Intracellular signaling during skeletal muscle atrophy.
A variety of conditions lead to skeletal muscle atrophy including muscle inactivity or disuse, multiple disease states (i.e., cachexia), fasting, and age-associated atrophy (sarcopenia). Given the impact on mobility in the latter conditions, inactivity could contribute in a secondary manner to muscle atrophy. Because different events initiate atrophy in these different conditions, it seems that the regulation of protein loss may be unique in each case. In fact differences exist between the regulation of the various atrophy conditions, especially sarcopenia, as evidenced in part by comparisons of transcriptional profiles as well as by the unique triggering molecules found in each case. By contrast, recent studies have shown that many of the intracellular signaling molecules and target genes are similar, particularly among the atrophies related to inactivity and cachexia. This review focuses on the most recent findings related to intracellular signaling during muscle atrophy. Key findings are discussed that relate to signaling involving muscle ubiquitin ligases, the IGF/PI3K/Akt pathway, FOXO activity, caspase-3 activity, and NF-kappaB signaling, and an attempt is made to construct a unifying picture of how these data can be connected to better understand atrophy. Once more detailed cellular mechanisms of the atrophy process are understood, more specific interventions can be designed for the attenuation of protein loss.


Hemoglobinuria misidentified as hematuria: review of discolored urine and paroxysmal nocturnal hemoglobinuria.
Discolored urine is a common reason for office visits to a primary care physician and urology referral. Early differentiation of the type or cause of discolored urine is necessary for accurate diagnosis and prompt management. Paroxysmal nocturnal hemoglobinuria is a clonal disorder caused by acquired somatic mutations in the PIG-A gene on the X- chromosome of hemopoietic stem cells and leads to deficiency of surface membrane anchor proteins. The deficiency of these proteins leads to an increased risk of hemolysis of erythrocytes and structural damage of platelets, resulting in a clinical syndrome characterized by complement-mediated intravascular hemolytic anemia, bone marrow failure, and venous thrombosis. Patients with this clinical syndrome present with paroxysms of hemolysis, causing hemoglobinuria manifesting as discolored urine. This can be easily confused with other common causes of discolored urine and result in extensive urologic work-up. Three commonly confused entities of discolored urine include hematuria, hemoglobinuria, and myoglobinuria. Specific characteristics in a dipstick test or urinalysis can guide differentiation of these three causes of discolored urine. This article begins with a case summary of a woman presenting with cranberry-colored urine and a final delayed diagnosis of paryxysmal nocturnal hemoglobinuria. Her hemoglobinuria was misdiagnosed as hematuria, leading to extensive urologic work-up. The article also gives an overview of the approach to diagnosing and treating discolored urine.


Ion gradient-driven bifurcations of a multi-scale neuronal model.
Metabolic limitations within the brain frequently arise in the context of aging and disease. As the largest consumers of energy within the brain, ion pumps that maintain the neuronal membrane potential are the most affected when energy supply becomes limited. To characterize the effects of such limitations, we analyze the ion gradients present in a conductance-based (Morris-Lecar) neural mass model. We show the existence and locations of Neimark-Sacker and period-doubling bifurcations in the sodium, calcium, and potassium reversal potentials and demonstrate that these bifurcations form physiologically relevant bounds of ion gradient variability. Within these bounds, we show how depolarization of the gradients causes decreased neural activity. We also show that the depolarization of ion gradients decreases inter-regional coherence, causing a shift in the critical point at which the coupling occurs and thereby inducing loss of synchrony between regions. In this way, we show that the Larter-Breakspear model captures ion gradient variability present at the microscale level and propagates these changes to the macroscale effects such as those observed in human neuroimaging studies.


Terpestacin core structure. control of stereochemistry.
[reaction: see text] The alpha-hydroxycyclopentenone core structure of terpestacin has been prepared in a model system through an allene ether Nazarov cyclization of an alkylidene-gamma-butyrolactone followed by regio- and stereoselective alkylation reactions. The stereochemistry at C15 (terpestacin numbering) has been used to control stereochemistry at C1 and at C23. The use of E-alkylidene-gamma-butyrolactones extends the scope of the cationic cyclopentannelation reaction.


Open-label assessment of levofloxacin for the treatment of acute bacterial sinusitis in adults.
To evaluate the efficacy and safety of levofloxacin (500 mg orally once daily for 10 to 14 days) in treating adult outpatients with acute bacterial sinusitis. A total of 329 patients enrolled in the study at 24 centers. All patients had a pre-therapy Gram's stain and culture of sinus exudate obtained by antral puncture or nasal endoscopy. Clinical response was assessed on the basis of signs and symptoms and sinus radiograph or computed tomography results. Microbiologic cure rates were determined on the basis of presumed plus documented eradication of the pre-therapy pathogen(s). The most common pathogens were Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus, and Moraxella catarrhalis. Of 300 clinically evaluable patients, 175 (58%) were cured and 90 (30%) were improved at the post-therapy evaluation, resulting in a clinical success rate of 88%. Thirty-five patients (12%) clinically failed treatment. The microbiologic eradication rate (presumed plus documented) among 138 microbiologically evaluable patients was 92%. Microbiologic eradication rates (presumed plus documented) of the most common pathogens ranged from 93% (M. catarrhalis) to 100% (S. pneumoniae) at the post-therapy visit. All but one of the 265 patients who were cured or improved at post-therapy returned for a long-term follow-up visit; 243 (92%) remained well 4 to 6 weeks after therapy; and 21 (8%) had a relapse of symptoms. Adverse events considered to be related to levofloxacin administration were reported by 29 patients (9%). The most common drug-related adverse events were diarrhea, flatulence, and nausea; most adverse events were mild to moderate in severity. The results of this study indicate that levofloxacin 500 mg once daily is an effective and safe treatment for acute bacterial sinusitis.


[The role of low grade glioma prognostic factors in therapeutic choices - summary of international literature and recommendations with conclusions].
Our knowledge on low grade gliomas has grown extensively recently. Both molecular alterations and clinical trials unraveling their clinical significance are difficult to get familiar with. Thus, efforts made to reach any consensus are of upmost importance, so that multidisciplinary teams involved in patient management can make up-to-date, individually-tailored therapeutic plans. Our aims were to synthesize all the molecular and clinical investigations, recommendations and guidelines related to low grade gliomas in Hungarian language, and to define low and high risk prognostic groups with different therapeutic strategies. The roles of 21 molecular pathological markers and their significance levels in low grade gliomas are summarized in this paper. Data from relevant literature, as well as recommendations of neuro-oncological organizations were included. This summary could help to integrate diverse therapeutic plans of the past decades in low grade gliomas. Moreover, this paper may serve as a source for future revisions when updating low and high risk groups in low grade gliomas.


Case Report: Disseminated Talaromyces (Penicillium) marneffei and Mycobacterium tuberculosis Coinfection in a Japanese Patient with Acquired Immunodeficiency Syndrome.
Talaromyces marneffei is a dimorphic fungus endemic mainly in southeast and south Asia. It causes severe mycosis, usually in immunocompromised individuals, such as those with human immunodeficiency virus (HIV) infection. Concomitant infection with T. marneffei and other opportunistic pathogens is plausible because the majority of T. marneffei infections occur in patients with advanced HIV infection. Nonetheless, coinfection in the same site has rarely been reported, and poses a considerable diagnostic and therapeutic challenge. We report the case of an HIV-infected Japanese patient who had lived in Thailand for 6 years. The patient developed T. marneffei and Mycobacterium tuberculosis coinfection, and both pathogens were isolated from the same sites: a blood specimen and a lymph node aspirate. Clinicians should be aware of concomitant infection with T. marneffei and other pathogens in patients with advanced HIV disease who are living in or who have visited endemic areas.


Bouveret syndrome: two approaches one stone.
Bouveret syndrome is a rare cause of gastric outlet obstruction, a consequence of a large impacted gallstone leading to the formation of a bilioenteric fistula. We present a case of a 79-year-old female who presented with a history of persistent nausea and vomiting. Computed tomography of the abdomen revealed a large gallstone impacted in the second part of the duodenum, complicated by a cholecystoduodenal fistula, leading to gastric outlet obstruction. After nasogastric decompression, the patient underwent an upper gastrointestinal endoscopy and attempted stone retrieval which was unsuccessful. Consequently, she underwent laparotomy, gastrotomy, and extraction of the stone. This case highlights the pitfalls of managing Bouveret syndrome via an endoscopic or an open surgical approach.


Computational prediction of one-electron reduction potentials and acid dissociation constants for guanine oxidation intermediates and products.
Reduction potentials and pK(a) values were calculated for intermediates and products along three major pathways for guanine oxidation using the B3LYP and CBS-QB3 levels of theory with the SMD implicit solvation model. N-methylated nucleobases were used as models for nucleoside species. Ensemble averaged reduction potentials at pH 7 (E7) were obtained by combining calculated standard reduction potentials with calculated pKa values in addition to accounting for tautomerization energies. Calculated pK(a) values are reasonable based on experimental estimates and chemical intuition. Pathway A leads to guanidinohydantoin (Gh) and spiroiminodihydantoin (Sp). The first step is the oxidation of 8-oxoguanine which proceeds by the loss of an electron followed by the loss of two protons and loss of another electron, yielding 8-oxopurine. The calculated E7 values for the remaining intermediates and products are at least 0.3 V higher than that of guanine, indicating that further oxidation of these species is unlikely. Pathway B leads to two formamidopyrimidine isomers (FAPyG and 2,5FAPyG). Species along this pathway have calculated reduction potentials that are much lower than the oxidation potential for guanine and would likely be very short-lived in an oxidatively stressed environment. Pathway C leads to reduced spiroiminodihydantoin and 5-carboxamido-5-formamido-2-iminohydantoin (2Ih). Similar to pathway A, the calculated reduction potentials for species along this pathway are at least 0.4 V higher than that of guanine.


[Intraoperative autohemotransfusion during correction of congenital heart defects].
Autohemotransfusion is one of the perspective methods of transfusion used in cardiosurgery. Intraoperative autohemotransfusion was used in surgical correction of congenital heart diseases in patients of various age groups, including children aged 6 to 8. The exfusion volume made up 300-600 ml, depending on the patient's body mass and the hematologic parameters. Clinical follow-up and assessment of the laboratory parameters have proved the possibility of blood exfusion in the patients with the blue congenital heart disease. Autoblood infusion was performed directly after artificial circulation switch-off, this providing a better hemostasis stabilization and correction of the patient's hemogram. Autoblood volume in blood substitution made up 30% on an average, this saving donor blood.


