Phylogeography of hepatitis B virus: The role of Portugal in the early dissemination of HBV worldwide.
In Portugal, the genetic diversity, origin of HBV and the Portuguese role in the dissemination of HBV worldwide were never investigated. In this work, we studied the epidemic history and transmission dynamics of HBV genotypes that are endemic in Portugal. HBV pol gene was sequenced from 130 patients followed in Lisbon. HBV genotype A was the most prevalent (n = 54, 41.5%), followed by D (n = 44, 33.8%), and E (n = 32, 24.6%). Spatio-temporal evolutionary dynamics was reconstructed in BEAST using a Bayesian Markov Chain Monte Carlo method, with a GTR nucleotide substitution model, an uncorrelated lognormal relaxed molecular clock model, a Bayesian skyline plot, and a continuous diffusion model. HBV subgenotype D4 was the first to be introduced in Portugal around 1857 (HPD 95% 1699-1931) followed by D3 and A2 a few decades later. HBV genotype E and subgenotype A1 were introduced in Portugal later, almost simultaneously. Our results indicate a very important role of Portugal in the exportation of subgenotypes D4 and A2 to Brazil and Cape Verde, respectively, in the beginning of the XX century. This work clarifies the epidemiological history of HBV in Portugal and provides new insights in the early and global epidemic history of this virus.


Rod photoreceptor cells dissociated from mature mice retinas.
Intact rod photoreceptors were dissociated from pronase-treated whole retinas of adult mice by repeated passage through a plastic pipette tip. Hemocytometer counts of the cell suspensions indicate that, during a series of ten dissociation steps, a total of about 1-2 million intact photoreceptor cells are dissociated from one adult mouse retina, with less than 5% contamination from Müller cells and neurons of the inner retina. Visual cells with rod outer segments (ROS) and synaptic terminals are released in each step, but they occur in the greatest number during the sixth to ninth steps; detached ROS are released most frequently in the early steps, and neurons of the inner retinal layers appear in the later steps of dissociation. Nuclei are found in each step. Cell intactness was estimated by Trypan blue and Erythrosin B exclusion and by microscopic analysis using differential interference optics or scanning electron microscopy. The cells bind lectins (concanavalin A, Ricinis communis, and wheat germ agglutinin but not peanut agglutinin), displaying surface topography like that observed in situ. The metabolic capacity of dissociated cells was assessed by measuring the utilization of 32P inorganic phosphate for the synthesis of phospholipids and for the light-dependent phosphorylation of rhodopsin. Mature photoreceptor cells were estimated to contain, on average, 6.4 X 10(-12) g DNA, 2.3 X 10(-12) g RNA and 42-64 X 10(-12) g protein. The dissociation procedure provides a population of photoreceptor cells that appears suitable for microscopic, electrophysiological, and biochemical analysis.


Molecular characterization of antimicrobial multi-drug resistance in non-typhoidal Salmonellae from chicken and clam in Mangalore, India.
Salmonella enterica has been documented as one of the leading causes of salmonellosis throughout the world and is most commonly associated with the consumption of contaminated food products. Thus, this research was aimed at studying the antimicrobial susceptibility pattern and detection of quinolone resistance in Salmonella spp isolated from food of animal origin. Thirty-six Salmonella isolates comprising 8 from poultry and 28 from seafood (clams) were identified, serotyped and characterized for their antimicrobial susceptibility against 10 different antibiotics. Plasmid DNA was isolated from all the isolates by alkaline lysis, quinolone resistant non-typhoidal S.Weltevreden were examined for mutation in the DNA gyrase coding gene. Among the 36 Salmonella isolates, 20 were S. weltevreden (8 from poultry and 12 from seafood) and 16 were S.Typhimurium (from seafood). All the isolates showed multiple resistance to nalidixic acid, tetracycline, co-trimoxazole and nitrofurantoin, but, interestingly, the isolates were 100% susceptible to ampicillin, chloramphenicol and gentamicin. Resistant isolates from the study carried the genes responsible for resistance to respective antibiotics. The strain S130 isolated in the study showed single point mutation, Asp87Gly, at position 87 in quinolone resistance determining region. It revealed mutation in quinolone resistance determining region as a cause for quinolone resistance in non-typhoidal Salmonellae. The occurrence of genes accountable for plasmid mediated resistance to quinolones (viz., qnrA, qnrB and qnrS) in plasmid of non-typhoidal Salmonellae isolates provides evidence for plasmid mediated quinolone resistance.


Successful truncated osteomyelitis treatment for chronic osteomyelitis secondary to pressure ulcers in spinal cord injury patients.
Time-tested treatments for chronic osteomyelitis involve prolonged courses of costly antibiotic treatment. Although such treatment remains unquestioned in acute osteomyelitis, it is an excessive regiment for chronic osteomyelitis. With appropriate surgical debridement and careful operative care, antibiotic treatment can be truncated in diagnoses of chronic osteomyelitis. This study represents the clinical practice of the pressure ulcer management program at Rancho Los Amigos National Rehabilitation Center in dealing with this difficult problem. One hundred fifty-seven patients with similar pressure ulcer wounds were studied retrospectively. Three groups of patients with pathologic diagnoses of acute osteomyelitis, chronic osteomyelitis, and negative osteomyelitis were compared for (1) postoperative stay, (2) wound infection, (3) wound breakdown requiring reoperation, and (4) same-site ulcer recurrence. In all cases, shallow bone shavings were sent for diagnosis via histologic study, and deep shavings were also sent to ensure adequate bone debridement and microbiologic study. All ulcers were subsequently closed with muscle and/or myocutaneous flaps. The negative and chronic osteomyelitis groups were treated with 5 to 7 days of IV antibiotics, whereas the acute group underwent a full 6-week course according to bone bacteriological culture and sensitivity. There was no statistical difference between the chronic osteomyelitis group and the control (negative) osteomyelitis group with respect to postoperative stay (70 days for chronic group, 72.4 for control), wound breakdown rate (10.7% for chronic, 10.2% for control), or ulcer recurrence (1.8% for chronic, 4.1 for control). The acute osteomyelitis group incurred longer hospital stays, greater incidence of wound breakdown, and statistically significantly greater ulcer recurrence (78.6 days, 13.2% and 17.0%, respectively). In cases of pressure ulcer management with bony involvement, bone pathologic diagnosis of chronic osteomyelitis allows for a shorter antibiotic course with better results when the offending tissue has been adequately debrided and closed with viable tissue flap coverage, than simple long-term (4-6 weeks) antibiotic treatment. Because of the extreme contaminated nature of these wounds, if such therapy works in these patients, it may be applicable to chronic osteomyelitis in more varied contaminated surgical cases involving bone.


Stability of physiological variables in chronic tinnitus sufferers.
The etiological tinnitus models propose that suffering can be caused and aggravated by heightened physiological arousal. Therefore psychophysiological treatments are applied. Stability of the measured parameters is essential for the use of biofeedback as well as to permit the attribution of changes to the administered treatment. The aim of our study was to investigate the 3-month reproducibility of psychophysiological parameters in 60 tinnitus patients. Using a repeated-measures design, the activity of these parameters was assessed twice during various stress and relaxation trials. The results showed that the measurements of frontalis, masseter and trapezius muscles were stable, while for the sternocleidomastoid, the skin conductance level (SCL) and the skin temperature retest-stability could not be evidenced. For all parameters, test-retest stability was weak for the relative scores. In conclusion, our study has important implications for applied psychophysiology research: (1) the measurement of EMG assessed in a clinical sample is stable over a 3-month interval; (2) in contrast, the measurements of SCL and skin temperature as well as all relative scores are less stable; and (3) the stability of EMG-parameters in our sample gives first hints that physiological changes can be attributed to an administered biofeedback treatment but further research is required.


Prognostic Significance of Ambulatory BP Monitoring in CKD: A Report from the Chronic Renal Insufficiency Cohort (CRIC) Study.
Whether ambulatory BP monitoring is of value in evaluating risk for outcomes in patients with CKD is not clear. We followed 1502 participants of the Chronic Renal Insufficiency Cohort (CRIC) Study for a mean of 6.72 years. We evaluated, as exposures, ambulatory BP monitoring profiles (masked uncontrolled hypertension, white-coat effect, sustained hypertension, and controlled BP), mean ambulatory BP monitoring and clinic BPs, and diurnal variation in BP-reverse dipper (higher at nighttime), nondipper, and dipper (lower at nighttime). Outcomes included cardiovascular disease (a composite of myocardial infarction, cerebrovascular accident, heart failure, and peripheral arterial disease), kidney disease (a composite of ESKD or halving of the eGFR), and mortality. Compared with having controlled BP, the presence of masked uncontrolled hypertension independently associated with higher risk of the cardiovascular outcome and the kidney outcome, but not with all-cause mortality. Higher mean 24-hour systolic BP associated with higher risk of cardiovascular outcome, kidney outcome, and mortality, independent of clinic BP. Participants with the reverse-dipper profile of diurnal BP variation were at higher risk of the kidney outcome. In this cohort of participants with CKD, BP metrics derived from ambulatory BP monitoring are associated with cardiovascular outcomes, kidney outcomes, and mortality, independent of clinic BP. Masked uncontrolled hypertension and mean 24-hour BP associated with high risk of cardiovascular disease and progression of kidney disease. Alterations of diurnal variation in BP are associated with high risk of progression of kidney disease, stroke, and peripheral arterial disease. These data support the wider use of ambulatory BP monitoring in the evaluation of hypertension in patients with CKD. This article contains a podcast at https://www.asn-online.org/media/podcast/JASN/2020_09_24_JASN2020030236.mp3.


Reasons providers form PHOs.
According to a recent survey, providers form physician-hospital organizations (PHOs) to improve their contracting positions with managed care organizations, to facilitate collaborative efforts with physicians, and to enhance their abilities to accept and manage capitation. The survey also revealed that PHOs are still in their infancy and operate amid regulatory uncertainty as they develop the expertise and infrastructure necessary to successfully compete in a managed care environment.


