific strategies individuals found helpful as well as the perceived impact of training on overall functioning. Conclusions. GOALS training shows promising long-term benefits for individuals in the chronic phase of brain injury. Identifying individual- and injury-level factors that account for variability in continued strategy use and the perceived long-term benefits of training will help with ongoing intervention development.


INVERSE RELATIONSHIP BETWEEN FUNCTIONAL MATURITY AND EXPONENTIAL GROWTH RATE OF AVIAN SKELETAL MUSCLE: A CONSTRAINT ON EVOLUTIONARY RESPONSE.
In this study, we investigate whether a tissue-level constraint can explain the general inverse relationship between growth rate and precocity of development in birds. On the whole, altricial (dependent) chicks grow three to four times faster than the less dependent, more able chicks of precocial species of similar adult mass. We suggest that an antagonism between growth and acquisition of mature function in skeletal muscle constrains postnatal growth and development in most species of birds. Altricial species, represented by European starlings in this study, hatch with skeletal muscle having low capacity for generating force but grow rapidly. Conversely, precocial species (northern bobwhite quail and Japanese quail), hatch with relatively mature skeletal muscle, especially in their legs, but grow more slowly. As development proceeds in all species, exponential growth rates decrease as muscles acquire adult levels of function. Among four variables associated with muscle function, exponential growth rate (EGR) was negatively correlated with pyruvate kinase activity (glycolysis), potassium concentration (electrical potential), and dry weight fraction (contractile proteins) in both pectoral and leg muscles but not with citrate synthase activity (aerobic metabolism) in either set of muscles. For pectoral muscle, these variables accounted for 87% of the total variation in EGR in all three species combined despite a twofold difference in growth rates between the starling and quail. EGRs of leg muscle (51% of variation accounted for) were less than predicted by the pectoral-muscle equation in quail during the early part of the postnatal period and in starlings during the late postnatal period. This result would not contradict a growth rate/maturity constraint hypothesis if EGRs were down-regulated for allometric or other considerations.


Differences in the Effects of Pentobarbital Anesthetic and Combination of Medetomidine Hydrochloride, Midazolam, and Butorphanol Tartrate Anesthetic on Electroretinogram in Spontaneously Diabetic Torii Fatty Rats.
The aim of this study was to investigate the effects of different anesthetic agents on electroretinograms (ERGs) in Spontaneously Diabetic Torii fatty rats (SDT fatty rats). The ERG recordings were measured under general anesthesia using pentobarbital or a combination of medetomidine hydrochloride, midazolam, and butorphanol (MMB) tartrate anesthesia in 12 9-week-old normal Sprague-Dawley rats (Jcl:SD rats) and 16 SDT fatty rats. Each animal model was divided into 2 groups, the pentobarbital group and MMB group. The amplitudes and peak times of the a- and b-waves and oscillatory potentials (OPs) were measured from 0.0001 candela per square meter (cd.s/m2) to 10.0 cd.s/m2. The amplitude of the a-wave was significantly higher in the MMB group of Jcl:SD rats, but there was no significant difference in amplitude between the two groups of SDT fatty rats. There was no significant difference in the OP1 amplitude between both groups of Jcl:SD rats, but the OP1 amplitude was significantly higher in the MMB group of SDT fatty rats. The OP2 amplitude was significantly higher in the pentobarbital group in both the Jcl:SD rats and SDT fatty rats. There was no significant difference in the OP3 amplitude between the Jcl:SD and SDT fatty rat groups. The amplitude of the OP4 waves was significantly higher in the MMB group for both Jcl:SD and SDT fatty rats. There was no significant difference in the sums of the OP1 to OP4 (ΣOPs) amplitudes between the Jcl:SD and SDT fatty rat groups. There was no significant difference in the b-wave amplitude between the Jcl:SD rat groups, but the b-wave amplitude was significantly higher in the SDT fatty rats that received pentobarbital. The peak times for a-wave, OP1, OP2, OP3, OP4, and ΣOPs were significantly longer in the pentobarbital group of SD rats. The peak time of the b-wave was significantly longer in the MMB group of Jcl:SD rats, but the same result was obtained in the SDT fatty rats except that there was no significant difference in the a-wave. The overall ERG results vary depending on the anesthetic agent used. The OPs can be observed in detail when using MMB. Since the SDT fatty rat is a diabetic model animal, we recommend MMB as the anesthesia of choice when studying the OP waves in detail.


