Expression and characterization of a rabbit liver cytochrome P450 belonging to P450IIB subfamily with the aid of the baculovirus expression vector system.
Using baculovirus a cDNA for cytochrome P450 (P450F1) belonging to rabbit P450IIB subfamily was expressed in Spodoptera frugiperda cells, where P450F1 was located on electron-dense structures (derived from the endoplasmic reticulum) present in both the cytoplasm and nucleus. Partially purified P450F1 exhibited absorption spectra similar to those of P450(1), the major phenobarbital-inducible form in rabbit liver. Like P450(1), P450F1 could oxidize aminopyrine, benzphetamine, 7-ethoxycoumarin, 1-nitropropane, and 2-nitropropane, though its activities toward benzphetamine and 7-ethoxycoumarin were about 50 and 5%, respectively, of those of P450(1). It is concluded that the members of P450IIB subfamily can act on a variety of xenobiotics, although substrate preferences are different among them.


Identification of small-molecule inhibitors of ricin and shiga toxin using a cell-based high-throughput screen.
The Category B agents, ricin and shiga toxin (Stx), are RNA N-glycosidases that target a highly conserved adenine residue within the sarcin-ricin loop of eukaryotic 28S ribosomal RNA. In an effort to identify small-molecule inhibitors of these toxins that could serve as lead compounds for potential therapeutics, we have developed a simple Vero cell-based high-throughput cytotoxicity assay and have used it to screen approximately 81,300 compounds in 17 commercially available chemical libraries. This initial screen identified approximately 300 compounds with weak (>or=30 to <50%), moderate (>or=50 to <80%), or strong (>or=80%) ricin inhibitory activity. Secondary analysis of 244 of these original "hits" was performed, and 20 compounds that were capable of reducing ricin cytotoxicity by >50% were chosen for further study. Four compounds demonstrated significant dose-dependent ricin inhibitory activity in the Vero cell-based assay, with 50% effective inhibitory concentration (EC(50)) values ranging from 25 to 60microM. The same 20 compounds were tested in parallel for the ability to inhibit ricin's and Stx1's enzymatic activities in an in vitro translation reaction. Three of the 20 compounds, including the most effective compound in the cell-based assay, had discernible anti-toxin activity. One compound in particular, 4-fluorophenyl methyl 2-(furan-2-yl)quinoline-4-carboxylate ("compound 8"), had 50% inhibitory concentration (IC(50)) of 30microM, a value indicating >10-fold higher potency than is the case for previously described ricin-Stx1 inhibitors. Computer modeling predicted that compound 8 is capable of docking within the ricin active site. In conclusion, we have used a simple high-throughput cell-based method to identify several new small-molecule inhibitors of ricin and Stx.


A model of the smooth pursuit eye movement system.
Human, horizontal, smooth-pursuit eye movements were recorded by the search coil method in response to Rashbass step-ramp stimuli of 5 to 30 deg/s. Eye velocity records were analyzed by measuring features such as the time, velocity and acceleration of the point of peak acceleration, the time and velocity of the peaks and troughs of ringing and steady-state velocity. These values were averaged and mean responses reconstructed. Three normal subjects were studied and their responses averaged. All showed a peak acceleration-velocity saturation. All had ringing frequencies near 3.8 Hz and the mean steady-state gain was 0.95. It is argued that a single, linear forward path with any transfer function G(s) and a 100 ms delay (latency) cannot simultaneously simulate the initial rise of acceleration and ring at 3.8 Hz based on a Bode analysis. Also such a simple negative feedback model cannot have a steady-state gain greater than 1.0; a situation that occurs frequently experimentally. L.R. Young's model, which employs internal positive feedback to eliminate the built-in unity negative feedback, was felt necessary to resolve this problem and a modification of that model is proposed which simulates the data base. Acceleration saturation is achieved by borrowing the idea of the local feedback model for saccades so that one nonlinearity can account for the acceleration-velocity saturation: the main sequence for pursuit. Motor plasticity or motor learning, recently demonstrated for pursuit, is also incorporated and simulated. It was noticed that the offset of pursuit did not show the ringing seen in the onset so this was quantified in one subject. Offset velocity could be characterized by a single exponential with a time constant of about 90 ms. This observation suggests that fixation is not pursuit at zero velocity and that the pursuit system is turned on when needed and off during fixation.


Sodium phenylbutyrate improved the clinical state in an adult patient with arginase 1 deficiency.
An adult female patient was diagnosed with arginase 1 deficiency (ARG1-D) at 4 years of age, and had been managed with protein restriction combined with sodium benzoate therapy. Though the treatment was successful in ameliorating hyperammonemia, hyperargininemia persisted. After being under control with a strict restriction of dietary protein, severe fall of serum albumin levels appeared and her condition became strikingly worsened. However, after sodium phenylbutyrate (NaPB) therapy was initiated, the clinical condition and metabolic stability was greatly improved. Current management of ARG1-D is aimed at lowering plasma arginine levels. The nitrogen scavengers, such as NaPB can excrete the waste nitrogen not through the urea cycle but via the alternative pathway. The removal of nitrogen via alternative pathway lowers the flux of arginine in the urea cycle. Thereby, the clinical complications due to insufficient amount of protein intake can be prevented. Thus, NaPB therapy can be expected as a useful therapeutic option, particularly in patients with ARG1-D.


A validation study of a virtual-based haptic system for endoscopic sinus surgery training.
The development of endoscopic sinus surgery (ESS) training simulators for clinical environment applications has reduced the existing shortcomings in conventional teaching methods, creating a standard environment for trainers and trainees in a more accurate and repeatable fashion. In this research, the validation study of an ESS training simulator has been addressed. It is important to consider components that guide trainees to improve their hand movements control in the orbital floor removal in an ESS operation. Therefore, we defined three tasks to perform: pre-experiment learning, training, and evaluation. In these tasks, the critical regions introduced in the virtual training environment are forbidden to be touched. Recruiting 20 participants, divided into two groups, we investigated the performance metrics: quality (the percentage of the realism for the generated force for orbital floor removal and the usefulness of the proposed training system for the surgical educational curricula.), efficiency (time, path length), and safety (touching the goal and forbidden wall). All recruited participants answered a post-evaluation questionnaire regarding their perceptions of training system realism, potential educational benefits, and practiced skills. We investigate the differences between groups' performance metrics by utilizing the analysis of variance-Kruskal-Wallis test. Acquired results indicate that training before the actual process of the surgery has a significant effect on the accuracy and validity of the process for surgeons. Utilizing a standardized environment, trainers and trainees are able to carry out a process with regular features. In addition to traditional education methods, trainees can learn the risk of surgical operations. The training simulators can, also, provide a standard method for assessing the skills of surgical and medical students.


[Effectiveness of a school-based program to prevent obesity].
Intervention for childhood obesity is a public health priority. The purpose of this study was to evaluate the effectiveness of an elementary school-based intervention against obesity in children. Non-randomised controlled trial was conducted on children from first to fifth grade from two public schools of Avilés (Spain). The intervention lasted for 2 school years comprising healthy diet workshops, educational chats, educational meetings, informative written material, and promotion of physical activities. Primary outcome measure was body mass index z-score. Secondary outcomes included: obesity and overweight prevalence, waist circumference, dietary habits, and physical activity. A total of 382 (177 girls, 205 boys) out of 526 pupils of both schools were included in the study. Complete anthropometric data were obtained in 340 of the 382 individuals. Compared to children in control group, those in intervention group decreased body mass index z-score from 1.14 to 1.02 (P=.017), and improved KIDMED score from 7.33 to 7.71 points (P=.045). The percentage of students who carried on an optimal diet increased from 42.6% to 52.3% (P=.021). There were no statistical differences in the prevalence of obesity and overweight, or in waist circumference between the intervention and control groups. This school-based program resulted in modest beneficial changes in body mass index and diet quality.


Effect of a novel 5-hydroxytryptamine3 (5-HT3) receptor antagonist, GK-128, on 5-HT3 receptors mediating contractions and relaxations in guinea-pig distal colon.
1. We investigated 5-hydroxytryptamine3 (5-HT3) receptor-mediating contractions and relaxations in the guinea-pig isolated distal colon using various 5-HT3 receptor agonists and antagonists, including GK-128 (2-[(2-methylimidazol-1-yl) methyl] benzo[f] thiochromen-1-one monohydrochloride hemihydrate). 2. Selective 5-HT3 receptor agonists, 2-methyl-5-HT and m-chlorophenylbiguanide, produced spantide-insensitive contraction and atropine-insensitive contraction and the relaxation. These agonists showed a small, but significant, difference of potency between contraction and relaxation. 3. GK-128 competitively blocked both 2-methyl-5-HT- and m-chlorophenylbiguanide-induced responses with similar potency. The affinities of GK-128 for spantide-insensitive contraction and atropine-insensitive contraction were ten-fold higher than for relaxation. 4. Other selective 5-HT3 receptor antagonists, azasetron and tropisetron, also exhibited higher affinity in contraction than in relaxation, but the extent of their affinity differences was smaller than that observed in GK-128. In contrast, granisetron, ramosetron and ondansetron exhibited no significant differences in their affinity values among the three responses. 5. These results suggest that the 5-HT3 receptors which mediate contraction and relaxation in the guinea-pig distal colon may not be the same, and that GK-128 is a 5-HT3 receptor antagonist with a stronger potency for contraction.


Enhancement by L-methionine on the contractile response of uterine segments to acetylcholine and high KCl is mainly due to enhancement of Ca uptake.
Acetylcholine (ACh)- and high KCl-stimulated 45Ca uptake into rat uterine segments was inhibited by 3-deazaadenosine (3-DAA) plus homocysteine thiolactone (HCTL), and this inhibitory effect was attenuated by L-methionine (L-Met). Ca-depleted Ringer solution in which uterine muscle had been incubated with L-Met did not enhance the contractile response of another uterine segment to ACh and high KCl in the presence of 3-DAA plus HCTL. These findings together with previous results suggest that the enhancing effect of L-Met on the contractile responses to ACh and high KCl is mainly due to an increase in Ca2+ uptake into the uterine muscle.


Effects of a nitric oxide synthase inhibitor on NMDA receptor function in organotypic hippocampal cultures.
Nitric oxide (NO) has been proposed to trigger long-term potentiation (LTP) at CA3 to CA1 synapses. We previously reported that NO synthesis inhibitors and blockers reduce an electrophysiological index of NMDA receptor activation in acute hippocampal slices. We now show that the NOS inhibitor, NG-methyl-L-arginine (MLA), also reversibly prevents LTP induction in organotypic hippocampal slices and significantly reduces a biochemical index of NMDA receptor function. These results results further indicate that MLA inhibits LTP induction by interfering with NMDA receptor functions.


