Expression of vascular addressins and ICAM-1 by endothelial cells in the spinal cord during chronic relapsing experimental allergic encephalomyelitis in the Biozzi AB/H mouse.
The expression of adhesion molecules on central nervous system (CNS) endothelia was examined during chronic relapsing experimental allergic encephalomyelitis (CREAE) in the Biozzi AB/H mouse. Active disease episodes (acute and relapse) were associated with the up-regulation of MALA-2, the murine homologue of intercellular adhesion molecule-1 (ICAM-1), on CNS endothelia and the infiltration of ICAM-1-positive mononuclear cells. In addition, the high endothelial venule (HEV)-associated MECA-325 antigen was evident in perivascular lesions, particularly in relapsing disease. The peripheral lymph node HEV-associated vascular addressin defined by MECA-79 antibody was not detectable in the CNS during CREAE. However, the mucosal HEV addressin was evident in lesions, which ultrastructurally was found to be expressed on the surface of endothelial cells by immunoelectron microscopy. The expression of adhesion molecules, such as ICAM-1, may provide a means by which both the initial neuroantigen-specific and the subsequent antigen-non specific cells extravasate into the CNS. Such infiltration may induce the expression of the vascular addressins which may then provide a means of site-selective cellular recruitment leading to disease progression.


Necessity and Sufficiency of Ldb1 in the Generation, Differentiation and Maintenance of Non-photoreceptor Cell Types During Retinal Development.
During mammalian retinal development, the multipotent progenitors differentiate into all classes of retinal cells under the delicate control of transcriptional factors. The deficiency of a transcription cofactor, the LIM-domain binding protein Ldb1, has been shown to cause proliferation and developmental defects in multiple tissues including cardiovascular, hematopoietic, and nervous systems; however, it remains unclear whether and how it regulates retinal development. By expression profiling, RNA in situ hybridization and immunostaining, here we show that Ldb1 is expressed in the progenitors during early retinal development, but later its expression gradually shifts to non-photoreceptor cell types including bipolar, amacrine, horizontal, ganglion, and Müller glial cells. Retina-specific ablation of Ldb1 in mice resulted in microphthalmia, optic nerve hypoplasia, retinal thinning and detachment, and profound vision impairment as determined by electroretinography. In the mutant retina, there was precocious differentiation of amacrine and horizontal cells, indicating a requirement of Ldb1 in maintaining the retinal progenitor pool. Additionally, all non-photoreceptor cell types were greatly reduced which appeared to be caused by a generation defect and/or retinal degeneration via excessive cell apoptosis. Furthermore, we showed that misexpressed Ldb1 was sufficient to promote the generation of bipolar, amacrine, horizontal, ganglion, and Müller glial cells at the expense of photoreceptors. Together, these results demonstrate that Ldb1 is not only necessary but also sufficient for the development and/or maintenance of non-photoreceptor cell types, and implicate that the pleiotropic functions of Ldb1 during retinal development are context-dependent and determined by its interaction with diverse LIM-HD (LIM-homeodomain) and LMO (LIM domain-only) binding protein partners.


Cellular and extracellular myeloperoxidase in pyogenic inflammation.
We explored the effect of in vitro phagocytosis and in vivo inflammation on the MPO content of functioning neutrophils and on the ability of these cells to export active MPO into the extracellular environment. After ingestion of staphylococci, neutrophils retained 52% of their MPO and released 8% into the medium in active form; the remaining 40% of their MPO could no longer be detected. During bacterial infection induced by intradermally injecting staphylococci, neutrophils harvested from minced infected lesions contained 52% of the MPO of circulating neutrophils that had not reached the lesions. Extracellular fluid from the lesions contained active MPO secreted by the neutrophils, and concentrations of 10-45 U/ml were detected. These data demonstrate that functioning neutrophils can lose approximately half of their MPO. In vitro, 4%-8% of neutrophilic MPO appears in the extracellular space and 40% is inactivated. In vivo, the MPO content of inflammatory neutrophils also decreases, and MPO appears in the extracellular fluid in active form where it is available to participate in a variety of physiologic processes.


Accuracy of single-voxel proton MR spectroscopy in distinguishing neoplastic from nonneoplastic brain lesions.
To measure the accuracy of single-voxel, image-guided proton MR spectroscopy in distinguishing normal from abnormal brain tissue and neoplastic from nonneoplastic brain disease. MR spectroscopy was performed at 0.5 T with the point-resolved spectroscopic pulse sequence and conventional postprocessing techniques. Subjects consisted of a consecutive series of patients with suspected brain neoplasms or recurrent neoplasia and 10 healthy adult volunteers. Fifty-five lesions in 53 patients with subsequently verified final diagnoses were included. Spectra were interpreted qualitatively by visual inspection by nonblinded readers (prospectively) with the benefit of prior clinical data and imaging studies, and by blinded readers (retrospectively). The nonblinded readers interpreted the spectra as diagnostic or not, and, if diagnostic, as neoplastic or nonneoplastic. The blinded readers classified the spectra as diagnostic or not, and, if diagnostic, as normal or abnormal and as neoplastic or nonneoplastic (when abnormal). The sensitivity, specificity, positive and negative predictive values, and accuracy were calculated from blinded and nonblinded MR spectroscopy interpretations. A receiver operator characteristic (ROC) curve analysis was performed on blinded MR spectroscopy interpretations. The diagnostic accuracy averaged across four blinded readers in differentiating patients from control subjects was .96, while the area under the aggregate (pooled interpretations) ROC curve approached unity. Accuracy in the nonblinded and blinded discrimination of neoplastic from nonneoplastic disease was .96 and .83, respectively. The area under the aggregate ROC curve in the blinded discrimination of neoplasm from nonneoplasm was .89. Image-guided proton spectra obtained at 0.5 T from patients with suspected neoplasia can be distinguished from spectra in healthy control subjects, and neoplastic spectra can be distinguished from nonneoplastic spectra with a high degree of diagnostic accuracy.


Advancement of NF-κB Signaling Pathway: A Novel Target in Pancreatic Cancer.
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers and is the third highest among cancer related deaths. Despite modest success with therapy such as gemcitabine, pancreatic cancer incidence remains virtually unchanged in the past 25 years. Among the several driver mutations for PDAC, Kras mutation contributes a central role for its development, progression and therapeutic resistance. In addition, inflammation is implicated in the development of most human cancer, including pancreatic cancer. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is recognized as a key mediator of inflammation and has been frequently observed to be upregulated in PDAC. Several lines of evidence suggest that NF-κB pathways play a crucial role in PDAC development, progression and resistance. In this review, we focused on emphasizing the recent advancements in the involvement of NF-κB in PADC's progression and resistance. We also highlighted the interaction of NF-κB with other signaling pathways. Lastly, we also aim to discuss how NF-κB could be an excellent target for PDAC prevention or therapy. This review could provide insight into the development of novel therapeutic strategies by considering NF-κB as a target to prevent or treat PDAC.


Stopping Criminalization at the Bedside.
Low-income women and, disproportionately low-income women of color seeking reproductive and pregnancy care are increasingly subject to what this article terms carceral care - care compromised by its' proximity to punishment systems. This article identifies the legal and health care practice mechanisms leading to carceral care and proposes solutions designed to stop criminalization at the bedside.


Demographic and personal factors associated with metabolic control and self-care in youth with type 1 diabetes: a systematic review.
Optimal use of recent technological advances in insulin delivery and glucose monitoring remain limited by the impact of behaviour on self-care. In recent years, there has been a resurgence of interest in psychosocial methods of optimizing care in youth with type 1 diabetes. We therefore sought to examine the literature for demographic, interpersonal and intrapersonal correlates of self-care and/or metabolic control. Studies for this systematic review were obtained via an electronic search of Medline, Embase, Cumulative Index to Nursing and Allied Health Literature and PsycINFO databases. Seventy studies fulfilled the inclusion criteria. These studies have indicated that identifiable individual characteristics in each domain are robustly associated with metabolic control and/or self-care in children and adolescents. We present these characteristics and propose a theoretical model of their interactions and effect on diabetes outcomes. There is currently no consensus regarding patient selection for insulin pump therapy. In this era of scarce healthcare resources, it may be prudent to identify youth requiring increased psychosocial support prior to regimen intensification. The importance of this review lies in its potential to create a framework for rationally utilizing resources by stratifying costly therapeutic options to those who, in the first instance, will be most likely to benefit from them.


Cloning and characterization of PBP 1C, a third member of the multimodular class A penicillin-binding proteins of Escherichia coli.
All proteins of Escherichia coli that covalently bind penicillin have been cloned except for the penicillin-binding protein (PBP) 1C. For a detailed understanding of the mode of action of beta-lactam antibiotics, cloning of the gene encoding PBP1C was of major importance. Therefore, the structural gene was identified in the E. coli genomic lambda library of Kohara and subcloned, and PBP1C was characterized biochemically. PBP1C is a close homologue to the bifunctional transpeptidases/transglycosylases PBP1A and PBP1B and likewise shows murein polymerizing activity, which can be blocked by the transglycosylase inhibitor moenomycin. Covalently linked to activated Sepharose, PBP1C specifically retained PBP1B and the transpeptidases PBP2 and -3 in addition to the murein hydrolase MltA. The specific interaction with these proteins suggests that PBP1C is assembled into a multienzyme complex consisting of both murein polymerases and hydrolases. Overexpression of PBP1C does not support growth of a PBP1A(ts)/PBP1B double mutant at the restrictive temperature, and PBP1C does not bind to the same variety of penicillin derivatives as PBPs 1A and 1B. Deletion of PBP1C resulted in an altered mode of murein synthesis. It is suggested that PBP1C functions in vivo as a transglycosylase only.


Rapid diagnosis of mediastinal tuberculosis with polymerase chain reaction evaluation of aspirated material taken by endobronchial ultrasound-guided transbronchial needle aspiration.
Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a diagnostic method for tuberculosis (TB). This study was conducted to determine the efficiency of polymerase chain reaction (PCR) testing for detecting TB lymphadenitis in samples obtained by EBUS-TBNA. A total of 93 consecutive patients with hilar/mediastinal lymphadenopathies and diagnosed with granulomatous diseases through histopathological evaluation were included in the study. The specimens provided by EBUS-TBNA were evaluated through pathological, microbiological, and molecular tests. Eighty-nine (95.7%) of the 93 patients had histopathologically granulomatous diseases by EBUS-TBNA. Tuberculosis was diagnosed in 27 (30.3%) patients and sarcoidosis was diagnosed in 62 (69.7%) patients. Four (4.3%) patients were diagnosed through mediastinoscopy. Endobronchial ultrasound-guided transbronchial needle aspiration had an overall diagnostic efficiency in TB of 96.9%, a sensitivity of 90.9%, and a specificity of 100%. Mycobacterium tuberculosis PCR was positive in 17 of the 30 patients. The sensitivity of PCR was 56.7%, the specificity was 100%, and the general efficiency of the test was 96.4%. As a result, the use of M. tuberculosis PCR in the EBUS-TBNA specimens provides a rapid and an accurate diagnosis of TB. Therefore, we recommend the use of M. tuberculosis PCR in the EBUS-TBNA specimens as a rapid diagnostic method for mediastinal lymphadenopathies in patients with suspected TB.


