Enhanced Average Thermoelectric Figure of Merit of p-Type Zintl Phase Mg2ZnSb2 via Zn Vacancy Tuning and Hole Doping.
Isoelectronic Zn substitution at the Mg site has been proved to be effective in regulating the carrier concentration of p-type Mg3Sb2 Zintl phase. However, the reported thermoelectric performance is still unsatisfactory compared with that of n-type Mg3Sb2 due to the poor electrical transport properties. Here, we report an enhanced average ZT through improving low-temperature ZTs by introducing Zn vacancy followed suppressing the bipolar effect by doping. First, the Zn vacancy simultaneously increases the power factor and decreases the thermal conductivity, leading to a peak ZT value of ∼0.52 at 773 K in Mg2Zn0.98Sb2. Additionally, doping Li or Ag at the Mg site is identified as a high-efficiency strategy for further increasing the carrier concentration and hence suppressing the bipolar effect. Finally, a peak ZT of ∼0.73 at 773 K and an average ZT of ∼0.46 between 300 and 773 K were obtained in Mg1.98Li0.02Zn0.98Sb2.


Effect and safety of duodenal levodopa infusion in advanced Parkinson's disease: a retrospective multicenter outcome assessment in patient routine care.
Duodenal levodopa infusion represents an effective strategy to manage motor and non-motor complications in patients with advanced Parkinson's disease (PD). However, most published clinical series regard small numbers of patients and do not exceed 1 year follow-up. In this multi-national observational cohort study conducted in seven specialised PD clinics and university hospitals we assessed long-term safety and outcome of chronic treatment with intra-duodenal levodopa infusions in a large population of patients with advanced PD. The starting population consisted of 98 treated patients (safety population). We report clinical outcomes of 73 patients with subsequent efficacy assessment(s) (efficacy population) over a follow-up period up to 2 years. Follow-up periods and collection of clinical observations varied based on individual routine care program. At last follow-up there was a significant (p ≤ 0.05) reduction in duration of "Off" periods as well as dyskinesia duration and severity that was associated with an improvement of quality of life. Twenty three patients (25.3 % of the safety population) withdraw, due to adverse drug reaction (5), procedure and device related events (7), compliance (3) and lack of efficacy (8). The mean duration for last value reported after baseline (LV) was 608 ± 292 days (median: 697 days). Our results demonstrate significant and sustained benefit over a long observation period in motor complications and in quality of life following a change from oral pulsatile to continuous levodopa delivery. The relatively large number of withdrawals reflects the current use of duodenal levodopa infusion in very advanced PD patients.


Circulating RNA: looking at the liver through a frosted glass.
The evaluation of the liver condition, based on serum enzymatic activity and biopsies, is insufficient. Therefore, it is a priority to find a correlation between circulating RNAs and liver damage. Publications were retrieved by the search terms "circulating RNA AND liver". Although differences exist between studies, a profile of RNAs that repeatedly appeared as indicators of liver damage was identified. We highlight those circulating RNAs useful to diagnostic, and discuss the transport mechanisms. Several studies have proven that circulating RNAs are useful to establish a diagnostic and a prognosis of liver diseases.


Role of the lectin complement pathway in kidney transplantation.
In the last 15 years two major advances in the role of complement in the kidney transplant have come about. The first is that ischaemia reperfusion injury and its profound effect on transplant outcome is dependent on the terminal product of complement activation, C5b-9. The second key observation relates to the function of the small biologically active fragments C3a and C5a released by complement activation in increasing antigen presentation and priming the T cell response that results in transplant rejection. In both cases local synthesis of C3 principally by the renal tubule cells plays an essential role that overshadows the role of the circulating pool of C3 generated largely by hepatocyte synthesis. More recent efforts have investigated the molecules expressed by renal tissue that can trigger complement activation. These have revealed a prominent effect of collectin-11 (CL-11), a soluble C-type lectin that is expressed in renal tissue and aligns with its major ligand L-fucose at sites of complement activation following ischaemic stress. Biochemical studies have shown that interaction between CL-11 and L-fucose results in complement activation by the lectin complement pathway, precisely targeting the innate immune response to the ischaemic tubule surface. Therapeutic approaches to reduce inflammatory and immune stimulation in ischaemic kidney have so far targeted C3 or its activation products and several are in clinical trials. The finding that lectin-fucose interaction is an important trigger of lectin pathway complement activation within the donor organ opens up further therapeutic targets where intervention could protect the donor kidney against complement.


