Carbohydrates Alone or Mixing With Beef or Whey Protein Promote Similar Training Outcomes in Resistance Training Males: A Double-Blind, Randomized Controlled Clinical Trial.
Beef powder is a new high-quality protein source scarcely researched relative to exercise performance. The present study examined the impact of ingesting hydrolyzed beef protein, whey protein, and carbohydrate on strength performance (1RM), body composition (via plethysmography), limb circumferences and muscular thickness (via ultrasonography), following an 8-week resistance-training program. After being randomly assigned to one of the following groups: Beef, Whey, or Carbohydrate, twenty four recreationally physically active males (n = 8 per treatment) ingested 20 g of supplement, mixed with orange juice, once a day (immediately after workout or before breakfast). Post intervention changes were examined as percent change and 95% CIs. Beef (2.0%, CI, 0.2-2.38%) and Whey (1.4%, CI, 0.2-2.6%) but not Carbohydrate (0.0%, CI, -1.2-1.2%) increased fat-free mass. All groups increased vastus medialis thickness: Beef (11.1%, CI, 6.3-15.9%), Whey (12.1%, CI, 4.0, -20.2%), Carbohydrate (6.3%, CI, 1.9-10.6%). Beef (11.2%, CI, 5.9-16.5%) and Carbohydrate (4.5%, CI, 1.6-7.4%), but not Whey (1.1%, CI, -1.7-4.0%), increased biceps brachialis thickness, while only Beef increased arm (4.8%, CI, 2.3-7.3%) and thigh (11.2%, 95%CI 0.4-5.9%) circumferences. Although the three groups significantly improved 1RM Squat (Beef 21.6%, CI 5.5-37.7%; Whey 14.6%, CI, 5.9-23.3%; Carbohydrate 19.6%, CI, 2.2-37.1%), for the 1RM bench press the improvements were significant for Beef (15.8% CI 7.0-24.7%) and Whey (5.8%, CI, 1.7-9.8%) but not for carbohydrate (11.4%, CI, -0.9-23.6%). Protein-carbohydrate supplementation supports fat-free mass accretion and lower body hypertrophy. Hydrolyzed beef promotes upper body hypertrophy along with similar performance outcomes as observed when supplementing with whey isolate or maltodextrin.


[The model casting method for inlays and bridgework].
The authors deal with the advantages and disadvantages of the direct and the indirect method of inlay making and describe the precision casting technique for inlays and bridges. Furthermore, they present the telescopic tray which has been developed in the Rostock Clinic. This tray permits to apply the impression material under increased pressure. The use of the compound embedding material and dental alloys indicated allows to obtain good treatment results in a rational manner.


Teaching integrative physiology using the quantitative circulatory physiology model and case discussion method: evaluation of the learning experience.
One of the problems that we have found when teaching human physiology in a Spanish medical school is that the degree of understanding by the students of the integration between organs and systems is rather poor. We attempted to remedy this problem by using a case discussion method together with the Quantitative Circulatory Physiology (QCP) program. QCP is a Windows-based computer simulation program that offers almost real-time simulation and allows users to examine the time-dependent interactions of over 750 parameters. We evaluated students' perceptions by an anonymous questionnaire. Teachers' perceptions of this teaching approach were highly positive, as it improved students' perceptions of the complexity of biological processes, their ability to differentiate between acute and chronic responses, and promoted an integrative understanding of human body function. Teachers also identified some problems with the approach, including student difficulties in adopting self-directed learning, a lack of precision in student questions during the discussion sessions, and the lack of a tradition of using several textbooks to explain the changes observed. The results of the student questionnaire revealed that >70% of the students reported that this type of learning gave them a better understanding of the complexity of physiological processes and the role of coordinated actions of several systems in the homeostatic response and enabled them to acquire a better understanding of human body functions. Thus, we conclude that this approach promotes an integrative understanding of cardiovascular and renal functions that is difficult to achieve with other methods.


Valuation in major depression is intact and stable in a non-learning environment.
The clinical diagnosis and symptoms of major depressive disorder (MDD) have been closely associated with impairments in reward processing. In particular, various studies have shown blunted neural and behavioral responses to the experience of reward in depression. However, little is known about whether depression affects individuals' valuation of potential rewards during decision-making, independent from reward experience. To address this question, we used a gambling task and a model-based analytic approach to measure two types of individual sensitivity to reward values in participants with MDD: 'risk preference,' indicating how objective values are subjectively perceived, and 'inverse temperature,' determining the degree to which subjective value differences between options influence participants' choices. On both of these measures of value sensitivity, participants with MDD were comparable to non-psychiatric controls. In addition, both risk preference and inverse temperature were stable over four laboratory visits and comparable between the groups at each visit. Neither valuation measure varied with severity of clinical symptoms in MDD. These data suggest intact and stable value processing in MDD during risky decision-making.


An immunocytochemical study of a G-protein-gated inward rectifier K+ channel (GIRK2) in the weaver mouse mesencephalon.
It has been suggested that a mutation in a G-protein-gated inward rectifier K+ channel (GIRK2) is responsible for inducing cell death in the cerebellum of homozygous weaver (wv/wv) mutant mice. These mice also display a progressive, massive loss of mesencephalic dopaminergic neurones. Using an immunocytochemical method, we detected GIRK2-positive cell bodies and fibres in the substantia nigra pars compacta (SNC) and the ventral tegmental area (VTA) of control (+/+) mice. Cell counts of both GIRK2- and tyrosine hydroxylase (TH)-positive neurones demonstrated a marked loss of SNC cell bodies, especially in 12-month-old (12M) wv/wv mice. A considerable proportion of GIRK2-positive cell bodies were preserved, however. In addition, no loss of GIRK2-positive neurones was observed in the VTA of 12M wv/wv mice, despite of a significant reduction in TH-positive cell bodies. These results suggest that expression of the mutated channel is not a sufficient condition to induce cell death in the ventral mesencephalon of the wv/wv mice.


[Health threats for children in the modern building trade].
Changes in building industry during last 30 years in search of economic technologies and building materials ended in creating airtight and energy-saving constructions with reduced ventilation. As a result, diminish exchange between internal and external air, leads to cumulation of various chemicals and organic substances in our houses. Concentrated oxidation products (CO2, CO, NO2, nicotine smoke), vaporizing substances (formaldehyde, NH3, aromatic hydrocarbons) might irritate mucouses, promote or intense respiratory tract infections, allergic diseases or bronchial asthma. Higher risk of atopic diseases and bronchial asthma also arises from proliferation of fungus, bacteria and mites in modern interiors, which are quite convenient for it. Buildings with microclimate, which is dangerous for human health, are termed "sick buildings". Diseases that develop under their influence are called BRI (building related illnesses). Children are most exposed on them, especially under municipal conditions, because they spend majority of their time at home.


Experimental Investigation on Post-Fire Mechanical Properties of Glass Fiber-Reinforced Polymer Rebars.
Glass fiber-reinforced polymer (GFRP) rebars are commonly used as an alternative to conventional steel reinforcement in a variety of structural applications due to their superior low cost, strength-to-weight ratio, and durability. However, their mechanical properties after exposure to elevated temperatures, particularly in fire-prone environments, remain a significant concern. To address this concern, the present study focuses on investigating the residual tensile behavior, specifically the tensile strength and elastic modulus, of GFRP rebars exposed to high temperatures that are realistically encountered during fire incidents. The temperature range considered in this analysis spans from 100 °C to 400 °C, with a heating rate of 20 °C/min. The fire duration of 1 h is used. This comprehensive analysis is essential for enhancing our understanding of the performance and applicability of GFRP rebars in fire-prone environments. Based on their actual application in the construction industry, five specimens of three different rebar sizes (16, 20, and 25 mm) were examined for the effect of rebar size on tensile behavior after fire exposure. In addition, the effects were investigated of air- and water-cooling methods on residual tensile behavior. The nominal tensile strength, elastic modulus, and ultimate strain of GFRP rebars at ambient temperature are 930 MPa, 50.2 GPa and 1.85%, respectively. The test results indicated that as the temperature increased to 400 °C, the ultimate tensile strength of the GFRP bars decreased by up to 55%, while the ultimate strain increased by up to 44%, regardless of the cooling method. In addition, when rebars of sizes 16-25 mm were subjected to a 400 °C fire treatment, the smaller the rebar, the greater the percentage of ultimate tensile and strain reduction. These findings hold great significance for the utilization of GFRP bars within the construction industry. This study offers valuable insights into the design of fire-resilient structures, emphasizing the importance of considering rebar size and cooling methods due to their impact on the post-fire tensile strength and strain of GFRP rebars.


Microstructure evaluation of dermally applicable liquid crystals as a function of water content and temperature: Can electron paramagnetic resonance provide complementary data?
Insight into the microstructure of lyotropic liquid crystals (LCs) is of crucial importance for development of novel dermal delivery systems. Our aim was to evaluate the phase behaviour of dermally applicable LCs composed of isopropyl myristate/Tween 80/lecithin/water, along the dilution line, where phase transitions are predominantly driven by increased water content. Additionally, identification of LC temperature dependence is of great importance for skin application. Selected LCs were evaluated using electron paramagnetic resonance (EPR) plus conventionally used methods of polarization microscopy, small-angle X-ray scattering, differential scanning calorimetry, and rheological measurements. Depending on water content, LCs formed diverse microstructures, from (pseudo)hexagonal (LC1) and lamellar (LC2-LC7) liquid crystalline phases that possibly co-exist with rod-like micelles (LC4-LC7), to a transitional micellar phase (LC8). Furthermore, the LCs microstructure remained unaltered within the tested temperature range. EPR was shown to detect microstructural transitions of LCs and to provide complementary data to other techniques. These data thus confirm the applicability of EPR as a complementary technique for better understanding of LC microstructural transitions that are expected to contribute greatly to studies oriented towards the drug release characteristics from such systems.


Predictive Value of the C-Reactive Protein to Albumin Ratio in 30-Day Mortality after Hip Fracture in Elderly Population: A Retrospective Observational Cohort Study.
C-reactive protein (CRP) to Albumin ratio (CAR) has been used in multiple clinical settings to predict early mortality. However, there is a lack of evidence on the predictive role of CAR in 30-day mortality after a hip fracture. The purpose of this study was to establish a potential association between CAR and 30-day mortality and to assess if the CAR Receiving Operating Characteristics curve (ROC) can be a reliable predictor of early mortality. We retrospectively reviewed the charts of 676 patients (>65 years) treated for hip fracture between 2006 and 2018. All hip fractures were included. Treatment strategies included closed reduction and internal fixation, open reduction and internal fixation, hemiarthroplasty, or total joint arthroplasty. Statistical analysis included T-test, Pearson correlation for CAR and other markers, ROC curves and area under the curve, Youden Model, and Odds Ratio. The 30-day mortality rate analysis showed that higher preoperative levels of CAR were associated with higher early mortality. When analyzing the area under the ROC curve (AUROC) for 30-day mortality, the reported value was 0.816. The point of the ROC curve corresponding to 14.72 was considered a cut-off with a specificity of 87% and a sensibility of 40.8%. When analyzing values higher than 14.72, the 30-day mortality rate was 17.9%, whilst, for values lower than 14.72, the 30-day mortality rate was 1.8%. Patients older than 65 years affected by a hip fracture with increased preoperative levels of CAR are associated with higher 30-day mortality. Despite a moderate sensibility, considering the low cost and the predictivity of CAR, it should be considered a standard predictive marker.


