Profiling and integrated analysis of whole-transcriptome changes in uterine caruncles of pregnant and non-pregnant buffaloes.
Improved reproductive performance in buffaloes can be achieved by understanding the basic mechanism governing the embryonic attachment and feto-maternal communication. Considering this, trascriptomic profiling and integrative analysis of long intergenic non-coding RNAs were carried out in the uterine caruncles of pregnant and non-pregnant buffaloes. Transcriptome data of pregnant and non-pregnant uterine caruncles after quality control was used to perform the analysis. Total of 86 novel lincRNAs expressed in uterine caruncular tissues were identified and characterized. Differential expression analysis revealed that 447 mRNAs and 185 mRNAs were up- and down- regulated, respectively. The number of up- and down- regulated lincRNAs were 114 and 13, respectively. Of the identified 86 novel lincRNAs, six novel lincRNAs were up-regulated in the pregnant uterine caruncles. GO terms (biological process) and PANTHER pathways associated with reproduction and embryogenesis were over-represented in differentially expressed genes. Through miRNA interaction analysis, interactions of 16 differentially expressed lincRNAs with mi-RNAs involved in reproduction were identified. This study has provided a catalogue of differentially expressed genes and novel regions previously unknown to play a significant role in buffalo reproduction. The results from the current study extends the buffalo uterine lncRNAs database and provides candidate regulators for future molecular genetic studies on buffalo uterine physiology to improve the embryo implantation and successful completion of pregnancy.


Effect of heterologous antimacrophage serum on growth of Rous virus-induced sarcoma in the allogeneic and syngeneic system.
The effect of heterologous antimacrophage serum (AMS) and normal rabbit serum (NRS) on the immune reaction against Rous virus-induced sarcoma (RSL) was studied in rats. The growth of RSL sarcoma transplanted against the H-1 barrier in AMS-treated rats was more progressive than in the untreated or NRS-treated control group. On the other hand, the growth of RSL sarcoma was significantly suppressed in syngeneic AMS- or NRS-treated recipients compared to the untreated control rats.


Effects of naturally occurring arginine 14 deletion on phospholamban conformational dynamics and membrane interactions.
Phospholamban (PLN) is a single-pass membrane protein that regulates the sarco(endo)plasmic reticulum Ca²⁺-ATPase (SERCA). Phosphorylation of PLN at Ser16 reverses its inhibitory function under β-adrenergic stimulation, augmenting Ca²⁺ uptake in the sarcoplasmic reticulum and muscle contractility. PLN exists in two conformations; a T state, where the cytoplasmic domain is helical and adsorbed on the membrane surface, and an R state, where the cytoplasmic domain is unfolded and membrane detached. Previous studies have shown that the PLN conformational equilibrium is crucial to SERCA regulation. Here, we used a combination of solution and solid-state NMR to compare the structural topology and conformational dynamics of monomeric PLN (PLN(AFA)) with that of the PLN(R14del), a naturally occurring deletion mutant that is linked to the progression of dilated cardiomyopathy. We found that the behavior of the inhibitory transmembrane domain of PLN(R14del) is similar to that of the native sequence. Conversely, the conformational dynamics of R14del both in micelles and lipid membranes are enhanced. We conclude that the deletion of Arg14 in the cytoplasmic region weakens the interactions with the membrane and shifts the conformational equilibrium of PLN toward the disordered R state. This conformational transition is correlated with the loss-of-function character of this mutant and is corroborated by SERCA's activity assays. These findings support our hypothesis that SERCA function is fine-tuned by PLN conformational dynamics and begin to explain the aberrant regulation of SERCA by the R14del mutant.


Effect of mobile phase pH on liquid chromatography retention of mepartricin related compounds and impurities as support to the structural investigation by liquid chromatography-mass spectrometry.
Mepartricin is a semisynthetic polyene macrolide with antifungal and anti-protozoal activities, and it is widely used for the treatment of benign prostatic hyperplasia. Mepartricin is produced by synthetic methyl esterification of the more toxic partricin, and its activity is due to a complex of related compounds. Among them, the main ones are mepartricin B and mepartricin A which are characterized by the presence of a primary and a secondary amine group, respectively. In this work a previously reported HPLC-UV method was properly modified to make it MS-compatible. The selected conditions entail the use of a C18 reverse phase column, and a mobile phase composed by ammonium formate and acetonitrile, with the addition of heptafluorobutyric acid as modifier. The developed method was applied to the characterization of a mepartricin reference standard and a mepartricin experimental batch. All the UV responding peaks, 30 for the standard and 21 for the experimental batch, were successfully detected by MS, allowing to define their m/z values and acquire their fragmentation spectra. For the structural elucidation of isobaric species and, in particular, the identification of toxic partricin-related impurities, the presence of differently ionisable chemical groups was considered, as partricins contain free caboxy-groups, while mepartricins represent their estherified counterparts. A deep study of the effect of mobile phase pH on the chromatographic retention of partricin and mepartricin related compounds was performed in the pH range 2.5-6.5. This study allowed to successfully cluster all the detected species and asses, in the considered batch, the absence of other partricin-related impurities in addition to partricin B and partricin A.


Neuropathogenesis of HIV-1 infection: interactions between interleukin-1 and transforming growth factor-beta 1.
Cytokines are widely considered to function as major mediators of neuropathogenesis of HIV-1 infection. This view is based on a large amount of data obtained in vitro, in animal models and in human brain tissue obtained postmortem. Evidence for the involvement of interleukin-1 and transforming growth factor-beta 1, summarized here, indicates that these cytokines likely control HIV-1 expression in the brain and astrocytosis, the two hallmarks of brain in AIDS patients. Although the data do not reveal the precise time course of molecular and cellular changes in vivo, they strongly suggest a complex pattern of interactions whose ordering in time determines when and where HIV-1 is expressed in the brain. Further kinetic data are therefore urgently needed to shed light on the heterogeneity of HIV-1 expression in the brain.


Evaluation of 99mTc-labeled iminodiacetic acid derivatives of substituted 2-aminopyrroles as hepatobiliary imaging agents. I.
N-(3-Cyano-4,5-dimethyl-2-pyrrylcarbamoylmethyl)iminodiacetic acid (IIa) and N-(3-cyano-4-methyl-5-benzyl-2-pyrrylcarbamoylmethyl)iminodiacetic acid (IIb) were synthesized, labeled with technetium 99m, and compared with 99mTc-labeled p-isopropylacetanilidoiminodiacetic acid (I) for hepatobiliary activity in rats. All three compounds showed similar clearance of radioactivity from the blood. Comparison of the amount of radioactivity in various organs 1 hr after injection showed no significant difference between I and IIb. Compound IIa showed significantly less radioactivity in the GI tract and a higher amount in the kidneys and bladder.


Management strategies for colorectal liver metastases--Part II.
Liver metastases are relatively common in colorectal cancer and a small proportion of patients may benefit from resection of these liver metastases. In a selected subgroup of patients, 5-year survival rates of 25-35% may be achieved following liver resection. These survival figures compare favourably with those of patients with untreated liver secondaries. In the second part of this review the surgical and non-surgical treatment options for treating colorectal liver metastases are examined in detail.


New insights into membrane dynamics from the analysis of cell surface interactions by physical methods.
The physical, chemical and mechanical properties of the cell surface can be probed using a variety of microscopy-based techniques. The movements of membrane components are currently being characterized, and recent experiments have begun to define the structural origins of these modes of transport at a molecular level. However, explicit relationships between new knowledge of membrane structure and complex, linked functions, such as signal transduction and adhesion, remain elusive.


Strategies for maximizing photothermal conversion efficiency based on organic dyes.
Photothermal therapy (PTT) has emerged as a promising therapeutic approach for tumor control and ablation. Attention has focused on exploring advanced organic photothermal agents (OPTAs), with advantages of easy modification, adjustable photophysical and photochemical properties, good compatibility, and inherent biodegradability. However, few detailed studies on how to maximally channelize nonradiative heat generation from the viewpoint of the photothermal conversion mechanism have been reported. Thus, here we assimilate and elaborate on several available action mechanisms to maximize the photothermal conversion efficiency (PCE) of organic dyes. Moreover, we also propose several potential challenges that require substantial future work to address.


Studying Lipid-Protein Interactions Using Protein-Lipid Overlay and Protein-Liposome Association Assays.
The study of lipid-protein interactions is crucial for understanding reactions of proteins involved in lipid metabolism, lipid transport, and lipid signaling. Different detection methods can be employed for the identification of lipid-binding interactions. Isothermal titration calorimetry (ITC) and surface plasmon resonance (SPR) spectroscopy enable real-time monitoring of lipid protein interactions and provide thermodynamic parameters of the interacting partners. However, these technologies depend on the availability of the large equipment, limiting the practicability in many laboratories. Protein-lipid overlay assays are a simple first approach to screen for protein interactions with different lipids or lipid intermediates and are independent of large equipment. Subsequently, specific interactions can be analyzed in detail using protein-liposome association assays.


Quantitative dynamic susceptibility contrast perfusion-weighted imaging-guided customized gamma knife re-irradiation of recurrent high-grade gliomas.
Treatment of recurrent high-grade gliomas (rHGG) has always been challenging. This study aimed to explore the treatment effect of quantitative dynamic susceptibility contrast perfusion-weighted imaging (DSC-PWI)-guided gamma knife radiosurgery (GKRS) on rHGG. Between April 2014 and July 2016, 26 consecutive patients were treated by quantitative DSC-PWI-guided GKRS as salvage treatment for rHGG. The gross tumor volume (GTV) was defined as the high perfusion area on absolute cerebral blood volume maps, with a cutoff value of 22 ml/100 g. The clinical target volume (CTV) encompassed the GTV by 3 mm. Overall survival (OS) and progression-free survival (PFS) were calculated by the Kaplan-Meier method. Prognostic factors were tested by the log-rank (Mantel-Cox) test. With a median follow-up of 32 months, the median PFS after GKRS was 8 months (95% CI [6, 12]); the 1- and 2-year survival rates were 30.8 and 11.5%, respectively. The median OS was 25.5 months (95% CI [18, 40]); the 1- and 2-year survival rates were 96.2 and 57.7%, respectively. Pathology grade and CTV were identified as prognostic factors for PFS. However, none of the parameters tested were independent prognostic factors for OS among these selected patients. No severe radiotoxicity was observed among all patients. Quantitative DSC-PWI-guided GKRS is feasible for the treatment of rHGG and that these outcomes remain to be validated. Despite this, we think that carefully selected patients can benefit from this treatment method.


