Function and mechanism of toll-like receptors in cerebral ischemic tolerance: from preconditioning to treatment.
Increasing evidence suggests that toll-like receptors (TLRs) play an important role in cerebral ischemia-reperfusion injury. The endogenous ligands released from ischemic neurons activate the TLR signaling pathway, resulting in the production of a large number of inflammatory cytokines, thereby causing secondary inflammation damage following cerebral ischemia. However, the preconditioning for minor cerebral ischemia or the preconditioning with TLR ligands can reduce cerebral ischemic injury by regulating the TLR signaling pathway following ischemia in brain tissue (mainly, the inhibition of the TLR4/NF-κB signaling pathway and the enhancement of the interferon regulatory factor-dependent signaling), resulting in TLR ischemic tolerance. Additionally, recent studies found that postconditioning with TLR ligands after cerebral ischemia can also reduce ischemic damage through the regulation of the TLR signaling pathway, showing a significant therapeutic effect against cerebral ischemia. These studies suggest that the ischemic tolerance mediated by TLRs can serve as an important target for the prevention and treatment of cerebral ischemia. On the basis of describing the function and mechanism of TLRs in mediating cerebral ischemic damage, this review focuses on the mechanisms of cerebral ischemic tolerance induced by the preconditioning and postconditioning of TLRs and discusses the clinical application of TLRs for ischemic tolerance.


4'-(9-acridinylamino)methane-sulfon-m-anisidide (m-AMSA) and 5-azacytidine (AZA) in the treatment of relapsed adult acute leukemia.
Between March 1980 and December 1981, 22 patients were treated with 4'(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) and 5-azacytidine (AZA), each given by I.V. push in a dosage of 150 mg/m2 for 5 days. Seven of 12 prior-remitting, acute nonlymphoblastic leukemia (ANLL) patients achieved complete remission (58%). Six ANLL patients who failed to remit on standard daunorubicin-cytosine arabinoside programs also failed to remit on the m-AMSA-AZA combination. Two patients with relapsed acute lymphatic leukemia (ALL) also failed while two patients with chronic myelocytic leukemia (CML) in evolution were cytoreduced. The seven patients who achieved remission had additional relapse-free survival for a median of six months (range 1-23+ months). One patient obtained a second remission with m-AMSA-AZA after relapse which followed a 9-month period of nonmaintained remission. Most patients demonstrated mild to moderate nausea and vomiting. Hepatic toxicity was mild to infrequent. Only four patients showed cardiac toxicity which was not life-threatening. The most troublesome toxicity was mucositis and was seen in 11 patients; four whom required I.V. hyperalimentation. We conclude that this combination is an effective salvage program for relapsed prior-remitting ANLL. Future studies should be conducted in three areas. The first study might be a comparison of relapsed prior-remitting ANLL with single-agent m-AMSA. The second, in untreated ANLL, following induction with DAT, might use m-AMSA-AZA in consolidation and maintenance arms of future protocols. The final study should explore m-AMSA-AZA activity in evolved CML in a greater number of patients.


Glans Anthropometry for Preputial Reconstruction in Hypospadias.
Cases of hypospadias present for poor stream or cosmetic appearance. The main aim is to provide a visibly normal phallus. Preputial reconstruction is technical. A properly planned reconstruction based on anthropometry may improve the result. We are presenting our experience of reconstruction based on glans anthropometry. The aim of the study was to evaluate the importance of glans anthropometry in preputial reconstruction in cases of hypospadias. All cases of hypospadias operated between June 2014 and March 2022 were included. Glans width was measured at the base. The marking sutures for preputial reconstruction were taken at distance thrice the glans width at base. Those requiring religious circumcision along with repair, associated significant chordee, catheter came out before 2 weeks, or history of any previous penile surgery were excluded. All the cases were subjected to urethroplasty, meatoplasty, and preputioplasty. The results obtained were analyzed. One hundred and forty-eight out of 159 cases formed the study group. There were 31 glanular, 42 distal penile, 58 mid-penile, and 17 proximal penile hypospadias. Mean glans width at base was 16 mm (range: 11-21 mm). Mean distance of marking suture at prepuce was 38 mm (range: 33-63 mm). Mean follow-up was 12 months (range: 1-36 months). Mean age at presentation was 23 months (range: 14-72 months). Mean operating time was 50 min (range: 45-60 min). Fistula at the base of preputioplasty was seen in four. Dehiscence of preputioplasty was seen in six. Meatal stenosis was seen in three cases. Preputial reconstruction improves the cosmetic appearance of the hypospadiac penis. Reconstruction based on glans anthropometry improves the result and avoids complications.


Neuromuscular electrical stimulation for muscle strengthening in elderly with knee osteoarthritis - a systematic review.
To identify if there is evidence in favor of the use of NMES to quadriceps muscle strengthening in elderly with knee OA. A search of PubMed/Medline, PEDro and Cochrane Library produced a total of 76 relevant trials. Six studies that met the inclusion criteria were selected for this review. Trials were addressed by inclusion and exclusion criteria and scoring internal validity using PEDro scale. A summary of the sample and design characteristics, and muscle strength results from each study were presented on table. The best-evidence analysis showed moderate evidence in favor of NMES alone or combined with exercise for isometric quadriceps strengthening in elderly with OA. In addition, for the effects of NMES intervention as an adjunct therapy on isokinetic strength at different angular velocities, there was a limited quality of evidence assessed.


Positive and negative AIT trials: What makes the difference?
Allergen immunotherapy has proven to be efficacious in allergic rhinitis and asthma. However, results from randomised clinical trials may vary substantially. Clinical trials may unexpectedly fail. The purpose of this review is to discuss the possible factors that may contribute to a successful or unsuccessful study. Descriptive review exploring the possible causes of negative outcomes in allergen immunotherapy trials. A series of factors may lead to negative results. Among of these are underpowering of the study, low allergen content in tested extracts, insufficient allergen exposure during monitoring and recruitment of inappropriate patients. In addition, the choice of the primary endpoint may be critical. A clinical trial aims to evaluate the efficacy of an agent. However, studies with potential effective compounds may fail because of methodical issues. Sometimes, they are the cause of discrepancies between successful phase II and unsuccessful phase III trials. To understand more about failure of studies, investigators and editors should be encouraged to publish negative trials.


Trunk muscles in persons with hemiparetic stroke evaluated with computed tomography.
To analyse side difference in bilateral trunk muscles in patients with hemiparetic stroke, to relate it with impairment and disability variables and to evaluate longitudinal changes. In a sample of 83 inpatients with hemiparetic stroke undergoing rehabilitation, we measured the cross-sectional area of the paravertebral muscle and thigh muscles using computed tomography at admission and discharge. Classifying them by paravertebral muscle side difference (group I: contralateral > ipsilateral; II: contralateral = ipsilateral; III: contralateral < ipsilateral) we analysed group difference in the Stroke Impairment Assessment Set, the Functional Independence Measure and walk velocity. In contrast to thigh muscles, the paravertebral muscle cross-sectional area was significantly greater on the side contralateral to the brain lesion. Discharge paravertebral muscle cross-sectional area increased significantly from admission values. The Stroke Impairment Assessment Set, Functional Independence Measure and walk velocity were significantly lower in group I. The contralateral paravertebral muscle cross-sectional area was larger than the ipsilateral ones, and this was related to the degree of impairment and functional limitations.


Radiological Evaluation of the Relationship Between Cortical Hypertrophy and Stress Shielding After Total Hip Arthroplasty Using a Cementless Stem.
Unloading of the proximal medial femoral cortex is usually associated with an increased bone strain at the distal part of the prosthesis, which may cause distal femoral cortical hypertrophy (CH). The objective of this study was to determine the factors that may be considered a predisposition to distal femoral CH and its effect on the stress shielding (SS) or durability of the fixation of the stem. A total of 240 total hip arthroplasties were performed between January 2006 and December 2016, with all hips implanted with a Bicontact stem. The minimum follow-up period was more than 2 years, and the mean follow-up period was 7.2 years. The radiographic outcome was assessed on an anteroposterior hip radiograph. CH and SS were assessed on postoperative radiographs in the Gruen zone. We defined CH that appeared in zone 3 or 5 as 'the focal type' and defined CH that appeared in zones 2, 3, 4, 5, and 6 as 'the diffuse type.' SS followed the procedures from the Engh classification. CH was found in 72 hips (30% of the 240 hips), the focal type was found in 23 hips (9.6% of the 240 hips), and the diffuse type was found in 49 hips (20.4% of the 240 hips). SS was found in 41 hips (17.1% of 240 hips), including 32 hips with SS, which was found after the development of CH. One hip was from the focal-type CH and 31 hips were from the diffuse-type CH. SS, which is typically found in Engh classification types 1 and 2 developed in 13 hips, and SS, which is widely seen in Engh classification types 3 and 4 developed in 19 hips. All 19 hips with progressed SS were found after the diffuse-type CH had developed. In addition, among the 19 hips with progressed SS, Dorr type A was found in 0 hips, Dorr type B in 8 hips, and Dorr type C in 11 hips. According to the results of our radiological evaluation, development of the diffuse-type CH after total hip arthroplasty using Bicontact stems is one of the critical causes of the later development of SS and could be predicted to progress to SS. To prevent the development of the diffuse-type CH, the indication to choose a Bicontact stem for a Dorr type C with osteoporotic bone should be considered.


High altitude journeys and flights are associated with an increased risk of flares in inflammatory bowel disease patients.
Hypoxia can induce inflammation in the gastrointestinal tract. However, the impact of hypoxia on the course of inflammatory bowel disease (IBD) is poorly understood. We aimed to evaluate whether flights and/or journeys to regions lying at an altitude of >2000 m above the sea level are associated with flare-ups within 4 weeks of the trip. IBD patients with at least one flare-up during a 12-month observation period were compared to a group of patients in remission. Both groups completed a questionnaire. A total of 103 IBD patients were included (43 with Crohn's disease (CD): mean age 39.3 ± 14.6 years; 60 with ulcerative colitis (UC): mean age 40.4 ± 15.1 years). Fifty-two patients with flare-ups were matched to 51 patients in remission. IBD patients experiencing flare-ups had more frequently undertaken flights and/or journeys to regions >2000 m above sea level within four weeks of the flare-up when compared to patients in remission (21/52 [40.4%] vs. 8/51 [15.7%], p=0.005). Journeys to high altitude regions and/or flights are a risk factor for IBD flare-ups occurring within 4 weeks of travel.


The structure of the neuraminic acid-containing capsular polysaccharide of Escherichia coli serotype K9.
The acidic capsular polysaccharide isolated from Escherichia coli O9:K9:H12 was investigated by using n.m.r. spectroscopy, methylation analysis, periodate oxidation, and bacteriophage-borne enzyme degradation. The polysaccharide, the structure of which is shown below, is the third E. coli capsular polysaccharide reported to contain neuraminic acid, the others being the K1 and K92 polysaccharides, and it is the first in the E. coli series shown to contain a 4-linked neuraminic acid unit. (formula; see text).


