Amputation-Free Survival after Crural Percutaneous Transluminal Angioplasty for Critical Limb Ischemia.
To evaluate the amputation-free survival after below the knee percutaneous transluminal angioplasty in a consecutive group of patients with critical ischemia of the lower extremity. A total of 70 consecutive patients with critical ischemia were treated with below the knee percutaneous transluminal angioplasty at the vascular center at Rigshospitalet with the purpose of limb salvage. All patients were deemed unfit for major surgery due to anatomical limitations or severe co-morbidity, and no prior attempts of revascularization were performed. Follow-up clinical examinations were performed within 6 weeks and after 1 year. All medical records were crosschecked with the national vascular registry ensuring a valid 1-year status in 97% of the patients. A total of 15 major amputations were performed during follow-up, with 11 amputations performed within the first year. Complications after percutaneous transluminal angioplasty were rare. Cumulative mortality after 1 and 2 years was 22% and 34%, respectively. Amputation-free survival at 1 and 2 years of follow-up was 68% and 58%, respectively. There were no association between known risk factors such as diabetes, ischemic ulcers, cardiac disease, history of smoking, major amputation, or overall amputation. Below the knee percutaneous transluminal angioplasty in patients with end-stage peripheral arterial disease and critical limb ischemia is a safe procedure in relieving critical ischemia, reducing the short-term rate of a major amputation as opposed to best medical treatment alone.


Posterior Glenoid Bone Block Reconstruction: Indications, Techniques, and Outcomes.
Posterior shoulder instability is of particular therapeutic interest, as it typically affects patients with high functional demands such as young athletes and active adults. Although posterior capsulolabral repair has high return-to-sport rates, it is associated with recurrent instability of up to 11%. Posterior glenoid bone loss and significant glenoid retroversion have been identified as risk factors for recurrent instability and failure after primary arthroscopic soft-tissue repair. Therefore, posterior glenoid bone block reconstruction may be indicated for glenoid bone loss 20% or greater (as measured by the perfect circle technique) or greater than 10% in the setting of pathologic glenoid, failed primary posterior labral repair, incompetent posterior capsular tissue, or significant risk factors for failure of soft-tissue repair. This procedure may be performed arthroscopically or with a posterior open approach using distal tibial allograft, iliac crest autograft, or scapular spine autograft. Although short-term to midterm outcomes have been promising, there remain concerns regarding long-term outcomes, with potentially high rates of late recurrence, revision, and secondary osteoarthritis.


Do beta-blockers alter dyspnea and fatigue in advanced lung cancer? A retrospective analysis.
Dyspnea is common in lung cancer and may be partially attributable to increased ventilatory drive due to muscle weakness. The sympathetic component of this pathway might be mitigated by β-blockers. A retrospective review of new patients with stage III-IV non-small lung cancer or any small cell lung cancer was undertaken to assess the impact of β-blocker use on dyspnea and fatigue. Data were abstracted for clinical characteristics, β-blocker use, and pre-treatment Edmonton Symptom Assessment System dyspnea and fatigue scores. Of 348 patients assessed, 202 met eligibility criteria. The median age was 67, 55.4% were female, 18.8% had chronic obstructive pulmonary disease (COPD), and 5.9% had active coronary artery disease. Over 60% of patients scored 4/10 or higher on their dyspnea and fatigue scores. While dyspnea and fatigue were moderately associated, no association was found between β-blocker use and either symptom. Recorded dosages of β-blockers were low. COPD was associated with dyspnea and fatigue, while anemia was associated with fatigue. Dyspnea and fatigue are prevalent and increased in the presence of COPD and anemia. No association between β-blocker use and dyspnea or fatigue scores was observed. This may be attributable to inadequate dosing or to retrospective bias.


Interaction of environmental contaminants with zebrafish (Danio rerio) multidrug and toxin extrusion protein 7 (Mate7/Slc47a7).
Zebrafish Mate7 belongs to solute carrier protein superfamily and specifically to subfamily of multidrug and toxin extruders. It is co-orthologous to mammalian Mates, and is ubiquitously expressed in zebrafish tissues with the highest expression in kidney. It has been shown to interact with both endogenous (steroid hormones) and xenobiotic compounds (pharmaceuticals), implying a role in efflux of toxic compounds. The objective of our study was to analyse interaction of environmental contaminants with zebrafish Mate7 using a newly developed high throughput screening (HTS) Mate7 assay. A full-length zebrafish mate7 sequence was obtained from zebrafish cDNA originating from male kidney, and a stable expression of Mate7 in genetically engineered HEK293 Flp-In cells was achieved. Stable Mate7 transfectants were then used for development and optimization of a new HTS cellular uptake protocol, with DAPI and ASP + as model fluorescent substrates. The developed assay was used for identifying zebrafish Mate 7 interactors and discerning the type of interaction. A series of 89 diverse environmental contaminants, including industrial chemicals, pesticides, and pharmaceuticals, was tested and highly effective Mate7 interactors were identified in all of the aforementioned groups. Some of the inhibitors identified could be of environmental concern because they may potentially impair Mate7 efflux function, lowering the fish defence capacity against environmental contaminants, or interfering with transport of yet unidentified physiological substrates. In addition, we found significant differences between zebrafish Mate7 and mammalian Mates' substrate preferences, a finding that should be taken into consideration when using zebrafish as a model organism in toxicokinetic studies.


NADPH oxidase-dependent formation of reactive oxygen species contributes to angiotensin II-induced epithelial-mesenchymal transition in rat peritoneal mesothelial cells.
The objective of the present study was to investigate the role of NADPH oxidase-dependent formation of reactive oxygen species (ROS) in the angiotensin II (Ang II)-induced epithelial-mesenchymal transition (EMT) and in the accumulation of extracellular matrix (ECM) in rat peritoneal mesothelial cells (RPMCs). Primary cultured RPMCs were incubated with serum-free media for 24 h in order to arrest and synchronize cell growth. The cells were treated with Ang II (10⁻⁷ M) up to 48 h. Cells were pretreated with an Ang II type I receptor antagonist (losartan, 10⁻⁵ M), or an inhibitor of NADPH, oxidase diphenyleneiodonium (DPI) (10⁻⁵ M), for 1 h before addition of Ang II. The dichlorofluorescein (DCF)-sensitive cellular ROS were measured by fluorometric assay and confocal microscopy. RT-PCR was employed to detect the mRNA expression for the NADPH oxidase subunit p47phox, plasminogen activator inhibitor-1 (PAI-1), α-smooth muscle actin (α-SMA) and E-cadherin. PAI-1, α-SMA and p47phox protein expression were examined by Western blot analysis. Ang II significantly induced the production of intracellular ROS. DPI and losartan inhibited Ang II-induced ROS generation by 86.8% and 77.4% (p<0.05), respectively. Ang II significantly stimulated NADPH oxidase subunit p47phox mRNA and protein expression in RPMCs. Both losartan and DPI inhibited Ang II-induced up-regulation of p47phox mRNA by 37.3% and 67.8% (p<0.05), respectively. Ang II also stimulated α-SMA mRNA and protein expression and down-regulated E-cadherin mRNA expression in RPMCs. This effect was suppressed by both losartan and DPI. Ang II significantly up-regulated PAI-1 mRNA and protein expression and these were significantly suppressed by both losartan and DPI. In conclusion, NADPH oxidase-dependent formation of ROS mediates Ang II dependent EMT and accumulation of ECM in rat peritoneal mesothelial cells. NADPH oxidase may represent a potential therapeutic target in the management of peritoneal fibrosis.


A novel Rac1 GAP splice variant relays poly-Ub accumulation signals to mediate Rac1 inactivation.
Spatial control of RhoGTPase-inactivating GAP components remains largely enigmatic. We describe a brain-specific RhoGAP splice variant, BARGIN (BGIN), which comprises a combination of BAR, GAP, and partial CIN phosphatase domains spliced from adjacent SH3BP1 and CIN gene loci. Excision of BGIN exon 2 results in recoding of a 42-amino acid N-terminal stretch. The partial CIN domain is a poly-ubiquitin (poly-Ub)-binding module that facilitates BGIN distribution to membranous and detergent-insoluble fractions. Poly-Ub/BGIN interactions support BGIN-mediated inactivation of a membranous Rac1 population, which consequently inactivates membrane-localized Rac1 effector systems such as reactive oxygen species (ROS) generation by the Nox1 complex. Given that Ub aggregate pathology and proteotoxicity are central themes in various neurodegenerative disorders, we investigated whether BGIN/Rac1 signaling could be involved in neurodegenerative proteotoxicity. BGIN/Ub interactions are observed through colocalization in tangle aggregates in the Alzheimer's disease (AD) brain. Moreover, enhanced BGIN membrane distribution correlates with reduced Rac1 activity in AD brain tissue. Finally, BGIN contributes to Rac1 inhibition and ROS generation in an amyloid precursor protein (APP) proteotoxicity model. These results suggest that BGIN/poly-Ub interactions enhance BGIN membrane distribution and relay poly-Ub signals to enact Rac1 inactivation, and attenuation of Rac1 signaling is partially dependent on BGIN in a proteotoxic APP context.


Tetrahydroisoquinolines and beta-carbolines: specific binding to human platelet alpha 2-receptors in vitro.
Previous human platelet aggregation studies indicated that tetrahydroisoquinoline (TIQ) and beta-carboline (BC) compounds act as competitive antagonists for epinephrine for the platelet alpha 2-adrenergic receptor. In this study, the relative binding affinities of 1,2,3,4-TIQ (THIQ), salsolinol (SAL), norharman (NH), harmaline (HAR) and tetrahydronorharman (THN) for the platelet alpha 2-receptor were determined using the selective antagonist [3H]-yohimbine. The order of potency in yohimbine-displacing ability was THIQ = THN greater than HAR greater than NH greater than SAL, with IC50's ranging from 10 microM to 170 microM. A structure-activity relationship could also be identified for the condensation products examined.


[Uncommon course of radiation-induced pneumonitis with subsequent bronchiolitis obliterans with organizing pneumonia (BOOP) in a female with breast cancer].
Radiation-induced pneumonitis is a familiar complication of breast cancer radiotherapy, whereas bronchiolitis obliterans with organizing pneumonia occurs extremely rarely after this treatment. Consequently, testing for BOOP is rarely included in differential diagnosis. This results in delayed diagnosis, so that treatment is ultimately commenced too late. The infiltrations are often located in the unirradiated lung, impeding diagnosis. The radiotherapy-induced BOOP-reaction that can also occur after typical radiation pneumonitis is illustrated by reference to a characteristic case report.


