Multimeric composition of plasma von Willebrand factor in chronic myelocytic leukaemia.
We studied the multimeric composition of plasma von Willebrand factor (vWf) in 26 patients with chronic myelocytic leukaemia (CML); 13 in chronic phase, 8 in blast crisis, 5 in both chronic phase and blast crisis. The relative amount of large (multimer band greater than or equal to 11) multimers calculated by densitometer scan following SDS-agarose gel electrophoresis was 14.6 +/- 2.9% (mean +/- SD) in normal controls, 8.7 +/- 4.7% in chronic phase and 15.0 +/- 5.2% in blast crisis. CML patients in chronic phase (but not in blast crisis) had a significantly lower percentage of large multimers than normal controls (p less than 0.001). The relative amount of large multimers was positively correlated with a ratio of ristocetin cofactor/vWf antigen (p less than 0.005), and was negatively correlated with platelet count (p less than 0.001), WBC count (p less than 0.05) and granulocyte count (p less than 0.05). We conclude that some patients with CML, especially in chronic phase, lack large multimers. The negative correlation of the relative amount of large multimers with platelet and granulocyte count suggests that large multimers may be consumed in high platelet count states or degraded by protease(s) from increased blood cells.


Dimensionality Analysis of the Thought Suppression Inventory: Combining EFA, MSA, and CFA.
The Thought Suppression Inventory (TSI; Rassin, European Journal of Personality 17: 285-298, 2003) was designed to measure thought intrusion, thought suppression and successful thought suppression. Given the importance to distinguish between these three aspects of thought control, the aim of this study was to scrutinize the dimensionality of the TSI. In a sample of 333 Dutch senior citizins, we examined (1) the dimensionality of the TSI using various procedures such as PAF, Mokken scale analysis (MSA) and CFA, and (2) the scale properties of the TSI. PAF favored a two factor solution, however, MSA and CFA suggested that three dimensions most adequately capture the structure of the TSI. Although all scales obtained at least medium scalability coefficients, several items were identified that are psychometrically unsound and may benefit from rewording or replacement. The findings suggest that the TSI is a three-dimensional questionnaire as originally proposed by Rassin (European Journal of Personality 17: 285-298, 2003) measuring thought intrusion, thought suppression, and successful thought suppression.


Nasal lavage technique reveals regular inhalation exposure of microplastics, not associated from face mask use.
During the COVID-19 pandemic, the use of face masks has been a worldwide primary protection measure to contain the spread of the virus. However, very little information is known about the possible inhalation of microplastics (MP) from wearing masks. This pilot study evaluates the presence of MP accumulated in nasal cavities through the nasal lavages technique. Six different commercial face masks were tested in 18 participants during five working days (8 h use/day). Eight different polymers (polystyrene, polyamide, poly(ethylene - propylene) diene monomer, polyester, polyethylene, polyvinylidene fluoride, polypropylene, and polyvinyl chloride) predominantly within the 20-300 µm size were detected in nasal lavages, with an average concentration of 28.3 ± 15.6 MP/5 mL nasal solution. Results demonstrate that MP in the nasal cavity are not associated to face mask use but rather to general exposure to airborne MP. We highlight the use of nasal lavages to evaluate human inhalation of MP and associate it to potential sources and risks.


Patients with mild cognitive impairment diagnosed at dementia clinic display decreased maximum occlusal force: a cross-sectional study.
Previous research indicates that patients with mild cognitive impairment (MCI) are more likely to have poor oral health and impairments in oral functions, which may be due to few remaining teeth and impaired tongue and lip motor function. However, the oral health of those patients following comprehensive cognitive assessment by a dementia specialist has not been sufficiently investigated. Therefore, this study aimed to clarify the oral function of patients with MCI and the association between oral health and lower cognitive function. This cross-sectional study included 96 participants (men: 35; women: 61; mean age: 73.3 ± 8.5 years) who visited a dementia clinic between December 2017 and January 2020. Participants' cognitive function was assessed by a dementia specialist using neuropsychological and hematological tests and neuroimaging immediately after enrollment. The participants were divided into the healthy and MCI groups according to comprehensive cognitive assessment. Participants' age, sex, body mass index, primary disease, education level, drinking habits, smoking habits, living environment, employment status, and exercise habits were evaluated. Moreover, oral outcomes, including the number of existing teeth, number of functional teeth (natural and prosthetic teeth which were occluded with antagonists), denture use, oral dryness, tongue and lip motor function, tongue pressure, occlusal force, masticatory ability, and swallowing ability were recorded. The Mann-Whitney U test, χ2, and Fisher's exact tests were used for between-group comparisons. Furthermore, logistic regression analysis using MCI diagnosis as the target variable was performed. A comprehensive evaluation of the cognitive function of the study participants by the dementia specialist revealed that 48 participants (mean age: 69.8 ± 8.8 years) were healthy and 48 (mean age: 76.9 ± 6.7 years) had MCI. MCI participants were significantly older (p < 0.001) and had significantly fewer existing teeth (p = 0.031) and lower maximum occlusal force (p = 0.019) than healthy participants. Age (odds ratio: 1.126, p = 0.002) and maximum occlusal force (odds ratio: 0.978, p = 0.048) were significantly associated with lower cognitive function. Patients with MCI had poorer oral health than healthy individuals. Decreased maximum occlusal force was independently associated with lower cognitive function, even when adjusted for age and sex.


Design and synthesis of active site inhibitors of the human farnesyl pyrophosphate synthase: apoptosis and inhibition of ERK phosphorylation in multiple myeloma cells.
Human farnesyl pyrophosphate synthase (hFPPS) controls intracellular levels of FPP and post-translational prenylation of small GTPase proteins, which are essential for cell signaling and cell proliferation. Clinical investigations provide evidence that N-BP inhibitors of hFPPS are disease modifying agents that improve survival of multiple myeloma (MM) patients via mechanisms unrelated to their skeletal effects. A new series of N-BPs was designed that interact with a larger portion of the GPP subpocket, as compared to the current therapeutic drugs, and rigidify the (364)KRRK(367) tail of hFPPS in the closed conformation in the absence of IPP. An analogue of this series was used to demonstrate inhibition of the intended biological target, resulting in apoptosis and down-regulation of ERK phosphorylation in human MM cell lines.


Knowing Your Preference: The Nexus of Personality and Leadership.
Prelicensure nursing students must be prepared to address the new challenges that will confront them in the modern health care environment. Leadership development, the gaining of tools and education about the process of influencing and persuading others, is important when working with groups and teams in the work place. Recognition of one's personality preferences using self-assessment is a critical dimension of leadership development. This study examined the personality preferences of a cohort of prelicensure nursing students (N = 14) enrolled in an 18-month leadership program. Students completed the Myers-Briggs assessment before starting and at the completion of the program. Through active student-centered learning and experiential exercises, students became more aware of how they preferred to relate to others and how this might affect their work in groups and leading interprofessional teams. The most prominent personality type for both pre- and postassessment was extroversion, sensing, thinking, and judging.


[Idiopathic lipoatrophic panniculitis in an adult treated with hydroxychloroquine and adipocyte grafting].
Idiopathic lipoatrophic panniculitis is a rare disease. Various terms are used in the literature to describe similar entities: annular lipoatrophy of the ankles, lipophagic panniculitis and lipoatrophic panniculitis. In any event, it consists of an inflammatory process progressing to necrosis of the fatty tissue. Herein we report the case of a 37-year-old woman presenting characteristic signs: erythematous, annular, symmetrical, painful, inflammatory lesions of the lower extremities, progressing to areas of atrophy with an indurated inflammatory periphery. Histopathology showed lobular panniculitis composed primarily of lymphocytes and macrophages. The etiological investigations ruled out all other causes of lobular panniculitis. The patient was successfully treated with hydroxychloroquine 400mg/day for 1 year and she subsequently underwent fat grafting on the secondary lesions. Our literature review identified 23 reported cases of idiopathic lipoatrophic panniculitis since 2006, including 10 cases of annular ankle lipoatrophy. The most commonly used treatments are corticosteroids, hydroxychloroquine and methotrexate, with good efficacy being seen on the inflammatory phase. This disease seems a good indication for fat grafting to limit aesthetic sequelae. Lipoatrophic panniculitis, a rare disease, results in significant aesthetic sequelae which may be limited by early treatment initiation. The benefit-risk ratio of hydroxychloroquine suggests its value as first-line therapy in this pathology. Our case also demonstrates the value of filling of the secondary atrophy by fat grafting after the inflammatory period has ended.


Effect of productivity and seasonal variation on phytoplankton intermittency in a microscale ecological study using closure approach.
A microscale ecological study using the closure approach to understand the impact of productivity controlled by geographical and seasonal variations on the intermittency of phytoplankton is done in this paper. Using this approach for a nutrient-phytoplankton model with Holling type III functional response, it has been shown how the dynamics of the system can be affected by the environmental fluctuations triggered by the impact of light, temperature, and salinity, which fluctuate with regional and seasonal variations. Reynold's averaging method in space, which results in expressing the original components in terms of its mean (average value) and perturbation (fluctuation) has been used to determine the impact of growth fluctuation in phytoplankton distribution and in the intermittency of phytoplankton spreading (variance). Parameters are estimated from the nature of productivity and spread of phytoplankton density during field observation done at four different locations of Tokyo Bay. The model validation shows that our results are in good agreement with the field observation and succeeded in explaining the intermittent phytoplankton distribution at different locations of Tokyo Bay, Japan, and its neighboring coastal regions.


Fluorescent differential display analysis of gene expression in apoptotic neuroblastoma cells.
Identification of differentially expressed genes will provide leads in the elucidation of the molecular mechanisms underlying neuronal cell death associated with neurodegenerative disorders. Using a high-throughput fluorescent differential display (FDD) system based on an automated DNA sequencer, we analyzed global patterns of gene expression during the apoptosis of neuroblastoma SH-SY5Y cells induced by a neurotoxin, colchicine. Initial screening of approximately 24000 cDNA bands displayed with 320 primer combinations has revealed 263 fragments showing differential expression patterns, suggesting that approximately 1% of transcripts are modulated in their expression level. Of these differentially displayed bands, we cloned 18 fragments composed of 17 distinct species and confirmed differential expression of each species by reverse transcription-PCR or Northern blot hybridization, thereby proving the reliability of the approach. These include eight derived from seven known genes, five homologous to expressed sequence tags (ESTs), and five totally lacking any homology to those deposited in the database. Among these, a novel transcript SAI1 induced prominently was characterized further and revealed to encode a putative RNA-binding protein NAPOR (neuroblastoma apoptosis-related RNA-binding protein), containing three copies of evolutionarily conserved RNA recognition motif. Since several RNA-binding proteins have been known to play crucial roles in other apoptosis systems, it is conceivable that NAPOR is also involved in the process of neuronal cell death.