Evaluation of a miniaturized NIR spectrometer for cultivar identification: The case of barley, chickpea and sorghum in Ethiopia.
Crop cultivar identification is fundamental for agricultural research, industry and policies. This paper investigates the feasibility of using visible/near infrared hyperspectral data collected with a miniaturized NIR spectrometer to identify cultivars of barley, chickpea and sorghum in the context of Ethiopia. A total of 2650 grains of barley, chickpea and sorghum cultivars were scanned using the SCIO, a recently released miniaturized NIR spectrometer. The effects of data preprocessing techniques and choosing a machine learning algorithm on distinguishing cultivars are further evaluated. Predictive multiclass models of 24 barley cultivars, 19 chickpea cultivars and 10 sorghum cultivars delivered an accuracy of 89%, 96% and 87% on hold-out sample. The Support Vector Machine (SVM) and Partial least squares discriminant analysis (PLS-DA) algorithms consistently outperformed other algorithms. Several cultivars, believed to be widely adopted in Ethiopia, were identified with perfect accuracy. These results advance the discussion on cultivar identification survey methods by demonstrating that miniaturized NIR spectrometers represent a low-cost, rapid and viable tool. We further discuss the potential utility of the method for adoption surveys, field-scale agronomic studies, socio-economic impact assessments and value chain quality control. Finally, we provide a free tool for R to easily carry out crop cultivar identification and measure uncertainty based on spectral data.


Thermodynamics of phosphopeptide binding to the human peptidyl prolyl cis/trans isomerase Pin1.
Proteins containing phosphorylated Ser/Thr-Pro motifs play key roles in numerous regulatory processes in the cell. The peptidyl prolyl cis/trans isomerase Pin1 specifically catalyzes the conformational transition of phosphorylated Ser/Thr-Pro motifs. Here we report the direct analysis of the thermodynamic properties of the interaction of the PPIase Pin1 with its substrate-analogue inhibitor Ac-Phe-D-Thr(PO3H2)-Pip-Nal-Gln-NH2 specifically targeted to the PPIase active site based on the combination of isothermal titration calorimetry and studies on inhibition of enzymatic activity of wt Pin1 and active site variants. Determination of the thermodynamic parameters revealed an enthalpically and entropically favored interaction characterized by binding enthalpy deltaH(ITC) of -6.3 +/- 0.1 kcal mol(-1) and a TdeltaS(ITC) of 4.1 +/- 0.1 kcal mol(-1). The resulting dissociation constant KD for binding of the peptidic inhibitor with 1.8 x 10(-8) M resembles the dissociation constant of a Pin1 substrate in the transition state, suggesting a transition state analogue conformation of the bound inhibitor. The strongly decreased affinity of Pin1 for ligand at increasing ionic strength implicates that the potential of bidentate binding of a substrate protein by the PPIase and the WW domain of Pin1 may be required to deploy improved efficiency and specificity of Pin1 under conditions of physiological ionic strength.


[Feasibility low cryptorchidism surgery following modified day surgical procedures].
To explore the feasibility and safety of cryptorchidism surgery in the day surgery center. This retrospective study included 122 cases of unilateral low cryptorchidism (ULC) and 27 cases of bilateral low cryptorchidism (BLC) treated by orchidopexy from July 2018 to July 2022 in the Second Hospital of Hebei Medical University. We divided the patients with ULC into an Ad (day surgery following modified day surgical procedures) and an Ac (conventional surgery) group, and those with BLC into a Bd and a Bc group. We analyzed the clinical data and compared the surgical parameters and patients' satisfaction between different groups. There were no statistically significant differences in the operation age, operation time, intraoperative blood loss, or postoperative complications between the Ad and Ac groups (P > 0.05), but the hospital stay and total cost were markedly reduced in the Ad group by 69% and 10%, respectively, compared with those in the Ac group (P < 0.05). No statistically significant differences were observed between the Bd and Bc groups in the operation age or intraoperative blood loss (P > 0.05), but the Bd group showed significant decreases in the operation time, hospital stay (62%) and total cost (14%) in comparison with the Bc group (P < 0.05). The satisfaction of the patients was remarkably higher in the former than in the latter group. Low cryptorchidism surgery following the modified day surgical procedures in the day surgery center is safe and feasible, with the advantages of lower cost and shorter hospital stay.


How is flow experienced and by whom? Testing flow among occupations.
The aims of this paper are to test (1) the factorial structure of the frequency of flow experience at work; (2) the flow analysis model in work settings by differentiating the frequency of flow and the frequency of its prerequisites; and (3) whether there are significant differences in the frequency of flow experience depending on the occupation. A retrospective study among 957 employees (474 tile workers and 483 secondary school teachers) using multigroup confirmatory factorial analyses and multiple analyses of variance suggested that on the basis of the flow analysis model in work settings, (1) the frequency of flow experience has a two-factor structure (enjoyment and absorption); (2) the frequency of flow experience at work is produced when both challenge and skills are high and balanced; and (3) secondary school teachers experience flow more frequently than tile workers.


Formulation by design of felodipine loaded liquid and solid self nanoemulsifying drug delivery systems using Box-Behnken design.
To design and develop liquid and solid self-nanoemulsifying drug delivery systems (SNEDDS and S-SNEDDS) of felodipine (FLD) using Box-Behnken design (BBD). Solubility study was carried out in various vehicles. Ternary phase diagram was constructed to delineate the boundaries of the nanoemulsion domain. The content of formulation variables, X1 (Acconon E), X2 (Cremophor EL) and X3 (Lutrol E300) were optimized by assessment of 15 formulations (as per BBD) for mean globule sizes in Millipore water (Y1), 0.1 N HCl (Y2), phosphate buffer (pH 6.4) (Y3); emulsification time (Y4) and T85% (Y5). The responses (Y1-Y5) were evaluated statistically by analysis of variance and response surface plots to obtain optimum points. The optimized formulations were solidified by adsorption to solid carrier technique using Aerosil 200 (AER). Transmission electron microscopy images confirmed the spherical shape of globules with the size range concordant with the globule size analysis by dynamic light scattering technique (<60 nm). The surface morphology of S-SNEDDS (before release) by scanning electron microscopy and atomic force microscopy indicated that SNEDDS are adsorbed uniformly on the surface of AER. The dried residue of S-SNEDDS (after release) revealed the presence of nanometric pores vacated by the previously adsorbed SNEDDS onto AER. Differential scanning calorimetry and X-ray powder diffraction studies illustrated the change of FLD from crystalline to amorphous state. This study indicates that owing to nanosize, SNEDDS and S-SNEDDS of FLD have potential to enhance its absorption and may serve an efficient oral delivery.


A synthetic glycopeptide of substance P analogue (SP6-11) with enhanced NK-1 receptor specificity.
A new glycopeptide analogue of substance P (6-11) (SP6-11), namely, N1,6 (beta-D-glucopyranosyl) [Glu6, Pro9]SP6-11, has been synthesized and found to be water soluble. The in vitro biological activity of this glycopeptide was determined for spasmogenic activity in the guinea pig ileum and for potentiation of electrically evoked contractions in the rat vas deferens. Thus, activities on NK-1, NK-2, and NK-3 receptor types have been differentiated by two assays and, in the case of NK-1 and NK-3, receptors in guinea pig ileum (GPI) were assayed using specific pharmacological procedures. The ED50 values for the analogue and reference peptides substance P (SP), neurokinin A(NKA), and neurokinin B (NKB) were determined and potencies relative to SP were calculated. The analogue is three times more potent than the potent NK-1 agonist SP on NK-1 receptors. Moreover, this glycopeptide proved to be as selective for the NK-1 receptor as the specific agonist SPOMe (the methyl ester of substance P).


Biliary complications during and after laparoscopic cholecystectomy.
Bile duct injury and bile leak are the most serious complications of laparoscopic cholecystectomy. The purpose of this study to present our experience in the management of biliary complications during and after laparoscopic cholecystectomy. There were eight biliary complications (0.72%) in 1115 consecutive laparoscopic cholecystectomies during the period from January 1991 to December 1995. The biliary complications included: bile duct injuries in 3 patients, bile leak in 4 patients and malapplication of the endoclips on the common bile duct in patient. Three biliary complications were corrected by immediate conversion to laparotomy with good outcomes. Two patients with immediate postoperative bile leakage required laparotomy for religation of the cystic duct and one patient with delayed bile leakage was successfully corrected with conservative treatment. One common hepatic duct and right hepatic duct developed necrosis due to electrocoagulation and required a laparotomy with T-tube stent and had repeated attacks of cholangitis during the 21 month follow-up period. Another patient with common hepatic duct stricture due to endoclip injury needed re-laparotomy with T-tube stent and remained stationary over the 9 month follow-up period. Bile leak and bile duct injuries after laparoscopic cholecystectomy present a difficult surgical problem, surgical or endoscopic interventions are needed to correct the biliary problem after the diagnosis was established by the radiological image study.


Blood gene expression correlated with tic severity in medicated and unmedicated patients with Tourette Syndrome.
Tourette Syndrome (TS) has been linked to both genetic and environmental factors. Gene-expression studies provide valuable insight into the causes of TS; however, many studies of gene expression in TS do not account for the effects of medication. To investigate the effects of medication on gene expression in TS patients, RNA was isolated from the peripheral blood of 20 medicated TS subjects (MED) and 23 unmedicated TS subjects (UNMED), and quantified using whole-genome Affymetrix microarrays. D2 dopamine receptor expression correlated positively with tic severity in MED but not UNMED. GABA(A) receptor ε subunit expression negatively correlated with tic severity in UNMED but not MED. Phenylethanolamine N-methyltransferase expression positively correlated with tic severity in UNMED but not MED. Modulation of tics by TS medication is associated with changes in dopamine, norepinephrine and GABA pathways.