Dichotic listening performance in young adults using low-pass filtered speech.
Assessment of interaural asymmetry (IA) on dichotic listening tests becomes challenging when accuracy on one or both ears are at ceiling. Cognitive task demands are often increased to avoid this situation, raising the possibility that non-auditory-specific processes will further influence IA estimation. To investigate the utility of low-pass filtered dichotic speech stimuli (dichotic filtered words [DFWs]) as a potential auditory-specific technique for increasing task difficulty in the dichotic listening paradigm. A prospective experimental study investigating differences in IA observed for a group of young adults on three dichotic listening tasks differentiated on the basis of stimulus type (unfiltered words, DFWs) and/or mode of test administration (divided attention [DIV]; directed attention [DIR]). Thirty-two adults between 18 and 34 yr of age participated in the study. Accuracy scores on each ear and normalized values of IA (via laterality index) served as dependent measures evaluated in a repeated-measures ANOVA design. Correlation and regression analyses were carried out to investigate potential relationships between participants' behavioral accuracy to experimental stimuli and the magnitude of observed IA. Behavioral profiles of IA were constructed for each participant. Using a traditional DIV test mode, DFW stimuli produced a significantly larger right-ear advantage (REA) as compared to unfiltered speech. The magnitude of the average REA to DFW stimuli was not statistically different between DIV and DIR test modes for the group. Inspection of individual performances, however, revealed that out of the participants who demonstrated meaningful IA during DIV, approximately half produced the same or greater amount of IA during DIR whereas half showed a relative decrease. Participants' accuracy to left-sided stimuli was most related to the magnitude of observed IA across tasks. The utility of low-pass filtered speech may be helpful in the evaluation of IA obtained during dichotic testing.


Head injury and alexithymia: implications for family practice care.
Alexithymia, a deficit in emotional information processing, and a history of head injury have both been found to be related to high rates of psychosomatic illness, substance abuse, depression, and utilization of primary care services. To date, no study has examined the potential comorbidity of alexithymia and head injury in a family practice setting, a necessary step in evaluating the aetiologic role of head injury in the development of alexithymia. The goals of this study are to establish prevalence of head injury and alexithymia in a family practice setting and to evaluate the relation, if present, between the two. Patients (n =135) of a family practice residency facility were screened using the Traumatic Brain Injury Questionnaire and the Toronto Alexithymia Scale-20. Forty-nine per cent of the participants reported a history of head injury and 18% were alexithymic. Those with a history of head injury had significantly higher scores of alexithymia. Chi-square analysis indicated a relation between head injury and alexithymia. The high rates of self-reported history of head injury in family practice settings, particularly in the context of alexithymia, may adversely affect a physician's ability to care for these patients. Increasing physicians' awareness of head injury and the potential mediating role of alexithymia in medical and psychological illness may facilitate effective diagnosis and patient-physician communication.


Cosmesis in patients with breast neoplasia submitted to the hypofractionated radiotherapy with of intensity-modulated beam.
To assess the cosmetic satisfaction of patients diagnosed with breast cancer submitted to the hypofractionated radiotherapy with IMRT (hIMRT) technique and its correlation with dosimetric data of the radiotherapy planning. The retrospective cohort study that assessed women with a diagnosis of malignant breast neoplasia submitted to the conservative treatment or radical mastectomy and treated with hIMRT. In the period between August 2007 to December 2014, in a philanthropic / private institution, 170 records were selected. The cosmetic assessment was carried out by means of the Harvard/RTOG/NSABP scale with one-year minimum range after treatment. The collected dosimetric data were: breast / chest wall volume, volume that received 95% (V95%) and 107% (V107%) of the prescribed dose. The volume of the treated breasts ranged from 169 to 2.103 ml (median = 702; IQR: 535 to 914 ml). Median V95% was 86.7% (54.6-96.6%; IQR: 80.0% to 90.6%); eight (5.7%) patients had V95% higher than 95%. Median V107% was 0% (0%-16.3%; IQR: 0.0% to 0.3% and 13); 9.3% patients had V107% higher than 2%. One hundred and thirty-three (78.2%) patients responded to the cosmetic assessment: 99 (74.4%) considered the cosmetic results excellent. Significant associations between cosmetic assessment and breast volume (p=0.875), V95% (p=0.294) e V107% (p=0.301) were not found. The cosmetic results showed favorable when using hIMRT, and the lack of correlation with usual the dosimetric data illustrates the capacity of hIMRT to minimize the heterogeneity of the dose in this endpoint, even in voluminous breasts.


Attractor concretion as a mechanism for the formation of context representations.
Complex tasks often require the memory of recent events, the knowledge about the context in which they occur, and the goals we intend to reach. All this information is stored in our mental states. Given a set of mental states, reinforcement learning (RL) algorithms predict the optimal policy that maximizes future reward. RL algorithms assign a value to each already-known state so that discovering the optimal policy reduces to selecting the action leading to the state with the highest value. But how does the brain create representations of these mental states in the first place? We propose a mechanism for the creation of mental states that contain information about the temporal statistics of the events in a particular context. We suggest that the mental states are represented by stable patterns of reverberating activity, which are attractors of the neural dynamics. These representations are built from neurons that are selective to specific combinations of external events (e.g. sensory stimuli) and pre-existent mental states. Consistent with this notion, we find that neurons in the amygdala and in orbitofrontal cortex (OFC) often exhibit this form of mixed selectivity. We propose that activating different mixed selectivity neurons in a fixed temporal order modifies synaptic connections so that conjunctions of events and mental states merge into a single pattern of reverberating activity. This process corresponds to the birth of a new, different mental state that encodes a different temporal context. The concretion process depends on temporal contiguity, i.e. on the probability that a combination of an event and mental states follows or precedes the events and states that define a certain context. The information contained in the context thereby allows an animal to assign unambiguously a value to the events that initially appeared in different situations with different meanings.


Associations between Cognitive and Affective Responses to Tobacco Advertisements and Tobacco Use Incidence: A Four-Year Prospective Study among Adolescent Boys.
Exposure to tobacco advertisements is associated with initiation of tobacco use among youth. The mechanisms underlying this association are less clear. We estimated longitudinal associations between youths' cognitive and affective responses to advertisements for cigarettes, e-cigarettes, and smokeless tobacco (SLT) and initiation of these products. N = 1220 Ohio-residing boys of ages 11-16 were recruited into a cohort in 2015 and 2016. Participants completed surveys every six months for four years. Surveys assessed cognitive and affective responses to tobacco advertisements (which included health warnings) and tobacco use after an advertisement viewing activity. We used mixed-effects Poisson regression models with robust standard errors to estimate risk of initiating use of each tobacco product according to participants' cognitive (i.e., memorability of health risks) and affective (i.e., likability of advertisement) responses to advertisements for that product. No associations between affective responses to advertisements and tobacco use outcomes were detected in adjusted models. However, finding health risks memorable was associated with reduced risk of ever smoking initiation (aRR = 0.57; 95% CI: 0.34, 0.95) and a reduced risk of ever SLT initiation that approached statistical significance (aRR = 0.61; 95% CI: 0.36, 1.05). Measures to increase saliency of health risks on cigarette and SLT advertisements might reduce use among youth.


A randomised prospective study to evaluate a rapid HIV-antibody assay in the management of cases of percutaneous exposure amongst health care workers.
A rapid start of post-exposure prophylaxis with an antiretroviral regime is recommended after percutaneous exposure to blood from an HIV-positive source. Since the HIV-antibody status of the source is usually not known at the time of injury, antiretroviral treatment is started pending the results of HIV testing of the source. A randomised prospective study was designed to compare the use of a rapid-screening assay in the management of cases of percutaneous exposure with the conventional procedure. Prior to the comparative study, the accuracy of a rapid-screening assay performed by non-laboratory trained personnel was evaluated. 123 blinded HIV-positive and HIV-negative samples were correctly identified. In a randomised comparison with the conventional procedure, the application of the rapid-screening assay resulted in a significant reduction of psychological stress, drug use and cost. The estimated net benefit per case was CHF 93.-(62 US$). This study strongly supports the use of the rapid-screening assay in the management of post-exposure prophylaxis for HIV after percutaneous exposure in health care workers.


Are sports bettors looking at responsible gambling messages? An eye-tracking study on wagering advertisements.
The broadcast of wagering advertisements during televised sports matches has been associated with various adverse outcomes. In order to counter these effects, legislative bodies require wagering operators to include responsible gambling messages in their advertisements; however, the effectiveness of these messages is unclear. This study sought to examine the extent to which responsible gambling messages are looked at, in the wider context of gambling advertisements. Forty-nine regular sports bettors and 10 non-gamblers viewed a series of sports betting advertisements, while an eye-tracker recorded the number of fixations placed on responsible gambling messages, as well as other text-based wagering content. Responsible gambling messages were, generally, presented in a non-conspicuous manner. Eye-tracking data revealed that significantly fewer fixations were placed on responsible gambling messages, compared to wagering information (p < .001); however, this effect did not differ according to level of gambling risk (p = .169). The number of fixations placed on the different types of responsible gambling messages was found to vary, based on gambling risk (p = .006), as well as, what appears to be, the physical characteristics of these messages. Very few fixations were placed on, or near, responsible gambling messages, compared to other wagering information, meaning that, in their current form, they are unlikely to be effective in protecting against gambling harm. Preliminary evidence shows that presenting messages on a high-contrast/block-color background increases the number of fixations on these. Further research is needed to identify ways of increasing the effectiveness of responsible gambling initiatives in the sports betting context.


Topology-driven phase transitions in the classical monomer-dimer-loop model.
In this work, we investigate the classical loop models doped with monomers and dimers on a square lattice, whose partition function can be expressed as a tensor network (TN). In the thermodynamic limit, we use the boundary matrix product state technique to contract the partition function TN, and determine the thermodynamic properties with high accuracy. In this monomer-dimer-loop model, we find a second-order phase transition between a trivial monomer-condensation and a loop-condensation (LC) phase, which cannot be distinguished by any local order parameter, while nevertheless the two phases have distinct topological properties. In the LC phase, we find two degenerate dominating eigenvalues in the transfer-matrix spectrum, as well as a nonvanishing (nonlocal) string order parameter, both of which identify the topological ergodicity breaking in the LC phase and can serve as the order parameter for detecting the phase transitions.