Potential of Bambara groundnut (Vigna subterranea (L.) Verdc) milk as a probiotic beverage-a review.
Bambara groundnut (Vigna subterraenea (L.) verdc) (BGN) is a legume; its origin have been traced back to Africa, and it is the third important legume; however, it is one of the neglected crops. It is highly nutritious, and has been termed a complete food. Its seed consist of 49%-63.5% carbohydrate, 15%-25% protein, 4.5%-7.4% fat, 5.2%-6.4% fiber, 3.2%-4.4% ash and 2% mineral compared to whole fresh cow milk 88% moisture, 4.8% carbohydrate, 3.2% proteins, 3.4% fat, 0.7% ash, and 0.01% cholesterol. Its chemical composition is comparable to that of soy bean. Furthermore, BGN has been reported to be a potential crop, owing to its nutritional composition, functional properties, antioxidant potential, and a drought resistant crop. Bambara groundnut milk (BGNM) had been rated higher in acceptability than milk from other legumes like soybean and cowpea. Probiotics have been defined as live microorganisms which when administered in adequate amount confer a health benefit on the host. These benefits have been reported to be therapeutic, suppressing the growth and activity in conditions like infectious diarrhea, irritable bowel syndrome, and inflammatory bowel disease. The nutritional profile of BGNM is high enough to sustain the growth of probiotics. BGNs are normally boiled and salted, eaten as a relish or roasted, and eaten as a snack. Hence, BGNM can also be fermented with lactic acid bacteria to make a probiotic beverage that not only increase the economic value of the nutritious legume but also help in addressing malnutrition.


Cognitive Interventions to Improve a Specific Cognitive Impairment for Adults With TBI (June 2013-October 2020).
Systematic Review Briefs provide a summary of the findings from systematic reviews developed in conjunction with the American Occupational Therapy Association's Evidence-Based Practice Program. Each Systematic Review Brief summarizes the evidence on a theme related to a systematic review topic. This Systematic Review Brief presents findings from the systematic review on cognitive interventions to improve a specific cognitive impairment for adults with TBI.


T-Peak to T-End Improvements After Beta-Blocker Administration in Peripartum Cardiomyopathy Patients.
Many studies have shown that T-peak to T-end (TPTE) interval was associated with sudden cardiac events. Peripartum cardiomyopathy (PPCM) causes reversible left ventricle systolic dysfunction which may deteriorate into sudden cardiac death. This study aimed to evaluate beta-blocker as an antiarrhythmic agent to improve TPTE interval as a prognostic value of sudden cardiac death. A cohort experimental prospective study was performed. The PPCM was diagnosed from the emergency ward. A total of 54 cases were identified from 2014 to 2016. Thirty-four patients were followed up for further analysis. Electrocardiograms were conducted in all the patients, and TPTE interval was measured. After a follow-up of 6 months of beta-blocker treatment, the echocardiography and TPTE interval were measured again to obtain the repolarization heterogeneity. The mean age of subjects was 32 ± 6.4 years. The mean left ventricular ejection fraction (LVEF) was 32.24±6.3%. The mean TPTE interval was 123.7 ± 28.2 ms. After 6 months of beta-blocker administration, the mean LVEF was 58.26±4.4% and the mean TPTE was 98.7 ± 39.5 ms. The paired t-test showed a significant difference between TPTE interval pre- and post-administration of beta-blocker (P value < 0.001). There is an improvement of TPTE in PPCM patients after 6 months of beta-blocker administration. Administration of beta-blocker in PPCM patients is expected to prevent sudden cardiac death in PPCM populations.


Estrogenic activity of coumestrol, DDT, and TCDD in human cervical cancer cells.
Endogenous estrogens have dramatic and differential effects on classical endocrine organ and proliferation. Xenoestrogens are environmental estrogens that have endocrine impact, acting as both estrogen agonists and antagonists, but whose effects are not well characterized. In this investigation we sought to delineate effects of xenoestrogens. Using human cervical cancer cells (HeLa cells) as a model, the effects of representative xenoestrogens (Coumestrol-a phytoestrogen, tetrachlorodioxin (TCDD)-a herbicide and DDT-a pesticide) on proliferation, cell cycle, and apoptosis were examined. These xenoestrogens and estrogen inhibited the proliferation of Hela cells in a dose dependent manner from 20 to 120 nM suggesting, that 17-beta-estrtadiol and xenoestrogens induced cytotoxic effects. Coumestrol produced accumulation of HeLa cells in G2/M phase, and subsequently induced apoptosis. Similar effects were observed in estrogen treated cells. These changes were associated with suppressed bcl-2 protein and augmented Cyclins A and D proteins. DDT and TCDD exposure did not induce apoptosis. These preliminary data taken together, suggest that xenoestrogens have direct, compound-specific effects on HeLa cells. This study further enhances our understanding of environmental modulation of cervical cancer.


A novel member of the SAF (scaffold attachment factor)-box protein family inhibits gene expression and induces apoptosis.
The SLTM [SAF (scaffold attachment factor)-like transcription modulator] protein contains a SAF-box DNA-binding motif and an RNA-binding domain, and shares an overall identity of 34% with SAFB1 {scaffold attachment factor-B1; also known as SAF-B (scaffold attachment factor B), HET [heat-shock protein 27 ERE (oestrogen response element) and TATA-box-binding protein] or HAP (heterogeneous nuclear ribonucleoprotein A1-interacting protein)}. Here, we show that SLTM is localized to the cell nucleus, but excluded from nucleoli, and to a large extent it co-localizes with SAFB1. In the nucleus, SLTM has a punctate distribution and it does not co-localize with SR (serine/arginine) proteins. Overexpression of SAFB1 has been shown to exert a number of inhibitory effects, including suppression of oestrogen signalling. Although SLTM also suppressed the ability of oestrogen to activate a reporter gene in MCF-7 breast-cancer cells, inhibition of a constitutively active beta-galactosidase gene suggested that this was primarily the consequence of a generalized inhibitory effect on transcription. Measurement of RNA synthesis, which showed a particularly marked inhibition of [(3)H]uridine incorporation into mRNA, supported this conclusion. In addition, analysis of cell-cycle parameters, chromatin condensation and cytochrome c release showed that SLTM induced apoptosis in a range of cultured cell lines. Thus the inhibitory effects of SLTM on gene expression appear to result from generalized down-regulation of mRNA synthesis and initiation of apoptosis consequent upon overexpressing the protein. While indicating a crucial role for SLTM in cellular function, these results also emphasize the need for caution when interpreting phenotypic changes associated with manipulation of protein expression levels.


Inhibition of PFKFB3 Expression Stimulates Macrophage-Mediated Lymphangiogenesis Post-Acute Myocardial Infarction.
The dilation of lymphatic vessels plays a critical role in maintaining heart function, while a lack thereof could contribute to heart failure (HF), and subsequently to an acute myocardial infarction (AMI). Macrophages participate in the induction of lymphangiogenesis by secreting vascular endothelial cell growth factor C (VEGF-C), although the precise mechanism remains unclear. Intramyocardial injections of adeno-associated viruses (AAV9) to inhibit the expression of VEGFR3 (VEGFR3 shRNA) or promote the expression of VEGFR3 (VEGFR3 ORF) in the heart; Myh6-mCherry B6 D2-tg mice and flow cytometry were used to evaluate the number of myocellular debris in the mediastinal lymph nodes; fluorescence staining and qPCR were used to evaluate fluorescence analysis; seahorse experiment was used to evaluate the level of glycolysis of macrophages; Lyz2𝐶𝑟𝑒, VEGFCfl/fl, and PFKFB3fl/fl mice were used as a model to knock out the expression of VEGF-C and PFKFB3 in macrophages. The escalation of VEGFR3 in cardiac tissue can facilitate the drainage of myocardial debris to the mediastinal lymph nodes, thereby improving cardiac function and reducing fibrosis after reperfusion injury. Conversely, myeloid VEGF-C deficiency displayed an increase in macrophage counts and inflammation levels following reperfusion injury. The inhibition of the critical enzyme PFKFB3 in macrophage glycolysis can stimulate the manifestation of VEGF-C in macrophages. A deficiency in myeloid PFKFB3 is associated with induced lymphangiogenesis following reperfusion injury. Our initial investigations suggest that the suppression of PFKFB3 expression in macrophages could potentially stimulate the production of VEGF-C in these immune cells, which in turn may facilitate lymphangiogenesis and mitigate the inflammatory effects of I/R injury.


Pharmacokinetics of contrast agents targeted to the tumor vasculature in molecular magnetic resonance imaging.
Molecular magnetic resonance imaging (MRI) is increasingly used to investigate tumor angiogenic activity non-invasively. However, the pharmacokinetic behavior and tumor penetration of the often large contrast agent particles is thus far unknown. Here, pharmacokinetic analysis of cyclic asparagine-glycine-arginine (cNGR) labeled paramagnetic quantum dots (pQDs) was developed to quantify the contrast agent's homing efficacy to activated endothelial cells of angiogenic tumor vessels using dynamic contrast-enhanced (DCE) MRI. cNGR homes to CD13, an overexpressed aminopeptidase on angiogenic tumor endothelial cells. First, a two-compartment pharmacokinetic model, comprising the blood space and endothelial cell surface, was compared with a three-compartment model additionally including the extravascular-extracellular component. The resulting extravasation parameter was irrelevantly small and was therefore neglected. Next, the association constant K(a), the dissociation constant k(d) and the fractional plasma volume v(P) were determined from the time-series data using the two-compartment model. Magnitude and spatial distribution of the parameters were compared for cNGR-labeled and unlabeled pQDs. The tumor area with significant K(a) values was approximately twice as large for cNGR-pQDs compared with unlabeled pQDs (p < 0.05), indicating more contrast agent binding for cNGR-pQDs. Using cNGR-pQDs, a two-fold larger area with significant K(a) was also found for the angiogenic tumor rim compared with tumor core (p < 0.05). It was furthermore found that both contrast agents perfused the tumor at all depths, thereby providing unequivocal evidence that rim/core differences can indeed be ascribed to stronger angiogenic activity in the rim. Summarizing, molecular DCE-MRI with pharmacokinetic modeling provides unique information on contrast agent delivery and angiogenic activity in tumors.


