8-Chloro-cAMP inhibits transforming growth factor alpha transformation of mammary epithelial cells by restoration of the normal mRNA patterns for cAMP-dependent protein kinase regulatory subunit isoforms which show disruption upon transformation.
Differential regulation of the regulatory subunits of cAMP-dependent protein kinase isozymes correlates with the growth inhibitory effect of site-selective 8-Cl-cAMP demonstrated in cancer cell lines (Ally, S., Tortora, G., Clair, T., Grieco, D., Merlo, G., Katsaros, D., Ogreid, D., Døskeland, S.O., Jahnsen, T., and Cho-Chung, Y.S. (1988) Proc. Natl. Acad. Sci. U. S. A. 85, 6319-6322). Such selective modulation of protein kinase isozyme regulatory subunits was also found in the 8-Cl-cAMP-induced inhibition of both transformation and transforming growth factor alpha (TGF alpha) production in Ki-ras-transformed rat kidney fibroblasts (Tortora, G., Ciardiello, F., Ally, S., Clair, T., Salomon, D. S., and Cho-Chung, Y. S. (1989) FEBS Lett. 242, 363-367). In this work, we have demonstrated that 8-Cl-cAMP antagonizes the TGF alpha effect in TGF alpha-transformed mouse mammary epithelial cells (NOG-8TFC17) at the level of gene expression for cAMP receptor protein isoforms, RI and RII (the regulatory subunits of protein kinase isozymes). Northern blot analysis demonstrated that in the transformed NOG-8TFC17 cells, compared with the nontransformed counterpart NOG-8 cells, the mRNA levels for the RI alpha cAMP receptor protein markedly increased, whereas the mRNA levels for the RII alpha and RII beta cAMP receptor proteins decreased. 8-Cl-cAMP, which induced growth inhibition and phenotypic reversion in NOG-8TFC17 cells, caused an inverse change in the mRNA patterns of the cAMP receptor proteins; RI alpha cAMP receptor mRNA sharply decreased to levels comparable with that of the nontransformed NOG-8 cells, whereas RII beta mRNA increased to a level even greater than that in the NOG-8 cells. In addition, one mRNA species of RII alpha increased, whereas the other RII alpha mRNA species decreased during the treatment. The mRNA level for the catalytic subunit of protein kinase, however, did not change during 8-Cl-cAMP treatment. In addition, 8-Cl-cAMP brought about a reduction in both TGF alpha mRNA and protein levels. These coordinated changes in the expression of the cAMP receptor proteins and TGF alpha were not observed during cis-hydroxyprolineor TGF beta-induced growth inhibition of the NOG-8TFC17 cells. Thus, the antagonistic effect of 8-Cl-cAMP toward TGF alpha-induced transformation involves modulation of the expression of a specific set of cellular genes.


Intravenous clonidine as a part of balanced anaesthesia for controlled hypotension in functional endoscopic sinus surgery: A randomised controled trial.
Controlled hypotension with balanced anaesthesia minimises blood loss. This study was done to evaluate the effectiveness of intravenous clonidine as a single bolus dose to establish controlled hypotension during functional endoscopic sinus surgery (FESS). This randomised, double-blind, placebo-controlled study was done in a tertiary hospital in India. Sixty American Society of Anesthesiologists physical status I and II patients (18-65 years) undergoing FESS were randomly allocated to one of the two groups. Placebo group (group A, n = 30) received sterile water whereas the clonidine group (group B, n = 30) received 3μg/kg of clonidine intravenously, 30 min prior to induction of anaesthesia. The primary outcome was to achieve a target mean arterial blood pressure (MAP) of 55-65 mmHg intraoperatively. The secondary outcomes measured were requirement of additional fentanyl and metoprolol, intra-operative blood loss, surgeon's opinion on the surgical field, pain, sedation score and complications requiring treatment. Target MAP was easily achieved in clonidine group as against the placebo group (P < 0.001). Significant reduction in intra-operative blood loss (P = 0.0449), a better surgical site scoring (P = 0.02), less requirement of additional hypotensive drugs and good analgesia (P = 0.01) were seen in clonidine group. The complication rates were similar in both the groups. Clonidine is effective in achieving controlled hypotension in patients undergoing FESS. It reduces intra-operative blood loss, requirement of additional hypotensive drugs, improves the surgical field and offers good analgesia without significant side effects.


Targeted therapy for orbital and periocular basal cell carcinoma and squamous cell carcinoma.
To review the literature on targeted therapy for orbital and periocular basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (SCC) and provide examples of patients recently treated with such therapy. The authors reviewed the literature on clinical results of targeted therapy and the molecular basis for targeted therapy in orbital and periocular BCC and cutaneous SCC. The authors also present representative cases from their practice. Mutation in the patched 1 gene (PTCH1) has been implicated in BCC, and overexpression of epidermal growth factor receptor (EGFR) has been shown in SCC. Vismodegib, an inhibitor of smoothened, which is activated upon binding of hedgehog to Ptc, has been shown to significantly decrease BCC tumor size or even produce complete resolution, especially in cases of basal cell nevus syndrome. Similarly, EGFR inhibitors have been shown to significantly decrease SCC tumor size in cases of locally advanced and metastatic disease. The authors describe successful outcomes after vismodegib treatment in a patient with basal cell nevus syndrome with numerous bulky lesions of the eyelid and periocular region and erlotinib (EGFR inhibitor) treatment in a patient with SCC who was deemed not to be a good surgical candidate because of advanced SCC of the orbit with metastasis to the regional lymph nodes, advanced age, and multiple medical comorbidities. Targeted therapy using hedgehog pathway and EGFR inhibitors shows significant promise in treatment of orbital and periocular BCC and cutaneous SCC, respectively. Such targeted therapy may be appropriate for patients who are not good candidates for surgery.


Measurement of xylem translocation of weak electrolytes with the pressure chamber technique.
Xylem translocation and root uptake of weak electrolytes were investigated with the pressure chamber technique (PCT) using de-topped soybean plants. Two compounds were organic bases (fenpropimorph and imazalil) and four were organic acids (bentazone, primisulfuron-methyl, rimsulfuron and triasulfuron). The compounds covered a wide range of log KOW and pKa values. Concentrations in external solution and in xylem sap were measured by HPLC at pH values in external solution of 4.5, 6.5 and 8.5. For weak bases, translocation was higher at low pH and the transpiration stream concentration factors (TSCF) were in the range 0.31-0.95. At pH 8.5, the concentrations in leaking xylem sap were very low for fenpropimorph, and steady-state was probably not reached. For weak acids, TSCF values derived with external pH from 4.5 to 8.5 were in the range 0.55-1.50 for primisulfuron-methyl, 0.64-1.35 for rimsulfuron, 0.81-0.93 for triasulfuron and 0.69-0.92 for bentazone. The variation of TSCF of the weak electrolytes was much smaller in these PCT experiments than in recent experiments with intact plants. The likely reason is that de-topped soybean plants in the pressure chamber seemed to be unable to regulate their xylem sap pH, which was almost identical to the pH in external solution. Without pH differences, the ion-trap process, which is responsible for accumulation or exclusion of weak acids and bases in the xylem of living plants, does not take place. Model simulations carried out for intact and de-topped plants supported this hypothesis. By variation of the pH of the xylem sap, good agreement between measurements and simulations could be achieved.


Diet-induced expansion of pathobionts in experimental colitis: implications for tailored therapies.
Evidence presented in our recent study and elsewhere suggests that the interplay of dietary macronutrients with the intestinal lumen alters the microbial environment, and thus host-microbe interactions, in ways that are not always in a favorable, mutualistic fashion. Specifically, in inflammatory bowel diseases (IBD), experimental and clinical observations have implicated a detrimental impact of environmental/microbial factors on the etiopathogenesis of IBD in individuals with a background of genetic susceptibility to the disease. Thus, now more than ever, we are realizing that specific intestinal microbes can metabolize and react to a wide array of dietary compositions that, in turn, markedly alter microbial populations. We aimed to understand if certain dietary fats that are prevalent in Western diets are capable of precipitating colonic inflammation through their actions on the enteric microbiota. On a background of genetic susceptibility, these microbial changes can impact host immune homeostasis and increase risk for disease. Here we elaborate on our findings and their potential implications for future medical care.


Diameter-Dependent photocurrent in InAsSb nanowire infrared photodetectors.
Photoconductors using vertical arrays of InAs/InAs(1-x)Sb(x) nanowires with varying Sb composition x have been fabricated and characterized. The spectrally resolved photocurrents are strongly diameter dependent with peaks, which are red-shifted with diameter, appearing for thicker wires. Results from numerical simulations are in good agreement with the experimental data and reveal that the peaks are due to resonant modes that enhance the coupling of light into the wires. Through proper selection of wire diameter, the absorptance can be increased by more than 1 order of magnitude at a specific wavelength compared to a thin planar film with the same amount of material. A maximum 20% cutoff wavelength of 5.7 μm is obtained at 5 K for a wire diameter of 717 nm at a Sb content of x = 0.62, but simulations predict that detection at longer wavelengths can be achieved by increasing the diameter. Furthermore, photodetection in InAsSb nanowire arrays integrated on Si substrates is also demonstrated.


[Magnetic resonance imaging of mesenchymal stem cells transplanted intravascularly in treatment of acute renal failure:in vivo experiment with rats].
To evaluate the efficacy of in vivo magnetic resonance imaging (MRI) of mesenchymal stem cells (MSCs) injected intravascularly in treatment of acute renal failure (ARF) , and to investigate the changes of renal function and pathology of ARF after MSC transplantation. Rat MSCs were isolated and labeled with Fe2O3-PLL in vitro. Thirty SD rats underwent intramuscular injection of glycerol so as to establish ARF models and then randomly divided into 3 equal groups: Group I undergoing injection of labeled MSCs into abdominal aorta via transcatheter, Group II injected with unlabelled MSCs, and Group III injected with normal saline as controls. MRI of kidney was conducted before injection, and 0.5 h, and 1, 2, and 5 days after injection. One and 2 days after the transplantation 3 rats from each group underwent MRI and extraction of blood samples from the abdominal aorta and then killed with their kidneys taken out, and 5 days after the rest rats were all killed after MRI with their kidneys taken out. Serum creatinine (Scr) and blood urea nitrogen (BUN) were examined so as to evaluate the renal function. Microscopy was conducted to observe the pathological changes. Prussian blue + CD68 antibody staining was performed to identify the labeled MSCs. MRI showed decrease of signal intensity in renal cortex on the T2 *-weighted MR images up to 5 days after transplantation. Histological analysis showed that most Prussian blue-positive cells were in the glomerular capillaries, corresponding to the areas where signal intensity decrease was observed by MRI. The Scr and BUN levels 2 and 5 days after the implantation of Group I were both lower than those of the control group, and there were not significant differences in the Scr and BUN levels between Groups I and II. Renal tubular injury scoring showed that the renal tubular injury was significantly lighter than that of the control group. 1.5-T MRI seems a good in vivo technique to monitor the magnetically labeled MSCs administered into the abdominal aorta of ARF animals, which are distributed in the glomerular capillaries in the early stage after transplantation. MSCs may promote the recovery of ARF.


