[Mechanisms of myocardial damage progression in heart failure].
Cardiac Failure is an increasing health problem in the world. Several mechanisms have been proposed as the cause of this epidemiological transition. The main reason is the increase in the survival of patients with coronary heart disease and the improvement in the management of cardiac failure with new drugs. Knowledge of new mechanisms including gene regulation, extracelullar matrix function, intracardiac vessels, neuroendocrine interrelations, inflammatory activity, immune balance, signalling intracellular and extracellular cascade, and mechanical integrity, have permitted a better and rational approach. The influence of paradigms such as endothelin system, sympathovagal balance, oxidative system, angiotensin receptors, aldosterone receptors have been demonstrated on progression of the cellular damage's patients with cardiac failure. Apoptosis is recognized as a common final way. In this review all these topics are analyzed. Emphasis is made on the new therapeutics strategies of treatment.


Variant-to-function analysis of the childhood obesity chr12q13 locus implicates rs7132908 as a causal variant within the 3' UTR of FAIM2.
The ch12q13 obesity locus is among the most significant childhood obesity loci identified in genome-wide association studies. This locus resides in a non-coding region within FAIM2; thus, the underlying causal variant(s) presumably influence disease susceptibility via an influence on cis-regulation within the genomic region. We implicated rs7132908 as a putative causal variant at this locus leveraging a combination of our inhouse 3D genomic data, public domain datasets, and several computational approaches. Using a luciferase reporter assay in human primary astrocytes, we observed allele-specific cis-regulatory activity of the immediate region harboring rs7132908. Motivated by this finding, we went on to generate isogenic human embryonic stem cell lines homozygous for either rs7132908 allele with CRISPR-Cas9 homology-directed repair to assess changes in gene expression due to genotype and chromatin accessibility throughout a differentiation to hypothalamic neurons, a key cell type known to regulate feeding behavior. We observed that the rs7132908 obesity risk allele influenced the expression of FAIM2 along with other genes, decreased the proportion of neurons produced during differentiation, up-regulated cell death gene sets, and conversely down-regulated neuron differentiation gene sets. We have therefore functionally validated rs7132908 as a causal obesity variant which temporally regulates nearby effector genes at the ch12q13 locus and influences neurodevelopment and survival.


[Love bite on the neck resulted in an embolic stroke].
A 35-year-old woman experienced sudden onset of right-sided weakness due to a left middle cerebral artery stroke 12 hours after she had obtained a love bite on the left side of her neck. Duplex ultrasonography showed a near-occlusion of the left internal carotid artery (ICA) and CT angiography revealed a mural thrombus at the same location. This case report shows that love bites on the neck are a rare cause of embolic stroke. The most likely aetiology is embolization of thrombus material from a local intimal lesion of the ICA.


Recognition of novel artifacts produced during the microsomal incubation of secondary alicyclic amines in the presence of cyanide.
1. During the in vitro microsomal metabolism of the secondary alicyclic amines, nornicotine, anabasine or 4-benzylpiperidine in the presence of cyanide, a new product was formed. 2. Comparison of these new products with authentic compounds by hplc and ms showed they were the corresponding 1'-N-cyanomethyl compounds. 3. The source of the methylene group was shown to be formaldehyde, arising during incubation, from either microsomal lipid and/or glycerol used to store microsomes for long periods at low temperature. 4. The formation of the 1'-N-cyanomethyl compounds was enhanced in the presence of substrates producing formaldehyde during their metabolism, in direct relationship to the amount of formaldehyde generated. 5. The results indicate that care should be taken in interpreting data obtained from incubates containing secondary amines and cyanide, especially in the presence of substrates capable of donating formaldehyde.


Evolving Trends in Surgical Management of Breast Cancer: An Analysis of 30 Years of Practice Changing Papers.
The management of breast cancer has evolved into a multidisciplinary evidence-based surgical speciality, with emphasis on conservative surgery. A number of landmark trials have established lumpectomy followed by radiation as the standard of care for many patients. The aim of this study is to construct a narrative review of recent developments in the surgical management of breast cancer and how such developments have impacted surgical practice. A comprehensive literature search of Pubmed was conducted. The latest search was performed on October 31st, 2020. Search terms "breast cancer" were used in combinations with specific key words and Boolean operators relating to surgical management. The reference lists of retrieved articles were comprehensively screened for additional eligible publications. Articles were selected and reviewed based on relevance. We selected publications in the past 10 years but did not exclude commonly referenced and highly regarded previous publications. Review articles and book chapters were also cited to provide reference on details not discussed in the academic literature. This article reviews the current evidence in surgical management of early-stage breast cancer, discusses recent trends in surgical practice for therapeutic and prophylactic procedures and provides commentary on implications and factors associated with these trends.


Clinical, serologic, and immunogenetic studies in patients with dermatomyositis.
Dermatomyositis is a disease of unknown etiology characterized by progressive, symmetrical, proximal muscle weakness with accompanying compatible cutaneous findings. Thirty-nine patients with dermatomyositis from the Louisville, Kentucky area were enrolled in this study. Patients were grouped into those with or without a malignancy. Ten patients (26%) either had or have had a malignancy. Twenty-five Caucasian patients were HLA typed for the A, B, DR and DQ locus antigens, of whom 5 had an associated malignancy and 20 did not have a malignancy. We found that no single antigen had a significantly increased or decreased frequency as compared with our control population for the entire group, or for any clinical subset we examined. Serologic testing revealed 4 patients with anti-Mi-2 antibodies and 1 patient with anti-PM-SCL antibodies. No patient had a positive anti-Jo-1 antibody in this group. The results of serologic tests in this group did not correlate with any clinical subset or HLA antigen. Our findings were in agreement with the previous reports in which approximately 25% of patients with DM have an associated malignancy. Our findings also support the notion that untargeted malignancy searches are not warranted. Contrary to previous reports we did not observe an inverse relationship between cancer and pulmonary disease in the dermatomyositis patient. This study does not indicate that there are any HLA associations or clinical associations, other than age, that distinguish patients with dermatomyositis as running a greater risk of developing malignancy.


Mild hyponatremia is a common finding in children evaluated at the emergency department and it is significantly related to plasma C-reactive protein value.
During infectious diseases, mild hyponatremia is supposed to derive from a transient secretion of vasopressin mediated by non--osmotic stimuli. This study provides data supporting that mild hyponatremia during acute illnesses is related to the systemic inflammatory condition. I retrospectively analyzed 328 consecutive children (aged 3 months to 17 years) who received blood tests at the pediatric emergency department in 2 months' period. hyponatremia was found in 98 patients, most of them being mildly hyponatremic. A significant trend towards lower levels of plasmatic sodium, paralleling the increase of C--reactive protein, was showed. A significant relationship between plasmatic sodium levels and C--reactive protein was found, apart from the underlying disease.


Correlation of Long Non-coding RNA LncRNA-FA2H-2 With Inflammatory Markers in the Peripheral Blood of Patients With Coronary Heart Disease.
Objective: To characterize the expression of long non-coding RNA LncRNA-FA2H-2 in coronary heart disease (CHD) and its correlation with inflammatory markers. Methods: From December 2018 to December 2020, 316 patients at Henan Provincial People's Hospital who complained of chest tightness or chest pain and had coronary angiography to clarify their coronary artery conditions for definitive diagnoses were selected as the study subjects. Plasma was collected to detect white blood cells (WBCs), total cholesterol (TG), triglyceride cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein A1 (ApoA1), and C-reactive protein (CRP) levels. Tumor necrosis factor (TNF-α), monocyte chemotactic protein 1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1), intercellular cell adhesion molecule-1 (ICAM-1), and interleukin-6 (IL-6) levels were also measured using ELISA. The expression levels of lncRNA-FA2H-2 were measured using quantitative real-time PCR. The data obtained were analyzed by independent sample t-tests, rank sum tests, regression analyses, Pearson's or Spearman's correlation analyses, and receiver operating characteristic curves. Results: (1) Compared with the control group, the differences in age, sex, diabetes, smoking, drinking, body mass index (BMI), WBC, TC, and LDL-C in CHD were not statistically significant, while the differences in hypertension, TG, HDL-C, ApoA1, and CRP were statistically significant. (2) In the grouping of coronary lesion branches, patients with age, sex, hypertension, diabetes, smoking, drinking, BMI, WBC, TC, LDL-C, HDL-C, and ApoA1 differences were not statistically significant, but TG and CRP differences were statistically significant. (3) The relative expressions of TNF-α, MCP-1, VCAM-1, ICAM-1, and IL-6 were significantly upregulated in the CHD group (P < 0.001). (4) The results showed that the relative levels of TNF-α, MCP-1, VCAM-1, ICAM-1, and IL-6 between the two comparative analyses (high risk, moderate risk, and low risk groups) were statistically significant. In addition, positive correlations were found between the Gensini score and TNF-α, MCP-1, VCAM-1, ICAM-1, and IL-6 in CHD patients. (5) LncRNA-FA2H-2 relative expression in the CHD group was significantly downregulated (P < 0.001). (6) The differences in the expression levels of LncRNA-FA2H-2 were statistically significant between the two comparative analyses (P < 0.01), except between the 2-branch lesion and 3-branch lesion groups. (7) LncRNA-FA2H-2 was not associated with age, sex, hypertension, diabetes, smoking, drinking, BMI, WBC, TG, TC, LDL-C, HDL-C, and ApoA1 (P > 0.05). (8) A correlation was found between LncRNA-FA2H-2 and MCP-1, and VCAM-1, ICAM-1, IL-6, and Gensini. (9) The results indicated that the relative levels of LncRNA-FA2H-2 between the two comparative analyses (high risk, moderate risk, and low risk groups) were statistically significant. A negative correlation was found between the Gensini score and LncRNA-FA2H-2. (10) ROC curve analyses of TNF-α, MCP-1, VCAM-1, ICAM-1, and IL-6 in CHD showed the area under the curve (AUC) = 0.832 (0.77, 0.893) with a cut-off value of 290.5, a sensitivity of 73%, and a specificity of 64%; AUC = 0.731 (0.653, 0.809) with a cut-off value of 396 and with a sensitivity of 59% and specificity of 79%; AUC = 0.822 (0.757, 0.887) with a cut-off value of 264 and with a sensitivity of 72% and specificity of 83%; AUC = 0.794 (0.715, 0.874) with a cut-off value of 201.5 and with a sensitivity of 75% and specificity of 65%; AUC = 0.760 (0.685, 0.834) with a cut-off value of 328 and with a sensitivity of 55% and specificity of 90%. (11) ROC curve analysis of LncRNA-FA2H-2 in CHD patients showed AUC = 0.834 (0.688, 0.85) with a cut-off value of 3.155 and with a sensitivity of 85% and specificity of 82%. (12) Logistic analyses showed that TNF-α, MCP-1, VCAM-1, IL-6, and LncRNA-FA2H-2 were independent risk factors for CHD. Conclusions: The expression of LncRNA-FA2H-2 was reduced and inversely correlated with inflammation-related factors in CHD patients. LncRNA-FA2H-2 may have potential as an inflammatory marker for risk assessment of CHD development.


