AMP-activated protein kinase α2 subunit is required for the preservation of hepatic insulin sensitivity by n-3 polyunsaturated fatty acids.
The induction of obesity, dyslipidemia, and insulin resistance by high-fat diet in rodents can be prevented by n-3 long-chain polyunsaturated fatty acids (LC-PUFAs). We tested a hypothesis whether AMP-activated protein kinase (AMPK) has a role in the beneficial effects of n-3 LC-PUFAs. Mice with a whole-body deletion of the α2 catalytic subunit of AMPK (AMPKα2(-/-)) and their wild-type littermates were fed on either a low-fat chow, or a corn oil-based high-fat diet (cHF), or a cHF diet with 15% lipids replaced by n-3 LC-PUFA concentrate (cHF+F). Feeding a cHF diet induced obesity, dyslipidemia, hepatic steatosis, and whole-body insulin resistance in mice of both genotypes. Although cHF+F feeding increased hepatic AMPKα2 activity, the body weight gain, dyslipidemia, and the accumulation of hepatic triglycerides were prevented by the cHF+F diet to a similar degree in both AMPKα2(-/-) and wild-type mice in ad libitum-fed state. However, preservation of hepatic insulin sensitivity by n-3 LC-PUFAs required functional AMPKα2 and correlated with the induction of adiponectin and reduction in liver diacylglycerol content. Under hyperinsulinemic-euglycemic conditions, AMPKα2 was essential for preserving low levels of both hepatic and plasma triglycerides, as well as plasma free fatty acids, in response to the n-3 LC-PUFA treatment. Our results show that n-3 LC-PUFAs prevent hepatic insulin resistance in an AMPKα2-dependent manner and support the role of adiponectin and hepatic diacylglycerols in the regulation of insulin sensitivity. AMPKα2 is also essential for hypolipidemic and antisteatotic effects of n-3 LC-PUFA under insulin-stimulated conditions.


A Brief Review of Inpatient Palliative Rehabilitation.
Cancer patients face many challenges that can have a significant impact on their quality of life (QOL). When patients experience multiple functional impairments due to disease or treatment, their QOL and the efficient use of healthcare resources can be compromised. This is particularly true for patients who are nearing the end of their lives, as the physical and emotional burden of cancer can have a profound effect on both the individual and their caregivers. One approach to improving QOL in these patients is through palliative rehabilitation. Despite being an underutilized and understudied resource, palliative rehabilitation has shown promise in helping patients with advanced cancer retain their dignity and sense of control. By maximizing functional independence and reducing symptom burdens, palliative rehabilitation can provide a vital source of support for patients and their caregivers during this challenging time. Inpatient rehabilitation is one way that palliative rehabilitation can be applied in a healthcare setting. While further research is needed to fully understand the benefits of this approach, it is clear that palliative rehabilitation has the potential to play a key role in helping patients and their caregivers navigate the challenges of cancer treatment and end-of-life care. This approach is specific to the USA context but can be applied in other settings where cancer patients require such care.


Characterization of the major surface glycoconjugates of Trypanosoma theileri.
Trypanosoma theileri maintains a long-term extracellular infection with a low parasitaemia in bovids. The surface of this parasite is predicted to be decorated with several surface molecules including membrane surface proteases (MSPs), trans-sialidases and T. theileri putative surface proteins (TTPSPs). However, there are no experimental data to verify this hypothesis. Here, we have purified and partially characterized the surface glycoconjugates of T. theileri using biochemical and mass spectrometry-based approaches. The glycoconjugates fall into two classes: glycoproteins and glycolipids. Proteomic analysis of the glycoprotein fraction demonstrated the presence of MSPs and abundant mucin-like TTPSPs, with most predicted to be GPI-anchored. Mass spectrometric characterization of the glycolipid fraction showed that these are mannose- and galactose-containing glycoinositolphospholipids (GIPLs) that are larger and more diverse than those of its phylogenetic relative T. cruzi, containing up to 10 hexose residues and carrying either alkylacyl-phosphatidylinositol or inositol-phospho-ceramide (IPC) lipid components.


Viscoelasticity of blood and viscoelastic blood analogues for use in polydymethylsiloxane in vitro models of the circulatory system.
The non-Newtonian properties of blood are of great importance since they are closely related with incident cardiovascular diseases. A good understanding of the hemodynamics through the main vessels of the human circulatory system is thus fundamental in the detection and especially in the treatment of these diseases. Very often such studies take place in vitro for convenience and better flow control and these generally require blood analogue solutions that not only adequately mimic the viscoelastic properties of blood but also minimize undesirable optical distortions arising from vessel curvature that could interfere in flow visualizations or particle image velocimetry measurements. In this work, we present the viscoelastic moduli of whole human blood obtained by means of passive microrheology experiments. These results and existing shear and extensional rheological data for whole human blood in the literature enabled us to develop solutions with rheological behavior analogous to real whole blood and with a refractive index suited for PDMS (polydymethylsiloxane) micro- and milli-channels. In addition, these blood analogues can be modified in order to obtain a larger range of refractive indices from 1.38 to 1.43 to match the refractive index of several materials other than PDMS.


Tradition, not science, is the basis of animal model selection in translational and applied research.
National and international laws and regulations exist to protect animals used for scientific purposes in translational and applied research, which includes drug development. However, multiple animal models are available for each disease. We evaluated the argumentation behind the selection of a specific animal model using thematic content analysis in project applications issued in 2017-2019 in the Netherlands. In total, 125 animal models for translational and applied research from 110 project applications were assessed. Explanations to select a specific model included: the model's availability (79%); the availability of expertise (62%); and the model showing similar disease pathology/symptoms (59%) to humans. Therefore, current selection of a specific animal model seems to be based on tradition rather than its potential predictive value for clinical outcome. The applicants' explanations for the implementation of the 3R principles (replacement, reduction and refinement) as to the animal model were unspecific. Replacement was achieved by using data from prior in vitro studies, reduction by optimal experimental design and statistics, and refinement by reducing discomfort. Additionally, due to the stated need for a test model with high complexity (47%) and intactness (30%), the full replacement of animal models with alternative (non-live animal) approaches was thought unachievable. Without a clear, systematic and transparent justification for the selection of a specific animal model, the likelihood of poorly translatable research remains. It is not only up to the researcher to demonstrate this, as ethical committees and funding bodies can provide positive stimuli to drive this change.


In vitro combinations of natamycin with voriconazole, itraconazole and micafungin against clinical Fusarium strains causing keratitis.
Fusarium species cause a broad spectrum of infections, from superficial to disseminated disease. Because Fusarium species are intrinsically resistant to most antifungal drugs, new approaches are needed. The aim of the present study was to evaluate the in vitro combination of natamycin with currently used antifungal drugs. The in vitro interactions of combinations between natamycin and voriconazole, itraconazole and micafungin applied to 20 clinical Fusarium strains (members of Fusarium falciforme, Fusarium napiforme, Fusarium petroliphilum, Fusarium proliferatum, Fusarium pseudensiforme and Fusarium sacchari) were evaluated using a chequerboard microdilution method. The MICs of all drugs alone and in combination were determined visually after 48 h and interactions were assessed using fractional inhibitory concentration index (FICI) analysis. MICs of voriconazole and natamycin alone were 4 to >16 and 4-8 mg/L, respectively. Values were reduced 3.5-10-fold to 0.02-0.5 mg/L and 0.5-5-fold to 0.13-2 mg/L in combination, for the currently used antifungals and natamycin, respectively, demonstrating additive to synergistic interactions. The combinations natamycin/voriconazole, natamycin/itraconazole and natamycin/micafungin were synergistic (FICI ≤0.5) for 70%, 15% and 5% of the strains, respectively. No antagonism was found. The combination of natamycin with voriconazole was strongly synergistic at clinically achievable serum concentrations.


18F-fluoro-deoxy-glucose positron emission tomography combined with computed tomography can reliably rule-out infection and cancer in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis suspected of disease relapse.
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of autoimmune diseases characterized by systemic inflammation in small- to medium-sized blood vessels. Although immunosuppressive therapy has greatly improved the prognosis for these patients, there are still significant comorbidities, such as cancer and infection, associated with AAV. These comorbidities are often indistinguishable from an underlying AAV disease relapse, and create a clinical conundrum, as these conditions are normally contraindications for immunosuppressive treatment. Thus, it is important to be able to rule out these comorbidities before initiation of immunosuppressive treatment. We examined F-fluoro-deoxy-glucose positron emission tomography combined with computed tomography (FDG-PET/CT)'s value in ruling out cancer or infection in patients with AAV.Data were obtained retrospectively for a clinically based cohort of AAV patients who underwent FDG-PET/CT during 2009 to 2014 owing to a suspicion of cancer, infection, or both cancer and infection indistinguishable from disease relapse. FDG-PET/CT conclusions were compared to the final diagnoses after follow-up analysis (mean 43 months).A total of 19 patients were included who underwent a total of 26 scans. The results of FDG-PET/CT outcome compared to final diagnosis were: 9 true positives, 3 false positives, 13 true negatives, and 1 false negative. The diagnostic probabilities for FDG-PET/CT with respect to overall comorbidity (i.e., cancer or infection) were: sensitivity 90% ( 95% confidence interval [CI] 60%-98%), specificity 81% ( 95% CI 57%-93%), positive predictive value 75% (95% CI 47%-91%), negative predictive value 93% (95% CI 68%-99%), and accuracy 84% (95% CI 66%-94%).FDG-PET/CT had a high negative predictive value and ruled out the comorbidities correctly in all but one case of urinary tract infection, a well-known limitation. Our study showed FGD-PET/CT's promise as an effective tool for ruling out cancer or infection in patients with AAV albeit in a limited population.