An ensemble of the iCluster method to analyze longitudinal lncRNA expression data for psoriasis patients.
Psoriasis is an immune-mediated, inflammatory disorder of the skin with chronic inflammation and hyper-proliferation of the epidermis. Since psoriasis has genetic components and the diseased tissue of psoriasis is very easily accessible, it is natural to use high-throughput technologies to characterize psoriasis and thus seek targeted therapies. Transcriptional profiles change correspondingly after an intervention. Unlike cross-sectional gene expression data, longitudinal gene expression data can capture the dynamic changes and thus facilitate causal inference. Using the iCluster method as a building block, an ensemble method was proposed and applied to a longitudinal gene expression dataset for psoriasis, with the objective of identifying key lncRNAs that can discriminate the responders from the non-responders to two immune treatments of psoriasis. Using support vector machine models, the leave-one-out predictive accuracy of the 20-lncRNA signature identified by this ensemble was estimated as 80%, which outperforms several competing methods. Furthermore, pathway enrichment analysis was performed on the target mRNAs of the identified lncRNAs. Of the enriched GO terms or KEGG pathways, proteasome, and protein deubiquitination is included. The ubiquitination-proteasome system is regarded as a key player in psoriasis, and a proteasome inhibitor to target ubiquitination pathway holds promises for treating psoriasis. An integrative method such as iCluster for multiple data integration can be adopted directly to analyze longitudinal gene expression data, which offers more promising options for longitudinal big data analysis. A comprehensive evaluation and validation of the resulting 20-lncRNA signature is highly desirable.


Hidden contributions of the enamel rods on the fracture resistance of human teeth.
The enamel of human teeth is generally regarded as a brittle material with low fracture toughness. Consequently, the contributions of this tissue in resisting tooth fracture and the importance of its complex microstructure have been largely overlooked. In this study an experimental evaluation of the crack growth resistance of human enamel was conducted to characterize the role of rod (i.e. prism) orientation and degree of decussation on the fracture behavior of this tissue. Incremental crack growth was achieved in-plane, with the rods in directions longitudinal or transverse to their axes. Results showed that the fracture resistance of enamel is both inhomogeneous and spatially anisotropic. Cracks extending transverse to the rods in the outer enamel undergo a lower rise in toughness with extension, and achieve significantly lower fracture resistance than in the longitudinal direction. Though cracks initiating at the surface of teeth may begin extension towards the dentin-enamel junction, they are deflected by the decussated rods and continue growth about the tooth's periphery, transverse to the rods in the outer enamel. This process facilitates dissipation of fracture energy and averts cracks from extending towards the dentin and vital pulp.


[Treatment of idiopathic juxtafoveolar retinal telangiectasis with bevacizumab (avastin)].
Idiopathic juxtafoveolar retinal telangiectasis presents areas of occult capillary telangiectasis involving the temporal half of the fovea. Its treatment by laser photocoagulation, photodynamic therapy or intravitreal injection of triamcinolone is unsatisfying concerning visual acuity. Recently it has been demonstrated that intravitreal bevacizumab injection could be successful in the treatment of choroidal neovascularisations secondary to ARMD. The principle of this treatment may be successful for the treatment of idiopathic juxtafoveolar retinal telangiectasis as well. We report about 3 cases treated with three monthly intravitreal injections of bevacizumab. Fluorescein angiographies and OCT measurements of retinal thickness were performed. The mean increase of VA was 2 visual steps. In two cases an increase of 5 and 1 visual steps, respectively, could be determined, in the other case no increase was found. The mean retinal thickness decreased from 300 microns to 287 microns. According to our results bevacizumab seems to be less suitable for treatment of idiopathic juxtafoveolar retinal telangiectasis because only a small decrease of retinal thickness can be observed.


Essential oils of Citrus aurantifolia, Anthemis nobile and Lavandula officinalis: in vitro anthelmintic activities against Haemonchus contortus.
Infections of sheep with gastrointestinal parasites, especially Haemonchus contortus, have caused serious losses in livestock production, particularly after the emergence of resistance to conventional anthelmintics. The search for new anthelmintic agents, especially those of botanical origin, has grown substantially due to the perspective of less contamination of meat and milk, as well as other advantages related to their cost and accessibility in less developed countries. The aim of this study was to evaluate the in vitro anthelmintic activity of essential oils of the plant species Citrus aurantifolia, Anthemis nobile and Lavandula officinalis against the main developmental stages of the parasite H. contortus. Plant species were selected based on substantial ethnopharmacological information. Analysis of the composition of each oil by gas chromatography coupled to mass spectrometry (GC-MS) demonstrated the presence of limonene (56.37%), isobutyl angelate (29.26%) and linalool acetate (35.97%) as the major constituents in C. aurantifolia, A. nobile and L. officinalis, respectively. Different concentrations of each oil were tested in vitro for their capacity to inhibit egg hatching (EHT), larval development (LDT) and adult worm motility (AWMT) using a multidrug-resistant strain of H. contortus (Embrapa 2010). The IC50 values obtained for the oils of C. aurantifolia, A. nobile and L. officinalis were 0.694, 0.842 and 0.316 mg/ml in the EHT and 0.044, 0.117 and 0.280 mg/ml in the LDT, respectively. The three oils were able to inhibit adult worm motility completely within the first 8-12 h of observation in the AWMT. The present results demonstrate significant anthelmintic activity of the three oils against the different developmental stages of H. contortus. Furthermore, this study is of ethnopharmacological importance by validating the anthelmintic activity of the oils studied. Although new experiments are necessary, these data contribute to the development of pharmaceutical-veterinary products for sheep farming by opening up new therapeutic possibilities against gastrointestinal infections caused by H. contortus.


Modulatory mechanisms of copperII-albumin complex toward N-nitrosodiethylamine-induced neurotoxicity in mice via regulating oxidative damage, inflammatory, and apoptotic signaling pathways.
N-nitrosodiethylamine (ND) is an extremely toxic unavoidable environmental contaminant. CopperII-albumin (CuAB) complex, a newly developed Cu complex, showed antioxidant and anti-inflammatory potential. Hereby, we explored the plausible neuroprotective role of CuAB complex toward ND-evoked neurotoxicity in mice. Twenty-four male mice were sorted into 4 groups (6 mice each). Control group, mice were administered oral distilled water; and CuAB group, mice received CuAB complex at a dose of 817 µg/kg orally, three times weekly. In ND group, ND was given intraperitoneally (50 mg/kg body weight, once weekly for 6 w). CuAB+ND group, mice were administered a combination of CuAB and ND. The brain was quickly extracted upon completion of the experimental protocol for the evaluation of the oxidative/antioxidative markers, inflammatory cytokines, and histopathological examination. Oxidative stress was induced after ND exposure indicated by a reduction in GSH and SOD1 level, with increased MDA level. In addition, decreased expression of SOD1 proteins, Nrf2, and 5-HT mRNA expression levels were noticed. An apoptotic cascade has also been elicited, evidenced by overexpression of Cyt c, Cl. Casp 3. In addition, increased regulation of proinflammatory genes (TNF-α, IL-6, iNOS, Casp1, and NF-κB (p65/p50); besides, increment of protein expression of P-IKBα and reduced expression of IKBα. Pretreatment with CuAB complex significantly ameliorated ND neuronal damage. Our results recommend CuAB complex supplementation because it exerts neuroprotective effects against ND-induced toxicity.


Non-conventional caries management techniques for children show promise.
Secondary care-based, three-arm parallel-group, randomised controlled trial. Children aged three to eight years old with at least one primary molar tooth with caries into dentine involving two dental surfaces were randomised to either; conventional restoration (CR) with local anaesthesia, Hall technique (HT) or non-restorative caries treatment (NRCT) with no local anaesthetic. Only one tooth per child was included and parents were present during treatment. Child's pain perception (Visual Analogue Scale of Faces); behaviour (Frankl scale); and parents' and dentists' treatment opinions (five-point Likert scales). One hundred and sixty-nine children (96 boys and 73 girls) were randomised; 52 received HT; 52 NRCT and 65 CR. Children showed more negative behaviour in the CR group (37%) compared to NRCT (21%) and HT (13%) (P = 0.047, CI = 0.41 to 0.52). Pain intensity was rated 'very low' or 'low' in 88% NRCT, 81% HT, and 72% CR (P = 0.11, CI = 0.10 to 0.12). NRCT and HT were 'very easy' or 'easy' to perform for >77% of dentists, compared to 50% in CR group (P < 0.000). There were no statistically significant differences in parents' rating of their child's level of comfort (P = 0.46, CI = 0.45 to 0.48). Dentists reported more negative behaviour in the CR group. For all techniques, children's pain perception and dentist/parent acceptability were similar.


Disseminated intravascular coagulation: diagnostic and therapeutic considerations.
Disseminated intravascular coagulation, although an uncommon diagnosis on a general medical service, is one of the most common, acquired disorders of coagulation. With more aggressive therapy of critically ill patients it is also a diagnosis which is increasing in frequency. Recent advances in our understanding of the underlying causes for DIC and its pathophysiology have led to the establishment of diagnostic criteria and guidelines for the management of patients. Hemorrhage and thrombosis are the major criteria for initiation of therapy, and heparin is the most efficacious approach when correction of underlying causes is inadequate. Frequent monitoring of patients on heparin therapy can improve the benefit-to-risk ratio for this disorder.


Biodynamic signatures from ex vivo bone marrow aspirates are associated with chemotherapy-induced neutropenia in cancer-bearing dogs.
Neutropenia is the most common dose-limiting side effect of cytotoxic chemotherapy in cancer-bearing dogs. Biodynamic imaging (BDI) is a functional imaging technology that measures dynamic light scattering from living, three-dimensional tissues to characterize intracellular motion within those tissues. Previous studies have associated BDI biomarkers with tumour sensitivity to chemotherapy agents in dogs with naturally occurring cancer. We hypothesized that BDI, performed ex vivo on bone marrow aspirate samples, would identify dynamic biomarkers associated with the occurrence of specific degrees of neutropenia in tumour-bearing dogs receiving doxorubicin chemotherapy. Bone marrow aspirates were collected from 10 dogs with naturally occurring cancers prior to initiation of doxorubicin treatment. BDI was performed on bone marrow samples treated ex vivo with doxorubicin at 0.1, 1, 10 and 100 μM along with 0.1% DMSO as a control. Dogs then were treated with doxorubicin (30 mg/m2 , intravenously). Peripheral blood neutrophil counts were obtained on the day of treatment and again 7 days later. Receiver operating characteristic curves identified provisional breakpoints for BDI biomarkers that correlated with specific changes in neutrophil counts between the two time points. Provisional breakpoints for several BDI biomarkers were identified, specifying dogs with the largest proportionate change in neutrophils and with neutropenia that was grade 2 or higher following doxorubicin treatment. Biodynamic imaging of bone marrow aspirates may identify those dogs at greater risk for neutropenia following doxorubicin chemotherapy. This approach may be useful for pre-emptively modifying chemotherapy dosing in dogs to avoid unacceptable side effects.