Adapting World Health Organization Disability Assessment Schedule 2.0 for Nepal.
Disability is a vital public health issue for health care programs. Affluent countries usually prioritize disability-related research, while often it remains neglected in resource-poor countries like Nepal. The aim of this study was to make available a translated and culturally adapted version of the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) for measuring disability in the Nepalese population. WHODAS 2.0 (12-items version) was translated into Nepali using a standard forward-backward translation protocol. Purposive and convenience recruitment of participants with psychiatric disabilities was done at the Psychiatry services in a tertiary care hospital. Age and gender-matched participants with physical disabilities were selected from the Internal Medicine department, and participants with no disability were recruited from their accompanying persons. A structured interview in Nepali including the translated WHODAS 2.0 was administered to all participants. Exploratory factor analysis and parallel analysis assessed the construct validity. Content validity was explored, and a quality of life instrument was used for establishing criterion validity. Reliability was measured via Cronbach alpha. Mann-Whitney test explored score differences between the disabled and non-disabled. In total, 149 persons [mean age: 40.6 (12.8); 43.6% males, 56.4% females; 61.7% disabled, 38.3% non-disabled] consented to participate. Parallel analysis indicated that a single factor was adequate for the Nepali WHODAS version that captured 45.4% of the total variance. The translated scale got a good Cronbach alpha (= 0.89). Satisfactory construct, content and criterion validity was found. The WHODAS total scores showed a significant difference between the disabled and non-disabled (U = 2002.5; p = 0.015). However, the difference between psychiatric and physical disabilities was not significant, which underscores that the scale is rating disability in general. The one-factor structure of the translated and culturally adapted Nepali-version of WHODAS 2.0 showed acceptable validity and an adequate reliability. For epidemiological research purposes, this version of WHODAS 2.0 is now available for measuring global disability in Nepal.


Iron deprivation enhances transcriptional responses to in vitro growth arrest of Mycobacterium tuberculosis.
The establishment of Mycobacterium tuberculosis (Mtb) long-term infection in vivo depends on several factors, one of which is the availability of key nutrients such as iron (Fe). The relation between Fe deprivation inside and outside the granuloma, and the capacity of Mtb to accumulate lipids and persist in the absence of growth is not well understood. In this context, current knowledge of how Mtb modifies its lipid composition in response to growth arrest, depending on iron availability, is scarce. To shed light on these matters, in this work we compare genome-wide transcriptomic and lipidomic profiles of Mtb at exponential and stationary growth phases using cultures with glycerol as a carbon source, in the presence or absence of iron. As a result, we found that transcriptomic responses to growth arrest, considered as the transition from exponential to stationary phase, are iron dependent for as many as 714 genes (iron-growth interaction contrast, FDR <0.05), and that, in a majority of these genes, iron deprivation enhances the magnitude of the transcriptional responses to growth arrest in either direction. On the one hand, genes whose upregulation upon growth arrest is enhanced by iron deprivation were enriched in functional terms related to homeostasis of ion metals, and responses to several stressful cues considered cardinal features of the intracellular environment. On the other hand, genes showing negative responses to growth arrest that are stronger in iron-poor medium were enriched in energy production processes (TCA cycle, NADH dehydrogenation and cellular respiration), and key controllers of ribosomal activity shut-down, such as the T/A system mazE6/F6. Despite of these findings, a main component of the cell envelope, lipid phthiocerol dimycocerosate (PDIM), was not detected in the stationary phase regardless of iron availability, suggesting that lipid changes during Mtb adaptation to non-dividing phenotypes appear to be iron-independent. Taken together, our results indicate that environmental iron levels act as a key modulator of the intensity of the transcriptional adaptations that take place in the bacterium upon its transition between dividing and dormant-like phenotypes in vitro.


Clinical effects of non-ablative and ablative fractional lasers on various hair disorders: a case series of 17 patients.
Both ablative and non-ablative fractional lasers have been applied to various uncommon hair disorders. The purpose of this study was to demonstrate the clinical effects of fractional laser therapy on the course of primary follicular and perifollicular pathologies and subsequent hair regrowth. A retrospective review of 17 patients with uncommon hair disorders - including ophiasis, autosomal recessive woolly hair/hypotrichosis, various secondary cicatricial alopecias, pubic hypotrichosis, frontal fibrosing alopecia, and perifolliculitis abscedens et suffodiens - was conducted. All patients had been treated with non-ablative and/or ablative fractional laser therapies. The mean clinical improvement score in these 17 patients was 2.2, while the mean patient satisfaction score was 2.5. Of the 17 subjects, 12 (70.6%) demonstrated a clinical response to non-ablative and/or ablative fractional laser treatments, including individuals with ophiasis, autosomal recessive woolly hair/hypotrichosis, secondary cicatricial alopecia (scleroderma and pressure-induced alopecia), frontal fibrosing alopecia, and perifolliculitis abscedens et suffodiens. Conversely, patients with long-standing ophiasis, surgical scar-induced secondary cicatricial alopecia, and pubic hypotrichosis did not respond to fractional laser therapy. Our findings demonstrate that the use of non-ablative and/or ablative fractional lasers promoted hair growth in certain cases of uncommon hair disorders without any remarkable side effects.


Effects of space flight factors on the heredity of higher and lower plants.
The effects were studied of a long-term space exposure (72 days) aboard the Salyut orbital station on the following: dry seeds of Crepis capillaris (L.) Wallr. and Arabidopsis thaliana (L.) Heynh, haploid and diploid strains of Saccharomyces cerevisiae mutant for adenine locus (ad) and strain LARG-I of Chlorella vulgaris Beijer. A modifying effect of space factors on radiobiological action of gamma-irradiation from 137Cs was determined with the higher plant seeds and Chlorella culture. For this, the material was partly irradiated prior to, and partly after the flight at doses of 3, 30 and 10 kr for C. capillaris, A. thaliana and Chl. vulgaris, respectively. It was shown that: (1) Space factors caused reduced survival of Arabidopsis seedlings and Chlorella and yeast cultures, reduced productivity of Chlorella cells, increased mutability of Chlorella and yeast cells and increased frequency of chromosome aberrations in cells of Crepis root meristem. There are, however, a few exceptions: cell germination of C. capillaris was enhanced while mutability of A. thaliana seeds declined. (2) Space factors increased the adverse effects of the pre-flight irradiation on all the parameters of the cultures tested. (3) Space factors had no genetic effect on the objects tested. They have, however, caused a stronger inhibition of seed germination and augmenting survival of A. thaliana seedlings and Chlorella cells.


Risk estimation of degenerative joint disease in temporomandibular disorder patients with different types of sagittal and coronal disc displacements: MRI and CBCT analysis.
Degenerative joint disease (DJD) can be associated with disc displacement (DD) in temporomandibular disorder (TMD) patients. However, the relationship between different types of DDs and DJD remains unclear. To investigate the odds ratios of different types of sagittal and coronal DDs confirmed by magnetic resonance imaging (MRI) and DJD confirmed by cone-beam computed tomography (CBCT) in TMD patients. Radiographic data from 69 males and 232 females were collected for analysis. CBCT was used to diagnose DJD, with criteria including erosion, osteophytes, generalised sclerosis and cysts in the joint. Eight types of DDs were evaluated by sagittal and coronal MRIs: NA, no abnormality; SW, sideways; ADDR, anterior with reduction; ADDR+SW; ADDNR, anterior without reduction; ADDNR + SW; single SW; PDD, posterior; PDD + SW. The odds ratios of DJD in joints with different types of DDs were determined after joint correlation, age and gender adjustment. Compared with NA, the odds ratio of DJD in ADDR was 2.397 (95% CI [confidence interval]: 1.070-5.368), ADDR + SW was 4.808 (95% CI: 1.709-3.528), ADDNR was 29.982 (95% CI: 15.512-57.950) and ADDNR + SW was 25.974 (95% CI: 12.743-52.945). Erosion was significantly increased in ADDR, ADDR + SW, ADDNR and ADDNR + SW; osteophytes were significantly increased in ADDR + SW, ADDNR and ADDNR + SW; and generalised sclerosis and cysts were significantly increased in ADDNR and ADDNR + SW. There were no significant associations between single SW, PDD, PDD + SW and the DJD. ADDR, ADDR+SW, ADDNR and ADDNR+SW were associated with DJD. ADDNR had a significantly higher prevalence of DJD than ADDR. There were no significant relationships between single SW, PDD, PDD + SW and the DJD.


IMM47, a humanized monoclonal antibody that targets CD24, exhibits exceptional anti-tumor efficacy by blocking the CD24/Siglec-10 interaction and can be used as monotherapy or in combination with anti-PD1 antibodies for cancer immunotherapy.
This study evaluates the anti-tumor mechanism of IMM47, a humanized anti-CD24 mAb. Biolayer interferometry, ELISA and flow cytometry methods were used to measure the IMM47 binding, affinity, ADCC, ADCP, ADCT and CDC activities. In vivo therapeutical efficacy was measured in transplanted mouse models. IMM47 significantly binds granulocytes but not human erythrocytes and blocks CD24's ability to bind to Siglec-10. IMM47 has strong ADCC, ADCT and ADCP activity against REH cells. IMM47's in vivo pharmacodynamics showed that IMM47 has strong anti-tumor effects in human siglec-10 transgenic mouse models with a memory immune response. IMM47 also has powerful synergistic therapeutic efficacy when combined with Tislelizumab, Opdivo and Keytruda, by blocking CD24/Siglec-10 interaction through macrophage antigen presentation with strong ADCC, ADCP, ADCT and CDC activities and with a safe profile. IMM47 binding to CD24 is independent of N-glycosylation modification of the extracellular domain.


Balloon dilation atrial septostomy for advanced pulmonary hypertension in patients on prostanoid therapy.
Prostanoid therapy improves quality of life and may increase survival in patients with advanced pulmonary hypertension (PH). Balloon dilated atrial septostomy (BDAS) can palliate or bridge to transplantation for patients resistant to medical therapy. The safety and efficacy of BDAS in the prostanoid era has not previously been reported. All patients had progressive symptoms despite prostanoid therapy at the time of their first BDAS. Sixteen patients who underwent a total of 23 septostomies between 2004 and 2014 were included in this retrospective case series. Patients were aged 47.6 years ± 11.3 with 12/16 women. Etiologies included idiopathic (7), methamphetamine (6), scleroderma (1), and anorexigen (2). One patient died within 24 hr post-procedure. Thirty-day and 1-year survival were 75% and 64%, respectively. Six of the septostomies were revisions, including two which were ultimately stented. Three subjects were successfully bridged to transplant. Pulmonary capillary wedge pressure (PCWP) increased from a mean of 13 to 17 mm Hg, cardiac index increased from 2.1 to 2.4 L/min/m(2) , and arterial saturation decreased from 90.7 ± 4.3 to 82.5 ± 5.6%. All non-survivors at 30 days were male and had higher baseline serum creatinine, mean RAP, right ventricular end diastolic pressure (RVEDP), and left ventricle (LV) filling pressures, and lower right ventricle (RV) ejection fraction. Mortality was associated with unchanged post-septostomy cardiac output despite an increase in left ventricular end diastolic pressure (LVEDP). BDAS may be an alternate therapy for select PH patients who have symptomatic progression despite prostanoid therapy. Survival is comparable to prior reports of BDAS in the pre-prostanoid era.