The Efficacy and Safety of Additional Anti-HER2-Targeting Drugs in the Treatment of HER2-Positive Advanced Breast Cancer: A Meta-Analysis.
HER2-positive breast cancer patients account for one-fifth of the total breast cancer population. Besides, more anti-HER2-targeting drugs have appeared clinically. This study aimed to analyze the efficacy and safety of additional anti-HER2 (Human Epidermal growth Factor Receptor 2)-targeting drugs in the treatment of HER2-positive advanced breast cancers. The following databases were searched for published articles containing data on the efficacy and safety of additional anti-HER2-targeting drugs in HER2-positive advanced breast cancer from the time of their inception until December 2019: PubMed, Web of Science, EBSCO, and Cochrane library. The primary outcomes were Progression-Free Survival (PFS) and Overall Survival (OS). The additional anti-HER2-targeting drugs significantly improved the PFS (HR: 0.66, p<0.001) and OS (HR: 0.77, p<0.001) of HER2-positive advanced breast cancer patients. Regarding drug types, lapatinib was the most effective (HR: 0.53, 95% Cl: 0.39-0.67, p<0.001), followed by pertuzumab (HR: 0.72, 95% Cl: 0.55-0.89, p=0.001). Trastuzumab was the least beneficial (HR: 0.87, 95% Cl: 0.31-1.44, p=0.594). Concerning treatment regimen, first-line treatment (HR: 0.67, 95% Cl: 0.52-0.82, p<0.001) was more effective than non-first-line treatment (HR: 0.82, 95% Cl: 0.71-0.94, p=0.004). The main Adverse Events (AEs) observed were diarrhea and decreased ejection fraction. Additional anti-HER2-targeting drugs can improve long-term prognosis in HER2-positive advanced breast cancers. Besides, they are associated with fewer AEs and are tolerable. Lapatinib is the most effective drug, followed by pertuzumab, whereas trastuzumab is the least effective. Concerning treatment, we recommend the use of anti-HER2-targeting drugs in first-line therapy of HER2-positive advanced breast cancers.


Use of hospital-related health care among Health Links enrollees in the Central Ontario health region: a propensity-matched difference-in-differences study.
Health Links are a new model of providing care coordination for high-cost, high-needs patients in Ontario. We evaluated use of hospital-related health care services among Health Links patients in the Central Local Health Integration Network (LHIN) of Ontario in the year before versus after program enrolment and compared rates of use with those among similar patients with complex needs not enrolled in the program (comparator group). We identified all patients who received a Health Links coordinated care plan before Jan. 1, 2015, using linked registry and health administrative data. We used propensity scores to match (1:1) enrollees (registry) with comparator patients (administrative data). Using a difference-in-differences approach with generalized estimating equations, we evaluated 5 measures of Health Link performance: rates of hospital admission, emergency department visits, days in acute care, 30-day readmissions and 7-day postdischarge primary care follow-up. Of the 344 enrollees in the registry, we matched 313 [91.0%] to comparator patients. All measured sociodemographic, comorbidity and health care use characteristics were balanced between the 2 groups (all standardized differences < 0.10). For enrollees, the rate of days in acute care per person-year increased by 35% (incidence rate ratio 1.35 [confidence interval 1.11-1.65]) after versus before the index date, but differences were nonsignificant for all other measures. Difference-in-differences analyses revealed greater reductions in hospital admissions, emergency department visits and acute care days after the index date in the comparator group than among enrollees. Initial implementation of the Health Link program in the Central LHIN did not reduce selected indicators of Health Link performance among enrollees. As the Health Link program evolves and standardization is implemented, future research may reveal effects from the initiative in other outcomes or with longer follow-up.


The Relationship Between Environmental Sound Awareness and Speech Recognition Skills in Experienced Cochlear Implant Users.
1) Environmental sound awareness (ESA) and speech recognition skills in experienced, adult cochlear implant (CI) users will be highly correlated, and, 2) ESA skills of CI users will be significantly lower than those of age-matched adults with normal hearing. Enhancement of ESA is often discussed with patients with sensorineural hearing loss as a potential benefit of implantation and, in some cases, ESA may be a major motivating factor. Despite its ecological validity and patients' expectations, ESA remains largely a presumed skill. The relationship between ESA and speech recognition is not well-understood. ESA was assessed in 35 postlingually deaf, experienced CI users and a control group of 41 age-matched, normal hearing listeners using the validated, computerized familiar environmental sounds test-identification (FEST-I) and a diverse speech recognition battery. Demographic and audiological factors as well as nonverbal intelligence quotient (IQ)/nonverbal reasoning and spectral resolution were assessed. Six of the 35 experienced CI users (17%) demonstrated FEST-I accuracy within the range of the NH controls. Among CI users all correlations between FEST-I accuracy and speech recognition scores were strong. Chronological age at the time of testing, duration of deafness, spectral resolution, and nonverbal IQ/nonverbal reasoning were strongly correlated with FEST-I accuracy. Partial correlation analysis showed that correlations between FEST-I and speech recognition measures remained significant when controlling for the demographic and audiological factors. Our findings reinforce the hypothesis that ESA and speech perception share common underlying processes rather than reflecting truly separate auditory domains.


A Bayesian procedure for estimating the causal effects of nursing home bed-hold policy.
Nursing home bed-hold policies provide continuity of care for Medicaid beneficiaries by paying nursing homes to reserve beds so residents can return to their facility of occupancy following an acute hospitalization. In 2001, Michigan implemented bed-hold policies in nursing homes. We investigated the impact of these policies on mortality and hospitalizations using 1999-2004 quarterly data from nursing homes in Michigan and nursing homes in 11 states that did not implement such policies. Synthetic Control has been used to estimate the effects of policies by accounting for changes over time unrelated to the intervention. Synthetic Control is intended for scalar continuous outcome at each period, and assumes a single treated unit and multiple control units. We propose a Bayesian procedure to overcome these limitations. It imputes the outcomes of nursing homes in Michigan if they were not exposed to the policy by matching to non-exposed nursing homes that are associated with the exposed ones in the pre-policy period. Because sampling from a Bayesian model is computationally challenging, we describe an approximation procedure that can be implemented using existing software. Our approach can be applied to other studies that examine the impact of policies.


A nickel nanocatalyst within a h-BN shell for enhanced hydrogen oxidation reactions.
The development of low-cost and high-performance electrocatalysts remains a challenge for the hydrogen oxidation reaction (HOR) in alkaline membrane fuel cells. Here, we have reported novel Ni@h-BN core-shell nanocatalysts consisting of nickel nanoparticles encapsulated in few-layer h-BN shells. The Ni@h-BN catalysts exhibit an improved HOR performance compared with the bare Ni nanoparticles. In situ characterization experiments and density functional theory calculations indicate that the interactions of the O, H, and OH species with the Ni surface under the h-BN shell are weakened, which helps to maintain the active metallic Ni phase both in air and in the electrolyte and strengthen the HOR processes occurring at the h-BN/Ni interfaces. These results suggest a new route for designing high-performance non-noble metal electrocatalysts with encapsulating two-dimensional material overlayers for HOR reactions.


Ultradian corticosterone rhythm and the propensity to behave aggressively in male rats.
Ultradian fluctuations in plasma glucocorticoids have been demonstrated in a variety of species including humans. The significance of such rhythms is poorly known, although disorganized ultradian glucocorticoid rhythms have been associated with behavioural disorders. Here we report that ultradian glucocorticoid rhythms may establish the propensity to behave aggressively in male rats. Male rats were significantly more aggressive in the increasing phase of their corticosterone fluctuation when confronting a male intruder than counterparts in the decreasing phase of their corticosterone fluctuations facing such opponents. Corticosterone fluctuations were mimicked by a combination of treatments with the corticosterone synthesis inhibitor metyrapone and corticosterone. Again, males with increased plasma corticosterone levels were more aggressive than counterparts with a decreased plasma corticosterone concentration. These data suggest that the behavioural response to an aggressive challenge may vary in the same animal across the day due to the pulsating nature of corticosterone secretion. Aggressive behaviour is also episodic in humans; moreover, intermittent explosive behaviour is recognized as a psychological disorder. It can be hypothesized that a temporal coincidence between the occurrence of a challenge and a surge in plasma corticosterone concentration may be one of the factors that promote episodic aggressive outbursts.


Antiobesity effects of Bifidobacterium breve strain B-3 supplementation in a mouse model with high-fat diet-induced obesity.
The aim of the present study was to evaluate the anti-obesity activity of a probiotic bifidobacterial strain in a mouse model with obesity induced by a high-fat diet. The mice were fed a high-fat diet supplemented with Bifidobacterium breve B-3 at 10(8) or 10(9) CFU/d for 8 weeks. B. breve B-3 supplementation dose-dependently suppressed the accumulation of body weight and epididymal fat, and improved the serum levels of total cholesterol, fasting glucose and insulin. The bifidobacterial counts in the caecal contents and feces were significantly increased with the B. breve B-3 administration. The expression of genes related to fat metabolism and insulin sensitivity in the gut and epididymal fat tissue was up-regulated by this administration. These results suggest that the use of B. breve B-3 would be effective in reducing the risk of obesity.


Esomeprazole regimens for reflux symptoms in Chinese patients with chronic gastritis.
To compare symptom control with esomeprazole regimens for non-erosive reflux disease and chronic gastritis in patients with a negative endoscopy. This randomized, open-label study was designed in line with clinical practice in China. Patients with typical reflux symptoms for ≥ 3 mo and a negative endoscopy who had a Gastroesophageal Reflux Disease Questionnaire score ≥ 8 were randomized to initial treatment with esomeprazole 20 mg once daily either for 8 wk or for 2 wk. Patients with symptom relief could enter another 24 wk of maintenance/on-demand treatment, where further courses of esomeprazole 20 mg once daily were given if symptoms recurred. The primary endpoint was the symptom control rate at week 24 of the maintenance/on-demand treatment period. Secondary endpoints were symptom relief rate, success rate (defined as patients who had symptom relief after initial treatment and after 24 wk of maintenance treatment), time-to-first-relapse and satisfaction rate. Based on the data collected in the modified intention-to-treat population (MITT; patients in the ITT population with symptom relief after initial esomeprazole treatment, n = 262), the symptom control rate showed a small but statistically significant difference in favor of the 8-wk regimen (94.9% vs 87.3%, P = 0.0473). Among the secondary endpoints, based on the data collected in the ITT population (n = 305), the 8-wk group presented marginally better results in symptom relief after initial esomeprazole treatment (88.3% vs 83.4%, P = 0.2513) and success rate over the whole study (83.8% vs 72.8%, P = 0.0258). The 8-wk regimen was found to provide a 46% reduction in risk of relapse vs the 2-wk regimen (HR = 0.543; 95%CI: 0.388-0.761). In addition, fewer unscheduled visits and higher patient satisfaction supported the therapeutic benefits of the 8-wk regimen over the 2-wk regimen. Safety was comparable between the two groups, with both regimens being well tolerated. Chinese patients diagnosed with chronic gastritis achieved marginally better control of reflux symptoms with an 8-wk vs a 2-wk esomeprazole regimen, with a similar safety profile.