Multi-Omics Analysis of Mammary Metabolic Changes in Dairy Cows Exposed to Hypoxia.
Hypoxia exposure can cause a series of physiological and biochemical reactions in the organism and cells. Our previous studies found the milk fat rate increased significantly in hypoxic dairy cows, however, its specific metabolic mechanism is unclear. In this experiment, we explored and verified the mechanism of hypoxia adaptation based on the apparent and omics results of animal experiments and in vitro cell model. The results revealed that hypoxia exposure was associated with the elevation of AGPAT2-mediated glycerophospholipid metabolism. These intracellular metabolic disorders consequently led to the lipid disorders associated with apoptosis. Our findings update the existing understanding of increased adaptability of dairy cows exposure to hypoxia at the metabolic level.


Rational multivalency construction enables bactericidal effect amplification and dynamic biomaterial design.
The multivalency of bioligands in living systems brings inspiration for not only the discovery of biological mechanisms but also the design of extracellular matrix (ECM)-mimicking biomaterials. However, designing controllable multivalency construction strategies is still challenging. Herein, we synthesized a series of well-defined multivalent antimicrobial peptide polymers (mAMPs) by clicking ligand molecules onto polymers prepared by reversible addition-fragmentation chain transfer polymerization. The multiple cationic ligands in the mAMPs could enhance the local disturbance of the anionic phospholipid layer of the bacterial membrane through multivalent binding, leading to amplification of the bactericidal effect. In addition to multivalency-enhanced antibacterial activity, mAMPs also enable multivalency-assisted hydrogel fabrication with an ECM-like dynamic structure. The resultant hydrogel with self-healing and injectable properties could be successfully employed as an antibacterial biomaterial scaffold to treat infected skin wounds. The multivalency construction strategy presented in this work provides new ideas for the biomimetic design of highly active and dynamic biomaterials for tissue repair and regeneration.


Modifying the rheological properties, in vitro digestion, and structure of rice starch by extrusion assisted addition with bamboo shoot dietary fiber.
This paper investigated the effect of extrusion treatment on the rheological properties, in vitro digestibility, and multi-structure of starch with or without bamboo shoot dietary fiber (BSDF). The viscoelasticity and thixotropy decreased after extrusion treatment, however, they increased after BSDF addition, and decreased with increasing BSDF content. The starch granules became smooth and formed big lumps after extrusion treatment. The dense lumps became loose after the addition of BSDF. Extrusion treatment changed the movement and arrangement of starch chains and thus the relative crystallinity and branching degree decreased by 92.6% and 40.9%, respectively. The disruption of starch further increased rapid digestion starch (RDS) content by 10%. The decreased disruption of starch granules and increased entanglement between BSDF and starch decreased the RDS content. The addition of BSDF is a novelty method to enhance the nutritional properties and control the physicochemical properties of extruded starchy foods.


Peptidergic neurohormonal systems in the basal hypothalamus of the ferret and the mink: immunocytochemical study of variations during the annual reproductive cycle.
The hypothalamic systems secreting corticotropin-releasing hormone (CRF), somatostatin, oxytocin, vasopressin and luteinizing hormone-releasing hormone (LHRH) were characterized using immunochemistry, and variations were studied in relation to the recrudescence of testicular activity in the ferret and the mink, two species with opposite photoregulation of their annual reproductive cycles. Under the present conditions of study, the immunoreactivity of the CRF, somatostatin, and oxytocin systems showed no significant variation in either species. In contrast, in these two species, the immunoreactivity of the LHRH system varied considerably depending on the date of observation. The increase in the number and immunoreactivity of the LHRH-secreting neurons that occurred in November in the mink and in January in the ferret, is in agreement with previous results showing that the photoperiod plays an essential role in regulating the annual activity of the testis and that the photoperiodic environmental conditions required for the activation of the LHRH system differ between the species. Similarly, correlations could be found between an increase in immunoreactivity of the vasopressinergic axons projecting to the external median eminence and the recrudescence of testicular activity.


Nonlinear decoding and asymmetric representation of neuronal input information by CaMKIIα and calcineurin.
How information encoded in glutamate release rates at individual synapses is converted into biochemical activation patterns of postsynaptic enzymes remains unexplored. To address this, we developed a dual fluorescence resonance energy transfer (FRET) imaging platform and recorded CaMKIIα and calcineurin activities in hippocampal neurons while varying glutamate uncaging frequencies. With little spine morphological change, 5 Hz spine glutamate uncaging strongly stimulated calcineurin, but not CaMKIIα. In contrast, 20 Hz spine glutamate uncaging, which induced spine growth, activated both CaMKIIα and calcineurin with distinct spatiotemporal kinetics. Higher temporal resolution recording in the soma revealed that CaMKIIα activity summed supralinearly and sensed both higher frequency and input number, thus acting as an input frequency/number decoder. In contrast, calcineurin activity summated sublinearly with increasing input number and showed little frequency dependence, thus functioning as an input number counter. These results provide evidence that CaMKIIα and calcineurin are fine-tuned to unique bandwidths and compute input variables in an asymmetric manner.


Inhibition of allergen-induced lung eosinophilia by type-III and combined type III- and IV-selective phosphodiesterase inhibitors in brown-Norway rats.
We examined the effect of a type IV (rolipram) and a combined type III and IV (Org 20421) isoenzyme-selective phosphodiesterase inhibitor upon allergen-induced pulmonary eosinophil recruitment in sensitised Brown Norway rats. Rats were sensitised with ovalbumin intraperitoneally and later challenged with ovalbumin aerosol which induced a significant increase in the total eosinophil and neutrophil count in bronchovalveolar lavage fluid at 24 hours (from 0.38 +/- 0.12 to 1.36 +/- 0.18 x 10(6), p < 0.01 and from 0.06 +/- 0.01 to 0.33 +/- 0.07 x 10(6), p < 0.01) respectively. Pretreatment with rolipram (30 mumol/kg) and Org 20421 (30 mumol/kg) abolished the eosinophilia and neutrophilia evoked by ovalbumin. We conclude that type IV and possibly type III isozyme phosphodiesterase inhibitors may regulate, directly or indirectly, eosinophil and neutrophil activity and/or those cells responsible for attracting them into the lung.


[Physical forces in blister formation. I. Direct measurement of blister fluid colloid osmotic pressure in suction blisters and in bullous diseases (author's transl)].
The physical forces operative in the fluid migration from the interstitial spaces into the blister cleft have not been directly measured until now. The colloid osmotic pressure was determined in suction blister fluid after mild suction blister production by a modified "Dermovac" and in blister fluid of patients with dermatitis herpetiformis, bullous allergic contact dermatitis and pemphrigus vulgaris and in the sera of healthy persons. The colloid osmotic pressure was measured by means of a recently developed osmometer with a semipermeable membrane between two chambers, one of them filled with Ringer solution, the other with the blister fluid sample. The negative pressure in the first chamber was determined. The colloid osmotic pressure of suction blister fluid averages approximately 7 cm H2O, the values reach about 20 cm H2O in bullous diseases and about 38 cm H2O in the normal sera. The blister fluid colloid osmotic pressure has to rise to about 15 cm H2O or more to cause the fluid transport from the interstitial spaces of the surrounding tissue into the blister because of the negative interstitial fluid pressure and the colloid osmotic pressure of the interstitial fluid. Otherwise the blister fluid is reabsorbed back into the interstitial spaces.


NO involvement in the inhibition of ghrelin on voltage-dependent potassium currents in rat hippocampal cells.
Ghrelin is a peptide hormone that plays an important role in promoting appetite, regulating distribution and rate of use of energy, cognition, and mood disorders, but the relevant neural mechanisms of these function are still not clear. In this study, we examined the effect of ghrelin on voltage-dependent potassium (K+) currents in hippocampal cells of 1-3 days SD rats by whole-cell patch-clamp technique, and discussed whether NO was involved in this process. The results showed that ghrelin significantly inhibited the voltage-dependent K+ currents in hippocampal cells, and the inhibitory effect was more significant when l-arginine was co-administered. In contrast, N-nitro- l-arginine methyl ester increased the ghrelin inhibited K+ currents and attenuated the inhibitory effect of ghrelin. While d-arginine (D-AA) showed no significant impact on the ghrelin-induced decrease in K+ current. These results show that ghrelin may play a physiological role by inhibiting hippocampal voltage dependent K+ currents, and the NO pathway may be involved in this process.


Matching Clostridioides difficile strains obtained from shoe soles of healthcare workers epidemiologically linked to patients and confirmed by whole-genome sequencing.
The source of transmission of Clostridioides difficile in healthcare institutions is frequently unknown. The aim of this prospective cohort study was to assess the association between strains cultured from patients and shoe soles of healthcare workers (HCWs), as already shown in the operating theatre, but not on general hospital wards in an acute-care institution. We conducted a study at a university tertiary care centre in Switzerland. From October 2019 to July 2020, shoe soles of HCWs were cultured for C. difficile twice per shift while taking care of a patient infected with toxigenic C. difficile. Additional risk factors were assessed by interviewing involved HCWs. Patients' faecal samples were processed by routine microbiological methods. Similarity of the HCWs' and patients' strains was determined by whole-genome sequencing (WGS). A total of 103 HCWs exposed to 42 hospitalized patients participated in the study, providing 206 samples. Contamination of shoe soles with C. difficile was detected in 37 samples (17.8%) of HCWs taking care of patients infected with C. difficile. Overall, transmission was suspected by epidemiological link and matching strains demonstrated by WGS in 74%. HCWs' shoe soles were positive in 17.8% with C. difficile strains linked epidemiologically and confirmed by WGS to infected patients suggesting potential transmission by HCWs' shoe soles. This pilot study provides sufficient evidence to further evaluate this potential mode of healthcare-associated transmission of C. difficile by a larger clinical trial.


