Type-specific detection of human papillomaviruses in a routine laboratory setting--improved sensitivity and specificity of PCR and sequence analysis compared to direct hybridisation.
Human papillomaviruses (HPV) are known to cause cervical dysplasia and cervical carcinoma. We used a 3-step PCR protocol that allows rapid type-specific HPV testing in a routine laboratory setting: HPV-16-positive samples were determined using a specific LightCycler PCR; HPV-16-negative samples were amplified by nested PCR and typed by sequence analysis. During a period of 7 months, 1275 PCR-based HPV tests were performed. Of the 1275 samples, 829 samples tested negative for HPV and 446 tested positive, including 124 positives found in the initial HPV-16-specific LightCycler assay. Sequence analysis of 132 samples detected 18 HPV types that are not included in the widely used Hybrid Capture II assay. For comparison, the first 100 cervical specimens were tested in parallel using PCR and direct hybridisation (Hybrid Capture II assay). PCR detected HPV DNA in 23 samples that tested negative in the Hybrid Capture assay. Four out of 37 samples that tested positive for HPV in the Hybrid Capture test may be false positives, because sequence analysis detected HPV types not included in the probe mixtures. As rare and novel HPV types may also confer an oncogenic risk, highly sensitive and specific PCR assays will help in understanding cervical HPV infection and cervical cancer of unknown causes.


Nitric oxide: role in venular permeability recovery after histamine challenge.
Histamine is an inflammatory mediator produced by mast cells that reside close to blood vessels. It causes a transient increase in venular permeability and stimulates endothelial production of nitric oxide (NO). In this study, we investigated the role that NO plays in the permeability recovery and evaluated the response of mast cells. The mesenteric microvasculature of anesthetized rats was suffused with 10(-3) M histamine for 3 min and then perfused with the NO donor sodium nitroprusside (SNP; 10(-6) M), the NO inhibitor N(G)-monomethyl-L-arginine (L-NMMA; 10(-5) M), its enantiomer (D-NMMA; 10(-5) M), or HEPES-buffered saline containing 0.5% BSA for 15 min. This was replaced by FITC-albumin for 3 min, followed by fixative. The vasculature was visualized using epifluorescence microscopy and was stained for mast cells. Preparations treated with histamine only showed discrete FITC-albumin leaks. Subsequent inhibition of NO increased venular FITC-albumin leaks and prevented permeability recovery, whereas subsequent treatment with SNP decreased the histamine-induced venular leaks. Mast cells degranulated due to histamine and the other treatment combinations. In conclusion, inhibition of NO prevented permeability recovery and depleted mast cells of their histamine content.


BPIFB3 Regulates Endoplasmic Reticulum Morphology To Facilitate Flavivirus Replication.
Flaviviruses, including dengue virus (DENV) and Zika virus (ZIKV), rely heavily on the availability of endoplasmic reticulum (ER) membranes throughout their life cycle, and degradation of ER membranes restricts flavivirus replication. Accordingly, DENV and ZIKV restrict ER turnover by protease-mediated cleavage of reticulophagy regulator 1 (RETREG1), also known as FAM134B, an autophagy receptor responsible for targeted ER sheet degradation. Given that the induction of autophagy may play an important role in flavivirus replication, the antiviral role of RETREG1 suggests that specialized autophagic pathways may have differential effects on the flavivirus life cycle. We previously identified BPI fold-containing family B member 3 (BPIFB3) as a regulator of autophagy that negatively controls enterovirus replication. Here, we show that in contrast to enteroviruses, BPIFB3 functions as a positive regulator of DENV and ZIKV infection and that its RNA interference-mediated silencing inhibits the formation of viral replication organelles. Mechanistically, we show that depletion of BPIFB3 enhances RETREG1-dependent reticulophagy, leading to enhanced ER turnover and the suppression of viral replication. Consistent with this, the antiviral effects of BPIFB3 depletion can be reversed by RETREG1 silencing, suggesting a specific role for BPIFB3 in regulating ER turnover. These studies define BPIFB3 as a required host factor for both DENV and ZIKV replication and further contribute to our understanding of the requirements for autophagy during flavivirus infection.IMPORTANCE Flaviviruses and other arthropod-transmitted viruses represent a widespread global health problem, with limited treatment options currently available. Thus, a better understanding of the cellular requirements for their infection is needed. Both DENV and ZIKV rely on expansion of the endoplasmic reticulum (ER) and the induction of autophagy to establish productive infections. However, little is known regarding the interplay between the requirements for autophagy initiation during infection and the mechanisms used by these viruses to avoid clearance through the autophagic pathway. Our study highlights the importance of the host factor BPIFB3 in regulating flavivirus replication and further confirms that the RETREG1-dependent reticulophagy pathway is antiviral to both DENV and ZIKV.


The Stanford Hall consensus statement for post-COVID-19 rehabilitation.
The highly infectious and pathogenic novel coronavirus (CoV), severe acute respiratory syndrome (SARS)-CoV-2, has emerged causing a global pandemic. Although COVID-19 predominantly affects the respiratory system, evidence indicates a multisystem disease which is frequently severe and often results in death. Long-term sequelae of COVID-19 are unknown, but evidence from previous CoV outbreaks demonstrates impaired pulmonary and physical function, reduced quality of life and emotional distress. Many COVID-19 survivors who require critical care may develop psychological, physical and cognitive impairments. There is a clear need for guidance on the rehabilitation of COVID-19 survivors. This consensus statement was developed by an expert panel in the fields of rehabilitation, sport and exercise medicine (SEM), rheumatology, psychiatry, general practice, psychology and specialist pain, working at the Defence Medical Rehabilitation Centre, Stanford Hall, UK. Seven teams appraised evidence for the following domains relating to COVID-19 rehabilitation requirements: pulmonary, cardiac, SEM, psychological, musculoskeletal, neurorehabilitation and general medical. A chair combined recommendations generated within teams. A writing committee prepared the consensus statement in accordance with the appraisal of guidelines research and evaluation criteria, grading all recommendations with levels of evidence. Authors scored their level of agreement with each recommendation on a scale of 0-10. Substantial agreement (range 7.5-10) was reached for 36 recommendations following a chaired agreement meeting that was attended by all authors. This consensus statement provides an overarching framework assimilating evidence and likely requirements of multidisciplinary rehabilitation post COVID-19 illness, for a target population of active individuals, including military personnel and athletes.


Enhanced platelet reactivity in pediatric depression: an observational study.
Depression is associated with poor prognosis for cardiovascular disease (CVD) including mortality. Among multiple mechanisms linking depression and CVD, changes in platelet reactivity are known to be one of the major confounders of such adverse association. However, there are very limited data in children. Thus, we evaluated some conventional hemostatic indices including whole blood platelet aggregation in patients with documented pediatric depression and compared these data with those obtained from healthy children. The pediatric patients fulfilled criteria for major depression with a minimum score of 19 on the 21-item Beck Depression Inventory Scale. Plasma fibrinogen, D-dimer, platelet count, mean platelet volume, and platelet aggregation induced by ADP and collagen were measured in 67 pediatric patients with depression and matched by age and sex with 78 healthy controls. As expected, the depressed children had significantly higher BECK scales (P = 0.001) compared with the normal subjects. Platelet aggregation induced by ADP and collagen (P = 0.0001 for both) was significantly higher in depressed children. BECK scale scores correlated significantly with platelet aggregation induced by ADP (r = 0.3, P = 0.001) and collagen (r = 0.4, P = 0.01). In contrast, platelet counts, fibrinogen, D-dimer, mean platelet volume, and antithrombin-III levels were almost identical between both groups. Children with depression exhibit mostly intact hemostatic parameters, with the exception of significantly higher platelet activity when compared with healthy controls. These data match well with prior evidence from depressed adults supporting the hypothesis that platelets participate in the pathogenesis of depression. However, beyond pure assessment of platelet activity, other elements including serotonin content and cell receptor changes in pediatric depression should be elucidated before randomized trial(s) can be justified.


[Influence of Adamantilbromphenylamine on Parameters of Immunity and Symptoms of Asthenia in Patients with Non-Psychotic Mental Disorders].
Our aim was to assess effect of antiasthenic drug adamantilbromphenylamine on the immune system and symptoms of asthenia in patients with non-psychotic mental disorders and to reveal possible criteria for prediction of treatment efficiency. Uncontrolled study with interrupted time series was carried out. According to efficiency of treatment patients were divided into two groups (group 1 (n=21)--very much improved and much improved; group 2 (n=9)--minimally improved). Adamantilbromphenylamine was administered to patients as a monotherapy 100 mg a day for 28 days. Examination was conducted before and after therapy. Severity of asthenic symptoms according to MFI-20 scale was identified; cellular and humoral immunity parameters, mitogen-induced production of interleukins (IL) 1β and IL 4 by immunocompetent cells of patients were assessed. 30 patients with non-psychotic mental disorders with predominance of asthenic symptomatology in clinical picture of the disease were examined. Before therapy every proband had over 60 points across 5 items of MFI-20 scale. As compared with control decrease of number of lymphocytes of CD3+-, HLA-DR+, CD16+-phenotypes; increase in the ratio of CD4+/CD8+; concentration of serum IgM; phagocytic activity of neutrophils were revealed. In the end of therapy in group 1, sum total of points of asthenia decreased up to 26(23-37) (p<0.001); in group 2--up to 57(47-61). Only in group 1 positive dynamic of immune parameters was revealed. It was shown that baseline level of proinflammatory cytokine IL 1β in group with apparent therapeutic effect of the drug was reliably lower, than in group with minimal improvement (p=0.005). These differences remained also after course of therapy (p=0.042). Interrelationship of clinical-immunological effect of adamantilbromphenylamine has been revealed; intensity of production of IL 1β may be considered as a criterion of prognosis of efficiency of treatment with adamantilbromphenylamine in patients with non-psychotic mental disorders.


