Are PARKIN patients ideal candidates for dopaminergic cell replacement therapies?
Parkinson's is a heterogeneous, complex condition. Stratification of Parkinson's subtypes will be essential to identify those that will benefit most from a cell replacement therapy. Foetal mesencephalic grafts can alleviate motor symptoms in some Parkinson's patients. However, on-going synucleinopathy results in the grafts eventually developing Lewy bodies, and they begin to fail. We propose that Parkinson's patients with PARKIN mutations may benefit most from a cell replacement therapy because (a) they often lack synucleinopathy, and (b) their neurodegeneration is often confined to the nigrostriatal pathway. While patients with PARKIN mutations exhibit clinical signs of Parkinson's, post-mortem studies to date indicate the majority lack Lewy bodies suggesting the nigral dopaminergic neurons are lost in a cell autonomous manner independent of α-synuclein mechanisms. Furthermore, these patients are usually younger, slow progressing and typically do not suffer from complex non-nigral symptoms that are unlikely to be ameliorated by a cell replacement therapy. Transplantation of dopaminergic cells into the putamen of these patients will provide neurons with wild-type PARKIN expression to re-innervate the striatum. The focal nature of PARKIN-mediated neurodegeneration and lack of active synucleinopathy in most young-onset cases makes these patients ideal candidates for a dopaminergic cell replacement therapy. Strategies to improve the outcome of cell replacement therapies for sporadic Parkinson's include the use of adjunct therapeutics that target α-synuclein spreading and the use of genetically engineered grafts that are resistant to synucleinopathy.


Role of Vasodilator Therapy in Acute Heart Failure.
Over the past decade, several trials have questioned the efficacy of vasodilator therapy in acute heart failure (AHF) in the absence of uncontrolled hypertension. In this article, we provide a unique review of the most valuable four trials that present the role of vasodilator therapy in the management of patients with AHF. These four trials have evaluated the efficacy of different types of vasodilators such as nesiritide, ulatritide, and serelaxin in the setting of AHF. Also, we compared comprehensive vasodilator therapy versus standard therapy to see if there is any effect on mortality and re-hospitalization.


Fully automated dried blood spot sample preparation enables the detection of lower molecular mass peptide and non-peptide doping agents by means of LC-HRMS.
The added value of dried blood spot (DBS) samples complementing the information obtained from commonly routine doping control matrices is continuously increasing in sports drug testing. In this project, a robotic-assisted non-destructive hematocrit measurement from dried blood spots by near-infrared spectroscopy followed by a fully automated sample preparation including strong cation exchange solid-phase extraction and evaporation enabled the detection of 46 lower molecular mass (< 2 kDa) peptide and non-peptide drugs and drug candidates by means of LC-HRMS. The target analytes included, amongst others, agonists of the gonadotropin-releasing hormone receptor, the ghrelin receptor, the human growth hormone receptor, and the antidiuretic hormone receptor. Furthermore, several glycine derivatives of growth hormone-releasing peptides (GHRPs), arguably designed to undermine current anti-doping testing approaches, were implemented to the presented detection method. The initial testing assay was validated according to the World Anti-Doping Agency guidelines with estimated LODs between 0.5 and 20 ng/mL. As a proof of concept, authentic post-administration specimens containing GHRP-2 and GHRP-6 were successfully analyzed. Furthermore, DBS obtained from a sampling device operating with microneedles for blood collection from the upper arm were analyzed and the matrix was cross-validated for selected parameters. The introduction of the hematocrit measurement method can be of great value for doping analysis as it allows for quantitative DBS applications by managing the well-recognized "hematocrit effect." Graphical abstract.


Multifocal epithelial hyperplasia: report of 3 cases.
Multifocal epithelial hyperplasia (MEH) is a rare disorder characterized by multiple painless discrete and soft flattened papules on the oral mucosa. It is caused by human papilloma virus 13 and 32. The frequency of this disease varies widely from one geographic region to another. Generally it is very rare in Asia. Herein we report 3 Iranian cases with oral lesions, which showed clinical and histopathological characteristics of MEH disease. Two of them were siblings and HPV13 was detected in one of the patients.


Non-Random Variability in Functional Composition of Coral Reef Fish Communities along an Environmental Gradient.
Changes in the coral reef complex can affect predator-prey relationships, resource availability and niche utilisation in the associated fish community, which may be reflected in decreased stability of the functional traits present in a community. This is because particular traits may be favoured by a changing environment, or by habitat degradation. Furthermore, other traits can be selected against because degradation can relax the association between fishes and benthic habitat. We characterised six important ecological traits for fish species occurring at seven sites across a disturbed coral reef archipelago in Indonesia, where reefs have been exposed to eutrophication and destructive fishing practices for decades. Functional diversity was assessed using two complementary indices (FRic and RaoQ) and correlated to important environmental factors (live coral cover and rugosity, representing local reef health, and distance from shore, representing a cross-shelf environmental gradient). Indices were examined for both a change in their mean, as well as temporal (short-term; hours) and spatial (cross-shelf) variability, to assess whether fish-habitat association became relaxed along with habitat degradation. Furthermore, variability in individual traits was examined to identify the traits that are most affected by habitat change. Increases in the general reef health indicators, live coral cover and rugosity (correlated with distance from the mainland), were associated with decreases in the variability of functional diversity and with community-level changes in the abundance of several traits (notably home range size, maximum length, microalgae, detritus and small invertebrate feeding and reproductive turnover). A decrease in coral cover increased variability of RaoQ while rugosity and distance both inversely affected variability of FRic; however, averages for these indices did not reveal patterns associated with the environment. These results suggest that increased degradation of coral reefs is associated with increased variability in fish community functional composition resulting from selective impacts on specific traits, thereby affecting the functional response of these communities to increasing perturbations.


Molecular basis of fructose utilization by the wine yeast Saccharomyces cerevisiae: a mutated HXT3 allele enhances fructose fermentation.
Fructose utilization by wine yeasts is critically important for the maintenance of a high fermentation rate at the end of alcoholic fermentation. A Saccharomyces cerevisiae wine yeast able to ferment grape must sugars to dryness was found to have a high fructose utilization capacity. We investigated the molecular basis of this enhanced fructose utilization capacity by studying the properties of several hexose transporter (HXT) genes. We found that this wine yeast harbored a mutated HXT3 allele. A functional analysis of this mutated allele was performed by examining expression in an hxt1-7Delta strain. Expression of the mutated allele alone was found to be sufficient for producing an increase in fructose utilization during fermentation similar to that observed in the commercial wine yeast. This work provides the first demonstration that the pattern of fructose utilization during wine fermentation can be altered by expression of a mutated hexose transporter in a wine yeast. We also found that the glycolytic flux could be increased by overexpression of the mutant transporter gene, with no effect on fructose utilization. Our data demonstrate that the Hxt3 hexose transporter plays a key role in determining the glucose/fructose utilization ratio during fermentation.


Ancient traces of tailless retropseudogenes in therian genomes.
Transposable elements, once described by Barbara McClintock as controlling genetic units, not only occupy the largest part of our genome but are also a prominent moving force of genomic plasticity and innovation. They usually replicate and reintegrate into genomes silently, sometimes causing malfunctions or misregulations, but occasionally millions of years later, a few may evolve into new functional units. Retrotransposons make their way into the genome following reverse transcription of RNA molecules and chromosomal insertion. In therian mammals, long interspersed elements 1 (LINE1s) self-propagate but also coretropose many RNAs, including mRNAs and small RNAs that usually exhibit an oligo(A) tail. The revitalization of specific LINE1 elements in the mammalian lineage about 150 Ma parallels the rise of many other nonautonomous mobilized genomic elements. We previously identified and described hundreds of tRNA-derived retropseudogenes missing characteristic oligo(A) tails consequently termed tailless retropseudogenes. Additional analyses now revealed hundreds of thousands of tailless retropseudogenes derived from nearly all types of RNAs. We extracted 2,402 perfect tailless sequences (with discernible flanking target site duplications) originating from tRNAs, spliceosomal RNAs, 5S rRNAs, 7SK RNAs, mRNAs, and others. Interestingly, all are truncated at one or more defined positions that coincide with internal single-stranded regions. 5S ribosomal and U2 spliceosomal RNAs were analyzed in the context of mammalian phylogeny to discern the origin of the therian LINE1 retropositional system that evolved in our 150-Myr-old ancestor.


The Fine-Tuning Approach for Training Monitoring.
Monitoring is a fundamental part of the training process to guarantee that the programmed training loads are executed by athletes and result in the intended adaptations and enhanced performance. A number of monitoring tools have emerged during the last century in sport. These tools capture different facets (eg, psychophysiological, physical, biomechanical) of acute training bouts and chronic adaptations while presenting specific advantages and limitations. Therefore, there is a need to identify what tools are more efficient in each sport context for better monitoring of training process. We present and discuss the fine-tuning approach for training monitoring, which consists of identifying and combining the best monitoring tools with experts' knowledge in different sport settings, designed to improve (1) the control of actual training loads and (2) understanding of athletes' training adaptations. Instead of using single-tool approaches or merely subjective decision making, the identification of the best combination of monitoring tools to assist experts' decisions in each specific context (ie, triangulation) is necessary to better understand the link between acute and chronic adaptations and their impact on health and performance. Future studies should elaborate on the identification of the best combination of monitoring tools for each specific sport setting. The fine-tuning monitoring approach requires the simultaneous use of several valid and practical tools, instead of a single tool, to improve the effectiveness of monitoring practices when added to experts' knowledge.


[International comparison of 19 clinical guideline programs--a survey of the AGREE Collaboration].
Clinical practice guidelines are being developed in many countries throughout the world to improve quality of patient care. However, the methods used to develop guidelines vary among organisations. Therefore an international task group, the AGREE (Appraisal Guideline Research and Evaluation Europe) Collaboration, started in 1998 to work on the harmonisation and coordination of guideline development. Within this context a survey of national guideline programmes was conducted. Nineteen programmes from nine European countries, Australia, Canada, New Zealand and United States were described using a questionnaire. The items concerned the type of organisation, scope and purpose of the guidelines, people involved, methodology, products, implementation, evaluation, update procedure, and future plans. The results of this survey revealed a growing international consensus on the essential features of good guideline programmes. Most guideline programmes combine an evidence-based approach with informal and/or formal consensus procedures. No significant differences were found between governmental agencies and professional organisations. The budget for developing a single guideline varies from 10,000 to 200,000 EURO.