Pulmonary artery rupture with pseudoaneurysm formation secondary to Swan-Ganz catheter balloon inflation.
Pulmonary artery catheters have been extensively used for hemodynamic assessment over the past several decades. We present a case that highlights the management of a known, but rare and catastrophic complication of pulmonary artery catheter based therapy. An elderly lady with acute decompensated heart failure, severe pulmonary hypertension, and atrial fibrillation on anticoagulation had a pulmonary artery catheter inserted for hemodynamic monitoring. Subsequently, the patient developed acute hemoptysis and damped pulmonary artery pressure waveforms during inflation of the catheter tip balloon. The possibility of pulmonary artery rupture was immediately recognized and confirmed with CT angiogram of the chest. Emergent interventional radiology guided coil embolization of pulmonary artery rupture and pseudoaneurysm was successful.


Sir Michael Foster MD FRS (1836-1907): the rise of the British school of physiology.
In 1867 William Sharpey (1802-80), Professor of General Anatomy and Physiology at University College, London, appointed Michael Foster to the unique post of Teacher of Practical Physiology; in Britain the study of experimental physiology was dormant. In 1870 Foster accepted a Praelectorship in Physiology at Trinity College, Cambridge, and soon established a school of physiology. He was the first Cambridge Professor of Physiology (1883-1903). Foster, a great teacher, had a remarkable ability to attract talented students and to inspire them to undertake research. He himself took inspiration from the scientific philosophy of Thomas Henry Huxley (1825-95) and of Claude Bernard (1813-78). Foster was active in the foundation of the Physiological Society (1876), and founded and edited the Journal of Physiology (1878). He was interested in the scientific training of medical students and wrote a highly lauded Text Book of Physiology (1877). Physiology became a profession in its own right and British physiologists were in the vanguard of research.


Aberrant retinotectal pathways induced by larval unilateral optic nerve section in Xenopus.
Following unilateral optic nerve section in Xenopus tadpoles and toadlets, the reformation of visual pathways and retinotectal projections was analyzed using [3H]proline autoradiography. Bilateral retinotectal projections were found in 61% of the animals operated on between stages 42 and 58. In these animals, the projections were established through multiple aberrant pathways which included the oculomotor nerve, the trigeminal nerve and the posterior commissure. In contrast, in animals with optic nerve section at stage 62 or after metamorphosis, the regenerated optic fibres arrived at the contralateral and ipsilateral tecta through normal visual pathways.


Management of gastric mucosa-associated lymphoid tissue lymphoma in patients with extra copies of the MALT1 gene.
To identify the clinical features of gastric mucosa-associated lymphoid tissue (MALT) lymphoma with extra copies of MALT1. This is a multi-centered, retrospective study. We reviewed 146 patients with MALT lymphoma in the stomach who underwent fluorescence in situ hybridization analysis for t(11;18) translocation. Patients were subdivided into patients without t(11;18) translocation or extra copies of MALT1 (Group A, n = 88), patients with t(11;18) translocation (Group B, n = 27), and patients with extra copies of MALT1 (Group C, n = 31). The clinical background, treatment, and outcomes of each group were investigated. Groups A and C showed slight female predominance, whereas Group B showed slight male predominance. Mean ages and clinical stages at lymphoma diagnosis were not different between groups. Complete response was obtained in 61 patients in Group A (69.3%), 22 in Group B (81.5%), and 21 in Group C (67.7%). Helicobacter pylori (H. pylori) eradication alone resulted in complete remission in 44 patients in Group A and 13 in Group C. In Group B, 14 patients underwent radiotherapy alone, which resulted in lymphoma disappearance. Although the difference was not statistically significant, event-free survival in Group C tended to be inferior to that in Group A (P = 0.10). Patients with t(11;18) translocation should be treated differently from others. Patients with extra copies of MALT1 could be initially treated with H. pylori eradication, similar to patients without t(11;18) translocation or extra copies of MALT1.


