Gastric organoids-an in vitro model system for the study of gastric development and road to personalized medicine.
Gastric cancer ranks as the fifth most common human malignancy and the third leading cause of cancer related deaths. Depending on tumor stage, endoscopic or surgical resection supported by perioperative chemotherapy is the only curative option for patients. Due to late clinical manifestation and missing reliable biomarkers, early detection is challenging and overall survival remains poor. Organoids are cell aggregates cultured in three-dimensions that grow with similar characteristics as their tissue-of-origin. Due to their self-renewal and proliferative capacity, organoids can be maintained long term in culture and expanded in many cases in an unlimited fashion. Patient-derived organoid (PDO) libraries function as living biobanks, allowing the in depth analysis of tissue specific function, development and disease. The recent successful establishment of gastric cancer PDOs opens up new perspectives for multiple translational clinical applications. Here, we review different adult stem cell derived gastric organoid model systems and focus on their establishment, phenotypic and genotypic characterizations as well as their use in predicting therapy response.


New concepts in blood pressure-lowering management in diabetic patients: the case for early ACE inhibitor combination therapy with diuretics.
Type II diabetes and the dysmetabolic syndrome are becoming more and more prevalent, not only in the Western world, but also in many developing countries. The key issue is early prevention and treatment, not only antihyperglycaemic and antihyperlipidaemic treatment, but also, and maybe in particular, antihypertensive treatment. The first issue is first of all screening patients for elevated blood pressure and for microalbuminuria, especially if blood pressure elevation or diabetes is present. Especially, diabetic patients are at risk. The key feature in the therapeutic approach is blocking the renin-angiotensin system, which has proven effective in many original studies. Also the combination with diuretics is a key issue, since these patients have sodium retention. It has been discussed whether ACEi, ARBs or diuretics should be initial treatment, but usually a combination treatment is recommended to reduce blood pressure early and efficiently. The PREMIER study emphasized combination therapy, since the study had very efficient outcomes with combination therapy compared to an ACEi alone as far as blood pressure lowering is concerned, but also with reduction in microalbuminuria and, indeed, end point-reduction. Cardiovascular events showed a decreased incidence with the combination therapy with Preterax (perindopril/indapamide) compared with the enalapril group.


Modeling the impact of genetic screening technologies on healthcare: theoretical model for asthma in children.
This study focuses on the potential impact of genetic screening technologies on healthcare. Genetic screening for asthma in children was chosen as a case study to explore the cost effectiveness of applying early genetic screening to infants, and preventive treatment to the population at risk. Early intervention could prevent progression and facilitate clinical management of the disease. From the elite group of genetic markers that have been associated with asthma-related phenotypes, ADAM33 was the first published candidate gene detected by a positional cloning approach, marking the entry of asthma research into the genomic era. The model was, therefore, initially set for an ex ante analysis of the cost effectiveness of applying the preventive program to an infant population at risk, i.e. infants presenting wheezing episodes during the first year of life, and the ADAM33 ST+7 genetic marker, with the idea of expanding to further markers and their combinations lat a later date. In accordance with the US National Heart, Lung, and Blood Institute, four categories of asthma were considered. A Markov model was constructed, consisting of six mutually exclusive disease states (including healthy and dead states) with a simulation horizon of 100 years and a cycle length of 1 year. We define a scenario where early genetic screening was applied to infants presenting wheezing episodes during the first year of life and a preventive treatment to those children within this group who tested positive for selected ADAM33 polymorphism (ST+7). The cost-effectiveness analysis was performed from the third-party payer and patient perspective after year 6. We applied our model to a hypothetical cohort of 100 European infants. The number of quality-adjusted life-years (QALYs) gained during the 6 years was 1.483, and the incremental cost-effectiveness ratio per QALY gained was euro 10,100/QALY. A sensitivity analysis was carried out that varied the discount rate and cost of genetic testing, and considered two different transition matrices for the preventive program. Three main conclusions were drawn from the sensitivity analysis. Firstly, if the discount rate for both cost and health outcomes is increased by 2%, the cost effectiveness of the preventive program does not vary significantly. Discounting costs and benefits at 5%, the preventive program appears cost effective (euro 11,100/QALY). Secondly, if the cost of genetic testing is increased to euro 100, the cost effectiveness of the preventive program remains within the limits of cost effectiveness. Thirdly, the cost of genetic screening, together with transition probabilities between health states, will determine the cost effectiveness of applying a preventive program based on genetic information. Preventive treatment based on an early genetic screening of those children who present wheezing episodes during the first year of life, with treatment applied to those who test positive for the asthma-associated genetic marker ADAM33 ST+7, is theoretically cost effective. The model is a valuable tool for the ex ante assessment of the cost effectiveness of preventive schemes based on genetic screening. The value of modeling prior to clinical trials lies in informing study design and setting priorities for future research.


Marker-less tracking of brain surface deformations by non-rigid registration integrating surface and vessel/sulci features.
To compensate for brain shift in image-guided neurosurgery, we propose a new non-rigid registration method that integrates surface and vessel/sulci feature to noninvasively track the brain surface. Textured brain surfaces were acquired using phase-shift three-dimensional (3D) shape measurement, which offers 2D image pixels and their corresponding 3D points directly. Measured brain surfaces were noninvasively tracked using the proposed method by minimizing a new energy function, which is a weighted combination of 3D point corresponding estimation and surface deformation constraints. Initially, the measured surfaces were divided into featured and non-featured parts using a Frangi filter. The corresponding feature/non-feature points between intraoperative brain surfaces were estimated using the closest point algorithm. Subsequently, smoothness and rigidity constraints were introduced in the energy function for a smooth surface deformation and local surface detail conservation, respectively. Our 3D shape measurement accuracy was evaluated using 20 spheres for bias and precision errors. In addition, the proposed method was evaluated based on root mean square error (RMSE) and target registration error (TRE) with five porcine brains for which deformations were produced by gravity and pushing with different displacements in both the vertical and horizontal directions. The minimum and maximum bias errors were 0.32 and 0.61 mm, respectively. The minimum and maximum precision errors were 0.025 and 0.30 mm, respectively. Quantitative validation with porcine brains showed that the average RMSE and TRE were 0.1 and 0.9 mm, respectively. The proposed method appeared to be advantageous in integrating vessels/sulci feature, robust to changes in deformation magnitude and integrated feature numbers, and feasible in compensating for brain shift deformation in surgeries.


Usefulness of quantitative 99mTc-pyrophosphate SPECT/CT for predicting the prognosis of patients with wild-type transthyretin cardiac amyloidosis.
Wild-type transthyretin-related amyloidosis cardiomyopathy (ATTRwt-CM) is an increasingly recognized cause of heart failure especially in elderly patients. The purpose of the present study was to determine retrospectively whether the quantitative indices of 99mTc-pyrophosphate (PYP) SPECT/CT help to predict the prognosis of ATTRwt-CM patients when compared with other clinical parameters. Sixty-eight patients with biopsy-proven ATTRwt-CM who underwent PYP SPECT/CT were enrolled. Baseline clinical characteristics, echocardiographic parameters, and qualitative and/or quantitative indices of planar and SPECT/CT imaging in PYP scintigraphy for each patient were included. For quantitative analysis of SPECT/CT, the accumulation ratio of PYP in the septum, posterior, anterior, lateral, and apex walls to the cavity pool was calculated as the septal wall-to-cavity ratio (Se/C), lateral wall-to-cavity ratio (La/C), anterior wall-to-cavity ratio (An/C), inferior wall-to-cavity ratio (In/C), and apical wall-to-cavity ratio (Ap/C), respectively. Endpoints for prognostic accuracy evaluation were cardiac death or hospitalization due to heart failure. Event-free survival rate was evaluated through Cox proportional hazards regression analysis, providing estimated hazard ratios (HRs) with 95% confidence intervals (CIs) and Kaplan-Meier curves. High-sensitivity cardiac troponin T (hs-cTnT), La/C, age, interventricular septal thickness in diastole, and E/e' ratio in the septal wall were significantly associated with event-free survival (P < 0.05). For a multivariable Cox proportional hazards analysis, hs-cTnT (HR 1.153; 95% CI 1.034-1.286; P < 0.01), La/C (HR 2.091; 95% CI 1.012-4.322; P = 0.046), and age (HR 1.116; 95% CI 1.007-1.238; P = 0.037) were significant independent prognostic factors. This study indicated that the quantitative indices of PYP SPECT/CT can help to predict the prognosis of ATTRwt-CM patients.


Ascorbic acid accumulates as a defense response to Turnip mosaic virus in resistant Brassica rapa cultivars.
We initially observed that Brassica rapa cultivars containing the Turnip mosaic virus (TuMV) resistance gene, Rnt1-1, accumulated a high level of endogenous ascorbic acid (AS) and dehydroascobic acid (DHA) when infected with TuMV. We here hypothesized a possible contribution of an elevated level of AS+DHA (TAA) to the Rnt1-1-mediated resistance, and conducted a series of experiments using B. rapa and Arabidopsis plants. The application of l-galactose (the key substrate in AS synthesis) to a susceptible cultivar could increase the TAA level ~2-fold, and simultaneously lead to some degree of enhanced viral resistance. To confirm some positive correlation between TAA levels and viral resistance, we analyzed two Arabidopsis knockout mutants (ao and vtc1) in the AS pathways; the TAA levels were significantly increased and decreased in ao and vtc1 plants, respectively. While the ao plants showed enhanced resistance to TuMV, vtc1 plants were more susceptible than the control, supporting our hypothesis. When we analyzed the expression profiles of the genes involved in the AS pathways upon TuMV infection, we found that the observed TAA increase was mainly brought about by the reduction of AS oxidation and activation of AS recycling. We then investigated the secondary signals that regulate endogenous TAA levels in response to viral infection, and found that jasmonic acid (JA) might play an important role in TAA accumulation. In conclusion, we reason that the elevated TAA accumulation in B. rapa plants would be at least partly mediated by the JA-dependent signaling pathway and may significantly contribute to viral resistance.


Effect of oxidizing disinfectants (chlorine, monochloramine, and ozone) on Helicobacter pylori.
The susceptibility of Helicobacter pylori to disinfectants was compared to that of Escherichia coli. H. pylori is more resistant than E. coli to chlorine and ozone but not monochloramine. H. pylori may be able to tolerate disinfectants in distribution systems and, therefore, may be transmitted by a waterborne route.