Decisions on train rescheduling and locomotive assignment during the COVID-19 outbreak: A case of the Beijing-Tianjin intercity railway.
Travel restriction measures have been widely implemented to curb the continued spread of COVID-19 during the Chinese Lunar New Year celebrations. Many operation lines and train schedules of China's railway were either heavily adjusted or canceled. In this study, a mixed-integer linear programming model and a two-step solution algorithm were developed to handle such large-scale adjustments. The formulation considers a flexible time window for each operation line and locomotive traction operations, and minimizes the number of locomotives utilized with their total idle time for train rescheduling and locomotive assignment, respectively. The solution algorithm determines the minimum locomotive fleet size based on the optimal train rescheduling results; it then reduces the traction idle time of locomotives. In response to the uncertainty of COVID-19, two tailored approaches were also designed to recover and remove operation lines, which can insert and cut operation lines based on the results of locomotive assignment. Finally, we conducted a case study of the Beijing-Tianjin intercity railway from the start of the COVID-19 outbreak to the recovery of operations.


The Impact of Preoperative Depression on Hospital Consumer Assessment of Healthcare Providers and Systems Survey Results in a Cervical Spine Surgery Setting.
Retrospective cohort study using prospectively collected data. The aim of this study was to determine the association between preoperative depression and patient experience in a cervical spine surgery population. The Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey is used to measure patient experience and its scores directly influence reimbursement in the United States. Although it is well-established in the literature that untreated depression is associated with worse patient-reported outcomes in cervical spine surgery, no previous studies have analyzed the association between depression and patient satisfaction for these patients. HCAHPS survey responses from patients undergoing cervical spine surgery between 2013 and 2015 were collected at a tertiary care center. HCHAPS survey responses were linked to demographic data as well as patient-reported quality of life (QOL) metrics including Patient Health Questionnaire, EuroQol 5 Dimensions index, and Visual Analog Scale for neck pain for each patient. Preoperative PHQ-9 scores of ≥10 (moderate to severe depression) was used to define preoperative depression. Uni- and multivariable analyses were performed to investigate the association of preoperative depression and top-box scores on several dimensions on the HCAHPS survey. In our 145-patient cohort, depressed patients were on average younger, had higher preoperative neck pain scores, and had a lower health-related QOL. Depressed patients were less likely to report satisfaction with questions related to doctor respect (P = 0.020) and doctors listening (P = 0.030). After adjusting for covariates, multivariable logistic regression analysis revealed that patients with preoperative depression had lower odds of feeling respected by their physicians (odds ratio = 0.14, 95% confidence interval: 0.02-0.87, P = 0.035). In patients undergoing cervical spine surgery, preoperative depression was found to have a negative association with patient perceptions of doctor communication as measured by the HCAHPS survey. These results highlight depression as a risk factor for worse patient experience communicating with their spine surgeon. 3.


Simulated confluence on micropatterned substrates correlates responses regulating cellular differentiation.
While cells are known to behave differently based on the size of micropatterned islands, and this behavior is thought to be related to cell size and cell-cell contacts, the exact threshold for this difference between small and large islands is unknown. Furthermore, while cell size and cell-cell contacts can be easily manipulated on small islands, they are harder to measure and continually monitor on larger islands. To investigate this size threshold, and to explore cell size, cell-cell contacts, and differentiation, we use a previously established simulation to plan experiments and explain results that we could not explain from experiments alone. We use five seeding densities covering three orders of magnitude over 25-500 µm diameter islands to examine markers of proliferation and differentiation in bone marrow-derived mesenchymal cells (cell line). We show that osteogenic markers are most accurately described as a function of confluence for larger islands, but a function of time for smaller islands. We further show, using results of the simulation, that cell size and cell-cell contacts are also related to confluence on larger islands, but only cell-cell contacts are related to confluence on small islands. This study uses simulations to explain experimental results that could not be explained from experiments alone. Together, the simulations and experiments in this study show different differentiation patterns on large and small islands, and this simulation may be useful in planning future studies related to this study.


Minimally invasive perventricular device closure of perimembranous ventricular septal defect without cardiopulmonary bypass: multicenter experience and mid-term follow-up.
To summarize the clinical experiences and mid-term follow-up results of perventricular closure of perimembranous ventricular septal defect without cardiopulmonary bypass under transesophageal echocardiography guidance. A total of 408 patients with perimembranous ventricular septal defects, aged 5 months to 15 years (3.1 +/- 1.7 years) with a body weight of 4.5 to 26 kg (13.6 +/- 5.5 kg), underwent perventricular device closure. The procedure was performed via a small lower sternal incision. A guidewire was inserted through the ventricular septal defect to the left ventricle under transesophageal echocardiography guidance after a pursestring suture was placed on the right ventricular free wall. A modified delivery sheath was introduced over the guidewire to establish the delivery pathway. Proper devices were delivered and then deployed if no atrioventricular or aortic valvular disturbance, or residual shunt was detected by transesophageal echocardiography. Patients were followed up with a standard protocol, which is once every month in the first 3 postoperative months and then once every 3 months with echocardiography, electrocardiography, and chest radiography in each follow-up. A total of 393 patients in this group underwent successful closure (96.3%), and the procedure was converted to conventional open repair in 15 patients (3.7%). A total of 213 symmetric devices (54.2%) and 180 asymmetric devices (45.8%) were implanted. Only 6 of the 393 patients (3.5%) received transfusion of blood products. New trivial or mild tricuspid regurgitation was found in 13 patients (3.3%), and there was no worsening of regurgitation in those patients with existing tricuspid regurgitation before operation. Eleven patients (2.8%) had incomplete right bundle branch block. Most of the patients were discharged 3 to 5 days after the operation. Follow-up in all patients ranged from 3 months to 2 years (14.6 +/- 6.2 months) and revealed no residual shunt, new or aggravating aortic regurgitation, obstruction of left or right ventricular outflow tract, or device dislocation. Minimally invasive perventricular device closure of ventricular septal defect without cardiopulmonary bypass is a simple, effective, and relatively safe intervention under guidance of transesophageal echocardiography. This method should be considered for patients with ventricular septal defect. Long-term follow-up is necessary.


Feasibility study on the use of infrared spectroscopy for the direct authentication of Iberian pig fattening diet.
The feasibility of using both middle- and near-infrared spectroscopy for discrimination between subcutaneous fat of Iberian pigs reared on different fattening diets has been evaluated. The sample set was formed by subcutaneous fat of pigs fattened outdoors (extensively) with natural resources (montanera) and pigs fattened on commercial feeds, either with standard feed or with especial formulations with higher content in oleic acid (HO-formulated feed). Linear discriminant analysis was used to classify the samples according to the fattening diet using the scores obtained from principal component analysis of near- and middle-infrared spectra as variables to construct the discriminant functions. The most influential variables were identified using a stepwise procedure. The discriminant potential of each spectral region was investigated. Best results were obtained with the combination of both regions with 91.7% of the standard feed and 100% of montanera and HO-formulated feed samples correctly classified. Chemical explanations are provided based on the correlation of these variables with fatty acid content in the samples.


Clinical Characteristics and Prognostic Factors of Testicular Sarcoma: A Population-Based Study.
To study clinical characteristics and factors that may affect the prognosis of testicular sarcoma patients. In the Surveillance Epidemiology and End Results database (2006-2016), people with testicular sarcoma were enrolled in our research. Multivariable Cox proportional hazard model and Multivariable Logistic regression model were used to compare the impact of different factors on cancer-specific survival, localized metastasis, and distant metastasis. This research was based on the registry information of 158 testicular sarcoma patients. All patients with a median age of 17.00 (1.00-93.00) years were pathologically diagnosed with orchiectomy or needle biopsy specimens. Patients with Grade I, II, III, and IV testicular sarcoma accounted for 34.29% (n = 24), 10.10% (n = 7), 22.86% (n = 16), and 32.86% (n = 23) of all patients, respectively. There were 42 (30.43%), 53 (38.41%), 15 (10.87%), 20 (14.49%), 5 (3.62%), 3 (2.17%) patients with Tis, T1, T2, T3, T4, and >T4 (the invasion degree exceeded the staging system of testicular cancer) disease respectively. Among all included patients, localized metastasis occurred in 31 (20.13%) patients, distant metastasis was found in 28 (18.18%) patients during observation, and 61.69% (n = 95) had no metastasis. Thirty-two (20.25%) patients died of this cancer. According to our study, patients with distant metastasis [OR = 17.86, 95% CI (4.63-68.84), p < 0.0001] and T3 disease [OR = 4.13, 95% CI (1.10-15.53), p = 0.0359] were more likely to die of this cancer. Patients with advanced T stage were more likely to occur distant metastasis, [OR = 13.91, 95% CI (1.80-107.54), p = 0.0116] for T3 and [OR = 16.36, 95% CI (1.36-196.21), p = 0.0275] for T4. According to our research, factors including metastasis and higher T stage were significantly related with poorer prognosis of testicular sarcoma. Higher T stage was also found to be a risk factor of distant metastasis. The recognization of these poor prognostic factors may allow physicians to make comprehensive and appropriate management decision for testicular sarcoma patients.


Albumin microbubbles conjugated with zinc and aluminum phthalocyanine dyes for enhanced photodynamic activity.
Gas-liquid interfaces are reaching a particular interest in biomedicine. Microbubbles, ultrasound contrast agents of clinical routine, gained increasing attention as theranostic platforms due to the preserved acoustic response, drug conjugation capabilities, and applicability in biological barrier opening. A combination of microbubbles and photodynamic therapy agents can enhance the photodynamic effect, yet the evaluation of agent conjugation on microbubble stabilization and photodynamic effect is needed. Hence, two commercially available phthalocyanine photosensitizers - Holosens® (ZnPc) and Photosens® (AlPc) - were coupled with bovine serum albumin before microbubble synthesis. We demonstrated an albumin: phthalocyanine ratio of 1:1 and covalent attachment for ZnPc, a ratio of 1:3 with electrostatic binding for AlPc. Submicron-sized microbubbles (air- and SF6- filled) had a diameter of 0.8 µm. Albumin-phthalocyanine conjugates increased the microbubble concentration and shelf-life stability compared to plain ones. We hypothesized that phthalocyanine fluorescence lifetime values decreased after conjugation with microbubbles due to narrow distance between conjugates in the shell. Agents based on AlPc demonstrated higher photodynamic activity than agents based on ZnPc, and microbubbles preserved acoustic stability in human blood plasma. The biodistribution of AlPc-conjugated microbubbles was evaluated. We conclude that our microbubble platforms demonstrate greater photodynamic activity and prolonged stability for further applications in photodynamic therapy.