Local Structure in U(IV) and U(V) Environments: The Case of U3O7.
A comprehensive analysis of X-ray absorption data obtained at the U L3-edge for a systematic series of single-valence (UO2, KUO3, UO3) and mixed-valence uranium compounds (U4O9, U3O7, U3O8) is reported. High-energy resolution fluorescence detection (HERFD) X-ray absorption near-edge spectroscopy (XANES) and extended X-ray absorption fine structure (EXAFS) methods were applied to evaluate U(IV) and U(V) environments, and in particular, to investigate the U3O7 local structure. We find that the valence state distribution in mixed-valence uranium compounds cannot be confidently quantified from a principal component analysis of the U L3-edge XANES data. The spectral line broadening, even when applying the HERFD-XANES method, is sensibly higher (∼3.9 eV) than the observed chemical shifts (∼2.4 eV). Additionally, the white line shape and position are affected not only by the chemical state, but also by crystal field effects, which appear well-resolved in KUO3. The EXAFS of a phase-pure U3O7 sample was assessed based on an average representation of the expanded U60O140 structure. Interatomic U-O distances are found mainly to occur at 2.18 (2), 2.33 (1), and 3.33 (5) Å, and can be seen to correspond to the spatial arrangement of cuboctahedral oxygen clusters. The interatomic distances derived from the EXAFS investigation support a mixed U(IV)-U(V) valence character in U3O7.


Molecular biology of bcr-abl1-positive chronic myeloid leukemia.
Chronic myeloid leukemia (CML) has been regarded as the paradigmatic example of a malignancy defined by a unique molecular event, the BCR-ABL1 oncogene. Decades of research zeroing in on the role of BCR-ABL1 kinase in the pathogenesis of CML have culminated in the development of highly efficacious therapeutics that, like imatinib mesylate, target the oncogenic kinase activity of BCR-ABL1. In recent years, most research efforts in CML have been devoted to developing novel tyrosine kinase inhibitors (TKIs) as well as to elucidating the mechanisms of resistance to imatinib and other TKIs. Nonetheless, primordial aspects of the pathogenesis of CML, such as the mechanisms responsible for the transition from chronic phase to blast crisis, the causes of genomic instability and faulty DNA repair, the phenomenon of stem cell quiescence, the role of tumor suppressors in TKI resistance and CML progression, or the cross-talk between BCR-ABL1 and other oncogenic signaling pathways, still remain poorly understood. Herein, we synthesize the most relevant and current knowledge on such areas of the pathogenesis of CML.


Organizing the transfer of patient care information: the development of a computerized resident sign-out system.
The problem of safe and efficient transfer of care has increased over the years as new and complex diagnostic tools and more complex treatment options became available. Traditionally, residents ensured continuity of care by working long hours and minimizing the transfer of significant diagnostic or therapeutic responsibilities to other providers. The new 80-hour workweek has curtailed that practice and increased the pressure on trainees for workflow efficiency. We report on a study of information-handling routines among residents for the separate tasks of transfer of care ("sign-out") and daily patient care work (ward work). Using these results, an institution-wide computerized system was developed to centralize information-handling tasks and facilitate the management and transfer of patient care information. House staff from 31 resident-run inpatient and consult services at 2 teaching hospitals described current methods of maintaining patient information used during ward rounds and during sign-out. A subgroup of 28 residents then participated in the design of a computerized resident sign-out system to centralize patient information and produce lists for rounding and transferring care duties. Accuracy, flexibility, and portability were identified as key elements by the design team. Analysis of the type of information handled by residents caring for inpatients at our institution demonstrated common elements across many services. Most services used a paper patient list to manage both nightly sign-out and daily ward work, which required repeated recopying of patient data during the day. Utilizing medical information systems tools and rapid application development concepts, we constructed a computerized resident sign-out system ("UWCores"). This system combines the patient sign-out and daily ward work information in one central location. We believed this would improve the quality of information transferred during sign-out and enhance resident efficiency. During the design process, we identified rules that govern the type of clinical information that should be automatically versus manually updated. We observed an immediate acceptance by all residents and services that tried the system. This study shows that by combining downloaded patient data from hospital systems with resident-entered patient details, a computerized resident sign-out system can be a feasible, powerful, and popular tool. While its effect on patient safety and resident efficiency await the results of further studies, our study shows that this tool rapidly captured the attention of resident physicians and became widely used as a valuable means to centralize and organize sign-out and daily ward work information.


Education Moderates the Relation Between APOE ɛ4 and Memory in Nondemented Non-Hispanic Black Older Adults.
The APOEɛ4 allele is a well-known risk factor for Alzheimer's disease (AD). Previous research argues that higher education helps to preserve cognition in older adults with AD pathology because of its key role in cognitive reserve and resilience. To test if higher educational level buffers the effect of APOEɛ4 on cognition among older non-Hispanic Blacks. Participants were 849 non-demented older non-Hispanic Blacks (38.3% APOEɛ4+), who underwent a comprehensive neuropsychological evaluation. Multiple linear regression models tested the relationship between APOEɛ4 status and twelve cognitive measures with education (up to high school and beyond high school) as a moderator. Education buffered the effects of the APOEɛ4 allele, such that there was no impact of APOEɛ4 status on word-list memory retention and working memory among participants with more than a high school degree. This pattern was not observed for ten other cognitive measures of verbal and visual episodic memory, semantic memory, executive function, and processing speed-although a similar trend was observed for switching ability in executive functioning. The buffering effect of education was stronger among women than men. Our findings suggest that genetic effects on late-life cognition may be modified by environmental factors such as educational attainment. These results are consistent with the framework of cognitive reserve such that engaging in cognitively enriching activities and acquiring skills and knowledge with more years of education may increase the capacity to maintain cognitive function despite high genetic risk for impairment.


Automated anatomical labeling of the bronchial branch and its application to the virtual bronchoscopy system.
This paper describes a method for the automated anatomical labeling of the bronchial branch extracted from a three-dimensional (3-D) chest X-ray CT image and its application to a virtual bronchoscopy system (VBS). Automated anatomical labeling is necessary for implementing an advanced computer-aided diagnosis system of 3-D medical images. This method performs the anatomical labeling of the bronchial branch using the knowledge base of the bronchial branch name. The knowledge base holds information on the bronchial branch as a set of rules for its anatomical labeling. A bronchus region is automatically extracted from a given 3-D CT image. A tree structure representing the essential structure of the extracted bronchus is recognized from the bronchus region. Anatomical labeling is performed by comparing this tree structure of the bronchus with the knowledge base. As an application, we implemented the function to automatically present the anatomical names of the branches that are shown in the currently rendered image in real time on the VBS. The result showed that the method could segment about 57% of the branches from CT images and extracted a tree structure of about 91% in branches in the segmented bronchus. The anatomical labeling method could assign the correct branch name to about 93% of the branches in the extracted tree structure. Anatomical names were appropriately displayed in the endoscopic view.


Removal of sodium dodecyl sulfate in an intermittent cycle extended aeration system.
The objective of this study was to investigate the removal of an anionic surfactant from wastewater in ICEAS. The surfactant considered here was anionic SDS being widely used in the household and industrial detergents. Basic wastewater COD was 260 mg L(-1) and SDS surfactant added in range 20 to 400 mg L(-1). The effect of the inlet SDS concentration and reaction time on COD and SDS removal was investigated. The results from this study indicated that the aeration time of 2 h was sufficient for removal of SDS ranged 20 to 400 mg L(-1). Obtained data showed low effluent SDS concentrations of 0.3 to 5 mg L(-1) and removal of SDS was more than 98%. These results revealed that biological treatment using ICEAS process is capable to treating wastewaters containing high concentration of SDS surfactant.


Reduced graphene oxide-incorporated calcium phosphate cements with pulsed electromagnetic fields for bone regeneration.
Natural calcium phosphate cements (CPCs) derived from sintered animal bone have been investigated to treat bone defects, but their low mechanical strength remains a critical limitation. Graphene improves the mechanical properties of scaffolds and promotes higher osteoinduction. To this end, reduced graphene oxide-incorporated natural calcium phosphate cements (RGO-CPCs) are fabricated for reinforcement of CPCs' characteristics. Pulsed electromagnetic fields (PEMFs) were additionally applied to RGO-CPCs to promote osteogenic differentiation ability. The fabricated RGO-CPCs show distinct surface properties and chemical properties according to the RGO concentration. The RGO-CPCs' mechanical properties are significantly increased compared to CPCs owing to chemical bonding between RGO and CPCs. In in vitro studies using a mouse osteoblast cell line and rat-derived adipose stem cells, RGO-CPCs are not severely toxic to either cell type. Cell migration study, western blotting, immunocytochemistry, and alizarin red staining assay reveal that osteoinductivity as well as osteoconductivity of RGO-CPCs was highly increased. In in vivo study, RGO-CPCs not only promoted bone ingrowth but also enhanced osteogenic differentiation of stem cells. Application of PEMFs enhanced the osteogenic differentiation of stem cells. RGO-CPCs with PEMFs can overcome the flaws of previously developed natural CPCs and are anticipated to open the gate to clinical application for bone repair and regeneration.


Transfer of PCBs from Microplastics under Simulated Gut Fluid Conditions Is Biphasic and Reversible.
The role of plastic as a vector for bioaccumulation of toxic chemicals is central to the risk assessment of microplastic for human health and the environment. However, transfer kinetics of sorbed contaminants from ingested microplastics are poorly understood. We develop and parametrize a chemical exchange model on microplastics in a gut fluid mimic of aquatic biota, and also included food to provide a better representation of contaminant dynamics when plastic and food are ingested, as would occur in nature. The transfer kinetics of 14 polychlorinated biphenyls (PCBs) were measured in gut fluid mimic systems under three environmentally relevant exposure scenarios of plastic ingestion by organisms, for low-density polyethylene (LDPE) and polyvinyl chloride (PVC), and were evaluated with the model. Chemical transfer was demonstrated to be biphasic and fully reversible, with fast exchange within hours followed by a slow transfer lasting for weeks to months. In clean gut systems, the bioavailability of plastic-associated PCBs for lugworms and cod ranged from 14 to 42% and 45-83% respectively. However, in contaminated gut systems, clean microplastic was capable of rapidly extracting ("cleaning") PCBs from food inside the gut, thus demonstrating that the effect of microplastic is context dependent. Therefore, chemical contamination and cleaning are likely to occur simultaneously due to the ingestion of microplastic.


