Preclinical evaluation of group B Neisseria meningitidis and Escherichia coli K92 capsular polysaccharide-protein conjugate vaccines in juvenile rhesus monkeys.
We reported the first use of group B meningococcal conjugate vaccines in a nonhuman primate model (S. J. N. Devi, C. E. Frasch, W. Zollinger, and P. J. Snoy, p. 427-429, in J. S. Evans, S. E. Yost, M. C. J. Maiden, and I. M. Feavers, ed., Proceedings of the Ninth International Pathogenic Neisseria Conference, 1994). Three different group B Neisseria meningitidis capsular polysaccharide (B PS)-protein conjugate vaccines and an Escherichia coli K92 capsular polysaccharide-tetanus toxoid (K92-TT) conjugate vaccine are here evaluated for safety and relative immunogenicities in juvenile rhesus monkeys with or without adjuvants. Monkeys were immunized intramuscularly with either B PS-cross-reactive material 197 conjugate, B PS-outer membrane vesicle (B-OMV) conjugate, or N-propionylated B PS-outer membrane protein 3 (N-pr. B-OMP3) conjugate vaccine with or without adjuvants at weeks 0, 6, and 14. A control group of monkeys received one injection of the purified B PS alone, and another group received three injections of B PS noncovalently complexed with OMV. Antibody responses as measured by enzyme-linked immunosorbent assay varied among individual monkeys. All vaccines except B PS and the K92-TT conjugate elicited a twofold or greater increase in total B PS antibodies after one immunization. All vaccines, including the K92-TT conjugate, elicited a rise in geometric mean B PS antibody levels of ninefold or more over the preimmune levels following the third immunization. Antibodies elicited by N-pr. B-OMP3 and B-OMV conjugates were directed to the N-propionylated or to the spacer-containing B PS antigens as well as to the native B PS complexed with methylated human serum albumin. None of the vaccines caused discernible safety-related symptoms.


ER-BOC calculations of crystal bulk properties from smallest-cluster models.
Ab initio calculation of bulk properties of crystals with a high accuracy, which is a long-time goal of solid chemistry and physics, is still difficult and expensive because a large cluster is required as a crystal structure model. This article proposes a model based on density functional theory (DFT) quantum chemistry calculations and the assumption that the bond order of a given atom with its nearest atoms in a compound is conserved over the entire range from its diatomic molecules to clusters and further to crystals. This entire range bond order conservation (ER-BOC) provides an effective way to correlate bulk properties of crystals with those of the corresponding molecules and small clusters. By combining this ER-BOC principle with hybrid DFT quantum chemistry calculations, accurate predictions of the bulk bond lengths of a crystal can be made using calculations on small clusters.


Comparison of Surgical Outcomes, Narcotics Utilization, and Costs After an Anterior Cervical Discectomy and Fusion: Stand-alone Cage Versus Anterior Plating.
Retrospective cohort analysis of a prospectively maintained registry. To compare the surgical outcomes, narcotic utilization, and costs between a stand-alone (SA) cage and anterior plating (AP) with an interbody device for 1-level anterior cervical discectomy and fusion (ACDF). ACDF with a SA cage has gained popularity as a potential alternative to anterior cervical plating. Few studies have compared the surgical outcomes, narcotic utilization, and costs of ACDF utilizing a SA cage versus AP with an interbody device. Patients who underwent a primary 1-level ACDF for degenerative spinal pathology between 2010 and 2013 were analyzed. Patients were stratified on the basis of the type of implant system (SA cage vs. AP) and assessed with regard to demographics, comorbidities, smoking, visual analogue scale (VAS) scores (preoperative/postoperative), procedural time, estimated blood loss (EBL), length of hospitalization, complications, reoperations, narcotic consumption, and total costs. Statistical analysis was performed with independent sample T tests for continuous variables and χ analysis for categorical data. An α level of <0.05 denoted statistical significance. Of the 93 patients included, 52 (55.9%) underwent an ACDF with a SA cage system. Patient demographics, comorbidity burden, body mass index, smoking status, and preoperative VAS score were similar between cohorts. The SA cohort incurred a significantly lower EBL (P<0.001) than the AP cohort. However, none required a transfusion and the procedural time, length of hospitalization, postoperative VAS score, complication rates, 1-year arthrodesis rate, and reoperation rates were similar between cohorts. Postoperative narcotics consumption and total costs were also similar between groups. Our findings suggest that the SA cage may be associated with a significantly lower EBL, which may not be clinically relevant. Perioperative outcomes, complications, reoperation rates, narcotics consumption in the immediate postoperative period, and total costs may be similar regardless of the instrumentation utilized in a 1-level ACDF.


Stomach conservation in stages IE and IIE gastric non-Hodgkin's lymphoma.
Thirty-four patients with stages IE and IIE gastric lymphoma were treated with chemotherapy and radiotherapy combinations without stomach resection. In 20 patients, the diagnosis was established by endoscopic biopsy only; the other 14 had laparotomy and biopsy. No patient had a gastrectomy before treatment. Nineteen patients had stage IE disease and 15 had stage IIE. Lymphoma diagnoses were: diffuse large-cell, 26; immunoblastic, three; diffuse well-differentiated, three; nodular mixed, one; and unclassified, one. The treatment plan was to deliver an initial four cycles of chemotherapy, followed by radiotherapy, and finally, more chemotherapy. Thirty-three patients received cyclophosphamide, doxorubicin, vincristine, prednisone, and bleomycin (CHOP-Bleo). Four patients with stage IIE disease received cyclophosphamide, methotrexate, etoposide, and dexamethasone (CMED). Twenty-three patients (68%) never had a relapse. Three patients had successful salvage therapy, one for local recurrence and two for tumor dissemination. Five patients died of recurrent abdominal disease, and one died of tumor dissemination. Two died of treatment-related complications, one of sepsis during treatment with CMED and one of bleomycin-induced lung fibrosis. No patient developed stomach perforation or bleeding as a result of chemotherapy or radiotherapy. Twenty-four of the 26 surviving patients were able to retain their stomachs. One patient required a gastrectomy for progressive disease during chemotherapy, and another required a subtotal gastrectomy for relief of an obstruction caused by cicatrization. These data show that surgery is not a necessary procedure in gastric lymphoma. Favorable results can be achieved by combining effective chemotherapy and local radiation.


Improved islet morphology after blockade of the renin- angiotensin system in the ZDF rat.
The renin-angiotensin system (RAS) has an important role in the endocrine pancreas. Although angiotensin II has significant effects on cell proliferation and apoptosis, the contribution of the RAS to changes in islet structure and function associated with type 2 diabetes is yet to be defined. This study examined the specific effects of RAS blockade on islet structure and function in diabetes. Thirty-six male Zucker diabetic fatty (ZDF) rats, 10 weeks of age, were randomized to receive the angiotensin-converting enzyme inhibitor perindopril (8 mg/l in drinking water; n = 12), irbesartan (15 mg/kg via gavage; n = 12), or no treatment (n = 12) for 10 weeks. Results were compared with lean littermates (ZL) (n = 12) studied concurrently. ZDF rats had increased intra-islet expression of components of the RAS correlating with increased intraislet fibrosis, apoptosis, and oxidative stress. Disordered islet architecture, seen in ZDF rats, was attenuated after treatment with perindopril or irbesartan. Islet fibrogenesis was also diminished, as measured by picrosirius staining and expression of collagens I and IV. Gene expression of transforming growth factor-beta1 was increased in the ZDF pancreas (ZL, 1.0 +/- 0.1; ZDF, 2.0 +/- 0.3; P < 0.05) and reduced after blockade of the RAS (ZDF + P, 1.3 +/- 0.2; ZDF + I, 1.5 +/- 0.1; vs. ZDF, both P < 0.05). Improvements in structural parameters were also associated with functional improvements in first-phase insulin secretion. These findings provide a possible mechanism for the reduced incidence of new-onset diabetes that has been observed in clinical trials of RAS blockade.


The need for an international debate in pediatrics about obesity and nutrition.
Non-communicable diseases are at the center of international consultation and there's a general agreement on saying that several issues need to be solved before implementing prevention strategies and intervention programs. A sound knowledge of all the factors involved in the epidemic spread of a disease is the first target that has to be achieved in order to provide governments and policy makers with the best evidence-based conclusions. Present data are still too weak to gather solid decisions. Lack of standardized methods, common definitions or coherence with real life performances results therefore in conclusions that oscillate from one statement to its contrary. From this perspective, pediatricians and general practitioners are of great importance, being the direct link between the scientific community and children, having therefore the possibility to act at the first phases of obesity development, forging the best possible knowledge in order to transform prevention in the best possible cure.


Influence of the renin-angiotensin system on the effect of prostaglandin synthesis inhibitors in the renal vasculature.
The effect of meclofenamate and indomethacin on renal blood flow and renal vascular resistance was determined under basal experimental conditions and during renal ischemia in pentobarbital-anesthetized dogs. Renal blood flow was measured with an electromagnetic flowmeter and renal arterial pressure was recorded from a catheter in the renal artery. Intra-arterial infusion of indomethacin or meclofenamate in concentrations of 4 and 4 to 8 mu-g/ml, respectively, did not cause any significant change in renal blood flow or renal vascular resistance under basal conditions. During the period of ischemia (50% reduction in renal blood flow), 4 mu-g/ml of either prostaglandin synthetase inhibitor caused a marked increase in renal vascular resistance. Prostaglandin E in the renal venous blood was decreased at the time renal vascular resistance was increased by meclofenamate. The renal vasoconstrictor response to angiotensin II injected intravenously was potentiated by both inhibitors under basal as well as ischemic conditions, which also suggested that prostaglandin synthesis was inhibited. The angiotensin antagonist 1-sar-8-ala-angiotensin II was infused intra-arterially in concentrations of 20 and 40 mmu-g/ml during renal ischemia. Subsequent administration of meclofenamate increased renal vascular resistance only slightly. The results of these experiments indicated that renal prostaglandins have more influence on renal blood flow during renal ischemia than under basal conditions, and that the renin-angiotensin system may be involved in activating synthesis and release of prostaglandins during ischemia.


