Care of the dying: a Catholic perspective. Part III: Clinical context--good palliative care eases the dying process. Catholic Health Association.
In the midst of a push for legalized euthanasia and assisted suicide in the United States, the Catholic healing tradition should provide good palliative care and support for dying patients. Catholic healthcare institutions can have a counterinfluence on the euthanasia movement if they strive to relieve all forms of pain-physical, psychological, social, and spiritual. Care givers must adapt their pain management methods to diverse groups of patients and their needs. Comprehensive pain management includes not only specialized clinical programs to control physical pain, but also counseling and human support to minimize psychological pain, community support groups to counter social pain, and pastoral care resources to address spiritual pain. Truthful communication lies at the heart of the therapeutic relationship. Healthcare institutions can likewise organize themselves internally to offer optimal support programs for those who are dying, their families, and their care givers. Necessary ingredients for a comprehensive approach include integrated treatment plans, hospitable environments, policies on advance directives and collaborative decision making, ethics committees that are well versed in end-of-life issues, education programs, and a hospice philosophy of care.


Neuroimaging-informed phenotypes of suicidal behavior: a family history of suicide and the use of a violent suicidal means.
The identification of brain markers of suicidal risk is highly expected. However, neuroimaging studies have yielded mixed results, possibly due to phenotypic heterogeneity. In the present study, we addressed this issue using structural brain imaging. First, two independent samples of suicide attempters (n = 17 in Montreal, 32 in Jena), patient controls (n = 26/34), and healthy controls (n = 66/34) were scanned with magnetic resonance imaging. Groups were compared with FSL. We then reviewed the literature and run a GingerALE meta-analysis of 12 structural imaging studies comparing suicide attempters and patient controls with whole-brain analyses (n = 693). Finally, we explored the potential contribution of two variables previously associated with biological/cognitive deficits: a family history of suicide (FHoS), and the use of a violent suicidal means (VSM). Here, we added two groups of healthy first-degree biological relatives of suicide victims and depressed patients (n = 32). When comparing all suicide attempters and controls, very limited between-group differences were found in the two samples, and none in the meta-analysis. In contrast, a FHoS was associated with reduced volumes in bilateral temporal regions, right dorsolateral prefrontal cortex, and left putamen, several of these differences being observed across groups. VSM was associated with increased bilateral caudate (and left putamen) volumes. Some morphometric variations in cortico-subcortical networks may therefore be endophenotypes increasing the suicidal vulnerability, while others (notably in striatum) may modulate action selection. These results therefore confirm at the neural level two phenotypes at high lethal risk with a strong biological background, and uncover motives of heterogeneous findings in neuroimaging studies of suicidal behavior.


Structural basis of the γ-lactone-ring formation in ascorbic acid biosynthesis by the senescence marker protein-30/gluconolactonase.
The senescence marker protein-30 (SMP30), which is also called regucalcin, exhibits gluconolactonase (GNL) activity. Biochemical and biological analyses revealed that SMP30/GNL catalyzes formation of the γ-lactone-ring of L-gulonate in the ascorbic acid biosynthesis pathway. The molecular basis of the γ-lactone formation, however, remains elusive due to the lack of structural information on SMP30/GNL in complex with its substrate. Here, we report the crystal structures of mouse SMP30/GNL and its complex with xylitol, a substrate analogue, and those with 1,5-anhydro-D-glucitol and D-glucose, product analogues. Comparison of the crystal structure of mouse SMP30/GNL with other related enzymes has revealed unique characteristics of mouse SMP30/GNL. First, the substrate-binding pocket of mouse SMP30/GNL is designed to specifically recognize monosaccharide molecules. The divalent metal ion in the active site and polar residues lining the substrate-binding cavity interact with hydroxyl groups of substrate/product analogues. Second, in mouse SMP30/GNL, a lid loop covering the substrate-binding cavity seems to hamper the binding of L-gulonate in an extended (or all-trans) conformation; L-gulonate seems to bind to the active site in a folded conformation. In contrast, the substrate-binding cavities of the other related enzymes are open to the solvent and do not have a cover. This structural feature of mouse SMP30/GNL seems to facilitate the γ-lactone-ring formation.


Collagen structure deterioration in the skin of patients with pelvic organ prolapse determined by atomic force microscopy.
We used atomic force microscopy (AFM) to diagnose pathological changes in the extracellular matrix (ECM) of skin connective tissue in patients with pelvic organ prolapse (POP). POP is a common condition affecting women that considerably decreases the patients' quality of life. Deviations from normal morphology of the skin ECM from patients with POP occur including packing and arrangement of individual collagen fibers and arrangement of collagen fibrils. The nanoindentation study revealed significant deterioration of the mechanical properties of collagen fibril bundles in the skin of POP patients as compared with the skin of healthy subjects. Changes in the skin ECM appeared to correlate well with changes in the ECM of the pelvic ligament tissue associated with POP. AFM data on the ECM structure of normal and pathologically altered connective tissue were in agreement with results of the standard histological study on the same clinical specimens. Thus, AFM and related techniques may serve as independent or complementary diagnostic tools for tracking POP-related pathological changes of connective tissue.


The genetic variant Voila causes gustatory defects during Drosophila development.
Voila(1), an enhancer-trap strain in Drosophila melanogaster, expresses GAL4 in most gustatory neurons, both before and after metamorphosis. Voila(1) expression starts at embryonic stage 10. In the periphery, it labels larval gustatory sensilla in the antennomaxillary complex as well as in the pharynx. GAL4 is also expressed in the CNS in a manner that prefigures expression in adult flies. Most Voila(1/1) homozygotes die between second larval instar and early adulthood. Moreover, escaping Voila(1/1) larvae do not show gustatory responses to NaCl and sucrose. The simultaneous rescue of normal larval gustation together with adult viability after removal of the transposable PGAL4 element suggests that both these phenotypes are caused by the same inserted element.


The effects of age and gender on plasma levels of 63 cytokines.
Cytokines play important roles as regulators of cell functions, and over the last decades a number of cytokine assays have been developed. The aim of the present study was to investigate the effects of age and gender on a large number of cytokines. Plasma samples were collected from 33 healthy blood donors. The samples were analyzed using a multiplex proximity extension assay (PEA) allowing simultaneous measurement of 92 cytokines and four technical controls. Biomarkers with less than 80% quantitative results were excluded leaving 63 cytokines that were analyzed for the effects of gender and age. The plasma level of three of the investigated biomarkers (DNER, MCP-4 and MMP-10) were found to be significantly different for the two genders (adjusted p-value<0.05), and 15 of the biomarkers (CCL11, CCL25, CDCP1, CSF-1, CXCL11, CXCL9, FGF-23, Flt3L, HGF, IL-10RB, MCP-3, MCP-4, MMP-10, OPG, VEGF-A) were significantly associated with age. This study reveals the effects of age and gender on a large number of cytokine assays. CXCL5 and TNFB were significantly higher in females, while the other markers with significant gender-dependent differences were higher in males. For the markers that were significantly associated with age, only CXCL6 was found to decrease with age, while the other biomarkers increased with age.


Ultrasound-guided continuous interscalene block: the influence of local anesthetic background delivery method on postoperative analgesia after shoulder surgery: a randomized trial.
Automated bolus delivery has recently been shown to reduce local anesthetic consumption and improve analgesia, compared with continuous infusion, in continuous sciatic and epidural block. However, there are few data on the influence of local anesthetic delivery method on local anesthetic consumption following interscalene blockade. This randomized, double-blind trial was designed to determine whether hourly automated perineural boluses (4 mL) of local anesthesia delivered with patient-controlled pro re nata (PRN, on demand) boluses would result in a reduction in total local anesthesia consumption during continuous interscalene blockade after shoulder surgery compared with continuous perineural infusion (4 mL/h) plus patient-controlled PRN boluses. One hundred one patients undergoing major shoulder surgery under general anesthesia with ultrasound-guided continuous interscalene block were randomly assigned to receive 0.2% ropivacaine via interscalene end-hole catheter either by continuous infusion 4 mL/h (n = 50) or as automated bolus 4 mL/h (n = 51). Both delivery methods were combined with 5 mL PRN boluses of 0.2% ropivacaine with a lockout time of 30 minutes. Postoperative number of PRN boluses, 24- and 48-hour local anesthetic consumption, pain scores, rescue analgesia (morphine), and adverse events were recorded. There were no significant differences in either the number of PRN ropivacaine boluses or total 48 hour local anesthetic consumption between the groups (18.5 [11-25.2] PRN boluses in the continuous infusion group vs 17 [8.5-29] PRN boluses in the automated bolus group). Postoperative pain was similar in both groups; on day 2, the median average pain score was 4 (2-6) in the continuous infusion group versus 3 (2-5) in the automated bolus group (P = 0.54). Nor were any statistically significant intergroup differences observed with respect to morphine rescue, incidence of adverse events, or patient satisfaction. In continuous interscalene blockade under ultrasound guidance after shoulder surgery, automated boluses of local anesthetic combined with PRN boluses did not provide any reduction in local anesthetic consumption or rescue analgesia, compared with continuous infusion combined with PRN boluses.


Dark rearing alters the normal development of spatiotemporal response properties but not of contrast detection threshold in mouse retinal ganglion cells.
The mouse visual system is immature when the eyes open two weeks after birth. As in other mammals, some of the maturation that occurs in the subsequent weeks is known to depend on visual experience. Development of the retina, which as the first stage of vision provides the visual information to the brain, also depends on light-driven activity for proper development but has been less well studied than visual cortical development. The critical properties for retinal encoding of images include detection of contrast and responsiveness to the broad range of temporal stimulus frequencies present in natural stimuli. Here we show that contrast detection threshold and temporal frequency response characteristics of ON and OFF retinal ganglion cells (RGCs), which are poor at eye opening, subsequently undergo maturation, improving RGC performance. Further, we find that depriving mice of visual experience from before birth by rearing them in the dark causes ON and OFF RGCs to have smaller receptive field centers but does not affect their contrast detection threshold development. The modest developmental increase in temporal frequency responsiveness of RGCs in mice reared on a normal light cycle was inhibited by dark rearing only in ON but not OFF RGCs. Thus, these RGC response characteristics are in many ways unaffected by the experience-dependent changes to synaptic and spontaneous activity known to occur in the mouse retina in the two weeks after eye opening, but specific differences are apparent in the ON vs. OFF RGC populations.