Type II collagen fragment HELIX-II is a marker for early cartilage lesions but does not predict the progression of cartilage destruction in human knee joint synovial fluid.
To determine whether there is a direct correlation between the concentration of type II collagen fragment HELIX-II in synovial fluid and the severity of cartilage damage at the knee joint, 83 patients who had undergone knee arthroscopy or total knee replacement were enrolled in this study (49% women, mean ± SD age 49.5 ± 19). The content of HELIX-II in the synovial fluid samples was measured by enzyme-linked immunosorbent assay (ELISA). Cartilage damage at the knee joint was classified during arthroscopy or direct surgical observation, using the Outerbridge cartilage damage scoring system. The maximum damage score was defined as the highest score among the six areas of the knee joint, and the cumulative score was defined as the sum of the scores of the six areas of the knee joint. The intra-assay and inter-assay variations of the HELIX-II ELISA were lower than 13 and 15%, respectively. The level of HELIX-II in the severely damaged cartilage groups (cumulative scores = 11-24 or maximum score = 2-4) was much higher than in the slightly damaged cartilage groups (cumulative scores = 0-10 or maximum score = 0-1). The level of HELIX-II in cartilage from severely damaged cartilage groups was significantly higher than in the slightly damaged groups, but no significant difference was detected in the level of HELIX-II among the severely damaged cartilage sub-groups. There was a significant correlation between the HELIX-II concentration in the synovial fluid and the cumulative (r = 0.807) and maximum scores (r = 0.794). Thus, elevated HELIX-II level is correlated with early cartilage lesions, but does not have the sensitivity to predict the progression of severity of cartilage damage in the knee joint.


In Vitro Biochemical Analysis of Recombinant Plant Proteins Under Oxidation.
Biochemical analysis is crucial for determining protein functionality changes during various conditions, including oxidative stress conditions. In this chapter, after giving brief guidelines for experimental design, we provide step-by-step instructions to purify recombinant plant proteins from E. coli, to prepare reduced and oxidized proteins for activity assay, and to characterize the protein under reducing and oxidizing conditions, with a focus on thiol-based oxidative modifications, like S-sulfenylation and disulfide formations.


Clinical outcomes and costs for patients with type 2 diabetes mellitus initiating insulin therapy in Greece: two-year experience from the INSTIGATE study.
To evaluate the quality of metabolic control, clinical outcomes, resource costs, and quality of life among patients with type 2 diabetes mellitus (T2DM), who initiated insulin for the first time as part of routine clinical practice. The INSTIGATE study is a prospective, multicentric, observational study of patients initiating insulin treatment. This sub-cohort analysis focuses on Hellenic outcomes. At baseline, 263 Greek patients were enrolled just before initiating insulin for the first time. At the 6-month visit, 237 patients (90.1%) remained and consented to an additional 18-month observation period. In these 237 extension patients, over the 24-month post-initiation period, HbA1c (mean(SD)) decreased from 9.7%(1.6%) to 7.1%(0.9%) and body weight and BMI increased (+3(6)kg and +1.1(2.2)kg/m(2), respectively). At each post-baseline visit approximately one in five patients reported ≥1 episodes of hypoglycaemia in the preceding 3-6 months. Median total costs fluctuated from 438€ at baseline to 538€ up to 6 months and 451€ at 24 months; mean costs were 496(383)€, 573(276)€ and 485(247)€, respectively. In this cohort, insulin treatment seems to be effective with little long-term impact on cost. Findings should be interpreted in the context of an observational study.


Prognostic value of timing and duration characteristics of exercise oscillatory ventilation in patients with heart failure.
Exercise oscillatory ventilation (EOV) occurs in a sub-group of patients with increased heart failure (HF) severity and poorer prognosis. The purpose of this investigation was to examine the prognostic value of the largest ventilatory oscillation characteristics in HF patients. One hundred fifty-four subjects diagnosed with HF underwent cardiopulmonary exercise testing. Subjects with EOV were then divided into two sub-groups: (1) largest ventilatory oscillation during the first half of exercise with an oscillation width > or =30 seconds; and (2) largest ventilatory oscillation during the second half of exercise or an oscillation width <30 seconds. Subjects were tracked for major cardiac events after the exercise test. The fifty-five subjects (35.7%) in the overall group demonstrating EOV during the exercise test were at significantly higher risk for adverse events (hazard ratio = 3.0, 95% confidence interval 1.6 to 5.5, p < 0.001). The prognostic value of this ventilatory phenomenon improved when only subjects with the largest ventilatory oscillation during the first half of exercise with an oscillation width > or =30 seconds were defined as having EOV (hazard ratio = 3.6, 95% confidence interval 1.6 to 7.9, p = 0.002). In this study we found that the characteristics of the largest oscillatory ventilation provide valuable prognostic information in patients with EOV.


Letter to the Editor: Insights into migraine surgery - An ACS-NSQIP data analysis over a 13- year period.
We demonstrate the safety of MS based on big data database research and outline the clinical relevance of white female migraineurs affected by menstrual migraines.


Role of GM3-enriched microdomains in signal transduction regulation in T lymphocytes.
Gangliosides, sialic acid containing glycosphigolipids, are ubiquitous constituents of cell plasma membranes. Each cell type shows a peculiar ganglioside expression pattern. In human T lymphocytes monosialoganglioside GM3 represents the main ganglioside constituent of cell plasma membrane where it is concentrated in glycosphingolipid-enriched microdomains (GEM). The presence of tyrosine kinase receptors, mono- (Ras, Rap) and heterotrimeric G proteins, Src-like tyrosine kinases (lck, lyn, fyn), PKC isozymes, glycosylphosphatidylinositol (GPI)-anchored proteins and, after T cell activation, the Syk-family kinase Zap-70, prompts these portions of the plasma membrane to be considered as "glycosignaling domains." In particular, during T cell activation and/or other dynamic functions of the cell, such as apoptosis, key signaling molecules are recruited to these microdomains, where they strictly interact with GM3. The association of transducer proteins with GM3 in microdomains suggests that this ganglioside is the main marker of GEM in human lymphocytes and is a component of a cell plasma membrane multimolecular signaling complex involved in cell-cell interaction, signal transduction, and cell activation.


Fetal assessment based on fetal biophysical profile scoring: experience in 19,221 referred high-risk pregnancies. II. An analysis of false-negative fetal deaths.
The incidence of false-negative fetal death, which is defined as stillbirth unrelated to major anomaly or alloimmunization occurring after a last normal fetal biophysical score, was determined in 19,221 referred high-risk pregnancies. The calculated rate of fetal death after a last normal test was 0.726/1000 (14 deaths), which remained relatively constant despite a progressive increase in tests and patients studied. We conclude that a normal fetal biophysical profile score confers a high probability of perinatal survival.


Recontouring teeth and closing diastemas with direct composite buildups: a 5-year follow-up.
Adhesive resin composite technology enables dentists to add composite material to tooth surfaces to close gaps and reshape tooth form without cavity preparation. This option creates new possibilities for minimally invasive dentistry as the tooth shape, position and colour can be altered without loss of tooth substance. However, evidence-based data on direct composite buildups are rare. The purpose of this study was to evaluate the outcome and to document the occurrence of unfavourable events and clinical findings of 176 direct composite buildups that had been performed in the Department of Conservative Dentistry, University Hospital Heidelberg, Germany, between 2002 and 2008. Outcome was categorised as failure (F), survival (SR) or success (S). Restorations still in place and without prior failure at follow-up were qualitatively rated using modified USPHS/FDI criteria. During the follow-up period, 30 restorations were found to have had unfavourable events or clinical findings. All restorations were repaired, and they remained in situ (SR). No complete loss (F) was recorded. The overall survival rate was 84.6% after 60 months (95%, confidence interval [CI]: 78.5 and 90.6). Clinical quality was rated excellent or good for most (>90%) of the restorations examined. The direct composite buildups observed in this study were found to have promising clinical outcome and good quality parameters after 5 years. If a noninvasive or minimally invasive treatment approach is indicated, direct composite buildups provide an acceptable treatment alternative for the aesthetic correction and reshaping of anterior teeth. The application of direct composite buildups in clinical cases in which a non- or minimally invasive treatment approach is indicated provides an excellent treatment alternative for gold-standard treatment options like laboratory-made crowns and porcelain veneers. Restorations in the present investigation showed a functional survival rate of 100%, an overall survival rate of 84.6% after 5 years.


Analysis of endocannabinoids in plasma samples by biocompatible solid-phase microextraction devices coupled to mass spectrometry.
Anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) represent two of the most important endocannabinoids (ECs) investigated in neurobiology as therapeutic targets for several mental disorders. However, the determination of these ECs in biological matrices remains a challenging task because of the low concentrations, low stability and high protein-bound (LogP ∼ 6). This work describes innovative analytical methods based on biocompatible SPME (Bio-SPME), SPME-UHPLC-MS/MS and Bio-SPME-Nano-ESI-MS/MS, to determine AEA and 2-AG in human plasma samples. The direct coupling of Bio-SPME with nano-ESI-MS/MS can be considered an alternative tool for faster analysis. Different Bio-SPME fibers based on silica and polymeric coating (i.e. C18, C30, and HLB) were evaluated. Different desorption solvents based on combinations of methanol, acetonitrile, and isopropanol were also evaluated for efficient elution with minimum carry-over. Given the high protein binding analytes and the fact that SPME extracts the free-concentration of the analytes, the plasma samples were modified with additives such as guanidine hydrochloride (Gu-HCl), trifluoroacetic acid, and acetonitrile. This study was carried out by experimental design to achieve complete protein denaturation and the release of target analytes. The maximum extraction efficiency was obtained under the following conditions: HLB coated fibers (10 mm length, 20 μm coating thickness), matrix modified (300 μL of plasma) with 50 μL of Gu-HCL 1 mol L-1, 75 μL of ACN and 75 μL of water, and desorption with methanol/isopropanol solution (50:50, v/v). Both methods were validated based on current international guidelines and can be applied for monitoring of concentrations of endocannabinoids in plasma samples. SPME-UHPLC-MS/MS method presented lower LOQ values than SPME-nanoESI-MS/MS. The additional separation (chromatographic column) favored the detectability of LC-MS/MS method. However, the SPME-nano-ESI-MS/MS decrease the total analysis time, due to significant reductions in desorption and detection times.


Embodied experiences and existential reflections of the oldest old.
The aim of this study was to learn more about the embodied experiences of people over 85 years and to gain a better understanding of how they make sense of the existential issues faced at this unique stage of life. This research is philosophically and methodologically underpinned by existential phenomenology, in particular embodiment theory, which allows exploration of everyday experiences and the personal meanings attributed to them. In-depth interviews with twenty purposively selected individuals were analysed using Interpretive Phenomenological Analysis. Findings indicated that ways of being, relationships with others and one's place in the world continue to evolve into late life. Gerotranscendence theory best encapsulates lived experiences, with salient features including an increased need for deep reflection, positive solitude and meaningful relationships, among other features. This research provides new insights into how identity, meaning and the experience of the broader lifeworld are influenced by corporeal ageing.


