Imipramine prevents stress gastric glandular lesions in rats.
Intraperitoneal (i.p.) administration of imipramine dose-dependently inhibited gastric lesions induced by 3 h of cold restraint stress. The high dose of imipramine (5 mg/kg) almost completely abolished gastric lesion formation, and also suppressed acid secretion in rats with pyloric ligation. Intracisternal imipramine (1 microgram) was also protective. These findings suggest that tricyclic antidepressants may play an important role in preventing the deleterious effects of stress on the gut.


Outcomes in mild or rapidly improving stroke not treated with intravenous recombinant tissue-type plasminogen activator: findings from Get With The Guidelines-Stroke.
Mild or rapidly improving stroke is a frequently cited reason for not giving intravenous recombinant tissue-type plasminogen activator (rtPA), but some of these patients may have poor outcomes. We used data from a large nationwide study (Get With The Guidelines-Stroke) to determine risk factors for poor outcomes after mild or improving stroke at hospital discharge. Between 2003 and 2009, there were 29,200 ischemic stroke patients (from 1092 hospitals) arriving within 2 hours after symptom onset with mild or rapidly improving stroke symptoms as the only contraindication to rtPA. Logistic regression was used to determine the independent predictors of discharge to home. Among 93,517 patients arriving within 2 hours, 31.2% (29,200) did not receive rtPA solely because of mild/improving stroke. Among the 29,200 mild/improving cases, 28.3% were not discharged to home, and 28.5% were unable to ambulate without assistance at hospital discharge. The likelihood of home discharge was strongly related to initial National Institutes of Health Stroke Scale score (P<0.001). In multivariable-adjusted analysis, patients not discharged to home were more likely to be older, female, and black; have a higher National Institutes of Health Stroke Scale score and vascular risk factors; and were less likely to be taking lipid-lowering medication before admission. In this large, nationwide study, a sizeable minority of patients who did not receive intravenous rtPA solely because of mild/improving stroke had poor short-term outcomes, raising the possibility that stroke-related disability is relatively common, even in "mild" stroke. A controlled trial of reperfusion therapy in this population may be warranted.


Decoy-state quantum key distribution with biased basis choice.
We propose a quantum key distribution scheme that combines a biased basis choice with the decoy-state method. In this scheme, Alice sends all signal states in the Z basis and decoy states in the X and Z basis with certain probabilities, and Bob measures received pulses with optimal basis choice. This scheme simplifies the system and reduces the random number consumption. From the simulation result taking into account of statistical fluctuations, we find that in a typical experimental setup, the proposed scheme can increase the key rate by at least 45% comparing to the standard decoy-state scheme. In the postprocessing, we also apply a rigorous method to upper bound the phase error rate of the single-photon components of signal states.


Correlative changes of plasma renin activity and serum testosterone in human internal spermatic vein after single administration of human chorionic gonadotropin.
To study changes in renin secretion from the human testis at various days after hCG treatment, plasma renin activity in the internal spermatic vein (ISV) and cubital vein (CV) was measured at the time of surgical repair of varicocele in 79 patients. Sixty-five of them were given a single administration of hCG (10,000 IU/m2) 1 to 10 days before operation. Although the mean PRA levels in CV in both treated and untreated groups were similar, the mean PRA levels in ISV obtained 1 to 5 days after hCG treatment were significantly higher than that in the untreated group. However, the mean PRA levels in ISV returned to that in the untreated group 6-10 days after treatment. Serum testosterone levels in the same ISV were also much higher 1 to 6 days after hCG treatment, compared with those in the untreated group. On the basis of these results it is concluded that (a) the secretion of renin from the testis into ISV can be demonstrated for 5 days after hCG treatment; (b) the parallel increases in PRA with testosterone in ISV seem to suggest a possible influence of androgen on renin production in Leydig cells of human testis.


1,4-Aryl migration in ketene-derived enolates by a polar-radical-crossover cascade.
The arylation of carboxylic acid derivatives via Smiles rearrangement has gained great interest in recent years. Both radical and ionic approaches, as well as radical-polar crossover concepts, have been developed. In contrast, a reversed polar-radical crossover approach remains underexplored. Here we report a simple, efficient and scalable method for the preparation of sterically hindered and valuable α-quaternary amides via a polar-radical crossover-enolate oxidation-aryl migration pathway. A variety of easily accessible N-alkyl and N-arylsulfonamides are reacted with disubstituted ketenes to give the corresponding amide enolates, which undergo upon single electron transfer oxidation, a 1,4-aryl migration, desulfonylation, hydrogen atom transfer cascade to provide α-quaternary amides in good to excellent yields. Various mono- and di-substituted heteroatom-containing and polycyclic arenes engage in the aryl migration reaction. Functional group tolerance is excellent and substrates as well as reagents are readily available rendering the method broadly applicable.


Hyperferritinemia and iron metabolism in Gaucher disease: Potential pathophysiological implications.
Gaucher disease (GD) is characterized by large amounts of lipid-storing macrophages and is associated with accumulation of iron. High levels of ferritin are a hallmark of the disease. The precise mechanism underlying the changes in iron metabolism has not been elucidated. A systematic search was conducted to summarize available evidence from the literature on iron metabolism in GD and its potential pathophysiological implications. We conclude that in GD, a chronic low grade inflammation state can lead to high ferritin levels and increased hepcidin transcription with subsequent trapping of ferritin in macrophages. Extensive GD manifestations with severe anemia or extreme splenomegaly can lead to a situation of iron-overload resembling hemochromatosis. We hypothesize that specifically this latter situation carries a risk for the occurrence of associated conditions such as the increased cancer risk, metabolic syndrome and neurodegeneration.


Energy transfer in artificial membrane systems. Singlet-singlet energy transfer from alloxazines to isolloxazines in dipamitoyl phosphatidylcholine liposomes and dialkylammonium chloride vesicles.
The singlet-singlet energy transfer from alloxazines to isoalloxazines has been investigated in dialmitoyl phosphatidylcholine (DPPC) liposomes and dioctadecyltrimethylammonium chloride (2C18NC) vesicles to clarify the role of the artificial membranes in the energy transfer phenomenon. The structures of the artificial membranes were divided into two types: the single-walled (sonicated DPPC) and the multi-compartment vesicles (unsonicated DPPC and sonicated 2C18NC). In the DPPC single-walled liposomes, the energy of the donor lost by quenching is efficiently transferred to the acceptor via the Förster-type dipoledipole interaction. In the case of multi-compartment liposomes of DPPC, the mean distance between donor and acceptor is so small because the external surface of a bilayer is in the vicinity of the internal surface of another bilayer. As a consequence, efficiencies both of energy transfer and of energy loss were greater than those in single-walled liposomes. The fluid property of the 2C18NC bilayer allowed the preferential collisional quenching. The marked reduction in the efficiencies of both energy transfer and energy loss were attributed to the elongation of donor-acceptor distances due to the increase of the size of liposome.


Co-exposure of organophosphorus pesticides is associated with increased risk of type 2 diabetes mellitus in a Chinese population.
The epidemiological evidence of human exposure to organophosphorus pesticides (OPPs) with type 2 diabetes mellitus (T2DM) and prediabetes (PDM) is scarce. We aimed to examine the association of T2DM/PDM risk with single OPP exposure and multi-OPP co-exposure. Plasma levels of ten OPPs were measured using the gas chromatography-triple quadrupole mass spectrometry (GC-MS/MS) among 2734 subjects from the Henan Rural Cohort Study. We used generalized linear regression to estimate odds ratios (ORs) or β with 95% confidence intervals (CIs), and constructed quantile g-computation and Bayesian kernel machine regression (BKMR) models to investigate the association of OPPs mixture with the risk of T2DM and PDM. High detection rates ranged from 76.35% (isazophos) to 99.17% (malathion and methidathion) for all OPPs. Several plasma OPPs concentrations were in positive correlation with T2DM and PDM. Additionally, positive associations of several OPPs with fasting plasma glucose (FPG) values and glycosylated hemoglobin (HbA1c) levels were observed. In the quantile g-computation, we identified significantly positive associations between OPPs mixtures and T2DM as well as PDM, and fenthion had the greatest contribution for T2DM, followed by fenitrothion and cadusafos. As for PDM, the increased risk was largely explained by cadusafos, fenthion, and malathion. Furthermore, BKMR models suggested that co-exposure to OPPs was linked to an increased risk of T2DM and PDM. Our findings suggested that the individual and mixture of OPPs exposure were associated with an increased risk of T2DM and PDM, implying that OPPs might act an important role in the development of T2DM.


Elevated circulating CD19+CD24hiCD38hi B cells display pro-inflammatory phenotype in idiopathic membranous nephropathy.
CD19+CD24hiCD38hi regulatory B cells exert immunosuppressive functions by producing IL-10, but their role in idiopathic membranous nephropathy (IMN) remains elusive. Here, we investigated the frequency and functional changes of circulating CD19+CD24hiCD38hi B cells and evaluated the correlation of CD19+CD24hiCD38hi B cells with clinical features and T helper cell subsets in IMN patients. Compared with healthy controls (HCs), IMN patients showed an increased frequency of CD19+CD24hiCD38hi B cells, but a significant reduction in the percentage of CD19+CD24hiCD38hi B cells was observed 4 weeks after cyclophosphamide treatment. The frequency of CD19+CD24hiCD38hi B cells was positively correlated with the levels of 24h urinary protein, but negatively correlated with serum total protein and serum albumin, respectively. CD19+CD24hiCD38hi B cells in IMN patients displayed a skewed pro-inflammatory cytokine profile with a higher level of IL-6 and IL-12, but a lower concentration of IL-10 than their healthy counterparts. Accompanied by upregulation of Th2 and Th17 cells in IMN patients, the percentage of CD19+CD24hiCD38hi B cell subset was positively associated with Th17 cell frequency. In conclusion, CD19+CD24hiCD38hi B cells were expanded but functionally impaired in IMN patients. Their altered pro-inflammatory cytokine profile may contribute to the pathogenesis of IMN.