Initial partition and aggregation of uncharged polyaromatic molecules at the oil-water interface: a molecular dynamics simulation study.
Initial partitioning and aggregation of several uncharged polyaromatic (PA) molecules with the same polyaromatic core but different terminal moieties at oil-water interfaces from the bulk oil phase were studied by molecular dynamics simulation. The partition of the PA molecules between the bulk organic phase and oil-water interface was highly dependent on the terminal moiety structure of the PA molecules and aromaticity of the organic phase. The polarity ratio between the oil and water phases showed a significant influence on adsorption of the PA molecules at the oil-water interface. The presence of hydrophobic aromatic moieties in PA molecules hindered the adsorption process. Larger aromatic rings in PA molecules lowered the interfacial activity due to strong intermolecular π-π interactions and molecular aggregation in the bulk oil phase. The presence of a terminal carboxylic functional group on the side chain enhanced the adsorption of the PA molecules at the oil-water interface. The fused ring plane of the uncharged PA molecules was found to preferentially adsorb at the oil-water interface in a head-on or side-on orientation with the polyaromatic core staying in the nonaqueous phase (i.e., the principal plane of the molecule perpendicular to the oil-water interface). The results obtained from this study could provide a scientific direction for the design of proper chemical demulsifiers for PA molecule-mediated emulsions formed under specific process conditions of temperature, pressure, and pH.


Outcomes following thoracotomy or thoracoscopic vascular ring division in children and young adults.
To determine the short- and intermediate-term outcomes following vascular ring division by video-assisted thoracoscopic (VATS) or thoracotomy approach. This study is a retrospective review of patients with double aortic arch or right aortic arch with aberrant left subclavian artery and left ligamentum (RAA with LSCA/LL) who underwent division via left thoracotomy or VATS approach at a single institution. Outcome measures included operation duration (OR time), hospital length of stay (LOS), postoperative complications, and freedom from reintervention. A total of 200 patients underwent vascular ring division by VATS (n = 115) or thoracotomy (n = 85). Of 200 patients, 125 (56%) displayed respiratory symptoms at presentation, 29 (11%) displayed digestive tract symptoms, and 41 (32%) displayed both. Median follow-up was 2.1 years (interquartile range: 1 month to 7.1 years). Overall cohort mortality was 1 (0.5%) of 200 at 11 years after surgery. Fifteen (7.5%) experienced immediate postoperative complications. At follow-up visit within 1 month after surgery, 92 (74%) of 125 patients reported improvement in symptoms. Freedom from reintervention was 96% and 90% at 5 years and 10 years, respectively. Among patients with RAA with LSCA/LL (n = 113), VATS was associated with shorter LOS compared with thoracotomy (1.2 vs 3.4 days; P < .001), but rates of complications were not significantly different (9% vs 4%, P = .68). Vascular ring division by either thoracotomy or VATS can be performed with low rates of complication and need for reintervention. Compared with thoracotomy, VATS is associated with shorter operative duration and hospital LOS among patients with RAA with LSCA/LL.


Nitric oxide reduces paracellular resistance in rat thick ascending limbs by increasing Na+ and Cl- permeabilities.
About 50% of the Na+ reabsorbed in thick ascending limbs traverses the paracellular pathway. Nitric oxide (NO) reduces the permselectivity of this pathway via cGMP, but its effects on absolute Na+ ([Formula: see text]) and Cl- ([Formula: see text]) permeabilities are unknown. To address this, we measured the effect of l-arginine (0.5 mmol/l; NO synthase substrate) and cGMP (0.5 mmol/l) on [Formula: see text] and [Formula: see text] calculated from the transepithelial resistance (Rt) and [Formula: see text]/[Formula: see text] in medullary thick ascending limbs. Rt was 7,722 ± 1,554 ohm·cm in the control period and 6,318 ± 1,757 ohm·cm after l-arginine treatment (P < 0.05). [Formula: see text]/[Formula: see text] was 2.0 ± 0.2 in the control period and 1.7 ± 0.1 after l-arginine (P < 0.04). Calculated [Formula: see text] and [Formula: see text] were 3.52 ± 0.2 and 1.81 ± 0.10 × 10-5 cm/s, respectively, in the control period. After l-arginine they were 6.65 ± 0.69 (P < 0.0001 vs. control) and 3.97 ± 0.44 (P < 0.0001) × 10-5 cm/s, respectively. NOS inhibition with Nω-nitro-l-arginine methyl ester (5 mmol/l) prevented l-arginine's effect on Rt Next we tested the effect of cGMP. Rt in the control period was 7,592 ± 1,470 and 4,796 ± 847 ohm·cm after dibutyryl-cGMP (0.5 mmol/l; db-cGMP) treatment (P < 0.04). [Formula: see text]/[Formula: see text] was 1.8 ± 0.1 in the control period and 1.6 ± 0.1 after db-cGMP (P < 0.03). [Formula: see text] and [Formula: see text] were 4.58 ± 0.80 and 2.66 ± 0.57 × 10-5 cm/s, respectively, for the control period and 9.48 ± 1.63 (P < 0.007) and 6.01 ± 1.05 (P < 0.005) × 10-5 cm/s, respectively, after db-cGMP. We modeled NO's effect on luminal Na+ concentration along the thick ascending limb. We found that NO's effect on the paracellular pathway reduces net Na+ reabsorption and that the magnitude of this effect is similar to that due to NO's inhibition of transcellular transport.


Susceptibility to heartwater of calves born to non-immune cows.
The resistance to artificial infection with Cowdria ruminantium of calves born to cows fully susceptible to heartwater is no different from that of calves bred in heartwater endemic areas where the tick challenge is negligible to considerable. The sub-inoculation into mice of blood collected 14-26 days after infection proved the presence of the heartwater agent in the blood of 8 out of 10 calves with no other clinical signs than mild to moderate fever. The combined use of a mouse model and the indirect fluorescent antibody test revealed considerable variation in the degrees to which calves become infected and react to artificial infection.


Cross-kingdom auxiliary subunit modulation of a voltage-gated sodium channel.
Voltage-gated, sodium ion-selective channels (NaV) generate electrical signals contributing to the upstroke of the action potential in animals. NaVs are also found in bacteria and are members of a larger family of tetrameric voltage-gated channels that includes CaVs, KVs, and NaVs. Prokaryotic NaVs likely emerged from a homotetrameric Ca2+-selective voltage-gated progenerator, and later developed Na+ selectivity independently. The NaV signaling complex in eukaryotes contains auxiliary proteins, termed beta (β) subunits, which are potent modulators of the expression profiles and voltage-gated properties of the NaV pore, but it is unknown whether they can functionally interact with prokaryotic NaV channels. Herein, we report that the eukaryotic NaVβ1-subunit isoform interacts with and enhances the surface expression as well as the voltage-dependent gating properties of the bacterial NaV, NaChBac in Xenopus oocytes. A phylogenetic analysis of the β-subunit gene family proteins confirms that these proteins appeared roughly 420 million years ago and that they have no clear homologues in bacterial phyla. However, a comparison between eukaryotic and bacterial NaV structures highlighted the presence of a conserved fold, which could support interactions with the β-subunit. Our electrophysiological, biochemical, structural, and bioinformatics results suggests that the prerequisites for β-subunit regulation are an evolutionarily stable and intrinsic property of some voltage-gated channels.


The role of AKT1 and autophagy in the protective effect of hydrogen sulphide against hepatic ischemia/reperfusion injury in mice.
Hydrogen sulphide (H 2S) exerts a protective effect in hepatic ischemia-reperfusion (I/R) injury. However, the exact mechanism of H 2S action remains largely unknown. This study was designed to investigate the role of the PtdIns3K-AKT1 pathways and autophagy in the protective effect of H 2S against hepatic I/R injury. Primary cultured mouse hepatocytes and livers with or without NaHS (a donor of H 2S) preconditioning were exposed to anoxia/reoxygenation (A/R) and I/R, respectively. In certain groups, they were also pretreated with LY294002 (AKT1-specific inhibitor), 3-methyladenine (3MA, autophagy inhibitor) or rapamycin (autophagy enhancer), alone or simultaneously. Cell viability, expression of P-AKT1, T-AKT1, LC3 and BECN1 were examined. The severity of liver injury was measured by the levels of serum aminotransferase and inflammatory cytokine, apoptosis and histological examination. GFP-LC3 redistribution and transmission electron microscopy were used to test the activity of autophagy. H 2S preconditioning activated PtdIns3K-AKT1 signaling in hepatocytes. LY294002 could abolish the AKT1 activation and attenuate the protective effect of H 2S on hepatocytes A/R and hepatic I/R injuries. H 2S suppressed hepatic autophagy in vitro and in vivo. Further reducing autophagy by 3MA also diminished the protective effect of H 2S, while rapamycin could reverse the autophagy inhibitory effect and enhance the protective effect of H 2S against hepatocytes A/R and hepatic I/R injuries, consequently. Taken together, H 2S protects against hepatocytic A/R and hepatic I/R injuries, at least in part, through AKT1 activation but not autophagy. An autophagy agonist could be applied to potentiate this hepatoprotective effect by reversing the autophagy inhibition of H 2S.


Seat influences on female neck responses in rear crashes: a reason why women have higher whiplash rates.
Since the earliest crash investigations, whiplash has been found to occur more often in women than men. This study addresses seat properties that may explain a reason for the higher rates in women, and changes in whiplash in general over the past two decades. Three exemplar seats were defined on the basis of seat stiffness (k) and frame rotation stiffness (j) for rearward occupant load. Stiff seats have k=40 kN/m and j=1.8 degrees /kN representing a foreign benchmark loaded by a male. One yielding seat had k=20 kN/m and j=1.4 degrees /kN simulating a high-retention seat (1997 Grand Prix) and another k=20 kN/m and j=3.4 degrees /kN simulating a 1980s to 1990s yielding seat (1990 Buick Park Avenue). Constant vehicle acceleration for 100 msec gave delta-V of 6, 10, 16, and 24 km/h. The one-dimensional model included a torso mass loading the seatback with flexible neck and head mass. Based on biomechanical data and scaling, neck stiffness was 5 kN/m and 3 kN/m for the male and female, respectively. Based on validation tests, seat stiffness was 25% less with the female. Occupant dynamics were simulated in a step-forward solution based on the differential displacement between the head, torso, and seat up to head restraint contact. Neck responses were 30% higher in the female than male through most of the rear impact and are proportional to (kF/mTF)/(kM/mTM), which is the ratio of seat stiffness divided by torso mass for the female and male. Neck displacements were higher with the stiff seat than the 1990 C car seat for both the female and male. They peaked at 10 km/h and dropped off for higher severity crashes due to the shorter time to head contact. Neck displacements were greater in the female than male for the lowest severity crashes with the stiff and 1990 C car seats, when displacement was scaled for equal tolerance. The female in 1997 W car seat had the lowest neck displacements. Stiff seats increased neck displacements over the yielding seats of the 1980s in rear crashes. The trend is similar in men and women, but early neck displacements are greater in women because of a higher ratio of seat stiffness to torso mass. This implies that seat stiffness is not sufficiently low in proportion to the female mass in comparison to males. The j and k seat properties influence neck biomechanics and occupant dynamics, but k is important in determining early response differences between males and females.