The distribution of DR5, MT2, and MB3 specificities on human Ia subsets.
Human Ia molecules were isolated from cells of LG-38, an HLA-homozygous lymphoid cell line of DR5 specificity. Three Ia subsets could be distinguished and separated by using specific alloantisera and a monoclonal antibody with polymorphic reactivity. These subsets carried the specificities DR5 and MT2, MT2 alone and MB3 alone. The structure of the three molecular species was analyzed by microfingerprinting. The subset carrying only MT2 was similar, in both the component alpha and beta chains, to the major subset carrying DR5 and MT2, whereas the subset carrying MB3 was distinct in both chains from the other two subsets. These data are compatible with our previous findings obtained for the products of two Ia loci closely linked to the DR locus and provisionally called DC and BR; they also support the conclusion that the subset carrying only MT2 is an allelic product of the BR locus, whereas the MB3 subset is an allelic product of the DC locus. MT2 appears to be a shared specificity of DR and BR loci products.


Xenograft as In Vivo Experimental Model.
The identification of experimental models that recapitulate human cancers designed to predict patient clinical response to therapies is a major break in oncology. Cancer stem cells (CSCs) represent a small tumor cell population responsible for drug resistance, where their effective killing may lead to identifying better treatment options. While the CSCs hypothesis highlights the need for a specific tumor target, patient-derived xenografts (PDXs) should also be considered for drug development as they better represent tumor heterogeneity and the environment in which a tumor develops.


[Multidisciplinary consultation for patients with HPV-related invasive carcinoma or precancerous lesions].
Given the recent increase in the number of human papillomavirus (HPV)-induced cancers in other locations than gynaecological, the number of patients with two cancers at distinct sites, and because of the lack of exhaustive data, we decided to create a multidisciplinary network around an HPV consultation at the Georges-Pompidou European Hospital (HEGP). This network aims to set up the best tools for detecting HPV-associated "multisite" precancerous lesions in order to determine the possible impact of dedicated care for this at-risk population. This monthly consultation was created at the HEGP in June 2014. It is currently organized around five consultations: gynaecological, ENT, urological, digestive and immunological. Every patient who has been diagnosed with HPV-related cancer and whose care is provided at the HEGP is offered this particular follow-up: systematically, once the initial lesion has been treated, the patient is convened annually for a day during which it benefits from the consultations mentioned above. A consultation with a psychologist is systematically proposed. Local samples are taken at each site: a cytological examination, the analysis of known predictive and prognostic virological markers are carried out. This study fits more broadly in a theme of clinical and fundamental research around cancers related to HPV.


Corrigendum: Determinants of Conductive Hearing Loss in Tympanic Membrane Perforation: Correction of the Sixth Author Name.
[This corrects the article on p. 92 in vol. 8, PMID: 26045905.].


Optical indications of electrical activity and excitation-contraction coupling in the early embryonic heart.
Complete understanding of the ontogenesis and early development of electrical activity and its related contraction has been hampered by our inability to apply conventional electrophysiological techniques to the early embryonic heart. Direct intracellular measurement of electrical events in the early embryonic heart is impossible because the cells are too small and frail to be impaled with microelectrodes. Optical signals from voltage-sensitive dyes have provided a new and powerful tool for monitoring changes in membrane potential in a wide variety of living preparations. With this technique it is possible to make optical recordings from cells which are inaccessible to microelectrodes. An additional advantage of the optical method for recording membrane potential activity is that electrical activity can be monitored simultaneously from many sites in a preparation. Thus, applying a multiple-site optical recording method with a 100- or 144-element photodiode array and voltage-sensitive dyes, we have been able to monitor for the first time spontaneous electrical activity in pre-fused cardiac primordia in early chick embryos at the 6- and early 7-somite stages of development; we have been able to determine that the time of initiation of the heartbeat is the middle period of the 9-somite stage. In the rat embryonic heart, the onset of spontaneous electrical activity and contraction occurs at the 3-somite stage. This article describes ionic properties of the spontaneous action potential and genesis of excitation-contraction coupling in the early embryonic chick and rat hearts. In addition, an improved view of the ontogenetic sequence of spontaneous electrical activity and its implications for excitation-contraction coupling in the early embryonic heart are proposed and discussed.


[Oscillation method in the diagnosis of respiratory function in adults--classification and possibilities for optimization. 1. Basic problems and introduction to the method].
There is pointed to the necessity, to clear up pathophysiologically a limitation of the maximum available respiratory volume or flow. The required investigations of breathing mechanics for registering the impedance under quiet breathing and measuring the residual volume are possible with the oscillation method at the base. There are listed the insecurities of the taken parameter with a short description of the basic theory of the oscillation method (fixed frequency technique).


Periodontal disease preceding osteonecrosis of the jaw (ONJ) in cancer patients receiving antiresorptives alone or combined with targeted therapies: report of 5 cases and literature review.
We present clinical and radiologic data of periodontal tissue involvement preceding the appearance of osteonecrosis of the jaw (ONJ) in 5 patients with solid tumors, who received antiresorptives alone or in combination with targeted therapies. Five patients with osteonecrosis before dental extraction were studied. Periodontal involvement was evidenced by pain, bleeding, fistula, purulence, swelling, periodontal pocket, and tooth mobility. Combined endoperiodontal lesions were considered in 1 patient. Duration of symptoms before ONJ diagnosis lasted 8 to 24 weeks. Routine therapy was performed in 2 of 5 patients. Widening of the periodontal ligament was observed in 4 patients, and dense alveolar bone was seen in 1 patient. Local complications of ONJ required dental extractions in 4 of 5 patients. Spontaneous tooth exfoliation was observed in 1 patient. Alveolar bone biopsies, after the extraction in 2 patients, confirmed osteonecrosis. Osteonecrosis healed in 2 patients--1 after the dental extraction and 1 after 3 dental extractions and surgical debridement. Postextraction socket healed in 1 patient, and the area with exposed bone remained asymptomatic. Osteonecrosis progressed in 2 patients. Clinical and radiologic signs of periodontal tissue involvement, before dental extraction in patients treated with antiresorptives alone or in combination with targeted therapy, may represent developing osteonecrosis.


Structural models of the membrane anchors of envelope glycoproteins E1 and E2 from pestiviruses.
The membrane anchors of viral envelope proteins play essential roles in cell entry. Recent crystal structures of the ectodomain of envelope protein E2 from a pestivirus suggest that E2 belongs to a novel structural class of membrane fusion machinery. Based on geometric constraints from the E2 structures, we generated atomic models of the E1 and E2 membrane anchors using computational approaches. The E1 anchor contains two amphipathic perimembrane helices and one transmembrane helix; the E2 anchor contains a short helical hairpin stabilized in the membrane by an arginine residue, similar to flaviviruses. A pair of histidine residues in the E2 ectodomain may participate in pH sensing. The proposed atomic models point to Cys987 in E2 as the site of disulfide bond linkage with E1 to form E1-E2 heterodimers. The membrane anchor models provide structural constraints for the disulfide bonding pattern and overall backbone conformation of the E1 ectodomain.


Efficacy in the treatment of malaria by Plasmodium vivax in Oiapoque, Brazil, on the border with French Guiana: the importance of control over external factors.
Plasmodium vivax malaria is an important public health issue in the Amazon region, and it accounts for approximately 84 % of cases of the disease. Migration across the border between Brazil and French Guiana contributes to the maintenance of the disease. The aim of this study was to evaluate the therapeutic and parasitological responses of patients with P. vivax malaria treated with chloroquine and primaquine in the socio-environmental context of cross-border interactions between Brazil and French Guiana. The factors controlled were diagnostic agreement, adherence, adjustment of primaquine doses for patient weight, and quality of the drugs used. A prospective study was conducted in 2011 with 103 individuals aged 10-60 years with a positive diagnosis of P. vivax treated with chloroquine (10 mg base/kg on the first day, followed by 7.5 mg/kg on the second and third days) and primaquine for 7 days, who were followed for 28 days. The primaquine doses were adjusted for the patients' weight. A number of factors were determined: epidemiological characteristics, origin of patients, signs and symptoms, initial parasitaemia and parasitaemia clearance time, blood concentrations of chloroquine and primaquine, quality of anti-malarial drugs and diagnostic agreement. Ninety-five patients were followed for 28 days. There was a 100 % agreement in microscopic diagnosis between field laboratory and reference centre. The adhesion to the treatment was 100 %. Of these patients, 32.6 % received a weight-adjusted dose of primaquine. The chloroquine and primaquine tablets were consistent with the optimal quality limits for human consumption. The investigated patients achieved optimal blood exposure to anti-malarial drugs. The parasitological and therapeutic response was adequate in 99.0 % of cases. In the municipality of Oiapoque, the therapeutic regime used for the treatment of P. vivax malaria using chloroquine combined with primaquine remains effective, when external factors are controlled, such as the quality of anti-malarial drugs, the adhesion to the treatment prescribed, the correct diagnostic and the adjustment of primaquine dose for patient body weight.


Morphological alterations caused by manual venom extraction on the main venom gland of Bothrops asper and Crotalus simus snakes (Serpentes: Viperidae): Long-term implications for antivenom production.
The only scientifically validated treatment for snakebite envenomation is the administration of antivenoms. For their production, small quantities of snake venom are injected in animals to elicit a specific antibody response. Snakes are kept in captivity, and their venom is regularly extracted to assure antivenom access. It has already been reported that the pressure exerted upon the venom gland during this extraction can cause tissue damage and fibrosis, leading to a decrease in the venom yield. We described the histopathology of venom glands for B. asper and C. simus snakes used for antivenom production. Based on these reported tissue abnormalities, we quantify the tissue injury by a generated damage-SCORE and fibrosis. A variety of histopathological damages were found such as fibrosis, edema, necrosis, hemorrhage, and formation of anomalous structures, especially in C. simus, which is more prone to suffer severe damage. The level and severity of the damage depend on the frequency and the number of venom extractions. Furthermore, we design an experimental intensive venom extraction scheme with which we could confirm the causality of these effects. In addition to the histopathological damages, the LD50 and biochemical venom composition were also affected giving experimental evidence that the venom extraction not only causes tissue damage but also affects the composition stability and toxicity of the venom. In order to produce quality and effective antivenoms, an improvement of the management of snake collections could be established, such as rotation groups to assure the quality of the venom yielded.