Peripheral blood circular RNA hsa_circ_0058493 as a potential novel biomarker for silicosis and idiopathic pulmonary fibrosis.
Existing studies reported that some circular RNAs (circRNAs) play vital roles in the development of pulmonary fibrosis. However, few studies explored the biomarker potential of circRNAs for pulmonary fibrosis based on population data. Therefore, we aimed to identify peripheral blood circRNAs as potential biomarkers for diagnosing silicosis and idiopathic pulmonary fibrosis (IPF). In brief, an RNA-seq screening based on 4 silicosis cases and 4 controls was initially performed. Differentially expressed circRNAs were combined with the human serum circRNA dataset to identify overlapping serum-detectable circRNAs, followed by validation using the GEO dataset (3 IPF cases and 3 controls) and subsequent qRT-PCR, including 84 additional individuals. Following the above steps, 243 differentially expressed circRNAs were identified during the screening stage, with fold changes ≥ 1.5 and P < 0.05. Of note, the human serum circRNA dataset encompassed 28 of 243 circRNAs. GEO (GSE102660) validation revealed two highly expressed circRNAs (P < 0.05) in the IPF case group. Furthermore, at the enlarged sample validation stage, hsa_circ_0058493 was highly expressed in both silicosis and IPF cases (silicosis: P = 1.16 × 10-6; IPF: P = 7.46 × 10-5). Additionally, hsa_circ_0058493 expression was significantly increased in MRC-5 cells upon TGF-β1 treatment, while hsa_circ_0058493 knockdown inhibited the expression of fibrotic molecules by affecting the epithelial-mesenchymal transition process. These shreds of evidence indicated that hsa_circ_0058493 might serve as a novel biomarker for diagnosing silicosis and IPF.


Mechanochemical strengthening of a synthetic polymer in response to typically destructive shear forces.
High shear stresses are known to trigger destructive bond-scission reactions in polymers. Recent work has shown that the same shear forces can be used to accelerate non-destructive reactions in mechanophores along polymer backbones, and it is demonstrated here that such mechanochemical reactions can be used to strengthen a polymer subjected to otherwise destructive shear forces. Polybutadiene was functionalized with dibromocyclopropane mechanophores, whose mechanical activation generates allylic bromides that are crosslinked in situ by nucleophilic substitution reactions with carboxylates. The crosslinking is activated efficiently by shear forces both in solvated systems and in bulk materials, and the resulting covalent polymer networks possess moduli that are orders-of-magnitude greater than those of the unactivated polymers. These molecular-level responses and their impact on polymer properties have implications for the design of materials that, like biological materials, actively remodel locally as a function of their physical environment.


An archived serum sample as a clue for identifying the primary source of a nosocomial hepatitis C virus outbreak in a haemodialysis unit.
Due to an unexpected technical error, patients at a dialysis unit who were seronegative for hepatitis C virus (HCV) were temporarily transferred to another dialysis unit next to a ward reserved for HCV-seropositive patients. In the following 7 months, 17 patients were diagnosed as anti-HCV positive. The aim of the study was to reveal the cause of this nosocomial infection. Anti-HCV-positive sera were further tested by molecular methods. Data collection and on-site epidemiologic inspections were carried out. The source of the nosocomial infection proved to be a seropositive patient treated at the unit, who died before the outbreak was recognized. The exact date of the infection was determined.


Influence of age on diurnal rhythms of adrenal norepinephrine, epinephrine, and corticosterone levels in soft-shelled turtles (Lissemys punctata punctata).
An investigation was made of what role aging plays on diurnal rhythms of norepinephrine, epinephrine, and corticosterone contents in the adrenal gland of soft-shelled turtles. To resolve this problem, juvenile and adult soft-shelled turtles were sacrificed at four different time intervals (0600, 1200, 1800, and 2400 hr) and adrenal hormonal levels were measured by spectrofluorometer. The findings revealed that peak norepinephrine, epinephrine, and corticosterone values were observed at 2400, 0600, and 2400 hr, respectively, and trough values for all the hormones were found at 1200 hr in both juvenile and adult animals. Thus, diurnal rhythms for all the hormones studied exist in both juvenile and adult animals. It is suggested that aging apparently has no influence on diurnal variations of adrenal hormones in turtles.