Determination of both mechanical and electronic shifts in cone beam SPECT.
The difference between the displacement of the centre of rotation (mechanical shift, MS) and the electronic centring misalignment (electronic shift, ES) in cone beam SPECT is evaluated. A method is proposed to determine both MS and ES using the centroid of a projected point source sampled over 360 degrees and the Marquardt non-linear fitting algorithm. Both shifts are characterized by two orthogonal components. This method is verified using Monte Carlo simulated point source data with different combinations of mechanical and electronic shifts. Both shifts can be determined correctly. We have also applied the proposed method to our cone beam SPECT system to determine both shifts as well as the focal length. The determined ES parameters are then used to correct the projections and the MS parameters are incorporated into a reconstruction algorithm. The point source images are reconstructed and the image resolutions with and without the shift corrections are measured. The experimental results demonstrate that the image resolution is improved after shift corrections. The experimental results also indicate that the shift parameters determined in the same experiment with the point source located at different places are consistent but change from time to time, suggesting that calibration of the system is needed on a periodic basis.


Specific antidotes in development for reversal of novel anticoagulants: a review.
In the last decade, several direct oral anticoagulants (DOAC; dabigatran, rivaroxaban, apixaban, edoxaban) have been marketed for prophylaxis and/or treatment of thromboembolism without having specific antidotes available for their reversal. Current management of bleeding associated to DOAC includes the removal of all antithrombotic medications and supportive care. Non-specific procoagulant agents (prothrombin complex concentrates and activated factor VIIa) have been used in case of serious bleeding. Currently, some specific antidotes for the DOAC are under development. Idarucizumab (BI 655075; Boehringer Ingelheim) is a fragment of an antibody (Fab), which is a specific antidote to the oral direct thrombin inhibitor dabigatran. Andexanet alfa (r-Antidote, PRT064445; Portola Pharmaceuticals) is a truncated form of enzymatically inactive factor Xa, which binds and reverses the anticoagulant action of the factor Xa inhibitors (e.g.: rivaroxaban, apixaban and edoxaban). Aripazine (PER-977, ciraparantag; Perosphere Inc.) is a synthetic small molecule (~500 Da) that reverses oral dabigatran, apixaban, rivaroxaban, as well as subcutaneous fondaparinux and LMWH in vivo. These antidotes could provide an alternative for management of life-threatening bleeding events occurring with the above-mentioned anticoagulants. In addition, the specific antidote anivamersen (RB007; Regado Biosciences Inc.) is an RNA aptamer in clinical development to reverse the anticoagulant effect of the parenteral factor IXa inhibitor pegnivacogin, which is also in development. This anticoagulant-antidote pair may provide an alternative in situations in which a fast onset and offset of anticoagulation is needed, like in patients undergoing cardiac surgery with extracorporeal circulation, as an alternative to the heparin/protamine pair. This patent review includes a description of the pharmacological characteristics of the novel specific antidotes, the available results from completed non-clinical and clinical studies and the description of ongoing clinical trials with the new compounds.


Exposure to endocrine disrupting chemicals (EDCs) and cardiometabolic indices during pregnancy: The HOME Study.
Toxicology studies have identified pregnancy as a window of susceptibility for endocrine disrupting chemicals (EDCs) and cardiometabolic indices in women. No study in humans, however, has examined EDC mixtures and cardiometabolic indices during pregnancy. We used the Health Outcomes and Measures of the Environment (HOME) Study to examine whether bisphenol A (BPA), polybrominated diphenyl ethers (PBDEs), per- and polyfluoroalkyl substances (PFAS), and phthalates are associated with blood pressure, glucose, and lipids in 388 pregnant women. We measured PBDEs and PFAS in serum at 16 weeks gestation, while BPA and phthalate metabolites were quantified in urine at 16 and 26 weeks gestation. We used linear regression and Bayesian Kernel Machine Regression (BKMR) to estimate covariate-adjusted associations of individual EDCs and their mixtures with cardiometabolic indices during pregnancy. A 10-fold increase in BDE-28 was associated with a 13.1 mg/dL increase in glucose (95% Confidence Interval [CI] 2.9, 23.2) in linear regression. The BKMR model also identified BDE-28 as having a positive association with glucose. BDE-28, BDE-47, and BDE-99 were positively associated with total cholesterol in both single- and multi-pollutant models, whereas a suggestive negative association was noted with BDE-153. Mono-n-butyl phthalate (MBP) (β = -7.9 mg/dL, 95% CI -12.9, -3.0) and monobenzyl phthalate (MBzP) (β = -6.3 mg/dL, 95% CI -10.6, -2.0) were both associated with significant decreases in cholesterol in linear regression, but only MBzP was identified as an important contributor in the BKMR model. Overall, we observed positive associations between PBDEs with glucose and cholesterol levels during pregnancy, while negative associations were found between some phthalate biomarkers and cholesterol. No relationship was noted for BPA or PFAS with cardiometabolic indices during pregnancy across both models.


Extensive nasopharyngeal angiofibromas: the maxillary swing approach.
The objective of this study was to evaluate the efficacy and outcome using the maxillary swing approach for the management of extensive nasopharyngeal angiofibromas. A retrospective analysis in a tertiary care center revealed five cases with extensive nasal angiofibromas operated using the maxillary swing approach between 2010 and 2012. All patients had tumor extension to the lateral-most portions of the infratemporal fossa with complete occupation and destruction of the lateral wall of the sphenoid sinus causing abutment to the cavernous sinus and complete involvement of the pterygopalatine fossa and pterygoid base. One patient displayed full occupancy of the maxillary sinus as a consequence of erosion of the posterior and medial walls of the maxillary sinus, while another had severe temporal lobe compression through the roof of the infratemporal fossa. All patients underwent tumor excision using the maxillary swing approach. Patients were followed up for a minimum period of 1 year after surgery. The maxillary swing approach gave optimal exposure of the entire central skull base including the infratemporal fossa and its extreme lateral and superior aspects. Adequate tumor exposure and vascular control could be achieved in all cases resulting in complete tumor excision. The mean operative time was 4.5 h. Post-operative healing was satisfactory with palatal fistula formation in two cases and all patients remaining disease-free up to the present time. One had minimal misalignment of the halves of the upper jaw and two had epiphora, of which one required dacryocystorhinostomy. The maxillary swing is an effective approach in the management of extensive nasopharyngeal angiofibromas and leads to optimal anatomical exposure with minimal morbidity.


Photoinduced Transformation of Cs2Au2Br6 into CsPbBr3 Nanocrystals.
Lead-free halide double perovskites offer an environmentally friendly alternative to lead halide perovskites for designing optoelectronic solar cell devices. One simple approach to synthesize such double halide perovskites is through metal ion exchange. CsPbBr3 nanocrystals undergo exchange of Pb2+ with Au(I)/Au(III) to form double perovskite Cs2Au2Br6. When excited, a majority of the charge carriers undergo quick recombination in contrast to long-lived charge carries of excited CsPbBr3 nanocrystals. This metal ion exchange process is reversible as one can regenerate CsPbBr3 by adding excess PbBr2 to the suspension. Interestingly, when subjected to visible light irradiation, Cs2Au2Br6 nanocrystals eject reduced Au from the lattice as evidenced from the formation of larger gold nanoparticles. The presence of residual Pb2+ ions in the suspension restores the original CsPbBr3 composition. The results presented here provide insight into the dynamic nature of Au within the perovskite lattice under both chemical and light stimuli.


Glycaemic and insulin responses of diabetic patients to traditional Malaysian meals and the effect of guar gum.
The aims of the project were to determine the glycaemic and insulin responses of non-insulin dependent diabetic patients (NIDDM) to 3 traditional Malaysian meals compared to oral glucose, and to determine whether guar gum would affect these responses. Patients with NIDDM were tested with 75 g oral glucose and three common breakfast meals of the three main ethnic groups of Malaysia. When compared with the oral glucose group, significantly by lower blood glucose responses were seen at 90 and 120 minutes post prandial for nasi lemak (p<0.05) and at 60, 75 and 90 minutes for mee sup (p<0.05). No significant difference was seen for roti telur. There was no significant difference in plasma glucose at any time point of the study when the three test meals were compared with each other. Addition of 5g granulated guar gum mixed with water taken prior to the glucose significantly lowered the plasma glucose at 60, 120 and 150 minutes postprandially (p<0.05). Similarly for the test meals, guar gum significantly lowered plasma glucose concentration between 15 and 45 minutes (p<0.03) postprandial for nasi lemak and between 15 and 30 minutes (p<0.03) for mee sup but not with roti telur. With addition of guar gum, there was no significant change of insulin responses with the three meals but a significant increase was seen at 30 minutes (p<0.02) after ingestion of glucose.


Effectiveness of preoperative chemotherapy for far advanced gastric cancer.
We herein report a case in which preoperative chemotherapy with cisplatin and 5-fluorouracil was found to effectively treat far advanced gastric cancer invading the pancreas forming a huge mass with regional and distant lymph node metastases. As a result of this treatment regimen, a potentially curative resection was performed which led to a substantially increased survival. The patient was treated with 10 mg of cisplatin and 1000 mg of 5-fluouracil each day preoperatively. After the continuous administration of these drugs for 28 days, the findings of extensive pancreas invasion and lymph node metastases dramatically disappeared. The tumor could be curatively resected by a total gastrectomy with lymph nodes dissection, combined with a distal pancreatectomy and splenectomy. A histological study of a resected specimen showed some cancer cell infiltration remaining within the muscularis propria with fibrous change. There was no evidence of either pancreas invasion or lymph node metastasis. As a result, postoperative adjuvant chemotherapy was performed, 14 months later lymph nodes recurrence was detected and the patient died 20 months after surgery. Our findings suggest that preoperative chemotherapy may thus be effective for the treatment of gastric cancer by both reducing the tumor burden and prolonging survival.