Iterative Multiview Subspace Learning for Unpaired Multiview Clustering.
In real applications, several unpredictable or uncertain factors could result in unpaired multiview data, i.e., the observed samples between views cannot be matched. Since joint clustering among views is more effective than individual clustering in each view, we investigate unpaired multiview clustering (UMC), which is a valuable but insufficiently studied problem. Due to lack of matched samples between views, we could fail to build the connection between views. Therefore, we aim to learn the latent subspace shared by views. However, existing multiview subspace learning methods usually rely on the matched samples between views. To address this issue, we propose an iterative multiview subspace learning strategy iterative unpaired multiview clustering (IUMC), aiming to learn a complete and consistent subspace representation among views for UMC. Moreover, based on IUMC, we design two effective UMC methods: 1) Iterative unpaired multiview clustering via covariance matrix alignment (IUMC-CA) that further aligns the covariance matrix of subspace representations and then performs clustering on the subspace and 2) iterative unpaired multiview clustering via one-stage clustering assignments (IUMC-CY) that performs one-stage multiview clustering (MVC) by replacing the subspace representations with clustering assignments. Extensive experiments show the excellent performance of our methods for UMC, compared with the state-of-the-art methods. Also, the clustering performance of observed samples in each view can be considerably improved by those observed samples from the other views. In addition, our methods have good applicability in incomplete MVC.


Cytologic diagnosis of leishmaniasis in HIV infection. A report of eight cases.
Leishmania organisms are among the intracellular microorganisms with a tendency to develop in patients with the acquired immunodeficiency syndrome (AIDS). With increasing travel to endemic areas by patients with human immunodeficiency virus (HIV) infection, it is becoming a more-frequent diagnosis in nonendemic areas. Ten cytologic specimens from eight patients with leishmaniasis and AIDS were reviewed. Eight samples were obtained from lymph nodes through fine needle aspiration (FNA). Another sample was obtained after scraping a tongue ulcer. The last one was an ascitic fluid specimen. Smears showed numerous parasitized histiocytes with abundant intracellular Leishmania organisms (amastigotes). Extracellular microorganisms were also abundant. Diff-Quik-stained smears allowed the clear recognition of the characteristic morphologic appearance with a deep-staining area (nuclei) and paranuclear zone (kinetoplast). Intracellular organisms were round, while single, extracellular forms were a more elongated. The polymorphous clinical manifestations usually seen in patients suffering from leishmaniasis and AIDS constitute a diagnostic challenge that can be facilitated by cytopathologic examination. Cytology permits easy and rapid identification of Leishmania amastigotes, allowing a specific diagnosis and treatment.


A survey of invasive plants on grassland soil microbial communities and ecosystem services.
Invasive plants can cause changes in the structure and function of the ecosystem being invaded. Any changes in ecosystem diversity and community composition will likely alter ecosystem services provided by that ecosystem. However, how these ecosystem services may change is poorly understood. To elucidate how these ecosystem services will change with invasion, we sampled 561 plots undergoing invasion by smooth brome (Bromus inermis) and four other invasive species at a native Rough Fescue prairie located near Saskatoon, Saskatchewan, Canada. Soil and plant surveys were undertaken weekly for 26 weeks between May of 2014 and November of 2014, or the growing season. We measured a suite of ecosystem services, including greenhouse gasses, extracellular enzyme function, forage production, glyphosate degradation and decomposition. Furthermore, soil physical and chemical properties were measured, and soil bacterial and fungal communities were sequenced. This is a large and multifaceted dataset with complex temporal and spatial attributes which can be used to answer numerous questions regarding the functioning of prairie ecosystems and how invasive species will impact that functioning.


[Predictive model for additional intraoperative placement of chest drainage after thoracoscopic lobectomy].
To create a prognostic model determining the risk of tension pneumothorax and the need for intraoperative installation of additional drainage after thoracoscopic lobectomy. A retrospective multiple-center study included patients who underwent thoracoscopic lobectomy for lung cancer between 2016 and 2022. One drainage tube was used after surgery in all cases. We synthesized data to expand patient selection using the Riley method and machine learning algorithm. In total, treatment outcomes in 1458 patients were analyzed. After identifying significant factors, we performed binary logistic regression analysis using backward stepwise inclusion of variables in accordance with the Akaike information criterion. After validating the model using the Bootstrap method (400 iterations) and original data set, we created a nomogram determining scoring characteristics, linear predictors and risk of postoperative tension pneumothorax. The incidence of tension pneumothorax was 4.53% (n=66). The most significant variables associated with pneumothorax and the need for additional pleural drainage were adhesions, intraoperative lung suturing, unclear interlobar groove, enlarged intrapulmonary lymph nodes and chronic obstructive pulmonary disease (p<0.001). The model's C-index was 0.957, mean absolute calibration error - 0.6%, calibration curve slope - 0.959. A score of 26 indicated a 95% risk of postoperative pneumothorax. We developed a prognostic model for tension pneumothorax after thoracoscopic lobectomy. Nomogram makes it possible to make a decision on intraoperative installation of additional pleural drainage tube and prevent complications associated with postoperative lung collapse.


Impact of co-occurring posttraumatic stress disorder on suicidal women with borderline personality disorder.
The authors examined the impact of co-occurring posttraumatic stress disorder (PTSD) on women with borderline personality disorder who had attempted suicide in the preceding year. Female borderline personality disorder outpatients (N=94) either with (N=53, 56.4%) or without PTSD (N=41, 43.6%) and with recent and repeated suicidal or self-injurious behavior were compared in nine areas of functioning. Borderline personality disorder patients with and without PTSD differed in the lethality, intent, and triggers for intentional self-injury, trauma history, emotion regulation, and axis I comorbidity. The two groups did not differ in borderline personality disorder severity, axis II comorbidity, psychosocial functioning, or mental health or medical treatment utilization. The results indicate greater impairment among individuals with both disorders and suggest that there are some unique features associated with co-occurring borderline personality disorder and PTSD that require further attention in assessment and treatment.


Robust dynamic balance of AP-1 transcription factors in a neuronal gene regulatory network.
The octapeptide Angiotensin II is a key hormone that acts via its receptor AT1R in the brainstem to modulate the blood pressure control circuits and thus plays a central role in the cardiac and respiratory homeostasis. This modulation occurs via activation of a complex network of signaling proteins and transcription factors, leading to changes in levels of key genes and proteins. AT1R initiated activity in the nucleus tractus solitarius (NTS), which regulates blood pressure, has been the subject of extensive molecular analysis. But the adaptive network interactions in the NTS response to AT1R, plausibly related to the development of hypertension, are not understood. We developed and analyzed a mathematical model of AT1R-activated signaling kinases and a downstream gene regulatory network, with structural basis in our transcriptomic data analysis and literature. To our knowledge, our report presents the first computational model of this key regulatory network. Our simulations and analysis reveal a dynamic balance among distinct dimers of the AP-1 family of transcription factors. We investigated the robustness of this behavior to simultaneous perturbations in the network parameters using a novel multivariate approach that integrates global sensitivity analysis with decision-tree methods. Our analysis implicates a subset of Fos and Jun dependent mechanisms, with dynamic sensitivities shifting from Fos-regulating kinase (FRK)-mediated processes to those downstream of c-Jun N-terminal kinase (JNK). Decision-tree analysis indicated that while there may be a large combinatorial functional space feasible for neuronal states and parameters, the network behavior is constrained to a small set of AP-1 response profiles. Many of the paths through the combinatorial parameter space lead to a dynamic balance of AP-1 dimer forms, yielding a robust AP-1 response counteracting the biological variability. Based on the simulation and analysis results, we demonstrate that a dynamic balance among distinct dimers of the AP-1 family of transcription factors underlies the robust activation of neuronal gene expression in the NTS response to AT1R activation. Such a differential sensitivity to limited set of mechanisms is likely to underlie the stable homeostatic physiological response.


1-Benzyl-indole-3-carbinol is a highly potent new small molecule inhibitor of Wnt/β-catenin signaling in melanoma cells that coordinately inhibits cell proliferation and disrupts expression of microphthalmia-associated transcription factor isoform-M.
1-Benzyl-indole-3-carbinol (1-benzyl-I3C), a synthetic analogue of the crucifer-derived natural phytochemical I3C, displayed significantly wider sensitivity and anti-proliferative potency in melanoma cells than the natural compound. Unlike I3C, which targets mainly oncogenic BRAF-expressing cells, 1-benzyl-I3C effectively inhibited proliferation of melanoma cells with a more extensive range of mutational profiles, including those expressing wild-type BRAF. In both cultured melanoma cell lines and in vivo in melanoma cell-derived tumor xenografts, 1-benzyl-I3C disrupted canonical Wnt/β-catenin signaling that resulted in the downregulation of β-catenin protein levels with a concomitant increase in levels of the β-catenin destruction complex components such as glycogen synthase kinase-3β (GSK-3β) and Axin. Concurrent with the inhibition of Wnt/β-catenin signaling, 1-benzyl-I3C strongly downregulated expression of the melanoma master regulator, microphthalmia-associated transcription factor isoform-M (MITF-M) by inhibiting promoter activity through the consensus lymphoid enhancer factor-1 (LEF-1)/T-cell transcription factor (TCF) DNA-binding site. Chromatin immunoprecipitation revealed that 1-benzyl-I3C downregulated interactions of endogenous LEF-1 with the MITF-M promoter. 1-Benzyl-I3C ablated Wnt-activated LEF-1-dependent reporter gene activity in a TOP FLASH assay that was rescued by expression of a constitutively active form of the Wnt co-receptor low-density lipoprotein receptor-related protein (LRP6), indicating that 1-benzyl-I3C disrupts Wnt/β-catenin signaling at or upstream of LRP6. In oncogenic BRAF-expressing melanoma cells, combinations of 1-benzyl-I3C and Vemurafenib, a clinically employed BRAF inhibitor, showed strong anti-proliferative effects. Taken together, our observations demonstrate that 1-benzyl-I3C represents a new and highly potent indolecarbinol-based small molecule inhibitor of Wnt/β-catenin signaling that has intriguing translational potential, alone or in combination with other anti-cancer agents, to treat human melanoma.