Differential but Complementary HIF1α and HIF2α Transcriptional Regulation.
Effective vascular regeneration could provide therapeutic benefit for multiple pathologies, especially in chronic peripheral artery disease (PAD) and myocardial ischemia. The hypoxia inducible factors (HIFs) mediate the cellular transcriptional response to hypoxia and regulate multiple processes that are required for angiogenesis to ultimately restore perfusion and oxygen supply. In endothelial cells, both HIF1α and HIF2α are known to contribute to this role; however, the extent and individual roles of each of these HIFα remain unclear. To characterize the individual roles of HIFα, we sequenced the transcriptional outputs of stabilized forms of HIF1α and HIF2α, where they regulated 701 and 1,454 genes, respectively. HIF1α transcription primarily regulated metabolic reprogramming, whereas HIF2α exerted a larger role in regulating angiogenic extracellular signaling, guidance cues, and extracellular matrix remodeling factors. Furthermore, HIF2α almost exclusively regulated a large and diverse subset of transcription factors and coregulators that contribute to its diverse roles in hypoxia. Further understanding of how HIFs regulate cellular processes in hypoxia and angiogenesis could offer new avenues to modulate physiological angiogenesis to enhance revascularisation in ischemic conditions and other pathologies.


A routine for safe, effective endotracheal suctioning.
A routine for safe, effective endotracheal suctioning is delineated. This routine was established by correlating various periods of augmented tidal ventilation and endotracheal suctioning with continuous arterial oxygen tension measurements. Patients were evaluated at bronchography to determine the effect of head position on suction catheter placement. Inspired oxygen concentrations were measured via an intratracheal catheter during various forms of inhalation therapy and modes of breating. Using these observations, guidelines were established to maximize the benefits and minimize the risks of an endotracheal suction routine.


White Blood Cell Count Improves Prediction of Delayed Cerebral Ischemia Following Aneurysmal Subarachnoid Hemorrhage.
Immune dysregulation has long been implicated in the development of delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH). To determine the relationship of inflammatory cell biomarkers with DCI. We evaluated 849 aSAH patients who were enrolled into a prospective observational cohort study and had a white blood cell (WBC) differential obtained within 72 h of bleed onset. WBC count > 12.1 × 109/L (odds ratio 4.6; 95% confidence interval [CI]: 1.9-11, P < 0.001) was the strongest Complete Blood Count (CBC) predictor of DCI after controlling for clinical grade (P < .001), thickness of SAH blood on admission computed tomography (P = .002), and clipping aneurysm repair (P < .001). A significant interaction between clinical grade and WBC count (odds ratio 0.8, 95% CI: 0.6-1.0, P = .02) revealed that good-grade patients with elevated WBC counts (49%: 273/558) had increased odds for DCI indistinguishable from poor-grade patients. Multivariable Cox regression also showed that elevated WBC counts in good-grade patients increased the hazard for DCI to that of poor-grade patients (hazard ratio 2.1, 95% CI 1.3-3.2, P < .001). Receiver operating characteristic curve analysis of good-grade patients revealed that WBC count (area under the curve [AUC]: 0.63) is a stronger DCI predictor than the modified Fisher score (AUC: 0.57) and significantly improves multivariable DCI prediction models (Z = 2.0, P = .02, AUC: 0.73; PPV: 34%; NPV: 92%). Good-grade patients with early elevations in WBC count have a similar risk and hazard for DCI as poor-grade patients. Good-grade patients without elevated WBC may be candidates to be safely downgraded from the intensive care unit, leading to cost savings for both patient families and hospitals.


'I'm never going to change unless someone tells me I need to': fostering feedback dialogue between general practice supervisors and registrars.
Feedback is often unidirectional and focused on learners receiving feedback. Learning relationships are viewed as influential to promoting feedback dialogue. The aim of this study was to explore factors that facilitate or impede feedback between general practice supervisors and registrars. An in-depth qualitative study was conducted. Data collection featured semistructured interviews with registrars (n = 9) and supervisors (n = 5). Interviews were audio recorded and analysed interpretatively. Feedback was affected by personal (i.e. resilience, humility), relational (i.e. strength of supervisory relationship, power differentials) and contextual (i.e. culture) factors. Registrars are not accustomed to providing feedback and supervisors do not typically request feedback. Past feedback experiences affect registrar engagement in feedback exchanges. A culture of feedback dialogue within training organisations and training practices is essential. Power imbalance needs to be addressed, particularly for feedback by registrars. Strategies to develop feedback skills and promote an open feedback culture are essential.


Arginine and polyamines in Helicobacter pylori-induced immune dysregulation and gastric carcinogenesis.
L-arginine (L-Arg) is metabolized by nitric oxide synthase and arginase enzymes. The gastric pathogen Helicobacter pylori causes peptic ulcer disease and gastric cancer. We have shown that alterations in L-Arg availability and metabolism into polyamines contribute significantly to the dysregulation of the host immune response to this infection. Nitric oxide (NO) derived from inducible NO synthase (iNOS) can kill H. pylori. There are multiple mechanisms leading to failure of this process, including competition for L-Arg substrate by H. pylori arginase, and induction of host macrophage arginase II (Arg2) and ornithine decarboxylase (ODC). Generation of spermine by ODC inhibits iNOS translation and NO-mediated H. pylori killing. Expression of ODC is dependent on formation of a unique AP-1 complex, leading to upregulation of c-Myc as a transcriptional enhancer. Macrophage apoptosis is mediated by oxidation of spermine via the enzyme spermine oxidase (SMO) that generates hydrogen peroxide (H(2)O(2)), and thus oxidative stress-induced mitochondrial membrane polarization. Our studies have demonstrated that apoptosis occurs through a pERK → pc-Fos/c-Jun → c-Myc → ODC → SMO pathway. In gastric epithelial cells, activation of oxidative stress by H. pylori is dependent on SMO induction and results in both apoptosis and DNA damage, such that inhibition or knockdown of SMO markedly attenuates these events. In summary, L-Arg metabolism by the arginase-ODC pathway and the activation of SMO leads to H. pylori-induced DNA damage and immune dysregulation through polyamine-mediated oxidative stress and impairment of antimicrobial NO synthesis. Our studies indicate novel targets for therapeutic intervention in H. pylori-associated diseases, including gastritis, ulcer disease, and gastric cancer.


Student and faculty performance in clinical simulations with access to a searchable information resource.
In this study we explore how students' use of an easily accessible and searchable database affects their performance in clinical simulations. We do this by comparing performance of students with and without database access and compare these to a sample of faculty members. The literature supports the fact that interactive information resources can augment a clinician's problem solving ability in small clinical vignettes. We have taken the INQUIRER bacteriological database, containing detailed information on 63 medically important bacteria in 33 structured fields, and incorporated it into a computer-based clinical simulation. Subjects worked through the case-based clinical simulations with some having access to the INQUIRER information resource. Performance metrics were based on correct determination of the etiologic agent in the simulation and crosstabulated with student access of the information resource; more specifically it was determined whether the student displayed the database record describing the etiologic agent. Chi-square tests show statistical significance for this relationship (chi 2 = 3.922; p = 0.048). Results support the idea that students with database access in a clinical simulation environment can perform at a higher level than their counterparts who lack access to such information, reflecting favorably on the use of information resources in training environments.


Ontological Security in Nursing Homes for Older Persons - Person-Centred Care is the Power of Balance.
The Swedish national guidelines for elderly care describe how older persons should be able to trust that their care is permeated with security. Different theoretical perspectives can be found that describe what creates security. Many studies have been done about security. However, few studies have explicitly asked older persons what security in nursing homes means to them. The aim of the study was to describe how older persons in nursing homes talked and reflected about security in their daily lives. Nine older persons were interviewed in, in-depth interviews one to three times and the resulting data was analysed using content analysis. The older persons adapted to having their own needs and those of the other older persons met and to the staff routines which created a sense of security. At the same time, they longed for security in which they could trust themselves and create their own daily life. Further to have a sense of belonging and of being liked for created an internal, interpersonal and external security. This can be linked to an ontological security which means having a sense of confidence in the continuity of self-identity and order in events, a being in the world. Person-centred instead of institution- centred care can provide the balance of power that allows the older person to obtain ontological security in which the staff's ability to create a relationship with the older persons becomes crucial.


Breathing nitric oxide plus hydrogen gas reduces ischemia-reperfusion injury and nitrotyrosine production in murine heart.
Inhaled nitric oxide (NO) has been reported to decrease the infarct size in cardiac ischemia-reperfusion (I/R) injury. However, reactive nitrogen species (RNS) produced by NO cause myocardial dysfunction and injury. Because H₂ is reported to eliminate peroxynitrite, it was expected to reduce the adverse effects of NO. In mice, left anterior descending coronary artery ligation for 60 min followed by reperfusion was performed with inhaled NO [80 parts per million (ppm)], H₂ (2%), or NO + H₂, starting 5 min before reperfusion for 35 min. After 24 h, left ventricular function, infarct size, and area at risk (AAR) were assessed. Oxidative stress associated with reactive oxygen species (ROS) was evaluated by staining for 8-hydroxy-2'-deoxyguanosine and 4-hydroxy-2-nonenal, that associated with RNS by staining for nitrotyrosine, and neutrophil infiltration by staining for granulocyte receptor-1. The infarct size/AAR decreased with breathing NO or H₂ alone. NO inhalation plus H₂ reduced the infarct size/AAR, with significant interaction between the two, reducing ROS and neutrophil infiltration, and improved the cardiac function to normal levels. Although nitrotyrosine staining was prominent after NO inhalation alone, it was eliminated after breathing a mixture of H₂ with NO. Preconditioning with NO significantly reduced the infarct size/AAR, but not preconditioning with H₂. In conclusion, breathing NO + H₂ during I/R reduced the infarct size and maintained cardiac function, and reduced the generation of myocardial nitrotyrosine associated with NO inhalation. Administration of NO + H₂ gases for inhalation may be useful for planned coronary interventions or for the treatment of I/R injury.