[Fluorescence endoscopy of the respiratory tract].
Autofluorescence endoscopy has been used for more than 10 years in the diagnosis of early lung cancers and precancerous lesions of the bronchial tree. The technique has been extensively evaluated during the past decade and two recent large randomised studies have shown a 2 to 5 times increase in the detection of high grade pre-cancerous lesions compared with conventional white light endoscopy. This paper reviews the principal applications and results of the use of autofluorescence endoscopy in high risk individuals as well as innovative endoscopic approaches using the fluorescent properties of the respiratory tract.


Biomolecule-to-fluorescent-color encoder: modulation of fluorescence emission via DNA structural changes.
A biomolecule-to-fluorescent-color (B/F) encoder for optical readout of biomolecular information is proposed. In the B/F encoder, a set of fluorescence wavelengths and their intensity levels are used for coding of a biomolecular signal. A hybridization chain reaction of hairpin DNAs labeled with fluorescent reporters was performed to generate the fluorescence color codes. The fluorescence is modulated via fluorescence resonance energy transfer, which is controlled by DNA structural changes. The results demonstrate that fluorescent color codes can be configured based on two wavelengths and five intensities using the B/F encoder, and the assigned codes can be retrieved via fluorescence measurements.


Progressive clinical effects of the combination omalizumab and HDM - allergen immunotherapy in asthma.
The combination of allergen immunotherapy (AIT) and omalizumab is used to treat patients at risk of anaphylaxis. There is currently a very little evidence that this combination increases the effectiveness of AIT in patients with inhalant allergies. The study aimed to evaluate the effectiveness of HDM-SCIT therapy (injection immunotherapy for house dust mites) in combination with omalizumab in treating HDM-induced asthma. This study was a placebo-controlled, randomized, multicenter trial including 82 patients with HDM-driven mild to moderate asthma. Omalizumab alone (A), HDM SCIT + omalizumab (B), SCIT alone (C), or placebo (D) for 24 months were applied. All patients received asthma treatment in accordance with GINA recommendations. The treatment efficacy was defined by a reduction in the daily dose of inhaled steroids (ICS) and a reduction in the number of asthma exacerbations (AX). After 24 months of therapy, a statistically significant reduction in the daily doses of ICS in groups A and B was observed (p = 0.021 and p = 0.008). Daily ICS reduction was considerably more significant in group B (p = 0.01). During 24 months of observation, the AX was significantly reduced in all study groups, with the greatest significant difference observed between groups A and B and groups C and D (placebo) as follows: 0.42 patient/per year vs. 0.39 vs. 0.84 vs. 0.91 (p = 0.023). The combination of HDM SCIT and omalizumab is significantly and progressively reducing ICS use and AX in a 24-month study. The combination is significantly more effective than the single treatments or placebo.


Review of successful litigation against english health trusts in the treatment of adults with orthopaedic pathology: clinical governance lessons learned.
Reviewing litigation brought against health institutions is a clinical governance issue and can help to prevent further cases. While large-scale databases are rare, the British National Health Service Litigation Authority deals with claims brought against all public health trusts in England. We reviewed all 2312 successful cases pertaining to adult orthopaedic claims between 2000 and 2006 in an effort to establish trends of litigation and highlight specific areas of concern such that orthopaedic health care could be potentially improved. A total of 1473 entries had sufficient detail to be considered in our study. There were 4,847,841 elective and trauma-related orthopaedic procedures performed between 2000 and 2006 in the United Kingdom. Compared with the number of cases performed, the frequency of successful litigation is relatively low but financially costly to the National Health Service. From 2000 to 2006, a total of more than US$321,695,072 was paid in adult orthopaedic surgery-related settlements. The most common reason for successful litigation was due to the presence and sequelae of infection (123 cases). In the remaining cases, successful litigation appeared to be related to two common themes: the consent process and the mismanagement of orthopaedic conditions, particularly fractures, cauda equina syndrome, and compartment syndrome. These findings highlight the fact that education and vigilance remain important components of orthopaedic training as many of the cases of successful litigation had a preventable cause.


Why does anatabine, but not nicotine, accumulate in jasmonate-elicited cultured tobacco BY-2 cells?
Suspension-cultured cells of Nicotiana tabacum cv. Bright Yellow-2 (BY-2) grow rapidly in a highly homogenous population and still exhibit the general behavior of plant cells, and thus are often used as model systems in several areas of plant molecular and cellular biology, including secondary metabolism. While the parental tobacco variety synthesizes nicotine as a major alkaloid, the cultured tobacco cells mainly produce a related alkaloid anatabine, instead of nicotine, when elicited with jasmonates. We report here that cultured BY-2 cells scarcely express N-methylputrescine oxidase (MPO) genes even after jasmonate elicitation. MPO is the second enzyme in the biosynthetic pathway that supplies the pyrrolidine moiety of nicotine and nornicotine, but is predicted to be dispensable for the biosynthesis of anatabine, anabasine and anatalline, which do not contain the pyrrolidine moiety. When MPO was overexpressed in tobacco BY-2 cells, nicotine synthesis was dramatically enhanced while anatabine formation was effectively suppressed. As a complementary approach, we suppressed MPO expression by RNA interference in tobacco hairy roots that normally accumulate nicotine. In the MPO-suppressed roots, the contents of anatabine, anabasine and anatalline, as well as N-methylputrescine and putrescine, markedly increased to compensate for suppressed formation of nicotine and nornicotine. These results identify the transcriptional regulation of MPO as a critical rate-limiting step that restricts nicotine formation in cultured tobacco BY-2 cells.


Quantitative image contrast enhancement in time-gated transillumination of scattering media.
Experimental work in turbid media has shown that trans-illumination images can be significantly improved by limiting light collection to a subset of photons which are minimally distorted by scattering. The literature details numerous schemes (commonly termed ballistic imaging), most often based on time-gating and/or spatially filtering the detected light. However, due to the complex nature of the detected signal, analysis of this optical filtering process has been heretofore limited to qualitative comparisons of image results. In this article we present the implementation of a complete system model for the simulation of light propagation, including both the scattering medium and all stages of the optical train. Validation data from ballistic imaging (BI) measurements of monodisperse scatterers with diameter, d = 0.7 µm, at optical depths 5, 10, and 14, are compared with model results, showing excellent agreement. In addition, the validated model is subsequently applied to a modified time-gated optical system to probe the comparative performance of the BI system used in validation and the modified BI system. This instrument comparison examines scatterers with diameters of 0.7 and 15 µm at optical depths 10 and 14, and highlights the benefits of each system design for these specific scattering conditions. These results show that the modified optics configuration is more suitable for particles which are much larger than the incident wavelength, d >> λ, while the configuration employed in the validation system provides a better contrast for particle diameters on the order of the wavelength, d ~λ, where the scattering process exhibits a more homogeneous phase function. The insights and predictions made available by the full numerical model are important for the design of optimized imaging systems suited to specific turbid media, and make possible the quantitative understanding of both the effects of light propagation in the measurement and the performance of the complete imaging system.


Enzymatic modification of transfer RNA.
The molecular events leading to the synthesis of mature tRNA are only now becoming amenable to experimental study. In bacterial and mammalian cells tRNA genes are transcribed into precursor tRNA. These molecules, when isolated, contain additional nucleotides at both ends (20) of the mature tRNA and lack most modified nucleosides. Presumably, specific nucleases ("trimming" enzymes) cut the precursor to proper tRNA size. The C-C-A nucleotide sequence of the amino acid acceptor end common to all tRNA's does not seem to be coded by tRNA genes (30), and may be added to the trimmed molecules by the tRNA-CMP-AMP-pyrophosphorylase (71). Modifications at the polynucleotide level of the heterocyclic bases or the sugar residues give rise to the modified nucleosides in tRNA. Although newly available substrates have allowed the detection of more of the enzymes involved in these reactions, there is still no knowledge about the sequence of modification or trimming events leading to the synthesis of active tRNA. Progress in these studies may not be easy because enzyme preparations free of nucleases or other tRNA modifying enzymes are required. The role of the modified nucleosides in the biological functions of tRNA is still unknown. Possibly pseudouridine is required for ribosome mediated protein synthesis; some other modified nucleosides in tRNA are not required for this reaction, but may enhance its rate. What might be the role of the large variety of modified nucleosides in tRNA? One is tempted to speculate that such nucleosides are important in other cellular processes in which tRNA is thought to participate such as virus infection, cell differentiation, and hormone action (2, 3). Mutants in a number of tRNA-modifying enzymes are needed in order to extend our knowledge of their purpose and of tRNA involvement in other biological processes. But unless tRNA-modifying enzymes specific for a particular tRNA species exist, no simple selection procedure can be devised. Possibly some of the regulatory mutants of amino acid biosynthesis may prove to affect tRNA-modifying enzymes (72). Transfer RNA's are macromolecules well suited for the study of nucleic acid-protein interactions. The tRNA molecules are structurally very similar, and they interact with a large number of enzymes or protein factors (2, 3). Each aminoacyl-tRNA synthetase, for instance, very precisely recognizes a set of cognate isoacceptor tRNA's (2, 73). The availability of the tRNA- modifying enzymes adds another dimension to the problem of the nature of specific recognition of tRNA by proteins. There are some tRNA-modifying enzymes, such as the uracil-tRNA methylase, which may recognize all tRNA species, while others, such as the isopentenyl-tRNA transferase, probably recognize only a selected set of tRNA molecules, even with different amino acid accepting capacities. With well-characterized RNA precursor and tRNA molecules we can hope to delineate those features of primary, secondary, and tertiary structure involved in the specific interactions of tRNA with these enzymes.