Anxiety and depression in burn patients.
The psychological aspects of burn injury have been researched in different parts of world producing different outcomes. Therefore objective of this research is to determine the frequency of Anxiety and Depression in burn patients. To assess the socio-demographic distribution of patients developing Anxiety and Depression and to determine the effects of burn related factors on development of Anxiety and Depression. A Case series was conducted at the Department of Burn, Pakistan Ordinance Factory Hospital, Wah Cantt. for a duration of 12 months commencing from June 2007 and concluded in May 2008. The study population comprised of hospitalized patients with 1% to 50%, selected through non probable sampling technique who were assessed for Anxiety and Depression on fifteen day after burn injury. Testing protocol comprised of questionnaire having socio-demographic variables and burn related variables. Beck Depression Inventory and Beck Anxiety Inventory was applied to evaluate Anxiety and Depression in Burn patients. Descriptive statistics like mean with Standard Deviation was calculated for age. Frequencies along with percentages were calculated for socio-demographic variables. The frequencies and proportions were also calculated for presence and extent of severity of depression and anxiety in burn patients. Fifty patients were included in the study, thirty patients (60%) were male and 20 (40%) were females. The mean age of participants was 33.64 +/- 19 years. Majority of participants, 38 (76%) had sustained burn injury up to 25%. Flame was found to be most common agent of burn injuries affecting 19 (38%) patients. Depression was seen amongst 29 (58%) patients. Thirteen (26 %) patients had mild, 7 (14%) had moderate and 9 (18%) had severe Depressive symptoms. Anxiety was seen among 41 (82%) patients, thirteen (26%) patients had mild, 11 (22%) had moderate and 17 (34%) had severe Anxiety symptoms. Anxiety was present in 41 (82%) and Depression was present in 29 (58%) patients following burn injury. This study highlights the importance of the simultaneous evaluation and management of Anxiety and Depression in burn injured patients.


Impact of BMI on exacerbation and medical care expenses in subjects with mild to moderate airflow obstruction.
The rate of obesity is increasing in Asia, but the clinical impact of body mass index (BMI) on the outcome of chronic obstructive pulmonary disease (COPD) remains unknown. We aimed to assess this impact while focusing on the risk of exacerbation, health-care utilization, and medical costs. We examined 43,864 subjects registered in the Korean National Health and Nutrition Examination Survey (KNHANES) database from 2007 to 2012, and linked the data of COPD patients who had mild to moderate airflow obstruction (n = 1,320) to National Health Insurance (NHI) data. COPD was confirmed by spirometry. BMI was used to stratify patients into four categories: underweight (BMI <18.5 kg/m2), normal range (18.5-22.9 kg/m2), overweight (23-24.9 kg/m2), and obese (≥25 kg/m2). Of the 1,320 patients with COPD with mild to moderate airflow obstruction, 27.8% had a BMI ≥25 kg/m2. Compared with normal-weight patients, obese patients tended to experience fewer exacerbations (incidence rate ratio [IRR] 0.88; 95% CI 0.77-0.99; P = 0.04), although this association was not significant in a multivariable analysis. COPD-related health-care utilization and medical expenses were higher among underweight patients than the other groups. After adjustment, the risk of COPD-related hospitalization was highest among underweight and higher among overweight patients vs normal-weight patients (adjusted IRRs: 7.12, 1.00, 1.26, and 1.02 for underweight, normal, overweight, and obese groups, respectively; P = 0.01). Decreased weight tends to negatively influence prognosis of COPD with mild to moderate airflow obstruction, whereas higher BMI was not significantly related to worse outcomes.


Commentary: What's in a word (or words) - on the relations among self-regulation, self-control, executive functioning, effortful control, cognitive control, impulsivity, risk-taking, and inhibition for developmental psychopathology - reflections on Nigg (2017).
In Nigg's excellent article, he deals with a variety of complex conceptual issues related to the constructs of self-regulation and executive functioning (EF). Overall, I agree that the terminology proposed by Nigg should be adopted; moreover, the conceptual distinctions he provides should help the field to move forward with regard to the understanding of varied constructs related to self-regulation. In the spirit of further clarification, I questioned Nigg's suggestions that (a) working memory should be considered as part of the construct of top-down regulation and (b) planning is a higher level component of EF but not part of effortful control. In addition, I discussed my perspective on the role of automaticity in defining top-down versus bottom-up self-regulatory processes and the role of flexibility in top-down self-regulatory processes and their relation to personality resiliency.


Pre-surgical assessment of mandibular bone invasion from oral cancer: comparison between different imaging techniques and relevance of radiologist expertise.
To compare diagnostic performance between computed tomography (CT) and magnetic resonance imaging (MRI) for the detection of bone infiltration from oral cancer, and to test interobserver agreement between radiologists with different expertises. Pre-surgical CT and MRI were reviewed independently by two radiologists with different expertises in head and neck oncology. A third radiologist reviewed CT and MRI simultaneously. Interobserver agreement was calculated by Cohen test. Association between radiological evidence of bone infiltration and histological reference was tested by Fisher's exact test or Chi-squared test, as appropriate. Receiving operator curve was calculated and area under the curve (AUC) was compared between CT, MRI, and both methods together. Interobserver agreement was moderate: the trainee under-reported periosteal reaction on CT and inferior alveolar canal involvement on MRI. Imaging findings associated with histologic evidence of bone infiltration were: periosteal reaction and cortical erosion on CT; bone marrow involvement, contrast enhancement within bone; and inferior alveolar canal involvement on MRI. Sensitivity of MRI alone (74 %) was higher than CT (52 %). Simultaneous review of CT and MRI showed the highest specificity (91 %), with the increase of diagnostic performance in the subgroup of subjects with positive MRI (AUC = 0.689; p = 0.044). Higher expertise allows pre-surgical detection of clinically relevant signs of bone infiltration sensitivity of MRI alone is higher than CT for the detection of bone infiltration from oral cancer. In MRI positive cases, diagnostic integration with combined review of CT and MRI is suggested for optimal diagnostic performance.


Morphological variation of Aphidius ervi Haliday (Hymenoptera: Braconidae) associated with different aphid hosts.
Parasitoids are frequently used in biological control due to the fact that they are considered host specific and highly efficient at attacking their hosts. As they spend a significant part of their life cycle within their hosts, feeding habits and life history of their host can promote specialization via host-race formation (sequential radiation). The specialized host races from different hosts can vary morphologically, behaviorally and genetically. However, these variations are sometimes inconspicuous and require more powerful tools in order to detect variation such as geometric morphometrics analysis. We examined Aphidius ervi, an important introduced biological control agent in Chile associated with a great number of aphid species, which are exploiting different plant hosts and habitats. Several combinations (biotypes) of parasitoids with various aphid/host plant combinations were analyzed in order to obtain measures of forewing shape and size. To show the differences among defined biotypes, we chose 13 specific landmarks on each individual parasitoid wing. The analysis of allometric variation calculated in wing shape and size over centroid size (CS), revealed the allometric changes among biotypes collected from different hosts. To show all differences in shape of forewings, we made seven biotype pairs using an outline-based geometric morphometrics comparison. The biotype A. pis_pea (Acyrthosiphon pisum on pea) was the extreme wing size in this study compared to the other analyzed biotypes. Aphid hosts have a significant influence in the morphological differentiation of the parasitoid forewing, splitting biotypes in two groups. The first group consisted of biotypes connected with Acyrthosiphon pisum on legumes, while the second group is composed of biotypes connected with aphids attacking cereals, with the exception of the R. pad_wheat (Rhopalosiphum padi on wheat) biotype. There was no significant effect of plant species on parasitoid wing size and shape. Although previous studies have suggested that the genotype of parasitoids is of greater significance for the morphological variations of size and shape of wings, this study indicates that the aphid host on which A. ervi develops is the main factor to alter the structure of parasitoid forewings. Bigger aphid hosts implied longer and broader forewings of A. ervi.


Effect of low level laser therapy on orthodontic tooth movement: a review article.
Increased duration of fixed orthodontic treatments leads to increased tooth root degeneration, gum inflammation and tooth caries. To decrease the time period of orthodontic treatment, it is essential to facilitate tooth movement or in other words increase the speed of bone remodeling. Use of low level laser therapy is a method for achieving this goal.


Developing examinations that use equal raw scores for cut scores.
This study describes and demonstrates a set of processes for developing new forms of examinations which are intended to have equivalent cut scores in the raw score metric. This approach goes beyond the traditional Rasch-based approach which develops forms with cut scores that are equated in the logit metric. The methods described in this study can be used to create multiple forms of an assessment, all of which have the same raw score cut score (i.e., the number correct required to pass each examination form represents the same amount of the underlying construct). This paper provides an overview of equating standards, the research related specifically to pre-equating procedures, and three guidelines which can be used to achieve equal raw score cut scores. Three examples of how to use the guidelines as part of an iterative form-development process are provided using simulated data sets.


Polyneuropathy and myopathy in the elderly.
Critical illness polyneuropathy and myopathy is associated with intensive care unit therapies; it is an independent predictor of mortality and will be increasingly affecting the practice of critical care. Most patients with this illness are over 50 years of age, and as our population demographics shift in favor of an aging population, physicians must be aware that this malady will have a rising incidence in the perioperative period. Intensivists, anesthesiologists, surgeons, and geriatricians/internists must remain vigilant. Here we present a concise overview of critical illness polyneuropathy and myopathy, its diagnosis, associations, and possible interventions.