Lateral specialization and psychiatric issues: speculations on development and the evolution of consciousness.
At the start of this lecture, I invited you to indulge with me in a "dessert" of speculations. I hope it has been a sufficiency, not a surfeit. In summary, we have examined a hypothetical model of some dissociations of consciousness and the expression of unconscious symptoms in adults; we then explored some possible conditions that would account for the development of separate mental streams. In the course of this exploration we were led to question some basic assumptions about the unity of the self, and we proposed some possible mechanisms by which lateral specialization develops in children. This model of the development of lateral specialization has some implications for the study of evolution of the human brain and consciousness. It would seem useful to examine the relationship between the evolution of the commissural systems and the evolution of different capacities for consciousness. According to this model, the full development of lateral specialization depends upon the later myelination of the commissures, which makes possible the autonomy and competition between hemispheres. By this means, only minimal differences between hemispheres need to be specified genetically, since the rest of lateralization can be produced by progressive differentiation, through interactions with the environment. Thus man's eternal, internal struggle may be the price paid for the evolution of lateral specialization.


Gene flow among different taxonomic units: evidence from nuclear and cytoplasmic markers in Cedrus plantation forests.
Hybridization and introgression are important natural evolutionary processes that can be successfully investigated using molecular markers and open- and controlled-pollinated progeny. In this study, we collected open-pollinated seeds from Cedrus atlantica, Cedrus libani and C. libani x C. atlantica hybrids from three French-plantation forests. We also used pollen from C. libani and Cedrus brevifolia to pollinate C. atlantica trees. The progeny were analyzed using three different types of molecular markers: RAPDs, AFLPs and cpSSRs. Chloroplast DNA was found to be paternally inherited in Cedrus from the progeny of controlled-crosses. Heteroplasmy, although possible, could not be undoubtedly detected. There was no indication of strong reproductive isolating barriers among the three Mediterranean Cedrus taxa. Gene flow between C. atlantica and C. libani accounted for 67 to 81% of viable open-pollinated seedlings in two plantation forests. We propose that Mediterranean Cedrus taxa should be considered as units of a single collective species comprising two regional groups, North Africa and the Middle East. We recommend the use of cpSSRs for monitoring gene flow between taxa in plantation forests, especially in areas where garden specimens of one species are planted in the vicinity of selected seed-stands and gene-conservation reserves of another species.


Assessment of molecular similarity from the analysis of randomly generated structural fragment populations.
A novel method termed MolBlaster is introduced for the evaluation of molecular similarity relationships on the basis of randomly generated fragment populations. Our motivation has been to develop a similarity method that does not depend on the use of predefined structural or property descriptors. Fragment profiles of molecules are generated by random deletion of bonds in connectivity tables and quantitatively compared using entropy-based metrics. In test calculations, MolBlaster accurately reproduced a structural key-based similarity ranking of druglike molecules.


Direct injection horse-urine analysis for the quantification and confirmation of threshold substances for doping control. IV. Determination of 3-methoxytyramine by hydrophilic interaction liquid chromatography/quadrupole time-of-flight mass spectrometry.
Levodopa and dopamine have been abused as performance-altering substances in horse racing. Urinary 3-methoxytyramine is used as an indicator of dopaminergic manipulation resulting from dopamine or levodopa administration and is prohibited with a urinary threshold of 4 microg mL(-1) (free and conjugated). A simple liquid chromatographic (LC)/mass spectrometric (MS) (LCMS) method was developed and validated for the quantification and identification of 3-methoxytyramine in equine urine. Sample preparation involved enzymatic hydrolysis and protein precipitation. Hydrophilic interaction liquid chromatography (HILIC) was selected as a separation technique that allows effective retention of polar substances like 3-methoxytyramine and efficient separation from matrix compounds. Electrospray ionization (ESI) in positive mode with product ion scan mode was chosen for the detection of the analytes. Quantification of 3-methoxytyramine was performed with fragmentation at low collision energy, resulting in one product ion, while a second run at high collision energy was performed for confirmation (at least three abundant ions). Studies on matrix effects showed ion suppression depending on the horse urine used. To overcome the variability of the results originating from the matrix effects, isotopic labelled internal standard was used and linear regression calibration methodology was applied for the quantitative determination of the analyte. The tested linear range was 1-20 microg mL(-1). The relative standard deviations of intra- and inter- assay analysis of 3-methoxytyramine in horse urine were lower than 4.2% and 3.2%, respectively. Overall accuracy (relative percentage error) was less than 6.2%. The method was applied to case samples, demonstrating simplicity, accuracy and selectivity.


[Anaerobic reduction of humus/Fe (III) and electron transport mechanism of Fontibacter sp. SgZ-2].
Humus and Fe(III) respiration are important extracellular respiration metabolism. Electron transport pathway is the key issue of extracellular respiration. To understand the electron transport properties and the environmental behavior of a novel Fe(III)- reducing bacterium, Fontibacter sp. SgZ-2, capacities of anaerobic humus/Fe(III) reduction and electron transport mechanisms with four electron acceptors were investigated in this study. The results of anaerobic batch experiments indicated that strain SgZ-2 had the ability to reduce humus analog [ 9,10-anthraquinone-2,6-disulfonic acid (AQDS) and 9,10-anthraquinone-2-sulfonic acid (AQS)], humic acids (HA), soluble Fe(III) (Fe-EDTA and Fe-citrate) and Fe(III) oxides [hydrous ferric oxide (HFO)]. Fermentative sugars (glucose and sucrose) were the most effective electron donors in the humus/Fe(III) reduction by strain SgZ-2. Additionally, differences of electron carrier participating in the process of electron transport with different electron acceptors (i. e. , oxygen, AQS, Fe-EDTA and HFO) were investigated using respiratory inhibitors. The results suggested that similar respiratory chain components were involved in the reducing process of oxygen and Fe-EDTA, including dehydrogenase, quinones and cytochromes b-c. In comparison, only dehydrogenase was found to participate in the reduction of AQS and HFO. In conclusion, different electron transport pathways may be employed by strain SgZ-2 between insoluble and soluble electron acceptors or among soluble electron acceptors. Preliminary models of electron transport pathway with four electron acceptors were proposed for strain SgZ-2, and the study of electron transport mechanism was explored to the genus Fontibacter. All the results from this study are expected to help understand the electron transport properties and the environmental behavior of the genus Fontibacter.


Vascular function and inflammation in rheumatoid arthritis: the role of physical activity.
Inflammation disturbs biochemical pathways involved in homeostasis of the endothelium. Research has established clear links between inflammatory mediators, particularly C-reactive protein and tumour necrosis factor alpha, endothelial dysfunction, and atherosclerosis. Endothelial dysfunction and atherosclerosis may be subclinical at early stages, and thus the ability to detect them with non-invasive techniques is crucially important, particularly in populations at increased risk for cardiovascular disease, such as those with rheumatoid arthritis. This may allow the identification of interventions that may reverse these processes early on. One of the best non-pharmacological interventions that may achieve this is physical activity. This review explores the associations between inflammation, endothelial dysfunction, and atherosclerosis and discusses the role of exercise in blocking specific pathways in the inflammation, endothelial dysfunction - atherosclerosis network.


Factors affecting response of chemotherapy in women with ovarian cancer.
Chemotherapy plays an important role in the treatment of ovarian cancer. Patients' response to chemotherapy is determined by a variety of acknowledged factors, but one might expect that many of them are yet to be described. The aim of this paper was to present the most essential yet still to be generally assessed in clinical practice, factors, which include: E-cadhedrin, hypoxia inducible factor alpha, survivin, COX-2, clusterin, BRCA1 protein, TP53 protein, YY1 protein, multidrug resistance protein, and interleukin-8.


The Intersectionality of Sex and Race in the Relationship Between Posttraumatic Stress Disorder and Cardiovascular Disease: A Scoping Review.
Objectives: Posttraumatic stress disorder (PTSD) has been linked with cardiovascular disease (CVD), suggesting a risk for negative health outcomes among individuals with PTSD. This review synthesizes the temporal relationship between PTSD and CVD and highlights the intersection of sex and race. Methods: Covidence was used to systematically review the literature published between 1980 and 2020. Results: 176 studies were extracted. 68 (38.64%) of the studies were a predominantly male sample. 31 studies (17.61%) were a predominantly female sample. Most reported participants of both sexes (n = 72; 40.91%) and only 5 (2.84%) did not report respondent sex. No studies reported transgender participants. 110 (62.5%) studies reported racial and ethnic diversity in their study population, 18 (10.22%) described a completely or predominantly white sample, and 48 (27.27%) did not report race or ethnicity of their study population. Conclusion: A compelling number of studies did not identify sex differences in the link between PTSD and CVD or failed to report race and ethnicity. Investigating sex, race, ethnicity, and the temporal relationship between PTSD and CVD are promising avenues for future research.


Mesothelial differentiation as reflected by differential gene expression.
Human mesothelial cells obtained from benign effusions retain their proliferative capacity and grow uniformly either with a fibroblastic or epithelioid morphology in vitro. These cultures therefore provide a model for the process of mesothelial differentiation in vivo. To study this differentiation, we isolated differentially expressed genes obtained by suppression subtractive hybridization. Of the nine genes found to be overexpressed in fibroblastic mesothelial cells, three are matrix-associated (integrin alpha5, collagen binding protein 2, human cartilage glycoprotein 39), whereas the others are associated with a proliferative cell type (14-3-3 epsilon, plexin B2, N33, and three genes encoding ribosomal elements). Seven of the eight genes upregulated in the epithelioid phenotype are related rather to specialized functions, such as metabolism (aldose reductase, lecithin:cholesterol acyltransferase, ATPase 6), cytoskeletal composition (cytokeratins 7 and 8), and regulation of differentiation (granulin, annexin II). Immunohistochemistry with available antibodies to six of the differentially expressed gene products confirmed the differences also in pleural tissues, where submesothelial cells displayed the fibroblastic markers, whereas surface cells displayed the epithelioid markers. In summary, this approach revealed a pattern of genes coordinately regulated during mesothelial differentiation and suggests that mesothelium may regenerate also by recruiting cells from the submesothelial layer. Some of the gene products may also be useful markers for differentiation and activation in serosal tissues.