Characterization of human nasal primary culture systems to investigate peptide metabolism.
The objectives of this study were to validate and compare the suitability of different primary cell culture systems as models to investigate peptide enzymatic stability following nasal administration. The degradation kinetics of a model peptide, leucine enkephalin (Tyr-Gly-Gly-Phe-Leu, Leu-Enk), was determined in four nasal cell culture systems: immersion, air-liquid interface, sequential monolayer-suspension, floating collagen. The influence of enzyme inhibitors (bestatin, puromycin) and Leu-Enk metabolite analogs (Tyr-Gly, Phe-Leu, Tyr-Gly-Gly, Gly-Phe-Leu) on the Leu-Enk degradation profile was also investigated. The disappearance of Leu-Enk in all the cell culture systems followed first order kinetics. The specific activity in the cell culture systems followed the rank: sequential monolayer-suspension (32.60 microM min(-1) mg(-1)) >air-liquid interface (15.19 microM min(-1) mg(-1)) >immersion (11.49 microM min(-1) mg(-1)) >floating collagen (4.57 microM min(-1) mg(-1)). At equimolar concentration, bestatin had a higher inhibitory effect than puromycin. The rate of hydrolysis of Leu-Enk was reduced significantly by co-incubation with Leu-Enk metabolite analogs. This study showed that immersion, sequential monolayer-suspension and air-liquid interface culture systems may be potentially suitable for further studies on peptide enzymatic stability following nasal administration.


[Development and Evaluation of a New Selective Culture Medium, KBM Anaero RS-GNR, for Detection of Anaerobic Gram Negative Rods].
The laboratory culture methods for isolating drug-resistant pathogens has been the gold standard in medical microbiology, and play pivotal roles in the overall management of infectious diseases. Recently, several reports have emphasized the development of antibiotics-resistance among anaerobic gram-negative rods, especially Genus Bacteroides and Prevotella. Therefore, a selective culture method to detect these pathogens is needed. We developed here the new selective culture medium, termed "KBM Anaero RS-GNR," for detecting anaerobic Gram-negative rods. Growth capability and selectivity of the agar medium were assessed by using the pure culture suspensions of more than 100 bacterial strains as well as the 13 samples experimentally contaminated with these bacterial strains. This new medium, "KBM Anaero RS-GNR," successfully showed the selective isolation of anaerobic Gram-negative rods. Compared with commercially available medium, "PV Brucella HK Agar, " which is also designed to detect anaerobic Gram-negative rods, there was no significant difference of the overall detection efficiency between two media. However, "KBM Anaero RS-GNR" showed superior to selectivity for anaerobic Gram-negative rods, especially from the samples contaminated with Candida species. Thus, the culture method using KBM Anaero RS-GNR is relevant for isolation of anaerobic Gram-negative rods especially from clinical specimens.


Effects of sildenafil treatment on thermogenesis and glucose homeostasis in diet-induced obese mice.
Stimulation of thermogenic pathways appears to be a promising approach to find new ways of tackling metabolic diseases like obesity and diabetes mellitus type 2. Thermogenic, weight reducing and insulin sensitizing effects of phosphodiesterase 5 (PDE 5) inhibitors have recently been postulated, suggesting that modulators of endogenous cGMP signaling have the therapeutic potential to treat metabolic disorders. However, most studies have been performed in vitro or in animals that were not glucose intolerant. We, thus, aimed to test the metabolic effects of the PDE 5 inhibitor sildenafil by treating diet-induced obese (DIO) mice orally for 8 days. Surprisingly, our results revealed no changes in body temperature, brown adipose tissue (BAT) thermogenesis and gene expression in BAT and inguinal white adipose tissue (iWAT), thus excluding a thermogenic or 'browning' effect of sildenafil in preexisting obesity. In contrast, sildenafil-treated DIO mice displayed changes in liver metabolism and glucose homeostasis resulting in impaired glucose tolerance (P < 0.05), demonstrating for the first time an unfavorable metabolic effect of increased hepatic cGMP signaling in obesity. As sildenafil is commonly prescribed to treat pulmonary arterial hypertension and erectile dysfunction in diabetic and/or obese patients, follow up studies are urgently required to re-evaluate the drug safety.


Within-host microevolution of Pseudomonas aeruginosa in Italian cystic fibrosis patients.
Chronic infection with Pseudomonas aeruginosa is a major cause of morbidity and mortality in cystic fibrosis (CF) patients, and a more complete understanding of P. aeruginosa within-host genomic evolution, transmission, and population genomics may provide a basis for improving intervention strategies. Here, we report the first genomic analysis of P. aeruginosa isolates sampled from Italian CF patients. By genome sequencing of 26 isolates sampled over 19 years from four patients, we elucidated the within-host evolution of clonal lineages in each individual patient. Many of the identified mutations were located in pathoadaptive genes previously associated with host adaptation, and we correlated mutations with changes in CF-relevant phenotypes such as antibiotic resistance. In addition, the genomic analysis revealed that three patients shared the same clone. Furthermore, we compared the genomes of the Italian CF isolates to a panel of genome sequenced strains of P. aeruginosa from other countries. Isolates from two of the Italian lineages belonged to clonal complexes of P. aeruginosa that have previously been identified in Danish CF patients, and our genomic comparison showed that clonal isolates from the same country may be more distantly related than clonal isolates from different countries. This is the first whole-genome analysis of P. aeruginosa isolated from Italian CF patients, and together with both phenotypic and clinical information this dataset facilitates a more detailed understanding of P. aeruginosa within-host genomic evolution, transmission, and population genomics. We conclude that the evolution of the Italian lineages resembles what has been found in other countries.


Large-scale intermittency in two-dimensional driven turbulence.
It is generally believed that two-dimensional turbulence is immune to intermittency possibly due to the absence of vortex stretching. However, in turbulence created in a freely suspended soap film by electromagnetic forcing, it is found that intermittency is not insignificant. We draw this conclusion based on the measured velocity structure function Sp(l) (identical to </deltavl/p>) proportional to l(zeta(p)) on scales l greater than the energy injection scale l(inj) . The scaling exponent zeta(p) vs p deviates from the expected linear relation and shows intermittent behavior comparable to that observed in fully developed three-dimensional turbulence in wind tunnels. Our measurements demonstrate that intermittency can be accounted for by the nonuniform distribution of saddle points in the flow.


Application of Extracorporeal Membrane Oxygenation in Patients with Scrub Typhus Complicated with Acute Respiratory Distress Syndrome.
A 68-year-old woman was diagnosed with scrub typhus and acute pneumonia. Acute respiratory distress syndrome (ARDS) occurred on day 4 after admission and was treated with extracorporeal membrane oxygenation (ECMO). After 7 days of ECMO assistance, her respiratory condition gradually improved, and ECMO was removed. On day 20 after admission, she was discharged without any sequelae. The results suggest that ECMO should be considered as early as possible for patients with ARDS caused by scrub typhus.


Adrenal and vascular renin-like activity in chronic 'two-kidney, one-clip' hypertensive rats.
In order to study the vascular and adrenal renin angiotensin system in the chronic phase (4 months after clipping) of 'two-kidney, one-clip' hypertension in rats, systolic blood pressure, plasma renin activity, and tissue renin-like activity in both aorta and adrenal have been measured. Renin activity in adrenal gland was studied in both the zona glomerulosa (GLO) and the remainder of the gland. Results showed an increase in vascular renin activity in chronic hypertensive rats. Moreover it was found that GLO of hypertensive rats presented a significant increase in renin-like activity compared with controls (349.43 +/- 43.86 versus 167 +/- 34.25 ng AI/g/20 h, p less than 0.01) and the fasciculata-reticular-medullar (FRM) portion also showed greater renin activity (345.16 +/- 64.36 versus 57.90 +/- 4.83 ng AI/g/20 h, p less than 0.01). The higher levels of vascular and FRM renin-like activity in chronic renal hypertension are probably a consequence of plasma renin increase. This hypothesis is supported by the fact that bilateral nephrectomy in normal rats induces a significant decrease in plasma renin activity and both aortic and FRM renin-like activity. On the other hand the GLO renin-like activity could depend on both plasma renin and local synthesis since bilateral nephrectomy induces an increase in the renin-like activity in this tissue. These data support the idea that aortic and FRM renin are, at least in part, due to plasma renin uptake and GLO renin is an autonomic system.


TLR4/ROS/miRNA-21 pathway underlies lipopolysaccharide instructed primary tumor outgrowth in lung cancer patients.
Activation of Toll-like receptor 4 (TLR4) signaling in human lung cancer with lipopolysaccharide (LPS) enhances tumor progression. However, whether primary human lung cancer outgrowth could respond to LPS and underlying mechanisms are unclear. Here we determined that TLR4 activation with LPS promoted outgrowth of primary human lung cancer cells in vitro and in vivo. Mechanistically, LPS stimulation increased expression levels of microRNA-21 (miR-21) in primary human lung cancer cells. Inhibition of miR-21 blocked the enhanced lung cancer growth induced by LPS in vitro and in vivo. Up-regulation of miR-21 promoted outgrowth of primary human lung cancer. Down-regulation of miR-21 limited primary human lung cancer outgrowth. Further, TLR4 activation in primary human lung cancer cells increased their ROS levels. Scavenge of ROS abrogated the up-regulation of miR-21 in primary human lung cancer cells and attenuated LPS-induced outgrowth. For in vivo relevance, expression of TLR4 was correlated with miR-21 expression and ROS production in freshly isolated, untreated primary human lung cancer cells. These findings demonstrate an essential role of TLR4/ROS/miR-21 pathway in LPS-induced outgrowth of primary human lung cancer. Our study connected a framework of innate signaling, oxidative stress and microRNA in tumor immunity and provided clues for developing new therapeutics for lung cancer.


Short GeLC-SWATH: a fast and reliable quantitative approach for proteomic screenings.
The quantification of large proteomes across multiple samples has become the major focus of proteomics. In addition to the advantages of in-gel digestion, the extensive time and sample handling required have precluded the use of this type of method for large quantitative screens. Therefore, an adaptation of the in-gel digestion method, termed short-GeLC, is proposed as a faster and more reproducible sample preparation method for quantitative approaches. The proposed methodology was compared with two well-established procedures for sample preparation, GeLC-MS and the classic liquid digestion followed by LC-MS, using a membrane protein-enriched sample. The results show that the short-GeLC approach substantially reduces the amount of sample handling and the overall time required for analysis compared with the gel-based methods without compromising the overall results at the protein identification level. Furthermore, the short-GeLC approach in combination with the SWATH acquisition method leads to the best quantitative results: more proteins were quantified, and the reproducibility was improved. Finally, this method performed well even on challenging samples enriched in membrane proteins.


