Detecting plasma Epstein-Barr virus DNA to diagnose postradiation nasopharyngeal skull base lesions in nasopharyngeal carcinoma patients: a prospective study.
The diagnosis of postradiation nasopharyngeal skull base lesions in petients with nasopharyngeal carcinoma (NPC) is still a tough problem in clinical practice. An early and accurate diagnosis is important for subsequent management. We prospectively evaluated the diagnostic value of plasma Epstein-Barr virus(EBV) DNA in detecting postradiation nasopharyngeal skull base lesions in NPC patients. From July 2006 to September 2010, 90 patients with postradiation NPC (34 women and 56 men; median age: 42 years) met the selection criteria and were recruited in this study. All postradiation nasopharyngeal skull base lesions were found in the latest magnetic resonance imaging (MRI) examinations before endoscopic surgery, and the nasopharyngeal cavity was normal under flexible nasopharyngoscopy. Plasma EBV DNA detection was performed within 2 weeks before endoscopic surgery. A total of 90 endoscopic operations were successfully performed without any postoperative complications. Recurrences confirmed by postoperative pathology were found in 30 patients. The specificity, positive and negative predictive values of plasma EBV DNA detection were better than those of MRI. In addition, combining plasma EBV DNA detection with MRI improved the specificity and positive predictive values of MRI. Plasma EBV DNA detection followed by MRI would help to diagnose recurrence whereas MRI was unable. These results indicate that plasma EBV DNA is an effective and feasible biomarker for detecting postradiation nasopharyngeal skull base lesions in NPC patients.


Anticoagulation, atrial fibrillation, and chronic kidney disease-whose side are you on?
Whether to initiate oral anticoagulant therapy in advanced chronic kidney disease patients with atrial fibrillation remains debatable. Although randomized trial data are lacking, observational studies yield controversial results. Keskar and colleagues analyzed data from a Canadian health care system and found that in elderly chronic kidney disease patients with atrial fibrillation, oral anticoagulant therapy did not prevent ischemic strokes, induced hemorrhages, but prolonged life. These paradoxical findings emphasize the dire need for an adequately powered randomized trial.


Functional mutants of phenylalanine transfer RNA from Escherichia coli.
The gene pheV from Escherichia coli, coding for tRNAPhe and carried on a plasmid, has been mutagenised with hydroxylamine. Mutants in the structural gene have been identified using two criteria: (i) de-attenuation of beta-galactosidase expression, while under the control of the attenuator region of the pheS,T operon by means of an operon fusion; (ii) loss of ability to complement thermosensitivity of a mutant Phe-tRNA synthetase. Mutants showing de-attenuation were sequenced and two nucleotide changes identified: G44----A44 (found five times) and m7G46----A46 (found once). Sequencing of mutants that lost complementation identified two further tRNA mutants, C2---U2 and G15----A15; the mutant m7G46----A46 was also re-isolated by this criterion. Three of the mutants involve bases implicated in tertiary rather than secondary structure hydrogen bonding. One hypothesis for the mechanism of de-attenuation is that mutant tRNAPhe molecules compete with the wild-type tRNAPhe on the ribosome but are inefficient at some step in the elongation process.


PROGNOSTIC VALUE OF THE MULTIPLE MINI-INTERVIEW FOR EMERGENCY MEDICINE RESIDENCY PERFORMANCE.
The Multiple Mini-Interview (MMI) uses short, structured contacts, and is known to predict medical school success better than traditional interviews and application materials. Its utility in Emergency Medicine residency selection is untested. We investigate whether it provides additional information regarding future first-year resident performance that can be useful in resident selection. From three Emergency Medicine residency programs, 71 interns in their first month completed an MMI developed to focus on desirable resident characteristics. Application data were reviewed. First-year resident performance assessments covering the American Council for Graduate Medical Education (ACGME) core competencies, along with professionalism and performance concerns, were obtained. Multiple logistic regressions were employed and MMI correlations were compared with program rank lists and typical selection factors. An individual's score on the MMI correlated with overall performance (p < 0.05) in single logistic regression. MMI correlated with ACGME individual competencies patient care and procedural skills at a less robust level (p < 0.1), but not with any other outcomes. Rank list position correlated with the diagnostic skill competency (p < 0.05), but no others. Traditional selection factors correlated with overall performance, disciplinary action, patient care, medical knowledge, and diagnostic skills (p < 0.05). MMI was not correlated significantly with the outcomes when included in multiple ordinal logistic regression with other selection factors. MMI scores correlate with overall performance, but are not statistically significant when other traditional selection factors were considered. The MMI process seems potentially superior to program rank list at correlating with first-year performance. The MMI may provide additional benefit when examined using a larger and more diverse sample.


Immobilization of poly-L-lysine brush via surface initiated polymerization for the development of long-term antibacterial coating for silicone catheter.
Bacterial colonization of indwelling catheter remains a major threat in healthcare units worldwide. Developing approaches to prevent catheter-associated infections (CAIs) is, therefore, in great demand. Herein, to endow silicone catheter with long-term antibacterial properties, antimicrobial poly-L-lysine (PLL) brush was developed on the surface of catheter via surface initiated ring open polymerization. Surface characterizations confirmed the successful immobilization of PLL. The PLL-tethered catheter showed potent antibacterial activities against catheter-associated urinary tract infections (CAUTIs) related pathogens. Moreover, after immersing in simulated body fluid for 28 days or incubating at 60 °C for 65 days, the bactericidal properties of PLL-tethered catheter were still retained. Furthermore, the PLL-tethered catheter exhibited good anti-infection activity and biocompatibility in vivo. The PLL-tethered surfaces hold great potential in the development of antibacterial silicone catheter to combat CAIs in clinical applications.


Transcranial Doppler is Complementary to Echocardiography for Detection and Risk Stratification of Patent Foramen Ovale.
In patients with patent foramen ovale (PFO), strategies are needed to identify patients at higher risk, who might benefit from PFO closure. We studied the frequency of detection of a right-to-left shunt (RLS) using transesophageal echocardiography (TEE) among patients with cryptogenic stroke and transcranial Doppler (TCD) to detect RLS, and analyzed the prediction of recurrent stroke according to TCD shunt grade, by detection of RLS on TEE, and by atrial septal aneurysm or mobility. Among 334 patients with TCD, 69.8% were female, with a mean (SD) age of 53 (14) years, with a median follow-up of 420 days. There were 284 cases with TCD and TEE; 54 (19%) had atrial septal aneurysm or mobility. Echocardiography failed to show a RLS in 43 (15.1%) of the patients who had TCD and TEE, even in some patients with high-grade shunts on TCD: 18 (42%) were grade 3 or higher on TCD. Survival free of stroke or transient ischemic attack was predicted significantly by TCD shunt grade < 2 (P = 0.028), shunt grade < 3 (P = 0.03), and shunt grade < 4 (P < 0.0001); this was attenuated by adjustment for risk factors in Cox regression (P = 0.08). Neither RLS on TEE (P = 0.47), or atrial septal aneurysm or mobility (P = 0.08), predicted events. Our findings suggest that TCD might be more sensitive than TEE for detection of RLS, which misses some cases with substantial RLS, and might be valuable for prediction of recurrent stroke or transient ischemic attack in patients with PFO. TCD complements TEE for management of suspected paradoxical embolism.


The Role of TLR4 in the Immunotherapy of Hepatocellular Carcinoma: Can We Teach an Old Dog New Tricks?
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is a leading cause of cancer-related death worldwide. Immunotherapy has emerged as the mainstay treatment option for unresectable HCC. Toll-like receptor 4 (TLR4) plays a crucial role in the innate immune response by recognizing and responding primarily to bacterial lipopolysaccharides. In addition to its role in the innate immune system, TLR4 has also been implicated in adaptive immunity, including specific anti-tumor immune responses. In particular, the TLR4 signaling pathway seems to be involved in the regulation of several cancer hallmarks, such as the continuous activation of cellular pathways that promote cell division and growth, the inhibition of programmed cell death, the promotion of several invasion and metastatic mechanisms, epithelial-to-mesenchymal transition, angiogenesis, drug resistance, and epigenetic modifications. Emerging evidence further suggests that TLR4 signaling holds promise as a potential immunotherapeutic target in HCC. The aim of this review was to explore the multilayer aspects of the TLR4 signaling pathway, regarding its role in liver diseases and HCC, as well as its potential utilization as an immunotherapy target for HCC.


Trajectories, Risk Factors, and Impact of Persistent Pain After Major Musculoskeletal Surgery in Adolescents: A Replication Study.
Studies have identified high rates of chronic postsurgical pain in adolescents. Characterizing patterns of pain in the transition from acute to chronic following major surgery may pinpoint critical periods of recovery. This observational study modelled pain trajectories over 1-year following surgery to attempt replication of prior work and evaluate baseline psychosocial factors and 12-month health outcomes. Adolescents 10 to 18 years completed electronic daily pain reporting for 7 days and self-reported health outcomes, at 5 assessment timepoints. Group-based trajectory modelling identified two trajectories with similar starting points in-hospital but distinct recovery courses at home. Pain declined steadily in one group across the study period ("Declining Pain"; estimated probability,18.9%), but pain increased after hospital discharge and remained high through 12-months in the other group ("High and Persistent Pain"; estimated probability,81.1%). Pre-surgery pain (Aor = 1.86, P = .001) and sleep quality (Aor = 0.49, P = .029) were associated with the High and Persistent pain trajectory in multivariate regressions. This trajectory was associated with lower total quality of life (B=-9.79, P = .002), physical health (B = -15.93, P < .001), psychosocial health (B = -6.73, P = .06), and greater fatigue (B = -13.61, P = .001). This study replicated prior findings identifying two post-surgical pain trajectories with diverging pain in the first two weeks. Clinical detection of those with increasing pain and early intervention may interrupt persistence of pain. PERSPECTIVE: This article replicates a prior study identifying distinct post-surgical pain trajectories, Declining Pain and High and Persistent Pain. The High and Persistent pain trajectory is associated with pre-surgery pain, pre-surgery sleep quality, and lower quality of life (total, physical, and psychosocial health as well as fatigue) at 12-month follow-up.