A comparison of anti-HER2 IgA and IgG1 in vivo efficacy is facilitated by high N-glycan sialylation of the IgA.
Monomeric IgA has been proposed as an alternative antibody format for cancer therapy. Here, we present our studies on the production, purification and functional evaluation of anti-HER2 IgA antibodies as anti-cancer agents in comparison to the anti-HER2 IgG1 trastuzumab. MALDI-TOF MS analysis showed profound differences in glycosylation traits across the IgA isotypes and cell lines used for production, including sialylation and linkage thereof, fucosylation (both core and antennary) and the abundance of high-mannose type species. Increases in sialylation proved to positively correlate with in vivo plasma half-lives. The polymerization propensity of anti-HER2 IgA2m2 could be suppressed by an 18-aa deletion of the heavy chain tailpiece - coinciding with the loss of high-mannose type N-glycan species - as well as by 2 cysteine to serine mutations at positions 320 and 480. The HER2 F(ab')2-mediated anti-proliferative effect of the IgA2m1 and IgA2m2 subtypes was similar to IgG1, whereas the IgA1 isotype displayed considerably lower potency and efficacy. The Fc-mediated induction of antibody-dependent cell-mediated cytotoxicity (ADCC) using human whole blood ADCC assays did not demonstrate such clear differences between the IgA isotypes. However, the potency of the anti-HER2 IgA antibodies in these ADCC assays was found to be significantly lower than that of trastuzumab. In vivo anti-tumor activity of the anti-HER2 IgA antibodies was compared to that of trastuzumab in a BT-474 breast cancer xenograft model. Multiple dosing and sialylation of the IgA antibodies compensated for the short in vivo half-life of native IgA antibodies in mice compared to a single dose of IgG1. In the case of the IgA2m2 antibody, the resulting high plasma exposure levels were sufficient to cause clear tumor stasis comparable to that observed for trastuzumab at much lower plasma exposure levels.


[Preparation of liposomal sparfloxcain lactate and its corneal penetration and antibacterial activity in vitro].
To prepare sparfloxcain lactate (SPLX) loaded liposomes and study its corneal penetration and bacterial inhibitory in vitro. Liposomal SPLX (mass ratio of phospholipids/ cholesterol/drug at 18:6:1) was prepared by pH-gradients. The transcorneal penetration experiments of liposomal SPLX were performed in modified Franz's cells with the rabbit's corneal. The concentration of SPLX was determined by high-performance liquid chromatography. The penetration parameters were calculated. The in vitro antibacterial activities on S. aureus, P. aeruginusa, E. coli, and B. subtilis were determined by two fold dilutions. The entrapment efficiency of SPLX in the liposomes by pH-gradients was (81.61 +/- 1.98)%, which was significantly higher than that by film dispersion method (11.48 +/- 0.86)% and reverse evaporating method (18.64 +/- 1.05)% (both P < 0.01). The permeability coefficient and corneal deposition quantity of SPLX liposomes were 1.65- and 4.98-folds higher as compared with those of free drug solutions. The minimal inhibitory concentrations (MICs) of liposomal SPLX against S. aureus, P. aeruginosa, E. coli, and B. subtilis were 1/4, 1/2, 1/1, 1/17 times lower than those of free drug, respectively, and the minimal bactericide concentrations (MBCs) were 1/4, 1/2, 1/1, 1/4 times lower than those. In addition, the time-kill values of liposomal SPLX were better than those of free. The pH gradient technique is suitable for preparing SPLX liposomes, which can improve the transcorneal penetration and antibacterial activity of SPLX in vitro.


Ni/Photoredox-Dual-Catalyzed Functionalization of 1-Thiosugars.
A general protocol for functionalization of glycosyl thiols has been reported. This protocol is based on a single-electron Ni/photoredox dual-catalyzed cross coupling between 1-thiosugars and a broad range of aryl bromides and iodides as well as alkenyl and alkynyl halides. This base-free method gives access to a series of functionalized thioglycosides in moderate to excellent yields with a perfect control of the anomeric configuration. Moreover, it has been shown that this methodology may be transposed successfully to the continuous-flow photoredox chemistry.


A comparison of methods for assessing thyroid function in nonthyroidal illness.
We studied various tests of thyroid function in sick patients with nonthyroidal illness (NTI) in order to determine the utility of each test for differentiating these patience from a group with hypothyroidism. We evaluated each test in 22 healthy volunteers who served as controls, 20 patients with hypothyroidism, 14 patients admitted to medical intensive care unit whose serum T4 was less than 5 micrograms/dl, 13 patients with chronic liver disease, 32 patients on chronic hemodialysis for renal failure, 13 ambulatory oncology patients receiving chemotherapy, 16 pregnant women, 7 women on estrogens, and 20 hyperthyroid patients. On all samples, we measured serum T4, the free T4 index by several methods, free T4 by equilibrium dialysis, free T4 calculated from thyronine-binding globulin (TBG) RIA, free T4 by three commercial kits (Gammacoat, Immophase, and Liquisol), T3, rT3, and TSH (by 3 different RIAs). Although all of the methods used for measuring free T4 (including free T4 index, free T4 by dialysis, free T4 assessed by TBG, and free T4 assessed by the 3 commercial kits) were excellent for the diagnosis of hypothyroidism, hyperthyroidism, and euthyroidism in the presence of high TBG, none of these methods showed that free T4 was consistently normal in patients with NTI; with each method, a number of NTI patients had subnormal values. In the NTI groups, free T4 measured by dialysis and the free T4 index generally correlated significantly with the commercial free T4 methods. Serum rT3 was elevated or normal in NTI patients and low in hypothyroid subjects. Serum TSH provided the most reliable differentiation between patients with primary hypothyroidism and those with NTI and low serum T4 levels.


Children with cerebral palsy participate: a review of the literature.
To review research that examined the participation in activities of children who have cerebral palsy, in order to understand their extent of participation and the factors that influenced participation. A comprehensive search of seven databases retrieved 2,111 papers, 40 of which met criteria and were relevant for critique. As this paper intended to examine participation broadly, an ecological framework was used to organise the relevant papers into those studies that considered personal, environmental and occupational factors related to participation. Children with cerebral palsy participated in a diverse array of activities across a range of occupational contexts. Their participation was not always a positive experience. Factors most commonly identified as barriers to participation were social attitudes and the physical environment. This review identified only emergent understandings of the naturally occurring changes in the participation of children with cerebral palsy that come with increasing age and, concurrently, with increasing social and environmental demands. Future research designs must accommodate the complexity of participation to further our knowledge and improve our ability to target therapeutic interventions at community, family and child levels.


Eotaxin-2 and colorectal cancer: a potential target for immune therapy.
To study the production of chemokines by colorectal hepatic metastases. Biopsies of resected colorectal hepatic metastases and nonneoplastic adjacent liver tissue were screened for chemokines using protein arrays and results were confirmed by ELISA and immunohistochemistry. Two chemokines, eotaxin-2 and MCP-1, were found at elevated levels within the tumor biopsy compared with adjacent liver. The relative increase in expression from tumor was much higher for eotaxin-2 than MCP-1, with 10 of 25 donors having a >100-fold increase in expression compared with 0 of 24 donors for MCP-1. In a parallel analysis, eotaxin-2 was also found at elevated levels in the tumor region of primary colorectal cancer biopsies. Immunohistochemical staining indicated that carcinoembryonic antigen-positive tumor cells stained strongly for eotaxin-2, implicating these cells as the predominant source of the chemokine. In vitro studies confirmed that several colorectal tumor lines produce eotaxin-2 and that secretion of this chemokine could be depressed by IFN-gamma and enhanced by the Th2-type cytokines interleukin-4 and interleukin-13. Jurkat T cells were engineered to express the receptor for eotaxin-2 (CCR3). These cells effectively migrated in response to eotaxin-2 protein, suggesting that immune cells gene modified to express a chemokine receptor may have improved abilities to home to tumor. Taken together, these observations confirm eotaxin-2 as a chemokine strongly associated with primary and metastatic tumors of colorectal origin. Furthermore, the importance of this result may be a useful tool in the development of targeted therapeutic approaches to colorectal tumors.


Overexpression of PGC-1α influences the mitochondrial unfolded protein response (mtUPR) induced by MPP+ in human SH-SY5Y neuroblastoma cells.
Parkinson's disease (PD) is a common dyskinesia disease, the mitochondrial unfolded protein response (mtUPR) may be directly or indirectly involved in the occurrence and development of PD, although the exact mechanism is unclear. We established a dopaminergic neuronal-like cell model of PD, by overexpression of PGC-1α to detect evaluate the expression of proteases and molecular chaperones of involved in the mtUPR, as well as the expression of PGC-1α and LRPPRC, illustrated the distribution of LRPPRC. Remarkably, the mtUPR activation reached maximal at 24 h after MPP+ treatment in SH-SY5Y cells, which the protein and transcription levels of the proteases and molecular chaperones reached maximal. The proteases and molecular chaperones were significantly increased when overexpressed PGC-1α, which indicated that PGC-1α overexpression activated the mtUPR, and PGC-1α had a protective effect on SH-SY5Y cells. The expression levels of PGC-1α and LRPPRC were significantly improved in the PGC-1α overexpression groups. LRPPRC was markedly reduced in the nucleus, suggesting that PGC-1α overexpression may play a protective role to the mitochondria through LRPPRC. Our finding indicates that overexpression of PGC-1α may activate mtUPR, reducing the oxidative stress injury induced by MPP+ through LRPPRC signaling, thus maintain mitochondrial homeostasis.