Examining the Conditions Under Which Internalized Homophobia Is Associated with Substance Use and Condomless Sex in Young MSM: the Moderating Role of Impulsivity.
Internalized homophobia (IH) is the internalization of homophobic attitudes by sexual minorities due to social bias. IH has been inconsistently related to substance use and condomless sex for young men who have sex with men (YMSM). We examined negative urgency (the tendency to act impulsively in response to negative emotional experiences), positive urgency (the tendency to act impulsively in response to positive emotional experiences), and sensation seeking as independent moderators of the association of IH with binge drinking, drug use, and condomless anal sex. Data were collected from 450 YMSM (mean age = 18.9) over the course of 18 months (baseline, 6-, 12-, and 18-month follow-up). Hierarchical generalized linear modeling revealed that there was a significant moderation for binge drinking and receptive condomless anal sex, with the association between IH and these risk behaviors increased for those with higher levels of negative urgency and positive urgency. IH is important to the negative health outcomes of binge drinking and condomless anal sex for individuals high in negative and/or positive urgency, who may act impulsively to avoid subjective negative experiences or in the face of positive emotional experiences. Future research is needed to further establish additional conditions under which IH may be important to understanding risk behaviors in YMSM, which is essential to developing targeted prevention and intervention efforts.


Enabling perfusion through multicellular tumor spheroids promoting lumenization in a vascularized cancer model.
A tumor is composed of heterogeneous cell population, which is known as tumor stroma. In particular, blood vessels have an indispensable role in the tumor microenvironment acting as a key player in anti-cancer drug delivery. Recently, efforts have been made to accurately recapitulate the microenvironment by employing distinct cell types, however, the proper formation of perfusable tumor tissue is challenging. Here, perfusable tumor tissue is engineered by implanting multicellular tumor spheroids inside the microfluidic devices. Blood perfusion, spheroid growth, and vascular dynamics were monitored according to the spheroid composition and the contribution of internal and external vascular cells to spheroid perfusion was analyzed. Most notably, the increased penetration depth of fluorescence conjugated anti-cancer drug was observed in tri-culture spheroids. The implementation of tumor microenvironment reconstruction developed in this study not only creates a perfusable tumor vascular model but can also be utilized as a novel drug screening platform with patient-derived samples.


Experimental investigation of beam heating in a soft X-ray scanning transmission X-ray microscope.
A variable temperature sample holder with an operational range of 15 to 200 °C and an accuracy of ±1 °C has been fabricated for scanning transmission X-ray microscopes (STXM). Here we describe the device, and use it to image the polycrystalline morphology of solid stearic acid and palmitic acid at temperatures near their respective melting points as a means of checking for possible sample heating caused by the focused X-ray beam. The melting points observed in STXM were identical to those observed by conventional methods within measurement uncertainty, even under the most extreme, high dose rate imaging conditions investigated. The beam-induced temperature rise in the sample is inferred to be below 1 °C for dose rates of up to 2.7 GGy/s.


Impact of gene patents and licensing practices on access to genetic testing for inherited susceptibility to cancer: comparing breast and ovarian cancers with colon cancers.
Genetic testing for inherited susceptibility to breast and ovarian cancer can be compared with similar testing for colorectal cancer as a "natural experiment." Inherited susceptibility accounts for a similar fraction of both cancers and genetic testing results guide decisions about options for prophylactic surgery in both sets of conditions. One major difference is that in the United States, Myriad Genetics is the sole provider of genetic testing, because it has sole control of relevant patents for BRCA1 and BRCA2 genes, whereas genetic testing for familial colorectal cancer is available from multiple laboratories. Colorectal cancer-associated genes are also patented, but they have been nonexclusively licensed. Prices for BRCA1 and 2 testing do not reflect an obvious price premium attributable to exclusive patent rights compared with colorectal cancer testing, and indeed, Myriad's per unit costs are somewhat lower for BRCA1/2 testing than testing for colorectal cancer susceptibility. Myriad has not enforced patents against basic research and negotiated a Memorandum of Understanding with the National Cancer Institute in 1999 for institutional BRCA testing in clinical research. The main impact of patenting and licensing in BRCA compared with colorectal cancer is the business model of genetic testing, with a sole provider for BRCA and multiple laboratories for colorectal cancer genetic testing. Myriad's sole-provider model has not worked in jurisdictions outside the United States, largely because of differences in breadth of patent protection, responses of government health services, and difficulty in patent enforcement.


LuxS-mediated signaling in Streptococcus mutans is involved in regulation of acid and oxidative stress tolerance and biofilm formation.
LuxS-mediated quorum sensing has recently been shown to regulate important physiologic functions and virulence in a variety of bacteria. In this study, the role of luxS of Streptococcus mutans in the regulation of traits crucial to pathogenesis was investigated. Reporter gene fusions showed that inactivation of luxS resulted in a down-regulation of fructanase, a demonstrated virulence determinant, by more than 50%. The LuxS-deficient strain (TW26) showed increased sensitivity to acid killing but could still undergo acid adaptation. Northern hybridization revealed that the expression of RecA, SmnA (AP endonuclease), and Nth (endonuclease) were down-regulated in TW26, especially in early-exponential-phase cells. Other down-regulated genes included ffh (a signal recognition particle subunit) and brpA (biofilm regulatory protein A). Interestingly, the luxS mutant showed an increase in survival rate in the presence of hydrogen peroxide (58.8 mM). The luxS mutant formed less biofilm on hydroxylapatite disks, especially when grown in biofilm medium with sucrose, and the mutant biofilms appeared loose and hive-like, whereas the biofilms of the wild type were smooth and confluent. The mutant phenotypes were complemented by exposure to supernatants from wild-type cultures. Two loci, smu486 and smu487, were identified and predicted to encode a histidine kinase and a response regulator. The phenotypes of the smu486 smu487 mutant were, in almost all cases, similar to those of the luxS mutant, although our results suggest that this is not due to AI-2 signal transduction via Smu486 and Smu487. This study demonstrates that luxS-dependent signaling plays critical roles in modulating key virulence properties of S. mutans.


Oromandibular reconstruction using microvascular composite flaps: report of 210 cases.
To review the experience of 1 microvascular surgeon during an 11-year period in performing 210 vascularized bone-containing free flaps for oromandibular reconstruction. Retrospective medical records review of patients who underwent primary and secondary oromandibular reconstruction with the use of vascularized bone free flaps. Academic medical center. A total of 201 patients underwent 210 composite free-flap reconstructions of the mandible for various disorders and with a range of bony and soft tissue defects. All patients underwent the microvascular transfer of vascularized bone flaps from the ilium, fibula, or scapula. In selected cases, 2 simultaneous free flaps were transferred to achieve an optimal bone and soft tissue reconstruction. Endosteal dental implants were used in 81 patients, with a total of 360 fixtures placed during these 11 years. The success of microvascular free tissue transfer, dental implant extrusion, and short- and long-term complications at the recipient and donor sites. Of the 210 mandibular reconstructions that were performed, 202 were successful in reestablishing mandibular continuity. Reexploration for vascular-related complications was done in 16 patients, 8 of whom were successfully treated, yielding an overall success rate of 96%. The overall success rate for endosteal dental implants was 92%. The implant success rate was 86% when the bone in which the fixtures were placed was irradiated postoperatively. The success rate was 64% in the 14 fixtures that were placed into previously irradiated bone. The success of the use of vascularized bone free flaps in restoring continuity to the mandible is clearly demonstrated in this series. There was an acceptable incidence of donor- and recipient-site complications that resulted in minimal long-term morbidity. The careful selection of a donor site(s) for oromandibular reconstruction allows for an optimal restoration of bony and soft tissue defects. Dental implants can be safely used in oromandibular reconstruction with a high level of success. Placing these implants during the initial surgery shortens the duration for achieving dental rehabilitation and enhances the success of the implants when postoperative radiotherapy is administered.


Cigarette smoking and risk of uterine myoma: systematic review and meta-analysis.
To review the literature on the relationship between smoking and the risk of uterine myoma, we conducted a systematic review and a meta-analysis of published studies. In this meta-analysis, we included all identified studies of association between smoking and uterine myoma where these were case-control or cohort studies, reporting original data, ultrasound or histological confirmed diagnosis of myomas and information on the association between tobacco smoking and myomas. We carried out a literature search on MEDLINE/EMBASE of all studies published as original articles in English up to October 2015, using the Medical Subject Heading terms and free search terms about myoma and smoking. We selected only studies published in English. Moreover, bibliographies of the retrieved papers were reviewed, to identify any other relevant publication. A total of 14 different studies were eligible for a qualitative synthesis and data extract from 10 studies were combined in a meta-analysis. The summary OR of former compared to never smokers was 0.93 (0.88-0.99) with no heterogeneity. The summary OR of current smokers compared to never smokers, was 0.83 (0.65-1.04), even if the subtotal OR in cohort studies was 0.85 (0.73-0.98) with no heterogeneity. When sensitivity analysis was performed the summary OR was 0.83 (0.71-0.97). The primary meta-analyses found no significant effect of smoking on risk of uterine myoma. Subgroup analysis for study design showed a small risk reduction for current and former smokers in cohort studies. A sensitivity analysis showed an inverse association between ever smoking and uterine myoma. However, given the limited number of studies in each sub-analysis, weak associations and the absence of a dose dependent effect, caution should be paid in the interpretation of these findings and further investigation are needed.


Does it matter who owns health facilities?
The rhetoric of governments 'steering not rowing' and of purchaser-provider splits is still part of the language of public sector reform throughout the world, despite some retreat in the National Health Service in the UK. Implementation of separation of purchaser and provider roles has often been associated with suggestions that the private sector is better able to manage hospitals. The evidence for this assertion is mixed, especially when possible quality differences are also considered. This essay suggests that the ownership question is a second-order issue and that policy-makers should ensure that existing public hospitals are funded in a way that encourages efficiency.


Immunogenicity of "single component" port insulin.
Twelve diabetic subjects who were not previously treated with insulin were divided into two groups of six each. Group I was treated with single component pork insulin and Group II was treated with standard (USP) insulin for 5 to 10 months. Three out of six in Group I, and five in Group II, developed circulating insulin antibodies. Daily insulin requirement in the two groups were almost the same. Insulin antibody titer did not fall in three insulin-treated diabetic subjects when single component pork insulin was substituted for USP beef-pork insulin. This study shows that the single component insulin is antigenic in human subjects.