Genome-wide association study for colorectal cancer identifies risk polymorphisms in German familial cases and implicates MAPK signalling pathways in disease susceptibility.
Genetic susceptibility accounts for approximately 35% of all colorectal cancer (CRC). Ten common low-risk variants contributing to CRC risk have been identified through genome-wide association studies (GWASs). In our GWAS, 610 664 genotyped single-nucleotide polymorphisms (SNPs) passed the quality control filtering in 371 German familial CRC patients and 1263 controls, and replication studies were conducted in four additional case-control sets (4915 cases and 5607 controls). Known risk loci at 8q24.21 and 11q23 were confirmed, and a previously unreported association, rs12701937, located between the genes GLI3 (GLI family zinc finger 3) and INHBA (inhibin, beta A) [P = 1.1 x 10(-3), odds ratio (OR) 1.14, 95% confidence interval (CI) 1.05-1.23, dominant model in the combined cohort], was identified. The association was stronger in familial cases compared with unselected cases (P = 2.0 x 10(-4), OR 1.36, 95% CI 1.16-1.60, dominant model). Two other unreported SNPs, rs6038071, 40 kb upstream of CSNK2A1 (casein kinase 2, alpha 1 polypeptide) and an intronic marker in MYO3A (myosin IIIA), rs11014993, associated with CRC only in the familial CRC cases (P = 2.5 x 10(-3), recessive model, and P = 2.7 x 10(-4), dominant model). Three software tools successfully pointed to the overrepresentation of genes related to the mitogen-activated protein kinase (MAPK) signalling pathways among the 1340 most strongly associated markers from the GWAS (allelic P value < 10(-3)). The risk of CRC increased significantly with an increasing number of risk alleles in seven genes involved in MAPK signalling events (P(trend) = 2.2 x 10(-16), OR(per allele) = 1.34, 95% CI 1.11-1.61).


A systematic review of evidence-based practices for clinical education and health care delivery in the clinical teaching unit.
The clinical teaching unit is a widespread clinical training model that requires reform to prepare physicians for practice in the 21st century. In this systematic review, we aimed to identify evidence-based practices in internal medicine clinical teaching units that contribute to improved clinical education and health care delivery. We searched several databases from 1993 until Apr. 5, 2021, to identify published studies in inpatient clinical teaching units that involved medical trainees and reported outcomes related to trainee education or health care delivery. We identified emergent themes using a narrative approach and determined confidence in review findings using the Grading of Recommendations Assessment, Development and Evaluation Confidence in the Evidence from Reviews of Qualitative Research (GRADE-CERQual) methodology. We included 107 studies of internal medicine clinical teaching units, of which 93 (87%) were conducted in North America. Surveys (n = 31, 29%), trials (n = 17, 16%) and narrative studies (n = 15, 14%) were the most prevalent study designs. Practices identified as contributing to improved clinical education or health care delivery included purposeful rounding (high confidence), bedside rounding (moderate confidence), resource stewardship interventions (high confidence), interprofessional rounds (moderate confidence), geographic wards (moderate confidence), allocating more trainee time to patient care or educational activities (moderate confidence), "drip" continuous models of admission (moderate confidence), limiting duty hours (moderate confidence) and limiting clinical workload (moderate confidence). In this review, we identified several evidence-based practices that may contribute to improved educational and health care outcomes in clinical teaching unit settings. These findings may offer guidance for policies, resource allocation and staffing of teaching hospitals.


Estrogen receptor-β activation in combination with letrozole blocks the growth of breast cancer tumors resistant to letrozole therapy.
Treatment with anti-estrogens or aromatase inhibitors (AI) is the main therapeutic strategy used against estrogen receptor ERα-positive breast cancer. Resistance to these therapies presents a major challenge in the management of breast cancer. Little is known about ERβ in breast carcinogenesis. Our aim in this study is to examine potential novel strategies utilizing ERβ activity to overcome AI resistance. We provide evidence that ERβ agonist can reduce the growth of AI-resistant breast cancer cells. Our data further confirm that therapeutic activation of ERβ by DPN, an ERβ agonist, blocks letrozole-resistant tumor growth in a xenograft model. Interestingly, DPN exerted tumor growth inhibition only in the presence of the AI letrozole, suggesting that combination therapy including ERβ activators and AI may be used in the clinical setting treating AI resistant breast cancer. An increase in ERβ levels, with diminished ERα/ERβ ratio, was observed in the tumors from mice treated with DPN/letrozole combination compared to single agents and control. Decreased Cyclin D1 and increased CyclinD1/CDK inhibitors p21 and p27 levels in DPN/letrozole treated tumors were observed, suggesting that the combination treatment may inhibit tumor growth by blocking G1/S phase cell cycle progression. Our data show a decrease in MAPK phosphorylation levels without affecting total levels. In addition to providing evidence suggesting the potential use of ERβ agonists in combination with letrozole in treating AI resistant breast cancer and prolonging sensitivity to AI, we also provide mechanistic evidence supporting the role of ERβ in altering the expression profile associated with resistance.


Clostridium difficile toxins may augment bacterial penetration of intestinal epithelium.
Clostridium difficile can be recovered from many high-risk hospitalized patients receiving broad-spectrum antibiotic therapy. Clostridium difficile toxins A and B have been associated with increased intestinal permeability in vitro and there is growing evidence that increased intestinal permeability may be a common mechanism whereby enteric bacteria penetrate the intestinal epithelium. Clostridium difficile-induced alterations in the intestinal barrier facilitate microbial penetration of the intestinal epithelium, which in turn facilitates the translocation of intestinal bacteria. Mature Caco-2 enterocytes were pretreated with varying concentrations of toxin A or toxin B followed by 1 hour of incubation with pure cultures of either Salmonella typhimurium, Escherichia coli, or Proteus mirabilis. The effects of toxins A and B on enterocyte viability, cytoskeletal actin, and ultrastructural topography were assessed using vital dyes, fluorescein-labeled phalloidin, and scanning electron microscopy, respectively. The toxins' effects on bacterial adherence and bacterial internalization by cultured enterocytes were assessed using enzyme-linked immunosorbent assay and quantitative culture, respectively. Epithelial permeability was assessed by changes in transepithelial electrical resistance and by quantifying paracellular bacterial movement through Caco-2 enterocytes cultivated on permeable supports. Neither toxin A nor toxin B had a measurable effect on the numbers of enteric bacteria internalized by Caco-2 enterocytes; however, both toxins were associated with alterations in enterocyte actin, decreased transepithelial electrical resistance, and increased bacterial adherence and paracellular transmigration. Clostridium difficile toxins A or B may facilitate bacterial adherence and penetration of the intestinal epithelial barrier.


Curvature of n-dimensional space curves in grey-value images.
Local curvature represents an important shape parameter of space curves which are well described by differential geometry. We have developed an estimator for local curvature of space curves embedded in n-dimensional (n-D) grey-value images. There is neither a segmentation of the curve needed nor a parametric model assumed. Our estimator works on the orientation field of the space curve. This orientation field and a description of local structure is obtained by the gradient structure tensor. The orientation field has discontinuities; walking around a closed contour yields two such discontinuities in orientation. This field is mapped via the Knutsson mapping to a continuous representation; from a n-D vector to a symmetric n2-D tensor field. The curvature of a space curve, a coordinate invariant property, is computed in this tensor field representation. An extensive evaluation shows that our curvature estimation is unbiased even in the presence of noise, independent of the scale of the object and furthermore the relative error stays small.


Experimental assessment of CT-based thermometry during laser ablation of porcine pancreas.
Laser interstitial thermotherapy (LITT) is employed to destroy tumors in organs, and its outcome strongly depends on the temperature distribution inside the treated tissue. The recent introduction of computed tomography (CT) scan thermometry, based on the CT number dependence of the tissue with temperature, overcomes the invasiveness of other techniques used to monitor temperature during LITT. The averaged CT number (ROI = 0.02 cm(2)) of an ex vivo swine pancreas is monitored during LITT (Nd:YAG laser power of 3 W, treatment time: 120 s) at different distances from the applicator (from 4 to 30 mm). The averaged CT number shows a clear decrease during treatment: it is highest at 4 mm from the applicator (mean variation in the whole treatment of -0.256 HU s(-1)) and negligible at 30 mm, since the highest temperature increase is present close to the applicator (i.e., 45 °C at 4 mm and 25 °C at 6 mm). To obtain the relationship between CT numbers and pancreas temperature, the reference temperature was measured by 12 fiber Bragg grating sensors. The CT number decreases as a function of temperature, showing a nonlinear trend with a mean thermal sensitivity of -0.50 HU °C(-1). Results here reported are the first assessment of pancreatic CT number dependence on temperature, at the best of our knowledge. Findings can be useful to further investigate CT scan thermometry during LITT on the pancreas.


Ortho-Substituted α-Phenyl Mannoside Derivatives Promoted Early-Stage Adhesion and Biofilm Formation of E. coli 83972.
Prevention of catheter-associated urinary tract infection (CAUTI) over long-term usage of urinary catheters remains a great challenge. Bacterial interference using nonpathogenic bacteria, such as E. coli 83972, have been investigated in many pilot-scale clinical studies as a potentially nonantibiotic based strategy for CAUTI prevention. We have demonstrated that preforming a dense and stable biofilm of the nonpathogenic E. coli greatly enhances their capability to prevent pathogen colonization. Such nonpathogenic biofilms were formed by E. coli 83972 expressing type 1 fimbriae (fim+ E. coli 83972) on mannoside-presenting surfaces. In this work, we report the synthesis of a series of mannoside derivatives with a wide range of binding affinities, all being equipped with a handle for covalent attachment to silicone surfaces. We established a high-throughput competitive assay based on mannoside-modified particles and flow-cytometry to directly measure the binding affinity between the mannoside ligands and fim+ E. coli 83972. We demonstrated that the bacterial adhesion and biofilm formation were strongly correlated to the binding affinity of the immobilized mannoside ligands. Mass spectrometry based proteomic analysis indicated a substantial difference in the proteome of the extracellular polymeric substance (EPS) secreted by biofilms on different mannoside surfaces, which might be related to the biofilm stability.


Investigating a relevance of fuzzy mappings.
The study introduces a concept of relevance of fuzzy mappings regarded as fundamental constructs of granular computing and rule-based systems, in particular. The notion of relevance of the fuzzy mappings is instrumental in the quantification of the quality of such mappings prior to their detailed construction. For the purposes of such quantification, we introduce shadowed sets and discuss as an algorithmic framework to be instrumental in expressing and quantifying the property of relevance of the fuzzy mappings. It is revealed that shadowed sets provide an interesting three-valued quantification of this property (such as acceptable mapping, marginal mapping, and a lack of mapping). The paper includes a number of detailed calculations concerning two commonly exploited classes of triangular and Gaussian fuzzy sets. Numerical studies are discussed as well.