Prevalence and adverse consequences of delayed diagnosis and misdiagnosis in thrombotic antiphospholipid syndrome. An observational cohort study and a review of the literature.
This study aims to prospectively evaluate the frequency and adverse consequences of diagnostic delay and misdiagnosis in a cohort of patients with thrombotic antiphospholipid syndrome (TAPS). In addition, a systematic review of the literature concerning the diagnostic delay and misdiagnosis of TAPS was carried out. Patient enrollment occurred between 1999 and 2022. The study group was formed by TAPS patients whose diagnosis was delayed and those who were misdiagnosed. The control group was made up of patients who were timely and correctly diagnosed with TAPS. The literature review showed 42 misdiagnosed patients, 27 of them were in one retrospective cohort study and 15 in 13 case reports. One hundred sixty-one out of 189 patients (85.2%) received a timely, correct diagnosis of TAPS; 28 (14.8%) did not. The number of patients with diagnostic issues was significantly higher for the first period (1999-2010), and the number of patients with a correct diagnosis was significantly higher for the second one (2011-2022). When the clinical and laboratory characteristics of the patients with delayed diagnosis were compared with those with misdiagnosis, there was a significantly higher number of severe adverse consequences characterized by permanent disability or death in the latter group. The two most common types of misdiagnoses were systemic lupus erythematosus (6 cases, 46.1%) and cardiovascular diseases (4 cases, 30.8%). The study demonstrates that although knowledge about TAPS has improved over time, diagnostic delays and errors remains to be addressed as they are strongly associated to adverse consequences. Key Points •Although knowledge of thrombotic antiphospholipid syndrome has improved over time, it is still limited. •Diagnostic delay and misdiagnosis are still an important issue that remains to be addressed as they are strongly associated to adverse consequences. •The three more frequent misdiagnoses are multiple sclerosis, systemic lupus erythematosus and cardiovascular diseases.


[Study on antidepressant effect of total alkaloids of Fibraurea recisa].
This study aimed to investigate the antidepressant effects of total alkaloids of Fibraurea recisa in HT22 cells damaged by corticosterone (CORT) in vitro and in a mouse model of chronic unpredictable mild stress (CUMS) as well as the underlying mechanisms.In cellular experiments,the viability of CORT-damaged HT22 cells was detected using cell counting kit-8 (CCK-8),and the cell apoptosis was detected by Hoechst 33258 staining.In animal experiments,C57BL/6N mice were randomly divided into the control group,model group,low (100 mg·kg~(-1)),medium (200 mg·kg~(-1)) and high (400 mg·kg~(-1))-dose of total alkaloids of F.recisa groups,and positive control group.After 21 days of CUMS exposure,their depressive behaviors were observed in behavioral and Morris water maze tests.The serum levels of 5-hydroxytryptamine (5-HT),dopamine (DA),and norepinephrine (NE) were assessed by ELISA.The expression levels of apoptosis-related proteins Bcl-2,Bax and cleaved caspase-3 in HT22 cells and mouse hippocampus were detected by Western blot.The results suggested that total alkaloids of F.recisa alleviated the damage of HT22 cells induced by CORT in a dose-dependent manner.The Hoechst 33258 staining uncovered that total alkaloids of F.recisa better reduced the blue spots and inhibited cell apoptosis.The results of animal experiments showed that total alkaloids of F.recisa significantly improved the depression-like behaviors of mice and increased the serum levels of 5-HT,DA and NE as compared with those in the model group.The Western blot assays revealed a significant up-regulation of Bcl-2 protein expression,but an obvious reduction in Bax and cleaved caspase-3protein expression in the total alkaloids of F.recisa group.In conclusion,total alkaloids of F.recisa inhibited depression possibly by regulating the apoptosis-related protein expression or elevating the monoamine neurotransmitter levels in the brain.


Induction of cortical endoplasmic reticulum by dimerization of a coatomer-binding peptide anchored to endoplasmic reticulum membranes.
Cortical endoplasmic reticulum (cER) is a permanent feature of yeast cells but occurs transiently in most animal cell types. Ist2p is a transmembrane protein that permanently localizes to the cER in yeast. When Ist2 is expressed in mammalian cells, it induces abundant cER containing Ist2. Ist2 cytoplasmic C-terminal peptide is necessary and sufficient to induce cER. This peptide sequence resembles classic coat protein complex I (COPI) coatomer protein-binding KKXX signals, and indeed the dimerized peptide binds COPI in vitro. Controlled dimerization of this peptide induces cER in cells. RNA interference experiments confirm that coatomer is required for cER induction in vivo, as are microtubules and the microtubule plus-end binding protein EB1. We suggest that Ist2 dimerization triggers coatomer binding and clustering of this protein into domains that traffic at the microtubule growing plus-end to generate the cER beneath the plasma membrane. Sequences similar to the Ist2 lysine-rich tail are found in mammalian STIM proteins that reversibly induce the formation of cER under calcium control.


Cadazolid for the treatment of Clostridium difficile.
Antibiotic development goals for CDI include potent antimicrobial effect against C. difficile, limited killing of host microbiota, potential effect on spores, and ability to interfere with toxin production. Cadazolid, a novel, non-absorbable hybrid antibiotic has many of these criteria. In phase I and II clinical trials, cadazolid was shown to be safe, well tolerated, and efficacious positioning itself as a potential future viable therapeutic option for CDI. Areas covered: This review provides an in-depth evaluation of the chemistry, microbiology, pharmacodynamics, pharmacokinetics, and clinical trial results for cadazolid. Clinical therapeutic outcomes are compared between cadazolid, fidaxomicin, and surotomycin. Expert opinion: Preclinical and early clinical studies demonstrated that cadazolid has unique properties that will likely be valuable to treat CDI and reduce recurrent infection. With compelling phase II clinical results, results from the ongoing phase III trial will better define the role of cadazolid for treating CDI in the future.


[The prospect of gene therapy for lipid disorders].
The refractory hyperlipoproteinemia that is associated with atherosclerotic vascular disease is a good candidate for somatic gene therapy. The molecular etiology and pathophysiology of these diseases are mostly well understood, the animal models for these diseases have been extensively developed, and the preclinical proof-of-principle gene transfer studies have already been performed. The clinical gene therapy trials performed in the last decade raised the issue of the necessity for the development of refined vectors that can stand for clinical usage. Recent progress in basic researches implies the feasibleness of the development of vectors that provide long-term and highly-efficient gene expression, which would potentially lead to the beginning of a new era in the field of gene therapy for lipid disorders.


Socio-sexual functioning in autism spectrum disorder: A systematic review and meta-analyses of existing literature.
Socio-sexual functioning encompasses an individual's interests, behaviors, and knowledge with respect to sexual, romantic, and social aspects of life. An individual's understanding of these domains is developed through a range of informal and formal avenues of sexual health education. The current model demonstrated this and proposed that, compared to typically developing individuals, those with ASD develop socio-sexual functioning differently due to having less peer engagement, less relationship experience, more parental guidance, greater use of online materials, receive less school-based sexual health education, and more support from wellbeing services. Systematic review and meta-analysis of existing literature revealed that individuals with ASD have greater difficultly adhering to privacy norms, engage in less social behavior, are described as engaging in less appropriate sexual behavior, have greater concerns about themselves, and receive less sexual health education. Having fewer opportunities for appropriate informal and formal sexual health education leaves them at a double disadvantage from others who are receiving this information from both of these avenues. Some of the current meta-analytic results are cautioned by large l-square statistics which suggest that a degree of variance is being caused by extraneous factors. Further empirical research in this area is needed to overcome current design and sample limitations. Finally, the Sexual Behavior Scale was the most commonly utilized tool in the meta-analyzed studies, thus comprehensive evaluation of its functioning is warranted. The importance of work in this area is highlighted by the central role of social and sexual wellbeing on one's quality of life. Autism Res 2017, 10: 1823-1833. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. Review of existing literature revealed that individuals with ASD have greater difficultly adhering to privacy norms, engage in less social behavior, are described as engaging in less appropriate sexual behavior, have greater concerns about themselves, and receive less sexual health education. Having fewer opportunities for appropriate informal and formal sexual health education leaves them at a double disadvantage from others who are receiving this information from both of these avenues.


Systematic identification of allosteric protein-metabolite interactions that control enzyme activity in vivo.
Recent data suggest that the majority of proteins bind specific metabolites and that such interactions are relevant to metabolic and gene regulation. However, there are no methods to systematically identify functional allosteric protein-metabolite interactions. Here we present an experimental and computational approach for using dynamic metabolite data to discover allosteric regulation that is relevant in vivo. By switching the culture conditions of Escherichia coli every 30 s between medium containing either pyruvate or (13)C-labeled fructose or glucose, we measured the reversal of flux through glycolysis pathways and observed rapid changes in metabolite concentration. We fit these data to a kinetic model of glycolysis and systematically tested the consequences of 126 putative allosteric interactions on metabolite dynamics. We identified allosteric interactions that govern the reversible switch between gluconeogenesis and glycolysis, including one by which pyruvate activates fructose-1,6-bisphosphatase. Thus, from large sets of putative allosteric interactions, our approach can identify the most likely ones and provide hypotheses about their function.


Membranous Nephropathy (MN) Recurrence After Renal Transplantation.
Primary membranous nephropathy (MN) is a frequent cause of NS in adults. In native kidneys the disease may progress to ESRD in the long term, in some 40-50% of untreated patients. The identification of the pathogenic role of anti-podocyte autoantibodies and the development of new therapeutic options has achieved an amelioration in the prognosis of this disease. MN may also develop in renal allograft as a recurrent or a de novo disease. Since the de novo MN may have some different pathogenetic and morphologic features compared to recurrent MN, in the present paper we will deal only with the recurrent disease. The true incidence of the recurrent form is difficult to assess. This is mainly due to the variable graft biopsy policies in kidney transplantation, among the different transplant centers. Anti-phospholipase A2 receptor (PLA2R) autoantibodies are detected in 70-80% of patients. The knowledge of anti-PLA2R status before transplant is useful in predicting the risk of recurrence. In addition, the serial survey of the anti-PLA2R titers is important to assess the rate of disease progression and the response to treatment. Currently, there are no established guidelines for prevention and treatment of recurrent MN. Symptomatic therapy may help to reduce the signs and symptoms related to the nephrotic syndrome. Anecdotal cases of response to cyclical therapy with steroids and cyclophosphamide have been published. Promising results have been reported with rituximab in both prophylaxis and treatment of recurrence. However, these results are based on observational data, and prospective controlled trials are still missing.