Ultrasound-enhanced tissue plasminogen activator thrombolysis in an in vitro porcine clot model.
Thrombolytics such as recombinant tissue plasminogen activator (rt-PA) have advanced the treatment of ischemic stroke, myocardial infarction, deep vein thrombosis and pulmonary embolism. To improve the efficacy of this thrombolytic therapy, the synergistic effect of rt-PA and 120 kHz or 1.0 MHz ultrasound was assessed in vitro using a porcine clot model. Fully retracted whole blood clots prepared from fresh porcine blood were employed to compare rt-PA thrombolytic treatment with and without exposure to 120-kHz or 1-MHz ultrasound. For sham studies (without ultrasound), clot mass loss was measured as a function of rt-PA concentration from 0.003 to 0.107 mg/ml. For combined ultrasound and rt-PA treatments, peak-to-peak pressure amplitudes of 0.35, 0.70 or 1.0 MPa were employed. The range of duty cycles varied from 10% to 100% (continuous wave) and the pulse repetition frequency was fixed at 1.7 KHz. For rt-PA alone, the mass loss increased monotonically as a function of rt-PA concentration up to approximately 0.050 mg/ml. With ultrasound and rt-PA exposure, clot mass loss increased by as much as 104% over rt-PA alone. Ultrasound without the presence of rt-PA did not significantly enhance thrombolysis compared to control treatment. The ultrasound-mediated clot mass loss enhancement increased with the square root of the overall treatment duration. Both 120-kHz and 1-MHz pulsed and CW ultrasound enhanced rt-PA thrombolysis in a porcine whole blood clot model in vitro. No clear dependence of the observed thrombolytic enhancement on ultrasound duty cycle was evident. The lack of duty cycle dependence suggests a more complex mechanism that could not be sustained by merely increasing the pulse duration.


Early results of secondary bone grafts in 106 alveolar clefts.
Eighty-three patients with cleft lip and cleft palate were treated by secondary bone grafts to the 106 alveolar clefts. In 98% of the alveolar clefts, the graft was successful and the oronasal fistula was closed. There were only occasional other complications, all but one of which were minor and did not affect the final result. Morbidity was low. Compared with older patients, the pre-teen group of patients not only had no complications of consequence but experienced less morbidity. The 100% success rate and the lower morbidity in the pre-teen group of patients thus favor operating on patients at the younger age.


Optimizing Excipient Properties to Prevent Aggregation in Biopharmaceutical Formulations.
Excipients are included within protein biotherapeutic solution formulations to improve colloidal and conformational stability but are generally not designed for the specific purpose of preventing aggregation and improving cryoprotection in solution. In this work, we have explored the relationship between the structure and antiaggregation activity of excipients by utilizing coarse-grained molecular dynamics modeling of protein-excipient interaction. We have studied human serum albumin as a model protein, and we report the interaction of 41 excipients (polysorbates, fatty alcohol ethoxylates, fatty acid ethoxylates, phospholipids, glucosides, amino acids, and others) in terms of the reduction of solvent accessible surface area of aggregation-prone regions, proposed as a mechanism of aggregation prevention. Polyoxyethylene sorbitan had the greatest degree of interaction with aggregation-prone regions, decreasing the solvent accessible surface area of APRs by 20.7 nm2 (40.1%). Physicochemical descriptors generated by Mordred are employed to probe the structure-property relationship using partial least-squares regression. A leave-one-out cross-validated model had a root-mean-square error of prediction of 4.1 nm2 and a mean relative error of prediction of 0.077. Generally, longer molecules with a large number of alcohol-terminated PEG units tended to interact more, with qualitatively different protein interactions, wrapping around the protein. Shorter or less ethoxylated compounds tend to form hemimicellar clusters at the protein surface. We propose that an improved design would feature many short chains of 5 to 10 PEG units in many distinct branches and at least some hydrophobic content in the form of medium-length or greater aliphatic chains (i.e., six or more carbon atoms). The combination of molecular dynamics simulation and quantitative modeling is an important first step in an all-purpose protein-independent model for the computer-aided design of stabilizing excipients.


Keratophakia with lyophilized cornea lathed at room temperature: new techniques and experimental surgical results.
A modified method of prelathing lyophilized corneal tissue at room temperature for refractive keratoplasty is described. This method allows perfect centration of a lyophilized corneal button on the plastic base and thus more accurate lathing. Keratophakia was performed with lenticules prepared in this fashion on a series of eight cats which were followed for 30 weeks postoperatively. All lenticules were clear ten weeks following surgery and the final optical correction obtained varied +/- 2.5 D from the intended correction.


Cardiac syndrome X and microvascular coronary dysfunction.
Women with cardiac chest pain indicated by signs and symptoms of myocardial ischemia in the absence of obstructive CAD are often labelled as cardiac syndrome X (CSX). A subset of patients with CSX may have symptoms of ischemia due to microvascular dysfunction. Angina due to microvascular coronary dysfunction (MCD) is an etiologic mechanism in women with vascular dysfunction. New data provide improve understanding of coronary vascular dysfunction and resultant myocardial ischemia that characterize MCD among patients with cardiac syndrome X. MCD has an adverse prognosis and health care cost expenditure comparable to obstructive CAD. The high prevalence of this condition, particularly in women, adverse prognosis and substantial health care costs, coupled with a lack of evidence regarding treatment strategies, places MCD as a research priority area.


[Specific determination of hemoglobin A1c on Biorex 70 microcolumn (author's transl)].
The addition of ethyl alcohol to the elution buffer permits one to separate hemoglobin A1c from other glycosylated hemoglobins on a Biorex 70 microcolumn.


Effect of Thyroxin Treatment on Carotid Intima-Media Thickness (CIMT) Reduction in Patients with Subclinical Hypothyroidism (SCH): a Meta-Analysis of Clinical Trials.
Research shows that subclinical hypothyroidism (SCH) is related to an increased carotid intima-media thickness (CIMT), a surrogate marker of subclinical cardiovascular disease (CVD). It is controversial whether or not SCH should be treated to reduce CVD morbidity and mortality. This meta-analysis aimed to determine whether SCH is associated with an increase in CIMT as compared to Euthyroidism (EU) and whether thyroxin (T4) treatment in SCH can reverse the change in CIMT. Two independent reviewers conducted an extensive database research up to December 2016. A total of 12 clinical trials discussed the effect of Thyroxin on CIMT values at pre- and post-treatment in subjects with SCH. CIMT was significantly higher among SCH (n=280) as compared to EU controls (n=263) at baseline; the pooled weighted mean difference (WMD) of CIMT was 0.44 mm [95% confidence interval (CI) 0.14, 0.74], p=0.004; I2=65%. After treatment with thyroxin in subjects with SCH (n=314), there was a statistically significant decrease in CIMT from pre- to post-treatment; the pooled WMD of CIMT decrease was [WMD -0.32; 95% CI (-0.47, -0.16), p=<0.0001; I2=2%], and it was no longer different from EU controls [WMD 0.13 mm; 95% CI (-0.04, 0.30); p=0.14; I2=27%]. The total cholesterol (TC), triglycerides (TG), and low-density lipoprotein (LDL) were higher in SCH as compared to EU controls and decreased significantly after treatment with thyroxin. This meta-analysis shows that thyroxin therapy in subjects with SCH significantly decreases CIMT and improves lipid profile, modifiable CVD risk factors. Thyroid hormone replacement in subjects with SCH may play a role in slowing down or preventing the progression of atherosclerosis.


Frequency, Timing, Risk Factors, and Outcomes of Desaturation in Infants With Acute Bronchiolitis and Initially Normal Oxygen Saturation.
Little is known about the natural course of oxygen desaturation in acute bronchiolitis. Information on risk factors associated with desaturation as well as the time to desaturation in infants with bronchiolitis could help physicians better treat these infants before deciding whether to hospitalize them. To prospectively determine the frequency of desaturation in infants with bronchiolitis, along with the time to desaturation and risk factors associated with desaturation, and to compare infants who were hospitalized with those discharged home and evaluate risk factors for rehospitalization. This cohort study was conducted during the 2017 to 2018 and 2018 to 2019 respiratory syncytial virus seasons in a tertiary care pediatric emergency department in Switzerland. Included individuals were 239 otherwise-healthy infants aged younger than 1 year, diagnosed with acute bronchiolitis and oxygen saturation of 90% or more on arrival. Data were analyzed from July 2019 to October 2020. After receiving triage care, study participants admitted to the emergency department were equipped with a pulse oximeter to continuously record oxygen saturation (Spo2 levels), regardless of subsequent hospitalization or discharge home. The primary outcome was desaturation (ie, Spo2 < 90%) during the first 36 hours. Of 239 infants enrolled, with a median (interquartile range [IQR]) age of 3.9 (1.5-6.5) months, 116 (48.5%) were boys and desaturation occurred in 165 infants (69.0%). Median (IQR) time to desaturation was 3.6 (1.8-9.4) hours. The rate of desaturation was similar between infants hospitalized and those discharged home (137 of 200 infants [68.5%] vs 28 of 39 infants [71.8%]; difference, -3.3%; 95% CI, -18.8% to 12.2%; P = .85). A more severe initial clinical presentation with moderate or severe retractions was the only independent risk factor associated with desaturation (odds ratio, 2.73; 95% CI, 1.49 to 5.02; P = .001). Of 39 infants discharged home, 22 infants (56.4%) experienced major desaturations. However, infants with desaturations, including those with major desaturations, had rates of rehospitalization similar to those of infants without desaturations (8 of 28 infants [28.5%] vs 3 of 11 infants [27.3%]; difference, 1.2%; 95% CI, -29.9% to 32.5; P > .99). These findings suggest that rates of desaturation in infants with acute bronchiolitis were high and similar between infants who were hospitalized and those discharged home. A more severe initial clinical presentation was the only risk factor associated with desaturation. However, for infants discharged home, desaturation was not a risk factor associated with rehospitalization.