[High-risk percutaneous coronary intervention using hemodynamic support device eight years after transcatheter aortic valve implantation].
Coronary artery disease is a frequent comorbidity in patients with severe aortic stenosis undergoing trans-catheter aortic valve implantation (TAVI) and the need to ensure coronary access after TAVI is fundamental. This aspect is becoming increasingly relevant as TAVI indication expand to younger and lower-risk patients. Moreover, the longer life expectancy of subjects who are currently treated with TAVI could result in an increased need for TAVI-in-TAVI due to valve degeneration. As the implantation of a second transcatheter bioprosthesis might impair coronary access, TAVI-in-TAVI will be unfeasible in a significant proportion of cases, particularly if they received a tall-frame transcatheter heart valve at the time of the first intervention. Thus, patients might experience the paradox of needing surgical aortic valve replacement when they are older and frailer. Here we report the case of a patient with history of coronary artery disease and severe aortic stenosis treated with TAVI, presenting with an acute coronary syndrome 8 years after percutaneous aortic valve implantation. Thanks to the low frame height of the transcatheter aortic valve, it was possible to easily perform coronary angiography and high-risk percutaneous coronary intervention using hemodynamic support device (Impella CP). Moreover, this case highlights how the implantation of a low-frame transcatheter prosthesis can increase the possibility of achieving coronary access even after TAVI-in-TAVI, if needed.


Complete Revascularization of Reimplanted Talus After Isolated Total Talar Extrusion: A Case Report.
Total traumatic extrusion of the talus is a rare and disabling ankle injury. Treatment may include talar reimplantation or talar body removal, but an optimal treatment protocol has not yet been established. Several case reports showed that disruption of the vascular supply and contamination could lead to major complications, such as infection and avascular necrosis, with the high risk of these complications being associated with both the traumatic ankle injury itself and subsequent talar reimplantation. No report to date has described the revascularization of a completely extruded talus, as shown by serial MRI, a less invasive surgical strategy consisting of immediate reimplantation, early administration of antibiotics, and a short period of cast immobilization followed by early motion exercises. The present study describes complete revascularization and good clinical outcomes in a 30-year-old man who underwent talus reimplantation after isolated total talar extrusion.


An interprofessional programme to culturally sensitise students to the needs of patients and realities of practice in rural areas.
The University of North Dakota programme, Students/residents Experiences And Rotations in Community Health (SEARCH), was implemented to address recruitment and retention problems and stereotypes associated with practicing in rural areas by providing an opportunity for health profession students to gain experience living and practicing in rural areas and observing interprofessional practice. Each health profession student in the programme (n = 181) from 2001 to 2011 (excluding 2009) kept a four-week journal detailing daily or weekly interactions, general thoughts, and experiences. Students who participated were from medical, psychology, dental, social work, nurse practitioner, and physician assistant professions. Results were grouped into three major themes around whether the experience increased their knowledge of healthcare issues in rural areas in North Dakota, increased their knowledge about interprofessional teams, and expanded their rural awareness. Overall, students valued this interprofessional experience, learned how to work in collaborative teams, and reported having a better understanding of the needs and problems in rural healthcare. Recruitment and retention of healthcare professionals in rural healthcare exhibit many challenges. The SEARCH programme has helped to alleviate some of these challenges; however, continued support for these programmes is necessary to sustain the delivery of interprofessional healthcare in rural areas.


The map kinase ERK regulates renal activity of cyclin-dependent kinase 2 in experimental glomerulonephritis.
In vitro, the extracellular signal-regulated kinase (ERK) is an intracellular convergence point of multiple stimuli, which affect the cell cycle. However, the role of ERK in cell cycle regulation in vivo is unknown. To address this issue, ERK activity was blocked both in vitro in mesangial cells (MC) and in vivo in experimental glomerulonephritis (GN) by a pharmacological inhibitor (U0126) of the ERK-activating kinase. In stimulated MC, inhibition of ERK reduced cyclin-dependent kinase 2 (CDK2) phosphorylation, CDK2 activity and cyclin E/A expression, whereas downregulation of CDK inhibitor p27(Kip1) expression was inhibited. In vivo, U0126 was given to rats in the acute phase of anti-Thy 1.1 GN. We previously showed that glomerular cell proliferation was reduced by 67% upon treatment with the inhibitor compared to nephritic controls. Now, we detected a significant increase in renal CDK2-activity/phosphorylation in the nephritic controls, that was significantly and dose-dependently reduced by ERK inhibition. CDK2 activation was accompanied by an increase in renal expression of cyclins E/A and the enhanced binding of these cyclins to CDK2 in the nephritic controls. These changes were blunted by U0126 treatment. Finally, we noted an increased expression and CDK2-binding of p27(KIP1) protein in the nephritic controls which was decreased in U0126 treated rats. Our observations provide the first evidence that ERK is an intracellular regulator of renal CDK2 activity in vivo in a glomerulonephritis model.


Structural aspects of survivors' thinking about the Holocaust.
Videotaped interviews of 30 Holocaust survivors were scored for integrative complexity, the recognition of alternate perspectives or dimensions of a topic ("differentiation") and the joint consideration of several perspectives or dimensions ("integration"). Memories showed decreased differentiation and integration as they moved from pre-war life to the shock and upheaval when organized persecution began. High complexity levels reflected survivors mustering their resources to enhance their chances of survival and successful postwar adaptation. These findings demonstrate the usefulness of quantitative, objective content analytic methods in Holocaust survivor research, add a cognitive dimension to the study of survival during and after extreme situations, and confirm theoretical propositions about decision making and information processing under stress.


Frail phenotype might herald bone health worsening among end-stage renal disease patients.
Frailty exhibits a high prevalence in end-stage renal disease (ESRD) patients and is associated with adverse health-related outcomes, including falls and fractures. Available studies do not address whether frailty is associated with temporal changes in BMD. We evaluated this issue by analyzing the follow-up dual energy X-ray absorptiometry (DXA) results in an ESRD cohort. In 2015, we enrolled forty-three ESRD patients, divided into frail, pre-frail, and robust ones based on a validated simple FRAIL scale, all receiving DXA at baseline. After one year of follow-up, survivors received another DXA, and we calculated the absolute and percentage changes in area, bone mineral density (BMD), T-, and Z-scores of lumbar spine and femoral neck (FN) between baseline and follow-up examinations. Among all, frail individuals with ESRD had significantly lower average lumbar spine area, lower L4, FN, and total BMD and T-scores, lower FN and total Z-scores than non-frail ones, without differences in gender, body mass index, dialysis duration, and comorbidities. Furthermore, we discovered frail ESRD patients had significantly more prominent decrease in average lumbar spine area, percentage changes in L1 Z-scores and average lumbar spine area, and a trend toward more prominent decrease in L4 area than non-frail ones after one year of follow-up. Baseline frailty might be associated with deteriorating bone health, including shrinking L-spine areas and a more rapid decrease in L-spine Z scores, among ESRD patients. This frailty-bone association should be highlighted during our care of frail individuals with ESRD.


Contributions to Estimation of Polychoric Correlations.
This research concerns the estimation of polychoric correlations in the context of fitting structural equation models to observed ordinal variables by multistage estimation. The first main contribution of this research is to propose and evaluate a Monte Carlo estimator for the asymptotic covariance matrix (ACM) of the polychoric correlation estimates. In multistage estimation, the ACM plays a prominent role, as overall test statistics, derived fit indices, and parameter standard errors all depend on this quantity. The ACM, however, must itself be estimated. Established approaches to estimating the ACM use a sample-based version, which can yield poor estimates with small samples. A simulation study demonstrates that the proposed Monte Carlo estimator can be more efficient than its sample-based counterpart. This leads to better calibration for established test statistics, in particular with small samples. The second main contribution of this research is a further exploration of the consequences of violating the normality assumption for the underlying response variables. We show the consequences depend on the type of nonnormality, and the number and location of thresholds. The simulation study also demonstrates that overall test statistics have little power to detect the studied forms of nonnormality, regardless of the ACM estimator.


Development of functional diversity in mouse macrophages. Mutual exclusion of two phenotypic states.
The objective of this study was to investigate the mechanisms that contribute to the generation of macrophage functional diversity. Exposure of mouse bone marrow-derived macrophages to beta-1,3-glucan, a particulate inflammatory stimulus, or polyinosinate-polycytidylate (poly[I:C]), a stimulus of macrophage cytocidal activation, induced distinct and stimulus-specific patterns of gene expression. These changes were characterized by an up-regulation of the expression of the acid hydrolase beta-glucuronidase and platelet-derived growth factor B following incubation with beta-1,3-glucan and a stimulation of the expression of the complement component Bf, beta-interferon, and the reactive nitrogen intermediates NO2/NO3 during incubation with poly[I:C]. The induction of Bf expression by poly[I:C] could not be explained on the basis of distinct subpopulations of cells since in situ hybridization with a mouse Bf cRNA probe revealed a uniform and substantial increase in Bf expression by the entire population of cells. Incubation of macrophages with beta-1,3-glucan before stimulation with poly[I:C] was found to strongly attenuate the expression of Bf and beta-interferon. Conversely, incubation with poly[I:C] prior to exposure to beta-1,3-glucan substantially blocked the stimulation of beta-glucuronidase and platelet-derived growth factor B expression, indicating that these two responses were expressed in a mutually antagonistic fashion. However, after removal of either stimulus and following a period in which the primary response was allowed to decay, the cells regained their capacity to subsequently respond to either the same stimulus or to a different stimulus. Collectively, these findings indicate, first, that the heterogeneity of gene expression seen in response to poly[I:C] represents an adaptive response of the entire macrophage population rather than the restricted responses of distinct subpopulations of cells. Second, macrophages respond to these stimuli in a sequential fashion. These findings thus have a significant bearing on our understanding of the regulation of macrophage heterogeneity in host defense.


Effects of relaxin on rat atrial myocytes. I. Inhibition of I(to) via PKA-dependent phosphorylation.
The peptide hormone relaxin has direct, positive inotropic and chronotropic effects on rat hearts in vivo and in vitro. Relaxin's effects on the electrophysiological properties of single quiescent atrial cells from normal rats were investigated with a whole cell patch clamp. Relaxin had a significant inhibitory effect on outward potassium currents. The outward potassium current consisted of a transient component (I(to)) and a sustained component (I(S)). The addition of 100 ng/ml of relaxin inhibited the peak I(to) in a voltage-dependent manner (74% inhibition at a membrane potential of -10 mV to 30% inhibition at +70 mV). The time to reach peak I(to) and the apparent time constant of inactivation of I(to) were increased by relaxin. Dialysis with the protein kinase A inhibitor 5-24 amide (2 microM) prevented relaxin's effects, suggesting an obligatory role for this kinase in the relaxin-dependent regulation of the potassium current.