When intraclass correlation coefficients go awry: a case study from a school-based smoking prevention study in South Africa.
We conducted a group randomized trial of 2 South African school-based smoking prevention programs and examined possible sources and implications of why our actual intraclass correlation coefficients (ICCs) were significantly higher than the ICC of 0.02 used to compute initial sample size requirements. Thirty-six South African high schools were randomly assigned to 1 of 3 experimental groups. On 3 occasions, students completed questionnaires on tobacco and drug use attitudes and behaviors. We used mixed-effects models to partition individual and school-level variance components, with and without covariate adjustment. For 30-day smoking, unadjusted ICCs ranged from 0.12 to 0.17 across the 3 time points. For lifetime smoking, ICCs ranged from 0.18 to 0.22; for other drug use variables, 0.02 to 0.10; and for psychosocial variables, 0.09 to 0.23. Covariate adjustment substantially reduced most ICCs. The unadjusted ICCs we observed for smoking behaviors were considerably higher than those previously reported. This effectively reduced our sample size by a factor of 17. Future studies that anticipate significant cluster-level racial homogeneity may consider using higher-value ICCs in sample-size calculations to ensure adequate statistical power.


Telemedicine and Palliative Care: an Increasing Role in Supportive Oncology.
With the emergence of telemedicine as a routine form of care in various venues, the opportunities to use technology to care for the most vulnerable, most ill cancer patients are extremely appealing. Increasingly, evidence supports early integration of palliative care with standard oncologic care, supported by recent NCCN guidelines to increase and improve access to palliative care. This review looks at the use of telemedicine to expand access to palliative care as well as provide better care for patients and families where travel is difficult, if not impossible. When telemedicine has been used, often in Europe, for palliative care, the results show improvements in symptom management, comfort with care as well as patient and family satisfaction. One barrier to use of telemedicine is the concerns with technology and technology-related complications in population that is often elderly, frail and not always comfortable with non-face-to-face physician care. There remain significant opportunities to explore this intersection of supportive care and telemedicine.


Theorizing the relationship between NGOs and the state in medical humanitarian development projects.
Social scientists have fiercely debated the relationship between non-governmental organizations (NGOs) and the state in NGO-led development projects. However, this research often carries an implicit, and often explicit, anti-state bias, suggesting that when NGOs collaborate with states, they cease to be a progressive force. This literature thus fails to recognize the state as a complex, heterogeneous, and fragmented entity. In particular, the unique political context within which an NGO operates is likely to influence how it carries out its work. In this article, we ask: how do NGOs work and build relationships with different types of states and--of particular relevance to practitioners--what kinds of relationship building lead to more successful development outcomes on the ground? Drawing on 29 in-depth interviews with members of Partners in Health and Oxfam America conducted between September 2010 and February 2014, we argue that NGOs and their medical humanitarian projects are more likely to succeed when they adjust how they interact with different types of states through processes of interest harmonization and negotiation. We offer a theoretical model for understanding how these processes occur across organizational fields. Specifically, we utilize field overlap theory to illuminate how successful outcomes depend on NGOs' ability to leverage resources--alliances and networks; political, financial, and cultural resources; and frames--across state and non-state fields. By identifying how NGOs can increase the likelihood of project success, our research should be of interest to activists, practitioners, and scholars.


Change of government and health services policy in Victoria, 1992-93 [see comment].
Although constrained by Federal financial dominance, State governments can, nevertheless, significantly shape a number of aspects of health policy within their own jurisdiction. New governments often seek to implement both substantive and symbolic policy changes. This is often also accompanied by alterations to organisational structures and personnel with a view to making implementation more effective. This article chronicles the continuities and changes in health services policy in the first year of the Liberal-National Coalition State Government in Victoria. These include institutional changes, key ministerial and bureaucratic appointments, health workforce issues, health services funding decisions, public and community health, and relations with the Federal Government. The decision-making style of the new government is also discussed. The authors regard the economic imperatives of Victoria's severe deficit as the dominant influence in all areas of public policy, including health services policy, although certain ideological predilections have also been evident. They further argue that the new government has primarily sought legitimacy by appealing to what it regards as its mandate to rectify Victoria's 'economic crisis' by reducing public expenditure and reforming managerial practices in the public sector.


Deep vein thrombosis after monoclonal gammopathy of undetermined significance and multiple myeloma.
Patients with multiple myeloma (MM) have an increased risk of deep venous thrombosis (DVT), particularly when treated with immunomodulatory drugs. Recently, 2 small hospital-based studies observed persons with the MM precursor condition, monoclonal gammopathy of undetermined significance (MGUS), to be at increased risk of developing DVT. Among 4 196 197 veterans hospitalized at least once at US Veterans Affairs hospitals, we identified a total of 2374 cases of MGUS, and 39 272 persons were diagnosed with DVT (crude incidence 0.9 per 1000 person-years). A total of 31 and 151 DVTs occurred among MGUS and MM patients, respectively (crude incidence 3.1 and 8.7 per 1000 person-years, respectively; P < .01). Compared with the entire study population, the relative risk (RR) of DVT after a diagnosis of MGUS and MM was 3.3 (95% confidence interval [CI], 2.3-4.7) and 9.2 (95% CI, 7.9-10.8), respectively. The most prominent excess risk of DVT was found during the first year after diagnosis of MGUS (RR = 8.4; 95% CI, 5.7-12.2) and MM (RR = 11.6; 95% CI, 9.2-14.5). Among 229 MGUS cases (9.5%) that progressed to MM, only one person had a DVT diagnosis before transformation. Our findings suggest the operation of shared underlying mechanisms causing coagulation abnormalities among patients with MGUS and MM.


Finasteride 5 mg and sexual side effects: how many of these are related to a nocebo phenomenon?
Sexual adverse experiences such as erectile dysfunction (ED), loss of libido, and ejaculation disorders have been consistent side effects of finasteride in a maximum percentage of 15% after 1 year of therapy. Such data could be seen as far from reality, if compared to a higher percentage that may be found in any common clinical practice. This study aims to explain the dichotomy between literature's data and clinical practice data. One hundred twenty patients with a clinical diagnosis of benign prostatic hyperplasia (BPH), sexually active and with an International Index of Erectile Function-erectile function (IIEF-EF) domain >/=25 were randomized to receive finasteride 5 mg concealed as an "X compound of proven efficacy for the treatment of BPH" for 1 year with (group 2) or without (group 1) counseling on the drug sexual side effect. The phrase used to inform group 2 patients was ". . . it may cause erectile dysfunction, decreased libido, problems of ejaculation but these are uncommon". The estimation of side effect was conducted at 6 and 12 months using the male sexual function-4 (MSF-4 item) questionnaire and a self-administered questionnaire. One hundred seven patients completed the study. Group 2 patients (N = 55) reported a significant higher proportion of one or more sexual side effects as compared to group 1 (N = 52) (43.6% vs. 15.3%) (P = 0.03). The incidence of ED, decreased libido, and ejaculation disorders were 9.6, 7.7, and 5.7% for group 1, and 30.9, 23.6, and 16.3% for group 2, respectively (P = 0.02, P = 0.04, and P = 0.06). In the current study, blinded administration of finasteride was associated with a significantly higher proportion of sexual dysfunction in patients informed on sexual side effects (group 2) as compared to those in which the same information was omitted (group 1) (P = 0.03). A scenario similar to group 2 of the current study is likely to occur in clinical practice, where the patient is counseled by the physician and has access to the drug information sheet. The burden of this nocebo effect (an adverse side effect that is not a direct result of the specific pharmacological action of the drug) has to be taken into account when managing finasteride sexual side effects.


[Percutaneous needle biopsy in the diagnosis of pancreatic cancer].
The data on two procedures of ultrasound-guided fine-needle biopsy of pancreatic masses in 81 patients are presented (1999-2001): for cutting biopsy--64, and aspiration--and 17. Pancreatic cancer was identified in 41, non-epithelial tumor--3, metastasis to pancreas--2 and indurative pancreatitis--21. Complication were rare: hematoma formation after interstitial biopsy--1 (1.6%) and subcutaneous seeding--1 (5.9%) after aspiration biopsy. Sensitivity, specificity and accuracy for cutting biopsy were 96.7, 100 and 96.9%, respectively: aspiration--90.9, 90.9 and 88.3%, respectively. Ultrasound-guided transabdominal fine-needle biopsy of pancreas is a low-invasive and effective method of diagnostic verification. The cutting procedure was more effective than aspiration biopsy: also, it helped identify histological pattern of tumor and grade of malignancy. Patients with chronic indurative pancreatitis are to be followed up even when primary fine-needle biopsy results are negative.


Changing shape: workforce and the implementation of Aboriginal health policy.
Thirty-five interviews were conducted in a case study on the implementation of the Northern Territory Preventable Chronic Disease Strategy (PCDS) to explore the role of the health workforce in the implementation of Aboriginal health policy. There was a tendency for the workforce to implement those aspects of the policy that drew on existing skills in treatment and management and to avoid or delay implementation that required the acquisition of new skills in primary prevention. Factors that facilitated the implementation of the PCDS included the addition of new resources, employment of additional staff, training, increased commitment from managers, and the creation of dedicated chronic disease positions. Factors impeding implementation included insufficient numbers of service providers, too little support for current Aboriginal Health Workers, and high staff turnover.


Cervical cancer coexisting with small lymphocytic lymphoma detected during positron emission tomography/computed tomography simulation: a case report.
Positron emission tomography (PET)/computed tomography (CT) simulation in cervical cancer may help radiation oncologists to better define the target volumes. It may also detect extrapelvic lesions and incidental second malignancies, leading to significant changes in treatment management. A 63-year-old woman who was deemed inoperable due to carcinoma of the cervical stump extending to the parametria and paraaortic lymph nodes detected on MR images presented for extended field radiotherapy. PET/CT simulation revealed an FDG avid mass in the cervical stump, and an enlarged axillary lymphadenopathy showing moderate FDG uptake. The excisional biopsy was consistent with small lymphocytic lymphoma (SLL). In our case, PET/CT simulation not only led to changes in treatment management, but also revealed a very rare coexistence of SLL and invasive squamous cell carcinoma of the cervix.