Case report: chronic relapsing cryptococcal meningitis in a patient with low mannose-binding lectin and a low naïve CD4 cell count.
Cryptococcal meningitis is most commonly found in HIV-infected patients. In HIV-negative patients, its low incidence can lead to prolonged time to diagnosis. Detailed case reports of chronic cryptococcal meningitis are scarce, but could provide clues for earlier diagnosis in this patient category. A 60-year old man presented June 2015 with intermittent headaches for several months without any fever. Initial work-up showed a leukocytosis, raised CSF opening pressure and raised leukocytes and protein in the CSF. An MRI revealed leptomeningeal contrast enhancement and cerebellar oedema. While malignancy and various infectious causes were excluded, the patient had a spontaneous clinical and radiological recovery. One year later, the patient returned with complaints of headaches. Also, cerebellar oedema and leptomeningeal contrast enhancement had recurred. Eventually in March 2017, the novel cryptococcal antigen lateral flow assay (CrAg LFA) was positive on CSF, and one colony of Cryptococcus neoformans was cultured from CSF. The patient was treated with the standard antifungal regimen which resulted in resolution of his headaches. In retrospect, the cryptococcal antigen test was already positive on a serum sample from June 2015. Interestingly, post-treatment immunological analysis revealed both a low mannose-binding lectin (MBL) concentration and low naïve CD4 counts. We present a patient with cryptococcal meningitis in an HIV-negative patient with low MBL and low naïve CD4 count suffering a chronic relapsing meningo-encephalitis with relatively mild symptoms for around 2 years. In patients with an unexplained meningo-encephalitis such as this case, early performance of CrAg LFA on serum and/or CSF is an inexpensive and rapid method to reduce time-to diagnosis.


Bioengineered and biohybrid bacteria-based systems for drug delivery.
The use of bacterial cells as agents of medical therapy has a long history. Research that was ignited over a century ago with the accidental infection of cancer patients has matured into a platform technology that offers the promise of opening up new potential frontiers in medical treatment. Bacterial cells exhibit unique characteristics that make them well-suited as smart drug delivery agents. Our ability to genetically manipulate the molecular machinery of these cells enables the customization of their therapeutic action as well as its precise tuning and spatio-temporal control, allowing for the design of unique, complex therapeutic functions, unmatched by current drug delivery systems. Early results have been promising, but there are still many important challenges that must be addressed. We present a review of promises and challenges of employing bioengineered bacteria in drug delivery systems and introduce the biohybrid design concept as a new additional paradigm in bacteria-based drug delivery.


Long-term efficacy of a tele-health intervention for acute coronary syndrome patients with depression: 12-month results of the MoodCare randomized controlled trial.
Depression is common after a cardiac event; however it often remains untreated. Previously, we reported the efficacy and feasibility of a 6-month tele-health programme (MoodCare), which integrates depression management into a cardiovascular disease (CVD) risk reduction programme for Acute Coronary Syndrome (ACS) patients with low mood. Here, we evaluate the long-term efficacy of the programme at 12-month follow-up. A two-arm, parallel, randomized design to compare the long-term effects of 'MoodCare' (n = 61) to usual care (UC) (n = 60) at 12 months. 121 ACS patients recruited from six hospitals in Victoria and Brisbane, Australia were randomized to a telephone-delivered cognitive behavioural therapy and risk-reduction programme or usual medical care. Mixed-model repeated measurements (MMRM) analysis was applied with results expressed as estimated marginal mean changes in depression and health-related quality of life (HRQOL) outcomes by group. After 12 months, treatment effects were observed for those with major depressive disorder (MDD) for PHQ-9 depression (MoodCare: mean score: 6.5; 95% CI: 4.9-8.0 versus UC: 9.3; 95% CI: 7.7-10.9, p = 0.012)) and SF-12 mental health scores (MoodCare: 42.5; 95% CI: 39.8-45.2 versus UC: 36.8; 95% CI: 34.1-39.6, p = 0.005). No beneficial treatment effects were observed in those with no MDD at baseline. After 12 months, MoodCare was superior to UC for improving mental health outcomes for those with a clinical diagnosis of major depression. Our findings support the implementation of depression-based interventions for cardiac patients with a clinical diagnosis of depression and provide evidence of longer term efficacy to one year.


Design of potent fluoro-substituted chalcones as antimicrobial agents.
Owing to ever-increasing bacterial and fungal drug resistance, we attempted to develop novel antitubercular and antimicrobial agents. For this purpose, we developed some new fluorine-substituted chalcone analogs (3, 4, 9-15, and 20-23) using a structure-activity relationship approach. Target compounds were evaluated for their antitubercular efficacy against Mycobacterium tuberculosis H37Rv and antimicrobial activity against five common pathogenic bacterial and three common fungal strains. Three derivatives (3, 9, and 10) displayed significant antitubercular activity with IC50 values of ≤16,760. Compounds derived from trimethoxy substituent scaffolds with monofluoro substitution on the B ring of the chalcone structure exhibited superior inhibition activity compared to corresponding hydroxy analogs. In terms of antimicrobial activity, most compounds (3, 9, 12-14, and 23) exhibited moderate to potent activity against the bacteria, and the antifungal activities of compounds 3, 13, 15, 20, and 22 were comparable to those of reference drugs ampicillin and fluconazole.


[Physiotherapy from the view of health insurance financing].
Physiotherapy lacks studies performed with the use of the modern research methodology and, therefore, its use based on empirical considerations. International practice guidelines do not recommend unequivocally the use of all kinds of physiotherapy with the exception of exercise therapy, but Hungarian guidelines support its use in the treatment of several different conditions. National health insurance in Hungary provides financial support for the use of physiotherapy in the fields of home care, out- and inpatient care and spa treatment. In 2011 national health insurance in Hungary supported spa treatments with 4 billion HUF, and the most frequently used treatment was thermal bath in about 2 million occasions. National health insurance in Hungary spent about 1 billion HUF for physiotherapy used in outpatient care; both ultrasound and interference treatments were financed in 2 million occasions in 2011.


Non-rigid multimodal image registration based on local variability measures and optical flow.
In this paper, we present a novel methodology for multimodal non-rigid medical image registration. The proposed approach is based on combining an optical flow technique with a pixel intensity transformation by using a local variability measure, such as statistical variance or Shannon entropy. The methodology is basically composed by three steps: first, we approximate the global deformation using a rigid registration based on a global optimization technique, called particle filtering; second, we transform both target and source images into a new intensity space where they can be compared; and third, we obtain the optical flow between them by using the Horn and Shuck algorithm in an iterative scales-space framework. After these steps, the non-rigid registration is made up by adding the resulting vector fields, computed by the rigid registration, and the optical flow. The proposed algorithm was tested using a synthetic intensity mapping and non-rigid deformation of MRI images. Preliminary results show that the methodology seems to be a good alternative for non-rigid multimodal registration, obtaining an average error of less than two pixels in the estimation of the deformation vector field.


Predetermination of sexual fate in a turtle with temperature-dependent sex determination.
Egg incubation temperature determines offspring sex in many reptilian species, including red-eared slider turtles, where embryos incubated at low temperatures during the initial stages of gonad formation develop as males, while those kept at higher temperatures develop as females. Incubation at the threshold, or pivotal, temperature (PvT) yields an even ratio of males and females. This strong susceptibility to temperature indicates that each embryo of this species is competent to develop as a male or a female. However, the mechanism that determines sexual fate at the PvT has not been identified. One possibility is that sexual fate is stochastic at the PvT, but coordinated by systemic signals within a single embryo. If this is the case, gonads explanted separately to culture should not coordinate their fate. Here we show that gonad pairs from embryos incubated at the PvT share a strong predisposition for one sex or the other when cultured in isolation, indicating that they were affected by shared genetic signals, maternally-deposited yolk hormones or other transient influences received prior to the stage of dissection. In ovo studies involving shifts from the male- or female-producing temperature to the PvT further indicate that embryos adopt a sexual differentiation trajectory many days prior to the onset of morphological differentiation into testes or ovaries and usually maintain this fate in the absence of an extreme temperature signal favoring the development of the other sex. Our findings therefore suggest that the outcome of sex determination in these reptiles is heavily influenced (i) by an inherent predisposition at the PvT and (ii) by the sexual differentiation trajectory established early in gonad development under male- or female-producing temperatures.


Enzymatic changes in pectic polysaccharides related to the beneficial effect of soaking on bean cooking time.
Cooking time decreases when beans are soaked first. However, the molecular basis of this decrease remains unclear. To determine the mechanisms involved, changes in both pectic polysaccharides and cell wall enzymes were monitored during soaking. Two cultivars and one breeding line were studied. Soaking increased the activity of the cell wall enzymes rhamnogalacturonase, galactanase and polygalacturonase. Their activity in the cell wall was detected as changes in chemical composition of pectic polysaccharides. Rhamnose content decreased but galactose and uronic acid contents increased in the polysaccharides of soaked beans. A decrease in the average molecular weight of the pectin fraction was induced during soaking. The decrease in rhamnose and the polygalacturonase activity were associated (r = 0.933, P = 0.01, and r = 0.725, P = 0.01, respectively) with shorter cooking time after soaking. Pectic cell wall enzymes are responsible for the changes in rhamnogalacturonan I and polygalacturonan induced during soaking and constitute the biochemical factors that give bean cell walls new polysaccharide arrangements. Rhamnogalacturonan I is dispersed throughout the entire cell wall and interacts with cellulose and hemicellulose fibres, resulting in a higher rate of pectic polysaccharide thermosolubility and, therefore, a shorter cooking time.


Robotic-assisted laparoscopic partial cystectomy for symptomatic urachal hamartoma.
We report a case of an urachal hamartoma in a 30-year-old African American woman. The urachal lesion was excised with a robotic-assisted laparoscopic partial cystectomy. Pathologic analysis revealed cysts, smooth muscle, and ciliated epithelium consistent with a hamartoma. The patient recovered without complication. This case highlights an unusual pathology that is infrequently reported following urachal remnant excision.