Emergence of modern marine ecosystems.
The structure and function of marine ecosystems are not fixed. Instead, major innovations - from the origin of oxygenic photosynthesis, to the evolution of reefs or of deep bioturbation, to the rise of pelagic calcifiers - have changed biogeochemical cycles and ecosystem dynamics. As a result, modern marine ecosystems are fundamentally different from those in the distant past.


Size and transmural extent of first-time reperfused myocardial infarction assessed by cardiac magnetic resonance can be estimated by 12-lead electrocardiogram.
The ability of the 12-lead electrocardiogram (ECG) to quantify size and transmural extent of myocardial infarction (MI) is not fully explored. Q waves are still thought of as indicative of transmural MI despite that several studies have rejected this association. We hypothesized that size and transmural extent of acute MI indeed can be estimated by QRS scoring on the 12-lead ECG using delayed, contrast-enhanced magnetic resonance imaging (DE-MRI) as gold standard and that Q waves are not predictive of transmural MI. Twenty-nine patients with first-time reperfused MI were studied. Delayed, contrast-enhanced magnetic resonance imaging was performed and 12-lead ECG was recorded 8 +/- 1 days after the acute event. Myocardial infarction size and transmurality were determined by DE-MRI and compared with Selvester QRS score from the ECG recorded on the same day. There was a good correlation (r = 0.79, P < .001) between MI size by QRS scoring and DE-MRI. As local MI transmurality increased as assessed by DE-MRI, the local QRS score increased progressively (P < .001). There was no significant difference in the number of Q-wave-related QRS points between nontransmural and transmural MI (1.8 +/- 0.6 vs 2.9 +/- 0.4, P = .14). The global QRS score, however, differed significantly (3.1 +/- 0.8 vs 5.1 +/- 0.6, P < .05). QRS score is significantly related to both MI size and transmurality by DE-MRI in patients with first-time reperfused MI. Presence of Q waves, however, is not indicative of transmural MI in these patients. Thus, QRS scoring could potentially be used for diagnosing and characterizing MI in patients with suspected recent MI.


Acute atrial tachyarrhythmia induces angiotensin II type 1 receptor-mediated oxidative stress and microvascular flow abnormalities in the ventricles.
Patients with paroxysmal atrial fibrillation (AF) often present with typical angina pectoris and mildly elevated levels of cardiac troponin (non ST-segment elevation myocardial infarction) during an arrhythmic event. However, in a large proportion of these patients, significant coronary artery disease is excluded by coronary angiography. Here we explored the potential underlying mechanism of these events. A total of 14 pigs were studied using a closed chest, rapid atrial pacing (RAP) model. In five pigs RAP was performed for 7 h (600 b.p.m.; n = 5), in five animals RAP was performed in the presence of angiotensin-II type-1-receptor (AT(1)-receptor) inhibitor irbesartan (RAP+Irb), and four pigs were instrumented without intervention (Sham). One-factor analysis of variance was performed to assess differences between and within the three groups. Simultaneous measurements of fractional flow reserve (FFR) and coronary flow reserve (CFR) before, during, and after RAP demonstrated unchanged FFR (P = 0.327), but decreased CFR during RAP (RAP: 67.7 +/- 7.2%, sham: 97.2 +/- 2.8%, RAP+Irb: 93.2 +/- 3.3; P = 0.0013) indicating abnormal left ventricular (LV) microcirculation. Alterations in microcirculatory blood flow were accompanied by elevated ventricular expression of NADPH oxidase subunit Nox2 (P = 0.039), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1, P = 0.004), and F(2)-isoprostane levels (P = 0.008) suggesting RAP-related oxidative stress. Plasma concentrations of cardiac troponin-I (cTn-I) increased in RAP (RAP: 613.3 +/- 125.8 pmol/L vs. sham: 82.5 +/- 12.5 pmol/L; P = 0.013), whereas protein levels of eNOS and LV function remained unchanged. RAP+Irb prevented the increase of Nox2, LOX-1, and F(2)-isoprostanes, and abolished the impairment of microvascular blood flow. Rapid atrial pacing induces AT(1)-receptor-mediated oxidative stress in LV myocardium that is accompanied by impaired microvascular blood flow and cTn-I release. These findings provide a plausible mechanism for the frequently observed cTn-I elevation accompanied with typical angina pectoris symptoms in patients with paroxysmal AF and normal (non-stenotic) coronary arteries.


Model invariance of the Motor Competence Assessment (MCA) from early childhood to young adulthood.
The Motor Competence Assessment (MCA) is an innovative instrument to assess motor competence along the lifespan. The MCA model and normative values were recently established from the age of 3-to-23 years old. The purpose of this study was to validate MCA from early childhood to young adulthood.One thousand participants representing four age groups (3-6, 7-10, 11-16, 17-22 years) with 250 participants each, were assessed. Invariance of the MCA model along the age groups - configural, metric and structural - was tested using multigroup CFA.The MCA model showed to fit well all age groups. The multigroup unconstrained model showed a very good fit (NFI=0.99; TLI=0.99; CFI=0.99; RMSEA=0.03). A formal test for the invariance of loading coefficients returned a non-satisfactory goodness-of-fit adjustment and a significant difference with the unconstrained model (Δχ2 = 539.57; Δdf = 18; p= .00) . The structural invariance testing did not show formal invariance between factor correlations (Δχ2 = 73.04; Δdf = 9; p= .00) but the fit of the model was acceptable (above 0.96 and a RMSEA of 0.05), indicating that correlation values inter factors are stable.This study adds information for the validation of the MCA as a useful instrument for assessing motor competence throughout the life cycle.


Follicular tissue fragments in fine-needle aspiration cytology of lymph nodes: A useful clue in differential diagnosis of follicular lymphoma and reactive follicular hyperplasia.
In Fine-needle aspiration cytology (FNAC) of lymph nodes, tissue fragments derived from follicular structures may be observed in specimens. We defined such tissue fragments as follicular tissue fragments (FTF), and investigated differences in cytological findings for FTFs of each histological type. A total of 41 cases with FNAC of lymph nodes were examined. In these cases, the histopathological diagnoses were reactive lymphoid hyperplasia (RLH) (n = 17), follicular lymphoma (FL) (n = 13), diffuse large B-cell lymphoma (DLBCL) (n = 18), and Burkitt lymphoma (n = 1). Specimens were analyzed for the presence of FTFs, and for tingible-body macrophages (TBMs) and monomorphism of lymphocytes in FTFs. FTFs with a maximum diameter of >500 μm were defined as large-FTFs. FTFs were identified in RLH (14/17, 82.4%), FL (13/13, 100%), and DLBCL (3/18, 16.7%). In the RLH subtypes, FTFs were present only in follicular hyperplasia (FH) (14/15, 93.3%) and not in paracortical hyperplasia (0/2). The number of cases with large FTFs among those with FTFs were as follows: RLH (10/14, 71.4%), FL (11/13, 84.6%), and DLBCL (0/3). Similarly, those with TBMs in FTFs were as follows: RLH (13/14, 92.9%), FL (0/13) and DLBCL (2/3, 66.7%). Monomorphism was observed in RLH (1/14, 7.1%) and FL (11/13, 84.6%), but not in DLBCL (0/3). Distinction between FL and FH is possible by identifying large-FTFs. In FL, TBMs are absent in FTFs and lymphocytes often show monomorphism. Therefore, recognizing FTFs and observing details inside the FTFs are useful for identification and differential diagnosis of FL and FH in FNAC of lymph nodes.


Investigation of the Association between High Arachidonic Acid Synthesis and Colorectal Polyp Incidence within a Generally Healthy UK Population: A Mendelian Randomization Approach.
Arachidonic acid (ARA) is associated with colorectal cancer (CRC), a major public health concern. However, it is uncertain if ARA contributes to the development of colorectal polyps which are pre-malignant precursors of CRC. The study aimed to investigate the association between lifelong exposure to elevated ARA and colorectal polyp incidence. Summary-level GWAS data from European, Singaporean, and Chinese cohorts (n = 10,171) identified 4 single-nucleotide polymorphisms (SNPs) associated with blood ARA levels (p < 5 × 10-8). After pruning, 1 SNP was retained (rs174547; p = 3.0 × 10-971) for 2-stage Mendelian randomization. No association between ARA and colorectal polyp incidence was observed (OR = 1.00; 95% CI: 0.99, 1.00; p value = 0.50) within the UK Biobank (1,391 cases; 462,933 total). Blood levels of ARA do not associate with colorectal polyp incidence in a general healthy population. Although not providing direct evidence, this work supports the contention that downstream lipid mediators, such as PGE2 rather than ARA itself, are key for polyp formation during early-stage colorectal carcinogenesis.


Incidence and fracture morphology of posterolateral fragments in lateral and bicondylar tibial plateau fractures.
This study aimed to evaluate the incidence and morphologic features of posterolateral fragments in lateral and bicondylar tibial plateau fractures. This study used retrospective chart and computed tomography (CT) reviews. The study was conducted in a university hospital. All patients in whom lateral and bicondylar tibial plateau fractures had been diagnosed from May 2005 to December 2011 were reviewed. Two hundred seventy-eight OTA type B and type C tibial plateau fractures were identified using a retrospective chart review. Of the 197 patients who underwent CTs before surgery, 7 CTs were excluded because they had no sagittal or axial view, and the remaining 190 cases were enrolled to determine the incidence and morphologic characteristics of posterolateral fragments. The parameters for the morphologic evaluation included the lateral major articular fracture angle, posterior major articular fracture angle, diagonal distance, lateral anteroposterior distance (LAPD), posterior horizontal distances, posterior cortical height, sagittal fracture angle, and articular surface area. The displacement of posterolateral fragment was measured on axial image and classified as none, minor, or major by a gap of 5 mm. The incidence of posterolateral fragments included 84 cases (44.2%). Based on the OTA fracture classification system, 37 type B (35.9%) and 47 type C (54%) posterolateral fragments were identified. The mean lateral major articular fracture angle was 12.69 degrees (range, -56.02 to 72.44 degrees), and the mean posterior major articular fracture angle was 19.13 degrees (range, -39.47 to 61.10 degrees). The average diagonal distance was 32.75 mm (range, 15.03-59.14 mm). The LAPD averaged 10.22 mm (range, -11.18 to 31.17 mm), and the mean posterior horizontal distance was 22.93 mm (range, 4.1 to 49.95 mm). The average posterior cortical height was 31.12 mm (range, 10.84-63.93 mm), and the average sagittal fracture angle was 78.48 degrees (range, 41.69-105.12 degrees). The mean articular surface area was 522.18 mm2 (14.5%) of the total tibial articular surface. Posterolateral fragments are not uncommon in lateral and bicondylar tibial plateaus. This fragment has an inverted conical shape that is in a vertically oriented pattern and occupied nearly one-third of the surface area of the lateral tibial plateau. The preoperative CT measurement, especially for the LAPD, can be used for determining the best fixation strategy for the posterolateral fragment. Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.