Orange-fleshed sweet potato (Ipomoea batatas) composite bread as a significant source of dietary vitamin A.
Refining food recipes with orange-fleshed sweet potato (OFSP) has the potential to improve dietary intake of vitamin A. The objectives of this study were to utilize OFSP in the development of two composite bread types and to assess their contribution to dietary intake of vitamin A using the dietary reference intake of lactating mothers. Two composite OFSP-wheat flour bread recipes-vita butter bread and vita tea bread-were developed by incorporating 46% OFSP puree in existing 100% wheat flour bread recipes consumed by Ghanaians. A paired-preference test was used to profile the appearance, aroma, sweetness, and overall degree of liking of the vita butter bread and vita tea bread and their respective 100% wheat flour bread types. Weighed bread intake by lactating mothers (n = 50) was used to estimate the contribution to dietary vitamin A based on the trans β-carotene content. The developed vita butter bread and vita tea bread were most preferred by at least 77% (p < .05) of consumers (n = 310) for all the attributes considered. The average daily intake by the lactating mothers for vita butter bread was 247 g, and for vita tea bread was 196 g. The trans β-carotene content of vita butter bread and vita tea bread were found to be 1.333 mg/100 g and 0.985 mg/100 g, respectively. The estimated trans-β-carotene intake was 3,293 μg/day (vita butter) and 1,931 μg/day (vita tea) based on the weighed bread intake, respectively, meeting 21% and 12% of the daily requirement (1,300 μg RAE/day) for lactating mothers, the life stage group with the highest vitamin A requirement. OFSP therefore could composite wheat flour to bake butter and tea bread, and will contribute to significant amount of dietary intake of vitamin A.


Field isolates of Mycoplasma ovipneumoniae exhibit distinct cytopathic effects in ovine tracheal organ cultures.
Ovine tracheal ring explants were infected with four different Mycoplasma ovipneumoniae and one M. arginini field isolate and their ability to induce cytopathic effects was tested by measuring ciliary activity and intracellular calmodulin release. Infected tracheal rings showed significantly decreased ciliary activity as compared to the non-infected control rings. There were, however, marked differences between isolates in the onset and severity of the effects which correlated with their ability to produce hydrogen peroxide. Infected tracheal rings released more calmodulin than the non-infected controls. The amount of calmodulin released also varied between isolates, and somewhat reflected the degree of loss of ciliary activity in the corresponding rings induced by the different isolates. Light and electron microscopic examinations of infected tracheal rings revealed disorganisation and sloughing of the epithelium, and association of mycoplasmas only with the cilia. Following repeated in vitro passages, the organisms had reduced ability to inhibit ciliary activity which correlated with decreased hydrogen peroxide production. Addition of catalase to the organ cultures delayed loss of ciliary activity. These results suggest that M. ovipneumoniae induced ciliostasis in ovine tracheal ring explants which correlated with hydrogen peroxide production. Furthermore, these M. ovipneumoniae-induced injuries to respiratory epithelial cells could contribute to the role that this organism may play in sheep respiratory disease.


Varieties of Confidence Intervals.
Error bars are useful to understand data and their interrelations. Here, it is shown that confidence intervals of the mean (CI M s) can be adjusted based on whether the objective is to highlight differences between measures or not and based on the experimental design (within- or between-group designs). Confidence intervals (CIs) can also be adjusted to take into account the sampling mechanisms and the population size (if not infinite). Names are proposed to distinguish the various types of CIs and the assumptions underlying them, and how to assess their validity is explained. The various CIs presented here are easily obtained from a succession of multiplicative adjustments to the basic (unadjusted) CI width. All summary results should present a measure of precision, such as CIs, as this information is complementary to effect sizes.


Temporary employees in Singapore: what drives them?
In this study the authors provide an empirical analysis of the job attitudes and behavior of temporary workers in Singapore, compiling and categorizing the various reasons individuals choose temporary jobs, in an effort to provide a clear and comprehensive understanding of why people choose this work arrangement. A profile of temporary employees showed that job attitudes are affected by the importance of the various reasons given for being a temporary worker. This exploratory study provides a foundation on which more complex relationships between these variables can be examined.


Efficacy of superoxide dismutase mimetic M40403 in attenuating radiation-induced oral mucositis in hamsters.
M40403 is a small-molecule superoxide dismutase mimetic that has shown efficacy in animal model disease states in which superoxide anions are thought to play a key role. Radiation treatment and chemotherapy for cancer generate free oxygen radicals that are hypothesized to trigger unwanted side effects in healthy tissue. For some patients undergoing these antineoplastic treatments, one of the most prevalent side effects is oral mucositis, which is a painful, often dose-limiting condition. Preclinical and clinical studies of this condition have shown the positive effect of treatment with compounds that decrease free oxygen radicals. This study investigated the efficacy M40403 in a clinically relevant hamster model of acute, radiation-induced oral mucositis. Oral mucositis was induced in hamsters by irradiation of the cheek pouch. The ability of i.p. administered M40403 to decrease the duration and severity of oral mucositis was assessed after treatment at different doses and dosing schedules. Oral mucositis was scored using the WHO grading scale. Compared with placebo-treated animals, those irradiated on day 0 and treated twice daily with 30 mg/kg M40403 had significantly less severe and shorter duration mucositis over a range of treatment schedules, including from days -1 to 3, day 0 to 3, and day 0 alone. Similar efficacy was achieved at doses of 10 and 3 mg/kg twice daily on days -1 to 3. These results implicate free oxygen radicals in the onset of oral mucositis and also provide the basis for further development of M40403 in the prevention of this condition in at-risk cancer patients.


Toward a theory of process.
This article starts by finding a lack of procedural ethics in the usual debates over the functioning of ethics committees and the proper relationship of ethics committees and the courts, and traces this lack to the absence of a theory of process and process values. I then show why ethics commmittees are an excellent place to start in working on process. I therefore turn to the task of developing process values, and specifically a notion of patient-centered process. Here I recommend both process values commanded by our underlying substantive values, and further independent process values. I specifically suggest that surfacing problems of gender, racial, and economic bias make certain processes ethically mandatory. Having thus indicated what the needed process values might look like, I sketch their considerable theoretical potential. I return to the particular problem of ethics committees and the courts, and use my notion of patient-centered process to derive an answer to the question of how the two entities should interrelate. Finally, I step back to suggest where we might go from here in developing a theory of process.


The first buckybowl aryne. Corannulyne: a nonplanar benzyne.
[reaction: see text] Treatment of bromocorannulene with NaNH(2)/tBuOK in THF in the presence of furans or amines leads to formation of addition products in good yields, presumably through formation of 1,2-didehydrocorannulene (corannulyne). HDFT calculations predict that corannulyne exists as a bowl-shaped entity and that the didehydrogenation energy of corannulene is slightly lower than that of benzene.


Kidney Calculi: Pathophysiology and as a Systemic Disorder.
The pathophysiology of urinary stone formation is complex, involving a combination of metabolic, genetic, and environmental factors. Over the past decades, remarkable advances have been emerged in the understanding of the pathogenesis, diagnosis, and treatment of calcium kidney calculi. For this review, both original and review articles were found via PubMed search on pathophysiology, diagnosis, and management of urinary calculi. These resources were integrated with the authors' knowledge of the field. Nephrolithiasis is suggested to be associated with systemic disorders, including chronic kidney insufficiency, hematologic malignancies, endocrine disorders, autoimmune diseases, inflammatory bowel diseases, bone loss and fractures, hypertension, type 2 diabetes mellitus, metabolic syndrome, and vascular diseases like coronary heart diseases and most recently ischemic strokes. This is changing the perspective of nephrolithiasis from an isolated disorder to a systemic disease that justifies further research in understanding the underlying mechanisms and elaborating diagnostic-therapeutic options.


What promotes smectic order: Applying mean-field theory to the ends.
Not every particle that forms a nematic liquid crystal makes a smectic. The particle tip is critical for this behavior. Ellipsoids do not make a smectic, but spherocylinders do. Similarly, only those N-CB alkylcyanobiphenyls with sufficiently long (N≥8 carbons) alkane tails form smectics. We understand the role of the particle tip in the smectic transition by means of a simple two-dimensional model. We model spherocylinders by "boubas" with rounded tips, and ellipsoids by "kikis" with pointed tips. The N-CB molecules are modeled by a small body with a polymer tail. We find that rounded tips and longer polymer tails lead to a smectic at lower densities by making the space between layers less accessible, destabilizing the nematic.


Proteomic analysis of bronchoalveolar lavage fluid proteins from mice infected with Francisella tularensis ssp. novicida.
Francisella tularensis causes the zoonosis tularemia in humans and is one of the most virulent bacterial pathogens. We utilized a global proteomic approach to characterize protein changes in bronchoalveolar lavage fluid from mice exposed to one of three organisms, F. tularensis ssp. novicida, an avirulent mutant of F. tularensis ssp. novicida (F.t. novicida-ΔmglA), and Pseudomonas aeruginosa. The composition of bronchoalveolar lavage fluid (BALF) proteins was altered following infection, including proteins involved in neutrophil activation, oxidative stress, and inflammatory responses. Components of the innate immune response were induced including the acute phase response and the complement system; however, the timing of their induction varied. F. tularensis ssp. novicida infected mice do not appear to have an effective innate immune response in the first hours of infection; however, within 24 h, they show an upregulation of innate immune response proteins. This delayed response is in contrast to P. aeruginosa infected animals which show an early innate immune response. Likewise, F.t. novicida-ΔmglA infection initiates an early innate immune response; however, this response is diminished by 24 h. Finally, this study identifies several candidate biomarkers, including Chitinase 3-like-1 (CHI3L1 or YKL-40) and peroxiredoxin 1, that are associated with F. tularensis ssp. novicida but not P. aeruginosa infection.


Cooperation Between Systemic IgG1 and Mucosal Dimeric IgA2 Monoclonal Anti-HIV Env Antibodies: Passive Immunization Protects Indian Rhesus Macaques Against Mucosal SHIV Challenges.
Understanding the interplay between systemic and mucosal anti-HIV antibodies can provide important insights to develop new prevention strategies. We used passive immunization via systemic and/or mucosal routes to establish cause-and-effect between well-characterized monoclonal antibodies and protection against intrarectal (i.r.) SHIV challenge. In a pilot study, for which we re-used animals previously exposed to SHIV but completely protected from viremia by different classes of anti-HIV neutralizing monoclonal antibodies (mAbs), we made a surprise finding: low-dose intravenous (i.v.) HGN194-IgG1, a human neutralizing mAb against the conserved V3-loop crown, was ineffective when given alone but protected 100% of animals when combined with i.r. applied HGN194-dIgA2 that by itself had only protected 17% of the animals. Here we sought to confirm the unexpected synergy between systemically administered IgG1 and mucosally applied dIgA HGN194 forms using six groups of naïve macaques (n=6/group). Animals received i.v. HGN194-IgG1 alone or combined with i.r.-administered dIgA forms; controls remained untreated. HGN194-IgG1 i.v. doses were given 24 hours before - and all i.r. dIgA doses 30 min before - i.r. exposure to a single high-dose of SHIV-1157ipEL-p. All controls became viremic. Among passively immunized animals, the combination of IgG1+dIgA2 again protected 100% of the animals. In contrast, single-agent i.v. IgG1 protected only one of six animals (17%) - consistent with our pilot data. IgG1 combined with dIgA1 or dIgA1+dIgA2 protected 83% (5/6) of the animals. The dIgA1+dIgA2 combination without the systemically administered dose of IgG1 protected 67% (4/6) of the macaques. We conclude that combining suboptimal antibody defenses at systemic and mucosal levels can yield synergy and completely prevent virus acquisition.