Ventral root elicited depression of the dorsal root evoked response in frog motoneurons.
Recurrent inhibition of the dorsal root (DR) evoked responses of frog motoneurons was studied by intracellular recording. Monosynaptic and early polysynaptic action potentials, as well as compound EPSPs initiated by a DR volley in motoneurons were depressed by an antidromic volley in motor axons. The depression had about 10 msec latency, reached maximum at 20-30 msec, and was maintained for 80 msec. The depression was associated with a slow, negative dorsal root potential (VR-DRP) of similar time course. No sign of recurrent postsynaptic inhibition of the motoneuron somata was found. Decrease in excitability of the motoneurons was also observed during the afterhyperpolarization (AHP) associated with either antidromic or direct spikes in the motoneurons. This excitability decrease was detectable at the time of recurrent depression of the DR-evoked responses. The data are explained by the assumption that two mechanisms are involved in the recurrent depression of the DR-evoked responses: the excitability decrease during the AHP in the motoneurons themselves, and the inhibition transmitted by a recurrent pathway which may depress the DR inputs to motoneurons presynaptically.


Treatment with laser CO2 cordectomy and clinical implications in management of mild and moderate laryngeal precancerosis.
All the classification of precancerous lesions are based on the progression of specific histopathological characteristics, which in turn considers the grade of epithelial hyperplasia and dysplasia, nevertheless the transformation of laryngeal keratosis into carcinoma occurs through progressive modifications of normal epithelium in keratosis without dysplasia, to the point of degenerating into carcinoma in situ. The treatment of laringeal precancerosis has not yet defined a gold standard: according to some authors, a simple excision biopsy may be sufficient, others, instead, perform the stripping of the involved vocal cord, while others yet perform vaporization by means of CO2 laser. The aim of this paper is to evaluate and possibly validate the treatment of mild and moderate laryngeal dysplasia (LIN1-2) by CO2 laser, with particular attention to oncological and functional results. Fifty-eight patients (44 males and 14 females, mean age 54.3 years) affected by mild and moderate dysplasia (32 LIN I and 26 LIN II) diagnosed by a bioptic exam, were treated by performing a CO2 laser cordectomy (following the European Society of Laryngology's criteria). Before surgery to the patients was given a questionnaire to identify primary risk factors such as smoking, alcohol use and gastroesophageal reflux, were also handed a Vocal Performance Questionnaire. In all patients was performed a pH measurement over a 24-h period, a voice evaluation using a Kay digital Strobe 920. 84% of patients were smokers; the presence of reflux was reported in 11 patients (19%). The 32 LIN1 cases treated with type I cordectomy determined four recurrences (12.4%), of which two LIN1, one LIN2 and one carcinoma in situ. Of the 26 LIN2 cases examined, the 12 treated with type 1 cordectomy generated 1 recurrence alone with the presence of an invasive carcinoma (T1a) (8.3%), while no recurrences were reported in the group of 14 LIN2 cases treated with type II cordectomy. 93.1% (54/58) of cases showed a complete closing of the glottal plane over time. Considering the results in terms of disease control, and functional outcomes, our experience suggests subepithelial cordectomy (ELS I) for LIN 1 and subligament cordectomy (ELS II) for LIN 1 recurrences; therefore we suggest subligament cordectomy (ELS II) in LIN 2 cases.


The association between personal sun exposure, serum vitamin D and global methylation in human lymphocytes in a population of healthy adults in South Australia.
There is a positive association between solar UV exposure and micronucleus frequency in peripheral blood lymphocytes (PBL) and this association may be stronger when serum vitamin D (25(OH)D) levels are insufficient (<50 nmol/L). Micronucleus formation can result from global hypomethylation of DNA repeat sequences. The aim of this analysis was to evaluate the relationship between solar UV exposure and methylation pattern in LINE-1 repetitive elements in PBL DNA and to see if serum 25(OH)D levels modify it. Personal solar UV exposure was estimated from hours of outdoor exposure over 6 weeks recalled at the time of blood collection in 208 male and female participants living in South Australia. Methylation in LINE-1 repetitive elements was assessed in PBL using pyrosequencing. Methylation in LINE-1 decreased with increasing solar UV exposure (% decrease = 0.5% per doubling of sUV; 95%CI: -0.7 to -0.2 p(value) = 0.00003). Although there was no correlation between LINE-1 methylation and micronucleus frequency, there was a 4.3% increase (95%CI: 0.6-8.1 p-value = 0.02) in nucleoplasmic bridges and a 4.3% increase in necrosis (CI: 1.9-6.8 p-value = 0.0005) for every 1% increase in LINE-1 methylation. Serum 25(OH)D was not associated with DNA methylation; or did it modify the association of solar UV with DNA methylation. Exposure to solar UV radiation may reduce DNA methylation in circulating lymphocytes. This association does not appear to be influenced or mediated by vitamin D status.


A cure for xerostomia? Free jejunal patch graft in oral reconstruction.
A case of oral carcinoma associated with extensive leukoplakia and severe xerostomia is presented. The advantage of using a free jejunal patch graft to restore large intra-oral mucosal defects and concurrently eradicate xerostomia is demonstrated. Further, it is recommended that a tracheostomy be used routinely in such cases to avoid postoperative aspiration of the graft secretions. Following healing the use of osseointegrated implants can complete oral rehabilitation without compromising the graft.


Complexation efficiency of differently fixed 8-hydroxyquinoline and salicylic acid ligand groups for labile aluminium species determination in soils--comparison of two methods.
Two methods utilizing the complexation of labile Al species by 8-hydroxyquinoline (HQN) and salicylic acid (SA) ligand groups were developed for aluminium operationally defined fractionation in acid soils. First, the solid phase extraction (SPE) procedure by a short-term ion-exchange batch reaction with chelating resins Iontosorb Oxin and Iontosorb Salicyl containing both ligand groups was used previously. Second, the 8-hydroxyquinoline, salicylic acid and ammonium salicylate agents with different concentrations by a single extraction protocol were applied in this paper. The flame atomic absorption spectrometry (FAAS) and optical emission spectrometry with inductively coupled plasma were used for aluminium quantification. The comparison of results from both methods show the possibility to supersede the first laborious method for the second simpler one in Al environmental risk assessment. The use of 1% 8-hydroxyquinoline in 2% acetic acid and 0.2% salicylic acid by a single extraction protocol without a need of sample filtration can supersede the SPE procedure in the Al pollution soil monitoring. Finally, the new scheme usable in a laboratory and moreover, directly in a field was proposed for Al fractionation in solid and liquid environmental samples. The labile Al species in soils and sediments are separated after their single leaching by 8-hydroxyquinoline or salicylic acid without a need of sample filtration. The labile Al species in soil solutions and natural waters are separated after their ultrafiltration followed by the SPE procedure with Iontosorb Oxin or Iontosorb Salicyl.


Heart Failure-Related Iron Deficiency Anemia Pathophysiology and Laboratory Diagnosis.
The goal of the current review is to give an overview regarding the pathophysiology of iron deficiency in heart failure and how different laboratory tests change in the setting of heart failure. Recent studies have questioned the current employed definition of iron deficiency in the field of heart failure, as patients with ferritin < 100ng/ml but TSAT > 20% have a better prognosis, no iron deficiency on bone marrow staining, and altered treatment response to ferric carboxymaltose. This review summarizes changes in iron parameters in the setting of heart failure and underscores the importance of a reduced bioavailability of iron documented by a low serum iron or TSAT, irrespective of the presence of anemia.


Sexual Satisfaction in Men Suffering From Erectile Dysfunction After Robot-Assisted Radical Prostatectomy for Prostate Cancer: An Observational Study.
Preservation of erectile function is an important postoperative quality of life concern for patients after robot-assisted radical prostatectomy (RARP) for prostate cancer. Although erectile function may recover, many men continue to suffer from erectile dysfunction (ED). This study aims to determine whether satisfaction with sexual life improves in patients with ED after RARP and which factors are associated with satisfaction during follow-up. A review was carried out of a prospectively maintained database of patients with prostate cancer who underwent a RARP between 2006 and 2019. The "International Index of Erectile Function" questionnaire was used to describe ED (range 5-25), overall satisfaction with sexual life and sexual desire (range for both: 2-10). Patients with ED due to RARP were compared with those without ED after RARP. Mixed effect model was used to test differences in satisfaction over time. Mann-Whitney U tests and multiple logistic regression were used to assess factors associated with being satisfied at 24 and 36 months. The main outcomes of this study are the overall satisfaction with sexual life score over time and factors which influence sexual satisfaction. Data of 2808 patients were reviewed. Patients whose erectile function was not known (n = 643) or who had ED at the baseline (n = 1281) were excluded. About 884 patients were included for analysis. They had an overall satisfaction score of 8.4. Patients with ED due to RARP had mean overall satisfaction scores of 4.8, 4.8, 4.9, and 4.6 at 6 mo, 12 mo, 24 mo, and 36 mo. These scores were significantly lower than those of patients without ED at every time point. In multiple regression analysis, higher overall satisfaction score at the baseline and higher sexual desire at 24 and 36 months' follow-up were associated with satisfaction with sexual life at 24 and 36 months' follow-up. No association was found for erectile function. Interventions focusing on adjustment to the changes in sexual functioning might improve sexual satisfaction; especially for those men who continue to suffer from ED. Strengths of this study are the large number of patients, time of follow-up, and use of multiple validated questionnaires. Our results must be interpreted within the limits of retrospectively collected, observational data. Satisfaction with sexual life in men with ED due to RARP may take a long time to improve. One could counsel patients that sexual satisfaction is based on individual baseline sexual satisfaction and the return of sexual desire after RARP. Albers LF, Tillier CN, van Muilekom HAM, et al. Sexual Satisfaction in Men Suffering From Erectile Dysfunction After Robot-Assisted Radical Prostatectomy for Prostate Cancer: An Observational Study. J Sex Med 2021;18:339-346.


Outcomes for the First Year of Ontario's Birth Center Demonstration Project.
In 2014, Ontario opened 2 stand-alone midwifery-led birth centers. Using mixed methods, we evaluated the first year of operations for quality and safety, client experience, and integration into the maternity care community. This article reports on our study of safety and quality of care. This descriptive evaluation focused on women admitted to a birth center at the beginning of labor. For context, we matched this cohort (on a 1:4 basis) with similar low-risk midwifery clients giving birth in a hospital. Data sources included Ontario's Better Outcomes Registry and Network (BORN) Information System, the Canadian Institute for Health Information, Ontario census data, and birth center records. Of 495 women admitted to a birth center, 87.9% experienced a spontaneous vaginal birth, regardless of the eventual location of birth, and 7.7% had a cesarean birth. The transport rate to a hospital was 26.3%. When compared with midwifery clients with a planned hospital birth, rates of intervention (epidural analgesia, labor augmentation, assisted vaginal birth, and cesarean birth) were significantly lower in the planned birth center group, even when controlled for previous cesarean birth and body mass index. Markers of potential morbidity were identified in about 10% of birth center births; however, there were no short-term health impacts up to discharge from midwifery care at 6 weeks postpartum. Care was low in intervention and safe (minimal negative outcomes and transport rates comparable to the literature). In the first year of operation, care was consistent with national guidelines, and morbidity and mortality rates and intervention rates were low for women with low-risk pregnancies seeking a low-intervention approach for labor and birth. Further evaluation to confirm these findings is required as the number of births grows.