Arm/hand swelling and perceived functioning among breast cancer survivors 12 years post-diagnosis: CALGB 79804.
Lymphedema is an under-reported and debilitating consequence of axillary node dissection among breast cancer survivors. This study describes the characteristics of arm and hand swelling in relation to perceived physical and mental health functioning among breast cancer survivors 9-16 years post-diagnosis who previously participated in a clinical trial coordinated by the Cancer and Leukemia Group B (CALGB 8541). Eligible survivors of CALGB 8541 completed questionnaires assessing demographics, arm/hand swelling, perceived physical functioning, and mental health. Two hundred forty-five women (94% white, mean age = 63, on average 12.4 years post-diagnosis) completed questionnaires (participation rate = 78%). Seventy-five women (31%) reported arm/hand swelling since their surgery. Of these women, 76% reported current swelling and half reported constant swelling, mainly in the upper arm. Swelling was reported as mild or moderate in 88% of the women. Women who reported severe swelling had significantly worse physical functioning and trended toward worse depressive symptoms and poorer mental health (lower mental SF-36 scores) as well. Activity-limiting swelling was also significantly associated with worse physical functioning. Although swelling interfered with wearing clothing (36%) and perceptions about general appearance (32%), only 37% of women sought treatment for swelling. Arm/hand swelling is a chronic problem for a subgroup of long-term survivors of breast cancer, negatively affecting physical functioning. Educational efforts are needed as part of a comprehensive survivorship care plan to raise awareness about lymphedema so that survivors may identify this complication, seek treatment early, and potentially improve their physical functioning.


[Thyroid cancer in childhood (author's transl)].
The authors present three cases of thyroid cancer in the child with comments on the etiologic, clinical and therapeutic aspects of this rare disease. The authors insist on the danger of local radiotherapy and on the need to suspect thyroid cancer in cases of persistent laterocervical adenopathies whose diagnosis can only be confirmed by means of a biopsy. It is of note that the illness took a favourable course and various therapeutic criteria are discussed.


Independence of the pituitary-interrenal axis and melanotroph activity in the brown trout, Salmo trutta L., under conditions of environmental stress.
Adaptation of brown trout to a black or white background had no statistically significant influence on the activity of the pituitary-interrenal axis in unstressed fish, in fish under conditions of mild chronic stress, or in fish under conditions of severe, acute stress. This finding is in contrast to several other studies on salmonid fish in which background color adaptation has been shown to modulate the pituitary-interrenal response to environmental stress. It is argued that these differences in results may be related to the prior history of interrenal activation in the experimental fish and that in previously unstressed brown trout the activity of the pituitary-interrenal axis is independent of melanotroph activity in the pars intermedia when fish are exposed to subsequent stress.


Effects of insulin, glucocorticoids and adrenaline on the activity of rat adipose-tissue lipoprotein lipids.
The lipoprotein lipase activity of epididymal fat-bodies from starved rats was measured during incubations at 37 degrees C in vitro. Protein synthesis independent activation of the enzyme, previously observed during incubations at 25 decrease C, also occurs at 37 degrees C. Protein-synthesis-dependent increases in the activity of the enzyme occur in the presence of insulin and are markedly potentiated by glucocorticoids. The effects on the activity of the enzyme of insulin alone, or in the presence of glucocorticoids, are correlated with its effects on total protein synthesis in the tissue. Adrenaline antagonizes the increase in activity of the enzyme brought about by insulin and abolishes the potentiation of insulin action by glucocorticoids. These changes may be due, at least in part, to its stimulation of inactivation of the enzyme in the tissue. It is suggested that changes in adipose-tissue lipoprotein lipase activity that occur with changes in nutritional status in vivo result from the combined effects of changes in plasma insulin and glucocorticoid concentrations.


Isolation of a Lewis base stabilized parent phosphenium (PH2(+)) and related species.
The parent phosphenium ion (PH2(+)), and even any phosphenium salts bearing a hydrogen (HRP(+)), have never been observed. The addition of trifluoromethanesulfonic acid and carbon electrophiles to an NHC-PH adduct, featuring a very bulky NHC, allows for the preparation and isolation of such compounds. Computational investigations show that most of the positive charge is localized at phosphorus, demonstrating the phosphenium nature of this compound. Further, the PH moiety is able to utilize one or both of its lone pairs to bind to one or two metals.


Minnesota Multiphasic Personality Inventory-2-Restructured Form markers of future suicidal behavior in a forensic psychiatric hospital.
Past research indicates a need to integrate objective psychological testing with clinical interview data during suicide risk assessment. The current study evaluated the utility of the Minnesota Multiphasic Personality Inventory (MMPI)-2 Restructured Form (MMPI-2-RF) in the prediction of future suicidal behaviors in a sample of 1,110 forensic inpatients (807 males, 303 females). Results indicated that scales from all substantive domains of the MMPI-2-RF were significantly positively associated with future suicidal behaviors. Consistent with expectations, the best predictors were scale scores from the internalizing and externalizing domains of the inventory. Relative Risk Ratios indicated that individuals producing elevations on these scales were at 2 to 4 times greater risk of future suicidal behaviors compared with those who did not produce elevations. Implications of these findings and limitations of this study are discussed. (PsycINFO Database Record


A three-dimensional atlas of child's cardiac anatomy and the unique morphological alterations associated with obesity.
Statistical shape models (SSMs) of cardiac anatomy provide a new approach for analysis of cardiac anatomy. In adults, specific cardiac morphologies associate with cardiovascular risk factors and early disease stages. However, the relationships between morphology and risk factors in children remain unknown. We propose an SSM of the paediatric left ventricle to describe its morphological variability, examine its relationship with biometric parameters and identify adverse anatomical remodelling associated with obesity. This cohort includes 2631 children (age 10.2 ± 0.6 years), mostly Western European (68.3%) with a balanced sex distribution (51.3% girls) from Generation R study. Cardiac magnetic resonance short-axis cine scans were segmented. Three-dimensional left ventricular (LV) meshes are automatically fitted to the segmentations to reconstruct the anatomies. We analyse the relationships between the LV anatomical features and participants' body surface area (BSA), age, and sex, and search for features uniquely related to obesity based on body mass index (BMI). In the SSM, 19 modes described over 90% of the population's LV shape variability. Main modes of variation were related to cardiac size, sphericity, and apical tilting. BSA, age, and sex were mostly correlated with modes describing LV size and sphericity. The modes correlated uniquely with BMI suggested that obese children present with septo-lateral tilting (R2 = 4.0%), compression in the antero-posterior direction (R2 = 3.3%), and decreased eccentricity (R2 = 2.0%). We describe the variability of the paediatric heart morphology and identify anatomical features related to childhood obesity that could aid in risk stratification. Web service is released to provide access to the new shape parameters.


TREM-1 promoted apoptosis and inhibited autophagy in LPS-treated HK-2 cells through the NF-κB pathway.
Triggering receptor expressed by myeloid cells (TREM-1) is an amplifier of inflammatory responses triggered by bacterial or fungal infection. Soluble TREM-1 (sTREM-1) expression was found to be upregulated in sepsis-associated acute kidney injury (SA-AKI) and predicted to be a potential biomarker. However, the mechanism remains unclear. The human kidney-2 (HK-2) cell line was treated with lipopolysaccharide (LPS) and used to examine the potential roles of TREM-1 in apoptosis and autophagy. A cell viability assay was employed to assess the number of viable cells and as a measure of the proliferative index. The concentrations of sTREM-1, interleukin (IL)-1β, tumor necrosis factor-α (TNFα) and IL-6 in cell-free culture supernatants were measured by enzyme-linked immunosorbent assay (ELISA). Western blot analysis was performed to analyze apoptosis, autophagy and the relevant signaling pathways. The results suggested that TREM-1 overexpression after LPS treatment decreased proliferation and increased apoptosis. The concentrations of sTREM-1, IL-1β, TNFα and IL-6 in cell-free culture supernatants were increased in the TREM-1 overexpression group after LPS treatment. Expression of the antiapoptotic gene Bcl-2 was downregulated in the TREM-1 overexpression group, while that of the proapoptotic genes Bax, cleaved caspase-3 and cleaved caspase-9 was upregulated. Overexpression of TREM-1 downregulated expression of the autophagy genes Beclin-1, Atg-5 and LC3b and increased the gene expression of p62, which inhibits autophagy. Conversely, treatment with TREM-1-specific shRNA had the opposite effects. The nuclear factor-κB (NF-κB) signaling pathway (P-p65/p65 and P-IκBα/IκBα) in LPS-induced HK-2 cells was regulated by TREM-1. In summary, TREM-1 promoted apoptosis and inhibited autophagy in HK-2 cells in the context of LPS exposure potentially through the NF-κB pathway.


Breast cancer progression when definitive surgery is delayed.
Deferment of definitive surgery for some breast cancers has been proposed as a way to conserve hospital resources during the COVID-19 pandemic. However, it is currently unknown which, if any, breast cancers are capable of progressing during a few to several months of observation. The difference between clinical size at diagnosis and final pathology size was assessed in 315 stage I-III primary invasive breast cancer patients who were divided into three groups based on the time between diagnosis and definitive surgery. Size differences over time were used to estimate specific growth rates. Compared with the group with ≤60 days between diagnosis and surgery, tumor growth was observed for 12% of tumors in the 61- to 120-day group and 17% of tumors in the >120-day group (p for trend = 0.032). Significantly greater specific growth rates were observed for tumors >2 cm by pathology measurement and for pathology node-positive patients (p < 0.0001 and p = 0.006, respectively). Specific growth rates were significantly greater for luminal B breast cancers than for luminal A breast cancers (p = 0.029) but not for triple-negative or HER2-positive breast cancers not selected for neo-adjuvant chemotherapy. There was no evidence of nodal progression with surgery delay. Fewer than 20% of stage I-III breast cancers not selected for neo-adjuvant chemotherapy evidence size progression during follow-up periods ranging from 61 to 294 days. Clinical-pathological features cannot reliably predict which tumors will grow. Luminal B phenotype was the only clinical variable known at the time of diagnosis that strongly predicted growth. If resource limitations mandate prioritization schemes for breast cancer surgery, luminal B breast cancer may be the highest priority.