Architectured design of superparamagnetic Fe3O4 nanoparticles for application as MRI contrast agents: mastering size and magnetism for enhanced relaxivity.
This work reports the mastered design of novel water-dispersible superparamagnetic iron oxide nanomaterials with enhanced magnetic properties and reduced size. A straightforward cost-effective aqueous coprecipitation route was developed, based on the use of three new coprecipitation agents: the polydentate bases diethanolamine, triethanolamine and triisopropanolamine. Through the selection of these alkanolamines which presented different complexing properties, an improvement of the surface spin order could be achieved upon the reduction of the nanomaterial dimensions (from 8.7 to 3.8 nm) owing to the complexation of the polydentate bases with the subcoordinated iron cations on the particle surface. In particular, the alkanolamine with the highest chelating ability (triethanolamine) led to the nanomaterial with the smallest size and the thinnest magnetic "dead" layer. In order to evaluate the importance of the dual control of size and magnetism, the relaxometric properties of the nanomaterials were investigated, whereby maximum values of transverse relaxivity r2 of 300.30 and 253.92 mM-1 s-1 at 25 and 37 °C, respectively (at 20 MHz) were achieved, making these nanomaterials potential T2-weighted MRI contrast agents. Moreover, these values were significantly higher than those reported for commercial T2 contrast agents and other iron oxides with identical dimensions. Hence, we were able to demonstrate that the r2 enhancement cannot only be achieved by an increase of particle/cluster size, but also through the precise control of the surface magnetic properties while constraining the nanomaterial dimensions. These achievements open up new perspectives on the mastered design of magnetic nanoprobes, overcoming the limitations related to the deleterious effect of size reduction.


Saprolegnia diclina IIIA and S. parasitica employ different infection strategies when colonizing eggs of Atlantic salmon, Salmo salar L.
Here, we address the morphological changes of eyed eggs of Atlantic salmon, Salmo salar L. infected with Saprolegnia from a commercial hatchery and after experimental infection. Eyed eggs infected with Saprolegnia spp. from 10 Atlantic salmon females were obtained. Egg pathology was investigated by light and scanning electron microscopy. Eggs from six of ten females were infected with S. parasitica, and two females had infections with S. diclina clade IIIA; two Saprolegnia isolates remained unidentified. Light microscopy showed S. diclina infection resulted in the chorion in some areas being completely destroyed, whereas eggs infected with S. parasitica had an apparently intact chorion with hyphae growing within or beneath the chorion. The same contrasting pathology was found in experimentally infected eggs. Scanning electron microscopy revealed that S. parasitica grew on the egg surface and hyphae were found penetrating the chorion of the egg, and re-emerging on the surface away from the infection site. The two Saprolegnia species employ different infection strategies when colonizing salmon eggs. Saprolegnia diclina infection results in chorion destruction, while S. parasitica penetrates intact chorion. We discuss the possibility these infection mechanisms representing a necrotrophic (S. diclina) vs. a facultative biotrophic strategy (S. parasitica).


Eye Movements in Neuropsychological Tasks.
This chapter reviews how recording and analysis of eye movements have been applied to understanding cognitive functioning in patients with neurological disease. Measures derived from the performance of instructed eye movement tests such as the anti-saccade and memory-guided saccade tasks have been shown to be associated with cognitive test performance and the early stages of neurodegenerative disorders including Alzheimer's and Parkinson's disease. Other researchers have taken an ecological approach and recorded the uninstructed pattern of saccades made by patients during performance of established neuropsychological tasks. Studies that have analysed the eye movement strategies used in a number of widely used tests are reviewed, including the Corsi blocks, Tower of London, 'CANTAB' Spatial Working Memory and Brixton Spatial Anticipation test. The findings illustrate that eye movements are not purely in the service of vision, but support visuospatial working memory and forward action planning. Eye movement tests and measures also have potential for application in the assessment and diagnosis of neurological disease and cognitive impairment. Establishing large-scale normative data sets in healthy older adults and use of machine learning multivariate classifier algorithms may be key to further developing eye tracking applications in neuropsychological assessment.


Schizophrenia and mania in identical twin brothers.
Each of a pair of identical twin brothers was independently remanded for mental health assessment. The results of the assessment reliably revealed schizophrenia in one twin and mania in the other. The implications for genetic models of mental disorder are discussed.


Chitotriosidase as a Novel Biomarker for Therapeutic Monitoring of Nephropathic Cystinosis.
Nephropathic cystinosis, a hereditary lysosomal storage disorder caused by dysfunction of the lysosomal cotransporter cystinosin, leads to cystine accumulation and cellular damage in various organs, particularly in the kidney. Close therapeutic monitoring of cysteamine, the only available disease-modifying treatment, is recommended. White blood cell cystine concentration is the current gold standard for therapeutic monitoring, but the assay is technically demanding and is available only on a limited basis. Because macrophage-mediated inflammation plays an important role in the pathogenesis of cystinosis, biomarkers of macrophage activation could have potential for the therapeutic monitoring of cystinosis. We conducted a 2-year prospective, longitudinal study in which 61 patients with cystinosis who were receiving cysteamine therapy were recruited from three European reference centers. Each regular care visit included measuring four biomarkers of macrophage activation: IL-1β, IL-6, IL-18, and chitotriosidase enzyme activity. A multivariate linear regression analysis of the longitudinal data for 57 analyzable patients found chitotriosidase enzyme activity and IL-6 to be significant independent predictors for white blood cell cystine levels in patients of all ages with cystinosis; a receiver operating characteristic analysis ranked chitotriosidase as superior to IL-6 in distinguishing good from poor therapeutic control (on the basis of white blood cell cystine levels of <2 nmol 1/2 cystine/mg protein or ≥2 nmol 1/2 cystine/mg protein, respectively). Moreover, in patients with at least one extrarenal complication, chitotriosidase significantly correlated with the number of extrarenal complications and was superior to white blood cell cystine levels in predicting the presence of multiple extrarenal complications. Chitotriosidase enzyme activity holds promise as a biomarker for use in therapeutic monitoring of nephropathic cystinosis.


Treatment and Survivorship Interventions to Prevent Poor Body Image Outcomes in Breast Cancer Survivors.
Body image concerns often arise during and after treatment and are a major concern in up to 67% of breast cancer survivors. Negative changes in body image are a predictor of worse satisfaction with appearance and poor quality of life outcomes. Opportunities to mitigate the negative impact of cancer treatment on a patient's body image present during preoperative education or in the neoadjuvant setting, or during surgical management, adjuvant therapy delivery, and survivorship. The surgical management of breast cancer has evolved from breast amputations to procedures that provide improved cosmesis without compromising the oncologic outcome. The advent of the sentinel lymph node biopsy and lymphatic reconstruction techniques has led to decreased axillary morbidity. Modified radiation techniques and systemic therapies tailored to subtype limit unnecessary exposure to skin and systemic toxicities. Finally, incorporating prehabilitation and survivorship support optimizes the physical and psychosocial well-being of these patients. Setting expectations, treatment de-escalation when appropriate, morbidity risk reduction and improved screening and management of psychological sequelae during survivorship can decrease breast cancer treatment's negative impact on body image. The following review synthesizes interventions during preoperative planning, local and systemic treatment, and survivorship to prevent poor body image outcomes without compromising oncologic success.


Unilateral versus bilateral pedicle screw fixation with posterior lumbar interbody fusion for lumbar degenerative diseases: A meta-analysis.
Both unilateral pedicle screw fixation with posterior lumbar interbody fusion (PLIF) and bilateral pedicle screw fixation with PLIF are used to treat lumbar degenerative diseases (LDD). However, which one is a better treatment for LDD remains considerable controversy. Therefore, the focus of this meta-analysis was to assess the merits and shortcomings of efficacy of these 2 surgical procedures for LDD. An extensive search of literature was performed in Pubmed/MEDLINE, Embase, CNKI, and WANFANG databases on unilateral versus bilateral pedicle screw fixation with PLIF fusion for LDD, from January 2007 to January 2017 and language was restricted to Chinese or English. The following variables were extracted: blood loss, operation time, length of hospital stay, Japanese Orthopedic Association (JOA) scores, visual analog scale (VAS) and Oswestry disability index (ODI) scores, fusion rate, total complications, infection, dural injury, and nerve injury. Data analysis was conducted with RevMan 5.3 and STATA 12.0. A total of 11 studies containing 844 patients were included in our study. The results showed that unilateral is better than bilateral pedicle screw fixation with PLIF in blood loss (P < .00001), operation time (P < .00001), the length of hospital stay (P = .003), and the final follow-up ODI scores (P = .04). However, there are no significant differences in JOA, VAS, and preoperative ODI scores. There are also no significant differences in fusion rate and complications (all P > .05). Based on our meta-analysis, our results suggest that both unilateral pedicle screw fixation with PLIF and bilateral pedicle screw fixation with PLIF for LDD have effective results in clinical outcomes. Both 2 methods may result in clinical improvement and similar outcomes of fusion rate and complications; However, compared with bilateral fixation, unilateral fixation produces more satisfactory efficacy in the blood loss and the operation time.


Structural Characterization of Lignins from Willow Bark and Wood.
Understanding the chemical structure of lignin in willow bark is an indispensable step to design how to separate its fiber bundles. The whole cell wall and enzyme lignin preparations sequentially isolated from ball-milled bark, inner bark, and wood were comparatively investigated by nuclear magnetic resonance (NMR) spectroscopy and three classical degradative methods, i.e., alkaline nitrobenzene oxidation, derivatization followed by reductive cleavage, and analytical thioacidolysis. All results demonstrated that the guaiacyl (G) units were predominant in the willow bark lignin over syringyl (S) and minor p-hydroxyphenyl (H) units. Moreover, the monomer yields and S/G ratio rose progressively from bark to inner bark and wood, indicating that lignin may be more condensed in bark than in other tissues. Additionally, major interunit linkage substructures (β-aryl ethers, phenylcoumarans, and resinols) together with cinnamyl alcohol end groups were relatively quantitated by two-dimensional NMR spectroscopy. Bark and inner bark were rich in pectins and proteins, which were present in large quantities and also in the enzyme lignin preparations.


Game theory in the operating room environment.
To optimize the functioning of an operating room the interactions of the staff (physicians and nurses) and other stakeholders (administrators) must be understood. Game theory provides a representation of the interactions that typically take place in the operating room environment. By understanding the types of games/interactions that occur the participants can better predict outcome and adapt their own behavior to optimize that outcome. Types of games seen in the operating room include fixed-sum, zero-sum, and non-zero-sum games. The Prisoner's Dilemma game and some of its variations are used to illustrate common interactions in the operating room. Examples of strategies for typical scenarios are discussed as well as ways to improve the outcome of the games. A better understanding of human behavior can improve the functioning of complex systems such as that found in the operating room.