Differentiation of left atrial appendage thrombus from circulatory stasis using cardiac CT radiomics in patients with valvular heart disease.
To determine whether quantitative radiomic features from cardiac CT could differentiate the left atrial appendage (LAA) thrombus from circulatory stasis in patients with valvular heart disease. Ninety-five consecutive patients with valvular heart disease and filling defects in LAA on two-phase cardiac CT from March 2016 to August 2018 were retrospectively enrolled and classified as having thrombus or stasis by transesophageal echocardiography or cardiac surgery. The ratio of Hounsfield units in the filling defects to those in the ascending aorta (AA) was calculated on early- and late-phase CT (LAA/AAE and LAA/AAL, respectively). Radiomic features were extracted from semi-automated three-dimensional segmentation of the filling defect on early-phase CT. The diagnostic ability of radiomic features for differentiating thrombus from stasis was assessed and compared to LAA/AAE and LAA/AAL by comparing the AUC of ROC curves. Diagnostic performances of CT attenuation ratios and radiomic features were validated with an independent validation set. Thrombus was diagnosed in 25 cases and stasis in 70. Sixty-eight radiomic features were extracted. Values of 8 wavelet-transformed features were lower in thrombus than in stasis (p < 0.001). The AUC value of a radiomic feature, wavelet_LHL, for diagnosing thrombus was 0.78, which was higher than that of LAA/AAE (AUC = 0.54, p = 0.025) and similar to that of LAA/AAL (AUC = 0.76, p = 0.773). In the validation set, the AUC of wavelet_LHL was 0.71, which was higher than that of LAA/AAE (AUC = 0.57, p = 0.391) and similar to that of LAA/AAL (AUC = 0.75, p = 0.707). Quantitative radiomic features from the early phase of cardiac CT may help diagnose LAA thrombus in patients with valvular heart disease. • Wavelet-transformed grey-level non-uniformity values from radiomic analysis are significantly lower for LAA thrombus than for circulatory stasis. • Radiomic features may have an additional value for differentiating LAA thrombus from circulatory stasis when interpreting single-phase cardiac CT. • Radiomic features extracted from single-phase images may show similar diagnostic ability as conventional quantitative analysis from two-phase images.


No Evidence of Increased Risk of Stroke with Consumption of Refined Grains: A Meta-analysis of Prospective Cohort Studies.
Results of the relationships between dietary consumption of refined grains and the risk of stroke are mixed. This study was based on a meta-analysis of prospective cohort studies. We systematically searched the MEDLINE (from January 1, 1966) and EMBASE (from January 1, 1974) databases up to November 30, 2014. Random-effects models were used to calculate summary relative risks (SRRs) and 95% confidence intervals (CIs). Between-study heterogeneity was assessed using Cochran's Q and I(2) statistics. Eight prospective studies (7 publications) with a total of 410,821 subjects and 8284 stroke events were included in the meta-analysis. Overall, a diet containing greater amounts of refined grains was not associated with risk of stroke, with no evidence of heterogeneity among studies (SRR = 1.02; 95% CI, .93-1.10; P(heterogeneity) = .970; I(2) = 0). In addition, no significant associations between consumption of refined grains and risk of stroke were found for both women and men, for both hemorrhagic and ischemic strokes, and for both incident and fatal strokes. These null results are consistent with those of linear dose-response meta-analyses (SRR = .98; 95% CI, .73-1.03 for per 3 servings/day). Consumption of white rice was not associated with risk of stroke (SRR = 1.01; 95% CI, .93-1.11; P(heterogeneity) = .966; I(2) = 0). The current meta-analysis provides some evidence for the hypothesis that consumption of refined grains was not associated with risk of stroke and its subtypes.


The effect of ageing on between-limb centre of pressure coordination in standing balance: Is there evidence for reactive control challenges among older adults?
Interlimb temporal synchrony and spatial symmetry of centre of pressure (COP) displacements may be vital contributors to standing balance control. In previous work among stroke survivors, low-frequency COP displacements (< 0.4 Hz) were proposed to arise from centre of mass (COM) dynamics, or from proactive exploratory processes. COP displacements among higher frequencies (>0.4 Hz), in contrast, have been attributed to corrective balance responses to internal perturbations. The present study extends this work to explore age-related alterations in such stability control processes during standing balance. The combined COP displacements from both limbs (COPnet) in addition to individual-limb COP timeseries were calculated from synchronous force platform data obtained from 19 younger adults and 19 older adults during a 60 s trial of quiet standing. The discrete wavelet transform was used to decompose the anteroposterior and mediolateral COPnet, in addition to the individual-limb timeseries, into low-frequency and high-frequency bandwidths. Root-mean-squared (RMS) amplitudes of high- and low-frequency COPnet displacements were calculated. The cross-correlation coefficient was used to assess the extent of between-limb temporal synchronization, while the ratio of individual-limb RMS amplitudes was used to assess between-limb spatial symmetry within each high- and low-frequency bandwidth. We observed greater high-frequency anteroposterior COPnet displacements among older adults, without age related differences in the lower frequency bandwidth or in the mediolateral direction. Further, older adults exhibited greater high-frequency anteroposterior between-limb synchronization, without age-related differences in the low frequency bandwidth, or among any of the spatial symmetry variables. The present age-related alterations in COPnet could represent a conservative strategy to ensure stability, whereby age-related challenges in stability maintenance during standing are offset by greater demands on stability control. Further, increased high frequency between-limb temporal synchronization among older adults may suggest a loss of adaptability in balance corrective responses during standing.


Communication in the Operating Room Setting.
Ideal and effective communication consists of a clear, audible, and focused message from a transmitter that is delivered to an attentive, undistracted receiver, and consists of both verbal and nonverbal types. Communication in the health care setting is highly complex and dynamic, involving multiple settings, participants, and unique challenges. Effective communication in the perioperative environment is a requirement for safe patient care delivery and an important element of teamwork. A message must be accurately delivered in a uniquely high-risk and time-sensitive location, beset with numerous distractions, barriers, and challenges. Surgical checklists and time-out procedures have promoted a standardized, "all-hands" approach to addressing some of the challenges to effective communication in the perioperative environment. Postoperative debriefing sessions have demonstrated effectiveness in improving team functioning in the simulated learning environment and hold promise as another strategy to address these challenges, but require further research and development. Other promising strategies to improve effective perioperative communication are focused on team building activities and minimizing distractions at critical time points within patient care delivery, but to date are not substantiated by evidence. Future research is necessary to examine these novel approaches to improving communication in the perioperative environment to influence the safety of patient care delivery in this highly challenging health care setting. Wise men speak because they have something to say; Fools because they have to say something. Plato.


Social capital and neo-materialist contextual determinants of sense of insecurity in the neighbourhood: a multilevel analysis in Southern Sweden.
The aim of this study was to investigate the influence of contextual (social capital and neo-materialist) and individual factors on sense of insecurity in the neighbourhood. The 2000 public health survey in Scania is a cross-sectional study. A total of 13,715 persons answered a postal questionnaire, which is 59% of the random sample. A multilevel logistic regression model, with individuals at the first level and municipalities at the second, was performed. The effect (median odds ratios, intra-class correlation, cross-level modification and odds ratios) of individual and municipality/city quarter (social capital and police district) factors on sense of insecurity was analysed. The crude variance between municipalities/city quarters was not affected by individual factors. The introduction of administrative police district in the model reduced the municipality variance, although some of the significant variance between municipalities remained. The introduction of social capital did not affect the municipality variance. This study suggests that the neo-materialist factor administrative police district may partly explain the individual's sense of insecurity in the neighbourhood.


Cardiovascular disease risk profile of Indian young adults with type 1 diabetes compared to general population - A sub-study from the Young Diabetes Registry (YDR), India.
We estimated the prevalence of traditional CVD risk factors among young adults with type 1 diabetes and compared them with the general population without diabetes. Participants were young adults (aged 20 years and above) with type 1 diabetes, from the Delhi and Chennai sites of the ICMR -Young Diabetes Registry (YDR) and their age, gender and location matched controls, without diabetes from the CARRS (Cardio metabolic Risk Reduction in South Asia) cohort. YDR and CARRS used similar standard methodologies to quantify the CVD risk factors. Linear and logistic regression models were used to compare the adjusted means and proportions of risk factors. Individuals with type 1 diabetes had lower levels of mean BMI (21.9 kg/m2 vs 24.3 kg/m2), waist circumference (76.8 cm vs 82.1 cm), favourable lipid profile (lower LDL and higher HDL), higher mean systolic blood pressure (122.1 mmHg vs 118.7 mmHg) and hypertension (29.2% vs 21.0%), compared to controls. The extent of clustering of two or more traditional CVD risk factors was higher among general population compared to people with type 1 diabetes. We found that young adults with type 1 diabetes have relatively low prevalence and clustering of traditional CVD risk factors compared to general population.


On the use of volume maps in the conformational analysis of vitamin D analogs.
Dot maps used to represent the calculated conformations of the side chain of vitamin D derivatives are improved by replacing dots by coloured balls to create volume maps and to identify particular energy windows. Two procedures to define a relative activity volume, based on a pair of analogs with distinctly different biological activity and conformational behaviour, are presented.