Allosteric modulation of the M₃ muscarinic receptor by amiodarone and N-ethylamiodarone: application of the four-ligand allosteric two-state model.
We have reported previously that amiodarone interacts with muscarinic receptors via a novel allosteric site. This study presents mechanistic details on the nature of that interaction. Amiodarone enhanced the maximal level of agonist-stimulated release of arachidonic acid (AA) from Chinese hamster ovary cells that expressed M₃ muscarinic receptors; this enhancement was observed for acetylcholine and for the partial agonist pilocarpine. A similar effect of amiodarone was observed when pilocarpine was used to stimulate inositol phosphate (IP) metabolism, but not when acetylcholine was used. Subsequent studies showed that the IP response exhibited a much larger receptor reserve than the AA response, and reduction of that reserve by receptor alkylation unmasked amiodarone's enhancement of the maximal IP response to acetylcholine. Modulating the receptor reserve also revealed acetylcholine's greater affinity (K(A)) for the conformation of the receptor that mediates the AA response. The amiodarone analog N-ethylamiodarone (NEA) did not alter maximal agonist response but merely reduced agonist potency (that is, it appeared to be an antagonist). However, the action of NEA could be clearly distinguished from the action of the orthosteric antagonist NMS. Demonstration of this point was facilitated by an elaboration of Hall's allosteric two-state model; this new model represents a system composed of two ligands that compete with each other at the orthosteric site and two ligands that compete with each other at the allosteric site. In conclusion, amiodarone competes with NEA at a novel, extracellular, allosteric site to enhance the maximal stimulation evoked by acetylcholine and pilocarpine in two different responses.


Time-resolved IR studies on the mechanism for the functionalization of primary C-H bonds by photoactivated Cp*W(CO)3(Bpin).
Recently, transition-metal-boryl compounds have been reported that selectively functionalize primary C-H bonds in alkanes in high yield. We have investigated this process with one of the well-defined systems that reacts under photochemical conditions using both density functional theory calculations and pico- through microsecond time-resolved IR spectroscopy. UV irradiation of Cp*W(CO)(3)(Bpin) (Cp* = C(5)(CH(3))(5); pin = 1,2-O(2)C(2)-(CH(3))(4)) in neat pentane solution primarily results in dissociation of a single CO ligand and solvation of the metal by a pentane molecule from the bath within 2 ps. The spectroscopic data imply that the resulting complex, cis-Cp*W(CO)(2)(Bpin)(pentane), undergoes C-H bond activation by a sigma-bond metathesis mechanism--in 16 micros, a terminal hydrogen on pentane appears to migrate to the Bpin ligand to form a sigma-borane complex, Cp*W(CO)(2)(H-Bpin)(C(5)H(11)). Our data imply that the borane ligand rotates until the boron is directly adjacent to the C(5)H(11) ligand. In this configuration, the B-H sigma-bond is broken in favor of a B-C sigma-bond, forming Cp*W(CO)(2)(H)(C(5)H(11)-Bpin), a tungsten-hydride complex containing a weakly bound alkylboronate ester. The ester is then eliminated to form Cp*W(CO)(2)(H) in approximately 170 micros. We also identify two side reactions that limit the total yield of bond activation products and explain the 72% yield previously reported for this complex.


The influence of gingerol treatment on aluminum toxicity in rats.
Ginger is widely used as a medicine in the Ayurvedic system. It contains the active compound gingerol, which scavenges free radicals. Prolonged intake of aluminum (Al) in drinking water and from other sources may lead to neurological, renal, and hepatic dysfunction. The present study was designed to evaluate the protective effect of gingerol, an active principal of ginger against aluminum as Al (NO3)3 -induced toxicity in rats. Al (NO3)3 at 32.5 mg/kg body weight was administered to female albino rats intraperitoneally once only, followed by treatment with gingerol at 25, 50, and 100 mg/kg p.o. for 3 consecutive days beginning 24 h after Al exposure. Animals of all of the groups were sacrificed after 48 h of the last gingerol treatment for experimental observations. Significant elevations were observed in serum tranaminases, cholesterol, triglyceride, creatinine, urea, and blood δ-aminolevulinic acid dehydratase (ALAD) after Al exposure. In liver, kidney, and brain tissues, the thiobarbituric acid reactive substances (TBARS) level and total and esterified cholesterol were significantly increased, whereas glutathione (GSH), acetyl cholinesterase (AChE), and δ-aminolevulinic acid synthetase (ALAS) were significantly decreased. Treatment of gingerol for 3 days surprisingly reversed almost all of the biochemical variables toward control levels in a significant manner. Treatment with gingerol (50 mg/kg body weight) was most effective in coping with aluminum-induced toxicity in rats. The antioxidant activity of gingerol might be due not only to the radical scavenging activity of antioxidants but also to the affinity of these antioxidants to the substrates.


[The mechanisms of morphine dependence and it's withdrawal syndrome: study in mutant mice].
To investigate the involvement of catecholamines and/or the cyclic AMP (cAMP) systems in the development of drug dependence, we examined whether morphine dependence was developed in tyrosine hydroxylase (TH) heterozygous (TH+/-) and cAMP response element binding protein (CREB) binding protein (CBP) heterozygous (CBP+/-) mice. Morphine (10 mg/kg) induced place preference in the wild-type mice. In the TH+/- and CBP+/- mice, however, we could not find any morphine-induced place preference. When the wild-type mice pretreated with morphine (10 mg/kg) twice a day for 5 days were challenged with naloxone (5 mg/kg), they showed increased numbers of jumping, rearing and forepaw tremor as a sign of withdrawal symptom and increased level of cAMP in the thalamus/hypothalamus, but not in the striatum. However, increased numbers of jumping and forepaw tremor in the TH+/- and CBP+/- mice and increased level of cAMP in the thalamus/hypothalamus of TH+/- mice were not observed. These results suggest that catecholamines and CBP are involved in the development of morphine dependence, and that some changes in the catecholaminergic and/or cAMP system induced by repeated morphine treatment play an important role in the addiction of morphine.


Rational Coupled Dynamics Network Manipulation Rescues Disease-Relevant Mutant Cystic Fibrosis Transmembrane Conductance Regulator.
Many cellular functions necessary for life are tightly regulated by protein allosteric conformational change, and correlated dynamics between protein regions has been found to contribute to the function of proteins not previously considered allosteric. The ability to map and control such dynamic coupling would thus create opportunities for the extension of current therapeutic design strategy. Here, we present an approach to determine the networks of residues involved in the transfer of correlated motion across a protein, and apply our approach to rescue disease-causative mutant cystic fibrosis transmembrane regulator (CFTR) ion channels, ΔF508 and ΔI507, which together constitute over 90% of cystic fibrosis cases. We show that these mutations perturb dynamic coupling within the first nucleotide-binding domain (NBD1), and uncover a critical residue that mediates trans-domain coupled dynamics. By rationally designing a mutation to this residue, we improve aberrant dynamics of mutant CFTR as well as enhance surface expression and function of both mutants, demonstrating the rescue of a disease mutation by rational correction of aberrant protein dynamics.


[Chronic hepatitis C--clinical and autonomic characteristics].
The article presents the results of a survey of 62 patients with chronic hepatitis C and 103 patients with liver cirrhosis of viral etiology. Besides clinical parameters studied autonomic features by analysis of heart rate variability at rest and active orthostasis. Indicators of frequency and spectral analysis of heart rate in study patients with chronic hepatitis C and cirrhosis of viral etiology confirmed increase in sympathetic activity and weakening of parasympathetic activity in all respects, with the sympathetic influence of enhanced active orthostasis. Indices of regulatory systems of the autonomic nervous system (stress index and the index of autonomic regulation) also indicated a statistically significant predominance sympathicotonia at rest and active orthostasis, indicating serious violations of adaptation in the examinees.


Neuroanatomical term generation and comparison between two terminologies.
An approach and software tools are described for identifying and extracting compound terms (CTs), acronyms and their associated contexts from textual material that is associated with neuroanatomical atlases. A set of simple syntactic rules were appended to the output of a commercially available part of speech (POS) tagger (Qtag v 3.01) that extracts CTs and their associated context from the texts of neuroanatomical atlases. This "hybrid" parser. appears to be highly sensitive and recognized 96% of the potentially germane neuroanatomical CTs and acronyms present in the cat and primate thalamic atlases. A comparison of neuroanatomical CTs and acronymsbetween the cat and primate atlas texts was initially performed using exact-term matching. The implementation of string-matching algorithms significantly improved the identification of relevant terms and acronyms between the two domains. The End Gap Free string matcher identified 98% of CTs and the Needleman Wunsch (NW) string matcher matched 36% of acronyms between the two atlases. Combining several simple grammatical and lexical rules with the POS tagger ("hybrid parser") (1) extracted complex neuroanatomical terms and acronyms from selected cat and primate thalamic atlases and (2) and facilitated the semi-automated generation of a highly granular thalamic terminology. The implementation of string-matching algorithms (1) reconciled terminological errors generated by optical character recognition (OCR) software used to generate the neuroanatomical text information and (2) increased the sensitivity of matching neuroanatomical terms and acronyms between the two neuroanatomical domains that were generated by the "hybrid" parser.


Alcohol Use in China: Unrecorded and Recorded Bai Jiu in Three Rural Regions.
In China, approximately 70% of beverage alcohol is consumed in the form of spirits. An estimated 25% of all alcohol consumed is unrecorded, mostly spirits (bai jiu), produced outside regulatory systems in small neighborhood distilleries, mostly in rural areas. Unrecorded bai jiu drinkers are generally older, male, prefer higher-strength bai jiu, and drink daily and mostly at home. To explore possible regional differences, researchers used interview data from 2919 bai jiu drinkers in rural areas in Hebei, Anhui, and Hubei provinces in China. Results confirmed that patterns varied by province. The sample in Hubei preferred unrecorded bai jiu with a more stable preference to alcohol type, tended to drink less frequently, and reported experiencing less drinking pressure, suggesting lower-risk drinking patterns in this region. The Hebei and Anhui sample reported higher frequency and greater amount of alcohol consumption, were more likely to experience drinking pressure, indicating higher-risk patterns in alcohol use in these two regions. The results provide needed details about regional differences in unrecorded bai jiu drinking patterns that are not evident in aggregated data and suggest variations in drinking patterns that may reflect local geography, local values, traditions, and ethnic differences.