Content analysis of gay male and lesbian personal advertisements.
396 randomly selected gay and lesbian personal advertisements were analyzed for content. Analysis supported the hypotheses that the 198 men are more interested in sexuality and physical attractiveness, while the 198 women are more concerned with the personality characteristics of prospective partners.


Nonmutational alteration in glucocorticoid sensitivity of lymphosarcoma P1798.
The sensitivity of lymphosarcoma P1798 to glucocorticoids varied as a function of growth conditions. Cells grown in the ascitic fluid were very sensitive to cortisol inhibition of tritiated thymidine ([3H]dThd) incorporation. When ascites cells were inoculated sc into BALB/c mice receiving daily injections of 2 mg cortisol, tumors did not form. However, as tumors grew subcutaneously in control mice, glucocorticoid sensitivity decreased to the arrested by cortisol injection. Cortisol also did not inhibit incorporation of [3H]dThd in cells prepared from large subcutaneous tumors. Measurement of cytoplasmic receptors in cell-free extracts revealed that both ascites and subcutaneous tumor cells contained about 11-12 x 10(4) glucocorticoid binding sites per cell. Receptors in ascites cells had a higher affinity for glucocorticoids than did receptors in subcutaneous cells, which indicated that sensitive and resistant cells contain chemically different classes of receptors. Loss of sensitivity occurred as tumors attained a diameter greater than approximately 1.5 cm. The reproducibility of this transition did not appear to be consistent with a random mechanism for loss of glucocorticoid sensitivity in vivo. Thus the acquisition of resistance by lymphosarcoma P1798 in vivo was concluded to be nonmutational and probably resulted from differentiational alteration in gene expression.


[Hypertension in the elderly].
Systolic blood pressure rises with age, and the prevalence of hypertension (systolic pressure of 140 mmHg or more and diastolic pressure below 90 mmHg) exceeds 70% after the age of 70. At any age, high systolic pressure is associated with an increased risk of cardiovascular death, stroke and myocardial infarction. Antihypertensive drugs reduce cardiovascular mortality and morbidity in patients with systolic pressure exceeding 160 mmHg. The ability of blood pressure reduction to prevent cardiovascular events in elderly hypertensive patients is often compromised by poor systolic pressure control. This is due to the relatively limited efficacy of antihypertensive medications to normalize systolic blood pressure, but also to the fact that many physicians fail to follow systolic hypertension treatment guidelines.


Diagnosis and management of acute osteoarticular infections in children.
Acute hematogenous osteomyelitis and septic arthritis are not uncommon infections in children and should be considered as part of the differential diagnosis of limb pain and pseudoparalysis. Most bone infections in children arise secondary to hematogenous seeding of bacteria into bone. The most common pathogens are Staphylococcus aureus and Kingella kingae. Children with septic arthritis should be evaluated promptly by orthopedic specialists for aspiration and possible debridement of concomitant osteomyelitis. Optimal empiric therapy after appropriate cultures continues to be intravenous cefazolin. In most cases, conversion to oral antimicrobials should occur when the patient has clinically improved and has decreasing inflammatory markers. For most uncomplicated cases of osteomyelitis, current recommendations are 3 to 4 weeks of antimicrobial therapy compared with the 6 weeks previously recommended.


An adaptive algorithm for the automatic segmentation of continuous stuttered speech.
This paper presents an adaptive algorithm for the automatic segmentation of continuous speech into voiced, unvoiced, and silence regions (V/U/S). The procedure presented is based on the use of a digital filter bank with control parameters established using formant frequencies of voiced segments of speech. This procedure makes it possible to separate continuous speech into syllable like structures. The use of these speech segments makes possible the determination of stuttered speech. Special care is given to the handling of prolongations and repetitions (audible and silent) to insure they are properly handled by the segmenting algorithm. Segmentation experiments have been conducted on male and female subjects to test the reliability of the system at segmenting fluent and stuttered continuous speech.