Antioxidant activity and free radical-scavenging capacity of a selection of wild-growing Colombian plants.
The replacement of some synthetic food antioxidants by safe natural antioxidants has fostered research on the screening of raw materials to find new vegetable sources of antioxidants. In this study the antioxidant activity of eight wild-growing Colombian plants was assessed by four complementary assays. An evaluation of the antioxidant activity of ten ethanolic extracts from Baccharis chilco, Cinnamomum triplinerve, Ilex laurina, Lachemilla orbiculata, Lepechinia conferta, Quercus humboldtii, Rubus urticifolius and Tephrosia cinerea was carried out. Furthermore, the total phenolic content was determined by the Folin-Ciocalteu method, and the relationship between phenolic content and activity was also statistically investigated. Cinnamomum triplinerve, L. conferta and I. laurina were found to have the highest phenolic contents. Baccharis chilco, C. triplinerve, I. laurina, L. conferta, Q. humboldtii and R. urticifolius showed higher radical-scavenging activity (DPPH and superoxide assays) than commercial rosemary oleoresin (reference). Lachemilla orbiculata and R. urticifolius showed higher antioxidant activity (β-carotene-bleaching test) than the reference. The protection factor of all studied plant extracts was below that of the reference according to the Rancimat test. On the basis of the results obtained, C. triplinerve, Q. humboldtii and R. urticifolius seem to be the most promising species for further investigation in order to identify the compounds responsible for their activity.


Alloxan reversibly impairs glucagon release and glucose oxidation by pancreatic A2-cells.
Alloxan is known as a selective B-cell cytotoxic substance, and there is so far little evidence for a direct toxic effect on the other islet cell types. To elucidate further whether such effects occur, the actions of alloxan on glucagon release and glucose oxidation were studied in isolated normal or A(2)-cell-rich pancreatic islets of the guinea pig. The A(2)-cell-rich islets were obtained from animals injected with streptozotocin 1-2 weeks before islet isolation. After exposure to alloxan (2 or 5mm) in vitro for 30min at 4 degrees C, the islets were incubated in media containing either 1.7mm-glucose or 16.7mm-glucose plus 30m-i.u. of bovine insulin/ml. In both types of islet, alloxan abolished the ability of glucose and insulin both to decrease glucagon release and to increase the rate of glucose oxidation. A high concentration of glucose (28mm) during exposure to alloxan protected against these injurious effects. Tissue culture of alloxan-treated islets for 24h in 5.5mm-glucose restored neither the suppressive effect of glucose on glucagon release nor the inhibition of glucose oxidation of the A(2)-cells. However, culture for 1 week completely normalized both the glucagon-secretory response and glucose oxidation by both kinds of islets. It is therefore concluded that alloxan affects the secretory mechanism of not only the B-cell but also of the islet A(2)-cell, although this latter cell type is not primarily destroyed by the drug. The data furthermore support the concept of a relationship between glucose metabolism and the glucose-mediated glucagon release of the A(2)-cell.


ACVIM small animal consensus statement on safe use of cytotoxic chemotherapeutics in veterinary practice.
The purpose of this report is to offer a consensus opinion of ACVIM oncology diplomates and technicians on the safe use of cytotoxic chemotherapeutics in veterinary practice. The focus is on minimizing harm to the personnel exposed to the drugs: veterinary practitioners, veterinary technicians, veterinary staff, and pet owners. The safety of the patient receiving these drugs is also of paramount importance, but is not addressed in this statement. Much of the information presented is based on national recommendations by Occupational Safety and Health Administration, National Institute for Occupational Safety and Health, United States Pharmacopeia, and other published regulations. These directives reflect an abundance of caution to minimize exposure to medical personnel, but large-scale studies about the consequences of long-term occupational exposure are not available in veterinary medicine. Challenges in the delivery of optimal treatment safely and economically to veterinary patients in general practice without access to a veterinary oncologist or other specialist, because of costs or proximity, remain.


RNA interference: biology, mechanism, and applications.
Double-stranded RNA-mediated interference (RNAi) is a simple and rapid method of silencing gene expression in a range of organisms. The silencing of a gene is a consequence of degradation of RNA into short RNAs that activate ribonucleases to target homologous mRNA. The resulting phenotypes either are identical to those of genetic null mutants or resemble an allelic series of mutants. Specific gene silencing has been shown to be related to two ancient processes, cosuppression in plants and quelling in fungi, and has also been associated with regulatory processes such as transposon silencing, antiviral defense mechanisms, gene regulation, and chromosomal modification. Extensive genetic and biochemical analysis revealed a two-step mechanism of RNAi-induced gene silencing. The first step involves degradation of dsRNA into small interfering RNAs (siRNAs), 21 to 25 nucleotides long, by an RNase III-like activity. In the second step, the siRNAs join an RNase complex, RISC (RNA-induced silencing complex), which acts on the cognate mRNA and degrades it. Several key components such as Dicer, RNA-dependent RNA polymerase, helicases, and dsRNA endonucleases have been identified in different organisms for their roles in RNAi. Some of these components also control the development of many organisms by processing many noncoding RNAs, called micro-RNAs. The biogenesis and function of micro-RNAs resemble RNAi activities to a large extent. Recent studies indicate that in the context of RNAi, the genome also undergoes alterations in the form of DNA methylation, heterochromatin formation, and programmed DNA elimination. As a result of these changes, the silencing effect of gene functions is exercised as tightly as possible. Because of its exquisite specificity and efficiency, RNAi is being considered as an important tool not only for functional genomics, but also for gene-specific therapeutic activities that target the mRNAs of disease-related genes.


Meta-analysis of studies of lung cancer among silicotics.
The relation between exposure to crystalline silica and lung cancer has been a controversial topic, and findings have appeared inconsistent. In this paper, we focus on lung cancer risks in epidemiologic studies of silicotics. We abstracted data from 29 studies for quantitative evaluation. We identified several studies that suffered from biases due to competing risks of different causes of death--in particular, death due to silicosis itself. After adjustment for competing risks, all 29 studies demonstrated lung cancer relative risk (RR) estimates greater than one. The pooled RR estimate for the 23 studies that could be combined was 2.2, with a 95% confidence-interval (CI) of 2.1-2.4. The pooled estimates by study design were 2.0 (95% CI = 1.8-2.3) for cohort studies and 2.5 (95% CI = 1.8-3.3) for case-control studies. The proportional mortality studies combined gave a summary RR of 2.0 (95% CI = 1.7-2.4), whereas the studies of cancer incidence gave a summary RR of 2.7 (95% CI = 2.3-3.2). Although statistical tests demonstrated heterogeneity between studies, and the confidence intervals given above may therefore be a little too narrow, the overall findings could not be attributed to chance, confounding by smoking, or other sources of bias. We conclude that the association between silicosis and lung cancer is causal, either due to silicosis itself, or due to a direct effect of the underlying exposure to silica.


The simple in vitro thrombogenic test: modified methods for same priming pumps.
The improvement of antithrombogenicity is one of the major objectives for the development of blood pumps. Previously we reported that an in vitro thrombogenic test was useful as a pilot study, especially to predict thrombogenic areas. In this study we modified the method for testing pumps with identical priming volumes by eliminating the blood reservoir. Identical compact mock loops (priming volume of 53 ml, without pump) were constructed and tested with the same priming volume of Nikkiso centrifugal pumps, noncoated verus heparin-coated. Two pumps were run simultaneously using the same source of fresh heparinized human blood (activated clotting time [ACT] 150-250 s) for 4 or 6 h. Results indicated that the heparin-coated pump had a longer thrombus free period than the noncoated one. The thrombi location and forms were consistently in the same places the in vivo study had identified. It is suggested that this modified in vitro thrombogenic test is a feasible pilot study, as well as the one previously reported. The minimal priming volume will allow evaluation of multiple pumps simultaneously with the same source blood.


Dose quality assurance for stereotactic radiotherapy treatments.
A simple Perspex phantom is presented for routine dosimetry checks of stereotactic radiotherapy procedures, along with a procedure for checking the planning process. The phantom is hemispherical and water filled. It can be fitted into the Brown-Robert-Wells fiducial system for CT scanning and attached to the stereotactic frame for treatment. Both arcing and fixed field plans can be carried out on the phantom. We present our results, performed on a Varian 600C linac, which were found to be within 2% of the expected dose.


Resting frontal brain asymmetry is linked to future depressive symptoms in women.
This longitudinal pilot study examined whether baseline resting frontal electroencephalographic (EEG) asymmetry correlates with depressive symptoms during the most impaired two-week period in the following year. Current-source-density (CSD) transformed resting frontal EEG asymmetry, severity of depression symptoms (Beck Depression Inventory - II), and stress (indexed by negative life events; NLE) were recorded in never-depressed young adults with no current DSM-IV diagnosis (38 women, 16 men) at baseline. One year later, depression symptoms and NLEs experienced during the interim were assessed. Individuals who reported greater interim NLEs also endorsed interim higher depression symptoms, a pattern that replicated when first accounting for baseline stress and depression. For women, higher depression reported at follow-up was linked to lower left than right frontal EEG activity at baseline, a pattern that replicated when first accounting for depressive symptoms at baseline. Despite the modest sample size of the present analysis, findings are consistent with prior reports of sex differences in patterns of brain laterality and support the idea that CSD-referenced EEG asymmetry may be a risk marker for future depression in previously healthy young women.


[A remote access system for inquiry of centrally stored data on patients suspected of malignant hyperthermia . A prototypical development for the Internet].
Malignant hyperthermia (MH) is an inherited, potentially life-threatening syndrome of the skeletal muscles. It is a life-threatening complication of anaesthesia with a high mortality (8-10%). The risk of the patient during anaesthesia due to an overlooked predisposition for MH can be reduced by organisational measures, such as, all data of MH-susceptible patients and their families known in Germany must be brought together in a central register, MH-relevant data of patients must be readily retrievable, optional oral advice for those making an inquiry must be available. To achieve this goal, a client-server system has been implemented: Standard Multimedia personal computers installed at the user's (anaesthetist's) site, linked to the Internet, will act as clients. On a server, relevant data of patients concerning MH-susceptibility are integrated in a central database. The newly developed software of this project ensures the legally prescribed data security on the server and the data routes. At the client's site, standard software together with automatically installed programmes from the server using Java applets ensure easy use and maintenance. The total system was implemented and tested. Its functionality and high availability was demonstrated during this test period. Relevant aspects of data security were successfully examined by the data security officer of the University Hospitals of Baden-Württemberg. The user can optionally call a multifunctional teleconference which secures on-line advice if needed. This system demonstrates a safe and quick retrieval of MH relevant data of patients via Internet while at the same time guaranteeing all aspects of data protection and security. A prototypical database access system is described. It ensures safe access to patient data via Internet, while guaranteeing all aspects of data security.