American Association of Neuromuscular & Electrodiagnostic Medicine evidenced-based review: use of surface electromyography in the diagnosis and study of neuromuscular disorders.
Surface electromyography (sEMG) measures myoelectrical signals recorded from sensors placed on the skin surface. The non-invasive nature of sEMG makes it a potentially useful technology for studying diseases of muscle and nerve. Reviews published by the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM) and the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology (AAN), covering 1964-1994 and 1952-1998, respectively, concluded that sEMG adds no clinical utility over conventional needle EMG (nEMG) for the diagnosis of neuromuscular disease. The AANEM sEMG task force reevaluated the diagnostic utility and added value of this technology for the study of neuromuscular disease based on a contemporary review of relevant literature published between January 1994 and February 2006. The present review concludes that sEMG may be useful to detect the presence of neuromuscular disease (level C rating, class III data), but there are insufficient data to support its utility for distinguishing between neuropathic and myopathic conditions or for the diagnosis of specific neuromuscular diseases. sEMG may be useful for additional study of fatigue associated with post-poliomyelitis syndrome and electromechanical function in myotonic dystrophy (level C rating, class III data).


The challenge of evaluating pain and a pre-incisional local anesthetic block.
Background. Our objective was to test the effectiveness of a local anesthetic line block administered before surgery in reducing postoperative pain scores in dogs undergoing ovariohysterectomy (OVHX). Methods. This study is a prospective, randomized, blinded, clinical trial involving 59 healthy female dogs. An algometric pressure-measuring device was used to determine nociceptive threshold, and compared to three subjective pain scales. Group L/B received a line block of lidocaine (4 mg/kg) and bupivacaine (1 mg/kg) subcutaneously in the area of the incision site and saline subcutaneously as premedication; group L/BM (positive control) received a similar block and morphine (0.5 mg/kg) subcutaneously for premedication; and group SS (negative control) received a saline line block and saline premedication. Criteria for rescue analgesia were defined before the study. Dogs were assessed prior to surgery, at extubation (time 0) and at 2, 4, 6, 8 and 24 h post-recovery. The data were analyzed with one-way ANOVA, and a Split Plot Repeated Measures ANOVA with one grouping factor and one repeat factor (time). P < 0.05 was considered statistically significant. Results. Approximately 33% of dogs required rescue analgesia at some point during the study, with no significant difference between groups. There was no significant difference between treatment groups with any assessment method. Conclusions. As there were no statistically significant differences between positive and negative controls, the outcome of this technique cannot be proven.


Value of epidemiologic studies in determining the true incidence of adverse events. The nonsteroidal anti-inflammatory drug story.
Evidence supporting differential toxic effects of nonsteroidal anti-inflammatory drugs (NSAIDs) often is derived from spontaneous reports of adverse events to the US Food and Drug Administration (FDA). These reports represent observations from an undefined, exposed population that are not collected in a standardized manner and therefore are subject to reporting biases. Epidemiologic studies, in which the numbers of patients experiencing an adverse event and exposed to the drug are known, provide more reliable measures of risk and can place spontaneous reports in perspective. To compare both data sources with regard to NSAID-associated gastrointestinal, liver, and skin events. We obtained spontaneous reports of these adverse events for diclofenac, nabumetone, naproxen, and piroxicam. Published epidemiologic studies of these events were reviewed. Spontaneous reports did not mirror reliably the results of epidemiologic studies. Spontaneous reports showed higher associations of gastrointestinal and skin events with nabumetone and piroxicam and hepatic events with diclofenac. Epidemiologic studies generally did not show differential risk among these NSAIDs. When the 4 NSAIDs are compared in epidemiologic studies, there is no quantitative basis for identifying 1 as more or less toxic than the others, underlining the hazard of deriving quantitative conclusions from spontaneous reports. Spontaneous reports are an unreliable measure of risk; rather, they may provide evidence of the relative awareness of specific toxic effects among physicians.


Dietary fish oil attenuates cardiac hypertrophy in lipotoxic cardiomyopathy due to systemic carnitine deficiency.
1,2-Diacylglycerol (DAG), a lipid second messenger that activates protein kinase C (PKC), is increased with a distinct fatty acid composition in the heart of the juvenile visceral steatosis (JVS) mouse, which develops pathological cardiac hypertrophy with lipid accumulation induced by the perturbation of fatty acid beta-oxidation due to systemic carnitine deficiency. Fish oil (FO) may exert its beneficial effects on the cardiomyopathy in JVS mice by modifying the molecular species composition of myocardial DAG. To test this hypothesis, we investigated the effects of dietary FO on the hypertrophied hearts in JVS mice. Both control and JVS mice were fed a FO diet (containing 10% FO) or a standard diet from 4 weeks of age. At 8 weeks of age, the ventricular-to-body weight ratio in JVS mice was 2.7-fold higher than that in controls (9.9 +/- 0.1 vs. 3.7 +/- 0.1 mg/g, P < 0.01) and was reduced by dietary FO (7.7 +/- 0.1 mg/g, P < 0.01 vs. JVS mice). In JVS mice, myocardial DAG levels were elevated by 2.3-fold with a distinct fatty acid composition with increases in C18:1n-7,9 and C18:2n-6 fatty acids compared with controls; dietary FO had no effects on the total DAG levels but significantly altered the fatty acid composition of DAG with reduction of both fatty acid species. Immunoblot analysis showed that dietary FO prevented the membrane translocation of cardiac PKCs alpha, beta2, and epsilon in JVS mice. Dietary FO did not affect the plasma and myocardial total carnitine levels in JVS mice. Furthermore, dietary FO significantly improved the progressive left ventricular dysfunction and survival rate in JVS mice. Dietary FO may attenuate cardiac hypertrophy with improvements in cardiac function and survival in JVS mice via modification of the molecular species composition of myocardial DAG and the consequent inhibition of PKC redistribution. These results suggest the implication of the molecular species composition of DAG in the pathogenesis of lipotoxic cardiomyopathy due to perturbations of fatty acid beta-oxidation.


[Linguistics in blood group serology].
With a view to terminological uniformity, blood group serologists, immunologists and transfusion physicians should refer only to the "ABo' (zero) in stead of the "ABO' system. They also should use "HLA antibodies' in stead of "anti HLA antibodies'. The new Dutch spelling "resus' in stead of "Rhesus' is incorrect from a historical point of view.


Drug intake and the dexamethasone suppression test.
The dexamethasone suppression test (DST) is being used clinically as a diagnostic laboratory test for depression. Drug histories collected from 336 psychiatric inpatients revealed that 60% were taking one or more drugs suspected of altering DST results in either a false-positive or false-negative manner. Practical limitations of the DST as a biologic marker of affective syndromes in relation to patient drug use are discussed.


Quantifying the environmental impact of a major coal mine project on the adjacent Great Barrier Reef ecosystems.
A major coal mine project in Queensland, Australia, is currently under review. It is planned to be located about 10 km away from the Great Barrier Reef World Heritage Area (GBRWHA). Sediment dispersal patterns and their impact on marine ecosystems have not been properly assessed yet. Here, we simulate the dispersal of different sediment types with a high-resolution ocean model, and derive their environmental footprint. We show that sediments finer than 32 μm could reach dense seagrass meadows and a dugong sanctuary within a few weeks. The intense tidal circulation leads to non-isotropic and long-distance sediment dispersal patterns along the coast. Our results suggest that the sediments released by this project will not be quickly mixed but rather be concentrated where the most valuable ecosystems are located. If accepted, this coal mine could therefore have a far-reaching impact on the GBRWHA and its iconic marine species.


Preferred conformation of the glycosidic linkage of methyl-beta-mannose.
The conformational preference of the glycosidic linkage of methyl-beta-mannose was studied in the gas phase and in aqueous solution by ab initio calculations, and by molecular dynamics (MD) and Car-Parrinello molecular dynamics (CPMD) simulations. MD simulations were performed with various water potential functions to study the impact of the chosen water potential on the predicted conformational preference of the glycosidic linkage of the carbohydrate in solution. This study shows that the trans (t) orientation of the glycosidic linkage of methyl-beta-mannose is preferred over its gauche clockwise (g+) orientation in solution. CPMD simulations clearly indicate that this preference is due to intermolecular hydrogen bonding with surrounding water molecules, whereas no such information could be demonstrated by MD simulations. This study demonstrates the importance of ab initio molecular dynamics simulations in studying the structural properties of carbohydrate-water interactions.


Intestinal lipid absorption and transport.
The purpose of this review is to update the reader on our current knowledge of the digestion, uptake, and transport of dietary lipid. In particular, it discusses how intestinal lipid transporters may play a role in the uptake of lipids by the enterocytes, and how chylomicrons are formed in the enterocytes and packaged for export into the lymphatic system through exocytosis. The classification and properties of lipids is first described followed by a discussion of structured lipids and their role in human nutrition. Digestion of triacylglycerols takes place in the stomach aided by the enzyme gastric lipase. The origin and properties of lingual and gastric lipase are reviewed. Most digestion of triacylglycerols by pancreatic lipase occurs in the intestinal lumen. Similarly, digestion of cholesteryl ester and phospholipids also takes place in the intestinal lumen. This review describes in considerable detail the uptake of lipid digestion products by the enterocytes, particularly the role of recently identified lipid transporters. The intracellular trafficking and the resynthesis of complex lipids from the lipid digestion products are talked about, particularly within the context of the recently generated knockout mouse that lacks the key lipid reesterification enzymes. Finally, the mechanisms of the formation and secretion of chylomicrons is described and clinical disorders discussed.