Nitric oxide synthesis and L-arginine in uremia.
Nitric oxide (NO), an L-arginine derivative, is implicated in neuronal transmission, immune response and vasodilation, and acts as a modulator of platelet function. Recent studies in the experimental model of renal mass reduction (RMR) in rats have generated the hypothesis that abnormalities in the NO synthetic pathway could play a key role in mediating the complex hemodynamic and hemostatic disorders associated with the progression of renal disease. Thus, renal NO generation is lower than normal in rats with RMR 7 days after surgery and progressively worsens with time in close correlation with signs of renal injury. This abnormality is due to a major defect in inducible NO synthase (iNOS) content in the kidney. In the same model, administration of either the NO precursor, L-arginine, or a NO-releasing compound reduces proteinuria, slows renal disease progression, and prolongs survival. In contrast, in the systemic circulation of uremic rats, NO is formed in excessive amounts, possibly caused by higher release from systemic vessels due to the augmented expression of both iNOS and endothelial NOS. Up-regulation of systemic NO synthesis might be a defense mechanism against uremic hypertension. On the other hand, a greater availability of NO to circulating cells may sustain the bleeding tendency, a well-known complication of uremia.


Current health care experiences, medical trust, and COVID-19 vaccination intention and uptake in Black and White Americans.
The COVID-19 pandemic spotlighted Black Americans' inequitable health care experiences. Across two studies, we tested the associations between health care experiences, historical knowledge of medical mistreatment, medical trust, and COVID-19 vaccination intention and uptake in Black and White Americans. We hypothesized that Black Americans' worse current health care experiences (rather than historical knowledge) and lower medical trust would be associated with lower COVID-19 vaccination intention (Study 1) and that feeling less cared for by their personal physician would be associated with Black Americans' lower medical trust (Study 2). In convenience (Study 1, December 2020) and nationally representative samples (Study 2, March-April 2021), participants completed online surveys. In Study 1 (N = 297), Black (relative to White) Americans reported lower vaccination intention (Cohen's d = -.55, p < .001) and lower medical trust (Cohen's d = -.72, p < .001). Additionally, less positive health care experiences among Black participants (Cohen's d = -.33, p = .022) were associated with less medical trust and in turn lower vaccination intention. Tuskegee Study knowledge was not associated with vaccination intention or medical trust. Study 2 (N = 12,757) data revealed no statistically significant racial differences in COVID-19 vaccination receipt or intention. Black (relative to White) Americans reported feeling less cared for by their personal physician (Cohen's d = -.44, p < .001), which was associated with lower medical trust (Cohen's d = -.51, p < .001). Findings highlight factors that may contribute to Black Americans' vaccination hesitancy and medical trust. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Shared social environment and psychiatric disorder: a multilevel analysis of individual and ecological effects.
We examined associations, in terms of relative and population-attributable risks, between shared social environment at the neighbourhood level and (1) treated incidence of non-psychotic, non-organic disorders, and (2) subsequent level of service consumption. The multilevel analysis used linked records of all individuals in contact for the first time with any catchment area mental health service for non-psychotic, non-organic disorder over various specified time periods between 1981 and 1995. Socioeconomic indicators of 36 neighbourhoods in the city of Maastricht yielded a multivariately defined neighbourhood deprivation score. There were significant linear trends in the association between level of deprivation and treated incidence, especially in the population under 35 years of age (adjusted rate ratio for linear trend 1.17, 95% confident interval 1.11-1.23), who constituted around half of the patient population. The fraction of the incidence of psychiatric disorder attributable to deprivation was 17.8%. Multilevel analyses of rates of a second cohort, with cases divided according to level of service use over a standardised follow-up of 5 years after first contact with psychiatric services, revealed that the effect of deprivation scores on rates declined with intensity of out-patient service use, but increased with level of in-patient use. Up to 50% of in-patient episodes in this group could be attributed to neighbourhood level of deprivation. The increase in risk conferred by neighbourhood deprivation remained after adjustment for the individual-level equivalent. The findings therefore suggest that elements in the shared social environment influence both incidence and severity of non-psychotic, non-organic disorders, over and above any individual-level effect.


Prevalence and distribution pattern of AmpC β-lactamases in ESBL producing clinical isolates of Klebsiella spp. in parts of Assam, India.
The production of extended-spectrum β-lactamases (ESBLs) and AmpC β-lactamases is the most common explanation of multidrug resistance in clinical isolates of Klebsiella spp. In the present study, a total of 160 isolates of Klebsiella spp. were procured from the DBT-NER project with ethical clearance no. DU/Dib/ECBHR(Human)/2021-22/02). These were collected from various health settings of Assam and identified as drug-resistant. The isolates were screened for antibiotic susceptibility and phenotypic tests were performed on multidrug resistant isolates to confirm ESBL and AmpC β-lactamases production. The distribution pattern of ESBL and AmpC β-lactamase genotype was investigated by polymerase chain reaction (PCR). The results showed that among 107 multidrug-resistant (MDR) isolates of Klebsiella spp., 67.28% of isolates were ESBL producers and 56.07% were potential AmpC producers. The PCR results revealed that blaCTX-M was the most prevalent ESBL genotype. Among the ESBL producers, 11.11% of isolates showed co-occurrence with plasmid-mediated AmpC β lactamases genotype which indicated the high prevalence of ESBL and AmpC co-producers in K. pneumoniae and K. oxytoca, suggesting the possibility of serious public health concerns. Therefore, it is crucial to regularly monitor the spread of multidrug resistance among clinical isolates.


[Possibilities of study of the main cytokines of the immune system in patients with osteogenic sarcoma].
The aim of the study was to investigate the spontaneous production of the major cytokines of the immune system in patients with osteogenic sarcoma. There were studied serum concentrations of pro-inflammatory and anti-inflammatory cytokines (IL-1beta, TNF-alpha, IL-2, IL-6 and IL-10) as well as the presence of vascular endothelial growth factor (VEGF). It was revealed a misbalance in the presence of the main cytokines of the immune system in patients with osteosarcoma appeared by a significant increase in both pro-and anti-inflammatory cytokines. There was found an increase of the most aggressive tissue cytokines (IL-6 and VEGF), which played an important role in the formation and progression of the disease. Identified immunological characteristics can be an important predictor in determining the future tactics of treatment of patients with osteosarcomas that needs further study.


[Use of ocular drugs in pregnancy].
The information available on the safety of medicines in pregnant women is limited and must be suitably channeled. Medication that is applied topically or as eye drops can present relevant systemic absorption and cross the placenta barrier or enter maternal milk. We have reviewed ophthalmic medicines according to the fetal risk categories proposed by the classification of the Food and Drug Administration (FDA). We evaluate the medicines of choice in the most frequent ophthalmic pathologies, as well as the medicines that must be avoided.


Stackebrandtia endophytica sp. nov., an actinobacterium isolated from Tripterygium wilfordii.
A novel endophytic actinobacterium, designated strain YIM 64602T, was isolated from healthy stems of Tripterygium wilfordii. It grew at 15-40 °C, pH 6.0-9.0 and in the presence of 0-3 % (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequence showed that strain YIM 64602T belongs to the genus Stackebrandtia. Whole-cell hydrolysates of strain YIM 64602T contained the amino acid meso-diaminopimelic acid with the sugars mannose, rhamnose and glucose, and a trace of ribose. The major polar lipids were diphosphatidylglycerol, phosphatidylmethylethanolamine and phosphatidylethanolamine. MK-10(H6), MK-10(H4) and MK-11(H4) were the predominant components in the quinone system. The fatty-acid pattern was mainly composed of the saturated branched-chain acids iso-C16 : 0, anteiso-C17 : 0, iso-C15 : 0 and iso-C17 : 0. The DNA G+C content was 72.4 mol%. 16S rRNA gene sequence analysis showed the highest pairwise sequence identity (96.0-98.5 %) with the members of the genus Stackebrandtia. Strain YIM 64602T displayed a DNA-DNA relatedness of 43.9±0.4 % with the type strain Stackebrandtia albiflava YIM 45751T. Based on evidence from this polyphasic study, strain YIM 64602T ( = BCRC 16954T = DSM 45928T) is considered to represent a novel species of the genus Stackebrandtia, for which the name Stackebrandtia endophytica is proposed.


[Phonocardiogram characteristics in different forms of pulmonary hypertension].
To study the peculiarities of phonocardiogrammes in pulmonary hypertension of different genesis a comparison was conducted between the phonocardiographic data and those of heart catheterization and zonotomography. The study was conducted in 49 normal individuals and 177 patients with various lesions accompanied by an elevated pressure in the pulmonary vessels. It was found that no phonocardiographic peculiarities inherent in pulmonary hypertension are typical for any of the examined entities. The common features of pulmonary hypertension are: 1) growing amplitude of the pulmonary component of the II sound, increasing parallel to the degree of hypertension (with the exception of patients with chronic non-specific pulmonary lesions in whom the pulmonary component of the II sound does not grow, in absolute figures); 2) reduction of the coefficient II/IIIP of the II sound components, also developing parallel to the growth of hypertension; 3) detection of the ejection sound on the phonocardiogramme, as well as of a systolic murmur of the ejection and of a diastolic murmur; 4) increasing indices of the IV sound recordings in primary vascular hypertension. Not infrequently the amplitude of the Isound is also increased in cases of pulmonary hypertension, although its direct relationship with pulmonary hypertension is hardly possible.


Feasibility of Using a Single Heart Rate-Based Measure for Real-time Feedback in a Voluntary Deep Breathing App for Children: Data Collection and Algorithm Development.
Deep diaphragmatic breathing, also called belly breathing, is a popular behavioral intervention that helps children cope with anxiety, stress, and their experience of pain. Combining physiological monitoring with accessible mobile technology can motivate children to comply with this intervention through biofeedback and gaming. These innovative technologies have the potential to improve patient experience and compliance with strategies that reduce anxiety, change the experience of pain, and enhance self-regulation during distressing medical procedures. The aim of this paper was to describe a simple biofeedback method for quantifying breathing compliance in a mobile smartphone app. A smartphone app was developed that combined pulse oximetry with an animated protocol for paced deep breathing. We collected photoplethysmogram data during spontaneous and subsequently paced deep breathing in children. Two measures, synchronized respiratory sinus arrhythmia (RSAsync) and the corresponding relative synchronized inspiration/expiration heart rate ratio (HR-I:Esync), were extracted from the photoplethysmogram. Data collected from 80 children aged 5-17 years showed a positive RSAsync effect in all participants during paced deep breathing, with a median (IQR; range) HR-I:Esync ratio of 1.26 (1.16-1.35; 1.01-1.60) during paced deep breathing compared to 0.98 (0.96-1.02; 0.82-1.18) during spontaneous breathing (median difference 0.25, 95% CI 0.23-0.30; P<.001). The measured HR-I:Esync values appeared to be independent of age. An HR-I:Esync level of 1.1 was identified as an age-independent threshold for programming the breathing pattern for optimal compliance in biofeedback.