Review of Reported Adverse Events Occurring Among the Homeless Veteran Population in the Veterans Health Administration.
United States veterans face an even greater risk of homelessness and associated medical conditions, mental health conditions, and fatal and nonfatal overdose as compared with nonveterans. Beginning 2009, the Department of Veterans Affairs developed a strategy and allocated considerable resources to address veteran homelessness and the medical conditions commonly associated with this condition. This study aimed to examine the Veterans Health Administration National Center for Patient Safety database for patient safety events in the homeless veteran population to mitigate future risk and inform policy. This was a retrospective, descriptive quality improvement study of reported patient safety events of homeless veterans enrolled in Veterans Health Administration care between January 2012 and August 2020. A validated codebook was used to capture individual patient characteristics, location and type of event, homeless status, and root causes of the events and proposed actions for prevention. Suicide attempt or death, elopement, delay in care, and unintentional opioid overdose were the most common adverse events reported for this population. Root causes include issues with policies, procedures, and care processes for managing and evaluating homeless patients for the risk of suicidal or overdose behaviors and discharge, poor interdisciplinary communication, and coordination of patient care. Actions included standardization of procedures for discharge, overdose and suicide risk, staff education, and purchasing new equipment. Suicide and opioid overdose are the most serious reported health care-related adverse events in the unsheltered homeless veteran population. Failures to recognize homelessness status, communicate status, and coordinate available services are root causes of these events.


Morphine upregulates functional expression of neurokinin-1 receptor in neurons.
Neuronkinin-1 receptor (NK-1R), the neuropeptide substance P (SP) preferring receptor, is highly expressed in areas of the central nervous system (CNS) that are especially implicated in depression, anxiety, and stress. Repeated exposure to opioids may sensitize neuronal systems involved in stress response. We examined the effects of morphine, the principal metabolite of heroin, on the functional expression of NK-1R in the cortical neurons. NK-1R and mu-opioid receptor (MOR) are co-expressed in the cortical neurons. Morphine enhanced NK-1R expression in the cortical neurons at both the mRNA and protein levels. The upregulated NK-1R by morphine had functional activity, because morphine-treated cortical neurons had greater SP-induced Ca(2+) mobilization than untreated neurons. Blocking opioid receptors on the cortical neurons by naltrexone or CTAP (a mu-opioid receptor antagonist) abolished the morphine action. Investigation of the mechanism(s) responsible for the morphine action showed that morphine activated NK-1R promoter and induced the phosphorylation of p38 MAPK protein in the cortical neurons. These in vitro data provide a plausible cellular mechanism for opioid-mediated neurological disorders.


Emission Properties of Diblock Copolymers Composed of Poly(ethylene glycol) and Dense 1,2,3-Triazole Blocks.
This article describes a new block copolymer (EGm-b-APn, where m and n denote the degrees of polymerization) of poly(ethylene glycol) (PEG) and poly(1,4-(1-H-1,2,3-triazolylene)methylene) prepared by copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) polymerization of 3-azido-1-propyne (AP) in the presence of PEG carrying a propargyl moiety. The EGm-b-APn samples are well soluble in polar organic solvents. Unexpectedly, we observed that solutions of EGm-b-APn in N,N-dimethylformamide emitted fluorescence. We systematically studied absorption and emission properties of the block copolymers. The experimental data have exhibited that APn block is an intrinsic fluorophore. Interestingly, the emission of EGm-b-APn can be easily tuned from ultraviolet to green fluorescence by changing the excitation wavelength. This enables fine-tuning of its optical property without the need of changing the chromophore. Moreover, the block copolymers show a fluorescence response to metal ions (e.g., Cu2+). Our discoveries contribute to the fundamental understanding of the optical properties of dense triazole-based polymer and raise intriguing prospects for fabricating novel emissive triazole-based materials.


Mass action effects on competitive adsorption of fibrinogen from hemoglobin solutions and from plasma.
The strong effect of protein adsorption on blood and tissue compatibility is well known. Little is presently known about the mechanisms which control the composition of the adsorbed protein layer which forms upon exposure of surfaces to mixtures of proteins. Reexamination of the ability of hemoglobin to inhibit the adsorption of 125I fibrinogen to polyethylene revealed that the inhibition was strongly dependent on the fibrinogen concentration. These results suggested that fibrinogen adsorption from more complex mixtures such as plasma should also be strongly dependent on total concentration. Fibrinogen adsorption from plasma was found to be maximal at intermediate plasma concentrations, and was reduced at both low and high plasma concentrations. The plasma concentration at which this maximum occurred was 10% for polytetrafluoroethylene, 1% for polyethylene, and 0.1% for glass. The unusual concentration dependence is attributed to mass action effects on the competitive adsorption of proteins, specifically that competitive effectiveness is expected to increase as unoccupied surface adsorptive sites become less frequent. Analogous effects of adsorption time on competitive adsorption are also predicted due to the changing concentration at the interface as the buffer is gradually replaced by protein solution. These mass action effects are very similar to previous qualitative observations by Vroman and are therefore dubbed the " Vroman effect".


Autoantibody binding to steroid 21-hydroxylase--effect of five mutations.
Steroid 21-hydroxylase (21-OH) is a key haem containing steroidogenic enzyme and a major adrenal specific autoantigen. Cys 428 in 21-OH is thought to have an important role in haem binding and we now describe the effects of mutations at Cys 428 (to Ser, Arg and Phe) on 21-OH autoantibody binding. Expression of wild type and mutated 21-OH was carried out using an in vitro transcription/translation (TnT) system and reactivity of 21-OH autoantibodies with mutated 21-OH analysed by western blotting (in the case of unlabelled proteins) or immunoprecipitation assay (IPA) (in the case of 35S-labelled proteins). All 3 substitutions at Cys 428 had similar effects on 21-OH autoantibody binding and each one caused a reduction in autoantibody binding to about 50% of wild type in the case of IPA and to about 70% of wild type in the case of western blotting analysis. In addition to mutations at Cys 428, we studied 2 naturally occurring mutations at Pro 30 to Leu and Ile 172 to Asn which are associated with diminished 21-OH enzyme activity. The Pro 30 mutation had no effect, but the Ile 172 mutation caused a reduction in 21-OH autoantibody binding in the IPA to about 80% of wild type. Overall, our studies emphasise the close relationship between the 21-OH aminoacid sequences important for 21-OH enzyme activity and 21-OH autoantibody binding.


Inhibition of phosphatidylinostol 3-kinase uncouples H2O2-induced senescent phenotype and cell cycle arrest in normal human diploid fibroblasts.
Exposure of WI38 human diploid fibroblasts (HDFs) to hydrogen peroxide (H2O2) induced premature senescence. The senescent HDFs were permanently arrested and exhibited a senescent phenotype including enlarged and flattened cell morphology and increased senescence-associated beta-galactosidase (SA-beta-gal) activity. The induction of HDF senescence was associated with an activation of p53, increased expression of p21Cip1/WAF1, and hypophosphorylation of retinoblastoma protein (Rb), while no changes in the expression of p16Ink4a, p27Kip1, and p14Arf were observed. Exposure of WI38 cells to H2O2 also selectively activated phosphatidylinostol 3-kinase (PI3 kinase) and mitogen-activated protein kinase (MAPK) kinase (MEK), while no changes in p38 MAPK and Jun kinase (JNK) activities were observed. Selective inhibition of PI3 kinase activity with LY294002 abrogated H2O2-induced cell enlargement and flattened morphology and significantly attenuated the increase in SA-beta-gal activity, but did not affect H2O2-induced cell cycle arrest. In contrast, selective inhibition of MEK and p38 MAPK with PD98059 and SB203580, respectively, produced no significant effect on H2O2-induced senescent phenotype and cell cycle arrest. These findings demonstrate that expression of the senescent phenotype can be uncoupled from cell cycle arrest in prematurely senescent cells induced by H2O2 and does not contribute to the maintenance of permanent cell cycle arrest.


Autoantigen-specific TGFbeta-induced Foxp3+ regulatory T cells prevent autoimmunity by inhibiting dendritic cells from activating autoreactive T cells.
Several strategies are being designed to test the therapeutic potential of Ag-specific regulatory T cells to prevent or treat autoimmune diseases. In this study, we demonstrate that naive CD4+ Foxp3- T cells specific for a naturally expressed autoantigen (H+/K+ ATPase) can be converted to Foxp3+ T regulatory cells (Tregs) when stimulated in presence of TGFbeta. TGFbeta-induced Tregs (iTregs) have all the characteristics of naturally generated regulatory T cells in vitro, and more importantly, are effective at preventing organ-specific autoimmunity in a murine model of autoimmune gastritis. H+/K+ ATPase specific iTregs were able to inhibit the initial priming and proliferation of autoreactive T cells, and appear to do so by acting on H+/K+ ATPase presenting dendritic cells (DC). DC exposed to iTregs in vivo were reduced in their ability to stimulate proliferation and cytokine production by H+/K+ ATPase specific T cells. iTregs specifically reduced CD80 and CD86 expression on the surface of H+/K+ ATPase presenting DC in vitro. These studies reveal the therapeutic potential of Ag specific iTregs to prevent autoimmunity, and provide a mechanism by which this population of regulatory T cells, and perhaps others, mediate their suppressive effects in vivo.


Trends concerning a common medical school interview question, revisited.
To assess the validity of asking prospective medical school students about their planned field of practice during their admissions interview at one United States allopathic medical school, and to compare and contrast the results with the results from a similar study conducted in 2004. Anonymous one-page surveys were voluntarily filled out and immediately collected from matriculated freshman medical students who wished to participate in this Institutional Review Board (IRB) approved study. Ninety five medical students voluntarily completed and returned the anonymous survey; 82 were filled out correctly. Of the 82 respondents, 32 were uncertain about the field of medicine they plan to pursue. Of the 50 remaining respondents who felt certain of their future direction, 58% (29/50) reported telling the truth when asked about their future direction during the admissions interview, 34% (17/50) were not completely forthcoming and truthful, and 8% (4/50) were not asked at all. The findings of this study, along with the findings from our 2004 study, strongly suggest that asking prospective medical students during their medical school interview what type of medicine they wish to practice may not yield valid responses.