Acylation versus sulfonylation in the inhibition of elastase by 3-oxo-beta-sultams.
beta-Sultams are the sulfonyl analogues of beta-lactams, and 3-oxo-beta-sultams are both beta-lactams and beta-sultams and, therefore, susceptible to nucleophilic attack at either the acyl or the sulfonyl center. They are novel inactivators of serine enzymes. The second-order rate constant for the inactivation of elastase at pH 6 by N-benzyl-4,4-dimethyl-3-oxo-beta-sultam is 768 M-1 s-1, which is 103-fold greater than that with N-benzoyl beta-sultam. However, in contrast to N-acyl beta-sultams, which sulfonylate the active site serine residue to form a sulfonate ester, 3-oxo-beta-sultams inhibit the enzyme by acylation followed by slow deacylation to regenerate the active enzyme.


Capillary basement membrane thickening associated with the small intestine of the ketonuric diabetic Chinese hamster.
Morphometric evaluation of intestinal capillary basement membranes demonstrated a significant thickening in those of ketonuric diabetic Chinese hamsters compared to age-matched nondiabetic controls. A highly significant correlation was found between increased capillary basement membrane thickness and progression of ketonuria. Age was also positively related to elevation in capillary basement membrane thickness of control and diabetic hamsters. Capillary basement membrane thickness of diabetic animals was not significantly related to a combination of progredient ketonuria and advance in age.


Targets for Optimizing Oral Antibiotic Prescriptions for Pediatric Outpatients in Japan.
In Japan, 92.6% of antibiotics consumed are oral agents; most of these are for outpatients. A significant proportion is known to be dispensed for children; however, the specific pattern of antibiotic prescription in accordance with clinical specialty is still unclear. The aim of our study was to identify the key targets for the optimization of oral antibiotic use in children. We analyzed data on oral antimicrobial prescription patterns for children < 16 years old of age in 3 urban districts by using a national database in Japan. Oral prescriptions were categorized according to their class, spectrum, clinical specialty, and type of clinical setting. The antibiotic spectrum was categorized as narrow, broad, or ultra-broad. In total, 132,869,332 antibiotic prescriptions were collected for analysis. The proportions of narrow-spectrum, broad-spectrum, and ultra-broad-spectrum antibiotics were 10.9%, 73.7%, and 15.4% in primary care clinics and 23.4%, 71.1%, and 5.4% in hospitals, respectively. Prescriptions from pediatricians and otolaryngologists in primary care clinics were predominant in the 3 studied areas. Third-generation cephalosporins, quinolones, penems, and carbapenems were prescribed mostly by pediatricians and otolaryngologists. Ultra-broad spectrum antibiotics used in primary care clinics and antibiotics particular to each specialty were identified as key targets for the optimization of oral antibiotic use for pediatric outpatients.


[Post-operative complications following Caesarean section. A comparative study of the years 1957-1958 and 1977-1978].
104 Caesarean sections of the Obstetric Department of the University in Hamburg-Eppendorf of the years 1957-1958 were compared with 399 Caesarean sections of the years 1977-1978 in a retrospective study. An attempt was made to correlate the post-operative complications with possible causes. There was a marked rise in wound infections, endometritis, post-operative pyrexia and a decrease of thromboembolic complications and retained lochia. Differences in the old and new years were in the management of labour, the operative technique and the post-operative treatment. In the Caesarean sections of 1977 to 1978 a clear cut correlation between wound infections uterine complications and pyrexia and the number of vaginal examination following rupture of the membranes the duration of rupture of the membranes and the length of labour was found. To reduce the post-operative complication rate at attempt should be made to reduce the number of vaginal examinations, to be stringent in the indications for rupture of the membranes and to avoid delay in inevitable Caesarean sections.


Flicker and movement constituents of the pattern reversal response.
A counterphase-modulated (i.e. contrast reversing) pattern will affect hypothetical neural elements sensitive to motion as well as hypothetical elements sensitive to changes in contrast and other elements sensitive to local luminance. Attempts to describe visual evoked potentials (VEPs) to contrast reversal entirely in terms of luminance change or entirely in terms of contrast change have been unsuccessful; strong interactions between responses to contrast decrease and increase had to be postulated ad hoc in order to account for the contrast reversal VEP, and no explanation for these interactions has been proposed. Rather than attempting to separate the reversal VEP into responses to contrast decrease and increase, we attempt here to analyze the reversal VEP into responses to motion onset and offset. We find that VEPs to an abrupt displacement of less than one square's width of a checkerboard pattern are qualitatively similar to the contrast reversal VEP, and that the displacement VEP can be seen as the limiting case of a motion onset response shortly followed by a motion offset response. When displacement occurs during steady motion, the displacement and motion responses interact. We conclude that the contrast reversal VEP is better described in terms of motion onset and offset response than in terms of contrast onset and offset responses.


MicroRNAs in respiratory disease. A clinician's overview.
Since their initial discovery in the early 1990s, microRNAs have now become the focus of a multitude of lines of investigation ranging from basic biology to translational applications in the clinic. Previously believed to be of no biological relevance, microRNAs regulate processes fundamental to human health and disease. In diseases of the lung, microRNAs have been implicated in developmental programming, as drivers of disease, potential therapeutic targets, and clinical biomarkers; however, several obstacles must be overcome for us to fully realize their potential therapeutic use. Here, we provide for the clinician an overview of microRNA biology in selected diseases of the lung with a focus on their potential clinical application.


[Effects of planting years of vegetable solar greenhouse on soil microbial flora and enzyme activities].
Taking the vegetable solar greenhouses having been planted for 2, 4, 6, 11, 13, 16, and 19 years as test objects, and with the open vegetable field as the control, this paper studied the variations of soil microbial flora and enzyme activities. With the increasing years of planting, the numbers of soil bacteria, actinomycetes, and total microbes in vegetable solar greenhouses decreased after an initial increase, and reached the maximum in the greenhouse of 11 years planting, with a significant increment of 54.8%, 63.7%, and 55.4%, respectively, as compared to the control. The number of soil fungi in the vegetable solar greenhouses increased steadily with increasing planting years, being about 2.2 times higher in the greenhouse of 11 years planting. Among the microbial physiological groups, the numbers of aerobic cellulose-decomposer, aerobic azotobacter, nitrite bacteria, denitrifier, and sulphur reducer showed the same variation trend as the soil bacteria's, and those in the greenhouse of 11 years planting being 1.5, 1.6, 1.9, 1.4, and 1.1 times of the control, respectively. The number of ammonifiers increased after an initial decrease, reached the minimum in the greenhouse of 13 years planting, being only 56.0% of the control. The enzyme activities of soil urease, polyphenol oxidase, sucrase, protease, cellulase, and alkaline phosphatase increased firstly and then decreased with the increasing years of planting, but soil catalase activity was relatively stable. Correlation analysis showed that the numbers of soil bacteria, actinomycetes, and total microbes were significantly positively correlated with all test soil enzyme activities, while the number of soil fungi had significant negative correlation with the activity of soil catalase.


Age-related loss of calcium buffering and selective neuronal vulnerability in Alzheimer's disease.
The reasons for the selective vulnerability of distinct neuronal populations in neurodegenerative disorders are unknown. The cholinergic neurons of the basal forebrain are vulnerable to pathology and loss early in Alzheimer's disease and in a number of other neurodegenerative disorders of the elderly. In the primate, including man, these neurons are rich in the calcium buffer calbindin-D(28K). Here, we confirm that these neurons undergo a substantial loss of calbindin in the course of normal aging and report a further loss of calbindin in Alzheimer's disease both at the level of RNA and protein. Significantly, cholinergic neurons that had lost their calbindin in the course of normal aging were those that selectively degenerated in Alzheimer's disease. Furthermore, calbindin-containing neurons were virtually resistant to the process of tangle formation, a hallmark of the disease. We conclude that the loss of calcium buffering capacity in these neurons and the resultant pathological increase in intracellular calcium are permissive to tangle formation and degeneration.


Delayed onset of transversus abdominus in long-standing groin pain.
Long-standing groin pain is a persistent problem that is commonly difficult to rehabilitate. Theoretical rationale indicates a relationship between the motor control of the pelvis and long-standing groin pain; however, this link has not been investigated. The current experiment aimed to evaluate motor control of the abdominal muscles in a group of Australian football players with and without long-standing groin pain. Ten participants with long-standing groin pain and 12 asymptomatic controls were recruited for the study. Participants were elite or subelite Australian football players. Fine-wire and surface electromyography electrodes were used to record the activity of the selected abdominal and leg muscles during a visual choice reaction-time task (active straight leg raising). When the asymptomatic controls completed the active straight leg raise (ASLR) task, the transversus abdominus contracted in a feed-forward manner. However, when individuals with long-standing groin pain completed the ASLR task, the onset of transversus abdominus was delayed (P < 0.05) compared with the control group. There were no differences between groups for the onset of activity of internal oblique, external oblique, and rectus abdominus (all P > 0.05). The finding that the onset of transversus abdominus is delayed in individuals with long-standing groin pain is important, as it demonstrates an association between long-standing groin pain and transversus abdominus activation.


[A priori calculations of spatial structure of neurotoxin. Fragment Leu1-Cys23].
Conformational properties of a linear and cyclic Leu1-Cys23 neurotoxine fragment have been investigated. Starting from a linear array, the most favourable cyclic form with the Cys3-Cys23 disulfide bond is shown to arise from one of the low-energy extended structures. The formation of the disulfide bond does not interfere with stabilising contacts: the proximation of S-atoms to the valence distance can be effected by small changes of the labile fragment geometry. The results obtained are indicative of the strictly predetermined mechanism of the protein folding into the native conformation with the proximal Cys residues, forming a disulfide bridge. The calculated low-energy Leu1-Cys23 neurotoxine form coincides with the X-ray structure of the corresponding fragment of erabutoxine b. For the neurotoxine II homologies, neurotoxines alpha, D, 4, CM-14 and beta, optimal orientations of side chains are determined. The amino acid changes in the 1--23 fragment are shown not to disturb the backbone form established for the neurotoxine II, and thus not to change the geometry necessary for the formation of the Cys3-Cys23 bridge.