Whole-brain multimodal MRI phenotyping of periventricular nodular heterotopia.
To test the hypothesis that in periventricular nodular heterotopia (PVNH) structure and function of cortical areas overlying the heterotopic gray matter are preferentially affected. We studied a group of 40 patients with PVNH and normal-appearing cortex and compared their quantitative MRI markers of brain development, structure, and function to those of 43 age- and sex-matched healthy controls. Inspired by models of neocortical development suggesting that neuronal migration follows a curvilinear path to preserve topologic correspondence between the outer ventricular zone and the cortical surface, we computationally defined the overlying cortex using the Laplace equation and generated synthetic streamlines that link the ventricles, where nodules are located, and the neocortex. We found multilobar cortical thickening encompassing prefrontal, latero-basal temporal, and temporoparietal cortices largely corresponding with the PVNH group-averaged map of the overlying cortex, the latter colocalized with areas of abnormal function, as defined by resting-state fMRI. Patients also presented hippocampal functional hyperconnectivity and malrotation, the latter positively correlating with neocortical maldevelopment indexed by increased folding complexity of the parahippocampus. In clusters of thickness and curvature findings, there were no significant differences between unilateral and bilateral PVNH; contrasting brain-wide metrics between cohorts was also unrevealing. There was no relationship between imaging markers and disease duration except for positive correlation with functional anomalies. Our quantitative image analysis demonstrates widespread structural and functional alterations in PVNH with differential interaction with the overlying cortex and the hippocampus. Right hemispheric predominance may be explained by an early insult, likely genetically determined, on brain morphogenesis.


Brain pharmacology of intrathecal antisense oligonucleotides revealed through multimodal imaging.
Intrathecal (IT) delivery and pharmacology of antisense oligonucleotides (ASOs) for the CNS have been successfully developed to treat spinal muscular atrophy. However, ASO pharmacokinetic (PK) and pharmacodynamic (PD) properties remain poorly understood in the IT compartment. We applied multimodal imaging techniques to elucidate the IT PK and PD of unlabeled, radioactively labeled, or fluorescently labeled ASOs targeting ubiquitously expressed or neuron-specific RNAs. Following lumbar IT bolus injection in rats, all ASOs spread rostrally along the neuraxis, adhered to meninges, and were partially cleared to peripheral lymph nodes and kidneys. Rapid association with the pia and arterial walls preceded passage of ASOs across the glia limitans, along arterial intramural basement membranes, and along white-matter axonal bundles. Several neuronal and glial cell types accumulated ASOs over time, with evidence of probable glial accumulation preceding neuronal uptake. IT doses of anti-GluR1 and anti-Gabra1 ASOs markedly reduced the mRNA and protein levels of their respective neurotransmitter receptor protein targets by 2 weeks and anti-Gabra1 ASOs also reduced binding of the GABAA receptor PET ligand 18F-flumazenil in the brain over 4 weeks. Our multimodal imaging approaches elucidate multiple transport routes underlying the CNS distribution, clearance, and efficacy of IT-dosed ASOs.


Pattern recognition in coupled chemical kinetic systems.
A network of open, bistable reaction systems coupled by mass transfer is simulated. The mass transfer rates are determined by a Hebb-type rule, and the programmable network can store patterns of high and low concentrations in each bistable system. In a parallel computation, the network recognizes patterns similar, but not necessarily identical, to stored patterns.


Attenuation of acute graft-versus-host disease in the absence of the transcription factor RORγt.
Graft-versus-host disease (GVHD) remains the most significant complication after allogeneic stem cell transplantation. Previously, acute GVHD had been considered to be mediated predominantly by Th1-polarized T cells. Recently, investigators have identified a second proinflammatory lineage of T cells termed Th17 that is critically dependent on the transcription factor retinoic acid-related orphan receptor (ROR)γt. In this study, we have evaluated the role of Th17 cells in murine acute GVHD by infusing donor T cells lacking RORC and as a consequence the isoform RORγt. Recipients given donor CD4(+) and CD8(+) T cells lacking RORC had significantly attenuated acute GVHD and markedly decreased tissue pathology in the colon, liver, and lung. Using a clinically relevant haploidentical murine transplantation model, we showed that RORC(-/-) CD4(+) T cells alone diminished the severity and lethality of acute GVHD. This was not found when CD4(+) T cells from RORC(-/-) mice were given to completely mismatched BALB/c mice, and it was correlated with absolute differences in the generation of TNF in the colon after transplant. Thus, CD4(+) T cell expression of RORC is important in the pathogenesis of acute GVHD.


2008 American Association of Feline Practitioners' feline retrovirus management guidelines.
Feline leukemia virus (FeLV) and feline immunodeficiency virus (FIV) are among the most common infectious diseases of cats. Although vaccines are available for both viruses, identification and segregation of infected cats form the cornerstone for preventing new infections. Guidelines in this report have been developed for diagnosis, prevention, treatment, and management of FeLV and FIV infections. All cats should be tested for FeLV and FIV infections at appropriate intervals based on individual risk assessments. This includes testing at the time of acquisition, following exposure to an infected cat or a cat of unknown infection status, prior to vaccination against FeLV or FIV, prior to entering group housing, and when cats become sick. No test is 100% accurate at all times under all conditions; results should be interpreted along with the patient's health and risk factors. Retroviral tests can diagnose only infection, not clinical disease, and cats infected with FeLV or FIV may live for many years. A decision for euthanasia should never be based solely on whether or not the cat is infected. Vaccination against FeLV is highly recommended in kittens. In adult cats, antiretroviral vaccines are considered non-core and should be administered only if a risk assessment indicates they are appropriate. Few large controlled studies have been performed using antiviral or immunomodulating drugs for the treatment of naturally infected cats. More research is needed to identify best practices to improve long-term outcomes following retroviral infections in cats.


Association of Intrathecal Immunoglobulin G Synthesis With Disability Worsening in Multiple Sclerosis.
Reliable biomarkers associated with disability worsening in multiple sclerosis (MS) are still needed. To determine a possible association of intrathecal IgG synthesis and early disability worsening as measured by Expanded Disability Status Scale (EDSS) scoring in patients with relapsing-remitting MS or clinically isolated syndrome. Cerebrospinal fluid measurements and clinical data from the observational longitudinal German national multiple sclerosis cohort were analyzed. Patients were recruited between August 2010 and November 2015 from 18 centers. Data analysis was completed from August 2018 to December 2018. Patients were offered standard immunotherapies per national treatment guidelines. A possible association between intrathecal IgG synthesis and risk of EDSS worsening 4 years after study inclusion was tested as the primary end point by multivariable binomial regression analysis. Kaplan-Meier analysis with a log-rank test was used to assess the association of intrathecal IgG synthesis with the time to EDSS worsening. Associations between intrathecal IgM or IgA synthesis and other cerebrospinal fluid parameters and EDSS worsening were analyzed as exploratory end points. Data collection began before the hypotheses were formulated. Of all 1376 patients in the German Competence Network of Multiple Sclerosis cohort, 703 patients were excluded owing to missing cerebrospinal fluid or EDSS data. Of the 673 included patients, 459 (68.2%) were women. The mean (SD) age at baseline was 34 (10) years. Intrathecal IgG synthesis was associated with a higher risk of EDSS worsening after 4 years (odds ratio, 2.02 [95% CI, 1.15-3.58]; P = .01), independent of the occurrence of relapses and disease-modifying therapy. Additionally, intrathecal IgG synthesis was associated with earlier EDSS worsening; 4 years after study entry, worsening occurred in 28.4% (95% CI, 22.7%-34.1%) and 18.1% (95% CI, 12.4%-23.9%) of patients with and without intrathecal IgG synthesis, respectively. No association of other routine cerebrospinal fluid parameters with EDSS worsening was found. Patients with new diagnoses of relapsing-remitting multiple sclerosis or clinically isolated syndrome with intrathecal IgG synthesis had a higher risk of and shorter time to EDSS worsening across a 4-year period of follow-up. Intrathecal IgG synthesis is a potentially useful marker for disability worsening in patients with multiple sclerosis and may be useful for early treatment decisions.


[Evaluation of Sysmex UF-5000 flow cytometer flag BACT-info for Gram discrimination in urinary tract infection].
Urine culture as a gold standard for the diagnosis of urinary tract infection (UTI) involves a considerable workload in Clinical Microbiology Departments, due to the high number of samples received that will ultimately be negative. Therefore, it is necessary to use screening systems that also reduce the turnaround time for UTI diagnosis. The new flow cytometer UF-5000 (Sysmex Corporation) is able to differentiate between Gram-negative and Gram-positive bacteria using the BACT-info parameter according to manufacturer. The aim of our study was to evaluate the gram discrimination ability of the UF-5000 cytometer. A prospective study with 449 urine samples collected consecutively was conducted, in the period 7/3/2022-27/5/2022, in which the BACT-info flag was compared with urine culture as the reference method. The sensitivity obtained for both Gram-negative and Gram-positive bacteria was above 95%. However, for Gram-positive bacteria, the moderate Kappa index (0.49) and the low positive predictive value (37.1%) indicated that the correlation between BACT-info flag and urine culture was not acceptable and should not be reported to the requesting clinician. Implementation of the third generation UF-5000 cytometer represents a significant advance in the aetiological orientation of UTIs caused by Gram-negative bacteria. Reporting the Gram morphology in the urine samples reduces the response time in the microbiological diagnosis of UTI, which would have an impact on the reduction and optimisation of empirical treatment, and thus on the generation of antimicrobial resistance.