Evaluation of infection and nutritional status as determinants of cellular immunosuppression.
While an association between severe protein-energy malnutrition and diminished cellular immunity has been documented, the impact of lesser grades of malnutrition on cellular immunosuppression is less clear. This study emphasizes that the relationship between mild-to- moderate malnutrition and cellular immune function, assessed through delayed-type hypersensitivity testing, is often obscured by the immunosuppressive effects of concurrent infection. Results from an 18-month prospective field study of nutritional status, cellular immune function and morbidity among 62 nomadic Turkana children ages 8 months to 10 years were used to quantify the immunosuppressive effects of mild-to-moderate malnutrition and infection. When controlling for infection at the time of DTH testing, children below -2 s.d. of the reference median weight- for-height or weight-for-age were at least 3 times as likely to be anergic (non-responsive) as children at the reference median. At the same time, infected children experienced a 4.9 times higher risk of being anergic compared to uninfected children. These findings suggest that mild-to-moderate malnutrition and infection are significant independent risk factors for impaired cellular immune function among Turkana children. Am. J. Hum. Biol. 9:381-390, 1997. © 1997 Wiley-Liss, Inc.


Note: Low density and long plasma channels generated by laser transversely ignited ablative capillary discharges.
A technique is developed to reduce the jitter associated with ablative capillary discharges. A laser pulse propagating perpendicularly to the axis of the capillary and focused onto a copper wire creates a plasma that initiates the discharge. This transverse laser ignition method has several advantages over previous techniques employing a laser pulse collinear with the capillary, including increased capillary lifetime and simpler arrangement of the igniting and the driving pulses for laser-wakefield acceleration. Using this technique long, low density plasma channels are produced with low jitter.


[Clinical observation on nanometer acupoint mounting method for alleviation of myospasm complicated by spinal injury].
To observe clinical effect of nanometer acupoint mounting method for alleviation of myospasm complicated by spinal injury. Sixty cases were randomly divided into an observation group and a control group, 30 cases in each group. The observation group were treated by nanometer mounting at 4 Jiaji (EX-B 2) points each on both sides of the affected spine and Shenshu (BL 23), Shangliao (BL 31), Ciliao (BL 32), Yang-lingquan (GB 34), Xuanzhong (GB 39); and the control group by mounting zinc oxide sticking tablets at the above acupoints. The mounting was replaced once each two days, 7 times constituting one course. One week and one month after the end of 3 courses, their results were recorded, respectively. Before treatment, there was no significant difference between the two groups in grades of the myospasm degree (P > 0.05). One week after the end of treatment, 15 cases were grade I of myospasm, 9 cases were grade II, 5 cases were grade III and 1 case was grade IV in the observation group, and 1 cases grade I, 7 cases grade II, 14 cases grade III, 8 cases grade IV in the control group. Ridit analysis on the data indicated that there were significant differences before and after treatment in the myospasm degree (P < 0.01) and between the two groups after treatment (P < 0.01). One month after the end of treatment, the results were similar to those one week after the end of treatment. Nanometer acupoint mounting method is a new one for alleviation of myospasm complicated by spinal injury, with convenience, safety and no side effect.


The effect of N-terminal changes on arginyl-tRNA synthetase from Escherichia coli.
An Asn(2) deleted mutant of Escherichia coli arginyl-tRNA synthetase deleted Asn(2) and a chimera mutant, in which the N-terminal 23 amino acid residues of yeast arginyl-tRNA synthetase were appended to the N-terminus of Escherichia coli synthetase, were synthesized and studied. The expression of the deletion and chimera mutants in Escherichia coli formed inclusion bodies, presumably due to improper folding of the proteins. Relative to the native enzyme, the deletion mutant showed full amino acid activation activity and a 26% reduction in aminoacylation activity, while the chimera mutant lost 93% and 96% activities in aminoacid activation and aminoacylation, respectively, and did not aminoacylate yeast tRNA(Arg) at all. The mutant deleted Asn(2) and Ile(3) was able to be expressed in Escherichia coli but not stable to be purified. The emission maximum wavelength in the fluorescence spectra of the chimera mutants shifted to longer one and the corresponding intensities decreased, when compared with those of the native enzyme. The data show that the conformation of the mutants are different and the tryptophan residues in the mutants are more exposed than those in the native enzyme. An estimate of the secondary structure of the mutant enzymes from their far ultraviolet CD spectra showed that the chimera mutant contained less alpha-helix, more beta-sheet and slightly higher fraction of random coil, as compared with the native enzyme. The results indicate that an intact N-terminal domain of E.coli arginyl-tRNA synthetase is important to its activity and correct folding.


Microporous Lead-Organic Framework for Selective CO2 Adsorption and Heterogeneous Catalysis.
A novel microporous metal-organic framework, {[Pb4(μ8-MTB)2(H2O)4]·5DMF·H2O}n (1; MTB = methanetetrabenzoate and DMF = N,N'-dimethylformamide), was successfully synthesized by a solvothermal reaction and structurally characterized by single-crystal X-ray diffraction. The framework exhibits a unique tetranuclear [Pb4(μ3-COO)(μ2-COO)6(COO)(H2O)4] secondary building unit (SBU). The combination of the SBU with the tetrahedral symmetry of MTB results in a three-dimensional network structure, with one-dimensional jarlike cavities having sizes of about 14.98 × 7.88 and 14.98 × 13.17 Å2 and propagating along the c axis. Due to the presence of four coordinately unsaturated sites per one metal cluster, an activated form of compound 1 (i.e., desolvated form denoted as 1') was tested in gas adsorption and catalytic experiments. The studies of gas sorption revealed that 1' exhibits a surface area (Brunauer-Emmett-Teller) of 980 m2·g-1. This value is the highest reported for any compound from the MTB group. Interactions of carbon dioxide (CO2) molecules with the framework, confirmed by density functional theory calculations, resulted in high CO2 uptake and significant selectivity of CO2 adsorption with respect to methane (CH4) and dinitrogen (N2) when measured from atmospheric pressure to 21 bar. The high selectivity of CO2 over N2 is mostly important for capturing CO2 from the atmosphere in attempts to decrease the greenhouse effect. Moreover, compound 1' was tested as a heterogeneous catalyst in Knoevenagel condensation of active methylene compounds with aldehydes. Excellent catalytic conversion and selectivity in the condensation of benzaldehyde and cyclohexanecarbaldehyde with malononitrile was observed, which suggests that accessible lead(II) sites play an important role in the heterogeneous catalytic process.


Design and properties of efficient tRNA:EF-Tu FRET system for studies of ribosomal translation.
Formation of the ternary complex between GTP-bound form of elongation factor Tu (EF-Tu) and aminoacylated transfer RNA (aa-tRNA) is a key event in protein biosynthesis. Here we show that fluorescently modified Escherichia coli EF-Tu carrying three mutations, C137A, C255V and E348C, and fluorescently modified Phe-tRNA(Phe) form functionally active ternary complex that has properties similar to those of the naturally occurring (unmodified) complex. Similarities include the binding and binding rate constants, behavior in gel retardation assay, as well as activities in tRNA protection and in vitro translation assays. Proper labeling of EF-Tu was demonstrated in MALDI mass spectroscopy experiments. To generate the mutant EF-Tu, a series of genetic constructions were performed. Two native cysteine residues in the wild-type EF-Tu at positions 137 and 255 were replaced by Ala and Val, respectively, and an additional cysteine was introduced either in position 324 or 348. The assembly FRET assay showed a 5- to 7-fold increase of Cy5-labeled EF-Tu E348C mutant fluorescence upon formation of ternary complex with charged tRNA(Phe)(Cy3-labeled) when the complex was excited at 532 nm and monitored at 665 nm. In a control experiment, we did not observe FRET using uncharged tRNA(Phe)(Cy3), nor with wild-type EF-Tu preparation that was allowed to react with Cy5 maleimide, nor in the absence of GTP. The results obtained demonstrate that the EF-Tu:tRNA FRET system described can be used for investigations of ribosomal translation in many types of experiments.


Pumping of nuclear spins by optical excitation of spin-forbidden transitions in a quantum dot.
We demonstrate that efficient optical pumping of nuclear spins in semiconductor quantum dots (QDs) can be achieved by resonant pumping of optically forbidden transitions. This process corresponds to one-to-one conversion of a photon absorbed by the dot into a polarized nuclear spin, and also has potential for initialization of hole spin in QDs. We find that by employing this spin-forbidden process, nuclear polarization of 65% can be achieved, markedly higher than from pumping the allowed transition, which saturates due to the low probability of electron-nuclear spin flip-flop.


Recent Advances in the Neoadjuvant Treatment of Breast Cancer.
In the last few decades, neoadjuvant therapy for breast cancer has gained considerable therapeutic importance. Despite extensive clinical investigations, it has not yet been clarified whether neoadjuvant therapy would result in improved survival in comparison with the standard adjuvant setting in any subgroups of patients with breast cancer. Chemotherapy is especially effective in the treatment of endocrine insensitive tumors, and such ther-apeutic benefit can be assumed for patients with triple-negative, or hormone receptor-negative and human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, dose escalation, modification of the therapeutic regimens according to early tumor response, as well as the optimal sequence of administration are still matters of debate. There is a current debate between clinical experts regarding the concomitant and sequential administration of carboplatin and capecitabine, respectively, as part of the standard neoadjuvant treatment, as well as the use of bevacizumab, as part of the preoperative treatment. In case of HER2 positive tumors, an anti-HER2 agent can be administered as part of the preoperative treatment, and according to preliminary clinical data, dual HER2 blockade can also be reasonable. Further, chemotherapy-free regimens can be justified in highly endocrine sensitive tumors, while immune modulating agents may also gain particular importance in the case of certain subtypes of breast cancer. Several small-molecule targeted therapies are under clinical investigation and are expected to provide new neoadjuvant treatment options. However, novel, more predictive biomarkers are required for further evaluation of the neoadjuvant therapies, as well as the effect of novel targeted agents intended to be incorporated into neoadjuvant therapy.