Accuracy of finite element predictions in sideways load configurations for the proximal human femur.
Subject-specific finite element models have been used to predict stress-state and fracture risk in individual patients. While many studies analysed quasi-axial loading configurations, only few works simulated sideways load configurations, such as those arising in a fall. The majority among these latter directly predicted bone strength, without assessing elastic strain prediction accuracy. The aim of the present work was to evaluate if a subject-specific finite element modelling technique from CT data that accurately predicted strains in quasi-axial loading configurations is suitable to accurately predict strains also when applying low magnitude loads in sideways configurations. To this aim, a combined numerical-experimental study was performed to compare finite element predicted strains with strain-gauge measurements from three cadaver proximal femurs instrumented with sixteen strain rosettes and tested non-destructively under twelve loading configurations, spanning a wide cone (0-30° for both adduction and internal rotation angles) of sideways fall scenarios. The results of the present study evidenced a satisfactory agreement between experimentally measured and predicted strains (R(2) greater than 0.9, RMSE% lower than 10%) and displacements. The achieved strain prediction accuracy is comparable to those obtained in state of the art studies in quasi-axial loading configurations. Still, the presence of the highest strain prediction errors (around 30%) in the lateral neck aspect would deserve attention in future studies targeting bone failure.


The Effectiveness of a New School-Based Media Literacy Intervention on Adolescents' Doping Attitudes and Supplements Use.
The aim of the study was to evaluate the effectiveness of a media literacy intervention targeting, for the first time, the specific topic of Performance and Appearance Enhancing Substances (PAESs) use in high-school students. Overall, 389 students (52% male) aged between 13 and 19 years (mean = 16.56 year; SD = 1.26) participated to a media literacy intervention (i.e., "intervention group") while 103 students aged between 14 and 19 year (mean = 16.10 year; SD = 1.38) were considered as the control group (i.e., "control group"). In two separate occasions over the course of six consecutive months, students in both groups filled out a set of questionnaires which included measures of social-cognitive beliefs (i.e., attitudes, subjective norms, intentions) and a self-reported measure of retrospective use of doping (Yes/No) and supplements (Yes/No). Compared to students in the control group (Mean(time1) = 1.96; SD(time1) = 0.85; and Mean(time2) = 2.09; SD(time2) = 0.94), intervention students on average expressed relatively stronger attitudes against doping use over time (Mean(time1) = 2.2; SD(time1) = 0.85; and Mean(time2) = 2.05; SD(time2) = 0.82). Students in the latter group also showed a statistically significant decrease in self-reported supplement use (Use(time1) = 6.7%; Use(time2) = 3.8%; p = 0.05, McNemar Test). Interestingly, albeit marginally significant, students in the control group showed a relative increment in the self-reported use of supplements over time (Use(time1) = 4.9%; Use(time2) = 8.7%; p = 0.22, McNemar Test). Overall, the media literacy intervention investigated in the present study was effective in decreasing adolescent student's positive attitudes toward doping use and in reducing the use of legal PAES. These findings supported the generalizability and the usefulness of a media literacy approach in the specific field of PAES.


[An interpretation of the expert consensus on standards for the management of patients with primary mitochondrial disease from the Mitochondrial Medicine Society].
Primary mitochondrial disease is the most common inborn error of metabolism and is highly heterogeneous in terms of clinical manifestations and inheritance pattern. It has high mortality and disability rates. Multiple systems are often involved in this disease, and it is necessary to perform comprehensive evaluation and multidisciplinary management. The Mitochondrial Medicine Society issued the standard for the management of patients with primary mitochondrial disease: consensus statements from the Mitochondrial Medicine Society in 2017. The statements provided recommendations based on such consensus to guide the management and care of patients. This article interprets and summarizes the screening of organs and systems commonly involved in primary mitochondrial disease and the management of patients according to the consensus.


Cellular density-dependent down-regulation of EP4 prostanoid receptors via the up-regulation of hypoxia-inducible factor-1α in HCA-7 human colon cancer cells.
Increases in prostaglandin E2 (PGE2) and cyclooxygenase-2 (COX-2) levels are features of colon cancer. Among the different E-type prostanoid receptor subtypes, EP4 receptors are considered to play a crucial role in carcinogenesis by, for example, inducing COX-2 when stimulated with PGE2. However, EP4 receptor levels and PGE2-induced cellular responses are inconsistent among the cellular conditions. Therefore, the connections responsible for the expression of EP4 receptors were investigated in the present study by focusing on cell density-induced hypoxia-inducible factor-1α (HIF-1α). The expression of EP4 receptors was examined using immunoblot analysis, quantitative polymerase chain reaction, and reporter gene assays in HCA-7 human colon cancer cells with different cellular densities. The involvement of HIF-1α and its signaling pathways were also examined by immunoblot analysis, reporter gene assays, and with siRNA. We here demonstrated that EP4 receptors as well as EP4 receptor-mediated COX-2 expression levels decreased with an increase in cellular density. In contrast, HIF-1α levels increased in a cellular density-dependent manner. The knockdown of HIF-1α by siRNA restored the expression of EP4 receptors and EP4 receptor-mediated COX-2 in cells at a high density. Thus, the cellular density-dependent increase observed in HIF-1α expression levels reduced the expression of COX-2 by decreasing EP4 receptor levels. This novel regulation mechanism for the expression of EP4 receptors by HIF-1α may provide an explanation for the inconsistent actions of PGE2. The expression levels of EP4 receptors may vary depending on cellular density, which may lead to the differential activation of their signaling pathways by PGE2. Thus, cellular density-dependent PGE2-mediated signaling may determine the fate/stage of cancer cells, i.e., the surrounding environments could define the fate/stage of malignancies associated with colon cancer.


Hypericin damages the ectatic capillaries in a Roman cockscomb model and inhibits the growth of human endothelial cells more potently than hematoporphyrin does through induction of apoptosis.
Hypericin (HY) is a promising photosensitizer (PS) for use in photodynamic therapy (PDT). Port-wine stains (PWSs) are congenital superficial dermal capillary malformations. In this study, we evaluated the photocytotoxic effects of HY for PDT in human vascular endothelial cells and a chicken cockscomb model. HY significantly inhibited the growth of human umbilical vein endothelial cells (HUVECs), as determined by colorimetric assays and morphological observation, and flow cytometry assays indicated induction of apoptosis and collapse of the mitochondrial membrane potential. In addition, HY more effectively inhibited growth of and induced apoptosis in HUVECs compared with hematoporphyrin (HP). Further experiments performed in a Roman chicken cockscomb model also showed a clear photocytotoxic effect on the cockscomb dermal capillary upon intravenous injection of HY. This effect may be due to the role of HY in the induction of apoptosis. Transmission electron microscopical analysis showed mitochondrial morphological changes such as incomplete ridges and swelling, and immunohistochemical assays showed an increase in the release of cytochrome c. In conclusion, HY exhibited a greater photocytotoxic activity than did HP toward the growth of endothelial cells and may thus represent a potent PS for PWS PDT.


Epidemiology of lawn-mower-related injuries to children in the United States, 1990-2004.
Our objective for this study was to describe the epidemiology of lawn mower-related injuries among children in the United States. A retrospective analysis was conducted of data from children who were 20 years and younger in the National Electronic Injury Surveillance System of the United States Consumer Product Safety Commission for 1990-2004. There were an estimated 140700 lawn mower-related injuries to children who were 20 years and younger and treated in hospital emergency departments in the United States during the 15-year period of 1990-2004. This yielded an average of 9400 injuries annually, or 11.1 injuries per 100000 US children per year. The mean age was 10.7 (SD: 6.0) years, and 78% were boys. The leading type of lawn mower-related injury sustained by patients was a laceration (41.2%), followed by soft tissue injury (21.4%), burn (15.5%), and fracture (10.3%). The most common body region injured was the hand/finger (34.6%), followed by lower extremity (18.9%) and foot/toe (17.7%). The eyeball/face and upper extremity accounted for 10.6% and 7.4% of injuries, respectively. Burns accounted for 34.5% of injuries to the hand/finger compared with 5.5% to other body regions. Ninety-seven percent of amputation injuries occurred to the foot/toe (49.5%) and hand/finger (47.5%) compared with 3% of amputations to other body regions. Burns accounted for 41.8% of injuries among children who were < or = 5 years of age compared with 6.5% of injuries to children who were older than 5 years. Foreign body injuries accounted for 4.8% of injuries among children who were > or = 12 years of age compared with 1.6% of injuries to children who were younger than 12 years. Amputations (31.9%), lacerations (28.8%), and fractures (26.0%) accounted for almost 87% of injuries among children who were admitted or transferred to another hospital. In contrast, lacerations (42.3%), soft tissue injuries (23.3%), and burns (16.9%) predominated among children who were treated and released to home from the emergency department. Children with amputations were more likely to be admitted than children with other types of injury. Injuries related to lawn mowers are an important cause of pediatric morbidity. The relative consistency of the number of lawn mower-related injuries to children during the 15-year study period is evidence that current prevention strategies are inadequate. Passive protection that is provided by safer product design is the strategy with the highest likelihood of success in preventing these ongoing injuries. The lawn mower voluntary safety standard American National Standards Institute/Outdoor Power Equipment Institute B71.1-2003 should be revised to include more rigorous performance provisions regarding prevention of penetration of feet and toes under the mower and into the path of the blades, shielding of hot mower parts from access by young children, and equipping all ride-on lawn mowers with a no-mow-in-reverse default feature with location of its override switch behind the seating position of the ride-on mower operator. By locating the no-mow-in-reverse override switch behind the ride-on mower operator, the operator would be required to look behind the mower before mowing in reverse.


Understanding the motivation and performance of community health volunteers involved in the delivery of health programmes in Kampala, Uganda: a realist evaluation protocol.
The recruitment of community health volunteers to support the delivery of health programmes is a well-established approach in many countries, particularly where health services are not readily available. However, studies on management of volunteers are scarce and current research on human resource management of volunteers faces methodological challenges. This paper presents the protocol of a realist evaluation that aims at identifying the factors influencing the performance of community health volunteers involved in the delivery of a Red Cross immunisation programme in Kampala (Uganda) with a specific focus on motivation. The realist evaluation cycle structures the protocol. To develop the theoretical basis for the evaluation, the authors conducted interviews and reviewed the literature on community health volunteers' performance, management and organisational behaviour. This led to the formulation of the initial programme theory, which links the intervention inputs (capacity-building strategies) to the expected outcomes (positive work behaviour) with mechanisms that point in the direction of drivers of motivation. The contextual elements include components such as organisational culture, resource availability, etc. A case study design will be adopted. We define a case as a Red Cross branch, run by a programme manager, and will select two cases at the district level in Kampala. Mixed methods will be used in data collection, including individual interviews of volunteers, participant observation and document review. The thematic analysis will be based on the initial programme theory and will seek for context-mechanism-outcome configurations. Findings from the two cases will be compared. We discuss the scope for applying realist evaluation and the methodological challenges we encountered in developing this protocol. The study was approved by the Ethical Committee at Rennes University Hospital, France. Results will be published in scientific journals, and communicated to respondents and relevant institutions.