Orchestration of signaling by structural disorder in class 1 cytokine receptors.
Class 1 cytokine receptors (C1CRs) are single-pass transmembrane proteins responsible for transmitting signals between the outside and the inside of cells. Remarkably, they orchestrate key biological processes such as proliferation, differentiation, immunity and growth through long disordered intracellular domains (ICDs), but without having intrinsic kinase activity. Despite these key roles, their characteristics remain rudimentarily understood. The current paper asks the question of why disorder has evolved to govern signaling of C1CRs by reviewing the literature in combination with new sequence and biophysical analyses of chain properties across the family. We uncover that the C1CR-ICDs are fully disordered and brimming with SLiMs. Many of these short linear motifs (SLiMs) are overlapping, jointly signifying a complex regulation of interactions, including network rewiring by isoforms. The C1CR-ICDs have unique properties that distinguish them from most IDPs and we forward the perception that the C1CR-ICDs are far from simple strings with constitutively bound kinases. Rather, they carry both organizational and operational features left uncovered within their disorder, including mechanisms and complexities of regulatory functions. Critically, the understanding of the fascinating ability of these long, completely disordered chains to orchestrate complex cellular signaling pathways is still in its infancy, and we urge a perceptional shift away from the current simplistic view towards uncovering their full functionalities and potential. Video abstract.


Parkin-mediated ubiquitination inhibits BAK apoptotic activity by blocking its canonical hydrophobic groove.
BAK permeabilizes the mitochondrial outer membrane, causing apoptosis. This apoptotic activity of BAK is stimulated by binding prodeath activators within its canonical hydrophobic groove. Parkin, an E3 ubiquitin (Ub) ligase, can ubiquitinate BAK, which inhibits BAK apoptotic activity. However, the molecular mechanism underlying the inhibition of ubiquitination remains structurally uncharacterized. Here, we utilize truncated and soluble BAK to construct a mimetic of K113-ubiquitinated BAK (disulfide-linked UbG76C ~ BAKK113C) and further present its NMR-derived structure model. The classical L8-I44-H68-V70 hydrophobic patch of the conjugated Ub subunit binds within the canonical hydrophobic groove of BAK. This Ub occludes the binding of prodeath BID activators in the groove and impairs BID-triggered BAK activation and membrane permeabilization. Reduced interaction between Ub and BAK subunits allows BID to activate K113-ubiquitinated BAK. These mechanistic insights suggest a nonsignaling function of Ub in that it directly antagonizes stimuli targeting Ub-modified proteins rather than by recruiting downstream partners for cellular messaging.


Comparative genomics reveals the correlations of stress response genes and bacteriophages in developing antibiotic resistance of Staphylococcus saprophyticus.
Staphylococcus saprophyticus is the second most common bacteria associated with urinary tract infections (UTIs) in women. The antimicrobial treatment regimen for uncomplicated UTI is normally nitrofurantoin, trimethoprim-sulfamethoxazole (TMP-SMX), or a fluoroquinolone without routine susceptibility testing of S. saprophyticus recovered from urine specimens. However, TMP-SMX-resistant S. saprophyticus has been detected recently in UTI patients, as well as in our cohort. Herein, we investigated the understudied resistance patterns of this pathogenic species by linking genomic antibiotic resistance gene (ARG) content to susceptibility phenotypes. We describe ARG associations with known and novel SCCmec configurations as well as phage elements in S. saprophyticus, which may serve as intervention or diagnostic targets to limit resistance transmission. Our analyses yielded a comprehensive database of phenotypic data associated with the ARG sequence in clinical S. saprophyticus isolates, which will be crucial for resistance surveillance and prediction to enable precise diagnosis and effective treatment of S. saprophyticus UTIs.


MAP6 is an intraluminal protein that induces neuronal microtubules to coil.
Neuronal activities depend heavily on microtubules, which shape neuronal processes and transport myriad molecules within them. Although constantly remodeled through growth and shrinkage events, neuronal microtubules must be sufficiently stable to maintain nervous system wiring. This stability is somehow maintained by various microtubule-associated proteins (MAPs), but little is known about how these proteins work. Here, we show that MAP6, previously known to confer cold stability to microtubules, promotes growth. More unexpectedly, MAP6 localizes in the lumen of microtubules, induces the microtubules to coil into a left-handed helix, and forms apertures in the lattice, likely to relieve mechanical stress. These features have not been seen in microtubules before and could play roles in maintaining axonal width or providing flexibility in the face of compressive forces during development.


A short delirium caregiver questionnaire for triage of elderly outpatients with cognitive impairment: a development and test accuracy study.
Delirium is often missed in older outpatients. Caregivers can give valuable information that might improve identification rates. The aim of this study was to develop a short and sensitive delirium caregiver questionnaire (DCQ) for triage of elderly outpatients with cognitive impairment by telephone. The pilot questionnaire was administered to 112 caregivers of patients who were referred for dementia screening to our clinic for geriatric psychiatry, and the final DCQ to 234 other caregivers. In phase I (2013-2014), we tested a pilot questionnaire with 17 items. Health professionals who established delirium diagnoses were blinded to the results. We then used the results and other information available at referral to construct the final DCQ with seven items. During phase II (2015-2016), we investigated the test accuracy of the final DCQ in a subsequent cohort. In both phases, the patients received a structured diagnostic workup. Time between referral and first visit was a secondary outcome. The final DCQ consisted of the following items: emergency visit required, sleeping disorder, fluctuating course, hallucinations, suspicious thoughts, previous delirium, and recent discharge from hospital. DCQ results indicated that urgent intake was required in 85 of 234 patients. Sensitivity was 73.5% (95% CI: 58.9-85.1%) and specificity 73.5% (95% CI: 66.5-79.7%). The mean number of days to first visit dropped from 31.6 to 11.2 in delirious patients (p = 0.001). Triage with the easy-to-use DCQ among patients referred for cognitive screening leads to earlier assessment and higher detection rates of delirium.


New directions in ophthalmic optical coherence tomography.
The rapid development of optical coherence tomography (OCT) and its ophthalmic applications has resulted in the emergence of new laboratory and commercial systems that vary in performance and functionality. The introduction of high-speed imaging capabilities has abrogated the primary limitation of early OCT technology by providing in vivo three-dimensional volumetric reconstructions of both anterior and posterior segments of the human eye within reasonable time constraints. Currently, high-speed swept source OCT technology has made it possible to achieve OCT acquisition speeds of several million A-scans/s. Another direction of OCT development includes the introduction of adaptive optics to imaging of the posterior segment of the eye that allows correction of the eye's static and dynamic aberrations, resulting in the achievement of volumetric cellular resolution retinal imaging. In this review, we introduce readers to various aspects of the development of OCT technology within the context of its ophthalmic applications. We point out directions for future development and indicate different perspectives on this dynamically expanding method. We give a few examples of how OCT has been used over the past few years and describe how high-speed OCT imaging may be used in the future in clinical practice.


[D-2-hydroxyglutaric aciduria. Report of two cases].
D-2-hydroxyglutaric aciduria (D-2-HGA) is a cerebral organic aciduria characterized by the accumulation of abnormal amounts of D-2-hydroxyglutaric acid in cerebrospinal fluid, blood, and urine. The clinical phenotype varies widely from neonatal severe epileptic encephalopathy to asymptomatic. Magnetic resonance imaging of affected patients typically show signs of delayed cerebral maturation, ventricular abnormalities and the presence of sub-ependymal cysts in the first months of life. We present clinical, biochemical and brain magnetic resonance imaging data of two pediatric patients with D-2-hydroxyglutaric aciduria. One patient presented with severe early infantile-onset epileptic encephalopathy, marked hypotonia, visual deficit, developmental delay and abnormal neuroradiological findings; while the other had hypotonia and development delay. Our findings reinforce the described phenotype of this rare neurometabolic inherited disorder. The diagnostic approach is based on clinical findings and the neuroimaging pattern and is established by the detection of D-2-hydroxyglutaric acid in body fluids. We suggest considering D-2-hydroxyglutaric aciduria in the differential diagnosis of any neonate or infant with epileptic encephalopathy and CNS dysfunction of unknown origin.


Cardioprotection and attenuation of endothelial dysfunction by organic nitric oxide donors in myocardial ischemia-reperfusion.
The effects of two nitric oxide (NO) donors were evaluated in a 6-h model of feline myocardial ischemia-reperfusion. After 80 min of a 90-min ischemic period, SIN-1 or C87-3754 or their respective controls (i.e., 0.9% NaCl or C88-3934, a control compound which does not release NO) were given i.v. as a bolus (0.1 mg/kg) and infused at 1 mg/kg/h for the entire 4.5-h reperfusion period. Administration of the active NO donors significantly decreased the necrotic area/area-at-risk ratio from 29 +/- 3% in the vehicle group to 9 +/- 2 and 11 +/- 5% in the SIN-1 and C87-3754 groups, respectively (P less than .001). The inactive NO donor C88-3934 failed to reduce infarct size (31 +/- 3%). Neither NO donor reduced the accumulation of neutrophils in the necrotic area when compared to their respective control groups, but both agents significantly attenuated coronary endothelial dysfunction as shown by a vasorelaxation to acetylcholine of 62 +/- 2 and 64 +/- 3% in the SIN-1- and C87-3754-treated arteries, as compared to only a 27 +/- 3 and 34 +/- 4% vasorelaxation in the vehicle and inactive NO donor groups, respectively (P less than .001). Our studies show that SIN-1 and C87-3754 exert beneficial effects in a 6-h model of myocardial ischemia-reperfusion. Both NO donors decreased myocardial necrosis and decreased the reperfusion-induced endothelial dysfunction without significantly altering the pressure-rate index (i.e., an index of myocardial oxygen demand).