Discontinuation and re-initiation of antidepressants during pregnancy: A nationwide cohort study.
Women tend to discontinue antidepressants during pregnancy. We examined the rate of and factors associated with antidepressant discontinuation and re-initiation during pregnancy. We conducted a nationwide cohort study using Korea's healthcare database. The study cohort included women who were aged 15-50 years, gave birth during 2013-2017, had ≥1 depression diagnosis, ≥2 antidepressant prescriptions within 6 months (one within one month of preconception). Cox proportional hazards model was used to evaluate factors associated with antidepressant discontinuation and re-initiation during pregnancy. Among 5207 pregnancies, 4954 (95.1%) discontinued antidepressants during pregnancy, which included 4657 (89.4%) in the first trimester, 1810 (38.9%) of whom re-initiated them during pregnancy or postpartum period. The risk of antidepressant discontinuation increased in women with substance-related disorders (HR 1.17, 95% CI 1.01-1.35), but decreased in women receiving medical aid (0.53, 0.46-0.62) and patients suggestive of severe depression, such as psychiatric comorbidities and long-term antidepressant use before pregnancy. Antidepressant re-initiation occurred frequently in medical aid recipients (1.25, 1.06-1.47), nulliparous women (1.11, 1.01-1.22), and women with severe symptoms. We found high rates of antidepressant discontinuation and re-initiation during pregnancy. Although women suggestive of severe symptoms were less likely to discontinue antidepressants during pregnancy, they were more likely to re-initiate them during their perinatal period, which warrants more detailed guidelines on perinatal depression.


Numerical simulation and scaling of droplet deformation in a hyperbolic flow.
Motivated by a recent experiment (C. Ulloa et al., Phys. Rev. E 89, 033004 (2014)), droplet deformation in a flat microfluidic channel having a cross intersection with two inlet channels and two outlet channels, i.e. hyperbolic flow, is numerically investigated. Employing the boundary element method (BEM), we numerically solve the Darcy equation in the two dimensions and investigate droplet motion and droplet deformation as the droplet enters the cross intersection. We numerically find that the maximum deformation of droplet depends on droplet size, capillary number, viscosity ratio and flow rate ratio of the two inlets. Our numerical scaling is in good agreement with the experimental scaling report.


Loxoprofen sodium treatment for elderly men with refractory nocturia: effect on night-time urine production.
We evaluated the efficacy of loxoprofen sodium for refractory nocturia. Twelve men (mean age, 75.1 +/- 5.7) with nocturia were enrolled in this study. All patients received 60 mg loxoprofen sodium prior to sleeping at night for 14 days. Nine of 12 patients (75%) felt more satisfaction than previous treatments. Patients were grouped into a loxoprofen sodium-effective (n = 7) and ineffective groups (n = 5) based on the results of the frequency-volume chart. In the effective group, interestingly, night-time urine volume showed significant reduction (P < 0.05). On the other hand, the average single voided volume at night and 24-h urine volume showed no significant change. There was a statistically significant difference in the night-time urine volume after treatment between groups (P < 0.01). Loxoprofen sodium is an effective treatment for some patients with refractory nocturia. The main effect mechanism of loxoprofen sodium may involve the reduction of night-time urine production.


Automated conformational energy fitting for force-field development.
We present a general conformational-energy fitting procedure based on Monte Carlo simulated annealing (MCSA) for application in the development of molecular mechanics force fields. Starting with a target potential energy surface and an unparametrized molecular mechanics potential energy surface, an optimized set of either dihedral or grid-based correction map (CMAP) parameters is produced that minimizes the root mean squared error RMSE between the parametrized and targeted energies. The fitting is done using an MCSA search in parameter space and consistently converges to the same RMSE irrespective of the randomized parameters used to seed the search. Any number of dihedral parameters can be simultaneously parametrized, allowing for fitting to multi-dimensional potential energy scans. Fitting options for dihedral parameters include non-uniform weighting of the target data, constraining multiple optimized parameters to the same value, constraining parameters to be no greater than a user-specified maximum value, including all or only a subset of multiplicities defining the dihedral Fourier series, and optimization of phase angles in addition to force constants. The dihedral parameter fitting algorithm's performance is characterized through multi-dimensional fitting of cyclohexane, tetrahydropyran, and hexopyranose monosaccharide energetics, with the latter case having a 30-dimensional parameter space. The CMAP fitting is applied in the context of polypeptides, and is used to develop a parametrization that simultaneously captures the phi,psi energetics of the alanine dipeptide and the alanine tetrapeptide. Because the dihedral energy term is common to many force fields, we have implemented the dihedral-fitting algorithm in the portable Python scripting language and have made it freely available as "fit_dihedral.py" for download at http://mackerell.umaryland.edu.


Honeybees mark with scent and reject recently visited flowers.
Experimental evidence is reported for flower-marking by honeybees (Apis mellifera ligustica) while they were foraging on an artificial patch of flowers yielding a continuous and equal flow of sucrose solution. Honeybees marked with scent and rejected all recently visited and nectar-depleted flowers. The short fade-out time of this scent allowed discrimination of flowers that temporarily provided no food. The repellent nature of this scent mark was demonstrated by the use of an air extractor connected to the patch; when the apparatus was turned on, the rejection behaviour disappeared. The movement pattern of foraging bees also contributed to foraging efficiency, as the probability of an immediate return to the flower just abandoned was very low. However, when a quick repeat visit took place, the presence of the repellent scent-mark promoted rapid rejection.


CT analysis demonstrates that cochlear height does not change with age.
CH measurements can often be useful in the diagnosis of inner ear malformations associated with SNHL. Our aim was to establish the relationship between CH and age by using analysis of CT images in patients who underwent coronal CT scans of the temporal bone between 2001 and 2007. We measured CH on coronal CT scans of the temporal bone of 422 ears scanned from 2001 to 2007 in 211 patients, 1 month to 23 years of age. Using multivariate linear regression analysis, we determined the relationship of CH to age, sex, and HL type. In addition, 11 patients with multiple scans at different ages were assessed for change in CH with age. Average CH was 5.3 mm (normal range, 4.4-6.2 mm). Analysis showed no statistically significant change in CH across ages from 1 month to 23 years (95% CI for regression line slope = -0.003, 0.013). Likewise, there were no statistically significant differences in CH for patients with multiple scans at different ages. ICW increased with age as expected with increased cranial size. A small difference in CH between sexes was noted with males having greater CHs than females (P < .01). All patients with hypoplastic cochleas, defined by a CH <2 SDs from the mean (4.48 mm for males and 4.25 mm for females), had HL with a positive predictive value of 86%. CH does not change from 1 month of age to adulthood and is slightly greater in males than in females.


Design of europium(III) complexes with high quantum yield.
This work describes a rational planning of a new light-conversion molecular device with high quantum yield. For this, we made modifications in the 3-amino-2-carboxypyridine and 3-amino-2-carboxypirazine acid ligands, generating eight different complexes. Theoretical methods have been used to calculate the quantum yield of each of the complexes. We first used the Sparkle model to calculate the ground-state geometries of the eight complexes. These data were used to perform theoretical predictions of the energy transitions using the INDO/S-CI method. After having obtained the geometry and the energy transitions, the energy transfer rates and quantum yield were calculated using a theoretical approach based on the application of the 4f-4f transition theory. The results show that the modifications in the 3-amino-2-carboxypyridine ligand had generated three complexes with high quantum yield (about 52.8, 51.6 and 52.8%). On the other hand, the modifications in the 3-amino-2-carboxypirazine led to only one complex with quantum yield larger than 50%, but it is the most efficient complex projected.


Cross-talk from β-adrenergic receptors modulates α2A-adrenergic receptor endocytosis in sympathetic neurons via protein kinase A and spinophilin.
Inter-regulation of adrenergic receptors (ARs) via cross-talk is a long appreciated but mechanistically unclear physiological phenomenon. Evidence from the AR literature and our own extensive studies on regulation of α2AARs by the scaffolding protein spinophilin have illuminated a potential novel mechanism for cross-talk from β to α2ARs. In the present study, we have characterized a mode of endogenous AR cross-talk in native adrenergic neurons whereby canonical βAR-mediated signaling modulates spinophilin-regulated α2AAR endocytosis through PKA. Our findings demonstrate that co-activation of β and α2AARs, either by application of endogenous agonist or by simultaneous stimulation with distinct selective agonists, results in acceleration of endogenous α2AAR endocytosis in native neurons. We show that receptor-independent PKA activation by forskolin is sufficient to accelerate α2AAR endocytosis and that α2AAR stimulation alone drives accelerated endocytosis in spinophilin-null neurons. Endocytic response acceleration by β/α2AAR co-activation is blocked by PKA inhibition and lost in spinophilin-null neurons, consistent with our previous finding that spinophilin is a substrate for phosphorylation by PKA that disrupts its interaction with α2AARs. Importantly, we show that α2AR agonist-mediated α2AAR/spinophilin interaction is blocked by βAR co-activation in a PKA-dependent fashion. We therefore propose a novel mechanism for cross-talk from β to α2ARs, whereby canonical βAR-mediated signaling coupled to PKA activation results in phosphorylation of spinophilin, disrupting its interaction with α2AARs and accelerating α2AAR endocytic responses. This mechanism of cross-talk has significant implications for endogenous adrenergic physiology and for therapeutic targeting of β and α2AARs.


Atherosclerosis precursors in Finnish children and adolescents. X. Leisure-time physical activity.
As part of the more extensive project concerned with atherosclerosis precursors in Finnish children, this article aims at describing the method developed for epidemiological estimation of habitual physical activity, discussing the reliability and validity of the method and reporting the results of the application of this strategy in the measurement of habitual physical activity among 3 to 18-year-old Finnish boys and girls. The questionnaire for the measurement of physical activity was addressed to the parents of 3- and 6-year-old subjects (younger group) and to the subjects themselves in 9- to 18-year-olds (older group). Using four variables in the younger group and nine variables in the older group, sum indices of physical activity were made. Internal consistency coefficients (Kuder--Richardson) varied in the younger group from .57 to .63 and in the older group from .56 to .79. Most Finnish children and adolescents were physically active during their leisure-time. For comparison of passive and active children, screening for passive ones was difficult. Differences between East and West Finland associated with many risk factors, were not detected in the physical activity patterns of children and adolescents. On the other hand, the physical activity pattern was significantly determined by the local environment. In sparsely populated areas, young people were more inactive than in densely populated areas.


Do orthodontic movements of traumatized teeth induce dental pulp necrosis? A systematic review.
Usually, orthodontic movements encompass children and young adult patients, which are more susceptible to the occurrence of traumatic dental injuries. It is necessary to understand whether the effects of orthodontic movements on traumatized teeth could induce pulp necrosis. The aim of this study was to answer the following question: "Do orthodontic movements of traumatized teeth induce dental pulp necrosis?". Searches were performed for studies published up to May 11, 2023, in the MEDLINE/PubMed, Cochrane Library, Scopus, SciELO Citation Index, Web of Science, EMBASE, and Grey Literature Report databases, without restriction for language or year of publication. The revised Cochrane risk of bias tools for nonrandomized interventions (ROBINS-I) was used to assess the quality of the included studies. The overall quality of evidence was assessed through the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tool. Of 2671 potentially relevant studies, five were included. Four were classified as having a moderate risk of bias and one as a serious risk of bias. It was reported a higher susceptibility to pulp necrosis in teeth subjected to orthodontic movements with history of trauma involving periodontal tissues. Additionally, orthodontic movements of traumatized teeth with total pulp obliteration had an increased risk of pulp necrosis. GRADE analysis presented a moderate certainty of evidence. An increased risk for pulp necrosis when traumatized teeth are subjected to orthodontic movements was verified. However, this is based on evaluations performed with subjective tests. Further well-designed studies are necessary to confirm this trend. Clinicians must be aware of the possibility of pulp necrosis. However, endodontic treatment is recommended when verified signs and symptoms of pulp necrosis.