Switching state-space modeling of neural signal dynamics.
Linear parametric state-space models are a ubiquitous tool for analyzing neural time series data, providing a way to characterize the underlying brain dynamics with much greater statistical efficiency than non-parametric data analysis approaches. However, neural time series data are frequently time-varying, exhibiting rapid changes in dynamics, with transient activity that is often the key feature of interest in the data. Stationary methods can be adapted to time-varying scenarios by employing fixed-duration windows under an assumption of quasi-stationarity. But time-varying dynamics can be explicitly modeled by switching state-space models, i.e., by using a pool of state-space models with different dynamics selected by a probabilistic switching process. Unfortunately, exact solutions for state inference and parameter learning with switching state-space models are intractable. Here we revisit a switching state-space model inference approach first proposed by Ghahramani and Hinton. We provide explicit derivations for solving the inference problem iteratively after applying a variational approximation on the joint posterior of the hidden states and the switching process. We introduce a novel initialization procedure using an efficient leave-one-out strategy to compare among candidate models, which significantly improves performance compared to the existing method that relies on deterministic annealing. We then utilize this state inference solution within a generalized expectation-maximization algorithm to estimate model parameters of the switching process and the linear state-space models with dynamics potentially shared among candidate models. We perform extensive simulations under different settings to benchmark performance against existing switching inference methods and further validate the robustness of our switching inference solution outside the generative switching model class. Finally, we demonstrate the utility of our method for sleep spindle detection in real recordings, showing how switching state-space models can be used to detect and extract transient spindles from human sleep electroencephalograms in an unsupervised manner.


Alzheimer's vulnerable brain region relies on a distinct retromer core dedicated to endosomal recycling.
Whether and how the pathogenic disruptions in endosomal trafficking observed in Alzheimer's disease (AD) are linked to its anatomical vulnerability remain unknown. Here, we began addressing these questions by showing that neurons are enriched with a second retromer core, organized around VPS26b, differentially dedicated to endosomal recycling. Next, by imaging mouse models, we show that the trans-entorhinal cortex, a region most vulnerable to AD, is most susceptible to VPS26b depletion-a finding validated by electrophysiology, immunocytochemistry, and behavior. VPS26b was then found enriched in the trans-entorhinal cortex of human brains, where both VPS26b and the retromer-related receptor SORL1 were found deficient in AD. Finally, by regulating glutamate receptor and SORL1 recycling, we show that VPS26b can mediate regionally selective synaptic dysfunction and SORL1 deficiency. Together with the trans-entorhinal's unique network properties, hypothesized to impose a heavy demand on endosomal recycling, these results suggest a general mechanism that can explain AD's regional vulnerability.


Effect of trivalent arsenicals on cell proliferation in mouse and human microvascular endothelial cells.
Chronic exposure to high levels of inorganic arsenic (iAs) has been associated with cancerous and non-cancerous health effects, including cardiovascular effects. However, the mechanism for a presumed toxic effect of arsenic on vascular tissue is not clear. Our working hypothesis is that inorganic trivalent arsenic and its methylated metabolites react with cysteine-containing cellular proteins and alter their function leading to adverse events such as cytotoxicity or proliferation. In this study, human microvascular endothelial cells (HMEC1) and mouse microvascular endothelial cells (MFP-MVEC) were exposed to arsenite (iAsIII), monomethylarsonous acid (MMAIII), or dimethylarsinous acid (DMAIII) for 72 h to evaluate cytotoxicity, and for 24, 48 or 72 h to evaluate cell proliferation. Both cell lines showed similar LC50 values, from 0.1 to 2.4 μM, for all three trivalent arsenicals. The endothelial cells treated with1 nM to 1 μM concentrations of the three trivalent arsenicals did not show increased cell proliferation at 24, 48 or 72 h or increased rate of proliferation at 72 h of exposure. Overall, cytotoxicity of trivalent arsenicals to microvascular endothelial cells is similar to their cytotoxicity to epithelial cells, and that these compounds are not mitogenic.


Intestinal wall thickness detected by multidetector spiral computed tomography enterography predicts the disease severity of Crohn's disease.
Multidetector spiral computed tomography enterography (MSCTE) and ileocolonoscopy are used in evaluating inflammatory situation of Crohn's disease (CD) patients. The purpose of this study was to determine the disease severity of CD patients by combining the intestinal wall thickness by MSCTE with ileocolonoscopy. This retrospective study included 50 patients with terminal ileal CD. Diagnosis was confirmed based on clinical features, endoscopy, and pathology. Patients underwent both MSCTE and ileocolonoscopy. Ileal wall thickness was measured and the disease severity was evaluated by CD activity index (CDAI). Intestinal mucosal lesions were scored by the simple endoscopic score for CD (SES-CD). Of the 50 patients with active terminal ileal CD, the comparison of scores between SES-CD and CDAI showed significant association with Spearman's rank correlation coefficient (p < 0.01). There were statistically significant correlation between the wall thickness and the SES-CD (p < 0.0001) as well as CDAI (p < 0.001), respectively, but no significant correlation between the wall thickness and the C-reactive protein (CRP) was found (p = 0.43). Moreover, we found that the wall thickness was preferential to predict the disease severity in the terminal ileal CD. MSCTE, in combination with ileocolonoscopy, is reliable to identify disease severity in CD patients and provides more accurate information in the diagnosis and treatment.


Altered neural mechanisms of deception in individuals with autistic traits.
A successful deception involves making a decision, acting on it, and evaluating results. Here, we investigated deception in a non-clinical sample (n = 36) with varying autism traits using a coin-toss paradigm of active deception. The subjects were asked to react to the instructions by clicking one of the two boxes that could mislead their opponents, followed by feedback on their success or failure. During this reaction, their EEG activity was recorded, and the results suggested that people with high autistic traits exhibited longer reaction times and lower amplitude of P3 in the decision-making stage compared to individuals with low autistic traits. The feedback evaluation stage in the high autistic trait group elicited lower amplitude of FRN and P3. Overall, these results indicated that people with high autistic traits experienced difficulties in deceiving, which could be related to atypical neural mechanisms.


Signaling downstream of p38 in psoriasis.
Psoriasis is an inflammatory skin disease characterized by infiltration of the skin by T cells and increased production of pro-inflammatory cytokines. Two recent reports show that the p38-activated kinases mitogen-activated protein kinase-activated protein kinase 2 and mitogen- and stress-activated protein kinase are activated in psoriatic skin and may contribute to the production of pro-inflammatory cytokines.


Unusual glomerulopathy with aggregated subepithelial microspheric particles resembling membranous nephropathy: a variant of glomerulopathy associated with podocytic infolding?
A 69-year-old woman presented with unusual electron microscopic findings. The patient was admitted to ascertain the cause of her persistent proteinuria, and kidney biopsy was performed. While light microscopic findings and immunofluorescence study suggested membranous nephropathy, electron microscopic study showed microspheric particles aggregated in the subepithelial space where electron-dense deposits should have existed. While the microspheric particles could have been unusual and rough deposits, detailed study suggested that the particles could be parts of glomerular podocytes, for example foot processes. This unusual finding was considered as being in a unique clinical course of membranous nephropathy, but a variant of glomerulopathy associated with podocytic infolding, proposed by Joh et al. (J Nephrol 49:61-67, 2007), could not be excluded.


Demonstration that fbiC is required by Mycobacterium bovis BCG for coenzyme F(420) and FO biosynthesis.
Using the nitroimidazopyran-based antituberculosis drug PA-824 as a selective agent, transposon-generated Mycobacterium bovis strain BCG (M. bovis) mutants that could not make coenzyme F(420) were identified. Four independent mutants that could not make F(420) or the biosynthesis intermediate FO were examined more closely. These mutants contained transposons inserted in the M. bovis homologue of the Mycobacterium tuberculosis gene Rv1173, which we have named fbiC. Complementation of an M. bovis FbiC(-) mutant with fbiC restored the F(420) phenotype. These data demonstrate that fbiC is essential for F(420) production and that FbiC participates in a portion of the F(420) biosynthetic pathway between pyrimidinedione and FO. Homologues of fbiC were found in all 11 microorganisms that have been fully sequenced and that are known to make F(420). Four of these homologues (all from members of the aerobic actinomycetes) coded for proteins homologous over the entire length of the M. bovis FbiC, but in seven microorganisms two separate genes were found to code for proteins homologous with either the N-terminal or C-terminal portions of the M. bovis FbiC. Histidine-tagged FbiC overexpressed in Escherichia coli produced a fusion protein of the molecular mass predicted from the M. bovis BCG sequence (approximately 95,000 Da), as well as three other histidine-tagged proteins of significantly smaller size, which are thought to be proteolysis products of the FbiC fusion protein.


Central tolerance regulates B cells reactive with Goodpasture antigen alpha3(IV)NC1 collagen.
Patients and rodents with Goodpasture's syndrome (GPS) develop severe autoimmune crescentic glomerulonephritis, kidney failure, and lung hemorrhage due to binding of pathogenic autoantibodies to the NC1 domain of the alpha3 chain of type IV collagen. Target epitopes are cryptic, normally hidden from circulating Abs by protein-protein interactions and the highly tissue-restricted expression of the alpha3(IV) collagen chain. Based on this limited Ag exposure, it has been suggested that target epitopes are not available as B cell tolerogens. To determine how pathogenic anti-GPS autoantibody responses are regulated, we generated an Ig transgenic (Tg) mouse model that expresses an Ig that binds alpha3(IV)NC1 collagen epitopes recognized by serum IgG of patients with GPS. Phenotypic analysis reveals B cell depletion and L chain editing in Tg mice. To determine the default tolerance phenotype in the absence of receptor editing and endogenous lymphocyte populations, we crossed Tg mice two generations with mice deficient in Rag. Resulting Tg Rag-deficient mice have central B cell deletion. Thus, development of Tg anti-alpha3(IV)NC1 collagen B cells is halted in the bone marrow, at which point the cells are deleted unless rescued by a Rag enzyme-dependent process, such as editing. The central tolerance phenotype implies that tolerizing self-Ag is expressed in bone marrow.


Atorvastatin but not L-arginine improves endothelial function in type I diabetes mellitus: a double-blind study.
We sought to determine the effects of oral L-arginine and the hexamethylglutaryl coenzyme A reductase inhibitor atorvastatin on endothelial function in young patients with type I diabetes mellitus (DM). Endothelial dysfunction, a key early event in atherosclerosis, occurs in young patients with type I DM, and its reversal may benefit the progression of vascular disease. Cholesterol reduction in L-arginine improve endothelial function in nondiabetic subjects, but their effect in patients with type I DM is unknown. In a double-blind, 2x2 factorial study, we investigated the effect of L-arginine (7 g twice daily) and atorvastatin (40 mg/day) on conduit artery vascular function in 84 normocholesterolemic young adults (mean+/-SD: age 34 years [range 18 to 46], low density lipoprotein [LDL] cholesterol 2.96+/-0.89 mmol/liter) with type I DM. Brachial artery dilation to flow (flow-mediated dilation [FMD]) and to the direct smooth muscle dilator glyceryl trinitrate (GTN) were assessed noninvasively using high resolution ultrasound at baseline and after six weeks of treatment. Atorvastatin resulted in a 48+/-10% decrease in serum LDL cholesterol levels, whereas L-arginine levels increased by 247+/-141% after L-arginine therapy. By analysis of covariance, treatment with atorvastatin resulted in a significant increase in FMD (p = 0.018. L-Arginine therapy had no significant effect on endothelial function, and there was no significant change in dilation to GTN after either intervention. In young patients with type I DM, improvement in endothelial dysfunction can be demonstrated after just six weeks of treatment with atorvastatin. In contrast to studies of hypercholesterolemia, however, L-arginine had no benefit. Treatment with atorvastatin at an early stage may have an impact on the progression of atherosclerosis in these high risk patients.