Psychosocial Correlates of Medication Adherence among HIV-Positive, Cognitively Impaired Individuals.
Although cognitive impairment has been shown to adversely affect antiviral medication adherence, a subset of cognitively impaired adults nonetheless are able to adequately adhere to their medication regimen. However, little is known about factors that serve as buffers against suboptimal adherence among the cognitively impaired. This study consisted of 160 HIV-positive, cognitively impaired adults (Global Deficit Score ≥ 0.50) whose medication adherence was monitored over 6-months using an electronic monitoring device (MEMS caps). Logistic regressions were run to determine psychosocial variables associated with medication adherence. Higher self-efficacy and treatment related support, a stable medication regimen, stable stress levels, and absence of current stimulant use were predictive of optimal adherence. A distinct array of psychosocial factors was found that buffer against the adverse effects of cognitive impairment on medication adherence. Assessment and interventions targeting these factors may improve adherence rates among cognitively impaired adults.


Influence of supplemental canola or soybean oil on milk yield, fatty acid profile and postpartum weight changes in grazing dairy goats.
This experiment was designed to evaluate the effect of supplementation with soybean or canola oil on milk production and the composition of long chain fatty acids as well as weight changes in the goats and their kids. Thirty nine mulitparous crossed Alpine×Nubian goats (initial body weight [BW] 43.5±1.7 kg) from the day of parturition were assigned to the treatments: grazing control (n = 15); grazing plus 20 mL/goat/d of supplemental soybean oil (n = 12); and grazing plus 20 mL/goat/d of supplemental canola oil (n = 12) from November 26, 2014 to March 7, 2015. The planned contrasts were: CI (control vs supplemented with oils); CII (soybean vs canola oil) to compare the treatment effects. The vegetable oil supplementation reduced weight losses in lactating goats (CI: -0.060 vs 0.090 kg/d; p = 0.03) but did not improve milk production or affect kids' growth. The content of C4, C6, C8, C10, C11, C14, and C18:1n9t in the milk was increased (p<0.05) with respect to control. However, C12, C14, C16, C18, C18:1n9c, C18:2n6c, and C18:3n3 were reduced (p<0.05) in supplemented goats. Conjugated linoleic acid (CLA) was increased (p<0.05) in goats supplemented with oils compared to the control group. Supplementation with 20 mL/d of soybean or canola oil did not affect milk production or kids' performance; however, it increased CLA concentration and reduced the reduced weight losses in lactating goats.


Inference of temperature and density profiles via forward modeling of an x-ray imaging crystal spectrometer within the Minerva Bayesian analysis framework.
At the Wendelstein 7-X stellarator, the X-ray imaging crystal spectrometer provides line integrated measurements of ion and electron temperatures, plasma flows, as well as impurity densities from a spectroscopic analysis of tracer impurity radiation. In order to infer the actual profiles from line integrated data, a forward modeling approach has been developed within the Minerva Bayesian analysis framework. In this framework, the inversion is realized on the basis of a complete forward model of the diagnostic, including error propagation and utilizing Gaussian processes for generation and inference of arbitrary shaped plasma parameter profiles. For modeling of line integrated data as measured by the detector, the installation geometry of the spectrometer, imaging properties of the crystal, and Gaussian detection noise are considered. The inversion of line integrated data is achieved using the maximum posterior method for plasma parameter profile inference and a Markov chain Monte Carlo sampling of the posterior distribution for calculating uncertainties of the inference process. The inversion method shows a correct and reliable inference of temperature and impurity density profiles from synthesized data within the estimated uncertainties along the whole plasma radius. The application to measured data yields a good match of derived electron temperature profiles to data of the Thomson scattering diagnostic for central electron temperatures between 2 and 5 keV using argon impurities.


From gamma-carboxy-glutamate to protein C.
The story I shall recount started in 1969, when I was given the opportunity to join the Department of Clinical Chemistry at the University Hospital in Malmö. I had just finished medical school at the university in the neighboring town of Lund. Parallel to pursuing my medical studies I had spent some time in the Department of Biochemistry. I did not know much about biochemistry, but it was enough for me to realize that I wanted to do laboratory research rather than developing a clinical career. I was happy to accept an offer to start working in the laboratory, particularly as the head of the department, Professor Carl-Bertil Laurell, had an excellent reputation. As it turned out, I came to spend almost all of my professional life in the laboratory.


TAp63 regulates VLA-4 expression and chronic lymphocytic leukemia cell migration to the bone marrow in a CD74-dependent manner.
The hallmark of chronic lymphocytic leukemia (CLL) is the relentless accumulation of mature lymphocytes, mostly due to their decreased apoptosis. CD74 was recently shown to serve as a survival receptor on CLL cells. In this study, we show that stimulation of CD74 with its natural ligand, migration inhibitory factor, initiates a signaling cascade that results in upregulation of TAp63, which directly regulates CLL survival. In addition, TAp63 expression elevates the expression of the integrin VLA-4, particularly during the advanced stage of the disease. Blocking of CD74, TAp63, or VLA-4 inhibits the in vivo homing of CLL cells to the bone marrow (BM). Thus, CD74 and its target genes TAp63 and VLA-4 facilitate migration of CLL cells back to the BM, where they interact with the supportive BM environment that rescues them from apoptosis. These results could form the basis of novel therapeutic strategies aimed at blocking homing of CLL cells in their return to the BM and attenuating their survival.


"Magnetic attraction" in the pediatric emergency department: the case of a malfunctioning implantable cardioverter-defibrillator.
The use of implantable cardioverter-defibrillators (ICDs) in pediatric patients has increased substantially over the past 3 decades. We report the case of a 15-year-old boy with congenital heart disease who presented with recurrent inappropriate ICD shocks due to a lead malfunction. Inaccessibility of a magnet to inactivate shock therapy in the pediatric emergency department (PED) resulted in numerous additional inappropriate shocks. Herein, we provide a brief overview of ICD care relevant to the PED. The complexities of these devices and their associated therapies require pediatric emergency physicians caring for these patients to recognize basic ICD functions and troubleshoot malfunctions to provide timely management. In particular, it is essential that PEDs be equipped with magnets and that physicians are trained in their appropriate use.


[Coimmobilization of proteolytic and bacteriolytic enzymes and properties of isolated materials].
Coimmobilization of proteolytic and bacteriolytic enzymes on a carboxyl-containing grafted cellulose copolymer was studied. The resistance of lysozyme to gamma-sterilization significantly increased after coimmobilization with a proteolytic enzyme. The resulting material accelerated the cleansing of wounds.


Enhanced baroreflex-mediated inhibition of respiration after muscimol dialysis in the rostroventral medulla.
The rostral ventral medulla (RVM) may be important in the control of cardiorespiratory interactions. We hypothesized that inhibition of the RVM would enhance inhibition of breathing associated with transient blood pressure elevations. In 25 piglets 3-16 days of age, we studied the effect of acutely increasing blood pressure, by systemic infusion of phenylephrine, on respiratory activity before and after inhibition of neural activity in the RVM by dialysis of 10 mM muscimol, a GABA(A)-receptor agonist. Muscimol dialysis through probes that were placed along the ventral medullary surface from approximately 1 mm rostral to the facial nucleus to approximately 0.5 mm caudal to the facial nucleus augmented the respiratory inhibition associated with acute increases in blood pressure. No similar enhancement of respiratory inhibition after phenylephrine treatment was seen in six control animals that did not receive muscimol dialysis. We conclude that the piglet RVM participates in cardiorespiratory interactions and that dysfunction of homologous regions in the human infant could lead to cardiorespiratory instability and may be involved in the pathogenesis of sudden infant death syndrome.


Correlates of resistin and retinol-binding protein 4 in metabolic syndrome patients with and without prediabetes.
Background Resistin and retinol-binding protein 4 (RBP4) can work in an intricate in metabolic syndrome (MetS) and prediabetes (PreDM) molecular crosstalk. Materials and methods Resistin and RBP4 were evaluated using colorimetric enzyme-linked immunosorbent assays (ELISAs) in 29 normoglycemic MetS, 30 newly diagnosed drug naïve MetS-preDM patients and 29 lean and normoglycemic controls. Results In this cross-sectional design; the gradual increase in resistin levels (ng/mL), though not ascribed any statistically marked variation, was appreciable in both normoglycemic and preDM MetS groups vs. controls. RBP4 mean circulating levels (ng/mL) in both MetS groups (non-diabetic and preDM) invariably lacked discrepancy vs. controls. Except for fasting plasma glucose (FPG) and A1C; no further intergroup discrepancy could be identified between MetS arms. Adiposity indices: body mass index (BMI), body adiposity index (BAI) and lipid accumulation product (LAP) (but not conicity index) were substantially higher in both MetS (non- and preDM) groups vs. those of controls. Likewise, the atherogenicity index of plasma [but not non-high-density lipoprotein-cholesterol (nonHDL-C)/HDL-C ratio, or triglyceride (TG)/HDL-C ratio] or any of the hematological indices [red cell distribution width (RDW-CV %), monocyte to lymphocyte ratio (MLR), neutrophil to lymphocyte ratio (NLR) and platelet (PLT) to lymphocyte ratios (PLR)] had any marked variations as compared to controls. Low-density lipoprotein-cholesterol (LDL-C)/HDL-C ratio,visceral adiposity index, and waist circumference (WC)/hip circumference (HC) ratio were noticeably greater in MetS-preDM vs. normoglycemic MetS recruits. Neither biomarker could relate to each other, or any of the atherogenecity indices in 59 MetS participants (non- and preDM). Unlike RBP4; resistin associated proportionally with each of HC, BAI, MLR and NLR. Conclusions Both biomarkers can be putative indicator/surrogate prognostic tools for the prediction/prevention and pharmacotherapy of MetS anomalies.


White Matter Hyperintensity Predicts the Risk of Incident Cognitive Decline in Community Dwelling Elderly.
Unlike western countries, data on white matter hyperintensity (WMH) in community dwelling elderly in Asian population is very limited. To examine the relation between baseline WMH burden and the risk of incident cognitive decline in a community-based cohort with Chinese-dwelling elderly. We prospectively evaluated the incident cognitive decline for 226 participants in the Shanghai Aging Study. Baseline WMH severity was visually rated by the age-related white matter changes (ARWMC) scale based on MRI. Cox proportional hazards regression model was used to estimate the relative risk (RR) of total ARWMC scale, global ARWMC score, presence of lacune and microbleed, for incident cognitive decline by adjusting potential confounders. Forty subjects were identified with incident cognitive decline (new onset 34 mild cognitive impairment and 6 dementia) during a median duration of 6 years follow-up. The incidence of cognitive decline was 3.0 (95% confidence interval [CI] 2.2-4.1) per 100 person-years. Increasing total ARWMC scale [RR1.21 (95% CI 1.06-1.39), p = 0.004)], confluent WMH [RR3.16 (95% CI 1.50-6.64), p = 0.002), and presence of lacunes [RR 2.73 (95% CI 1.21-6.15)] at baseline were independent predictors of incident cognitive decline. Our study demonstrated that confluent WMH may increase the risk of incident cognitive decline by 3 folds in community dwelling subjects. Small vessel disease may cause heavy burden of cognitive impairment in the elderly in China.