Integrin structure and functional relation with ion channels.
Physical and functional link between cell adhesion molecules and ion channels provide a rapid connection between extracellular environment and cell physiology. Growing evidence does shows that frequent cross talk occurs between these classes of membrane proteins. These interactions are being addressed in ever increasing molecular detail. Recent advances have given X-ray resolved structure of the extracellular domains of integrin receptors. Such a level of resolution is still not available for the transmembrane and intracellular domains. Nonetheless, current molecular biological work is unraveling an intricate network connecting the cytoplasmic integrin domains with the cytoskeleton, ion channels and variety of cellular messengers. Overall, these studies show that integrins and ion channels both present bidirectional signaling features. Extracellular signals are usually transduced by integrins to trigger cellular responses that may involve ion fluxes, which can offer further relay. Intracellular processes and ion channel engagement can in turn affect integrin activation and expression and thus cell adhesion to the extracellular matrix. Moreover, ion channels themselves can communicate extracellular messages to both the cytoplasmic environment and integrin themselves. These interactions appear to often depend on formation of multiprotein membrane complexes that can recruit other elements, such as growth factor receptors and cytoplasmic signaling proteins. This chapter provides a general introduction to the field by giving a brief historical introduction and summarizing the main features of integrin structure and link to the cytoplasmic proteins. In addition, it outlines the main cellular processes inwhich channel-integrin interplay is known to exert clear physiological and pathological roles.


Anorexia nervosa and the hypothalamus.
A new name, "puberal starvation-amenorrhea", is proposed as more descriptive of the syndrome and less committal concerning its etiology. Though the etiology remains uncertain, a growing body of evidence--deranged hormonal secretory patterns, deficient thermal and water regulation, and other physiologic abnormalities--indicates that a specific hypothalamic dysfunction is responsible for this bizarre, sometimes lethal disease.


[Mutations in the Effector Domain of RhoV GTPase Impair Its Binding to Pak1 Protein Kinase].
Atypical RhoV GTPase (Chp/Wrch-2) is a member of the human Rho GTPase family, which belongs to the superfamily of Ras-related small GTPases. The biological functions of RhoV, regulation of its activity, and mechanisms of its action remain largely unexplored. Rho GTPases regulate a wide range of cellular processes by interacting with protein targets called effectors. Several putative RhoV effectors have been identified, including protein kinases of the Pak (p21-activated kinase) family: Pak1, Pak2, Pak4, and Pak6. RhoV GTPase activates Pak1 protein kinase and simultaneously induces its ubiquitin-dependent degradation. Pak1 regulates E-cadherin localization at adherens junctions downstream of RhoV during gastrulation in fish. The effector domain of RhoV mediates its binding to the CRIB (Cdc42/Rac1 interactive binding) motif in the N-terminal p21-binding domain (PBD) of Pak6 protein kinase. The role of the RhoV effector domain in mediating interaction with Pak1 has not been studied. This study has identified mutations in the effector domain of RhoV GTPase (Y60K, T63A, L65A, and D66A) that impair its interaction with Pak1 in the GST-PAK-PBD pull-down assay and coimmunoprecipitation. Our results suggest that the effector domain of RhoV mediates its binding to Pak1, complementing the current view of the molecular basics of RhoV binding to effectors of the Pak family. These data lay the basis for further studies on the role of Pak1 in RhoV-activated signaling pathways and cellular processes.


Frailty and Risk of Falls in Community-Dwelling Older Adults Living in a Rural Setting. The Atahualpa Project.
Data supporting a link between frailty and risk of falls is mostly confined to individuals living in urban centers, where risk factors and lifestyles are different from that of rural settings. To assess the association between frailty and risk of falls in older adults living in rural Ecuador. Population-based cross-sectional study. Community-dwellers aged ≥60 years living in a rural Ecuadorian village, in whom frail status and risk of falls were assessed. Frailty was evaluated by the Edmonton Frailty Scale (EFS) and risk of falls by the Downton Fall Risk Index (DFRI). Multivariate models were fitted to evaluate whether frailty was associated with risk of falls (dependent variable), after adjusting for demographics, alcohol intake, cardiovascular risk factors, sleep quality, symptoms of depression, and history of an overt stroke. Correlation coefficients were constructed to assess confounders modifying this association. A total of 324 participants (mean age: 70.5±8 years) were included. The mean EFS score was 4.4±2.5 points, with 180 (56%) participants classified as robust, 76 (23%) as pre-frail and 68 (21%) as frail. The DFRI was positive in 87 (27%) participants. In univariate analysis, the EFS score was higher among participants with a positive DFRI (p<0.001). The number of frail individuals was higher (p<0.001), while that of robust individuals was lower (p<0.001) among those with a positive DFRI. Adjusted logistic regression models showed no association between frailty and the DFRI. Correlation coefficients showed that age, high glucose levels, and history of an overt stroke tempered the association between frailty and the risk of falls found in univariate analyses. Frailty is not independently associated with risk of falls in older adults living in a remote rural setting. Further studies are needed to assess the impact of frailty on the risk of falls in these populations.


Pathogenic mechanisms in inflammatory and paraproteinaemic peripheral neuropathies.
This review summarizes the major recent developments in understanding of pathogenic mechanisms in inflammatory and paraproteinaemic neuropathies. In the inflammatory neuropathies, there has been a particular focus on antibody-mediated disease affecting the nodal/paranodal regions. Disruption of electrical integrity at these sites on the axonal membrane can cause conduction block without other electrophysiological features of demyelination, which has led to calls for a revision in the classification of axonal versus demyelinating neuropathies to include the new category of 'nodo-paranodopathies'. There has likewise been an expansion in knowledge regarding the diverse disease mechanisms of the paraproteinaemic neuropathies. These also include disease mediated by antibodies binding to peripheral nerve antigens, but additionally encompass immune complex deposition, cellular infiltration, and cytokine production. An increasing range of laboratory tests for antibodies, growth factors, and cytokines are proposed as useful in the management of inflammatory and paraproteinaemic neuropathies. Furthermore, the traditional electrodiagnostic classification into axonal and demyelinating neuropathy may not always accurately reflect the underlying disease process. Understanding how these paraclinical tests aid in identifying the underlying disease has relevance to the practising clinician both in terms of diagnosis and for the selection of rational treatments.


Hydrogen inhalation ameliorates oxidative stress in transplantation induced intestinal graft injury.
Ischemia/reperfusion (I/R) injury during small intestinal transplantation (SITx) frequently causes complications including dysmotility, inflammation and organ failure. Recent evidence indicates hydrogen inhalation eliminates toxic hydroxyl radicals. Syngeneic, orthotopic SITx was performed in Lewis rats with 3 h of cold ischemic time. Both donor and recipient received perioperative air or 2% hydrogen inhalation. SITx caused a delay in gastrointestinal transit and decreased jejunal circular muscle contractile activity 24 h after surgery. Hydrogen treatment resulted in significantly improved gastrointestinal transit, as well as jejunal smooth muscle contractility in response to bethanechol. The transplant induced upregulation in the inflammatory mediators CCL2, IL-1 beta, IL-6 and TNF-alpha were mitigated by hydrogen. Hydrogen significantly diminished lipid peroxidation compared to elevated tissue malondialdehyde levels in air-treated grafts demonstrating an antioxidant effect. Histopathological mucosal erosion and increased gut permeability indicated a breakdown in posttransplant mucosal barrier function which was significantly attenuated by hydrogen treatment. In recipient lung, hydrogen treatment also resulted in a significant abatement in inflammatory mRNA induction and reduced neutrophil recruitment. Hydrogen inhalation significantly ameliorates intestinal transplant injury and prevents remote organ inflammation via its antioxidant effects. Administration of perioperative hydrogen gas may be a potent and clinically applicable therapeutic strategy for intestinal I/R injury.


Classification of viral zoonosis through receptor pattern analysis.
Viral zoonosis, the transmission of a virus from its primary vertebrate reservoir species to humans, requires ubiquitous cellular proteins known as receptor proteins. Zoonosis can occur not only through direct transmission from vertebrates to humans, but also through intermediate reservoirs or other environmental factors. Viruses can be categorized according to genotype (ssDNA, dsDNA, ssRNA and dsRNA viruses). Among them, the RNA viruses exhibit particularly high mutation rates and are especially problematic for this reason. Most zoonotic viruses are RNA viruses that change their envelope proteins to facilitate binding to various receptors of host species. In this study, we sought to predict zoonotic propensity through the analysis of receptor characteristics. We hypothesized that the major barrier to interspecies virus transmission is that receptor sequences vary among species--in other words, that the specific amino acid sequence of the receptor determines the ability of the viral envelope protein to attach to the cell. We analysed host-cell receptor sequences for their hydrophobicity/hydrophilicity characteristics. We then analysed these properties for similarities among receptors of different species and used a statistical discriminant analysis to predict the likelihood of transmission among species. This study is an attempt to predict zoonosis through simple computational analysis of receptor sequence differences. Our method may be useful in predicting the zoonotic potential of newly discovered viral strains.


Classification for treatment urgency for the microphthalmia/anophthalmia spectrum using clinical and biometrical characteristics.
Current clinical classifications do not distinguish between the severity of the MICrophthalmia/Anophthalmia (MICA) spectrum with regard to treatment urgency. We aim to provide parameters for distinguishing mild, moderate and severe MICA using clinical and biometrical characteristics. We performed a single-centre, cross-sectional analysis of prospective cohort of 58 MICA children from September 2013 to February 2018 seen at the Amsterdam University Medical Center, The Netherlands. All patients with a visible underdeveloped globe were included. We performed full ophthalmic evaluation including horizontal palpebral fissure length, axial length by ultrasound and/or MRI measurements, paediatric and genetic evaluation. Cases were subdivided based on clinical characteristics. Biometrical data were used to calculate the relative axial length (rAL) and the relative horizontal palpebral fissure length (rHPF) compared with the healthy contralateral eye for unilateral cases. In previously untreated patients, a strong correlation exists between rAL and rHPF, distinguishing between severe, moderate and mild subjects using rAL of 0-45%, 45-75% and 75%-100%, respectively. Clinical subgroups were randomly dispersed throughout the scatterplot. Current classifications lack clinical implications for MICA patients. We suggest measuring eyelid length and axial length to classify the severity and determine treatment strategy. The 'severe' group has obvious asymmetry and abnormal socket configuration for which therapy should quickly be initiated; the 'moderately' affected group has normal socket anatomy with a microphthalmic eye with disturbing asymmetry for which treatment should be initiated within months of development; the 'mild' group has a slightly smaller axial length or less obvious eyelid asymmetry for which reconstructive correction is possible, but expansive conformer treatment is unnecessary.