A novel eye drop application monitor to assess patient compliance with a prescribed regimen: a pilot study.
To assess the ability of a novel imaging device to allow physicians to personalize therapeutic regimens based on objective patient drop administration data. A novel imaging system was used to record video of the drop technique of subjects in clinic (n=25) or at home (n=17) for 1 week. Video assessment by a reading center was compared with patient reporting and their prescribed regimen with respect to how many drops were applied and how many landed in the eye. Reading center assessment of both drops dispensed and drops landing in the eye was significantly different from the prescribed regimen in the clinic (Pd=0.005, Pi<0.001, respectively) and at-home arms (Pd=0.003, Pi<0.001, respectively). This imaging system is a powerful tool to help physicians tailor patient therapy more accurately, to help researchers evaluate new drop therapies with objective rather than subjective data, and to potentially facilitate better patient training for improved drug delivery.


Dizocilpine inhibits amphetamine-induced formation of nitric oxide and amphetamine-induced release of amino acids and acetylcholine in the rat brain.
Glutamate receptor activation participates in mediation of neurotoxic effects in the striatum induced by the psychomotor stimulant amphetamine. The effects of the non-competitive NMDA receptor antagonist dizocilpine (MK-801) on amphetamine-induced toxicity and formation of nitric oxide (NO) in both striatum and cortex and on induced transmitter release in the nucleus accumbens were investigated. Repeated, systemic application of amphetamine elevated striatal and cortical lipid peroxidation and NO production. Moreover, amphetamine caused an immediate release of acetylcholine and aspartate and a delayed release of GABA in the nucleus accumbens. Surprisingly, glutamate release was not affected. Dizocilpine abolished the amphetamine-induced lipid peroxidation and NO production in striatum and cortex and diminished the elevation of neurotransmitter release. These findings suggest that amphetamine evokes neurotoxic effects in both striatal and cortical brain areas that are prevented by inhibiting NMDA receptor activation. The amphetamine-induced acetylcholine, aspartate and GABA release in the nucleus accumbens is also mediated through NMDA receptor-dependent mechanisms. Interestingly, the enhanced aspartate release might contribute to NMDA receptor activation in the nucleus accumbens, while glutamate does not seem to mediate amphetamine-evoked transmitter release in this striatal brain area.


Cell kinetics in ovarian cancer. Relationship to clinicopathologic features, responsiveness to chemotherapy, and survival.
The tumor proliferative activity of 74 previously untreated epithelial ovarian carcinomas was evaluated by the thymidine labeling index (TLI) and the primer-dependent alpha DNA polymerase assay (PDP-LI). The median TLI and PDP-LI were 2% (0.1 to 28.0) and 10% (3.0 to 80.0), respectively. The TLI was significantly correlated to tumor grade, International Federation of Gynecology and Obstetrics (FIGO) stage, and residual disease. However, neither the TLI nor the PDP-LI was a predictor of survival. A higher response rate was observed in the case of rapidly proliferating tumors: an objective response (OR) was observed in 38.4% of the patients with a low TLI and in 53.6% of the patients with a high TLI. The advantage of an OR in favor of the high TLI group was significant for patients treated with regimens containing doxorubicin (high TLI, 72.2% OR; low TLI, 40% OR; P = 0.03).


[Mechanical ventilation and pulmonary vascular resistance: comparison of IPPV, CPPV, CPAP, and PSV in decompensated chronic obstructive bronchopneumopathy with pulmonary hypertension].
Alterations of pulmonary vascular resistance were studied using four different methods of mechanical ventilation. A Servo Ventilator 900 C respirator was used for three of these techniques (IPPV, CPPV and PSV); CPAP was performed using a continuous-flow system because of the latter's advantages compared to demand-flow systems. Five patients (aged 64-75) affected by BPCO uncompensation and pulmonary hypertension (PAP 40 +/- 8 mmHg) were included in the study. A complete hemodynamic test was performed in each patient for each of the methods used by inserting a Swan-Ganz catheter through the right-hand internal jugular vein; intrapleural pressure were also measured using an esophageal balloon. The results of the study revealed a low level of tolerance to CPAP. Of the other methods, PSV was found to be particularly useful since it produced significant constant reductions of PVR and increased levels of CO compared to other techniques. These positive hemodynamic effects may be explained by the pattern of intrapleural pressures and the possibility of "self-adjustment" which this method allows.


Brominated flame retardants (BFRs) in indoor and outdoor air in a community in Guangzhou, a megacity of southern China.
Indoor environments contribute a significant portion of human exposure to brominated flame retardants (BFRs) because of their extensive use in various household products. This study investigates the occurrence of a number of BFRs in the indoor and outdoor air in a megacity in southern China, in which little information on indoor BFRs contamination is available. The estimated total PBDE concentrations ranged from 1.43 to 57 pg/m(3) indoors and from 1.21 to 1522 pg/m(3) outdoors. The indoor concentrations of lower brominated PBDEs that are mainly derived from the technical penta- and octa-BDE mixtures were higher than or comparable to the outdoors, while the indoor levels of DecaBDEs and decabromodiphenyl ethane (DBDPE) were apparently lower than the outdoors. The seasonal variations of BFR concentrations indicated that evaporation from old indoor products is the primary source of Penta- and OctaBDEs in the air, whereas most DecaBDEs and DBDPE concentrations showing weak temperature-dependence are largely released from industrial activities. The PBDE congener profiles in the air were generally similar, which were dominated by BDE209, 28, and 47; whereas the appreciable indoor-outdoor differences in the compositions are possibly due to emission sources, photochemical degradation, or congener-specific transport of BFRs in the indoor and outdoor air. Significant correlations between the indoor and outdoor BFRs were observed suggesting the exchange of BFRs between the two compartments, which are more noticeable for PentaBDEs and DecaBDEs with strong indoor and outdoor emission sources, respectively. This study provides significant insights into the sources of BFRs in urban air in China.


What is the ultimate fate of presented abstracts? The conversion rates of presentations to publications over a five-year period from three North American plastic surgery meetings.
Advancements in clinical decision-making are influenced by presentations made at scientific conferences or publications in journals with extensive readership. However, many ideas shared at annual conferences fail to be published, and most surgeons attend these meetings only sporadically. To quantify the conversion rates of meeting presentations to publications in North American plastic surgery. MEDLINE (OvidSP) and PubMed databases were cross-referenced with abstracts accepted for podium presentation at the Canadian Society of Plastic Surgeons, American Society of Plastic Surgeons, and American Association of Plastic Surgeons annual meetings from 2003 to 2007. Parameters reviewed included publication rate, time to publication, subspecialty, trial type, publication journal and journal impact factor. Over the five-year study period, 45.00% of the 888 presentations were published in peer-reviewed journals. The mean time to publication was 22 months (range 1.00 to 85.90 months). In total, 57.00% of the 400 publications appeared in Plastic and Reconstructive Surgery; 47.20% of publications were case series study design. The majority of publications were of the reconstruction subspecialty (31.00%). Abstracts from the American Society of Plastic Surgeons had the highest conversion rate (57.70%). Publications based on abstracts presented at the American Association of Plastic Surgeons had the highest mean journal impact factor (2.33). The Canadian Society of Plastic Surgeons had the highest total number of publications (n=161). From the three North American annual general meetings reviewed, there was a modest conversion rate of mainly reconstructive case series published predominantly in a single journal, Plastic and Reconstructive Surgery. Several years often pass from the genesis of a research hypothesis to final publication, and because the majority of presentations fail to be published, presentations should be observed with a critical eye given the more stringent peer review process and time required for final publication. In an effort to improve conversion rates, departments and faculty members must foster a culture that prioritizes publication.


[Cardiogenic shock: pathophysiology, clinics, therapeutical options and perspectives].
Documented mortality from myocardial infarction (MI) has significantly decreased from around 30% in the 1960s to 6-7% currently, following the introduction of intensive care treatment, thrombolysis, effective antithrombotic therapy and coronary angioplasty. However, the approximate mortality of 70-80% of patients with cardiogenic shock following acute MI has hardly improved despite the introduction of modern treatment strategies. The major cause of in-hospital MI mortality remains myocardial failure with consecutive cardiogenic shock and multi-organ failure. Prompt coronary revascularisation by "facilitated" or "adjunctive" percutaneous coronary intervention (PCI), is currently considered the best method to reduce the high mortality in these patients. Facilitated PCI includes administration of glycoproteine receptor antagonists, mechanical circulation support strategies, such as, intraaortic balloon counterpulsation and potentially prehospital thrombolysis.


Selective and comparative genome architecture of Asian cultivated rice (Oryza sativa L.) attributed to domestication and modern breeding.
Rice, Oryza sativa L. (Os), is one of the oldest domesticated cereals that has also gone through extensive improvement in modern breeding. How rice was domesticated and impacted by modern breeding. We performed comprehensive analyses of genomic sequences of 504 accessions of Os and 456 accessions of O. rufipogon/O. nivara (Or). The natural selection on Or before domestication and the natural and artificial selection during domestication together shaped the well-differentiated genomes of two subspecies, geng(j) (japonica) and xian(i) (indica), while breeding has made apparent genomic imprints between landrace and modern varieties of each subspecies, and also between primary modern and advanced modern varieties of xian(i). Selection during domestication and breeding left genome-wide selective signals covering ∼ 22.8 % and ∼ 8.6 % of the Os genome, significantly reduced within-population genomic diversity by ∼ 22 % in xian(i) and ∼ 53 % in geng(j) plus more pronounced subspecific differentiation. Only ∼ 10 % reduction in the total genomic diversity was observed between the Os and Or populations, indicating domestication did not suffer severe genetic bottleneck. Our results revealed clear differentiation of the Or accessions into three large populations, two of which correspond to the well-differentiated Os subspecies, geng(j) and xian(i). Improved productivity and common changes in the same suit of adaptive traits in xian(i) and geng(j) during domestication and breeding resulted apparently from compensatory and convergent selections for different genes/alleles acting in the common KEGG terms and/or same gene families, and thus maintaining or even increasing the within population diversity and subspecific differentiation of Os, while more genes/alleles of novel function were selected during domestication than modern breeding. Our results supported the multiple independent domestication of Os in Asia and suggest the more efficient utilization of the rich diversity within Os by exploiting inter-subspecific and among population diversity in future rice improvement.


Effect of a post-dinner snack and partial meal replacement program on weight loss.
The objectives of this study were to examine whether providing a structured post-dinner snack would enhance weight loss among obese night snackers participating in a novel partial meal replacement (PMR) program and to examine the efficacy of that program. Sixty adults (age 18-65 years; body mass index >or=30 kg/m2), 29 randomized to the 'post-dinner snack' and 32 to the 'no snack' groups, completed the 8-week program. Both groups showed improvements in weight (-4.23 kg, P < 0.0001), body mass index (-1.48 kg/m2, P < 0.0001), body fat (-1.36%, P < 00.0001), waist circumference (-6.40 cm, P < 0.0001), and high-density lipoprotein-cholesterol (-2.72 mmol/l, P < 0.01), and on a night snacking question (-1.31, P < 0.0001). The 'post-dinner snack' group did not show significantly greater weight loss outcomes than the 'no snack' group either before or after taking compliance into consideration. Providing a structured post-dinner snack along with a PMR program did not enhance weight loss treatment outcomes; however, the PMR program produced beneficial weight loss changes for obese night snackers.