Electrofusion of Chinese hamster ovary cells after ethanol incubation.
Electrofusion of Chinese hamster ovary cells is obtained with cells growing in monolayers on a culture dish. The cells were incubated with increasing amounts of ethanol before the field pulsation. The electroperforation was apparently not affected by the incubation but the threshold field intensity required to induce the fusion was shifted to higher values. This effect is tentatively explained by a decrease in size of the field-induced pores as a consequence of an increase in the lipid matrix fluidity.


Ischemic cholangitis in hepatic allografts.
In this report, our objectives are to introduce the term "ischemic cholangitis" as an etiologic designation and to describe its manifestations. Herein we use the label "ischemic cholangitis" as a collective term for ischemic bile duct necrosis, cholangitis caused by ischemia but without necrosis, and biliary fibrosis as a manifestation of ischemic damage. The condition was observed in 12 allografts, either at the time of retransplantation (9 cases) or at autopsy (3 cases). Ischemic cholangitis involved primarily perihilar extrahepatic and intrahepatic bile ducts. The findings included duct necroses (eight cases), strictures (four cases), and cholangiectases (four cases); some of these features coexisted. In addition, complicating ascending cholangitis and cholangitic abscesses were noted in three cases. Ischemic cholangitis was caused by hepatic artery thrombosis (in nine patients) or stenosis (in one) or by occlusion of parabiliary arteries by fibrointimal proliferations, probably attributable to old thromboses (in two, in conjunction with associated foam cell arteriopathy in one). Biopsy specimens before retransplantation or autopsy were obtained in 11 patients, only 1 of whom had an infarct as direct evidence of ischemia. Nine patients had evidence of biliary obstruction or bile flow impairment; in two cases, specimens were normal or nondiagnostic relative to cholangitis. Features of cellular rejection associated with the manifestations of bile flow impairment and ischemia were noted in five cases. Thus, biopsy features that suggest biliary obstruction, with or without cellular rejection, may be a manifestation of ischemic cholangitis. We conclude that ischemic cholangitis is an important cause of cholestatic graft failure but that this type of cholangitis is difficult to diagnose because of its misleading biopsy manifestations.


Biochemical and serological properties of Actinobacillus pleuropneumoniae biotype 2 strains isolated from swine.
The biochemical and serological properties of 21 strains of Actinobacillus pleuropneumoniae biotype 2 isolated from haemorrhagic necrotic pleuropneumonia of swine were examined. For serologic typing, the indirect haemagglutination (IHA) and the double gel-diffusion tests were used. On the basis of their soluble surface antigens, our A. pleuropneumoniae biotype 2 isolates could be assigned to two proposed serotypes. Serotype 1 comprised 11 strains and serotype 2 comprised 10 strains. All strains contained two surface antigen components. In the strains belonging to serotype 1, one of the antigens was identical with the serotype-specific antigen of Pasteurella haemolytica T4. Both antigens of serotype 2 strains proved to be type-specific. Four strains received from Switzerland, including the holotype strain of A. pleuropneumoniae biotype 2, and three strains isolated from swine in the G.D.R. belonged to serotype 2. Both the double gel diffusion and the IHA tests detected a 2-way cross-reaction between biotype 1, serotype 2 and biotype 2, serotype 2 strains of A. pleuropneumoniae, which could be eliminated using cross-absorbed sera.


Nitrogen-sulfur co-doped pH-insensitive fluorescent carbon dots for high sensitive and selective hypochlorite detection.
Carbon dots (CDs) are novel fluorescent carbon nanomaterial with exceptional properties and have drawn great attention in recent years. However, the preparation and applications of high-quality carbon dots remain challenging. Here, we describe a simple hydrothermal synthesis route using citric acid as a carbon source for stable fluorescent CDs. The CDs are modified with glutathione and exhibit high fluorescent quantum yields (30.2%) and excellent photo-stability. In addition, the fluorescence intensity of CDs remains stable over a wide range of pH values (3-12). Hypochlorite (ClO-) can effectively quench the fluorescence of the CDs by destroying the pyrrolic ring and conjugate structure of the CDs. Thus, the CDs can be used to detect ClO-. Under optimized conditions, the fluorescence intensity changes of CDs correspond selectively to ClO- in the range of 100-800 nmol/L with a LOD of 16 nmol/L. Practical applications of the proposed method for free chlorine detection in tap water show similar results and recovery compared to the standard DPD-based method. These results suggest that the pH-insensitive CDs prepared via this facile procedure are a promising chemosensor for free chlorine and have great potential in analytical applications.


Hepatic protein synthesis rate of liver specimens as a predictor of viability in rat cold ischemia liver transplantation model.
We have previously reported that the hepatic protein synthesis rate, calculated as the uptake rate of L-[4.5 3H] leucine by the protein fraction during a 10-min incubation of a 16-G needle biopsy specimen of liver tissue, represents a high level of liver function and is therefore useful for evaluating liver function. We investigated the hepatic protein synthesis rate level in a pre-transplant liver to learn if it might predict the outcome in a rat orthotopic liver transplantation model. Grafts were stored, liver specimens were obtained using a 21-G Chiba type II skinny needle, and the hepatic protein synthesis rate was calculated. Subsequently, liver transplantation was performed, and the hepatic protein synthesis rate level of revascularized liver, tissue blood flow rate, serum alanine aminotransferase, lactate dehydrogenase, hyaluronic acid, ketone body rate, and 2-week survival were examined. The hepatic protein synthesis rate of pretransplant liver was correlated with parameters of post-transplant liver function: hepatic protein synthesis rate of the revascularized liver (r=0.92, p<0.0001), tissue blood flow rate (r=0.77, p<0.004), serum alanine aminotransferase (r=-0.69, p<0.003), lactate dehydrogenase (r=-0.54, p<0.03), hyaluronic acid (r=-0.86, p<0.0002), and ketone body rate (r=0.57, p<0.02). Pretransplant hepatic protein synthesis rate in survivors was 263.6+/-54.2 nmol/mg protein/10 min, while that in nonsurvivors was significantly lower at 162.0+/-39.0 (p<0.0001). When evaluation was made using a logistic regression model, the accuracy predicted using the value of hepatic protein synthesis rate was 95% (19/20). These results suggest that measuring the hepatic protein synthesis rate of the grafts with a 21-G Chiba type II skinny needle may be a predictive criterion in the assessment of graft viability.


Reconsidering patient empowerment in chronic illness: a critique of models of self-efficacy and bodily control.
Studies that focus on patient empowerment tend to address more specifically two issues of patients' experience of illness: managing regimens and relating to health-care providers. Other aspects of illness experience, such as coming to terms with disrupted identities, tend to be overlooked. The outcome of empowerment is therefore usually referred to as achieving self-efficacy, mastery and control. We conducted an inductive exploratory study, based on individual in-depth interviews with 40 chronically ill patients in Belgium and Italy, in order to understand the process of empowerment as it may occur in patients whose experience of illness has at some point induced a feeling of powerlessness, which we conceptualised as a threat to their senses of security and identity. Our findings show that empowerment and control are not one and the same thing. We describe patient empowerment as a process of personal transformation which occurs through a double process of (i) "holding on" to previous self-representations and roles and learning to control the disease and treatment, so as to differentiate one's self from illness on the one hand, and on the other hand (ii) "letting go", by accepting to relinquish control, so as to integrate illness and illness-driven boundaries as being part of a reconciled self. Whereas the process of separating identities ("holding on") was indeed found to be linked to efforts aimed at taking control and maintaining or regaining a sense of mastery, the process of reconciling identities ("letting go") was found to be linked to a need for coherence, which included a search for meaning and the acceptance that not everything is controllable. We argue that the process of relinquishing control is as central to empowerment as is the process of gaining control. As a "successful" process of empowerment occurs when patients come to terms with their threatened security and identity, not only with their treatment, it may be facilitated by health-care providers through the use of narratives.


Streamlining Workflow for Endovascular Mechanical Thrombectomy: Lessons Learned from a Comprehensive Stroke Center.
Recently, 5 randomized controlled trials confirmed the superiority of endovascular mechanical thrombectomy (EMT) to intravenous thrombolysis in acute ischemic stroke with large-vessel occlusion. The implication is that our health systems would witness an increasing number of patients treated with EMT. However, in-hospital delays, leading to increased time to reperfusion, are associated with poor clinical outcomes. This review outlines the in-hospital workflow of the treatment of acute ischemic stroke at a comprehensive stroke center and the lessons learned in reduction of in-hospital delays. The in-hospital workflow for acute ischemic stroke was described from prehospital notification to femoral arterial puncture in preparation for EMT. Systematic review of literature was also performed with PubMed. The implementation of workflow streamlining could result in reduction of in-hospital time delays for patients who were eligible for EMT. In particular, time-critical measures, including prehospital notification, the transfer of patients from door to computed tomography (CT) room, initiation of intravenous thrombolysis in the CT room, and the mobilization of neurointervention team in parallel with thrombolysis, all contributed to reduction in time delays. We have identified issues resulting in in-hospital time delays and have reported possible solutions to improve workflow efficiencies. We believe that these measures may help stroke centers initiate an EMT service for eligible patients.


Targeting the Gut Microbiome to Mitigate Immunotherapy-Induced Colitis in Cancer.
Immune checkpoint inhibitors (ICIs) have been a transformational advance in cancer therapy in the past decade. However, ICIs can produce immune-related adverse effects (irAEs), which can lead to both morbidity and premature termination of therapy. Recent studies suggest that the gut microbiota and its metabolites affect ICI efficacy and toxicity. Herein, we review such evidence in the context of ICI-induced colitis. In particular, the short-chain fatty acid butyrate, a microbial metabolite, has known protective effects on the intestine. We discuss how the use of dietary prebiotics, which can be metabolized by bacteria to produce butyrate, can be an intriguing new investigational approach to prevent ICI-associated colitis and lead to improved patient outcomes.