Additional prognostic values of strain and strain rate over late gadolinium enhancement in hypertrophic cardiomyopathy patients.
Late gadolinium enhancement (LGE) has some shortcomings in the risk stratification in hypertrophic cardiomyopathy (HCM). Myocardial strain/strain rate (SR) can be acquired from unenhanced cardiovascular magnetic resonance (CMR) images and detect cardiac dysfunction sensitively. The present study aimed to evaluate the additional prognostic values of myocardial strain/SR beyond LGE for the risk stratification in patients with HCM. 293 patients with HCM who underwent CMR were enrolled in this prospective study. LGE/left ventricular (LV) mass, LV global strain, and SR were acquired based on CMR. Also, conventional clinical, echocardiography, and CMR parameters and established risk factors for HCM were evaluated. 14/293 patients had major adverse cardiovascular events (MACEs) during the median follow-up of 15.0 months, including eight all-cause deaths, four resuscitated cardiac arrests and two cardiac transplantations. Peak systolic (PS)-global longitudinal SR (GLSR) was independently associated with MACEs (hazard ratio: 15.297, P < 0.001) after adjusting for conventional clinical characteristics, echocardiography, and CMR parameters. The model constructed by conventional variables plus PS-GLSR had significantly stronger predictive ability than the model constructed by conventional variables plus LGE/LV mass (C-statistic: 0.850 vs 0.708, P = 0.030). The addition of PS-GLSR to the conventional model also significantly improved the sensitivity (92.9% vs 71.4%) and specificity (71.0% vs 57.3%), and lowered false positives (81 patients vs 119 patients) compared to the addition of LGE/LV mass. LV PS-GLSR derived from CMR has the potential to be a novel biomarker for risk stratification of HCM and provide additional prognostic value over LGE/LV mass.


Islet amyloid polypeptide triggers α-synuclein pathology in Parkinson's disease.
Pathologic aggregation and prion-like propagation of α-synuclein (α-syn) are the hallmarks of Parkinson's disease (PD). Emerging evidence shows that type 2 diabetes mellitus (T2DM) is a risk factor for PD. Interestingly, T2DM is characterized by the amyloid deposition of islet amyloid polypeptide (IAPP) in the pancreas. Although T2DM and PD share pathological similarities, the underlying molecular mechanisms bridging these two diseases remain unknown. Here, we report that IAPP co-deposits with α-syn in the brains of PD patients. IAPP interacts with α-syn and accelerates its aggregation. In addition, the IAPP-seeded α-syn fibrils show enhanced seeding activity and neurotoxicity compared with pure α-syn fibrils in vitro and in vivo. Strikingly, intravenous injection of IAPP fibrils into α-syn A53T transgenic mice or human SNCA transgenic mice accelerated the aggregation of α-syn and PD-like motor deficits. Taken together, these findings support that IAPP acts as a trigger of α-syn pathology in PD, and provide a mechanistic explanation for the increased risk and faster progression of PD in patients with T2DM.


The individual and population effects of tetracycline on Daphnia magna in multigenerational exposure.
Multigenerational exposure of Daphnia magna to tetracycline was carried out through four consecutive generations. The effects of tetracycline on the survival, reproduction and growth of D. magna were assessed over a period of 21 days per generation. The evaluated endpoints were overall fecundity (total mean neonates per female over 21 days), time to first reproduction, longevity, molting number and somatic growth, such as body weight and body length. Using the results obtained for reproduction and survival rates, the intrinsic population growth rate (PGR) was calculated and compared throughout the generations. Reproductive impairment was observed in all generations and magnified with increasing generation number. The value of no observed effect concentration on D. magna also markedly decreased with increasing generation number. This subsequently resulted in a reduction of the PGR value. In addition, the PGR value was decreased with increasing exposure concentration, decreasing by about 30 and 60% at 0.1 and 5.0 mg/L tetracycline, respectively. On the other hands, somatic growth increased with increasing generation number, because the remaining input energy from the reduced reproduction was mainly used for body maintenance. As a result, the somatic growth and reproduction showed reversed trends on continuous exposure of tetracycline to four generations. In conclusion, multigenerational exposure of tetracycline can induce overall responses on reproduction and the somatic growth of D. magna. Moreover, the PGR value of D. magna exposed to tetracycline was reduced with increasing generation number; thereby, inhibiting the long term propagation of D. magna.


Expression and Functional Studies of Leaf, Floral, and Fruit Developmental Genes in Non-model Species.
Researchers working on evolutionary developmental plant biology are inclined to choose non-model taxa to address how specific features have been acquired during ontogeny and fixed during phylogeny. In this chapter we describe methods to extract RNA, to assemble de-novo transcriptomes, to isolate orthologous genes within gene families, and to evaluate expression and function of target genes. We have successfully optimized these protocols for non-model plant species including ferns, gymnosperms, and a large assortment of angiosperms. In the latter, we have ranged a large number of families including Aristolochiaceae, Apodanthaceae, Chloranthaceae, Orchidaceae, Papaveraceae, Rubiaceae, Solanaceae, and Tropaeolaceae.


Modulation of recombinant human cardiac L-type Ca2+ channel alpha1C subunits by redox agents and hypoxia.
1. Whole-cell patch clamp recordings were used to investigate the modulation by reducing and oxidizing agents of recombinant human cardiac L-type Ca2+ channel alpha1C subunits stably expressed in human embryonic kidney (HEK 293) cells. 2. The oxidizing agents thimerosal (10 microM) and p-chloromercuribenzene sulphonic acid (PCMBS; 2 microM to 2 mM) caused irreversible inhibition of Ca2+ channel currents. The reducing agent 1,4-dithiothreitol (DTT; 2 mM) was without effect on Ca2+ channel currents, but reversed the inhibitory actions of thimerosal and PCMBS. 3. Ca2+ channel currents were also inhibited by pretreatment with the methanethiosulphonate compound (2-aminoethyl)methanethiosulphonate (MTSEA, 2.5 mM), but were unaffected by identical pretreatment with (2-sulphonatoethyl)methanethiosulphonate (MTSES, 10 mM). The effects of MTSEA could be fully reversed by DTT (2 mM). The degree of current inhibition caused by 200 microM PCMBS was not significantly affected by pretreatment with MTSEA, and following PCMBS treatment, MTSEA caused a similar degree of inhibition to that observed in cells that were not previously treated with PCMBS. These findings suggested that distinct thiol groups were modulated by these two agents. 4. Hypoxic inhibition of Ca2+ channel currents was unaffected by pretreatment of cells with MTSEA but was fully prevented by treatment with PCMBS. Our results indicate that distinct cysteine residues on the alpha1C subunit can undergo redox modulation and in so doing alter channel function. Some, but not all, of these residues appear to be associated with the mechanism underlying inhibition of this channel by hypoxia.


Current and investigational medications for the treatment of sarcopenia.
Sarcopenia, defined as the loss of muscle mass and function, is a widely prevalent and severe condition in older adults. Since 2016, it is recognized as a disease. Strength exercise training and nutritional support are the frontline treatment of sarcopenia, with no drug currently approved for this indication. However, new therapeutic options are emerging. In this review, we evidenced that only very few trials have focused on sarcopenia/sarcopenic patients. Most drug trials were performed in different clinical older populations (e.g., men with hypogonadism, post-menopausal women at risk for osteoporosis), and their efficacy were tested separately on the components of sarcopenia (muscle mass, muscle strength and physical performances). Results from trials testing the effects of Testosterone, Selective Androgen Receptor Modulators (SARMs), Estrogen, Dehydroepiandrosterone (DHEA), Insulin-like Growth Factor-1 (IGF-1), Growth Hormone (GH), GH Secretagogue (GHS), drug targeting Myostatin and Activin receptor pathway, Vitamin D, Angiotensin Converting Enzyme inhibitors (ACEi) and Angiotensin Receptor Blockers (ARBs), or β-blockers, were compiled. Although some drugs have been effective in improving muscle mass and/or strength, this was not translated into clinically relevant improvements on physical performance. Finally, some promising molecules investigated in on-going clinical trials and in pre-clinical phase were summarized, including apelin and irisin.


Sensitivity to inflectional morphology in agrammatism: investigation of a highly inflected language.
We present the results of a study with six Serbo-Croatian-speaking agrammatic patients on a test of inflectional morphology in which subjects judged whether spoken sentences were grammatical or ungrammatical. Sensitivity to two kinds of syntactic features was investigated in these aphasic patients: (1) subcategorization rules for transitive verbs (which must be followed by a noun in the accusative case; intransitive verbs can be followed by nouns in other noun cases); (2) sensitivity to the inflectional morphology marking noun case. The test items consisted of three-word sentences (noun-verb-noun) in which verb transitivity and appropriateness of the case inflection of the following noun were manipulated. Results of the grammaticality judgment task show that both syntactic properties are preserved in these patients.


Liquid chromatography-mass spectrometry approach for the characterization and purification of crude synthetic peptide hormones.
In this study, conditions for the optimal separation by LC-UV and characterisation by LC-ES-MS of crude mixtures generated during SPPS of several peptide hormones are compiled. The linear solvation energy relationship (LSER) methodology has been used to predict the retention of the target peptides and their side products and then to develop a separation LC methodology with applicability on both the analytical and preparative scale. Identification of these side products by LC-ES-MS analysis has been made on the basis of their calculated molecular masses. This method may be regarded as a key tool for the optimisation of the synthetic procedures and for complying with regulatory agencies' requirements before commercialisation of a safe and effective peptide-based pharmaceutical drug.