Metabolomics in childhood diabetes.
Recent increases in the incidence of both type 1 (T1D) and type 2 diabetes (T2D) in children and adolescents point to the importance of environmental factors in the development of these diseases. Metabolomic analysis explores the integrated response of the organism to environmental changes. Metabolic profiling can identify biomarkers that are predictive of disease incidence and development, potentially providing insight into disease pathogenesis. This review provides an overview of the role of metabolomic analysis in diabetes research and summarizes recent research relating to the development of T1D and T2D in children.


Role of redchilli (Capsaicin) in the formation of colonic carcinoma.
The effect of feeding redchilli (Capsaicin) powder on the histopathological changes occurring in the colonic mucosa was studied in rats. These animals were compared with those treated with a colonic carcinogen 1,2-dimethylhydrazine (DMH). Animals fed with redchilli, dimethylhydrazine, dimethylhydrazine plus redchilli powder showed polyp and dysplasia, malignant tumour and malignant tumour with transitional area of dysplasia.


Development and characterization of a transient-replication assay for the genotype 2a hepatitis C virus subgenomic replicon.
Dicistronic, subgenomic hepatitis C virus (HCV) replicons were constructed containing sequences from JFH1, a genotype 2a strain, that also incorporated the firefly luciferase gene under the control of the HCV internal ribosome entry site element. Luciferase activity in Huh-7 cell extracts containing in vitro-transcribed subgenomic JFH1 RNA was monitored over a 72 h period to examine early stages of HCV replication in the absence of any selective pressure. Enzyme activities produced by the replicon were almost 200-fold greater than those generated from corresponding genotype 1b replicons and correlated with an accumulation of NS5A protein and replicon RNA. Transient replication was sensitive to IFN treatment in a dose-dependent manner and, in addition to Huh-7 cells, the U2OS human osteosarcoma cell line supported efficient replication of the JFH1 replicon. Thus, this system based on JFH1 sequences offers improvements over prior genotype 1b replicons for quantitative measurement of viral RNA replication.


New sulfurated derivatives of cinnamic acids and rosmaricine as inhibitors of STAT3 and NF-κB transcription factors.
A set of new sulfurated drug hybrids, mainly derived from caffeic and ferulic acids and rosmaricine, has been synthesized and their ability to inhibit both STAT3 and NF-κB transcription factors have been evaluated. Results showed that most of the new hybrid compounds were able to strongly and selectively bind to STAT3, whereas the parent drugs were devoid of this ability at the tested concentrations. Some of them were also able to inhibit the NF-κB transcriptional activity in HCT-116 cell line and inhibited HCT-116 cell proliferation in vitro with IC50 in micromolar range, thus suggesting a potential anticancer activity. Taken together, our study described the identification of new derivatives with dual STAT3/NF-κB inhibitory activity, which may represent hit compounds for developing multi-target anticancer agents.


Crosstalk between Wnt and Notch signaling in intestinal epithelial cell fate decision.
Continuous renewal of the intestinal epithelium requires coordinated regulation to maintain the balance between proliferation and differentiation of the epithelial stem cells and immature progenitor cells. Canonical Wnt signaling has long been regarded as the signaling pathway playing a central role in this epithelial cell fate determination; however, recent studies have shown that Notch signaling is also indispensable for this process. Here, we review the current concepts of how the Wnt and Notch pathways control intestinal epithelial cell fate decisions, particularly focusing on their crosstalk at both tissue and cellular levels. As several features are shared between stem cell renewal and cancer cell renewal, comprehensive understanding of how the Wnt and Notch signaling pathways cooperate and integrate in the gut epithelium has significant implications for the development of novel therapeutic modalities for intestinal neoplasia.


Strategies for preventing the recurrence of bipolar disorder.
In interpreting the maintenance literature for bipolar disorder, attention needs to be paid to important methodological issues. In this article, we initially examine the methodological topics that need to be considered, and we then examine the content of the evidence regarding maintenance treatments. Agents used in the long-term treatment of bipolar disorder possess varying degrees of supportive evidence. By consensus, the number of randomized studies and years of clinical experience with lithium mark it as the evidentially strongest long-term agent for bipolar disorder. Recent studies also demonstrate likely long-term benefit with lamotrigine, and possibly olanzapine. Although we possess fewer randomized data, some such evidence exists and, along with clinical experience, supports the likely long-term utility of valproate in the treatment of bipolar disorder as well. Some psychotherapies also may possess adjunctive maintenance efficacy.


Microdevice-based delivery of gene products using sonoporation.
This paper presents a proof-of-concept miniature device for delivery of antisense oligonucleotides (ASO). A piezoelectric, lead zirconate titanate (PZT) plate (0.5 cm(2) x 0.75 mm) is used to transfect cells using cavitation-induced sonoporation. Both human umbilical vein endothelial cells (HUVEC) and human prostate cancer cells (PC3) are investigated in vitro. Preliminary results show that after sonication, the transfection rate for HUVEC increases by 96% compared to controls (p < 0.01). For PC3, the transfection rate increases by 31% compared to controls (p < 0.02). This research can potentially be applied in realizing a microelectromechanical system (MEMS)-based device for gene therapy in cancer treatment.


Does cold water truly promote diver's ear?
Ninety-seven Japanese military divers from two districts, Mutsu (Northern Japan) and Yokosuka (Central Japan), were examined for the incidence of diver's ear (exostosis of the external auditory canal). The average temperature of sea water of the two districts is different because of their latitude, but the two groups had no significant difference in diving career. The incidence of exostosis in the Mutsu (cold area) group showed a significant increase as the diving career progressed. This tendency was not seen in the Yokosuka (warm area) group. The severity of exostosis increased in divers in both districts. The incidence of exostosis in Mutsu was significantly higher than in Yokosuka. The Mutsu group also showed a higher ratio of exostosis grade 2 than the Yokosuka group. These results may support the hypothesis that cold water facilitates formation of external auditory canal exostosis.


Collection protocol for human pancreas.
This dissection and sampling procedure was developed for the Network for Pancreatic Organ Donors with Diabetes (nPOD) program to standardize preparation of pancreas recovered from cadaveric organ donors. The pancreas is divided into 3 main regions (head, body, tail) followed by serial transverse sections throughout the medial to lateral axis. Alternating sections are used for fixed paraffin and fresh frozen blocks and remnant samples are minced for snap frozen sample preparations, either with or without RNAse inhibitors, for DNA, RNA, or protein isolation. The overall goal of the pancreas dissection procedure is to sample the entire pancreas while maintaining anatomical orientation. Endocrine cell heterogeneity in terms of islet composition, size, and numbers is reported for human islets compared to rodent islets. The majority of human islets from the pancreas head, body and tail regions are composed of insulin-containing β-cells followed by lower proportions of glucagon-containing α-cells and somatostatin-containing δ-cells. Pancreatic polypeptide-containing PP cells and ghrelin-containing epsilon cells are also present but in small numbers. In contrast, the uncinate region contains islets that are primarily composed of pancreatic polypeptide-containing PP cells. These regional islet variations arise from developmental differences. The pancreas develops from the ventral and dorsal pancreatic buds in the foregut and after rotation of the stomach and duodenum, the ventral lobe moves and fuses with the dorsal. The ventral lobe forms the posterior portion of the head including the uncinate process while the dorsal lobe gives rise to the rest of the organ. Regional pancreatic variation is also reported with the tail region having higher islet density compared to other regions and the dorsal lobe-derived components undergoing selective atrophy in type 1 diabetes. Additional organs and tissues are often recovered from the organ donors and include pancreatic lymph nodes, spleen and non-pancreatic lymph nodes. These samples are recovered with similar formats as for the pancreas with the addition of isolation of cryopreserved cells. When the proximal duodenum is included with the pancreas, duodenal mucosa may be collected for paraffin and frozen blocks and minced snap frozen preparations.


Multiplex analysis of single-nucleotide extension products on a 16-capillary, denaturing, high-performance liquid chromatography array.
We constructed a high-performance liquid chromatography array consisting of 16 monolithic poly(styrene/divinylbenzene) capillaries for the parallel multiplex analysis of fluorescent dye-labeled single-nucleotide extension products. Because of the high chemical and physical robustness of the column bed that is covalently linked to the inner surface of the fused silica capillary, the array can be reused thousands of times without replenishment. The choice of fluorophore exerts a significant effect on resolution of the extension products. FAM, HEX, and TAMRA allowed complete resolution of all four possible allelic extension products not only from the extension primer but also from each other. The quantitative accuracy of the method enables the genetic typing of bi- and triallelic single-nucleotide polymorphisms in polyploid genomes and pooled samples.


Managing emotion in a maltreating context: a pilot study examining child neglect.
The primary goal of this pilot study was to examine emotion management skills (i.e., emotional understanding, emotion regulation) in children who had experienced neglect and a control group to determine the ways that neglect may interfere with children's emotional development. Participants included children 6--12 years of age and their mothers (neglect group, N=24; control, N=24). Participants completed questionnaires and an interview that assessed children's emotional understanding and emotion regulation. Findings indicated that neglected children, compared to their non-maltreated peers, demonstrated lower understanding of negative emotions (i.e., anger, sadness) and fewer adaptive emotion regulation skills. Further, neglected children expected less support and more conflict from mothers in response to displays of negative emotion and reported that they were more likely to attempt to inhibit the expression of negative emotion. Findings suggest that neglect may interfere with the normal acquisition of emotional understanding and emotion regulation skills, highlighting the importance of addressing these skills in the context of clinical intervention with neglected children.