Urgent endoscopy in elderly patients with non-variceal upper gastrointestinal bleeding.
Age of the patient is an important prognostic factor in patients with non-variceal upper gastrointestinal bleeding (UGIB). Despite that fact, current treatment algorithms do not differentiate UGIB management according to the patient's age. To compare treatment outcomes in patients below and above 75 years of age, treated for UGIB with urgent endoscopy. Prospective analysis of treatment outcomes in 295 patients with non-variceal UGIB divided into two age groups (group A < 75 years of age, group B > 75 years of age). Urgent endoscopy (up to 3 h since admission) was performed in 292 patients. The groups were compared in regards to the duration of symptoms, previous UGIB, presence of factors predisposing to UGIB (NSAIDs, peptic ulcer disease, liver cirrhosis, and previous gastrointestinal surgery), haemodynamic state and haemoglobin (Hb) levels on admission. We analysed the causes of UGIB, severity of UGIB on the Forrest scale, type of endoscopic bleeding control method, and co-morbidities with use of the Charlson Co-morbidity Index (CCI). Treatment outcomes were assessed in regard of mortality rate, UGIB-recurrence rate, duration of hospital stay, amount of transfused blood products and the requirement of intensive therapy unit (ITU) or other departments' admissions. Patients were followed until their discharge home. Mortality rate was 6.8% (group A vs. B: 3.5% vs. 18.7%; p = 0.001). Upper gastrointestinal bleeding recurrence was noted in 12.2% of patients (group A vs. B: 12.5% vs. 10.9%; p = 0.73). 2.4% of patients required surgery for UGIB (group A vs. B: 1.7% vs. 4.7%; p = 0.16). Patients in group B required ITU admission more frequently (group A vs. B: 1% vs. 4.7%; p < 0.01). The mean hospital stay (4.3 days) and the mean number of transfused packed red blood cells (PRBCs) (2.35 Units) did not differ between the groups. Patients in group B used NSAIDS much more frequently, more often had hypovolaemic shock and had a higher CCI score. Urgent endoscopy is an important and broadly accepted method of treatment of UGIB. Despite strict adherence to the modern UGIB-treatment algorithms, mortality remains high in the elderly. Thus, these patients need particular attention. The presented study indicates that the standard management might not be sufficient in elderly patients.


Management of Guillain-Barré syndrome in Bangladesh: Clinical practice, limitations and recommendations for low- and middle-income countries.
Considerable variation in clinical practice for management of Guillain-Barré syndrome (GBS) has been observed worldwide. Diagnosis and treatment are challenging in low- and middle-income countries (LMIC) due to lack of facilities and treatment availability. We aimed to evaluate current clinical practice and limitations and to provide recommendation for GBS management in low-resource settings. We conducted an explanatory-sequential mixed-methods survey among neurologists and internists working in tertiary and secondary government hospitals in Bangladesh. There were two phases: (1) quantitative (cross-sectional survey to evaluate clinical practice and limitations); (2) qualitative (key informant interview to explain certain clinical practice and provide recommendations for GBS management in LMIC). Data were analyzed by frequencies, χ2 test and thematic analysis. Among 159 physicians (65 neurologists and 94 internists), 11% and 8% physicians used Brighton and NINDS criteria respectively to diagnose GBS. Specific treatment protocols of GBS were used by 12% physicians. Overcrowding of patients, inadequate diagnostic facilities, high costs of standard therapy, and inadequate logistics and trained personnel for intensive care unit and rehabilitation services were considered major challenges for GBS management. In qualitative part, respondents recommended regular training for the physicians, development of cost-effective treatment strategies and appropriate patients' referral and management guideline considering existing limitations in health service delivery and socio-economic status of the country. Current study design and recommendations might be applied for other LMIC. Such data can assist policymakers to identify areas requiring urgent attention and take required action to improve GBS management in LMIC.


Convergent Validity of the PUTS.
Premonitory urges are a cardinal feature in Gilles de la Tourette syndrome. Severity of premonitory urges can be assessed with the "Premonitory Urge for Tic Disorders Scale" (PUTS). However, convergent validity of the measure has been difficult to assess due to the lack of other urge measures. We investigated the relationship between average real-time urge intensity assessed by an in-house developed real-time urge monitor (RUM), measuring urge intensity continuously for 5 min on a visual analog scale, and general urge intensity assessed by the PUTS in 22 adult Tourette patients (mean age 29.8 ± 10.3 SD, 19 males). Additionally, underlying factors of premonitory urges assessed by the PUTS were investigated in the adult sample using factor analysis and were replicated in 40 children and adolescents diagnosed with Tourette syndrome (mean age 12.05 ± 2.83 SD, 31 males). Cronbach's α for the PUTS 10 was acceptable (α = 0.79) in the adult sample. Convergent validity between average real-time urge intensity scores (as assessed with the RUM) and the 10-item version of the PUTS (r = 0.64) and the 9-item version of the PUTS (r = 0.66) was good. A factor analysis including the 10 items of the PUTS and average real-time urge intensity scores revealed three factors. One factor included the average real-time urge intensity score and appeared to measure urge intensity, whereas the other two factors can be assumed to reflect the (sensory) quality of urges and subjective control, respectively. The factor structure of the 10 PUTS items alone was replicated in a sample of children and adolescents. The results indicate that convergent validity between the PUTS and the real-time urge assessment monitor is good. Furthermore, the results suggest that the PUTS might assess more than one dimension of urges, and it may be worthwhile developing different subscales of the PUTS assessing premonitory urges in terms of intensity and quality, as well as subjectively experienced control over tics and premonitory urges.


A MITF mutation associated with a dominant white phenotype and bilateral deafness in German Fleckvieh cattle.
A dominantly inherited syndrome associated with hypopigmentation, heterochromia irides, colobomatous eyes and bilateral hearing loss has been ascertained in Fleckvieh cattle (German White Fleckvieh syndrome). This syndrome has been mapped to bovine chromosome (BTA) 22 using a genome-wide association study with the bovine high density single nucleotide polymorphism array. An R210I missense mutation has been identified within microphthalmia-associated transcription factor (MITF) as responsible for this syndrome. The mutation is located in the highly conserved basic region of the protein and causes a negative-dominant effect. SOX10 and PAX3 promoter binding site mutations in MITF could be ruled out as causative for the German White Fleckvieh syndrome. Molecular characterization of this newly detected bovine syndrome means a large animal model is now available for the Tietz syndrome in humans.


Long-term survival and vascular event risk after transient ischaemic attack or minor ischaemic stroke: a cohort study.
Determinants of survival and of risk of vascular events after transient ischaemic attack (TIA) or minor ischaemic stroke are not well defined in the long term. We aimed to restudy these risks in a prospective cohort of patients after TIA or minor ischaemic stroke (Rankin grade< or =3), after 10 years or more. We assessed the survival status and occurrence of vascular events in 2473 participants of the Dutch TIA Trial (recruitment in 1986-89; arterial cause of cerebral ischaemia). We included 24 hospitals in the Netherlands that recruited at least 50 patients. Primary outcomes were all-cause mortality and the composite event of death from all vascular causes, non-fatal stroke, and non-fatal myocardial infarction. We assessed cumulative risks by Kaplan-Meier analysis and prognostic factors with Cox univariate and multivariate analysis. Follow-up was complete in 2447 (99%) patients. After a mean follow-up of 10.1 years, 1489 (60%) patients had died and 1336 (54%) had had at least one vascular event. 10-year risk of death was 42.7% (95% CI 40.8-44.7). Age and sex-adjusted hazard ratios were 3.33 (2.97-3.73) for age over 65 years, 2.10 (1.79-2.48) for diabetes, 1.77 (1.45-2.15) for claudication, 1.94 (1.42-2.65) for previous peripheral vascular surgery, and 1.50 (1.31-1.71) for pathological Q waves on baseline electrocardiogram. 10-year risk of a vascular event was 44.1% (42.0-46.1). After falling in the first 3 years, yearly risk of a vascular event increased over time. Predictive factors for risk of vascular events were similar to those for risk of death. Long-term secondary prevention in patients with cerebral ischaemia still has room for further improvement.


N-acetylcysteine improves oxidative stress and inflammatory response in patients with community acquired pneumonia: A randomized controlled trial.
Oxidative stress is considered to be part of the pathogenic mechanism for community-acquired pneumonia (CAP) and is closely linked to inflammation. Attenuation of oxidative stress would be expected to reduce pulmonary damage. Antioxidants have been found to be effective in alleviating lung injury and protecting against damage of other organs.The aim of the study was to compare the effect of adding N-acetylcysteine (NAC) to conventional treatment versus conventional treatment on oxidative stress, inflammatory factors, and radiological changes in CAP patients.Eligible CAP patients at Weihai Municipal Hospital were stratified and randomly assigned to either NAC group or non-NAC group between August 2016 and March 2017. The NAC group received conventional treatment for pneumonia and NAC (1200 mg/d). Thenon-NAC group received conventional therapy. malondialdehyde (MDA), superoxide dismutase (SOD), total antioxidant capacity (TAOC), tumor necrosis factor-α (TNF-α), and computed tomography (CT) images were evaluated at baseline and after treatment. The primary endpoint indicators were the changes in oxidative stress parameters (MDA, TAOC, SOD) and TNF-α after treatment in the NAC group compared with those in the non-NAC group. The secondary endpoint indicator was any difference in CT scores after treatment in the NAC group compared with the non-NAC group.Baseline levels of MDA, TAOC, SOD, and TNF-α were similar between the 2 groups before treatment. Plasma levels of MDA and TNF-α decreased more (P < .05 MDA:p 0.004, TNF-α:p <0.001) in the NAC group than the non-NAC group, and there was a reliable increase in TAOC content (p 0.005). There was no significant difference in increased plasma SOD activity between the groups (p 0.368), and the NAC group did not show a greater improvement from CT scores. No NAC-related adverse effects were observed.Addition of NAC therapy for CAP patients reduced MDA and TNF-α and increased TAOC. Treatment with NAC may help to reduce oxidative and inflammatory damage in pneumonia patients.


Muscular Fitness and Cardiometabolic Variables in Children and Adolescents: A Systematic Review.
The importance of muscular fitness (MF) in the performance of activities of daily living is unequivocal. Additionally, emerging evidence has shown MF can reduce cardiometabolic risk in children and adolescents. The purpose of this study was to examine and summarize the evidence regarding the relationship between MF phenotypes (i.e., maximum muscular strength/power, muscular endurance, and maximum muscular strength/power/endurance) and cardiometabolic variables (obesity, blood pressure, lipids, glucose homeostasis, inflammatory markers, and clustered cardiometabolic variables) in children and adolescents. This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and was registered with PROSPERO, number CRD42020179273. A systematic review was performed on five databases (PubMed, EMBASE, SciELO, Scopus, and Web of Knowledge) from database inception to May 2020, with complementary searches in reference lists. Eligibility criteria included (1) a study sample of youth aged ≤ 19 years, (2) an assessment of MF with individual or clustered cardiometabolic variables derived from adjusted models (regardless of test/measurement adopted or direction of reported association), and (3) a report of the association between both, using observational studies. Only original articles published in peer-reviewed journals in English, Portuguese, and Spanish languages were considered. The quality of the included studies was assessed by using the National Heart, Lung, and Blood Institute checklist. The percentage of results reporting a statistically significant inverse association between each MF phenotype and cardiometabolic variables was calculated. Of the 23,686 articles initially identified, 96 were included (77 cross-sectional and 19 longitudinal), with data from children and adolescents from 35 countries. The score for the quality of evidence ranged from 0.33 to 0.92 (1.00 maximum). MF assessed by maximum muscular strength/power was inversely associated with lower obesity (64/113 total results (56.6%)) and reduction in clustered cardiometabolic risk (28/48 total results (58.3%)). When assessed by muscular endurance, an inverse association with obesity (30/44 total results (68.1%)) and cardiometabolic risk (5/8 total results (62.5%)) was identified. Most of the results for the relationship between MF phenotypes with blood pressure, lipids, glucose homeostasis, and inflammatory markers indicated a paucity of evidence for these interrelationships (percentage of results below 50.0%). MF assessed by maximum muscular strength/power or muscular endurance is potentially associated with lower obesity and lower risk related to clustered cardiometabolic variables in children and adolescents. There is limited support for an inverse association between MF with blood pressure, lipids, glucose homeostasis biomarkers, and inflammatory markers in children and adolescents.