Membrane potential, resting calcium and calcium transients in isolated muscle fibres from normal and dystrophic mice.
1. Single skeletal muscle fibres were enzymatically isolated from the flexor digitorum brevis muscles (FDB) of dystrophic mdx and control C57BL/10 mice aged 3-9 weeks. In this age range the majority (> 95%) of the mdx fibres were morphologically normal. 2. There was no significant difference between the resting membrane potential (RMP) of mdx and control mice, -71.2 +/- 1.21 (n = 26) and -70.6 +/- 1.15 mV (n = 42), respectively. 3. At RMP more negative than -60 mV the resting calcium (recorded with fura-2, free acid ionophoresed into cell) in the dystrophic mdx cells was not significantly different from the normal animals, 45.7 +/- 4.1 (n = 10) and 46.2 +/- 3.9 nM (n = 9), respectively. 4. The resting cytosolic calcium concentration was measured simultaneously with the RMP. At RMP between -60 to -17 mV there was an increase in the resting calcium concentration in both mdx and control ranging from 79.3 to 252 nM. This increase was most probably due to the activation of the slow calcium current. 5. Fura-2 calcium transients were produced via single action potential stimulation using an intracellular microelectrode both to stimulate the cell and record potential changes. There was no significant difference between the rise time (Tp) or half-decay time (T1/2) at 22 degrees C of the calcium transient in response to a single action potential in mdx compared to normal animals, 5.9 +/- 0.34 (n = 8) and 5.4 +/- 0.36 ms (n = 7); 39.5 +/- 2.9 (n = 8) and 40.75 +/- 3.7 ms (n = 7), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)


Visual metamorphoses in insects and malacostracans: Transitions between an aquatic and terrestrial life.
Arthropods operate in an outrageous diversity of environments. From the deep sea to dense tropical forests, to wide open arctic tundra, they have colonized almost every possible habitat. Within these environments, the presence of light is nearly ubiquitous, varying in intensity, wavelength, and polarization. Light provides critical information about the environment, such as time of day or where food sources may be located. Animals take advantage of this prevalent and informative cue to make behavioral choices. However, the types of choices animals face depend greatly on their environments and needs at any given time. In particular, animals that undergo metamorphosis, with arthropods being the prime example, experience dramatic changes in both behavior and ecology, which in turn may require altering the structure and function of sensory systems such as vision. Amphibiotic organisms maintain aquatic lifestyles as juveniles before transitioning to terrestrial lifestyles as adults. However, light behaves differently in water than in air, resulting in distinct aquatic and terrestrial optical environments. Visual changes in response to these optical differences can occur on multiple levels, from corneal structure down to neural organization. In this review, we summarize examples of alterations in the visual systems of amphibiotic larval and adult insects and malacostracan crustaceans, specifically those attributed to environmental differences between metamorphic phases.


Comparison of preoperative versus postoperative transversus abdominis plane and rectus sheath block in patients undergoing minimally invasive colorectal surgery.
Ultrasound-guided transversus abdominis plane and rectus sheath block (TAPRSB) decreases pain scores and narcotic use postoperatively after colorectal surgery (CRS). It is unclear if the effectiveness of TAPRSB varies according to whether it is performed preoperatively or postoperatively. Our aim was to investigate this. We compared patients who underwent preoperative TAPRSB or postoperative TAPRSB during minimally invasive CRS. Primary end-points were pain scores and oral morphine milligram equivalent (MME) use postoperatively. Secondary end-points included perioperative factors affecting pain scores and postoperative MME. Summary statistics and univariate analysis by nonparametric tests were utilized. The mixed-effect model was applied to model the repeatedly measured pain score. From April 2015 until May 2018 168 patients received TAPRSB before (115) or after (53) minimally invasive CRS. The cohort included 79 (47.0%) women, and had an average age of 59.11 (±12.32) years and mean body mass index of 28.32 (±5.82) kg/m2 . Indication for surgery was cancer in 66 (39.3%), polyp in 43 (25.6%) and diverticulitis in 43 (25.6%). Right colectomy was performed in 61 (36.3%), low anterior resection in 46 (27.4%) and sigmoid colectomy in 40 (23.8%) patients. The demographics of the groups were similar. Postoperative TAPRSB was only associated with lower pain scores at 12 h postoperatively. As secondary outcomes, average pain scores and MME were lower in patients who were older, had right colectomy or intracorporeal anastomosis. Postoperative TAPRSB resulted in lower pain scores than preoperative TAPRSB 12 h after minimally invasive CRS, but otherwise no differences were seen in pain scores or MME use.


Clinical Significance of Non-Coding RNA Regulation of Programmed Cell Death in Hepatocellular Carcinoma.
Hepatocellular carcinoma (HCC) is a widely prevalent and malignantly progressive tumor. Most patients are typically diagnosed with HCC at an advanced stage, posing significant challenges in the execution of curative surgical interventions. Non-coding RNAs (ncRNAs) represent a distinct category of RNA molecules not directly involved in protein synthesis. However, they possess the remarkable ability to regulate gene expression, thereby exerting significant regulatory control over cellular processes. Notably, ncRNAs have been implicated in the modulation of programmed cell death (PCD), a crucial mechanism that various therapeutic agents target in the fight against HCC. This review summarizes the clinical significance of ncRNA regulation of PCD in HCC, including patient diagnosis, prognosis, drug resistance, and side effects. The aim of this study is to provide new insights and directions for the diagnosis and drug treatment strategies of HCC.


Apurinic site induction in the DNA of cells heated at hyperthermic temperatures.
The induction of DNA damage in cells heated at hyperthermic (43-48 degrees C) temperatures was determined by alkaline filter elution and alkaline sucrose gradient-sedimentation analysis of cell DNA denatured at pH 13.0. A class of DNA lesion which converted to strand breaks during denaturation of DNA at pH 13.0 was produced randomly throughout the cell DNA at temperatures as low as 43 degrees C. Induction of this lesion occurred with a T0 of 90 and 10 min at 45 and 48 degrees C, respectively. We estimate that these pH 13.0-detectable DNA lesions are produced in the cell DNA with a frequency of approximately 75 and 660 per min of heating at 45 and 48 degrees C, respectively. Since the lesions were quantitatively converted to DNA strand breaks at pH 13.0 with a half-time of 30 min, or less, we suggest that these pH 13.0-detectable DNA lesions are heat-induced, abasic DNA sites. The induction of these lesions does not appear to be directly involved in the initial heat-induced inhibition of DNA synthesis. The presence of these lesions cannot be excluded as an explanation for the long-term inhibition of replicon initiated in heated cells.


Perioperative Cost Comparison between Percutaneous Microwave Ablation and Partial Nephrectomy for Localized Renal Masses.
We sought to determine and compare the perioperative cost associated with percutaneous microwave ablation (MWA) and robot-assisted partial nephrectomy (RA-PN) for treatment of localized renal masses (LRMs). We conducted a retrospective cohort analysis of a prospectively maintained IRB-approved LRM database. The database was queried for patients treated with microwave ablation or partial nephrectomy from 2015 to 2020. Allocated costs related to the procedural encounter and related to complications were collected. Allocated cost was calculated using ratio of cost-to-charges cost accounting methodology. Total cost was the sum of medical center cost and physician related cost. Statistical analysis was performed in SAS using Student's t-test and the Wilcoxon rank-sum test. A total of 279 patients were identified, of whom 165 underwent percutaneous MWA and 114 underwent RA-PN. All partial nephrectomies were robot-assisted. The mean total cost was $20,536 for RA-PN and $6,470 for percutaneous MWA (p <0.0001). Five patients (3%) who underwent MWA and 7 (6%) who underwent RA-PN experienced complications. Patients who underwent MWA and did not have a major complication had an average medical center cost of $5,174, compared to $8,990 for those with a major complication (p=0.36). Among patients who underwent RA-PN, those who did not have a major complication had an average medical center cost of $15,138, compared to $28,940 for those who did have a major complication (p=0.008). MWA demonstrates lower perioperative cost and lower cost of complications than RA-PN for treatment of LRM. Further cost-effectiveness studies for LRM treatment should be performed with this updated cost information.


Bartonella endocarditis in patients with right ventricle-to-pulmonary artery conduit: 2 case reports and literature review.
Bartonella species are Gram-negative bacilli and fastidious bacteria that can cause a number of clinical syndromes, including blood culture-negative infective endocarditis (IE). The two most commonly isolated species in humans are Bartonella quintana, the agent of trench fever, and Bartonella henselae, mostly known for causing cat scratch disease (Edouard et al., 2015 [1]; Edouard and Raoult, 2010 [2]). Both species also cause bacillary angiomatosis, primarily in immunocompromised patients (Edouard et al., 2015 [1]; Fournier et al., 2001 [3]). The risk of B. henselae IE is increased in patients with cardiac valvular disease and congenital heart disease (CHD) (Edouard and Raoult, 2010 [2]; Das et al., 2009 [4]; Abandeh et al., 2012 [5]; Ouellette et al., 2016 [6]; Hoffman et al., 2007 [7]; Georgievskaya et al., 2014 [8]). In this article, we detail two cases of Bartonella IE in patients with right ventricle-to-pulmonary artery (RV-PA) conduits who presented to our institution. We also perform a literature review on Bartonella IE in patients with a history of RV-PA conduit or pulmonary valve replacement.


A discrete adjuvant-induced monoarthritis in the rat: effects of adjuvant dose.
Much evidence suggests an important role for the nervous system in the pathogenesis of peripheral inflammatory conditions such as arthritis. The classical adjuvant-induced arthritis model in the rat is a severe condition in which polyarthritis is accompanied by widespread systemic disease, complicating the interpretation of data. We have developed an adjuvant-induced arthritis of the tibio-tarsal joint in the rat, using a low dose of Freund's adjuvant administered locally. Initial inflammation is followed, after 14 days, by chronic monoarthritis which is maintained without generalised effects or loss of use of the limb until at least 30 days postinjection. A higher dose of adjuvant produces contralateral inflammation and arthritis, but only after 14 days, and without the complicating effects seen in classical adjuvant disease. Indirect measures of arthritis (joint circumference, inflammation score and nociceptive threshold) correlate closely with the histological state of the joint, supporting the use of these indices. This model can be easily exploited by alteration of adjuvant dose, to determine the roles of the nervous system in the pathogenesis, maintenance and symmetrical spread of inflammatory arthritis.