Risk Haplotypes Uniquely Associated with Radioiodine-Refractory Thyroid Cancer Patients of High African Ancestry.
Thyroid cancer patients with radioiodine-refractory (RAI-R) disease, resulting from insufficient RAI delivery and/or RAI resistance, have increased mortality and limited treatment options. To date, studies have largely focused on tumor mutations associated with different stages of disease, which could provide prognostic value for RAI-R disease. It was hypothesized that germline variants contributing to intrinsic differences in iodine metabolism, tumor microenvironment, and/or immune surveillance are associated with RAI-R disease. Whole-genome genotyping data analysis was performed on 1145 Caucasian (CAU) patients, 244 of whom were RAI-R, and 55 African American (AA) patients, nine of whom were RAI-R. Germline-variant association studies were conducted using candidate genes involved in iodine metabolism or DNA-damage repair, as well as genome-wide association analysis. Initial data indicated several notable variants in a small number of patients (n = 7), who were later determined to be AA patients of >80% African ancestry (n = 37). This led to the study focusing on germline single nucleotide polymorphisms uniquely associated with RAI-R AA patients. Sanger sequencing was performed to validate risk alleles and identify the incidence of the common somatic mutations BRAFV600E, NRASQ61R, and HRASQ61R in AA patients whose primary tumor samples were available (28/55). TG, BRCA1, and NSMCE2 haplotypes were identified as being uniquely associated with RAI-R AA patients of >80% African ancestry. All patients with the TG haplotype (n = 4) had a biochemical incomplete response to RAI therapy. Patients with the NSMCE2 haplotype (n = 4) were diagnosed at a young age (13, 17, 17, and 26 years old) with distant metastatic disease at initial diagnosis. The BRCA1 haplotype co-occurred in three out of four patients with the NSMCE2 haplotype. The incidence of BRAFV600E appears lower in papillary thyroid carcinomas from AA patients of >80% African ancestry (3/14; 21%) than in AA patients of <80% African ancestry (6/9; 67%), albeit only just approaching statistical significance (p = 0.077). The tumors available from three RAI-R AA patients were negative for BRAFV600E, NRASQ61R, and HRASQ61R. The identification of candidate RAI-R risk haplotypes may allow early stratification of clinical manifestations of RAI-R disease followed by early intervention and personalized treatment strategies. Functional annotation of candidate RAI-R risk haplotypes may provide insights into the mechanisms underlying RAI-R disease.


Evidence for novel viruses by analysis of nucleic acids in virus-like particle fractions from Ambrosia psilostachya.
To test the hypothesis that many viruses remain to be discovered in plants, a procedure was developed to sequence nucleic acids cloned randomly from virus-like particle fractions of plant homogenates. As a test of the efficiency of the procedure we targeted Ambrosia psilostachya, western ragweed, plants growing at the Tallgrass Prairie Preserve of northeastern Oklahoma. Amplifiable nucleic acid was found in the fractions from six of twelve specimens and sequences were characterized from four of them. Evidence was obtained for the presence of viruses belonging to two families (Caulimoviridae, Flexiviridae). Multiple viral species were found in two of the four specimens and their level within the isolated nucleic acid population varied from less than 1-37%. None of the sequences were derived from reported sequences of known viruses. Thus, the analysis of nucleic acid from virus-like particles is a useful tool to expand our knowledge of the universe of viruses to non-cultivated species.


Associations of retention on buprenorphine for opioid use disorder with patient characteristics and models of care in the primary care setting.
Buprenorphine, a medication for opioid use disorder (OUD), can be administered within primary care; however, little is known about characteristics associated with retention on buprenorphine in these settings. This study examines patient correlates of buprenorphine retention and whether an integrated, interdisciplinary treatment model (buprenorphine and behavioral health) is associated with higher odds of buprenorphine retention than a primarily medication-only treatment model. Electronic health record data from adult patients with an OUD, ≥1 buprenorphine order and ≥1 visit to either of two primary care clinics between 9/2/2014-6/27/2018 were extracted (N = 494 patients). Two research team members reviewed the medication start and stop dates for each buprenorphine order and classified as retained (≥6 months of orders) or not retained (<6 months of orders). Logistic regressions estimated the odds of retention on buprenorphine by 1) patient characteristics and 2) timing of patient's engagement in buprenorphine treatment (pre- or post-implementation of an integrated treatment model). Of the study sample, 53% had ≥6 months of buprenorphine orders. Almost two times higher odds of retention were found among patients with ≥1 psychiatric comorbidity (versus none) and among those with buprenorphine orders in the post- versus pre-period. An integrated, interdisciplinary model of OUD treatment was associated with ≥6 months of buprenorphine orders among our study population. Continued research is needed in real-world primary care settings to understand the impact of OUD treatment models on patient outcomes. A more nuanced examination of the associations between psychiatric diagnoses and buprenorphine treatment retention is warranted.