New ex-vivo organ model for percutaneous renal surgery.
Percutaneous Renal Surgery (PRS) is a demanding procedure and success is mostly hampered by the lacking of training facilities. Thus, the purpose of the study was to evaluate a significantly improved pre-existing porcine kidney-training model for percutaneous renal access and PRS. A biologic training model using porcine kidneys coated by a full-thickness porcine skin flap was prepared. The ureter was dissected, stones were placed into the collecting system using an 18F amplatz sheath, and a catheter was placed in the ureter for further irrigation with saline or contrast medium. For initial training with an easy access, a standard guide-wire was inserted in the ureter through the renal parenchyma. The kidney was punctured with radiographic or ultrasound guidance. Minimally invasive percutaneous nephrolithotomy (MIP) was then tested using the model under radiographic or ultrasound guidance. The model was then evaluated in MIP training courses, which are regularly held at The Hannover Medical School. All trainees were urologists with experience in endourologic surgery but lacked practice in PRS. In conclusion, all 36 participants attained access to the collecting system using models with readily placed guide-wires. Subsequently, PRS was successful in all cases. Percutaneous puncture under ultrasound guidance and following intrarenal surgery was successful in 30 (83.3%) cases. Therefore, all participants rated the model useful for simulating percutaneous renal surgery. This new porcine kidney model is easy to build and is made cost effective by using readily available material. Moreover, it provides realistic and reproducible training model for PRS. The "organ" model mimics the retroperitoneum by having a full-thickness skin flap with a layer of subcutaneous fatty tissue.


Epithelial and surfactant changes in influenzal pulmonary lesions.
Pulmonary epithelial cell destruction in mice infected with PR8-A influenza virus has been studied with light and electron microscopy and enzyme histochemistry, and correlated with pulmonary surfactant activity. All epithelial cell types were infected by the virus, resulting in destruction, pneumonitis, and atelectasis by seven to ten days. Pulmonary surfactant activity decreased progressively following onset of infection, and was minimal by seven to ten days. Before types 1 and 2 alveolar pneumocytes regenerated, the regenerating bronchial cells grew peripherally into some of the denuded alveolar ducts and alveoli to form epithelial nodules. Eventually the types 1 and 2 pneumocytes regenerated to cover the alveolar surfaces that were not invaded by bronchial epithelium. This regeneration was associated with increased surfactant activity in the postinfluenzal lesions, suggesting that the type 2 pneumocytes are a source of surfactant.


Effectiveness of Supplementary Cognitive-Behavioral Therapy for Pharmacotherapy-Resistant Depression: A Randomized Controlled Trial.
Antidepressant medication is efficacious in the treatment of depression, but not all patients improve with antidepressant medication alone. Despite this treatment gap, limited evidence regarding the effectiveness of supplementing psychotherapy for pharmacotherapy-resistant depression is available. Therefore, we investigated the effectiveness of supplementing usual medication management (treatment as usual [TAU]) with cognitive-behavioral therapy (CBT) in patients with pharmacotherapy-resistant depression seeking psychiatric specialty care. A 16-week assessor-masked randomized controlled trial with a 12-month follow-up was conducted in 1 university hospital and 1 psychiatric hospital from September 2008 to December 2014. Outpatients aged 20-65 years with pharmacotherapy-resistant depression (taking antidepressant medications for ≥ 8 weeks, 17-item GRID-Hamilton Depression Rating Scale [GRID-HDRS₁₇] score ≥ 16, Maudsley Staging Method for treatment-resistant depression score ≥ 3, and DSM-IV criteria for major depressive disorder) were randomly assigned (1:1) to CBT combined with TAU or to TAU alone. The primary outcome was the alleviation of depressive symptoms, as measured by change in the total GRID-HDRS₁₇ score from baseline to 16 weeks; primary analysis was done on an intention-to-treat basis. A total of 80 patients were randomized; 78 (97.5%) were assessed for the primary outcome, and 73 (91.3%) were followed up for 12 months. Supplementary CBT significantly alleviated depressive symptoms at 16 weeks, as shown by greater least squares mean changes in GRID-HDRS₁₇ scores in the intervention group than in the control group (-12.7 vs -7.4; difference = -5.4; 95% CI, -8.1 to -2.6; P < .001), and the treatment effect was maintained for at least 12 months (-15.4 vs -11.0; difference = -4.4; 95% CI, -7.2 to -1.6; P = .002). Patients with pharmacotherapy-resistant depression treated in psychiatric specialty care settings may benefit from supplementing usual medication management with CBT. UMIN Clinical Trials Registry identifier: UMIN000001218.


Glucose intolerance and cardiometabolic risk in children exposed to maternal gestational diabetes mellitus in utero.
The goal was to examine the carbohydrate tolerance and cardiometabolic risk among children exposed to maternal gestational diabetes mellitus in utero. In this study, 164 Chinese children whose mothers had participated in a previous study on the screening and diagnosis of gestational diabetes mellitus (63 had gestational diabetes mellitus and 101 had normal glucose tolerance during the index pregnancies) underwent follow-up evaluations at a median age of 8 years (range: 7-10 years). Children's weight, height, hip and waist circumferences, and blood pressure were measured, and weight-adjusted oral glucose tolerance tests were performed. Six children (3.7%) demonstrated impaired glucose regulation or diabetes mellitus at the follow-up evaluation. Children exposed to maternal gestational diabetes mellitus had significantly higher systolic (94+/-1.2 vs 88+/-0.9 mmHg) and diastolic (62+/-0.8 vs 57+/-0.6 mmHg) blood pressure values and lower high-density lipoprotein cholesterol (1.58+/-0.04 vs 1.71+/-0.03 mmol/L) levels, after adjustment for age and gender. A high (>or=90th percentile) umbilical cord insulin level at birth was associated with abnormal glucose tolerance in the offspring. Maternal gestational diabetes mellitus increases the offspring's cardiometabolic risk, and in utero hyperinsulinemia is an independent predictor of abnormal glucose tolerance in childhood.


The cancer-associated cell migration protein TSPAN1 is under control of androgens and its upregulation increases prostate cancer cell migration.
Cell migration drives cell invasion and metastatic progression in prostate cancer and is a major cause of mortality and morbidity. However the mechanisms driving cell migration in prostate cancer patients are not fully understood. We previously identified the cancer-associated cell migration protein Tetraspanin 1 (TSPAN1) as a clinically relevant androgen regulated target in prostate cancer. Here we find that TSPAN1 is acutely induced by androgens, and is significantly upregulated in prostate cancer relative to both normal prostate tissue and benign prostate hyperplasia (BPH). We also show for the first time, that TSPAN1 expression in prostate cancer cells controls the expression of key proteins involved in cell migration. Stable upregulation of TSPAN1 in both DU145 and PC3 cells significantly increased cell migration and induced the expression of the mesenchymal markers SLUG and ARF6. Our data suggest TSPAN1 is an androgen-driven contributor to cell survival and motility in prostate cancer.


Light and electron microscopic study of autologous implants of dental roots in the subcutaneous tissue of rats.
Maxillary first molars of rats were extracted. The roots were separated and subsequently implanted in the dorsal subcutaneous tissue of the same animal. In Experiment 1, the roots were implanted immediately after removal; in Experiment 2, the roots were subjected to freeze-thawing (devitalized) before implantation. After 4, 8, and 15 weeks of implantation, the roots were removed and processed for light and transmission electron microscopy. Roots of Experiment 1 showed an amorphous clear material filling depressions on the irregular surface of the cementum. This material consisted predominantly of collagen fibrils. Cells adjacent to the amorphous clear material exhibited numerous cytoplasmic processes surrounded by collagen fibrils. Globular structures with an electron-opacity similar to that of neighbouring cementum were observed within the bundles of collagen fibrils. Multinucleated cells with features of osteo/odontoclasts were often closely apposed to deep depressions of the cementum. In Experiment 2, only large multinucleated giant cells appeared around the surfaces of the roots. It seems therefore that, in Experiment 1, precementum formation and osteo/odontoclast mediated destruction occurred. It is likely that these activities may have originated from periodontal ligament cells carried to the implantation site. This conclusion is supported by the observation that such activities were absent in Experiment 2. Devitalized roots were unable to form precementum and were surrounded by foreign body giant cells.


Bayesian Chance-Constrained Hydraulic Barrier Design under Geological Structure Uncertainty.
The groundwater community has widely recognized geological structure uncertainty as a major source of model structure uncertainty. Previous studies in aquifer remediation design, however, rarely discuss the impact of geological structure uncertainty. This study combines chance-constrained (CC) programming with Bayesian model averaging (BMA) as a BMA-CC framework to assess the impact of geological structure uncertainty in remediation design. To pursue this goal, the BMA-CC method is compared with traditional CC programming that only considers model parameter uncertainty. The BMA-CC method is employed to design a hydraulic barrier to protect public supply wells of the Government St. pump station from salt water intrusion in the "1500-foot" sand and the "1700-foot" sand of the Baton Rouge area, southeastern Louisiana. To address geological structure uncertainty, three groundwater models based on three different hydrostratigraphic architectures are developed. The results show that using traditional CC programming overestimates design reliability. The results also show that at least five additional connector wells are needed to achieve more than 90% design reliability level. The total amount of injected water from the connector wells is higher than the total pumpage of the protected public supply wells. While reducing the injection rate can be achieved by reducing the reliability level, the study finds that the hydraulic barrier design to protect the Government St. pump station may not be economically attractive.


Prognostic significance of Ki-67 index value at the primary breast tumor in recurrent breast cancer.
The Ki-67 index value is a prognostic factor in primary breast cancer and is a proliferation marker that also distinguishes between luminal type A and type B breast cancer. Moreover, a change in Ki-67 index values due to treatment and recurrence is considered to be important in treating breast cancer. In this study, we investigated whether the baseline Ki-67 value in the primary tumor is useful as a prognostic factor following disease recurrence. Immunohistochemical analysis of the Ki-67 index was performed on 4,701 patients with primary breast cancer from 1987 until March, 2013. Among these patients, there were 666 consecutive cases exhibiting recurrence after primary surgery. The fraction of proliferating cells was based on a count of at least 500 tumor cells in the area including the hot spot. The Ki-67 values were divided into 3 groups, namely <20, ≥20 and ≥50%. The investigated items included estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), tumor size, nodal status for the primary tumor, recurrence site (soft tissue, bone and viscera) and disease-free interval (DFI). The Cox's proportional hazard model was used to perform univariate and multivariate analyses of the factors associated with overall survival (OS) following recurrence. The median follow-up period was 65.9 months in the surviving group. The median Ki-67 value at baseline was 20% in all the cases and 27% in the recurrent cases. The Ki-67 values were low (24%) in patients with bone metastasis and significantly higher in patients with liver or brain metastasis (38 and 55%, respectively). Moreover, DFI was found to be inversely correlated with the Ki-67 values. Univariate analysis was performed to identify the prognostic factors for OS after recurrence. The significant factors included tumor size, lymph node status, ER, PgR, DFI, recurrence site and Ki-67 index value. Among these factors, a multivariate analysis identified the Ki-67 index value in the primary tumor as an independent significant factor, particularly in luminal type tumors. The Ki-67 index value in the primary tumor was a significant prognostic factor for OS after disease recurrence. It is, therefore, important to take the Ki-67 index value into consideration for the treatment and follow-up of breast cancer patients.