Importance of water level management for peatland outflow water quality in the face of climate change and drought.
The impact of different climate scenarios, drought, and water level management on the outflow water quality of peatlands has been investigated. A mesocosm experiment has been conducted within climate control chambers to simulate current (2016-2019 real-time) and future representative concentration pathway (RCP) climate scenarios (RCP 2.6, 4.5 and 8.5). To assess the efficiency of a management strategy for improving peatland water quality, water level adjustment was applied to half of the system at the same time for each climate scenario. Furthermore, the mesocosm experienced the 2018 European drought during the simulation years, and the corresponding impact was analyzed. The results of this study revealed a substantial and favorable impact of water level management on water quality of peatlands under different climate scenarios. The effect of water level management was the largest for ammonium (NH4-N) and 5-day biochemical oxygen demand (BOD5), and the smallest for total phosphorus (TP). Drought had a strong impact on chemical variables, increasing their concentration and deteriorating the water quality of peatland outflow. However, water level management can stabilize the nutrient levels in peatland outflows, particularly during drought and under warmer climate scenarios, thus mitigating the adverse effects of climate change.


Platelet membrane glycoprotein changes during the preparation and storage of platelet concentrates.
Previous studies of platelet membrane glycoproteins during blood bank storage have reported conflicting results. This study assessed two major plasma membrane glycoproteins (GP Ib and GP IIb), an alpha-granule membrane protein (GMP-140), and the concentration of platelet membrane microparticles in cell-free plasma during routine hospital blood bank platelet storage. 125I-monoclonal antibody binding was used to measure membrane glycoproteins on the surface of intact platelets and to measure the concentration of membrane microparticles in cell-free plasma. Platelet concentrates were stored at room temperature in polyolefin bags for 7 days. In this blood bank, two types of rotators are routinely used for platelet concentrate storage: a 2-rpm circular tumbler rotator and a 6-rpm elliptical rotator. Different results were obtained with the rotators. With the tumbler rotator, there was no loss of platelets and antibody binding to GP Ib remained normal. With the elliptical rotator, one third of platelets were lost into clumps during storage, and a 50 percent decrease of antibody binding to GP Ib occurred in the remaining single platelets. There was no loss of antibody binding to GP IIb with either rotator. Antibody binding to GMP-140 increased equally in both rotators indicating that the remaining single platelets had secreted about 16 percent of their alpha-granule contents. The plasma concentration of platelet membrane microparticles was greater in the bags stored in the elliptical rotator. These results indicate that it is possible to maintain the normal concentration of platelet membrane glycoproteins Ib and IIb during 7 days of room-temperature blood bank storage.(ABSTRACT TRUNCATED AT 250 WORDS)


Characterization and differential expression of a ferritin protein from Fasciola hepatica.
Ferritins are proteins that play a central role in maintaining intracellular iron balance. A cDNA clone of Fasciola hepatica (687 bp long) encoding a putative 228-amino acid polypeptide (FhFtn-1) homologous with ferritins of vertebrates and invertebrates was identified. FhFtn-1 contains a conserved motif of the ferroxidase center typical of vertebrate ferritins. Phylogenetic tree analysis showed that FhFtn-1 clusters with two ferritins of Paragonimus westermani, which suggests a common ancestry for the ferritins of these two trematodes. Recombinant FhFtn-1 protein expressed and purified from an Escherichia coli system showed iron-uptake ability. Moreover, FhFtn-1 showed strong reactivity with sera from rabbits infected with F. hepatica for 2-12 weeks, which suggests that this protein could be a potential antigen for immunodiagnosis of fascioliasis. qPCR analysis demonstrated that FhFtn-1-mRNA is expressed at significantly higher levels in adults and unembryonated eggs than in juveniles or miracidia. These results represent the first characterization of a ferritin protein from the liver fluke F. hepatica.


Release of endogenous 5-hydroxytryptamine from the myenteric plexus of the guinea-pig isolated small intestine.
The presence of 5-hydroxytryptamine (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in, and the release of these substances from, the myenteric plexus-longitudinal muscle (MPLM) layer of the guinea-pig isolated small intestine were investigated. 5-HT and 5-HIAA were measured by high performance liquid chromatography and electrochemical detection. Freshly prepared MPLM contained measurable amounts of 5-HT and 5-HIAA. For the release experiments, the MPLM was incubated in a medium containing the 5-HT uptake inhibitor fluoxetine and the monoamine oxidase inhibitor nialamide; this led to a decrease in the 5-HIAA content of the MPLM whereas the 5-HT content remained unchanged. There was a spontaneous release of 5-HT and 5-HIAA from the MPLM. The release of 5-HT was so small that it was just detectable; it seemed equivalent to about 0.8% of the tissue stores released per min. Depolarization of the tissue by increasing the [K+] or by exposing it to veratridine enhanced the release of 5-HT in a Ca2+-dependent manner whereas the release of 5-HIAA was not increased. Tetrodotoxin inhibited the veratridine-evoked release of 5-HT but did not affect the K+-evoked release of 5-HT. The presence of 5-HT in myenteric neurones and the characteristics of the release of 5-HT from these neurones strongly support the hypothesis that 5-HT is an enteric neurotransmitter.


Value of electroencephalography (EEG) before and after surgery of intracranial aneurysms.
Electroencephalographic (EEG) investigations were done in 36 patients with intracranial aneurysms, before and after surgery. Thirty five of them suffered from subarachnoid hemorrhage (SAH). Pre-operatively, there was no correlation between patients' age or sex and localisation of the aneurysm or degree of EEG disturbances. The most frequent finding was a generalised slowing, the degree of which depended on the time from bleeding to EEG. Focal abnormalities were due to spasms of the vessels or intracerebral haematomas. There was a high correlation with neurological deficits. Post-operatively, EEG disturbances became worse in 21 cases. Generalised and focal abnormalities increased. These were due to focal oedema and the operative approach. The EEG could be correlated very well with the findings from other investigative methods (CT scanning, angiography). The EEG, as a functional method, showed very well the whole state of the brain after bleeding and after operation.


Errors in Zernike transformations and non-modal reconstruction methods.
Wavefront aberrometers often represent the wavefront in terms of Zernike polynomials. The fit coefficients for these polynomials are pupil-size dependent; hence it is desirable to be able to calculate polynomial coefficients at a different pupil size from the initial measurement. We developed a method for scaling the Zernike fit coefficients for different sized pupils and compared them to the coefficients calculated by reanalyzing the original data. We evaluated cases where the initial set of Zernike coefficients was an accurate representation of the data as well as cases where the Zernike polynomials fit the data poorly. The rescaling methods work well in all cases with a good original fit (as measured by the gradient root-mean-square [RMS] fit error). Rescaling and reanalyzing also agree well over a small scaling range. However, if the original fit was poor, large errors result if the rescaling is more than approximately 25%. Rescaling works well and is useful as long as the RMS fit error can be evaluated. The RMS difference between the zonal reconstruction and the Zernike fit is useful for determining this fit error.


Experience with Combining Pediatric Procedures into a Single Anesthetic.
The combination of multiple procedures within a single anesthetic may provide many challenges for the perioperative team. Coordination of specialties, consideration for parental time burdens, and travel expenses as well as limiting multiple anesthetic exposures to the children are pertinent factors to consider when advocating the combination of surgical procedures. The electronic medical record at Nationwide Children's Hospital was retrospectively queried to obtain information on patients having a single anesthetic encounter for 2 or more procedures involving 2 or more services over 1 year (July 2015-June 2016). One thousand one hundred twenty patients had 2 procedures during a single anesthetic encounter. The average anesthesia time was 127 ± 102 minutes, and average PACU time was 64 ± 37 minutes. The unanticipated admission rate was 85 of 1,120 cases (7.6%). Five (6%) of the unanticipated admission cases were ASA status 1, 33 (39%) were ASA status 2, and 47 (55%) were ASA status ≥3; compared with 87 (9%), 481 (50%), and 391 (41%) in the group not requiring unanticipated admission (P = 0.032) (see Fig. 1). These data demonstrate the feasibility of combining several procedures during a single anesthetic encounter and may result in decreased healthcare costs as well as limitation of parental cost and time obligations.


Ventilatory responses to hypercapnia in divers and non-divers: effects of posture and immersion.
The aim of this study was to determine the effects on respiratory drive of two factors, one mechanical (lung volume) and one chemical (sensitivity to hypercapnia), that are involved in determining the breath-hold duration (BHD). Functional residual capacity was measured by helium dilution with the subject seated in air, seated in water and in the prone position in water. Hyperoxic hypercapnia rebreathing (Read's method) was carried out under identical environmental conditions to assess the effects of CO2 pressure on respiratory centre output by measuring ventilation, mean inspiratory flow and occlusion pressure. Sixteen healthy volunteers were tested. 8 trained divers and 8 non-divers. Functional residual capacity decreased for the postures seated in water (30.8%-34.8%) and for prone position in water (20.3%-20.9%) when compared to the posture seated in air (P<0.0001), all subjects pooled. No difference was found between groups. The slopes of the linear regression, which characterised the sensitivity to CO2 and were determined with the rebreathing tests, revealed differences between the two populations (ventilation: P < 0.0001; mean inspiratory flow: P < 0.05). No difference was found for occlusion pressure or between the different postures. These results confirmed a lower sensitivity to CO2 for trained divers. This adaptation was shown to decrease respiratory centre activity at the origin of the breath-hold breaking point. The immersion, did not influence respiratory drive, despite a decrease in lung volumes. The authors suggest that these findings may be explained by a specific apnoea training and a pronounced bradycardia in immersion.


Somatic VHL gene deletion and point mutation in MEN 2A-associated pheochromocytoma.
Multiple endocrine neoplasia type 2 (MEN 2) is an inherited cancer syndrome that includes pheochromocytoma. Germline mutations in RET are responsible for MEN 2 but the precise pathogenetic mechanisms of tumorigenesis are unknown. We have recently identified possible mechanisms of tumor formation in patients with MEN 2A-related pheochromocytoma. Two of nine tumors investigated, however, did not reveal either of these mechanisms. In the present study, we therefore searched for other possible mechanisms underlying the pathogenesis of MEN 2A-related pheochromocytoma. Hereditary pheochromocytoma also occurs in patients with von Hippel-Lindau (VHL) disease, a syndrome consisting of tumors caused by inactivation of the VHL tumor suppressor gene. A subset of sporadic pheochromocytomas have somatic mutations in RET or VHL, suggesting that both genes contribute to pheochromocytoma pathogenesis in a subset of tumors. It is unknown, however, whether VHL gene alterations would be associated with tumorigenesis in hereditary, MEN 2-related pheochromocytoma. We therefore investigated four pheochromocytomas from patients with MEN 2A and RET germline mutations for the presence of allelic deletion and/or somatic mutation of the VHL gene. LOH analysis using the polymorphic markers D3S1038 and D3S1110 that map to the VHL gene locus 3p25/26, revealed evidence for somatic VHL gene deletion in all four MEN 2A-related pheochromocytomas. Mutation analysis of the VHL gene showed frameshift mutations in two tumors and a splice acceptor mutation in one tumor. The remaining tumor did show LOH but not mutation of the VHL gene. These results suggest that somatic genetic alterations of the VHL gene may play a role in the tumorigenesis of some MEN 2A-related pheochromocytomas.