Assessing mental well-being in a Sinhala speaking Sri Lankan population: validation of the WHO-5 well-being index.
The WHO-5 well-being index is a widely used, short rating scale that measures subjective well-being. We translated the WHO-5 index into Sinhala and tested its psychometric properties including measurement invariance among diverse groups in a community sample in Sri Lanka. The sample of 267 persons aged between 16 and 75 years was recruited from a semi-urban area. 219 completed a paper-based questionnaire and 48 responded to an online survey. Construct validity was tested for factorial validity (Confirmatory Factor Analysis -CFA), convergent validity and known group validity. Composite reliability for congeneric measures and test-retest reliability were also tested. Multi-group CFA (MG-CFA) was used to test measurement invariance. The translated Sinhala version demonstrated good content and face validity. Internal consistency reliability of the five items had a Cronbach's alpha of 0.85 and test-retest reliability over 2 weeks was satisfactory (Pearson r = 0.72, p < 0.001, ICC = 0.82). Confirmatory factor analysis supported factorial validity with a [Formula: see text] =4.99 (p = 0.28), a RMSEA of 0.03 (90% C.I. =0.00-0.10), a SRMR of 0.02, a TLI of 0.99 and a CFI of 0.99; factor loadings were between 0.55 and 0.89. Measurement invariance was acceptable for configural, metric and scalar invariance for gender. WHO-5 scores were significantly negatively correlated with the Patient Health Questionnaire (PHQ-9) (Pearson's r = - 0.45, p < 0.001) scores and the Kessler Psychological Distress Scale (K10) scores (Pearson's r = - 0.56, p < 0.001). The Sinhala translation of WHO-5 well-being index has shown acceptable psychometric properties and can be used for assessing mental well-being in the community in Sri Lanka. Further testing of the measure with larger and diverse (including different ethnic/cultural) groups are indicated to test measurement invariance of the measure.


The Quick Inventory of Depressive Symptomatology, Adolescent Version (QIDS-A17): A Psychometric Evaluation.
The current study aimed to evaluate the psychometric features of the Quick Inventory of Depressive Symptomatology, Adolescent version (QIDS-A17) and the clinician-rated Children's Depression Rating Scale-Revised (CDRS-R). Altogether, 103 outpatients (8 to 17 years) completed the self-report QIDS-A17-SR. Clinician interviews of adolescents (QIDS-A17-C (Adolescent)) and of parents (QIDS-A17-C (Parent)) were combined to create the QIDS-A17-C(Composite) and the CDRS-R. All QIDS-A17 measures and the CDRS-R evidenced high total score correlations and internal consistency. Factor analysis found all four measures to be unidimensional. Item Response Theory (IRT) analysis found results that complemented the reliability results found in CTT. All four also demonstrated discriminant diagnostic validity based on logistic regression and ANOVA analyses. The psychometric properties of the self-report and composite versions of the QIDS-A17 suggest acceptability as a measure of depression in adolescents either as a measure of depressive symptoms or severity of illness in adolescents. The self-report version may be a helpful tool in busy clinical practices.


Characterization of mouse homolog of brain acyl-CoA hydrolase: molecular cloning and neuronal localization.
Acyl-CoA hydrolase could provide a mechanism via its potency to modulate cellular concentrations of acyl-CoAs for the regulation of various cellular events including fatty acid metabolism and gene expression. However, only limited evidence of this is available. To better understand the physiological role of this enzyme, we characterized a mouse brain acyl-CoA hydrolase, mBACH. The cloned cDNA for mBACH encoded a 338-amino-acid polypeptide with >95% identity to the human and rat homologs, indicating that the BACH gene is highly conserved among species. This was supported by the similarity in genomic organization of the BACH gene between humans and mice. Bacterially expressed mBACH was highly active against long-chain acyl-CoAs with a relatively broad specificity for chain length. While palmitoyl-CoA hydrolase activity was widely distributed in mouse tissues, it was marked in the brain, consistent with mBACH being almost exclusively distributed in this tissue, where >80% of the enzyme activity was explained by mBACH present in the cytosol. Immunohistochemistry demonstrated a neuronal localization of mBACH in both the central and peripheral nervous systems. In neurons, mBACH was distributed throughout the cell body and neurites. Although four isoforms except mBACH itself, that may be generated by the alternative use of exons of a single mBACH gene, were cloned, their mRNA levels in the brain were estimated to be negligible. However, a 50-kDa polypeptide besides the major one of 43-kDa seemed to be translated from the mBACH mRNA with differential in-frame ATG triplets used as the initiation codon. These findings will contribute to the functional analysis of the BACH gene using mice including genetic studies.


[Field 1. Safety practices and safety indicators: Definition and terminology. French-speaking Society of Intensive Care. French Society of Anesthesia and Resuscitation].
In the literature, the distinction between medical errors, adverse events, complications of care and other terms related to patient safety is not well-established. Accordingly these terms are commonly interchangeable. There is consensus that common terminology and classification scheme (taxonomy) with standardisation of patient safety data would facilitate improvement in incidents reporting, tracking and analysis. In this report medical errors, adverse events, safety indicators and other terms such as preventability and safety practices are defined and submitted to the expert panel rating.


Fatigue data for polyether ether ketone (PEEK) under fully-reversed cyclic loading.
In this article, the data obtained from the uniaxial fully-reversed fatigue experiments conducted on polyether ether ketone (PEEK), a semi-crystalline thermoplastic, are presented. The tests were performed in either strain-controlled or load-controlled mode under various levels of loading. The data are categorized into four subsets according to the type of tests, including (1) strain-controlled fatigue tests with adjusted frequency to obtain the nominal temperature rise of the specimen surface, (2) strain-controlled fatigue tests with various frequencies, (3) load-controlled fatigue tests without step loadings, and (4) load-controlled fatigue tests with step loadings. Accompanied data for each test include the fatigue life, the maximum (peak) and minimum (valley) stress-strain responses for each cycle, and the hysteresis stress-strain responses for each collected cycle in a logarithmic increment. A brief description of the experimental method is also given.


Decision-making biases in suicide attempters with major depressive disorder: A computational modeling study using the balloon analog risk task (BART).
In the last decade, suicidality has been increasingly theorized as a distinct phenomenon from major depressive disorder (MDD), with unique psychological and neural mechanisms, rather than being mostly a severe symptom of MDD. Although decision-making biases have been widely reported in suicide attempters with MDD, little is known regarding what components of these biases can be distinguished from depressiveness itself. Ninety-three patients with current MDD (40 with suicide attempts [SA group] and 53 without suicide attempts [NS group]) and 65 healthy controls (HCs) completed psychometric assessments and the balloon analog risk task (BART). To analyze and compare decision-making components among the three groups, we applied a five-parameter Bayesian computational modeling. Psychological assessments showed that the SA group had greater suicidal ideation and psychological pain avoidance than the NS group. Computational modeling showed that both MDD groups had higher risk preference and lower ability to learn and adapt from within-task observations than HCs, without differences between the SA and NS patient groups. The SA group also had higher loss aversion than the NS and HC groups, which had similar loss aversion. Our BART and computational modeling findings suggest that psychological pain avoidance and loss aversion may be important suicide risk factor that are distinguishable from depression illness itself.


Comparison of 6-Month Outcomes of Endovascular vs Surgical Revascularization for Patients With Critical Limb Ischemia.
The Bypass Versus Angioplasty for Severe Ischemia of the Leg randomized controlled trial showed comparable outcomes between endovascular revascularization (ER) and surgical revascularization (SR) for patients with critical limb ischemia (CLI). However, several observational studies showed mixed results. Most of these studies were conducted before advanced endovascular technologies were available. To compare ER and SR treatment strategies for 6-month outcomes among patients with CLI. This retrospective, population-based cohort study used the Nationwide Readmissions Database to identify 66 277 patients with CLI who underwent ER or SR from January 1, 2016, to December 31, 2018. Data analyses were conducted from January 1, 2022, to February 8, 2022. A propensity score with 1:1 matching was applied. Patients with CLI who underwent ER or SR were identified, and those with missing information on the length of stay and/or younger than 18 years were excluded. Endovascular or surgical revascularization. The primary outcome was a major amputation at 6 months. Significant secondary outcomes were in-hospital and 6-month mortality and an in-hospital safety composite of acute kidney injury, major bleeding, and vascular complication. Subgroup analysis was conducted for major amputation in high-volume centers. A total of 66 277 patients were identified between 2016 and 2018 who underwent ER or SR for CLI. The Nationwide Readmissions Database does not provide racial and ethnic categories. The mean (SD) age of the cohort was 69.3 (12) years, and 62.5% of patients were male. A total of 54 546 patients (82.3%) underwent ER and 11 731 (17.7%) underwent SR. After propensity score matching, 11 106 matched pairs were found. Endovascular revascularization was associated with an 18% higher risk of major amputation compared with SR (997 of 10 090 [9.9%] vs 869 of 10 318 [8.4%]; hazard ratio, 1.18; 95% CI, 1.08-1.29; P = .001). However, no difference was observed in major amputation risk when both procedures were performed in high-volume centers. Endovascular revascularization and SR had similar mortality rates (517 of 11 106 [4.7%] vs 490 of 11 106 [4.4%]; hazard ratio, 1.06; 95% CI, 0.93-1.20; P = .39). However, the ER group had a 17% lower risk of in-hospital safety outcomes compared with the SR group (2584 of 11 106 [23.3%] vs 2979 of 11 106 [26.8%]; odds ratio, 0.83; 95% CI, 0.78-0.88; P < .001). The results of this study suggest that ER was safer, without any difference in mortality, but ER was associated with an increased risk of major amputation compared with SR. However, the risk of major amputation was similar when both procedures were performed at high-volume centers.