Long-term trends in juvenile Mugil liza abundance in relation to selected environmental and fisheries influences in southern Brazil.
Overfishing constitutes a major threat affecting marine fish population worldwide, including mullet species that have been exploited by fisheries during the reproductive migration in temperate and tropical latitudes for millennia. In the present study, we investigated the relationship of fishing intensity of mullet Mugil liza during its reproductive migration and the abundance of their juveniles in an essential nursery ground for the species in the southwest Atlantic Ocean. To carry out this analysis, we used a 23-year standardized long-term time series (1997-2019) of monthly abundance of M. liza juveniles, local/regional (water temperature, salinity, water transparency and river discharge) and global (ENSO) environmental factors, along with compilations of fishing landing data for the species. Generalized Additive Models (GAM) revealed the negative effect of fishing adult populations on the abundance of juveniles when they reach the marine surf-zone and after recruiting into the estuary. Our results reinforce the importance of adequate conservation and fishery regulation policies to prevent the species' stock from collapsing.


Brain responses to repetitions of human and animal faces, inverted faces, and objects: an MEG study.
Recent studies have identified a prominent face-selective ERP response to immediate repetitions of faces approximately 250 ms (N250r) which was strongly attenuated or eliminated for control stimuli (Schweinberger, Huddy, and Burton 2004, NeuroReport, 15, 1501-1505). In the present study we used a 148-channel whole head neuromagnetometer to investigate event-related magnetic fields (ERMFs) elicited by repetitions of exemplars of human faces, inverted human faces, primate faces, and car fronts. Participants counted rare pictures of butterflies interspersed in a series of pairs of one of these categories. The second stimulus of each pair could either be a repetition or a non-repetition of the first stimulus. We observed prominent M100 (90-140 ms) and M170 (140-220 ms) responses. Both M100 and M170 were insensitive to repetition and showed little differences between stimulus categories, except for a slight increase and delay of M170 to inverted faces. By contrast, we observed a repetition-sensitive M250r response (220-330 ms). This M250r was larger for upright human and primate faces when compared to both inverted human faces and cars, a finding that was specific for right hemispheric sensors. Source localization suggested different generators for M170 and M250r in occipitotemporal and fusiform areas, respectively. These findings suggest that repetition-sensitive brain activity approximately 250 ms reflects the transient activation of object representations, with largest responses for upright faces, in the right hemisphere.


Late-onset autosomal recessive cerebellar ataxia and neuropathy with a novel splicing mutation in the ATM gene.
Autosomal recessive cerebellar ataxias comprise many types of diseases. The most frequent autosomal recessive cerebellar ataxias are Friedreich ataxia, but other types are relatively rare. We encountered a consanguineous family with two cases of late-onset cerebellar ataxia with neuropathy. We performed whole-exome sequencing in one patient and confirmed by Sanger sequencing in other family members. Neurological examination revealed cerebellar ataxia, hand tremor, and neck dystonia, distal muscle wasting, and diminished tendon reflexes. The patients had no conjunctival telangiectasia or immunodeficiency. Blood examination revealed slightly elevated α-fetoprotein. Brain MRI demonstrated marked cerebellar atrophy and mild brainstem atrophy. The electrophysiologic study and nerve biopsy showed axonal neuropathy. Whole-exome sequencing revealed a novel homozygous missense variant (NM_000051.3: c.496G > C) in the ataxia-telangiectasia mutated gene. This homozygous variant was found in another patient, co-segregated within the family members-this variant results in aberrant splicing (skipping exon 5) on RT-PCR analysis. We identified the ataxia-telangiectasia mutated variant in an adult, late-onset autosomal recessive cerebellar ataxias family. We should consider ataxia-telangiectasia even in late-onset autosomal recessive cerebellar ataxias without telangiectasia or immunodeficiency.


Application of a Machine Learning Algorithm in Prediction of Abusive Head Trauma in Children.
We explored the application of a machine learning algorithm for the timely detection of potential abusive head trauma (AHT) using the first free-text note of an encounter and demographic information. First free-text physician notes and demographic information were collected for children under 5 years of age at a Level 1 Trauma Center. The control group, which included patients with head/neck injury, was compared to those with AHT diagnosed by the Child Protective Team. Differential scores accounted for words overrepresented in AHT patient vs. control notes. Sentiment scores were reflective of note positivity/negativity and subjectivity scores accounted for note subjectivity/objectivity. The composite scores reflected the patient's differential score modified by the subjectivity score. Composite, sentiment, and subjectivity scores combined with demographic information trained a Random Forest (RF) machine learning algorithm to predict AHT. Final composite scores with demographic information were highly associated with AHT in a test dataset. The control group included 587 patients and the test group included 193 patients. Combining composite scores with demographic information into the RF model improved AHT classification area under the curve (AUC) from 0.68 to 0.78, with an overall accuracy of 84%. Feature importance analysis of our RF model revealed that composite score, sentiment, age, and subjectivity were the most impactful predictors of AHT. The sentiment was not significantly different between control and AHT notes (p = 0.87), while subjectivity trended higher for AHT notes (p = 0.081). We conclude that a machine learning algorithm can recognize patterns within free-text notes and demographic information that aid in AHT detection in children. III.


[Results of combination therapy of rectal cancer].
A comparative study of the results of treatment in 264 patients treated surgically and in 236 patients subjected to a combination treatment, using an intensive concentration gammatherapy (500 rad daily up to 3000 rad), has demonstrated that preoperative irradiation does not result in a higher postoperative mortality. In the combination therapy all kinds of surgery performed for rectal cancer seem to be feasible.


Enhancement of stem cell engraftment on a WHIM.
WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome is a genetic autoimmune disorder that results from gain-of-function mutations in the gene encoding chemokine receptor CXCR4. A previous study characterized a patient with WHIM who underwent a chromothriptic event that resulted in spontaneous deletion of the WHIM allele in a single hematopoietic stem cell and subsequent cure of the disease. In this issue of the JCI, Gao et al. extend this work and show that Cxcl4-haplosufficient bone marrow has a selective advantage for long-term engraftment in murine WHIM models. Moreover, successful engraftment occurred without prior conditioning of recipients. Together, these results have important implications for improving hematopoietic stem/progenitor cell transplant not only for patients with WHIM but also for all patients who may require the procedure.


Asthma pharmacogenetics and the development of genetic profiles for personalized medicine.
Human genetics research will be critical to the development of genetic profiles for personalized or precision medicine in asthma. Genetic profiles will consist of gene variants that predict individual disease susceptibility and risk for progression, predict which pharmacologic therapies will result in a maximal therapeutic benefit, and predict whether a therapy will result in an adverse response and should be avoided in a given individual. Pharmacogenetic studies of the glucocorticoid, leukotriene, and β2-adrenergic receptor pathways have focused on candidate genes within these pathways and, in addition to a small number of genome-wide association studies, have identified genetic loci associated with therapeutic responsiveness. This review summarizes these pharmacogenetic discoveries and the future of genetic profiles for personalized medicine in asthma. The benefit of a personalized, tailored approach to health care delivery is needed in the development of expensive biologic drugs directed at a specific biologic pathway. Prior pharmacogenetic discoveries, in combination with additional variants identified in future studies, will form the basis for future genetic profiles for personalized tailored approaches to maximize therapeutic benefit for an individual asthmatic while minimizing the risk for adverse events.


Quantitation of triacylglycerols in plant oils using HPLC with APCI-MS, evaporative light-scattering, and UV detection.
The main constituents of plant oils are complex mixtures of TGs differing in acyl chain lengths, number and positions of double bonds, and regioisomerism. A non-aqueous reversed-phase HPLC method with acetonitrile-2-propanol gradient and 30 + 15 cm NovaPak C18 columns makes possible an unambiguous identification of the highest number of TGs ever reported for these oils, based on positive-ion APCI mass spectra. A new approach to TG quantitation is based on the use of response factors with three typical detection techniques for that purpose (APCI-MS, evaporative light-scattering detection, and UV at 205 nm). Response factors of 23 single-acid TGs (saturated TGs from C7 to C22, 7 unsaturated TGs), 4 mixed-acid TGs, diolein and monoolein are calculated from their calibration curves and related to OOO. Due to differences between saturated and unsaturated acyl chains, the use of response factors significantly improves the quantitation of TGs. 133 TGs containing 22 fatty acids with 8-25 carbon atoms and 0-3 double bonds are identified and quantified in 9 plant oils (walnut, hazelnut, cashew nut, almond, poppy seed, yellow melon, mango, fig, date) using HPLC/APCI-MS with a response factor approach. Average parameters and relative fatty acid concentrations are calculated with both HPLC/APCI-MS and GC/ FID.


Influence of the kallikrein-kinin system on prostate and breast tumour angiogenesis.
Angiogenesis is important for the growth and progression of cancer cells. There is some evidence that the kallikrein-kinin system (KKS) is involved in cancer and angiogenesis. The present study investigated the effect of increasing concentrations of prostate and breast tumour cell metabolites on the proliferation of cultured endothelial cells, their tissue kallikrein (TK) secretion and KKS expression. Expression of TK and kinin receptors was investigated by immunochemistry, and secretion of TK by ELISA. Cell proliferation was measured by a chromogenic assay. KKS proteins were also immunolocalised in an endothelial tumour co-culture model. KKS proteins were found in projections of all cell types as well as at points of heterogeneous contact. Tumour metabolites increased the secretion of TK from endothelial cells, with corresponding decreases in intracellular amounts, while also increasing proliferation of the endothelial cells. These findings indicate that the KKS may be one of the more important players in angiogenesis associated with prostate and breast tumours.


Mitochondrial superoxide: production, biological effects, and activation of uncoupling proteins.
Mitochondria are potent producers of cellular superoxide, from complexes I and III of the electron transport chain, and mitochondrial superoxide production is a major cause of the cellular oxidative damage that may underlie degradative diseases and aging. This superoxide production is very sensitive to the proton motive force, so it can be strongly decreased by mild uncoupling. Superoxide and the lipid peroxidation products it engenders, including hydroxyalkenals such as hydroxynonenal, are potent activators of proton conductance by mitochondrial uncoupling proteins such as UCP2 and UCP3, although the mechanism of activation has yet to be established. These observations suggest a hypothesis for the main, ancestral function of uncoupling proteins: to cause mild uncoupling and so diminish mitochondrial superoxide production, hence protecting against disease and oxidative damage at the expense of a small loss of energy. We review the growing evidence for this hypothesis, in mitochondria, in cells, and in vivo. More recently evolved roles of uncoupling proteins are in adaptive thermogenesis (UCP1) and perhaps as part of a signaling pathway to regulate insulin secretion in pancreatic beta cells (UCP2).