Correlation of the findings of thallium-201 chloride scans with those of other imaging modalities and histology following therapy in patients with bone and soft tissue sarcomas.
We performed a retrospective [corrected] study to evaluate the imaging potential of thallium-201 as compared with other imaging modalities in differentiating residual/recurrent tumors from post-therapy changes in patients with musculoskeletal sarcomas. 201Tl scans, magnetic resonance imaging (17), X-ray computed tomography (6) or contrast angiography (6) studies in 29 patients previously treated for musculoskeletal sarcomas were correlated with either histopathologic findings (26 patients) or 2-year clinical follow-up (three patients). All imaging studies were acquired within 2 weeks. Ratios of 201Tl tumor uptake to the contralateral (28 patients) or adjacent region of interest were calculated. When qualitative interpretation was in doubt, only those cases with a ratio of 1.5 or more were considered suggestive of recurrent of residual viable tumor tissue. Residual or recurrent tumor tissue was verified in 21 patients by biopsy. All had true-positive 201Tl scans while the other imaging modalities were true-positive in 20 and equivocal in one. In eight patients, there was no evidence of viable tumor tissue as proven by biopsy in five and long-term clinical follow-up in three. 201Tl scan was false-positive (ratio 1.5) in one patient and true-negative in seven while the other imaging modalities had four false-positives. The average 201Tl ratios were 2.8+/-1.1 in the true-positive cases and 1.3+/-0.3 in the true-negative cases. The percentage sensitivities, specificities, and accuracy for 201Tl were 100%, 87.5%, and 96.5% versus 95%, 50%, and 82.7% respectively for other imaging modalities. These results indicate that 201Tl scintigraphy is more accurate than other imaging modalities in differentiating residual/recurrent musculoskeletal sarcomas from post-therapy changes.


Encouraging physical activity through dog walking: why don't some owners walk with their dog?
To identify factors associated with owners not walking with their dog. Dog owners (n=629) taking part in the RESIDE study, Perth, Western Australia completed a self-administered questionnaire in 2005-06 that included items about the dog, dog-owner relationship, dog walking and intrapersonal and environmental factors associated with dog walking. Physical activity data were also collected using NPAQ. Overall, 23% of dog owners did not walk with their dog. More dog walkers achieved 150 min of physical activity/week than owners who did not walk with their dog (72% vs. 44%, p<0.001). Not walking with a dog was significantly more likely in owners who did not perceive that their dog provided motivation (OR 9.60, 95% CI: 4.37, 21.08) or social support (OR 10.84, 95% CI: 5.15, 22.80) to walk, independent of other well-known correlates of physical activity. There would be a significant impact on community physical activity levels if owners who do not walk with their dog could be persuaded to begin dog walking. Understanding the factors that discourage or facilitate owners to walk with their dog will assist in tailoring interventions designed to encourage both the uptake and maintenance of regular dog walking.


'Every bone of my body:' domestic violence and the diagnostic body.
Diagnostic categories for domestic violence have shifted over time, transforming from a disorder of psychological passivity and acute injury into a chronic and somatically invasive condition. This paper links these changing diagnoses to constructions of the abused body and to victim-blaming narratives. Based on an analysis of medical journal articles, this research identifies two logics that undergird domestic violence diagnoses, the body, and victim-blaming: 1) the logic of injury (1970s-1980s); and 2) the logic of health (late 1980s-present). The logic of injury is associated with overt victim-blaming, a temporally bounded and injured body, and psychological passivity. Once the feminist anti-violence movement gained mainstream credibility, however, the logic of injury fell out of favor as an explanation for domestic violence. What surfaced next was the logic of health, which is associated with chronic diagnoses and what the author calls a temporally extended body. The temporally extended body is flexible and layered, linking up past, present, and future states of disordered embodiment. The author suggests that, rather than ushering in hope and possibility via the logic of health's somatic flexibility, this abused body creates spaces into which new forms of blame and self-responsibility can take shape.


An independent analysis of flexible cystoscope repairs and cost.
To establish the repair patterns of flexible cystoscopes we performed a systematic review of repairs performed at an independent endoscope repair company. Repair and cost data for 2000 to 2004 were obtained from an independent endoscope repair company. All cystoscopes underwent a detailed inspection using a preset protocol and the frequency of individual repair descriptions was extracted from a computer database. A total of 1,150 repairs were performed on the Olympus CYF (3%), CYF-2 (21%), CYF-3 (56%) and CYF-4 (20%) flexible cystoscopes. Repairs to the distal tip (28% of all repairs) most commonly involved the bending rubber or outer polymer sheath. Repairs to the hand control segment (14% of all repairs) most commonly involved the ocular. Repairs for image (14% of all repairs) and deflection (9%) were most commonly performed on the fiberoptic bundle and wires, respectively. Repairs to the deflection apparatus comprised a significantly greater proportion of total repairs in the early CYF models than in the CYF-4 model (10% to 12% vs 3%, p <0.01, chi-square 10.73). Less than 1% of all cystoscopes needed more than 2 repairs. Olympus cystoscopes require repair every 2 to 3 years and they appear to be durable. The distal deflection tip, specifically the outer bending rubber, is the most common site of flexible cystoscope damage. Although it appears that significant improvements have been made to the deflection apparatus, the number of repairs to other areas has not changed significantly with time. Improvements in form and function of the distal tip, the hand control segment and the fiberoptic bundles may enhance the durability of flexible cystoscopes.


Mechanisms exploration of Xiaojin Pills on lung cancer based on metabolomics and network pharmacology.
This study was designed to evaluate the pharmacological activity and therapeutic mechanism of Xiaojin Pills (XJW) on lung cancer. Mice were orally administered with Xiaojin Pills for 21 days. Tumour samples were collected to evaluate the antilung cancer effect, and blood samples were collected to identify differential metabolites with metabolomics. Through the analysis of network pharmacology, the active ingredients and targets related to XJW therapy for lung cancer were filtered. Different expression of seven metabolites related to seven pathways, including Arachidonic acid metabolism, Citrate cycle, tryptophan metabolism, glyoxylate and dicarboxylate metabolism, arginine and proline metabolism, primary bile acid biosynthesis and nicotinate and nicotinamide metabolism, were demonstrated to explain the efficacy of XJW in the treatment of lung cancer. Furthermore, a total of 19 active ingredients (ursolic acid, α-thujone, pelargonidin, succinic acid, boswellic acid, muscone, daidzein, xanthorrhizol, isoeugenol, oleic acid, β-caryophyllene, vanillin, β-sitosterol, lupeol, palmitic acid, eugenol, methylbutenol, β-elemene and quercetin) acted directly on 9 targets (CAT, PTGS2, PTGS1, CTH, ABTA, ALT1, ME2, AGXT and AGXT 2) and regulated 3 out of 7 metabolites (3-Hydroxyanthranilic acid, Pyruvate and Prostaglandin G2). Through metabolomics and network pharmacology analyses, this study demonstrated that the major metabolites of XJW in treating lung cancer were regulated by multitarget and multicomponent interaction network.


Time course of continuous positive airway pressure effects on central sleep apnoea in patients with chronic heart failure.
Continuous positive airway pressure (CPAP) causes a variable immediate reduction in the frequency of central apnoeas and hypopnoeas in patients with congestive heart failure (CHF) and central sleep apnoea (CSA), but has beneficial mid-term effects on factors known to destabilize the ventilatory control system. We, therefore, tested whether CPAP therapy leads, in addition to its short-term effects on CSA, to a significant further alleviation of CSA after 12 weeks of treatment on the same CPAP level in such patients. CPAP therapy was initiated in 10 CHF patients with CSA. During the first night on CPAP, the pressure was stepwise increased to a target pressure of 8-12 cmH(2)O or the highest level the patients tolerated (<12 cmH(2)O). Throughout the second night (baseline CPAP), the achieved CPAP of the first night was applied. After 12 weeks of CPAP treatment, we performed a follow-up polysomnography (12 weeks CPAP) on the same CPAP level (8.6 +/- 1.1 cmH(2)0). We found a significant reduction of the apnoea-hypopnoea index (AHI) between the diagnostic polysomnography and baseline CPAP night (41.8 +/- 19.2 versus 22.2 +/- 12.6 events per hour; P = 0.005). The AHI further significantly decreased between the baseline CPAP night and the 12 weeks CPAP night on the same CPAP level (22.2 +/- 12.6 versus 12.8 +/- 11.0 events per hour; P = 0.028). We conclude that, in addition to its immediate effects, CPAP therapy leads to a time-dependent alleviation of CSA in some CHF patients, indicating that in such patients neither clinical nor scientific decisions should be based on a short-term trial of CPAP.


Hippocampal GABA levels correlate with retrieval performance in an associative learning paradigm.
Neural plasticity is a complex process dependent on neurochemical underpinnings. Next to the glutamatergic system which contributes to memory formation via long-term potentiation (LTP) and long-term depression (LTD), the main inhibitory neurotransmitter, GABA is crucially involved in neuroplastic processes. Hence, we investigated changes in glutamate and GABA levels in the brain in healthy participants performing an associative learning paradigm. Twenty healthy participants (10 female, 25 ± 5 years) underwent paired multi-voxel magnetic resonance spectroscopy imaging before and after completing 21 days of a facial associative learning paradigm in a longitudinal study design. Changes of GABA and glutamate were compared to retrieval success in the hippocampus, insula and thalamus. No changes in GABA and glutamate concentration were found after 21 days of associative learning. However, baseline hippocampal GABA levels were significantly correlated with initial retrieval success (pcor = 0.013, r = 0.690). In contrast to the thalamus and insula (pcor>0.1), higher baseline GABA levels in the hippocampus were associated with better retrieval performance in an associative learning paradigm. Therefore, our findings support the importance of hippocampal GABA levels in memory formation in the human brain in vivo.


In vivo and in vitro emergence of simultaneous resistance to both beta-lactam and aminoglycoside antibiotics in a strain of Serratia marcescens.
In a patient with Serratia marcescens bacteraemia, a variant resistant to cefotaxime and amikacin was isolated in a blood culture under combined treatment with cefotaxime and amikacin. In addition, in vitro selection on cefotaxime and/or amikacin yielded resistant mutants from the sensitive parent strain. These mutants displayed the same type of cross-resistance as the clinical strain to all beta-lactam and aminoglycoside antibiotics. The mechanism for this resistance was a decrease in the permeability of the cell. To our knowledge, the isolation of such strains from blood cultures and the mechanism responsible for this "broad-spectrum resistance" have not been previously described.


Effects of cryopreservation with a newly-developed magnetic field programmed freezer on periodontal ligament cells and pulp tissues.
The purpose of this study was to evaluate the effects of long-term cryopreservation on the isolated human periodontal ligament cells (PDL) and pulp tissues. In the first part of study, 10 freshly extracted teeth were selected and divided into two groups. In the cryopreserved group, the teeth were frozen for 5 years using a programmed freezer combined with a magnetic field, known as Cells Alive System "CAS". As for the control group, freshly extracted teeth were used. In each group, extracted PDL tissues were cultured and gene expression and protein concentration of collagen type I, alkaline-phosphatase (ALP) and vascular endothelial growth factor (VEGF) was compared between the two groups. In the second part, pulp tissues were obtained from 10 mature and immature third molars which were freshly extracted or cryopreserved for three months. Expression of VEGF and nerve growth factor (NGF) mRNAs and the protein concentration in the supernatant were investigated. Results indicated that long-term cryopreservation with the use of CAS freezer cannot affect the growth rate and characteristics of PDL cells. There was no significant difference in VEGF expression and VEGF and NGF protein concentration of pulp cells derived from cryopreserved teeth with immature apex and control group with mature root formation. Finally, proper PDL regeneration and appropriate apexogenesis after transplanting magnetically cryopreserved immature tooth was clinically confirmed. These findings demonstrate that teeth banking with the use of magnetic field programmed freezer can be available for future autotransplantation as a treatment modality for replacing missing teeth.