The Efficacy and Safety of Sodium-Glucose Cotransporter-2 Inhibitors in Patients with Advanced-Stage Diabetic Kidney Disease Taking Renin-Angiotensin System Blockers.
We investigated the efficacy and safety of sodium-glucose cotransporter-2 (SGLT-2) inhibitors as an add-on therapy in patients with advanced-stage diabetic kidney disease taking renin-angiotensin system (RAS) blockers. Changes in glycated hemoglobin (HbA1c), urine protein-to-creatinine ratio (UACR), body weight, systolic blood pressure, and annual change in estimated glomerular filtration rate (eGFR) were retrospectively analyzed in 20 patients after 12 months of SGLT-2 inhibitor administration (mean eGFR: 22.8 ± 9.7 mL/min/1.73 m2). All patients had advanced-stage diabetic kidney disease and were taking RAS blockers. Twenty patients matched with similar propensity scores who were not taking SGLT-2 inhibitors served as the control group. The annual change in eGFR improved significantly from -8.6 ± 12.5 mL/min/1.73 m2/year to -2.6 ± 5.0 mL/min/1.73 m2/year after 12 months by SGLT-2 inhibitor administration (p < 0.05), but did not change in the control group. Other clinical parameters, such as HbA1c, UACR, body weight, blood pressure, serum lipids, and electrolytes did not change in either group. No adverse effects were observed by taking SGLT-2 inhibitors. Using SGLT-2 inhibitors as an add-on therapy may have beneficial effects on renal function in patients with advanced-stage diabetic kidney disease taking RAS blockers without any adverse effects.


[Effect of masticatory load on oxygen tension in periodontal tissues].
Relationship between the effect of occlusional loading (weak, 10-15 H, and strong, 120-150 H) and oxygen tension (pO2) in periodontal tissues adjacent to the first molar on the working and resting sides was carried out in 57 subjects with different clinical status of the periodontium and with partial secondary adentia. pO2 decreased during exercise, the most pronounced drop (to 12 mm Hg) being observed during intensive exercise. The level of pO2 decreased greater on the resting side and in patients with periodontal diseases. The longest period of pO2 recovery (up to 50 min) was observed after intensive exercise.


A Detailed Study on Understanding Glycopolymer Library and Con A Interactions.
Synthetic glycopolymers are important natural oligosaccharides mimics for many biological applications. To develop glycopolymeric drugs and therapeutic agents, factors that control the receptor-ligand interaction need to be investigated. A library of well-defined glycopolymers has been prepared by the combination of copper mediated living radical polymerization and CuAAC click reaction via post-functionalization of alkyne-containing precursor polymers with different sugar azides. Employing Concanavalin A as the model receptor, we explored the influence of the nature and densities of different sugars residues (mannose, galactose, and glucose) on the stoichiometry of the cluster, the rate of the cluster formation, the inhibitory potency of the glycopolymers, and the stability of the turbidity through quantitative precipitation assays, turbidimetry assays, inhibitory potency assays, and reversal aggregation assays. The diversities of binding properties contributed by different clustering parameters will make it possible to define the structures of the multivalent ligands and densities of binding epitopes tailor-made for specific functions in the lectin-ligand interaction. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 2588-2597.


Unresponsiveness of rat peritoneal mast cells to immunologic reactivation.
Rat peritoneal mast cells cocultured with 3T3 fibroblasts (MC/3T3) were activated with Ag or with anti-IgE antibodies in the presence of Ca2+, and their responsiveness to a second similar challenge was evaluated. MC/3T3 were presensitized with IgE anti-DNP antibodies and activated with DNP-human serum albumin. When these MC/3T3 were reactivated with the same Ag 2 and 6 h later, they released only a minimal percentage of histamine. A gradual recovery of responsiveness was detected during the first 7 days after activation, and a full recovery was attained by days 14 to 21. A similar pattern of unresponsiveness was observed when MC/3T3 were challenged and rechallenged with cercarial Ag after presensitization with anticercarial serum. Activation of MC/3T3 with one Ag (DNP-human serum albumin or cercarial) and rechallenge 3 days later with the other Ag did not overcome the state of partial unresponsiveness. Challenging MC/3T3 with anti-IgE led to a subsequent unresponsiveness to rechallenge with the same ligand, regardless of whether or not the cells were presensitized with IgE antibodies. Cross-linkage with anti-IgE resulted in a more intense and prolonged state of unresponsiveness in comparison with that observed with Ag. When MC/3T3 activated with anti-IgE were rechallenged with various IgE-independent agents they released a percentage of histamine comparable to that of control cultures challenged with these secretagogues for the first time. MC/3T3 partially resynthesized their histamine content during the two-week period after activation. Our results suggest that MC undergo a temporary state of "physiologic" unresponsiveness after immunologic activation in the presence of calcium ions.


Filarial huge splenomegaly dramatically regressed by anti-filarial medication: A rare clinical scenario.
Lymphatic filariasis is caused by nematodes Wuchereria bancrofti, Brugia malayi and Brugia timori. Lymphatic filariasis is a spectrum of illness and can manifest as, asymptomatic microfilaraemia, acute lymphatic filariasis (lymphangitis and lymphoedema), chronic lymphoedema, elephantiasis, hydrocele, tropical pulmonary eosinophilia and some systemic manifestations which involves joint, heart, kidney, nerve, etc. We here present a case of huge splenomegaly caused by lymphatic filariasis which is a rare presentation and only few cases had been reported in the world literature so far. After treatment of filariasis spleen size was reduced dramatically and patient is doing well even after 6 months of follow up after therapy.


Tetralogy of Fallot Surgical Repair: Shunt Configurations, Ductus Arteriosus and the Circle of Willis.
In this study, hemodynamic performance of three novel shunt configurations that are considered for the surgical repair of tetralogy of Fallot (TOF) disease are investigated in detail. Clinical experience suggests that the shunt location, connecting angle, and its diameter can influence the post-operative physiology and the neurodevelopment of the neonatal patient. An experimentally validated second order computational fluid dynamics (CFD) solver and a parametric neonatal diseased great artery model that incorporates the ductus arteriosus (DA) and the full patient-specific circle of Willis (CoW) are employed. Standard truncated resistance CFD boundary conditions are compared with the full cerebral arterial system, which resulted 21, -13, and 37% difference in flow rate at the brachiocephalic, left carotid, and subclavian arteries, respectively. Flow splits at the aortic arch and cerebral arteries are calculated and found to change with shunt configuration significantly for TOF disease. The central direct shunt (direct shunt) has pulmonary flow 5% higher than central oblique shunt (oblique shunt) and 23% higher than modified Blalock Taussig shunt (RPA shunt) while the DA is closed. Maximum wall shear stress (WSS) in the direct shunt configuration is 9 and 60% higher than that of the oblique and RPA shunts, respectively. Patent DA, significantly eliminated the pulmonary flow control function of the shunt repair. These results suggests that, due to the higher flow rates at the pulmonary arteries, the direct shunt, rather than the central oblique, or right pulmonary artery shunts could be preferred by the surgeon. This extended model introduced new hemodynamic performance indices for the cerebral circulation that can correlate with the post-operative neurodevelopment quality of the patient.


Placental retention in a golden lion tamarin (Leontopithecus rosalia).
A 4-yr-old female golden lion tamarin (Leontopithecus rosalia) had placental retention after delivery of a stillborn fetus. Conservative therapy with oxytocin and dinoprost tromethamine did not result in placental expulsion and ovariohysterectomy was performed. Placental retention is a rare condition in humans and has not been well documented in non-human primates.


Scoring the 5-level EQ-5D: can latent utilities derived from a discrete choice model be transformed to health utilities derived from time tradeoff tasks?
The EuroQol Group is evaluating the use of discrete choice experiments (DCEs) in valuing health states from the 5-level EQ-5D. Notably, a discrete choice (DC) model yields a latent utility that is ordinal and unbounded, whereas health utilities must have interval properties and be anchored at 0 (representing death) and 1 (representing full health). Latent utilities must therefore be transformed to health utilities. This pilot study investigated the feasibility of performing such a transformation. 545 respondents from Canada and 403 respondents from the UK each completed a series of DC and time tradeoff (TTO) tasks. Generalized linear mixed models were used to derive latent utilities. Linear regression models incorporating logarithmic and polynomial terms, as well as nonparametric LOESS and spline models, were assessed as candidate functions for transforming the latent utilities onto the health utilities. There was a high correlation between health utilities measured through TTO tasks and latent utilities derived from modeling of DC data (Spearman rho of 0.79 in Canada and 0.86 in the UK). All transforming functions explained the between-state variation in health utilities and, upon cross-validation, had minimal bias and small mean squared errors. Although the transformation functions derived through linear regression had the desirable feature of being monotone, the LOESS transform in Canada and the spline transform in the UK lacked monotonicity. This pilot study suggests that transforming latent utilities to health utilities is feasible, and the study provides preliminary evidence that linear regression involving polynomial and logarithmic terms may be more desirable than nonparametric spline or LOESS functions.


[Ventilator modes and settings during non-invasive ventilation: effects on respiratory events and implications for their identification. 2011].
Compared with invasive ventilation, non-invasive ventilation (NIV) has two unique characteristics: its non-hermetic nature and the fact that the ventilator-lung assembly cannot be considered as a single-compartment model because of the presence of variable resistance represented by the upper airways. When NIV is initiated, the ventilator settings are determined empirically based on clinical evaluation and blood gas variations. However, NIV is predominantly applied during sleep. Consequently, to assess overnight patient-machine "agreement" and efficacy of ventilation, more specific and sophisticated monitoring is needed. The effectiveness of NIV might therefore be more correctly assessed by sleep studies than by daytime assessment. The simplest monitoring can be done from flow and pressure curves from the mask or the ventilator circuit. Examination of these tracings can give useful information to evaluate if the settings chosen by the operator were the right ones for that patient. However, as NIV allows a large range of ventilatory parameters and settings, it is mandatory to have information about this to better understand patient-ventilator interaction. Ventilatory modality, mode of triggering, pressurization slope, use or not of positive end expiratory pressure and type of exhalation as well as ventilator performances may all have physiological consequences. Leaks and upper airway resistance variations may, in turn, modify these patterns. This article discusses the equipment available for NIV, analyses the effect of different ventilator modes and settings and of exhalation and connecting circuits on ventilatory traces and gives the background necessary to understand their impact on nocturnal monitoring of NIV.