[Seroprevalence of Toxoplasma gondii in dairy goats in the São Paulo State, Brazil].
Four hundred forty-two serum samples were collected from dairy goats in seven regions of São Paulo State. These were tested for Toxoplasma gondii antibodies using the indirect immunofluorescent antibody test. Sixty-four (14.5%) serologically positive animals were found from all these goat farms studied.


Inpatient adolescents with borderline personality disorder features: Identity diffusion and narrative incoherence.
Borderline personality disorder (BPD) is a severe disorder with poor prognosis. Therefore, a growing number of researchers emphasize the need to evaluate correlates of BPD present during adolescence that can be identified and targeted to prevent exacerbation over time. A core feature of BPD is a disturbed sense of self; however, such disturbances can manifest themselves in different ways in adolescence. In this study, we examined whether such disturbances would appear through self-reported identity disturbance and more indirectly through incoherent oral narratives, rated based on the content derived from the Child Attachment Interview. Thus, higher levels of identity diffusion and lower levels of narrative coherence of past events were expected to associate with BPD features in 70 inpatient adolescents. Findings confirmed hypotheses; however, when considering covariance between narrative coherence and identity diffusion, only identity diffusion remained significant. Findings are discussed in terms of how both constructs might be underlying mechanisms of a disturbed sense of self in BPD and how they speak to future treatment and a more dimensional conceptualization of personality disorders. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Evaluation of periodontal parameters in patients undergoing peritoneal dialysis or hemodialysis.
To analyze and compare periodontal parameters in chronic renal failure (CRF) patients undergoing peritoneal dialysis (PD) therapy with a group of patients on hemodialysis (HD) treatment and healthy controls (C). Seventy-five PD patients (mean age: 44 +/- 12 years) were matched with 41 HD patients (mean age: 46 +/- 15 years) and 61 C (mean age: 46 +/- 18 years). Plaque (PI) and calculus (CSI) accumulation and gingival bleeding (GI) were recorded with the appropriate indices. Periodontal condition was assessed using the probing pocket depth (PPD). One-way anova test, Pearson chi-squared test, Mann-Whitney U-test and Kruskal-Wallis test were performed to compare PD patients with HD patients and healthy C. Plaque Index values were significantly higher (P < 0.001) in the PD and HD groups than the C group. GI values were significantly higher (P < 0.01) in the HD group than the PD group. Finally, CSI values in the PD and HD groups were also significantly higher (P < 0.001) than the C group. Chronic renal failure patients on PD treatment are more susceptible to periodontal diseases like HD patients. Thus, it is very important to maintain an optimal oral hygiene level. Further studies on periodontal parameters of only PD patients are needed to get more information on the oral health status of this patient group.


Trends in lifestyle 1986-99 in a 25- to 64-year-old population of the Northern Sweden MONICA project.
The authors explore the time trends in lifestyle factors in the Northern Sweden MONICA population, including physical activity, intake of certain foods, coffee and alcohol consumption, smoking, and the use of smokeless tobacco. Four health surveys during a 14-year time span were compared (1986, 1990, 1994, and 1999). The participation rate in all surveys was high. A questionnaire with similar or comparable questions about lifestyle factors was used across all health surveys. A large variation was demonstrated in the consumption of saturated fat in dairy products across the surveys. The use of butter on bread and of 3% fat milk clearly declined in favour of using low-fat margarine and 1-1.5% fat milk. A decline in the intake of boiled or baked potatoes together with an increase in the intake of pasta and rice was demonstrated. There were no changes in leisure-time physical activity. The proportion of the population using tobacco was unaltered. In men, smoking declined during the period but simultaneously there was an increase in the use of smokeless tobacco. The use of "boiled" or Scandinavian coffee diminished and more frequent use of alcohol was seen, especially in men. Pronounced changes were seen in food consumption with a decrease in saturated fat intake, boiled coffee, and potatoes and an increase in alcohol, rice, and pasta consumption. No clear time trends were found in physical activity or in the use of tobacco.


Behavioral state-dependent lateralization of dorsal dentate gyrus c-Fos expression in mice.
Hemispheric lateralization is a fundamental organizing principle of nervous systems across taxonomic groups with bilateral symmetry. The mammalian hippocampus is lateralized anatomically, physiologically, and chemically; however, functional asymmetries are not yet well understood. Imaging studies in humans have implicated the left and right hippocampus in specialized processing. However, it is not clear if lateralized activity occurs in the rodent hippocampus. c-Fos imaging in animals provides a measure of neuronal activity with a resolution at the level of single cells. The aim of the present study was to determine whether lateralized activity-dependent c-Fos expression occurs in the rodent hippocampus. To understand functional lateralization of hippocampal processing, we compared interhemispheric expression of c-Fos in the dentate gyrus (DG), a structure involved in encoding new experiences, in mice that ran on a wheel, encoded a novel object, or remained in home cages. We found that wheel running (WR) induced the greatest amount of DG c-Fos expression in both hemispheres, with no difference between hemispheres. Object exploration (OB) resulted in left-lateralized DG c-Fos expression, whereas control (CON) mice were not lateralized. We then sought to determine whether differential consideration of hemispheres might influence the conclusions of a study by simulating common cell quantitation methods. We found that different approaches led to different conclusions. These data demonstrate lateralization of neuronal activity in the mouse DG corresponding to the experience of the animal and show that differentially considering hemisphere leads to alternative conclusions.


A scope of the problem: Post-deployment reintegration challenges in a National Guard Unit.
More Reserve and Guard members have been activated in the past few years than in any other time in history. In addition to the high rates of psychological and behavioral challenges among military personnel, there are other equally important post-deployment reintegration challenges. Post-deployment reintegration challenges are particularly important to Reserve and Guard members, who transition rapidly from civilian-military-civilian. This study aims to describe the scope of challenges that a battalion of National Guard members (NGM) report experiencing after returning from a one-year deployment to Iraq. This article reports data from a sample of 126 NGM who recently returned from a one-year deployment to Iraq. The scope of post-deployment problems at baseline, 3- and 6-month post-deployment are presented. Overall, the rates of post-deployment psychological and behavioral problems were elevated upon returning from deployment and remained fairly constant for up to 6 months post-deployment. Approximately 30% of respondents were unsatisfied with their relationship and upwards of 30% reported family reintegration challenges. Comparisons with similar research and implications for prevention and improvement of post-deployment quality of life are addressed.


Cascade alkyl migration in 2-alkynylanilines for the synthesis of benzenoid ring multi-functionalized indoles.
Cascade alkyl migration of 2-alkynylanilines via an aromaticity destruction and reconstruction process is reported. The first alkyl migration is triggered by generation of a dearomatized arenium species via oxidation and cyclization, and the second is driven by the force to restore the aromaticity of rearrangement products. The reaction gave rise to a range of multi-functionalized indoles.


Changing carbon isotope ratio of atmospheric carbon dioxide: implications for food authentication.
Carbon isotopes are often used to detect the addition of foreign sugars to foods. This technique takes advantage of the natural difference in carbon isotope ratio between C(3) and C(4) plants. Many foods are derived from C(3) plants, but the low-cost sweeteners corn and sugar cane are C(4) plants. Most adulteration studies do not take into account the secular shift of the carbon isotope ratio of atmospheric carbon dioxide caused by fossil fuel burning, a shift also seen in plant tissues. As a result statistical tests and threshold values that evaluate authenticity of foods based on carbon isotope ratios may need to be corrected for changing atmospheric isotope values. Literature and new data show that the atmospheric trend in carbon isotopes is seen in a 36-year data set of maple syrup analyses (n = 246), demonstrating that published thresholds for cane or corn sugar adulteration in maple syrup (and other foods) have become progressively more lenient over time.


Dextrorphan and levorphanol selectively block N-methyl-D-aspartate receptor-mediated neurotoxicity on cortical neurons.
Neocortical neurons in cell cultures prepared from fetal mice were impaled for intracellular recording. Dextrorphan (DX), a clinically tested dextrorotatory morphinan lacking opioid action, did not alter neuronal membrane potential or conductance, but produced a selective attenuation of N-methyl-D-aspartate (NMDA) responses; kainate and quisqualate responses were not affected. DX also antagonized morphological and chemical (lactate dehydrogenase efflux) evidence of cortical neuronal cell injury produced by toxic bath exposure to NMDA, quinolinate or glutamate, but did not affect toxic exposure to quisqualate or kainate. This selective antagonism of neurotoxicity was apparent at micromolar concentrations of DX with an ED50 of 13 to 17 microM. A similar, but less potent neuron-protective effect, was seen with the opioid levorotatory enantiomer of DX, levorphanol (ED50, 40 microM). The O-methyl derivative of DX, dextromethorphan, also antagonized NMDA and glutamate neurotoxicity, but with possibly lower efficacy than DX. The higher potency of DX over levorphanol suggests that this novel neuron-protective action is not mediated by classic opiate receptors; it may be mediated at the "sigma opiate"/phencyclidine site. If further studies establish that DX and related compounds retain neuron-protective efficacy in appropriate animal models, the established clinical safety record of DX and dextromethorphan may allow prompt investigation of the NMDA receptor-blockade strategy in certain neurological disease states.


[Psychotic disorders in ICD-11: the revisions].
Psychotic disorders in ICD-11: the revisions Abstract. This article provides an overview of the main changes to the chapter "Schizophrenia or Other Primary Psychotic Disorders" (6A2) from ICD-10 to ICD-11 and compares them with the psychosis chapter of DSM-5. These changes include abandoning the classical subtypes of Schizophrenia as well as of the special significance of Schneider's first-rank symptoms, resulting in the general requirement of two key features (one must be a positive symptom) in the definition of "Schizophrenia" (6A20) and the allowance for bizarre contents in "Delusional Disorder" (6A24), which now includes "Induced Delusional Disorder" (F24). Further introduced are the focus on the current episode, the restriction of "Acute and Transient Psychotic Disorder" (6A23) to the former Polymorphic Disorder Without Schizophrenic Symptoms (F23.0), the diagnosis of delusional "Obsessive-Compulsive or Related Disorders" (6B2) exclusively as Obsessive-Compulsive Disorders, the specification of "Schizoaffective Disorder" (6A21), and the formulation of a distinct subchapter "Catatonia" (6A4) for the assessment of catatonic features in the context of several disorders. In analogy to DSM-5, ICD-11 now includes the optional category "Symptomatic Manifestations of Primary Psychotic Disorders" (6A25) for the dimensional quantification of symptoms. Again, developmental aspects remain unattended in in the ICD-11-definitions of psychotic disorders.