Mobilization of peripheral blood stem cells in CLL patients after front-line fludarabine treatment.
Autologous peripheral blood stem cell transplantation is performed in an increasing number of chronic lymphocytic leukaemia (CLL) patients who are in the first remission following fludarabine treatment. There are contradictory data about the adverse impact of fludarabine on stem cell harvest. We analysed retrospectively mobilization results in 56 poor-risk CLL patients (median age: 56 years) who underwent first-line treatment with fludarabine and cyclophosphamide. The mobilization, consisting of cyclophosphamide 3 g/m(2) and granulocyte colony-stimulating factor (G-CSF) 10 microg/kg per day, was performed with a median of 77 days following the last fludarabine course. The target yield was >or=2.0x10(6) CD34+ cells/kg. The procedure was successful in 23 (41%) patients. A median of 3.3x10(6) CD34+ cells/kg was collected per patient. The successful mobilization was associated with a longer interval from the last chemotherapy (>2 months). The mobilization result was not influenced by the number of fludarabine cycles. No correlation was found in other parameters such as disease stage at diagnosis, disease status at stimulation or age. The poorly mobilized patients had significantly lower prestimulation blood counts (platelets, WBC and haemoglobin). Our data show that fludarabine does not generally prevent the stem cell mobilization; nevertheless, mechanisms related to the impact of fludarabine on stem cell harvest must be further investigated.


Factors Associated with Nursing Home Admission after Stroke in Older Women.
We examined the social and economic factors associated with nursing home (NH) admission in older women, overall and poststroke. The Women's Health Initiative (WHI) included women aged 50-79 years at enrollment (1993-1998). In the WHI Extension Study (2005-2010), participants annually reported any NH admission in the preceding year. Separate multivariate logistic regression models analyzed social and economic factors associated with long-term NH admission, defined as an admission on 2 or more questionnaires, overall and poststroke. Of 103,237 participants, 8904 (8.6%) reported NH admission (2005-2010); 534 of 2225 (24.0%) women with incident stroke reported poststroke NH admission. Decreased likelihoods of NH admission overall were demonstrated for Asian, Black, and Hispanic women (versus whites, adjusted odds ratio [aOR] = .35-.44, P < .001) and women with higher income (aOR = .75, 95% confidence interval [CI] = .63-.90), whereas increased likelihoods of NH admission overall were seen for women with lower social support (aOR = 1.34, 95% CI = 1.16-1.54) and with incident stroke (aOR = 2.59, 95% CI = 2.15-3.12). Increased odds of NH admission after stroke were demonstrated for women with moderate disability after stroke (aOR = 2.76, 95% CI = 1.73-4.42). Further adjustment for stroke severity eliminated the association found for race/ethnicity, income, and social support. The level of care needed after a disabling stroke may overwhelm social and economic structures in place that might otherwise enable avoidance of NH admission. We need to identify ways to provide care consistent with patients' preferences, even after a disabling stroke.


Sequencing Heparan Sulfate Using HILIC LC-NETD-MS/MS.
Heparan sulfate (HS) mediates a wide range of protein binding interactions key to normal and pathological physiology. Though liquid chromatography coupled with mass spectrometry (LC-MS) based disaccharide composition analysis is able to profile changes in HS composition, the heterogeneity of modifications and the labile sulfate group present major challenges for liquid chromatography tandem mass spectrometry (LC-MS/MS) sequencing of the HS oligosaccharides that represent protein binding determinants. Here, we report online LC-MS/MS sequencing of HS oligosaccharides using hydrophilic interaction liquid chromatography (HILIC) and negative electron transfer dissociation (NETD). A series of synthetic HS oligosaccharides varying in chain length (tetramers and hexamers), number of sulfate groups (3-7), sulfate patterns (sulfate positional isomers), and uronic acid epimerization (epimers) were separated and sequenced. The LC elution order of isomeric compounds was associated with their fine structure. The application of an online cation exchange device (ion suppressor) enhanced the precursor charge states, and the subsequent NETD produced abundant glycosidic fragments, allowing the characterization of both lowly sulfated and highly sulfated HS oligosaccharides. Furthermore, the diagnostic cross-ring ions differentiated the 6-O sulfation and 3-O sulfation, allowing unambiguous structural assignment. Collectively, this LC-NETD-MS/MS method is a powerful tool for sequencing of heterogeneous HS mixtures and is applicable for the differentiation of both isomers and epimers, for the characterization of saccharide mixtures with a varying extent of sulfation and even for the determination of both predominant and rare modification motifs. Thus, LC-NETD-MS/MS has great potential for further application to biological studies.


Screening for malnutrition in oral cavity cancer patients prior to treatment: A cross-sectional study.
This study was conducted to assess the frequency of pre-operative malnourishment in patients being treated for oral cavity squamous cell carcinoma. A retrospective chart review was carried out at the Aga Khan University Hospital, Karachi, on 62 patients. Patients were screened pre-operatively through a standard nutritional assessment tool at the time of admission to assess for malnutrition. Mean age of presentation was 48.34±13.11 years, mean height was 165 ± 8.62cm, weight 66.09±14.98 kg and BMI of 24.09±4.84. Males were 82.3% and 17.7% were females. At the time of admission, a significant number or patients, 12 (19.4%) were prone to malnourishment, while 3 (4.8%) patients were malnourished: Assessment was done by using a standardised nutritional assessment tool.


Disorganization of the retinal inner layers as a predictor of visual acuity in eyes with center-involved diabetic macular edema.
Biomarkers that predict future visual acuity (VA) in eyes with baseline diabetic macular edema (DME) would substantively improve risk assessment, management decisions, and selection of eyes for clinical studies targeting DME. To determine whether baseline or early change in the novel spectral domain-optical coherence tomography (SD-OCT) parameter disorganization of the retinal inner layers (DRIL) is predictive of VA in eyes with center-involved DME. At a tertiary care referral center for diabetic eye disease, a retrospective, longitudinal cohort study obtained demographics, VA, and SD-OCT images from baseline, 4-month, and 8-month visits in 96 participants (120 eyes) with diabetes mellitus and baseline center-involved DME (SD-OCT central subfield thickness, ≥ 320 µm for men and ≥ 305 µm for women). Exclusion criteria included substantial media opacity, cataract surgery within 6 months, and nondiabetic retinal pathology affecting VA. On SD-OCT, the 1-mm-wide retinal area centered on the fovea was evaluated by masked graders for DRIL extent, cysts, hyperreflective foci, microaneurysms, cone outer segment tip visibility, and external limiting membrane or photoreceptor disruption and reflectivity. Visual acuity and SD-OCT-derived retinal morphology. Greater DRIL extent at baseline correlated with worse baseline VA (point estimate, 0.04; 95% CI, 0.02-0.05 per 100 µm; P < .001). An increase in DRIL during 4 months was associated with VA worsening at 8 months (point estimate, 0.03; 95% CI, 0.02-0.05 per 100 µm; P < .001). A multivariate model that included a 4-month change in VA, DRIL, and external limiting membrane disruption was predictive of an 8-month VA change (r = 0.80). Each approximately 300-µm DRIL increase during 4 months predicted a 1-line, 8-month VA decline. When DRIL increased at least 250 µm at 4 months, no eyes had VA improvement of at least 1 line at 8 months. When DRIL decreased at least 250 µm at 4 months, no eyes had VA decline of at least 1 line at 8 months, and 77.7% had VA improvement of at least 1 line. Disorganization of the retinal inner layers in the 1-mm foveal area is associated with VA, and change in DRIL predicts future change in VA. Early change in DRIL prospectively identifies eyes with a high likelihood of subsequent VA improvement or decline. Therefore, DRIL warrants further study as a robust, readily obtained, and noninvasive biomarker of future VA response in eyes with DME.


Interactive Effects of HIV Infection and Cannabis Use on Insula Subregion Functional Connectivity.
Chronic inflammation in the central nervous system is one mechanism through which human immunodeficiency virus (HIV) may lead to progressive cognitive decline. Given cannabis's (CB's) anti-inflammatory properties, use prevalence among people living with HIV (PLWH), and evidence implicating the insula in both, we examined independent and interactive effects of HIV and CB on insular circuitry, cognition, and immune function. We assessed resting-state functional connectivity (rsFC) of three insula subregions among 106 participants across four groups (co-occurring: HIV+/CB+; HIV-only: HIV+/CB-; CB-only: HIV-/CB+; controls: HIV-/CB-). Participants completed a neurocognitive battery assessing functioning across multiple domains and self-reported somatic complaints. Blood samples quantified immune function (T-cell counts) and inflammation (tumor necrosis factor alpha [TNF-α]). We observed interactive HIV × CB effects on rsFC strength between two anterior insula (aI) subregions and sensorimotor cortices such that, CB appeared to normalize altered rsFC among non-using PLWH. Specifically, compared to controls, HIV-only and CB-only groups displayed decreased dorsal anterior insula (DI) - postcentral gyrus rsFC and increased ventral anterior insula (VI) - supplementary motor area rsFC, whereas the co-occurring group displayed DI and VI rsFC more akin to that of controls. Altered DI - postcentral rsFC correlated with decreased processing speed and somatic complaints, but did not significantly correlate with inflammation (TNF-α). These outcomes implicate insula - sensorimotor neurocircuitries in HIV and CB and are consistent with prior work suggesting that CB use may normalize insula functioning among PLWH.