Recirculation, urea disequilibrium, and dialysis efficiency: peripheral arteriovenous versus central venovenous vascular access.
When accurate, non-urea-based methods of measuring recirculation are used, recirculation is usually absent in arteriovenous (AV) accesses. When urea-based methods are used to measure recirculation in AV accesses, falsely elevated recirculation rates are common. These errors are due to AV and venovenous disequilibrium (peripheral vein method), delayed systemic sampling (two-needle methods), and errors in urea measurement (all methods). The literature suggests that recirculation in central venovenous (CV) catheters is approximately 5%. The methods used for these determinations have all been urea based. However, there are few theoretical problems in using urea-based measurements for measuring recirculation in this setting, making it more likely that these values are accurate. When hemodialysis via CV and AV accesses are compared, equilibrated Kt/V values differ significantly for the same single-pool Kt/V when 15-second postdialysis blood urea nitrogen values are used for modeling, but differ minimally when 2-minute postdialysis samples are used. The impact of transient retrograde blood flow in the superior vena cava on recirculation and whether dialysis efficiency is influenced by the exact site of CV catheter placement (superior vena cava v right atrium) is uncertain.


Alcohol and nutrient intake: mechanisms of reinforcement and dependence.
Alcohol is not only a drug of abuse but is also a food. This combination has a significant impact on the development and consequences of alcohol abuse and dependence. Understanding the neurobiological and behavioral processes that mediate them is perhaps best approached from the perspective of ingestive behavior. Research from the Hoebel laboratory has provided innovation and leadership in understanding that feeding neuropeptides plays a significant role in alcohol intake. The research reviewed here shows that galanin and other feeding peptides increase intake and also motivate abuse and the development of dependence. In addition, the consequences of long term alcohol abuse and dependence alter nutritional systems and drinking behavior. A major challenge is understanding the role of alcohol's dual properties and feeding neuropeptide in the motivation to drink.


Application of Three-dimensional (3D) Tumor Cell Culture Systems and Mechanism of Drug Resistance.
The in-vitro experimental model for the development of cancer therapeutics has always been challenging. Recently, the scientific revolution has improved cell culturing techniques by applying three dimensional (3D) culture system, which provides a similar physiologically relevant in-vivo model for studying various diseases including cancer. In particular, cancer cells exhibiting in-vivo behavior in a model of 3D cell culture is a more accurate cell culture model to test the effectiveness of anticancer drugs or characterization of cancer cells in comparison with two dimensional (2D) monolayer. This study underpins various factors that cause resistance to anticancer drugs in forms of spheroids in 3D in-vitro cell culture and also outlines key challenges and possible solutions for the future development of these systems.


Spondylolysis and spondylolisthesis after five-level lumbosacral laminectomy for selective posterior rhizotomy in cerebral palsy.
Of 163 children who have undergone five-level lumbosacral laminectomies for selective posterior rhizotomy, 20% of those re-X-rayed post-operatively (19/99) have developed incidental isthmic spondylolysis or grade I spondylolisthesis. The majority of patients were ambulatory, active, spastic diplegics. There were five children with isthmic defects at L3-4, three at L4-5 and 11 at L5-S1. Six of the 19 children had grade I spondylolisthesis, but none were symptomatic nor has there been any evidence of further slipping to date. It is postulated that the laminectomy, associated lordosis and increased mobility after rhizotomy may be factors in the causation.


Comparison of five protocols to extract DNA from paraffin-embedded tissues for the detection of human papillomavirus.
Formalin-fixed paraffin-embedded (FFPE) tissues are a valuable source of DNA with which to perform large retrospective studies on the epidemiology of HPV infection. Five different DNA extraction protocols were carried out to evaluate the DNA obtained from FFPE samples with polymerase chain reaction (PCR) using two primer sets to amplify a constitutive human gene, β-globin, and two primer sets to detect the L1 and E6 HPV genes. From the five DNA extraction protocols evaluated, the best results were obtained with protocol A, corresponding to a crude extract from the sample. With the procedures described herein, we were able to amplify DNA extracted from archival paraffin blocks stored for six years. However, the amplification products were more efficiently obtained with primers that amplified shorter fragments. This result indicates that a major factor limiting the extraction process in these samples is DNA fragmentation, a factor that will naturally vary between the different specimens evaluated. Also, depending upon the extraction method, PCR amplification of a human gene does not necessarily guarantee the successful extraction of viral DNA. In conclusion, different DNA and HPV detection methods can significantly influence the results. Therefore, the DNA extraction methods and primers used for DNA amplification in fixed tissues need to be chosen carefully, depending on the specific requirements of the study being carried out.


Coelobillardin, an iridoid glucoside dimer from Coelospermum billardieri.
A new iridoid glucoside dimer, coelobillardin (1), was isolated from the aerial parts of Coelospermum billardieri. Its structure has been elucidated on the basis of MS and NMR data. From a biogenetic point of view, this compound, which includes a cyclobutane basic core, should be considered as a [2+2] dimerization product of (E)-10-(4-hydroxycinnamoyloxy)loganin, which is the major iridoid isolated from the plant.


Synthesis of magnetic CoFe2O4/ordered mesoporous carbon nanocomposites and application in Fenton-like oxidation of rhodamine B.
CoFe2O4/ordered mesoporous carbon (OMC) nanocomposites were synthesized and tested as heterogeneous peroxymonosulfate (PMS) activator for the removal of rhodamine B. Characterization confirmed that CoFe2O4 nanoparticles were tightly bonded to OMC, and the hybrid catalyst possessed high surface area, pore volume, and superparamagnetism. Oxidation experiments demonstrated that CoFe2O4/OMC nanocomposites displayed favorable catalytic activity in PMS solution and rhodamine B degradation could be well described by pseudo-first-order kinetic model. Sulfate radicals (SO4-·) were verified as the primary reactive species which was responsible for the decomposition of rhodamine B. The optimum loading ratio of CoFe2O4 and OMC was determined to be 5:1. Under optimum operational condition (catalyst dosage 0.05 g/L, PMS concentration 1.5 mM, pH 7.0, and 25 °C), CoFe2O4/OMC-activated peroxymonosulfate system could achieve almost complete decolorization of 100 mg/L rhodamine B within 60 min. The enhanced catalytic activity of CoFe2O4/OMC nanocomposites compared to that of CoFe2O4 nanoparticles could be attributable to the increased adsorption capacity and accelerated redox cycles between Co(III)/Co(II) and Fe(III)/Fe(II).


Economic burden of cholera in Asia.
The economic burden data can provide a basis to inform investments in cholera control and prevention activities. However, treatment costs and productivity loss due to cholera are not well studied. We included Asian countries that either reported cholera cases to the World Health Organization (WHO) in 2015 or were considered cholera endemic in 2015 global burden of disease study. Public health service delivery costs for hospitalization and outpatient costs, out-of-pocket costs to patients and households, and lost productivity were extracted from literature. A probabilistic multivariate sensitivity analysis was conducted for key outputs using Monte Carlo simulation. Scenario analyses were conducted using data from the WHO cholera reports and conservative and liberal disease burden estimates. Our analysis included 14 Asian countries that were estimated to have a total of 850,000 cholera cases and 25,500 deaths in 2015 While, the WHO cholera report documented around 60,000 cholera cases and 28 deaths. We estimated around $20.2 million (I$74.4 million) in out-of-pocket expenditures, $8.5 million (I$30.1 million) in public sector costs, and $12.1 million (I$43.7 million) in lost productivity in 2015. Lost productivity due to premature deaths was estimated to be $985.7 million (I$3,638.6 million). Our scenario analyses excluding mortality costs showed that the economic burden ranged from 20.3% ($8.3 million) to 139.3% ($57.1 million) in high and low scenarios when compared to the base case scenario ($41 million) and was least at 10.1% ($4.1 million) when estimated based on cholera cases reported to WHO. The economic burden of cholera in Asia provides a better understanding of financial offsets that can be achieved, and the value of investments on cholera control measures. With a clear understanding of the limitations of the underlying assumptions, the information may be used in economic evaluations and policy decisions.


RALYL increases hepatocellular carcinoma stemness by sustaining the mRNA stability of TGF-β2.
Growing evidences suggest that cancer stem cells exhibit many molecular characteristics and phenotypes similar to their ancestral progenitor cells. In the present study, human embryonic stem cells are induced to differentiate into hepatocytes along hepatic lineages to mimic liver development in vitro. A liver progenitor specific gene, RALY RNA binding protein like (RALYL), is identified. RALYL expression is associated with poor prognosis, poor differentiation, and metastasis in clinical HCC patients. Functional studies reveal that RALYL could promote HCC tumorigenicity, self-renewal, chemoresistance, and metastasis. Moreover, molecular mechanism studies show that RALYL could upregulate TGF-β2 mRNA stability by decreasing N6-methyladenosine (m6A) modification. TGF-β signaling and the subsequent PI3K/AKT and STAT3 pathways, upregulated by RALYL, contribute to the enhancement of HCC stemness. Collectively, RALYL is a liver progenitor specific gene and regulates HCC stemness by sustaining TGF-β2 mRNA stability. These findings may inspire precise therapeutic strategies for HCC.


Female sexual behavior is inhibited by short- and long-term food restriction.
In female musk shrews, sexual receptivity is not restricted to the periovulatory period. Several copulatory bouts that occur over a number of days are required to induce the first ovulation. We tested the hypothesis that food restriction would have a minimal impact on female musk shrew sexual behavior because mating behavior may be uncoupled from ovulation in this species. Three testing conditions were used. In the first study, food-restricted females were maintained at their weaning day weight for 17 days. Food restriction resulted in a significant reduction in the number of females that allowed males to mount, intromit, or ejaculate compared with ad lib-fed controls. In the second experiment, sexually experienced females that were food-restricted for 2 weeks also displayed reduced sexual behavior compared to that in ad lib-fed controls. In the last study, we examined the effects of short-term food fluctuations on sexual behavior. Females food-restricted for 48 h showed reduced mating behavior compared to that in ad lib-fed controls. This was reversed after 24 h of refeeding. These studies show that, even under conditions where copulation does not lead to pregnancy, small reductions in food availability can inhibit female sexual behavior.