Double amplified colorimetric detection of DNA using gold nanoparticles, enzymes and a catalytic hairpin assembly.
The authors describe an isothermal and ultrasensitive colorimetric DNA assay that consists of two amplification stages using enzymes and a catalytic hairpin assembly (CHA). The first step consists in the selective amplification of DNA using Klenow fragment and nicking enzyme. The second step consists in the amplification of the optical signal by using a catalytic hairpin assembly. After two amplification steps, the DNA reaction induces the aggregation of the red gold nanoparticles to give a blue color shift. The degree of aggregation can be quantified by measurement of the ratio of the UV-vis absorbances of the solutions at 620 and 524 nm which are the wavelengths of the aggregated gold nanoparticles and bare gold nanoparticles. The detection limit is as low as 3.1 fM. Due to the use of a specific enzyme, only the desired DNAs will be detected. The method can be applied to the determination of DNA of various lengths. Despite the presence of large amounts of wildtype DNA, it can readily detect a target DNA. Conceivably, the technique has a large potential because of its high sensitivity and selectivity. Graphical abstract Schematic presentation of DNA detection using gold nanoparticles (AuNP), enzymes and catalytic hairpin assembly (CHA). Effective DNA detection is achieved through the aggregation of AuNPs which is caused by DNA amplification using enzymes and signal amplification using CHA.


[Effect of neuroleptic, adreno- and cholinolytic agents on cerebral cortical function in edema].
Experiments on rats with experimental brain edema under water intoxication were made to study the effects of the neuroleptics aminazine and propazine, the central M-cholinoblocker amizyl and the alpha-adrenoblocker phentolamine on the time-course of the recovery of cortical electric activity after passing of the wave of Leao's spreading depression (SD). The drugs under study were demonstrated to have antiedematous properties under water intoxication and to make to a considerable degree for disorders in the processes of the recovery of cortical electrogenesis after SD. It is assumed that the action of the drugs on the electrophysiological parameters under study is associated with their effects on metabolic processes and with the presence of antiedematous properties.


The in vitro effect of antirheumatic drugs on platelet function.
Several antirheumatic drugs lower the cardiovascular risk among rheumatoid arthritis patients. It is, however, unknown whether inhibition of platelet function contributes to this risk reduction. Only few studies have investigated the potential role of platelets as a target of antirheumatic drugs. In this study, platelet function was tested in vitro in samples from 24 healthy individuals spiked with antirheumatic drugs in clinically relevant concentrations or vehicle. Platelet aggregation was tested with 96-well light transmission aggregometry (LTA), and when an effect ≥20% compared to vehicle was observed, flow cytometric platelet aggregation and activation were evaluated and closure time was measured by Platelet Function Analyzer (PFA-200). When evaluated by LTA, teriflunomide (the active metabolite of leflunomide), tocilizumab, and prednisolone reduced ADP- and collagen-induced platelet aggregation ≥20%, while adalimumab increased TRAP-induced platelet aggregation ≥20%. Using flow cytometry, agonist-induced platelet aggregation with teriflunomide or vehicle was mean ± standard deviation (SD); 30.7% ± 5.8 vs. 41.7% ± 6.5, p = 0.02 using ADP, and 34.7% ± 13.9 vs. 55.8% ± 3.9, p = 0.01 using collagen. Results indicate that teriflunomide, prednisolone, and tocilizumab inhibit, and adalimumab increases platelet aggregation. The study suggests that the majority of antirheumatic drugs mainly reduced cardiovascular risk through indirect effects (e.g., reducing inflammation).


Impaired generalization of speaker identity in the perception of familiar and unfamiliar voices.
In 2 behavioral experiments, we explored how the extraction of identity-related information from familiar and unfamiliar voices is affected by naturally occurring vocal flexibility and variability, introduced by different types of vocalizations and levels of volitional control during production. In a first experiment, participants performed a speaker discrimination task on vowels, volitional (acted) laughter, and spontaneous (authentic) laughter from 5 unfamiliar speakers. We found that performance was significantly impaired for spontaneous laughter, a vocalization produced under reduced volitional control. We additionally found that the detection of identity-related information fails to generalize across different types of nonverbal vocalizations (e.g., laughter vs. vowels) and across mismatches in volitional control within vocalization pairs (e.g., volitional laughter vs. spontaneous laughter), with performance levels indicating an inability to discriminate between speakers. In a second experiment, we explored whether personal familiarity with the speakers would afford greater accuracy and better generalization of identity perception. Using new stimuli, we largely replicated our previous findings: whereas familiarity afforded a consistent performance advantage for speaker discriminations, the experimental manipulations impaired performance to similar extents for familiar and unfamiliar listener groups. We discuss our findings with reference to prototype-based models of voice processing and suggest potential underlying mechanisms and representations of familiar and unfamiliar voice perception. (PsycINFO Database Record


General practice service use at the end-of-life before and during the COVID pandemic: a population-based cohort study using primary care electronic health records.
Globally, the COVID pandemic has caused unprecedented strain in healthcare systems, but little is known about how it affected patients needing palliative and end-of-life care from general practitioners (GPs). To evaluate the impact of the pandemic on primary care service use in the last three months of life, including consultations and prescribing, and to identify associated factors DESIGN & SETTING: A retrospective cohort study in United Kingdom (UK), using data from the Clinical Practice Research Datalink (CPRD). The study cohort included those who died between 2019 and 2020. Poisson regression models using generalised estimation equations (GEE) were used to examine the association between primary care use and patient characteristics. Adjusted Rate Ratios (aRRs) and 95% Confidence Intervals (95%CI) were estimated. A total of 44,534 patients died during the study period. The pandemic period was associated with an 8.9% increase in the rate of consultations from 966.4 to 1052.9 per 1,000 person-months and 14.3% longer telephone consultation duration (from 10.1 to 11.5 minutes), with a switch from face-to-face to telephone/video consultations. The prescription of end-of-life care medications increased by 6.3%, from 1313.7-1396.3 per 1,000 person-months. The adjusted rate ratios for consultations (aRRs: 1.08, 95% CI: 1.06-1.10, P<0.001) and prescriptions (aRRs 1.05: 95% CI 1.03-1.07, P<0.001) also increased during the pandemic. The pandemic had a major impact on GP service use, leading to longer consultations, shifts from face-to-face to telephone/video consultations, and increased prescriptions. GP workload-related issues must be addressed urgently to ease the pressure on GPs.


Multiclass Skin Lesion Classification Using Hybrid Deep Features Selection and Extreme Learning Machine.
The variation in skin textures and injuries, as well as the detection and classification of skin cancer, is a difficult task. Manually detecting skin lesions from dermoscopy images is a difficult and time-consuming process. Recent advancements in the domains of the internet of things (IoT) and artificial intelligence for medical applications demonstrated improvements in both accuracy and computational time. In this paper, a new method for multiclass skin lesion classification using best deep learning feature fusion and an extreme learning machine is proposed. The proposed method includes five primary steps: image acquisition and contrast enhancement; deep learning feature extraction using transfer learning; best feature selection using hybrid whale optimization and entropy-mutual information (EMI) approach; fusion of selected features using a modified canonical correlation based approach; and, finally, extreme learning machine based classification. The feature selection step improves the system's computational efficiency and accuracy. The experiment is carried out on two publicly available datasets, HAM10000 and ISIC2018. The achieved accuracy on both datasets is 93.40 and 94.36 percent. When compared to state-of-the-art (SOTA) techniques, the proposed method's accuracy is improved. Furthermore, the proposed method is computationally efficient.


[Prognostic features of upper gastro-intestinal hemorrhages in adult over 65 (author's transl)].
Some prognostic features out of 57 cases at upper gastrointestinal hemorrhage, in people more than 65 years old, are reported. The age has no significance but after 70, gastroduodenal ulcers represent the more frequent etiology, with a very particular severity in cases of chronic and acute gastric ulceration. The mortality is still high, mainly due to decompensation of pre-existent renal, cardio-vascular or pulmonary taints, frequent in aged people.


Broad-spectrum antimicrobials and the treatment of serious bacterial infections: getting it right up front.
The treatment of serious bacterial infections is complicated by the fact that time to initiation of effective antimicrobial therapy is a strong predictor of mortality. Therefore, therapy must be initiated before the causative pathogen is identified. However, inappropriate or inadequate initial empirical therapy is associated with increased mortality, morbidity, and length of hospital stay. Initial empirical therapy with broad-spectrum antimicrobials attempts to address this dilemma by "getting it right up front." The goal is to provide treatment active against the most likely pathogens until culture/susceptibility test results are obtained. After the causative pathogen is identified, streamlining to more-precise therapy of the shortest acceptable duration is implemented. In this way, the risks of death, morbid complications, increased duration of hospital stay (as a result of ineffective initial treatment), and emergence of resistance (due to extended treatment with broad-spectrum agents) are lowered. Improved clinical and economic outcomes after such an approach have been demonstrated.


Stakeholders' experiences of comprehensive geriatric assessment in an inpatient hospital setting: a qualitative systematic review and meta-ethnography.
Comprehensive geriatric assessment (CGA) is considered the gold standard approach to improving a range of outcomes for older adults living with frailty admitted to hospital. To date, research has predominantly focused on quantitative syntheses of the international evidence with limited focus on qualitative synthesis of stakeholder perspectives. This review aims to resolve this research gap by identifying and synthesising qualitative studies reporting multiple stakeholders' experiences of inpatient CGA. A systematic search of five electronic databases was conducted. Qualitative or mixed methods studies that included qualitative findings on the experiences of CGA in an inpatient hospital setting from the perspective of healthcare professionals (HCP), older adults, and those important to them were included. The protocol was registered on PROSPERO (Registration: CRD42021283167) and the 10-item Critical Appraisal Skills Programme checklist was used to appraise the methodological quality of included studies. Results were synthesised as a meta-ethnography. Eleven studies, which reported on the experiences of 153 HCPs, 91 older adults and 57 caregivers were included. The studies dated from 2011 to 2021 and three key themes were identified: (1) HCPs, older adults and caregivers report conflicting views on CGA as a holistic process, (2) most HCPs, but only some older adults and caregivers view CGA goalsetting and care planning as collaborative, and (3) all stakeholders value care continuity during the transition from hospital to home but often fail to achieve it. While HCPs, older adults, and caregivers' values and ambitions related to CGA broadly align, their experiences often differ. The identified themes highlight organisational and relational factors, which positively and negatively influence CGA practices and processes in an inpatient hospital setting.