High Flow Nasal Cannula Therapy in Children with Acute Respiratory Insufficiency in the Pediatric Intensive Care Unit of a Resource-limited Country: A Preliminary Experience.
A retrospective study was performed in children (aged one month - 16 years) receiving HFNC to determine the frequency, efficacy and adverse effects of high flow nasal cannula (HFNC) therapy in the pediatric intensive care unit (PICU), from January to December 2017. Treatment failure was defined as clinical deterioration on HFNC therapy such that mechanical ventilation (MV) was required. Clinical parameters before and after HFNC were assessed using repeated measures analysis of variance. A total of 120 patients received HFNC therapy (21% of total admissions). Primary diagnosis were respiratory disease (50%), central nervous system diseases (14.2%), sepsis (10.8%), and postoperative care (10%). Mean duration of HFNC was 27.5 ±19.7 hours and mean PICU length of stay was 6 ± 6 days. Pneumothorax developed in four patients. MV was required in 28 patients, and subsequently, 15 deaths occurred in that group. HFNC is a frequently used, safe and effective therapy for children requiring respiratory support in PICU. Key Words: Respiratory insufficiency, Non-invasive ventilation, Paediatric intensive care unit.


Evaluation of the impact of single-walled carbon nanotubes in an activated sludge wastewater reactor.
This paper evaluated the impact of single-walled carbon nanotubes (SWCNTs) on the performance and activated sludge properties in an activated sludge wastewater reactor. The reactor was shock loaded with 270 mg/L of 90% purified SWCNTs after the reactor reached quasi-steady state and the reactor was monitored for 18 days after the shock loading. Various experimental parameters were measured and compared. Overall the addition of SWCNTs did not negatively impact the performance of the activated sludge reactor; on the other hand, SWCNTs improved sludge settleability and sludge dewaterability. The cake solids of the sludge were increased and the activated sludge flocs became less negatively charged. The positive impacts were more significant in Phase II (after running the reactor for one solids retention time, SRT) than that in Phase III (after running for additional 1.5 SRT).


Evaluating 'Enhancing Pragmatic Language skills for Young children with Social communication impairments' (E-PLAYS): a feasibility cluster-randomised controlled trial.
This article reports the results from a feasibility study of an intervention ('E-PLAYS') aimed at supporting children who experience difficulties with social communication. E-PLAYS is based around a dyadic computer game, which aims to develop collaborative and communication skills. A pilot study found that when E-PLAYS was delivered by researchers, improvements on communication test scores and on collaborative behaviours were observed. The aim of this study was to ascertain the feasibility of running a full-scale trial to test the effectiveness of E-PLAYS in a National Health Service (NHS) setting with delivery by speech and language therapists and teaching assistants. The study was a two-arm feasibility cluster-randomised controlled trial of the E-PLAYS intervention with a treatment as usual control arm. Data relating to recruitment and retention, treatment fidelity, acceptability to participants, suitability of outcomes and feasibility of collecting health economic measures and of determining cost-effectiveness were collected. Speech and language therapists selected suitable children (ages 4-7 years old) from their caseload. E-PLAYS intervention (experimental group) was then delivered by teaching assistants overseen by speech and language therapists. The control group received usual care. Assessments included blinded language measures and observations, non-blinded teacher-reported measures of peer relations and classroom behaviour and non-blinded parent-reported use of health and education resources and quality of life. Planned recruitment was for 70 children, in the event, 50 children were recruited which was sufficient for feasibility purposes. E-PLAYS was very highly rated by children, teaching assistants and speech and language therapists and treatment fidelity did not pose any issues. We were able to collect health economic data which suggests that E-PLAYS would be a low-cost intervention. Based on recruitment, retention and adherence rates and our outcome measures, a full-scale randomised controlled trial estimated appears feasible and warranted to assess the effectiveness of E-PLAYS for use by the NHS and schools. ISRCTN 14818949 (retrospectively registered).


Enriched domain detector: a program for detection of wide genomic enrichment domains robust against local variations.
Nuclear lamins contact the genome at the nuclear periphery through large domains and are involved in chromatin organization. Among broad peak calling algorithms available to date, none are suited for mapping lamin-genome interactions genome wide. We disclose a novel algorithm, enriched domain detector (EDD), for analysis of broad enrichment domains from chromatin immunoprecipitation (ChIP)-seq data. EDD enables discovery of genomic domains interacting with broadly distributed proteins, such as A- and B-type lamins affinity isolated by ChIP. The advantages of EDD over existing broad peak callers are sensitivity to domain width rather than enrichment strength at a particular site, and robustness against local variations.


Chemical speciation of trace metals in seawater: a review.
The recent development of the chemical speciation of trace metals in seawater is described. The speciation studies reveal that metal ion complexation is one of the most important processes in seawater; especially, most bioactive trace metals, such as Fe(III) and Cu, exist as complexes with ligands in dissolved organic matter. The organic ligands in seawater are characterized with metal ions selected by the HSAB concept. A strong organic ligand, which originates from marine microorganisms, is classified as a hard base including carboxylates. The free organic ligand concentrations in seawater are buffered by complexation with excess amounts of Ca and Mg in seawater. The chemical equilibrium model suggested that the concentrations of bioactive free metal ions are at an optimal level to activities of marine microorganisms. For chemical speciation, it is important to have a better understanding of the ecological roles of trace metals in seawater.


Effects of activated protein C on the mesenteric microcirculation and cytokine release during experimental endotoxemia.
Activated protein C (APC) is the first anti-inflammatory drug to be approved for the treatment of severe sepsis. However, the underlying mechanisms are not completely elucidated. Therefore, the aim of our study was to evaluate the effects of APC on the microcirculation (mesenteric leukocyte-endothelial interaction, plasma extravasation) using intravital microscopy (IVM) and on cytokine release during experimental endotoxemia in rats. We divided forty, male, Lewis rats into four groups (n = 10 per group): Controls, LPS (15 mg x kg(-1) lipopolysaccharide iv), APC (2 mg x kg(-1) APC iv), and LPS+APC. We determined mesenteric leukocyte-endothelial interactions and plasma extravasation at zero, one and two hours following administration of LPS and APC by IVM. Plasma levels of tumour necrosis factor-alpha, IL-1beta, interleukin (IL)-6, and IL-10 were measured at zero and at two hours. Leukocyte adherence (-74%) and plasma extravasation (-28%) during endotoxemia were diminished significantly following APC treatment, compared to untreated LPS animals (P = 0.0001 and P = 0.0004, respectively). Interleukin-1ss release was also significantly reduced by APC treatment (2567.4 +/- 320.9 pg x mL(-1) in the LPS group vs 1626.1 +/- 427.2 pg x mL(-1) in the LPS+APC group; P = 0.001). These rodent experiments showed that APC treatment significantly attenuated deterioration of the mesenteric microcirculation and systemic IL-1ss release caused by endotoxin challenge. Because of the crucial role of the microcirculation in ongoing sepsis pathogenesis and multiple organ dysfunction syndrome, these effects may be of clinical importance.


Psychiatric problems in intensive care. Five patients with acute confusional states and depression.
Five case histories are presented of patients with multiple trauma or severe infection, who developed psychiatric symptoms after an initially favourable response to intensive therapy. Alterations in the level of consciousness and behavioural pattern were observed, associated with the presence of acute depression, possibly primarily endogenous in origin. Following intravenous Clomipramine administration, considerable improvement was noted in all five patients, regarding both the depressive state and the clouding of consciousness. The importance of recognising psychiatric disorder in severly ill patients in an intensive therapy environment is stressed.


Cell membrane sialoglycopeptides of corticoid-sensitive and -resistant lymphosarcoma P1798.
Cells of corticoid-sensitive (CS) and corticoid-resistant (CR) lymphosarcoma P1798 were labeled in vivo with either [14C]- or [3H]fucose before and after treatment with 9-alpha-fluoroprednisolone (9-FP). Labeled glycopeptides, derived from isolated, Pronase-digested cell membranes of both tumors were separated by gel filtration on Bio-Gel P-10 by a double-label technique. Elution profiles of CS and CR fractions showed significant differences in early eluting material. Desialylation of glycopeptides by neuraminidase lowered the molecular weight of both CS and CR fractions, and altered 3H:14C ratios indicated that CS and CR sialoglycopeptides are different. 9-FP treatment for 7 hr increased the density of isolated P1798-CS and -CR cell membranes. All CS and CR glycopeptides from treated tumors eluted faster than did those of untreated preparations. Both CS and CR sialoglycopeptides were altered, although differences in CS and CR profiles persisted. Histochemical investigations indicated that negative charge, present on surfaces of untreated CS cells, is lost between 6 and 8 hr after exposure in vivo to 9-FP. CR cells had no or few anionic sites on their surfaces before and after steroid administration. We demonstrated that glycopeptides of both CS and CR tumors contain sialic acid, although only CS cells carry a surface-exposed negative charge that is lost after 9-FP treatment. Glucocorticoids alter both P1798-CS and -CR sialoglycopeptides, but the consistent differences between their chromatographic patterns suggest that steroid-induced changes in cell membranes of the two tumors are not identical. Cell death or survival of glucocorticoid-treated P1798 cells may, therefore, be influenced by specific structural characteristics involving cell surface sialoglycoproteins.


Matrix metalloproteinase-9 promoter gene polymorphism (-1562C>T) in nasal polyposis.
Expression of matrix metalloproteinase (MMP)-9 increases in nasal polyp tissues. However, the impact of MMP-9 genotypes on the development of nasal polyposis (NP) is unknown. The aim of this study was to examine a potential association of MMP-9 promoter gene polymorphism with the development of NP. A prospective and case-control study was performed on 93 patients with NP and 115 controls without sinonasal disease. Genotypes of MMP-9 (-1562C>T) were identified by restriction fragment length polymorphism analyses after polymerase chain reaction. The frequency of -1562CT genotype of MMP-9 was significantly high in NP patients with aspirin-induced asthma (p = 0.014). Distribution of T allele was significantly high in NP patients with aspirin-induced asthma (p = 0.013). MMP-9 genotypes were not associated with gender or the presence of atopy. In this study, MMP-9 -1562CT genotype was associated with susceptibility to NP in aspirin-induced asthmatic patients. Because this report is a population-based study, further research should be performed on larger study subjects to reveal the precise role of MMP-9 promoter gene polymorphism in the development of NP.