Longitudinal associations among primary and secondary psychopathic traits, anxiety, and borderline personality disorder features across adolescence.
The individual and societal burden of psychopathy warrants an investigation into identifying its early precursors and developmental course. Accordingly, we examined the longitudinal pathways between primary and secondary psychopathic traits, anxiety, and borderline personality disorder (BPD) features across adolescence. Participants included 572 Canadian adolescents (253 girls; aged 13.96 [SD = 0.37] in Grade 8; 70.6% Caucasian) who were assessed annually on five occasions (Grades 8-12) using the Antisocial Process Screening Device (psychopathic traits), the Behavior Assessment System for Children-2 (symptoms of anxiety), and the Borderline Personality Features Scale for Children (features of BPD). Autoregressive latent trajectory models with structured residuals provided stringent tests of within-person cross-lagged associations, while controlling for sex, race/ethnicity, household income, and parental education. Results indicated that primary psychopathic traits were preceded by and predicted anxiety such that individuals who increased in primary psychopathic traits subsequently declined in anxiety, and vice versa. Results also indicated that BPD features were associated with secondary psychopathic traits and anxiety. Specifically, increases in BPD features were linked with increases in secondary psychopathic traits and anxiety. Our results suggest that even after accounting for between-person associations and other known correlates, the development of psychopathic traits is embedded within the development of emotional characteristics and personality features. This highlights areas for intervention in adolescence, particularly around the core, shared trait of impulsivity and anger. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Association between delirium superimposed on dementia and mortality in hospitalized older adults: A prospective cohort study.
Hospitalized older adults with preexisting dementia have increased risk of having delirium, but little is known regarding the effect of delirium superimposed on dementia (DSD) on the outcomes of these patients. Our aim was to investigate the association between DSD and hospital mortality and 12-mo mortality in hospitalized older adults. This was a prospective cohort study completed in the geriatric ward of a university hospital in São Paulo, Brazil. We included 1,409 hospitalizations of acutely ill patients aged 60 y and over from January 2009 to June 2015. Main variables and measures included dementia and dementia severity (Informant Questionnaire on Cognitive Decline in the Elderly, Clinical Dementia Rating) and delirium (Confusion Assessment Method). Primary outcomes were time to death in the hospital and time to death in 12 mo (for the discharged sample). Comprehensive geriatric assessment was performed at admission, and additional clinical data were documented upon death or discharge. Cases were categorized into four groups (no delirium or dementia, dementia alone, delirium alone, and DSD). The no delirium/dementia group was defined as the referent category for comparisons, and multivariate analyses were performed using Cox proportional hazards models adjusted for possible confounders (sociodemographic information, medical history and physical examination data, functional and nutritional status, polypharmacy, and laboratory covariates). Overall, 61% were women and 39% had dementia, with a mean age of 80 y. Dementia alone was observed in 13% of the cases, with delirium alone in 21% and DSD in 26% of the cases. In-hospital mortality was 8% for patients without delirium or dementia, 12% for patients with dementia alone, 29% for patients with delirium alone, and 32% for DSD patients (Pearson Chi-square = 112, p < 0.001). DSD and delirium alone were independently associated with in-hospital mortality, with respective hazard ratios (HRs) of 2.14 (95% CI = 1.33-3.45, p = 0.002) and 2.72 (95% CI = 1.77-4.18, p < 0.001). Dementia alone did not have a significant statistical association with in-hospital mortality (HR = 1.69, 95% CI = 0.72-2.30, p = 0.385). Finally, while 24% of the patients died after discharge, 12-mo mortality was not associated with dementia or delirium in any of the diagnostic groups (DSD: HR = 1.15, 95% CI = 0.79-1.68, p = 0.463; delirium alone: HR = 1.05, 95% CI = 0.71-1.54, p = 0.810; dementia alone: HR = 1.19, 95% CI = 0.79-1.78, p = 0.399). Limitations to this study include not exploring the effects of the duration and severity of delirium on the outcomes. DSD and delirium alone were independently associated with a worse prognosis in hospitalized older adults. Health care professionals should recognize the importance of delirium as a predictor of hospital mortality regardless of the coexistence with dementia.


Creating demand for long-acting formulations for the treatment and prevention of HIV, tuberculosis, and viral hepatitis.
Long-acting parenteral drug delivery is an established and widely accepted solution to the problem of poor adherence when daily oral medications are used to treat or prevent chronic medical conditions. Poor adherence to oral formulations remains a major barrier to successfully treating or preventing HIV, tuberculosis (TB), and viral hepatitis. The uptake of long-acting formulations developed for these infections is uncertain, despite their promise. This review addresses the current state of development of long-acting and extended-release approaches to HIV, TB, and viral hepatitis in the context of creating market demand for such products. Two nanoformulated long-acting injectable antiretroviral compounds, cabotegravir and rilpivirine, recently completed Phase 2 clinical trials demonstrating safety, tolerability, and antiretroviral activity, and should be available in high income countries following completion of ongoing Phase 3 trials. Long-acting polymer implants of the antiretroviral nucleosides tenofovir alafenamide and 4'-ethynyl-2-fluoro-2'-deoxyadenosine are being tested in animals and should soon enter human studies; tenofovir alafenamide also has activity against hepatitis B virus. Long-acting versions of several broadly neutralizing monoclonal antibodies are in advanced clinical trials for HIV prevention and treatment. Long-acting formulations for TB are in preclinical development. There is no evidence that comparable formulations for viral hepatitis are being developed at present. Long-acting and extended release formulations are promising approaches to the treatment and prevention of common infectious diseases, but their availability is limited at this time. These products hold great promise for the global control of important human infections. Based on experience with other diseases, it is likely that their use will become more widespread if they are cost competitive with generic oral formulations.


Identification of Translin/Trax complex as a glucose response element binding protein in liver.
Previously, we found a novel protein factor in the livers of rats fed a high-carbohydrate diet, which binds to the major late transcription factor (MLTF)-like site within the glucose response element (GRE) of the liver-type pyruvate kinase (L-PK) gene [J. Biol. Chem. 274 (1999) 1100]. This factor, termed glucose response element binding protein (GRBP), exists in both liver cytosol and nucleus. In order to identify GRBP, we purified to homogeneity cytosolic GRBP from rat liver extract and identified it as a Translin/Trax heteromeric complex. Based on partial amino acid sequences, we have cloned full-length rat cDNAs of both Translin and Trax. The nuclear and the cytosolic Translin/Trax complex were both large polymers of 240 and 420 kDa, respectively. The molar ratio of Translin/Trax in the polymers was 2:1 in the liver cytosols. The nuclear and cytosolic Translin/Trax complexes as well as expressed His-tagged Translin bound to double- and single-stranded MLTF sites of the GRE of L-PK gene more avidly than to single-stranded Bcl-CL1, which was initially thought to be specific for Translin. Our findings indicate that the Translin/Trax complex constitutes the previously described GRBP, and that this complex binds the GRE of the L-PK gene with high affinity. The precise physiologic role of GRBP, however, remains unclear.


The murine orthologue of human antichymotrypsin: a structural paradigm for clade A3 serpins.
Antichymotrypsin (SERPINA3) is a widely expressed member of the serpin superfamily, required for the regulation of leukocyte proteases released during an inflammatory response and with a permissive role in the development of amyloid encephalopathy. Despite its biological significance, there is at present no available structure of this serpin in its native, inhibitory state. We present here the first fully refined structure of a murine antichymotrypsin orthologue to 2.1 A, which we propose as a template for other antichymotrypsin-like serpins. A most unexpected feature of the structure of murine serpina3n is that it reveals the reactive center loop (RCL) to be partially inserted into the A beta-sheet, a structural motif associated with ligand-dependent activation in other serpins. The RCL is, in addition, stabilized by salt bridges, and its plane is oriented at 90 degrees to the RCL of antitrypsin. A biochemical and biophysical analysis of this serpin demonstrates that it is a fast and efficient inhibitor of human leukocyte elastase (ka: 4 +/- 0.9 x 10(6) m(-1) s(-)1) and cathepsin G (ka: 7.9 +/- 0.9 x 10(5) m(-1) s(-)1) giving a spectrum of activity intermediate between that of human antichymotrypsin and human antitrypsin. An evolutionary analysis reveals that residues subject to positive selection and that have contributed to the diversity of sequences in this sub-branch (A3) of the serpin superfamily are essentially restricted to the P4-P6' region of the RCL, the distal hinge, and the loop between strands 4B and 5B.


Comparison of diffusion tensor image study in association fiber tracts among normal, amnestic mild cognitive impairment, and Alzheimer's patients.
To compare diffusion tensor image (DTI) study in association fiber tracts among normal control (NC), amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD) subjects. To assess diagnostic value of DTI in aMCI and differential diagnosis of DTI study between aMCI and AD. DTI was used to assess changes in cerebral association fiber tracts in NC, aMCI, and AD subjects (n = 20/group). Regions of interest included the inferior fronto-occipital fascicles (IFOF), superior longitudinal fascicles and cingulum tract, genu of corpus callosum (Gcc) was set right, splenium of corpus callosum was set left. Bilateral fractional anisotropy (FA) and apparent diffusion coefficient values were compared in three groups. Relative to NC, aMCI subjects had significantly different FA values for the IFOF and cingulum tract, while AD subjects had significantly different FA values of IFOF, Gcc, and cingulum tract. Relative to aMCI, AD subjects had significantly different FA values of cingulum tract. Based on the results, DTI could be used as a diagnostic method for aMCI with abnormal changes in IFOF and cingulum tract. DTI could also be used for differential diagnosis of aMCI and AD by comparing FA values of the cingulum tract. Abnormal FA values of IFOF, Gcc, and cingulum tract in AD patients may help to elucidate the pathological processes in this disease.