Association of beta-2-microglobulin, cystatin C and lipocalin-2 with stroke risk in the general Chinese population.
Beta-2-microglobulin (B2M), cystatin C and lipocalin-2 (LCN-2) are established renal biomarkers, yet their roles in stroke have not been fully evaluated. We aimed to investigate the relationship of B2M, cystatin C, and LCN-2 with stroke risk in a general Chinese population. We used ordinal regression to study the relationship between serum B2M, cystatin C, and LCN-2 with stroke risk in 1060 participants (mean age 45.4 ± 10.8 years, 46% male) from the Shenzhen-Hong Kong United Network on Cardiovascular Disease (SHUN-CVD) study. Stroke risk was classified into low-risk, middle-risk and high-risk groups according to the China National Stroke Screening Survey criteria. Serum biomarker levels were measured using immunoturbidimetric assays. Participants with valid data on serum biomarker levels and stroke risk were included in the analysis. The number of participants in the low-risk, middle-risk and high-risk stroke risk groups were 663, 143 and 254 respectively. Elevated serum B2M, cystatin C, and LCN-2 levels were associated with being male, overweight/obesity, hypertension, alcohol consumption and smoking. Serum B2M, cystatin C and LCN-2 levels were significantly associated with stroke risk in the overall population (B2M: β = 0.595, p < .001; cystatin C: β = 3.718, p < .001; LCN-2: β = 0.564, p < .001) after adjustment for age. Elevated serum B2M, cystatin C and LCN-2 levels are associated with stroke risk. They may be novel biomarkers for clinicians to assess stroke risk.Key messagesSerum beta-2-microglobulin, cystatin C and lipocalin-2 levels are significantly associated with stroke risk.Beta-2-microglobulin, cystatin C and lipocalin-2 may serve as useful biomarkers for stroke risk stratification in the general population.


Alterations of Transcription of Genes Coding Anti-oxidative and Mitochondria-Related Proteins in Amyloid β Toxicity: Relevance to Alzheimer's Disease.
A growing body of evidence indicates that pathological forms of amyloid beta (Aβ) peptide contribute to neuronal degeneration and synaptic loss in Alzheimer's disease (AD). In this study, we investigated the impact of exogenous Aβ1-42 oligomers (AβO) and endogenously liberated Aβ peptides on transcription of genes for anti-oxidative and mitochondria-related proteins in cell lines (neuronal SH-SY5Y and microglial BV2) and in brain cortex of transgenic AD (Tg-AD) mice, respectively. Our results demonstrated significant AβO-evoked changes in transcription of genes in SH-SY5Y cells, where AβO enhanced expression of Sod1, Cat, mt-Nd1, Bcl2, and attenuated Sirt5, Sod2 and Sdha. In BV2 line, AβO increased the level of mRNA for Sod2, Dnm1l, Bcl2, and decreased for Gpx4, Sirt1, Sirt3, mt-Nd1, Sdha and Mfn2. Then, AβO enhanced free radicals level and impaired mitochondrial membrane potential only in SH-SY5Y cells, but reduced viability of both cell types. Inhibitor of poly(ADP-ribose)polymerase-1 and activator of sirtuin-1 more efficiently enhanced viability of SH-SY5Y than BV2 affected by AβO. Analysis of brain cortex of Tg-AD mice confirmed significant downregulation of Sirt1, Mfn1 and mt-Nd1 and upregulation of Dnm1l. In human AD brain, changes of microRNA pattern (miRNA-9, miRNA-34a, miRNA-146a and miRNA-155) seem to be responsible for decrease in Sirt1 expression. Overall, our results demonstrated a diverse response of neuronal and microglial cells to AβO toxicity. Alterations of genes encoding Sirt1, Mfn1 and Drp1 in an experimental model of AD suggest that modulation of mitochondria dynamics and Sirt1, including miRNA strategy, may be crucial for improvement of AD therapy.


Mimosa pudica may possess antidepressant actions in the rat.
In Mexico, aqueous extracts from dried leaves of Mimosa puolica are employed to alleviate depression. In this study, the behavioral actions of aqueous extracts of M. pudica at various concentrations were tested. Rats having received saline (0.9%; 0.30 ml; I.P.), clomipramine, desipramine or several dosages of aqueous extracts from M. pudica (ml = 2.0 mg/kg; m2 = 4.0 mg/kg; m3 = 6.0 mg/kg; m4 = 8.0 mg/kg) during a 30-day period were submitted to the forced swimming test and to the test for differential reinforcement of low rates of response at 72 sec (DRL-72s). Any possible anxiolytic action resulting from several doses (ml = 2.0 mg/kg; m2 = 4.0 mg/kg; m3 = 6.0 mg/kg; m4 = 8.0 mg/kg) of extracts of M. pudica were compared with those caused by diazepam (1.3 mg/kg, I.P.) in the elevated plus-maze test. Results showed that clomipramine (1.25 mg/kg, I.P.), desipramine (2.14 mg/kg, I.P.) and M. pudica (6.0 mg/kg and 8.0 mg/kg, I.P.) reduced immobility in the forced swimming test and increased the rate of reinforcers received in the DRL-72s test; these data suggest that M. pudica produces antidepressant effects in the rat. Diazepam increased the open-arms exploration time in the elevated plus-maze test, but M. pudica did not show any comparable action at any tested dose. M. pudica therefore produced an antide-pressant-like profile similar to two tricyclic antidepressants.


Syncope in the Wolff-Parkinson-White syndrome: incidence and electrophysiologic correlates.
Syncope in the patient with Wolff-Parkinson-White (WPW) syndrome raises the specter of rapid tachyarrhythmias and the possibility of sudden cardiac death. We reviewed the records of 55 consecutive WPW patients referred for electrophysiologic evaluation of known or suspected arrhythmias to determine the incidence and significance of syncope. Twelve patients (22.6%) reported the occurrence of at least one episode of syncope. In eleven (20%) of these, syncope was preceded by rapid palpitations. Forty-three patients (77.4%) had no syncopal episodes. These two groups did not differ significantly with regard to age, sex, presence of associated cardiac or neurologic disease, drug history or accessory pathway location. There was no significant difference in cycle length of reciprocating tachycardia (syncope = 295.6 +/- 59.8 vs non-syncope = 334.5 +/- 59.6 ms, p less than .5), shortest R-R intervals between preexcited beats (260 +/- 78.6 vs 246.7 +/- 55.4 ms, p less than .5) and average R-R interval (364.4 +/- 37.9 vs 367.4 +/- 77.5 ms, p less than .5) measured during atrial fibrillation. The anterograde effective refractory period of the accessory pathway (292.1 +/- 31.9 vs 299 +/- 58.1 ms, p less than .5) and the shortest cycle length with 1:1 conduction over the accessory pathway (306.7 +/- 75 vs 289.1 +/- 77.5 ms, p less than .5) similarly did not differ. We conclude that syncope occurs in approximately 20% of patients with the Wolff-Parkinson-White syndrome referred for assessment of tachycardia. Patients with syncope do not have distinct clinical features or a more malignant electrophysiologic profile, suggesting that other extracardiac factors may play an important role in the genesis of syncope in this group.


One Solution Fits All? Evaluating Different Communication Strategies of a Light-based External Human-Machine Interface for Differently Sized Automated Vehicles from a Pedestrian's Perspective.
Differently sized automated vehicles (AVs) will enter the roads of tomorrow and will interact with other road users. Pedestrians as vulnerable road users heavily rely on the communication with other road users, especially for the interaction with larger vehicles, as miscommunication pose a high risk. Therefore, AVs need to provide communication abilities to safely interact with pedestrians. This study's focus was on the explicit communication which is highly relevant in low-speed and low-distance traffic scenarios to clarify misunderstandings before they result in accidents. External human-machine interfaces (eHMIs) placed on the outside of AVs can be used as a communication tool to explicitly inform the surrounding traffic environment. Although research manifested effects of vehicle size on pedestrians' perceived safety and crossing behavior, little research about the eHMI design for differently sized AVs exists. This experimental online study (N = 155) aimed at investigating the application of a light-based eHMI on two differently sized AVs (car, bus) by focusing on the overall goal of ensuring traffic safety in future traffic. The light-based eHMI showed different communication strategies, i.e., a static eHMI and three dynamic eHMIs. The results revealed that an automated car was perceived as safer and affectively rated as more positive compared to an automated bus. Nevertheless, no significant differences were found between the two AVs in terms of the eHMI communication. A dynamic eHMI was perceived as safer and evaluated affectively as more positive compared to a static eHMI or no eHMI for both AVs. In conclusion, the use of a light-based eHMI had a positive effect on pedestrians' interaction with an automated car and an automated bus and, therefore, could contribute to the overall traffic safety in this study. Implications for the design of eHMIs for differently sized AVs were discussed.


Intermittent mandatory ventilation and controlled mechanical ventrilation without positive end-expiratory pressure following cardio-pulmonary bypass.
In a group of 18 male patients undergoing coronary artery bypass grafting with cardiopulmonary bypass, the overall incidence of post-operative atelectasis was 60%. Nearly three-quarters occurred during anaesthesia. After operation there was no difference whether CMV or IMV without PEEP was provided overnight. Atelectasis already present did not improve and further atelectasis occurred. A role for IMV is not excluded, since it facilitates the use of PEEP. Many factors operate and interact to provoke atelectasis during anaesthesia, which increases post-operative morbidity. Many of these factors are prevertible or reversible if their physiological basis is understood. Optimal post-operative ventilation should be tailored to the needs of the individual patient and demands close co-operation between anaesthetist and surgeon.


Evolution of hepatitis A antibodies prevalence in young French military recruits.
Hepatitis A antibodies (anti-HAV) were surveyed in 1000 French recruits during 1990. The prevalence of anti-HAV in this group was 21.35%. Compared to a 1985 survey a 9% fall in the anti-HAV prevalence rate was observed. Living in a coastal area, low educational level, stay overseas were the main risk factors, as already noted in 1985.


First assessment of butyltins (BuTs) contamination of the Montenegrin coast (Southeast Adriatic): Tributyltin (TBT) poses a threat to the marine ecosystem.
This study presents the first assessment of butyltins (BuTs) pollution of the Montenegrin coast. The distribution of tributyltin (TBT), dibutyltin (DBT) and monobutyltin (MBT) was investigated in mussels, sediments and water overlying sediment after the sediment resuspension. The results showed that the investigated sites (marinas, ports, shipyards) are contaminated with BuTs (19-402 ng (Sn)/g in mussels; 43-20,641 ng (Sn)/g in sediments; 9-566 ng (Sn)/L in overlying waters). The measured TBT concentrations indicate that toxic effects on marine organisms are expected at most locations. The simultaneous analysis of BuTs and total Sn in sediment cores allowed the assessment of TBT historical input, while it was demonstrated that resuspension of contaminated sediments leads to the release of all BuTs into the water column. This study shows that, despite the ban of TBT-based antifouling paints more than a decade ago, pollution of the marine environment with TBT is still a problem and regular monitoring remains essential.