Hematological Effects, Serum, and Pulmonary Cytokine Profiles in a Melanoma Mouse Model Treated with GK1.
In a previous study, we demonstrated the therapeutic efficacy of a subcutaneous injection of GK1 peptide in a melanoma mouse model, effectively increasing the mean survival time by 42.58%, delaying tumor growth, and increasing intratumoral necrosis compared with the control. As a first approach to investigate the anti-melanoma effect of GK1, this study was carried out to determine the hematological effects along with both serum and lung cytokine profiles in a melanoma lung metastatic model. Thirteen C57BL6 female mice were transfected in the lateral tail vein with 2×10(5) B16-F0 melanoma cells. After 7 days, mice were separated in two different groups and treatments were initiated (day 0): The GK1-treated group (seven mice) were injected every 5 days intravenously with GK1 (10 μg) in the lateral tail vein, and the control group (six mice) were injected every 5 days with intravenous saline solution. Blood samples were collected every 5 days from day 0; tumor samples were obtained for cytokine measurements on the day of sacrifice. In the peripheral blood, mice treated with GK1 presented a statistically significant decrease in IFN-γ (p<0.05), and lymphocytes tended to be lower compared with the control mice (p=0.06). Lung metastatic analysis demonstrated a significant increase in IFN-γ and IL-12p70 (p<0.05); a significant decrease in IL-17, IL-4, IL-22, IL-23, and IL-12p40 (p<0.05); and a marginal decrease in IL-1β (p=0.07) compared with the control. Our results suggest that an intratumoral increase of cytokines with antitumor activity along with an intratumoral decrease of cytokines with protumor activity could explain, in part, the anti-melanoma effects of GK1 in a lung metastatic melanoma mouse model. Further studies must be performed to elucidate the precise mechanisms of action for GK1 peptide against melanoma, and their eventual application in humans.


Sequence-only evolutionary and predicted structural features for the prediction of stability changes in protein mutants.
Even a single amino acid substitution in a protein sequence may result in significant changes in protein stability, structure, and therefore in protein function as well. In the post-genomic era, computational methods for predicting stability changes from only the sequence of a protein are of importance. While evolutionary relationships of protein mutations can be extracted from large protein databases holding millions of protein sequences, relevant evolutionary features for the prediction of stability changes have not been proposed. Also, the use of predicted structural features in situations when a protein structure is not available has not been explored. We proposed a number of evolutionary and predicted structural features for the prediction of stability changes and analysed which of them capture the determinants of protein stability the best. We trained and evaluated our machine learning method on a non-redundant data set of experimentally measured stability changes. When only the direction of the stability change was predicted, we found that the best performance improvement can be achieved by the combination of the evolutionary features mutation likelihood and SIFT score in conjunction with the predicted structural feature secondary structure. The same two evolutionary features in the combination with the predicted structural feature accessible surface area achieved the lowest error when the prediction of actual values of stability changes was assessed. Compared to similar studies, our method achieved improvements in prediction performance. Although the strongest feature for the prediction of stability changes appears to be the vector of amino acid identities in the sequential neighbourhood of the mutation, the most relevant combination of evolutionary and predicted structural features further improves prediction performance. Even the predicted structural features, which did not perform well on their own, turn out to be beneficial when appropriately combined with evolutionary features. We conclude that a high prediction accuracy can be achieved knowing only the sequence of a protein when the right combination of both structural and evolutionary features is used.


Who needs a permanent pacemaker after transcatheter aortic valve implantation?
We aimed to identify predictive factors for pacemaker requirement and determine the rate of pacemaker dependency in a single centre patient group. Out of 116 patients, who underwent transcatheter aortic valve implantation at our institution. Absence of atrial fibrillation at time of procedure, pulmonary hypertension, obesity and severity of aortic valve stenosis were predictive for the need of permanent pacemaker implantation after transcatheter aortic valve implantation. Only persisting periprocedural and early-onset complete heart block were permanent and resulted in patients' pacemaker dependency. Definite predictors of persistence of conduction impairment are yet to be identified. We can predict only pacemaker dependency, but the real need of pacing in our risky patients with softer indications for permanent pacemaker after transcatheter aortic valve implantation cannot be clearly identified, essential in context of improving quality of their lives in avoiding symptomatic bradycardia, which can be intermittent, especially in such a group of elderly patients often with fragile and degenerate conduction system (Tab. 5, Ref. 34).


Survival outcomes 1 year after reperfusion therapy with either alteplase or reteplase for acute myocardial infarction: results from the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) III Trial.
New recombinant plasminogen activators have been developed to simulate the fibrinolytic action of the physiological serine protease tissue plasminogen activator (alteplase, t-PA), and have prolonged half-life features permitting bolus administration. One such activator, reteplase (r-PA), was compared with t-PA in the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO)-III Trial. At 1-year follow-up, survival status was ascertained in 97.4% of the 15 059 patients enrolled in the GUSTO-III trial. At 1 year, the mortality rate for the t-PA-assigned group was 11.06%, and for r-PA it was 11.20% (P:=0. 77). The absolute mortality difference of 0.14% has 95% CIs of -1. 21% to 0.93%. There were no significant differences in outcome by intention-to-treat for the 2 different plasminogen activators in the prespecified groups (age, infarct location, time-to-treatment). The absolute difference in mortality rates between t-PA and r-PA progressively narrowed over the predetermined observation times after random assignment; it was 0.31% at 24 hours, 0.26% at 7 days, 0.23% at 30 days, and 0.14% at 1 year. Of note, mortality rate in the trial between 30 days and 1 year in 13 883 patients was 4.02% and did not differ between the treatment groups. However, this mortality rate was substantially greater than in GUSTO-I, in which mortality rate for t-PA versus streptokinase between 30 days and 1-year was 2.97% (heart rate 1.36, 95% CI 1.23, 1.50, P:<0.001). The r-PA and t-PA strategies yielded similar survival outcomes after 30 days in this trial. The increase in mortality rate during extended follow-up compared with previous trials may reflect higher-risk patients and highlights the need for improved secondary prevention strategies.


A cost analysis of producing vaccines in developing countries.
Developing country vaccine manufacturers (DCVMs) supply over half of the vaccines used in developing country immunisation programs. Decisions by developing countries to establish vaccine manufacturing should be based on economic viability, however reliable assessments of vaccine production costs are lacking. This study aimed to quantify the cost of establishing vaccine manufacturing facilities and producing vaccines in developing countries. This study estimates vaccine production costs in developing countries based on twelve vaccines produced by eight DCVMs. The results were based on estimates of the capital and operating costs required to establish vaccine manufacturing facilities under three hypothetical scenarios of production scale and scope. Cost patterns were then compared to vaccine prices paid by countries in both industrialized and developing country markets. The cost of producing vaccines in developing countries was estimated to be on average US$ 2.18 per dose, ranging between US$ 0.98 and US$ 4.85 for different vaccine types and formulations. Vaccine costs-per-dose decrease as production scale and scope increase. Cost-per-dose is mainly driven by fixed costs, but at a scale of production over 20 million doses per year it becomes driven by variable costs. Under the three hypothetical scenarios used, costs-per-dose of vaccines produced by developing countries were around 47% lower than vaccine prices in developing-country markets and 84% lower than prices in industrialized-country markets. This study has found that local production of vaccines in developing countries exhibits both economies of scale and economies of scope. The lower costs relative to prices suggests that a producer surplus and potential profits may be attainable in both developing and developed country markets, supporting sustainable production.


HPV-related oropharyngeal carcinoma with Overt Level II and/or III metastases at presentation: The risk of subclinical disease in ipsilateral levels IB, IV and V.
To assess the risk of subclinical neck nodal involvement of levels IB, IV and V for early T-stage, node positive, human papilloma virus (HPV)-related oropharyngeal carcinoma. We retrospectively identified the patients with clinically positive and un-violated neck that underwent upfront ipsilateral neck dissection for HPV-related oropharyngeal cancer between 1998 and 2010. From the pathology report we extracted the prevalence rate of involvement of each selected level and then estimated the risk that a level that does not contain any node larger than 10 mm at computed tomography (CT) harbors subclinical disease. Predictors of involvement were investigated as well. Ninety-one patients were analyzed. The risk of subclinical disease in both levels IB and V is < 5%, while it is 6.5% (95% CI 3.1-9.9%) for level IV. Level IB subclinical involvement slightly exceeds 5% when 2 + ipsilateral levels besides IB are involved. The risk of occult disease in level IV tends to be < 5% when level III is not involved. These data support the exclusion from the elective nodal volume of level V and level IB but when 2 + other levels are involved. Level IV might also be spared when level III is negative. Clinical implementation within a prospective study is justified.


The Role of Succinate in the Regulation of Intestinal Inflammation.
Succinate is a metabolic intermediate of the tricarboxylic acid (TCA) cycle within host cells. Succinate is also produced in large amounts during bacterial fermentation of dietary fiber. Elevated succinate levels within the gut lumen have been reported in association with microbiome disturbances (dysbiosis), as well as in patients with inflammatory bowel disease (IBD) and animal models of intestinal inflammation. Recent studies indicate that succinate can activate immune cells via its specific surface receptor, succinate receptor 1(SUCNR1), and enhance inflammation. However, the role of succinate in inflammatory processes within the gut mucosal immune system is unclear. This review includes current literature on the association of succinate with intestinal inflammation and the potential role of succinate⁻SUCNR1 signaling in gut immune functions.


The requirement for calcification differs between ecologically important coccolithophore species.
Coccolithophores are globally distributed unicellular marine algae that are characterized by their covering of calcite coccoliths. Calcification by coccolithophores contributes significantly to global biogeochemical cycles. However, the physiological requirement for calcification remains poorly understood as non-calcifying strains of some commonly used model species, such as Emiliania huxleyi, grow normally in laboratory culture. To determine whether the requirement for calcification differs between coccolithophore species, we utilized multiple independent methodologies to disrupt calcification in two important species of coccolithophore: E. huxleyi and Coccolithus braarudii. We investigated their physiological response and used time-lapse imaging to visualize the processes of calcification and cell division in individual cells. Disruption of calcification resulted in major growth defects in C. braarudii, but not in E. huxleyi. We found no evidence that calcification supports photosynthesis in C. braarudii, but showed that an inability to maintain an intact coccosphere results in cell cycle arrest. We found that C. braarudii is very different from E. huxleyi as it exhibits an obligate requirement for calcification. The identification of a growth defect in C. braarudii resulting from disruption of the coccosphere may be important in considering their response to future changes in ocean carbonate chemistry.