Approach to growth hormone therapy in children with chronic kidney disease varies across North America: the Midwest Pediatric Nephrology Consortium report.
Growth impairment remains common in children with chronic kidney disease (CKD). Available literature indicates low level of recombinant human growth hormone (rhGH) utilization in short children with CKD. Despite efforts at consensus guidelines, lack of high-level evidence continues to complicate rhGH therapy decision-making and the level of practice variability in rhGH treatment by pediatric nephrologists is unknown. Cross-sectional online survey electronically distributed to pediatric nephrologists through the Midwest Pediatric Nephrology Consortium and American Society of Pediatric Nephrology. Seventy three pediatric nephrologists completed the survey. While the majority (52.1%) rarely involve endocrinology in rhGH management, 26.8% reported that endocrinology managed most aspects of rhGH treatment in their centers. The majority of centers (68.5%) have a dedicated renal dietitian, but 20.6% reported the nephrologist as the primary source of nutritional support for children with CKD. Children with growth failure did not receive rhGH most commonly because of family refusal. Differences in initial work-up for rhGH therapy include variable use of bone age (95%), thyroid function (58%), insulin-like growth factor-1 (40%), hip/knee X-ray (36%), and ophthalmologic evaluation (7%). Most pediatric nephrologists (95%) believe that rhGH treatment improves quality of life, but only 24% believe that it improves physical function; 44% indicated that rhGH improves lean body mass. There is substantial variation in pediatric nephrology practice in addressing short stature and rhGH utilization in children with CKD. Hence, there may be opportunities to standardize care to study and improve growth outcomes in short children with CKD.


Secretory vesicle priming by CAPS is independent of its SNARE-binding MUN domain.
Priming of secretory vesicles is a prerequisite for their Ca(2+)-dependent fusion with the plasma membrane. The key vesicle priming proteins, Munc13s and CAPSs, are thought to mediate vesicle priming by regulating the conformation of the t-SNARE syntaxin, thereby facilitating SNARE complex assembly. Munc13s execute their priming function through their MUN domain. Given that the MUN domain of Ca(2+)-dependent activator protein for secretion (CAPS) also binds syntaxin, it was assumed that CAPSs prime vesicles through the same mechanism as Munc13s. We studied naturally occurring splice variants of CAPS2 in CAPS1/CAPS2-deficient cells and found that CAPS2 primes vesicles independently of its MUN domain. Instead, the pleckstrin homology domain of CAPS2 seemingly is essential for its priming function. Our findings indicate a priming mode for secretory vesicles. This process apparently requires membrane phospholipids, does not involve the binding or direct conformational regulation of syntaxin by MUN domains of CAPSs, and is therefore not redundant with Munc13 action.


[Stimulation of RNA synthesis in rat liver and isolated hepatocytes by silybin, an antihepatotoxic agent from Silybum marianum L. Gaertn (author's transl)].
The incorporation of [3H] orotic acid into RNA from rat livers is stimulated by the flavonolignane derivative Silybin. The time course of the RNA synthesis and its dose dependence were demonstrated with isolated hepatocytes and [3H]uridine. The specific radioactivity of the newly synthesized RNA in rats treated with silybin is markedly higher than that of the controls. From preliminary experiments there is no indication that the synthesis of a distinct species of RNA is stimulated preferentially.


Cellular endotoxin desensitization in patients with severe chronic heart failure.
Increased levels of bacterial lipopolysaccharide (LPS) have been demonstrated in chronic heart failure (CHF). LPS can induce cellular desensitization, with specific down-regulation of LPS-mediated cellular tumor necrosis factor (TNF-alpha) production which does not affect other cytokine parameters. It is not known if LPS desensitization occurs in CHF. Mononuclear cells from 24 CHF patients (mean age 70+/-2 years, age range 58 to 78 years, NYHA class 3.0+/-0.2) and 11 healthy controls (mean age 53+/-3 years, age range 39 to 75 years) were separated from venous blood and cultured for 24 h with LPS (E. coli, 0-10 ng/mL). Culture supernatants were tested for TNF-alpha and interleukin-1 receptor antagonist (IL-1RA). Patients were subgrouped into mild (n=10), moderate (n=5), and severe (n=9) CHF. Independently of age, mononuclear cells from patients with severe heart failure produced less TNF-alpha than controls (p<0.05) and patients with mild (p<0.001) or moderate CHF (p<0.05). IL-1RA release was higher for CHF patients as a group, compared with controls (p<0.05). There was no significant difference in IL-1RA release between CHF patient subgroups. Mononuclear cells from patients with severe heart failure produce significantly less TNF-alpha than healthy controls or patients with mild to moderate disease. Production of IL-1RA is not affected. This resembles a picture indicative of LPS desensitization occurring in patients with severe CHF.


Expression and prognostic significance of a new tumor metastasis suppressor gene LASS2 in human bladder carcinoma.
The LASS2 gene has been identified as a new tumor metastasis suppressor gene and has been seen to correlate with the degree of invasion and recurrence in carcinomas of prostate, breast, liver, ovarian, and pancreas. However, expression and prognostic significance of LASS2 in human bladder carcinoma are largely unknown. In this study, the protein expression of LASS2 in 80 patients with different stages was detected by immunohistochemical staining. The prognostic value of LASS2 in bladder cancers can also be assessed by a long-term follow-up investigation. The mRNA expression level of the LASS2 gene was examined using real-time quantitative PCR (qPCR) in human bladder carcinoma and paired non-tumor bladder tissues, which were obtained from 30 patients who underwent total cystectomy. We found that patients with LASS2-negative bladder cancer were linked to poor clinical prognosis. The expression of LASS2 mRNA was significantly correlated with clinical stage (P < 0.001), depth of tumor invasion (P < 0.001), and recurrence (P < 0.001). Thus, LASS2 expression may be correlated with the development and progression of human bladder carcinoma and may be a prognostic indicator for this carcinoma.


Content matters: Cyclic effects on women's voices depend on social context.
Women's voices reportedly sound more attractive during the fertile days compared to the non-fertile days of their menstrual cycle. Here we investigated whether the speech content modulates the cyclic changes in women's voices. We asked 72 men and women to rate how interested they were in getting to know the speaker based on her voice. Forty-two naturally cycling women were recorded once during the late follicular phase (high fertility) and once during the luteal phase (low fertility) while speaking sentences of neutral and social content. Listeners were more interested in getting to know the speakers when hearing sentences with social content. Furthermore, raters were more interested in getting to know the speakers when these were recorded in the late follicular than in the luteal phase, but only in sentences with social content. Notably, levels of reproductive hormones (EP ratio) across the cycle phases did not significantly predict the preference for late follicular voices, but echoing the perceptual ratings, there was a significant EP ratio x speech content interaction. Phonetic analyses of mean fundamental frequency (F0) revealed a main effect of menstrual cycle phase and speech content but no interaction. Employing an action-oriented task, the present study extends findings of cycle-dependent voice changes by emphasising that speech content critically modulates fertility effects.


Application of Augmented Intelligence for Pharmacovigilance Case Seriousness Determination.
Identification of adverse events and determination of their seriousness ensures timely detection of potential patient safety concerns. Adverse event seriousness is a key factor in defining reporting timelines and is often performed manually by pharmacovigilance experts. The dramatic increase in the volume of safety reports necessitates exploration of scalable solutions that also meet reporting timeline requirements. The aim of this study was to develop an augmented intelligence methodology for automatically identifying adverse event seriousness in spontaneous, solicited, and medical literature safety reports. Deep learning models were evaluated for accuracy and/or the F1 score against a ground truth labeled by pharmacovigilance experts. Using a stratified random sample of safety reports received by Celgene, we developed three neural networks for addressing identification of adverse event seriousness: (1) a binary adverse-event level seriousness classifier; (2) a classifier for determining seriousness categorization at the adverse-event level; and (3) an annotator for identifying seriousness criteria terms to provide supporting evidence at the document level. The seriousness classifier achieved an accuracy of 83.0% in post-marketing reports, 92.9% in solicited reports, and 86.3% in medical literature reports. F1 scores for seriousness categorization were 77.7 for death, 78.9 for hospitalization, and 75.5 for important medical events. The seriousness annotator achieved an F1 score of 89.9 in solicited reports, and 75.2 in medical literature reports. The results of this study indicate that a neural network approach can provide an accurate and scalable solution for potentially augmenting pharmacovigilance practitioner determination of adverse event seriousness in spontaneous, solicited, and medical literature reports.


In the collective amoebaDictyostelium minutum aggregation centers are founded by single cells which resemble the known "founder cells" inPolysphondylium violaceum. These founders arise in clonal as well as in mass cultures. They can be distinguished from the other cells only shortly before founding a center. Then they are characterized as rounded cells, which have stopped movement more or less completely. The differentiation of the founder cells is reversible.With the help of time lapse movies the exact time of the release of a chemotactic agent by founder cells could be determined. The release usually begins suddenly from one minute to the next. A founder cell is able to secrete this agentbefore having contact with a second cell. On the other hand the release begins onlyafter the founder cell characteristics become visible.In some strains ofD. minutum aggregation centers often are grouped together in the vicinity of one which originated spontaneously, the "primary center". From the time course of this "secondary center" formation, it can be concluded that these groups of centers are induced by the primary one. It seems that the inducing agent is not identical with the chemotactic substance. As is the case in the primary centers, the foundation of the secondary centers begins with the transformation of an amoeba cell into a founder.