Pharmacological actions of Y-24180: I. A potent and specific antagonist of platelet-activating factor.
The ability of Y-24180, 4-(2-chlorophenyl)-2-[2-(4-isobutylphenyl)ethyl]- 6,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a] [1,4]diazepine to inhibit platelet-activating factor (PAF)-induced reactions was investigated. Y-24180 (0.0003-0.003 mg/kg, i.v.) dose-dependently inhibited PAF-induced bronchoconstriction in guinea pigs, but even at a high dose of 10 mg/kg, i.v., it was either inactive or weakly active against the bronchoconstriction induced by histamine, serotonin, acetylcholine, arachidonic acid, bradykinin, or leukotriene D4. Oral doses (0.003-0.1 mg/kg) of Y-24180 also prevented hemoconcentration due to PAF in a dose dependent manner and produced a parallel shift of the PAF dose-response curve. Y-24180 (0.0003-0.1 mg/kg, i.v.) and WEB 2086 (0.03-1 mg/kg, i.v.) dose-dependently reversed PAF-induced hypotension in anesthetized rats. In mice, PAF-induced lethality was inhibited by Y-24180 and WEB 2086 with ED50 values of 0.022 and 1.42 mg/kg, p.o., and 0.023 and 0.12 mg/kg, i.v., respectively. This protective effect of Y-24180 given p.o. persisted for at least 6 hr. In actively sensitized mice lethal anaphylactic shock was prevented by oral doses of Y-24180 and WEB 2086 with ED50 values of 0.095 and 0.69 mg/kg, respectively. These results suggested that Y-24180 is an extremely potent and specific PAF antagonist with a good duration of action.


Psychometric properties of health-related quality of life instruments used in survivors of critical illness: a systematic review.
Health-related quality of life (HRQoL) is a patient-reported measure of health status. However, research on the psychometric properties of HRQoL instruments used post-critical care is less common. We conducted a systematic review assessing the psychometric properties of HRQoL instruments used in adult survivors following critical illness. Three databases were systematically searched between 1990 and June 2022. Screening articles for eligibility, we selected either development studies for new tools or studies that evaluated psychometric properties, and whose target population represented adult survivors following critical illness. Methodological quality was assessed using the COnsensus-Based Standards for the selection of health Measurement INstruments (COSMIN) checklist. The results of each psychometric property were then assessed for criteria of good psychometric properties (sufficient, insufficient or indeterminate) and qualitatively summarised. Finally, we graded the quality of the evidence using a modified GRADE approach. We retrieved 13 eligible studies from 2,983 records identifying 10 HRQoL instruments used post-critical illness. While high-quality evidence for the considered PROMs was limited primarily due to risk of bias, seven instruments demonstrated sufficient levels of reliability, four instruments presented sufficient hypothesis testing, and two instruments showed sufficient responsiveness. Except the Short Form-36, evidence for psychometric properties of other individual measures was limited to a few studies. There was limited evidence demonstrated for the psychometric properties of the included PROMs evaluating HRQoL. Further research is warranted to evaluate the psychometric properties of HRQoL measures, strengthening the evidence for administering these instruments in survivors following critical illness.


Implementing targeted therapies in the treatment of glioblastoma: Previous shortcomings, future promises, and a multimodal strategy recommendation.
The introduction of targeted therapies to the field of oncology has prolonged the survival of several tumor types. Despite extensive research and numerous trials, similar outcomes have unfortunately not been realized for glioblastoma. For more than 15 years, the standard treatment of glioblastoma has been unchanged. This review walks through the elements that have challenged the success of previous trials and highlight some future promises. Concurrently, this review describes how institutions, through a multimodal and comprehensive strategy with 4 essential components, may increase the probability of finding a meaningful role for targeted therapies in the treatment of glioblastoma. These components are (1) prudent trial designs, (2) considered drug and target selection, (3) harnessed real-world clinical and molecular evidence, and (4) incorporation of translational research.


Study of antigenic structure and inhibition of activity of human growth hormone and chorionic somatomammotropin by monoclonal antibodies.
Distinct antigenic determinants were identified on native molecules of human growth hormone (hGH) and chorionic somatomammotropin (hCS) on the basis of competitive inhibition assays with eight murine monoclonal antibodies. Effective competition for antigen binding within a pair of antibodies indicated overlapping combining site specificities whereas a lack of competition suggested binding to sterically distinct structural moieties. An antigenic determinant, specific for hGH was detected by antibodies QA68 and NA27, whilst another marginally hCS-cross-reactive site was bound by NA71. Two distinct determinants fully expressed by either hGH or hCS were bound by antibody pairs NA39/EB2 and EB1/EB3 respectively, whereas a single hCS-specific determinant was recognized by antibody EB4. An unexpected reciprocal cross-inhibition of soluble antigen antibody complex binding was observed between antibodies reacting to distinct determinants, i.e. for NA27 towards NA39/EB2 and for NA71 towards EB1/EB3. These results were tentatively interpreted in terms of conformational changes of antigen when bound in soluble immune complexes, but an alternative explanation of steric hindrance cannot yet be excluded. The effect of monoclonal antibodies on the hormonal biological activity was investigated in a dose response study of the hormone-dependent growth stimulation of NB2 lymphoma cells in tissue culture. Although all eight antibodies were specifically growth-inhibitory, major quantitative differences in their efficacies have been observed. At limiting hormone doses antibodies EB2 NA39 were most effective whereas QA68 and NA71 were the most potent at excess hormone input. Various mechanisms operating through inhibition of hormone binding and/or modulation of cell receptor-bound complexes have been considered.


[Preoperative determination of the position of mandibular canal for planning sagittal ramus osteotomy of the mandible].
In the literature the incidence of permanent nerve lesions ranges from 3 to 39%. Therefore, we think that it is necessary to discuss the procedure of individual risk assessment and management. Standard imaging techniques for the preoperative planning and preparation of a sagittal split osteotomy usually include a panoramic radiograph and lateral cephalometric radiograph. If an assessment of the transversal thickness of the lower jaw and cortical substance is required, or the position of the inferior alveolar nerve needs to be determined for preoperative planning, computed tomography of the viscerocranium has to be performed. By employing the conventional computed tomographic X-ray imaging system CommCAT, we are able to determine preoperatively both the transversal thickness of the lower jaw including the cortical substance and the diameter of the ascending ramus of the mandible at the proximal osteotomy site. We examined prospectively the value of these additional investigations and compared them with the intraoperative findings in 29 patients. With these tomograms, the relation between the position of the inferior alveolar nerve and the vestibular cortical bone was metrically evaluated. In 17 of 58 jaw sides we detected the nerve at a distance from the outer cortical bone of 2 mm or less. The situation for the upper osteotomy was critical in eight cases where the thickness of the mandibular ramus was only 3 mm. By using of the conventional computed tomography system CommCAT, we have the preoperative opportunity to determine the transversal thickness of the mandibular ramus as well as the exact position of the inferior alveolar nerve and its distance from the cortical bone of the mandibular corpus. By predicting the nerve's position and its relation to the osteotomy site, we are able to individualize the operation procedure so that a high standard of safety can be achieved.


Onset of the action of intravesical lidocaine after spinal cord injury.
To obtain objective evidence for the time to onset of action for intravesical lidocaine utilizing exaggerated sympathetic blood-pressure responsiveness in patients with spinal cord injuries (SCI). This prospective observational cohort study analyzed blood pressure responses in individuals with SCI at or above T6 who did (lidocaine-instillation group) or did not (control group) receive 10 ml of 2% lidocaine gel instilled through their catheters before routine suprapubic catheter change. Care was taken to minimize any potentially confounding position change or catheter manipulation. Given the potential for C-fiber mediated systolic blood pressure (SBP) increases after SCI, the time to lidocaine's onset of action for blocking these C-fibers (as seen by the decrease in SBP more than and equal to 10 mm Hg) was assessed with serial blood pressures for 4 to 6 minutes. Blood pressures were evaluated in 32 individuals with SCI (lidocaine-instillation group n = 22, control group n = 10). In the lidocaine-instillation group, 45% individuals demonstrated a sustained decrease in SBP more than and equal to 10 mm Hg, which occurred at a mean of 98.1 seconds (SD 59 seconds) after lidocaine instillation. Despite up to 6 minutes of serial monitoring, the remainder of the lidocaine-instillation group and the entire control group had SBP fluctuations less than 10 mm Hg. The serial mean SBPs of those who responded to lidocaine were significantly less than the remaining groups (P < .001 for both comparisons). Utilizing lidocaine's properties to decrease sympathetic-inducing afferents after SCI, the time to onset of action for intravesical lidocaine was found to be approximately 90 seconds. This relatively rapid initial onset on action is especially pertinent when managing autonomic dysreflexia.


Auditory event-related brain potentials in fibromyalgia syndrome.
The aim of this study was to investigate cognitive functions using auditory event-related brain potentials (ERP) in fibromyalgia syndrome (FMS). The P300 component of ERP was studied in 36 female FMS patients and 22 control subjects. The short form 36 (SF-36) medical outcome study was used to determine quality of life. Number of tender points and disease duration were noted. Cognitive functions were evaluated with P300. The symptoms were discrepant in FMS (P<0.001). The scores of the eight SF-36 subgroups in FMS patients were significantly lower than in the control group (P<0.001). Fibromyalgia syndrome patients had prolonged latency and reduced amplitude of P300 (P<0.001). No correlation was found between the subgroups of SF-36, tender point count, disease duration, and P300. The results of our study reveal that FMS affects quality of life and dysfunction in cognitive abilities can be determined by brain event-related potentials.


Myocardial scintigraphy. Post-Vineberg study.
In order to assess myocardial perfusion of Vineberg implants, tracer particles (99mCc and 131I-MAA) were injected into the internal mammary implants of 7 patients (6 years after the operation) after selective contrast visualization. The myocardial perfusion images were correlated with the internal mammary arteriographic findings. Of those patients with patent implants with communication, the myocardial scintigrams demonstrated even distribution of radioactive particles reflecting myocardial perfusion at the capillary or precapillary bed.


High-resolution methylation analysis and in vivo protein-DNA binding at the promoter of the viral oncogene LMP2A in B cell lines carrying latent Epstein-Barr virus genomes.
Latency protein LMP2A of Epstein-Barr virus (EBV) has been implicated in EBV related tumorigenesis. To understand the host cell dependent expression of the LMP2A gene, it is necessary to analyse the regulatory mechanisms of the LMP2A promoter (LMP2Ap). By transient transfection and in vitro binding analyses two CBF1 sites have previously been shown to be involved in the regulation of LMP2Ap. However, the promoter structure has not been examined at the nucleotide level in vivo. Therefore we undertook a comprehensive analysis of in vivo protein binding and of CpG-methylation patterns at LMP2Ap in a panel of B cell lines carrying latent EBV genomes. The presence of characteristic footprints on two CBF1 and further binding-sites, together with overall hypomethylation of CpG dinucleotides correlated well with promoter activity. In contrast, the absence of several genomic footprints, as well as the presence of patches of highly methylated CpG dinucleotides were characteristic of silent LMP2Aps.