Enhancement of cancer invasion and growth via the C5a-C5a receptor system: Implications for cancer promotion by autoimmune diseases and association with cervical cancer invasion.
Autoimmune diseases are caused by immune complex-induced activation of the complement system and subsequent inflammation. Recent studies have revealed an association between autoimmune diseases and worse survival in patients with cancer; however, the underlying mechanism is still unknown. The C5a-C5a receptor (C5aR) system has been shown to enhance cancer activity and recruit myeloid-derived suppressor cells (MDSCs) that suppress the anti-tumor immune response. The Arthus reaction is inflammation caused by complement system activation by the immune complex and thus is a model of autoimmune diseases. To explore the effect of the Arthus reaction on cancer progression, mouse cancer cells were inoculated in syngeneic mouse skin, where the Arthus reaction was induced simultaneously. The Arthus reaction enhanced invasion and tumor growth of C5aR-positive cancer cells, but not control cells, and induced MDSC recruitment. Intravenous injection of C5a-stimulated C5aR-positive cancer cells into nude mice resulted in more lung nodules than injection of nontreated C5aR-positive cells and C5a-stimulated C5aR-negative cells, supporting C5a-C5aR-mediated enhancement of cancer growth. C5aR expression in uterine cervical carcinoma stage I cells, which invade into the deeper tissues, was significantly higher than that in CIN3 cells, which remain in the epithelium. These results indicate that cancer promotion by the C5a-C5aR system may underlie poor prognosis in cancer patients with autoimmune diseases, particularly in patients with C5aR-positive cancer, and may be associated with cervical cancer invasion. The enhancement of cancer cell invasion and growth by the C5a-C5aR system suggests that this system is a possible target of cancer therapy.


Skin colonization with antibiotic-resistant (JK group) and antibiotic-sensitive lipophilic diphtheroids in hospitalized and normal adults.
A strict nutritional requirement for lipid and similar components of cell wall fatty acids and sugars are features common to both JK coryneforms (JK) that are resistant to multiple antibiotics and to lipophilic diphtheroids (LD) that are sensitive to antibiotics. We surveyed 123 subjects for LD and JK. Twenty-eight patients with leukemia (776 samples) were cultured longitudinally during 42 hospitalizations; 15 other patients hospitalized for at least two weeks and 80 controls were sampled once. JK were isolated from at least one of four skin sites in 82.1% of the leukemic patients, 73.3% of other patients, and 15.7% of controls. There was an inverse correlation between the density of LDs and JKs in all groups (P = .03). The perineum was the most frequent, and usually the first, site of JK colonization. Once present, colonization persisted for as long as follow-up continued. Systemic vancomycin did not eliminate or prevent skin colonization with JK. Leukemic patients may have a greater risk of JK infection but probably no increased risk of skin colonization.


Cefazolin versus anti-staphylococcal penicillins for treatment of methicillin-susceptible Staphylococcus aureus bacteraemia: a narrative review.
Anti-staphylococcal penicillins (ASPs) are recommended as first-line agents in methicillin-susceptible Staphylococcus aureus (MSSA) bacteraemia. Concerns about their safety profile have contributed to the increased use of cefazolin. The comparative clinical effectiveness and safety profile of cefazolin versus ASPs for such infections remain unclear. Furthermore, uncertainty persists concerning the use of cefazolin due to controversies over its efficacy in deep MSSA infections and its possible negative ecological impact. The aim of this narrative review was to gather and balance available data on the efficacy and safety of cefazolin versus ASPs in the treatment of MSSA bacteraemia and to discuss the potential negative ecological impact of cefazolin. PubMed and EMBASE electronic databases were searched up to May 2017 to retrieve available studies on the topic. Although described in vitro and in experimental studies, the clinical relevance of the inoculum effect during cefazolin treatment of deep MSSA infections remains unclear. It appears that there is no significant difference in rate of relapse or mortality between ASPs and cefazolin for the treatment of MSSA bacteraemia but these results should be cautiously interpreted because of the several limitations of the available studies. Compared with cefazolin, there is more frequent discontinuation for adverse effects with ASP use, especially because of cutaneous and renal events. No study has evidenced any change in the gut microbiota after the use of cefazolin. Based on currently available studies, there are no data that enable a choice to be made of one antibiotic over the other except in patients with allergy or renal impairment. This review points out the need for future prospective studies and randomized controlled trials to better address these questions.


[Prevention of ischemic heart disease with hyperlipidemia].
Atherosclerotic vascular diseases are expected to remain the major cause of mortality and morbidity globally well. Preventive measures by lifestyle changes(diet, exercise) will play an important role in retarding the onset of these diseases. The 4S, CARE and LIPID study demonstrated the efficacy of a statin on cardiovascular morbidity and mortality and on total mortality. The cardioprotective effect of statin is partially due to the cholesterol independent effect. Fibrate also decrease the mortality of patients with ischemic heart disease by improving the fiblolytic state. The association of a statin and a fibrate is reserved to specialized centers, however we should not forget the usefulness of diet.


EVOLUTION OF VEGETATIVE INCOMPATIBILITY IN FILAMENTOUS ASCOMYCETES. I. DETERMINISTIC MODELS.
In ascomycetes vegetative incompatibility can prevent the somatic exchange of genetic material between conspecifics. It must occur frequently in natural populations, since in all species studied many vegetative compatibility groups (VCGs) are found. Using a population-genetic approach, this paper explores two possible selective explanations for the evolution of vegetative incompatibility in asexual fungi: selection by a nuclear parasitic gene, and selection by a harmful cytoplasmic element. In a deterministic model, assuming a random spatial distribution of VCGs in an infinitely sized population, it is found that neither of these forms of frequency-dependent selection can explain the large number of VCGs found in nature. The selective pressure for more VCGs disappears once a limited number of VCGs exist, because the frequency of compatible interactions decreases when the number of VCGs increases. In comparing the two selective explanations, selection by a cytoplasmic element seems a more plausible explanation than selection by a nuclear gene.


Steatocystoma multiplex.
A 40-year-old man presented with multiple papules on his head and neck. The lesions had been present for about 15 years. The patient was treated for acne for 6 months, but no improvement was noted. A biopsy was performed and microscopic findings were consistent with steatocystoma multiplex.


The Chondroprotective Role of TMF in PGE2-Induced Apoptosis Associating with Endoplasmic Reticulum Stress.
Endoplasmic reticulum stress (ERS) has been demonstrated to exhibit a critical role in osteoarthritic chondrocytes. Whether 5,7,3',4'-tetramethoxyflavone (TMF) plays the chondroprotective role in inhibition of PGE2-induced chondrocytes apoptosis associating with ERS has not been reported. To investigate this, the activation of PERK, ATF6, and IRE1 signaling pathways in ERS in chondrocytes pretreated with PGE2 was studied. By treatment with PGE2, the chondrocytes apoptosis was significantly increased, the proapoptotic CHOP and JNK were upregulated, the prosurvival GRP78 and XBP1 were downregulated, and GSK-3β was also upregulated. However, TMF exhibited the effectively protective functions via counteracting these detrimental effects of PGE2. Finally, the inflammatory cytokine PGE2 can activate ERS signaling and promote chondrocytes apoptosis, which might be associated with upregulation of GSK-3β. TMF exhibits a chondroprotective role in inhibiting PGE2-induced ERS and GSK-3β.


'Targeting' sedation: the lived experience of the intensive care nurse.
To discuss the findings from a phenomenological study that provides insights into the intensive care nurses' 'world' following changes in the sedation management of patients in an intensive care unit. Intensive care sedation practices have undergone significant changes. Patients, where possible, are now managed on lighter levels of sedation, often achieved through the performance of sedation holds (SHs). The performance of SHs is normally carried out by the bedside nurse but compliance is reported to be poor. There has been little exploration of the nurses' experiences of these changes and the implications of SHs and subsequent wakefulness on their delivery of care. Following ethical approval, 16 intensive care nurses, experienced and inexperienced, from within a general intensive care unit. A Heideggerian phenomenological approach was used. Data collection consisted of interviews guided by an aide memoir and a framework adapted from Van Manen informed the analysis. The findings reveal new insights into the world of the intensive care nurse in the light of the changes to sedation management. They demonstrate that there have been unforeseen outcomes from well-intentioned initiatives to improve the quality of patients' care. There were implications from the changes introduced for the nurses care delivery. The main themes that emerged were 'working priorities' and 'unintended consequences', in turn revealing embedded tensions between evidence-based targets and holistic care. Intensive care nurses find that the current approach to the changes in sedation management can threaten their professional obligation and personal desire to provide holistic care. The 'targeted' approach by healthcare organisations is perceived to militate against the patient-centred care they want to deliver. Sedation management is complex and needs further consideration particularly the potential constraints 'target-led' care has on nursing practice.


Brain-derived neurotrophic factor signaling rewrites the glucocorticoid transcriptome via glucocorticoid receptor phosphorylation.
Abnormal glucocorticoid and neurotrophin signaling has been implicated in numerous psychiatric disorders. However, the impact of neurotrophic signaling on glucocorticoid receptor (GR)-dependent gene expression is not understood. We therefore examined the impact of brain-derived neurotrophic factor (BDNF) signaling on GR transcriptional regulatory function by gene expression profiling in primary rat cortical neurons stimulated with the selective GR agonist dexamethasone (Dex) and BDNF, alone or in combination. Simultaneous treatment with BDNF and Dex elicited a unique set of GR-responsive genes associated with neuronal growth and differentiation and also enhanced the induction of a large number of Dex-sensitive genes. BDNF via its receptor TrkB enhanced the transcriptional activity of a synthetic GR reporter, suggesting a direct effect of BDNF signaling on GR function. Indeed, BDNF treatment induces the phosphorylation of GR at serine 155 (S155) and serine 287 (S287). Expression of a nonphosphorylatable mutant (GR S155A/S287A) impaired the induction of a subset of BDNF- and Dex-regulated genes. Mechanistically, BDNF-induced GR phosphorylation increased GR occupancy and cofactor recruitment at the promoter of a BDNF-enhanced gene. GR phosphorylation in vivo is sensitive to changes in the levels of BDNF and TrkB as well as stress. Therefore, BDNF signaling specifies and amplifies the GR transcriptome through a coordinated GR phosphorylation-dependent detection mechanism.