Presurgical planning of feeder resection with realistic three-dimensional virtual operation field in patient with cerebellopontine angle meningioma.
To devascularize meningiomas, the precise location of tumor attachment must be known. However, when a cerebellopontine angle (CPA) meningioma is in contact with many surrounding structures, it can be difficult to distinguish the most vascularized attachment (MVA) from other contact surfaces. To validate the usefulness of a virtual operation field (VOF) of a CPA meningioma by high-spatial-resolution three-dimensional computer graphics (hs-3DCG). Presurgical simulation with VOF was performed for eight CPA meningiomas to assess the MVA and the appropriate route to the main feeder. For hs-3DCG, the necessary preoperative radiographic images were fused. A hybrid model of volume and surface rendering was created from the fused images. The simulation results were compared with the operative results, and the MVA estimation rate was compared between VOF and contrast-enhanced fast imaging employing steady-state acquisition. By using VOF, the point at which the main feeder penetrated the tumor was estimated in all cases, and using this information, the MVA was detected. All patients underwent resection of the main feeder in the same way as simulated preoperatively. Estimation rates of MVA were 37.5% in CE-FIESTA and 100% in VOF (p = 0.02, Fisher's exact test). The hs-3DCG method was of sufficiently high quality to enable VOF of CPA meningioma. This method may facilitate estimation of MVA and the main feeder penetration point, and may aid in the determination of the most appropriate approach to the main feeder.


Symptom, diagnosis and mortality among respiratory emergency medical service patients.
Breathing difficulties and respiratory diseases have been under-reported in Emergency Medical Services research, despite these conditions being prevalent with substantial mortality. Our aim was two-fold; 1) to investigate the diagnostic pattern and mortality among EMS patients to whom an ambulance was dispatched due to difficulty breathing, and 2) to investigate the initial symptoms and mortality for EMS patients diagnosed with respiratory diseases in hospital. Population-based historic cohort study in the North Denmark Region 2012-2015. We included two patient groups; 1) patients calling the emergency number with breathing difficulty as main symptom, and 2) patients diagnosed with respiratory diseases in hospital following an emergency call. Main outcome was estimated 1- and 30-day mortality rates. There were 3803 patients with the symptom breathing difficulty, nearly half were diagnosed with respiratory diseases 47.3%, followed by circulatory diseases 13.4%, and symptoms and signs 12.0%. The 1-day mortality rate was highest for circulatory diseases, then respiratory diseases and other factors. Over-all 30-day mortality was 13.2%, and the highest rate was for circulatory diseases (17.7%) then respiratory diseases and other factors. A total of 4014 patients were diagnosed with respiratory diseases, 44.8% had the symptom breathing difficulty, 13.4% unclear problems and 11.3%. chest pain/heart disease. 1-day mortality rates were highest for decreased consciousness, then breathing difficulties and unclear problem. Over-all 30-day mortality rates were 12.5%, the highest with symptoms of decreased consciousness (19.1%), then unclear problem and breathing difficulty. There was an overlap of 1797 patients between the two groups. The over-all mortality rates alongside the distribution of symptoms and diagnoses, suggest the breathing difficulty patient group is complex and has severe health problems. These findings may be able to raise awareness towards the patient group, and thereby increase focus on diagnostics and treatment to improve the patient outcome.


Executive functions, selective attention and information processing in patients with obsessive compulsive disorder: A study from west of Iran.
Obsessive-compulsive disorder (OCD) is associated with cognitive dysfunction. Deeper and wider knowledge of the cognitive components of these patients can play an important role in better understanding of this disorder. This study aimed to compare executive function, selective attention and information processing in OCD patients and healthy controls. The current study was performed on 54 patients meeting DSM-5 criteria for OCD and 54 healthy subjects who matched with patients in gender, age, marital and educational status. The cognitive functions were assessed by The Stroop test, Wisconsin Cart Sorting Test (WCST), Paced Auditory Serial Addition Test (PASAT) and the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). The performance of the OCD group was significantly worse than the healthy group in comparison with the all subscales of the Stroop and WSCT tests. Also, functions in information processing among two groups were statistically significant for 3- and 2-second PASAT. The results demonstrated that OCD patients have deficits in several aspects of cognitive functions. Hence, the treatment of these patients can be contributed by paying more attention to these deficits.


Measuring the bronchial effect of bronchodilating drugs in healthy subjects after methacholine provocation. Salbutamol as a model drug.
To study whether it would be possible to assess bronchodilating drugs in healthy subjects with methacholine - induced bronchoconstriction, salbutamol 100, 200 and 300 micrograms was inhaled in random order by 12 healthy volunteers in a double-blind, placebo-controlled study. Dose response "slope" (DRS = maximum percentage fall in pulmonary function/maximal noncumulative methacholine dose (mumols] was used as an index of bronchial reactivity, and was calculated for forced expiratory flow volume in 1 s (DRSFEV1) and area under the flow-volume curve (DRSAEFV). Bronchial reactivity and its reproducibility were first tested by a standard methacholine provocation method. An abbreviated, single-dose method was used to measure the effect of salbutamol. The reproducibility of methacholine provocation was good, and the single-dose and standard methods gave comparable results. The DRS-values of all the doses of salbutamol differed significantly from placebo and from each other. AEFV did not show any advantage over the FEV1 in this context. A significant negative association between the dose of salbutamol (microgram/kg) and airway reactivity was observed. In conclusion, use of the DRS showed it possible to evaluate the protective efficacy of beta 2-adrenergic agonists against induced bronchoconstriction in healthy subjects.