Probing affective pictures: attended startle and tone probes.
Reflexive eyeblinks to a startle probe vary with the pleasantness of affective pictures, whereas the corresponding P300 varies with emotional arousal. The impact of attention to the probe on these effects was examined by varying task and probe type. Probes were either nonstartling tones or startling noises presented during affective picture viewing. Half the participants performed a task requiring attention to the probes; the other participants were told to ignore the probes. Blinks to the startle probe varied with picture pleasantness for both task and nontask conditions. In contrast, P300 magnitudes for both startle and tone probes were reduced during emotionally arousing pictures, irrespective of pleasantness, in task and nontask conditions. Further, attending to the startle probe prompted an augmentation of N100 during unpleasant pictures. The data suggest that affective modulation of probe responses reflects obligatory processes in picture perception.


Expression of the multidrug resistance-associated protein 1 (MRP1) and the lung resistance-related protein (LRP) in human lung cancer.
Fifty lung cancer samples (41 non-small cell lung cancer-NSCLC and 9 small cell lung cancer-SCLC) were immunohistochemically analyzed for lung resistance-related protein (LRP) and multidrug resistance-associated protein 1 (MRP1) expressions which were then correlated with histopathological subtype of the tumor. To detect these proteins, monoclonal antibodies LRP-56 and MRPm6 were used. NSCLC samples were divided into two groups, adenocarcinomas (17 samples) and squamous cell carcinomas (24 samples). Four categories of LRP and MRP1 quantity were distinguished: +++ = high level--90--100% of positive cells, ++ = lower level--10--90% of positive cells, + = low level--up to 10% of positive cells, - = negative cells--0% of positive cells. Within the NSCLC group the most samples (36/41) had the similar level of LRP and MRP1. Significantly higher expression of both proteins was observed in the adenocarcinomas in comparison with squamous cell carcinomas. The lowest positive staining for LRP and MRP1 proteins has been found in SCLC. It is suggested that our finding can confirm the overall empirical clinical knowledge about much higher chemosensitivity of untreated SCLC comparing to NSCLC.


Metformin-induced cholangiohepatitis.
Drug-induced cholangiohepatitis accounts for 20-50% of non-viral chronic hepatitis cases. Metformin is the most commonly prescribed oral anti-diabetic drug from the biguanide class used in treatment of overweight and obese type 2 diabetes mellitus patients. Metformin-induced cholangiohepatitis with marked elevations in serum liver transaminases and intrahepatic cholestasis has been infrequently reported. Here, we report a case of acute cholangiohepatitis after initiation of metformin treatment.


Isoquinoline-based Eu(iii) luminescent probes for citrate sensing in complex matrix.
A neutral Eu(iii) complex containing the S,S enantiomer of isoQC3A3- ligand (isoQC3A3- = N-isoquinolyl-N,N',N'-trans-l,2-cyclohexylenediaminetriacetate) was synthesized and characterized. The complex was spectroscopically investigated and the results compared with those obtained for the similar bis-anionic ligand bisoQcd2- (bisoQcd2- = N,N'-bis(2-isoquinolinmethyl)-trans-1,2-diaminocyclohexane N,N'-diacetate). Both Eu(iii)-complexes show similar binding constants upon titration with the main analytes contained in interstitial extracellular fluid (i.e. hydrogen carbonate, serum albumin and citrate). However, the analyte affinity is accompanied by different enhancements of the Eu(iii) intrinsic quantum yield (QY). Structures and hydration numbers of the complexes are determined by luminescence decay measurements and DFT calculations. The QYs as well as the binding constants of the individual adducts of the complexes with hydrogen carbonate, bovine serum albumin (BSA) and citrate are determined. The study of the Eu(iii) emission upon the systematic variation of one analyte in a complex mixture has been carried out to predict the performance of the luminescent sensor in conditions close to the real extracellular environment. Both Eu(iii) complexes can detect citrate at extracellular concentrations up to 500 μM, even at millimolar concentrations of the other interfering species. In the case of the Eu(bisoQcd)OTf complex, an increase of 23% of the Eu(iii) luminescence intensity at 615 nm upon addition of 0.3 mM of citrate was recorded. This feature makes the latter complex a viable probe for luminescence analysis of citrate in a complex matrix.


Associations between dietary habits, socio-demographics and gut microbial composition in adolescents.
The relationship between dietary habits and microbiota composition during adolescence has not been well examined. This is a crucial knowledge gap to fill considering that diet-microbiota interactions influence neurodevelopment, immune system maturation and metabolic regulation. This study examined the associations between diet and the gut microbiota in a school-based sample of 136 adolescents (Mage = 12·1 years; age range 11-13 years; 48 % female; 47 % Black, 38 % non-Hispanic White, 15 % Hispanic or other minorities) from urban, suburban and rural areas in the Southeast USA. Adolescents completed the Rapid Eating Assessment for Participants and provided stool samples for 16S ribosomal RNA gene sequencing. Parents reported their child and family socio-demographic characteristics. The associations between diet and socio-demographics with gut microbiota diversity and abundance were analysed using multivariable regression models. Child race and ethnicity, sex, socio-economic status and geographic locale contributed to variation within microbiota composition (β-diversity). Greater consumption of processed meat was associated with a lower microbial α-diversity after adjusting for socio-demographic variables. Multi-adjusted models showed that frequent consumption of nutrient-poor, energy-dense foods (e.g. sugar-sweetened beverages, fried foods, sweets) was negatively associated with abundances of genera in the family Lachnospiraceae (Anaerostipes, Fusicatenibacter and Roseburia), which are thought to play a beneficial role in host health through their production of short-chain fatty acids (SCFAs). These results provide new insights into the complex relationships among socio-demographic factors, diet and gut microbiota during adolescence. Adolescence may represent a critical window of opportunity to promote healthy eating practices that shape a homoeostatic gut microbiota with life-long benefits.


Effect of raloxifene on mammographic density and breast magnetic resonance imaging in premenopausal women at increased risk for breast cancer.
Mammographic density is a risk factor for breast cancer. Mammographic density and breast magnetic resonance imaging (MRI) volume (MRIV) assess the amount of fibroglandular tissue in the breast. Mammographic density and MRIV can be modulated with hormonal interventions, suggesting that these imaging modalities may be useful as surrogate endpoint biomarkers for breast cancer chemoprevention trials. We evaluated the effect of raloxifene on mammographic density and MRIV in premenopausal women at increased risk for breast cancer. Mammograms and MRI were obtained at baseline and after 1 and 2 years of 60 mg raloxifene by mouth daily for 27 premenopausal women. Mammographic percent dense area was calculated using a semiquantitative thresholding technique. T(1)-weighted spoiled gradient-echo MRI with fat suppression was used to determine breast MRIV using a semiautomatic method. Mean change in mammographic density and median change in MRIV were assessed by the Wilcoxon signed-rank test. No significant change in mammographic density was seen after treatment with raloxifene. Mean change after 1 year was 1% [95% confidence interval (95% CI), -3 to +5] and after 2 years was 1% (95% CI, -2 to +5). MRIV decreased on raloxifene. Median relative change in MRIV after 1 year was -17% (95% CI, -28 to -9; P = 0.0017) and after 2 years was -16% (95% CI, -31 to -4; P = 0.0004). In high-risk premenopausal women, mammographic density did not change on raloxifene, whereas MRIV significantly declined. Our findings suggest that MRIV is a promising surrogate biomarker in premenopausal women at increased risk for breast cancer and should be investigated further in breast cancer prevention trials.


Cation distribution in mammalian red blood cells: interspecies and intraspecies relationships between cellular ATP, potassium, sodium and magnesium concentrations.
The intracellular K+/Na+ ratio of erythrocytes of different mammalian species are known to differ markedly. These differences are sustained despite plasma potassium and sodium concentrations being almost identical, i.e. high [Na+] and low [K+], in all mammalian species. Conventional cell theory couples intracellular K+ and Na+ concentrations with Na+/K(+)-dependent ATPase activity. Ling's Association-Induction (AI) hypothesis couples intracellular K+ and Na+ concentrations with the concentration of ATP, by way of an inductive adsorption of both monovalent cations on the available terminal and lateral carboxyl groups of proteins. Based on the working hypothesis, different relationships are expected between the erythrocyte K+ and Na+ concentrations and ATP levels. Our results indicate that the intracellular ATP level in erythrocytes of different species corresponds with intracellular K+ and Na+ levels, K+/Na+ ratios and total K+ + Na+ levels. Similar relationships were revealed between the erythrocyte ATP and monovalent cation contents of different individual sheep.


Altered sense of humor in dementia.
Sense of humor is potentially relevant to social functioning in dementias, but has been little studied in these diseases. We designed a semi-structured informant questionnaire to assess humor behavior and preferences in patients with behavioral variant frontotemporal dementia (bvFTD; n = 15), semantic dementia (SD; n = 7), progressive nonfluent aphasia (PNFA; n = 10), and Alzheimer's disease (AD; n = 16) versus healthy age-matched individuals (n = 21). Altered (including frankly inappropriate) humor responses were significantly more frequent in bvFTD and SD (all patients) than PNFA or AD (around 40% of patients). All patient groups liked satirical and absurdist comedy significantly less than did healthy controls. This pattern was reported premorbidly for satirical comedy in bvFTD, PNFA, and AD. Liking for slapstick comedy did not differ between groups. Altered sense of humor is particularly salient in bvFTD and SD, but also frequent in AD and PNFA. Humor may be a sensitive probe of social cognitive impairment in dementia, with diagnostic, biomarker and social implications.


[Myocardial protective effect of ulinastatin against ischemia/reperfusion injury during open heart surgery with cardiopulmonary bypass].
To investigate the protective effect of ulinastatin on myocardium against ischemia-reperfusion injury in open heart surgery with cardiopulmonary bypass (CPB). Twenty ASA I-II patients undergoing atrioseptopexy or surgical repair of ventricular septal defect under CPB were randomly divided into two groups of 10 patients. The patients in the ulinastatin group (U), 5 males and 5 females, aged 6.7 +/- 2.6, received ulinastatin 12,000 unit/kg, half of the dose being given intravenously 10 min before aorta cannulation and another half being added into the priming fluid. The patients in the control group (C), 6 males and 4 females, aged 5.9 +/- 2.7, received the same volume of normal saline instead of ulinastatin. Arterial blood samples were taken before CPB (T1), at release of the aortic cross-clamp (T2), 30 min after aortic release (T3), 4 h and 24 h after discontinuation of CPB (T4, T5) for determination of plasma levels of cardiac troponin I (cTnI), creatine phosphokinase (CK) and creatine phosphokinase isoenzyme (CK-MB). The CPB time, aortic cross-clamping time and duration of operation were comparable between these 2 groups. The plasma cTnI level and CK and CK-MB activities were all within normal range before CPB in both groups. In group C the plasma level of cTnI started to increase at T2, peaked at T4 and started to decrease at T5. In group U the plasma levels of cTnI at T3 and T4 were significantly higher than the baseline value (both P<0.01) and returned to the baseline value at T5. The plasma cTnI levels at T(3-5) were significantly lower in group U than in group C (all P<0.01). The plasma CK and CK-MB activities increased significantly at T(2-5) in both groups (all P<0.01). There was no significant difference in plasma CK and CK-MB activity at T(2-4) between the two groups, but at T5 their activities were significantly lower in group U than in group C (P<0.05). The rate of spontaneous recovery of heart beat without defibrillation was higher in group U (8/10) than in group C (4/10) (P<0.05). The drainage volume during the 24 hours after operation was greater in group C than in group U (P<0.05). Ulinastatin effectively protects myocardium from ischemia-reperfusion injury during open heart surgery with CPB.