Polymorphism within a TCRAV family influences the repertoire through class I/II restriction.
Antibody-staining experiments have shown that closely related members of the TCRAV3 family are reciprocally selected into the CD4 or CD8 peripheral T cell subsets. This has been attributed to the individual AV3 members interacting preferentially with either MHC class I or MHC class II molecules. Single amino acid residues present in the complementarity-determining regions (CDR) CDR1alpha and CDR2alpha are important in determining MHC class specificity. We have now extended these observations to survey the expressed repertoire of the AV3 family in C57BL/6 mice. Three of the four expressed AV3 members are preferentially selected into the CD4+ subset of T cells. These share the same amino acid residue in both CDR1alpha and CDR2alpha that differ from the only CD8-skewed member. Preferential expression of an individual AV3 is not caused by other endogenous alpha- or beta-chains, by any conserved CDR3 sequence, or by the usage of TCRAJ regions. This study shows that residues in the CDR1 and CDR2 regions are primary determinants for MHC class discrimination and suggests that polymorphism found within a TCRAV family has an important effect on the overall shaping of the T cell repertoire.


Red Blood Cell Transfusion Prior to Lung Transplantation: Impact on Patient Outcomes.
There is an established association between red blood cell (RBC) transfusion and increased mortality and morbidity in cardiac surgery; however, there is little data demonstrating the influence of blood transfusion while awaiting lung transplantation. Therefore, our study compared the impact of pretransplant RBC transfusion on patient survival and post-transplantation adverse events. Adult lung transplant patient data were extracted retrospectively using the United Network for Organ Sharing thoracic database. Patients were stratified into two groups based on pretransplant transfusion status. In total, 28,217 patients were analyzed in our study (transfused: n = 1,415 and not transfused: n = 26,802). There was an increasing trend in pretransplant transfusion rates from 2006 to 2020. Transfused patients had a higher incidence of adverse events post-transplantation, including dialysis, stroke, and acute organ rejection before discharge. Multivariable survival analysis found an increased mortality risk in patients who required pretransplant transfusion(s) compared to those who did not have a transfusion (hazard ratio [HR]: 1.27; 95% confidence interval [CI]: 1.17-1.41; p < 0.001). There was no significant difference in bronchiolitis obliterans syndrome development between groups (HR: 0.92; 95% CI: 0.82-1.04; p = 0.185). To conclude, our study provides data to suggest that RBC transfusion(s) before lung transplantation are associated with increased patient morbidity and mortality, but have no association with chronic graft rejection development.


[Breast milk and drugs].
This review deals with the transfer of drugs into breastmilk and its possible threat for the infant. The following groups of pharmaca are discussed: antibiotics, antiepileptics, psychotropic drugs, cardiac drugs, diuretics as well as some other compounds. Social drugs and ecological poisons are also considered. Medications which are contraindicated during lactation and may lead to prohibition of nursing an infant have been tabulated. In general it still is valid, that despite of the vast number of possibly interfering substances in breast milk, nursing of the infant remains the best and most reliable means of infant feeding and rearing.


Cyclic GMP regulation of the plasma membrane (Ca2+-Mg2+)ATPase in vascular smooth muscle.
Plasma membrane (Ca2+-Mg2+)ATPase purified from bovine aortic microsomes by calmodulin affinity chromatography was incorporated into soybean phospholipid liposomes. In the reconstituted proteoliposomes, a protein corresponding to the ATPase was phosphorylated by [gamma-32P]ATP in the presence of cGMP and cGMP-dependent protein kinase. Both the affinity for Ca2+ and the maximum Ca2+ uptake activity by the proteoliposomes were increased by the cGMP-dependent phosphorylation, and there was good parallelism between the Ca2+-uptake rate and the extent of phosphorylation. These results strongly suggest that the Ca2+-transport ATPase of the vascular smooth muscle plasma membrane is regulated through its cGMP-dependent phosphorylation.


Large osteochondral defects of the femoral condyle: press-fit transplantation of the posterior femoral condyle (MEGA-OATS).
Large osteochondral defects in the weight-bearing zone of the knee remain a challenging therapeutic problem. Surgical options include drilling, microfracturing, and transplantation of osteochondral plugs but are often insufficient for the treatment of large defects of the femoral condyle. Large osteochondral defects of the femoral condyle (mean defect size 7.2 cm(2) range 3-20) were treated by transplantation of the autologous posterior femoral condyle. Between 1984 and 2000, 29 patients were operated on: in 22 the medial, in 6 the lateral femoral condyle, and in one the trochlear groove was grafted. Thirteen patients underwent simultaneous high tibial valgus osteotomy. In the first series (1984-1999) the graft was temporarily fixed with a screw ( n=12), but from 1999 we used a newly developed press-fit technique ( n=17) avoiding screw fixation of the graft. The operative technique comprising graft harvest, defect preparation, transplantation, and fixation is described. Patients were clinically evaluated using the Lysholm score, and magnetic resonance imaging with intravenous contrast was performed 6 and 12 weeks after surgery (mean follow-up 17.7 months (range 3-46). Pain and swelling were reduced in 26 patients. Three patients of the first series reported persistent problems and were subjectively not satisfied. The mean Lysholm score rose from preoperatively 52 to 77 points after 3 months, 74 after 6, 88 after 12, and 95 after 18. Magnetic resonance imaging showed good graft viability in all cases. We saw one arthrofibrosis after 6 months but noted no problems related to the loss of the missing posterior condyle. Large osteochondral defects of the femoral condyle can be treated by transplantation of the autologous posterior femoral condyle. The use of only one osteochondral piece renders better approximation of the femoral cartilage curvature and thus joint congruence than in mosaic plasty. However, whether loss of the posterior condyle has a long-term negative impact on the knee joint remains to be elucidated.


From genes to folds: a review of cortical gyrification theory.
Cortical gyrification is not a random process. Instead, the folds that develop are synonymous with the functional organization of the cortex, and form patterns that are remarkably consistent across individuals and even some species. How this happens is not well understood. Although many developmental features and evolutionary adaptations have been proposed as the primary cause of gyrencephaly, it is not evident that gyrification is reducible in this way. In recent years, we have greatly increased our understanding of the multiple factors that influence cortical folding, from the action of genes in health and disease to evolutionary adaptations that characterize distinctions between gyrencephalic and lissencephalic cortices. Nonetheless it is unclear how these factors which influence events at a small-scale synthesize to form the consistent and biologically meaningful large-scale features of sulci and gyri. In this article, we review the empirical evidence which suggests that gyrification is the product of a generalized mechanism, namely the differential expansion of the cortex. By considering the implications of this model, we demonstrate that it is possible to link the fundamental biological components of the cortex to its large-scale pattern-specific morphology and functional organization.


Merkel cell carcinoma of the scrotum.
We report a rare case of Merkel cell carcinoma arising from the scrotal skin of an 84-year-old man. The tumor was treated by wide, local excision and radiation. The man died due to extensive metastatic disease 16 months after his surgery. The natural history, histology, and pathogenesis of Merkel cell carcinoma are discussed briefly.


Communication training for health professionals who care for patients with cancer: a systematic review of effectiveness.
Effective communication is increasingly recognised as a core clinical skill. However, there is evidence that health and social care professionals still lack basic communication skills. To assess the effectiveness of different communication skills training courses for health professionals in cancer care. We searched six computerised databases and augmented this with a follow-up of references and grey (unpublished) literature. We included all studies evaluating communication training and assessed methodological quality according to the standard grading system of the Clinical Outcomes Group. Data on author, year, setting, objectives, study design and results were extracted and compared in tabular format. A total of 47 studies potentially assessing communication training in the area of cancer care were identified. Sixteen papers were included describing 13 interventions. Four were randomised controlled trials (RCTs) (grade I), with samples ranging from 72 to 233 subjects. The others were all grade III. Eleven interventions trained health professionals, two trained medical students. The outcomes measured included communication skills as assessed on audio or video, professionals' self-report and patient assessment. All the interventions demonstrated modest improvements (effect sizes ranged 0.15-2) and one found deterioration in the outcomes measured. Communication training improves basic communication skills. Positive attitudes and beliefs are needed to maintain skills over time in clinical practice and to effectively handle emotional situations.


Effects of electron transport inhibitors and uncouplers on the oxidation of ferrous iron and compounds interacting with ferric iron in Acidithiobacillus ferrooxidans.
Oxidation of Fe2+, ascorbic acid, propyl gallate, tiron, L-cysteine, and glutathione by Acidithiobacillus ferrooxidans was studied with respect to the effect of electron transport inhibitors and uncouplers on the rate of oxidation. All the oxidations were sensitive to inhibitors of cytochrome c oxidase, KCN, and NaN3. They were also partially inhibited by inhibitors of complex I and complex III of the electron transport system. Uncouplers at low concentrations stimulated the oxidation and inhibited it at higher concentrations. The oxidation rates of Fe2+ and L-cysteine inhibited by complex I and complex III inhibitors (amytal, rotenone, antimycin A, myxothiazol, and HQNO) were stimulated more extensively by uncouplers than the control rates. Atabrine, a flavin antagonist, was an exception, and atabrine-inhibited oxidation activities of all these compounds were further inhibited by uncouplers. A model for the electron transport pathways of A. ferrooxidans is proposed to account for these results. In the model these organic substrates reduce ferric iron on the surface of cells to ferrous iron, which is oxidized back to ferric iron through the Fe2+ oxidation pathway, leading to cytochrome oxidase to O2. Some of electrons enter the uphill (energy-requiring) electron transport pathway to reduce NAD+. Uncouplers at low concentrations stimulate Fe2+ oxidation by stimulating cytochrome oxidase by uncoupling. Higher concentrations lower deltap to the level insufficient to overcome the potentially uphill reaction at rusticyanin-cytochrome c4. Inhibition of uphill reactions at complex I and complex III leads to deltap accumulation and inhibition of cytochrome oxidase. Uncouplers remove the inhibition of deltap and stimulate the oxidation. Atabrine inhibition is not released by uncouplers, which implies a possibility of atabrine inhibition at a site other than complex I, but a site somehow involved in the Fe2+ oxidation pathway.


Three-dimensional OCT based guinea pig eye model: relating morphology and optics.
Custom Spectral Optical Coherence Tomography (SOCT) provided with automatic quantification and distortion correction algorithms was used to measure the 3-D morphology in guinea pig eyes (n = 8, 30 days; n = 5, 40 days). Animals were measured awake in vivo under cyclopegia. Measurements showed low intraocular variability (<4% in corneal and anterior lens radii and <8% in the posterior lens radii, <1% interocular distances). The repeatability of the surface elevation was less than 2 µm. Surface astigmatism was the individual dominant term in all surfaces. Higher-order RMS surface elevation was largest in the posterior lens. Individual surface elevation Zernike terms correlated significantly across corneal and anterior lens surfaces. Higher-order-aberrations (except spherical aberration) were comparable with those predicted by OCT-based eye models.