Folding of influenza hemagglutinin in the endoplasmic reticulum.
The folding of influenza hemagglutinin (HA0) in the ER was analyzed in tissue culture cells by following the formation of intrachain disulfides after short (1 min) radioactive pulses. While some disulfide bonds were already formed on the nascent chains, the subunits acquired their final disulfide composition and antigenic epitopes posttranslationally. Two posttranslational folding intermediates were identified. In CHO cells constitutively expressing HA0, mature HA0 subunits were formed with a half time of 3 min and their folding reached completion at 22 min. The rate of folding was highly dependent on cell type and expression system, and thus regulated by factors other than the sequence of the protein alone. Exposure of cells to stress conditions increased the level of glucose regulated proteins, including BiP, and decreased the folding rate. The efficiency of folding and subsequent trimerization was not dependent on the rate of translation, nor on temperature between 37 and 15 degrees C; however, the rates of folding and trimerization decreased with decreasing temperature. Whereas the rate of folding was independent of expression level, trimerization was accelerated at higher levels of expression.


Everyday occupation, well-being, and identity: the experience of caregivers in families with dementia.
The purpose of this study was to gain understanding of the nature of the daily occupations of caregivers for family members with dementia as related to the caregivers' perceptions of well-being. Qualitative telephone interviews, focused on the experience of caregiving, were conducted with 33 caregiver-respondents; the data were transcribed and analyzed using a phenomenological approach. Everyday occupation emerged as a phenomenon that was central to the caregivers' ways of evaluating and monitoring well-being in the care receivers and themselves. Further, occupational engagement served to help mitigate the potential biographical disruption of the dementia caregiving experience. The implications for occupational therapy personnel are convincing: Everyday occupation holds promise for contributing to the relative well-being of both caregivers and care receivers and for facilitating continuity of relationships and identity for the caregiver.


[Two patients with acute hepatitis B from the same piercing salon].
Hepatitis B was diagnosed in two homosexual men aged 41 and 31 years. Both had undergone piercing on the same day in the same saloon. The word piercing means application of decorations in the skin which is pierced for the purpose. The breeching of the skin combined with the conditions under which this is performed leads to a risk of transmission of especially viral infections. An assumed connection between the patients was supported by the results of molecular-biological examination of the hepatitis B virus isolates. The piercings were applied with the same pair of pincers, which was not sterilized in between. In view of these findings hygienic measures were taken in the piercing saloon in question to prevent future transmission of infections. Piercing entails health risks that are not always recognized either by those who do it or by those who have it done.


Ureteral stones: SWL treatment.
When stone removal is indicated SWL (Shock Wave Lithotripsy) and ureteroscopy (URS) are the two most commonly offered interventional procedures and they are both acceptable as first-line treatment. The choice of the procedure depends on several factors, including local experience, patient preference, available equipment, and associated costs. The meta-analysis by the EAU/AUA Guideline Panel in 2007 analysed SWL stone-free results for three locations in the ureter (proximal, mid, distal) and reported an overall stone-free rate for proximal ureteral stones of 82%, with no difference in stone-free rate from URS results. However, for stones < 10 mm SWL, at 90%, had a higher stone-free rate than URS and even for mid and distal ureter it reached a stone-free rate of 84% and 86% respectively. It does appear that SWL may be more effective in the paediatric subset than in the overall population, particularly in the mid and lower ureter with a stone free rate of 82% and 80% respectively. In fact, children appear to pass stone fragments after SWL more readily than adults. SWL is a safe method to treat ureteral stones and serious complications occur very rarely when proper indications are followed. A few published studies addressed the role of SWL in acute renal colic. The available data suggest that is a safe procedure, with an overall success of 70-80% and a need for further intervention in 2-20%. In choosing the optimal therapy for an individual patient, several factors that might affect the outcome should be considered to identify the best candidate for SWL. A superior success rate for proximal ureteral stones was reported in the EAU/AUA meta-analysis but stone size over 10 mm appears negatively correlated with the stone-free rate. About composition, calcium oxalate monohydrate, brushite, cystine and matrix are unfavourable compositions for SWL. Finally, impacted stones are often more resistant to fragmentation. Whether hydronephrosis affects the outcome of SWL remains controversial. A body mass index of over 30 has been found to be an independent factor in predicting failure of SWL treatment in ureteral stones. A number of treatment strategies have been proposed to increase SWL efficacy: a promising suggestion to improve SWL outcome is to reduce the shock wave rate. There have also been attempts to improve shock wave efficiency of stone fragmentation with new shock wave lithotriptor devices. But although these innovation are promising, no advantage in stone-free rate or retreatment rate have yet been proven. Acoustic coupling is a key factor affecting the efficacy of shock wave lithotripsy. An accurate pre-treatment assessment of stone burden and composition with unenhanced CT scan provides useful information to discern which treatment strategy should be favoured and may reduce SWL failure. The real cost for SWL and URS varies considerably from one centre to another, as a result of different internal organisations and also due to the principles of reimbursement from the health care system. SWL is the first treatment choice for stones smaller than 1 cm in the proximal ureter With a lower grade of invasiveness and the possibility to complete the treatment with only analgesics and sedation on an outpatient basis, SWL still appears an excellent alternative for removing ureteral stones and these properties compensate for the higher need for repeated treatments. An accurate pre-treatment assessment of stone and clinical factors to select the best candidates for SWL could improve the stone-free rate and reduce retreatments.


Blood pressure reduction in secondary stroke prevention.
: Risk factor modification plays an important role in recurrent stroke prevention. These modifiable risk factors tend to cluster in stroke patients, but for a significant subgroup the only identifiable risk factor is high blood pressure or chronic hypertension. This article reviews the current evidence for management of blood pressure in secondary stroke prevention. : Over the years, data from primary prevention trials have shown that antihypertensive drug treatment reduces the risk of first stroke by 32%. Similarly, various secondary prevention studies have shown a relative risk reduction in recurrent strokes of up to 30%. These trials have also shown that the impact of blood pressure reduction in stroke prevention is similar in patients with hypertension and patients without hypertension, and larger reductions in systolic blood pressure were associated with greater reduction in risk of recurrent stroke. : Although it is clear from the current evidence that long-term blood pressure control is one of the most important interventions for secondary stroke prevention, the optimal management of blood pressure in the immediate poststroke period is not well defined.


CYP2C19*17 May Increase the Risk of Death Among Patients with an Acute Coronary Syndrome and Non-Valvular Atrial Fibrillation Who Receive Clopidogrel and Rivaroxaban.
The aim of this study is to assess the influence of gene CYP2C19, CYP3A4, CYP3A5 and ABCB1 polymorphisms on clopidogrel antiplatelet activity, rivaroxaban concentration equilibrium, and clinical outcomes among patients with acute coronary syndrome and non-valvular atrial fibrillation. In the multicenter prospective registry study of the efficacy and safety of a combined antithrombotic therapy 103 patients with non-valvular atrial fibrillation both undergoing or not a percutaneous coronary intervention were enrolled. The trial assessed the primary outcomes (major bleeding, in-hospital death, cardiovascular death, stroke\transient ischaemic attack, death/renal insufficiency) and secondary outcomes (platelet reactivity units (PRU), rivaroxaban concentration). For none of the clinical outcomes when combined with other covariates, the carriership of polymorphisms CYP3A5*3 rs776746, CYP2C19*2 rs4244285;*17 rs12248560, ABCB1 3435 C>T, ABCB1 rs4148738 was significant. None of the markers under study (CYP3A5*3 rs776746, CYP2C19*2 rs4244285, *17 rs12248560, ABCB1 3435 C>T, ABCB1 rs4148738) has proven to affect rivaroxaban equilibrium concentration in blood plasma among patients with atrial fibrillation and acute coronary syndrome. In situations of double or triple antithrombotic rivaroxaban and clopidogrel therapy among patients with atrial fibrillation and acute coronary syndrome, the genetic factors associated with bleeding complications risk (CYP2C19*17) may prove to be clinically relevant.


The number of chloride-cation cotransport sites on Ehrlich ascites cells measured with [3H]bumetanide.
Simultaneous measurements were made of net Cl influxes and [3H]bumetanide binding to Ehrlich ascites tumor cells in which the chloride-cation cotransport pathway had been activated by hypertonic challenge. There was a good linear correlation between inhibition of Cl influx during regulatory volume increase and numbers of bumetanide molecules bound per cell, consistent with high specificity of bumetanide binding to cotransport sites. The extrapolation to the number of bumetanide binding sites per cell at maximal inhibition of Cl transport thus gives the number of cotransport sites per cell as 2.0 X 10(6). From this, and the fluxes measured (not necessarily maximum fluxes), the turnover number is calculated at 50 Cl ions per site per second. Unstimulated cells in isotonic medium, with negligible bumetanide-inhibitable fluxes, have the same number of bumetanide binding sites as the activated cells undergoing volume regulation.


Computational sequence analysis of predicted long dsRNA transcriptomes of major crops reveals sequence complementarity with human genes.
Long double-stranded RNAs (long dsRNAs) are precursors for the effector molecules of sequence-specific RNA-based gene silencing in eukaryotes. Plant cells can contain numerous endogenous long dsRNAs. This study demonstrates that such endogenous long dsRNAs in plants have sequence complementarity to human genes. Many of these complementary long dsRNAs have perfect sequence complementarity of at least 21 nucleotides to human genes; enough complementarity to potentially trigger gene silencing in targeted human cells if delivered in functional form. However, the number and diversity of long dsRNA molecules in plant tissue from crops such as lettuce, tomato, corn, soy and rice with complementarity to human genes that have a long history of safe consumption supports a conclusion that long dsRNAs do not present a significant dietary risk.


People with musculoskeletal shoulder pain demonstrate no signs of altered pain processing.
Central sensitisation may contribute to persistent musculoskeletal shoulder pain. Few studies have provided a comprehensive sensory and psychosocial evaluation of this population. To comprehensively assess whether sensory function and psychosocial aspects are impaired in people with shoulder pain and whether age, gender and clinical outcomes are related to impaired sensory function. Observational case-control study. Twenty-three participants with musculoskeletal shoulder pain and 23 age- and gender-matched healthy participants were included. Static (pressure and thermal pain thresholds) and dynamic (temporal summation) quantitative sensory testing was performed bilaterally at the shoulder and remote tibialis anterior muscle. Conditioned pain modulation was measured at the affected/matched shoulder. Shoulder function (SPADI), depression, anxiety and stress (DASS-21) and health-related quality of life (EQ-5D-5L) were also measured. Comparisons were performed between body regions and groups. Age and gender were included as factors in analyses. Clinical outcomes were tested for correlation with sensory measures. Shoulder pain group had higher local pressure pain threshold (i.e., hypoalgesia; p = 0.03; Z = 0-5.04), higher SPADI score (p < 0.01; Z = -5.76) and higher EQ-5D-5L (p < 0.01; Z = 5.23) compared to the control group. There was no difference between groups for thermal pain sensitivity, dynamic sensory testing or psychological measures. People with shoulder pain demonstrated mechanical hypoalgesia, increased upper limb disability and poorer quality of life compared with healthy controls. Central sensitisation seems not be a characteristic of musculoskeletal shoulder pain although it could be present in a subgroup of patients.