Efficacy of cinnamon in patients with type II diabetes mellitus: A randomized controlled clinical trial.
Multiple studies have evaluated the hypoglycemic effect of cinnamon in patients with diabetes mellitus (DM) type II, with conflicting results. Differences in Baseline Body Mass Index (BMI) of patients may be able to explain the observed differences in the results. This study was designed to evaluate the effect of cinnamon supplementation on anthropometric, glycemic and lipid outcomes of patients with DM type II based on their baseline BMI. The study was designed as a triple-blind placebo-controlled randomized clinical trial, using a parallel design. One hundred and forty patients referred to Diabetes Clinic of Yazd University of Medical Sciences with diagnosis of DM type II were randomly assigned in four groups: cinnamon (BMI ≥ 27, BMI < 27) and Placebo (BMI ≥ 27, BMI < 27). Patients received cinnamon bark powder or placebo in 500 mg capsules twice daily for 3 months. Anthropometric, glycemic and lipid outcomes were measured before and after the intervention. Cinnamon supplementation led to improvement of all anthropometric (BMI, body fat, and visceral fat), glycemic (FPG, 2hpp, HbA1C, Fasting Insulin, and Insulin Resistance), and lipids (Cholesterol Total, LDL-c and HDL-c) outcomes (except for triglycerides level). All observed changes (except for Cholesterol Total and LDL-c) were significantly more prominent in patients with higher baseline BMI (BMI ≥ 27). Based on the study findings, cinnamon may improve anthropometric parameters, glycemic indices and lipid profile of patients with type II diabetes. These benefits are significantly more prominent in patients with higher baseline BMI (BMI ≥ 27). The trial protocol was registered in Iranian Registry of Clinical Trials database (registration ID: IRCT2017031133015N1).


[Universal ethical principles and their application in clinical drug trials].
Since 1931, and especially since the Nuremberg Code of 1947, an increasing number of declarations, regulations, norms, guidelines, laws, resolutions, and rules intended to create conditions for better protection of subjects participating in research studies have been published, although some have meant setbacks in the human rights of vulnerable populations. As such, violations of the dignity of experimental subjects in clinical trials continue. What researchers investigate and how the research is done, the quality and transparency of the data, and the analysis and the publication of results (of both raw and processed data) respond to the financial interests of the pharmaceutical companies, coming into permanent tension with bioethical principles and the needs of society. The active participation of civil society is necessary to make it so that pharmaceutical research, results and applications subordinate economic benefits to the protection of human rights.


[The prospects of laser correlational spectroscopy in differential diagnosis of breast tumors and extreme cases in surgery].
The application possibility of the biophysical method laser correlational spectroscopy (LCS), permitting to obtain the information concerning the assortment of lightdispersing particles of different sizes, was studied up looking for a new approaches to trustful differential diagnosis of oncological diseases. Using the LCS method 57 healthy persons, 83 patients with the mammarial gland (MG) tumor, 26 with profuse abdominal bleeding, 32 with polytrauma, 68 in comatous state were examined. The histograms of the patients with MG cancer differed with such of the patients with benign MG tumor. In the patients with bleeding the histograms changes have preceded the arterial pressure, the erythrocytes quantity and the hemoglobin level lowering. In severe polytrauma the LCS application have permitted to disclose the internal bleeding while concurrent injury of sceleton bones. In comatous patients the histograms changes were revealed in severe craniocerebral trauma, alcoholic and narcotic intoxication and an acute disorder of cerebral blood circulation.


Is rural radiation oncology practice quality as good as the big smoke? Results of the Australian radiotherapy single machine unit trial.
Radiotherapy utilization rates in rural Australia are suboptimal, with one solution being the building of single machine units (SMUs). One concern raised with such an approach is the quality of care delivered in SMUs. The Australian and Victorian governments have established two SMUs in the state of Victoria, with each SMU operated as a satellite service of a major 'hub' site. We report on the planned evaluation of practice quality. Radiation oncologist (RO) clinical practice was externally audited using the Royal Australian and New Zealand College of Radiologists Peer Review Audit instrument. This tool splits RO clinical practice into documentation/quality assurance (QA) criteria and decision-making criteria. Over the four sites, 130 patients were randomly selected for audit. At hub sites, 79.6% of all criteria audited were adequate, compared with 84.4% of criteria audited at SMUs (P = 0.0002). This difference was largely because of better adherence to documentation/QA criteria at the SMU sites. RO decision-making and protocol adherence were routinely very high and consistent with other clinical practice audits. There were no significant differences between hubs and SMUs for adherence to decision-making criteria; however, the few potential deficiencies in patient care identified occurred only at the hub sites. In at least one of these cases, potential suboptimal management was as a direct result of inadequate documentation. This audit found that SMUs provide as high a standard of radiotherapeutic care as larger hub departments. The findings also emphasize the need for all departments to target clinical documentation.


Clinical aspects of immunosuppression in poultry.
Chickens, turkeys, and other poultry in a production environment can be exposed to stressors and infectious diseases that impair innate and acquired immunity, erode general health and welfare, and diminish genetic and nutritional potential for efficient production. Innate immunity can be affected by stressful physiologic events related to hatching and to environmental factors during the first week of life. Exposure to environmental ammonia, foodborne mycotoxins, and suboptimal nutrition can diminish innate immunity. Infectious bursal disease (IBD), chicken infectious anemia (CIA), and Marek's disease (MD) are major infectious diseases that increase susceptibility to viral, bacterial, and parasitic diseases and interfere with acquired vaccinal immunity. A shared feature is lymphocytolytic infection capable of suppressing both humoral and cell-mediated immune functions. Enteric viral infections can be accompanied by atrophic and depleted lymphoid organs, but the immunosuppressive features are modestly characterized. Some reoviruses cause atrophy of lymphoid organs and replicate in blood monocytes. Enteric parvoviruses of chickens and turkeys merit further study for immunosuppression. Hemorrhagic enteritis of turkeys has immunosuppressive features similar to IBD. Other virulent fowl adenoviruses have immunosuppressive capabilities. Newcastle disease can damage lymphoid tissues and macrophages. Avian pneumovirus infections impair the mucociliary functions of the upper respiratory tract and augment deeper bacterial infections. Recognition of immunosuppression involves detection of specific diseases using diagnostic tests such as serology, etiologic agent detection, and pathology. Broader measurements of immunosuppression by combined noninfectious and infectious causes have not found general application. Microarray technology to detect genetic expression of immunologic mediators and receptors offers potential advances but is currently at the developmental state. Control methods for immunosuppressive diseases rely largely on minimizing stress, reducing exposure to infectious agents through biosecurity, and increasing host resistance to infectious immunosuppressive diseases by vaccination. A longer-term approach involves genetic selection for resistance to immunosuppressive diseases, which has shown promising results for MD but equivocal results for IBD and CIA.


Evaluation of diagnostic tests for Johne's disease in young cattle.
To investigate the development of immune responses in calves experimentally and naturally infected with Mycobacterium paratuberculosis and to evaluate the potential for diagnostic tests to detect infected calves. Sequential testing of four treatment groups of calves over a 2 year period. Twenty-nine calves were allocated to four groups. Group D calves were orally dosed with M paratuberculosis, group N calves naturally exposed to M paratuberculosis, group V calves vaccinated for M paratuberculosis, and group C were control calves (not infected or vaccinated). Blood and faecal specimens were collected from each calf at monthly intervals to 18 months of age and then every 2 months until they were slaughtered between the ages of 21 and 29 months. Specimens were tested using absorbed EIA, IFN-gamma EIA and faecal culture. The infection status of the calves was confirmed by extensive histopathological examination and tissue culture. M paratuberculosis infection was confirmed in 10 calves, comprising six of eight orally dosed calves, three of five naturally exposed calves and one of nine vaccinated calves. The six artificially infected calves and one naturally infected calf were detected shedding M paratuberculosis in their faeces. Results with positive absorbed EIA were obtained from one artificially infected calf, one naturally infected calf and three vaccinated calves. All calves including controls had positive results on at least one occasion using the IFN-gamma EIA. In addition, seven calves had positive bovine tuberculosis results using the IFN-gamma EIA, even though bovine tuberculosis has been eradicated from Australia. Detection of M paratuberculosis infection in young cattle continues to be difficult using current tests.


Role of flexible bronchoscopic cryotechnology in diagnosing endobronchial masses.
Endobronchial masses obstruct the central airway, and cryotechnology is reportedly a feasible means of managing such masses. However, few reports have explored the role of cryotechnology in diagnosing endobronchial masses. All endobronchial masses were sampled for pathologic diagnosis by forceps biopsy and cryotechnology, performed during flexible bronchoscopy. The diagnostic accuracy of forceps biopsy and that of cryotherapy were compared by the χ(2) test, and the obtained specimen sizes were compared by the t test. Between 2007 and 2011, 75 patients with a median age of 64 years (interquartile range [IQR], 49-76; 48 men; 27 women; and 52 smokers [69.3%]) were diagnosed with endobronchial masses. The sites of these masses included the trachea (n = 17), left main bronchus (n = 16), right main bronchus (n = 11), right upper lobe bronchus (n = 11), right intermediate bronchus (n = 8), right lower lobe bronchus (n = 4), left upper lobe bronchus (n = 3), left lower lobe bronchus (n = 3), and right middle lobe bronchus (n = 2). Fifty-nine lesions were malignant, and 16 were benign. Lung squamous cell carcinoma (n = 23) was the leading cause of malignancy, and endobronchial tuberculosis (n = 9) was the most common benign disease. The diagnostic accuracy of cryotechnology was significantly higher than that of forceps biopsy (100% vs 69.3%, p < 0.0001). The specimen size obtained by cryotechnology was also significantly larger than that obtained by forceps biopsy (13.8 ± vs 1.9 ± 0.6 mm, p < 0.0001). The current study supports the view that cryotechnology is a good tool for diagnosing endobronchial masses. Cryotechnology also provides a better diagnostic specimen and has greater diagnostic accuracy than traditional forceps biopsy.