The impact of chronic kidney disease on bariatric perioperative outcome: a MBSAQIP matched analysis.
Morbid obesity is considered a strong independent risk factor for chronic kidney disease (CKD), and bariatric surgery remains the most effective treatment for obesity-related co-morbidities. Previous large database analyses have suggested that CKD does not independently increase the risk of adverse outcomes after bariatric surgery. The safety of elective bariatric surgery in this patient population remains unclear. To this end, we compared 30-day outcomes in this patient population after laparoscopic sleeve gastrectomy or Roux-en-Y gastric bypass. To compare 30-day outcomes in CKD patients after laparoscopic sleeve gastrectomy or gastric bypass. University Hospital, United States. Using the Metabolic and Bariatric Surgery Accreditation Quality Improvement Program database, we identified patients with CKD who underwent laparoscopic sleeve gastrectomy or Roux-en-Y gastric bypass in 2015 or 2016. An unmatched cohort analysis, a propensity-matched analysis, and a case-control, matched-cohort analysis was performed of patients with and without CKD. Of the 302,092 patients included in this study, 2362 (.7%) had CKD, of whom 837 (35.4%) required dialysis. CKD patients were older with significantly higher rates of co-morbid conditions. Hospital length of stay, intensive care unit admission, reoperation, readmission, bleeding, cardiopulmonary, infectious complications, and total morbidity were significantly higher in CKD patients. In propensity-matched and case-control matched analyses of 4006 patients and 2264 patients, respectively, poorer outcomes in CKD patients highlight it an independent risk factor for morbidity. In contrast to previously reported large database analysis, CKD and dependence on dialysis independently increases the risk of 30-day adverse outcomes after primary bariatric surgery. The benefits conferred by bariatric surgery should be carefully weighed against the increased risk of complications in this challenging population.


High potential of adhesion to biotic and abiotic surfaces by opportunistic Staphylococcus aureus strains isolated from orthodontic appliances.
Orthodontic and other oral appliances act as reservoir of opportunistic pathogens that can easily become resistant to antibiotics and cause systemic infections. The aim of this study was to investigate the ability of Staphylococcus aureus strains isolated from healthy patients with orthodontic appliances, to adhere to biotic (HeLa cells) and abiotic surfaces (polystyrene and dental alloy). Adhesive ability to polystyrene was tested by crystal violet staining and quantitative biofilm production on dental alloy surfaces was evaluated by MTT reduction assay. In addition, the presence of icaA and icaD genes was achieved by polymerase chain reaction (PCR). Qualitative biofilm production revealed that 70.6% of strains were slime producers. The metabolic activity of S. aureus biofilms on dental alloy surfaces was high and did not differ between tested strains. Moreover, all the isolates were adhesive to HeLa cells and 94% of them harbor icaA and icaD genes. Considerable adhesion and internalization capacity to the epithelial HeLa cells and strong biofilm production abilities together, with a high genotypic expression of icaA/icaD genes are an important equipment of S. aureus to colonize orthodontic appliances and eventually to disseminate towards other body areas.


First record of the bull shark Carcharhinus leucas (Valenciennes, 1839) from the Maldivian archipelago, central Indian Ocean.
Verified records of the bull shark Carcharhinus leucas are lacking in the Maldives. This study provides the first confirmed evidence of 23 sightings observed from 2013 to 2023 in the central and southern atolls of this archipelago. Most of the sightings occurred in close proximity to inhabited areas, where food waste is often discarded into the water, or in several dive sites, suggesting the presence of this species in different locations around central and southern atolls. Although further research is required to fully investigate the C. leucas population in the Maldives, this report documents and confirms its presence in this region.


Prediction of the therapeutic index of marketed anti-coagulants and anti-platelet agents by guinea pig models of thrombosis and hemostasis.
Animal models of thrombosis and hemostasis are critical for target validation in pharmaceutical research. Guinea pig haemostatic mechanisms, such as the platelet thrombin receptor repertoire, resemble those of humans. Measuring the performance characteristics of marketed antithrombotic drugs in guinea pig models is a key to predicting therapeutic indices of new agents. The goal of the current study was to benchmark representative marketed drugs in thrombosis and hemostasis models in guinea pigs. Effects of the cyclooxygenase inhibitor, aspirin, the P2Y(12) antagonist, clopidogrel, the glycoprotein IIb/IIIa inhibitor, tirofiban, and the direct thrombin inhibitors, argatroban and hirudin, were evaluated in this study. Antithrombotic agents were tested in FeCl(3)-induced carotid artery thrombosis and arterio-venous shunt thrombosis models. Haemostatic effects of drugs were evaluated in cuticle and renal bleeding models. Ex vivo measurements of platelet function and coagulation inhibition were performed to benchmark preclinical doses of each agent to those used clinically. The overall rank-order of potency in thrombosis models based on per cent of vessels occluded, average carotid blood flow, and thrombus weight was aspirin=argatroban=tirofiban<hirudin=clopidogrel. In bleeding models, the rank order was: aspirin<clopidogrel=argatroban=tirofiban<hirudin. This characterization of representative drugs from two important classes of anti-coagulant and anti-platelet agents in efficacy and bleeding models in guinea pigs provides a reference point for evaluation of new antithrombotic agents.


Banning reproductive travel: Turkey's ART legislation and third-party assisted reproduction.
In March 2010, Turkey became the first country to legislate against the cross-border travel of its citizens seeking third-party reproductive assistance. Although the use of donor eggs, donor spermatozoa and surrogacy had been illegal in Turkey since the introduction of a regulatory framework for assisted reproductive treatment in 1987, men and women were free to access these treatments in other jurisdictions. In some cases, such travel for cross-border reproductive care (CBRC) was even facilitated by sophisticated arrangements between IVF clinics in Turkey and in other countries, particularly in Cyprus. However, new amendments to Turkey's assisted reproduction legislation specifically forbid travel for the purposes of third-party assisted reproduction. This article outlines the cultural context of assisted reproductive treatment in Turkey; details the Turkish assisted reproduction legislation, particularly as it pertains to third-party reproductive assistance; explores Turkish attitudes towards donor gametes and surrogacy; assesses the existence and extent of CBRC prior to March 2010; and discusses some of the legal, ethical and practical implications of the new legislation. As CBRC becomes an increasingly pertinent issue, eliciting debate and discussion at both national and international levels, it is important to carefully consider the particular circumstances and potential consequences of this unique example.


Palatogingival groove: endodontic-periodontal management--case report.
This report presents a case of a maxillary lateral incisor with a deep palatogingival groove extending up to the root apex with severe periodontal destruction. Despite an apparently poor prognosis, the tooth was successfully managed by endodontic and surgical periodontal therapy. The rationale behind the treatment modalities is also discussed.


Response of xenografts of human malignant gliomas and squamous cell carcinomas to fractionated irradiation.
The response of xenografts of five human malignant glioma cell lines and two human squamous cell carcinomas to fractionated irradiation was studied. For this, the tumors were transplanted into nude mice which had been further immunosuppressed by 6 Gy whole-body irradiation. Radiation was given as 30 fractions applied under normal blood flow conditions in two sessions per day over 15 days. Absolute and specific tumor growth delay after 48 Gy, and tumor control dose 50% (TCD50) were evaluated. Using local tumor control as experimental endpoint, four out of five malignant gliomas were more resistant to fractionated radiation therapy than the two squamous cell carcinomas. The TCD50s of these four gliomas ranged from 73 Gy to more than 120 Gy, whereas the TCD50s of the squamous cell carcinomas were 51 and 60 Gy. Absolute tumor growth delay correlated well with TCD50, but no correlation was obtained between specific growth delay and TCD50. The response of the human tumor xenografts in vivo did not correlate with the surviving fractions at 2 Gy of the same cell lines in vitro which have been previously obtained in our laboratory. The results suggest that the unique radioresistance observed in malignant gliomas in patients is at least in part reflected in human tumor xenografts. The lack of correlation between the surviving fraction at 2 Gy in vitro and the tumor response in vivo could be a consequence of an immune response by the host, a difference in cell radiation sensitivity between cell lines and xenografted tumors, or of differences of parameters such as hypoxic fraction, rate of repopulation, and cell cycle effects between the different tumor lines studied. It illustrates the difficulties which might be involved in the prediction of the response of individual tumors to radiation therapy based solely on the intrinsic radiosensitivity of the tumor cells as assayed by in vitro assays of colony formation.


COVID-19 prevalence and mortality in longer-term care facilities.
This essay considers the factors that have contributed to very high COVID-19 mortality in longer-term care facilities (LTCFs). We compare the demographic characteristics of LTCF residents with those of community-dwelling older adults, and then we review the evidence regarding prevalence and infection fatality rates (IFRs), including links to frailty and some comorbidities. Finally, we discuss policy measures that could foster the physical and mental health and well-being of LTCF residents in the present context and in potential future pandemics.


Laryngeal cancer in Lower Silesia: descriptive analysis of 501 cases.
This paper presents a descriptive analysis of 501 cases of laryngeal cancer. The patients were classified according to their age, sex, primary tumour localisation and stage. There were 448 males and 53 females, with a male-to-female ratio of 8.5:1. The peak incidence of cancer was detected in the 6th and 7th decades of age. The most common primary tumour localisation was the glottis. Three-hundred-and-forty patients presented at advanced tumour stages (T3/T4). The proportion of patients presenting matastatic neck nodes was 29.3% and the incidence of metastatic lymph nodes increased with increasing T stage. Histopathological analysis revealed that 98% of tumours were squamous cell carcinomas. There were 125 well-differentiated, 235 moderately differentiated and 133 poorly differentiated carcinomas. Among other tumours, there was 1 adenoid squamous cell carcinoma, 1 giant cell carcinoma, 1 adenoma pleomorphicum, 1 adenoid cystic carcinoma (cylindroma), 1 haemangiopericytoma, 1 verrucous cell carcinoma, 1 lymphoepithelioma and 1 granular cell tumour.