Information, Motivation, and Self-Efficacy Among Men Who Have Sex With Men and Transgender Women in the State of Maharashtra, India.
India's National AIDS Control Programme calls for, among other things, targeted behavioral interventions that address determinants contributing to new infections among men who have sex with men (MSM) and hijras (transgender women). To determine if the information-motivation-behavioral skills model was transferable to an Indian context. We recruited 442 MSM and 7 hijras into an online cross-sectional study that asked questions about condom use knowledge, motivation, self-efficacy, and sexual behavior. Structural equation modeling was used to test the overall information-motivation-behavioral skills structure. Condom use and HIV risk knowledge did not significantly predict condom use self-efficacy or having condomless anal sex with more than one male partner in the past 3 months, and knowledge was not significantly correlated with attitudes toward barebacking. Despite this, the final structural model explained 14.4% of the variance in condom use self-efficacy and 20.0% of the variance in risky sexual behavior. Overall fit of the model was good: χ2(201, N = 447) = 445.002, p < .0001, root mean square error of approximation = .052, 90% CI [.046, .059], comparative fit index = .989, Tucker-Lewis Index = .987. The public health response to India's HIV epidemic is currently different than in the West due to differences in medication access and public health infrastructure. As Indian MSM and hijras learn more about the effectiveness of viral suppression and hopefully have greater access to preexposure prophylaxis, researchers should monitor for changing attitudes toward condoms and be prepared to collaborate with the public health infrastructure in order to develop interventions that reinforce positive attitudes toward condom use.


Epidemiologic and anatomic aspects comparing incidental and ruptured intracranial aneurysms: A single centre experience.
The feasibility of multicentric international data such as integrated in the PHASES score for patient counseling in unruptured intracranial aneurysms has recently been challenged. To determine, whether this data is applicable to local populations in a restricted catchment area, we performed a retrospective mono-centric analysis comparing patients with ruptured aneurysms to patients with incidental aneurysms. 200 patients with unruptured aneurysms and 197 patients after aneurysmal subarachnoid hemorrhage were analyzed for risk factors differing between the groups and to the general German population. Subgroup analysis was performed for 25 patients harboring multiple aneurysms, in 19 patients with intracavernous aneurysms and in 77 women of childbearing potential. While the preponderance of female patients was confirmed, significantly more men figured in the patient group with subarachnoid hemorrhage (36.4%) than among unruptured aneurysms (25%). Patients with bleeding events were significantly younger (51.6 years) than patients with incidental aneurysms (57.8 years). The rupture risk prediction of the PHASES score concerning aneurysm size below 7 mm and patient age over 70 years could not be confirmed, instead score points correlated to the clinical outcome after rupture. In our population, pregnant women were not overrepresented. Intracavernous carotid aneurysms contributed to the low risk profile of giant aneurysms. Thus, recommendations from pooled international data have to be adapted cautiously to local circumstances. We retained seven items with predictive value for outpatient counseling: age, smoking, hypertonus and concurrent vascular aberrations as patient characteristics and irregular shape, (increasing) largest diameter and the harboring vessel for the aneurysm.


The SIN kinase Sid2 regulates cytoplasmic retention of the S. pombe Cdc14-like phosphatase Clp1.
Cdc14-family phosphatases play a conserved role in promoting mitotic exit and cytokinesis by dephosphorylating substrates of cyclin-dependent kinase (Cdk). Cdc14-family phosphatases have been best studied in yeast (for review, see [1, 2]), where budding yeast Cdc14 and its fission yeast homolog Clp1 are regulated partly by their localization; both proteins are thought to be sequestered in the nucleolus in interphase. Cdc14 and Clp1 are released from the nucleolus in mitosis, and in late mitosis conserved signaling pathways termed the mitotic exit network (MEN) and the septation initiation network (SIN) keeps Cdc14 and Clp1, respectively, out of the nucleolus through an unknown mechanism [3-6]. Here we show that the most downstream SIN component, the Ndr-family kinase Sid2, maintains Clp1 in the cytoplasm in late mitosis by phosphorylating Clp1 directly and thereby creating binding sites for the 14-3-3 protein Rad24. Mutation of the Sid2 phosphorylation sites on Clp1 disrupts the Clp1-Rad24 interaction and causes Clp1 to return prematurely to the nucleolus during cytokinesis. Loss of Clp1 from the cytoplasm in telophase renders cells sensitive to perturbation of the actomyosin ring but does not affect other Clp1 functions. Because all components of this pathway are conserved, this might be a broadly conserved mechanism for regulation of Cdc14-family phosphatases.


Electric and magnetic fields from two-dimensional anisotropic bisyncytia.
Cardiac tissue can be considered macroscopically as a bidomain, anisotropic conductor in which simple depolarization wavefronts produce complex current distributions. Since such distributions may be difficult to measure using electrical techniques, we have developed a mathematical model to determine the feasibility of magnetic localization of these currents. By applying the finite element method to an idealized two-dimensional bisyncytium with anisotropic conductivities, we have calculated the intracellular and extracellular potentials, the current distributions, and the magnetic fields for a circular depolarization wavefront. The calculated magnetic field 1 mm from the tissue is well within the sensitivity of a SQUID magnetometer. Our results show that complex bisyncytial current patterns can be studied magnetically, and these studies should provide valuable insight regarding the electrical anisotropy of cardiac tissue.


A novel postoperative nomogram and risk classification system for individualized estimation of survival among patients with parotid gland carcinoma after surgery.
Parotid gland carcinoma (PGC) is a rare but aggressive head and neck cancer, and the prognostic model associated with survival after surgical resection has not yet been established. This study aimed to construct a novel postoperative nomogram and risk classification system for the individualized prediction of overall survival (OS) among patients with resected PGC. Patients with PGC who underwent surgery between 2004 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database were randomized into training and validation cohorts (7:3). A nomogram developed using independent prognostic factors based on the results of the multivariate Cox regression analysis. Harrell's concordance index (C-index), time-dependent area under the curve (AUC), and calibration plots were used to validate the performance of the nomogram. Moreover, decision curve analysis (DCA) was performed to compare the clinical use of the nomogram with that of traditional TNM staging. In this study, 5077 patients who underwent surgery for PGC were included. Age, sex, marital status, tumor grade, histology, TNM stage, surgery type, radiotherapy, and chemotherapy were independent prognostic factors. Based on these independent factors, a postoperative nomogram was developed. The C-index of the proposed nomogram was 0.807 (95% confidence interval 0.797-0.817). Meanwhile, the time-dependent AUC (> 0.8) indicated that the nomogram had a satisfactory discriminative ability. The calibration curves showed good concordance between the predicted and actual probabilities of OS, and DCA curves indicated that the nomogram had a better clinical application value than the traditional TNM staging. Moreover, a risk classification system was built that could perfectly classify patients with PGC into three risk groups. This study constructed a novel postoperative nomogram and corresponding risk classification system to predict the OS of patients with PGC after surgery. These tools can be used to stratify patients with high or low risk of mortality and provide high-risk patients with more directed therapies and closer follow-up.


Safety and efficacy of inferior vena caval occlusion to rapidly alter ventricular loading conditions in idiopathic dilated cardiomyopathy.
To investigate the safety and efficacy of inferior vena caval (IVC) balloon occlusion for preload alteration in humans, 13 patients with dilated cardiomyopathy were studied before and during repeated (total of 78) IVC occlusions. Left and right ventricular (LV and RV) micromanometer pressures were simultaneously measured and M-mode and 2-D echocardiograms were recorded at end expiration. Complications were limited to abdominal discomfort in 2 patients. With IVC occlusion, RV collapse fluoroscopically shifted the heart toward midline and ventricular septal motion was frequently disordered. Significant (p = 0.001) changes occurred in RV and LV systolic peak pressures (from 19 +/- 6 to 12 +/- 5 mm Hg and from 129 +/- 34 to 109 +/- 25 mm Hg, respectively). LV and RV end-diastolic pressures also decreased significantly (from 18 +/- 7 to 6 +/- 6 mm Hg and from 5 +/- 3 to 2 +/- 2 mm Hg, respectively) (both p less than or equal to 0.0055). Similarly, LV end-diastolic diameter decreased 13% (from 61 +/- 11 to 53 +/- 12 mm, p = 0.0002). Mean heart rate did not change significantly (from 76 +/- 19 to 78 +/- 21 beats/min). Thus, IVC balloon occlusion provides a safe method of repeatedly altering loading conditions in humans. This approach allows for acquisition of important information regarding cardiac chamber dynamics while minimizing the effects of reflex mechanisms and avoiding use of pharmacologic agents.


The homeoprotein DLX4 controls inducible nitric oxide synthase-mediated angiogenesis in ovarian cancer.
Homeobox genes encode transcription factors that control patterning of virtually all organ systems including the vasculature. Tumor angiogenesis is stimulated by several homeobox genes that are overexpressed in tumor cells, but the mechanisms of these genes are poorly understood. In this study, we investigated the mechanisms by which DLX4, a homeobox gene that is associated with increased tumor microvessel density, stimulates ovarian tumor angiogenesis. Expression of DLX4 and nitric oxide synthases was analyzed in publicly available transcriptional profiles of ovarian cancer clinical specimens. Levels of inducible nitric oxide synthase (iNOS) were evaluated by quantitative RT-PCR, flow cytometry and nitric oxide assays using ovarian cancer cell lines in which DLX4 was overexpressed or knocked down. Signal Transducer and Activator of Transcription 1 (STAT1) expression and activity were evaluated by luciferase reporter assays, immunofluorescence staining, Western blot and immunoprecipitation. Endothelial cell growth and tumor angiogenesis were evaluated in in vitro assays and xenograft models. We identified that DLX4 induces expression of iNOS, an enzyme that stimulates angiogenesis by generating nitric oxide. Analysis of datasets of two independent patient cohorts revealed that high DLX4 expression in ovarian cancer is strongly associated with elevated expression of iNOS but not of other nitric oxide synthases. Studies using STAT1-expressing and STAT1-deficient cells revealed that DLX4 interacts with STAT1 and induces iNOS expression in part by stimulating STAT1 activity. Expression of DLX4 in ovarian cancer cells stimulated endothelial cell growth in vitro and increased microvessel density in xenograft models, and these stimulatory effects of DLX4 were abrogated when its induction of iNOS was inhibited. These findings indicate that DLX4 promotes ovarian tumor angiogenesis in part by stimulating iNOS expression.