Structural basis of the anionic interface preference and kcat* activation of pancreatic phospholipase A2.
Pancreatic phospholipase A(2) (PLA2) shows a strong preference for the binding to the anionic interface and a consequent allosteric activation. In this paper, we show that virtually all the preference is mediated through 3 (Lys-53, -56, and -120) of the 12 cationic residues of bovine pancreatic PLA2. The lysine-to-methionine substitution enhances the binding of the enzyme to the zwitterionic interface, and for the K53,56,120M triple mutant at the zwitterionic interface is comparable to that for the wild type (WT) at the anionic interface. In the isomorphous crystal structure, the backbone folding of K53,56M K120,121A and WT are virtually identical, yet a significant change in the side chains of certain residues, away from the site of substitution, mostly at the putative contact site with the interface (i-face), is discernible. Such reciprocity, also supported by the spectroscopic results for the free and bound forms of the enzyme, is expected because a distal structural change that perturbs the interfacial binding could also affect the i-face. The results show that lysine-to-methionine substitution induces a structural change that promotes the binding of PLA2 to the interface as well as the substrate binding to the enzyme at the interface. The kinetic results are consistent with a model in which the interfacial Michaelis complex exists in two forms, and the complex that undergoes the chemical step is formed by the charge compensation of Lys-53 and -56. Analysis of the incremental changes in the kinetic parameters shows that the charge compensation of Lys-53 and -56 contributes to the activation and that of Lys-120 contributes only to the structural change that promotes the stability of the Michaelis complex at the interface. The charge compensation effects on these three residues also account for the differences in the anionic interface preference of the evolutionarily divergent secreted PLA2.


Genetic Mapping by Integration of 55K SNP Array and KASP Markers Reveals Candidate Genes for Important Agronomic Traits in Hexaploid Wheat.
Agronomic traits such as heading date (HD), plant height (PH), thousand grain weight (TGW), and spike length (SL) are important factors affecting wheat yield. In this study, we constructed a high-density genetic linkage map using the Wheat55K SNP Array to map quantitative trait loci (QTLs) for these traits in 207 recombinant inbred lines (RILs). A total of 37 QTLs were identified, including 9 QTLs for HD, 7 QTLs for PH, 12 QTLs for TGW, and 9 QTLs for SL, which explained 3.0-48.8% of the phenotypic variation. Kompetitive Allele Specific PCR (KASP) markers were developed based on sequencing data and used for validation of the stably detected QTLs on chromosomes 3A, 4B and 6A using 400 RILs. A QTL cluster on chromosome 4B for PH and TGW was delimited to a 0.8 Mb physical interval explaining 12.2-22.8% of the phenotypic variation. Gene annotations and analyses of SNP effects suggested that a gene encoding protein Photosynthesis Affected Mutant 68, which is essential for photosystem II assembly, is a candidate gene affecting PH and TGW. In addition, the QTL for HD on chromosome 3A was narrowed down to a 2.5 Mb interval, and a gene encoding an R3H domain-containing protein was speculated to be the causal gene influencing HD. The linked KASP markers developed in this study will be useful for marker-assisted selection in wheat breeding, and the candidate genes provide new insight into genetic study for those traits in wheat.


[Treatment of hypertension in people over 80 years should not be discontinued].
The 'Hypertension in the very elderly trial' (HYVET) was designed to answer the question whether antihypertensive treatment reduces strokes (both fatal and non-fatal strokes) without increasing total mortality. A total of 3845 patients were assigned to active treatment or placebo. About 90% had a history of hypertension, 65% of which were being treated. At the start of the study all antihypertensive treatment was stopped and the subjects were randomized to either indapamide 1.5 mg with or without perindopril 2-4 mg or to identical looking placebo. After about 2 years the trial was discontinued for ethical reasons as there was less death from any cause in the intervention group. Blood pressure decreased with 30/13 mmHg in the treatment versus 15/7 mmHg in the placebo group. There was a 30% decrease of all strokes (p = 0.06) but a significant reduction in fatal strokes (p < 0.05). Unexpected was the 21% reduction in all-cause mortality (p < 0.02). The 23% reduction in the rate of cardiovascular death was not significant (p < 0.06). Heart failure and total cardiovascular events decreased (p < 0.001). There were fewer adverse effects in the treatment group (p = 0.001). In our opinion HYVET proves that antihypertensive medication should not be stopped when patients pass the age of 80 years. However, it remains to be established whether treatment should be started in new patients who present themselves with hypertension above the age of 80 years.


Contrast ultrasonography--a necessary procedure for a better characterization of digestive tract pathology.
The pathology of the digestive tract, extremely popular, with equal sex distribution, can have a clinical history of chronic illness or emergency. Diagnosis is based on endoscopy (identifies the lesion, permits histological sample under visual control, and minimally invasive treatment for polypoid benign tumors). Ultrasonography, being non-invasive and very accessible, is often used as the initial imaging procedure to detect or exclude digestive pathology with similar symptoms. Understanding digestive ultrasound is conditioned by the image quality which can be achieved by removing air and food debris. Even so, the characteristics of the inflammatory diseases and the detection of tumors, particularly those with endoluminal development, can be difficult. In recent years transabdominal ultrasound examination of the digestive tract was supplemented with more precise methods of investigation of the lumen and circulation of the intestinal wall. These methods are represented by the administration of oral or ano-rectal homogenous substances (hydrosonography) and the by intravenous administration of agents containing stabilized microbubbles (CEUS). With these methods useful information are being obtained, high in sensitivity and specificity of lesions characterization. Judicious selection of the cases and of the examination technique remains the key to a successful diagnosis in all situations.


Nonselective β-Blockers May Progress the Thrombosis of Portal Venous System in Cirrhotic Patients: A Retrospective Observational Study.
Occlusive portal venous system thrombosis (PVT) is significantly associated with poor outcomes in cirrhotic patients. Nonselective β-blockers (NSBBs) may be associated with the development of PVT. However, the role of NSBBs in progressing thrombosis remains unclear. Forty-three patients on whom contrast-enhanced computed tomography or magnetic resonance imaging was performed twice, and for whom there was detailed information regarding NSBBs, were eligible in this study, including 16 in the NSBBs group and 27 in the no NSBBs group. A composite endpoint of progressing thrombosis included the development of PVT in patients without PVT and aggravation of PVT in patients with PVT. Logistic regression analysis was employed to identify the effect of NSBBs on the progression of PVT. At the last admission, 13 patients had progressing thrombosis. The incidence of progressing thrombosis was significantly higher in the NSBBs group than in the no NSBBs group [50.0% (8/16) vs. 18.5% (5/27), P = 0.030]. The use of NSBBs (odds ratio 4.400, 95% confidence interval 1.107-17.482, P = 0.035) was significantly associated with progressing thrombosis in univariate logistic regression analyses, but not significant (odds ratio 4.084, 95% confidence interval 0.488-34.158, P = 0.194) in multivariate logistic regression analyses. NSBBs may play a role in the progression of PVT in liver cirrhosis. The benefits and risks of NSBBs in the management of liver cirrhosis should be fully weighed.


Parenting Styles and Practices in Enhancing Self-Determination of Children With Intellectual and Developmental Disabilities.
Parenting styles and practices are crucial in promoting the self-determination of children. The purpose of the current study was to investigate the role of parenting styles and practices in enhancing the self-determination of children with/without intellectual and developmental disabilities (IDD). The present study was carried out with a sample of 243 parents of children with/without IDD in Türkiye (Turkey). The results indicated that an authoritative parenting style and autonomy-supportive parenting practices positively affect the degree of child self-determination, whereas permissive and overprotective parenting practices may limit child opportunities in fostering self-determination. The study results also showed that urbanization, higher income, and higher education level of parents positively impacted the degree of child self-determination. Parents of typically developing children reported higher levels of overall self-determination for their typically developing children when compared with children with intellectual disability and autism spectrum disorder. On the other hand, parents of children with mild disabilities reported a higher level of self-determination than both children with moderate and severe disabilities. The results were discussed within the cultural context of the current sample.


Comparative venom gland transcriptome surveys of the saw-scaled vipers (Viperidae: Echis) reveal substantial intra-family gene diversity and novel venom transcripts.
Venom variation occurs at all taxonomical levels and can impact significantly upon the clinical manifestations and efficacy of antivenom therapy following snakebite. Variation in snake venom composition is thought to be subject to strong natural selection as a result of adaptation towards specific diets. Members of the medically important genus Echis exhibit considerable variation in venom composition, which has been demonstrated to co-evolve with evolutionary shifts in diet. We adopt a venom gland transcriptome approach in order to investigate the diversity of toxins in the genus and elucidate the mechanisms which result in prey-specific adaptations of venom composition. Venom gland transcriptomes were created for E. pyramidum leakeyi, E. coloratus and E. carinatus sochureki by sequencing approximately 1000 expressed sequence tags from venom gland cDNA libraries. A standardised methodology allowed a comprehensive intra-genus comparison of the venom gland profiles to be undertaken, including the previously described E. ocellatus transcriptome. Blast annotation revealed the presence of snake venom metalloproteinases, C-type lectins, group II phopholipases A2, serine proteases, L-amino oxidases and growth factors in all transcriptomes throughout the genus. Transcripts encoding disintegrins, cysteine-rich secretory proteins and hyaluronidases were obtained from at least one, but not all, species. A representative group of novel venom transcripts exhibiting similarity to lysosomal acid lipase were identified from the E. coloratus transcriptome, whilst novel metallopeptidases exhibiting similarity to neprilysin and dipeptidyl peptidase III were identified from E. p. leakeyi and E. coloratus respectively. The comparison of Echis venom gland transcriptomes revealed substantial intrageneric venom variation in representations and cluster numbers of the most abundant venom toxin families. The expression profiles of established toxin groups exhibit little obvious association with venom-related adaptations to diet described from this genus. We suggest therefore that alterations in isoform diversity or transcript expression levels within the major venom protein families are likely to be responsible for prey specificity, rather than differences in the representation of entire toxin families or the recruitment of novel toxin families, although the recruitment of lysosomal acid lipase as a response to vertebrate feeding cannot be excluded. Evidence of marked intrageneric venom variation within the medically important genus Echis strongly advocates further investigations into the medical significance of venom variation in this genus and its impact upon antivenom therapy.