Demographic and psychosocial factors associated with recent suicidal ideation and suicide attempts among trans and gender diverse people in Australia.
Correlates of suicidal ideation and suicide attempts among a large cross-section of trans and gender diverse populations in Australia were examined. A national survey was conducted that included 1466 trans and gender diverse participants aged 18+ years. Multivariable regressions identified factors associated with recent suicidal ideation and suicide attempts. Overall, 62.4% reported suicidal ideation and 9.5% suicide attempt in the past 12 months. The likelihood of suicidal ideation was higher for younger participants or those who felt treated unfairly or socially excluded due to their gender identity in the past 12 months. It was lower for those with a postgraduate degree, who felt accepted by family or work, or who felt their gender identity was respected when accessing a mainstream medical clinic in the past 12 months. The likelihood of suicide attempts was greater for those aged younger or who had recently experienced sexual harassment based on their sexual orientation or gender identity, and lower for those who were non-binary. Urgent attention for suicide prevention is necessary for trans and gender diverse communities. These findings point to a range of risk and protective factors, which may help inform the targeting and design of suicide prevention strategies.


Bioinformatics analysis reveals disturbance mechanism of MAPK signaling pathway and cell cycle in Glioblastoma multiforme.
To analyze the reversal gene pairs and identify featured reversal genes related to mitogen-activated protein kinases (MAPK) signaling pathway and cell cycle in Glioblastoma multiforme (GBM) to reveal its pathogenetic mechanism. We downloaded the gene expression profile GSE4290 from the Gene Expression Omnibus database, including 81 gene chips of GBM and 23 gene chips of controls. The t test was used to analyze the DEGs (differentially expressed genes) between 23 normal and 81 GBM samples. Then some perturbing metabolic pathways, including MAPK (mitogen-activated protein kinases) and cell cycle signaling pathway, were extracted from KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway database. Cancer genes were obtained from the database of Cancer Gene Census. The reversal gene pairs between DEGs and cancer genes were further analyzed in MAPK and cell cycle signaling pathway. A total 8523 DEGs were obtained including 4090 up-regulated and 4433 down-regulated genes. Among them, ras-related protein rab-13(RAB13), neuroblastoma breakpoint family member 10 (NBPF10) and disks large homologue 4 (DLG4) were found to be involved in GBM for the first time. We obtained MAPK and cell cycle signaling pathways from KEGG database. By analyzing perturbing mechanism in these two pathways, we identified several reversal gene pairs, including NRAS (neuroblastoma RAS) and CDK2 (cyclin-dependent kinase 2), CCND1 (cyclin D1) and FGFR (fibroblast growth factor receptor). Further analysis showed that NRAS and CDK2 were positively related with GBM. However, FGFR2 and CCND1 were negatively related with GBM. These findings suggest that newly identified DEGs and featured reversal gene pairs participated in MAPK and cell cycle signaling pathway may provide a new therapeutic line of approach to GBM.


COURTSHIP FEEDING AND THE FITNESS OF FEMALE KATYDIDS (ORTHOPTERA: TETTIGONIIDAE).
Katydid males (Requena verticalis) produce spermatophores with a large sperm-free spermatophylax, which is eaten by the female after mating. In this study, I asked 1) how do spermatophylax nutrients affect the fitness of the mated female and her progeny? 2) does this male-produced food substitute for other food in the diet of the female, or is it a source of specialized nutrients? and 3) does an increase in the size of the spermatophylax eaten influence female reproduction in the same way as the additional spermatophylaxes that would be obtained from multiple mating? An experimental increase either in dietary protein or the number of spermatophylaxes eaten increased the number of eggs produced. However, spermatophylax size had no effect on egg number. An increase in either the size or number of spermatophylaxes eaten resulted in an increase in egg size. There was no influence of protein in the general diet on egg size. This suggests that males provide nutrition not available from other sources. Although there were no direct effects of number of spermatophylaxes eaten by females on the overwintering survival of their progeny, offspring from females producing larger eggs had a relatively higher probability of surviving winter. The amount of spermatophylax eaten had no influence on the mean adult size of progeny but significantly increased the mean date at which sons matured to adulthood. There was no influence of dietary protein on these variables. Since maturation date is positively correlated with adult size in both sexes, it is suggested that the influence of courtship feeding on maturation date may result in an increase in adult size and thus the fitness of sons. A significant correlation between the size of the female and the mean size of her sons (but not daughters) suggests that there is also a heritable component to body size.


Dissociation kinetics of the uterine estrogen receptor-estradiol complex are unaltered in aging C57BL/6 mice.
Several, though not all, estrogen-dependent phenomena show reduced responsiveness to estradiol (E2) during aging. One factor contributing to this reduced sensitivity could be an increase in the dissociation rate of the estrogen receptor-hormone complex. We therefore studied the effect of aging on the dissociation rate of 3HE2 from the uterine cytosolic estrogen receptor (ER) of C57BL/6 mice that had been ovariectomized 48 h earlier. Measurements were made at 28 degrees C at two concentrations of cytosol. In dilute cytosol ([ER] = 0.01 nM) the dissociation of ER-3HE2 displayed a single phase, first order profile which did not differ among young (4-6 month), middle-aged (15-18 month) and old (23-30 month) mice. In more concentrated cytosol ([ER] = 2 or 6 nM) the dissociation of ER-3HE2 displayed a biphasic first order profile that consisted of an initial rapidly dissociating phase followed by a more slowly dissociating phase. There was no effect of age on the dissociation rate constant (K) of either the rapid (K-1) or slow (K-2) phase. Shortening the time allotted for the concentrated cytosol to equilibrate with 3HE2 before measuring the dissociation rate reduced the fraction of the receptor hormone complex that dissociated in the slow phase, but, once again, the dissociation profiles did not differ between age groups. These results indicate that uterine ER dissociation kinetics remain unaltered in middle-aged and old mice and are therefore unlikely to play a role in the attenuated responsiveness to estrogen during aging.


Knowledge and attitude about relining of complete dentures in clinical practice: A cross-sectional study.
Residual ridge resorption is crucial sequelae of tooth loss. Complete dentures are the most common way of rehabilitating edentulous patients. However, with continuing residual ridge resorption, dentures tend to become loose and unstable causing discomfort, chewing disability, and speech problems. Denture relining is an economical means of improving a denture's stability and retention. An understanding of the clinical indications and limitations of these materials and procedures is crucial for clinical success. The purpose of this survey was to assess knowledge, attitude, and practice in relining dentures among dental practitioners. The cross-sectional survey was conducted using a validated questionnaire on 200 (n = 200) dental practitioners in Nagpur city, Maharashtra. Data analysis was done using proportion test with SPSS EPI INFO software. Although all 200 practitioners were aware of the relining procedure and were routinely carrying out the procedure in their dental clinics, 50% of the practitioners were unaware of the correct relining step by step procedure and were also not sure about the antimicrobial properties of the relining material available in the market. Awareness and scientific knowledge about the relining materials and procedure should be enhanced within general dental practitioners through CDE program and workshops. Steps should be taken to include relining procedure as a part of undergraduate clinical curriculum as well as internship program.


Acute lymphoblastic leukemia cells treated with CpG oligodeoxynucleotides, IL-4 and CD40 ligand facilitate enhanced anti-leukemic CTL responses.
Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Although the majority of patients initially respond to upfront chemotherapy, relapses with poor prognosis occur in approximately 20% of cases. Thus, novel therapeutic strategies are required to improve long-term survival. B-cell precursor (BCP)-ALL cells express low levels of immunogenic molecules and, therefore, are poorly recognized by the immune system. In the present study, we investigated the effect of various combinations of potent B-cell stimulators including CpG, Interleukin (IL)-2 family cytokines and CD40 ligand (CD40L) on the immunogenicity of primary BCP-ALL cells and a series of BCP-ALL cell lines. The combination of CpG, IL-4 and CD40L was identified as most effective to enhance expression of immunogenic molecules on BCP-ALL cells, resulting in an increased capacity to induce both allogeneic and autologous cytotoxic T lymphocytes (CTL). Importantly, such CTL exhibited significant anti-leukemic cytotoxicity not only towards treated, but also towards untreated BCP-ALL cells. Our results demonstrate that the combination of CpG with other B-cell stimulators is more efficient than CpG alone in generating immunogenic BCP-ALL cells and anti-leukemic CTL. Our results may stimulate the development of novel adoptive T cell transfer approaches for the management of BCP-ALL.


Are the results of handheld auto-refractometer as valid as the result of table-mounted refractometer?
To determine the agreement of table-mounted and handheld auto-refractometers and to evaluate the effect of age and different types of refractive errors on this comparison. In this cross-sectional study conducted in 2015 using multi-stage cluster sampling, two underserved villages were selected randomly in the north and southwest of Iran. All the selected participants underwent optometric and ophthalmic examinations. Refraction was measured using handheld and table-mounted auto-refractometers in 652 subjects. The mean age of the subjects was 32.7 ± 18.72 years, and 58.3% of them were female. A significant difference was observed in the results of sphere, spherical equivalent (SE), and J45 vector between the two devices (P < 0.012), but there was no significant difference in J0 vector. There was a significant difference in the results of sphere between the two devices in all age groups under 50 years (P = 0.005), but there was no difference in age groups above 50 years. Correlation coefficients of the two devices were 0.989, 0.986, 0.908, and 0.951 for the results of sphere, SE, J0 vector, and J45 vector, respectively (P < 0.0001). The 95% limit of agreement (LOA) of the two devices was -0.31 to +0.53 for sphere, -0.27 to +0.63 for SE, -0.27 to +0.27 for J0 vector, and -0.16 to -0.17 for J45 vector. According to our findings, the spherical error and cylindrical power measurements of the two devices have a significant correlation. Although there is a significant difference in the mean values between the two devices, this difference may be considered clinically insignificant, and considering the narrow 95% LOA between the two devices, the results may be used interchangeably.