Chromatographic retention behaviour of n-alkylbenzenes and pentylbenzene structural isomers on porous graphitic carbon and octadecyl-bonded silica studied using molecular modelling and QSRR.
The retention behaviour of a series of 15 n-alkylbenzenes and pentylbenzene structural isomers and benzene were investigated using porous graphitic carbon (PGC) and octadecyl-bonded silica (ODS) stationary phases. Shorter chain n-alkylbenzenes and benzene (n=0-6), and all the pentylbenzene isomers were more strongly retained on ODS, although the selectivity was greater with PGC. For the pentylbenzene analytes the degree of branching in the alkyl chain at the position adjacent to the aromatic ring affects retention on PGC, with higher retention in less branched molecules. Molecular modelling studies have provided new insights into the geometry of aromatic π-π stacking interactions in retention on PGC. For alkylbenzenes with high branching at the position adjacent to the ring, the preferred geometry of association with the surface is with the branched chain directed away from the surface, a geometry not seen in the other alkylbenzenes. The most energetically favoured orientation for interaction between analytes and the PGC surface was found to be cofacial for toluene and ethylbenzene, whereas for other analytes this interaction was in a face-edge orientation. The alternative geometry of association observed with both toluene and ethylbenzene may explain the enhanced retention of these two analytes on PGC compared with their longer chain analogues. Quantitative structure-retention relationships revealed the importance of compactness in analyte structure during retention on PGC, with decreased compactness (associated with longer chain length and reduced chain branching) improving retention.


Cholangitis after the Kasai operation for biliary atresia.
One hundred seventy-nine episodes of cholangitis in 28 consecutive patients having a Kasai operation for biliary atresia during the past 3 1/2 years were analyzed. The diagnosis was made primarily on the basis of unexplained fever (greater than 38.0 degrees C). An increase in serum bilirubin or a decrease in bile volume and in bile bilirubin concentration were often confirmatory, but other laboratory data including serum hepatic enzymes and blood and bile culture data were of little or inconsistent value. All patients were treated with systemic antibiotics. The best results were obtained with third-generation cephalosporins or imipenemcilastatin with the addition of aminoglycosides in recalcitrant cases. Antibiotic therapy was modified if defervescence did not occur within the first 24 hours. Cholangitis refractory to antibiotics was aggressively treated with pulse steroid therapy, and in some cases, operative intervention, both with good clinical success (60% and 73%, respectively).


Pharmacological Therapy for the Prevention and Treatment of Weakness After Critical Illness: A Systematic Review.
ICU-acquired weakness is a common complication of critical illness and can have significant effects upon functional status and quality of life. As part of preliminary work to inform the design of a randomized trial of a complex intervention to improve recovery from critical illness, we sought to identify pharmacological interventions that may play a role in this area. We systematically reviewed the published literature relating to pharmacological intervention for the treatment and prevention of ICU-acquired weakness. We searched MEDLINE, EMBASE, CINAHL+, Web of Science, and both U.S. and European trial registries up to July 2014 alongside reviews and reference lists from populations with no age or language restrictions. We included studies that reported a measure of muscle structure or physical function as an outcome measure. We estimated pooled odds ratios and 95% CI using data extracted from published articles or where available, original data provided by the authors. Assessment of bias was performed using the Cochrane Collaboration's risk of bias tool. Ten studies met the inclusion criteria. The current body of evidence does not support the use of any pharmacological agent in this setting, although maintaining euglycemia may reduce the prevalence of critical illness polyneuropathy. At present, no pharmacological intervention can be recommended to prevent or treat ICU-acquired weakness. Further research is required into this field to include more novel agents such as myostatin inhibitors. Challenges in the conduct of research in this area are highlighted.


Adsorption of arsenite and selenite using an inorganic ion exchanger based on Fe-Mn hydrous oxide.
The adsorption behaviour and mechanism of As(III) and Se(IV) oxyanion uptake using a mixed inorganic adsorbent were studied. The novel adsorbent, based on Fe(III)-Mn(III) hydrous oxides and manganese(II) carbonate, was synthesised using a hydrothermal precipitation approach in the presence of urea. The inorganic ion exchanger exhibited a high selectivity and adsorptive capacity towards As(III) (up to 47.6 mg/g) and Se(IV) (up to 29.0 mg/g), even at low equilibrium concentration. Although pH effects were typical for anionic species (i.e., the adsorption decreased upon pH increase), Se(IV) was more sensitive to pH changes than As(III). The rates of adsorption of both oxyanions were high. Fourier transform infrared (FTIR) and X-ray photoelectron spectroscopy (XPS) studies showed that the ion exchange adsorption of both anions took place via OH(-) groups, mainly from Fe(III) but also Mn(III) hydrous oxides. MnCO(3) did not contribute directly to As(III) and Se(IV) removal. A higher adsorptive capacity of the developed material towards As(III) was partly due to partial As(III) oxidation during adsorption.


Significant hematuria secondary to sickle cell trait in a white family.
A 21-year-old blond, white woman was evaluated for recurrent episodes of significant painless gross hematuria. She was found to have sickle cell trait, and hematologic evaluation made through four generations isolated the trait to the paternal side.


A novel 5HT3 antagonist 4i (N-(3-chloro-2-methylphenyl)quinoxalin-2-carboxamide) prevents diabetes-induced depressive phenotypes in mice: Modulation of serotonergic system.
Despite the presence of a multitudinous pharmacotherapy, diabetes-induced depressive disorder remains undertreated. Evidence suggests that brain serotonergic deficits are associated with depressive-like behavior in diabetes and that 5HT3 receptor (5HT3R) antagonists have serotonergic facilitatory effects. This study examined the effects of a novel 5HT3R antagonist, 4i (N-(3-chloro-2-methylphenyl)quinoxalin-2-carboxamide), in diabetes-induced depressive phenotypes. Experimentally, (1) to evaluate the effects of 4i, mice with 8-weeks of diabetes (induced by streptozotocin, 200mg/kg, i.p.) were treated with vehicle, 4i (0.5 and 1mg/kg/day, i.p.), fluoxetine (10mg/kg/day, i.p.) for 4-weeks and subjected to neurobehavioral assays, followed by biochemical estimation of serotonin levels in midbrain, prefrontal-cortex and cerebellum. (2) To evaluate the role of 5HT3R in the postulated effect of 4i, diabetic mice were given 4i (1mg/kg/day, i.p.) after 1h of 1-(m-chlorophenyl)-biguanide (mCPBG, a 5HT3R agonist, 10mg/kg/day, i.p.) treatment and subjected to the same protocol. The results showed that diabetic mice exhibited a significant behavioral deficit, including depression-like behavior in forced swim test, anxiety-like in open field test and sociability deficits in social interaction test, along with a significant decrease in serotonin level in these brain regions. 4i (1mg/kg), similar to fluoxetine, prevented these behavioral abnormalities and normalized brain serotonin levels. 4i (0.5mg/kg) ameliorated only diabetes-induced depressive-like behavior and serotonin deficits, but not anxiety-like effects. mCPBG blunted 4i-mediated behavioral response and increase in brain serotonin levels. Altogether, this study suggests that 4i prevents diabetes-induced depressive phenotypes in mice, which may involve antagonism of 5HT3Rs and increase in serotonin levels in discrete brain regions.


Dataset of Fourier transform-infrared coupled with chemometric analysis used to distinguish accessions of Garcinia mangostana L. in Peninsular Malaysia.
In this dataset, we distinguish 15 accessions of Garcinia mangostana from Peninsular Malaysia using Fourier transform-infrared spectroscopy coupled with chemometric analysis. We found that the position and intensity of characteristic peaks at 3600-3100 cm(-) (1) in IR spectra allowed discrimination of G. mangostana from different locations. Further principal component analysis (PCA) of all the accessions suggests the two main clusters were formed: samples from Johor, Melaka, and Negeri Sembilan (South) were clustered together in one group while samples from Perak, Kedah, Penang, Selangor, Kelantan, and Terengganu (North and East Coast) were in another clustered group.


1,25(OH)2-vitamin D3, a steroid hormone that produces biologic effects via both genomic and nongenomic pathways.
The hormonally active form of vitamin D is 1,25(OH)2-vitamin D3 [1,25(OH)2D3]. This seco-steroid is the key mediator of the vitamin D endocrine system which produces biological effects in over 28 target tissues. In these target tissues, the biological responses may be generated both by a signal transduction mechanism which involves a nuclear receptor for 1,25(OH)2D3 that modulates gene transcription or a signal transduction pathway which involves rapid opening of Ca2+ channels which are externally located on the plasma membrane. This paper reviews the evidence in support of the pleiotropic effects of this steroid hormone and presents evidence that the receptor of the genomic effects is likely to be separate from the receptor/membrane recognition element which initiates the rapid nongenomic biological effects.


[Chemical Constituents from Pueraria alopecuroides Ratten].
To study the chemical constituents from the ratten of Pueraria alopecuroide. Column chromatography techniques were used for compounds separation. And their structures were elucidated by physico-chemical properties and means of spectral analysis. Five flavonoids were isolated from Pueraria alopecuroide and their structures were identified as: (3R)-2', 3'-dihydroxy-6,7,4'-trimethoxyisoflavane(1), (3R)-8,2'-dihydroxy-7,4'-dimethoxyisoflavane(2), (3S)-vestitol(3), (3R)-(-)-7,2'-dihydroxy-3',4'-dimethoxyisoflavane(4), and 5,7,4'-trihydroxy-2',3'-dimethoxyisoflavanone(5). Compounds 1 5 are isolated from this plant for the first time and compound 1 is a new compound.


Termination of pregnancy in women with epilepsy - A retrospective single center study.
Antiepileptic drugs (AEDs) are commonly prescribed to women of childbearing age. As 0.3%-0.7% of all pregnancies occur in women with epilepsy (WWE), the effect of recurrent seizures and teratogenicity on pregnancy outcome and the fetus have been widely studied. Most of these studies have focused on live births. A significant number of terminated pregnancies in WWE were ignored in past studies, thus reducing the calculated incidence of congenital malformations and possible influence of AED exposure. We scrutinized the medical records at our medical center for termination of pregnancy (TOP) in WWE for the years 2004-2016. Fifty-eight TOPs occurred in WWE during these years. Reasons for TOP included spontaneous abortions necessitating medical intervention (46.6%), patient's request (31.0%), medically recommended (10.3%), and unknown (12.1%).