[Not Available].
The influence of moulded hay (Alternaria alternata, Epicoccum nigrum, Mucor racemosus, Ulocladium chartarum) and the efficiency of Vitamin B1 substitution to cope these effects on rumen protozoa was investigated using the longterm rumen simulation technique (RUSITEC) for about 25 days. Moulded hay affected medium-sized protozoa to a different extent (Alternaria alternata: -16 %, Epicoccum nigrum: -27 %, Mucor racemosus: -9 %, Ulocladium chartarum: +2 %). The vitamin B1 substitution had positive effects during the feeding of Mucor racemosus and Ulocladium chartarum.


Tanshinone I increases CYP1A2 protein expression and enzyme activity in primary rat hepatocytes.
This study investigated the effects of Danshen and its active ingredients on the protein expression and enzymatic activity of CYP1A2 in primary rat hepatocytes. The ethanolic extract of Danshen roots (containing mainly tanshinones) inhibited CYP1A2-catalyzed phenacetin O-deethylation (IC(50)=24.6 μg/ml) in primary rat hepatocytes while the water extract containing mainly salvianolic acid B and danshenshu had no effect. Individual tanshinones such as cryptotanshinone, dihydrotanshinone, tanshinone IIA inhibited the CYP1A2-mediated metabolism with IC(50) values at 12.9, 17.4 and 31.9 μM, respectively. After 4-day treatment of the rat hepatocytes, the ethanolic extract of Danshen and tanshinone I increased rat CYP1A2 activity by 6.8- and 5.2-fold, respectively, with a concomitant up-regulation of CYP1A2 protein level by 13.5- and 6.5-fold, respectively. CYP1A2 induction correlated with the up-regulation of mRNA level of aryl hydrocarbon receptor (AhR), which suggested a positive feedback mechanism of tanshinone I-mediated CYP1A2 induction. A formulated Danshen pill (containing mainly danshensu and salvianolic acid B and the tanshinones) up-regulated CYP1A2 protein expression and enzyme activity, but danshensu and salvianolic acid B, when used individually, did not affect CYP1A2 activity. This study was the first report on the Janus action of the tanshinones on rat CYP1A2 activity.


Amiprilose in the prevention of restenosis after coronary intervention in a swine model.
Amiprilose hydrochloride is a synthetic carbohydrate with anti-inflammatory and antiproliferative properties. This study tested the potential benefit of amiprilose in preventing coronary artery restenosis in a swine model. The swine restenosis model was prepared using Hanford miniature swine made atherosclerotic with coronary abrasion, high-fat and high-cholesterol feeding, and intracoronary stenting. Eighteen animals were randomized to receive amiprilose, 100 mg/kg body weight orally twice per day (n = 9), or no amiprilose (n = 9) beginning 5 days before stenting and continuing through 4 weeks until sacrifice. Presacrifice quantitative coronary angiography and postsacrifice histologic examination revealed the degree of intimal proliferation. Coronary angiography revealed no difference in percentage-diameter stenosis between the amiprilose and control groups (left anterior descending artery [LAD], 46% +/- 10% vs 44% +/- 17%; circumflex artery [CFX], 43% +/- 21% vs 42% +/- 15%; right coronary artery [RCA], 37% +/- 11% vs 34% +/- 9%; P = not significant [NS]), respectively, or in change in lumen diameter from poststenting to presacrifice (LAD, -1.0 +/- 0.4 mm vs -1.1 +/- 0.7 mm; CFX, -1.2 +/- 0.8 mm vs -1.0 +/- 0.7 mm; RCA, -1.1 +/- 0.4 mm vs -1.0 +/- 0.4 mm; P = NS). Morphometric histologic analysis likewise showed no difference in percentage-area stenosis (LAD, 55% +/- 14% vs 55% +/- 15%; CFX, 53% +/- 15% vs 54% +/- 12%; RCA, 39% +/- 17% vs 39% +/- 20%; P = NS) or in maximal intimal thickness. Amiprilose hydrochloride did not prevent coronary intimal proliferation in this swine model of restenosis.


Variability of hematocrit value, blood serum beta- and gamma-globulin level and body weight in different transferrin genotypes of common vole (Microtus arvalis, Pallas 1779) from natural population.
1. Heterozygotes TfF/TfE of voles did not differ in body weight, they had higher hematocrit value (males and females), higher beta-globulin fraction (males) or higher gamma-globulin fraction (females). 2. A smaller variability of parameters studied was observed in heterozygotes than in homozygotes. Small and similar variability occurred in hematocrit value and beta-globulins while higher variability occurred in body weight and gamma-globulins. 3. In common voles the faster migrating E system of transferrin may have a higher capacity for iron transport than the F system. 4. Seasonal changes of hematocrit value in vole populations seems to result from genetical and physiological variability. 5. Sexual and seasonal changes in beta-globulin level appear to be related to changes in sexual activity of the animals during the seasons. 6. In autumn, low weight of animals and high serum gamma-globulin level, with the same physiological variability of these two parameters, suggest the synthesis of gamma-globulins with tissue (muscle) proteins. 7. Autumnal increase of gamma-globulin level seems to be very important, taking into consideration the role of the protein in water retention and its filtration from the tissues. Very high level of the protein fraction may play a role in winter high mortality of voles.


A new leech species (Hirudinida: Erpobdellidae: Erpobdella) from a cave in the West Azerbaijan province of Iran.
Erpobdella borisi n. sp. is a predatory leech inhabiting cave waters in Iran. Probably, it is either a troglobiont or troglophile. The leech has no eyes, and the complete mid-body somite is divided unequally into five annuli. Results of phylogenetic analysis based on morphological characters and COI gene sequence indicate the species to be closely related to Erpobdella japonica, E. octoculata and E. testacea.


Corneal accommodation in chick and pigeon.
We have investigated the role of changes in corneal radius of curvature in effecting accommodation in the bird's eye. It was found that in natural accommodation (measured by IR photoretinoscopy) changes of corneal radius of curvature (measured by IR photokeratometry) play an important role in both the chick and the pigeon. In the adult pigeon the cornea is indeed responsible for the largest part of natural accommodation (up to approx. 9 D). In this animal the corneal diameter (as seen from the optical axis of the eye) decreases in accommodation which can be taken to explain the change of corneal radius of curvature. In the chicken, corneal accommodation is combined with other mechanisms (total accommodative range 15-17 D, corneal accommodation about 8 D). The chicken's cornea is aspherical within the pupil area leading to large measurement variation in photokeratometry if the Purkinje images are not symmetrical to the pupillary axis.


Ablation of acardiac twin by alcohol injection into the intra-abdominal umbilical artery.
Twin reversed arterial perfusion sequence is a rare complication of monochorionic twinning, in which the normal pump twin perfuses the abnormal acardiac twin in a reversed fashion via an artery-to-artery placental anastomosis. Mortality in the normal twin exceeds 50% as a result of preterm labor, polyhydramnios, and congestive heart failure. A twin pregnancy complicated by the twin reversed arterial perfusion sequence developed early hemodynamic decompensation in the pump twin with increasing size of the acardiac twin. Ablation of the acardiac twin at 23 weeks' gestation was achieved successfully by injecting 1 mL of absolute alcohol into the intra-abdominal portion of the single umbilical artery. Direct ultrasound-guided intravascular injection of absolute alcohol is an easy and straightforward technique to occlude circulation to the acardiac twin. This vessel can be identified easily by color Doppler ultrasonography away from the main venous trunk. Selection of this target, rather than occlusion at the level of the umbilical cord, could reduce the risks of cord accidents and inadvertent intravenous injection of the ablative material.


Cognitive assessment of patients with minimal hepatic encephalopathy in Brazil.
Minimal hepatic encephalopathy is a syndrome caused by liver cirrhosis and accompanied by a broad spectrum of cognitive symptoms. The objective of the present study was to describe the prevalence of minimal hepatic encephalopathy in cirrhotic patients and to compare their cognitive performance with controls using standardized tests. Patients receiving medication or experiencing comorbidities associated with cognitive disorders were excluded. The final cohort was compared with a control-matched group using the Mini-Mental State Examination (MMSE), as well as Simple Drawing, Clock Drawing, Rey Auditory-Verbal Learning Test (RAVLT), Random Letter, Stroop, Trail-Making Test (TMT) A and B, Boston Naming, Category Verbal Fluency, Digit Span, Constructional Praxis, Processing Speed, and Similarities Tests. The results indicated no differences in the prevalence of cognitive complaints spontaneously reported by 29 patients with cirrhosis versus 22 healthy controls. The most affected tests included: MMSE (26.3 ± 2 vs. 28.1 ± 1.8 points; p = 0.004), learning (35.4 ± 9 vs. 41 ± 9.1 points; p = 0.041), retroactive interference (0.67 ± 0.22 vs. 0.84 ± 0.16 points; p = 0.004), and recognition (8.7 ± 2.6 vs. 11.2 ± 4.1 points; p = 0.024) in RAVLT, TMT-A (63.2 ± 29.3 vs. 47.6 ± 16.5 s; p = 0.029) and TMT-B (197.9 ± 88.1 vs. 146.8 ± 76.5 s; p = 0.03). No differences were observed with respect to age, gender, and education. In conclusion, MMSE proved to be a useful tool for detecting global cognitive impairment experienced by cirrhosis patients. Moreover, the most impaired cognitive functions were verbal episodic memory and information processing speed. These findings suggest that minimal hepatic encephalopathy represents a disorder that affects the medial temporal system and, possibly, the prefrontal cortex, and this requires further study.


Myeloma renal disease: presentation and outcome.
Renal disease can be the first presentation of multiple myeloma (MM) or develop during the disease process. To define the mode of presentation of MM to nephrologists and determine the association with patient characteristics and outcome. MM patients referred to a tertiary renal unit were studied retrospectively. Group I presented to nephrologists prior to MM diagnosis (n = 36); group II was referred to nephrology after diagnosis (n = 27), and group III was known only to haematology and never referred (n = 91). Age at presentation, gender, paraprotein type, need for dialysis, haematological and biochemical parameters, and survival were examined. Of the 154 MM patients, 23.4% presented with renal impairment (group I), 17.5% were referred to nephrology after MM diagnosis (group II) and 59.1% did not receive renal input (group III). On presentation, group I had a median serum creatinine (sCr) of 700 (range 341-1,023) micromol/l and 80% required dialysis. Although the median sCr on presentation for group II was 131 (range 103-373) micromol/l, median sCr on renal referral was 554 (range 181-807) micromol/l and 57% needed dialysis. In contrast, the median sCr on presentation for group III was only 99 (range 85-117) micromol/l. Group I was more anaemic (p < 0.001) and had higher beta(2)-microglobulin levels (p < 0.0001) on presentation compared to groups II and III. For groups I and II, the median survival after diagnosis (10.2 vs. 24.7 months, p = 0.11) and renal referral (10.5 vs. 20.0 months, p = 0.68) was not significantly different. Survival in myeloma renal disease remains poor regardless of the mode of presentation to nephrologists.