Effect of bezafibrate on HDL with APO A-I and APO A-II and on HDL with APO A-I without APO A-II in hyperlipidaemic patients.
On the basis of apoprotein composition, high-density lipoprotein (HDL) particles may be subdivided into two main subpopulations defined by the presence in the lipoprotein molecule of apo A-I (Lp A-I) and of both apo A-I and apo A-II (Lp A-I:A-II). The effect of slow-release bezafibrate 400 mg a day on Lp A-I and Lp A-I: A-II was evaluated in 34 hyperlipidaemic patients (19 with hypercholesterolaemia and 15 with hypertriglyceridaemia). Seventeen patients on low-fat low-cholesterol diet only were taken as the reference group. In the reference group, no change in HDL-C, apo A-I, apo A-II, Lp A-I and Lp A-I:A-II occurred during the 3 months of observation. In patients on bezafibrate, HDL-C, apo A-I and apo A-II significantly increased. Lp A-I:A-II increased by 33% in hypercholesterolaemic and by 29% in hypertriglyceridaemic patients. Lp A-I decreased by 15% in hypercholesterolaemic patients and did not change significantly in hypertriglyceridaemic patients. This differential effect of bezafibrate on apo-A-defined HDL subpopulations in hypertriglyceridaemia and in hypercholesterolaemia is in accord with previous studies on the effect of the drug on HDL subfractions defined by their density.


Urban health in India: who is responsible?
Urban health has received relatively less focus compared with rural health in India, especially the health of the urban poor. Rapid urbanization in India has been accompanied by an increase in population in urban slums and shanty towns, which are also very inadequately covered by basic amenities, including health services. The paper presents existing and new evidence that shows that health inequities exist between the poor and the non-poor in urban areas, even in better-off states in India. The lack of evidence-based policies that cut across sectors continues to be a main feature of the urban health scenario. Although the problems of urban health are more complex than those of rural health, the paper argues that it is possible to make a beginning fairly quickly by (i) collecting more evidence of health status and inequities in urban areas and (ii) correcting major inadequacies in infrastructure-both health and non-health-without waiting for major policy overhauls.


[Current diagnostics and therapy for carcinomas of the biliary tree and gallbladder].
Carcinoma of the biliary tree are rare tumours of the gastrointestinal tract with a rising incidence during the last years. Biliary neoplasms are classified into intra- and extrahepatic cholangiocarcinoma (Klatskin tumour, middle and distal extrahepatic tumours), gallbladder cancer, and ampullary carcinoma. Transformation of normal into malignant bile duct tissue requires a chain of consecutive gene mutations, similar to the adenoma-dysplasia-carcinoma-sequence in colon cancer. Abdominal ultrasound, combined non-invasive magnetic resonance cholangiography/tomography (MRC/MRT), and facultatively endoscopic retrograde cholangiography (ERC) for unclear diagnosis, represent the gold standard for primary diagnosis. For ampullary carcinoma, endosonography and endoscopic biopsy are the diagnostic tools of choice. Cure is attainable only by formal curative radical surgical resection. Increasing surgical radicality within the last years enabled clearly improved 5-year survival rates. In contrast, there has been no clinical benefit for adjuvant and neoadjuvant therapies. For palliation, bile duct stenting and photodynamic therapy are established methods. Radio- and chemotherapy should be reserved for clinical studies. New therapeutic approaches include brachytherapy, the use of modern chemotherapeutics, COX-2- and tyrosine kinase-receptor-inhibitors.


High-performance flexible inverted organic light-emitting diodes by exploiting MoS2 nanopillar arrays as electron-injecting and light-coupling layers.
Inverted organic light-emitting diodes (IOLEDs) on plastic substrates have great potential application in flexible active-matrix displays. High energy consumption, instability and poor electron injection are key issues limiting the commercialization of flexible IOLEDs. Here, we have systematically investigated the electrooptical properties of molybdenum disulfide (MoS2) and applied it in developing highly efficient and stable blue fluorescent IOLEDs. We have demonstrated that MoS2-based IOLEDs can significantly improve electron-injecting capacity. For the MoS2-based device on plastic substrates, we have achieved a very high external quantum efficiency of 7.3% at the luminance of 9141 cd m-2, which is the highest among the flexible blue fluorescent IOLEDs reported. Also, an approximately 1.8-fold improvement in power efficiency was obtained compared to glass-based IOLEDs. We attributed the enhanced performance of flexible IOLEDs to MoS2 nanopillar arrays due to their light extraction effect. The van der Waals force played an important role in the formation of MoS2 nanopillar arrays by thermal evaporation. Notably, MoS2-based flexible IOLEDs exhibit an intriguing efficiency roll-up, that is, the current efficiency increases slightly from 14.0 to 14.6 cd A-1 with the luminance increasing from 100 to 5000 cd m-2. In addition, we observed that the initial brightness of 500 cd m-2 can be maintained at 97% after bending for 500 cycles, demonstrating the excellent mechanical stability of flexible IOLEDs. Furthermore, we have successfully fabricated a transparent, flexible IOLED with low efficiency roll-off at high current density.


Ca2+ and calmodulin regulate the binding of filamin A to actin filaments.
Filamin A (FLNa) cross-links actin filaments (F-actin) into three-dimensional gels in cells, attaches F-actin to membrane proteins, and is a scaffold that collects numerous and diverse proteins. We report that Ca(2+)-calmodulin binds the actin-binding domain (ABD) of FLNa and dissociates FLNa from F-actin, thereby dissolving FLNa.F-actin gels. The FLNa ABD has two calponin homology domains (CH1 and CH2) separated by a linker. Recombinant CH1 but neither FLNa nor its ABD binds Ca(2+)-calmodulin in the absence of F-actin. Extending recombinant CH1 to include the negatively charged region linker domain makes it, like full-length FLNa, unable to bind Ca(2+)-calmodulin. Ca(2+)-calmodulin does, however, dissociate the FLNa ABD from F-actin provided that the CH2 domain is present. These findings identify the first evidence for direct regulation of FLNa, implicating a mechanism whereby Ca(2+)-calmodulin selectively targets the FLNa.F-actin complex.


Multi-stage 3D-2D registration for correction of anatomical deformation in image-guided spine surgery.
A multi-stage image-based 3D-2D registration method is presented that maps annotations in a 3D image (e.g. point labels annotating individual vertebrae in preoperative CT) to an intraoperative radiograph in which the patient has undergone non-rigid anatomical deformation due to changes in patient positioning or due to the intervention itself. The proposed method (termed msLevelCheck) extends a previous rigid registration solution (LevelCheck) to provide an accurate mapping of vertebral labels in the presence of spinal deformation. The method employs a multi-stage series of rigid 3D-2D registrations performed on sets of automatically determined and increasingly localized sub-images, with the final stage achieving a rigid mapping for each label to yield a locally rigid yet globally deformable solution. The method was evaluated first in a phantom study in which a CT image of the spine was acquired followed by a series of 7 mobile radiographs with increasing degree of deformation applied. Second, the method was validated using a clinical data set of patients exhibiting strong spinal deformation during thoracolumbar spine surgery. Registration accuracy was assessed using projection distance error (PDE) and failure rate (PDE > 20 mm-i.e. label registered outside vertebra). The msLevelCheck method was able to register all vertebrae accurately for all cases of deformation in the phantom study, improving the maximum PDE of the rigid method from 22.4 mm to 3.9 mm. The clinical study demonstrated the feasibility of the approach in real patient data by accurately registering all vertebral labels in each case, eliminating all instances of failure encountered in the conventional rigid method. The multi-stage approach demonstrated accurate mapping of vertebral labels in the presence of strong spinal deformation. The msLevelCheck method maintains other advantageous aspects of the original LevelCheck method (e.g. compatibility with standard clinical workflow, large capture range, and robustness against mismatch in image content) and extends capability to cases exhibiting strong changes in spinal curvature.


Prevalence of human T-lymphotropic virus type 1 and 2 infection in Sweden.
Prevalence data on human T-lymphotropic virus types 1 and 2 (HTLV-1/2) in Sweden have not been updated since 1995. The seroprevalence among blood donors at that time was 0.2/10,000. A few years earlier, a high prevalence of HTLV-2 was found in intravenous drug users (IDUs) in Stockholm (3.4%). The objective of this study was to update information on the seroprevalence of HTLV in several study groups. Serum samples from pregnant women, hepatitis C virus (HCV)-positive individuals, and IDUs in Stockholm were investigated for HTLV-1/2 antibodies. Data from the mandatory HTLV-1/2 screening (2003-2006) of in vitro fertilization (IVF) clients were compiled, as well as data from new blood donors. Eight out of 35,000 IVF patients were positive for anti-HTLV-1/2 (seroprevalence 2.3 per 10,000). Of the anti-HCV-positive individuals (n = 355), 1 sample was HTLV-1-positive (28.2 per 10,000). From 1995 to 2007, 18 HTLV-positive new blood donors were identified out of approximately 550,000 individuals tested (0.3 per 10,000). Thirty-five of 1079 tested IDUs were screening reactive. Since the start of screening in 1994, there has been no increased seroprevalence of HTLV-1/2 among blood donors in Sweden. Seroprevalence among Swedish IVF patients is 10 times higher than among blood donors. This finding is comparable to a 2003 European seroprevalence study of pregnant women in 7 countries. However, the possibility that the IVF group includes individuals with a higher risk of acquiring sexually transmitted infections, including HTLV, than the general population cannot be ruled out.