Percutaneous histopathologic evaluation of liver in treatment of non-Hodgkin's lymphoma.
The results of 25 percutaneous biopsies of the liver from 24 patients with non-Hodgkin's lymphoma are reported. In all cases, the value of their serum biochemistry (LDH, GOT, GPT and/or alkaline phosphatase) was abnormal and sufficient tissue material was biopsied to obtain a histopathological evaluation. Specimens from five ultrasonically suspected lymphoma of the liver showed tumor involvement histopathologically. Diffuse tumor involvement was also histologically found in three ultrasonically unsuspected livers. Six liver specimens showed degenerative and/or fibrotic change in the new and previously treated patients.


[Current State of Family-Based Prevention and Therapy of Substance-Use Disorders in Children and Adolescents: A Review].
Current State of Family-Based Prevention and Therapy of Substance-Use Disorders in Children and Adolescents: A Review Adolescence is a vulnerable period for substance use disorders (SUD) as indicated by epidemiological studies. Research demonstrates the family's role for the etiology of SUD and provides a rationale for interventions based on family-associated risk and resilience factors. In this article, we summarize published results for family-based interventions from 2008-2018. Taken together, prevention programs can be effective when they focus on the promotion of broader developmental competencies and familial resources, rather than narrowly addressing substance use. Moreover, programs could benefit from targeting youth and parents as done in the "Strengthening Families Program 10-14"; most existing programs however target parents and do not include the adolescents. Family-based treatment programs with an evidence base are Multisystemic Therapy, Functional Family Therapy, Multidimensional Family Therapy and Brief Strategic Family Therapy. Overall, the effects of family-based interventions are small-to-middle sized but vary significantly across populations. Across the field of family-based interventions, there is a need for more knowledge on effective components and differential effects. The results could be improved by translational research such as on the emerging concept of mindfulness. Moreover, there is a need for implementation research and the effectiveness of service delivery programs on the community level in Germany.


The Senator and the Sting Operation: Politics, the Media, and Frank Moss's Exposé of "Medicaid Mills".
In September 1975, Frank Moss, an eighteen-year veteran of the Senate from Utah, donned the scruffiest clothes he could find and walked into a small clinic in New York that catered to Medicaid patients. Using a phony Medicaid card supplied to him by a New York District Attorney, he posed as a patient with symptoms he feigned to assess the quality of care he would receive. Appalled by what he experienced, he and a team of staffers from his office embarked on a four-state tour of what he termed "Medicaid mills," visiting more than 200 clinics in an undercover investigation that exposed alarming levels of provider fraud and abuse of the government health insurance system. This dramatic expose was covered by CBS's widely watched Sunday-night news program 60 Minutes. The subsequent Senate hearings were a media sensation, leading to accusations that the Senator was "grandstanding." This article looks at the political climate in which the congressional sting operation, the media attention it garnered, and the subsequent legislation enacted sought to address a persistent, growing problem of fraud and abuse in Medicare and Medicaid. The article argues that Moss's effort was an example of entrepreneurial politics, as defined by Craig Volden and Alan Wiseman in 2016, and something more as well. Moss was reacting to a political setting in which the legitimate authority of political institutions, including Congress, had been called into question by the Watergate scandal and other revelations. At the same time, organized medicine in America was dealing with its own version of this challenge to its authority. The result was a dramatic episode that focused on fraud and abuse in the ten-year-old Medicare program and that raised wider questions about changes in cultural authority in politics and medicine.


[Cardiorenal links in systemic amyloidosis].
The paper gives current general data on the structure of amyloid fibril and the principles in the classification of amyloidosis, information on the clinical course of cardiac and renal involvements in systemic AL and AA amyloidosis, and that on diagnostic and prognostic criteria and the specific features of cardiorenal links. The authors draw the conclusion that the identification of acute and chronic cardiorenal links is of practical value for systemic amyloidosis. Cardiorenal and renocardiac syndromes are not always differentiated clearly in the systemacy of involvement.


Effective use of the built environment to manage behavioural and psychological symptoms of dementia: a systematic review.
To determine the effectiveness of built environment interventions in managing behavioural and psychological symptoms of dementia (BPSD) among residents in long-term care settings. Systematic review of literature published from 1995-2013. Studies were included if they: were randomized controlled trials, quasi-experimental trials, or comparative cohort studies; were in long-term or specialized dementia care; included residents with dementia and BPSD; and examined effectiveness of a built environment intervention on frequency and/or severity of BPSD. Quality of included studies was assessed using the Downs and Black Checklist. Study design, patient population, intervention, and outcomes were extracted and narratively synthesized. Five low to moderate quality studies were included. Three categories of interventions were identified: change/redesign of existing physical space, addition of physical objects to environment, and type of living environment. One of the two studies that examined change/redesign of physical spaces reported improvements in BPSD. The addition of physical objects to an existing environment (n = 1) resulted in no difference in BPSD between treatment and control groups. The two studies that examined relocation to a novel living environment reported decreased or no difference in the severity and/or frequency of BPSD post-intervention. No studies reported worsening of BPSD following a built environment intervention. The range of built environment interventions is broad, as is the complex and multi-dimensional nature of BPSD. There is inconclusive evidence to suggest a built environment intervention which is clinically superior in long-term care settings. Further high-quality methodological and experimental studies are required to demonstrate the feasibility and effectiveness of such interventions.


Role of personality traits for entrepreneurial intentions of young entrepreneurs: A case study of higher education institution.
Pakistan being a young country is struggling to provide employment opportunities. However, entrepreneurship is a perceived strategy for reducing unemployment. The trend of entrepreneurship is also emerging among university students. Thus, the ratio of entrepreneurial intention and start-ups is also increasing among university students and graduates. Therefore, this study aims to examine the role of personality traits in the entrepreneurial intentions of young entrepreneurs. Considering this, qualitative methodology was employed with the case study as the research design. A single case of a university with three different departments was taken. In total, n = 9 entrepreneurs were purposely selected from business (n = 3), computer science (n = 3), and education (n = 3) departments. The data were collected using semi-structured interviews and documentary analysis of their ventures and success stories. This study followed research ethics, including volunteer participation, confidentiality, and reciprocity. The collected data were analyzed using interpretative phenomenological analysis. The findings reveal three main themes: the desire to be an entrepreneur, learning attitude, and personality traits are the leading factors in the entrepreneurial intentions of students and graduates. However, within these themes, the effect of personality traits (consistency and determination, discipline and locus of control, and risk-taking and tolerance) is found to lead to entrepreneurial intentions among young entrepreneurs. This study concludes that most entrepreneurs believe that the role of personality traits is evident in entrepreneurial intentions. Moreover, the personality traits are further strengthened with entrepreneurial experience and help continue entrepreneurship.


Quantitative comparison of cerebral glucose metabolic rates from two positron emission tomographs.
The rapid progress in positron emission tomography technology has created the dilemma of how to compare data from old and new tomographs. We examined cerebral metabolic data from two scanners, with different spatial resolutions and methods of attenuation correction, to see if data from the lower resolution tomograph (ECAT II) could be "corrected" and then compared to data from the higher resolution scanner (Scanditronix PC1024-7B). Nine subjects were scanned on both tomographs after a single injection of [18F]2-fluoro-2-deoxy-D-glucose. Regional and lobar gray matter metabolic rates for glucose were obtained from comparable images from each scanner. Ratios of lobar to global gray matter metabolism also were calculated. Regression coefficients and percent differences were computed to compare ECAT II and PC1024 data. Twenty-four of the 36 regions showed significant regression slopes, and PC1024 measures of glucose utilization ranged from 30% to 120% higher than those from the ECAT II. Lobar differences between the two machines were less variable (50% to 80%), and ratios generally differed by only +/- 5%. Since there was no simple and consistent relation between regional metabolic rates on the two tomographs, an overall adjustment of regional ECAT values for comparison to PC1024 values would be impossible. A region-by-region adjustment would be necessary. On the other hand, ratios are sufficiently similar that direct comparisons could be made.


Improving the miscibility of biodegradable polyester/polyphosphazene blends using cross-linkable polyphosphazene.
Biodegradable polyesters and polyphosphazenes are both promising biomaterials for tissue regeneration. A combination of both materials would provide additional advantages over the individual components in aspects of biocompatibility and osteocompatibility. Applications of polyester/polyphosphazene composites, however, were limited due to the severe phase separation. In this study, cross-linkable poly(glycine ethyl ester-co-hydroxyethyl methacrylate)phosphazene (PGHP) was synthesized. It was blended with poly(L-lactide) (PLLA) or poly(L-lactide-co-glycolide) (PLGA), using chloroform as a mutual solvent, and photo-crosslinked before solvent removal. The resulting PLLA (or PLGA)/PGHP composites demonstrated no significant phase separation due to the restricting function of the crosslinked PGHP polymeric network. In comparison with uncrosslinked blends, the mechanical properties of crosslinked composites were remarkably improved, which indicated their strong potential in bone regeneration applications.


Conformations of silicon-containing rings. 5. Conformational properties of 1-methyl-1-silacyclohexane: gas electron diffraction, low-temperature NMR, and quantum chemical calculations.
The molecular structure of 1-methyl-1-silacyclohexane 3 has been determined by gas electron diffraction (GED). The conformational preference of the methyl group was studied experimentally in the gas phase (GED) and in solution (low-temperature (13)C NMR) and by quantum chemical calculations (HF, MP2, and B3LYP with 6-31G basis sets and mPW1PW91/6-311G(2df,p)). Both experimental methods result in a preference of the equatorial position of the methyl group, 68(7)% in the gas phase at 298 K and 74(1)% in solution at 110 K. The calculations predict 68-73% equatorial conformer at room temperature. From coalescence temperatures, Gibbs free energies of activation for ring inversion DeltaG++ (eq --> ax) = 5.81(18) and DeltaG++ (ax --> eq) = 5.56(18) kcal mol(-1) were derived. The calculated values for DeltaG++ (eq --> ax) are 5.92 (B3LYP) and 5.84 kcal mol(-1) (mPW1PW91).