Burden of Clostridium difficile infection between 2010 and 2013: Trends and outcomes from an academic center in Eastern Europe.
To analyze the incidence and possible risk factors in hospitalized patients treated with Clostridium difficile infection (CDI). A total of 11751 patients were admitted to our clinic between 1 January 2010 and 1 May 2013. Two hundred and forty-seven inpatients were prospectively diagnosed with CDI. For the risk analysis a 1:3 matching was used. Data of 732 patients matched for age, sex, and inpatient care period and unit were compared to those of the CDI population. Inpatient records were collected from an electronic hospital database and comprehensively reviewed. Incidence of CDI was 21.0/1000 admissions (2.1% of all-cause hospitalizations and 4.45% of total inpatient days). The incidence of severe CDI was 12.6% (2.63/1000 of all-cause hospitalizations). Distribution of CDI cases was different according to the unit type, with highest incidence rates in hematology, gastroenterology and nephrology units (32.9, 25 and 24.6/1000 admissions, respectively) and lowest rates in 1.4% (33/2312) in endocrinology and general internal medicine (14.2 and 16.9/1000 admissions) units. Recurrence of CDI was 11.3% within 12 wk after discharge. Duration of hospital stay was longer in patients with CDI compared to controls (17.6 ± 10.8 d vs 12.4 ± 7.71 d). CDI accounted for 6.3% of all-inpatient deaths, and 30-d mortality rate was 21.9% (54/247 cases). Risk factors for CDI were antibiotic therapy [including third-generation cephalosporins or fluoroquinolones, odds ratio (OR) = 4.559; P < 0.001], use of proton pump inhibitors (OR = 2.082, P < 0.001), previous hospitalization within 12 mo (OR = 3.167, P < 0.001), previous CDI (OR = 15.32; P < 0.001), while presence of diabetes mellitus was associated with a decreased risk for CDI (OR = 0.484; P < 0.001). Treatment of recurrent cases was significantly different from primary infections with more frequent use of vancomycin alone or in combination (P < 0.001), and antibiotic therapy duration was longer (P < 0.02). Severity, mortality and outcome of primary infections and relapsing cases did not significantly differ. CDI was accounted for significant burden with longer hospitalization and adverse outcomes. Antibiotic, PPI therapy and previous hospitalization or CDI were risk factors for CDI.


Improved Cochlear Implant Performance Estimation Using Tonotopic-Based Electrocochleography.
Cochlear implantation produces remarkable results in postlingual deafness, although auditory outcomes vary. Electrocochleography (ECochG) has emerged as a valuable tool for assessing the cochlear-neural substrate and evaluating patient prognosis. To assess whether ECochG-total response (ECochG-TR) recorded at the best-frequency electrode (BF-ECochG-TR) correlates more strongly with speech perception performance than ECochG-TR measured at the round window (RW-ECochG-TR). This single-center cross-sectional study recruited 142 patients from July 1, 2021, to April 30, 2022, with 1-year follow-up. Exclusions included perilymph suctioning, crimped sound delivery tubes, non-native English speakers, inner ear malformations, nonpatent external auditory canals, or cochlear implantation revision surgery. Cochlear implantation. Speech perception testing, including the consonant-nucleus-consonant (CNC) words test, AzBio sentences in quiet, and AzBio sentences in noise plus 10-dB signal to noise ratio (with low scores indicating poor performance and high scores indicating excellent performance on all tests), at 6 months postoperatively; and RW-ECochG-TR and BF-ECochG-TR (measured for 250, 500, 1000, and 2000 Hz). A total of 109 of the 142 eligible postlingual adults (mean [SD] age, 68.7 [15.8] years; 67 [61.5%] male) were included in the study. Both BF-ECochG-TR and RW-ECochG-TR were correlated with 6-month CNC scores (BF-ECochG-TR: r = 0.74; 95% CI, 0.62-0.82; RW-ECochG-TR: r = 0.67; 95% CI, 0.54-0.76). A multivariate model incorporating age, duration of hearing loss, and angular insertion depth did not outperform BF-ECochG-TR or RW-ECochG-TR alone. The BF-ECochG-TR correlation with CNC scores was significantly stronger than the RW-ECochG-TR correlation (r difference = -0.18; 95% CI, -0.31 to -0.01; z = -2.02). More moderate correlations existed between 6-month AzBio scores in noise, Montreal Cognitive Assessment (MoCA) scores (r = 0.46; 95% CI, 0.29-0.60), and BF-ECochG-TR (r = 0.42; 95% CI, 0.22-0.58). MoCA and the interaction between BF-ECochG-TR and MoCA accounted for a substantial proportion of variability in AzBio scores in noise at 6 months (R2 = 0.50; 95% CI, 0.36-0.61). In this case series, BF-ECochG-TR was identified as having a stronger correlation with cochlear implantation performance than RW-ECochG-TR, although both measures highlight the critical role of the cochlear-neural substrate on outcomes. Demographic, audiologic, and surgical factors demonstrated weak correlations with cochlear implantation performance, and performance in noise was found to require a robust cochlear-neural substrate (BF-ECochG-TR) as well as sufficient cognitive capacity (MoCA). Future cochlear implantation studies should consider these variables when assessing performance and related interventions.


Mineral and Anthropogenic Indicator Inorganics in Urban Stormwater and Snowmelt Runoff: Sources and Mobility Patterns.
Inorganic chemicals in urban stormwater and snowmelt runoff originate from catchment geology and anthropogenic activities. The occurrence, partitioning and mobility of six minerals and six trace metal (TM) indicators of anthropogenic activities were studied in stormwater, snowmelt and baseflow in four urban catchments, and the sampling of inorganics was supplemented by measurements of electrical conductivity (EC), pH and total suspended solids (TSSs). Minerals occurred at concentrations several orders of magnitude higher (1-102 mg/L) than those of TMs (10-2-102 μg/L) and reflected the composition of local groundwater seeping into sewers. Concentrations of Ca, K, Mg and Na were enhanced by baseflow contributions and followed closely the electrical conductivity. Al and Fe minerals occurred in insoluble forms, and their pollutographs were similar to those of TMs, whose concentrations mimicked, to some extent, the flux of TSS. The TMs with the highest and lowest particulate fractions were Cr&Pb and Cu&Zn, respectively. The concentrations of total TMs in snowmelt were two to four times higher than those in stormwater, and both sources likely exceeded some of the stormwater effluent limits (for Cd, Cu and Zn) proposed in Sweden. Where such concentrations depended on water hardness, the risk of toxicity might be reduced by elevated hardness of the monitored snowmelt and stormwater. Recognizing the good ecological status of the study area receiving water, Lake Storsjön, some protection against polluted runoff and snowmelt may be needed and could be achieved by implementing stormwater management measures controlling TSS and TMs.


The satisfaction with life scale: Psychometric properties in Pakistani population.
Background: The construct of satisfaction with life has been studied across various cultures through the Satisfaction with Life Scale. The Satisfaction with Life Scale (SWLS) has been validated across several populations and languages. There are no published psychometric properties of its Urdu version. Hence, the aim of this study was to ascertain the psychometric properties of the Urdu version of the SWLS among the Urdu speaking population of Pakistan. Methods: The SWLS has already been translated into Urdu, and the Urdu version is available on the author's website however there is no information about its psychometric properties. To establish the psychometric properties especially the factor structure of the already translated Urdu SWLS, the SWLS-Urdu was administered to Urdu speaking population residing in Pakistan. The statistical analyses (i.e., normality through skewness and kurtosis, Kaiser-Meyer-Olkin (KMO) and Bartlett's test of sphericity, and test and re-test reliability) were conducted through SPSS version 25.0. Structure Equation Modelling via maximum likelihood method of estimation was used to perform confirmatory factor analysis on the data using AMOS 20.0. The significance level was set at p < 0.05. Results: The study was completed by recruiting 120 participants from different universities in Lahore, Pakistan. The sample was equally divided between male and female participants. The mean age of participants was 22.7(3.6) years. Test of the adequacy of the sample through Kaiser-Mayer-Olkin showed KMO=0.88 and Bartlett's test of sphericity (p<0.001). The Cronbach's alpha reliability of the scale was 0.90 and Confirmatory Factor Analysis confirmed a one-factor model as a good fit with strong statistical evidence. No factorial group variances were noticed in male and female participants. Conclusion: This study shows that Urdu SWLS has sound psychometric properties, is linguistically and culturally acceptable, and equally useful in assessing satisfaction with life in the Urdu speaking population.


Unpacking policy formulation and industry influence: the case of the draft control of marketing of alcoholic beverages bill in South Africa.
Alcohol is a major contributor to the Non-Communicable Disease burden in South Africa. In 2000, 7.1% of all deaths and 7% of total disability-adjusted life years were ascribed to alcohol-related harm in the country. Regulations proposed to restrict alcohol advertising in South Africa present an evidence-based upstream intervention. Research on policy formulation in low- and middle-income countries is limited. This study aims to describe and explore the policy formulation process of the 2013 draft Control of Marketing of Alcoholic Beverages Bill in South Africa between March 2011 and May 2017. Recognising the centrality of affected actors in policy-making processes, the study focused on the alcohol industry as a central actor affected by the policy, to understand how they-together with other actors-may influence the policy formulation process. A qualitative case study approach was used, involving a stakeholder mapping, 10 in-depth interviews, and review of approximately 240 documents. A policy formulation conceptual framework was successfully applied as a lens to describe a complex policy formulation process. Key factors shaping policy formulation included: (1) competing and shared values-different stakeholders promote conflicting ideals for policymaking; (2) inter-department jostling-different government departments seek to protect their own functions, hindering policy development; (3) stakeholder consultation in democratic policymaking-policy formulation requires consultations even with those opposed to regulation and (4) battle for evidence-evidence is used strategically by all parties to shape perceptions and leverage positions. This research (1) contributes to building an integrated body of knowledge on policy formulation in low- and middle-income countries; (2) shows that achieving policy coherence across government departments poses a major challenge to achieving effective health policy formulation and (3) shows that networks of actors with commercial and financial interests use diverse strategies to influence policy formulation processes to avoid regulation.


Distinguished Scientists Lecture Series. HIV-associated nephropathy.
HIV-associated nephropathy is manifested by heavy proteinuria and renal insufficiency and characterized pathologically by the collapsing variant of focal and segmental glomerulosclerosis with acute tubular necrosis and mild interstitial inflammation. Untreated, it may result in end-stage renal disease in as little as 4 months. It may present in patients with any manifestation of HIV infection, and affects predominantly black individuals. Insights into pathogenesis have come from a transgenic mouse model, renal cell cultures, and from study of human biopsy material. Although the pathogenesis is not completely understood, current considerations revolve around the role of HIV or protein in renal epithelium and the effects of cytokines, including transforming growth factor-beta and basic fibroblast growth factor, on renal structures. Therapy with zidovudine, corticosteroids, or angiotensin-converting enzyme inhibitors has met with modest success; to date, protease inhibitors have not been assessed.


[Premorbid markers of cardiovascular diseases in mining industry workers].
Functional studies of cardiovascular system in mine cutting machine operators with 10 years of underground length of service under exposure to occupational hazards (air pollution with sylvinite dust, noise, general and local vibration, increased humidity, absent natural illumination, work hardiness and intensity), helped to establish premorbid markers of cardial diseases--labile arterial hypertension, disordered processes of myocardial excitability, conductivity and automatism, higher thickness of intima-media complex in extracranial branches of brachiocephalic arteries. To decrease cardiovascular morbidity in mine cutting machine operators, the authors recommend additional blood pressure monitoring and ultrasound study of intima-media complex of extracranial brachiocephalic arteries within periodic medical examinations.