Vestibular evoked myogenic potentials in acute acoustic trauma.
Anatomical proximity of the saccule to the stapedial footplate points to the possibility of acoustic trauma associated with saccular dysfunction. Therefore, it was the authors' premise that abnormal vestibular evoked myogenic potential (VEMP) after acute acoustic trauma may be caused by saccular damage from very high intensity noise; consequently, irreversible hearing loss ensued. The aim of this study was to investigate the VEMP responses in those with acute acoustic trauma. A prospective study. University hospital. Twenty patients (29 ears) without previous ear disorders diagnosed as acute acoustic trauma were enrolled in this study. Before treatment, each patient underwent pure tone audiometry and caloric and VEMP tests. Correlations between the hearing outcome and mean hearing level, sources of noise, caloric responses, or VEMP results were investigated. After 3 months of medication, complete recovery was achieved in 4 ears and hearing improvement in 4 ears, whereas hearing in 21 ears (72%) remained unchanged. Eighteen ears presenting normal VEMPs revealed hearing improvement in eight ears (44%) and unchanged hearing in ten ears (56%). However, hearing loss remained unchanged in all 11 ears (100%) with absent or delayed VEMPs, exhibiting a significant relationship between VEMP results and hearing outcome. Thus, VEMP test can predict the hearing outcome after acute acoustic trauma with a sensitivity of 44% and a specificity of 100%. The greater the noise intensity, the severer damage on the cochlea and saccule is shown. Absent or delayed VEMPs in ears after acute acoustic trauma may indicate poor prognosis with respect to hearing improvement, whereas normal VEMP is not a powerful indicator for expectation of hearing improvement.


Comparison of pressure differential procedures for dipping turkey hatching-eggs in gentamicin solution.
Studies have shown that antibiotics introduced into hatching eggs can destroy certain egg-borne bacterial pathogens. An investigation was made to determine an effective procedure to introduce gentamicin solutions into turkey eggs. The findings showed that a pressure differential (PD) method using a reduced pressure of 38 cm. (15 inches) Hg for 15 minutes followed by an absorption period of 15 minutes at atmospheric pressure was an effective method which did not cause excessive egg cracking nor adversely effect hatchability. In excess of two times more fluid was absorbed using a PD method compared to an established temperature differential procedure. For maximum absorption, eggs should be washed at collection time and stored for a period of up to two weeks prior to dipping.


[Electrocardiographic abnormalities during meningeal hemorrhage].
The electrocardiogram (E.C.G.) was recorded in 100 cases of meningeal hemorrhages. The most frequent abnormalies encountered were bradycardia (32%) and inversion of the T wave (34%). Rhythm and conduction problems were less frequently found. Bradycardia was frequently and T wave inversion rarely found in cases without disturbances of consciousness and those with favourable prognosis. The contrary was found in comatous patients and cases with lethal outcome. The existance of an aneurysm and the location of it did not influence the type of electrocardiographic abnormalies. The influence of the parasympathetic and especially the sympathetic nervous systems is emphasized.


Anthropometric indices among adult Melbourne Chinese Australians.
Anthropometric indices of adult Chinese living in Melbourne, Australia, were studied. 540 (271 men and 269 women) adult Melbourne Chinese were recruited for a study of food habits and cardiovascular risk factor prevalence; all had stature, body weight and waist and hip circumferences measured. Body mass index and waist-to-hip ratio were estimated, along with fat-free mass, total body fat and the percentage body fat, using established or published formulae. Stature was negatively associated with age and positively related to education level. The Australian-born Chinese had the greatest anthropometric indices; those born in China and Hong Kong had a similar anthropometric profile; the anthropometric profile of Vietnamese Chinese was similar to that of their Australian born counterparts and was significantly greater than that of their counterparts born in China and Hong Kong. Our study suggests that a favourable environment can promote full genetic potential in growth, as evident in the Australian-born Chinese. Those born in Vietnam appeared to have taken full advantage of the Australian environment and showed an elevation of body composition.


Health (il)literacy: Structural vulnerability in the nurse navigator service.
Health literacy is a contemporary term used in health services, often used to describe individuals requiring additional support to access, understand and implement health service information. It is used as a measure of self-efficacy in chronic disease models of care such as the nurse navigator service. The aim of the research was to investigate the concept of health literacy in the nurse navigator service, particularly in relation to the defined role objective of person-centred care. Fairclough's critical discourse analysis was used to analyse the experiential, relational and expressive elements of texts, investigating the hidden truths which are represented in discourse. Texts from a variety of health service micro-, meso- and macro-hierarchical sources were selected for analysis using the nurse navigator evaluation data set and other associated texts. Health literacy in the nurse navigator service is a technology of government used to increase participation of individuals in their own health and well-being. The discourse suggests that health literacy responsibilises both individuals and nurses and is discursively formed within a matrix of rational choice. In this context, health literacy contributes to structural vulnerability.


Design and implementation of high sampling rate and multichannel wireless recorder for EEG monitoring and SSVEP response detection.
The collection and process of human brain activity signals play an essential role in developing brain-computer interface (BCI) systems. A portable electroencephalogram (EEG) device has become an important tool for monitoring brain activity and diagnosing mental diseases. However, the miniaturization, portability, and scalability of EEG recorder are the current bottleneck in the research and application of BCI. For scalp EEG and other applications, the current study designs a 32-channel EEG recorder with a sampling rate up to 30 kHz and 16-bit accuracy, which can meet both the demands of scalp and intracranial EEG signal recording. A fully integrated electrophysiology microchip RHS2116 controlled by FPGA is employed to build the EEG recorder, and the design meets the requirements of high sampling rate, high transmission rate and channel extensive. The experimental results show that the developed EEG recorder provides a maximum 30 kHz sampling rate and 58 Mbps wireless transmission rate. The electrophysiological experiments were performed on scalp and intracranial EEG collection. An inflatable helmet with adjustable contact impedance was designed, and the pressurization can improve the SNR by approximately 4 times, the average accuracy of steady-state visual evoked potential (SSVEP) was 93.12%. Animal experiments were also performed on rats, and spike activity was captured successfully. The designed multichannel wireless EEG collection system is simple and comfort, the helmet-EEG recorder can capture the bioelectric signals without noticeable interference, and it has high measurement performance and great potential for practical application in BCI systems.


C. elegans cell migration gene mig-10 shares similarities with a family of SH2 domain proteins and acts cell nonautonomously in excretory canal development.
The mig-10 gene of Caenorhabditis elegans is required for the long-range anteroposterior migration of embryonic neurons CAN, ALM, and HSN and proper development of the excretory canals. Here, we report the cloning and initial molecular characterization of mig-10. The predicted MIG-10 proteins share a large region of similarity with a recently identified family of mammalian SH2 domain proteins, Grb7 and Grb10. We call this region of similarity the GM region (for Grb and Mig). MIG-10 proteins do not contain an SH2 domain, but share with the Grbs a pleckstrin homology (PH) domain and proline-rich regions, features commonly found in signal transduction proteins. The functions of Grb7 and Grb10 are unknown, but Grb7 is overexpressed in certain breast cancers, where it is bound to the growth factor receptor HER2, while Grb10 has been implicated in insulin signaling. We also report the isolation of a new mig-10(e2527) allele, as well as the molecular characterization of e2527 (splice acceptor mutation) and the canonical ct41 (amber) allele. Finally, we report the results of a genetic mosaic analysis which reveal that mig-10 acts cell nonautonomously in the development of the excretory canals and suggest a possible focus for mig-10 activity within descendants of the AB cell lineage. Elucidation of the role of mig-10 in C. elegans development should lead to a better understanding of cell migration and may shed light on the function of a family of SH2 domain proteins apparently involved in signal transduction and cancer.


The genetic architecture of nodal root number in maize.
The maize nodal root system plays a crucial role in the development of the aboveground plant and determines the yield via the uptake of water and nutrients in the field. However, the genetic architecture of the maize nodal root system is not well understood, and it has become the 'dark matter' of maize genetics. Here, a large teosinte-maize population was analyzed, and high-resolution mapping revealed that 62 out of 133 quantitative trait loci (QTLs), accounting for approximately half of the total genetic variation in nodal root number, were derived from QTLs for flowering time, which was further validated through a transgenic analysis and a genome-wide association study. However, only 16% of the total genetic variation in nodal root number was derived from QTLs for plant height. These results gave a hint that flowering time played a key role in shaping nodal root number via indirect selection during maize domestication. Our results also supported that more aerial nodal roots and fewer crown roots might be favored in temperate maize, and this root architecture might efficiently improve root-lodging resistance and the ability to take up deep water and nitrogen under dense planting.


Myocardial function and metabolism in pig hearts after relief from chronic partial coronary stenosis.
Metabolic behavior was compared during acute extracorporeal reperfusion after removal of a chronic 4-day partial coronary stenosis in eight pig hearts (RCS group) and during comparable extracorporeal perfusion in seven chronically prepared hearts (Sham group). Coronary stenosis in RCS hearts was induced in the left anterior descending (LAD) artery by partial inflation of a hydraulic occluder to restrict LAD peak phasic velocity by approximately 50%. Regional mechanical shortening was decreased in RCS compared with Sham hearts after 4 days of chronic coronary stenosis [diminished systolic shortening (P < 0.066) with systolic expansion (P < 0.015)] but was comparable to Sham hearts after relief from stenosis. At analogous workloads (left ventricular pressure and heart rate) during reperfusion, metabolic behavior was distinctive between groups. Specifically, compared with Sham hearts, myocardial O2 consumption was selectively increased in RCS hearts (+ 49 delta %, P < 0.026) as was fatty acid oxidation estimated from 14CO2 production from [U-14C]palmitate (+ 60 delta %, P < 0.061) and exogenous glucose utilization measured from the release of 3H2O from [5-3H]glucose (+ 517 delta %, P < 0.025). At the conclusion of the studies, triphenyltetrazolium chloride staining showed no gross evidence of macroinfarction in RCS or Sham hearts, and there was an essentially unremarkable histological survey of anterior myocardium for microscopic necrosis in either group. The level of O2 consumption and preservation of preferred fatty acid utilization indicate that metabolism remains or regains its aerobic pattern of activity in early recovery immediately after removal of chronic partial coronary stenosis.(ABSTRACT TRUNCATED AT 250 WORDS)


Fluid-Assisted Sorted Assembly of Graphene on Polymer.
The significant size distribution of as-synthesized nanomaterials presents a challenge for reproducable and reliable applications. In this paper, we report a fluidic-assisted sorted assembly method in which nanomaterial sorting and enhanced assembly can be achieved simultaneously. As a proof of concept, a two-dimensional (2D) graphene flake, with a large size variation, was chosen as the target nanomaterial system. This study synergizes a novel fluidic assembly design, suspending a rotating disk over a polydimethylsiloxane (PDMS) substrate, and a computational fluid dynamics (CFD) model using Ansys CFX to disclose the mechanism of sorted assembly. By controlling the rotating speed and the gap between the disk and the substrate, the flow field is altered. In contrast to centrifugal sorting, where larger particles move outward, in this study, the size of assembled graphene flake (average lateral size, Xc) reduces significantly from the center (Xc = 3 μm) to the edge of the disk (Xc = 2 μm). The particle sorting process is dictated by the fluid shear-stress, with higher shear-stress leading to smaller particles, while the assembly process is mainly dominated by the pressure field with higher pressure magnitude leading to better assembly. Near the edge of the disk, enhanced particle sorting is coupled with an enhanced assembly where a continuous graphene film with smaller Xc can be formed. To prove the potential application of this method, an ultrasensitive strain sensor with one of the lowest detection limits, 0.02%, is demonstrated. This research presents a novel route toward large-scale and cost-effective manufacturing of nanomaterial-based flexible electronics.