Splenic rupture after colonoscopy for colorectal cancer screening.
Colonoscopy is a frequently used procedure in our environment for the diagnosis, treatment and even prevention of colorectal cancer. Despite being a routine procedure, it is not exempt from possible complications. Bleeding and perforation are the main ones, with splenic rupture being extremely infrequent as well as one of the most serious complications derived from performing a colonoscopy. We present a patient with splenic rupture secondary to colorectal cancer screening colonoscopy who required urgent surgery for acute hemorrhagic shock.


Pre- and postnatal exposure to legacy environmental contaminants and sensation seeking in Inuit adolescents from Nunavik.
Despite extensive evidence from cohort studies linking exposure to lead (Pb), mercury (Hg) and polychlorinated biphenyls (PCBs) to numerous cognitive outcomes in children and adolescents, very few studies addressed reward sensitivity, a key dimension of emotional regulation. The present study aimed to examine associations between pre- and postnatal exposure to these environmental neurotoxicants and sensation seeking, a behavioral feature of reward. A total of 207 Inuit adolescents (mean age = 18.5, SD = 1.2) from Nunavik, Canada, completed the Brief Sensation Seeking Scale (BSSS-4) and Sensation Seeking- 2 (SS-2), two self-report questionnaires assessing proneness to sensation seeking. Prenatal, childhood and adolescent exposure to Pb, Hg and PCBs were measured in cord blood at birth and blood samples at 11 years of age and at time of testing. Multiple linear regression models were performed, potential confounders including participants' sociodemographic characteristics and nutrient fish intake were considered. Results showed that higher child blood levels of Pb (b = -0.18, p = 0.01) and PCB-153 (b = -0.16, p = 0.06) were associated with lower BSSS-4 total scores, while cord and adolescent blood PCB-153 levels were significantly related to lower SS2 total scores (b = -0.15, p = 0.04; b = -0.24, p = 0.004). Such associations persisted after further adjustment for co-exposure to concurrent contaminants. These associations were influenced by self-report positive affect and marginally moderated by sex. Sex differences were only observed for child PCB exposure, with the association for risk-taking sensation seeking observed only in girls but not in boys. Further research is warranted to assess the extent to which reduced sensation seeking in chronically exposed individuals affects their behaviors, well-being, and emotional regulation.


Contributions to understanding therapeutic change: now we have a playground.
The understanding of therapeutic change is explored in two ways. The first is by providing a model of change that emphasizes moment-to-moment, "local-level" interactions in the analytic dyad. The second is to offer detailed clinical information--taken from the videotape of a child analyst's first session with a three-year-old girl--that illustrates how this change model can be useful to clinicians. The clinical material is presented in the form of verbal trascripts and descriptions of nonverbal communicative exchanges between child and analyst. Both the model of change and the technique of videotape microanalysis build upon work by infant researchers and thus show how advances in related fields can supplement traditional psychoanalytic methods.


Thermal conductivity of van der Waals heterostructure of 2D GeS and SnS based on machine learning interatomic potential.
van der Waals heterostructures have provided an unprecedented platform to tune many physical properties for two-dimensional materials. In this work, thermal transport properties of van der Waals heterostructures formed by vertical stacking of monolayers GeS and SnS have been investigated systematically based on machine learning interatomic potential. The effect of van der Waals interface on the lattice thermal transport of 2D SnS and GeS can be well clarified by introducing various stacking configurations. Our results indicate that the van der Waals interface can strongly suppress the thermal transport capacity for the considered heterostructures, and either the average thermal conductivity per layer or the 2D thermal sheet conductance for the considered heterostructures is lower than that of corresponding monolayers. The suppressed thermal conductivity with tunable in-plane anisotropy in SnS/GeS heterostructures can be ascribed to the enhanced interface anharmonic scattering, and thus exhibits obvious interface-dependent characteristics. Therefore, this work highlights that the van der Waals interface can be employed to effectively modulate thermal transport for the 2D puckered group-IV monochalcogenides, and the suppressed lattice thermal conductivity together with interface-dependent phonon transport properties in the SnS/GeS heterostructure imply the great potential for corresponding thermoelectrical applications.