α-Mangostin induces apoptosis and suppresses differentiation of 3T3-L1 cells via inhibiting fatty acid synthase.
α-Mangostin, isolated from the hulls of Garcinia mangostana L., was found to have in vitro cytotoxicity against 3T3-L1 cells as well as inhibiting fatty acid synthase (FAS, EC 22.214.171.124). Our studies showed that the cytotoxicity of α-mangostin with IC(50) value of 20 µM was incomplicated in apoptotic events including increase of cell membrane permeability, nuclear chromatin condensation and mitochondrial membrane potential (ΔΨm) loss. This cytotoxicity was accompanied by the reduction of FAS activity in cells and could be rescued by 50 µM or 100 µM exogenous palmitic acids, which suggested that the apoptosis of 3T3-L1 preadipocytes induced by α-mangostin was via inhibition of FAS. Futhermore, α-mangostin could suppress intracellular lipid accumulation in the differentiating adipocytes and stimulated lipolysis in mature adipocytes, which was also related to its inhibition of FAS. In addition, 3T3-L1 preadipocytes were more susceptible to the cytotoxic effect of α-mangostin than mature adipocytes. Further studies showed that α-mangostin inhibited FAS probably by stronger action on the ketoacyl synthase domain and weaker action on the acetyl/malonyl transferase domain. These findings suggested that α-mangostin might be useful for preventing or treating obesity.


Sexual dimorphism and bilateral asymmetry of syrinx and vocal tract in the European starling (Sturnus vulgaris).
Sexually dimorphic vocal behavior in zebra finches (Taeniopygia guttata) is associated with a 100% larger syrinx in males and other morphological adaptations of the sound source. The songbird syrinx consists of two independent sound sources, whose specialization for different spectral ranges may be reflected in morphological properties, but the morphology of labia and syringeal skeleton have not been investigated for lateralized specializations. Similarly, little is known whether the morphology of the songbird vocal tract reflects differences in vocal behavior. Here, we tested the hypothesis that different vocal behavior and specialization is reflected in the morphology. We investigated syringeal and upper vocal tract morphology of male and female European starlings (Sturnus vulgaris). Female starlings exhibit smaller vocal repertoires and sing at lower rates than males. In males, the left syrinx produces mostly low frequencies, while the right one is used for higher notes. Macroscopic and histological techniques were used to record nineteen measurements from the syrinx and the vocal tract which were tested for sexual differences in syrinx and vocal tract and for lateral asymmetry within the syrinx. Sexually dimorphic vocal behavior is reflected in the morphology of the starling syrinx. Males have a larger syrinx with the size difference attributable to increased muscle mass and three enlarged elements of the syringeal skeleton. The upper vocal tract, however, does not differ between males and females. Distinct lateralization was found in two elements of the syringeal skeleton of females, and the labia in the left syrinx are larger than those on the right in both sexes. The sexual dimorphism of the syringeal size is smaller in starlings (35%) than in zebra finches (100%), which is consistent with the different vocal behavior of females in both species. The morphological differences between the two sound sources are discussed in relation to their vocal performance.


Outcomes Following Transcatheter Aortic Valve Replacement for Aortic Stenosis in Patients With Type 0 Bicuspid, Type 1 Bicuspid, and Tricuspid Aortic Valves.
Data concerning the outcomes of transcatheter aortic valve replacement in type 0 bicuspid aortic stenosis (AS) are scarce. The study aims to compare the outcomes of transcatheter aortic valve replacement for AS in patients with type 0 bicuspid, type 1 bicuspid, and tricuspid aortic valve anatomy. We enrolled consecutive patients undergoing transcatheter aortic valve replacement for severe AS between 2012 and 2022 in this single-center retrospective cohort study. The primary outcome was mortality, while secondary outcomes included in-hospital complications such as stroke and pacemaker implantation and transcatheter heart valve hemodynamic performance. The number of patients with AS with type 0 bicuspid, type 1 bicuspid, and tricuspid aortic valve anatomy was 328, 302, and 642, respectively. Self-expanding transcatheter heart valves were used in the majority of patients (n=1160; 91.4%). In the matched population, differences in mortality (30 days: 4.2% versus 1.7% versus 1.7%, Poverall=0.522; 1 year: 10% versus 2.3% versus 6.2%, Poverall=0.099) and all stroke (30 days: 1.0% versus 0.9% versus 0.0%, Poverall=0.765; 1 year: 1.4% versus 1.6% versus 1.3%, Poverall=NS) were nonsignificant, and the incidence of overall in-hospital complications was comparable among groups. Ascending aortic diameter was the single predictor of 1-year mortality in type 0 bicuspid patients (hazard ratio, 1.59 [95% CI, 1.03-2.44]; P=0.035). The proportion of patients with a mean residual gradient ≥20 mm Hg was the highest in those with type 0 bicuspid anatomy, although the need for permanent pacemaker implantation was the lowest in this group. Major clinical outcomes of transcatheter aortic valve replacement for AS in patients with type 0 bicuspid, type 1 bicuspid, and tricuspid aortic valve anatomy are equivalent at short- and mid-term follow-up. These observations merit further exploration in prospective international registries and randomized controlled trials.


Italian intersociety consensus on prevention, diagnosis, and treatment of delirium in hospitalized older persons.
Delirium is a severe neuropsychiatric syndrome characterized by inattention and global cognitive dysfunction in the setting of an acute medical illness, medical complication, drug intoxication, or drug withdrawal. The most important risk factors are advanced age and dementia, whereas pain, dehydration, infections, stroke, metabolic disturbances, and surgery are the most common triggering factors. Although delirium is a common clinical syndrome in different settings of care (acute care hospitals, inpatient rehabilitation facilities, nursing homes, and hospices), it often remains under-recognized, poorly understood, and inadequately managed. There exists a clear need for improved understanding to overcome cultural stereotypes, and for the development and dissemination of a comprehensive model of implementation of general good practice points. A network of Italian national scientific societies was thus convened (1) to develop a collaborative multidisciplinary initiative report on delirium in elderly hospitalized patients, (2) to focus the attention of health care personnel on prevention, diagnosis, and therapy of patients suffering from delirium, and (3) to make the health services research community and policy-makers more aware of the potential risks of this condition providing a reference for training activities and data collection.


[Forensic medical assessment of the origin of the missed early post-traumatic abortions].
The objective of the present study was to develop an algorithm for the forensic medical assessment of the origin of the missed early post-traumatic abortions. The analysis of the available data on the main variants of traumatic pregnancy interruption was carried out. Diagnostic features of the missed early post-traumatic abortions are considered along with the possible errors in the use of the current approaches to forensic medical assessment of their origin. The proposed algorithm for the forensic medical assessment of the origin of the missed early post-traumatic abortions takes into consideration the specific features of the objects of interest and includes the analysis of the results of ultrasonic studies of the uterine cavity and histological investigations of the scraps of endometrial tissue. Absolute and probabilistic criteria for spontaneous and traumatic origin of the missed early post-traumatic abortions. The proposed algorithm is recommended for the use in routine clinical practice for the elucidation of the causes of the missed early post-traumatic abortions.


Mesenchymal Remodeling during Palatal Shelf Elevation Revealed by Extracellular Matrix and F-Actin Expression Patterns.
During formation of the secondary palate in mammalian embryos, two vertically oriented palatal shelves rapidly elevate into a horizontal position above the tongue, meet at the midline, and fuse to form a single entity. Previous observations suggested that elevation occurs by a simple 90° rotation of the palatal shelves. More recent findings showed that the presumptive midline epithelial cells are not located at the tips of palatal shelves before elevation, but mostly toward their medial/lingual part. This implied extensive tissue remodeling during shelf elevation. Nevertheless, it is still not known how the shelf mesenchyme reorganizes during this process, and what mechanism drives it. To address this question, we mapped the distinct and restricted expression domains of certain extracellular matrix components within the developing palatal shelves. This procedure allowed to monitor movements of entire mesenchymal regions relative to each other during shelf elevation. Consistent with previous notions, our results confirm a flipping movement of the palatal shelves anteriorly, whereas extensive mesenchymal reorganization is observed more posteriorly. There, the entire lingual portion of the vertical shelves moves close to the midline after elevation, whereas the mesenchyme at the original tip of the shelves ends up ventrolaterally. Moreover, we observed that the mesenchymal cells of elevating palatal shelves substantially align their actin cytoskeleton, their extracellular matrix, and their nuclei in a ventral to medial direction. This indicates that, like in other morphogenetic processes, actin-dependent cell contractility is a major driving force for mesenchymal tissue remodeling during palatogenesis.