The Dlx5 and Dlx6 homeobox genes are essential for craniofacial, axial, and appendicular skeletal development.
Dlx homeobox genes are mammalian homologs of the Drosophila Distal-less (Dll) gene. The Dlx/Dll gene family is of ancient origin and appears to play a role in appendage development in essentially all species in which it has been identified. In Drosophila, Dll is expressed in the distal portion of the developing appendages and is critical for the development of distal structures. In addition, human Dlx5 and Dlx6 homeobox genes have been identified as possible candidate genes for the autosomal dominant form of the split-hand/split-foot malformation (SHFM), a heterogeneous limb disorder characterized by missing central digits and claw-like distal extremities. Targeted inactivation of Dlx5 and Dlx6 genes in mice results in severe craniofacial, axial, and appendicular skeletal abnormalities, leading to perinatal lethality. For the first time, Dlx/Dll gene products are shown to be critical regulators of mammalian limb development, as combined loss-of-function mutations phenocopy SHFM. Furthermore, spatiotemporal-specific transgenic overexpression of Dlx5, in the apical ectodermal ridge of Dlx5/6 null mice can fully rescue Dlx/Dll function in limb outgrowth.


Orthogonal supramolecular protein assembly on patterned bifunctional surfaces.
We report successful and selective dual protein assembly on patterned bifunctional βCD-Ni(ii)NTA surfaces, using red fluorescent protein variants with hexahistidine-tags and teal fluorescent protein variants conjugated with a peptide containing three adamantyl groups. We show that dual protein patterns can only be assembled, when opposing supramolecular interactions have been optimized and nonspecific interactions have been sufficiently suppressed.


Development of risk perception and substance use of tobacco, alcohol and cannabis among adolescents and emerging adults: evidence of directional influences.
While several studies have investigated the relationship between risk perception and substance use, surprisingly little is known about mutual influences between both variables over time. The present study aimed to explore two different hypotheses separately for tobacco, alcohol and cannabis: influences from risk perception on behavior (motivational hypothesis) and influences from behavior on risk perception (risk reappraisal hypothesis). A prospective and longitudinal cross-lagged panel design was used with substance use and risk perception measured five times over the course of 10 years. Participants were 318 German youths aged 14-15 at the beginning of the study. Risk perception and substance use frequency were measured using self-reports. Structural equation modeling indicated significant influences of risk perception on substance use behavior for all substances, which supports the motivational hypothesis. Changes in risk perception predict changes in future substance use of tobacco, alcohol and cannabis. Specifically for cannabis, influences of substance use on risk perception can also be shown, thus, supporting the risk reappraisal hypothesis. While there is support for the rationale behind adequate risk perception as a goal of preventive interventions, the possibility of risk reappraisal should not be neglected, especially regarding illicit substances.


Homogenate-assisted Vacuum-powered Bubble Extraction of Moso Bamboo Flavonoids for On-line Scavenging Free Radical Capacity Analysis.
A homogenate-assisted vacuum-powered bubble extraction (HVBE) method using ethanol was applied for extraction of flavonoids from Phyllostachys pubescens (P. pubescens) leaves. The mechanisms of homogenate-assisted extraction and vacuum-powered bubble generation were discussed in detail. Furthermore, a method for the rapid determination of flavonoids by HPLC was established. HVBE followed by HPLC was successfully applied for the extraction and quantification of four flavonoids in P. pubescens, including orientin, isoorientin, vitexin, and isovitexin. This method provides a fast and effective means for the preparation and determination of plant active components. Moreover, the on-line antioxidant capacity, including scavenging positive ion and negative ion free radical capacity of different fractions from the bamboo flavonoid extract was evaluated. Results showed that the scavenging DPPH˙ free radical capacity of vitexin and isovitexin was larger than that of isoorientin and orientin. On the contrary, the scavenging ABTS⁺˙free radical capacity of isoorientin and orientin was larger than that of vitexin and isovitexin.


Replication kinetics of Marek's disease vaccine virus in feathers and lymphoid tissues using PCR and virus isolation.
CVI988 (Rispens), an avirulent strain of Marek's disease virus, is the most widely used vaccine against Marek's disease. The kinetics of replication of CVI988 was examined in tissues of chickens vaccinated at either 1 day or 14 days of age and sampled regularly up to 28 days post-vaccination. Age at vaccination had no significant effect on the kinetics of CVI988 virus replication. During the cytolytic phase of infection (1-7 days), virus levels peaked in the spleen, bursa and thymus with very close correlation among these organs. Virus load in peripheral blood lagged behind and did not reach high levels. Significant numbers of virus genomes were detected in the feather tips only after 7 days, but subsequently rose to levels almost 10(3)-fold greater than in the other tissues. This is the first accurate quantitative data for kinetics of CVI988 replication in a variety of tissues. There was good correlation between data from virus isolation and PCR, with real-time PCR being the preferred method for rapid, accurate and sensitive quantification of virus. Feathers were ideal for non-invasive sampling to detect and measure CVI988 in live chickens and, from 10 days onwards, virus load in feather tips was predictive of virus load in lymphoid tissues where immune responses will occur. The potential for real-time PCR analysis of feather samples for further investigation of the mechanism of vaccinal protection, and to assist optimization of vaccination regimes, is discussed.


[Analysis of SLC25A13 gene mutations and prenatal diagnosis for 20 families affected with citrin deficiency].
To detect mutations of SLC25A13 gene in 20 families affected with citrin deficiency and provide prenatal diagnosis for them. The 20 probands and their parents were subjected to high-frequency mutation screening combined with Sanger sequencing. After confirming the genotype of each pedigree, genetic counseling and prenatal diagnosis were performed for their subsequent pregnancies. Biallelic pathogenic mutations of the SLC25A13 gene were identified in all probands. These included three deletions (c.851del4, c.1092_1095delT, and c.495delA), two splice-site mutations (IVS6+5G to A and IVS11+1G to A), two nonsense mutations (c.775C to T (p.Q259X) and c.72T to A (p.Y24X)), one duplication mutation (c.1638_1660dup), one insertion (IVSl6ins3kb), and one missense mutation (c.1775A to C (p.Q592P)). Among 24 fetuses undergoing prenatal diagnosis, 8 had normal genotypes, 11 were mutation carriers, while 5 harbored biallelic mutations. Those with wild type alleles or heterozygous SLC25A13 mutations were delivered. Two fetuses harboring homozygous c.851del4 mutations were also delivered. Three fetuses harboring biallelic mutations were terminated. Analysis of SLC25A13 gene mutations in families affected by citrin deficiency can provide evidence for molecular diagnosis and facilitate genetic counseling and prenatal diagnosis for the subsequent pregnancy, which can effectively reduce the risk of birth of further affected children.


Emotionally Intelligent People Use More High-Engagement and Less Low-Engagement Processes to Regulate Others' Emotions.
Existing research has linked emotional intelligence (EI) with intrinsic emotion regulation (processes people use to regulate their own emotions). However, there has not yet been an empirical examination of whether EI abilities relate to extrinsic emotion regulation (processes people use to regulate other people's emotions). This study (N = 178 undergraduates) examines whether ability EI (as measured by the Mayer-Salovey-Caruso Emotional Intelligence Test) correlates with eight extrinsic regulation processes (as measured by the Regulation of Others' Emotions Scale, including downward comparison, expressive suppression, humour, distraction, direct action, reappraisal, receptive listening and valuing). Total ability EI score is significantly positively correlated with three high-engagement processes (r = .24, .40, and .16 for reappraisal, receptive listening, and valuing) and negatively correlated with two low-engagement processes (r = -.30 and -.38 for downward comparison and expressive suppression). When all four EI branches predicted each regulation process in multiple regression, only emotion management significantly predicted downward comparison, receptive listening and valuing, and only emotion management and understanding predicted expressive suppression (no significant regression coefficients for reappraisal). We conclude that the drivers of EI/extrinsic regulation associations are engagement with the target's emotion and the emotion management branch of EI.


Antidepressants in pregnancy: applying causal epidemiological methods to understand service-use outcomes in women and long-term neurodevelopmental outcomes in exposed children.
Antidepressants are commonly prescribed during pregnancy, despite a lack of evidence from randomised trials on the benefits or risks. Some studies have reported associations of antidepressants during pregnancy with adverse offspring neurodevelopment, but whether or not such associations are causal is unclear. To study the associations of antidepressants for depression in pregnancy with outcomes using multiple methods to strengthen causal inference. This was an observational cohort design using multiple methods to strengthen causal inference, including multivariable regression, propensity score matching, instrumental variable analysis, negative control exposures, comparison across indications and exposure discordant pregnancies analysis. This took place in UK general practice. Participants were pregnant women with depression. The interventions were initiation of antidepressants in pregnancy compared with no initiation, and continuation of antidepressants in pregnancy compared with discontinuation. The maternal outcome measures were the use of primary care and secondary mental health services during pregnancy, and during four 6-month follow-up periods up to 24 months after pregnancy, and antidepressant prescription status 24 months following pregnancy. The child outcome measures were diagnosis of autism, diagnosis of attention deficit hyperactivity disorder and intellectual disability. UK Clinical Practice Research Datalink. Data on 80,103 pregnancies were used to study maternal primary care outcomes and were linked to 34,274 children with at least 4-year follow-up for neurodevelopmental outcomes. Women who initiated or continued antidepressants during pregnancy were more likely to have contact with primary and secondary health-care services during and after pregnancy and more likely to be prescribed an antidepressant 2 years following the end of pregnancy than women who did not initiate or continue antidepressants during pregnancy (odds ratioinitiation 2.16, 95% confidence interval 1.95 to 2.39; odds ratiocontinuation 2.40, 95% confidence interval 2.27 to 2.53). There was little evidence for any substantial association with autism (odds ratiomultivariableregression 1.10, 95% confidence interval 0.90 to 1.35; odds ratiopropensityscore 1.06, 95% confidence interval 0.84 to 1.32), attention deficit hyperactivity disorder (odds ratiomultivariableregression 1.02, 95% confidence interval 0.80 to 1.29; odds ratiopropensityscore 0.97, 95% confidence interval 0.75 to 1.25) or intellectual disability (odds ratiomultivariableregression 0.81, 95% confidence interval 0.55 to 1.19; odds ratiopropensityscore 0.89, 95% confidence interval 0.61 to 1.31) in children of women who continued antidepressants compared with those who discontinued antidepressants. There was inconsistent evidence of an association between initiation of antidepressants in pregnancy and diagnosis of autism in offspring (odds ratiomultivariableregression 1.23, 95% confidence interval 0.85 to 1.78; odds ratiopropensityscore 1.64, 95% confidence interval 1.01 to 2.66) but not attention deficit hyperactivity disorder or intellectual disability; however, but results were imprecise owing to smaller numbers. Several causal-inference analyses lacked precision owing to limited numbers. In addition, adherence to the prescribed treatment was not measured. Women prescribed antidepressants during pregnancy had greater service use during and after pregnancy than those not prescribed antidepressants. The evidence against any substantial association with autism, attention deficit hyperactivity disorder or intellectual disability in the children of women who continued compared with those who discontinued antidepressants in pregnancy is reassuring. Potential association of initiation of antidepressants during pregnancy with offspring autism needs further investigation. Further research on larger samples could increase the robustness and precision of these findings. These methods applied could be a template for future pharmaco-epidemiological investigation of other pregnancy-related prescribing safety concerns. This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (15/80/19) and will be published in full in Health Technology Assessment; Vol. 27, No. 15. See the NIHR Journals Library website for further project information.