Human milk oligosaccharide categories define the microbiota composition in human colostrum.
Human milk oligosaccharides (HMOs) are structurally diverse unconjugated glycans with a composition unique to each lactating mother. While HMOs have been shown to have an impact on the development of infant gut microbiota, it is not well known if HMOs also already affect milk microbial composition. To address this question, we analysed eleven colostrum samples for HMO content by high-pressure liquid chromatography and microbiota composition by quantitative PCR. Higher total HMO concentration was associated with higher counts of Bifidobacterium spp. (ρ=0.63, P=0.036). A distinctive effect was seen when comparing different HMO groups: positive correlations were observed between sialylated HMOs and Bifidobacterium breve (ρ=0.84, P=0.001), and non-fucosylated/non-sialylated HMOs and Bifidobacterium longum group (ρ=0.65, P=0.030). In addition to associations between HMOs and bifidobacteria, positive correlations were observed between fucosylated HMOs and Akkermansia muciniphila (ρ=0.70, P=0.017), and between fucosylated/sialylated HMOs and Staphylococcus aureus (ρ=0.75, P=0.007). Our results suggest that the characterised HMOs have an effect on specific microbial groups in human milk. Both oligosaccharides and microbes provide a concise inoculum for the compositional development of the infant gut microbiota.


Intra-articular epithelioid sarcoma of the knee: a diagnostic challenge.
Epithelioid sarcoma is a rare mesenchymal neoplasm characterized by aggregates of epithelioid cells. Intra-articular occurrence is exceedingly rare with only few reports described in the literature. A 22 year-old man presented a progressive mechanical knee pain. Initially, the investigation revealed a non-infectious unspecific synovitis. The patient gradually presented increasing knee enlargement and functional impairment. Intra-articular nodular proliferation with bone invasion was later observed on magnetic resonance imaging reevaluation. Pigmented villonodular synovitis hypothesis was considered. The biopsy ultimately revealed nodules of epithelioid cells with an immunoprofile compatible with epithelioid sarcoma diagnosis. The patient underwent neoadjuvant chemotherapy and radiotherapy and an above-knee amputation was performed.


[Inhibitory effect of somatostatin on the secretion of duodenal gastrin].
This study covers 14 patients subjected to truncal Vagotomy + Antrectomy acc. BI, in order to ascertain whether somatostatin is capable of inhibiting duodenal gastrin release. Somatostatin infusion significantly inhibits the gastrinic response to a protein meal, but does not affect basal levels of the hormone. This suggests that facilitation of duodenal gastrin release after vagal section may be mediated by the reduced somatostatin release.


Octreotide for enterocutaneous fistulas of Crohn's disease.
Crohn's disease is a chronic, life-long disease and has many troublesome complications. Fistulas are a part of Crohn's disease, and although there are many therapeutic modalities used in treating these fistulas they are only partially successful. As we are still very far from being able to cure it, the aim is to improve the patients' quality of life and to reduce the iatrogenic harm that may be caused by various treatment modalities. Somatostatin is an inhibitor of intestinal secretion and has been used to treat pancreatic and surgical fistulas. Therefore, we decided to treat enterocutaneous fistulas using somatostatin. Five patients with Crohn's disease were treated with four daily injections of 300 microg octreotide. The total period of treatment was eight weeks. Closure of fistulas was achieved in four of the five patients. Somatostatin may have a role in treating Crohn's disease enterocutaneous fistulas and may prevent surgery or prolonged immunosuppressive therapy.