Examination of differences between benzo[a]pyrene and steroid hydroxylases in guinea pig adrenal microsomes.
The effects of antibodies to cytochromes P-45017 alpha,lyase and P-450C21 on benzo[a]pyrene hydroxylase activity were measured in microsomes from guinea pig adrenals. Anti-cytochrome P-45017 alpha,lyase IgG inhibited about 30% of the benzo[a]pyrene hydroxylase activity of the microsomes in the presence of excess amounts of the IgG, but anti-cytochrome P-450C21 IgG did not affect the activity. In a reconstituted system, consisting of cytochrome P-450, NADPH-cytochrome-P-450 reductase and dilauroylphosphatidylcholine, cytochrome P-45017 alpha,lyase catalyzed, in addition to steroid hydroxylation, benzo[a]pyrene hydroxylation, but cytochrome P-450C21 did not hydroxylate benzo[a]pyrene. Since anti-cytochrome P-45017 alpha,lyase IgG inhibited benzo[a]pyrene hydroxylase activity completely in the reconstituted system with cytochrome P-45017 alpha,lyase, the presence of non-inhibited benzo[a]pyrene hydroxylase in the microsomes suggests that the residual activity in the microsomes may be due to some enzyme other than cytochrome P-45017 alpha,lyase. Benzo[a]pyrene hydroxylase activity was detected in detergent-solubilized microsomes from which cytochrome P-45017 alpha,lyase was removed by using an immobilized anti-cytochrome P-45017 alpha,lyase IgG-Sepharose column. This shows the existence in microsomes of a benzo[a]pyrene hydroxylase other than cytochrome P-45017 alpha,lyase. Benzo[a]pyrene hydroxylase in the solubilized microsomes required O2, NADPH and NADPH-cytochrome-P-450 reductase for its activity and was inhibited by CO. This suggests that benzo[a]pyrene hydroxylase is a cytochrome P-450-dependent monooxygenase. This novel enzyme was also active in xenobiotic metabolism, such as 2-nitropropane denitrification and aminopyrine demethylation.


The Feasibility of Creating Image-Based Patient-Specific Drill Guides for the Atlantoaxial Instabilities Using Open-Source CAD Software and Desktop 3D Printers.
C1/2 cervical pedicle screw fixation is a well-known procedure for treating severely damaged and unstable C1/2 fractures. On the other hand, C1/C2 screw fixation is not safe and can lead to potentially disastrous consequences. The importance of personalized 3-dimensional (3D) printed navigational guides in avoiding these consequences cannot be overstated. We retrospectively reviewed the neuroimaging data of 16 patients who had undergone fixation for treatment of C1/2 diseases. We created patient-specific C1/2 models and drill guide models using open-source 3D editing software and a desktop 3D printer. The drill guides were then placed over the respective vertebrae models and fixated with 3.5-mm screws. Following fixation, the parts were scanned with a thin-slice (01 mm) computed tomography scan, and the screw trajectories in the transverse and sagittal planes were measured at each level. Of the total of 62 screws, 58 were type I (93.54%), 4 were type II (6.45%), and no screws were type III. The results showed that there was no significant deviation in the screw trajectories and the accuracy of the drill guides was 93.54%. In our study, type I and type II screws were deemed acceptable, and the acceptable rates of C1/2 screw fixation were 100%. In this preclinical study, we demonstrated that it is possible to create patient-specific pedicle drill guides using open-source editing software and a commercially available desktop polylactic acid printer, resulting in high accuracy rates in pedicle screw placement in C1/2 patient models.