Role of Prophylactic Magnesium Supplementation in Prevention of Postoperative Atrial Fibrillation in Patients Undergoing Coronary Artery Bypass Grafting: a Systematic Review and Meta-Analysis of 20 Randomized Controlled Trials.
Several randomized trials have evaluated the efficacy of prophylactic magnesium (Mg) supplementation in prevention of post-operative atrial fibrillation (POAF) in patients undergoing cardiac artery bypass grafting (CABG). We aimed to determine the role of prophylactic Mg in 3 different settings (intraoperative, postoperative, intraoperative plus postoperative) in prevention of POAF. A systemic literature search was performed (until January 19, 2019) using PubMed, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials to identify trials evaluating Mg supplementation post CABG. Primary outcome of our study was reduction in POAF post CABG. We included a total of 2,430 participants (1,196 in the Mg group and 1,234 in the placebo group) enrolled in 20 randomized controlled trials. Pooled analysis demonstrated no reduction in POAF between the two groups (RR 0.90; 95% CI, 0.79-1.03; p=0.13; I2=42.9%). In subgroup analysis, significant reduction in POAF was observed with postoperative Mg supplementation (RR 0.76; 95% CI, 0.58-0.99; p=0.04; I2=17.6%) but not with intraoperative or intraoperative plus postoperative Mg supplementation (RR 0.77; 95% CI, 0.49-1.22; p = 0.27; I2=49% and RR 0.92; 95% CI, 0.68-1.24; p = 0.58; I2=51.8%, respectively). Magnesium supplementation, especially in the postoperative period, is an effective strategy in reducing POAF following CABG.


Synthesis and immunofluorescence assay of a new biotinylated paclitaxel.
7-(5'-Biotinylamidopropanoyl)paclitaxel was synthesised by chemical methods; its immunofluorescence assay and the cell uptake experiments were performed by use of human leukemia U937 cells. The results indicate that paclitaxel is arresting cell cycle at the G(2)M phase only.


Impact of lifestyle interventions on depressive symptoms in individuals at-risk of, or with, type 2 diabetes mellitus: A systematic review and meta-analysis of randomized controlled trials.
Depression affects one in four individuals with type 2 diabetes mellitus (T2DM). The impact of T2DM lifestyle interventions on depression is unclear. The aim of this analysis was to examine the influence of lifestyle interventions on depressive symptoms scores in individuals at-risk of or with T2DM. Major bibliographic databases were searched for studies published in English from 1990 to 2015. Meta-analysis was conducted by random-effects model. Nineteen studies were included in the meta-analyses. A significant reduction in depression scores was shown for lifestyle interventions in the pooled analysis (Standardized Mean Difference (SMD): -0.165; 95%CI: -0.265, -0.064; I(2):67.9%) and when limited to individuals with T2DM (SMD: -0.202; 95%CI: -0.288, -0.079; I(2):72.5%). In subgroup analyses the most effective intervention methods were face-to-face individual consultations (SMD: -0.241; 95%CI: -0.403, -0.078, I(2): 50.8%) with a duration of ≤6 months (SMD: -0.203; 95%CI: -0.381, -0.026, I(2):59.9%). Interventions were most effective when delivered four times a month (SMD: -0.247; 95%CI: -0.441, -0.053, I(2):76.3%). Lifestyle interventions were effective in improving depression among people with T2DM.


Deletion of the Ustilago maydis ortholog of the Aspergillus sporulation regulator medA affects mating and virulence through pheromone response.
Mating of compatible haploid cells of Ustilago maydis is essential for infection and disease development in the host. For mating and subsequent filamentous growth and pathogenicity, the transcription factor, prf1 is necessary. Prf1 is in turn regulated by the cAMP and MAPK pathways and other regulators like rop1 and hap1. Here we describe the identification of another putative Prf1 regulator, med1, the ortholog of the Aspergillus nidulans medusa (medA) transcription factor and show that it is required for mating and full virulence in U. maydis. med1 deletion mutants show both pre- and post-mating defects and are unresponsive to external pheromone. The expression of prf1 is down-regulated in Δmed1 compared to the wild type, suggesting that med1 is upstream of prf1. Additionally, indicative of a role in secondary metabolism regulation, deletion of the med1 gene de-represses the production of glycolipids in U. maydis.


Designing persuasive health education for patients seeking unproven stem cell interventions.
Misinformation among clinics advertising unproven stem cell interventions (SCIs) is pervasive and has resulted in patient and societal harms. Most bioethics commentaries have centered on advancing regulatory approaches to curtail the supply side of the market, but insufficient attention has been paid to considering strategies influencing patient demand. In this article, we offer an ethical justification for the design and deployment of persuasive patient education on unproven SCIs and distinguish it from didactic and manipulative education frames. Persuasive education should aim to correct and inoculate against misinformation about unproven SCIs and instill a sense of caution among patients considering experimental interventions outside of a clinical trial. We outline various communication strategies to effectively correct or inoculate against SCI misinformation. The stem cell community needs to invest in understanding patients' informational sources, attitudes, and beliefs about SCIs to develop and implement evidence-based persuasive education to promote informed decision-making about these therapies.


Leukocyte surface antigens in patients with multiple sclerosis.
Lymphocyte phenotypes have been measured in 20 normal females, 19 normal males, 3 females with acute exacerbations of MS and 21 females and 17 males with chronic progressive MS. Using a FACS IV, lymphocytes were gated by light scattering properties, and fluorescence was analyzed using a log amplifier. No abnormalities were found in the 3 females with acute exacerbations. In male patients the percentage of OKT8 was significantly reduced, the percentage of OKT4 was significantly increased, and the ratio of OKT4/T8 was increased. In females with chronic progressive disease the percentage of OKT8 was not statistically altered, but the percentage of OKT4 and the OKT4/T8 ratio were elevated. Interpretation of these findings requires more extensive study in control populations.


Finite element method (FEM) analysis of the force systems produced by asymmetric inner headgear bows.
Extra-oral traction appliances were introduced more than a century ago and continue to be used to produce orthopaedic and/or dental changes in the maxilla. While force systems produced by asymmetric outer bows have been studied extensively, the force systems produced by asymmetric inner bows have been overlooked. To analyse the forces acting on the maxillary first molars: when the size of one bayonet bend is increased; when the point of application of the distalising force on the inner bow is moved to one side; when one molar is displaced palatally. Four FEM models of cervical headgear attached to maxillary first molars were designed in SolidWorks 2010 and transferred to an ANSYS Workbench Ver. 12.1. Model 1, each molar was 23 mm from the midpalatal line and the inner bow was symmetrical; Model 2, the left molar was displaced 4 mm towards the midpalatal line and the inner bow was symmetrical; Model 3, the molars were equidistant (23 mm) from the midpalatal line, but the left molar was engaged by a 2 mm larger bayonet bend; Model 4, the molars were equidistant (23 mm) from the midpalatal line but the join between the inner and outer bows was displaced 2 mm towards the left molar. In all FEM models, a 2N force was applied to the inner bow at the join between inner and outer bows and the energy transmitted to the teeth and the von Mises stresses on the molar PDLs were assessed. There were marked differences in the strain energy on the teeth and the von Mises stresses on their PDLs. A 14 to 20 per cent increase in energy and force was produced on the tooth closer to the symmetric plane of the headgear. In addition, the increase in energy produced a 30 to 62 per cent increase in the von Mises stresses within the PDLs. Small asymmetries in molar position, the size of a bayonet bend and the point of application of a force on an inner bow resulted in asymmetrical forces on the molars. These forces were higher on the molar closer to the symmetric plane of the headgear.


Phosphorylation of nuclear proteins in a chronic, uncontrollable stress model.
The changes in the phosphorylation of nuclear proteins isolated from cell nuclei of hypothalamus, cerebral cortex, and hippocampus of rats subjected for varying times to a chronic uncontrollable stress model were investigated. A brief duration (24 h) induced a substantial increase of the phosphorylation of nuclear proteins isolated from hypothalamus (270%), from the cerebral cortex (ca. 230%), and from the hippocampus (ca. 160%). More extended durations (96 and 168 h) were accompanied by a statistically significant decrease in the degree of phosphorylation of proteins.


Cinchona-Diaminomethylenemalononitrile Organocatalyst for the Highly Enantioselective Hydrophosphonylation of Ketones and Enones.
The use of diaminomethylenemalononitrile (DMM) organocatalyst to promote the challenging 1,2-hydrophosphonylation of simple ketones and enones, which are also called α,β-unsaturated ketones, is proposed and validated. This reaction provided the corresponding chiral α-hydroxy phosphonates in high to excellent yields and with enantioselectivity up to 96% ee.


The role of Drosophila mismatch repair in suppressing recombination between diverged sequences.
DNA double-strand breaks (DSBs) must be accurately repaired to maintain genomic integrity. DSBs can be repaired by homologous recombination (HR), which uses an identical sequence as a template to restore the genetic information lost at the break. Suppression of recombination between diverged sequences is essential to the repair of DSBs without aberrant and potentially mutagenic recombination between non-identical sequences, such as Alu repeats in the human genome. The mismatch repair (MMR) machinery has been found to suppress recombination between diverged sequences in murine cells. To test if this phenomenon is conserved in whole organisms, two DSB repair systems were utilized in Drosophila melanogaster. The DR-white and DR-white.mu assays provide a method of measuring DSB repair outcomes between identical and diverged sequences respectively. msh6(-/-) flies, deficient in MMR, were not capable of suppressing recombination between sequences with 1.4% divergence, and the average gene conversion tract length did not differ between msh6(-/+) and msh6(-/-)flies. These findings suggest that MMR has an early role in suppressing recombination between diverged sequences that is conserved in Drosophila.


Essential oil composition and antimicrobial activity of Vismia macrophylla leaves and fruits collected in Táchira-Venezuela.
Hydrodistillation of Vismia macrophylla Kunth (Hypericaceae) leaves (L) and fruits (F) yielded 1.3%, v/w, and 5.6%, v/w, of essential oil, respectively. GC and GC-MS analyses showed the presence of twenty-four (96.4%, L) and thirty-one (96.6%, F) components, respectively. Major compounds identified in the leaf oil were γ-bisabolene (44.4%) and β-bisabolol (14.9%), while those in the fruit oil were germacrene-D (12.1%), 6-cadinene (10.7%) and γ-bisabolene (22.3 %). Oil obtained from the fruits of V. macrophylla showed antibacterial activity against Gram-positive (S. aureus ATCC 25923 and E. faecalis ATCC 29212) as well as Gram-negative bacteria (E. coli ATCC 25922), with MIC values ranging from 150 μL/mL to 740 μL/mL. Oil obtained from leaves were active only on the Gram-positive bacteria S. aureus (100 μL/mL) and E. faecalis (500 μL/mL), but also showed antiyeast activity against Candida albicans CDC-B385 and C. krusei ATCC 6258 (600 μL/mL, each).