Short- and long-term synergistic effects of human tumor necrosis factor and interferon-gamma on A549 human lung cancer cells maintained in three-dimensional culture.
We have studied the short- and long-term effects of human recombinant tumor necrosis factor (TNF) and TNF/recombinant human interferon-gamma (IFN-gamma) mixtures on A549 human lung carcinoma cells maintained in organotypic culture. Continuous treatments with 2 x 10; 2 x 10(2); 2 x 10(3) and 2 x 10(4) U/ml TNF or with mixtures of TNF/IFN-gamma at 2 x 10(2) and 10(3) U/ml, respectively, were administered. Nodule growth, cell proliferation and cell survival were studied. On the 2nd day of treatment with TNF, only the highest dose (2 x 10(4) U/ml) diminished cell proliferation significantly, as measured by tritiated thymidine uptake into DNA. On the 10th day, only the lowest TNF dose (2 x 10 U/ml) induced no significant growth inhibition. Necrosis and nodule disintegration were apparent in the 2 x 10(4) U/ml-treated nodules where DNA synthesis decreased. In this case, using agar cloning assays, no cell survival could be observed. Similar results could be obtained with TNF at low concentration (2 x 10(2) U/ml) in combination with INF-gamma (10(3) U/ml), showing a synergistic effect on inhibition of cell proliferation. In the long-term experiments, with the lower TNF doses, in situ evidence of regrowth was observed (outgrowing zones in the nodules) on about the 40th day of treatment, and nodule recovery was confirmed by the resumption of DNA synthesis measured on the 50th day of treatment. No regrowth, however, occurred when the IFN-gamma/TNF combination was used, and the nodules disintegrated completely on the 35th day of treatment without evidence of any cellular survival.


HDlive 3D ultrasound and follicular development.
Two-dimensional (2D) ultrasonography is the fundamental technology on which diagnosis, management, and control in reproductive medicine depends. Over the years there have been efforts to improve 2D ultrasound image quality. In recent years, a series of software has appeared that has generated enormous interest. The goal of these modes has been to improve image quality and diagnostic accuracy. HDlive incorporates a movable virtual adjustable light source which, as it penetrates, produces selective illumination with respective shadows that result from the structures where light is reflected. This combination of light and shadow results in spectacular images which appear much more real than those obtained with conventional 3D ultrasonography.


Resistance among Escherichia coli to sulphonamides and other antimicrobials now little used in man.
We investigated whether sulphonamide resistance in Escherichia coli remained prevalent in 2004, 9 years since the formal introduction of a UK prescribing restriction on co-trimoxazole. Resistance to other agents no longer in common use was also examined. Consecutive urinary E. coli isolates were obtained at the diagnostic microbiology laboratory of the Royal London Hospital from January to March 2004. The presence of the sulphonamide resistance genes, sul1, sul2 and sul3, and the class I integrase gene, int1, were determined by PCR. Of the 391 E. coli isolates recovered in 2004, 45.5% were sulphonamide-resistant compared with 46.0% in 1999 and 39.7% in 1991. The sul2 gene remained the most prevalent sulphonamide resistance determinant, present in 81% of resistant isolates in 2004 compared with 79% and 67% in 1999 and 1991, respectively; 28% of resistant isolates carried both sul1 and sul2 genes; sul3 was not found. Resistance to streptomycin also remained common, whereas resistance to chloramphenicol and kanamycin had decreased since 1999. Sulphonamide resistance in E. coli persists undiminished despite the prolonged withdrawal of this antibiotic in the UK; resistance to streptomycin also seems stable whilst that to chloramphenicol and kanamycin is declining.


Quantitative effects of antiplatelet therapy on healing of the endarterectomized canine aorta.
This study was designed to quantitatively evaluate the effects of an antiplatelet agent, ibuprofen, on mural thrombus formation and pseudointimal development in the endarterectomized canine aorta. A 3 cm segment of abdominal aorta was endarterectomized in 18 dogs. Nine dogs served as controls and nine dogs were treated with ibuprofen (12.5 mg/kg) given intravenously 1 hour preoperatively and orally (7.5 mg/kg) three times a day in the postoperative period. Three dogs were killed from each group at 7, 14, and 21 days. Healing of the endarterectomized aortic segment was assessed by means of computer-assisted surface morphometry, light microscopy, and both scanning and transmission electron microscopy. One week postoperatively, the thrombus-free surface in the treated dogs was 75 percent, compared with 20 percent in control animals; at 2 weeks 97 percent, compared with 38 percent and at 3 weeks 98 percent, compared with 38 percent (p less than 0.01 for each group). The thickness of the pseudointima was 9 percent of the aortic wall thickness in treated dogs compared with 60 percent in control animals 1 week postoperatively (p less than 0.001); at 2 weeks 24 percent in treated animals and 64 percent in control animals (p less than 0.001); and at 3 weeks 31 percent in treated animals and 55 percent in control animals (p less than 0.05). Partial reendothelialization was observed 1 week postoperatively and complete reendothelialization at 3 weeks in both the control and treated animals. These data suggest that administration of preoperative and maintenance therapy with ibuprofen significantly reduces mural thrombus formation and pseudointimal thickness in the endarterectomized canine aorta.


Randomized controlled trial of internet-delivered cognitive behaviour therapy comparing standard weekly versus optional weekly therapist support.
Internet-delivered cognitive behaviour therapy (ICBT) is effective for treating anxiety and depression. The relative benefits of offering standard weekly compared to optional weekly therapist support in conjunction with ICBT within routine care has not been examined. Patients seeking ICBT for depression and or anxiety in routine care were randomized to standard (n=92) or optional (n=88) weekly support. The optional approach resulted in therapists receiving half as many messages from (1.70 vs. 3.96) and sending half as many messages to patients (3.62 vs. 7.29). Optional Support was associated with lower completion rates (56.6% versus 82.4%), but, similar to Standard Support, resulted in large reductions on the GAD-7 (within Cohen's d≥1.08; avg. reduction ≥47%) and PHQ-9 (within Cohen's d≥0.82; avg. reduction ≥43%) at post-treatment and 3-month follow-up. Optional weekly support appears clinically effective and acceptable for many patients and may reduce costs, but safety requires monitoring given lower completion rates.


The NLRP3 inflammasome: activation and regulation.
The NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome is a cytoplasmic supramolecular complex that is activated in response to cellular perturbations triggered by infection and sterile injury. Assembly of the NLRP3 inflammasome leads to activation of caspase-1, which induces the maturation and release of interleukin-1β (IL-1β) and IL-18, as well as cleavage of gasdermin D (GSDMD), which promotes a lytic form of cell death. Production of IL-1β via NLRP3 can contribute to the pathogenesis of inflammatory disease, whereas aberrant IL-1β secretion through inherited NLRP3 mutations causes autoinflammatory disorders. In this review, we discuss recent developments in the structure of the NLRP3 inflammasome, and the cellular processes and signaling events controlling its assembly and activation.


VEGFR2 inhibition by RNA interference affects cell proliferation, migration, invasion, and response to radiation in Calu-1 cells.
To investigate the role of the vascular endothelial growth factor receptor 2 (VEGFR2) in the proliferation, migration, invasion, and radiation-induced apoptosis of the non-small cell lung cancer (NSCLC) cell line Calu-1. VEGFR2 gene was silenced by RNA interference in Calu-1 cells, and the expression of VEGFR2 was measured by qRT-PCR and Western blot analysis. The cells were divided into control, VEGF-treated, VEGFR2 knockdown, and VEGFR2 knockdown and VEGF-treated groups. A CCK8 assay and Transwell assay were performed to assess cell proliferation, migration, and invasion, respectively, after VEGFR2 knockdown. Western blot assays were used to detect signaling proteins downstream of VEGFR2. Cells in the groups listed above were also subjected to radiation treatment, followed by apoptosis analysis. (1) RNA interference of VEGFR2 in Calu-1 cells reduced VEGFR2 mRNA (P < 0.01) and protein levels (P < 0.01). (2) VEGFR2 knockdown inhibited proliferation (P < 0.05), migration (P < 0.05), and invasion (P < 0.05) in Calu-1 cells. (3) VEGFR2 knockdown blocked the phosphorylation of protein kinase B (Akt, also known as PKB), extracellular regulated kinase (ERK) 1/2, and p38 mitogen-activated protein kinase (p38 MAPK) to various extent (P < 0.05), but did not change their total protein expression. (4) Knockdown of VEGFR2 suppressed HIF-1α protein synthesis (P < 0.05), and exacerbated apoptosis induced by radiation (P < 0.05). VEGFR2 gene knockdown significantly suppressed a number of cellular activities in Calu-1 cells and increased radiation-induced cell death.


Leukoencephalopathy With Brain Stem and Spinal Cord Involvement and Lactate Elevation (LBSL): A Case With Long-term Follow-up.
Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) is caused by a recessive mutation in the DARS2 gene and can be recognized by specific magnetic resonance imaging patterns. A girl who developed leg tremors at age 4 years was diagnosed at age 17 years with LBSL -after evolution of ataxia and sensory loss. Examination at age 29 revealed mild spastic gait, ataxia, and sensory loss, and she did not require assistance to walk. This report illustrates the clinical and magnetic resonance imaging characteristics of a slowly progressive long-term course of childhood-onset LBSL.


Liver steatosis, cardiac and renal fibrosis, and hypertension in overweight rats: Angiotensin-(3-4)-sensitive hepatocardiorenal syndrome.
Overweight/obesity is a growing pandemic that affects many organs and tissues. We have investigated whether a high-lipid diet provokes an imbalance between type 1 and type 2 angiotensin II (Ang II) receptors signaling, leading to liver alterations associated with cardiovascular and kidney disturbances. Chronic administration of a high-lipid diet can provoke hepatocardiorenal syndrome resulting from activation of the Ang II→type 1 receptor axis, which is entirely counteracted by Ang-(3-4), the allosteric enhancer of the Ang II→type 2 receptor pathway.


Unraveling a tumor type-specific regulatory core underlying E2F1-mediated epithelial-mesenchymal transition to predict receptor protein signatures.
Cancer is a disease of subverted regulatory pathways. In this paper, we reconstruct the regulatory network around E2F, a family of transcription factors whose deregulation has been associated to cancer progression, chemoresistance, invasiveness, and metastasis. We integrate gene expression profiles of cancer cell lines from two E2F1-driven highly aggressive bladder and breast tumors, and use network analysis methods to identify the tumor type-specific core of the network. By combining logic-based network modeling, in vitro experimentation, and gene expression profiles from patient cohorts displaying tumor aggressiveness, we identify and experimentally validate distinctive, tumor type-specific signatures of receptor proteins associated to epithelial-mesenchymal transition in bladder and breast cancer. Our integrative network-based methodology, exemplified in the case of E2F1-induced aggressive tumors, has the potential to support the design of cohort- as well as tumor type-specific treatments and ultimately, to fight metastasis and therapy resistance.Deregulation of E2F family transcription factors is associated with cancer progression and metastasis. Here, the authors construct a map of the regulatory network around the E2F family, and using gene expression profiles, identify tumour type-specific regulatory cores and receptor expression signatures associated with epithelial-mesenchymal transition in bladder and breast cancer.