[Popular use of medicinal plants in infancy: implications for nursing].
An exploratory study is made by nurses -with a group of mothers with the purpose of identifying reasons for the popular use of medicinal plants by mothers caring for their children within the 0-2 years age range. Influence of the social, economical and cultural factores involved are considered. The implications of this data for nursing care and for teaching it are described.


Bacillus anthracis inosine 5'-monophosphate dehydrogenase in action: the first bacterial series of structures of phosphate ion-, substrate-, and product-bound complexes.
Inosine 5'-monophosphate dehydrogenase (IMPDH) catalyzes the first unique step of the GMP branch of the purine nucleotide biosynthetic pathway. This enzyme is found in organisms of all three kingdoms. IMPDH inhibitors have broad clinical applications in cancer treatment, as antiviral drugs and as immunosuppressants, and have also displayed antibiotic activity. We have determined three crystal structures of Bacillus anthracis IMPDH, in a phosphate ion-bound (termed "apo") form and in complex with its substrate, inosine 5'-monophosphate (IMP), and product, xanthosine 5'-monophosphate (XMP). This is the first example of a bacterial IMPDH in more than one state from the same organism. Furthermore, for the first time for a prokaryotic enzyme, the entire active site flap, containing the conserved Arg-Tyr dyad, is clearly visible in the structure of the apoenzyme. Kinetic parameters for the enzymatic reaction were also determined, and the inhibitory effect of XMP and mycophenolic acid (MPA) has been studied. In addition, the inhibitory potential of two known Cryptosporidium parvum IMPDH inhibitors was examined for the B. anthracis enzyme and compared with those of three bacterial IMPDHs from Campylobacter jejuni, Clostridium perfringens, and Vibrio cholerae. The structures contribute to the characterization of the active site and design of inhibitors that specifically target B. anthracis and other microbial IMPDH enzymes.


Volumetric capnography as a noninvasive diagnostic procedure in acute pulmonary thromboembolism.
Pulmonary thromboembolism is a common condition. Its diagnosis usually requires pulmonary scintigraphy, computed angiotomography, pulmonary arteriography and, in order to rule out other diagnoses, the measurement of D-dimer levels. Due to the fact that these diagnostic methods are not available in most Brazilian hospitals, the validation of other diagnostic techniques is of fundamental importance. We describe a case of a woman with chronic pulmonary hypertension who experienced a pulmonary thromboembolism event. Pulmonary scintigraphy, computed angiotomography and pulmonary arteriography were used in the diagnosis. The D-dimer test result was positive. Volumetric capnography was performed at admission and after treatment. The values obtained were compared with the imaging test results.


Effects of topological constraints on linked ring polymers in solvents of varying quality.
We investigate the effects of topological constraints in catenanes composed of interlinked ring polymers on their size in a good solvent as well as on the location of their θ-point when the solvent quality is worsened. We mainly focus on poly[n]catenanes consisting of n ring polymers each of length m interlocked in a linear fashion. Using molecular dynamics simulations, we study the scaling of the poly[n]catenane's radius of gyration in a good solvent, assuming in general that Rg∼mμnν and we find that μ = 0.65 ± 0.02 and ν = 0.60 ± 0.01 for the range of n and m considered. These findings are further rationalized with the help of a mean-field Flory-like theory yielding the values of μ = 16/25 and ν = 3/5, consistent with the numerical results. We show that individual rings within catenanes feature a surplus swelling due to the presence of NL topological links. Furthermore, we consider poly[n]catenanes in solvents of varying quality and we demonstrate that the presence of topological links leads to an increase of its θ-temperature in comparison to isolated linear and ring chains with the following ordering: T > T > T. Finally, we show that the presence of links similarly raises the θ-temperature of a single linked ring in comparison to an unlinked one, bringing its θ-temperature close to the one of a poly[n]catenane.


The HAK1 gene of barley is a member of a large gene family and encodes a high-affinity potassium transporter.
The high-affinity K+ uptake system of plants plays a crucial role in nutrition and has been the subject of extensive kinetic studies. However, major components of this system remain to be identified. We isolated a cDNA from barley roots, HvHAK1, whose translated sequence shows homology to the Escherichia coli Kup and Schwanniomyces occidentalis HAK1 K+ transporters. HvHAK1 conferred high-affinity K+ uptake to a K(+)-uptake-deficient yeast mutant exhibiting the hallmark characteristics of the high-affinity K+ uptake described for barley roots. HvHAK1 also mediated low-affinity Na+ uptake. Another cDNA (HvHAK2) encoding a polypeptide 42% identical to HvHAK1 was also isolated. Analysis of several genomes of Triticeae indicates that HvHAK1 belongs to a multigene family. Translated sequences from bacterial DNAs and Arabidopsis, rice, and possibly human cDNAs show homology to the Kup-HAK1-HvHAK1 family of K+ transporters.


Comparison of the long-term efficacy of low dose 131I versus antithyroid drugs in the treatment of hyperthyroidism.
In China the therapeutic options to treat hyperthyroidism comprise antithyroid drugs (ATDs), radioiodine (131I) therapy and surgery. Physicians in China avoid the risk of hypothyroidism as a consequence of either treatment because patients from rural districts cannot easily comply with long-term medication. Therefore, we prospectively assessed the efficacy and safety of 131I versus ATDs. Of 2021 hyperthyroid patients 460 without any previous treatment were enrolled in a 9-year prospective, randomized, open-label blinded endpoint study and randomly assigned to receive either 131I or ATD. Follow-up was 98.4+/-5.5 months. The primary outcome was euthyroidism, persistent hyperthyroidism, recurrence, and hypothyroidism. Euthyroidism was achieved in 69.9 and 41.2% using either 131I or ATD, 2.4 and 19.2% remained hyperthyroid, hypothyroidism occurred in 21.5 and 9.0%, recurrence in 6.2 and 30.5%, respectively. Time to cure was shorter with 131I (44.8 vs. 74.8 months, P<0.01). Goiter size extended time to cure. Hard goiter, complications, or ophthalmopathy were protective against hypothyroidism after 131I therapy. Large goiters or long courses of hyperthyroidism predicted failure of ATD treatment. This study showed a shorter cure time using 131I. Time to remission in ATD patients was shorter during the first 9 months. Thereafter, the 131I group showed a higher remission rate. Low long-term hypothyroidism and low recurrence or persistent hyperthyroidism rates were achieved with our 131I dose regimen, regardless of the underlying disease. Lesser 131I activity was used as compared with current guidelines. Within limitations, our concept may simplify procedures in other geographical regions.


Efficient assessment of brain fog and fatigue: Development of the Fatigue and Altered Cognition Scale (FACs).
Debilitating symptoms of fatigue and accompanying "brain fog" are observed among patients with various chronic health conditions. Unfortunately, an efficient and psychometrically sound instrument to assess these co-occurring symptoms is unavailable. Here, we report the development and initial psychometric properties of the Fatigue and Altered Cognition Scale (the FACs), a measure of self-reported central fatigue and brain fog. Traumatic brain injury (TBI) was chosen to model and develop the FACs due to research team expertise and established links between TBI and the symptom complex. Potential items were generated by researchers and clinicians with experience treating these symptoms, drawing from relevant literature and review of patient responses to measures from past and current TBI studies. The 20 candidate items for the FACs-ten each to assess altered cognition (i.e., brain fog) and central fatigue-were formatted on an electronic visual analogue response scale (eVAS) via an online survey. Demographic information and history of TBI were obtained. A total of 519 participants consented and provided usable data (average age = 40.23 years; 73% female), 204 of whom self-reported a history of TBI (75% reported mild TBI). Internal consistency and reliability values were calculated. Confirmatory factor analysis (CFA) examined the presumed two-factor structure of the FACs and a one-factor solution for comparison. A measurement invariance test of the two latent constructs (altered cognition, fatigue) among participants with and without TBI was conducted. All items demonstrated normal distribution. Cronbach's alpha coefficients indicated good internal consistency for both factors (α's = .95). Omega reliability values were favorable (α's = .95). CFA supported the presumed two-factor model and item loadings which outperformed the one-factor model. Measurement invariance found the two-factor structure was consistent between the two groups. Implications of these findings, study limitations, and potential use of the FACs in clinical research and practice are discussed.


A radiometric technique for measuring L-asparagine in picomole quantities.
A radiometric technique for measuring l-asparagine in small samples of biological origin is presented. After removal of l-glutamate and l-aspartate by enzymic decarboxylation, l-asparagine in the sample is hydrolysed to l-aspartate with l-asparaginase from Escherichia coli. The l-aspartate so generated is then enzymically transaminated with 2-oxo[1-(14)C]glutarate yielding l-[1-(14)C]glutamate. After specific chemical removal of unchanged 2-oxo[1-(14)C]glutarate, the l-[1-(14)C]glutamate generated is determined by scintillation counting of the radioactivity. This technique can measure the concentration of l-asparagine present in approx. 1mul of mouse blood, and is capable of detecting as little as 25pmol of the amide. Illustrative applications of the method are presented and discussed, including measurement of the l-asparagine content of the mouse hypophysis.


A Novel COVID-19 Data Set and an Effective Deep Learning Approach for the De-Identification of Italian Medical Records.
In the last years, the need to de-identify privacy-sensitive information within Electronic Health Records (EHRs) has become increasingly felt and extremely relevant to encourage the sharing and publication of their content in accordance with the restrictions imposed by both national and supranational privacy authorities. In the field of Natural Language Processing (NLP), several deep learning techniques for Named Entity Recognition (NER) have been applied to face this issue, significantly improving the effectiveness in identifying sensitive information in EHRs written in English. However, the lack of data sets in other languages has strongly limited their applicability and performance evaluation. To this aim, a new de-identification data set in Italian has been developed in this work, starting from the 115 COVID-19 EHRs provided by the Italian Society of Radiology (SIRM): 65 were used for training and development, the remaining 50 were used for testing. The data set was labelled following the guidelines of the i2b2 2014 de-identification track. As additional contribution, combined with the best performing Bi-LSTM + CRF sequence labeling architecture, a stacked word representation form, not yet experimented for the Italian clinical de-identification scenario, has been tested, based both on a contextualized linguistic model to manage word polysemy and its morpho-syntactic variations and on sub-word embeddings to better capture latent syntactic and semantic similarities. Finally, other cutting-edge approaches were compared with the proposed model, which achieved the best performance highlighting the goodness of the promoted approach.