Use of logistic regression with dummy variables for modeling the growth-no growth limits of Saccharomyces cerevisiae IGAL01 as a function of sodium chloride, acid type, and potassium sorbate concentration according to growth media.
A global logistic model was used to study the effects of both quantitative variables (NaCl, acid, and potassium sorbate concentrations) and dummy variables (laboratory medium or brine, and citric, lactic, or acetic acids) on growth of Saccharomyces cerevisiae IGAL01. The deduced equations, with the significant coefficients selected by a backward stepwise procedure, allowed estimations of the simultaneous comparison of behaviors of levels of the qualitative variables as a function of the quantitative variables and the development of the growth-no growth limits according to laboratory medium or brine and the different types of acidifying agents. The S. cerevisiae growth region in yeast malt glucose peptone broth was always wider than that in brine, in which this yeast was inhibited by 0.03% potassium sorbate and 6% NaCl, when the acid concentration (regardless of type) was 0.2 to 0.3%. These results demonstrate the applicability of such model designs to include qualitative variables in investigations related to the development of growth-no growth limits.


The Power of Social Attribution: Perspectives on the Healing Efficacy of Ayahuasca.
During the last decades, ayahuasca gained much popularity among non-Indigenous and out-of-Amazonia based populations. In popular culture, it has been advertised as a natural remedy that was discovered by Indigenous peoples ante millennia and that has been used for shamanic healing of all kinds of ailments. This "neo-shamanic," and often recreational, use of ayahuasca, however, has to be distinguished from traditional Indigenous praxes on the one hand, and, on the other hand, from medical investigation in the modern world. The former, Indigenous use mainly understands ayahuasca as an amplifying power for interacting with non-human beings in the animal, plant, or spirit realms. Within this paradigm, efficacy is not dependent on the drug, but on the correct communication between the healer (or sorcerer) and the non-human powers that are considered real and powerful also without resorting to ayahuasca. The latter, modern mode of understanding, contrastingly treats the neurochemical processes of MAO inhibition and dimethyltryptamine activity as trigger mechanisms for a series of psychological as well as somatic responses, including positive outcomes in the treatment of various mental conditions. I argue that there is an ontological incommensurability occurring especially between the Indigenous and medicinal concepts of ayahuasca use (with recreational use in its widest understanding trying to make sense from both sides). Modern medical applications of ayahuasca are so fundamentally different from Indigenous concepts that the latter cannot be used to legitimate or confirm the former (and vice versa). Finally, the deep coloniality in the process of appropriation of the Indigenous by the modern has to be questioned and resolved in any case of ayahuasca application.


Predicting in vivo MRI Gradient-Field Induced Voltage Levels on Implanted Deep Brain Stimulation Systems Using Neural Networks.
MRI gradient-fields may induce extrinsic voltage between electrodes and conductive neurostimulator enclosure of implanted deep brain stimulation (DBS) systems, and may cause unintended stimulation and/or malfunction. Electromagnetic (EM) simulations using detailed anatomical human models, therapy implant trajectories, and gradient coil models can be used to calculate clinically relevant induced voltage levels. Incorporating additional anatomical human models into the EM simulation library can help to achieve more clinically relevant and accurate induced voltage levels, however, adding new anatomical human models and developing implant trajectories is time-consuming, expensive and not always feasible. MRI gradient-field induced voltage levels are simulated in six adult human anatomical models, along clinically relevant DBS implant trajectories to generate the dataset. Predictive artificial neural network (ANN) regression models are trained on the simulated dataset. Leave-one-out cross validation is performed to assess the performance of ANN regressors and quantify model prediction errors. More than 180,000 unique gradient-induced voltage levels are simulated. ANN algorithm with two fully connected layers is selected due to its superior generalizability compared to support vector machine and tree-based algorithms in this particular application. The ANN regression model is capable of producing thousands of gradient-induced voltage predictions in less than a second with mean-squared-error less than 200 mV. We have integrated machine learning (ML) with computational modeling and simulations and developed an accurate predictive model to determine MRI gradient-field induced voltage levels on implanted DBS systems.


Corrections for mRNA extraction and sample normalization errors find increased mRNA levels may compensate for cancer haplo-insufficiency.
The relative mRNA levels of differentially expressed (DE) and housekeeping (HK) genes of six aneuploid cancer lines with large-scale genomic changes identified by SNP/SKY analysis were compared with similar genes in diploid cells. The aneuploid cancer lines had heterogeneous genomic landscapes with subdiploid, diploid, and supradiploid regions and higher overall gene copy numbers compared with diploid cells. The mRNA levels of the haploid, diploid, and triploid HK genes were found to be higher after correction of easily identifiable mRNA measurement errors. Surprisingly, diploid and aneuploid HK gene mRNA levels were the same by standard expression array analyses, despite the higher copy numbers of the cancer cell HK genes. This paradoxical result proved to be due to inaccurate inputs of true intra-cellular mRNAs for analysis. These errors were corrected by analyzing the expression intensities of DE and HK genes in mRNAs extracted from equal cell numbers (50:50) of intact cancer cell and lymphocyte mixtures. Correction for both mRNA extraction/sample normalization errors and total gene copy numbers found the SUIT-2 and PC-3 cell lines' cancer genes both had ~50% higher mRNA levels per single allele than lymphocyte gene alleles. These increased mRNA levels for single transcribed cancer alleles may restore functional mRNA levels to cancer genes rendered haplo-insufficient by the genetic instability of cancer. © 2013 Wiley Periodicals, Inc.


The relentless rise of resistance?
Antibiotics have undoubtedly made a major contribution to improvements in both human and animal health and welfare. Recent years have brought alarming rises in the prevalence of resistance to some agents among certain groups of bacteria. Concern is growing that therapeutic options will become increasingly limited if resistance rates continue to rise. There is widespread agreement that action is required to reverse or at least slow this process. Necessary steps to manage the situation include better surveillance to assess accurately the extent of problems, more prudent use of the available antibiotics to conserve valuable therapeutic resources and improved infection control to limit the spread of resistant organisms. Achieving these goals will not be possible without government, the medical profession and the public being better informed and educated. Regulatory bodies and the pharmaceutical industry need to work together to ensure a steady supply of new antimicrobials. Our understanding of the processes driving resistance at both the molecular and population levels is advancing. However, the relative contributions of the various uses of antimicrobials to the resistance problem and which will be the most effective containment measures are still hotly debated. Progress is being made, but continued concerted action is necessary if the usefulness of this most important group of therapeutic agents is to be preserved.


The concept of disorder as a foundation for the DSM's theory-neutral nosology: response to Follette and Houts, Part 2.
Follette and Houts [Follette, W. C., Houts, A. C. (1996). Models of scientific progress and the role of theory in taxonomy development: a case study of the DSM. Journal of Consulting and Clinical Psychology, 64, 1120-1132] argue that 'mental disorder' and 'function' are value concepts that offer no scientific basis for the DSM's theory-neutral nosology or for distinguishing disorders from other behavioral problems. They also claim that the DSM presupposes a biological theory of etiology, thus is not really theory-neutral. They recommend replacing the DSM by theory-laden diagnostic manuals. I argue: (1) DSM criteria do not imply a biological model of disorder, (2) 'mental disorder' and 'function' have scientific content that allows one to distinguish disorder from nondisorder, (3) the evolutionary 'harmful dysfunction' analysis of disorder [Wakefield, J. C. (1992a). The concept of mental disorder: on the boundary between biological facts and social values. American Psychologist, 47, 373-388] coherently demarcates disorder from nondisorder, (4) the proposed behaviorist alternative to the DSM illustrated by the articles in Follette's special section [Follette, W. C. (Ed.) (1996a). Special section on the development of theoretically coherent alternatives to the DSM system. Journal of Consulting and Clinical Psychology, 64, 1117-1201] is incoherent because it does not distinguish disorder from nondisorder.


Extrusion of the anterior segment of the medial meniscus extrusion initiates knee osteoarthritis: evaluation using magnetic resonance imaging.
Meniscus extrusion contributes to the progression of knee osteoarthritis (OA). It is not clear which site of the medial meniscus (MM) extrusion (MME) is greatest. Moreover, the relationship between sites of MME and progression of OA has not yet been elucidated. The purpose of this study was to determine which sites of MME that showed the greatest extrusion and to investigate the relationship between the presence of MM tears and MME, the relationship between the progression of OA and MME. A cohort of 111 patients were studied retrospectively. The OA grade was classified using the Kellgren-Lawrence (K-L) grade. MME was measured at 13 positions from the anterior to the posterior segment using magnetic resonance imaging (MRI) with slices perpendicular to the MM (radial MRI). The relationship between the K-L grade and the site of the MME was investigated. The patients were grouped as follows: The patients over 40-years-old were grouped as follows: patients with the K-L grade ≤1 and without a MM tear (Group En (early, no meniscus tear)); patients with the K-L grade ≤1 with a MM tear (Group Ep (early, positive meniscus tear)); patients with the K-L grade ≥2 and without a MM tear (Group An (advanced, no meniscal tear)); patients over-40 years-old with the K-L grade ≥2 and with a MM tear (Group Ap (advanced, positive meniscus tear)). And patients between 15 and 39-years-old with no abnormal findings on MRI were defined as control group (Group C). In the Groups En and Ep, MME was greatest in the anterior segment, and was greater in Group Ep than in Group En. In Groups Ap and Group C, extrusion was greatest in the middle segment. The results suggest that MME predominantly occurred in the anterior segment with increasing age, after that, MM extruded at the middle segment with progression of OA and MM tear.