RAF inhibition overcomes resistance to TRAIL-induced apoptosis in melanoma cells.
Mutated BRAF represents a critical oncogene in melanoma, and selective inhibitors have been approved for melanoma therapy. However, the molecular consequences of RAF inhibition in melanoma cells remained largely elusive. Here, we investigated the effects of the pan-RAF inhibitor L-779,450, which inhibited cell proliferation both in BRAF-mutated and wild-type melanoma cell lines. It furthermore enhanced apoptosis in combination with the death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and overcame TRAIL resistance in melanoma cells. Enhanced apoptosis coincided with activation of mitochondrial pathways, seen by loss of mitochondrial membrane potential and release of cytochrome c, Smac (second mitochondria-derived activator of caspases), and apoptosis-inducing factor (AIF). Subsequently, caspase-9 and -3 were activated. Apoptosis induction by L-779,450/TRAIL was prevented by Bcl-2 overexpression and was dependent on Bax. Thus, activation of Bax by L-779,450 alone was demonstrated by Bax conformational changes, whereas Bak was not activated. Furthermore, the BH3-only protein Bim was upregulated in response to L-779,450. The significant roles of Smac, Bax, and Bim in this setting were proven by small interfering RNA (siRNA)-mediated knockdown experiments. L-779,450 also resulted in morphological changes indicating autophagy confirmed by the autophagy marker light chain 3-II (LC3-II). The pro-apoptotic effects of L-779,450 may explain the antitumor effects of RAF inhibition and may be considered when evaluating RAF inhibitors for melanoma therapy.


Coexistence of antibodies to tick-borne agents of babesiosis and Lyme borreliosis in patients from Cotia county, State of São Paulo, Brazil.
This paper reports a case of coinfection caused by pathogens of Lyme disease and babesiosis in brothers. This was the first case of borreliosis in Brazil, acquired in Cotia County, State of S o Paulo, Brazil. Both children had tick bite history, presented erythema migrans, fever, arthralgia, mialgia, and developed positive serology (ELISA and Western-blotting) directed to Borrelia burgdorferi G 39/40 and Babesia bovis antigens, mainly of IgM class antibodies, suggestive of acute disease. Also, high frequencies of antibodies to B. bovis was observed in a group of 59 Brazilian patients with Lyme borreliosis (25.4%), when compared with that obtained in a normal control group (10.2%) (chi-square = 5.6; p < 0.05). Interestingly, both children presented the highest titers for IgM antibodies directed to both infective diseases, among all patients with Lyme borreliosis.


The musculocutaneous nerve: ultrasound appearance for peripheral nerve block.
To gain complete anesthesia of the forearm, block of the musculocutaneous nerve is necessary. Variations in its course and position make localization of the musculocutaneous nerve problematic. The aim of the study is to describe the ultrasound appearance of the musculocutaneous nerve in the axilla and to suggest potential areas to target neural block. We scanned the axillary regions of 19 volunteers and assessed the size and shape of 34 musculocutaneous nerves at entry into, exit from, and in the center of the coracobrachialis muscle. Furthermore, we measured the depth of the musculocutaneous nerve under the skin surface and its distance from the axillary artery at those 3 measurement points. As it travels through the coracobrachialis muscle, the musculocutaneous nerve changes in shape from oval to flat-oval to triangular. During this course, the musculocutaneous nerve also separates from the axillary artery and becomes more lateral while changing its depth from the surface. The musculocutaneous nerve increases its transverse area along this nerve path. In 2 subjects, the musculocutaneous nerve could not be visualized unilaterally within the course of the coracobrachialis muscle. Knowledge of its ultrasound appearance facilitates localization and successful block of the musculocutaneous nerve. Because the distance between the musculocutaneous nerve and brachial plexus varies, different locations of musculocutaneous nerve puncture during ultrasound-guided regional anesthesia can be chosen.


Musculoskeletal involvement in systemic sclerosis.
Musculoskeletal involvement is more frequent than expected in patients with systemic sclerosis (SSc) and is a major cause of disability, even if the prognosis of the disease largely depends on visceral involvement. The most common clinical feature of musculoskeletal involvement is arthralgia; less frequent features are arthritis, flexion contractures, stiffness (affecting predominantly fingers, wrists and ankles), proximal muscle weakness (mainly of the shoulder and hip) and tendon sheath involvement. Tendon friction rubs are predictive of poor prognosis. If musculoskeletal involvement is suspected, serum creatinine phosphokinase, aldolase, lactate dehydrogenase, alkaline phosphate, rheumatoid factor and anticyclic citrullinated peptide autoantibodies should be checked routinely. Treatment for muscle involvement has not yet been considered adequately and, in the future, it is to be hoped that clinical trials will identify new drugs to control this aspect of SSc, which seriously compromises patients' quality of life.


Repeated clorgyline treatment inhibits methamphetamine-induced behavioral sensitization in mice.
Following the expression of the behavioral sensitization by repeated administration of methamphetamine (METH) (1 mg/kg, intraperitoneal (i.p.), once per day for five consecutive days), male ICR mice were treated with clorgyline (1 mg/kg, subcutaneous, once per day for five consecutive days), a monoamine oxidase-A inhibitor. Two hours after the final treatment with clorgyline, the mice were challenged with METH (1 mg/kg, i.p.) and locomotor activity was measured for 1 h. The mice treated with clorgyline showed a significant decrease in both vertical locomotion and horizontal rearing, compared with those treated with saline. Clorgyline treatment altered the effect of single METH challenges on apparent dopamine turnover in the cerebral cortex of the mice sensitized to METH. These results suggested a possible association of the inhibition by clorgyline of METH-induced behavioral sensitization with the alteration of dopamine turnover in the cerebral cortex of the mouse.


Enhancement of nitroaromatic compounds anaerobic biotransformation using a novel immobilized redox mediator prepared by electropolymerization.
Functionalized polypyrrole (PPy) composites were prepared by incorporation of a model redox mediator, anthraquinonedisulphonate (AQDS), as doping anion during the electropolymerization of pyrrole (Py) monomer on active carbon felt (ACF) electrode. Then, the resulting composite, ACF/PPy/AQDS as a novel immobilized redox mediator for catalyzing anaerobic biotransformation of the model nitroaromatic compounds (NACs), such as nitrobenzene (NB), 2,4- and 2,6-dinitrotoluene (DNT), were investigated in detail. The results showed that ACF/PPy/AQDS exhibited good catalytic activity and stability, and its addition effectively accelerated the NACs anaerobic reduction to the corresponding amino compounds. In order to estimate the relationship between community dynamics and the function of immobilized redox mediator, a combined method based on fingerprints (ribosomal intergenic spacer analysis, RISA) and 16S rRNA gene sequencing was used. The results indicated that the existence of ACF/PPy/AQDS made the potent AQDS-reducing bacteria keeping predominant in the catalytic systems. Based on the results above, it can be concluded that this novel immobilized redox mediator is feasible and potentially useful to enhance NACs anaerobic reduction.


Digital models for arterial pressure and respiratory waveforms.
Digital models for arterial pressure pulse (APP) and respiratory volume waveforms (RVW) are proposed for efficient representation of these signals. When these signals are discrete cosine transformed (DCT), the pole-zero technique of Steiglitz-McBride (SM) gave system functions of much lower order than those obtained directly from the signals. The DCT of a bell-shaped biphasic wave needed two poles and two zeros. Based on this, the model order is fixed by the number of distinct peaks in the magnitude spectrum of the transformed APP/RVW signal. The partial fraction expansion (PFE) of the system function allowed delineation of component waves present in the time signal. The angles of model poles and zeros enabled easy determination of several important features from both of these signals. The model performance is evaluated using the normalized root mean-square error (NRMSE). A Bayes classifier using the pole angles as the feature vector performed satisfactorily when a limited number of RVW's recorded under deep and rapid maneuver are classified into normal (n) and abnormal (ab) categories of respiratory pathways.


Social innovation in health and community-driven engagement as a key strategy for addressing COVID-19 crisis challenges: insights and reflections from the multicultural society of Iran.
Social innovation is one of the strategies for appealing to people and encouraging social cooperation and engagement in interventions during crisis periods. In this regard, community engagement is an operative and innovative community health approach for achieving successful health outcomes. There is limited information about the role and operational impact of social innovation on community engagement during the challenges posed by the COVID-19 crisis. In this study, we aim to contribute to the understanding of innovative social strategies to attract social participation in crises such as the COVID-19 pandemic by highlighting the experience of social innovative strategies based on community-driven engagement in Iran. This qualitative study was conducted in seven provinces of Iran-Mazandaran, Zanjan, Golestan, Lorestan, Tehran, Kurdistan, and Khuzestan-from 4 September 2021 to 1 March 2022. A sample of Iranians (15-71 years) was selected by purposeful and snowball sampling methods to participate in the study, and 187 semi-structured telephone interviews were conducted. Participants were recruited from three levels of the community: community leaders, healthcare providers, and laypeople. The data collection tool was an interview guide, which was designed based on a review of the literature. The data were analyzed using conventional content analysis. Exploratory analyses were performed to identify social innovative strategies based on community engagement used during the COVID-19 crisis in Iran. The interviews continued until data saturation was reached. Based on our findings, we distilled innovative strategies into 6 main themes and 37 categories: (1) information giving/sharing, (2) consultation, (3) involvement/collaboration, (4) health education and prevention, (5) empowering, and (6) advocacy. The results revealed that the participants were very driven to engage in the management and control of the COVID-19 crisis, even though they faced significant challenges. The spread of the COVID-19 pandemic required social- and community-based responses. These reactions increased the possibility of fair access to health services, especially for vulnerable groups and minorities. As with other epidemics, applying the experience of the comprehensive participation of communities played an important and active role in the prevention and control of COVID-19. In this regard, giving and sharing information, consultation, involvement/collaboration, health education/prevention, empowerment, and advocacy are the most important innovative strategies that might encourage the community to perform COVID-19 crisis management and control.