Prognostic Factors, Treatment, and Survival in Dermatofibrosarcoma Protuberans.
There is limited information regarding the influence of patient demographics, tumor characteristics, and treatment type on the survival of patients with dermatofibrosarcoma protuberans (DFSP). To assess prognostic factors and to evaluate the influence of treatment modality on overall survival of patients with DFSP. We examined DFSP using data for 3686 patients with histologically confirmed cases of DFSP diagnosed between 1972 and 2012 from the 18 US regional registries of the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program, with linkage to demographic data from the US Census Bureau for median household income (MHI). The analysis was performed in February 2016. The primary outcome measures were tumor characteristics, prognostic factors, and overall survival in months. There were 3686 cases of DFSP examined. Older age (hazard ratio [HR], 1.08; 95% CI, 1.06-1.10; P < .001), male sex (HR, 1.97; 95% CI, 1.09-3.55; P = .03), and tumor size (HR, 1.09; 95% CI, 1.01-1.18; P = .04) were significantly associated with poorer overall survival in a controlled analysis. Older age (odds ratio [OR], 1.01; 95% CI, 1.00-1.02; P = .01), male sex (OR, 1.95; 95% CI, 1.57-2.42; P < .001), and black race (OR, 1.78; 95% CI, 1.37-2.32; P < .001) were associated with larger (≥3.0 cm) tumors at presentation. Treatment modality did not influence overall survival; however, differences in patient characteristics affected the treatment received. Older age at presentation (OR, 1.02; 95% CI, 1.01-1.03; P =.01), black race (OR, 1.82; 95% CI, 1.13-2.92; P = .01), large tumor size (OR, 1.15; 95% CI, 1.09-1.21; P < .001), and head or neck location (OR, 4.63; 95% CI, 2.66-8.07; P <.001) increased the likelihood of a patient receiving surgery and radiation over surgery alone. In addition, white patients (OR, 0.51; 95% CI, 0.30-0.87; P=.01), women (OR, 0.53; 95% CI, 0.36-0.78; P <.001), and patients with a higher MHI (OR, 1.27; 95% CI, 1.11-1.46; P <.001) were more likely to receive Mohs micrographic surgery (MMS) over excision. Age at diagnosis, male sex, and DFSP tumor size appear to be important prognostic factors. Treatment modality did not significantly influence survival; however, patient and tumor characteristics influence treatment modality.


Structure-activity studies of pyridinylalkyl-isocytosine H1-receptor antihistamines and identification of an active conformation.
For a series of 2-(pyridin-2-ylbutylamino)-5-(3-picolinylmethyl)pyrimidin- 4(1H)-ones (isocytosines) substituted in the pyridine 3-position, activity as H1- and H2-receptor histamine antagonists appears to correlate with the size of the 3-substituent. Steric interaction between the substituent and the butyl chain is explored by conformational analysis using Molecular Mechanics and Molecular Orbital calculations on 2-propyl- and 2-propyl-3-methyl-pyridines; it appears that the substituent may alter activity by changing the preferred conformation of the drug. This observation is extended by synthesis of a semirigid bicyclic analogue wherein 3-methylpyridinylbutyl is replaced by tetrahydroquinolinylpropyl. This compound is 2-3 times more potent as an H1-receptor antagonist confirming that a trans/trans conformation favours activity. Although derived from an H2-antagonist structure, the compound is not an antagonist at histamine H2 receptors thus proving that the conformational requirements are different at H1 and H2 receptors.


Stress at the place of work and cognitive functions among women performing intellectual work during peri- and post-menopausal period.
The analysis of the relationship between stress at work and results of cognitive functions amongst women, at peri- and post-menopausal age, performing intellectual work. The study group included women, aged 45-66 years old, employed as intellectual workers. Research instruments were: the Montreal Cognitive Assessment; computer tests of the CNS Vital Signs; the Subjective Work Characteristics Questionnaire, and a questionnaire designed by the author. The results were statistically analyzed. Nearly a half of respondents experienced high stress at the place of work; 1/3 - on the average level, on a low level - every fifth. The largest number of respondents experienced stress caused by social contacts. Among a half of the women, stress was caused by the lack of awards at work, followed by the lack of support. Slightly fewer of them experienced stress caused by the feeling of psychological load related to the complexity of work or the feeling of uncertainty caused by the organization of work. Every third woman experienced stress due to the sense of responsibility or the lack of control. The smallest number experienced stress caused by physical arduousness, the sense of threat and unpleasant working conditions. The examined women obtained the best results with respect to simple attention, the worst results - with respect to the reaction time. The results concerning the remaining 9 cognitive functions were ranked in the middle of the aforementioned results. The intensity of stress at work and factors which caused this stress, negatively correlated with simple attention of women in the early peri-menopausal period, while positively correlating with the psychomotor and processing speed of women in the late peri-menopausal period. Among the post-menopausal women, negative correlations were observed between the majority of cognitive functions and the intensity of stress at work, and the majority of factors which caused this stress. Cognitive functions of the examined women remained within the range of average evaluations, and were correlated with stress-inducing factors at the place of work. Int J Occup Med Environ Health 2017;30(6):943-961.


Sensitive and specific LC-ESI-MS/MS method for determination of ZYDPLA1, a novel long-acting dipeptidyl peptidase 4 inhibitor in rat plasma: An application for toxicokinetic study in rats.
A rapid and highly specific assay was developed and validated for the estimation of ZYDPLA1 in rat plasma using liquid chromatography coupled to tandem mass spectrometry with positive electrospray ionization. Method validation comprised of parameters such as specificity, matrix effect, precision, accuracy, recovery, stability, etc. The assay procedure involved a simple protein precipitation of ZYDPLA1 and alprazolam (internal standard) from rat plasma using acetonitrile. Chromatographic separation was achieved with a gradient mobile phase comprising: (A) 0.2% ammonia in purified water; (B) 0.1% formic acid in isopropyl alcohol/methanol (1: 1 v/v); and (C) acetonitrile at a flow rate of 1 mL/min on an ACE-5, C18 (4.6 × 50 mm) column with a run time of 5.5 min. The quantitation of ZYDPLA1 was achieved by the summation of four multiple reaction mode transitions (m/z 399.7 → 383.0, 399.7 → 276.10, 399.7 → 153.20 and 399.7 → 127.20), while that of the internal standard was by a single multiple reaction mode transition (m/z 309.10 → 281.00). The lower limit of quantitation achieved was 0.01 μg/mL and the method showed linearity from 0.01 to 25 μg/mL. The intra- and inter-day precision (%CV) of the quality control samples was within 8.81% and accuracy was ±10% of nominal values. This novel method was applied for evaluation of toxicokinetics of ZYDLA1 in rats.


Profiling PI3K-AKT-MTOR variants in focal brain malformations reveals new insights for diagnostic care.
Focal malformations of cortical development including focal cortical dysplasia, hemimegalencephaly and megalencephaly, are a spectrum of neurodevelopmental disorders associated with brain overgrowth, cellular and architectural dysplasia, intractable epilepsy, autism and intellectual disability. Importantly, focal cortical dysplasia is the most common cause of focal intractable paediatric epilepsy. Gain and loss of function variants in the PI3K-AKT-MTOR pathway have been identified in this spectrum, with variable levels of mosaicism and tissue distribution. In this study, we performed deep molecular profiling of common PI3K-AKT-MTOR pathway variants in surgically resected tissues using droplet digital polymerase chain reaction (ddPCR), combined with analysis of key phenotype data. A total of 159 samples, including 124 brain tissue samples, were collected from 58 children with focal malformations of cortical development. We designed an ultra-sensitive and highly targeted molecular diagnostic panel using ddPCR for six mutational hotspots in three PI3K-AKT-MTOR pathway genes, namely PIK3CA (p.E542K, p.E545K, p.H1047R), AKT3 (p.E17K) and MTOR (p.S2215F, p.S2215Y). We quantified the level of mosaicism across all samples and correlated genotypes with key clinical, neuroimaging and histopathological data. Pathogenic variants were identified in 17 individuals, with an overall molecular solve rate of 29.31%. Variant allele fractions ranged from 0.14 to 22.67% across all mutation-positive samples. Our data show that pathogenic MTOR variants are mostly associated with focal cortical dysplasia, whereas pathogenic PIK3CA variants are more frequent in hemimegalencephaly. Further, the presence of one of these hotspot mutations correlated with earlier onset of epilepsy. However, levels of mosaicism did not correlate with the severity of the cortical malformation by neuroimaging or histopathology. Importantly, we could not identify these mutational hotspots in other types of surgically resected epileptic lesions (e.g. polymicrogyria or mesial temporal sclerosis) suggesting that PI3K-AKT-MTOR mutations are specifically causal in the focal cortical dysplasia-hemimegalencephaly spectrum. Finally, our data suggest that ultra-sensitive molecular profiling of the most common PI3K-AKT-MTOR mutations by targeted sequencing droplet digital polymerase chain reaction is an effective molecular approach for these disorders with a good diagnostic yield when paired with neuroimaging and histopathology.


[Legal and animal welfare aspects of the killing of fish].
The selection of methods for killing fish is determined by the number of fish to be killed, their utilization and the existing laws. No regulations exist for killing non-food fish. The methods for killing food-fish, however, are stipulated in a regulation from 1936. Mechanical or electrical stunning is obligatory except for flatfish and eel. Single fish should be stunned by a blow on the head, followed immediately by slaughtering or bleeding to be sure that the fish is really dead. When larger numbers of fish should be killed for food production only electrical methods are allowed as alternative. Chemicals can be used for killing non-food fish, the non-pollutant destruction of dead fish and chemical-contaminated water, however, has to be guaranteed. The methods are discussed with respect to practicability and animal welfare.