Obtaining a new empirical (n,2n) cross section formula using Flerov and Talyzin non-elastic cross sections at 14-15 MeV.
The knowledge of (n,2n) cross sections is required in shielding and breeding calculations. It's also important, in nuclear reactor applications, for neutron dosimetry research. In nuclear reaction mechanism, (n,2n) reaction channel is the dominant reaction for medium and heavy mass nuclei at 14 MeV energy range. The empirical and semi-empirical (n,2n) reaction cross sections have been investigated by many authors, but theoretical calculations have not been adequate because of the character of the nuclear structure is not exactly known. In this work, a new empirical formula has been proposed to calculate the (n,2n) reaction cross sections at 14-15 MeV neutron incident energy. In the calculations different fitting method have been used to obtain cross-section formula for target nuclei in the range 14 ≤ A ≤ 241 mass number. The (n,2n) experimental cross sections have been taken from EXFOR nuclear data library. In this new formula, the Flerov and Talyzin expression for the inelastic cross section σne was used to fit the experimental (n,2n) cross sections. It has been observed that the obtained formulas give quite coherent results with the experimental data.


Uptake of human pharmaceuticals in bull sharks (Carcharhinus leucas) inhabiting a wastewater-impacted river.
The presence of human pharmaceuticals in sewage-impacted ecosystems is a growing concern that poses health risks to aquatic wildlife. Despite this, few studies have investigated the uptake of active pharmaceutical ingredients (APIs) in aquatic organisms. In this study, the uptake of 9 APIs from human drugs was examined and compared in neonate bull sharks (Carcharhinus leucas) residing in pristine (Myakka River) and wastewater-impacted (Caloosahatchee River) tributaries of Florida's Charlotte Harbor estuary. The synthetic estrogen used in human contraceptives (17α-ethynylestradiol) and 6 of the selective serotonin/norepinephrine reuptake inhibitors (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine) used in human antidepressants were observed at detectable and, in some cases, quantifiable levels in plasma of Caloosahatchee River sharks. Comparatively, only venlafaxine was detected in the plasma of a single Myakka River shark at a level below the limit of quantitation. These results suggest that sharks residing in wastewater-impacted habitats accumulate APIs, a factor that may pose special risks to C. leucas since it is one of few shark species to regularly occupy freshwater systems. Further research is needed to determine if the low levels of API uptake observed in Caloosahatchee River bull sharks pose health risks to these animals.


Aortic root dilatation in athletic population.
Remodeling of the aortic root may be expected to occur in athletes as a consequence of hemodynamic overload associated with exercise training; however, there are few data reporting its presence or extent. This review reports the current knowledge regarding the prevalence, upper limits, and clinical significance of aortic remodeling induced by athletic training. Several determinants impact aortic dimension in healthy, nonathletic individuals, including height, body size, age, sex, and blood pressure. Of these factors, anthropometric variables have the greatest impact. In athletes, the effect of exercise training appears to have only a modest additional influence on aortic dimension, although previous studies have produced some conflicting results. Specifically, data derived from the largest available athletic cohort suggest that the most hemodynamically intense endurance disciplines (eg, cycling and swimming) are associated with a significant but mild increase in aortic dimensions. Power disciplines, instead, (eg, weight lifting, throwing events) have only trivial, if any, impact. In contrast, selected data from a different athlete population suggest a more significant dimensional aortic remodeling in strength-trained individuals. In our experience, the 99th percentile value of aortic root diameter corresponds to 40 mm in males and 34 mm in females, which can reasonably be considered the upper limits of physiologic aortic root remodeling. However, a small proportion of apparently healthy male athletes (approximately 1%) show aortic enlargement above the upper limits, in the absence of systemic disease (ie, Marfan syndrome). Athletes presenting with aortic enlargement may demonstrate a further dimensional increase in midlife leading to clinically relevant aortic dilatation. Occasionally, dilation may be severe enough to warrant consideration for surgical treatment. Therefore, serial clinical and echocardiographic evaluations are recommended in athletes when aortic root exceeds the sex-specific thresholds.


Comparison of thoracic and lumbar epidural infusions of bupivacaine and fentanyl for post-thoracotomy analgesia.
Epidural analgesia, via either a thoracic or lumbar route, is commonly used to provide postoperative analgesia following thoracotomy for pulmonary resection, but little data indicate which location is better in terms of postoperative analgesia, side effects, or associated complications. In this study, 45 patients, who were scheduled to have epidural analgesia and undergo a lateral thoracotomy, were randomized to receive either a thoracic or a lumbar catheter. Pain assessments and routine clinical data were recorded to determine if either thoracic or lumbar epidural catheters provided superior analgesia, fewer side effects, or fewer complications. This study found no statistical difference in pain relief or side effects between lumbar and thoracic epidural analgesia for post-thoracotomy pain. An increased infusion rate (6.4 +/- 1.9 v 5.1 +/- 1.4 mL/h, P = 0.02) was required in the lumbar group to achieve equivalent analgesic levels.


Genome Sequence of Clostridium tyrobutyricum ATCC 25755, a Butyric Acid-Overproducing Strain.
Clostridium tyrobutyricum ATCC 25755 is an efficient producer of butyric acid. Here we report a 3.01-Mb assembly of its genome sequence and other useful information, including the coding sequences (CDSs) responsible for an alternative pathway leading to acetate synthesis as well as a series of membrane transport systems.


Prostate-specific antigen levels and density in the internal and external glands of the prostate in benign prostatic hyperplasia patients with normal or gray-zone PSA levels.
In patients with benign prostatic hyperplasia (BPH) showing normal prostate-specific antigen (PSA) levels (normal PSA group) and those with BPH showing gray-zone PSA levels (gray-zone PSA group), we assessed PSA levels secreted from the internal and external glands. We performed transurethral enucleation of the prostate (TUE) in 102 BPH patients with normal PSA and 59 BPH patients with gray-zone PSA at our department from 1999 to 2001. Preoperatively and approximately 6 months postoperatively, we measured serum PSA levels and determined prostatic volumes via transrectal ultrasonography (TRUS) to calculate PSA levels secreted from the internal and external glands as well as various PSA density (PSAD) values. The total PSA level was 1.8 and 6.1 ng/ml in the normal and gray-zone PSA groups, respectively. The PSA level of the external gland was 0.6 and 0.8 ng/ml and the PSAD of the external gland was 0.07 and 0.08 ng/ml/cm(3) in the normal and gray-zone PSA groups, respectively. The internal gland PSA was 1.3 and 5.4 ng/ml and the internal gland PSAD value was 0.11 and 0.30 ng/ml/cm(3) in the normal and gray-zone PSA groups, respectively. Our results demonstrated that increased PSA levels in BPH cases with gray-zone PSA were attributable to increased PSA secreted from the internal gland rather than from the external gland. In our opinion, the determination of PSA and PSAD of the internal and external gland may be clinically significant in the future.


NEDD9 crucially regulates TGF-β-triggered epithelial-mesenchymal transition and cell invasion in prostate cancer cells: involvement in cancer progressiveness.
NEDD9 is one of the Crk-associated substrate (Cas) family proteins that mediate downstream signaling processes including cytoskeletal organization, cell-cycle and tumorigenesis. While NEDD9 plays a crucial role in epithelial-mesenchymal transition (EMT), the functional mechanism underlying NEDD9-mediated EMT in prostate cancer (PCa) remains uncertain. The expression levels of NEDD9 and its downstream molecules in PC-3, LNCaP, and VCaP cells exposed to transforming growth factor-β (TGF-β) were determined by western blotting. The invasion of these cells with ectopic overexpression of NEDD9 or silencing of NEDD9 expression was measured by transwell invasion assay. Human tissue samples comprising 45 PCa specimens and ten specimens of normal prostatic tissue were used for immunohistochemical (IHC) analysis of NEDD9 expression. Both NEDD9 and its downstream signaling molecules associated with EMT were strongly induced by TGF-β in PCa cells. PC-3 cells with stable overexpression of NEDD9 had a mesenchymal phenotype and significantly enhanced cell invasion, despite their decreased cell proliferation. Knockdown of endogenous NEDD9 expression completely diminished TGF-β-triggered tumor invasion in several PCa cell lines. The IHC data revealed a significant positive correlation between the NEDD9 staining score and tumor aggressiveness (e.g., Gleason grade, serum PSA level). The NEDD9 staining score in primary PCa with bone metastasis was significantly higher than that in PCa without metastasis. NEDD9 may be a key mediator involved in TGF-β-mediated EMT and cell motility in PCa cells and a novel target in the treatment of metastatic PCa and prevention of spread of localized PCa cells to other organs.


Polarization induced self-doping in epitaxial Pb(Zr0.20Ti0.80)O3 thin films.
The compensation of the depolarization field in ferroelectric layers requires the presence of a suitable amount of charges able to follow any variation of the ferroelectric polarization. These can be free carriers or charged defects located in the ferroelectric material or free carriers coming from the electrodes. Here we show that a self-doping phenomenon occurs in epitaxial, tetragonal ferroelectric films of Pb(Zr0.2Ti0.8)O3, consisting in generation of point defects (vacancies) acting as donors/acceptors. These are introducing free carriers that partly compensate the depolarization field occurring in the film. It is found that the concentration of the free carriers introduced by self-doping increases with decreasing the thickness of the ferroelectric layer, reaching values of the order of 10(26) m(-3) for 10 nm thick films. One the other hand, microscopic investigations show that, for thicknesses higher than 50 nm, the 2O/(Ti+Zr+Pb) atomic ratio increases with the thickness of the layers. These results suggest that the ratio between the oxygen and cation vacancies varies with the thickness of the layer in such a way that the net free carrier density is sufficient to efficiently compensate the depolarization field and to preserve the outward direction of the polarization.