Impulse control behavior in GBA-mutated parkinsonian patients.
To assess the prevalence and phenomenology of Impulse control behavior (ICB) in Parkinson's disease (PD) patients carrying mutations in the β-glucocerebrosidase (GBA) gene. GBA mutations are a common genetic factor predisposing to PD. ICB is among the most disabling non-motor complications of PD. The occurrence of ICB in PD patients carrying GBA gene mutations (GBA-PD) has not been yet established. Forty-six patients with clinically definite PD (23 GBA-PD and 23 non-mutated patients, NM-PD) were screened for ICB. Diagnosis was clinically and rating based on a specific questionnaire (QUIP-RS). Other demographic and clinical variables did not differ between groups. ICB occurred more frequently in GBA-PD patients (52.2%) compared to NM-PD (13%) and the total QUIP-RS score was higher in the GBA-PD group. Hypersexuality and compulsive shopping were the most prevalent ICB types occurring in GBA patients. ICB occurred only in one GBA-PD patient on levodopa monotherapy and in 11 patients taking dopamine agonists, either monotherapy or combined with levodopa (the corresponding figures in NM-PD patients were 0 and 3). Most GBA-PD patients were heterozygous for two common genetic variants, without appreciable difference in their ICB profile. ICB is more common in GBA-PD patients compared to NM-PD. Dopamine agonist therapy may be synergic to GBA carrier status for ICB occurrence.


Effects of different dopamine agonists and antagonists on post-menopausal hot flushes.
The dopaminergic system seems to be involved in both pulsatile luteinizing hormone (LH) secretion and hot flushes in post-menopausal women. With the aim of further clarifying its role, the effectiveness of dopaminergic and antidopaminergic drugs in the treatment of hot flushes was studied. Self-assessed scores for vasomotor symptoms were evaluated in 5 groups of 15 patients treated for 20 days with one of the following agents: placebo; the dopamine receptor agonist, bromocriptine; the indirect dopaminergic agent, Liposom; the antidopaminergic drug, veralipride or the peripheral antidopaminergic agent, domperidone. All of these treatment regimens were effective in alleviating hot flushes, but the pharmacological agents proved to be more effective than the placebo. A direct dopaminergic action is hypothesized in the case of bromocriptine and Liposom, while the antidopaminergic drugs might act through different indirect mechanisms such as the short-loop feedback exerted by hyperprolactinaemia on tuberoinfundibular dopamine (TIDA) neurons with a secondary dopamine-like activity, or stimulation of the opioid system.


A social history of racial disparities in breastfeeding in the United States.
Over the past five decades in the United States, White women have breastfed at higher rates than Black women. While a small but growing body of social historical research has examined racial disparities in breastfeeding over time, empirical research, particularly quantitative research, has focused on single historical snapshots, unintentionally treating the persistent racial disparities in breastfeeding as a static phenomenon, rather than one with distinct social mechanisms at different points in time. Further, few studies on racial disparities in health deconstruct difference both within and across racial groups. But what if we thought about persistent racial disparities instead as discrete trends with distinct social mechanisms at different points in time? In a binary logistic regression of breastfeeding initiation rates from 1973 to 2015 using the National Survey of Family Growth (NSFG), I found that the persistent racial disparities were actually comprised of three distinct types of changing racial disparities: (1) increases in racial disparities that derive from improvements for Whites not captured by Blacks (1973-1982); (2) decreases in racial disparities that stem from improvements for Whites captured even more strongly by Blacks (1995-2006); and, (3) leveling off of racial disparities (2006-2015). Placing results of this quantitative analysis within the context of public policy and social movement history, I identify three distinct mechanisms that drive the different trends in racial disparities in breastfeeding. This paper contributes to the literature on motherhood, race, and health a more nuanced understanding of the social historical mechanisms that pattern breastfeeding, and more broadly, racial disparities in health.


Flavan enantiomers from Daphne giraldii selectively induce apoptotic cell death in p53-null hepatocarcinoma cells in vitro.
Hepatocellular carcinoma (HCC) is a primary malignant tumor with very poor prognosis. To search for more effective compounds for HCC treatment, two new pairs of flavan enantiomers, daphnegiranol C1/C2 (1a/1b) and daphnegiranol D1/D2 (2a/2b), were isolated from the stem bark and roots of Daphne giraldii by using chiral chromatography. MTT assay was applied to evaluate their cytotoxicity against three hepatocarcinoma cell lines (Hep3B, MHCC97H, HepG2) as well as a normal liver cell line L02. The results showed that these compounds preferred to inhibit the growth of Hep3B cells (p53 null). Among them, 2a/2b (the IC50 value was 4.87 and 3.35 μM, respectively) exhibited a stronger cytotoxic effect than sorafenib (IC50 = 6.59 μM) in Hep3B cells. A further study demonstrated that 2a/2b could induce apoptotic cell death with an increase in reactive oxygen species (ROS) in Hep3B cells. In addition, the IC50 values of 2a/2b in HepG2 and MHCC97H cells (both harbored p53 gene) were more than 10-folds greater when compared with Hep3B cells, indicating that 2a/2b selectively exhibited cytotoxicity in p53-null hepatocarcinoma cells. Moreover, inhibition of p53 increased the inhibitory effect in p53-wild hepatocarcinoma cells, as well as apoptotic cells and ROS generation. Taken together, flavan enantiomers 2a/2b selectively induced apoptosis in Hep3B cells because of p53 deficiency.


Stereotactic body radiotherapy in the management of hepatocellular carcinoma: An Australian multi-institutional patterns of practice review.
Stereotactic body radiotherapy (SBRT) is an emerging, therapeutic option in the management of hepatocellular carcinoma (HCC). A multicentre Liver Ablative Stereotactic Radiation (LASR) database was established to provide a collaborative platform for Australian institutions to define the practice of liver SBRT for HCC. This study explores the patterns of SBRT practice amongst Australian institutions. This was a multi-institutional retrospective study of patients treated with SBRT for HCC at 10 institutions between January 2013 and December 2019. Patients' demographics, disease characteristics and SBRT details were evaluated. Three hundred and seventeen patients were evaluated with a median age of 67 years (range, 32-90). Liver cirrhosis was present in 88.6%, baseline Child-Pugh score was A5/6 in 85.1% and B7/8 in 13.2%. Median size of HCC treated was 30 mm (range, 10-280). 63.1% had early-stage disease (Barcelona clinic liver cancer (BCLC) stage 0/A) and 36% had intermediate/advanced-stage disease (BCLC B/C). In 2013/2014, six courses of SBRT were delivered, increasing to 108 in 2019. SBRT was prescribed in five fractions for 71.3% of the cohort. The most common dose fractionation schedule was 40 Gy in five fractions (24.3%). Median biologically effective dose (BED10 ) delivered was 85.5 Gy for early-stage and 60 Gy for intermediate/advanced disease, respectively. The most common prescription range was 100-120 Gy BED10 (32.8%). SBRT utilisation for HCC is increasing in Australia. There was wide variation in size of tumours and disease stages treated, and prescription patterns. Uniform reporting of clinical and dosimetric details are important in refining the role of liver SBRT.


Cathepsins Drive Anti-Inflammatory Activity by Regulating Autophagy and Mitochondrial Dynamics in Macrophage Foam Cells.
Atherosclerosis underlies the majority of cardiovascular events, consequent to non-resolving inflammation. Considerable evidence implicates autophagy dysfunction at the core of this inflammatory condition, but the basis of this dysfunction is not fully understood. Using an in vitro model of lipid-laden macrophages, activity-based probes and high-throughput techniques, we studied the role of the cysteine proteases cathepsins in autophagy. We showed that cathepsin activity is suppressed by oxidized lipids and that cathepsin has an indispensable role in the autophagy-lysosomal degradation pathway. Accordingly, loss of cathepsin function resulted in autophagy derangement. Shotgun proteomics confirmed autophagy dysfunction and unveiled a pivotal role of cathepsin L in a putative cathepsin degradation network. At the physiological level, cathepsin inhibition resulted in mitochondrial stress, which translated into impaired oxidative metabolism, excessive production of reactive oxygen species and activation of the cellular stress response, driven by ATF4-CHOP transcription factors. In addition, transcriptomic analysis of these cells uncovered some genetic similarities with the inflammatory macrophage phenotype (a.k.a M1 macrophages) and increased expression of inflammatory cytokines. Our data highlight the importance of cathepsins for mitochondrial quality control mechanisms and amelioration of vascular inflammation.


Correlates of depression and quality of life among patients with epilepsy in Nigeria.
To determine the prevalence of Major Depressive Disorders (MDD) and its relationship to Quality of life. A cross-sectional observational study. Out-Patient Clinic of the Neuropsychiatric Hospital, Abeokuta, Nigeria. Patients with diagnosis of Epilepsy with Electroencephalogram (EEG) confirmation. Depression and Quality of life. The prevalence of current MDD was 11.9 %, and patients having at least 1 seizure per week were 5 times more likely to develop MDD (OR = 5.104, p = 0.014). The mean (SD) QOLIE-31 scores was 77.98 (13.32), with presence of MDD (β = -11.101, p = 0.0001); having at least 1 seizure/week (β = -6.653, p = 0.037) being independent predictors. Depression is a common comorbidity in patients with epilepsy and is associated with a lower quality of life.


Nucleotide sequence analysis of a mouse Y chromosomal DNA fragment containing Bkm and LINE elements.
The strong suppression of crossing-over between the X and Y chromosomes permits rapid accumulation of repetitive sequences in the Y chromosome. To gain insight into the mechanism responsible for the sequence amplification, it is essential to characterize Y chromosomal repetitive sequences at the molecular level. Here, we report the entire nucleotide sequence (3,902bp) of AC11, a mouse sequence that is repeated 300 times in the Y chromosome. AC11 is AT rich (32.8% GC), and contains many short poly(A) sequences. In addition, it has Bkm and LINE sequences as well as a Y chromosome-specific sequence. The Bkm sequence consists of typical (GATA) and (GACA) repeating units, whereas the LINE sequence deviates considerably from other mouse LINE sequences (71-76% identity) and may be considered atypical. The Y chromosome-specific region seems to be unique and does not identify similar sequences in the GenBank library. The information obtained from the nucleotide sequence should form the foundation to study the evolutionary processes through which AC11-related sequences have accumulated in the mouse Y chromosome.


NewYork-Presbyterian Hospital: translating innovation into practice.
NewYork-Presbyterian (NYP) Hospital, a 2,242-bed not-for-profit academic medical center, was formed by a merger of The New York Hospital and The Presbyterian Hospital in the City of New York. It is also the flagship for the NewYork-Presbyterian Healthcare System, with 37 acute care facilities and 18 others. The hospital embeds safety in the culture through strategic initiatives and enhances service and efficiency using Six Sigma and other techniques to drive adoption of improvements. Goals are selected in alignment with the annual strategic initiatives, which are chosen on the basis of satisfaction surveys, patient and family complaints, community advisory groups, and performance measures, among other sources. A new business intelligence system enables online, dynamic analysis of performance results, replacing static paper reports. Advanced features in the clinical information systems include computerized physician order entry; interactive clinical alerts for decision support; a real-time infection control tracking system; and a clinical data warehouse supporting data mining and analysis for quality improvement, decision making, and education. To achieve clinical, service, and operational excellence, NYP focuses on all Institute of Medicine quality aims.