Low-rank tensor constrained co-regularized multi-view spectral clustering.
Due to the efficiency of exploiting relationships and complex structures hidden in multi-views data, graph-oriented clustering methods have achieved remarkable progress in recent years. But most existing graph-based spectral methods still have the following demerits: (1) They regularize each view equally, which does not make sense in real applications. (2) By employing different norms, most existing methods calculate the error feature by feature, resulting in neglecting the spatial structure information and the complementary information. To tackle the aforementioned drawbacks, we propose an enhanced multi-view spectral clustering model. Our model characterizes the consistency among indicator matrices by minimizing our proposed weighted tensor nuclear norm, which explicitly exploits the salient different information between singular values of the matrix. Moreover, our model adaptively assigns a reasonable weight to each view, which helps improve robustness of the algorithm. Finally, the proposed tensor nuclear norm well exploits both high-order and complementary information, which helps mine the consistency between indicator matrices. Extensive experiments indicate the efficiency of our method.


A fatal case of venlafaxine overdose.
Based on its primary action of serotonin reuptake inhibition, venlafaxine overdose would be expected to result in serotonergic effects. A 40 year old male ingested venlafaxine without co-ingestants in a suicide attempt. The patient developed refractory ventricular fibrillation and expired approximately 9 hours post-ingestion. ECG monitoring revealed significant QRS and QTC interval prolongation prior to his demise. A literature review of venlafaxine overdose cases and investigation into its mechanism of action was conducted. The potential for sodium channel blockade and implications for therapy are discussed.


Anomalous Origin of the Right Coronary Artery From the Left Anterior Descending Artery With Anomalous Course Between the Great Vessels: A Case for Conservative Management With Review of the Literature.
A single left coronary artery is a rare coronary anomaly. In such situations, the right coronary artery arises from the left anterior descending artery and traverses an unusual proximal course between the aorta and pulmonary trunk. There are only 10 such reported cases in the medical literature to date. After a detailed risk-to-benefit consideration, the decision was made for conservative management. In this report, we describe this rare case with a detailed review of the literature.


Anticipating clinical integration of pharmacogenetic treatment strategies for addiction: are primary care physicians ready?
Emerging pharmacogenomics research on addiction to nicotine, alcohol, cocaine, and opiates may soon lead to improved clinical outcomes by tailoring the type, dose and duration of treatment to individual patients' genotypes. To realize the potential of pharmacogenomics in reducing the burden of addiction, several challenges related to clinical integration of novel treatment strategies will need to be addressed concomitantly with ongoing empirical research. These challenges include the preparedness of primary care physicians (PCPs) to incorporate pharmacogenetics into clinical practice, patients' willingness to undergo genetic testing, the resources and infrastructure needed to deliver such services, adequate financing and reimbursement of pharmacogenetic testing, and privacy and antidiscrimination protections sufficient to reassure physicians and patients that genetic testing will not lead to stigmatization and discrimination.


The stereospecific suicide inhibition of human melanoma thioredoxin reductase by 13-cis-retinoic acid.
13-cis retinoic acid has been shown to be a stereospecific suicide inhibitor of thioredoxin reductase purified from human melanoma tissue. All trans retinoic acid does not inhibit this enzyme. The covalent addition of 13-cis retinoic acid to the thiolate active site of thioredoxin reductase produces a thioether enzyme-inhibitor complex. This has been established by a kinetic analysis and by active site labeling with 3H-13 cis retinoic acid. A mechanism involving Michael addition of the thiolate group in the active site of thioredoxin reductase to the 13-cis double bond of enzyme-bound inhibitor has been proposed. This reaction may be important in the human epidermis because thioredoxin reductase has been shown to be a major antioxidant catalyst in human keratinocytes, melanocytes, melanoma cells, and in human skin as well as in melanoma tissues.


Sentinel Lymph Node Sampling in Robot-Assisted Staging of Endometrial Cancer.
Sentinel lymph node (SLN) sampling in endometrial cancer staging has become an acceptable standard. Indocyanine green dye injected into the cervix and detected by near-infrared light is technically simple and sensitive. We aimed to evaluate SLN sampling in robot-assisted surgical staging of endometrial cancer at a university-affiliated teaching hospital. A retrospective chart review, from January 2016 to December 2017, of patients who underwent robot-assisted surgical staging with cervical injection of indocyanine green dye detected by near-infrared light. The map rate, sensitivity, false negatives, and negative predictive value were calculated. A total of 105 charts were reviewed; 79 patients met inclusion criteria. The mean age was 65 (range 38-93) and the mean body mass index was 33.3 (range 16-49). Most patients (72.2%) had stage I disease and grade 1 or 2 histology (77.1%). Eight (10.1%) patients had lymph node metastasis. Seventy-two (91.1%) patients had positive mapping to at least 1 SLN. Sixty-two (78.5%) patients had bilateral mapping. Forty-four patients had concurrent pelvic ± para-aortic lymph node dissection and were included in the sensitivity analysis. Five of 44 cases had LN metastasis. The sensitivity was 80%, and the negative predictive value of SLN sampling was 97.5%. SLN mapping and sampling at a university-affiliated teaching hospital have comparable map rate, sensitivity, and negative predictive value as demonstrated in multiple trials. The technique has the potential to standardize endometrial cancer staging across different practice settings.


Loading dose of quinine in African children with cerebral malaria.
The majority of deaths from cerebral malaria occur within 48 h after admission to hospital. Because of the possibility of inadequate treatment within this period, the use of a loading dose of quinine has been proposed. We reviewed clinical and laboratory data for 113 children with cerebral malaria, who were treated with intravenous quinine, 10 mg/kg every 8 h, at Macha Mission Hospital in rural Zambia. In 1990-1991, 39 children were not given a loading dose of quinine while, in 1992-1993, 74 children received a loading dose of 20 mg/kg. Elevated serum iron levels, as reflected in transferrin saturation, were strongly associated with higher mortality. A loading dose of quinine was associated with faster recovery from coma and enhanced clearance of parasitaemia and fever. The loading dose was also associated with trends to lower mortality and higher haemoglobin levels, but these differences were not statistically significant.


Acceptability of a Hypothetical Reduction in Routinely Scheduled Clinic Visits Among Patients With History of a Localized Melanoma (MEL-SELF): Pilot Randomized Clinical Trial.
After treatment for a localized melanoma, patients attend routinely scheduled clinics to monitor for new primary or recurrent melanoma. Patient-led surveillance (skin self-examination with patient-performed teledermoscopy) is an alternative model of follow-up that could replace some routinely scheduled visits. This study aims to assess the acceptability of a hypothetical reduction in routinely scheduled visits among participants of the Melanoma Self Surveillance (MEL-SELF) pilot randomized clinical trial of patient-led surveillance (intervention) versus usual care (control). Patients previously treated for localized melanoma in New South Wales who were participating in the MEL-SELF pilot randomized clinical trial were asked to respond to a web-based questionnaire at baseline and after 6 months on trial. We used mixed methods to analyze the data. The main outcome of interest was the acceptability of a hypothetical reduction in routinely scheduled visits for melanoma surveillance. Of 100 randomized participants, 87 answered the questionnaire at baseline, 66 answered the questionnaire at 6 months, and 79 provided a free-text explanation at either time point. At 6 months, 33% (17/51) of the control group and 35% (17/49) of the intervention group indicated that a hypothetical reduction in routinely scheduled visits with all melanoma doctors was at least slightly acceptable (difference in proportions -1%, 95% CI -20% to 17%; P=.89). Participants suggested that prerequisites for a reduction in routinely scheduled visits would include that sufficient time had elapsed since the previous diagnosis without a new primary melanoma or recurrence, an unscheduled appointment could be made at short notice if the patient noticed something concerning, their melanoma doctor had suggested reducing their clinic visit frequency, and patients had confidence that patient-led surveillance was a safe and effective alternative. Participants suggested that a reduction in routinely scheduled visits would not be acceptable where they perceived a very high risk of new or recurrent melanoma, low self-efficacy in skin self-examination and in the use of technologies for the patient-led surveillance intervention, and where they had a preference for clinician-led surveillance. Some patients said that a partial reduction to once a year may be acceptable. Some patients may be receptive to a reduction in routinely scheduled visits if they are assured that patient-led surveillance is safe and effective. Australian New Zealand Clinical Trials Registry ACTRN12616001716459; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=371865&isReview=true; ClinicalTrials.gov NCT03581188; https://clinicaltrials.gov/ct2/show/NCT03581188. RR2-10.1001/jamadermatol.2021.4704.


Histological Assessment of Gene Therapy in the Canine DMD Model.
Assessing histological changes is essential for characterizing muscle disease progression and for studying the response to therapies in Duchenne muscular dystrophy (DMD), an X-linked progressive muscle-wasting disease caused by the loss of the dystrophin protein. Canine models are by far the best-characterized large animal models for DMD. In this chapter, we describe methods for muscle tissue collection and storage, hematoxylin and eosin staining for studying general muscle morphology, and special staining protocols for evaluating fibrosis, calcification, and neuronal nitric oxide synthase (nNOS) activity. We also provide immunofluorescence staining protocols that are often used to characterize the expression and localization of dystrophin and components of the dystrophin-associated glycoprotein complex. Lastly, we presented immunohistochemical staining protocols that we use to assess muscle inflammation and immune responses.


Substrate recognition in nuclear protein quality control degradation is governed by exposed hydrophobicity that correlates with aggregation and insolubility.
Misfolded proteins present an escalating deleterious challenge to cells over the course of their lifetime. One mechanism the cell possesses to prevent misfolded protein accumulation is their destruction by protein quality control (PQC) degradation systems. In eukaryotes, PQC degradation typically proceeds via multiple ubiquitin-protein ligases that act throughout the cell to ubiquitinate misfolded proteins for proteasome degradation. What the exact feature of misfolding that each PQC ubiquitin-protein ligase recognizes in their substrates remains an open question. Our previous studies of the budding yeast nuclear ubiquitin-protein ligase San1 indicated that it recognizes exposed hydrophobicity within its substrates, with the threshold of hydrophobicity equivalent to that of 5 contiguous hydrophobic residues. Here, we uncover an additional parameter: the nature of the exposed hydrophobicity that confers San1-mediated degradation correlates with significant protein insolubility. San1 particularly targets exposed hydrophobicity that leads to insolubility and aggregation above a certain threshold. Our studies presented here provide additional insight into the details of misfolded nuclear protein recognition and demonstrate that there is selectivity for the type of exposed hydrophobicity.