Sequence-selective binding to DNA of bis(amidinophenoxy)alkanes related to propamidine and pentamidine.
The DNA sequences targeted by a complete homologous series of aromatic diamidines have been determined at single-nucleotide resolution via protection from cutting by the endonucleases DNase I, DNase II and micrococcal nuclease. Propamidine, pentamidine and to a lesser extent hexamidine bind selectively to nucleotide sequences composed of at least four consecutive A-T base pairs. In contrast, the binding to DNA of butamidine, heptamidine, octamidine and nonamidine is poorly sequence-selective. Sequences composed of only three consecutive A-T base pairs do not afford a potential binding site for propamidine or the longer homologues, and none of the drugs tolerate the presence of a G-C base pair within the binding site. Experiments with DNA molecules containing inosine in place of guanosine and 2,6-diaminopurine in place of adenine reveal that the lack of binding of propamidine to GC-containing sites is attributable to an obstructive effect of the exocyclic 2-amino group of guanosine. The present data support the view that the local conformation of the double helix (in particular the width of the minor groove) plays a dominant role in the binding reaction and that the capacity of diamidines to recognize AT-rich sequences selectively varies considerably depending on the length of the alkyl chain. The evidence indicates that binding to AT-tracts in DNA must play a role in the biological activity of these diamidines, but there is no simple correlation between binding and pharmacological efficacy.


Infantile choriocarcinoma. Re-examination of a potentially curable entity.
Choriocarcinoma presenting in an infant or neonate is a rare entity that in the past has been uniformly fatal. The authors present the first reported case of choriocarcinoma successfully treated in a 3-week-old infant. Choriocarcinoma was not suspected in this case until pathologic examination revealed the diagnosis. In retrospect, however, the case fits well into the classic "infantile choriocarcinoma syndrome" initially described by Witzleben in 1968. Review of additional cases reported since the initial description validates Witzleben's initial observations and also indicates that the original definition should be broadened to include other significant presentations of the disease not initially appreciated, specifically anemic infants with central nervous system symptoms as well as newborns and older children. The importance of making a correct and rapid diagnosis is emphasized by the successful outcome in this case where aggressive surgery and subsequent chemotherapy have been curative. Serum beta-human chorionic gonadotropin (beta-HCG) levels have been uniformly positive, providing easy confirmation of the diagnosis. Because the mother can also be affected, an appropriate diagnosis of the infant may also lead to more rapid diagnosis and treatment of the mother.


Elevated chemerin levels in Pakistani men: an interrelation with metabolic syndrome phenotypes.
Chemerin is a novel protein linked to adipocyte differentiation and the development of metabolic imbalances. We sought to examine the relationship of chemerin with metabolic syndrome disturbances including body fat percentage, serum lipid, glucose, insulin levels and body fat percentage in lean and obese volunteers. A cross-sectional study of 90 randomly selected healthy males from Pakistan were divided into three groups as per Body Mass Index (BMI) criteria for South Asian Population. Anthropometric measurements were taken for BMI, waist circumference, hip circumference and body fat percentage, while serum analyses were performed for fasting blood glucose, fasting insulin, fasting lipid profile and serum chemerin. Associations between serum chemerin levels and body fat and other metabolic syndrome parameters were performed using ANOVA and multiple regression analyses. Data was presented as Mean±SD. In all statistical analyses p-values <0.05 were considered significant. Circulating chemerin levels were significantly higher in obese subjects with BMI greater than 25 kg/m(2) compared with those with a BMI below 25 kg/m(2) (P = 0.001). Serum chemerin levels were found to be independently and significantly associated with serum levels of cholesterol (P = 0.0160; r = 0.255), fasting glucose (P = 0.002; r = 0.323), HOMA-IR (P = 0.004; r = 0.300) and hip circumference (P = 0.021; r = 0.246). This demonstrates that chemerin levels are associated with obesity and dyslipidemia and may play a role in the development of insulin resistance. This data suggests that chemerin may serve as an independent marker in diagnosing these conditions even before they become clinically symptomatic.


A comparative study of absorption in vertically and laterally oriented InP core-shell nanowire photovoltaic devices.
We have compared the absorption in InP core-shell nanowire p-i-n junctions in lateral and vertical orientation. Arrays of vertical core-shell nanowires with 400 nm pitch and 280 nm diameter, as well as corresponding lateral single core-shell nanowires, were configured as photovoltaic devices. The photovoltaic characteristics of the samples, measured under 1 sun illumination, showed a higher absorption in lateral single nanowires compared to that in individual vertical nanowires, arranged in arrays with 400 nm pitch. Electromagnetic modeling of the structures confirmed the experimental observations and showed that the absorption in a vertical nanowire in an array depends strongly on the array pitch. The modeling demonstrated that, depending on the array pitch, absorption in a vertical nanowire can be lower or higher than that in a lateral nanowire with equal absorption predicted at a pitch of 510 nm for our nanowire geometry. The technology described in this Letter facilitates quantitative comparison of absorption in laterally and vertically oriented core-shell nanowire p-i-n junctions and can aid in the design, optimization, and performance evaluation of nanowire-based core-shell photovoltaic devices.


Hyperglycemic condition during puberty increases collagen fibers deposition in the prostatic stroma and reduces MMP-2 activity.
Puberty is an important period for the growth and maturation of the male reproductive system, and is also a critical window for endocrine or environmental interference. The physiological levels of circulating insulin and hyperglycemic control are important factors for a normal prostate growth. Hyperglycemia during puberty is reported to retard the growth of the prostate gland, with remarkable effects on the epithelial compartment. Here, we investigated the impact of hyperglycemia along with a simultaneous or late insulin replacement on the ventral prostate growth in rats during puberty, paying special attention to the deposition of collagen fibers and activities of gelatinase, matrix metalloproteinase-2 (MMP-2), and -9 (MMP-9). Hyperglycemia was induced by streptozotocin (STZ) administration in 40-day-old male Wistar rats. A subset of hyperglycemic rats underwent an early insulin replacement (three days after the STZ administration), and another subset underwent a late insulin replacement (twenty days after the STZ administration). Animals were euthanized at 60 and/or 80 days of age. The ventral prostatic lobe was processed for picrosirius red staining, type I and III collagen immunohistochemistry, and gelatin zymography. Hyperglycemic animals showed an increased area of collagen fibers in the prostate, which was composed both types of collagens. MMP-2 activity was significantly reduced in the hyperglycemic animals, while MMP-9 activity was very low and showed no alteration. The simultaneous and late insulin administration restored collagen content and MMP-2 activity. In conclusion, puberty is a critical window for prostate maturation and type-1 diabetes-induced hyperglycemia affects the ratio of the prostatic parenchymal and stromal growth, leading to fibrotic tissues by also MMP-2 down regulation.


Double-phase-functionalized magnetic Janus polymer microparticles containing TiO2 and Fe2O3 nanoparticles encapsulated in mussel-inspired amphiphilic polymers.
Recently, anisotropic colloidal polymeric materials including Janus microparticles, which have two distinct aspects on their surfaces or interiors, have garnered much interest due to their anisotropic alignment and rotational orientation with respect to external electric or magnetic fields. Janus microparticles are also good candidates for pigments in "twisting ball type" electronic paper, which is considered promising for next-generation flexible display devices. We demonstrate here a universal strategy to encapsulate inorganic nanoparticles and to introduce different such inorganic nanoparticles into distinct polymer phases in Janus microparticles. TiO2 and Fe2O3 nanoparticles were separately encapsulated in two different mussel-inspired amphiphilic copolymers, and then organic-inorganic composite Janus microparticles were prepared by simple evaporation of solvent from the dispersion containing the polymer and nanoparticle. These Janus microparticles were observed to rotate quickly in response to applied magnetic fields.


The effects of inhaled NO on plasma vasoactive factor and CTnI level in rabbits with acute massive pulmonary embolism1.
To investigate changes in the plasma concentrations of cardiac troponin I (CTnI), thromboxane A2 (TXA2), prostaglandin I2 (PGI2) and endothelin-1 (ET-1) in rabbits with massive pulmonary embolism (AMPE) and the impact of nitric oxide inhalation (NOI) on these indices. A total of 30 Japanese rabbits were used to construct an MPE model and were divided into 3 groups equally (n=10), including an EXP group (undergoing modeling alone), an NOI group (receiving NOI 2 h post-modeling) and a CON group (receiving intravenous physiological saline). In the model group, plasma concentration of CTnI peaked at 16 h following modeling (0.46±0.10 µg/ml) and significantly decreased following NOI. Plasma levels of TXB2, PGI2 and ET-1 peaked at 12, 16 and 8 h following modeling, respectively, and significantly decreased at different time points (0, 2, 4, 8, 12, 16, 20 and 24 h) following NOI. A significant correlation was observed between the peak plasma CTnI concentration and peak TXB2, 6-keto prostaglandin F1α and ET-1 concentrations in the model and NOI groups. Increases in plasma TXA2, PGI2 and ET-1 levels causes myocardial damage in a rabbit model of AMPE; however, NOI effectively down regulates the plasma concentration of these molecules to produce a myocardial-protective effect.


Association of Early Childhood Caries with Feeding, Dietary Habits, and Oral Hygiene Practices among Rural and Urban School Children of Jaipur.
To determine possible associations of early childhood caries (ECC) with risk factors such as feeding and dietary habits of children and oral hygiene practices by the parents or caregiver in rural and urban school children in Jaipur, India. An observational cross-sectional study was designed with a dental examination and a standardized questionnaire. A total of 1,824 children, that is, 848 (46%) rural, and 976 (54%) urban school children were enrolled in the study. The data regarding their diet and feeding habits of children, oral hygiene practices of the parents or caregivers were collected with the help of a standardized questionnaire. The caries status of rural and urban school children was recorded using the decayed, missing, filled teeth (DMFT) index. Data thus collected were compiled, analyzed and were subjected to statistical analysis using Statistical Package for Social Sciences (SPSS v 26.0, IBM). Comparison of frequencies of categories of variables with groups was done using Chi-square test with p < 0.05 was considered to be statistically significant. The prevalence of ECC was 34.7% in rural and 45.5% in urban school children of Jaipur (p < 0.01). Caries risk increased with the use of both bottle and breast feeding, habit of milk at night, eating snacks between meals with no habit of rinsing teeth, and decrease in parental supervision during oral hygiene practices. In urban school children there is an increased access to junk food and refined sugar daily as compared to rural school children with more than two times in a week was found statistically highly significant in the study (p < 0.01). The prevalence of ECC was higher in urban school children as compared to rural school children in Jaipur. It was found that risk factors such as diet and feeding habits of children and oral hygiene practices by the parents or caregiver are strongly associated with the prevalence of ECC. It was concluded that the epidemiological data, which have been collected in a very comprehensive way can be utilized more effectively to eliminate the root cause of the disease by improving oral health services in the rural and urban school children in Jaipur, India. Yadav SP, Meghpara M, Marwah N, et al. Association of Early Childhood Caries with Feeding, Dietary Habits, and Oral Hygiene Practices among Rural and Urban School Children of Jaipur. Int J Clin Pediatr Dent 2022;15(3):273-279.