Atypical immune phenotype in severe combined immunodeficiency patients with novel mutations in IL2RG and JAK3.
Mutations in the common gamma chain of the interleukin 2 receptor (IL2RG) or the associated downstream signaling enzyme Janus kinase 3 (JAK3) genes are typically characterized by a T cell-negative, B cell-positive, natural killer (NK) cell-negative (T-B+NK-) severe combined immunodeficiency (SCID) immune phenotype. We report clinical course, immunological, genetic and proteomic work-up of two patients with different novel mutations in the IL-2-JAK3 pathway with a rare atypical presentation of T-B+NK- SCID. Lymphocyte subpopulation revealed significant T cells lymphopenia, normal B cells, and NK cells counts (T-B+NK+SCID). Despite the presence of B cells, IgG levels were low and IgA and IgM levels were undetectable. T-cell proliferation in response to mitogens in patient 1 was very low and T-cell receptor V-beta chain repertoire in patient 2 was polyclonal. Whole-exome sequencing revealed novel mutations in both patients (patient 1-c.923delC frame-shift mutation in the IL2RG gene, patient 2-c.G172A a homozygous missense mutation in the JAK3 gene). Bioinformatic analysis of the JAK3 mutation indicated deleterious effect and 3D protein modeling located the mutation to a surface exposed alpha-helix structure. Our findings help to link between genotype and phenotype, which is a key factor for the diagnosis and treatment of SCID patients.


The impact of the origin of surgical sperm retrieval on placental and embryonic development: The Rotterdam Periconception cohort.
In patients with azoospermia, pregnancy can be achieved after surgical techniques using sperm retrieved from the testis or epididymis, which can impact on DNA integrity and epigenetics. DNA of the fetus and placenta is equally derived from both parents; however, genes important for placental development are expressed from the paternal alleles. Therefore, the origin of sperm may affect fetal and placental development. To investigate whether first-trimester trajectories of embryonic and placental development of pregnancies conceived after intracytoplasmic sperm injection (ICSI) with testicular sperm extraction (TESE) or microsurgical epididymal sperm aspiration (MESA), are different from pregnancies after ICSI with ejaculated sperm or natural conceptions. A total of 147 singleton ICSI pregnancies, including pregnancies conceived after TESE (n = 23), MESA (n = 25) and ejaculated sperm (n = 99), and 380 naturally conceived and 140 after IVF treatment without ICSI were selected from the prospective Rotterdam periconception cohort. Crown-rump length (CRL), embryonic volume (EV), Carnegie stages, and placental volume (PV) at 7, 9, and 11 weeks of gestation were measured using 3D ultrasound and virtual reality technology. Linear mixed model analysis showed no differences in trajectories of CRL, EV, and Carnegie stages between pregnancies conceived after ICSI with testicular, epididymal, and ejaculated sperm. A significantly positive association was demonstrated for PV between pregnancies conceived after TESE-ICSI (adjusted beta: 0.28(95%CI: 0.05-0.50)) versus ICSI with ejaculated sperm. Retransformation to original values showed that the PV of pregnancies after TESE-ICSI is 14.6% (95%CI: 1.4%-25.5%) larger at 11 weeks of gestation compared to ICSI pregnancies conceived with ejaculated sperm. Here we demonstrate that the first-trimester growth trajectory of the placenta is increased in pregnancies conceived after TESE-ICSI compared to those conceived after ICSI with ejaculated sperm. Findings are discussed in the light of known differences in sperm DNA integrity, epigenetics, and placental gene expression.


Electrophoretically mediated microanalysis of ethanol.
Capillary electrophoresis was used to determine ethanol by the methodology of electrophoretically mediated microanalysis (EMMA). In EMMA, spatially distinct analyte and analytical reagent zones of differing electrophoretic mobility are merged under the influence of an electric field, and the resulting product is transported to the detector. The enzymatic oxidation of ethanol to acetaldehyde by alcohol dehydrogenase was utilized, and the concurrent reduction of NAD+ to NADH was monitored at 340 nm as a measure of the quantity of ethanol injected. Quantitation using an internal standard and normalization for peak migration time yielded a R.S.D. of 2.7%, and the linear range extended to that quantity of ethanol which could be reacted prior to passing by the detection window. Comparison of the EMMA technique to the Sigma spectrophotometric procedure revealed that the two methods do not yield significantly different values for the determination of ethanol. The EMMA method offered the advantages of electrophoretic mixing and miniaturization.


Tilapia lake virus downplays innate immune responses during early stage of infection in Nile tilapia (Oreochromis niloticus).
Tilapia lake virus (TiLV) causes high mortality and high economic losses in tilapines. We describe an experimental challenge study focusing on early post challenge innate immune responses. Nile tilapia (Oreochromis niloticus) were infected with 105 TCID50/mL TiLV intraperitoneally, followed by virus quantification, histopathology and gene expression analysis in target (brain/liver) and lymphoid (spleen/headkidney) organs at 3, 7, 12, 17, and 34 days post challenge (dpc). Onset of mortality was from 21 dpc, and cumulative mortality was 38.5% by 34 dpc. Liver and kidney histopathology developed over the period 3-17 dpc, characterized by anisocytosis, anisokaryocytosis, and formation of multinucleated hepatocytes. Viral loads were highest at early time (3 dpc) in liver, spleen and kidney, declining towards 34 dpc. In brain, viral titer peaked 17 dpc. Innate sensors, TLRs 3/7 were inversely correlated with virus titer in brain and headkidney, and IFN-ß and Mx showed a similar pattern. All organs showed increased mRNA IgM expression over the course of infection. Overall, high virus titers downplay innate responses, and an increase is seen when viral titers decline. In silico modeling found that TiLV segments 4, 5 and 10 carry nucleolar localization signals. Anti-viral effects of TiLV facilitate production of virus at early stage of infection.


The PAC-SYM questionnaire for chronic constipation: defining the minimal important difference.
The Patient Assessment of Constipation-Symptoms (PAC-SYM) questionnaire is frequently used in clinical trials of constipation. However, the threshold for reduction in total PAC-SYM score used to define a clinical response on this 0-4 point scale has not undergone formal appraisal, and its relationship with clinical benefit as perceived by patients has not been defined. To determine the minimal important difference in PAC-SYM score, and the optimum cut-off value for defining responders. The minimal important difference was estimated using data from six international phase 3/4, double-blind, randomised controlled trials of prucalopride in patients with chronic constipation (NCT01147926, NCT01424228, NCT01116206, NCT00485940, NCT00483886, NCT00488137), with anchor- and distribution-based approaches. Five appropriate patient-reported outcomes were selected as anchors. In addition, receiver operating characteristics (ROC) curve analyses were used to investigate responder discrimination for each anchor. Data from 2884 patients were included. Minimal important difference estimates ranged from -0.52 to -0.63 across the five anchors. Estimates were not affected by study location but were consistently lower for rectal symptoms than for abdominal and stool symptoms. Distribution-based estimates were considerably lower than anchor-based estimates. ROC curve analyses showed optimum cut-off scores for discriminating responders to be similar to anchor-based minimal important difference estimates. Anchor-based methods gave consistent results for the minimal important difference, at approximately -0.6, and this value was close to the ROC-determined optimal cut-off scores for responder discrimination. This value could be considered in clinical practice. A slightly more conservative threshold (eg -0.75) could be used in clinical trials to reduce the placebo response rate.


Murine in vivo carrier-specific IgG memory to DNP-Ficoll: variation among inbred strains.
BALB/cAnN and C3H/HeN mice were primed and challenged with DNP-Ficoll, a thymic independent (TI-2) antigen. They developed significant carrier-specific IgG memory responses: DNP-pneumococcal polysaccharide or DNP-hemocyanin challenge did not elicit memory responses. NZB/B1NJ mice failed to develop this memory response. Genetically controlled events apparently regulate the phenotypic expression of this effect.


Potentiation of acute opioid-induced respiratory depression and reversal of tolerance by the calcium antagonist nimodipine in awake rats.
The interaction between sufentanil, a mu-opioid agonist, and the Ca2+ antagonist nimodipine on respiration and on the development of opioid tolerance in awake rats has been analyzed. Our previous work demonstrated that chronic treatment with nimodipine together with sufentanil increases the analgesic potency of the opioid 50 fold. Therefore, we have investigated whether the opioid-induced respiratory depression is potentiated in parallel with the analgesia. Ventilation was measured by the whole body plethysmographic method. In naive rats, sufentanil (10-80 micrograms/kg) consistently induced a dose-dependent respiratory depression. Pretreatment with nimodipine (200 micrograms/kg) potentiated this effect but to a lesser extent than it potentiated analgesia. After chronic administration of the opioid (2 micrograms/h, 7 days) tolerance was manifested as a reduction in both the area under the time course curve and in the maximum effect. Nimodipine (1 microgram/h) administered concurrently with sufentanil for 7 days counteracted the tolerance to respiratory depression but no additional potentiation was observed. These results demonstrate that the interaction between nimodipine and sufentanil is not limited to antinociception but also extends to respiratory depression. However, compared with analgesia, the clinical relevance of a potential increase in opioid-induced respiratory depression by nimodipine may be negligible.


Poly-γ-glutamic acid nanoparticles as adjuvant and antigen carrier system for cancer vaccination.
Vaccination is an innovative strategy for cancer treatment by leveraging various components of the patients' immunity to boost an anti-tumor immune response. Rationally designed nanoparticles are well suited to maximize cancer vaccination by the inclusion of immune stimulatory adjuvants. Also, nanoparticles might control the pharmacokinetics and destination of the immune potentiating compounds. Poly-γ-glutamic acid (γ-PGA) based nanoparticles (NPs), which have a natural origin, can be easily taken up by dendritic cells (DCs), which leads to the secretion of cytokines which ameliorates the stimulation capacity of T cells. The intrinsic adjuvant properties and antigen carrier properties of γ-PGA NPs have been the focus of recent investigations as they can modulate the tumor microenvironment, can contribute to systemic anti-tumor immunity and subsequently inhibit tumor growth. This review provides a comprehensive overview on the potential of γ-PGA NPs as antigen carriers and/or adjuvants for anti-cancer vaccination.


Antimalarial efficacy of arteether against multiple drug resistant strain of Plasmodium yoelii nigeriensis.
New quick-acting blood schizontocides are needed to contain the spread of multiple drug resistant strains of P. falciparum and for the treatment of the cerebral malaria cases. A multiple drug resistant strain of P. yoelii nigeriensis resistant to mefloquine (128 mg/kg x 6 days), quinine (300 mg/kg x 7 days) and chloroquine (64 mg/kg x 8 days) was found to be completely susceptible to arteether (a 30:70 mixture of alpha and beta enantiomers) and a dose of 5 mg/kg x 3 days by i.m. route was curative in Swiss mice. Artemisinin at 50 mg/kg x 7 days had only suppressive action against this strain.