Early alterations of large-scale brain networks temporal dynamics in young children with autism.
Autism spectrum disorders (ASD) are associated with disruption of large-scale brain network. Recently, we found that directed functional connectivity alterations of social brain networks are a core component of atypical brain development at early developmental stages in ASD. Here, we investigated the spatio-temporal dynamics of whole-brain neuronal networks at a subsecond scale in 113 toddlers and preschoolers (66 with ASD) using an EEG microstate approach. We first determined the predominant microstates using established clustering methods. We identified five predominant microstate (labeled as microstate classes A-E) with significant differences in the temporal dynamics of microstate class B between the groups in terms of increased appearance and prolonged duration. Using Markov chains, we found differences in the dynamic syntax between several maps in toddlers and preschoolers with ASD compared to their TD peers. Finally, exploratory analysis of brain-behavioral relationships within the ASD group suggested that the temporal dynamics of some maps were related to conditions comorbid to ASD during early developmental stages.


Analysis of epitope information related to Bacillus anthracis and Clostridium botulinum.
We have reviewed the information about epitopes of immunological interest from Clostridium botulinum and Bacillus anthracis, by mining the Immune Epitope Database and Analysis Resource. For both pathogens, the vast majority of epitopes reported to date are derived from a single protein: the protective antigen of B. anthracis and the neurotoxin type A of C. botulinum. A detailed analysis of the data was performed to characterize the function, localization and conservancy of epitopes identified as neutralizing and/or protective. In order to broaden the scope of this analysis, we have also included data describing immune responses against defined fragments (over 50 amino acids long) of the relevant antigens. The scarce information on T-cell determinants and on epitopes from other antigens besides the toxins, highlights a gap in our knowledge and identifies areas for future research. Despite this, several distinct structures at the epitope and fragment level are described herein, which could be potential additions to future vaccines or targets of novel immunotherapeutics and diagnostic reagents.


[Protective efficacy of combined administration of the multicomponent vaccine and the immunomodulator myelopid in experimental infections in mice].
The influence of myelopid (MP) on the protective activity of polycomponent vaccine VP-4 prepared from the antigens of opportunistic bacteria was studied on experimental infections of mice, caused by Klebsiella pneumoniae, Salmonella typhimurium and Staphylococcus aureus. In staphylococcal and Klebsiella infections the joint administration of vaccine VP-4 and MP produced more pronounced protective effect than each of these preparations, introduced alone. The protective action of vaccine VP-4 was specially enforced by MP in cases of local staphylococcal infection. Recommendations on the joint use of two or more immunomodulating agents are possible only on the basis of the experimental substantiation of their effect in definite infections.


TET-catalyzed oxidation of intragenic 5-methylcytosine regulates CTCF-dependent alternative splicing.
Intragenic 5-methylcytosine and CTCF mediate opposing effects on pre-mRNA splicing: CTCF promotes inclusion of weak upstream exons through RNA polymerase II pausing, whereas 5-methylcytosine evicts CTCF, leading to exon exclusion. However, the mechanisms governing dynamic DNA methylation at CTCF-binding sites were unclear. Here, we reveal the methylcytosine dioxygenases TET1 and TET2 as active regulators of CTCF-mediated alternative splicing through conversion of 5-methylcytosine to its oxidation derivatives. 5-hydroxymethylcytosine and 5-carboxylcytosine are enriched at an intragenic CTCF-binding sites in the CD45 model gene and are associated with alternative exon inclusion. Reduced TET levels culminate in increased 5-methylcytosine, resulting in CTCF eviction and exon exclusion. In vitro analyses establish the oxidation derivatives are not sufficient to stimulate splicing, but efficiently promote CTCF association. We further show genomewide that reciprocal exchange of 5-hydroxymethylcytosine and 5-methylcytosine at downstream CTCF-binding sites is a general feature of alternative splicing in naïve and activated CD4(+) T cells. These findings significantly expand our current concept of the pre-mRNA "splicing code" to include dynamic intragenic DNA methylation catalyzed by the TET proteins.


The NSIGHT1-randomized controlled trial: rapid whole-genome sequencing for accelerated etiologic diagnosis in critically ill infants.
Genetic disorders are a leading cause of morbidity and mortality in infants in neonatal and pediatric intensive care units (NICU/PICU). While genomic sequencing is useful for genetic disease diagnosis, results are usually reported too late to guide inpatient management. We performed an investigator-initiated, partially blinded, pragmatic, randomized, controlled trial to test the hypothesis that rapid whole-genome sequencing (rWGS) increased the proportion of NICU/PICU infants receiving a genetic diagnosis within 28 days. The participants were families with infants aged <4 months in a regional NICU and PICU, with illnesses of unknown etiology. The intervention was trio rWGS. Enrollment from October 2014 to June 2016, and follow-up until November 2016. Of all, 26 female infants, 37 male infants, and 2 infants of undetermined sex were randomized to receive rWGS plus standard genetic tests (n = 32, cases) or standard genetic tests alone (n = 33, controls). The study was terminated early due to loss of equipoise: 73% (24) controls received genomic sequencing as standard tests, and 15% (five) controls underwent compassionate cross-over to receive rWGS. Nevertheless, intention to treat analysis showed the rate of genetic diagnosis within 28 days of enrollment (the primary end-point) to be higher in cases (31%, 10 of 32) than controls (3%, 1 of 33; difference, 28% [95% CI, 10-46%]; p = 0.003). Among infants enrolled in the first 25 days of life, the rate of neonatal diagnosis was higher in cases (32%, 7 of 22) than controls (0%, 0 of 23; difference, 32% [95% CI, 11-53%];p = 0.004). Median age at diagnosis (25 days [range 14-90] in cases vs. 130 days [range 37-451] in controls) and median time to diagnosis (13 days [range 1-84] in cases, vs. 107 days [range 21-429] in controls) were significantly less in cases than controls (p = 0.04). In conclusion, rWGS increased the proportion of NICU/PICU infants who received timely diagnoses of genetic diseases.


Implications of Disability Severity on 24-Hour Movement Guideline Adherence Among Children With Neurodevelopmental Disorders in the United States.
Research has established beneficial associations between 24-hour movement guideline adherence and several health outcomes in typically developing (TD) children, but these relationships are poorly understood in children with neurodevelopmental disorders (NDD). This study examined (1) 24-hour movement guideline adherence, (2) the influence of disability severity, and (3) associations between guideline adherence and health outcomes of TD children and children with NDD. This cross-sectional study used data from the 2018 and 2019 cycles of the US National Survey of Children's Health. Parental/caregiver reports of movement behaviors (physical activity, screen time, and sleep), disability severity (limitations to daily activities), and health outcomes (general health status, anxiety, and depression) were provided for 8554 children with NDD and 19,669 TD children aged 6-17 years. Children with NDD had significantly lower odds of meeting each movement behavior guideline compared to TD children; these effects were most pronounced for those who experienced consistent limitations to daily activities. Meeting at least 2 guidelines significantly lowered the odds for anxiety and depression, and increased the odds for better general health for children with NDD. These findings suggest that degree of disability severity has a strong influence on adherence to 24-hour movement guidelines among children with NDD.


Improved outcomes for newly diagnosed AL amyloidosis between 2000 and 2014: cracking the glass ceiling of early death.
In light of major advances in immunoglobulin light chain (AL) amyloidosis, we evaluated the trends in presentation, management, and outcome among 1551 newly diagnosed AL amyloidosis patients seen in our institution from 2000 to 2014. As compared with the 2 intervals 2000-2004 and 2005-2009, patients diagnosed in 2010-2014 were less likely to have >2 involved organs. Utilization of autologous stem cell transplant (ASCT) was similar across all periods, about one-third of patients, but there was an increase in the use of pre-ASCT bortezomib induction and of unattenuated melphalan conditioning in 2010-2014 compared with earlier periods. Non-ASCT first-line regimen changed with 65% of patients in 2010-2014 received bortezomib-based therapy, 79% of patients in 2005-2009 received melphalan-dexamethasone, and 64% of patients in 2000-2004 received melphalan-prednisone. The rate of better than very good partial response (VGPR) was higher in more recent periods (66% vs 58% vs 51%; P = .001), a change largely driven by improved VGPR rates in the non-ASCT population. Overall survival (OS) has improved, with inflection points for improvement differing for the ASCT and non-ASCT groups. In the ASCT population, the greatest gains were after 2010 (4-year OS, 91% compared with 73% and 65%). In the non-ASCT group, greatest gains were after 2005 (4-year OS, 38%, 32%, and 16%). Fewer patients died within 6 months of diagnosis in the 2 later periods (24% vs 25% vs 37%; P < .001). Overall, outcomes among patients with AL amyloidosis have improved with earlier diagnosis, higher rates of VGPR, lower early mortality, and improved OS.


[Basic concepts in epidemiology and statistics for reading controlled clinical trials].
The authors present the basic concepts in epidemiology and statistics needed for understanding properly the design and results of controlled clinical trials. Through a set of examples, the concepts of measures of association and effect, statistical significance tests, p-value, confidence interval and statistical power are presented and common their misinterpretations are discussed.


Determinants of Physical Fitness in Children with Repaired Congenital Heart Disease.
The aim of this study was to determine factors associated with physical fitness (PF) in children who underwent surgery for congenital heart disease (CHD). Sixty-six children (7-14 years) who underwent surgery for ventricular septal defect (n = 19), transposition of great arteries (n = 22), coarctation of aorta (n = 10), and tetralogy of Fallot (n = 15) were included. All children performed PF tests: cardiorespiratory fitness, upper- and lower-limb muscle strength, speed, balance, and flexibility. Cardiac evaluation was done via echocardiography and cardiopulmonary exercise test. Factors related to child's characteristics, child's lifestyle, physical activity motivators/barriers, and parental factors were assessed. Linear regression analyses were conducted. The results showed no significant differences in physical activity (PA) level by CHD type. Boys had better cardiorespiratory fitness (difference = 1.86 ml/kg/min [0.51;3.22]) and were more physically active (difference = 19.40 min/day [8.14;30.66]), while girls had better flexibility (difference = - 3.60 cm [- 7.07;- 0.14]). Physical activity motivators showed an association with four out of six PF components: cardiorespiratory fitness, coefficient = 0.063 [0.01;0.11]; upper-limb muscle strength, coefficient = 0.076 [0.01;0.14]; lower-limb muscle strength, coefficient = 0.598 [0.07;1.13]; and speed, coefficient = 0.03 [0.01;0.05]. Age, sex, and motivators together reached a maximum adjusted R2 = 0.707 for upper-limb strength. Adding other possible determinants did not significantly increase the explained variance. Apart from age and sex as non-modifiable determinants, the main target which might improve fitness would be the introduction of an intervention which increases the motivation to be active.