Real-world study of the effectiveness of BBIBP-CorV (Sinopharm) COVID-19 vaccine in the Kingdom of Morocco.
The Kingdom of Morocco approved BBIBP-CorV (Sinopharm) COVID-19 vaccine for emergency use on 22 January 2021 in a two-dose, three-to-four-week interval schedule. We conducted a retrospective cohort study to determine real-world BBIBP-CorV vaccine effectiveness (VE) against serious or critical hospitalization of individuals RT-PCR-positive for SARS-CoV-2 during the first five months of BBIBP-CorV use in Morocco. The study was conducted among adults 18-99 years old who were tested by RT-PCR for SARS-CoV-2 infection between 1 February and 30 June 2021. RT-PCR results were individually linked with outcomes from the COVID-19 severe or critical hospitalization dataset and with vaccination histories from the national vaccination registration system. Individuals with partial vaccination (< 2 weeks after dose two) or in receipt of any other COVID-19 vaccine were excluded. Unadjusted and adjusted VE estimates against hospitalization for serious or critical illness were made by comparing two-dose vaccinated and unvaccinated individuals in logistic regression models, calculated as (1-odds ratio) * 100%. There were 348,190 individuals able to be matched across the three databases. Among these, 140,892 were fully vaccinated, 206,149 were unvaccinated, and 1,149 received homologous BBIBP-CorV booster doses. Unadjusted, full-series, unboosted BBIBP-CorV VE against hospitalization for serious or critical illness was 90.2% (95%CI: 87.8-92.0%). Full-series, unboosted VE, adjusted for age, sex, and calendar day of RT-PCR test, was 88.5% (95%CI: 85.8-90.7%). Calendar day- and sex-adjusted VE was 96.4% (95%CI: 94.6-97.6%) for individuals < 60 years, and was 53.3% (95%CI: 39.6-63.9%) for individuals 60 years and older. There were no serious or critical illnesses among BBIBP-CorV-boosted individuals. Effectiveness of Sinopharm's BBIBP-CorV was consistent with phase III clinical trial results. Two doses of BBIBP-CorV was highly protective against COVID-19-associated serious or critical hospitalization in working-age adults under real-world conditions and moderately effective in older adults. Booster dose vaccination was associated with complete protection, regardless of age, although only a small proportion of subjects received booster doses.


A novel anti-thrombotic heparinoid (Org 10172) devoid of bleeding inducing capacity: a survey of its pharmacological properties in experimental animal models.
The pharmacological profile of Org 10172, a mixture of sulphated glycosaminoglycorunans derived from hog intestinal mucosa, has been assessed in experimental thrombosis and bleeding models in rats and compared with heparin USP. Org 10172 inhibited thrombus formation in arterio-venous shunts dose dependently, the dose required for 50% inhibition (ID50) of thrombus formation was 40 anti-Xa units/kg i.v. The ID50 for heparin USP was 70 anti-Xa units/kg i.v. Org 10172 hardly increased bleeding in doses upto 1600 anti-Xa units/kg i.v., whereas heparin USP dose dependently increased bleeding from 90 anti-Xa units/kg i.v. onwards. The benefit (anti-thrombotic)/risk (bleeding) ratio of Org 10172 was therefore considerably better than that of heparin USP. The improved profile of Org 10172 towards bleeding might be caused by differences in the interaction with blood platelets in comparison with heparin USP. Org 10172 had less effect on the platelet content in thrombi than heparin USP. Org 10172 did not inhibit collagen induced release of serotonin in contrast to heparin USP. Org 10172 inhibited factor Xa induced aggregation of rabbit platelets but only at anti-Xa levels which were fifteen times higher than for heparin USP. In contrast to heparin USP Org 10172 had only a very weak effect on the activated partial thromboplastin time (APTT) ex vivo.


Successful Systemic Lysis Therapy of a Floating Carotid Thrombus in an Acute Stroke Patient with Known Immune Thrombocytopenia (ITP) on Ongoing Eltrombopag Therapy and Acute COVID-19 Infection: a Case Report.
Patients with immune thrombocytopenia (ITP) under eltrombopag therapy are vulnerable to thrombotic disbalance, both due to the disease itself and therapy-related hypercoagulability. Vascular events such as the development of a free-floating carotid thrombus are known rare complications of acute COVID-19 infections due to endothelial inflammation and presumptive underlying hypercoagulable state. In patients at risk, the onset of new focal neurological symptoms should prompt immediate angiographic diagnostics and, if necessary, appropriate treatment. Here, we report a case of a 38-year-old female with a medical history of ITP and the presence of COVID-19 infection presenting an acute sensorimotor hemiparesis of the right side while on eltrombopag therapy. Initial CT angiography revealed a free-floating thrombus in the left common carotid artery. Upon admission, the patient's platelet count was significantly elevated at 896 × 109/l. After systemic lysis therapy, the thrombus was fully dissolved. Follow-up diffusion-weighted imaging revealed multilocular cortical infarction of the left MCA territory. The patient soon recovered and was discharged with residual mild sensorimotor deficits in the right arm. Eltrombopag was paused at admission, and the patient's platelet count was quickly returning to normal. She was discharged with a daily intake of acetylsalicylic acid, a reduced daily dose of eltrombopag, and weekly monitoring of her platelet count for the next three months. This unique case highlights the need for caution in patients at vascular risk who contract COVID-19 and discusses thrombocytic derailment under thrombopoietin receptor agonist therapy in the context of an acute COVID-19 infection.


Outcomes in pediatric epilepsy: seeing through the fog.
To identify clinical and predictive features of outcome in cryptogenic epilepsy in pediatric neurology practice, the medical records of all patients with cryptogenic epilepsy (as defined by the International League Against Epilepsy) in a single pediatric neurology practice over a 12-year interval with at least 2 years of follow-up were systematically and retrospectively reviewed. Review revealed 60 children with cryptogenic epilepsy: 32 (53.3%) males, 11 (18.3%) prior febrile seizure, 9 (15.0%) developmental delay at onset, and 38 (63.3%) placement in regular classes. Twenty-two (35.7%) had generalized seizures. Mean follow-up after initiating antiepileptic medication was 53 months (range 24-128 months). Four (6.7%) were intractable; 4 (6.7%) had very poor outcomes; 8 (13.3%) had poor outcomes; 44 (73.3%) were well controlled. Sixteen (26.7%) and 31 (51.7%) had seizure recurrence within the last 12 and 24 months, respectively. Twenty-nine (48.3%) were seizure-free for at least 24 months. Factors associated with a poor outcome include seizure recurrence in the 6- to 12-month interval after therapy initiation (P = 0.006) and developmental delay at onset (P = 0.023). This case series suggests that children with cryptogenic epilepsy tend to have a favorable outcome. Seizure recurrence in the first months after therapy initiation and developmental delay apparent at onset are predictive of poor outcome.


Understanding the task demands for powered wheelchair driving: a think-aloud task analysis.
Powered wheelchair use promotes participation in individuals with limited mobility, however training is required for safe and effective use. There is limited evidence on the task demands of powered wheelchair use to inform an evidence-based skills training programme. To conduct a systematic exploration of the task demands of indoor powered wheelchair use to identify frequently used skills, abilities, and knowledge. We used a two-phased think aloud process to conduct a task analysis of powered wheelchair use with experienced powered wheelchair users (n = 5) and expert clinicians (n = 5). Participants completed seven indoor driving tasks while speaking aloud (concurrent think aloud) and subsequently engaged in a structured qualitative interview to discuss skills, abilities, and knowledge used across each of the seven tasks (retrospective think aloud). We used directed content analysis to map the skills and abilities to the ICF framework and conventional content analysis to develop thematic areas of knowledge used while operating a powered wheelchair. One-hundred and ten (110) distinct skills and abilities were identified and mapped to the ICF; 80 in the Body Structures and Functions domain, and 30 in the Activities and Participation domain. Approximately 50% of skills and abilities were mental functions. Four thematic knowledge domains were identified: knowledge of self, environment, wheelchair, and task. Powered wheelchair use is complex and requires a variety of skills and abilities from all areas of human functioning, in addition to a wide range of knowledge. Training programmes should address a range of areas of skill development.IMPLICATIONS FOR REHABILITATIONPowered wheelchair use is a complex skill; training should develop skills from all.Domains of the ICF, including mental and physical functions.A range of knowledge is used while operating a powered wheelchair; training programs.Should include the development and application of necessary knowledge.Clinicians may consider a range of factors when assessing suitability for powered.Wheelchair user, however should acknowledge that while the range of skills idenotified.May be useful, they may not be critical for success in powered wheelchair use.


Tetraparental rabbits chimeric for their lymphoid system--II. Idiotype expression.
In order to test some aspects of the network theory of "idiotype-anti-idiotype" interactions, we studied the idiotypic specificities of anti-DNP antibodies produced by tetraparental rabbits, chimeric for their lymphoid system, under two different experimental conditions. In the first, the tetraparental rabbits were simply immunized against the hapten and we observed that the antibodies, totally different in their allotypy, produced by the lymphocytes of the two constitutive parental strains remained idiotypically independent in three cases out of three. In the second experimental regimen, the tetraparental rabbits underwent an anti-anti-idiotypic immunization before the anti-hapten one. In two out of the four cases studied we observed that anti-DNP antibodies different in their a- and b-series allotypic specificities can bear at least related idiotypic specificities.


Liver expression of Nrf2-related genes in different liver diseases.
The KEAP1-Nrf2 antioxidant signaling pathway is important in protecting liver from various insults. However, little is known about the expression of Nrf2-related genes in human liver in different diseases. This study utilized normal donor liver tissues (n=35), samples from patients with hepatocellular carcinoma (HCC, n=24), HBV-related cirrhosis (n=27), alcoholic cirrhosis (n=5) and end-stage liver disease (n=13). All of the liver tissues were from the Oriental Liver Transplant Center, Beijing, China. The expressions of Nrf2 and Nrf2-related genes, including its negative regulator Kelch-like ECH-associated protein 1 (KEAP1), its targeted gene NAD(P)H-quinone oxidoreductase 1 (NQO1), glutamate-cysteine ligase catalytic subunit (GCLC) and modified subunit (GCLM), heme oxygenase 1 (HO-1) and peroxiredoxin-1 (PRDX1) were evaluated. The expression of Nrf2 was decreased in HCC, increased in alcoholic cirrhosis and end-stage liver disease. The expression of KEAP1 was increased in all of the liver samples. The most notable finding was the increased expression of NQO1 in HCC (18-fold), alcoholic cirrhosis (6-fold), end-stage liver disease (5-fold) and HBV-related cirrhosis (3-fold). Peri-HCC also had 4-fold higher NQO1 mRNA as compared to the normal livers. GCLC mRNA levels were lower only in HCC, as compared to the normal livers and peri-HCC tissues. GCLM mRNA levels were higher in HBV-related cirrhosis and end-stage liver disease. HO-1 mRNA levels were increased in all liver tissues except for HCC. Peri-HCC had higher PRDX1 mRNA levels compared with HCC and normal livers. Nrf2 and Nrf2-related genes are aberrantly expressed in the liver in different diseases and the increase of NQO1 was the most notable finding, especially in HCC.


Intralipid removal from plasma of uraemic and intensive care patients.
The removal rates from plasma of Intralipid and (125)I-albumin, simultaneously injected i.v., were analyzed in 10 chronic renal failure (CRF) patients. The results were compared with 9 intensive care unit (ICU) patients and five healthy subjects as controls. The fractional removal rates of Intralipid (k2) were significantly lower for the CRF patients compared to both ICU patients and healthy subjects. The initial plasma concentration of Intralipid, calculated by extrapolation of the elimination curve back to zero-time (y0), showed significantly higher values for CRF patients and healthy subjects compared to ICU patients. Removal curves expressed as ratios between Intralipid and (125)I-albumin paralleled the elimination curves for Intralipid, which suggests that the slope of the curves depends on Intralipid removal and not on leakage of macromolecules from the circulation. The very low initial plasma concentration of Intralipid in the ICU patients cannot be explained by a hyperdynamic circulation, but may be attributed to a rapid first passage disappearance of Intralipid from plasma into tissues such as the pulmonary vasculature.