Nested PCR for the rapid detection of TB from pleural fluid at HUKM Malaysia.
The aim of the present study is rapid detection of tuberculosis from pleural effusion of suspected patients. Molecular technique Nested Polymerase Chain Reaction (PCR) was used for the purpose. A total of 67 pleural fluid collected at Hospital University Kebangsaan Malaysia during May 2005 to October 2006 were sent to Microbiology Laboratory enrolled in the study. Detection rate of Mycobacterium tuberculosis in pleural effusion was 0% by acid-fast bacilli (AFB) staining and 1.5% by culture on Lowenstein-Jensen medium. Mycobacterium tuberculosis was detected by PCR in 9% of the cases. PCR of pleural fluid had 19% sensitivity and 96% specificity, compared to AFB staining (0% sensitivity and 100% specificity) and culture (4% sensitivity and 100% specificity). PCR also has 67% Positive Predictive Value (PPV) and 72% Negative Predictive Value (NPV) in detecting Mycobacterium tuberculosis. Culture ofpleural fluid has 100% PPV and 71% NPV while AFB staining has 0% PPV and 31% NPV. This preliminary study showed that PCR is a rapid method for detection of Mycobacterium tuberculosis in pleural fluid but its sensitivity is not up the marked.


A model for achieving total quality-management information technology infrastructure within an integrated delivery system.
The strategic development and deployment of a health management information technology infrastructure is discussed from two perspectives for radiologists and for other medical technologists: the integrated delivery system (IDS) perspective and a total quality-management (TQM) perspective. On the one hand, an IDS perspective is important because of the need to prepare radiologists and other medical practitioners to thrive within rapidly changing health organizational models and evolving health service delivery partnership systems. On the other, a TQM perspective is important due to the need to realize an appropriate, efficient, and cost-effective health information infrastructure for developing seamless, integrated radiological and other medical imaging services. Apart from intelligently pursuing an aligned organizational business strategy with the organizational information system strategy, senior radiological managers and medical technologists of health organizations need to pay particular attention to key quality principles for effecting changes in organizational structures and processes to fit changes in information technological requirements, implementations, and innovations.


Direct observation of a long-lived single-atom catalyst chiseling atomic structures in graphene.
Fabricating stable functional devices at the atomic scale is an ultimate goal of nanotechnology. In biological processes, such high-precision operations are accomplished by enzymes. A counterpart molecular catalyst that binds to a solid-state substrate would be highly desirable. Here, we report the direct observation of single Si adatoms catalyzing the dissociation of carbon atoms from graphene in an aberration-corrected high-resolution transmission electron microscope (HRTEM). The single Si atom provides a catalytic wedge for energetic electrons to chisel off the graphene lattice, atom by atom, while the Si atom itself is not consumed. The products of the chiseling process are atomic-scale features including graphene pores and clean edges. Our experimental observations and first-principles calculations demonstrated the dynamics, stability, and selectivity of such a single-atom chisel, which opens up the possibility of fabricating certain stable molecular devices by precise modification of materials at the atomic scale.


Artificial sweeteners and lower urinary tract cancer: hospital vs. population controls.
In a case-control study conducted in 1978 in Detroit, Michigan, as part of the National Bladder Cancer Study, the proportions of artificial sweetener users in a hospital and a population control series were compared. The study was based on interviews with 305 hospital controls and 440 population controls, as well as 391 patients with transitional or squamous cell carcinoma of the lower urinary tract. The proportion of artificial sweetener users among all hospital controls was higher than that among population controls. Among male hospital controls, it was found that 44% had ever used artificial sweeteners, compared to 38% of the male population controls. For females, the corresponding proportions of artificial sweetener users were 55% and 42%. Thus, relative risks estimated using all hospital controls were lower than relative risks estimated using population controls. When controls hospitalized for obesity-related diseases were excluded from the hospital control group, the proportion of artificial sweetener users and the relative risks for males were identical to those estimated with population controls (relative risk = 1.1). These results suggest that restriction of the control group to those patients hospitalized for non-obesity related diseases is a satisfactory procedure for selecting a control group in hospital-based studies of the effects of artificial sweeteners. For females, little or no change in the proportion of artificial sweetener users or in the relative risks was observed after exclusion of controls hospitalized for obesity-related diseases. However, the number of female subjects was small, and the results noted for females may have been due to chance.


Electronic determinants of the anti-inflammatory action of benzoic and salicylic acids.
Ab initio, quantum chemical methods have been used to study the possible modes of binding of benzoic and salicylic acids to cyclooxygenase which lead to their anti-inflammatory action. The biological data for this work were obtained from full dose response curves of the inhibitory potency of active compounds on prostaglandin production in mouse macrophages. With the help of simple regression analysis the most important reactivity indices are identified and the ionization state of the active species is discussed. From the physical significance implied by these regressions and an analysis of the electronic charge distributions of the frontier orbitals, a two-way charge transfer model is proposed. The electrostatic potentials of active and inactive congeners have been analyzed, and it is shown that an electrostatic orientation effect seems to make an important contribution to the binding of the active molecules to their receptor site. An electrostatic potential model of the binding site is proposed, and it is shown that this model is able to rationalize the source of activity or inactivity of the investigated substances.


Mental health nurses employed in Australian general practice: dimensions of time and space.
Almost half the Australian population, aged 16-85 years, are affected by mental illness at some point in their life, and general practice plays a key role in providing effective mental health care. This paper presents the findings from a study that explored how people living with mental illness are supported in Australian general practice. A descriptive, exploratory study was conducted using semistructured interviews to gather data. The role of mental health nurses in the care and support of people with mental illness emerged from the data. This was explored further and resulted in two key themes: dimensions of time and dimensions of space. Findings from this study present key similarities and differences in the role of mental health nurses, as compared to general practitioners, in relation to dimensions of time and space. Dimensions of time and space are important considerations for general practices when planning to introduce a mental health nurse into their interprofessional team.


Relationship between clinical manifestations and pulsed-field gel profiles of Streptococcus canis isolates from dogs and cats.
Little is known regarding the degree of genotypic relatedness between Streptococcus canis isolates from dogs and cats. The purpose of this study was to determine whether correlations existed between the genotypes of canine and feline S. canis isolates as determined using pulsed-field gel electrophoresis (PFGE) and different clinical manifestations of disease. Eighty-two isolates of S. canis were examined that had been collected from dogs and cats presenting to the University of California, Davis Veterinary Medical Teaching Hospital (VMTH) between 1998 and 2005. Associated clinical manifestations included sepsis, otitis, pyometra, skin infections, necrotizing fasciitis, respiratory disease, and urinary tract infections. In addition, 9 feline isolates from a southern California shelter that experienced an outbreak of S. canis infection manifesting as necrotizing fasciitis and death were examined. Bacterial isolates were characterized by PFGE analysis using the restriction enzyme SmaI. The relationships between banding patterns were analyzed using gel analysis software combined with visual interpretation. The feline shelter isolates of S. canis were 99% similar in bacterial PFGE profile. The remainder of samples had less than 80% similarity in PFGE banding patterns. The relatedness of the PFGE profile in the feline shelter isolates suggested a clonal origin. In the isolates from the VMTH population, there was no relationship between specific disease manifestations and PFGE profile. PFGE typing does not appear to be useful for identifying isolates associated with specific disease presentations; however may be more useful to identify outbreaks of S. canis infections or to detect clonal populations in outbreaks.


Quantitative trait loci influencing honeybee alarm pheromone levels.
Quantitative trait loci (QTL) mapping procedures were used to identify loci that influence the levels of alarm pheromones found in the stinging apparatus of worker honeybees. An F1 queen was produced from a cross between a queen of European origin and a drone descended from an African subspecies. Haploid drones from the hybrid queen were individually backcrossed to European queens to produce 172 colonies. Samples of stings were taken from backcross workers of these colonies. Alarm pheromone levels were determined by gas chromatography. RAPD markers were scored from the haploid drone fathers of these colonies. The multiple-QTL model (MQM) of MapQTL was used to identify QTLs that influence the levels of four alarm pheromone components. Seven independent, potential QTLs were identified with LOD scores greater than two, and one at LOD 1.88. We identified one QTL for n-decyl acetate, three for n-octanol, four for isopentyl acetate, and one for hexyl acetate. One region of linkage group XI shows a strong influence on body size and the levels of three alarm pheromone components. This locus explained 40% of the variance for the amount of n-decyl acetate (LOD 6.57). In general, the QTLs influencing alarm pheromone levels were independent of previously identified loci that influenced the stinging behavior of these colonies. The only exception was a potential locus influencing levels of n-octanol, which was inversely correlated with stinging behavior.


Decoy TRAIL receptor CD264: a cell surface marker of cellular aging for human bone marrow-derived mesenchymal stem cells.
Mesenchymal stem cells (MSCs) are a mixture of progenitors that are heterogeneous in their regenerative potential. Development of MSC therapies with consistent efficacy is hindered by the absence of an immunophenotype of MSC heterogeneity. This study evaluates decoy TRAIL receptor CD264 as potentially the first surface marker to detect cellular aging in heterogeneous MSC cultures. CD264 surface expression, regenerative potential, and metrics of cellular aging were assessed in vitro for marrow MSCs from 12 donors ages 20-60 years old. Male and female donors were age matched. Expression of CD264 was compared with that of p16, p21, and p53 during serial passage of MSCs. When CD264+ cell content was 20% to 35%, MSC cultures from young (ages 20-40 years) and older (ages 45-60 years) donors proliferated rapidly and differentiated extensively. Older donor MSCs containing < 35% CD264+ cells had a small size and negligible senescence despite the donor's advanced chronological age. Above the 35% threshold, CD264 expression inversely correlated with proliferation and differentiation potential. When CD264+ cell content was 75%, MSCs were enlarged and mostly senescent with severely compromised regenerative potential. There was no correlation of the older donors' chronological age to either CD264+ cell content or the regenerative potential of the donor MSCs. CD264 was upregulated after p53 and had a similar expression profile to that of p21 during serial passage of MSCs. No sex-linked differences were detected in this study. These results suggest that CD264 is a surface marker of cellular age for MSCs, not the chronological age of the MSC donor. CD264 is first upregulated in MSCs at an intermediate stage of cellular aging and remains upregulated as aging progresses towards senescence. The strong inverse correlation of CD264+ cell content to the regenerative potential of MSCs has possible application to assess the therapeutic potential of patient MSCs, standardize the composition and efficacy of MSC therapies, and facilitate aging research on MSCs.