Human intravenous immunoglobulin use for hematological immune-mediated disease in dogs.
To report on survival rates and risk factors in dogs with immune-mediated hemolytic anemia (IMHA) and immune-mediated thrombocytopenia (ITP) treated with human IV immunoglobulin (hIVIG; Privigen). We hypothesized that hIVIG could be used as a salvage treatment to improve survival and reduce the requirement for ongoing blood transfusion therapy in IMHA and ITP patients. 52 client-owned dogs with IMHA or ITP were included, comprising 31 females (28 spayed and 3 entire) and 21 males (19 castrated and 2 entire). Miniature Schnauzers were the most common breed (5), with a further 24 different breeds identified. A retrospective cohort study was conducted between January 2006 and January 2022 that assessed the survival rates, risk factors, and need for ongoing transfusion in dogs with IMHA and ITP treated with hIVIG compared with those not receiving hIVIG. Of 36 dogs that did not receive hIVIG, 29 (80%) survived and 7 (24%) died, and of 16 dogs administered hIVIG, 11 (69%) survived and 5 (31%) died (P = .56). No effect of PCV at admission or age on the risk of death was detected (OR, 1.00; 95% CI, 0.94 to 1.08; P = .89; and OR, 1.10; 95% CI, 0.85 to 1.47; P = .47, respectively). This was the largest study to date of dogs with hematological immune-mediated disease treated with hIVIG. There was no difference in survival rates for dogs that received hIVIG versus those treated with standard immunosuppression. The benefit of hIVIG as a salvage treatment appears limited.


Cancer mortality in the European Union, 1988-1997: the fall may approach 80,000 deaths a year.
After the peak rate of cancer mortality reached in 1988 in the European Union, steady declines were observed: 9.1% for both sexes combined over the period 1988-1997 (from 147.0 to 133.6/100,000, world standard), corresponding to the avoidance of about 80,000 deaths in 1997 (approximately 39,000 below age 65 and 41,000 above). In 1997, the total number of cancer deaths also declined, for the first time. The major determining cancers for these favorable trends were stomach (-30%), lung (-10%), intestines (-15%), breast (-10%), uterus (mainly cervix; -22%), leukemias (-10%) and, after 1995, prostate (-3%).


Identification of components of immunoglobulins in senile plaques by means of fluorescent antibody technique.
Using a fluorescent antibody technique, sections of the brains of patients with senile dementia or Alzheimer's disease containing senile plaques were treated with rabbit antihuman immunoglobulins labelled with FITC (fluorescein isothiocyanate, BBL). The senile plaques and the cerebral amyloid angiopathy (drusige Entartung, Scholz, 1938) in the brains of patients with senile dementia or Alzheimer's disease showed specific fluorescence. Control sections from the brains of a girl who died from carcinoma of the stomach and of a female schizophrenic who died from lung abscess, showed only slight fluorescence in a few vessel walls. The presence of components or fragments of immunoglobulins in a senile plaques may mean that immunological factors are involved in their pathogenesis and probably also in that of senile dementia and Alzheimer's disease.


The Experiences of Women who Live with Pelvic Floor Disorders: A Qualitative Study.
Pelvic floor disorders (PFDs) are common and complicated problems that occur in women with different ages and cultural backgrounds and affect various dimensions of their life. Because of the dearth of information about how the Iranian women manage these disorders, this study was conducted to explore the experiences of women who live with PFDs. This qualitative study was conducted between 2018 -2019 on women who referred to the clinics of Mashhad educational hospitals . 25 deep and semi-structured interview with 22 patients with PFDs was done. They were recruited through a purposive sampling method among women with diagnosis of PFDs. Data were analyzed using conventional content analysis adopted by Graneheim and Lundman and organized using the MAXQDA software (Ver.10). The analysis of the data led to the emergence of a theme of "Acceptance and Tolerance", including four categories: "Trying to adopt sexual conflicts", " Concealing the disease", "Trying to modify the lifestyle", and "Controlling negative emotions", and 15 sub-categories. This study provides an insight into self-management strategies for different aspects of challenges faced by women with PFDs.They try to resolve, conceal, modify, and control some issues to accept and tolerate their disease. By identifying self-management strategies, care providers can design and implement counseling, educating and supporting interventions, and also a program through which the patients help and guide each other.


Biochemical markers of contamination in fish toxicity tests.
Markers of xenobiotic metabolization (cytochrome P450, ethoxyresorufin-O-deethylase, glutathione and glutathione-S-transferase) were investigated in the liver of the common carp Cyprinus carpio after 28-day exposure to different pesticide formulations.The fish exposed to herbicide Sencor 70 WG (metribuzin 700 g/kg) of 0.25 and 2.5 mg/l showed no change in cytochrome P450 and activity of ethoxyresorufin-O-deethylase when compared to control.Successor 600 (pethoxamid 600 g/l) of 0.06; 0.22 and 0.60 mg/l did not affect either cytochrome P450 or the activity of ethoxyresorufin-O-deethylase. However, in fish exposed to Successor 600 of 0.22 and 0.60 mg/l, there was a rise in glutathione and in the activity of glutathione-S-transferase (p<0.05), with Spearman's correlation r = 0.23 at p<0.05.Spartakus (prochloraz 450 g/l) of 0.36 and 1.08 mg/l induced cytochrome P450 and ethoxyresorufin-O-deethylase (p<0.05), with Spearman's correlation r=0.49 at p<0.01. Glutathione increased in fish exposed to 1.08 mg/l (p<0.05), the activity of glutathione-S-transferase rose (p<0.05) in all concentrations tested (0.108; 0.36 and 1.08 mg/l). Spearman's correlation between glutathione and GST was r=0.38; p<0.01).The obtained data contribute to a better understanding of detoxification of the selected xenobitics in fish. Although biomarkers of the first phase of metabolization are considered to be more sensitive, our results indicate higher sensitivity of the second phase biomarkers.


Hemodynamics and myocardial blood flow patterns after placement of a cardiac passive restraint device in a model of dilated cardiomyopathy.
The present study examined a cardiac passive restraint device which applies epicardial pressure (HeartNet Implant; Paracor Medical, Inc, Sunnyvale, Calif) in a clinically relevant model of dilated cardiomyopathy to determine effects on hemodynamic and myocardial blood flow patterns. Dilated cardiomyopatht was established in 10 pigs (3 weeks of atrial pacing, 240 beats/min). Hemodynamic parameters and regional left ventricular blood flow were measured under baseline conditions and after acute placement of the HeartNet Implant. Measurements were repeated after adenosine infusion, allowing maximal coronary vasodilation and coronary flow reserve to be determined. Left ventricular dilation and systolic dysfunction occurred relative to baseline as measured by echocardiography. Left ventricular end-diastolic dimension increased and left ventricular fractional shortening decreased (3.8 ± 0.1 vs 6.1 ± 0.2 cm and 31.6% ± 0.5% vs 16.2% ± 2.1%, both P < .05, respectively), consistent with the dilated cardiomyopathy phenotype. The HeartNet Implant was successfully deployed without arrhythmias and a computed median mid-left ventricular epicardial pressure of 1.4 mm Hg was applied by the HeartNet Implant throughout the cardiac cycle. Acute HeartNet placement did not adversely affect steady state hemodynamics. With the HeartNet Implant in place, coronary reserve was significantly blunted. In a large animal model of dilated cardiomyopathy, the cardiac passive restraint device did not appear to adversely affect basal resting myocardial blood flow. However, after acute HeartNet Implant placement, left ventricular maximal coronary reserve was blunted. These unique results suggest that cardiac passive restraint devices that apply epicardial transmural pressure can alter myocardial blood flow patterns in a model of dilated cardiomyopathy. Whether this blunting of coronary reserve holds clinical relevance with chronic passive restraint device placement remains unestablished.


Self-healing interventions for clinical practice: brief psychotherapy with WHEE--the wholistic hybrid of EMDR and EFT.
Potent self-healing approaches are now available to help people to deal with their stresses, anxieties and pains of physical and emotional origins. The author, a wholistic psychiatrist, shares his clinical experiences in helping his clients deal expeditiously and successfully with a variety of physical and psychological symptoms. This article focuses on WHEE, a brief, potent method for releasing psychological and physical pains, negative beliefs and disbeliefs, and for installing positive feelings and beliefs. To use modern terminology, this method allows you to correct the serious but not fatal error you have made in letting a child program your lifetime computer. WHEE is a method for reprogramming your default programs.


Cell type-specific mechanisms coupling protease-activated receptor-1 to infectious colitis pathogenesis.
Protease-activated receptor-1 (PAR-1) plays a major role in multiple disease processes, including colitis. Understanding the mechanisms coupling PAR-1 to disease pathogenesis is complicated by the fact that PAR-1 is broadly expressed across multiple cell types. Determine the specific contributions of PAR-1 expressed by macrophages and colonic enterocytes to infectious colitis. Mice carrying a conditional PAR-1 allele were generated and bred to mice expressing Cre recombinase in a myeloid- (PAR-1ΔM ) or enterocyte-specific (PAR-1ΔEPI ) fashion. Citrobacter rodentium colitis pathogenesis was analyzed in mice with global PAR-1 deletion (PAR-1-/- ) and cell type-specific deletions. Constitutive deletion of PAR-1 had no significant impact on weight loss, crypt hypertrophy, crypt abscess formation, or leukocyte infiltration in Citrobacter colitis. However, colonic shortening was significantly blunted in infected PAR-1-/- mice, and these animals exhibited decreased local levels of IL-1β, IL-22, IL-6, and IL-17A. In contrast, infected PAR-1ΔM mice lost less weight and had fewer crypt abscesses relative to controls. PAR-1ΔM mice had diminished CD3+ T cell infiltration into colonic tissue, but macrophage and CD4+ T cell infiltration were similar to controls. Also contrasting results in global knockouts, PAR-1ΔM mice exhibited lower levels of IL-1β, but not Th17-related cytokines (ie, IL-22, IL-6, IL-17A). Infected PAR-1ΔEPI mice exhibited increased crypt hypertrophy and crypt abscess formation, but local cytokine elaboration was similar to controls. These studies reveal complex, cell type-specific roles for PAR-1 in modulating the immune response to Citrobacter colitis that are not readily apparent in analyses limited to mice with global PAR-1 deficiency.


Dietary management of infants and young children with feeding difficulties and unsatisfactory weight gain using a nutritionally complete hypercaloric infant formula. practical considerations from clinical cases.
A decrease in weight velocity and feeding difficulties in infants may be caused by an inadequate caloric intake and underlying medical conditions. By focusing on four clinical cases, this article illustrates the temporary use of a special infant formula in orally-fed and enterally-fed infants with unsatisfactory weight gain and special medical conditions such as gastrointestinal and neurological disorders. The formula was a nutritionally complete hypercaloric infant formula containing partially hydrolyzed whey protein. It was used after full consideration of all feeding options including breastfeeding. Implementing appropriate feeding behaviors, adapted to age and potential comorbidities, is an essential prerequisite for therapeutic management. The use of a nutritionally complete hypercaloric infant formula can be helpful to manage unsatisfactory weight gain and feeding difficulties in infants.