A weekly vitamin A supplementary program alleviates social impairment in Chinese children with autism spectrum disorders and vitamin A deficiency.
Children in China with Autism Spectrum Disorders (ASD) are prone to vitamin A deficiency (VAD). The present study compared two vitamin A supplements (VAS) in two groups of children with ASD and VAD to explore a better VAS program for children with ASD. A total of 138 3-8-year-old children with ASD (118 males and 20 females) were enrolled in this 6-month study. Of these 138 children, 82 who had VAD (ASD-VAD) were divided into two VAS groups that received the recommended VAS program (RNI-VAS) or a weekly dose of VAS (WD-VAS). The 56 children who had normal vitamin A levels (ASD-VAN) served as a control group. The Social Responsiveness Scale (SRS) was used to assess the severity of social impairment before and after the interventions. Their serum retinol (VA) and oxytocin (OXT) concentrations, the mRNA expression of retinoic acid receptors (RARs), and CD38 gene in peripheral blood was measured before and after the 6-month intervention. The WD-VAS program increased VA levels better than the RNI-VAS program did (P < 0.01), and it significantly decreased SRS scores (P < 0.05). In addition, the change in VA was positively correlated with the change in mRNA levels in RARβ (r = 0.2441, P = 0.0092), the CD38 in PBMC (r = 0.2729, P = 0.0033), and the change in OXT concentration in serum (r = 0.3735, P < 0.0001). VA was also negatively correlated with changes in SRS scores across the three groups (r = -0.2615, P = 0.0026). The WD-VAS might be more suitable for children with ASD and VAD than other interventions to improve both VA and social functioning, which may be mediated through the RARβ-CD38-OXT axis.


Feasibility of a pulmonary rehabilitation programme for patients with symptomatic chronic obstructive pulmonary disease in Georgia: a single-site, randomised controlled trial from the Breathe Well Group.
To assess the feasibility of delivering a culturally tailored pulmonary rehabilitation (PR) programme and conducting a definitive randomised controlled trial (RCT). A two-arm, randomised feasibility trial with a mixed-methods process evaluation. Secondary care setting in Georgia, Europe. People with symptomatic spirometry-confirmed chronic obstructive pulmonary disease recruited from primary and secondary care. Participants were randomised in a 1:1 ratio to a control group or intervention comprising 16 twice-weekly group PR sessions tailored to the Georgian setting. Feasibility of the intervention and RCT were assessed according to: study recruitment, consent and follow-up, intervention fidelity, adherence and acceptability, using questionnaires and measurements at baseline, programme end and 6 months, and through qualitative interviews. The study recruited 60 participants (as planned): 54 (90%) were male, 10 (17%) had a forced expiratory volume in 1 second of ≤50% predicted. The mean MRC Dyspnoea Score was 3.3 (SD 0.5), and mean St George's Respiratory Questionnaire (SGRQ) 50.9 (SD 17.6). The rehabilitation specialists delivered the PR with fidelity. Thirteen (43.0%) participants attended at least 75% of the 16 planned sessions. Participants and rehabilitation specialists in the qualitative interviews reported that the programme was acceptable, but dropout rates were high in participants who lived outside Tbilisi and had to travel large distances. Outcome data were collected on 63.3% participants at 8 weeks and 88.0% participants at 6 months. Mean change in SGRQ total was -24.9 (95% CI -40.3 to -9.6) at programme end and -4.4 (95% CI -12.3 to 3.4) at 6 months follow-up for the intervention group and -0.5 (95% CI -8.1 to 7.0) and -8.1 (95% CI -16.5 to 0.3) for the usual care group at programme end and 6 months, respectively. It was feasible to deliver the tailored PR intervention. Approaches to improve uptake and adherence warrant further research. ISRCTN16184185.


Pregnancy and delivery in patients with von Willebrand's disease.
To explore the obstetrical problems that are encountered in women with von Willebrand's disease (vWD). Case histories of 6 women whose pregnancies were complicated by vWD were reviewed retrospectively over an 11-year period. The disease had been diagnosed before pregnancy in only 2 cases. The 6 women had a total of 10 deliveries, 3 induced abortions, and 1 spontaneous abortion. Although all 6 women had Type-I vWD, their laboratory data and bleeding symptoms varied. The 10 full-term deliveries were all vaginal. Heat-treated concentrated Factor-VIII preparations were administered in 2 cases, in both of which abortions were induced during the 2nd trimester. Genital bleeding persisted in the second case, so that the administration of Factor VIII was repeated, and the patient underwent uterine curettage on the 12th day after abortion. Desmopressin was administered before the early induction of abortion in 1 case. The patient with persistent genital bleeding after spontaneous abortion received Factor VIII for 5 consecutive days. Bleeding problems occurred about 1 week after delivery or at the time of induced abortion in the 6 women with vWD. Thus, such patients require special care during pregnancy.


Accumulation of 23 kDa lipocalin during brain development and injury in Hyphantria cunea.
The cDNA corresponding to a novel lipocalin was identified from the fall webworm, Hyphantria cunea. This lipocalin cDNA encodes a 194 residue protein with a calculated molecular mass of 23 kDa. Sequence analyses revealed that the 23 kDa lipocalin cDNA is most similar to Drosophila lazarillo, human apolipoprotein D, and Bombyrin. Northern blot analyses showed that 23 kDa lipocalin transcript is expressed in the whole body only in 4- and 6-day-old pupae. By Western blot analysis it was confirmed that 23 kDa lipocalin is mainly accumulated in brain and subesophageal ganglion, though it is detected in a small amount in fat body and epidermis of Hyphantria cunea. The accumulation of 23 kDa lipocalin in brain tissue was upregulated in response to injury. The putative function of 23 kDa lipocalin in brain is discussed.


Initial therapeutic results of atezolizumab plus bevacizumab for unresectable advanced hepatocellular carcinoma and the importance of hepatic functional reserve.
We analyzed the association between the modified albumin-bilirubin (mALBI) grade and therapeutic efficacy of atezolizumab plus bevacizumab (Atezo+Bev) for the treatment of unresectable hepatocellular carcinoma (u-HCC). In this retrospective observational study, we included 71 u-HCC patients treated with Atezo+Bev between September 2020 and September 2021. Patients were grouped corresponding to the mALBI grade at the start of treatment (mALBI 1+2a or mALBI 2b+3) and analyzed for therapeutic effect and the transition rate to secondary treatment. According to the Response Evaluation Criteria in Solid Tumors, the overall response rate was significantly higher for the mALBI 1+2a group, than for the mALBI 2b+3 group, with 26.2% and 3.4%, respectively. The progression-free survival (PFS) was significantly longer in the mALBI 1+2a group (10.5 months) than in the mALBI 2b+3 group (3.0 months). In the multivariate analysis, an mALBI of 1+2a was found to be an independent factor of PFS. The rate of second-line treatment with multi-targeted agents was also significantly higher in the mALBI 1+2a group. In real-world practice, Atezo+Bev treatment might have higher therapeutic efficacy in u-HCC patients with mALBI 1+2a.


Novel mortality-predicting index at diagnosis can effectively predict all-cause mortality in patients with antineutrophil cytoplasmic antibody-associated vasculitis.
This study investigated whether the inflammation prognostic index (IPI) and the mortality predicting index (MPI) at diagnosis could predict all-cause mortality in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We included 223 AAV patients and reviewed their medical records. Clinical and laboratory data and AAV-specific indices at diagnosis were assessed. The IPI was calculated as neutrophil-to-lymphocyte ratio (NLR) × C-reactive protein to albumin ratio (CAR). Here, we newly developed an MPI (NLR × CAR × monocyte counts). The mean age of 223 patients (122 MPA, 57 GPA and 44 EGPA patients) was 59 years. The rate of mortality was 11.2%. Using the receiver operator characteristic curve for all-cause mortality, the cut-offs were calculated as NLR: 3.22, CAR: 3.25, IPI: 18.53 and MPI: 8367.82. In the univariable Cox hazard analysis, age, gender, smoking history, BVAS, FFS and over the cut-off of each index showed statistical significance. As the indices share at least two mutual variables, the multivariable analysis was conducted four times based on each index. An IPI ≥18.53 (HR 3.162) and MPI ≥8367.82 (HR 3.356) were significantly associated with all-cause mortality. This study developed a novel indicator, MPI, that uses the existing NLR and CAR indices and proved that it could predict all-cause mortality in AAV patients.


[Squalene-cholesterol ratio in the amniotic fluid and gestational age: changes in the threshold in relation to the preparation of the sample].
The squalene/cholesterol ratio in pellets prepared from amniotic fluid is closely correlated to the gestation age and shows a marked increase in the 39th week of pregnancy. However, the absolute value of the squalene/cholesterol ratio may very considerably in relation to the process used to prepare the sample. The washing of the sedimentary cells seems to be critical point in this procedure; therefore, if it is not correctly standardized, erroneous result may be obtained.


Improved artificial saliva for studying the cariogenic effect of carbohydrates.
Saliva is a complex fluid that possesses many important functions regarding oral health. Many in vitro studies require relatively large quantities of saliva. While natural saliva would be the material of choice, it is difficult to obtain in sufficient quantities and varies in composition. Substitutes mimicking the physicochemical properties of saliva have been developed, but these are not appropriate to study the growth of mutans streptococci. Brain Heart Infusion (BHI) has been commonly used for this, but this medium is richer in nutrients than saliva. We therefore developed artificial saliva (AS) with nutrient levels resembling those in natural saliva as a substitute for natural human saliva (HS) to study the influence of different carbon sources on mutans streptococci growth. Growth of a wild-type Streptococcus mutans strain and S. mutans ATCC 15175 in BHI, HS, and AS was monitored anaerobically. Growth of S. mutans in the modified AS was very similar to the growth in HS, both in the absence and presence of different carbon sources. We therefore conclude that the developed AS is suitable for in vitro tests on S. mutans growth.


Personal genotyping and student outcomes in genetic and pharmacogenetic teaching: a systematic review and meta-analysis.
Aim: Teaching of genetics and pharmacogenetics with personal genotyping (PGT) is becoming commonplace. We aimed to perform a systematic review and meta-analysis to understand the effects of PGT on student outcomes. Methods: A systematic review was performed on studies that reported the effects of PGT on student attitudes, perceptions or knowledge. Extracted data were summarized qualitatively and when possible, quantitatively. Results: Student PGT has a positive effect on student attitude and perceptions survey responses in studies without a control group (p = 0.009) and in studies with a control group (p = 0.025). Knowledge increased after the use of PGT (p < 0.001) in studies without a control group. Conclusion: The findings here suggest that perceptions, attitudes and knowledge increase with PGT in the classroom.