Persistent organochlorines in the serum of the non-occupationally exposed New Zealand population.
Concentrations of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), polychlorinated biphenyls (PCBs), and organochlorine pesticides were measured in the serum of a sample of the New Zealand population aged 15 years and older. This was the first study to obtain representative measures of PCDDs, PCDFs and PCBs in the adult population of an entire country. Serum samples were obtained in 1996-1997. Potentially occupationally exposed individuals were excluded. Serum samples were pooled according to stratification criteria for area of residence, ethnicity, age, and sex. Of the 80 possible strata, sufficient serum for chemical analysis was available for 60, to which 1,834 individual samples contributed. For the PCDDs and PCDFs, most 2,3,7,8-chlorinated congeners were measured in all strata, with a mean toxic equivalents concentration across all strata of 12.8 ng TEQ kg(-1) lipid. Seven PCB congeners were frequently measured, including the coplanar congeners #126 and #169, quantified in all strata. Of the pesticides and their metabolites, only beta-HCH, dieldrin and pp'-DDE were consistently detected across strata. There was a general trend of increasing concentration with age. There were no consistent differences between the sexes, or between people of Maori (the indigenous people of New Zealand) and non-Maori ethnicity. Concentrations of PCDDs and PCDFs tended to increase in a North-South direction, possibly reflecting greater levels of industrialization and population concentration, and concentrations of the pesticide products were highest in the South, possibly reflecting historical use patterns. Results were consistent with a recent study of concentrations of these compounds in the milk of first-time mothers.


Analysis of influencing factors related to elevated serum troponin I level for COVID-19 patients in Yichang, China.
Cardiac injury is a common condition among hospitalized coronavirus disease 2019 (COVID-19) patients, and is associated with a higher risk of mortality. However, the mechanism of myocardial injury in COVID-19 remains unclear. In this retrospective study, we compared the clinical characteristics of COVID-19 patients with different troponin I (TnI) levels during hospitalization to provide a clinical reference for the identification of those at high-risk. In total, 218 patients diagnosed with COVID-19 in Yichang Central People's Hospital and Yichang Third People's Hospital between January 23 and February 19, 2020 were initially included. Of these patients, 89 underwent TnI testing during hospitalization and were finally included in the study. The medical history, clinical signs and symptoms at the time of admission, and laboratory test results were recorded. The patients were assigned to the normal TnI group (TnI <0.01 µg/L; n=67) or the elevated TnI group (TnI >0.01 µg/L; n=22). The incidence of elevated TnI in our patient cohort was 24.7%. There were significant differences between the two groups in the following factors: history of coronary heart disease (CHD), age, lymphocyte count, prothrombin time (PT), activated partial thromboplastin time (APTT), and levels of interleukin (IL)-6, C-reactive protein (CRP), myoglobin (MYO), lactate dehydrogenase (LDH), and albumin (all P<0.05). Binary logistic analysis showed that a history of CHD, age, lymphocyte count, IL-6, APTT, and MYO were influencing factors of elevated serum TnI. A history of CHD, advanced age, decreased lymphocyte count, increased IL-6, increased MYO, and prolonged APTT were independent influencing factors of elevated TnI in COVID-19 patients. COVID-19 patients with these characteristics are prone to myocardial injury.


Consumers' attitudes before and after the introduction of the Chilean regulation on food labelling.
The aim of the present study is to understand how the attitudes towards food labelling in the Chilean population have changed after the introduction of the Chilean law on food labelling and advertising. A computer-assisted telephone interview was conducted in 2012 and 2016, employing the same procedures. The difference in outcomes between 2012 and 2016 was assessed using a logistic regression model. One hundred and sixty-seven subjects responded to both the 2012 and 2016 survey editions (respondents). For both the unadjusted and adjusted analyses, the respondents in 2016 were more likely to be involved in a programme to lose weight and to consider food labelling the most effective intervention introduced to date to promote healthy nutrition. However, no significant differences were reported in both self-reported and objectively assessed understandings of front-of-pack-labelling. Evidence suggests a positive perception among Chileans regarding the effectiveness of the new law.


[Atypical optic neuritis in systemic lupus erythematosus (SLE)].
A 67-year-old woman experienced acute unilateral visual loss accompanied by pain with eye movements. There was a marked relative afferent pupillary defect and a nerve fiber bundle defect in the upper half of the visual field. Optic discs were normal. After 4 days vision worsened to motion detection and only a temporal island was left in the visual field. The optic disc margin was blurred. Since thirty years she had been suffering from renal insufficiency. Immunoserologic examination revealed elevated ANA and DS-DNA antibody titers. An optic neuritis in systemic lupus erythematosus was diagnosed, which is called atopic, because of its association to a systemic disease and the old age of the patient. The patient was treated with 100 mg prednisolone/day, slowly tapered. Within 6 weeks visual acuity improved to 0.6 and visual field normalized except for a small nerve fiber bundle defect. Autoimmune optic neuritis often responds to treatment with corticosteroids. Early onset of treatment is important. Immunopathologic examinations are an important diagnostic tool in atopic optic neuritis. Their results may even have consequences for the treatment of the underlying disease.


Effect of tranexamic acid on intracranial haemorrhage and infarction in patients with traumatic brain injury: a pre-planned substudy in a sample of CRASH-3 trial patients.
Early tranexamic acid (TXA) treatment reduces head injury deaths after traumatic brain injury (TBI). We used brain scans that were acquired as part of the routine clinical practice during the CRASH-3 trial (before unblinding) to examine the mechanism of action of TXA in TBI. Specifically, we explored the potential effects of TXA on intracranial haemorrhage and infarction. This is a prospective substudy nested within the CRASH-3 trial, a randomised placebo-controlled trial of TXA (loading dose 1 g over 10 min, then 1 g infusion over 8 hours) in patients with isolated head injury. CRASH-3 trial patients were recruited between July 2012 and January 2019. Participants in the current substudy were a subset of trial patients enrolled at 10 hospitals in the UK and 4 in Malaysia, who had at least one CT head scan performed as part of the routine clinical practice within 28 days of randomisation. The primary outcome was the volume of intraparenchymal haemorrhage (ie, contusion) measured on a CT scan done after randomisation. Secondary outcomes were progressive intracranial haemorrhage (post-randomisation CT shows >25% of volume seen on pre-randomisation CT), new intracranial haemorrhage (any haemorrhage seen on post-randomisation CT but not on pre-randomisation CT), cerebral infarction (any infarction seen on any type of brain scan done post-randomisation, excluding infarction seen pre-randomisation) and intracranial haemorrhage volume (intraparenchymal + intraventricular + subdural + epidural) in those who underwent neurosurgical haemorrhage evacuation. We planned to conduct sensitivity analyses excluding patients who were severely injured at baseline. Dichotomous outcomes were analysed using relative risks (RR) or hazard ratios (HR), and continuous outcomes using a linear mixed model. 1767 patients were included in this substudy. One-third of the patients had a baseline GCS (Glasgow Coma Score) of 3 (n=579) and 24% had unilateral or bilateral unreactive pupils. 46% of patients were scanned pre-randomisation and post-randomisation (n=812/1767), 19% were scanned only pre-randomisation (n=341/1767) and 35% were scanned only post-randomisation (n=614/1767). In all patients, there was no evidence that TXA prevents intraparenchymal haemorrhage expansion (estimate=1.09, 95% CI 0.81 to 1.45) or intracranial haemorrhage expansion in patients who underwent neurosurgical haemorrhage evacuation (n=363) (estimate=0.79, 95% CI 0.57 to 1.11). In patients scanned pre-randomisation and post-randomisation (n=812), there was no evidence that TXA reduces progressive haemorrhage (adjusted RR=0.91, 95% CI 0.74 to 1.13) and new haemorrhage (adjusted RR=0.85, 95% CI 0.72 to 1.01). When patients with unreactive pupils at baseline were excluded, there was evidence that TXA prevents new haemorrhage (adjusted RR=0.80, 95% CI 0.66 to 0.98). In patients scanned post-randomisation (n=1431), there was no evidence of an increase in infarction with TXA (adjusted HR=1.28, 95% CI 0.93 to 1.76). A larger proportion of patients without (vs with) a post-randomisation scan died from head injury (38% vs 19%: RR=1.97, 95% CI 1.66 to 2.34, p<0.0001). TXA may prevent new haemorrhage in patients with reactive pupils at baseline. This is consistent with the results of the CRASH-3 trial which found that TXA reduced head injury death in patients with at least one reactive pupil at baseline. However, the large number of patients without post-randomisation scans and the possibility that the availability of scan data depends on whether a patient received TXA, challenges the validity of inferences made using routinely collected scan data. This study highlights the limitations of using routinely collected scan data to examine the effects of TBI treatments. ISRCTN15088122.


Atrial fibrillation, bleeding, and coronary intervention: current recommendations.
The patient population with the need for oral anticoagulation to reduce stroke risk associated with atrial fibrillation (AF) and dual antiplatelet therapy to prevent stent thrombosis and myocardial infarction after percutaneous coronary intervention is increasing. However, patients treated with a triple therapy consisting of oral anticoagulation, aspirin, and a P2Y12 inhibitor have been demonstrated to be at high bleeding risk. The best combination of these agents and the duration of the different therapies are still uncertain. Recently, data on the safety of combinations including nonvitamin K antagonists have been published and evidence for the feasibility of a dual therapy is increasing. This review aims to provide insights to the pathophysiology of thrombus formation in AF versus coronary artery disease, summarize available data on postprocedural treatment strategies, and report current guidelines for AF patients after percutaneous coronary intervention. Furthermore, the role of stent type selection and tools to evaluate as well as strategies to reduce the individual bleeding risk will be discussed.


Follow-up of language and cognitive development in patients with mannosidosis.
Three brothers with mannosidosis were assessed both biochemically by levels of enzyme activities and developmentally by serial testing of language and cognitive development. The findings indicated that while the leukocyte enzyme activity of alpha-mannosidase was exceptionally low, only mild intellectual deficits were present that did not progress during a two-year follow-up. These results do not substantiate the expected relationship between the severities of enzyme deficiency and developmental delays. Language and cognitive deficits appeared uniform with no areas of strengths or weaknesses. Deficits in development did not progress during a two-year follow-up.