Characteristics and mechanism of lower limb injury induced by landmine blast: A research in a rabbit model.
Limb injuries caused by landmine explosions are tricky to treat and difficult to protect. It is necessary to establish an animal model for studying lower limb injury and to investigate the characteristics and mechanisms of lower limb injury induced by landmine blasts. Twenty-six mature white rabbits were randomly divided into sham group (n=10) and injury group (n=16). Landmine blast was simulated by electric detonators under the right lower limb in upright state by a special modified fixation frame. High-speed photography was used to observe the body movements. Vital signs, vascular injury (determining by digital subtraction angiography), pathological characteristics, and ATP concentration of the tibialis anterior muscle and triceps surae of shank were recorded for com-parison. Generally, middle and lower segment of the injured legs of the rabbits was seriously damaged. The limb stump presents a distribution of three areas, tissue free zone, contusion hematoma, and edema contusion. Sneak wound track, myofascial destruction, and periosteum stripping were typical characteristics of landmine blast injury. ATP concentration and pathological analysis showed that the tibialis anterior muscle was the most seriously injured, followed by the gastrocnemius and soleus. ATP concentration of affected muscle of both the contusion and commotio area declined remarkably over time, but the muscle in the avulsion area stayed at a low activity level with no change over the time. Small vascular injury in the contusion area was evident. The site of the sciatic nerve lesion was higher than the muscle. Injured site of sciatic nerve injury was higher than serious contusion muscle. High-speed photography demonstrated that the joints of the injured limb extremely flexed followed by a rapid stretch under the blast shock wave. The established experimental model presents typical effect of lower limbs wounded by the mine blast in war field. Landmine blast can cause typical damage on lower limbs including nerve lesion, knee injury, and microcirculation damage that is pro-gressive over time. The limb stump is divided into three zones based on gross pathology and micropathology, which can provide an important reference for clinical treatments and prognosis.


Membrane shapers from two distinct superfamilies cooperate in the development of neuronal morphology.
Membrane-shaping proteins are driving forces behind establishment of proper cell morphology and function. Yet, their reported structural and in vitro properties are noticeably inconsistent with many physiological membrane topology requirements. We demonstrate that dendritic arborization of neurons is powered by physically coordinated shaping mechanisms elicited by members of two distinct classes of membrane shapers: the F-BAR protein syndapin I and the N-Ank superfamily protein ankycorbin. Strikingly, membrane-tubulating activities by syndapin I, which would be detrimental during dendritic branching, were suppressed by ankycorbin. Ankycorbin's integration into syndapin I-decorated membrane surfaces instead promoted curvatures and topologies reflecting those observed physiologically. In line with the functional importance of this mechanism, ankycorbin- and syndapin I-mediated functions in dendritic arborization mutually depend on each other and on a surprisingly specific interface mediating complex formation of the two membrane shapers. These striking results uncovered cooperative and interdependent functions of members of two fundamentally different membrane shaper superfamilies as a previously unknown, pivotal principle in neuronal shape development.


Endoplasmic reticulum proteostasis impairment in aging.
Perturbed neuronal proteostasis is a salient feature shared by both aging and protein misfolding disorders. The proteostasis network controls the health of the proteome by integrating pathways involved in protein synthesis, folding, trafficking, secretion, and their degradation. A reduction in the buffering capacity of the proteostasis network during aging may increase the risk to undergo neurodegeneration by enhancing the accumulation of misfolded proteins. As almost one-third of the proteome is synthetized at the endoplasmic reticulum (ER), maintenance of its proper function is fundamental to sustain neuronal function. In fact, ER stress is a common feature of most neurodegenerative diseases. The unfolded protein response (UPR) operates as central player to maintain ER homeostasis or the induction of cell death of chronically damaged cells. Here, we discuss recent evidence placing ER stress as a driver of brain aging, and the emerging impact of neuronal UPR in controlling global proteostasis at the whole organismal level. Finally, we discuss possible therapeutic interventions to improve proteostasis and prevent pathological brain aging.


The use of complementary alternative medicine (CAM) in 1 001 German adults: results of a population-based telephone survey.
The objective of this study was to evaluate the patterns of use of complementary alternative medicine (CAM) in a representative adult population in Germany. A population-based telephone survey was conducted in Lübeck, Germany. We performed computer-assisted telephone interviews (CATI) in order to obtain information on demographics, health status, prevalence of CAM usage, motivation for using CAM, type of CAM and health problems for which CAM were used. 1,001 adults (median age 48 years) participated in the study (response 46.8%). 79.6% of the interviewed subjects reported health problems. The most frequently named problems were chronic pain (45.3%), circulation problems (32.9%) and colds with fever (27.8%). Non-users of CAM had a lower incidence (76.6%) of overall illness than users (83.5%) (OR 0.65, 0.47-0.89). 42.3% of the participants had used CAM. The CAM user group consisted of significantly more females (72.8 vs. 55.5%) (OR 2.32, 1.74-3.08) and involved better educated subjects (school education >12 years, 36.6 vs. 27.9%, OR 3.25, 1.35-7.81) than the non-user group. The main health problems for which CAM was used were chronic pain (36.3%), some cases of uncomplicated colds (16.9%) and for improving general health (14.7%). Three procedures accounted for the majority of usage: Acupuncture (34.5%), homeopathy (27.3%) and herbal medicine (9.7%). A large number of participants reported as the main reason for using CAM the wish to avoid drugs as much as possible (31.7%). 26.7% reported opting for CAM due to the recommendation of their physician. 23.9% gave unsatisfactory results of conventional medicine as reason for CAM usage. CAM is used widely for different complaints by the general population. This frequent use of CAM has implications for the health-care system and health policy.


Identifying tumor markers-stratified subtypes (CA-125/CA19-9/carcinoembryonic antigen) in cervical adenocarcinoma.
There is a lack of research evaluating the effect of tumor markers for prognosis in cervical adenocarcinoma. We aimed to develop and validate a preoperative tumor-marker-based model including clinicopathological factors to clarify the prognostic value of endocervical adenocarcinoma. A total of 572 patients with cervical adenocarcinoma who were staged at the International Federation of Gynecology and Obstetrics (FIGO) IA-IIA were reviewed retrospectively. Preoperative serum carcinoembryonic antigen (CEA), carbohydrate antigen (CA)-125 and CA19-9 levels were measured. The survival and recurrence patterns were analyzed according to the tumor-marker-related stratification. The predictive values of biomarkers and clinical variables were assessed with Cox regression and competing risk models. Patients with elevated preoperative tumor markers had evidently poor overall survival and recurrence-free survival. The triple-elevated tumor marker (TETM) subgroup had the worst overall survival and progression-free survival than the triple-negative tumor marker (TNTM) subgroup and the single-elevated tumor marker (SETM) subgroup. The most important predictors for overall survival were elevated tumor markers, FIGO-stage, tumor differentiation, lymphovascular space invasion (LVSI) and lymph nodes metastasis. The most important predictors for recurrence-free survival were elevated tumor markers, FIGO-stage, tumor differentiation, LVSI and deep stromal invasion. Stratified analysis showed that elevated CA-125 and CA19-9 were significantly associated with postoperative distant metastasis. A decision curve analysis confirmed that a combination of tumor markers as predictors significantly outperformed the other common predictors used (FIGO-stage, intermediate and high-risk factors, tumor differentiation, lymph nodes). Elevated preoperative serum CEA, CA-125, and CA19-9 levels exhibited poor overall survival and recurrence-free survival in cervical adenocarcinoma patients. Combined preoperative serum CA-125 and CA19-9 independently predicted distant metastasis in patients with endocervical adenocarcinoma.


Clinical review of radiofrequency catheter ablation for cardiac arrhythmias.
Clinical tachycardias are a major cause of morbidity with detrimental effects on quality of life, physical activity and health care costs. Catheter ablation delivered by radiofrequency energy (RFA) has gradually expanded as a therapeutic modality for cure or palliation and is being adapted to address the most difficult to treat tachycardias. The purpose of this paper is to inform decision makers about the current evidence base of RFA through a comprehensive literature review. Of the 968 citations identified through the literature search strategy, 111 studies (11%) met the inclusion criteria. Only 10 of these studies (9%) were randomized, controlled trials. RFA of paroxysmal supraventricular tachycardia, atrial flutter and focal atrial tachycardias are all procedures associated with high procedural success rates and sustained clinical improvement within two years of follow-up. Limited evidence also demonstrates that elimination of these tachycardias improves symptoms and quality of life. RFAs of atrial fibrillation and ventricular tachycardia secondary to underlying structural heart disease are currently considered experimental procedures because there remains insufficient published data to draw conclusions about their clinical efficacy and safety profile. For all of the ablation procedures, there is a paucity of high-quality outcome studies comparing ablation with alternative therapeutic approaches and this provides the opportunity for future research.


[Medical teaching and humanistic-communicative aspects: two step-children of quality evaluation. An example of a compact teaching experiment with integrated final examination shows better results].
Evaluation of teaching regarding the humanitarian communicative aspect can not take place without controls. However, isolated controls without other evaluative measures are irrational instruments. This specially holds true for final exams. It seems important to use methods of evaluation which at the same time improve the quality and do not in the negative sense (like a final exam) knock out and disqualify (Tab. 2). We can give some examples out of daily routine which--alas--are very wide reaching. The humanitarian communicative factor, which is an integrative part of medicine very badly is strongly disregarded in favour of educating towards a mechanistic apparatschikway, namely in medical education, carrier, supervision of hospitals. We need strong good will for reformation! We do not only raise postulates here but can show an example of a teaching experiment, where students were put in small groups for intensive teaching with an integrated final exam. This was possible without more costs, but with more human engagement on the side of the teachers.