Liraglutide Reduces Carotid Intima-Media Thickness by Reducing Small Dense Low-Density Lipoproteins in a Real-World Setting of Patients with Type 2 Diabetes: A Novel Anti-Atherogenic Effect.
Liraglutide has several non-glycemic effects, including those on plasma lipids and lipoproteins, contributing to its cardiovascular benefit; however, the exact underlying mechanisms remain unclear. We investigated a novel anti-atherogenic effect of liraglutide in a real-world prospective study on patients with type 2 diabetes (T2DM). Sixty-two patients with T2DM (31 men, 31 women; mean age ± standard deviation 61 ± 9 years) naïve to incretin-based therapies were treated with liraglutide (1.2 mg/day) as add-on therapy to metformin (1500-3000 mg/day) for 4 months. Laboratory analyses included the assessment of lipoprotein subclass profile by gel electrophoresis (Lipoprint; Quantimetrix Corp., Redondo Beach, CA, USA). Carotid intima-media thickness (cIMT) was assessed by Doppler ultrasonography. Statistical analyses included the paired t test, Spearman correlation and multiple regression analysis. The addition of liraglutide to metformin monotherapy resulted in significant reductions in fasting glycemia, hemoglobin A1c, body mass index, waist circumference, total cholesterol, triglycerides and low-density lipoprotein (LDL)-cholesterol, as well as in cIMT. There was an increase in the large LDL-1 subfraction, with a concomitant reduction in atherogenic small dense LDL-3 and LDL-4 subfractions. Correlation analysis revealed a significant association between changes in cIMT and changes in small dense LDL-3 subfraction (r = 0.501; p < 0.0001). Multivariate analysis, including all of the measured anthropometric and laboratory parameters, revealed that only changes in the small dense LDL-3 subfraction were independent predictors of changes in cIMT (p < 0.0001). Our findings are the first to show that the vascular benefit of liraglutide in patients with T2DM is associated with reductions in atherogenic small dense LDL. This effect is independent of glycemic control and body weight reduction and may represent one of the key mechanisms by which liraglutide is able to reduce cardiovascular events. ClinicalTrials.gov: NCT01715428.


The role of law in protecting the child. A critique of the English system.
We have undertaken a critical appraisal of the current English system of law regulating: (1) Provision of services designed to prevent children coming into care of local authorities, which are the authorised agencies for dealing with children who are abused or neglected. (2) Ways of receiving children into care and also ways of terminating care orders. We question whether, and under what circumstances, care orders are really necessary. (3) Periodic reviews of children in care. We are critical of the English system and look to models in the USA as guides towards the possible reform of English law. We take the same perspective when considering termination of parental rights. In our opinion good laws do not of themselves provide the care and love which a child requires, but they make the caring possible by loved and loving adults. We argue that the law must provide the best possible framework to allow adequate caring by members of the non-legal professions, such as social workers and foster parents. At the same time the law must ensure that the rights of parents and children are protected.


Inappropriate proton pump inhibitor lansoprazole prescription in older adults hospitalized in long-term care unit.
We evaluated the use of the PPI treatment by physicians in older adults hospitalized in a long-term care unit. We included 40 patients aged 65 years or older with a lansoprazole prescription hospitalized in long-term care unit from January 2018 to January 2022. Patient characteristics, gastroduodenal history, dose of lansoprazole, indication, days of prescription, and number of medications were collected from electronic patient records. The mean age of patients was 84.2 ± 9.3. Patients were taking between 5 and 24 (mean = 12.7, SD = 4.4) medications overall with 15 patients taking low dose of aspirin (75 mg daily) and 8 patients taking an antiplatelet. Most patients (82.5%) received once-daily lansoprazole treatment, 55% of whom took a dose of 15 mg. Five patients were treated with the maximum dose of lansoprazole 30 mg twice daily. Only seven patients had an appropriate indication. The minimum of treatment time was 3 days and the maximum was 1198 days; moreover, 24 patients (60%) were still in treatment. Few PPI prescriptions had an indication in the patient's electronic record. Prescriptions were ongoing with no date of discontinuation or re-evaluation.


Lead electrical parameters may not predict integrity of the Sprint Fidelis ICD lead.
The reported failure rate of the Medtronic Sprint Fidelis defibrillator lead continues to increase over time. Clinicians and patients count on the electrical analysis of leads through device interrogation to determine whether a lead is functioning "normally." Most importantly, this analysis is often the basis for decision making around the ongoing use of this lead at the time of generator change. Can clinicians count on this analysis and feel confident that this "advisory" lead is "normal?" To describe the incidence of unexpected lead abnormalities among Sprint Fidelis leads removed without prior evidence of electrical abnormalities. We performed a retrospective cohort study of Medtronic Sprint Fidelis (6930, 6931, 6948, 6949) leads extracted at a single high-volume center. Medtronic analyzed all returned leads for abnormalities. The presence and type of lead abnormalities in addition to patient characteristics, indications for extraction, implant duration, and use of extraction sheath assistance are reported. Between September 2005 and January 2011, 209 Sprint Fidelis leads were extracted from 208 patients. The average duration of implant was 38.9 months (range 0.2-67.2). Of the analyzed leads, the majority of the extracted leads (63.1%) were active, normal functioning leads (83.8% prophylactically, 9.1% infection, and 7.1% other indication) while 36.9% had clinical evidence of a fracture. Extraction was achieved with simple traction in 39.5% of the leads; extraction sheath assistance was employed in 94 cases (59.9%), and surgical extraction at the time of transplant occurred in 1 case. Analysis of the 99 functionally "normal" leads removed determined that 20 leads had evidence of fractures (20.2%) not related to extraction. Of the fractured leads, 4 leads (20%) had more than 1 fracture and 1 lead had 3 separate fracture sites. There were 17 pacing conductor (10 proximal and 7 distal conductor) and 6 high-voltage conductor (1 superior vena cava and 5 right ventricle defibrillator conductor) fractures observed. Five additional leads (5.2%) had evidence of explant damage. Functionally "normal" Fidelis leads demonstrate an alarmingly high rate of "subclinical" fractures. Recommendations regarding prophylactic Sprint Fidelis lead extraction, especially at the time of generator change, may warrant reconsideration. To aid in the design of better leads, all leads should be returned for analysis, regardless of the indication for extraction.


The adenosine-dependent angiogenic switch of macrophages to an M2-like phenotype is independent of interleukin-4 receptor alpha (IL-4Rα) signaling.
Murine macrophages are activated by interferon-γ (IFN-γ) and/or Toll-like receptor (TLR) agonists such as bacterial endotoxin (lipopolysaccharide [LPS]) to express an inflammatory (M1) phenotype characterized by the expression of nitric oxide synthase-2 (iNOS) and inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin (IL)-12. In contrast, Th2 cytokines IL-4 and IL-13 activate macrophages by inducing the expression of arginase-1 and the anti-inflammatory cytokine IL-10 in an IL-4 receptor-α (IL-4Rα)-dependent manner. Macrophages activated in this way are designated as "alternatively activated" (M2a) macrophages. We have shown previously that adenosine A2A receptor (A(2A)R) agonists act synergistically with TLR2, TLR4, TLR7, and TLR9 agonists to switch macrophages into an "M2-like" phenotype that we have termed "M2d." Adenosine signaling suppresses the TLR-dependent expression of TNF-α, IL-12, IFN-γ, and several other inflammatory cytokines by macrophages and induces the expression of vascular endothelial growth factor (VEGF) and IL-10. We show here using mice lacking a functional IL-4Rα gene (IL-4Rα(-/-) mice) that this adenosine-mediated switch does not require IL-4Rα-dependent signaling. M2d macrophages express high levels of VEGF, IL-10, and iNOS, low levels of TNF-α and IL-12, and mildly elevated levels of arginase-1. In contrast, M2d macrophages do not express Ym1, Fizz1 (RELM-α), or CD206 at levels greater than those induced by LPS, and dectin-1 expression is suppressed. The use of these markers in vivo to identify "M2" macrophages thus provides an incomplete picture of macrophage functional status and should be viewed with caution.


Inflammatory Cytokines, Endothelial Function, and Chronic Allograft Vasculopathy in Children: An Investigation of the Donor and Recipient Vasculature After Heart Transplantation.
Chronic allograft vasculopathy (CAV) limits the lifespan of pediatric heart transplant recipients. We investigated blood markers of inflammation, endothelial dysfunction, and damage to both the native and transplanted vasculature in children after heart transplantation. Serum samples were taken from pediatric heart transplant recipients for markers of inflammation and endothelial activation. The systemic vasculature was investigated using brachial artery flow-mediated dilatation and carotid artery intima-medial hyperplasia. CAV was investigated using intravascular ultrasound. Mean intima-media thickness (mIMT) > 0.5 mm was used to define significant CAV. Forty-eight children (25 male) aged 8-18 years were enrolled in the study. Patients were a median (interquartile range) 4.1 (2.2-8.7) years after transplant. Patients had increased levels of circulating IL6 (3.86 [2.84-4.95] vs. 1.66 [1.22-2.63] p < 0.0001), vascular cell adhesion molecule 1 (539 [451-621] vs. 402 [342-487] p < 0.001), intracellular adhesion molecule 1 305 (247-346) vs. 256 (224-294) p = 0.002 and thrombomodulin (7.1 [5.5-8.1] vs. 3.57 [3.03-4.71] p < 0.0001) and decreased levels of tumor necrosis factor-α, E selectin, and P selectin, compared with controls. The systemic vasculature was unaffected. Patients with severe CAV had raised serum von Willebrand factor and decreased serum thrombomodulin. Posttransplant thrombomodulin levels are elevated after transplant but significantly lower in those with mIMT > 0.5 mm. This suggests that subclinical inflammation is present and that natural anticoagulant/thrombomodulin activity is important after transplant.


The macro-epidemiology of influenza vaccination in 56 countries, 1997--2003.
The WHO Global Agenda on Influenza calls for measuring the progress of national influenza vaccination programs. In response, the Macro-epidemiology of Influenza Vaccination (MIV) Study Group has gathered information on influenza vaccination in 56 countries. During the period 1997--2003, influenza vaccine distribution increased considerably in almost all countries. In 2003, the countries with the highest levels of vaccination (doses distributed/1000 population) were Canada (344), the Republic of Korea (311), the United States (286) and Japan (230). Most countries recommended influenza vaccination for elderly persons and those with high-risk medical conditions, including immuno-compromise. Fewer countries provided public reimbursement for vaccination through national or social health insurance. Higher levels of vaccination were not closely related to higher levels of economic development, but in many instances public reimbursement for vaccination seemed to be associated with greater vaccine use. From 1994 to 2003, the global use of influenza vaccines increased more than two-fold. In 2003, the 56 MIV Study Group countries accounted for approximately 95% of the 292 million doses of influenza vaccine distributed worldwide, and 62% of these doses were distributed within nine vaccine-producing countries in North America, Western Europe, Japan and Australia. However, influenza vaccination was increasing rapidly in many non vaccine-producing countries, and this change has important implications for pandemic vaccination.