Platelet activation in patients with congestive heart failure: do we have enough evidence to consider clopidogrel?
Our understanding of the pathogenesis of congestive heart failure (CHF) has improved remarkably in recent years. However, despite better knowledge and novel pharmaceutical strategies, this disease is still one of the most brutal killers in the Western world. The pathophysiology of CHF is complex, and much of our comprehension revolves strictly around the neurohormonal and mechanical mechanisms involved. It has been suggested that CHF is associated with altered hemostasis, but whether a prothrombotic state contributes to the pathogenesis and progression of the disease is still not well known. The purpose of this review article is to discuss our current knowledge of platelet activation in patients with CHF and the potential role of antiplatelet agents in preventing these hemostatic abnormalities. Clopidogrel is an established medication that reduces the incidence of stroke, myocardial ischemia, or vascular death. It is currently the drug of choice in the prophylaxis of subacute stent thrombosis and postischemic stroke treatment. Promising results of the most resent trials (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events [CAPRIE] and Clopidogrel in Unstable angina to prevent Recurrent Events [CURE]) may expand future indications of this ADP receptor antagonist for prevention of thrombotic complications in the CHF population. Currently conducted clinical trials (Warfarin and Antiplatelet Therapy in Chronic Heart Failure [WATCH] and Plavix Use for Treatment of Congestive Heart Failure [PLUTO-CHF] should clarify the role of clopidogrel in these patients.


Tandem catalysis: a new approach to polymers.
The creation of polymers by tandem catalysis represents an exciting frontier in materials science. Tandem catalysis is one of the strategies used by Nature for building macromolecules. Living organisms generally synthesize macromolecules by in vivo enzyme-catalyzed chain growth polymerization reactions using activated monomers that have been formed within cells during complex metabolic processes. However, these biological processes rely on highly complex biocatalysts, thus limiting their industrial applications. In order to obtain polymers by tandem catalysis, homogeneous and enzyme catalysts have played a leading role in the last two decades. In the following feature article, we will describe selected published efforts to achieve these research goals.


In-lab demonstration of coherent one-way protocol over free space with turbulence simulation.
Over the last decade, free-space quantum key distribution (QKD), a secure key sharing protocol, has risen in popularity due the adaptable nature of free-space networking and the near-term potential to share quantum-secure encryption keys over a global scale. While the literature has primarily focused on polarization based-protocols for free-space transmission, there are benefits to implementing other protocols, particularly when operating at fast clock-rates, such as in the GHz. In this paper, we experimentally demonstrate a time-bin QKD system, implementing the coherent one-way (COW) at 1 GHz clock frequency, utilizing a free-space channel and receiver. We demonstrate the receiver's robustness to atmospheric turbulence, maintaining an operational visibility of 92%, by utilizing a lab-based turbulence simulator. With a fixed channel loss of 16 dB, discounting turbulence, we obtain secret key rate (SKR) of 6.4 kbps, 3.4 kbps, and 270 bps for three increasing levels of turbulence. Our results highlight that turbulence must be better accounted for in free-space QKD modelling due to the additional induced loss.


[Surgery for gallstone disease in two time periods].
Laparoscopic cholecystectomy was introduced at our institution in October 1990. The perioperative results from 1.1.1991 to 31.12.1995 (first period) are compared with those from 1.1.2001 to 31.12.2005 (second period). All patients who had undergone surgical treatment for gallstone disease at Asker and Baerum Hospital in the first or second period were included. Data retrieval was partly prospective and partly retrospective in both periods. Significantly more patients underwent cholecystectomy in the second than in the first period (843 vs. 342), but the proportion of patients that were operated on an acute indication was lower in the second (91 of 843) than in the first (79 of 342) period, p < 0.001. This coincided with a decline in the number of cholecystectomy patients with complications to gallstone disease (pancreatitis, cholangitis or acute cholecystitis) and a significant reduction of operating time and duration of hospital stay after the operation, whereas the number of per- and postoperative complications remained unchanged. The number of patients operated for gallstone disease during the first 15 years of laparoscopic surgery has increased significantly. Fewer patients with acute cholecystitis are treated surgically, and the proportion of patients suffering from pancreatitis, cholangitis or acute cholecystitis before surgery appears to have declined.


[Use of biologically active preparations in prevention of complication in patients with open traumatic mandible fractures].
Original scheme of clinico-diagnostic treatment of patients with open mandible fractures described, based on sufficient clinical material - 100 traumatic patients passing the course of stationary and clinic observation. Contemporary methods of the objective evaluation of the structural-functional restoration of the damaged bone tissues were used for diagnostic purposes. The positive results of the study and treatment were obtained. Practical conclusions were made.


The risk factors of antenatal depression: A cross-sectional survey.
To investigate the prevalence of depression in the third trimester of pregnancy and identify the related demographic risk factors. Antenatal depression as a disabling and treatable disease has a wide-ranging impact on perinatal women and has received extensive attention from researchers. A cross-sectional survey was conducted at three public hospitals. Demographic questionnaire was developed from the literature review, and depression was assessed using the Edinburgh Postnatal Depression Scale. A binary logistic regression model was used to assess the association between depression and demographic predictors. STROBE checklist for cross-sectional studies was applied in this paper (see Appendix S1). A total of 773 pregnant women participated in the study. 29.6% of participants scored more than 9 points on Edinburgh Postnatal Depression Scale. In the final logistic model, living in rural area, marital satisfaction, assisted reproductive technology, lacking of prenatal health knowledge and life events were strongly significantly associated with antenatal depression. Moreover, living in an extended family, without Medicare insurance, unemployed, working as civil servants or healthcare workers, and lower household income also predicted antenatal depression. However, education level, smoking or drinking before pregnancy was found not to be associated with antenatal depression. Our findings suggest that the prevalence of antenatal depression was high. Satisfied with the current marital status, pregnancy without assisted reproductive technology, knowledge of perinatal care and no life events recently were considered as the protective factors for antenatal depression. Antenatal psychological interventions should focus on how to improve the marital satisfaction and the relationship with their family members. More attentions should be paid to the women who have had some life events recently or received assisted reproductive technology for pregnancy.


An anti-CD5 monoclonal antibody ameliorates proteinuria and glomerular lesions in rat mesangioproliferative glomerulonephritis.
Increased numbers of lymphocytes have been identified in biopsy specimens of human mesangial proliferative glomerulonephritis (GN). However, the causal relationship between infiltrating T lymphocytes and mesangial changes in mesangial proliferative GN has not been previously evaluated. In this study, we elucidated the role of lymphocytes in the development of mesangial proliferative GN. Immunohistological and flow cytometric analyses as well as a reverse transcription-polymerase chain reaction (RT-PCR) studies were performed in monoclonal antibody (mAb) 1-22-3-induced Thy 1.1 GN. To elucidate the role of these lymphocytes, depletion studies were carried out using anti-CD8 mAb (OX-8), which depletes both CD8+ T lymphocytes and natural killer (NK) cells and anti-CD5 mAb (OX-19), which depletes both CD4+ and CD8+ T lymphocytes. Immunofluorescence (IF) studies revealed that NK cells and CD4+ T lymphocytes were recruited into glomeruli. Glomerular mRNA expression for interferon-gamma, interleukin-2 (IL-2), IL-10, and perforin increased after induction of GN. Increased expressions of several chemokines, which have the potential to attract lymphocytes, were also detected. Anti-CD8 mAb treatment completely prevented the recruitment of NK cells; however, it had no protective effect on proteinuria and mesangial injury. By contrast, anti-CD5 mAb treatment suppressed the recruitment of CD4+ T lymphocytes into glomeruli and reduced proteinuria (60.4 +/- 25.7 vs. 120.0 +/- 32.3 mg/day, P < 0.05) and mesangial changes evaluated by total number of cells in glomeruli (63.2 +/- 6.0 vs. 81.4 +/- 5.9, P < 0.01) and alpha-smooth muscle actin staining score (1.4 +/- 0.2 vs. 2.2 +/- 0. 4, cf2eth P < 0.01) on day 14 after induction of GN. mRNA expression for IL-2 was significantly reduced by OX-19 treatment. T lymphocytes participate in the development of mesangial proliferative GN.


Advances in coeliac disease.
To summarize the recent advances in coeliac disease. Details of the polygenic nature of coeliac disease with the human leukocyte antigen (HLA) locus as the dominating genetic element have been uncovered. The existence of a large number of non-HLA coeliac disease genes, only partly shared by each individual patient, suggests the genetic heterogeneity of the disease. The critical role for HLA-DQ-restricted CD4 T cells recognizing antigenic gluten peptides is further substantiated. Involvement of CD8 T cells has received new attention. Other components of wheat than gluten, in particular the amylase trypsin inhibitors, may also play a role. The disease is becoming more prevalent. New guidelines state that coeliac disease diagnosis in children can be made on the basis of clinical signs, serology and genetics without the need of biopsy. The clinical entity 'noncoeliac gluten sensitivity' has received much attention, but diagnostic and pathophysiological definitions are still elusive. The risk for mortality and morbidity in coeliac disease is less than previously thought. Our understanding of the basic and clinical aspects of coeliac disease increases. Coeliac disease stands out as a major health problem of almost global occurrence. Case finding, distinguishing coeliac disease from other gluten-sensitive conditions, better care and balanced use of resources are the current challenges.


[100 years radiotherapy. On the birth of a new specialty].
Radiotherapy was founded as a new scientific specialty by the Viennese physician Leopold Freund 100 years ago. Freund provided the world's first scientific proof of the biological effectiveness of x-rays and performed the first successful treatment with these new rays on a 5-year old girl suffering from a huge nevus pigmentosus pilosus (hairy nevus) on her back. Before Freund's historical three experimental x-ray treatments (the first of these began on November 24, 1896, in Vienna) there had been earlier attempts and suggestions to apply x-rays therapeutically during 1896. However, none of these previous therapeutic attempts was successful. Also, there was no scientific proof of the biological effectiveness of x-rays among the therapeutic attempts which preceded Freund's fundamental x-ray treatments. Modern radiotherapy and radiation oncology contribute towards nearly one half of all cancer cures. Two thirds of cancer patients need the help of radiation oncology, and this scientific specialty is, thus, the most frequently used treatment modality in the management of tumor patients.