Use of PCR for extranous agent testing in avian vaccines.
Quality control of biologicals, in particular avian vaccines, includes certification of freedom from extraneous agents (EA). Adventitious viruses have always represented a major concern as a potential risk associated with the use of biologicals. Extensive testing for the presence of potential extraneous agents is therefore required to ensure the safety of the vaccines. To replace the use of laboratory animals (the Three Rs-approach) we developed and implemented a series of alternative PCR tests for detection of extraneous agents in avian viral vaccines (the PCR-approach). The application of PCR to screen poultry vaccines for viral contaminants is an example of how PCR can be usefully employed in quality control assays. The object of this work is to show how the use of in vitro methods can contribute to reduction in animal testing in the quality control of biologicals.


Melatonin supplementation enhances pulmonary rehabilitation outcomes in COPD: a randomized, double-blind, placebo-controlled study.
Melatonin (MLT), the main product of the pineal gland, is involved in muscle tissue repair and regeneration, besides several other important physiologic functions. In COPD, MLT administration can improve lung oxidative stress and sleep quality, but its potential effects on the outcomes of pulmonary rehabilitation (PR) have not been previously investigated. A randomized controlled trial was undertaken to test the hypothesis that a combined approach of rehabilitative exercise training and MLT supplementation could maximize functional performance, health status and quality of life in patients with COPD. Thirty-nine individuals with COPD referred to a supervised PR program at the Federal University of Ceara, Brazil, were randomized to receive MLT (3 mg/day; n = 18) or placebo (n = 21). Exercise capacity (6-min walk test - 6MWT), health status (COPD assessment test), and quality of life (airways questionnaire 20) were investigated as primary outcomes. No differences were observed at baseline in demographic, anthropometric and clinical characteristics between MLT and placebo groups. At the end of PR, superiority of the MLT group was demonstrated in improvement in the distance covered in the 6MWT (71 ± 26 vs. 25 ± 36 m; p < 0.01), health status (-11 ± 6 vs. -3 ± 5; p < 0.01), and quality of life (-6.9 ± 3.0 vs. -1.9 ± 2.4; p < 0.01), compared to the placebo group. In conclusion, MLT supplementation during the course of 12 weeks of PR can improve functional capacity, health status and quality of life in patients with COPD. These findings may have significant implications for the management of this condition.


Protective effect of Withaferin-A on micronucleus frequency and detoxication agents during experimental oral carcinogenesis.
Our aim was to investigate the effect of Withaferin-A on bone marrow micronucleus frequency and buccal mucosa detoxication agents during 7, 12-dimethylbenz[a]anthracene (DMBA) induced hamster buccal pouch carcinogenesis. Oral squamous cell carcinoma was developed in hamsters' buccal pouches by painting 0.5% DMBA in liquid paraffin, three times per week for 14 weeks. We observed 100% tumor formation in DMBA painted hamsters. Elevated frequency of bone marrow micronucleated polychromatic erythrocytes (MnPCEs) and decrease in buccal mucosa phase II detoxication agents were noticed in tumor bearing hamsters. Oral administration of Withaferin-A significantly reduced the micronucleus frequency and brought back the status of phase II detoxication agents in DMBA painted hamsters. Our study thus demonstrated the protective effect of Withaferin-A on DMBA-induced micronucleus frequency in the bone marrow of golden Syrian hamsters. Also, Withaferin-A maintained the status of buccal mucosa detoxication agents during DMBA-induced hamster buccal pouch carcinogenesis.


The Children, Intimate Relationships, and Conflictual Life Events (CIRCLE) interview for simultaneous measurement of intimate partner and parent to child aggression.
Despite substantial rates of parent to child aggression (PCA) and intimate partner aggression (IPA) co-occurrence within families, the co-occurrence of PCA and IPA within incidents of aggression has not previously been examined. To do so, we developed the Children, Intimate Relationships, and Conflictual Life Events (CIRCLE) interview to simultaneously measure incidents of psychological and physical PCA and IPA. The CIRCLE interview was administered quarterly for approximately 1 year to 109 women and 94 men from 111 couples with a first born child approximately 32 months of age at study initiation. Demonstrating the CIRCLE interview's ability to yield new knowledge about the nature of family aggression, we describe the frequency of aggressive incidents, the average number of aggressive behaviors within incidents, the daily occurrence of multiple aggressive incidents, and rates of within-incident PCA and IPA co-occurrence. With the exception of men's physical IPA, aggression scores derived from the CIRCLE interview exhibited a relatively high degree of interpartner reporting concordance, as well as structural validity and convergent validity with common aggression measures. Aggression reports via repeated testing were not influenced by social desirability or attempts to avoid aggression. Participants who perceived enhanced memory for aggression as a function of study participation reported increasing PCA and IPA frequencies over time. In the prediction of child conduct and emotional problems, the CIRCLE interview demonstrated predictive validity and incremental validity over traditional aggression measures. For the first time, within-incident co-occurrence of PCA and IPA was documented and shown to uniquely impact child outcomes. (PsycINFO Database Record


Early prediction of blonanserin response in Japanese patients with schizophrenia.
Blonanserin is a second-generation antipsychotic used for the treatment of schizophrenia in Japan and Korea. The present study aimed to examine early prediction of blonanserin in patients with schizophrenia. An 8-week, prospective, single-arm, flexible-dose clinical trial of blonanserin in patients with schizophrenia was conducted under real-world conditions. The inclusion criteria were antipsychotic naïve, and first-episode schizophrenia patients or schizophrenia patients with no consumption of any antipsychotic medication for more than 4 weeks before enrollment in this study. The positive predictive value, negative predictive value, sensitivity, specificity, and predictive power were calculated for the response status at week 4 to predict the subsequent response at week 8. Thirty-seven patients were recruited (56.8% of them had first-episode schizophrenia), and 28 (75.7%) completed the trial. At week 8, blonanserin was associated with a significant improvement in the Positive and Negative Syndrome Scale (PANSS) total score (P<0.0001) and in positive (P<0.0001), negative (P<0.0001), and general subscale scores (P<0.0001). In terms of percentage improvement of PANSS total scores from baseline to week 8, 64.9% of patients showed a ≥20% reduction in the PANSS total score and 48.6% showed a ≥30% reduction. However, 8.1% of patients experienced at least one adverse event. Using the 20% reduction in the PANSS total score at week 4 as a definition of an early response, the negative predictive values for later responses (ie, reductions of ≥30 and ≥40 in the PANSS total scores) were 88.9% and 94.1%, respectively. The specificities were 80.0% and 51.6%, respectively. Our results suggest that the blonanserin response at week 4 could predict the later response at week 8.


Bladder cancer in young women.
The authors describe a population-based case-control study of cancer of the urinary bladder in New York State women aged 20-49 years (173 matched pairs) in 1975-1980. Both known and suspected risk factors for bladder cancer were examined for these rare, early-onset female cases. The odds ratio (OR) for cigarette smoking was 2.4 (95% confidence interval (CI) = 1.5-4.0). Cases consumed more coffee per day than did controls (p less than 0.05). More cases than controls reported heavy use of drugs that contained phenacetin (OR = 6.5, 95% CI = 1.5-59.2). In addition, more cases than controls reported that they had had a thyroid uptake procedure with radioactive iodine (iodine-131) (OR = 3.7, 95% CI = 1.4-11.0). The odds ratios for these factors remained elevated after simultaneous adjustment with conditional logistic regression models. Consumption of artificial sweeteners, occupational history, bladder or kidney cancer in a first-degree relative, and a history of bladder infections were examined and found not to be risk factors for bladder cancer in this study.


Traumatic Brain Injury: Imaging Patterns and Complications.
While the diagnosis of traumatic brain injury (TBI) is a clinical decision, neuroimaging remains vital for guiding management on the basis of identification of intracranial pathologic conditions. CT is the mainstay of imaging of acute TBI for both initial triage and follow-up, as it is fast and accurate in detecting both primary and secondary injuries that require neurosurgical intervention. MRI is more sensitive for the detection of certain intracranial injuries (eg, axonal injuries) and blood products 24-48 hours after injury, but it has limitations (eg, speed, accessibility, sensitivity to motion, and cost). The evidence primarily supports the use of MRI when CT findings are normal and there are persistent unexplained neurologic findings or at subacute and chronic periods. Radiologists should understand the role and optimal imaging modality to use, in addition to patterns of primary brain injury and their influence on the risk of developing secondary brain injuries related to herniation. ©RSNA, 2019 See discussion on this article by Mathur and Nicolaou.


An approach to solve group-decision-making problems with ordinal interval numbers.
The ordinal interval number is a form of uncertain preference information in group decision making (GDM), while it is seldom discussed in the existing research. This paper investigates how the ranking order of alternatives is determined based on preference information of ordinal interval numbers in GDM problems. When ranking a large quantity of ordinal interval numbers, the efficiency and accuracy of the ranking process are critical. A new approach is proposed to rank alternatives using ordinal interval numbers when every ranking ordinal in an ordinal interval number is thought to be uniformly and independently distributed in its interval. First, we give the definition of possibility degree on comparing two ordinal interval numbers and the related theory analysis. Then, to rank alternatives, by comparing multiple ordinal interval numbers, a collective expectation possibility degree matrix on pairwise comparisons of alternatives is built, and an optimization model based on this matrix is constructed. Furthermore, an algorithm is also presented to rank alternatives by solving the model. Finally, two examples are used to illustrate the use of the proposed approach.