Effect of bitter gourd (Momordica charantia) on glycaemic status in streptozotocin induced diabetic rats.
Bitter gourd (Momordica charantia), a commonly consumed vegetable is used as an adjunct in the management of diabetes mellitus. A study was carried out to examine the effect of edible portion of bitter gourd at 10% level in the diet in streptozotocin induced diabetic rats. To evaluate the glycaemic control of bitter gourd during diabetes, diet intake, gain in body weight, water intake, urine sugar, urine volume, glomerular filtration rate and fasting blood glucose profiles were monitored. Water consumption, urine volume and urine sugar were significantly higher in diabetic controls compared to normal rats and bitter gourd feeding alleviated this rise during diabetes by about 30%. Renal hypertrophy was higher in diabetic controls and bitter gourd supplementation, partially, but effectively prevented it (38%) during diabetes. Increased glomerular filtration rate in diabetes was significantly reduced (27%) by bitter gourd. An amelioration of about 30% in fasting blood glucose was observed with bitter gourd feeding in diabetic rats. These results clearly provided experimental evidence that dried bitter gourd powder in the diet at 10% level improved diabetic status signifying its beneficial effect during diabetes.


[The analysis of complex interventions in public health: the case of the prevention of sexually transmitted infections and blood-borne infections in Montreal].
Based on a theory of intervention as a complex action system, analyze collaboration among partners in Montréal's sexually transmitted and blood-borne infections (STBBI) prevention program to identify main operations problems and possible scenarios for change to achieve better outcomes. A descriptive study was conducted using three data sources - public policies and programs, system management documents, and interviews with three types of partners. The results were validated with stakeholders. Five main operations problems affecting the capacity of the system to provide expected services were identified, as well as strategies the partners use to address these. Two scenarios for system change to increase its effectiveness in achieving program goals are discussed.


Label-free and non-invasive discrimination of HaCaT and melanoma cells in a co-culture model by hyperspectral confocal reflectance microscopy.
A novel hyperspectral confocal microscopy method to separate different cell populations in a co-culture model is presented here. The described methodological and instrumental approach allows discrimination of different cell types using a non-invasive, label free method with good accuracy with a single cell resolution. In particular, melanoma cells are discriminated from HaCaT cells by hyperspectral confocal imaging, principal component analysis and optical frequencies signing, as confirmed by fluorescence labelling cross check. The identification seems to be quite robust to be insensitive to the cellular shape within the studied samples, enabling to separate cells according to their cytotype down to a single cell sensitivity. Set of hyperspectral images of melanoma-keratinocytes co-culture model (left), score plot of principal component analysis and spectral analysis of principal components coefficients (center), label-free spectral identification of cell populations (right).


Cardioprotective effects of lipoic acid, quercetin and resveratrol on oxidative stress related to thyroid hormone alterations in long-term obesity.
This study investigated possible mechanisms for cardioprotective effects of lipoic acid (LA), quercetin (Q) and resveratrol (R) on oxidative stress related to thyroid hormone alterations in long-term obesity. Female C57BL/6 mice were fed on high-fat diet (HFD), HFD+LA, HFD+R, HFD+Q and normal diet for 26weeks. Body weight, blood pressure, thyroid hormones, oxidative stress markers, angiotensin converting enzyme (ACE), nitric oxide synthase (NOS) and ion pump activities were measured, and expression of cardiac genes was analyzed by real-time polymerase chain reaction. HFD induced marked increase (P<.05) in body weight, blood pressure and oxidative stress, while plasma triidothyronine levels reduced. ACE activity increased (P<.05) in HFD mice (0.69±0.225U/mg protein) compared with controls (0.28±0.114U/mg protein), HFD+LA (0.231±0.02U/mg protein) and HFD+Q (0.182±0.096U/mg protein) at 26weeks. Moreover, Na(+)/K(+)-ATPase and Ca(2+)-ATPase activities increased in HFD mice whereas NOS reduced. A 1.5-fold increase in TRα1 and reduction in expression of the deiodinase iodothyronine DIO1, threonine protein kinase and NOS3 as well as up-regulation of AT1α, ACE, ATP1B1, GSK3β and Cja1 genes also occurred in HFD mice. Conversely, LA, Q and R inhibited weight gain; reduced TRα1 expression as well as increased DIO1; reduced ACE activity and AT1α, ATP1B1 and Cja1 gene expression as well as inhibited GSK3β; increased total antioxidant capacity, GSH and catalase activity; and reduced blood pressure. In conclusion, LA, resveratrol and quercetin supplementation reduces obesity thereby restoring plasma thyroid hormone levels and attenuating oxidative stress in the heart and thus may have therapeutic potential in heart diseases.


Construction of a porous three dimensional rare earth metal-sulfur-ligand open framework.
A slow reaction between Nd(3+) and piperazine-1,4-dicarbodithiolate disodium (Na2(pipzdtc)) affords a three dimensional (3D) anionic [Nd(pipzdtc)2]n(n-) framework with a dia net. The encapsulated disordered guest molecules could be partially exchanged by Ni(2+) accompanied by the quenching of the typical NIR luminescence of Nd(3+) ions.


Isavuconazole Treatment in a Mixed Patient Cohort with Invasive Fungal Infections: Outcome, Tolerability and Clinical Implications of Isavuconazole Plasma Concentrations.
Isavuconazole (ISA) is a triazole antifungal agent recommended for treatment of invasive aspergillosis or mucormycosis. The objective of this study was to evaluate ISA levels in a real world setting in a mixed patient cohort including patients with non-malignant diseases and extracorporeal treatments, and to correlate findings with efficacy and safety outcomes. We investigated 33 ISA treatment courses in 32 adult patients with hematological and other underlying diseases and assessed the clinical response, side effects and ISA trough plasma concentrations. ISA treatment led to complete and partial response in 87% of patients and was well tolerated. The median ISA plasma concentration was 3.05 µg/mL (range 1.38-9.1, IQR 1.93-4.35) in patients without renal replacement therapy (RRT) or extracorporeal membrane oxygenation (ECMO) and significantly lower in patients with RRT including cases with additional ECMO or Cytosorb® adsorber therapy (0.88 µg/mL, range 0.57-2.44, IQR 0.71-1.21). After exclusion of values obtained from four patients with ECMO or Cytosorb® adsorber the median concentration was 0.91 µg/mL (range 0.75-2.44, IQR 0.90-1.36) in the RRT group. In addition to previous recommendations we propose to monitor ISA trough plasma concentrations in certain circumstances including RRT, other extracorporeal treatments and obesity.


Investigation of the immunomodulatory effects of Lactobacillus casei and Bifidobacterium lactis on Helicobacter pylori infection.
Lactobacillus and Bifidobacterium species have shown beneficial effects in the treatment of Helicobacter pylori infection; however, the mechanisms behind such effects are not fully understood. In this study, we have investigated the immunomodulatory effects of probiotics in a mouse model of H. pylori infection. H. pylori-infected C57BL/6 mice were treated with L. casei L26, B. lactis B94, or no probiotics for 5 weeks, respectively. Mice not infected with H. pylori were included as normal controls. Gastric histology, protein levels of interleukin (IL)-1beta, IL-10, IL-12/23p40, and H. pylori colonization density in the gastric tissues, as well as H. pylori-specific antibodies were examined. In mice receiving L. casei L26 and B. lactis B94, gastric neutrophil infiltration and IL-1beta were significantly decreased and IL-10 was significantly increased as compared with mice receiving no probiotics. In mice receiving B. lactis B94, IL-12/23p40 was significantly increased and H. pylori IgG was significantly reduced as compared with mice receiving no probiotics. No significant difference of H. pylori colonization was observed among the three groups of mice. The reduced level of IL-1beta and neutrophil infiltration observed in mice infected with H. pylori following treatment with L. casei L26 and B. lactis B94 resulted from a modulation of immune response rather than a decrease of H. pylori colonization. Furthermore, B. lactis B94 has the intrinsic ability to promote a Th1 immune response through an increase in IL-12/IL-23.


What rhinologists and allergists should know about the medico-legal implications of corticosteroid use: a review of the literature.
Corticosteroids are a mainstay of treatment in the management of sinonasal inflammatory disease. Despite their common use, many practitioners are not well versed in their potential complications or the medico-legal ramifications of their use. The objectives of this review were to outline the existing data of the medico-legal implications of oral steroids. An OVID database search of the terms "corticosteroids OR adrenal cortex hormones" AND "medico-legal OR malpractice OR jurisprudence OR expert testimony OR informed consent" was performed. This search was then narrowed to English language articles and the titles and abstracts were searched for relevance. The OVID search identified 178 articles. This search was then narrowed, resulting in 9 articles that were relevant and included in the current review. Five articles involved database reviews of litigation associated with medications. Steroids were found to be a common medication associated with litigation and the cost of the litigation involving steroid use can be very high. Common themes associated with the litigation include poor communication and lack of informed consent regarding steroid use. Several additional articles addressed single cases and many addressed lawsuit prevention. Lawsuits associated with steroids are disproportionately costly and most of the allegations stem from a lack of informed consent over the use of steroids. Open dialogue with patients is the key to informed consent. Ideally, clinicians should discuss the rationale for steroid use, and the risks, expected benefits, and alternatives of the steroid therapy. Document this discussion and consider providing educational material for the patient to read and review.


Oxidant-induced atrogin-1 and transforming growth factor-beta1 precede alcohol-related myopathy in rats.
Alcohol-related chronic myopathy is characterized by severe biochemical and structural changes to skeletal muscle. Our goals were to: (1) identify early regulatory elements that precede the overt manifestation of plantaris atrophy; and (2) circumvent these derangements by supplementing alcohol-fed rats with the glutathione precursor, procysteine. After 6 weeks of daily ingestion, before the development of overt atrophy of the plantaris muscle, alcohol increased several markers of oxidative stress and increased gene expressions of atrogin-1 and transforming growth factor-beta1 (TGF-beta1) by approximately 60- and approximately 65-fold, respectively, which were attenuated by procysteine supplementation. Interestingly, after 28 weeks of alcohol ingestion, when overt plantaris atrophy had developed, atrogin-1 and TGF-beta1 gene expression had returned to baseline levels. Together, these findings suggest that alcohol-induced, redox-sensitive alterations drive pro-atrophy signaling pathways that precede muscle atrophy. Therefore, targeted anti-oxidant treatments such as procysteine supplementation may benefit individuals with chronic alcohol abuse, particularly if given prior to the development of clinically significant myopathy.