[Papillary adenocarcinoma of the rete testis. Report of a case].
Another case of adenocarcinoma of the rete testis is described and the literature on this uncommon tumor type reviewed. The clinical features, pathological findings and treatment of adenocarcinoma of the rete testis in a 72-year-old male are presented. Adenocarcinoma of the rete testis is a rare tumor type; few cases have been reported in the literature. Although treatment is primarily by surgery, recognition of new cases will provide further insight into this primary tumor of the rete testis.


ADAMTS5 deficiency protects against non-alcoholic steatohepatitis in obesity.
Increased prevalence of obesity is paralleled by an increase in non-alcoholic steatohepatitis (NASH). We previously found that the expression of ADAMTS5 (A Disintegrin And Metalloproteinase with Thrombospondin type 1 motifs; member 5) is enhanced in expanding adipose tissue. However, no information is available on a potential role in liver pathology. We studied the effect of ADAMTS5 deficiency on NASH in mice. Wild-type (Adamts5+/+ ) and deficient (Adamts5-/- ) mice were kept on a standard- or high-fat diet (HFD) for 15 weeks. Alternatively, steatohepatitis was induced with methionine/choline-deficient (MCD) diet. HFD feeding resulted in comparable body weights for both genotypes, but Adamts5-/- mice had approximately 40% lower liver weight (P = 0.0004). In the Adamts5-/- mice, the HFD as well as the MCD diet consistently induced less NASH with less fibrosis. The deteriorating effect of ADAMTS5 on the liver during diet-induced obesity may be due, at least in part, to proteolytic cleavage of the matrix components syndecan-1 and versican, thereby enhancing hepatic triglyceride clearance from the circulation. Plasma lipid levels were elevated in obese Adamts5-/- mice. There was no clear effect of ADAMTS5 deficiency on glycaemia or glucose tolerance, whereas insulin sensitivity was somewhat improved. Furthermore, Adamts5-/- mice were protected from hepatic mitochondrial dysfunction, as indicated by increased mitochondrial respiratory chain complex activity, higher ATP levels and higher expression of antioxidant enzymes. Absence of ADAMTS5 preserves liver integrity in a diet-induced obesity model. Selective targeting of ADAMTS5 could provide a new therapeutic strategy for treatment/prevention of NASH.


Metabolic actions of hypothalamic SIRT1.
The hypothalamus is a small structure located in the ventral diencephalon. Hypothalamic neurons sense changes in circulating metabolic cues (e.g. leptin, insulin, glucose), and coordinate responses aimed at maintaining normal body weight and glucose homeostasis. Recent findings indicate that a nicotinamide adenine dinucleotide (NAD(+))-dependent protein deacetylase (namely SIRT1) expressed by hypothalamic neurons is crucial for mounting responses against diet-induced obesity and type 2 diabetes mellitus (T2DM). Here, the repercussions of these findings will be discussed and particular emphasis will be given to the potential exploitation of hypothalamic SIRT1 as a target for the treatment of the rapidly-spreading metabolic disorders of obesity and T2DM. The possible roles of hypothalamic SIRT1 in regulating metabolic ageing processes will also be addressed.


Recognition of microbial infection by Toll-like receptors.
The Toll-like receptors (TLRs) of the innate immune system detect host invasion by pathogens and initiate immune responses. All of the TLRs use the adaptor MyD88 to transduce a signal; however, two newly identified signaling molecules, TIRAP and TRIF, interact with a subset of the TLRs, suggesting a signaling specificity that may be relevant to the type of infection. Activation of the TRIF pathway, for example, leads to the production of antiviral gene products via the transcription factor, IRF3. In vivo experiments in TLR-deficient mice underscore the importance of TLRs in overcoming infection.


Biosensors based on enzyme field-effect transistors for determination of some substrates and inhibitors.
This paper is a review of the authors' publications concerning the development of biosensors based on enzyme field-effect transistors (ENFETs) for direct substrates or inhibitors analysis. Such biosensors were designed by using immobilised enzymes and ion-selective field-effect transistors (ISFETs). Highly specific, sensitive, simple, fast and cheap determination of different substances renders them as promising tools in medicine, biotechnology, environmental control, agriculture and the food industry. The biosensors based on ENFETs and direct enzyme analysis for determination of concentrations of different substrates (glucose, urea, penicillin, formaldehyde, creatinine, etc.) have been developed and their laboratory prototypes were fabricated. Improvement of the analytical characteristics of such biosensors may be achieved by using a differential mode of measurement, working solutions with different buffer concentrations and specific agents, negatively or positively charged additional membranes, or genetically modified enzymes. These approaches allow one to decrease the effect of the buffer capacity influence on the sensor response in an aim to increase the sensitivity of the biosensors and to extend their dynamic ranges. Biosensors for the determination of concentrations of different toxic substances (organophosphorous pesticides, heavy metal ions, hypochlorite, glycoalkaloids, etc.) were designed on the basis of reversible and/or irreversible enzyme inhibition effect(s). The conception of an enzymatic multibiosensor for the determination of different toxic substances based on the enzyme inhibition effect is also described. We will discuss the respective advantages and disadvantages of biosensors based on the ENFETs developed and also demonstrate their practical application.


Superior outcome of women with stage I/II cutaneous melanoma: pooled analysis of four European Organisation for Research and Treatment of Cancer phase III trials.
Several studies observed a female advantage in the prognosis of cutaneous melanoma, for which behavioral factors or an underlying biologic mechanism might be responsible. Using complete and reliable follow-up data from four phase III trials of the European Organisation for Research and Treatment of Cancer (EORTC) Melanoma Group, we explored the female advantage across multiple end points and in relation to other important prognostic indicators. Patients diagnosed with localized melanoma were included in EORTC adjuvant treatment trials 18832, 18871, 18952, and 18961 and randomly assigned during the period of 1984 to 2005. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% CIs for women compared with men, adjusted for age, Breslow thickness, body site, ulceration, performed lymph node dissection, and treatment. A total of 2,672 patients with stage I/II melanoma were included. Women had a highly consistent and independent advantage in overall survival (adjusted HR, 0.70; 95% CI, 0.59 to 0.83), disease-specific survival (adjusted HR, 0.74; 95% CI, 0.62 to 0.88), time to lymph node metastasis (adjusted HR, 0.70; 95% CI, 0.51 to 0.96), and time to distant metastasis (adjusted HR, 0.69; 95% CI, 0.59 to 0.81). Subgroup analysis showed that the female advantage was consistent across all prognostic subgroups (with the possible exception of head and neck melanomas) and in pre- and postmenopausal age groups. Women have a consistent and independent relative advantage in all aspects of the progression of localized melanoma of approximately 30%, most likely caused by an underlying biologic sex difference.


Pantropical trends in mangrove above-ground biomass and annual litterfall.
A major paradigm in biosphere ecology is that organic production, carbon turnover and, perhaps, species diversity are highest at tropical latitudes, and decrease toward higher latitudes. To examine these trends in the pantropical mangrove forest vegetation type, we collated and analysed data on above-ground biomass and annual litterfall for these communities. Regressions of biomass and litterfall data show significant relationships with height of the vegetation and latitude. It is suggested that height and latitude are causally related to biomass, while the relationship with litterfall reflects the specific growing conditions at the respective study sites. Comparison of mangrove and upland forest litterfall data shows similar trends with latitude but indicates that mangrove litterfall is higher than upland forest litterfall. The regression equations allow the litterfall/biomass ratio to be simulated, and this suggests that the patterns of organic matter partitioning differ according to latitude.


The Impact of the Water Evaporation Rate and Saccharide Excipients on the Oxidative Degradation of Polysorbates During Oven Drying and Spray Drying.
In recent years, many fast drying techniques such as spray-drying are being explored as alternatives to biopharmaceutical freeze-drying. Thus, it is essential to understand how the processability of commonly used excipients will be affected when these new techniques are employed. This study reports a series of observations outlining how the thermally-induced oxidative degradation of polysorbates (PS) evolves in liquid to solid transitions, such as those expected in spray-drying. Firstly, the impact of different evaporation rates on the oxidative degradation of aqueous solutions of two different PS types namely, PS20 and PS80, were screened via evaporative solvent casting. The latter revealed that the evaporation rate could critically impact the rate-limiting steps of PS thermal oxidation. In addition, the potential of saccharides as excipients to mitigate the thermal oxidation of PS80 under slow and fast evaporation conditions was investigated. Five different saccharide excipients were screened, i.e., trehalose dihydrate, maltodextrin, hydroxypropyl-β-cyclodextrin, and Dextran 40. Under slow evaporation conditions, only trehalose dihydrate seemed to be beneficial in avoiding the thermal oxidation of PS80. For fast evaporation conditions, hydroxypropyl-β-cyclodextrin prevented the oxidative degradation of PS80. This implies that distinct strategies to mitigate PS oxidative degradation might be necessary depending on the drying process and rates.


Doppler ultrasound of the fetomaternal circulation: a preliminary study on differences between ethnic groups.
The aim of this study was to investigate whether the same reference values might be used for the pulsatility index obtained by Doppler examinations of the fetal umbilical and middle cerebral artery and the maternal uterine arteries in autochthonous Belgian, Turkish and Moroccan women in Belgium. Notching of the uterine artery was also studied in the three ethnic groups. Doppler measurements were performed in 206 autochthonous Belgian, 36 Moroccan and 36 Turkish pregnant women between 20 and 24 weeks gestational age for the umbilical artery, middle cerebral artery and uterine arteries. The mean uterine artery pulsatility index and the placentocerebral index were calculated. Intra-observer variation was calculated by repeat measurements on 20 videotaped examinations and intrapatient variation was determined by repeat examination in 60 patients. Maternal length was higher and body mass index lower in Belgian women; more of these admitted smoking during pregnancy. There were no statistically significant inter-ethnic differences for the pulsatility index of the umbilical artery, middle cerebral artery, placental-site uterine artery and the placentocerebral index. The pulsatility index in the non-placental-site uterine artery and the mean uterine artery was lower in the Moroccan group. Intra-patient variation expressed as intra-patient standard deviation of the umbilical and middle cerebral artery pulsatility index was relatively large compared to inter-patient variation, being 57% to 88% of the inter-patient standard deviation. This was not the case for the uterine artery. Notching of the uterine artery was not contributive for the prediction of intrauterine growth restriction or preeclampsia in these ethnic groups. Only small statistically significant differences were demonstrated. For clinical practice, the use of different reference charts for fetomaternal Doppler measurement in Belgian, Turkish and Moroccan women is not warranted.