Molecular evidence of Burkholderia pseudomallei genotypes based on geographical distribution.
Background. Central intermediary metabolism (CIM) in bacteria is defined as a set of metabolic biochemical reactions within a cell, which is essential for the cell to survive in response to environmental perturbations. The genes associated with CIM are commonly found in both pathogenic and non-pathogenic strains. As these genes are involved in vital metabolic processes of bacteria, we explored the efficiency of the genes in genotypic characterization of Burkholderia pseudomallei isolates, compared with the established pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) schemes. Methods. Nine previously sequenced B. pseudomallei isolates from Malaysia were characterized by PFGE, MLST and CIM genes. The isolates were later compared to the other 39 B. pseudomallei strains, retrieved from GenBank using both MLST and sequence analysis of CIM genes. UniFrac and hierachical clustering analyses were performed using the results generated by both MLST and sequence analysis of CIM genes. Results. Genetic relatedness of nine Malaysian B. pseudomallei isolates and the other 39 strains was investigated. The nine Malaysian isolates were subtyped into six PFGE profiles, four MLST profiles and five sequence types based on CIM genes alignment. All methods demonstrated the clonality of OB and CB as well as CMS and THE. However, PFGE showed less than 70% similarity between a pair of morphology variants, OS and OB. In contrast, OS was identical to the soil isolate, MARAN. To have a better understanding of the genetic diversity of B. pseudomallei worldwide, we further aligned the sequences of genes used in MLST and genes associated with CIM for the nine Malaysian isolates and 39 B. pseudomallei strains from NCBI database. Overall, based on the CIM genes, the strains were subtyped into 33 profiles where majority of the strains from Asian countries were clustered together. On the other hand, MLST resolved the isolates into 31 profiles which formed three clusters. Hierarchical clustering using UniFrac distance suggested that the isolates from Australia were genetically distinct from the Asian isolates. Nevertheless, statistical significant differences were detected between isolates from Malaysia, Thailand and Australia. Discussion. Overall, PFGE showed higher discriminative power in clustering the nine Malaysian B. pseudomallei isolates and indicated its suitability for localized epidemiological study. Compared to MLST, CIM genes showed higher resolution in distinguishing those non-related strains and better clustering of strains from different geographical regions. A closer genetic relatedness of Malaysian isolates with all Asian strains in comparison to Australian strains was observed. This finding was supported by UniFrac analysis which resulted in geographical segregation between Australia and the Asian countries.


Cardiac cryosurgery: effects of myocardial temperature on cryolesion size.
Cryothermic ablation of myocardium and portions of the specialized cardiac conduction tissue has been employed successfully for the treatment of both supraventricular and ventricular tachyarrhythmias. As more uses have been found for cardiac cryosurgery, increasing flexibility of the cryothermia system has been required. The present study was designed to develop a method for electively increasing or decreasing the dimensions and volume of cryolesions by altering adjacent myocardial temperatures. Fourteen dogs were subjected to cardiopulmonary bypass, and standard cryothermic exposures (4 mm cryoprobe, -60 degrees C for 120 seconds) were used to create cryolesions on the left ventricular free wall. The dimensions and volumes of cryolesions created at myocardial temperatures of 37 degrees, 32 degrees, and 6 degrees to 12 degrees C (hypothermic cardioplegic arrest) were compared. Cryolesions created at 6 degrees to 12 degrees C with the dogs under cardioplegic arrest were significantly larger (P less than 0.05) than cryolesions created t 37 degrees or 32 degrees C in the perfused beating heart. This information may be useful in improving the results of myocardial cryoablation, particularly in procedures requiring the ablation of large regions of myocardium or regions deep below the epicardial or endocardial surface.


Exhaled breath analysis by electronic nose in airways disease. Established issues and key questions.
Exhaled air contains many volatile organic compounds (VOCs) that are the result of normal and disease-associated metabolic processes anywhere in the body. Different omics techniques can assess the pattern of these VOCs. One such omics technique suitable for breath analysis is represented by electronic noses (eNoses), providing fingerprints of the exhaled VOCs, called breathprints. Breathprints have been shown to be altered in different disease states, including in asthma and COPD. This review describes the current status on clinical validation and application of breath analysis by electronic noses in the diagnosis and monitoring of chronic airways diseases. Furthermore, important methodological issues including breath sampling, modulating factors and incompatibility between eNoses are raised and discussed. Next steps towards clinical application of electronic noses are provided, including further validation in suspected disease, assessment of the influence of different comorbidities, the value in longitudinal monitoring of patients with asthma and COPD and the possibility to predict treatment responses. Eventually, a Breath Cloud may be constructed, a large database containing disease-specific breathprints. When collaborative efforts are put into optimization of this technique, it can provide a rapid and non-invasive first line diagnostic test.


Low-temperature pausing of cultivated mammalian cells.
There are currently two methods for maintaining cultured mammalian cells, continuous passage at 37 degrees C and freezing in small batches. We investigated a third approach, the "pausing" of cells for days or weeks at temperatures below 37 degrees C in a variety of cultivation vessels. High cell viability and exponential growth were observed after pausing a recombinant Chinese hamster ovary cell line (CHO-Clone 161) in a temperature range of 6-24 degrees C in microcentrifuge tubes for up to 3 weeks. After pausing in T-flasks at 4 degrees C for 9 days, adherent cultures of CHO-DG44 and human embryonic kidney (HEK293 EBNA) cells resumed exponential growth when incubated at 37 degrees C. Adherent cultures of CHO-DG44 cells paused for 2 days at 4 degrees C in T-flasks and suspension cultures of HEK293 EBNA cells paused for 3 days at either 4 degrees C or 24 degrees C in spinner flasks were efficiently transfected by the calcium phosphate-DNA coprecipitation method, yielding reporter protein levels comparable to those from nonpaused cultures. Finally, cultures of a recombinant CHO cell line (CHO-YIgG3) paused for 3 days at 4 degrees C, 12 degrees C, or 24 degrees C in bioreactors achieved the same cell mass and recombinant protein productivity levels as nonpaused cultures. The success of this approach to cell storage with rodent and human cell lines points to a general biological phenomenon which may have a wide range of applications for cultivated mammalian cells.


Triethylene-tetramine (trien) therapy for Wilson's disease.
Triethylene tetramine (trien), in increasing dose from 1.0-2.0 g/day to 2.5-3.0 g/day, was used for 4 Japanese patients with Wilson's disease who were intolerant of D-penicillamine (D-PC). Before the treatment, urinary copper excretion (UCE) was 70-96 micrograms/day. UCE increased to 1,512-2,352 micrograms/day on the day of initial administration, and remained at levels between 350-1,100 micrograms/day, thereafter. During 2 months of trien therapy, neurological deficits regressed in three patients, and only slightly in one patient. No adverse effects were observed. These results and the retrospective survey on 17 patients treated with D-PC confirmed that trien is less potent but a safer copper chelating agent than D-PC. The transient aggravation of neurological deficits seen in two patients during the early stage of the treatment suggested that trien, as D-PC, should be started in small doses and gradually increased.


Exploring cognitive complaints in schizophrenia: the subjective scale to investigate cognition in schizophrenia.
While it has become commonplace to test the various components of memory in schizophrenia with paper-and-pencil or in-lab tasks, very little data exist on the subjective complaints of patients regarding their memory. Few instruments have been designed to collect systematically the complaints of patients with schizophrenia. We present a work in progress on the Subjective Scale to Investigate Cognition in Schizophrenia (SSTICS), a 21-item, Likert-type scale that is simple and easy to use. It allows a quantitative approach to the subjective and cognitive dimensions of schizophrenia. Stip constructed the scale based on a questionnaire covering several cognitive domains: memory (working memory, explicit long-term memory), attention (divided, distractibility, alertness, sustained), language, and praxia. We evaluated the psychometric properties of the SSTICS in a population of 114 French-speaking patients in Montreal. Patients were recruited in the community and assessed with the Structured Clinical Interview for DSM-III-R (SCID), the Positive and Negative Syndrome Scale (PANSS), and the Extrapyramidal Symptoms Rating Scale (ESRS). Cognition was measured using the Rey Auditory Verbal Learning Test (RAVLT) (long-term memory), Controlled Oral Word Association Test (verbal fluency), and Trails A and B. Preliminary analyses showed very good internal consistency for the global score (alpha=0.88), and alphas varying from 0.57 to 0.72 for the subscales. Stability over time was very good. The principal components analysis accounted for a multiple structure. Correlations between subjective scores and objective cognitive assessment were significant for several domains. Validation of the SSTICS needs to be completed through further exploration of the factorial structure and testing of the English version.


Formulation and optimization of floating matrix tablets of clarithromycin using simplex lattice design.
The purpose of the present study was to prepare floating matrix tablets of clarithromycin employing simplex lattice design. Hydroxypropyl methylcellulose (HPMC) and Ethyl Cellulose (EC) were used as matrix forming agents; sodium bicarbonate and citric acid as effervescence producing agents. Simplex lattice design was used as optimization technique employing three independent formulation variables viz. concentration of HPMC (X1), Citric Acid (X2), EC (X3) whereas floating lag time, t50%, t90%, and MDT (Mean Dissolution Time) were the response (dependent) variables. Seven formulations (F1-F7) were prepared and evaluated for dissolution studies, floating characteristics, weight variation, hardness, thickness, friability.t50% of the formulations was found to be ranging from 317±2.54 to 522±2.39 minutes. The t90% and MDT of the tablets were found to be ranging between 659.65±1.89 to 967.35±1.67 minutes and 527.20±1.22 to 846.78±2.61 minutes respectively. Total floating time of the formulations was more than 12 hours and the drug content was in the range of 98.54±0.46 to 99.92±0.32. The amount of both HPMC and EC were found to play a dominating role in controlling the release of the drug from the formulation whereas ratios of sodium bicarbonate and citric acid were showing significant effect on the floating lag time. The release exponent (n) from Korsmeyer-Peppas model was found to be between 0.62 and 0.75 indicating non-Fickian or anomalous drug release behavior from the formulated floating matrix tablets. Simplex lattice design was reported to be an effective optimization technique for optimizing pharmaceutical formulations against desired responses.


Giant mediastinal parathyroid adenoma: a case report.
A 65 year old female patient suffering from multinodular goitre and from hypercalcaemic syndrome which had been and was being treated with drugs for a number of years. The patient undergoes total thyroidectomy. Surgical neck and anterior mediastinum exploration was negative for sick parathyroids. Neck and chest TC and 'TC sestamibi scintigraphy showed the presence of a 7 cm hyperfunctional ectopic parathyroid tissue in the postero-superior mediastinum infiltrating oesophagus. Video bronchoscopy revealed an extrinsic compression of the trachea. The patient underwent surgery. Through right postero-lateral thoracotomy and mediastinal pleura incision, the adenoma excision was carried out. The histological examination revealed a potentially malignant parathyroid adenoma with infiltration, without over-reaching the capsule. The surgical treatment resulted in an immediate resolution of the clinical symptomatology. One year later, the follow up was shown no observable relapse with normal calcium and PTH values. Today, the tendency to minimally invasive surgery, an accurate preoperative localization of the adenoma and the use of techniques such as intra-surgical nuclear mapping through manual gamma probes, selective angiography, venous intraoperative dosage of PTH and intra-surgical ultrasound scan.