Fasting alters somatostatin binding to liver membranes of rainbow trout (Oncorhynchus mykiss).
Somatostatins are a diverse family of peptides that influence various aspects of animal growth, development, and metabolism. Recent work in our laboratory has shown that somatostatins stimulate hepatic lipolysis in rainbow trout. In this study we characterized somatostatin-binding sites in trout hepatic membrane preparations. We also examined changes in binding characteristics brought about by food deprivation. Binding of [Tyr11]-somatostatin-14 (SS-14) was saturable, reversible, and time- and temperature-dependent. Under optimal conditions, [Tyr11]-SS-14 specific binding averaged 5.7 +/- 0.3%. While SS-14 and SS-28 (an N-terminally extended form of SS-14 and derived from the same gene as SS-14) displaced [Tyr11]-SS-14 specific binding (ED50 values of approximately 50 nM and 100 nM respectively), salmon SS-25 (containing [Tyr7,Gly10]-SS-14 at its C terminus and presumably derived from a gene different from that giving rise to SS-14/SS-28), except at pharmacological concentrations, did not. Significant specific binding was also detected in brain, esophagus, stomach, upper and lower intestine, pancreas, and adipose tissue. Scatchard analysis suggested the existence of two classes of hepatic somatostatin-binding sites: a high-affinity site with a Kd of 23 nM and Bmax of 1.4 pmol/mg protein and a low-affinity site with a Kd of 379 nM and Bmax of 4.9 pmol/mg protein. Fasting resulted in reduced growth and elevated plasma levels of SS-14 compared with fed animals. SS-14 binding capacity of the high-affinity class in liver membranes isolated from fasted fish increased by 120% over that from fed counterparts. No difference in Kd for the high-affinity binding class or in either Kd or Bmax of the low-affinity class was noted between fasted and fed animals. These data support the role of the liver as a target of somatostatin and suggest that fasting enhances hepatic sensitivity to SS-14 binding.


[End stage renal failure in the elderly. A therapeutic dilemma].
During the last 20 years the world population has aged at an exponential rate. At present, more than 35% of patients starting renal replacement therapy (RRT) in Europe are more than 75 years old. Several factors have contributed to this increment. The attitude towards chronological age as a factor in therapeutic decisions has changed. Modern techniques make dialysis better tolerated and effective treatments of anemia and mineral metabolism are available. The increased incidence of diabetic nephropathy, vascular diseases, endovascular procedures, congestive heart failure and use of nephrotoxic drugs are all frequent causes of RRT in the elderly. The results of RRT in the very elderly in terms of survival, morbidity and quality of life are unclear. The 1-year survival according to large registries like the USRDS and the EDTA-ERA Registry is 54-66%. Important comorbid conditions are frequent and the mortality from all causes is more than twofold that observed in the general population of the same age. Failure of vascular access surgery is common and the accepted guidelines are probably inapplicable to most elderly patients. Yet neither the KDOQI nor the EBPG consider the demographic aspect in their recommendations. Elderly patients are less frequently treated with peritoneal dialysis, possibly because the potential advantages of this technique are contrasted with perceived barriers due to physical handicaps, social and financial difficulties and housing problems. In most countries, old age is a practical obstacle to inclusion of patients in kidney transplantation waiting lists. This situation is slowing changing, however. In Europe, for instance, the Eurotransplant Senior Program ''Old For Old'' has been implemented during the last decade. The results, albeit limited, are encouraging. Because of the uncertainties regarding prognosis and quality of life and the difficulties of dialysis treatment, the alternative of continuing conservative treatment is often considered by elderly patients and their families. Based upon appropriate diet and active treatment of complications, conservative treatment may give results comparable to those of dialysis in selected and cooperative patients.


[Therapeutic Strategies in Patients with Stable Coronary Artery Disease: The Role of Coronary Revascularization].
Therapeutic Strategies in Patients with Stable Coronary Artery Disease: The Role of Coronary Revascularization Abstract. Coronary artery disease is the leading cause of death worldwide. Prevention and optimal treatment of patients with coronary artery disease is therefore crucial. Lifestyle changes, optimal medical therapy and aggressive risk factor control represent key elements in the management of patients with stable coronary artery disease. Coronary revascularization of flow-limiting coronary artery stenoses is indicated to reduce myocardial ischemia and related symptoms. This review summarizes treatment strategies of patients with stable coronary artery disease, focusing on the 2018 European Society of Cardiology (ESC) guidelines of myocardial revascularization.


Cellular Senescence in Neurodegenerative Diseases.
Cellular senescence is a homeostatic biological process characterized by a permanent state of cell cycle arrest that can contribute to the decline of the regenerative potential and function of tissues. The increased presence of senescent cells in different neurodegenerative diseases suggests the contribution of senescence in the pathophysiology of these disorders. Although several factors can induce senescence, DNA damage, oxidative stress, neuroinflammation, and altered proteostasis have been shown to play a role in its onset. Oxidative stress contributes to accelerated aging and cognitive dysfunction stages affecting neurogenesis, neuronal differentiation, connectivity, and survival. During later life stages, it is implicated in the progression of cognitive decline, synapse loss, and neuronal degeneration. Also, neuroinflammation exacerbates oxidative stress, synaptic dysfunction, and neuronal death through the harmful effects of pro-inflammatory cytokines on cell proliferation and maturation. Both oxidative stress and neuroinflammation can induce DNA damage and alterations in DNA repair that, in turn, can exacerbate them. Another important feature associated with senescence is altered proteostasis. Because of the disruption in the function and balance of the proteome, senescence can modify the proper synthesis, folding, quality control, and degradation rate of proteins producing, in some diseases, misfolded proteins or aggregation of abnormal proteins. There is an extensive body of literature that associates cellular senescence with several neurodegenerative disorders including Alzheimer's disease (AD), Down syndrome (DS), and Parkinson's disease (PD). This review summarizes the evidence of the shared neuropathological events in these neurodegenerative diseases and the implication of cellular senescence in their onset or aggravation. Understanding the role that cellular senescence plays in them could help to develop new therapeutic strategies.


Association between birth conditions and glucose and cortisol profiles of periparturient dairy cows and neonatal calves.
Parturition in cattle is a stressful event for both the dam and the offspring. Stress and pain can alter the energy profile of calves and calving cows, producing a metabolic imbalance at birth. This study aimed to assess the effects of dystocia and oxytocin and calcium infusion on metabolic homeostasis in dairy cows and calves. Thirty Holstein cows and their calves were divided into three groups: an eutocia group (n=10), in which no calving assistance was needed; a dystocia group, which required mild-to-severe obstetric assistance (n=10); and a uterine inertia group, which was treated with oxytocin and calcium (n=10). To assess serum cortisol and blood glucose levels, blood samples were collected during the peripartum period from cows and during the first hour since birth from calves. All groups were hyperglycaemic following parturition. Infusion of oxytocin and calcium resulted in lower maternal glucose concentrations and lower levels of stress than in cows in the dystocia group. Birth condition was significantly associated with blood glucose and cortisol concentrations in calves. Glucose concentration was lower in calves born with oxytocin and calcium infusion than those born with fetal extraction. In conclusion, assisted calving with fetal extraction causes important metabolic changes for the dam and calf. Conversely, the practice of oxytocin and calcium infusion for hypotonic cows has no harmful effects on metabolic balance and can be safely employed as a medical treatment.


Conservation of unfavorable sequence motifs that contribute to the chemokine quaternary state.
In the chemokine family, we characterize two examples of evolutionarily conserved unfavorable sequence motifs that affect quaternary structure. In contrast to the straightforward action of favorable sequences, these unfavorable motifs produce interactions disfavoring one outcome to indirectly promote another one but should not be confused with the broad sampling produced by negative selection and/or design. To identify such motifs, we developed a statistically validated computational method combining structure and phylogeny. This approach was applied in an analysis of the alternate forms of homodimerization exhibited in the chemokine family. While the chemokine family exhibits the same tertiary fold, members of certain subfamilies, including CXCL8, form a homodimer across the beta1 strand whereas members of other subfamilies, including CCL4 and CCL2, form a homodimer on the opposite side of the chemokine fold. These alternate dimerization states suggest that CCL4 and CCL2 contain specific sequences that disfavor CXCL8 dimerization. Using our computational approach, we identified two evolutionarily conserved sequence motifs in the CC subfamilies: a drastic two-residue deletion (DeltaRV) and a simple point mutation (V27R). Cloned into the CXCL8 background, these two motifs were experimentally proven to confer a monomeric state. NMR analyses indicate that these variants are structured in solution and retain the chemokine fold. Structurally, the motifs retain a chemokine tertiary fold while introducing unfavorable quaternary interactions that inhibit CXCL8 dimerization. In demonstrating the success of our computational method, our results argue that these unfavorable motifs have been evolutionarily conserved to specifically disfavor one dimerization state and, as a result, indirectly contribute to favoring another.


Discovery of natural product inhibitors of phosphodiesterase 10A as novel therapeutic drug for schizophrenia using a multistep virtual screening.
The major complaint that most of the schizophrenic patients' face is the cognitive impairment which affects the patient's quality of life. The current antipsychotic drugs treat only the positive symptoms without alleviating the negative or cognitive symptoms of the disease. In addition, the existing therapies are known to produce extrapyramidal side effects that affect the patient adherence to the treatment. PDE10A inhibitor is the new therapeutic approach which has been proven to be effective in alleviating the negative and cognitive symptoms of the disease. A number of PDE10A inhibitors have been developed, but no inhibitor has made it beyond the clinical trials so far. Thus, the present study has been conducted to identify a PDE10A inhibitor from natural sources to be used as a lead compound for the designing of novel selective PDE10A inhibitors. Ligand and structure-based pharmacophore models for PDE10A inhibitors were generated and employed for virtual screening of universal natural products database. From the virtual screening results, 37 compounds were docked into the active site of the PDE10A. Out of 37 compounds, three inhibitors showed the highest affinity for PDE10A where UNPD216549 showed the lowest binding energy and has been chosen as starting point for designing of novel PDE10A inhibitors. The structure-activity-relationship studies assisted in designing of selective PDE10A inhibitors. The optimization of the substituents on the phenyl ring resulted in 26 derivatives with lower binding energy with PDE10A as compared to the lead compound. Among these, MA 8 and MA 98 exhibited the highest affinity for PDE10A with binding energy (-10.90 Kcal/mol).