Effects of biochar on anaerobic treatment systems: Some perspectives.
Many anaerobic activities involve carbon, nitrogen, iron, and sulfur cycles. As a well-developed porous material with abundant functional groups, pyrolytic biochar has been widely researched in efforts to promote microbial activities. However, the lack of consensus on the biochar mechanism has limited its practical application. This review summarizes the effects of different pyrolysis temperatures, particle sizes, and dosages of biochar on microbial activities and community in Fe(III) reduction, anaerobic digestion, nitrogen removal, and sulfate reduction systems. It was found that biochar could promote anaerobic activities by stimulating electron transfer, alleviating toxicity, and providing suitable habitats for microbes. However, it inhibits microbial activities by releasing heavy metal ions or persistent free radicals and adsorbing signaling molecules. Finding a balance between the promotion and inhibition of biochar is therefore essential. This review provides valuable perspectives on how to achieve efficient and stable use of biochar in anaerobic systems.


Survey of substance use among high school students in Taipei: web-based questionnaire versus paper-and-pencil questionnaire.
To evaluate, using a randomized trial, whether a web-based self-administered questionnaire (web SAQ) can improve the reporting rate of substance use in adolescents compared with a paper-and-pencil self-administered questionnaire (paper SAQ). Students of junior high, senior high, and vocational high schools in Taipei City and County were selected by a stratified, two-stage, probability proportional to size, random sampling. For each class selected, half of the students were randomly assigned to paper SAQ (n = 990) and the other half to web SAQ (n = 928). The inverse of the sampling probability for each individual was then used as sampling weight in the estimation of prevalence and logistic regression analysis. For readily available substances, the lifetime prevalence in the web SAQ group was significantly higher for alcohol use and borderline higher for tobacco and betel nut use compared to those of the paper SAQ group. For illicit drug use, the lifetime prevalence for the web SAQ group was significantly higher for the use of amphetamines, and borderline higher for ketamine. In multiple logistic regression analysis, the differences between the two groups in the use of alcohol, tobacco, and amphetamines remained significant. Boys, as well as both junior-high and vocational high school students who responded using the web SAQ, were more likely to report alcohol or tobacco use than those using the paper SAQ. Web SAQ leads to higher reporting rates of commonly used substances in adolescents compared with those of paper SAQ.


Resilience, COVID-19-related stress, anxiety and depression during the pandemic in a large population enriched for healthcare providers.
COVID-19 pandemic is a global calamity posing an unprecedented opportunity to study resilience. We developed a brief resilience survey probing self-reliance, emotion-regulation, interpersonal-relationship patterns and neighborhood-environment, and applied it online during the acute COVID-19 outbreak (April 6-15, 2020), on a crowdsourcing research website ( www.covid19resilience.org ) advertised through social media. We evaluated level of stress (worries) regarding COVID-19: (1) contracting, (2) dying from, (3) currently having, (4) family member contracting, (5) unknowingly infecting others with (6) experiencing significant financial burden following. Anxiety (GAD7) and depression (PHQ2) were measured. Totally, 3042 participants (n = 1964 females, age range 18-79, mean age = 39) completed the resilience and COVID-19-related stress survey and 1350 of them (mean age = 41, SD = 13; n = 997 females) completed GAD7 and PHQ2. Participants significantly endorsed more distress about family contracting COVID-19 (48.5%) and unknowingly infecting others (36%), than getting COVID-19 themselves (19.9%), p < 0.0005 covarying for demographics and proxy COVID-19 exposures like getting tested and knowing infected individuals. Patterns of COVID-19 related worries, rates of anxiety (GAD7 > 10, 22.2%) and depression (PHQ2 > 2, 16.1%) did not differ between healthcare providers and non-healthcare providers. Higher resilience scores were associated with lower COVID-19 related worries (main effect F1,3054 = 134.9; p < 0.00001, covarying for confounders). Increase in 1 SD on resilience score was associated with reduced rate of anxiety (65%) and depression (69%), across healthcare and non-healthcare professionals. Findings provide empirical evidence on mental health associated with COVID-19 outbreak in a large convenience sample, setting a stage for longitudinal studies evaluating mental health trajectories following COVID-19 pandemic.


Donor-specific antibodies, glomerulitis, and human leukocyte antigen B eplet mismatch are risk factors for peritubular capillary C4d deposition in renal allografts.
The complement system plays an important role in the immune response to transplantation, and the diagnostic significance of peritubular capillary (PTC) C4d deposition (C4d+) in grafts is controversial. The study aimed to fully investigate the risk factors for PTC C4d+ and analyze its significance in biopsy pathology of kidney transplantation. This retrospective study included 124 cases of kidney transplant with graft biopsy and donor-specific antibody (DSA) testing from January 2017 to December 2019 in a single center. The effects of recipient pathological indicators, eplet mismatch (MM), and DSAs on PTC C4d+ were examined using univariate and multivariate logistic regression analyses. In total, 35/124 (28%) were PTC C4d+, including 21 with antibody-mediated rejection (AMR), eight with renal tubular injury, three with T cell-mediated rejection, one with glomerular disease, and two others. Univariate analysis revealed that DSAs (P < 0.001), glomerulitis (P < 0.001), peritubular capillaritis (P < 0.001), and human leukocyte antigen (HLA) B eplet MM (P = 0.010) were the influencing factors of PTC C4d+. According to multivariate analysis, DSAs (odds ratio [OR]: 9.608, 95% confidence interval [CI]: 2.742-33.668, P < 0.001), glomerulitis (OR: 3.581, 95%CI: 1.246-10.289, P = 0.018), and HLA B eplet MM (OR: 1.166, 95%CI: 1.005-1.353, P = 0.042) were the independent risk factors for PTC C4d+. In receiver operating characteristic curve analysis, the area under the curve was increased to 0.831 for predicting PTC C4d+ when considering glomerulitis, DSAs, and HLA B eplet MM. The proportions of HLA I DSAs and PTC C4d+ in active antibody-mediated rejection were 12/17 and 15/17, respectively; the proportions of HLA class II DSAs and PTC C4d+ in chronic AMR were 8/12 and 7/12, respectively. Furthermore, the higher the PTC C4d+ score was, the more serious the urinary occult blood and proteinuria of recipients at the time of biopsy. PTC C4d+ was mainly observed in AMR cases. DSAs, glomerulitis, and HLA B eplet MM are the independent risk factors for PTC C4d+.


Incidence and causes of pacemaker implantation during postoperative period of aortic valve replacement with rapid deployment prosthesis.
Aortic stenosis is currently the most frequently occurring valve pathology. Developments, such as transcatheter prostheses and rapid deployment prostheses, allow for the offer of a valve replacement to higher risk patients, but these techniques are linked with a higher need for a permanent pacemaker during the immediate postoperative period. We studied the incidence and the factors associated with permanent pacemaker implantation after aortic valve replacement with Edwards Intuity rapid deployment prosthesis. Between October 2012 and December 2016, the Edwards Intuity prosthesis was implanted in 71 patients (68% male, 75.3 ± 5 years old). Six patients (8%) required a permanent pacemaker during immediate postoperative period. Univariate analysis showed that a history of acute myocardial infarction (AMI) (P = .046, B = 7.5, 95% CI [1.039-54.1]) and preoperative amiodarone (P = .009, B = 31.5; 95% CI [2.32-426]) were associated with a higher need for a pacemaker during the postoperative period. The incidence of permanent pacemaker implantation during the immediate postoperative period of aortic valve replacement with Edwards Intuity prosthesis was 8%, a value which is within the limits reported for conventional aortic prostheses. Preoperative amiodarone treatment and previous AMI may increase the need for a pacemaker during the postoperative period of these aortic prostheses.


Cyproheptadine treatment of Nelson's syndrome: restoration of plasma ACTH circadian periodicity and reversal of response to TRF.
Administration of cyproheptadine for four months to a patient with Nelson's Syndrome was associated with evidence of skin lightening, decreased plasma ACTH concentrations, return of a normal circadian periodicity of plasma ACTH concentrations, and lack of responsiveness of plasma ACTH concentrations to TRF administration, in contrast to the response seen in the untreated state.


Cultured fetal rat pituitaries kept in synthetic medium are able to initiate synthesis of trophic hormones.
An immunohistochemical study was performed to determine the capacity of early fetal pituitaries to differentiate into specific hormone-synthesizing tissue in the absence of any influence from the central nervous system. Rathke's pouches from rats were removed from their juxtadiencephalic position on day 11 and 12 of gestation and maintained for 2-7 days in a chemically defined culture medium (M 199) without antibiotics and serum supplementation. The immunocytochemical observations provided evidence for the differentiation of ACTH-, TSH-beta-, LH-beta-, FSH-beta-, GH- and PRL-synthesizing cells in the isolated organ cultured from 11 to 12-day-old pituitary primordia. The appearance of specific hormone-synthesizing cells in vitro displayed a delay of 1.5-2 days compared to the day of appearance in vivo, however, the sequential order of developmental events occurred as observed in vivo. The present results suggest that endocrine or neuroendocrine signals are not required for the expression of specific secretory functions of fetal pituitaries, at least at an age of 11-12 days.


DNA topoisomerase II is essential for preimplantation mouse development.
Topoisomerase II (topo II) is an essential enzyme that alters DNA topology. This activity is important for a variety of chromosome functions including DNA replication, transcription, recombination, and chromosome condensation and segregation. Previously we localized topo II in mouse gametes and preimplantation embryos using isoform-specific antibodies demonstrating the presence of the enzyme in oocytes and embryos, but not sperm. To probe functions of topo II during preimplantation development, we treated mouse zygotes with 100 nM teniposide, and assessed embryo morphology and DNA replication. Teniposide blocked cleavage in 69% embryos; the remainder cleaved once but had abnormal nuclei. Teniposide-treated embryos were devoid of topo II immunofluorescence. Teniposide also prevented DNA replication, implicating topo II in this process. Embryos treated with a 2 hr pulse of teniposide recovered and developed to the blastocyst stage, indicating 100 nM teniposide did not induce apoptosis. To more specifically analyze topo IIalpha function, we treated zygotes with topo IIalpha-targeted antisense oligodeoxynucleotides. Most zygotes arrested at the 2-cell stage while controls developed into blastocysts indicating topo IIalpha is essential for preimplantation development. The absence of topo IIalpha, but not beta immunofluorescence in antisense-treated embryos confirms the specificity and impact of the treatment. In addition, topo IIalpha is newly synthesized at the 2-cell stage. These results establish an essential function for topo II in mouse preimplantation embryonic development.