A survey of problematic sexualized behaviors of children in the New York City Child Welfare System:estimates of problem, impact on services, and need for training.
Forty-eight of 52 (92%) agencies contracted with the New York City Administration for Children's Services (ACS) responded to a survey about problematic sexualized behaviors (PSB) of children in different levels of care within the child welfare system. Results revealed that almost all agencies reported PSB within their foster boarding home and residential treatment centers. A majority of agencies perceived PSB to be a significant problem for which staff and families were not sufficiently trained. These findings highlight many avenues for advocacy, clinical intervention, and staff development.


Hair cortisol concentration, cognitive, behavioral, and motor impairment in multiple sclerosis.
Multiple sclerosis (MS) is an autoimmune neurodegenerative disease that is characterized by the demyelinated inflammatory processes that occur within the central nervous system. Hypothalamus-pituitary-adrenal axis (HPA axis) dysfunctions have been associated with the triggering or increase in MS symptoms. We thus aimed at evaluating motor and behavioral functions, planning skills, processing speed, and their relationship with stress through measuring hair cortisol concentration from patients with MS. The sample was composed of 40 volunteers that were clinically diagnosed with MS, along with 33 healthy adults. Evaluations included: Clinical Evaluation Form, Mini-Mental State Exam, Hamilton Depression Rating Scale, Multiple Sclerosis Functional Composite Measure, Expanded Disability Status Scale, Berg Balance Scale, Perceived Stress Scale, Zoo Map task, and a hair sample to analyze cortisol levels in the last 30 days. MS patients showed highly elevated hair cortisol levels in comparison to the control group (p = 0.048). All groups presented some degree of depressive and anxiety symptoms, aside from considerable perceived stress levels. The MS group presented deficits in gait, balance, manual skills and processing speed, and this was particularly so in individuals with moderate impairments when compared to control group (p < 0.001). Individuals with MS spent less time planning on ZooMap1 (p = 0.024) and made more mistakes (p < 0.001). No correlation was found between hair cortisol and the symptoms we assessed. However, depressive symptoms and anxiety were related to perceived stress, and higher hair cortisol suggests a change in levels in the HPA axis in MS. Nevertheless, future studies will be necessary to further understand how basal hair cortisol is related to MS symptoms.


Risk factors associated with hypogonadism in β-thalassemia major patients: predictors for a frequent complication of a rare disease.
β-Thalassemia major (BTM) is a rare disease that challenges clinicians because of the high prevalence of complications despite progress in the development of new therapeutic methods. The aim of this study was to identify clinical and hematological parameters associated with hypogonadism, the most frequent iron overload-related complication found in Romanian patients. Patients with BTM were evaluated in the Endocrinology Department of Elias Hospital between February 2004 and December 2013. Only patients who provided written informed consent were included in the study. A complete physical and hormonal evaluation was performed on all patients, and data regarding treatment of the hematological disease were collected. Of the evaluable patients, 85 were included in the study (median age, 21[10] years; range, 13-36 years). We found that 30.6% of the study participants (26 of 85) had normal gonadal status, 54.1% (46 of 85) had early forms of hypogonadism (delayed or arrested puberty), and 15.3% (n = 13) developed hypogonadism after complete sexual maturation. Patients with any form of hypogonadism were older (median age 22 vs 16.5 years, P = 0.047), had significantly lower average hemoglobin levels (P = 0.003), and had higher levels of serum ferritin (P = 0.006) versus patients without hypogonadism. Patients with delayed puberty were associated with increased average serum ferritin levels (P = 0.007), decreased hemoglobin levels (P = 0.001), and increased age at initiation of iron chelation therapy (P < 0.01). We found no significant differences between patients with early forms of hypogonadism and those with hypogonadism after complete sexual maturation, with respect to the analyzed parameters. Patients with adult hypogonadism were significantly older (median age 26 vs 16.5 years, P = 0.007) and tended to have higher serum ferritin levels (P = 0.056) compared with patients without hypogonadism. Our data show that hypogonadism is highly prevalent among Romanian patients with BTM, its presence being associated with higher iron overload and lower hemoglobin values. The late start of iron chelation therapy was particularly associated with pubertal abnormalities.


Does the implicit models of leadership influence the scanning of other-race faces in adults?
The current study aims to identify the relationships between implicit leadership theoretical (ILT) prototypes / anti-prototype and five facial features (i.e., nasion, upper nose, lower nose, and upper lip) of a leader from a different race than respondents. A sample of 81 Asian respondents viewed a 30-second video of a Caucasian female who in a non-engaging manner talked about her career achievements. As participants watch the video, their eye movements were recorded via an eye tracking devise. While previous research has identified that ILT influences perceptional and attitudinal ratings of leaders, the current study extends these findings by confirming the impact of ILT on the gaze patterns of other race participants, who appear to adopt system one type thinking. This study advances our understanding in how cognitive categories or schemas influence the physicality of individuals (i.e., eye gaze or movements). Finally, this study confirms that individual ILT factors have a relationship with the eye movements of participants and suggests future research directions.


Cryo-EM structures of staphylococcal IsdB bound to human hemoglobin reveal the process of heme extraction.
Iron surface determinant B (IsdB) is a hemoglobin (Hb) receptor essential for hemic iron acquisition by Staphylococcus aureus. Heme transfer to IsdB is possible from oxidized Hb (metHb), but inefficient from Hb either bound to oxygen (oxyHb) or bound to carbon monoxide (HbCO), and encompasses a sequence of structural events that are currently poorly understood. By single-particle cryo-electron microscopy, we determined the structure of two IsdB:Hb complexes, representing key species along the heme extraction pathway. The IsdB:HbCO structure, at 2.9-Å resolution, provides a snapshot of the preextraction complex. In this early stage of IsdB:Hb interaction, the hemophore binds to the β-subunits of the Hb tetramer, exploiting a folding-upon-binding mechanism that is likely triggered by a cis/trans isomerization of Pro173. Binding of IsdB to α-subunits occurs upon dissociation of the Hb tetramer into α/β dimers. The structure of the IsdB:metHb complex reveals the final step of the extraction process, where heme transfer to IsdB is completed. The stability of the complex, both before and after heme transfer from Hb to IsdB, is influenced by isomerization of Pro173. These results greatly enhance current understanding of structural and dynamic aspects of the heme extraction mechanism by IsdB and provide insight into the interactions that stabilize the complex before the heme transfer event. This information will support future efforts to identify inhibitors of heme acquisition by S. aureus by interfering with IsdB:Hb complex formation.


Potential teratogenicity of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) in micromass in vitro test.
3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), a by-product of wood pulp manufacture and a contaminant of chlorinated drinking water, was investigated for potential teratogenicity using the micromass in vitro test system. Twelve-day rat embryo midbrain (central nervous system, CNS) and limb bud (LB) cells were exposed to MX at concentrations of 1, 2, 5, or 10 microg/ml in the culture medium with or without S9 mix. Under the experimental conditions, the amount of MX rapidly declined in the culture medium with a half-life of 56 min. Nevertheless, differentiation of CNS and LB cells was significantly inhibited at concentrations of 2 microg/ml or more, when the cells were exposed to MX in the absence of S9 mix. The estimated IC50 was approximately 3 microg/ml for both CNS and LB cell cultures. On the other hand, exposure of CNS and LB cells to MX along with S9 mix did not reduce the number of differentiated foci at any concentrations tested. These results suggest that MX may be a potential direct-acting in vitro teratogen.


Pistia stratiotes in the phytoremediation and post-treatment of domestic sewage.
This work aimed to evaluate the potential of phytoremediation using Pistia stratiotes as a plant for post-treatment of wastewater from domestic sewage. The experiment was conducted at Toledo-PR, Brazil, for 42 days, in a pilot scale model. In order to evaluate the efficiency of Pistia as a post-treatment of domestic sewage, parameters such temperature, pH, turbidity, total solids, COD, Ntotal and Ptotal contents were determined in the effluent, as well as the total contents of K, Ca, Mg, Cu, Zn, Fe, Mn, Cd, and Pb. The bioaccumulation of K, Ca, Mg, Cu, Zn, Fe, Mn, Cd, and Pb in the living tissues of P. stratiotes have also been detected. The results demonstrate efficiency removal of turbidity, Ntotal, Ptotal and COD of 98.5, 100, 100, and 79.18%, respectively. The effluent contents of nutrients and toxic metals fluctuated during the study. This can have occurred due to photosynthetic activities of microorganisms and the plant senescence. The evaluation of some parameters in the effluent, such as temperature, DO, and organic matter, influenced these facts. Low levels of DO were observed, in function to the physical barrier of macrophytes in water surface, preventing the entry of air and light. The use of P. stratiotes proved to be a good complement for post-treatment of wastewater from domestic sewage.


Fitness to fly in an infant with congenital lobar emphysema.
Determining fitness to fly is a difficult task for physicians, especially for those caring for children with respiratory disorders, as the available information for guidance is scarce. This case describes the use of a flight simulation in a decompression chamber in order to assess fitness to fly in an 18-mo-old infant with congenital lobar emphysema (CLE). The case discussion focuses on the need for an understanding of flight physiology in order for physicians to determine the most appropriate method to assess fitness to fly in children with medical concerns.