Glucose transporter expression and the potential role of fructose in renal cell carcinoma: A correlation with pathological parameters.
All mammalian cells contain one or more members of the facilitative glucose transporter (GLUT) gene family. Glucose transporter membrane proteins (GLUT) regulate the movement of glucose between the extracellular and intracellular compartments, maintaining a constant supply of glucose available for metabolism. Tumor cells are highly energy-dependent, therefore GLUT overexpression is often observed. In fact, overexpression of GLUT1 has been correlated with hypoxia markers in several tumor types, including renal cell carcinoma (RCC). We retrospectively analyzed 80 paraffin-embedded RCC samples. The pattern of GLUT1-5 expression in RCC specimens was evaluated using tissue-array technology and correlated with histological tumor characteristics. Pathological parameters included tumor location, renal pelvis, vein and lymph vessel invasion, capsule breakage, histological subtype, Furhman grade, hilar invasion and tumor stage at diagnosis. The expression of five facilitative glucose transporters, GLUT1 (erythrocyte type), GLUT2 (liver type), GLUT3 (brain type), GLUT4 (muscle/fat type) and GLUT5 (small intestinal type), was semi-quantitatively analyzed. In non-parametric, Mann-Whitney U and Kruskal-Wallis tests, a significant positive correlation was consistently found between moderately differentiated RCC tissues and the expression of GLUT5 (p=0.024). Patients who had pelvic invasion and capsule breakage at diagnosis also showed increased GLUT5 expression levels (p=0.039 and p=0.019, respectively). Moreover, GLUT5 showed statistical significance in those samples identified as being of clear cell histological type (p=0.001). A high expression of GLUT5 in human RCC was observed. GLUT5 appears to be correlated with grade II differentiation, locoregional invasion and aggressiveness, and may play a role in RCC development.


Herpes simplex virus non-structural proteins. III. Function of the major DNA-binding protein.
The herpes simplex virus type 2 major DNA-binding protein has been functionally characterized using temperature-sensitive mutants in the complementation group 2-2. The mutants were shown to be defective in the DNA-binding protein gene by mapping the mutants to the area of the genome known to code for the protein, and by demonstrating alterations in the major DNA-binding protein induced in mutant-infected cells. The mutants were shown to be defective in the replication of virus DNA. The nature of this defect was examined by studying virus DNA synthesis in vitro and by the examination of virus enzymes. An effect of mutation in the DNA-binding protein was to destabilize both the DNA polymerase and the alkaline exonuclease.


Tetrameric assembly of full-sequence protein zero myelin glycoprotein by synchrotron x-ray scattering.
Highly purified myelin P0 glycoprotein was solubilized to 1-8 mg/ml in 0.1% sodium dodecyl sulfate (SDS), and the solution structure of the P0 assembly was studied using synchrotron x-ray scattering. The full-length P0, which was isolated from bovine intradural roots, included both the extracellular and cytoplasmic domains of the molecule. At the higher concentrations (4, 6, and 8 mg/ml, respectively), an x-ray intensity maximum was observed at 316 A, 245 A, and 240 A Bragg spacing. Because the position of this intensity depended on P0 concentration, it is most likely due to interparticle interference. By contrast, the position of a second intensity maximum, which was at approximately 40 A Bragg spacing, was invariant with P0 concentration. This latter intensity was accounted for by monodispersed, 80 A-diameter particles that are composed of eight, approximately 30 A-diameter spheres. Chemical parameters suggest that the 80 A particles correspond to the size of a tetramer of P0 molecules. Therefore, the approximately 30 A spheres would correspond to the sizes of the extracellular and cytoplasmic domains for each of the P0 monomers. The invariance of the second intensity maximum with P0 concentration indicates that the structure of the 80 A-diameter, tetrameric particles is unaltered. According to the liquid model for interparticle interference from charged spheres, the 80 A-diameter particle has 10 negative surface charges which likely arise from negatively charged SDS molecules bound to the transmembrane domain of P0. This binding, however, apparently does not alter the tetrameric assembly of P0, suggesting that intermolecular interactions involving extracellular domains and cytoplasmic domains likely stabilize this assembly. Some of our results have been published in abstract form (Inouye, H., H. Tsuruta, D. A. Kirschner, J. Sedzik, and K. Uyemura. Abstracts of the 4th International School and Symposium on Synchrotron Radiation in Natural Science, June 15-20, 1998. Ustron-Jaszowiec, Poland. p. 31).


The MADS box genes SEEDSTICK and ARABIDOPSIS Bsister play a maternal role in fertilization and seed development.
The haploid generation of flowering plants develops within the sporophytic tissues of the ovule. After fertilization, the maternal seed coat develops in a coordinated manner with formation of the embryo and endosperm. In the arabidopsis bsister (abs) mutant, the endothelium, which is the most inner cell layer of the integuments that surround the haploid embryo sac, does not accumulate proanthocyanidins and the cells have an abnormal morphology. However, fertility is not affected in abs single mutants. SEEDSTICK regulates ovule identity redundantly with SHATTERPROOF 1 (SHP1) and SHP2 while a role in the control of fertility was not reported previously. Here we describe the characterization of the abs stk double mutant. This double mutant develops very few seeds due to both a reduced number of fertilized ovules and seed abortions later during development. Morphological analysis revealed a total absence of endothelium in this double mutant. Additionally, massive starch accumulation was observed in the embryo sac. The phenotype of the abs stk double mutant highlights the importance of the maternal-derived tissues, particularly the endothelium, for the development of the next generation.


Plasma immunoreactive gamma melanotropin in patients with idiopathic hyperaldosteronism, aldosterone-producing adenomas, and essential hypertension.
A non-ACTH aldosterone-stimulating factor(s) has been implicated in the pathogenesis of idiopathic hyperaldosteronism (IHA). Although this factor has not been fully characterized, some evidence suggests that it may be related to a pro-gamma-melanotropin (pro-gamma-MSH), derived from the NH2-terminal region of pro-opiomelanocortin. In the present study, plasma immunoreactive (IR-) gamma-MSH levels at 0800 h in patients with IHA were evaluated (90 +/- 17 fmol/ml; range: 13-173 fmol/ml) and found to be significantly higher (P less than 0.05) than those in subjects with aldosterone-producing adenomas (33 +/- 8 fmol/ml), essential hypertension (33 +/- 6 fmol/ml), and normotensive controls (19 +/- 2 fmol/ml). Seven of nine IHA subjects had circulating IR-gamma-MSH levels above the normal range (greater than 35 fmol/ml). In plasmas sampled at 1200 h, IR-gamma-MSH was significantly higher in patients with IHA (95 +/- 26 fmol/ml) and adenomas (63 +/- 23 fmol/ml), as compared with essential hypertensives (31 +/- 6 fmol/ml) and normotensives (19 +/- 3 fmol/ml). Mean plasma IR-ACTH, plasma cortisol, and urinary cortisol levels did not differ significantly between any of these groups. In order to evaluate the effect of a pro-gamma-MSH in vitro, adrenal adenoma tissue was obtained from two patients, one with elevated IR-gamma-MSH (61 fmol/ml) and a second with low IR-gamma-MSH (12 fmol/ml). Aldosterone secretion by dispersed adenoma cells from the former, but not the latter, underwent a fourfold dose-dependent (10(-14)-10(-9) M) increase in response to human Lys-gamma 3-MSH. These data suggest that a pro-gamma-MSH may be implicated as a pathogenic factor in a subset of patients with primary aldosteronism, particularly among those differentially diagnosed as having IHA.


Neurostructural correlate of math anxiety in the brain of children.
Adequate mathematical competencies are currently indispensable in professional and social life. However, mathematics is often associated with stress and frustration and the confrontation with tasks that require mathematical knowledge triggers anxiety in many children. We examined if there is a relationship between math anxiety and changes in brain structure in children with and without developmental dyscalculia. Our findings showed that math anxiety is related to altered brain structure. In particular, the right amygdala volume was reduced in individuals with higher math anxiety. In conclusion, math anxiety not only hinders children in arithmetic development, but it is associated with altered brain structure in areas related to fear processing. This emphasizes the far-reaching outcome emotional factors in mathematical cognition can have and encourages educators and researchers alike to consider math anxiety to prevent detrimental long-term consequences on school achievement and quality of life, especially in children with developmental dyscalculia.


Anti-inflammatory and antibacterial potential of Ajwa date (Phoenix dactylifera L.) extract in burn infection.
Thermal burns produce tissue damage, which eliminates the protective role of tissue. Due to the extensive tissue damage from severe burns, an overactive immune response occurs. Furthermore, this raises the possibility of getting sepsis, a condition in which a bacterial infection spreads throughout the body rather than only in the area of the injury or localized infection. To determine the compounds of Ajwa dates have the potential as an anti-inflammatory and antibacterial agent in infectious thermal burns. The research method used the Preferred Reporting Items for Systematic Review and Meta-Analyses guideline. Various references were collected from the online database Google Scholar and PubMed including reports, journals, and all references mostly published no more than the past 10 years. This systematic review revealed 16 research articles that were pertinent. Polyphenolic substances such as flavonoids, glycosides, and phenolic acids were found in ajwa dates. Specified polyphenol chemicals have the ability to interact with one or more immune cell receptors, moving intracellular messages and influencing the host's immunological response. Ajwa dates' polyphenol acts as an anti-inflammatory agent in severe burns by inhibiting the expression of pathogen-associated molecular pattern receptors, controlling transcription factors, and changing the phenotype of macrophage cells, among other ways. The bacterial activity and immune response regulation of Ajwa dates, on the other hand, also serve as an antibacterial agent directly. The polyphenol compounds in Ajwa dates have the potential to operate as an anti-inflammatory and antibacterial agent in infected thermal burns.