Norepinephrine Decreases Fluid Requirements and Blood Loss While Preserving Intestinal Villi Microcirculation during Fluid Resuscitation of Uncontrolled Hemorrhagic Shock in Mice.
Norepinephrine administration is controversial during hemorrhagic shock resuscitation to stabilize mean arterial pressure (MAP) level because it could have deleterious effects on local circulations. The authors investigated the effect of norepinephrine on intestinal microcirculation during fluid resuscitation in uncontrolled hemorrhagic shock. Mice (n = 6 per group) submitted to an uncontrolled hemorrhagic shock by tail section were randomly assigned to a resuscitation with fluid but without norepinephrine to target a MAP level of 50 mmHg (FR50) or 60 mmHg (FR60) or a resuscitation with fluid and norepinephrine to target a MAP level of 50 mmHg (FRNE50) or 60 mmHg (FRNE60). Intestinal microcirculation was observed by intravital microscopy. Fluid requirements were lower in groups resuscitated with fluid and norepinephrine than in groups resuscitated with fluid without norepinephrine (74.6 ± 45.1 in FR50 vs. 28.1 ± 10.0 µl/g in FRNE50; P = 0.004 and 161.9 ± 90.4 in FR60 vs. 44.5 ± 24.0 µl/g in FRNE60; P = 0.041). Blood loss was not statistically different between FR50 and FRNE50 (14.8 ± 8.3 vs. 8.5 ± 2.9 µl/g; P = 0.180) but was significantly lower in FRNE60 than in FR60 (10.1 ± 4.2 vs. 22.6 ± 9.6 µl/g; P = 0.015). This beneficial effect was associated with the restoration of intestinal microcirculation to the same extent in fluid resuscitated groups without norepinephrine (FR50 and FR60) and fluid resuscitated groups with norepinephrine (FRNE50 and FRNE60). During MAP-directed resuscitation of uncontrolled hemorrhagic shock, the administration of norepinephrine decreased blood loss and fluid requirements while preserving intestinal villi microcirculation.


A comparison of lipid metabolism in two human retinoblastoma cell lines.
A number of differences have been observed in the lipid metabolism of cultured Y79 and WERI Rb-1 retinoblastoma cells. The Y79 cells have a higher phospholipid content and a higher percentage of ethanolamine phosphoglycerides, whereas the WERI Rb-1 cells have more triglycerides. This is consistent with the finding that most of the polyunsaturated fatty acid taken up by the Y79 cells is incorporated into phospholipids, while a sizable amount of the uptake in WERI Rb-1 cells is incorporated into triglyceride. Polyunsaturated fatty acids of the n-6 class are taken up at about the same rate by both cells, but the n-3 polyunsaturates are taken up more rapidly by the Y79 cells. In addition, the Y79 cells convert a larger percentage of linoleic acid (18:2, n-6) to arachidonic acid (20:4, n-6) and of linolenic acid (18:3, n-3) to docosahexaenoic acid (22:6, n-3), and they accumulate these products when the precursors are added to the culture medium. When grown in 10% fetal bovine serum without supplemental fatty acid, however, the WERI Rb-1 contain more arachidonic and docosahexaenoic acids. These differences in lipid content and metabolism suggest that although the Y79 and WERI Rb-1 cell lines are derived from the same type of retinal tumor, they either originated from functionally different retinal neurons or have diverged biochemically during propagation in culture.


Perceptions of Healthy Lifestyles Among Children With Complex Heart Disease and Their Caregivers.
Children with complex heart problems may be at higher risk for sedentary lifestyle morbidities than their healthy peers. This project examined perceptions, barriers, and supports that influence healthy active lifestyles among children with complex heart problems and their caregivers, to enable effective health and quality-of-life interventions. Inductive thematic analysis was conducted of semi-structured guided discussions from 6 focus groups (young child [n = 2]; older child [n = 4]; parents of young child [n = 4]; parents of older child [n = 4]; pediatric cardiologist [n = 5]; pediatric cardiac nurse [n = 5]) and individual interviews with 7 parents, 5 parent/child dyads, 2 adults with complex heart problems, 6 pediatric cardiologists, 3 pediatric cardiac nurses, 4 pediatric cardiology mental health professionals, and 14 recreation professionals. Four interrelated themes were identified: (i) "It takes a village"-coordinated and collaborative interdisciplinary support; (ii) clear healthy lifestyle communication among children, families, and professionals is critically important; (iii) Ccreating supportive environments by building professional expertise; (iv) inspiring healthy lifestyles in the children's own environments. All groups identified a need to improve knowledge about childhood heart conditions among education and recreation professionals and to encourage effective communication between healthcare professionals and families. Participants indicated that these changes would support families, educators, and recreation professionals in engaging children with heart problems in healthy lifestyles in home, school, and community settings. Important healthy lifestyle barriers were identified within individuals and in their interactions. There is a profound need to enhance knowledge of childhood heart conditions and improve interactions among key stakeholders-children and families, educators, and recreation and healthcare professionals.


Intra and inter-annual structure of zooplankton communities in floodplain lakes: a long-term ecological research study.
Water flow management has significantly changed the natural dynamic of floods, which are responsible for the structure and dynamic of aquatic communities in river-floodplain systems. With the aim to elaborate a conceptual framework that describes the main ecological factors associated with zooplankton community structure in the Upper Paraná River, we investigated the mechanisms that regulate the communities structure and their response to inter-annual and hydro-sedimentological variations in the floodplain and the biological factors associated with species abundance in those communities. For this we conducted samplings every six months (potamophase in March and limnophase in September) to characterize intra and inter-annual variations in community structure between 2000 and 2008. The intra-annual differences on the species richness, abundance, Shannon diversity index, and evenness, were conducted using Bayesian procedures to show probabilistic predictions of the data fit to main variation sources. Non-metric multi-dimensional scaling (NMDS), multi-response permutation procedure (MRPP), and indicator species analysis (IndVal) were run to assess and characterize the seasonality of the community structure. During high water (potamophase), hydrologic connectivity favoured exchange and dispersal of species in some lakes, increasing local diversity; during low water (limnophase), higher local productivity favoured opportunistic taxa, increasing species dominance and decreasing local diversity. Food resources and density of small-size fish were biological factors associated with the seasonal dynamic of the zooplankton community; these factors were dependent on hydrosedimentological phase (potamophase or limnophase). Water levels and limnological modifications related to water flow management have promoted replacement and impoverishment of aquatic biota in affected lakes and have indicated the ecological importance of a natural dynamic flood, which displays regular flood pulses. The conceptual model presented encompassed interactions between diverse environmental variables to more understandable mechanisms of the main sources of community variation.


Nanotechnology Approaches to Modulate Immune Responses to Cell-based Therapies for Type 1 Diabetes.
Islet transplantation is a promising curative treatment option for type 1 diabetes (T1D) as it can provide physiological blood glucose control. The widespread utilization of islet transplantation is limited due to systemic immunosuppression requirements, persisting graft immunodestruction, and poor islet engraftment. Traditional macro- and micropolymeric encapsulation strategies can alleviate the need for antirejection immunosuppression, yet the increased graft volume and diffusional distances imparted by these coatings can be detrimental to graft viability and glucose control. Additionally, systemic administration of pro-engraftment and antirejection therapeutics leaves patients vulnerable to adverse off-target side effects. Nanoscale engineering techniques can be used to immunocamouflage islets, modulate the transplant microenvironment, and provide localized pro-engraftment cues. In this review, we discuss the applications of nanotechnology to advance the clinical potential of islet transplantation, with a focus on cell surface engineering, bioactive functionalization, and use of nanoparticles in T1D cell-based treatments.


Mammal collections of the Western Hemisphere: a survey and directory of collections.
As a periodic assessment of the mammal collection resource, the Systematic Collections Committee (SCC) of the American Society of Mammalogists undertakes decadal surveys of the collections held in the Western Hemisphere. The SCC surveyed 429 collections and compiled a directory of 395 active collections containing 5,275,155 catalogued specimens. Over the past decade, 43 collections have been lost or transferred and 38 new or unsurveyed collections were added. Growth in number of total specimens, expansion of genomic resource collections, and substantial gains in digitization and web accessibility were documented, as well as slight shifts in proportional representation of taxonomic groups owing to increasingly balanced geographic representation of collections relative to previous surveys. While we find the overall health of Western Hemisphere collections to be adequate in some areas, gaps in spatial and temporal coverage and clear threats to long-term growth and vitality of these resources have also been identified. Major expansion of the collective mammal collection resource along with a recommitment to appropriate levels of funding will be required to meet the challenges ahead for mammalogists and other users, and to ensure samples are broad and varied enough that unanticipated future needs can be powerfully addressed.


Patient age influences recognition of Alzheimer's disease.
This study evaluated whether patient age influences recognition of Alzheimer's disease (AD) as assessed by referrals to a specialty clinic. The age and Mini-Mental State Exam (MMSE) at the initial visit to a memory loss clinic of all patients with a diagnosis of AD (n = 533; 88.7%) or amnestic Mild Cognitive Impairment (n = 68; 11.3%) seen from 1992 through 2004 were examined. Only patients seen at least twice were considered so that the potentially confounding effects of age on rate of decline could be examined. There was a significant inverse correlation between age and MMSE score at initial visit (Spearman rho = -0.10, p =.016). Mixed-model regression analyses revealed significant effects of age and calendar year at initial visit on initial MMSE score and estimated the annual rate of decline on the MMSE at 1.58 points per year. Age at initial visit was not related to the rate of MMSE decline over time. Recognition of symptoms of AD is delayed as patients age. This delay is not explained by a difference in the rate of decline with age. Even though AD incidence increases dramatically with age, older patients were found to be more advanced in their disease at the time of referral to a dementia clinic.


Assessment of wild grapevine (Vitis vinifera ssp. sylvestris) chlorotypes and accompanying woody species in the Eastern Adriatic region.
The Eastern Adriatic region, encompassing Croatia and Bosnia and Herzegovina, is considered an important area of natural populations of wild grapevines (Vitis vinifera ssp. sylvestris). The wild grapevine arises in the Eastern Adriatic region in a contact zone of the EU-Mediterranean and the sub-Mediterranean characterized by typical karst relief. This study focuses on the chloroplast DNA (cpDNA) analysis of wild grapevines and the biodiversity of accompanying woody species to better understand the genetic variation of the sylvestris populations of the Eastern Adriatic region and to investigate how this variation fits within today's wild grapevine distribution in the European continent. The allelic variation at nine cpDNA microsatellite loci of wild individuals was used to characterize haplotype diversity in 53 individuals from four population sites. All individuals were grouped into two chlorotypes: A and D, D being the rare haplotype among wild populations on the European continent. In total, 52 woody plant species were identified. However, the studied vegetation structures have been affected by permanent human pressure on natural resources and the preservation status of the collection sites. Based on our results, we conclude that the investigated areas were probably shelter zones for wild grapevine preservation during the unfavorable glaciation era.