Cancer comorbidity in patients with non-obstructive coronary artery disease: Depressive symptoms related to C-reactive protein.
Based on guidelines for cardiovascular risk assessment among non-cancer populations, depression and anxiety can be seen as risk factors for CVD, on top of cardiotoxic cancer treatment and traditional CVD risk factors among cancer survivors. Increased inflammation can be a shared potential pathophysiological mechanism, as higher levels of inflammation (like C-reactive protein, CRP) are known associates of depression and anxiety. In turn, increased inflammation is involved in the pathogenesis of CVDs. Furthermore, both cancer and cancer treatment including chemotherapy and radiation can lead to elevated levels of inflammation. We will therefore examine whether the relation between depression and anxiety with inflammatory markers among patients with either CVD or cancer is different from those with both conditions. The TweeSteden Mild Stenosis (TWIST) study among patients with non-obstructive coronary artery disease (NOCAD, luminal narrowing <60%), a type of ischemic heart disease, previously reported a significant association between depressive symptoms and increased inflammation (measured by high-sensitive (hs)CRP). Of the included NOCAD-patients, 6% had a history of cancer. The TWIST patient sample was therefore used to explore whether the association between depression and elevated inflammation (hsCRP) was similar for NOCAD-patients with and without a history of cancer. The association between depressive symptoms and increased hsCRP levels is stronger among NOCAD-patients with a history of cancer than among NOCAD-patients without a history of cancer. Furthermore, whereas this relation is mediated by lifestyle factors among NOCAD-patients without cancer, the association remained significant after adjusting for BMI, smoking, and physical activity among NOCAD-patients with a history of cancer. The stronger association between depression and hsCRP among NOCAD-patients with a history of cancer indicates that there may be an additive or synergistic effect of having NOCAD and cancer for general inflammation and possibly depression.


Multivariable analysis of anesthetic factors associated with time to extubation in dogs.
The purpose of this study was to identify factors that prolong the time to extubation in dogs. Anesthetic records of 900 dogs at a university teaching hospital were searched. Multiple linear regression was used to compare independent predictors (patient demographics, anesthetic and intraoperative variables) with the dependent variable (time to extubation). Induction with propofol (P < 0.025) was associated with a shorter time to extubation, while premedication with acepromazine (P = 0.000) was associated with a longer time to extubation. Time to extubation was increased by 0.311 minutes for every kilogram increase in body weight (P = 0.000), 5.924 minutes for every 1 °C loss in body temperature (P = 0.0000), and by 0.096 minutes for every 1 minute increase in anesthetic duration (P = 0.000). Anesthetic variables, which can be manipulated by the anesthetist, include choice of premedication and induction drugs, hypothermia, and duration of anesthesia.


Nonrenal Complications of Contrast Media.
Nonrenal complications of contrast media are caused by chemotoxic or anaphylactoid reactions related to the contrast agent used. Chemotoxicity is mainly attributed to ionic concentration and osmolality. Anaphylactoid reactions are typically caused by direct activation of basophils, mast cells, and complement rather than an observable antigen-antibody interaction, and may be acute or delayed. History of an adverse reaction following prior exposure is the strongest predictor of a subsequent adverse reaction to contrast. Premedication regimens of corticosteroids or antihistamines can lower the risk of repeat adverse reactions. Treatment of anaphylactoid reactions depends on the severity of symptoms.


The effect of a short term saturated fat diet on the apoprotein composition and radioiodination properties of rat very low density lipoproteins.
The effect of a saturated fat diet on the apoprotein composition and radioiodination properties of plasma very low density lipoprotein (VLDL) was studied in rats. After feeding the diet for 10 days, the proportion of 125I attached to VLDL lipid decreased from 50% (control animals) to 8%, the remainder (92%) being bound to the apoprotein components. The decreased lipid labelling was associated with proportional changes in the fatty acid composition of serum and VLDL lipids, the most notable change being a reduction in linoleic acid (30-8%) content which occurred in all the major lipid classes of both serum and VLDL. Analysis of VLDL after radioiodination showed that most of the radioactivity incorporated into the lipid moiety was associated with phospholipid. The proportion of 125I bound to phospholipid decreased after feeding rats a saturated diet. The proportion of soluble (small molecular weight peptides and arginine rich peptide) to insoluble (B apoprotein) did not alter during the saturated fatty acid dietary regime and no differences in the distribution of soluble proteins were observed. It is concluded that feeding a saturated fat diet to rats for 10 days significantly improved 125I labelling of the apoprotein moiety while apparently not inducing changes in apoprotein composition.


Nucleation process of the 2011 northern Nagano earthquake from nearby seismic observations.
The 2011 magnitude (M) 9.0 Tohoku-oki earthquake was followed by seismicity activation in inland areas throughout Japan. An outstanding case is the M6.2 Northern Nagano earthquake, central Japan, occurred 13-h after the megathrust event, approximately 400 km away from its epicenter. The physical processes relating the occurrence of megathrust earthquakes and subsequent activation of relatively large inland earthquakes are not well understood. Here we use waveform data of a dense local seismic network to reveal with an unprecedented resolution the complex mechanisms leading to the occurrence of the M6.2 earthquake. We show that previously undetected small earthquakes initiated along the Nagano earthquake source fault at relatively short times after the Tohoku-oki megathrust earthquake, and the local seismicity continued intermittently until the occurrence of the M6.2 event, being likely 'modulated' by the arrival of surface waves from large, remote aftershocks off-shore Tohoku. About 1-h before the Nagano earthquake, there was an acceleration of micro-seismicity migrating towards its hypocenter. Migration speeds indicate potential localized slow-slip, culminating with the occurrence of the large inland earthquake, with fluids playing a seismicity-activation role at a regional scale.


Thrombus formation and microaggregate removal during prolonged extracorporeal circulation using a capillary membrane oxygenator. A scanning electron microscope study.
Despite adequate heparinization, thrombus formation occurs at the blood/foreign material interface. Depending on the part of the device, the material and the blood flow, the amount and the components of thrombi vary greatly. This is not dangerous by itself but clots can be expelled downstream and damage the lungs, brain, kidney and retina. Interposition of a filter may prevent risks of embolization. The present paper reports the scanning electron microscope study carried out on the Awad oxygenator after use during prolonged extracorporeal circulation on 13 dogs. No filter has been inserted in the circuit for the first six experiments. A screen filter (4) or a polyurethane foam filter (3) was employed in the following ones.


A scoping review and comparison of approaches for measuring genetic heterogeneity in psychiatric disorders.
An improved understanding of genetic etiological heterogeneity in a psychiatric condition may help us (a) isolate a neurophysiological 'final common pathway' by identifying its upstream genetic origins and (b) facilitate characterization of the condition's phenotypic variation. This review aims to identify existing genetic heterogeneity measurements in the psychiatric literature and provides a conceptual review of their mechanisms, limitations, and assumptions. The Scopus database was searched for studies that quantified genetic heterogeneity or correlation of psychiatric phenotypes with human genetic data. Ninety studies were included. Eighty-seven reports quantified genetic correlation, five applied genomic structural equation modelling, three evaluated departure from the Hardy-Weinberg equilibrium at one or more loci, and two applied a novel approach known as MiXeR. We found no study that rigorously measured genetic etiological heterogeneity across a large number of markers. Developing such approaches may help better characterize the biological diversity of psychopathology.


Use of absorbable material for the closure of experimental longitudinal nephrotomy.
Large nephrotomy incisions made in 15 dogs were closed by sewing up the cavity system with stitches of 5/0 catgut and by sealing the renal parenchyma with tissue adhesive being pinpointed at the opened vessels. The incision was covered with a preparation of oxidized cellulose which was then likewise impregnated with tissue adhesive. This technique was found rapid and convenient and provided for adequate haemostasis. Its essential advantage lies in eliminating the deep through-and-through sutures involving a major loss of functioning renal parenchyma. All substances used were absorbed in due time.


On the calculation of electrostatic interactions in proteins.
In this paper we present a classical treatment of electrostatic interactions in proteins. The protein is treated as a region of low dielectric constant with spherical charges embedded within it, surrounded by an aqueous solvent of high dielectric constant, which may contain a simple electrolyte. The complete analysis includes the effects of solvent screening, polarization forces, and self energies, which are related to solvation energies. Formulae, and sample calculations of forces and energies, are given for the special case of a spherical protein. Our analysis and model calculations point out that any consistent treatment of electrostatic interactions in proteins should account for the following. Solvent polarization is an important factor in the calculation of pairwise electrostatic interactions. Solvent polarization substantially affects both electrostatic energies and forces acting upon charges. No simple expression for the effective dielectric constant, Deff, can generally be valid, since Deff is a sensitive function of position. Solvent screening of pairwise interactions involving dipolar groups is less effective than the screening of charges. In fact for many interactions involving dipoles, solvent screening can be essentially ignored. The self energy of charges makes a large contribution to the total electrostatic energy of a protein. This must be compensated by specific interactions with other groups in the protein. Strategies for applying our analysis to proteins whose structures are known are discussed.


The influence of sensory experience on the glutamatergic synapse.
The ability of glutamatergic synaptic strength to change in response to prevailing neuronal activity is believed to underlie the capacity of animals, including humans, to learn from experience. This learning better equips animals to safely navigate challenging and potentially harmful environments, while reinforcing behaviours that are conducive to survival. Early descriptions of the influence of experience on behaviour were provided by Donald Hebb who showed that an enriched environment improved performance of rats in a variety of behavioural tasks, challenging the widely-held view at the time that psychological development and intelligence were largely predetermined through genetic inheritance. Subsequent studies in a variety of species provided detailed cellular and molecular insights into the neurobiological adaptations associated with enrichment and its counterparts, isolation and deprivation. Here we review those experience-dependent changes that occur at the glutamatergic synapse, and which likely underlie the enhanced cognition associated with enrichment. We focus on the importance of signalling initiated by the release of BDNF and a prime downstream effector, MSK1, in orchestrating the many structural and functional neuronal adaptations associated with enrichment. In particular we discuss the MSK1-dependent expansion of the dynamic range of the glutamatergic synapse, which may allow enhanced information storage or processing, and the establishment of a genomic homeostasis that may both stabilise the enriched brain, and may make it better able to respond to novel experiences.