A network analysis of DSM-5 posttraumatic stress disorder symptoms and correlates in U.S. military veterans.
Recent developments in psychometrics enable the application of network models to analyze psychological disorders, such as PTSD. Instead of understanding symptoms as indicators of an underlying common cause, this approach suggests symptoms co-occur in syndromes due to causal interactions. The current study has two goals: (1) examine the network structure among the 20 DSM-5 PTSD symptoms, and (2) incorporate clinically relevant variables to the network to investigate whether PTSD symptoms exhibit differential relationships with suicidal ideation, depression, anxiety, physical functioning/quality of life (QoL), mental functioning/QoL, age, and sex. We utilized a nationally representative U.S. military veteran's sample; and analyzed the data from a subsample of 221 veterans who reported clinically significant DSM-5 PTSD symptoms. Networks were estimated using state-of-the-art regularized partial correlation models. Data and code are published along with the paper. The 20-item DSM-5 PTSD network revealed that symptoms were positively connected within the network. Especially strong connections emerged between nightmares and flashbacks; blame of self or others and negative trauma-related emotions, detachment and restricted affect; and hypervigilance and exaggerated startle response. The most central symptoms were negative trauma-related emotions, flashbacks, detachment, and physiological cue reactivity. Incorporation of clinically relevant covariates into the network revealed paths between self-destructive behavior and suicidal ideation; concentration difficulties and anxiety, depression, and mental QoL; and depression and restricted affect. These results demonstrate the utility of a network approach in modeling the structure of DSM-5 PTSD symptoms, and suggest differential associations between specific DSM-5 PTSD symptoms and clinical outcomes in trauma survivors. Implications of these results for informing the assessment and treatment of this disorder, are discussed.


Molecular studies of BKCa channels in intracranial arteries: presence and localization.
Large conductance calcium-activated potassium channels (BK(ca)) are crucial for the regulation of cerebral vascular basal tone and might be involved in cerebral vasodilation relevant to migraine and stroke. We studied the differential gene expression of mRNA transcript levels and protein expression of the BK(Ca) channel in rat basilar, middle cerebral, and middle meningeal arteries by reverse transcription polymerase chain reaction (RT-PCR), quantitative real-time PCR, and Western blotting. Distribution patterns were investigated using in situ hybridization and immunofluorescence studies. RT-PCR and quantitative real-time PCR detected the expression of the BK(Ca) channel mRNA transcript in rat basilar, middle cerebral, and middle meningeal arteries, with the transcript being expressed more abundantly in rat basilar arteries than in middle cerebral and middle meningeal arteries. Western blotting detected the BK(Ca) channel protein in rat basilar and middle cerebral arteries. In situ hybridization and immunofluorescence studies confirmed that the BK(Ca) channel mRNA and protein expression was localized to smooth muscle cells in all three intracranial arteries. The data thus suggest the presence and localization of both mRNA and protein expression of the BK(Ca) channel in the smooth muscle cell layer in rat basilar, middle cerebral, and middle meningeal arteries.


Calcium dependent and independent cytokine synthesis by air pollution particle-exposed human bronchial epithelial cells.
Exposure to ambient air pollution particles with a diameter of <10 microm (PM(10)) has been associated with increased cardiopulmonary morbidity and mortality. We have shown that human bronchial epithelial cells (HBECs) exposed to PM(10) produce pro-inflammatory mediators that contribute to a local and systemic inflammatory response. Changes in intracellular calcium concentrations ([Ca(2+)](i)) have been demonstrated to regulate several functions of the airway epithelium including the production of pro-inflammatory mediators. The aim of the present study was to determine the nature and mechanism of calcium responses induced by PM(10) in HBECs and its relationship to cytokine synthesis. Primary HBECs were exposed to urban air pollution particles (EHC-93) and [Ca(2+)](i) responses were measured using the fluoroprobe (Fura-2). Cytokine levels were measured at mRNA and protein levels using real-time PCR and ELISA. PM(10) increased [Ca(2+)](i) in a dose-dependent manner. This calcium response was reduced by blocking the influx of calcium into cells (i.e. calcium-free medium, NiCl(2), LaCl(3)). PM(10) also decreased the activity of calcium pumps. PM(10) increased the production of IL-1beta, IL-8, GM-CSF and LIF. Preincubation with intracellular calcium chelator (BAPTA-AM) attenuated IL-1beta and IL-8 production, but not GM-CSF and LIF production. We conclude that exposure to PM(10) induces an increase in cytosolic calcium and cytokine production in bronchial epithelial cells. Our results also suggest that PM(10) induces the production of pro-inflammatory mediators via either intracellular calcium-dependent (IL-1beta, IL-8) or -independent (GM-CSF, LIF) pathways.


A new three way decision making technique for supplier selection in logistics service value Cocreation under intuitionistic double hierarchy linguistic term set.
In today's business world, choosing a logistics supplier is a critical factor for companies to improve operational efficiency and reduce business costs. With the development of market economy, it is very difficult for companies to choose a suitable logistics provider according to specific rules. Therefore, this study proposes a new three-way decision making (TWD) technique for supplier selection in logistics service value creation. For this, we first develop a new concept called intuitionistic double hierarchy linguistic term set (IDHLTSs) that can describe uncertainty and ambiguity in a more flexible way. Some Hamacher aggregation operators for collecting IDHLTSs information and its basic aspect are proposed. The unknown weight vector for decision experts and criteria is determined by using entropy measures. In addition, the conditional probability is determined using TOPSIS which makes the decision making process more rational. And the decision result is conducted according to minimum loss principle. Finally, an example of 3 PL supplier selection in the logistics service value co-creation environment and comparison is given to validate and demonstrate the effectiveness of the developed method.


Urokinase infusion for severe intraventricular haemorrhage.
The purpose of this study was to explore in patients with intraventricular haematomas the effectiveness and complication rate of a treatment protocol including standard ventriculostomy and application of urokinase via the catheter. Our series includes 16 patients with severe CT-diagnosed intraparenchymal and predominantly intraventricular haemorrhages. In all cases, ventricular drainage was performed. Urokinase treatment was started immediately with intraventricular infusions of 10,000 U urokinase in 5 ml sterile physiological saline every 12 hours. Twelve patients had an excellent outcome, three good and one poor. There were no complications related to urokinase therapy. Side effects of the infusion volume were profuse sweating and headache which were present at 10 ml total infusion volume, but disappeared after reduction to 5 ml. A group of five patients with comparable lesions treated only with ventriculostomy served as controls. Two of them had a good outcome, two a poor one and one died. The late results in the urokinase-treated group were also favourable. Only one of the patients developed hydrocephalus and was shunted. In the control group, two patients required shunting for delayed hydrocephalus. We conclude that this protocol for urokinase treatment is safe and effective and can be used in almost all patients with intracerebroventricular haemorrhage.


Functional and structural abnormalities in patients with dilated cardiomyopathy.
Passive diastolic properties of the left ventricle were determined in 10 control subjects and 12 patients with dilated cardiomyopathy. Simultaneous left ventricular angiography and high fidelity pressure measurements were performed in all patients. Left ventricular chamber stiffness was calculated from left ventricular pressure-volume and myocardial stiffness from left ventricular stress-strain relations with use of a viscoelastic model. Patients with dilated cardiomyopathy were classified into two groups according to the diastolic constant of myocardial stiffness (beta). Group 1 consisted of seven patients with a normal constant of myocardial stiffness less than or equal to 9.6 (normal range 2.2 to 9.6) and group 2 of 5 patients with a beta greater than 9.6. Structural abnormalities (percent interstitial fibrosis, fibrous content) in patients with dilated cardiomyopathy were assessed by morphometry from right ventricular endomyocardial biopsies. Heart rate was similar in the three groups. Left ventricular end-diastolic pressure was significantly greater in patients with cardiomyopathy (18 mm Hg in group 1 and 22 mm Hg in group 2) than in the control patients (10 mm Hg). Left ventricular ejection fraction was significantly lower in groups 1 (37%) and 2 (36%) than in the control patients (66%). Left ventricular muscle mass index was significantly increased in both groups with cardiomyopathy. The constant of chamber stiffness (beta*) was slightly although not significantly greater in groups 1 and 2 (0.58 and 0.58, respectively) than in the control group (0.35). The constant of myocardial stiffness beta was normal in group 1 (7.0; control group 6.9, p = NS) but was significantly increased in group 2 (23.5). Interstitial fibrosis was 19% in group 1 and 43% (p less than 0.001) in group 2 (normal less than or equal to 10%). There was an exponential relation between both diastolic constant of myocardial stiffness (beta) and interstitial fibrosis (IF) (r = 0.95; p less than 0.001) and beta and fibrous content divided by end-diastolic volume index (r = 0.93; p less than 0.001). It is concluded that myocardial stiffness can be normal in patients with dilated cardiomyopathy despite severely depressed systolic function. Structural alterations of the myocardium with increased amounts of fibrous tissues are probably responsible for the observed changes in passive elastic properties of the myocardium in patients with dilated cardiomyopathy. The constant of myocardial stiffness (beta) helps to identify patients with severe structural alterations (group 2), representing possibly a more advanced stage of the disease.


Recovery and its correlates in patients with schizophrenia.
Little information is available from India, on psychological recovery in patients with schizophrenia. Accordingly, this study aimed to evaluate the correlates and stages of the psychological recovery of patients with schizophrenia. 100 patients, in clinical remission, were evaluated on Stages of Recovery Instrument (STORI), Functional Social Support Questionnaire, WHO Quality of life-BREF, Ways of Coping Checklist, Internalised Stigma of Mental Illness Scale, Scale to Assess Unawareness of Mental Disorder and Knowledge of mental illness scale. Majority of the patients (N = 50) belonged to the stage-5 (Growth), and this was followed by those in the stage-4 (stage of rebuilding; N = 22) and stage-3 (stage of preparation; N = 16) of recovery. A higher stage of recovery was associated with lower stigma in all the domains except stigma resistance. Higher use of confrontative coping and accepting responsibility was associated with a higher score in the awareness stage of recovery. In terms of insight, higher awareness about the effect of medication was associated with a higher stage of recovery. Higher disability in the domain of self-care was seen in the lower stage of recovery. Better quality of life in the physical health domain was associated with being in a higher stage of recovery. To conclude, findings of the present study suggest that stigma plays a significant role in determining the outcome in the form of personal recovery. These findings suggest that to organize the services to promote personal recovery, clinicians should not only aim at symptom amelioration but also must focus on stigma to promote psychological recovery.