Lung transplantation following hematopoietic stem cell transplantation: report of two cases and systematic review of literature.
Non-infectious pulmonary complications following hematopoietic stem cell transplantation (HSCT) are major cause of morbidity and mortality with limited treatment options. Lung transplantation (LT) has been rarely reported as a treatment option for selected HSCT recipients with these problems. Describe the outcome of HSCT recipients who underwent LT. Two cases of LT following HSCT from our institution are presented. Cases reported in literature were identified using English language PubMed/MEDLINE with keywords hematopoietic stem cell transplantation, bone marrow transplantation, or bronchiolitis obliterans cross-referenced with lung transplantation. We extracted data on baseline characteristics and survival data following LT. Total of 84 patients are analyzed. Age at time of LT was median of 22 yr (range 1-66). Seventy-nine patients were recipients of allogeneic HSCT. The indications for LT were bronchiolitis obliterans syndrome (BOS; 63 patients), pulmonary fibrosis (13 patients), BOS/pulmonary fibrosis (five patients), and graft-versus-host-disease (GVHD) of lung (three patients). The median time between HSCT and LT was 52.3 months (range 6-240). The median follow-up after LT was 36 months (range 0-168). During this time, BOS was documented in 25 patients. Relapse of hematological malignancy was reported in two patients, and new malignancy developed in four patients. At the end of follow-up, 60 patients were alive and 24 patients died. The probability of survival following LT at 24 and 36 months was 0.88 (95% CI 0.78-0.93) and 0.79 (95% CI 0.67-0.87), respectively. LT is a potential therapeutic option in selected patients with severe chronic pulmonary disease following HSCT. Further studies are needed to determine the appropriate timing and the outcome of this approach.


Interaction of thyroxine and estrogen on the expression of estrogen receptor alpha, cholecystokinin, and preproenkephalin messenger ribonucleic acid in the limbic-hypothalamic circuit.
To study thyroid hormone and estrogen interactions in the central nervous system (CNS), the expression of estrogen sensitive genes was examined within the limbic-hypothalamic circuit. Estrogen up-regulates the expression of reproductively relevant neuropeptide messenger RNAs (mRNAs) encoding cholecystokinin (CCK) and enkephalin, peptides that stimulate lordosis. Estrogen down-regulates the expression of the estrogen receptor alpha (ER alpha) mRNA in the nuclei of the circuit. We examined the possibility that thyroid hormone treatment would block the estrogen modulation of these messages. Estradiol benzoate (EB), EB + thyroxine (T4), T4, or oil were administered to ovariectomized, adult female rats for 10 days. Isotopic in situ hybridization histochemistry revealed that within the limbic-hypothalamic nuclei, levels of CCK and preproenkephalin (PPE) mRNA levels were significantly higher in EB and EB + T4-treated animals compared with T4 or oil-treated animals. ER alpha mRNA levels were low in EB treated animals, elevated in T4 or oil-treated animals and further elevated in EB + T4-treated animals. In summary, T4 treatment had neither an independent nor an antagonistic effect on estrogen induced expression of CCK or PPE mRNA in the circuit. However, T4 did prevent the normal estrogenic decrease of ER alpha mRNA levels in the nuclei of the limbic-hypothalamic circuit.


Tocilizumab in isolated polymyalgia rheumatica: A systematic literature review.
We investigated the effectiveness of tocilizumab (an anti-interleukin-6 receptor antibody) in patients with polymyalgia rheumatica (PMR). We performed a systematic literature review from the inception dates until August 7, 2019 for articles reporting tocilizumab administration to treat isolated PMR. We identified 59 patients with isolated PMR treated with tocilizumab. All studies used intravenously administered tocilizumab at a dose of 8 mg/kg monthly. Tocilizumab monotherapy was administered to 24 and combination therapy (tocilizumab + glucocorticoid) to 35 patients. Tocilizumab monotherapy achieved low disease activity scores in only 17% of patients at week 4 and in only 71% patients even at week 12. Compared to glucocorticoid monotherapy, the reduction in the cumulative glucocorticoid dose was between 58% and 70% using a combination of tocilizumab and glucocorticoids, and 33-100% of the patients eventually showed glucocorticoid-free remission. All relapses occurred in patients administered tocilizumab monotherapy. No new safety event was reported. Tocilizumab is effective in cases of isolated PMR, particularly in combination with glucocorticoids. In addition to its glucocorticoid-sparing effect, it achieves glucocorticoid-free remission and reduces relapse rates. Tocilizumab monotherapy is not recommended.


Using organizational and clinical performance data to increase the value of mental health care.
U.S. health systems, policy makers, and patients increasingly demand high-value care that improves health outcomes at lower cost. This study describes the initial design and analysis of the Mental Health Management System (MHMS), a performance data and quality improvement tool used by the Veterans Health Administration (VHA) to increase the value of its mental health care. The MHMS evaluates access to and quality of mental health care, organizational structure and efficiency, implementation of innovative treatment options, and, in collaboration with management, resource needs for delivering care. Performance on 31 measures was calculated for all U.S. VHA facilities (N = 139). Pearson correlations revealed that better access to care was significantly associated with fewer mental health provider staffing vacancies (r = -.24) and higher staff-to-patient ratios for psychiatrists (r = .19) and other outpatient mental health providers (r = .27). Higher staff-to-patient ratios were significantly associated with higher performance on a number of patient and provider satisfaction measures (range of r = .18-.51) and continuity of care measures (range of r = .26-.43). Relationships observed between organizational and clinical performance measures suggest that the MHMS is a robust informatics and quality improvement tool that can serve as a model for health systems planning to adopt a value perspective. Future research should expand the MHMS framework to measure patient and health systems costs and psychosocial outcomes, as well as evaluate whether quality improvement solutions implemented as a result of using organizational information leads to higher-value mental health care. (PsycINFO Database Record


Imaging single-channel calcium microdomains by total internal reflection microscopy.
The microdomains of Ca2+ in the cytosol around the mouth of open Ca2+ channels are the basic 'building blocks' from which cellular Ca2+ signals are constructed. Moreover, the kinetics of local [Ca2+] closely reflect channel gating, so their measurement holds promise as an alternative to electrophysiological patch-clamp recording as a means to study single channel behavior. We have thus explored the development of optical techniques capable of imaging single-channel Ca2+ signals with good spatial and temporal resolution, and describe results obtained using total internal reflection fluorescence microscopy to monitor Ca2+ influx through single N-type channels expressed in Xenopus oocytes.


Pets, depression and long term survival in community living patients following myocardial infarction.
Evidence supports the contribution of depression, anxiety, and poor social support to mortality of hospitalized myocardial infarction (MI) patients. The contribution of depression to survival is independent of disease severity. Pet ownership, a non-human form of social support, has also been associated with one year survival of post-MI patients. The current study addresses whether pet ownership contributes independently to long term survival beyond the contributions of depression, anxiety, or low social support in post-MI patients who have already survived at least 6 months. Data from patients (N = 460) enrolled in the "Psychosocial Responses in the Home Automated External Defibrillator Trial (PR-HAT)"were used. Seventeen patients died during a median follow-up of 2.8 years. In Cox proportional hazards regression model that included depression, lack of pet ownership, and the interaction between depression and lack of pet ownership, not owning a pet was the only significant independent predictor of mortality (p = 0.036). The interaction between pet ownership and depression tended to be significant indicating that the effect of pet ownership on survival in this group of people who have supportive spouses/companions living with them may relate to depression.


A novel method for simple detection of mutations conferring drug resistance in Mycobacterium leprae, based on a DNA microarray, and its applicability in developing countries.
A simple method to detect mutations in the genome of Mycobacterium leprae that confer resistance to key drugs for leprosy was exploited on the basis of a reverse hybridization system. A series of oligonucleotide probes corresponding to each mutation in the folP1, rpoB and gyrA genes for dapsone, rifampicin and ofloxacin resistance, respectively, were selected and fixed on a glass slide as capture probes, to develop a DNA microarray termed the leprosy drug susceptibility-DNA microarray (LDS-DA). Mutations in clinical isolates of M. leprae were successfully identified by the LDS-DA. Feasibility studies were conducted to evaluate the performance of the LDS-DA in two developing countries, Myanmar and the Philippines. The high concordance of the results obtained by this method with the results of nucleotide sequencing strongly supports the applicability of the LDS-DA as a drug susceptibility test in place of sequencing, a time-consuming and costly procedure. This is a rapid and simple method for the simultaneous susceptibility testing of three front-line drugs for leprosy, and solves the problems of previously reported methods.


Evaluating Physiological MRI Parameters in Patients with Brain Metastases Undergoing Stereotactic Radiosurgery-A Preliminary Analysis and Case Report.
Brain metastases occur in ten to thirty percent of the adult cancer population. Treatment consists of different (palliative) options, including stereotactic radiosurgery (SRS). Sensitive MRI biomarkers are needed to better understand radiotherapy-related effects on cerebral physiology and the subsequent effects on neurocognitive functioning. In the current study, we used physiological imaging techniques to assess cerebral blood flow (CBF), oxygen extraction fraction (OEF), cerebral metabolic rate of oxygen (CMRO2) and cerebrovascular reactivity (CVR) before and three months after SRS in nine patients with brain metastases. The results showed improvement in OEF, CBF and CMRO2 within brain tissue that recovered from edema (all p ≤ 0.04), while CVR remained impacted. We observed a global post-radiotherapy increase in CBF in healthy-appearing brain tissue (p = 0.02). A repeated measures correlation analysis showed larger reductions within regions exposed to higher radiotherapy doses in CBF (rrm = -0.286, p < 0.001), CMRO2 (rrm = -0.254, p < 0.001), and CVR (rrm = -0.346, p < 0.001), but not in OEF (rrm = -0.004, p = 0.954). Case analyses illustrated the impact of brain metastases progression on the post-radiotherapy changes in both physiological MRI measures and cognitive performance. Our preliminary findings suggest no radiotherapy effects on physiological parameters occurred in healthy-appearing brain tissue within 3-months post-radiotherapy. Nevertheless, as radiotherapy can have late side effects, larger patient samples allowing meaningful grouping of patients and longer follow-ups are needed.


Topological quantum chemistry.
Since the discovery of topological insulators and semimetals, there has been much research into predicting and experimentally discovering distinct classes of these materials, in which the topology of electronic states leads to robust surface states and electromagnetic responses. This apparent success, however, masks a fundamental shortcoming: topological insulators represent only a few hundred of the 200,000 stoichiometric compounds in material databases. However, it is unclear whether this low number is indicative of the esoteric nature of topological insulators or of a fundamental problem with the current approaches to finding them. Here we propose a complete electronic band theory, which builds on the conventional band theory of electrons, highlighting the link between the topology and local chemical bonding. This theory of topological quantum chemistry provides a description of the universal (across materials), global properties of all possible band structures and (weakly correlated) materials, consisting of a graph-theoretic description of momentum (reciprocal) space and a complementary group-theoretic description in real space. For all 230 crystal symmetry groups, we classify the possible band structures that arise from local atomic orbitals, and show which are topologically non-trivial. Our electronic band theory sheds new light on known topological insulators, and can be used to predict many more.