Removal of fluoride from water with powdered corn cobs.
The adsorption of fluoride on corn cobs powder was investigated in the present study. Neat powdered corn cobs did not show remarkable adsorption but aluminium treated corn cobs had good adsorption capacity. The parameters studied include the contact time, concentration, temperature and pH. Near neutral pH was identified as the optimum condition of the medium, and 90 to 120 minutes was the best contact time for maximum fluoride adsorption. The adsorption process was found to follow Freundlich isotherm. The adsorption process was found to be exothermic as adsorption decreased with increasing temperature.


Flexible, Low-Power Thin-Film Transistors Made of Vapor-Phase Synthesized High-k, Ultrathin Polymer Gate Dielectrics.
A series of high-k, ultrathin copolymer gate dielectrics were synthesized from 2-cyanoethyl acrylate (CEA) and di(ethylene glycol) divinyl ether (DEGDVE) monomers by a free radical polymerization via a one-step, vapor-phase, initiated chemical vapor deposition (iCVD) method. The chemical composition of the copolymers was systematically optimized by tuning the input ratio of the vaporized CEA and DEGDVE monomers to achieve a high dielectric constant (k) as well as excellent dielectric strength. Interestingly, DEGDVE was nonhomopolymerizable but it was able to form a copolymer with other kinds of monomers. Utilizing this interesting property of the DEGDVE cross-linker, the dielectric constant of the copolymer film could be maximized with minimum incorporation of the cross-linker moiety. To our knowledge, this is the first report on the synthesis of a cyanide-containing polymer in the vapor phase, where a high-purity polymer film with a maximized dielectric constant was achieved. The dielectric film with the optimized composition showed a dielectric constant greater than 6 and extremely low leakage current densities (<3 × 10-8 A/cm2 in the range of ±2 MV/cm), with a thickness of only 20 nm, which is an outstanding thickness for down-scalable cyanide polymer dielectrics. With this high-k dielectric layer, organic thin-film transistors (OTFTs) and oxide TFTs were fabricated, which showed hysteresis-free transfer characteristics with an operating voltage of less than 3 V. Furthermore, the flexible OTFTs retained their low gate leakage current and ideal TFT characteristics even under 2% applied tensile strain, which makes them some of the most flexible OTFTs reported to date. We believe that these ultrathin, high-k organic dielectric films with excellent mechanical flexibility will play a crucial role in future soft electronics.


Molecular Vibrational Polariton Dynamics: What Can Polaritons Do?
ConspectusWhen molecular vibrational modes strongly couple to virtual states of photonic modes, new molecular vibrational polariton states are formed, along with a large population of dark reservoir modes. The polaritons are much like the bonding and antibonding molecular orbitals when atomic orbitals form molecular bonds, while the dark modes are like nonbonding orbitals. Because the polariton states are half-matter and half-light, whose energy is shifted from the parental states, polaritons are predicted to modify chemistry under thermally activated conditions, leading to an exciting and emerging field known as polariton chemistry that could potentially shift paradigms in chemistry. Despite several published results supporting this concept, the chemical physics and mechanism of polariton chemistry remain elusive. One reason for this challenge is that previous works cannot differentiate polaritons from dark modes. This limitation makes delineating the contributions to chemistry from polaritons and dark states difficult. However, this level of insight is critical for developing a solid mechanism for polariton chemistry to design and predict the outcome of strong coupling with any given reaction. My group addressed the challenge of differentiating the dynamics of polaritons and dark modes by ultrafast two-dimensional infrared (2D IR) spectroscopy. Specifically, (1) we found that polaritons can facilitate intra- and intermolecular vibrational energy transfer, opening a pathway to control vibrational energy flow in liquid-phase molecular systems, and (2) by studying a single-step isomerization event, we verified that indeed polaritons can modify chemical dynamics under strong coupling conditions, but in contrast, the dark modes behave like uncoupled molecules and do not change the dynamics. This finding confirmed the central concept of polariton chemistry: polaritons modify the potential energy landscape of reactions. The result also clarified the role of dark modes, which lays a critical foundation for designing cavities for future polariton chemistry. Aside from using 2D IR spectroscopy to study polariton chemistry, we also used the same technique to develop molecular polaritons into a potential quantum simulation platform. We demonstrated that polaritons have Rabi oscillations, and using a checkerboard cavity design, we showed that polaritons could have large nonlinearity across space. We further used the checkerboard polaritons to simulate coherence transfer and visualize it. A unidirectional coherence transfer was observed, indicating non-Hermitian dynamics. The highlighted efforts in this Account provide a solid understanding of the capability of polaritons for chemistry and quantum information science. I conclude this Account by discussing a few challenges for moving polariton chemistry toward being predictable and making the polariton quantum platform a complement to existing systems.


The impact of integrated prevention and treatment on child malnutrition and health: the PROMIS project, a randomized control trial in Burkina Faso and Mali.
Evidence suggests that both preventive and curative nutrition interventions are needed to tackle child acute malnutrition (AM) in developing countries. In addition to reducing the incidence of AM, providing preventive interventions may also help increase attendance (and coverage) of AM screening, a major constraint in the community-based management of child acute malnutrition (CMAM) model. There is a paucity of evidence-based strategies to deliver integrated preventive and curative interventions effectively and affordably at scale. The aim of the Innovative Approaches for the Prevention of Childhood Malnutrition (PROMIS) study is to assess the feasibility, quality of implementation, effectiveness and cost-effectiveness of an integrated child malnutrition prevention and treatment intervention package implemented through a community-based platform in Mali and a facility-based platform in Burkina Faso. The PROMIS intervention entails a comprehensive preventive package offered on a monthly basis to caregivers of children, while children are screened for acute malnutrition (AM). The package consists of behavior change communication on essential nutrition and hygiene actions, and monthly preventive doses of small quantity lipid-based nutrient supplements (SQ-LNS) for children aged 6 to 23.9 months. Positive AM cases are referred to treatment services offered by first-line health services according to the CMAM model. The PROMIS intervention will be evaluated using a mixed methods approach. The impact study encompasses two types of study design: i) repeated cross-sectional surveys conducted at baseline and at endline after 24 months of program implementation and ii) a longitudinal study with a monthly follow-up for 18 months. Primary study impact measures include the incidence and endpoint prevalence of AM, AM screening coverage and treatment compliance. A process evaluation will assess the feasibility and quality of implementation of the intervention guided by country specific program impact pathways (PIPs). Cost-effectiveness analysis will assess the economic feasibility of the intervention. The PROMIS study assesses the effectiveness of an innovative model to integrate prevention and treatment interventions for greater and more sustainable impacts on the incidence and prevalence of AM using a rigorous, theory-based randomized control trial approach. This type of programmatic research is urgently needed to help program implementers, policy makers, and investors prioritize, select and scale-up the best program models to prevent and treat AM and achieve the World Health Assembly goal of reducing childhood wasting to less than 5% globally by the year 2025. Clinicaltrials.gov NCT02323815 (registered on December 18, 2014) and NCT02245152 (registered on September 16, 2014).


Antidepressant side effects and physician prescribing patterns.
We studied the following questions: (1) Do physicians preferentially prescribe antidepressants (ADs) with the least side effects (SEs) of sedation, orthostatic hypotension, and anticholinergic activity; (2) Have there been any recent changes in prescribing patterns; and (3) Do patterns differ for psychiatrists and nonpsychiatrists. Data on psychiatrist and non-psychiatrist outpatient prescribing of specific ADs were obtained from the National Prescription Audit (NPA) for 1986 and 1989. In 1986, physicians did not minimize the use of ADs with the most of these SEs. The 1989 data indicate that psychiatrists made a major change toward prescribing more low SE ADs and less ADs with the most SEs. The data for nonpsychiatrists also suggest some movement in this direction. The availability of fluoxetine and the concomitant focus on SEs may have contributed to this shift. Further investigation is needed to clarify factors that influence physicians' choices of ADs.


Series Pneumatic Artificial Muscles (sPAMs) and Application to a Soft Continuum Robot.
We describe a new series pneumatic artificial muscle (sPAM) and its application as an actuator for a soft continuum robot. The robot consists of three sPAMs arranged radially round a tubular pneumatic backbone. Analogous to tendons, the sPAMs exert a tension force on the robot's pneumatic backbone, causing bending that is approximately constant curvature. Unlike a traditional tendon driven continuum robot, the robot is entirely soft and contains no hard components, making it safer for human interaction. Models of both the sPAM and soft continuum robot kinematics are presented and experimentally verified. We found a mean position accuracy of 5.5 cm for predicting the end-effector position of a 42 cm long robot with the kinematic model. Finally, closed-loop control is demonstrated using an eye-in-hand visual servo control law which provides a simple interface for operation by a human. The soft continuum robot with closed-loop control was found to have a step-response rise time and settling time of less than two seconds.


Glutamate uptake into synaptic vesicles--inhibition by sulphur amino acids.
In an attempt to investigate the apparent absolute selectivity of the synaptic vesicle L-glutamate carrier, L- and D-enantiomers of excitatory sulphur-containing amino acid (SAA) transmitter candidates (which are close structural analogues of L-glutamate) were tested for their capacity to compete for vesicular L-[3H]-glutamate uptake. All SAAs inhibited, to varying degrees (52-86%), the vesicular uptake of L-[3H]-glutamate. A similar level of inhibition was exerted by SAAs with either a shorter or equal carbon chain length to L-glutamate. Moreover, inhibition was stereospecific in favour of the D-enantiomers. These studies indicate an appreciable interaction of the SAAs with the recognition site of the vesicular L-glutamate carrier. Further investigations are required to establish the substrate potential of the SAAs.


Prioritizing growth opportunities.
Regional Medical Center is a 400-bed hospital located in the affluent northern suburbs of a medium-sized metropolitan area in the Midwest. Regional's revenues are approaching $200 million annually and have been increasing by an average of 10 percent per year for the past five years. Regional's operating margin has ranged between 4 and 6 percent per year during this period. By all measures, Regional is an incredibly successful organization with nearly unlimited opportunities.