[The clinical significance of the liver glutathione system in chronic lesions].
It is shown that chronic hepatobiliary pathology is associated with a fall in spontaneous metabolite conjugation related to reduced concentration of hepatic glutathione. There was also enhanced activity of glutathione-dependent enzymes. This indicates progress of compensatory processes associated with mobilization of detoxication phase 2, i.e. stimulation of conjugation processes under depression of cytochrome P-450 system. The authors ascertain high informative value of hepatic glutathione transferase in assessment of disease activity in patients with chronic active hepatitis and hepatic cirrhosis.


Mediterranean diet and magnetic resonance imaging-assessed cerebrovascular disease.
Cerebrovascular disease is 1 of the possible mechanisms of the previously reported relationship between Mediterranean-type diet (MeDi) and Alzheimer's disease (AD). We sought to investigate the association between MeDi and MRI infarcts. High-resolution structural MRI was collected on 707 elderly 65 years or older community residents of New York with available dietary assessments administered an average of 5.8 years (3.22 standard deviations [SDs]) before the MRI. Participants were divided into 3 groups of adherence to MeDi (low, middle, and high tertiles). We examined the association of increasing adherence to MeDi with presence of infarcts on MRI. Models were run without adjustment, adjusted for basic demographic and clinical factors, and adjusted for vascular risk factors. A total of 222 participants had at least 1 infarct. In the unadjusted model, compared to the low adherence group, those in the moderate MeDi adherence group had a 22% reduced odds of having an infarct (odds ratio [OR], 0.78; 95% confidence interval [CI], 0.55-1.14), while participants in the highest MeDi adherence group had a 36% reduced odds (OR, 0.64; 95% CI, 0.42-0.97; p for trend = 0.04). In adjusted models, the association between MeDi adherence and MRI infarcts remained essentially unchanged. The association of high MeDi adherence with infarcts was comparable to that of hypertension (40% reduced probability), did not vary by infarct size or after excluding patients with dementia (n = 46) or clinical strokes (n = 86). There was no association between MeDi and white matter hyperintensities. Higher adherence to the MeDi is associated with reduced cerebrovascular disease burden.


Design of organic scintillators for non-standard radiation field dosimetry: experimental setup.
This paper describes an experimental setup designed for sensing the luminescent light coming from an organic plastic scintillator stimulated with ionizing radiation. This device is intended to be a part of a complete dosimeter system for characterization of small radiation fields which is the project of the doctoral thesis of the medical physicist at the Radiation Oncology facility of Hospital San Vicente Fundación in conjunction with the Universidad de Antioquia of Medellín Colombia. Some preliminary results predict a good performance of the unit, but further studies must be conducted in order to have a completed evaluation of the system. This is the first step in the development of an accuracy tool for measurement of non-standard fields in the Radiotherapy or Radiosurgery processes.


Absolute surface metrology by rotational averaging in oblique incidence interferometry.
A modified method for measuring the absolute figure of a large optical flat surface in synchrotron radiation by a small aperture interferometer is presented. The method consists of two procedures: the first step is oblique incidence measurement; the second is multiple rotating measurements. This simple method is described in terms of functions that are symmetric or antisymmetric with respect to reflections at the vertical axis. Absolute deviations of a large flat surface could be obtained when mirror antisymmetric errors are removed by N-position rotational averaging. Formulas are derived for measuring the absolute surface errors of a rectangle flat, and experiments on high-accuracy rectangle flats are performed to verify the method. Finally, uncertainty analysis is carried out in detail.


Interaction Between Environmental Risk Factors and Catechol-O-Methyltransferase (COMT) and X-Ray Repair Cross-Complementing Protein 1 (XRCC1) Gene Polymorphisms in Risk of Lung Cancer Among Non-Smoking Chinese Women: A Case-Control Study.
BACKGROUND Various studies have highlighted the link between polymorphisms in the XRCC1 gene (encoding X-ray repair cross-complementing group 1) with the incidence of decreased DNA repair capacity and an increased predisposition to cancer. Catechol-O-methyltransferase (COMT) plays a crucial role in estrogen-induced cancers. In the present study was analyzed the potential influence of XRCC1 and COMT gene polymorphisms as predisposing factors from a lung cancer perspective, in addition to conducting an investigation into their interaction with environmental risk factors in relation to lung cancer among non-smoking Chinese women. MATERIAL AND METHODS The XRCC1 gene T-77C, Arg194Trp, Arg280His, Arg399Gln, COMT gene 186C>T, and Val158Met mutations were evaluated in peripheral blood collected from 261 non-smoking female patients diagnosed with primary lung cancer and 265 female patients with benign lung disease. RESULTS The results obtained from this study demonstrated that XRCC1-77TC + CC, XRCC1 399Gln/Gln, COMT 186CT + TT, COMT 158Val/Met genotypes, type of occupation, cooking-oil fumes, and soot exposures were all independent risk factors involved with the occurrence of lung cancer among non-smoking women. Moreover, interactions between environmental exposure factors as well as XRCC1 and COMT gene polymorphisms were determined to play significant contributory roles regarding susceptibility of non-smoking females to lung cancer. CONCLUSIONS Taken together, T-77C and Arg399Gln polymorphisms of the XRCC1 gene, as well as the 186C>T and Val158Met polymorphisms of the COMT gene, increased the risk of lung cancer in non-smoking women, with the factors of occupation type, cooking-oil fumes, and soot exposures representing key contributing factors.


Mutation analysis of the hMTH1 gene in sporadic human ovarian cancer.
8-oxo-deoxyguanosine triphosphate (8-oxo-dGTP) is a major oxidation product in the nucleotide pool of the cell and is a potent mutagen, because it can be incorporated into DNA with equal frequency opposite either template C or A. The human MTH1 gene (hMTH1) is a homologue of the E. coli mutator gene mutT, which encodes 8-oxo-dGTPase. hMTH1 protein reduces spontaneous mutations by removing 8-oxo-dGTP from the triphosphate pool. To determine whether this gene is associated with carcinogenesis of human ovarian cancer, the present study examined, for the first time, the hMTH1 sequence in 49 ovarian cancers and 9 ovarian cancer cell lines by means of polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and sequencing analyses. A Gright curved arrow A transition at codon 83 was detected in one patient and one cell line (3.4%), followed by an amino acid change (valineright curved arrow methionine) which was known to cause the protein to be less active in vitro. This one base substitution was found in normal and corresponding tumor DNA, and its allele type was heterozygous. The same change has been detected in HNPCC (hereditary non-polyposis colorectal cancer) and gastric cancer patients, and thus it may not represent a mutation specific for ovarian cancer. A silent Tright curved arrow C transition at codon 119 was detected in 12 patients and 2 cell lines (24.1%). No specific mutations in hMTH1 were found in either ovarian cancer patients or cell lines. Thus, it appears that hMTH1 is not directly associated with ovarian cancer.


CXCL12 Regulates through JAK1 and JAK2 Formation of Productive Immunological Synapses.
The adaptive immune response requires interaction between T cells and APC to form a specialized structure termed the immune synapse (IS). Although the TCR is essential for IS organization, other factors such as chemokines participate in this process. In this study, we show that the chemokine CXCL12-mediated signaling contributes to correct IS organization and therefore influences T cell activation. CXCR4 downregulation or blockade on T cells caused defective actin polymerization at the contact site with APC, altered microtubule-organizing center polarization and the IS structure, and reduced T cell/APC contact duration. T cell activation was thus inhibited, as shown by reduced expression of CD25 and CD69 markers and of IL-2 mRNA levels. The results indicate that, through Gi and JAK1 and 2 kinases activation, CXCL12 signaling cooperates to build the IS and to maintain adhesive contacts between APC and T cells, required for continuous TCR signaling.


Glycosaminoglycan sulphation affects the seeded misfolding of a mutant prion protein.
The accumulation of protease resistant conformers of the prion protein (PrP(res)) is a key pathological feature of prion diseases. Polyanions, including RNA and glycosaminoglycans have been identified as factors that contribute to the propagation, transmission and pathogenesis of prion disease. Recent studies have suggested that the contribution of these cofactors to prion propagation may be species specific. In this study a cell-free assay was used to investigate the molecular basis of polyanion stimulated PrP(res) formation using brain tissue or cell line derived murine PrP. Enzymatic depletion of endogenous nucleic acids or heparan sulphate (HS) from the PrP(C) substrate was found to specifically prevent PrP(res) formation seeded by mouse derived PrP(Sc). Modification of the negative charge afforded by the sulphation of glycosaminoglycans increased the ability of a familial PrP mutant to act as a substrate for PrP(res) formation, while having no effect on PrP(res) formed by wildtype PrP. This difference may be due to the observed differences in the binding of wild type and mutant PrP for glycosaminoglycans. Cofactor requirements for PrP(res) formation are host species and prion strain specific and affected by disease associated mutations of the prion protein. This may explain both species and strain dependent propagation characteristics and provide insights into the underlying mechanisms of familial prion disease. It further highlights the challenge of designing effective therapeutics against a disease which effects a range of mammalian species, caused by range of aetiologies and prion strains.


How to reduce your inventory: a real world case study.
This case study describes the use of a performance analysis system at the Safety Products Division of Mine Safety Appliances Company, which contributed to the reduction of excess inventories by more than $8,000,000 during the first two years of implementation.


Behavior of the IncP-7 carbazole-degradative plasmid pCAR1 in artificial environmental samples.
In artificial environmental samples, the behavior of the IncP-7 conjugative plasmid pCAR1, which is involved in the catabolism of carbazole, was monitored. Sterile soil and water samples supplemented with carbazole were prepared. After inoculation with Pseudomonas putida harboring pCAR1, seven species of the genus Pseudomonas, and three other bacterial species, were monitored for carbazole degradation, bacterial survival, and conjugative transfer of pCAR1. In artificial soils, more than 90% of the carbazole was degraded in samples with high water content, suggesting that the water content is a key factor in carbazole degradation in artificial soils. In three of the artificial environmental water samples, more than 95% of the carbazole was degraded. Transconjugants were detected in some artificial water samples, but not in the artificial soil samples, suggesting that pCAR1 is preferably transferred in aqueous environments. Composition analysis of the artificial water samples and examination of conjugative transfer indicated that the presence of the divalent cations Ca(2+) and Mg(2+) promoted the plasmid transfer. The presence of carbazole also increases in incidence of transconjugants, probably by enhancing their growth. In contrast, humic acids in the liquid layer of artificial soil samples appeared to prevent conjugative transfer.