"No more couch-potato!" Patients' experiences of a pre-operative programme of cardiac rehabilitation for those awaiting coronary artery bypass surgery.
The waiting period for coronary artery bypass surgery is a difficult time for patients and families. Pre-operative cardiac rehabilitation may be safe and effective, but there is limited evidence regarding patients' experience and perceptions of such intervention. To describe patients' experiences of a pre-operative programme of cardiac rehabilitation developed specifically for those awaiting coronary artery bypass surgery. A convenience sample of eight patients awaiting non-urgent surgery who had completed a 12 week pilot programme of cardiac rehabilitation were invited to be interviewed using a descriptive phenomenological approach. Domicillary interviews using an open technique were taped, transcribed and analysed using Colaizzi's framework. Participants described this programme as a useful means of improving exercise capacity and decreasing anxiety. Through the combination of exercise, advice and support participants stated that their initial fear that exercise would cause a heart attack was replaced with confidence, enabling them to become fitter and modify other risk factors. Findings of this study suggest that the programme was acceptable and perceived as beneficial by participants. Further research is required to evaluate the efficacy of pre-operative rehabilitation on risk factor modification.


Sequence studies of poliovirus RNA. IV. Nucleotide sequence complexities of poliovirus type 1, type 2 and two type 1 defective interfering particles RNAs, and fingerprint of the poliovirus type 3 genome.
The 32P-labelled genomes of poliovirus type 1, 2 and 3 have been digested with RNase T1 and the products separated by two-dimensional gel electrophoresis. All three fingerprints differ in the separation pattern of the large oligonucleotides. The molar yields of the large RNase T1-resistant oligonucleotides of type 1 and type 2 RNA of poliovirus RNA are close to one. By comparing the yields of these oligonucleotides to the amount of RNA from which they originated, the chain length of type 1 poliovirus RNA was found to be 7851 +/- 567 nucleotides (mol. wt. 2.66 +/- 0.19 x 10(6) and that of poliovirus type 2, 8181 +/- 578 nucleotides (mol. wt. 2.77 +/- 0.19 x 10(6). The chain length of two defective interfering particle (DI) RNAs of poliovirus type 1 were determined to be 7042 +/- 999 nucleotides for DI(1) and 6639 +/- 674 nucleotides for DI(2).


Specific and sensitive hydrolysis probe-based real-time PCR detection of epidermal growth factor receptor variant III in oral squamous cell carcinoma.
The tumor-specific EGFR deletion mutant, EGFRvIII, is characterised by ligand-independent constitutive signalling. Tumors expressing EGFRvIII are resistant to current EGFR-targeted therapy. The frequency of EGFRvIII in head and neck squamous cell carcinoma (HNSCC) is disputed and may vary by specific sub-site. The purpose of this study was to measure the occurrence of EGFRvIII mutations in a specific HNSCC subsite, oral squamous cell carcinoma (OSCC), using a novel real-time PCR assay. Pre-treatment Formalin Fixed Paraffin Embedded (FFPE) cancer specimens from 50 OSCC patients were evaluated for the presence of EGFRvIII using a novel hydrolysis probe-based real-time PCR assay. EGFR protein expression in tumor samples was quantified using fluorescent immunohistochemistry (IHC) and AQUA® technology. We detected EGFRvIII in a single OSCC patient in our cohort (2%). We confirmed the validity of our detection technique in an independent cohort of glioblastoma patients. We also compared the sensitivity and specificity of our novel real-time EGFRvIII detection assay to conventional RT-PCR and direct sequencing. Our assay can specifically detect EGFRvIII and can discriminate against wild-type EGFR in FFPE tumor samples. AQUAnalysis® revealed that the presence of EGFRvIII transcript is associated with very high EGFR protein expression (98(th) percentile). Contrary to previous reports, only 44% of OSCC over-expressed EGFR in our study. Our results suggest that the EGFRvIII mutation is rare in OSCC and corroborate previous reports of EGFRvIII expression only in tumors with extreme over-expression of EGFR. We conclude that EGFRvIII-specific therapies may not be ideally suited as first-line treatment in OSCC. Furthermore, highly specific and sensitive methods, such as the real-time RT-PCR assay and AQUAnalysis® described here, will provide accurate assessment of EGFR mutation frequency and EGFR expression, and will facilitate the selection of optimal tailored therapies for OSCC patients.


Investigating the affinity of BDE154 and 3OH-BDE154 with HSA: Experimental and simulation validation.
The physicochemical properties of polybrominated diphenyl ethers are important for modeling their transport, but these data are often missing. Here, satisfactory bioactivity results were obtained using human serum albumin as the carrier, 2,2',4,4',5,6'-hexabromodiphenyl ether (BDE154) and 3-hydroxy-2,2',4,4', 5,6'-hexabromodiphenyl ether (3OH-BDE154) as the ligands, using UV-visible absorbance, fluorescence, circular dichroism, molecular docking, and molecular dynamics methods. The interactions between human serum albumin and BDE154 or 3OH-BDE154 were verified, consistent with the static quenching procedure. At pH 7.4, the binding constants of the complexes for site I were relatively comparable and increased in the order BDE154<3OH-BDE154. Then, the secondary structure and kinetic parameters of albumin were analyzed using the circular dichroism spectra and GROMACS software. The data obtained from these simulations indicate that hydrophobic attraction might be the key factor for the stability of complexes. The docking experiments provided further insight into the hydrophobic pocket and showed that 3OH-BDE154 has a stronger binding affinity to human serum albumin than BDE154. The experimental spectral data were obtained and compared with the simulation results, showing good agreement. A detailed analysis of PBDEs-HSA interactions would provide valuable information to better understand the interaction on this class of compounds.


Panaxynol ameliorates cardiac ischemia/reperfusion injury by suppressing NLRP3-induced pyroptosis and apoptosis via HMGB1/TLR4/NF-κB axis.
Panaxynol (PNN) is a common natural minor component in Umbelliferae plants. Many clinical studies have shown that PNN exhibits nutritional value and anti-inflammatory and other pharmacological activities. However, whether PNN can mediate cardiac ischemia/reperfusion injury (IRI) remains unclear. Here, we aimed to determine the potential effects of PNN on myocardial IRI. Myocardial IRI was stimulated in a mouse IRI model, and neonatal rat ventricle myocytes (NRVMs) were exposed to hypoxia/reoxygenation to construct in an vitro model. Myocardial infarction size, myocardial tissue injury, myocardial apoptotic index, hemodynamic monitoring, pyroptosis-related proteins, cardiac enzyme activities and inflammatory responses were examined to assess myocardial injury. It was found that PNN administration markedly reduced myocardial infarct size and apoptosis, suppressed myocardial damage and cell pyroptosis, attenuated pro-inflammatory cytokines and neutrophil infiltration via NLRP3 inhibitor. More importantly, PNN treatment remarkably decreased the expression of TLR4/NF-κB pathway-associated proteins and NLRP3-related pyroptosis proteins by HMGB1 inhibitor. PNN also enhanced cell viability, reduced cardiac enzyme activities, suppressed apoptosis and attenuated inflammation in the isolated NRVMs. Furthermore, vitro studies indicated that MCC950 (a NLRP3 inhibitor) increased the anti-inflammatory and anti-apoptotic effects of PNN on NRVMs via HMGB1/TLR4 pathway. To sum up, our results demonstrate that PNN exhibits a cardioprotective effect by modulating heart IRI-induced apoptosis and pyroptosis via HMGB1/TLR4/NF-κB pathway, thereby inhibiting NLRP3 inflammasome stimulation.


Thyroid hormones, serotonin and mood: of synergy and significance in the adult brain.
The use of thyroid hormones as an effective adjunct treatment for affective disorders has been studied over the past three decades and has been confirmed repeatedly. Interaction of the thyroid and monoamine neurotransmitter systems has been suggested as a potential underlying mechanism of action. While catecholamine and thyroid interrelationships have been reviewed in detail, the serotonin system has been relatively neglected. Thus, the goal of this article is to review the literature on the relationships between thyroid hormones and the brain serotonin (5-HT) system, limited to studies in adult humans and adult animals. In humans, neuroendocrine challenge studies in hypothyroid patients have shown a reduced 5-HT responsiveness that is reversible with thyroid replacement therapy. In adult animals with experimentally-induced hypothyroid states, increased 5-HT turnover in the brainstem is consistently reported while decreased cortical 5-HT concentrations and 5-HT2A receptor density are less frequently observed. In the majority of studies, the effects of thyroid hormone administration in animals with experimentally-induced hypothyroid states include an increase in cortical 5-HT concentrations and a desensitization of autoinhibitory 5-HT1A receptors in the raphe area, resulting in disinhibition of cortical and hippocampal 5-HT release. Furthermore, there is some indication that thyroid hormones may increase cortical 5-HT2 receptor sensitivity. In conclusion, there is robust evidence, particularly from animal studies, that the thyroid economy has a modulating impact on the brain serotonin system. Thus it is postulated that one mechanism, among others, through which exogenous thyroid hormones may exert their modulatory effects in affective illness is via an increase in serotonergic neurotransmission, specifically by reducing the sensitivity of 5-HT1A autoreceptors in the raphe area, and by increasing 5-HT2 receptor sensitivity.


Smoking and weight control in adolescent females.
This paper examines the association between smoking and various weight control techniques among adolescent girls in two school-based samples. Previous studies have relied heavily on clinical trials of adults and have focused mainly on dietary restraint rather than purging behavior. This study seeks to determine whether purging is associated with smoking and if purging and dietary restraint effects upon smoking are additive or synergistic. Data from adolescent girls were gathered from two school-based surveys conducted in the upper Midwest. Assessments were conducted for smoking, dietary restraint, diet pill use, and purging. Logistic regression was used to test for main and interaction effects. Analysis revealed significant associations between smoking and weight control. Purging was more highly associated with smoking than dietary restraint or diet pill use. The form of these associations was interactive rather than additive in both data sets. Nonpurging girls were significantly more likely to smoke if they were dieting or using diet pills than if they were not practicing dieting behavior. Thus, the effect of dieting and diet pill use on smoking is dependent on purging behavior. Weight control is associated with smoking behavior in adolescent girls but the form of these associations may be more complex than originally thought. Future research is needed to determine if there are two subtypes of smoking-weight control girls.