Production of superoxide and hydrogen peroxide in medium used to culture Legionella pneumophila: catalytic decomposition by charcoal.
The difficulties associated with the growth of Legionella species in common laboratory media may be due to the sensitivity of these organisms to low levels of hydrogen peroxide and superoxide radicals. Exposure of yeast extract (YE) broth to fluorescent light generated superoxide radicals (3 microM/h) and hydrogen peroxide (16 microM/h). Autoclaved YE medium was more prone to photochemical oxidation than YE medium sterilized by filtration. Activated charcoals and, to a lesser extent, graphite, but not starch, prevented photochemical oxidation of YE medium, decomposed hydrogen peroxide and superoxide radicals, and prevented light-accelerated autooxidation of cysteine. Also, suspensions of charcoal in phosphate buffer and in charcoal yeast extract medium readily decomposed exogenous peroxide (17 and 23 nmol/ml per min, respectively). Combinations of bovine superoxide dismutase and catalase also decreased the rate of photooxidation of YE medium. Medium protected from light did not accumulate appreciable levels of hydrogen peroxide, and autoclaved YE medium protected from light supported good growth of Legionella micdadei. Various species of Legionella (10(4) cells per ml) exhibited sensitivity to relatively low levels of hydrogen peroxide (26.5 microM) in challenge experiments. The level of hydrogen peroxide that accumulated in YE medium over a period of several hours (greater than 50 microM) was in excess of the level tolerated by Legionella pneumophila, which contained no measurable catalase activity. Strains of L. micdadei, Legionella dumoffi, and Legionella bozmanii contained this enzyme, but the presence of catalase did not appear to confer appreciable tolerance to exogenously generated hydrogen peroxide.


Echocardiographic markers of severe tricuspid regurgitation associated with right-sided congestive heart failure.
Severe tricuspid regurgitation (TR), diagnosed with echocardiography, is not necessarily symptomatic. The study aim was to identify echocardiographic markers associated with right-sided congestive heart failure (RCHF) in patients with severe TR. Ninety-six patients (30 males, 66 females; mean age 67 +/- 11 years) with echocardiographic findings of severe TR were followed clinically and with transthoracic echocardiography (TTE). Clinical data were collected on heavy diuretic consumption and signs of volume overload (neck vein congestion, lower-limb edema, ascites). TTE included evaluation of the right heart chamber dimensions, systolic function, pulmonary pressure and change in inferior vena cava (IVC) diameter during respiration. Patients were subdivided according to the presence (group A, n = 52) or absence (group B, n = 44) of signs of RCHF that included volume overload and heavy diuretic consumption (i.e. > or = 80 mg furosemide/day or combined furosemide/spironolactone at any dosage). Among the patients, 52 (54.2%) had RCHF and 44 (45.8%) did not. Atrial fibrillation was present in 88% of group A and 76% of group B (p = NS). Group A patients had a significantly larger right ventricular area, right atrial area and IVC diameter than group B patients, but a significantly smaller variation in IVC diameter during respiration (11.2 +/- 8.5% versus 24.3 +/- 14.1%, p = 0.001). Right ventricular systolic function and systolic pulmonary pressure were similar in the two groups. On multivariate analysis, respiratory-related variation in IVC diameter (p <0.001) and systolic pulmonary artery pressure (p = 0.04) were the only independent echocardiographic markers of RCHE CONCLUSION: Diminished respiratory variation in IVC diameter and systolic pulmonary artery pressure are independent markers of volume overload in patients with severe TR. These findings may reflect exhaustion of IVC capacitance due to markedly increased right heart filling pressures, though intrinsic changes in IVC tonus may also be involved.


Intracerebral Nanoparticle Transport Facilitated by Alzheimer Pathology and Age.
Nanoparticles have emerged as potential transporters of drugs targeting Alzheimer's disease (AD), but their design should consider the blood-brain barrier (BBB) integrity and neuroinflammation of the AD brain. This study presents that aging is a significant factor for the brain localization and retention of nanoparticles, which we engineered to bind with reactive astrocytes and activated microglia. We assembled 200 nm-diameter particles using a block copolymer of poly(lactic-co-glycolic acid) (PLGA) and CD44-binding hyaluronic acid (HA). The resulting PLGA-b-HA nanoparticles displayed increased binding to CD44-expressing reactive astrocytes and activated microglia. Upon intravascular injection, nanoparticles were localized to the hippocampi of both APP/PS1 AD model mice and their control littermates at 13-16 months of age due to enhanced transvascular transport through the leaky BBB. No particles were found in the hippocampi of young adult mice. These findings demonstrate the brain localization of nanoparticles due to aging-induced BBB breakdown regardless of AD pathology.


Clinical and therapeutic features of nonpostoperative nosocomial intra-abdominal infections.
To compare the clinical, microbiological, and therapeutic features of nonpostoperative nosocomial intra-abdominal infections (non-PostopNAI) with community-acquired intra-abdominal infections (CAI). Prospective (June 2000 through January 2001) consecutive case series analysis of patients operated for secondary nonpostoperative intra-abdominal infections collected in 176 study centers (surgical wards and intensive care units). Clinical, microbiological, and therapeutic characteristics of CAI and non-PostopNAI infections were collected. Management of antibiotic therapy was decided by the attending physician. The efficacy of treatment was evaluated over a 30-day period after the index episode. Evaluatable observations (n = 1008) were collected (761 CAI and 247 non-PostopNAI), including 285 intensive care unit patients. When compared with CAI patients, non-PostopNAI patients presented an increased interval between admission to the surgical ward and operation (1.3 +/- 1.5 vs. 0.5 +/- 0.7 days in CAI patients; P < 0.001), increased proportions of underlying diseases, a more severe clinical condition as assessed by increased proportions of hospitalization in the intensive care unit (48% vs. 22% in CAI patients, P < 0.001) and a higher SAPS II score (34 +/- 15 vs. 24 +/- 14, P < 0.001). In non-PostopNAI patients, increased proportions of therapeutic failure (15% vs. 7% in CAI patients, P < 0.01) and of fatalities (12% vs. 4% in CAI patients, P < 0.001) were observed. Delayed diagnosis and increased severity are the main characteristics of non-PostopNAI infections. Microbiological features are quite similar in CAI and non-PostopNAI infections, suggesting that antibiotic therapy recommended for CAI infections could be applied to non-PostopNAI patients. Characteristics of non-PostopNAI patients should lead to identify them as a specific entity in clinical trials.


Hepatocyte adhesion to carbohydrate-derivatized surfaces. I. Surface topography of the rat hepatic lectin.
The rat hepatic lectins, galactose- and N-acetylgalactosamine-binding proteins found on the hepatocyte cell surface, mediate adhesion of isolated primary rat hepatocytes to artificial galactose-derivatized polyacrylamide gels. Biochemical and immunohistochemical techniques were used to examine the topographical redistribution of the rat hepatic lectins in response to galactose-mediated cell adhesion. Hepatocytes isolated from rat liver by collagenase perfusion had an average of 7 x 10(5) cell surface lectin molecules per cell, representing 30-50% of the total lectin molecules per cell, the remainder residing in intracellular pools. Hepatocytes incubated on galactose-derivatized surfaces, whether at 0-4 degrees C or 37 degrees C, rapidly lost greater than 80% of their accessible cell surface lectin binding sites into an adhesive patch of characteristic morphology. The kinetics of rat hepatic lectin disappearance were used to estimate a lateral diffusion coefficient greater than 9 x 10(-9) cm2/s at 37 degrees C, suggesting rapid and unimpeded lectin diffusion in the plane of the membrane. Indirect immunofluorescence labeling of adherent cells using antihepatic lectin antibody revealed a structured ring of receptors surrounding an area of exclusion (patch) of reproducible size and shape which represented approximately 8% of the hepatocyte cell surface. Notably, adherent cells, which had lost greater than 80% of their accessible surface binding sites, still endocytosed soluble galactose-terminated radioligand at greater than 50% of the rate of nonadherent control cells. No net movement of rat hepatic lectin from intracellular pools to the cell surface was found on cells recovered after adhesion to galactose-derivatized surfaces at 37 degrees C, suggesting that the physical size and/or lectin density of the patch was restricted by kinetic or topological constraints.


Prescribing pattern of Bryophyllum preparations among a network of anthroposophic physicians.
The use of preparations from Bryophyllum pinnatum for tocolysis (or to arrest labor) is supported by observations obtained mainly at empirical level, but also by preclinical experiments performed with uterus strips and myometrium cell lines. Furthermore, a retrospective matched-pair study revealed good tolerability and effectiveness. In anthroposophic medicine, however, Bryophyllum species are used for a broad spectrum of diagnoses. Here, we characterize the prescribing pattern of Bryophyllum preparations in a network of anthroposophic physicians in Germany. 38 primary-care physicians in Germany participated in the EvaMed network, a multi-center observational study. They documented anonymized prescriptions, diagnoses and demographic data (age and gender) for each consecutive patient between 01.01.2004 and 01.01.2010. Diagnoses were coded according to the 10th revision of the International Classification of Diseases (ICD-10). In the present analysis, all prescriptions of any Bryophyllum preparation in the resulting data bank were identified and the corresponding diagnoses were analyzed retrospectively. A total of 4,038 prescriptions of Bryophyllum preparations were identified in the EvaMed data bank. A variety of preparations could be found, 77.7% of which were prepared from Bryophyllum plants exclusively and 22.5% were combinations. Bryophyllum preparations were often prescribed to treat 'mental and behavioral disorders' (ICD-10 F00-F99, 35.7%) and 'diseases of the skin and subcutaneous tissue' (L00-L99, 16.0%), followed by 'symptoms, signs, and abnormal clinical and laboratory findings, not elsewhere classified diseases' (R00-R99, 15.2%) and 'diseases of the nervous system' (G00- G99, 9.7%). By revealing the use of Bryophyllum preparations in so many other indications than preterm delivery, our data clearly show the urgent need to conduct additional clinical trials.