Antibiotics for preterm rupture of membranes.
Premature birth carries substantial neonatal morbidity and mortality. Subclinical infection is associated with preterm rupture of membranes (PROM). Prophylactic maternal antibiotic therapy might lessen infectious morbidity and delay labour, but could suppress labour without treating underlying infection. To evaluate the immediate and long-term effects of administering antibiotics to women with PROM before 37 weeks, on maternal infectious morbidity, neonatal morbidity and mortality, and longer-term childhood development. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (29 April 2010). Randomised controlled trials comparing antibiotic administration with placebo that reported clinically relevant outcomes were included as were trials of different antibiotics. Trials in which no placebo was used were included for the outcome of perinatal death alone. We extracted data from each report without blinding of either the results or the treatments that women received. We sought unpublished data from a number of authors. We included 22 trials, involving 6800 women and babies.The use of antibiotics following PROM is associated with statistically significant reductions in chorioamnionitis (average risk ratio (RR) 0.66, 95% confidence interval (CI) 0.46 to 0.96, and a reduction in the numbers of babies born within 48 hours (average RR 0.71, 95% CI 0.58 to 0.87) and seven days of randomisation (average RR 0.79, 95% CI 0.71 to 0.89). The following markers of neonatal morbidity were reduced: neonatal infection (RR 0.67, 95% CI 0.52 to 0.85), use of surfactant (RR 0.83, 95% CI 0.72 to 0.96), oxygen therapy (RR 0.88, 95% CI 0.81 to 0.96), and abnormal cerebral ultrasound scan prior to discharge from hospital (RR 0.81, 95% CI 0.68 to 0.98). Co-amoxiclav was associated with an increased risk of neonatal necrotising enterocolitis (RR 4.72, 95% CI 1.57 to 14.23).One study evaluated the children's health at seven years of age (ORACLE Children Study) and found antibiotics seemed to have little effect on the health of children. The decision to prescribe antibiotics for women with PROM is not clearcut. Benefits in some short-term outcomes (prolongation of pregnancy, infection, less abnormal cerebral ultrasound before discharge from hospital) should be balanced against a lack of evidence of benefit for others, including perinatal mortality, and longer term outcomes. If antibiotics are prescribed it is unclear which would be the antibiotic of choice.Co-amoxiclav should be avoided in women at risk of preterm delivery due to increased risk of neonatal necrotising enterocolitis.


Diagnosing variant Creutzfeldt-Jakob disease with the pulvinar sign: MR imaging findings in 86 neuropathologically confirmed cases.
Variant Creutzfeldt-Jakob disease (vCJD) is a rare but important cause of dementia and death in young patients and is causally linked to bovine spongiform encephalopathy. Symmetrical hyperintensity in the pulvinar (posterior) nuclei of the thalamus (pulvinar sign) on brain MR images was described as a specific, noninvasive, diagnostic sign of vCJD in a previous small series. This purpose of this larger study was to evaluate this sign prospectively and further define the MR imaging characteristics of vCJD. As part of the ongoing surveillance program in the United Kingdom, MR images of suspected cases of vCJD were collected during a 6-year period. All available images were assessed prospectively by one observer for the presence of the pulvinar sign. Images of neuropathologically confirmed cases were then assessed independently by two neuroradiologists for the degree of hyperintensity of the pulvinar on images of different MR sequences, and for the presence of abnormal hyperintensity in other areas of the brain. Discrepancies were reviewed jointly and a consensus opinion formed. Prospective analysis identified the pulvinar sign in 74 of 82 cases of vCJD. In the retrospective study, the pulvinar sign, as defined by hyperintensity of the pulvinar relative to the anterior putamen, was present on seven (9%) of 75 T1-weighted, 77 (71%) of 108 T2-weighted, 47 (81%) of 58 proton density-weighted, and 30 (100%) of 30 fluid-attenuated inversion-recovery (FLAIR) images. Diffusion-weighted images were available in two cases and were positive for the pulvinar sign in one. Other features were hyperintensity of the dorsomedial thalamic nuclei (93%), caudate head (40%), and periaqueductal gray matter (83%) on FLAIR images. In the appropriate clinical context, demonstration of the pulvinar sign on MR images is a highly accurate diagnostic sign for vCJD. FLAIR sequence is more sensitive than other sequences. Positive MR images may obviate more invasive diagnostic tests in most cases.


A Breathtaking Case of Pulmonary Hypertension with Frightening Complications and Intertwining Different Etiologies.
Pulmonary hypertension (PH) is a major health problem with increasing awareness. Although most common cause of PH is left heart disease (Group 2 PH), life-threatening complications occur mostly in Group 1 (pulmonary arterial hypertension) and Group 4 (chronic thromboembolic PH) patients. Although external compression of the left main coronary artery (LMCA) due to pulmonary artery dilatation is rare, it is a life-threatening complication since it causes myocardial ischemia and sudden cardiac death. In addition, PH is more than a single clinical entity due to its complex mechanism in which more than one subgroup may develop over time in the same patient. This complex mechanism challenges us when diagnosing the patient and faces us with life-threatening complications. In this case; we report a pulmonary arterial hypertension patient applied to our clinic with progressive dyspnea and recent angina, after detection of LMCA ostial stenosis, the patient was treated with intravascular ultrasound-guided stent implantation. In the further follow-ups, the patient underwent the pulmonary endarterectomy operation due to the diagnosis of chronic thromboembolic pulmonary hypertension secondary to newly diagnosed primary antiphospholipid syndrome.


Expression of DNMTs and genomic DNA methylation in gastric signet ring cell carcinoma.
The aim of the present study was to investigate the protein expression of DNA methyltransferases (DNMTs) and genomic DNA methylation status of genomes in gastric signet ring cell carcinoma (SRC). Immunohistochemistry was performed to analyze DNMT expression and methylated DNA immunoprecipitation microarray (MeDIP‑chip) and MeDIP quantitative real‑time PCR (MeDIP‑qPCR) were performed to analyze the genomic DNA methylation status in gastric SRC tissue. An increase in DNMT1 and decrease in DNMT3A expression in SRC tissue was observed compared with matched non‑cancerous tissue. However, expression of other DNMTs, DNMT2, DNMT3B and DNMT3L, was not found to differ significantly between carcinoma and control. The MeDIP‑chip assay revealed that methylation of gene promoters and CpG islands in SRC was higher than those in matched control tissue. However, MeDIP‑qPCR analysis demonstrated that specific tumor‑related genes, including ABL2, FGF18, TRAF2, EGFL7 and RAB33A were aberrantly hypomethylated in SRC tissue. Results of the current study indicate that gastric SRC may produce complex patterns of aberrant DNA methylation and DNMT expression.


[Accidental hypothermia: an extreme case of successful resuscitation].
This case involved a 65-year-old male with severe hypothermia who presented a cardiorespiratory arrest on his arrival in hospital. He was treated by means of a cardiopulmonary bypass and subsequently made good recovery. In this article we summarise the signs and symptoms of hypothermia, the treatment of a patient with hypothermia and the different rewarming strategies, based on the current literature on the subject.


Actual Usage and Quality of Experimental Colitis Models in Preclinical Efficacy Testing: A Scoping Review.
There is no standardized validated experimental model used to predict human drug response, and the choice of model is not based on systematic evidence. Therefore, we decided to systematically investigate which models are currently used by selecting studies from literature that use prescribed inflammatory bowel disease medication as a positive control. A search of PubMed was performed using terms describing experimental colitis models and the drugs used in corresponding clinical practice followed by the application of an animal filter. Each article was read and scored using a predesigned form describing the characteristics of the study (17 items), a quality assessment (10 items) completed by a meta-analysis. One hundred ninety-four unique articles were included that met the selection criteria. A large heterogeneity was found regarding the characteristics of the animals used, induction methods, treatment protocol, and reporting quality. If categorized by colitis model only a small number of studies used a chronic model (10/194). Almost all use acute chemical models that investigate a response to epithelial damage, rather than chronic colitis. Fifty-six percent used a TNBS model and 20% used a dextran sodium sulfate model. In these models, an ameliorating effect of 5-ASA and corticosteroids was demonstrated and also a difference in outcome when male or female animals are used. This scope describes a huge heterogeneity in study designs for preclinical drug efficacy. In addition, more than three-quarters of the studies used an acute model irrelevant for testing new treatment options for inflammatory bowel disease.


The PGRS Domain of Mycobacterium tuberculosis PE_PGRS Protein Rv0297 Is Involved in Endoplasmic Reticulum Stress-Mediated Apoptosis through Toll-Like Receptor 4.
The genome of Mycobacterium tuberculosis, the causal organism of tuberculosis (TB), encodes a unique protein family known as the PE/PPE/PGRS family, present exclusively in the genus Mycobacterium and nowhere else in the living kingdom, with largely unexplored functions. We describe the functional significance of the PGRS domain of Rv0297, a member of this family. In silico analyses revealed the presence of intrinsically disordered stretches and putative endoplasmic reticulum (ER) localization signals in the PGRS domain of Rv0297 (Rv0297PGRS). The PGRS domain aids in ER localization, which was shown by infecting macrophage cells with M. tuberculosis and by overexpressing the protein by transfection in macrophage cells followed by activation of the unfolded protein response, as evident from increased expression of GRP78/GRP94 and CHOP/ATF4, leading to disruption of intracellular Ca2+ homeostasis and increased nitric oxide (NO) and reactive oxygen species (ROS) production. The consequent activation of the effector caspase-8 resulted in apoptosis of macrophages, which was Toll-like receptor 4 (TLR4) dependent. Administration of recombinant Rv0297PGRS (rRv0297PGRS) also exhibited similar effects. These results implicate a hitherto-unknown role of the PGRS domain of the PE_PGRS protein family in ER stress-mediated cell death through TLR4. Since this protein is already known to be present at later stages of infection in human granulomas it points to the possibility of it being employed by M. tuberculosis for its dissemination via an apoptotic mechanism.IMPORTANCE Apoptosis is generally thought to be a defense mechanism in protecting the host against Mycobacterium tuberculosis in early stages of infection. However, apoptosis during later stages in lung granulomas may favor the bacterium in disseminating the disease. ER stress has been found to induce apoptosis in TB granulomas, in zones where apoptotic macrophages accumulate in mice and humans. In this study, we report ER stress-mediated apoptosis of host cells by the Rv0297-encoded PE_PGRS5 protein of M. tuberculosis exceptionally present in the pathogenic Mycobacterium genus. The PGRS domain of Rv0297 aids the protein in localizing to the ER and induces the unfolded protein response followed by apoptosis of macrophages. The effect of the Rv0297PGRS domain was found to be TLR4 dependent. This study presents novel insights on the strategies employed by M. tuberculosis to disseminate the disease.