Tackling inpatient penicillin allergies: Assessing tools for antimicrobial stewardship.
Reported penicillin allergy rarely reflects penicillin intolerance. Failure to address inpatient penicillin allergies results in more broad-spectrum antibiotic use, treatment failures, and adverse drug events. We aimed to determine the optimal approach to penicillin allergies among medical inpatients. We evaluated internal medicine inpatients reporting penicillin allergy in 3 periods: (1) standard of care (SOC), (2) penicillin skin testing (ST), and (3) computerized guideline application with decision support (APP). The primary outcome was use of a penicillin or cephalosporin, comparing interventions to SOC using multivariable logistic regression. There were 625 patients: SOC, 148; ST, 278; and APP, 199. Of 278 ST patients, 179 (64%) were skin test eligible; 43 (24%) received testing and none were allergic. In the APP period, there were 292 unique Web site views; 112 users (38%) completed clinical decision support. Although ST period patients did not have increased odds of penicillin or cephalosporin use overall (adjusted odds ratio [aOR] 1.3; 95% CI, 0.8-2.0), we observed significant increased odds of penicillin or cephalosporin use overall in the APP period (aOR, 1.8; 95% CI, 1.1-2.9) and in a per-protocol analysis of the skin tested subset (aOR, 5.7; 95% CI, 2.6-12.5). Both APP and ST-when completed-increased the use of penicillin and cephalosporin antibiotics among inpatients reporting penicillin allergy. While the skin tested subset showed an almost 6-fold impact, the computerized guideline significantly increased penicillin or cephalosporin use overall nearly 2-fold and was readily implemented.


Cognitive workload across the spectrum of cognitive impairments: A systematic review of physiological measures.
Our objective was to identify the physiological measures that are sensitive to assessing cognitive workload across the spectrum of cognitive impairments. Three database searches were conducted: PubMed, PsychINFO, and Web of Science. Studies from the last decade that used physiological measures of cognitive workload in older adults (mean age >65 years-old) were reviewed. The cognitive workload of healthy older individuals was compared with the cognitive workload of younger adults, patients with mild cognitive impairment (MCI), and patients with Alzheimer's diseases (AD). The most common measures of cognitive workload included: electroencephalography, magnetoencephalography, functional magnetic resonance imaging, pupillometry, and heart rate variability. These physiological measures consistently showed greater cognitive workload in healthy older adults compared to younger adults when performing the same task. The same was observed in patients with MCI compared to healthy older adults. Behavioral performance declined when the available cognitive resources became insufficient to cope with the cognitive demands of a task, such as in AD. These findings may have implications for clinical practice and future cognitive interventions.


Emapalumab in Children with Primary Hemophagocytic Lymphohistiocytosis.
Primary hemophagocytic lymphohistiocytosis is a rare syndrome characterized by immune dysregulation and hyperinflammation. It typically manifests in infancy and is associated with high mortality. We investigated the efficacy and safety of emapalumab (a human anti-interferon-γ antibody), administered with dexamethasone, in an open-label, single-group, phase 2-3 study involving patients who had received conventional therapy before enrollment (previously treated patients) and previously untreated patients who were 18 years of age or younger and had primary hemophagocytic lymphohistiocytosis. The patients could enter a long-term follow-up study until 1 year after allogeneic hematopoietic stem-cell transplantation or until 1 year after the last dose of emapalumab, if transplantation was not performed. The planned 8-week treatment period could be shortened or extended if needed according to the timing of transplantation. The primary efficacy end point was the overall response, which was assessed in the previously treated patients according to objective clinical and laboratory criteria. At the cutoff date of July 20, 2017, a total of 34 patients (27 previously treated patients and 7 previously untreated patients) had received emapalumab; 26 patients completed the study. A total of 63% of the previously treated patients and 65% of the patients who received an emapalumab infusion had a response; these percentages were significantly higher than the prespecified null hypothesis of 40% (P = 0.02 and P = 0.005, respectively). In the previously treated group, 70% of the patients were able to proceed to transplantation, as were 65% of the patients who received emapalumab. At the last observation, 74% of the previously treated patients and 71% of the patients who received emapalumab were alive. Emapalumab was not associated with any organ toxicity. Severe infections developed in 10 patients during emapalumab treatment. Emapalumab was discontinued in 1 patient because of disseminated histoplasmosis. Emapalumab was an efficacious targeted therapy for patients with primary hemophagocytic lymphohistiocytosis. (Funded by NovImmune and the European Commission; NI-0501-04 and NI-0501-05 ClinicalTrials.gov numbers, NCT01818492 and NCT02069899.).