E proteins sharpen neurogenesis by modulating proneural bHLH transcription factors' activity in an E-box-dependent manner.
Class II HLH proteins heterodimerize with class I HLH/E proteins to regulate transcription. Here, we show that E proteins sharpen neurogenesis by adjusting the neurogenic strength of the distinct proneural proteins. We find that inhibiting BMP signaling or its target ID2 in the chick embryo spinal cord, impairs the neuronal production from progenitors expressing ATOH1/ASCL1, but less severely that from progenitors expressing NEUROG1/2/PTF1a. We show this context-dependent response to result from the differential modulation of proneural proteins' activity by E proteins. E proteins synergize with proneural proteins when acting on CAGSTG motifs, thereby facilitating the activity of ASCL1/ATOH1 which preferentially bind to such motifs. Conversely, E proteins restrict the neurogenic strength of NEUROG1/2 by directly inhibiting their preferential binding to CADATG motifs. Since we find this mechanism to be conserved in corticogenesis, we propose this differential co-operation of E proteins with proneural proteins as a novel though general feature of their mechanism of action.


Education and dementia in the context of the cognitive reserve hypothesis: a systematic review with meta-analyses and qualitative analyses.
Cognitive reserve (CR) or brain reserve capacity explains why individuals with higher IQ, education, or occupational attainment have lower risks of developing dementia, Alzheimer's disease (AD) or vascular dementia (VaD). The CR hypothesis postulates that CR reduces the prevalence and incidence of AD or VaD. It also hypothesizes that among those who have greater initial cognitive reserve (in contrast to those with less reserve) greater brain pathology occurs before the clinical symptoms of disease becomes manifest. Thus clinical disease onset triggers a faster decline in cognition and function, and increased mortality among those with initial greater cognitive reserve. Disease progression follows distinctly separate pathological and clinical paths. With education as a proxy we use meta-analyses and qualitative analyses to review the evidence for the CR hypothesis. We searched PubMed, PsycoINFO, EMBASE, HealthStar, and Scopus databases from January 1980 to June 2011 for observational studies with clear criteria for dementia, AD or VaD and education. One hundred and thirty-three articles with a variety of study designs met the inclusion criteria. Prevalence and incidence studies with odds ratios (ORs), relative risks or original data were included in the meta-analyses. Other studies were reviewed qualitatively. The studies covered 437,477 subjects. Prevalence and incidence studies with pooled ORs of 2.61 (95%CI 2.21-3.07) and 1.88 (95%CI 1.51-2.34) respectively, showed low education increased the risk of dementia. Heterogeneity and sensitivity tests confirmed the evidence. Generally, study characteristics had no effect on conclusions. Qualitative analyses also showed the protective effects of higher education on developing dementia and with clinical disease onset hastening a decline in cognition and function, and greater brain pathology. This systematic review and meta-analyses covering a wide range of observational studies and diverse settings provides robust support for the CR hypothesis. The CR hypothesis suggests several avenues for dementia prevention.


Endoscopic diagnosis of ureteral obstruction secondary to metastatic breast carcinoma.
Metastasis to the ureter is a very rare complication in patients with breast cancer and bone metastases. Retroperitoneal disease appears to be an uncommon manifestation of long-standing breast cancer which is usually hormonally dependent. In most published cases, the diagnosis is only made at postmortem examination. This report presents an uncommon case of ureteral obstruction secondary to breast cancer diagnosed with ureteroscopy.


Comparative Molecular Field Analysis Using Molecular Integral Equation Theory.
Recently, Güssregen et al. used solute-solvent distribution functions calculated by the three-dimensional Reference Interaction Site Model (3DRISM) in a 3D quantitative structure-activity relationship (QSAR) approach to model activity data for a set of serine protease inhibitors; this approach was referred to as Comparative Analysis of 3D RISM Maps (CARMa). [ J. Chem. Inf. 2017, 57, 1652-1666] Here we extend this idea by introducing probe atoms into the 3DRISM solvent model in order to directly capture other molecular interactions in addition to those related to hydration/dehydration. Benchmark results for six different protein-ligand systems show that CARMa models trained on probe atom descriptors give consistently more accurate predictions than Comparative Molecular Field Analysis (CoMFA) and other common QSAR approaches.


Optimization of square wave anodic stripping voltammetry (SWASV) for the simultaneous determination of Cd, Pb, and Cu in seawater and comparison with differential pulse anodic stripping voltammetry (DPASV).
Square wave anodic stripping voltammetry (SWASV) was optimized for the simultaneous determination of Cd, Pb and Cu in coastal seawater samples. Background subtraction was adapted to improve peak detection and quantification. Optimum background voltammograms were obtained by applying a 7.5 s equilibration potential at -975 mV (vs. Ag/AgCl, 3M KCl) before starting the background scan. Voltammetric scan parameters were optimized to obtain maximum sensitivity while retaining good peak resolution and discrimination from background. Optimal parameters were: frequency 100 Hz, pulse amplitude 25 mV, current sampling delay time 2 ms, step height 8 mV. The sensitivity of optimized SWASV proved to be more than double that of differential pulse anodic stripping voltammetry (DPASV), and analysis time was halved. Samples containing around 13 (Cd), 30 (Pb), 200 (Cu) ng/l (typical averages of the coastal area of the Marche region) can be analyzed using a 5 min deposition time and the total analysis time using three standard additions is about 1 h and half, excluding the mercury film preparation and the outgassing of the sample, which can be made in parallel using a second cell cup.


Immediate Effects of Ankle-Foot Orthosis Using Wire on Static Balance of Patients with Stroke with Foot Drop: A Cross-Over Study.
The aim of this study was to investigate the immediate static balance effects of bare foot, UD-Flex ankle-foot orthosis (AFO), and AFO using wire (AOW) of patients with stroke with foot drop. Seventeen patients with stroke with foot drop (8 men and 9 women) were randomized to three conditions (bare foot, UD-Flex AFO, or AOW made with a flexible material). Static balance was assessed using the Zebris (Zebris GmbH, Isny, Germany) and BioRescue (RM Ingenierie, Rodez, France) pressure platform by a single examiner, who did not design the AOW. The order of testing with the equipment was random. The center of pressure path length (mm) measured using Zebris showed significant differences among the three conditions (bare foot, 484.47 ± 208.42; UD-Flex AFO, 414.59 ± 144.43; AOW, 318.29 ± 157.60) (p < 0.05). The bare-foot condition was not significantly different from the UD-Flex AFO condition (p > 0.05), but was significantly different from the AOW condition (p < 0.05). The surface area ellipse (mm2) measured using BioRescue showed significant differences among the three conditions (bare foot, 241.35 ± 153.76; UD-Flex AFO, 277.41 ± 381.83; AOW, 68.06 ± 48.98) (p < 0.05). The bare-foot condition was not significantly different from the UD-Flex AFO condition (p > 0.05), but the AOW condition was significantly different from the bare-foot (p < 0.05) and from the UD-Flex AFO conditions (p < 0.05). We suggest using the AOW made of flexible materials and wire instead of the UD-Flex AFO to improve immediate static balance of patients with stroke with foot drop after stroke. Further studies on the effects of dynamic balance and gait are required.


Personalized Depression Prevention Reduces Dependent Stressors Among Adolescents: Results from a Randomized Controlled Trial.
Depression and stressors both increase during adolescence. The stress generation model posits that depression symptoms and associated impairment contribute to the generation of dependent stressors. Adolescent depression prevention programs have been shown to reduce the risk of depression. Recently, risk-informed personalization approaches have been adopted to enhance the efficacy of depression prevention, and preliminary evidence supports the beneficial effects of personalized prevention on depression symptoms. Given the close association between depression and stress, we examined the hypothesis that personalized depression prevention programs would reduce adolescents' experience of dependent stressors (interpersonal and non-interpersonal) over longitudinal follow-up. The present study included 204 adolescents (56% girls, 29% racial minority) who were randomized to receive either a cognitive-behavioral or an interpersonal prevention program. Youth were categorized as high or low on cognitive and interpersonal risk using a previously established risk classification system. Half of the adolescents received a prevention program that matched their risk profile (e.g., high cognitive risk randomized to cognitive-behavioral prevention); half received a mismatched program (e.g., high interpersonal risk randomized to cognitive-behavioral prevention). Exposure to dependent and independent stressors was assessed repeatedly over an 18-month follow-up period. Matched adolescents reported fewer dependent stressors during the post-intervention follow-up period (d = .46, p = .002) and from baseline through 18-months post-intervention (d = .35, p = .02) compared to mismatched youth. As expected, there were no differences between matched and mismatched youth on the experience of independent stressors. These findings further highlight the potential of personalized approaches to depression prevention and demonstrate benefits that go beyond depression symptom reduction.


The composition of glomerulosclerosis. I. Studies in focal sclerosis, crescentic glomerulonephritis, and membranoproliferative glomerulonephritis.
The composition of glomerulosclerosis was examined in focal sclerosis, membranoproliferative glomerulonephritis, and crescentic glomerulonephritis, using antisera specific for laminin and collagen types III and IV. Mesangial sclerosis consisted exclusively of extracellular matrix found in normal glomeruli, as did small synechiae in focal sclerosis and all synechiae in membranoproliferative glomerulonephritis. The large synechiae in focal sclerosis and all stages of the developing crescents associated with vasculitis contained mainly interstitial collagen, type III, a component not found in normal glomeruli. In the latter there were also disruptions of Bowman's capsule and an increase in the number of periglomerular interstitial cells. These observations suggested that glomerulosclerosis varied in composition and distribution, and some types of crescentic glomerulonephritis may have arisen from either cells resident in the glomerulus or cells coming from the interstitial space.


Hypertensive uveitis as a feature of multiple myeloma.
To report a masquerade syndrome secondary to multiple myeloma iris infiltration. Observational case report. A 74-year-old Caucasian woman presenting with unilateral hypertensive uveitis and past medical history significant for multiple myeloma underwent aqueous cytology and a trabeculectomy with iridectomy. Cytology revealed atypical plasma cells in the aqueous while the anatomopathologic analysis of iris tissue demonstrated a substitution of the iris tissue by neoplastic plasma cells. After surgery and a new cycle of chemotherapy best-corrected visual acuity and intraocular pressure improved. Masquerade syndrome should always be considered in elderly uveitis. A correct diagnosis can be life-saving.