Human endogenous retroviral K element encodes fusogenic activity in melanoma cells.
Nuclear atypia with features of multi nuclei have been detected in human melanoma specimens. We found that the K type human endogenous retroviral element (HERV K) is expressed in such cells. Since cellular syncytia can form when cells are infected with retroviruses, we hypothesized that HERV K expressed in melanoma cells may contribute to the formation of multinuclear atypia cells in melanoma. We specifically inhibited HERV K expression using RNA interference (RNAi) and monoclonal antibodies and observed dramatic reduction of intercellular fusion of cultured melanoma cells. Importantly, we identified loss of heterozygosity (LOH)of D19S433 in a cell clone that survived and proliferated after cell fusion. Our results support the notion that proteins encoded by HERV K can mediate intercellular fusion of melanoma cells, which may generate multinuclear cells and drive the evolution of genetic changes that provide growth and survival advantages.


Personal exposure to fine particulate matter (PM2.5) of pregnant women during three trimesters in rural Yunnan of China.
Little is known about fine particulate matter (PM2.5) exposure among pregnant women in rural China. This study aims to characterize exposure to PM2.5 among pregnant women in rural China, and investigate potential risk factors of personal exposure to PM2.5. The data were obtained from a birth cohort study that enrolled 606 pregnant women in Xuanwei, a county known for its high rates of lung cancer. The personal exposure to PM2.5 was measured using small portable particulate monitors during each trimester of pregnancy. Participants were interviewed using structured questionnaires that sought information on risk factors of PM2.5 exposure. The daily exposure to PM2.5 among the pregnant women ranged from 19.68 to 97.08 μg/m3 (median = 26.08). Exposure to PM2.5 was higher in winter and autumn than other seasons (p < 0.05); higher during the day than during the night (p < 0.001); and greater during cooking hours than during the rest of the day (p < 0.001). Using a mixed effects model, domestic solid fuel for cooking (β = 1.75, p < 0.001), winter and autumn (β = 2.96, p < 0.001), cooking ≥ once per day (β = 1.58, p < 0.05), heating with coal (β = 1.69, p < 0.001), secondhand smoke exposure (β = 1.59, p < 0.001) and township 1(β = 2.39, p < 0.001) were identified as risk factors for personal exposure to PM2.5 of pregnant women throughout pregnancy. Indirect effects of season and township factors on personal PM2.5 exposure were mediated by heating, cooking and domestic fuel using. In conclusion, PM2.5 levels in Xuanwei exceeded WHO guidelines. Seasonal and township factors and individual behaviors like domestic solid fuel using for cooking, heating with coal and secondhand smoke exposure are associated with higher personal PM2.5 exposure among pregnant women in rural China.


The influence of hydrogen peroxide concentration on the chemical kinetics of photo-accelerated tooth whitening.
The bleaching procedure consists of chemical principles of free radical release that react with chromophores, which results in an amount of energy released in this process. However, the evaluation of the electrical potential generated in these protocols has not yet been thoroughly investigated in the literature. Thus, this study aimed to examine variations in pH, mV, and temperature of different concentrations of hydrogen peroxide in the presence or absence of an intermittent LED/LASER photo acceleration system. The study was divided into six groups (n = 9) according to the concentration of hydrogen peroxide (6%, 15%, and 35%), associated or not with the photo acceleration system LED/LASER. We followed the variation of pH, mV, and temperature at 1, 5, 10, 15, and 30 min after gel manipulation. Data were evaluated by two-way ANOVA of repeated measures (α =0.05). pH, mV, and temperature of the groups showed statistical differences both in the light and bleach and in the interaction between the two factors (p < 0.0001), where pH and mV were more influenced by the bleach and light factor, while the temperature was influenced by the bleach factor associated with light. HP15 presented the most significant change in pH, mV, and temperature. The use of LED/laser increased the temperature of the gels and altered the pH and mV kinetics of HP6 and HP15, which did not occur in HP35, possibly due to the high ionic potential linked to the concentration.


Cognitive screening tools in multiple sclerosis revisited: sensitivity and specificity of a short version of Rao's Brief Repeatable Battery.
Cognitive deficits are common in multiple sclerosis (MS) and require continuous monitoring. In routine examinations, screening instruments such as the Brief Repeatable Battery (BRB) may serve this purpose. It was suggested that even a shortened version of the BRB, comprising the Symbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Test (PASAT) and Selective Reminding Test (SRT), may be feasible. However, an evaluation of sensitivity and specificity of the short BRB in comparison to an independent battery of established tests has not yet occurred. Therefore in the current study, this short version of the BRB was matched against the gold standard of an extensive test battery comprehensively assessing neuropsychological functions. 127 MS-patients were tested with a short version of the BRB and an extensive procedure. The latter served as the gold standard for defining sensitivity and specificity. For subtests of the short BRB, estimates of sensitivity (38-44 %) and specificity (81-94 %) were obtained. Combining subtests into a single indicator of cognitive deficits yielded increased sensitivity (78 %), while reducing specificity (65 %). The short BRB is reasonably sensitive and specific in detecting cognitive deficits. However, these qualities only emerge, if the short BRB is administered as a whole, whereas sensitivity is considerably lower than suggested by previous work, when relying on subtests separately (SDMT, PASAT, SRT). While the short BRB may not be regarded as conclusive as an extensive test battery, it represents a valid and economic screening instrument.


Unveiling the impacts of geothermal energy growth on food security in EU27 region: an empirical analysis.
There are many advantages of geothermal energy, as an environmental friend resource. This heat radiation emanating from beneath the earth's surface presents man with good opportunities to harness it and makes a good level of agricultural food production and its processing in the EU region. The primary objective of this research is to examine the impact of geothermal energy on agri-food supply among the 27 European countries (EU27), within the time frame 1990 to 2021. The study adopted the autoregressive distributed lag (ARDL), and the findings from this study revealed that agri-food supply can increase significantly among the 13 European countries (EU13 emerging economies), leveraging on geothermal energy and economic growth variables than in the EU14 emerged economies. Furthermore, the outcome of this study showed that there could be a significant decrease in the food products coming from agricultural practices among the 13 European countries (EU13 emerging economies), due to an ineffective population density than in EU14 emerged economies. Furthermore, fossil fuel and institutional quality contribute more positively to the agri-food supply in the EU14 emerged economies than in the EU13 emerging economies. This results in an outcome that means that the agri-food supply among the EU13 emerging economies could be greatly boosted by replacing fossil fuel consumption with geothermal energy, and this facilitates the attainment of the European energy goals by the year 2030. Substituting fossil fuels with geothermal will also assist in minimizing the risks of environmental pollution and climate change. All projected calculations were seen as valid in this study, and this was confirmed by the three estimators adopted which are the pooled mean group, the mean group, and the dynamic fixed effect. This study, therefore, recommends that the 27 European countries should lay more emphasis on geothermal energy production as this will help in ensuring food security in the region. Policymakers and other government authorities as well as local and foreign investors should make more investments in geothermal energy resources as this study has proven that this will lead to agri-food security and sustainability. Not only this, it will as well curb the incidence of climate change and environmental pollution.


Comparison of null models for combination drug therapy reveals Hand model as biochemically most plausible.
Null models for the effect of combination therapies are widely used to evaluate synergy and antagonism of drugs. Due to the relevance of null models, their suitability is continuously discussed. Here, we contribute to the discussion by investigating the properties of five null models. Our study includes the model proposed by David J. Hand, which we refer to as Hand model. The Hand model has been introduced almost 20 years ago but hardly was used and studied. We show that the Hand model generalizes the principle of dose equivalence compared to the Loewe model and resolves the ambiguity of the Tallarida model. This provides a solution to the persisting conflict about the compatibility of two essential model properties: the sham combination principle and the principle of dose equivalence. By embedding several null models into a common framework, we shed light in their biochemical validity and provide indications that the Hand model is biochemically most plausible. We illustrate the practical implications and differences between null models by examining differences of null models on published data.


Quality of information on the internet related to bladder pain syndrome: a systematic review of the evidence.
Bladder pain syndrome (BPS) has an impact on quality of life and available treatments often only provide temporary symptomatic relief. The information provided by websites can be valuable for patient education and management. The hypothesis was to assess medical information available on the internet related to bladder pain syndrome in terms of accuracy, credibility, readability and quality. A search was performed in the meta-search engine Copernic Agent, using the search terms "bladder pain syndrome, interstitial cystitis, painful bladder syndrome and pelvic pain", which simultaneously captured websites from a range of engines. Websites in the English language that were open-access were included. The four quality assessments used were: credibility using a ten-point scale, accuracy based on the American Urological Association guidelines, quality using the DISCERN questionnaire and readability using the Flesch Reading Ease Score. Inter-rater agreement was tested by intra-class coefficient (ICC). Eighteen suitable websites were identified; 7 (39%) were specialist or specific to BPS. The combined mean scores for accuracy, quality, credibility and readability ranged from 83 to 144 for specialist websites and 76 to 137 for non-specialist ones, with a maximum possible score of 208. There was good inter-observer agreement for the assessments performed with an ICC ranging from 0.80 for DISCERN to 0.53 for readability. Specialist websites had higher quality scores (median difference 10, p = 0.07) and readability scores (median difference 5.4, p = 0.05) compared with non-specialist websites whereas credibility and accuracy scores were no different. We found four websites that fulfilled our criteria for good quality information.