Toxicity and transformation of fenamiphos and its metabolites by two micro algae Pseudokirchneriella subcapitata and Chlorococcum sp.
The acute toxicity of an organophosphorous pesticide, fenamiphos and its metabolites, fenamiphos sulfoxide (FSO), fenamiphos sulfone (FSO(2)), fenamiphos phenol (FP), fenamiphos sulfoxide phenol (FSOP) and fenamiphos sulfone phenol (FSO(2)P), to the aquatic alga Pseudokirchneriella subcapitata and the terrestrial alga Chlorococcum sp. was studied. The toxicity followed the order: fenamiphos phenol>fenamiphos sulfone phenol>fenamiphos sulfoxide phenol>fenamiphos. The oxidation products of fenamiphos, FSO and FSO(2) were not toxic to the algal species up to 100 mg L(-1). Both algae were able to transform fenamiphos, FSO and FSO(2), while the phenols were found to be stable in the incubation media. Bioaccumulation of both fenamiphos and its metabolites was observed in the case of Chlorococcum sp. while only metabolites were accumulated in P. subcapitata. This study demonstrates that (i) the hydrolysis products of fenamiphos, FSOP and FSO(2)P are more toxic to both fresh water and soil algae than their parent chemicals, (ii) further fenamiphos can be transformed and bioconcentrated by these algae. Therefore, contamination of natural environments such as waterbodies with fenamiphos or its metabolites can have adverse impacts on the food chain and associated biota (especially to the primary consumers such as Daphnia) since algae are the primary producers located at the base of the food chain. Further, the finding that the fenamiphos phenols are more toxic to algae highlights the need to consider the transformation products in ecological risk assessment of fenamiphos.


An orange will do: Suspending learner disbelief in simulations.
Increasingly, educators are implementing simulation to supplement teaching. Where simulation is not already integral, difficulties have arisen with the utilization of simulation due to limited resources, training requirements, and educator uncertainty. A learner's ability to suspend disbelief in a simulation can impact the effectiveness of learning. In other words, they become so immersed in the simulation that they ignore obvious limitations and choose to believe the activity is realistic. When designing simulations, educators need to consider intended learning outcomes (ILOs), realism, and briefings/debriefings to help learners suspend disbelief. Realism encompasses physical realism (fidelity), conceptual realism, and emotional/experiential realism. The ILOs should drive the simulation design and type of realism required. These should be presented to learners in a briefing, explaining where and why they may need to suspend disbelief; this should be reiterated during a debriefing to centre a learner's focus on whether the ILOs were met. Without this, learners may not "buy into" the simulation and instead can get lost in detail not relevant to their learning. The use of cutting-edge equipment does not, on its own, ensure that learners get the most realistic learning experience. The goal of simulations should be to utilize resources in the most advantageous manner for attainment of ILOs. In a time when institutions may be pressured for time, staff, and resources, educators should remember that it is possible to facilitate effective learning in low-resource ways.


Intra-articular lesions and their relation to arthroscopic stabilization failure in young patients with first-time and recurrent shoulder dislocations.
This study aimed to compare the frequency of intra-articular lesions between young patients with first-time shoulder dislocations and those with recurrent shoulder dislocations and to assess the correlation between intra-articular lesions and failure of arthroscopic stabilization. The study enrolled 33 patients who underwent arthroscopic Bankart repair after first-time shoulder dislocation before the age of 30 years. There were 89 age-matched patients who were treated arthroscopically for recurrent dislocation included as a control group. Among intra-articular pathologic findings, anterior glenoid erosion (P = .043) and anterior labral periosteal sleeve avulsion lesions (P = .048) were found more frequently in the recurrent dislocation group. There was no statistically significant difference between the 2 groups in American Shoulder and Elbow Surgeons (P = .675) and Rowe (P = .132) scores at the last follow-up. However, there was a significant difference in the failure rate after operation between the 2 groups (P = .039). In the first-time dislocation group, 1 patient had redislocation and none showed positive apprehension. In the recurrent dislocation group, 6 patients had redislocation and 10 patients had positive apprehension. Eight of 10 patients who showed positive apprehension had either anterior labral periosteal sleeve avulsion lesions or anterior glenoid erosion. The patients' satisfaction with daily activities was significantly better in the first-time dislocation group (93.0 ± 5.2) than in the recurrent dislocation group (82.7 ± 7.2; P < .001). Primary surgical treatment for first-time traumatic anterior shoulder dislocation provided satisfactory functional outcomes and improved quality of life. Primary arthroscopic stabilization can be considered one of the treatment options in patients younger than 30 years with first-time shoulder dislocation to prevent further intra-articular injuries that may contribute to recurrence.


Lipid turnover during senescence.
Rapid turnover of stored triacylglycerol occurs after seed germination, releasing fatty acids that provide carbon and energy for seedling establishment. Glycerolipid and fatty acid turnover that occurs at other times in the plant life cycle, including senescence is less studied. Although the entire pathway of β-oxidation is induced during senescence, Arabidopsis leaf fatty acids turnover at rates 50 fold lower than in seedlings. Major unknowns in lipid turnover include the identity of lipases responsible for degradation of the wide diversity of galactolipid, phospholipid, and other lipid class structures. Also unknown is the relative flux of the acetyl-CoA product of β-oxidation into alternative metabolic pathways. We present an overview of senescence-related glycerolipid turnover and discuss its function(s) and speculate about how it might be controlled to increase the energy density and nutritional content of crops. To better understand regulation of lipid turnover, we developed a database that compiles and plots transcript expression of lipid-related genes during natural leaf senescence of Arabidopsis. The database allowed identification of coordinated patterns of down-regulation of lipid biosynthesis genes and the contrasting groups of genes that increase, including 68 putative lipases.


Throwing Injury Prevention Strategies with a Whole Kinetic Chain-Focused Approach.
This review examines the relationship between the baseball pitching motion and the kinetic chain. The goal was to determine the underlying causes of a deficiency in throwing mechanics throughout a throwing motion, and to provide an evidence-based approach on how to prevent injuries caused by a lack of proper mechanics. In doing so, we sought to provide a warm-up strategy that can be added to every baseball player's daily on-field routine that is tailored to each phase of the throwing motion. To help minimize the risk of injury to overhead throwing athletes, a thorough understanding of the throwing motion is critical. Throwing a ball places extreme stress on the body, notably the shoulder and elbow joints. With a clear understanding of the biomechanics of throwing, we can develop an injury prevention routine to minimize unnecessary stresses throughout the kinetic chain. The throwing cycle is a complex motion that places various stresses throughout the thrower's body, from the ankle to the core, and from the back to the shoulder and elbow. A thorough understanding of the mechanics of this motion, along with specific exercises to target the specific actions of each phase, may allow for throwers, regardless of their age and experience, to minimize injury risk.


Hydrophile scanning as a complement to alanine scanning for exploring and manipulating protein-protein recognition: application to the Bim BH3 domain.
Alanine scanning has been widely employed as a method of identifying side chains that play important roles in protein-protein and protein-peptide interactions. Here we show how an analogous and complementary technique, hydrophile scanning, can provide additional insight on such interactions. Mutation of a wild-type residue to alanine removes most of the side-chain atoms, and the effect of this removal is typically interpreted to indicate contribution of the deleted side chain to the stability of the complex. Hydrophile scanning involves systematic mutation of wild-type residues to a cationic or anionic residue (lysine or glutamic acid, in this case). We find that the results of these mutations provide insights on interactions between polypeptide surfaces that are complementary to the information obtained via alanine scanning. We have applied this technique to a peptide that corresponds to the BH3 domain of the pro-apoptotic protein Bim. The wild-type Bim BH3 domain binds strongly to the anti-apoptotic proteins Bcl-x(L) and Mcl-1. Combining information from the alanine, lysine, and glutamic acid scans has enabled us to identify Bim BH3 domain mutants containing only two or three sequence changes that bind very selectively either to Bcl-x(L) or Mcl-1. Our findings suggest that hydrophile scanning may prove to be a broadly useful tool for revealing sources of protein-protein recognition and for engineering selectivity into natural sequences.


Understanding the Mammography Audit.
Screening mammography aims to identify small, node-negative breast cancers when they are still curable while maintaining an acceptable range of false-positive recalls and biopsies. The mammography audit is a powerful tool to help radiologists understand their performance with respect to that goal. This article defines audit terms and describes how to use collected and derived data to perform a mammography audit. Accepted benchmarks are discussed as well as their applicability to radiologists and breast imaging practices in the United States. Special considerations regarding volumes and radiologist characteristics are explored, because these factors may affect audit results.


The association of markers of oxidative-inflammatory status with malnutrition in hemodialysis patients with serum ferritin lower than 500 ng/mL.
Enhanced inflammatory-oxidative status is well established in chronic kidney disease. The objective of this study was to evaluate the oxidative- inflammatory status and iron indices in patients undergoing maintenance hemodialysis (HD) with serum ferritin lower than 500 ng/mL, and to correlate them with nutritional status. In a cross-sectional survey 35 HD patients (23 with normal nutritional status, 12 with Protein-Energy-Wasting syndrome, PEW), and healthy volunteers (n = 35) were studied. Serum concentration of iron, ferritin, transferrin saturation, malondialdehyde (MDA), protein carbonyl (PC), high-sensitive serum C -reactive protein (hs-CRP) and blood counts were determined. The nutritional status was determined by anthropometric and biochemical criteria. HD patients showed low values of hemoglobin and higher values of ferritin, MDA and PC when compared with healthy volunteers. HD subjects with PEW had higher values of PC and hs-PCR as compared to HD patients with normal nutritional status. A multiple logistic regression analysis showed that the independent variables PC (Wald Statistic 4.25, p = 0.039) and hs-CRP (Wald Statistic 4.83, p = 0.028) where related with the patients' nutritional condition. In HD patients with serum ferritin below 500 ng/mL was observed one association of the markers of oxidative stress and inflammation with poor nutritional status independently of serum ferritin, gender and age.


Aedes aegypti (Diptera: Culicidae): monitoring of populations to improve control strategies in Argentina.
To study the seasonal fluctuations of populations of Aedes aegypti (L.), to improve control strategies, or to monitor chemical control interventions, a lightweight, inexpensive ovitrap made of black plastic, pail-shaped, stackable, and provided with a wood tongue depressor was used. Field assays were performed in the northeast and northwest part of Argentina. In a 1-year trial performed in Tartagal (Salta), almost 100% of the ovitraps were highly positive, collecting a total of 1,000/2,000 eggs during March and the first part of April. A focal treatment in the corresponding neighborhood, performed at this time, immediately began to reduce positive ovitraps in spite of the high temperatures registered, rising again in November after winter season. Another field trial was performed in the whole urban area of Iguazú (Misiones). Mosquito populations were evaluated after three weekly ultra low volume (ULV) applications with an EC formulation of permethrin in water. The number of positive ovitraps diminished from 49% to 10% after the treatments. The last one performed in Wanda (Misiones) showed that positive ovitraps inside the dwellings aided in determining reinfestation rates after an intervention with a smoke-generating formulation containing beta-cypermethrin. The work performed in three different situations in urban areas at high risk of dengue can be considered a preliminary assay to establish the effective performance of simple ovitraps, allowing the Vector Control Service of the Argentinian Ministry of Health its use to improve surveillance and control strategies.