Rivaroxaban Versus Apixaban for Stroke Prevention in Atrial Fibrillation: An Instrumental Variable Analysis of a Nationwide Cohort.
The comparative effectiveness of non-vitamin K antagonist oral anticoagulants (NOACs) is uncertain, as they have not been compared directly in randomized trials. Previous observational comparisons of NOACs are likely to be biased by unmeasured confounders. We sought to compare the efficacy and safety of rivaroxaban and apixaban for stroke prevention in patients with atrial fibrillation (AF), using practice variation in preference for NOAC as an instrumental variable. Patients started on apixaban or rivaroxaban after newly diagnosed AF were identified using Danish nationwide registries. Patients were categorized according to facility preferences for type of NOAC, independent of actual treatment, measured as fraction of the prior 20 patients with AF initiated on rivaroxaban in the same facility. Facility preference for NOAC was used as an instrumental variable. The occurrence of stroke/thromboembolism, major bleeding, myocardial infarction, and all-cause mortality over 2 years of follow-up were investigated using adjusted Cox regressions. We analyzed 6264 patients with AF initiated on rivaroxaban or apixaban. NOAC preference was strongly related to actual choice of treatment but not associated with any other measured baseline characteristics. Patients treated in facilities that had preference for rivaroxaban had more major bleeding: compared with patients treated in facilities that used rivaroxaban in 0% to 20% of cases, the adjusted hazard ratio for bleeding was 1.06 when treated in a facility with 25% to 40% use; 1.41 with 45% to 60% use; 1.51 with 65% to 80% use; and 1.81 with 0% to 100% use (Ptrend=0.01). Higher facility preference for rivaroxaban was not significantly associated with increased risk of stroke/thromboembolism (Ptrend=0.06), myocardial infarction (Ptrend=0.65), or all-cause mortality (Ptrend=0.89). When we used the instrumental variable to model the causal relationship between choice of NOAC and major bleeding, relative risk with rivaroxaban was 1.89 (95% CI, 1.06-2.72) compared with apixaban. Using instrumental variable estimation in a cohort of patients with AF, rivaroxaban was associated with higher risk of major bleeding compared with apixaban. No significant associations to other outcomes were found in main analyses.


Regional differences in levels of chlorinated and brominated pollutants in mother's milk from primiparous women in Sweden.
Early life exposure to halogenated persistent organic pollutants, such as polychlorinated biphenyls (PCBs), the DDT metabolite p,p'-dichlorodiphenyldichloroethane (p,p'-DDE), polybrominated diphenylethers (PBDEs), and hexabromocyclododecane (HBCD), may affect human health. We determined if there are regional differences in mother's milk levels of these compounds in Sweden. In year 2000-2004, milk was sampled from 204 randomly recruited primiparas from four regions of Sweden. Levels of the compounds were measured by gas chromatography with dual electron-capture detectors. Women were recruited at delivery in three hospitals located in urban areas in southern and central Sweden (Lund, Gothenburg and Uppsala), and in one hospital located in a more rural area in northern Sweden (Lycksele). Information about dietary habits and medical/life-style factors were collected by questionnaires. Among PCB congeners, CB 153, CB 138 and CB 180 showed the highest median concentrations (18-48 ng/g mother's milk lipid), whereas more than 50% of the women had CB 52, CB 101, CB 114, and CB 157 levels below the LOQ (0.3-1.5 ng/g lipid). Median p,p'-DDE levels were in the range of 46-78 ng/g lipid. BDE 47 showed the highest median concentrations (1-2 ng/g lipid) among the brominated compounds, whereas more than 50% of the women had levels of BDE 28, BDE 66, BDE 138, BDE 154, and HBCD below the LOQ (0.05-0.10 ng/g lipid). Regional differences in median organohalogen compound concentrations were small, less than 2-fold. Lycksele women generally had the lowest levels of Σmono-and Σdi-ortho PCBs, mainly due to a lower average age. In contrast, these women had higher tetra- to penta-brominated PBDE levels, but no diet or life-style factor could explain this finding. Wide ranges of PBDEs and HBCD levels (up to 200-fold) were found, especially in the Lycksele area. The highest levels of PBDE were in the range of average levels found in mother's milk from North America, suggesting that food may not be the only source of exposure to PBDEs among some individuals.


Hospital care may not affect the risk of readmission.
: Thirty-day readmissions have become a focal point for reducing health care spending, because they are viewed as a marker of the quality of hospital care. However, if increased time in the hospital is associated with better care, attempts to shorten length of stay (LOS) may result in increased rates of readmission. As such, we sought to explore the association of an incremental added day in LOS with the rate of readmission. : We examined the rate of readmission at 30 and 120 days for 4151 patients admitted to a general internal medicine unit between July 2004 and March 2006. We used binary logistic regression to examine the relationship between an incremental added day in LOS and the probability of readmission. : Readmission rates were 8.7% at 30 days and 21.0% at 120 days, respectively. After controlling for demographic characteristics and severity of illness, we found that the probability of readmission varied little for an incremental added day in LOS. : Our findings suggest that more hospital care may not affect the likelihood of readmission and thus denying payment for readmission may be unwarranted.


Beam spread function with time dispersion.
An analytical model for the beam spread function with time dispersion is modeled and validated against Monte Carlo calculations. The model, which is structured on simple statistical concepts and relies on only first and second moments for displacement, angle, and multipath time, is suitable for describing pulsed laser radiation propagation in nonconservative scattering media out to tens of scattering lengths. Numerical examples for marine environments are used to show its robustness and versatility.


The temporal aspects of clinical guidelines.
Temporal aspects play a major role within clinical guidelines. Temporal issues arise when considering both guidelines per se, and the application of guidelines to specific patients. As a matter of fact, guidelines per se specify different diagnostic and\or therapeutic patterns, and temporal constraints on the intended times of execution of the actions they contain are an intrinsic part of guidelines themselves. Moreover, guidelines must be executed on the basis of patients' data, which are intrinsically temporal data (consider, e.g., the time when symptoms hold). Devising suitable representation formalisms to properly model such pieces of temporal information is a challenging task, for which several solutions have been proposed in the last years. Besides representation formalisms, temporal reasoning methodologies are also needed. Temporal abstraction is needed in order to infer abstract temporal data (as described in guideline action conditions) from "raw" timestamped patient data. Moreover, temporal constraint propagationis also needed, both at acquisition and at execution time. During acquisition, temporal constraint propagation is used to detect whether the temporal constraints in the guideline are consistent. At execution time, it is needed in order to check whether the actual time of execution of actions has respected the temporal constraints in the guideline, and to detect which are the next candidate actions to be executed, on the basis of the temporal constraints in the guideline. This chapter sketches some of the most important recent results about the above issues.


Mitochondria-targeted chemotherapeutics: the rational design of gold(I) N-heterocyclic carbene complexes that are selectively toxic to cancer cells and target protein selenols in preference to thiols.
A family of lipophilic, cationic Au(I) complexes of N-heterocyclic carbenes (NHCs) have been designed as new mitochondria-targeted antitumor agents that combine both selective mitochondrial accumulation and selective thioredoxin reductase inhibition properties within a single molecule. Two-step ligand exchange reactions with cysteine (Cys) and selenocysteine (Sec) occur with release of the NHC ligands. At physiological pH the rate constants for the reactions with Sec are 20- to 80-fold higher than those with Cys. The complexes are selectively toxic to two highly tumorigenic breast cancer cell lines and not to normal breast cells, and the degree of selectivity and potency are optimized by modification of the substituent on the simple imidazolium salt precursor. The lead compound is shown to accumulate in mitochondria of cancer cells, to cause cell death through a mitochondrial apoptotic pathway and to inhibit the activity of thioredoxin reductase (TrxR) but not the closely related and Se-free enzyme glutathione reductase.


MADS-box genes active in developing pollen cones of Norway spruce (Picea abies) are homologous to the B-class floral homeotic genes in angiosperms.
The reproductive organs of conifers, the pollen cones and seed cones, differ in morphology from the angiosperm flower in several fundamental respects. In this report we present evidence to suggest that the two plant groups, in spite of these morphological differences and the long evolutionary distance between them, share important features in regulating the development of the reproductive organs. We present the cloning of three genes, DAL11, DAL12, and DAL13, from Norway spruce, all of which are related to the angiosperm B-class of homeotic genes. The B-class genes determine the identities of petals and stamens. They are members of a family of MADS-box genes, which also includes C-class genes that act to determine the identity of carpels and, in concert with B genes specify stamens in the angiosperm flower. Phylogenetic analyses and the presence of B-class specific C-terminal motifs in the DAL protein sequences imply homology to the B-class genes. Specific expression of all three genes in developing pollen cones suggests that the genes are involved in one aspect of B function, the regulation of development of the pollen-bearing organs. The different temporal and spatial expression patterns of the three DAL genes in the developing pollen cones indicate that the genes have attained at least in part distinct functions. The DAL11, DAL12, and 13 expression patterns in the pollen cone partly overlap with that of the previously identified DAL2 gene, which is structurally and functionally related to the angiosperm C-class genes. This result supports the hypothesis that an interaction between B- and C-type genes is required for male organ development in conifers like in the angiosperms. Taken together, our data suggests that central components in the regulatory mechanisms for reproductive organ development are conserved between conifers and angiosperms and, thus, among all seed plants.


Exploration Into the Business Priorities Related to Corporate Engagement in Community Health Improvement Partnerships.
To explore factors that matter to business in making decisions regarding engagement in community health improvement efforts. Using qualitative methods, domains of interest were identified through literature reviews and expert interviews. Relevance of the domains in terms of potential priorities for action was tested through employer and community stakeholder interviews. Factors that employers considered important to sustained community collaboration as a business priority included (1) credibility of the convener, (2) broad representation of the community, (3) strong mission and goals, (4) individual commitment to health, (5) organizational commitment to health, and (6) demonstrated commitment from leadership. Priorities have been identified for engaging business in community health efforts. Implications for research, practice, and policy include the need for measurement, transparency in reporting, and agreement on principles for public-private partnership in this area.


Posterior Fusiform and Midfusiform Contribute to Distinct Stages of Facial Expression Processing.
Though the fusiform is well-established as a key node in the face perception network, its role in facial expression processing remains unclear, due to competing models and discrepant findings. To help resolve this debate, we recorded from 17 subjects with intracranial electrodes implanted in face sensitive patches of the fusiform. Multivariate classification analysis showed that facial expression information is represented in fusiform activity and in the same regions that represent identity, though with a smaller effect size. Examination of the spatiotemporal dynamics revealed a functional distinction between posterior fusiform and midfusiform expression coding, with posterior fusiform showing an early peak of facial expression sensitivity at around 180 ms after subjects viewed a face and midfusiform showing a later and extended peak between 230 and 460 ms. These results support the hypothesis that the fusiform plays a role in facial expression perception and highlight a qualitative functional distinction between processing in posterior fusiform and midfusiform, with each contributing to temporally segregated stages of expression perception.