Nerve growth factor receptor from rabbit sympathetic ganglia membranes. Relationship between subforms.
The receptor for nerve growth factor (NGF) was purified from Triton X-100 extracts of sympathetic ganglia membranes by affinity chromatography on NGF-Sepharose. Elution of purified receptor was accomplished at pH 5 in the presence of 1 M NaCl. Sodium dodecyl sulfate gel electrophoresis of the purified iodinated receptor showed three major bands at Mr = 126,000, Mr = 105,000, and Mr = 81,000. Affinity labeling of the purified receptor using 125I-NGF and the photoreactive agent N-hydroxysuccinimidyl-p-azidobenzoate resulted in two major cross-linked complexes corresponding to Mr = 135,000 and Mr = 110,000. This labeling pattern is similar to that observed with sympathetic ganglia membranes (Massague, J., Guillette, B. J., Czech, M. P., Morgan, C. J., and Bradshaw, R. A. (1981) J. Biol. Chem. 256, 9419-9424) and indicates that these two forms do not arise from the cross-linking procedure. Reaction of the photoaffinity labeled NGF receptors with increasing amounts of trypsin resulted in a progressive decrease in the high molecular weight complex with a concomitant increase in the low molecular weight form. When the larger complex was isolated by electroelution from a sodium dodecyl sulfate gel and treated with trypsin, a species corresponding to Mr = 100,000 was generated. These observations are best explained by a precursor-product relationship for the two NGF receptor species of sympathetic neurons.


Assessment of intracellular magnesium depletion in rat striated muscle by in vivo 31P NMR.
Previous in vivo studies have demonstrated that alpha, beta, and gamma ATP chemical shifts measured by 31P NMR spectroscopy can be used to determine intracellular magnesium in erythrocytes, but up to now such results have not been confirmed in striated muscle in vivo. We report beta ATP chemical-shift in vivo measurements revealing the depletion of free intracellular magnesium in striated muscle of rats fed a magnesium deficient diet.


Holodiastolic reversal flow in the common carotid: another indicator of the severity of aortic regurgitation.
Aortic regurgitation (AR) causes an increased diastolic reverse flow at various levels of aorta and its branching vessels. A prospective study was designed to evaluate the feasibility and accuracy of duplex sonography of the common carotid artery (CCA) in patients with various degrees of AR quantified by cardiac angiography. Twenty-four patients, with pure angiographic AR, of mean age 63.5 + 2.5-year old were included. Holodiastolic reverse flow (HRF) was recorded in all seven patients with severe angiographic AR (five with grade III and two with grade IV) and in none of the seventeen patients (eight with grade I and nine with grade II) with mild angiographic AR (p < 0.001). Furthermore, HRF was recorded both in the CCA and in the aorta, where it represents another criterion of severe AR, of six patients with severe angiographic AR and was absent in the eleven patients with grade I or II AR (p < 0.001). Demonstration of HRF in the CCA may be a very helpful criterion in distinguishing patients with severe AR.


Correction to: Population genetic structure and demography of Magnolia kobus: variety borealis is not supported genetically.
The original article was updated.


Effects of a Whole-School Health Intervention on Clustered Adolescent Health Risks: Latent Transition Analysis of Data from the INCLUSIVE Trial.
Whole-school interventions are a promising approach to preventing bullying and aggression while promoting broader health. The main analyses from a trial of the INCLUSIVE whole-school intervention reported reductions in bullying victimisation but not aggression and improved mental well-being. Latent transition analysis can examine how interventions 'move' people between classes defined by multiple outcomes over time. We examined at baseline what classes best defined individuals' bullying, aggression and mental well-being and what effects did the intervention have on movement between classes over time? INCLUSIVE was a two-arm cluster-randomised trial with 20 high schools per arm, with 24-month and 36-month follow-ups. We estimated sequential latent class solutions on baseline data. We then estimated a latent transition model including baseline, 24-month and 36-month follow-up measurements. Our sample comprised 8179 students (4082 control, 4097 intervention arms). At baseline, classes were (1) bullying victims, (2) aggression perpetrators, (3) extreme perpetrators and (4) neither victims nor perpetrators. Control students who were extreme perpetrators were equally likely to stay in this class (27.0% probability) or move to aggression perpetrators (25.0% probability) at 24 months. In the intervention group, fewer extreme perpetrators students remained (5.4%), with more moving to aggression perpetrators (65.1%). More control than intervention extreme perpetrators moved to neither victims nor perpetrators (35.2% vs 17.8%). Between 24 and 36 months, more intervention students moved from aggression perpetrators to neither victims nor perpetrators than controls (30.1% vs 22.3%). Our findings suggest that the intervention had important effects in transitioning students to lower-risk classes.


[Acupuncture in headache therapy].
Acupuncture is now being increasingly used in the treatment of headache. Acupuncture is a technique originating in Asia, from countries that have a cultural background with a fundamentally different concept of disease and therapy. Up to now, sustained application of acupuncture in Western medicine has been impeded by the lack of a scientifically convincing explanation of the mechanisms of action in terms of neurobiological criteria. Acupuncture is being used empirically in the treatment of migraine; clinical studies have been published. A definitive evaluation of acupuncture based on well-founded clinical experimental studies has yet to be made. The investigation was carried out in migraine patients who were divided into two subgroups in a control group design with two different stimulation techniques. The verum group was treated with the correct point location, normal prick depth and elicitation of a needle sensation. The control group received treatment at points that are far away from the acupuncture points, using a superficial prick technique and without eliciting a needle sensation. The effect of therapy was appraised by means of headache diaries with subsequent interference statistical and individual case analysis. In the present study comprising 81 patients, the incidence of the attacks was significantly reduced in both subgroups. The effect of acupuncture treatment was of comparable magnitude to that of the beta-blocker metoprolol. The advantage of acupuncture treatment consists in the lack of side effects such as gastrointestinal symptoms or an increase in weight. A minor side effect was only reported in one case. In the data analysis with the interference statistical method, verum acupuncture was superior to the control in only one subgroup. The possibility that the addition of further points (distant points) can explain this effect on the basis of the hypothesis of a central modulation of the migraine process is discussed. Acupuncture shows a sufficiently pronounced and sustained therapeutic effect for its use to be considered in a possible interval treatment of migraine.


CMA down-regulates p53 expression through degradation of HMGB1 protein to inhibit irradiation-triggered apoptosis in hepatocellular carcinoma.
To investigate the mechanism of chaperone-mediated autophagy (CMA)-induced resistance to irradiation-triggered apoptosis through regulation of the p53 protein in hepatocellular carcinoma (HCC). Firstly, we detected expression of lysosome-associated membrane protein 2a (Lamp-2a), which is the key protein of CMA, by western blot in HepG2 and SMMC7721 cells after irradiation. We further used shRNA Lamp-2a HCC cells to verify the radioresistance induced by CMA. Next, we detected the HMGB1 and p53 expression after irradiation by western blot, and we further used RNA interference and ethyl pyruvate (EP), as a HMGB1 inhibitor, to observe changes of p53 expression. Finally, an immunoprecipitation assay was conducted to explore the interaction between Lamp-2a and HMGB1, and the data were analyzed. We found the expression of Lamp-2a was increased on irradiation while apoptosis decreased in HepG2 and SMMC7721 cells. The apoptosis was increased markedly in the shRNA Lamp-2a HepG2 and SMMC7721 cells as detected by western blot and colony formation assay. Next, we found p53 expression was gradually reduced on irradiation but obviously increased in shRNA Lamp-2a cells. Furthermore, p53 increased the cell apoptosis on irradiation in Hep3B (p53-/-) cells. Finally, p53 levels were regulated by HMGB1 as measured through RNA interference and the EP treatment. HMGB1 was able to combine with Lamp-2a as seen by immunoprecipitation assay and was degraded via the CMA pathway. The decreased HMGB1 inhibited p53 expression induced by irradiation and further reduced the apoptosis in HCC cells. CMA pathway activation appears to down-regulate the susceptibility of HCC to irradiation by degrading HMGB1 with further impact on p53 expression. These findings have clinical relevance for radiotherapy of HCC.


The path to the clinic: a comprehensive review on direct KRASG12C inhibitors.
The RAS oncogene is both the most frequently mutated oncogene in human cancer and the first confirmed human oncogene to be discovered in 1982. After decades of research, in 2013, the Shokat lab achieved a seminal breakthrough by showing that the activated KRAS isozyme caused by the G12C mutation in the KRAS gene can be directly inhibited via a newly unearthed switch II pocket. Building upon this groundbreaking discovery, sotorasib (AMG510) obtained approval by the United States Food and Drug Administration in 2021 to become the first therapy to directly target the KRAS oncoprotein in any KRAS-mutant cancers, particularly those harboring the KRASG12C mutation. Adagrasib (MRTX849) and other direct KRASG12C inhibitors are currently being investigated in multiple clinical trials. In this review, we delve into the path leading to the development of this novel KRAS inhibitor, starting with the discovery, structure, and function of the RAS family of oncoproteins. We then examine the clinical relevance of KRAS, especially the KRASG12C mutation in human cancer, by providing an in-depth analysis of its cancer epidemiology. Finally, we review the preclinical evidence that supported the initial development of the direct KRASG12C inhibitors and summarize the ongoing clinical trials of all direct KRASG12C inhibitors.


What's happening where when SARS-CoV-2 infects: are TLR7 and MAFB sufficient to explain patient vulnerability?
The present COVID-19 pandemic has revealed that several characteristics render patients especially prone to developing severe COVID-19 disease, i.e., the male sex, obesity, and old age. An explanation for the observed pattern of vulnerability has been proposed which is based on the concept of low sensitivity of the TLR7-signaling pathway at the time of infection as a common denominator of vulnerable patient groups.We will discuss whether the concept of established TLR-tolerance in macrophages and dendritic cells of the obese and elderly prior to infection can explain not only the vulnerability of these two demographic groups towards development of a severe infection with SARS-CoV-2, but also the observed cytokine response in these vulnerable patients, which is skewed towards pro-inflammatory cytokines with a missing interferon signature.


Nrf2-Mediated Expansion of Pilosebaceous Cells Accelerates Cutaneous Wound Healing.
The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) transcription factor is a key regulator of the cellular stress response. Therefore, pharmacologic Nrf2 activation is a promising strategy for skin protection and cancer prevention. This study found that genetic Nrf2 activation in keratinocytes accelerates wound repair. Enhanced proliferation of cells of the pilosebaceous unit peripheral to the wound and a concomitant acceleration of re-epithelialization were identified as the underlying mechanism. Nrf2 specifically promoted the expansion of pilosebaceous cells expressing markers of junctional zone and upper isthmus follicular stem cells. This may result, at least in part, from the up-regulation of the direct Nrf2 target epigen and a concomitant increase in epidermal growth factor receptor signaling. The increase in pilosebaceous cells provided a larger pool of keratinocytes that migrate into the wound, resulting in faster wound closure. These results unravel a novel function of Nrf2 in wound repair and suggest the use of NRF2-activating compounds in patients with impaired healing.