The effect of 'Traffic-Light' nutritional labelling in carbonated soft drink purchases in Ecuador.
Overweight and obesity have become global concerns in developed and developing countries due to their rise in recent years and their association with the prevalence of non-communicable diseases including diabetes, hypertension and cardiovascular diseases. In fact, it is estimated that roughly 39% of adults worldwide are overweight and 13% are obese. Ecuador is an example of a developing country concerned with the overweight and obesity problem, where it is estimated that 30% of children, 26% of teenagers and 63% of adults are either overweight or obese and where 1 in 4 deaths are attributed to chronic diseases. To address the overweight and obesity problem via the promotion of healthy eating habits, in 2013 the country approved technical regulation for the labelling of packed processed food products. The regulation included a mandatory traffic-light (TL) supplemental nutritional information labelling system to be displayed on the package of all processed foods for sale in the country. This new labelling system displays a traffic light panel for the product content of sugar, fat and salt in addition to the traditional nutrient declaration label. The objective of this paper was to evaluate the effect of the TL supplemental nutritional information on consumers' buying behavior in Ecuador. More specifically, we concentrated on the purchasing behavior of carbonated soft drinks. For our analysis, we used monthly aggregated purchase data (total expenditures, quantities and average prices) of carbonated soft drinks from January 2013 to December 2015 obtained from Kantar World Panel-Ecuador. We estimated a non-linear Almost Ideal Demand System where we model the demand for high sugar and low sugar carbonated soft drinks. We found that the introduction of the traffic light supplemental nutrition labelling did not have the expected effect of reducing purchases of carbonated soft drinks during its first year of implementation, especially those high in sugar. Additionally, we found that lower income-status households tend to spend more on and consume more calories from CSD than households with higher socio-economic status. Finally, we identified that over time purchases of high sugar soft drinks decreased while purchases of low and no sugar soft drinks increased. Beyond our contribution of evaluating the effect of the traffic light on the purchases of carbonated soft drinks, we also estimated price and income elasticities of carbonated soft drinks which can be useful in the evaluation of fiscal policies.


Tachycardia control with cardiac pacemakers.
Techniques used to treat tachyarrhythmias with brief electrical impulses are described. The disease process is described, identifying the prevention of one of the three conditions required for reentry (which provides the mechanism for most electrically convertible rhythms) as the basis for therapy. The risk of inducing fibrillation is discussed. The four major pacing techniques used to treat tachycardia are described. The first technique involves using additional pacemaker pulses to establish the appropriate conditions permitting interruption of the tachycardia. The second technique, which permits adaptation to the variations in tachycardia characteristics, is scanning. Scanning changes the intervals on successive bursts in an interactive process, allowing a series of paced intervals to be tested. The third technique is usually called an adaptive or automatic technique. The final technique is ramp pacing, which allows extrastimuli to be introduced at progressively premature intervals within a burst of stimuli.


Alterations in mechanical properties of rat papillary muscle during maturation.
Myocardial performance was measured during maturation using isolated left ventricular papillary muscles from female Wistar rats. Muscles were studied isometrically and isotonically, stimulated at 0.1 Hz, perfused with Tyrode solution having an external calcium concentration of 2.4 mM, and maintained at 30 degrees C. Heart and body weight increased rapidly during the first 6 mo and then stabilized. Peak isometric developed tension, time to peak isometric developed tension, and time to half relaxation increased substantially during the 1- to 10-mo period with little change in the peak rate of isometric tension rise and peak rate of isometric tension fall. No difference in resting tension was noted among any groups. Force-velocity curves from muscles from 2-, 6-, and 10-mo-old animals show a significant age-related decrease in the isotonic velocity of shortening by as much as 21% between 2 and 10 mo of age. Thus maturation profoundly affects the contractile state of cardiac muscle, with force of contraction increasing and velocity of shortening decreasing as a function of age in the rat.


Analyzing Migration Restriction Regimes.
This paper develops a framework for analyzing migration restriction regimes, and illustrates it with the case of U.S. immigration law and policy. Nation-states regulate the entry of foreign-born persons, and this regulation comprises three elements: the type of restriction, the apparatus of restriction, and the consequences of restriction. Restriction may be based on personal characteristics, numerical ceilings, or both. Personal restriction notices the characteristics of persons, using them as criteria for granting or denying admission. Numerical restriction places numerical ceilings on admissions. The apparatus of restriction may stipulate specific ceilings, whether some groups are exempt from the ceiling and, if so, by what criteria, and whether admission under the ceiling is first-come/first-served or by lottery or instead preferential and, if so, by what criteria. Two unintended consequences follow immediately: unauthorized migration (under both personal and numerical restriction); and visa-number backlogs (under numerical restriction). These in turn generate a range of policy devices: border enforcement, procedures for legalization and deportation, and procedures for clearing backlogs. Indeed, the history of a country's immigration law may be understood as a sequence of measures for first setting up the apparatus of restriction and then altering it in order not only to re-examine provisions of the initial setup but also to address unauthorized migration and visa-number backlogs. Viewing migration through this lens enables assessment of particular legislation and, more broadly, dynamics of a migration restriction regime, subject to world circumstances, including its possible inherent instability. The migration restriction lens also generates new metrics for a country's attractiveness and its innovativeness and creativity. To illustrate, the paper examines the migration restriction regime in the United States since the country's founding. Finally, the paper provides a checklist for a migration restriction setup that doubles as the basis for table shells for summarizing a country's migration restriction regime and its history.


Broadening Our Bandwidth: A Multiple Case Report of Expanded Use of Telehealth Technology to Perform Wound Consultations During the COVID-19 Pandemic.
Managing patients during the coronavirus disease-2019 (COVID-19) pandemic, and the associated severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) in particular, required the nimble responsiveness for which WOC nurses are known. Problem-solving skills were needed to continue the level of WOC nursing services expected by patients, families, and professional colleagues, while reducing the hours we were physically present at our clinical facility. In order to respond to these demands, our team realized it must create an innovative approach to provide efficient, cost-effective consultations during this global crisis. This Challenges in Practice article summarizes our experience with use of telemedicine technologies to perform remote consultations within the acute care setting. Case 1 was a 52-year-old woman with a history of paraplegia. She had several pressure injuries but had not received topical care for these wounds prior to admission. A consultation for the WOC nurse was requested and performed via telehealth services on a day our team was working off-site. This case illustrates the process our team used to perform a virtual consultation and demonstrates how the use of images placed in the electronic medical record aided in developing an effective plan of care. Case 2 was a 48-year-old man who tested positive for COVID-19. He developed bilateral unstageable pressure injuries on his cheeks after being placed in the prone position for a prolonged period while critically ill. This case describes multiple technologic platforms used for telemedicine consults in a patient with COVID-19 requiring isolation. Remote consultation by WOC nurses was possible in our healthcare system because of previous experience using telemedicine technology and well-established collaborative relationships with providers and bedside nurses. By expanding our use of telemedicine technology, we were able to provide ongoing care to a patient without COVID-19 who had WOC consultation needs, and a patient with strict isolation demands due to COVID-19.


Preoperative Dynamic Contrast-Enhanced and Diffusion-Weighted Breast Magnetic Resonance Imaging Findings for Prediction of Lymphovascular Invasion of the Lesions in Node-Negative Invasive Breast Cancer.
Purpose: Our single-center retrospective study aimed to investigate the relationship between preoperative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) findings and apparent diffusion coefficient (ADC) values and lymphovascular invasion (LVI) status of the lesions in patients with clinically-radiologically lymph node-negative invasive breast cancer. Methods: A total of 250 breast lesions diagnosed in preoperative magnetic resonance imaging were identified. All patients were divided into 2 subgroups: LVI-negative and LVI-positive according to the pathological findings of surgical specimens. The 2 groups' DCE-MRI findings, ADC values, and histopathological results of lesions were compared. Results: LVI was detected in 100 of 250 lesions. Younger age than 45 years and larger lesion size than 20 mm were found to be associated with the presence of LVI (P < .001). High histological and nuclear grade (P = .001), HER2-enriched molecular subtype (P = .001), and Ki-67 positivity (P = .016) were significantly associated with LVI. The LVI positivity rate was significantly higher in the lesions with medium-rapid initial phase kinetic curve and washout delayed phase kinetic curve (P = .001). The presence of LVI was significantly associated with the presence of peritumoral edema, sentinel lymph node metastasis, adjacent vessel sign, and increased whole breast vascularity (P < .001). When diffusion-weighted imaging findings were evaluated, it was determined that tumoral ADC values lower than 1068 × 10-6 mm2/second (P = .002) and peritumoral-tumoral ADC ratios higher than 1.5 (P = .001) statistically increased the probability of LVI. Conclusion: The patient's age, various histopathological and DCE-MRI findings, tumoral ADC value, and peritumoral-tumoral ADC ratio may be useful in the preoperative prediction of LVI status in breast cancer lesions.


[Failure in adaptation: a premise in juvenile delinquency].
The cause of failure to adjust are examined and measures that should be taken by families, school and society in general to prevent such failure from passing into juvenile delinquency are discussed.


Stress and transposable elements: co-evolution or useful parasites?
The activity of transposable elements can be induced by environmental and population factors and in particular by stresses in various organisms. A consequence of the increase in transposable element mobility is the creation of new genetic variability that can be useful in the face of stressful conditions. In this review, results supporting this hypothesis are presented and discussed. The main question is how stress induces the activity of transposable elements. We discuss hypotheses based upon the existence of promoters or fixation sites of transcription activators in the untranslated regions of transposable elements, similar to those found in regulatory regions of host defence genes.