Photoperiod-modulated testis maturation in Atlantic cod (Gadus morhua, L.).
Precocious male puberty is a significant problem in Atlantic cod aquaculture. While photoperiod manipulation can inhibit testis growth, a detailed analysis of effects on spermatogenesis is missing. Starting July 1, 2004, prepubertal fish were exposed to different photoperiod regimens in indoor tanks for 17 mo. Testis histology, germ cell dynamics (proliferation and apoptosis), and plasma androgen levels were analyzed. In the natural light (NL) group, testis growth started in September 2004 and was completed in February 2005, when a 2-mo spawning period started. In the constant light (LL) group, none or very few spermatogenic cysts were recruited into spermatogenesis, and apoptotic germ cell loss was high. A change of photoperiod from NL to LL at winter solstice (December 21, 2004) resulted in premature (2 mo) completion of the reproductive cycle, while changing from LL to NL at winter solstice triggered faster than normal testis development. Plasma testosterone levels increased in the NL group from spermatogonial proliferation toward meiosis, while those of 11-ketotestosterone increased toward spermiogenesis and spermiation. Plasma androgen levels did not rise under LL conditions. Comparing fish with developing testes from all groups indicated that low androgen levels were associated with a high incidence of spermatogonial apoptosis; we also found that androgen receptor mRNA expression was most prominent in Sertoli cells in contact with growing spermatogonial clones. Our data show that an inhibitory photoperiod (LL) reduced or blocked differentiation of spermatogonia, increased apoptosis (particularly among proliferating spermatogonia), and was associated with reduced androgen levels, a situation possibly reflecting insufficient gonadotropic stimulation.


MGAT2 deficiency ameliorates high-fat diet-induced obesity and insulin resistance by inhibiting intestinal fat absorption in mice.
Resynthesis of triglycerides in enterocytes of the small intestine plays a critical role in the absorption of dietary fat. Acyl-CoA:monoacylglycerol acyltransferase-2 (MGAT2) is highly expressed in the small intestine and catalyzes the synthesis of diacylglycerol from monoacylglycerol and acyl-CoA. To determine the physiological importance of MGAT2 in metabolic disorders and lipid metabolism in the small intestine, we constructed and analyzed Mgat2-deficient mice. In oral fat tolerance test (OFTT), Mgat2-deficient mice absorbed less fat into the circulation. When maintained on a high-fat diet (HFD), Mgat2-deficient mice were protected from HFD-induced obesity and insulin resistance. Heterozygote (Mgat2+/-) mice had an intermediate phenotype between Mgat2+/+ and Mgat2-/- and were partially protected from metabolic disorders. Despite of a decrease in fat absorption in the Mgat2-deficient mice, lipid levels in the feces and small intestine were comparable among the genotypes. Oxygen consumption was increased in the Mgat2-deficient mice when maintained on an HFD. A prominent upregulation of the genes involved in fatty acid oxidation was observed in the duodenum but not in the liver of the Mgat2-deficient mice. These results suggest that MGAT2 has a pivotal role in lipid metabolism in the small intestine, and the inhibition of MGAT2 activity may be a promising strategy for the treatment of obesity-related metabolic disorders.


Epilepsy induced collateral sprouting of hippocampal mossy fibers: does it induce the development of ectopic synapses with granule cell dendrites?
In the present study, using Golgi and electron microscopy techniques, experimentally induced epilepsy (kindling and kainate treatment) elicited collateral sprouting of mossy fibers in rat hippocampus. Collateral branches invade the hilus, cross the granule cell layer, and distribute throughout the inner third of the molecular layer. These newly developed collaterals may acquire the typical features of mossy fibers including giant fiber varicosities (mousses), although the mean surface of these mousses was thinner in these collaterals than in terminal branches. Granule cell dendrites may develop giant thorny excrescences, suggesting that the targets of these collaterals are granule cells. Giant synaptic boutons appear in the inner third of molecular layer of epileptic rats. These boutons acquire the morphological features of mossy fiber boutons and made multiple synaptic contacts with dendritic spines. The analysis of the profile types suggests that some of the newly developed collateral mossy fibers made hypotrophic synaptic contacts.


[Cystic lymphangioma of the adult: our experience and review of literature].
Cystic lymphangioma is an uncommon benign pathology, usually reported in children, rarely in adult. Its embryopathogenesis is still controversial: it seems to arise from the lymphatic vessels, mainly in the cervico-cranial district. It is macroscopically characterised by multiple cystic non-communicating concamerations. Definitive diagnosis used to be intraoperative and was usually an unexpected finding. Nowadays, with modern imaging technologies, CT and MRI, diagnosis can be assumed before intervention even though certain diagnosis can still be reached only with histological examination. Imaging techniques can help for a precise mapping of the lesion and definition of its limits with the other structures, improving therapeutic success. Various therapeutical options are reported in literature, but complete surgical excision is still considered the best approach and the most successful. The Authors report their experience and review the literature on cystic lymphangioma in adult.


Directionality of dihydrogen bonds: the role of transition metal atoms.
A theoretical study on two series of electron-rich group 8 hydrides is carried out to evaluate involvement of the transition metal in dihydrogen bonding. To this end, the structural and electronic parameters are computed at the DFT/B3PW91 level for hydrogen-bonded adducts of [(PP(3))MH(2)] and [Cp*MH(dppe)] (M = Fe, Ru, Os; PP(3) = κ(4)-P(CH(2)CH(2)PPh(2))(3), dppe = κ(2)-Ph(2)PCH(2)CH(2)PPh(2)) with CF(3)CH(2)OH (TFE) as proton donor. The results are compared with those of adduct [Cp(2)NbH(3)]⋅TFE featuring a "pure" dihydrogen bond, and classical hydrogen bonds in pyridine⋅TFE and Me(3)N⋅TFE. Deviation of the H⋅⋅⋅H-A fragment from linearity is shown to originate from the metal participation in dihydrogen bonding. The latter is confirmed by the electronic parameters obtained by NBO and AIM analysis. Considered together, orbital interaction energies and hydrogen bond ellipticity are salient indicators of this effect and allow the MH⋅⋅⋅HA interaction to be described as a bifurcate hydrogen bond. The impact of the M⋅⋅⋅HA interaction is shown to increase on descending the group, and this explains the experimental trends in mechanisms of proton-transfer reactions via MH⋅⋅⋅HA intermediates. Strengthening of the M⋅⋅⋅H interaction in the case of electron-rich 5d metal hydrides leads to direct proton transfer to the metal atom.


Coherent and incoherent electron-phonon coupling in graphite observed with radio-frequency compressed ultrafast electron diffraction.
Radio-frequency compressed ultrafast electron diffraction has been used to probe the coherent and incoherent coupling of impulsive electronic excitation at 1.55 eV (800 nm) to optical and acoustic phonon modes directly from the perspective of the lattice degrees of freedom. A biexponential suppression of diffracted intensity due to relaxation of the electronic system into incoherent phonons is observed, with the 250 fs fast contribution dominated by coupling to the E_{2g2} optical phonon mode at the Γ point (Γ-E_{2g2}) and A_{1}^{'} optical phonon mode at the K point (K-A_{1}^{'}). Both modes have Kohn anomalies at these points in the Brillouin zone. The result is a unique nonequilibrium state with the electron subsystem in thermal equilibrium with only a very small subset of the lattice degrees of freedom within 500 fs following photoexcitation. This state relaxes through further electron-phonon and phonon-phonon pathways on the 6.5 ps time scale. In addition, electronic excitation leads to both in-plane and out-of-plane coherent lattice responses in graphite whose character we are able to fully determine based on spot positions and intensity modulations in the femtosecond electron diffraction data. The in-plane motion is specifically a Γ point shearing mode of the graphene planes and the out-of-plane motion an acoustic breathing mode response of the film.


DNA methylation aberrancies as a guide for surveillance and treatment of human cancers.
DNA methylation aberrancies are hallmarks of human cancers and are characterized by global DNA hypomethylation of repetitive elements and non-CpG rich regions concomitant with locus-specific DNA hypermethylation. DNA methylation changes may result in altered gene expression profiles, most notably the silencing of tumor suppressors, microRNAs, endogenous retorviruses and tumor antigens due to promoter DNA hypermethylation, as well as oncogene upregulation due to gene-body DNA hypermethylation. Here, we review DNA methylation aberrancies in human cancers, their use in cancer surveillance and the interplay between DNA methylation and histone modifications in gene regulation. We also summarize DNA methylation inhibitors and their therapeutic effects in cancer treatment. In this context, we describe the integration of DNA methylation inhibitors with conventional chemotherapies, DNA repair inhibitors and immune-based therapies, to bring the epigenome closer to its normal state and increase sensitivity to other therapeutic agents to improve patient outcome and survival.


Genetic alterations associated with acquired temozolomide resistance in SNB-19, a human glioma cell line.
Gliomas are highly lethal neoplasms that cannot be cured by currently available therapies. Temozolomide is a recently introduced alkylating agent that has yielded a significant benefit in the treatment of high-grade gliomas. However, either de novo or acquired chemoresistance occurs frequently and has been attributed to increased levels of O6-methylguanine-DNA methyltransferase or to the loss of mismatch repair capacity. However, very few gliomas overexpress O6-methylguanine-DNA methyltransferase or are mismatch repair-deficient, suggesting that other mechanisms may be involved in the resistance to temozolomide. The purpose of the present study was to generate temozolomide-resistant variants from a human glioma cell line (SNB-19) and to use large-scale genomic and transcriptional analyses to study the molecular basis of acquired temozolomide resistance. Two independently obtained temozolomide-resistant variants exhibited no cross-resistance to other alkylating agents [1,3-bis(2-chloroethyl)-1-nitrosourea and carboplatin] and shared genetic alterations, such as loss of a 2p region and loss of amplification of chromosome 4 and 16q regions. The karyotypic alterations were compatible with clonal selection of preexistent resistant cells in the parental SNB-19 cell line. Microarray analysis showed that 78 out of 17,000 genes were differentially expressed between parental cells and both temozolomide-resistant variants. None are implicated in known resistance mechanisms, such as DNA repair, whereas interestingly, several genes involved in differentiation were down-regulated. The data suggest that the acquisition of resistance to temozolomide in this model resulted from the selection of less differentiated preexistent resistant cells in the parental tumor.