Gallbladder Cancer Risk and Indigenous South American Mapuche Ancestry: Instrumental Variable Analysis Using Ancestry-Informative Markers.
A strong association between the proportion of indigenous South American Mapuche ancestry and the risk of gallbladder cancer (GBC) has been reported in observational studies. Chileans show the highest incidence of GBC worldwide, and the Mapuche are the largest indigenous people in Chile. We set out to assess the confounding-free effect of the individual proportion of Mapuche ancestry on GBC risk and to investigate the mediating effects of gallstone disease and body mass index (BMI) on this association. Genetic markers of Mapuche ancestry were selected based on the informativeness for assignment measure, and then used as instrumental variables in two-sample Mendelian randomization analyses and complementary sensitivity analyses. Results suggested a putatively causal effect of Mapuche ancestry on GBC risk (inverse variance-weighted (IVW) risk increase of 0.8% per 1% increase in Mapuche ancestry proportion, 95% CI 0.4% to 1.2%, p = 6.7 × 10-5) and also on gallstone disease (3.6% IVW risk increase, 95% CI 3.1% to 4.0%), pointing to a mediating effect of gallstones on the association between Mapuche ancestry and GBC. In contrast, the proportion of Mapuche ancestry showed a negative effect on BMI (IVW estimate -0.006 kg/m2, 95% CI -0.009 to -0.003). The results presented here may have significant implications for GBC prevention and are important for future admixture mapping studies. Given that the association between the individual proportion of Mapuche ancestry and GBC risk previously noted in observational studies appears to be free of confounding, primary and secondary prevention strategies that consider genetic ancestry could be particularly efficient.


[Phenotypic characteristics of heat-resistant murine neuroblastoma cells].
One-step selection of murine neuroblastoma (N18TG2 cell line) for the resistance to injuring action of higher temperature resulted in obtaining cell line NTR1 stably capable of proliferating at 40 degrees C. The thermoresistance is shown to be coupled with the changes in some phenotypic features of NTR1 cells: the multiplication rate, saturation density of cells, morphological features, inducibility of long neurite-like processes and adhesion. A possible significance of plasma membrane changes in genetically stable thermoresistance of NTR1 neuroblastoma cells is discussed.


Balanced Salt Solutions for Critically Ill Patients: Nonplused and Back to Basics.
The purpose of this article is to summarize the results of major randomized controlled trials (RCTs) comparing clinical outcomes of critically ill patients treated with normal saline (NS) or balanced salt solutions (BSSs), address discordant results of these studies, and provide direction for future investigations. PubMed (2011 to January 2022) with bibliographies of retrieved articles searched for additional articles. RCTs comparing NS and BSSs in critically ill adult patients. Recently published large RCTs comparing NS with BSSs in heterogeneous populations of intensive care unit patients did not find significant differences in mortality, despite positive findings in some end points in prior RCTs. However, there were a number of methodologic issues common to the RCTs including: varying study designs and end points, clinician discretion for the majority or all treatments other than the primary intervention fluid, heterogeneous patients with varying levels of acuity, and lack of power to investigate potential subgroup differences. In addition, there were problematic issues related to blinding and use of nonstudy fluids. Intravenous fluids are a mainstay of supportive care for critically ill patients. Similar to the so-called crystalloid-colloid debate, there has been a long-standing debate among critical care clinicians and researchers concerning the preferred crystalloid solution, NS versus one of the available BSSs. Despite the recent publication of large multicenter RCTs, the preferred resuscitation fluid, NS or a BSS, for critically ill patients is still open for debate, although the available investigations do provide some direction for clinicians and for future investigations.


Tumor cell-activated CARD9 signaling contributes to metastasis-associated macrophage polarization.
Macrophages are critical immune effector cells of the tumor microenvironment that promote seeding, extravasation and persistent growth of tumor cells in primary tumors and metastatic sites. Tumor progression and metastasis are affected by dynamic changes in the specific phenotypes of macrophage subpopulations; however, the mechanisms by which tumor cells modulate macrophage polarization remain incompletely understood. Caspase recruitment domain-containing protein 9 (CARD9) is a central adaptor protein of innate immune responses to extracellular pathogens. We report that increased CARD9 expression is primarily localized in infiltrated macrophages and significantly associated with advanced histopathologic stage and the presence of metastasis. Using CARD9-deficient (CARD9(-/-)) mice, we show that bone marrow-derived CARD9 promotes liver metastasis of colon carcinoma cells. Mechanistic studies reveal that CARD9 contributes to tumor metastasis by promoting metastasis-associated macrophage polarization through activation of the nuclear factor-kappa B signaling pathway. We further demonstrate that tumor cell-secreted vascular endothelial growth factor facilitates spleen tyrosine kinase activation in macrophages, which is necessary for formation of the CARD9-B-cell lymphoma/leukemia 10-mucosa-associated lymphoid tissue lymphoma translocation protein 1 complex. Taken together, our results indicating that CARD9 is a regulator of metastasis-associated macrophages will lead to new insights into evolution of the microenvironments supporting tumor metastasis, thereby providing targets for anticancer therapies.


Risk Factors for Frailty in Critical Care Survivors: A secondary analysis.
The purpose of this study was to investigate the prevalence of frailty and its risk factors among critical care survivors who were discharged after receiving treatment in an intensive care unit. This was a secondary analysis using data from a methodological study conducted between June and August 2018. The sample included 494 adults who had been admitted to the intensive care unit for more than 48 hours within a year. Only post-intensive care frailty was evaluated using the Kihon Checklist. The sociodemographic and intensive care-related risk factors for frailty were analysed using multivariate logistic regression. The prevalence of frailty in the sample was 65.8%. The risk factors for frailty were female sex (adjusted odds ratio [aOR] = 1.68, 95% CI: 1.02-2.78), aged 70 years or older (aOR = 4.16, 95% CI: 2.00-8.65), unemployment (aOR = 2.41, 95% CI: 1.39-4.17) and longer ICU days (aOR = 2.29, 95% CI: 1.35-3.91). Analysis of differences in risk factors according to sex revealed that risk factors for frailty were unemployment and longer ICU length of stay for male and older age for female. Health care providers should be aware of frailty risk factors in female and male patients and provide patient-specific interventions for preventing frailty.


Brain structure in schizophrenia vs. psychotic bipolar I disorder: A VBM study.
While schizophrenia and bipolar disorder have been assumed to share phenotypic and genotypic features, there is also evidence for overlapping brain structural correlates, although it is unclear whether these relate to shared psychotic features. In this study, we used voxel-based morphometry (VBM8) in 34 schizophrenia patients, 17 euthymic bipolar I disorder patients (with a history of psychotic symptoms), and 34 healthy controls. Our results indicate that compared to healthy controls schizophrenia patients show grey matter deficits (p<0.05, FDR corrected) in medial and right dorsolateral prefrontal, as well as bilaterally in ventrolateral prefrontal and insular cortical areas, thalamus (bilaterally), left superior temporal cortex, and minor medial parietal and parietooccipital areas. Comparing schizophrenia vs. bipolar I patients (p<0.05, FDR corrected) yielded a similar pattern, however, there was an additional significant reduction in schizophrenia patients in the (posterior) hippocampus bilaterally, left dorsolateral prefrontal cortex, and left cerebellum. Compared to healthy controls, the deficits in bipolar I patients only reached significance at p<0.001 (uncorr.) for a minor parietal cluster, but not for prefrontal areas. Our results suggest that the more extensive prefrontal, thalamic, and hippocampal deficits that might set apart schizophrenia and bipolar disorder might not be related to mere appearance of psychotic symptoms at some stage of the disorders.


[Visceral leishmaniasis as an opportunistic infection. Our experience].
A case of visceral leishmaniasis in a female patient suffering from acute nonlymphoid leukaemia is reported. Stress is laid on the atypical nature of the clinical picture, falsified by the underlying disease, and attention is called to the behaviour of Leishmania as an opportunistic agent in the immunodepressed host.


Leukoencephalopathy With Predominant Infratentorial Involvement Caused by a Novel ABCD1 Mutation: Does the Spinocerebellar Variant of Adrenoleukodystrophy Exist?
X-linked adrenoleukodystrophy (X-ALD) encompasses several clinical and neuroimaging phenotypes, including cerebral X-ALD, the most common phenotype in children, and adrenomyeloneuropathy, the most common phenotype in adults. A spinocerebellar variant of X-ALD has been described in individuals from the Far East, but the criteria for its diagnosis are unclear. A 35-year-old man from Albania was assessed because of a familial, slowly progressive spastic-ataxic gait associated with neurogenic bladder, sexual dysfunctions, and manic-like behavior. There was no definite clinical feature that suggested cerebellar involvement (eg, cerebellar limb ataxia, nystagmus, and dysarthria). A few months earlier, he had received a diagnosis of Addison disease. Brain magnetic resonance imaging showed a leukoencephalopathy with predominant cerebellum and brainstem involvement, and FDG-PET revealed marked cerebellar hypometabolism. The diagnosis of X-ALD was made because we found an increase of very long chain fatty acids, and a new ABCD1 mutation (c.1627C>T, p.Pro543Ser). X-ALD should be included in the differential diagnosis of adult leukoencephalopathies with predominant involvement of infratentorial structures, that is, the cerebellum and brainstem. From a classification perspective, our patient (of white origin), like others (all of Asian origin), should be considered as suffering from a variant of adrenomyeloneuropathy rather than from spinocerebellar X-ALD. Actually, the term "spinocerebellar" or similar ones, such as "cerebello-brainstem dominant form," should be limited to those exceptional cases, in which both the clinical and neuroimaging findings point exclusively (or at least predominantly) to the involvement of infratentorial structures.


Cost effectiveness of bronchial thermoplasty in patients with severe uncontrolled asthma.
Based on its clinical effectiveness, bronchial thermoplasty (BT) was approved by the Food and Drug Administration in 2010 for the treatment of severe persistent asthma in patients 18 years and older whose asthma is not well-controlled with inhaled corticosteroids and long-acting beta-agonist medicines. Assess the 10 year cost-effectiveness of BT for individuals with severe uncontrolled asthma. Using a Markov decision analytic model, the cost-effectiveness of BT was estimated. The patient population involved a hypothetical cohort of 41-year-old patients comparing BT to usual care over a 10-year time frame. The main outcome measure was cost in 2013 dollars per additional quality adjusted life year (QALY). Treatment with BT resulted in 6.40 QALYs and $7512 in cost compared to 6.21 QALYs and $2054 for usual care. The incremental cost-effectiveness ratio for BT at 10 years was $29,821/QALY. At a willingness to pay per QALY of $50,000, BT continues to be cost effective unless the probability of severe asthma exacerbation drops below 0.63 exacerbation per year or the cost of BT rises above $10,384 total for all three bronchoscopic procedures needed to perform thermoplasty and to cover the entire bronchial tree (baseline = $6690). BT is a cost-effective treatment for asthmatics at high risk of exacerbations. Continuing to follow asthmatics treated with BT beyond 5 years will help inform longer efficacy and support its cost-effectiveness.