Animal behavior: the orphan rebellion.
After their queen has left with a swarm, orphaned larvae exhibiting rebel traits emerge in honeybee colonies. As adults, these orphans have reduced food glands to feed the colony's larvae and more developed ovaries to selfishly reproduce their own offspring.


Computational signatures for post-cardiac arrest trajectory prediction: Importance of early physiological time series.
There is an unmet need for timely and reliable prediction of post-cardiac arrest (CA) clinical trajectories. We hypothesized that physiological time series (PTS) data recorded on the first day of intensive care would contribute significantly to discrimination of outcomes at discharge. Adult patients in the multicenter eICU database who were mechanically ventilated after resuscitation from out-of-hospital CA were included. Outcomes of interest were survival, neurological status based on Glasgow motor subscore (mGCS) and surrogate functional status based on discharge location (DL), at hospital discharge. Three machine learning predictive models were trained, one with features from the electronic health records (EHR), the second using features derived from PTS collected in the first 24 h after ICU admission (PTS24), and the third combining PTS24 and EHR. Model performances were compared, and the best performing model was externally validated in the MIMIC-III dataset. Data from 2216 admissions were included in the analysis. Discrimination of prediction models combining EHR and PTS24 features was higher than models using either EHR or PTS24 for prediction of survival (AUROC 0.83, 0.82 and 0.79 respectively), neurological outcome (0.87, 0.86 and 0.79 respectively), and DL (0.80, 0.78 and 0.76 respectively). External validation in MIMIC-III (n = 86) produced similar model performance. Feature analysis suggested prognostic significance of previously unknown EHR and PTS24 variables. These results indicate that physiological data recorded in the early phase after CA resuscitation contain signatures that are linked to post-CA outcome. Additionally, they attest to the effectiveness of ML for post-CA predictive modeling.


Early vessel destabilization mediated by Angiopoietin-2 and subsequent vessel maturation via Angiopoietin-1 induce functional neovasculature after ischemia.
We assessed whether Angiopoietin-2 (Ang2), a Tie2 ligand and partial antagonist of Angiopoietin-1 (Ang1), is required for early vessel destabilization during postischemic angiogenesis, when combined with vascular growth factors. In vitro, matrigel co-cultures assessed endothelial-cell tube formation and pericyte recruitment after stimulation of VEGF-A, Apelin (APLN), Ang1 with or without Ang2. In a murine hindlimb ischemia model, adeno-associated virus (rAAV, 3×10(12) virusparticles) transduction of VEGF-A, APLN and Ang1 with or without Ang2 (continuous or early expression d0-3) was performed intramuscularly (d-14). Femoral artery ligation was performed at d0, followed by laser doppler perfusion meassurements (LDI) 7 and 14. At d7 (early timepoint) and d14 (late timepoint), histological analysis of capillary/muscle fiber ratio (CMF-R, PECAM-1) and pericyte/capillary ratio (PC-R, NG2) was performed. In vitro, VEGF-A, APLN and Ang1 induced ring formation, but only APLN and Ang1 recruited pericytes. Ang2 did not affect tube formation by APLN, but reduced pericyte recruitment after APLN or Ang1 overexpression. In vivo, rAAV.VEGF-A did not alter LDI-perfusion at d14, consistent with an impaired PC-R despite a rise in CMF-R. rAAV.APLN improved perfusion at d14, with or without continuous Ang2, increasing CMF-R and PC-R. rAAV.Ang1 improved perfusion at d14, when combined with rAAV.Ang2 (d0-3), accompanied by an increased CMF-R and PC-R. The combination of early vessel destabilization (Ang2 d0-3) and continuous Ang1 overexpression improves hindlimb perfusion, pointing to the importance of early vessel destabilization and subsequent vessel maturation for enhanced therapeutic neovascularization.


The impact of different closure materials on pharyngeal wound healing: an experimental animal study.
The formation of pharyngo-cutaneous fistula (PCF) is controversial and various predisposing factors have been proposed. This study aimed to compare different suture materials in the closure of pharyngeal wounds in experimental animals. Fifty-two Sprague-Dawley rats were divided into three groups. Artificial pharyngotomy was performed and was then repaired with Vicryl, polypropylene, and Vicryl plus fibrin glue, respectively. Outcome measurements included gross wound inspection and histological examination. There was a significant difference in the rates of PCF formation between group I and group II (Fisher's exact test, p = 0.046). In addition, minimal inflammatory response was found in the polypropylene group when compared to the other groups. The fibrin glue-treated group had the highest fibroblast activity and collagen deposition. Polypropylene produced minimal tissue reaction, which facilitated the healing process. Therefore, proper selection of suture material can probably reduce the rate of PCF but should not be substituted for proper aseptic and meticulous surgical techniques.


Binding and degradation of human 125I-HDL by rat adrenocortical cells.
In order to learn more about the mechanism by which high density lipoprotein (HDL) cholesterol is taken up by the adrenal cortex, binding and degradation of human 125I-HDL by suspensions of intact rat adrenal cortical cells have been examined. Cellular accumulation of 125I-HDL was found to occur in two phases. Our results indicate that the initial phase of association results from reversible binding of 125I-HDL to a specific saturable set of membrane binding sites. Binding site affinity appears equal for both rat and human HDL while affinity for human LDL is approximately one order of magnitude less on the basis of apoprotein weight. In addition, isolated rat adrenal cortical cells were found to degrade human 125I-HDL at a rapid rate. Degradation, like binding, can be prevented by addition of excess unlabeled HDL suggesting that binding and degradation are linked. Thus, one mechanism that could account for adrenal uptake of HDL cholesterol is endocytosis, initiated by lipoprotein binding to the HDL specific membrane binding site.


Insulin sensitizing and alpha-glucoamylase inhibitory action of sennosides, rheins and rhaponticin in Rhei Rhizoma.
Extracts from Rhei Rhizoma extracts (RR) have been reported to attenuate metabolic disorders such as diabetic nephropathy, hypercholesterolemia and platelet aggregation. With this study we investigated the anti-diabetic action of 70% ethanol RR extract in streptozotocin-induced diabetic mice, and determined the action mechanism of active compounds of RR in vitro. In the diabetic mice, serum glucose levels at fasting and post-prandial states and glucose area under the curve at modified oral glucose tolerance tests were lowered without altering serum insulin levels, indicating that RR contained potential anti-diabetic agents. The fractions fractionated from RR extracts by XAD-4 column revealed that 60%, 80% and 100% methanol fractions enhanced insulin sensitivity and inhibited alpha-glucoamylase activity. The major compounds of these fractions were sennosides, rhein and rhaponticin. Rhaponticin and rhein enhanced insulin-stimulated glucose uptake in 3T3-L1 adipocytes. Rhaponticin increased adipocytes with a differentiating effect similar to pioglitazone, but rhein and sennoside B decreased triglyceride accumulation. Sennoside A and B inhibited alpha-glucoamylase activity as much as acarbose. In conclusion, a crude extract of RR improves glucose intolerance by enhancing insulin-stimulated glucose uptake and decreasing carbohydrate digestion via inhibiting alpha-glucoamylase activity. Rhein and rhaponticin are potential candidates for hypoglycemic agents.


Complications of hysteroscopic Essure(®) sterilisation: report on 4306 procedures performed in a single centre.
To analyse the short-, medium- and long-term complications in women undergoing hysteroscopic tubal sterilisation with the Essure(®) device. Retrospective 7-year study. Office hysteroscopic unit in a teaching hospital. A total of 4306 women whoe underwent the Essure(®) sterilisation procedure from 2003 to 2010. Data on the success of the procedure and complications arising from outpatient hysteroscopic sterilisation using the Essure(®) system were collected from consecutive women undergoing the procedure over a 7-year period. Placement rate, successful bilateral tubal occlusion, perioperative adverse events, early postoperative (during the first 3 months of follow-up) and late complications (after the initial 3 months of follow-up). A total of 4108 (96.8%) women completed the standard 3-month follow-up protocol. Only 534 (13%) women had undergone the procedure within the previous year. There were 115 (out of 4306; 2.7%) recorded complications, none of which resulted in the need for hospitalisation or discharge later than 2 hours after the procedure. Vasovagal syncope was the most frequently encountered adverse event, occurring in 85 (2.0%) of 4306 cases. In 19 cases, one device was expelled, with most expulsions (14 out of 19) being detected before or during the 3-month follow-up. Outpatient hysteroscopic sterilisation using the Essure(®) system is safe, with a low rate of complications.


Theta rhythm related hippocampal cell discharges in the urethane anaesthetized rat: evidence for a predominant entorhinal input.
Unit spike activity and slow wave field potentials were recorded in the CA1 pyramidal layer and the dentate granular layer of the dorsal hippocampus of urethane anaesthetized rats during theta rhythm. 70% of the units in the pyramidal layer and all units in the granular layer, having a discharge pattern related to theta rhythm, had their mean moment of discharge in the positive phase of the theta wave recorded in the pyramidal layer. Combined with the results of a modelling study (Holsheimer et al. 1982) it appears that in rat under urethane the theta modulated input to the CA1 pyramidal cells and the dentate granular cells will be mediated predominantly by pathways which terminate distally at these cells: the perforant path.


Ossification of the cervical posterior longitudinal ligament with severe myelopathy and fatal outcome.
Ossification of the posterior longitudinal ligament is rare among Caucasians. We describe a new case with lethal outcome and we discuss the radiographic and pathologic findings. Posterior longitudinal ligament ossification is a benign disease in most cases, but it may cause severe myelopathy due to spinal stenosis. Diagnosis may be suspected or made on lateral views of the cervical spine and ascertained by CT.


A successful electroconvulsive treatment of neuroleptic malignant syndrome.
A case of neuroleptic malignant syndrome (NMS) treated successfully with electroconvulsive therapy (ETC) is described. Repeated exposures of the patients to succinylcholine during ECT did not cause malignant hyperthermia. The efficacy of ECT is probably related to its facilitatory effect upon dopamine (DA) activity in CNS.