The effect of physical exercise on disordered social communication in individuals with autism Spectrum disorder: a systematic review and meta-analysis of randomized controlled trials.
The aim of this systematic review and meta-analysis was to systematically investigate the intervention effect of physical exercise on disordered social communication in patients with autism spectrum disorders. This systematic review and meta-analysis used the PubMed, Web of Science, the Cochrane Library, and Embase electronic databases to conduct a systematic search of literature describing randomized controlled trials (RCTs) on the effect of physical exercise on disordered social communication in autistic patients from the first year of inclusion to 21 January 2023. A total of 14 RCTs including 460 autistic patients were analyzed. A meta-analysis showed that physical exercise had a positive effect on social communication disorder (SMD = 0.45, 95% CI: 0.15, 0.74, p < 0.05) in autistic patients. Subgroup analysis showed that exercise programs with multiple components (SMD = 0.73, 95% CI: 0.39, 1.06, P < 0.001), a moderate duration (SMD = 0.73, 95% CI: 0.38, 1.08, P < 0.001), a moderate-high frequency (SMD = 0.84, 95% CI: 0.53, 1.14, P < 0.001), and a long duration (SMD = 0.77, 95% CI: 0.36, 1.18, P < 0.001) led to significant improvement. Physical exercise can improve disordered social communication in patients with autism spectrum disorders. Specifically, early intervention, multi-component exercise, a moderate period, moderate and high frequency, long duration, and multi-participant programs were most effective. https://www.crd.york.ac.uk/prospero/ RecordID= CRD42023422482.


Soluble guanylate cyclase is allosterically inhibited by direct interaction with 2-substituted adenine nucleotides.
Nitric oxide (NO), the principal endogenous ligand for soluble guanylate cyclase (sGC), stimulates that enzyme and accumulation of intracellular cGMP, which mediates many of the (patho) physiological effects of NO. Previous studies demonstrated that 2-substituted adenine nucleotides, including 2-methylthioATP (2MeSATP) and 2-chloroATP (2ClATP), allosterically inhibit guanylate cyclase C, the membrane-bound receptor for the Escherichia coli heat-stable enterotoxin in the intestine. The present study examined the effects of 2-substituted adenine nucleotides on crude and purified sGC. 2-Substituted nucleotides inhibited basal and NO-activated crude and purified sGC, when Mg2+ served as the substrate cation cofactor. Similarly, 2-substituted adenine nucleotides inhibited those enzymes when Mn2+, which activates sGC in a ligand-independent fashion, served as the substrate cation cofactor. Inhibition of sGC by 2-substituted nucleotides was associated with a decrease in Vmax, consistent with a noncompetitive mechanism. In contrast to guanylate cyclase C, 2-substituted nucleotides inhibited sGC by a guanine nucleotide-independent mechanism. These studies demonstrate that 2-substituted adenine nucleotides allosterically inhibit basal and ligand-stimulated sGC. They support the suggestion that allosteric inhibition by adenine nucleotides is a general characteristic of the family of guanylate cyclases. This allosteric inhibition is mediated by direct interaction of adenine nucleotides with sGC, likely at the catalytic domain in a region outside the substrate-binding site.


Parkin promotes proteasomal degradation of synaptotagmin IV by accelerating polyubiquitination.
Parkin is an E3 ubiquitin ligase whose mutations cause autosomal recessive juvenile Parkinson's disease (PD). Unlike the human phenotype, parkin knockout (KO) mice show no apparent dopamine neuron degeneration, although they demonstrate reduced expression and activity of striatal mitochondrial proteins believed to be necessary for neuronal survival. Instead, parkin-KO mice show reduced striatal evoked dopamine release, abnormal synaptic plasticity, and non-motor symptoms, all of which appear to mimic the preclinical features of Parkinson's disease. Extensive studies have screened candidate synaptic proteins responsible for reduced evoked dopamine release, and synaptotagmin XI (Syt XI), an isoform of Syt family regulating membrane trafficking, has been identified as a substrate of parkin in humans. However, its expression level is unaltered in the striatum of parkin-KO mice. Thus, the target(s) of parkin and the molecular mechanisms underlying the impaired dopamine release in parkin-KO mice remain unknown. In this study, we focused on Syt IV because of its highly homology to Syt XI, and because they share an evolutionarily conserved lack of Ca2+-binding capacity; thus, Syt IV plays an inhibitory role in Ca2+-dependent neurotransmitter release in PC12 cells and neurons in various brain regions. We found that a proteasome inhibitor increased Syt IV protein, but not Syt XI protein, in neuron-like, differentiated PC12 cells, and that parkin interacted with and polyubiquitinated Syt IV, thereby accelerating its protein turnover. Parkin overexpression selectively degraded Syt IV protein, but not Syt I protein (indispensable for Ca2+-dependent exocytosis), thus enhancing depolarization-dependent exocytosis. Furthermore, in parkin-KO mice, the level of striatal Syt IV protein was increased. Our data indicate a crucial role for parkin in the proteasomal degradation of Syt IV, and provide a potential mechanism of parkin-regulated, evoked neurotransmitter release.


[Dexmedetomidine improves function of lung oxygenation in patients with moderate chronic obstructive pulmonary disease underwent lung cancer surgery].
To determine whether dexmedetomidine (Dex) improves oxygenation and lung mechanics in patients with moderate chronic obstructive pulmonary disease (COPD) during lung cancer surgery. Methods: Fifty-six patients with moderate COPD were randomly allocated to a control group and a Dex group (n=28 each). In the Dex group, dexmedetomidine was given as an initial loading dose at 1.0 μg/kg lasting for 10 min followed by a maintenance dose at 0.5 μg/(kg.h) during OLV while the control group was administered an equal volume of 0.9% saline accordingly. Results: Patients in the Dex group had a significantly higher oxygenation index (P<0.05) and higher dynamic lung compliance at Dex-30 and Dex-60 (P<0.05) compared with those in the control group. In the Dex group, oxygenation index in the postoperative period was significantly higher (P= 0.025) and postoperative complications were lower than those in the control group. Conclusion: Dex administration may provide clinically relevant benefits by improving o xygenation index and lung mechanics, and reducing postoperative pulmonary complications in patients with moderate COPD underwent lung cancer surgery.


Maps of current density using density-functional methods.
The performance of several density-functional theory (DFT) methods for the calculation of current densities induced by a uniform magnetic field is examined. Calculations are performed using the BLYP and KT3 generalized-gradient approximations, together with the B3LYP hybrid functional. For the latter, both conventional and optimized effective potential (OEP) approaches are used. Results are also determined from coupled-cluster singles-and-doubles (CCSD) electron densities by a DFT constrained search procedure using the approach of Wu and Yang (WY). The current densities are calculated within the CTOCD-DZ2 distributed origin approach. Comparisons are made with results from Hartree-Fock (HF) theory. Several small molecules for which correlation is known to be especially important in the calculation of magnetic response properties are considered-namely, O(3), CO, PN, and H(2)CO. As examples of aromatic and antiaromatic systems, benzene and planarized cyclooctatetraene molecules are considered, with specific attention paid to the ring current phenomenon and its Kohn-Sham orbital origin. Finally, the o-benzyne molecule is considered as a computationally challenging case. The HF and DFT induced current maps show qualitative differences, while among the DFT methods the maps show a similar qualitative structure. To assess quantitative differences in the calculated current densities with different methods, the maximal moduli of the induced current densities are compared and integration of the current densities to yield shielding constants is performed. In general, the maximal modulus is reduced in moving from HF to B3LYP and BLYP, and further reduced in moving to KT3, OEP(B3LYP), and WY(CCSD). The latter three methods offer the most accurate shielding constants in comparison with both experimental and ab initio data and hence the more reliable route to DFT calculation of induced current density in molecules.


[Reaching a team consensus in pediatric oncology when treatment proves ineffective].
Modern treatments are able to cure 3/4 of paediatric cancers, but on another hand there is still a too high number of patients which will enter a resistant phase and test the ability of the medical and nursing team to face together the new modalities of care. At diagnosis, the reasonable hope to cure the child and the exciting feeling to be endued with a repairing mission strengthen among the team both the self-esteem and a rational and emotional consensus. Conversely, at the time of relapse or resistant disease, the feeling of a failure, added to anxiety and reciprocal aggressiveness, will contradictorily affect the group. In this atmosphere of loss of control of reality and emotions, elaborating new priorities of care is mandatory: medical positions have of course to be in keeping, but this is not enough since the nursing team has, through sharing information and feeling, to give their cure project of the child's cancer as lost while retaining and expanding their ability to care the child with cancer. Thanks to an over-investment of the symptomatic, psychological, and affective help support to the child, the nursing team will succeed in regaining this self-esteem absolutely necessary to their own professional survival. Consensus in the team is ultimately linked to its empathic ability of exchanging with the families which in turn results in giving them guidelines for the last weeks and months of life and helping them to be less emotionally unprovided when bereavement time has come: a pedagogy of the continuity of care is thus taking place which, equally distant from forsaking and therapeutic relentlessness, chooses to give up the idea of curing in order to go on caring.


Acute treatment-related toxicity in elderly patients with good performance status compared to young patients in locally advanced esophageal carcinoma treated by definitive chemoradiation: A retrospective comparative study.
The benefit of definitive chemoradiotherapy (CRT) in elderly patients with locally advanced esophageal cancer is not well established. We perform a single institutional retrospective study of CRT in terms of toxicity in elderly patients (age more than 60 years) as compared with young cohort (age <60 years) in locally advanced nonmetastatic esophageal cancer. A total 145 of patients, 79 in young age (Group A) and 66 patients of elder age (Group B) with Stage II and III squamous cell carcinoma of the esophagus with ECOG PS of 0-1, who had undergone definitive CRT at our institute from January 2015 to November 2018 were selected for this analysis. Chemotherapy was cisplatin (40 mg/m2) given concurrently on weekly basis with radiotherapy (RT). Total prescribed dose of RT was 50.4 Gy at the rate of 1.8 Gy per fraction. Median age was 40 years (25-60 years) and 65 years (60-75 years) in young and elderly group, respectively. Follow-up is done at median of 28 months (1-48 months) after treatment. Acute Grade 2-3 esophagitis was seen in 48.10% in young cohort, while it was 60.6% in older group. Grade 2-3 nausea and vomiting was seen in 32.91% in young age patients, while it was 45.5% in elder patients. No statistically significant difference is seen in acute treatment-related toxicity in young and elderly group. Our conclusion is that patients with adequate functional status should not be excluded from curative CRT based on age alone.


Actin-associated Proteins in the Pathogenesis of Podocyte Injury.
Podocytes have a complex cellular architecture with interdigitating processes maintained by a precise organization of actin filaments. The actin-based foot processes of podocytes and the interposed slit diaphragm form the final barrier to proteinuria. The function of podocytes is largely based on the maintenance of the normal foot process structure with actin cytoskeleton. Cytoskeletal dynamics play important roles during normal podocyte development, in maintenance of the healthy glomerular filtration barrier, and in the pathogenesis of glomerular diseases. In this review, we focused on recent findings on the mechanisms of organization and reorganization of these actin-related molecules in the pathogenesis of podocyte injury and potential therapeutics targeting the regulation of actin cytoskeleton in podocytopathies.