Decreasing Number of Medication Prescriptions After e-Prescriptions Became Mandatory and Their Valid Period Was Extended: A Big Bang Policy Change in Finland in 2017.
We measured the first time the number of prescriptions in Finland by using a centralized national shared repository of e-prescriptions and their dispensing data. This was made possible by introducing two policy interventions that were effective since 1 January 2017: mandatory e-prescribing and extension of a prescription's valid period from 12 months to two years. The trend in recording e-prescriptions started decreasing since the 'big bang', but pharmacy dispensations were not affected, as followed up to September 2019. It is possible to monitor the effects of health policy interventions by utilizing national e-health data systems, especially at the occurrence of a natural experiment.


Characterization of the biology and infectivity of Leishmania infantum viscerotropic and dermotropic strains isolated from HIV+ and HIV- patients in the murine model of visceral leishmaniasis.
Leishmaniasis is a group of diseases with a variety of clinical manifestations. The form of the disease is highly dependent on the infective Leishmania species and the immunological status of the host. The infectivity of the parasite strain also plays an important role in the progression of the infection. The aim of this work is to understand the influence of the natural infectivity of Leishmania strains in the outcome of visceral leishmaniasis. In this study we have characterized four strains of L. infantum in terms of molecular typing, in vitro cultivation and differentiation. Two strains were isolated from HIV+ patients with visceral leishmaniasis (Bibiano and E390M), one strain was isolated from a cutaneous lesion in an immunocompetent patient (HL) and another internal reference strain causative of visceral leishmaniasis (ST) also from an immunocompetent patient was used for comparison. For this objective, we have compared their virulence by in vitro and in vivo infectivity in a murine model of visceral leishmaniasis. Molecular typing unraveled a new k26 sequence attributed to MON-284 zymodeme and allowed the generation of a molecular signature for the identification of each strain. In vitro cultivation enabled the production of promastigotes with comparable growth curves and metacyclogenesis development. The HL strain was the most infective, showing the highest parasite loads in vitro that were corroborated with the in vivo assays, 6 weeks post-infection in BALB/c mice. The two strains isolated from HIV+ patients, both belonging to two different zymodemes, revealed different kinetics of infection. Differences in in vitro and in vivo infectivity found in the murine model were then attributed to intrinsic characteristics of each strain. This work is supported by other studies that present the parasite's inherent features as factors for the multiplicity of clinical manifestations and severity of leishmaniasis.


An Update on Immune Based Therapies in Acute Myeloid Leukemia: 2021 and Beyond!
Despite advances in the treatment of acute myeloid leukemia (AML), relapse is still widely observed and represents the major cause of death among patients with AML. Treatment options in the relapse setting are limited, still relying predominantly on allogeneic hematopoietic stem cell transplantation (allo-HSCT) and cytotoxic chemotherapy, with poor outcomes. Novel targeted and venetoclax-based combinations are being investigated and have shown encouraging results. Immune checkpoint inhibitors in combination with low-intensity chemotherapy demonstrated encouraging response rates and survival among patients with relapsed and/or refractory (R/R) AML, especially in the pre- and post-allo-HSCT setting. Blocking the CD47/SIRPα pathway is another strategy that showed robust anti-leukemic activity, with a response rate of around 70% and an encouraging median overall survival in patients with newly diagnosed, higher-risk myelodysplastic syndrome and patients with AML with a TP53 mutation. One approach that was proven to be very effective in the relapsed setting of lymphoid malignancies is chimeric antigen receptor (CAR) T cells. It relies on the infusion of genetically engineered T cells capable of recognizing specific epitopes on the surface of leukemia cells. In AML, different CAR constructs with different target antigens have been evaluated and demonstrated safety and feasibility in the R/R setting. However, the difficulty of potently targeting leukemic blasts in AML while sparing normal cells represents a major limitation to their use, and strategies are being tested to overcome this obstacle. A different approach is based on endogenously redirecting the patient's system cells to target and destroy leukemic cells via bispecific T-cell engagers (BiTEs) or dual antigen receptor targeting (DARTs). Early results have demonstrated the safety and feasibility of these agents, and research is ongoing to develop BiTEs with longer half-life, allowing for less frequent administration schedules and developing them in earlier and lower disease burden settings.


Relationship between the plasma glucose level and glucose uptake in the conscious dog.
In the absence of a change in the pancreatic hormonal milieu, elevations in the normal fasting plasma glucose level have little effect on glucose clearance. In view of these data, and the previously established responsiveness of M to hormones, glucose clearance can be considered to represent a useful index of hormone action on glucose uptake in vivo. Care should be taken, however, when interpreting clearance data obtained under hypoglycemic conditions, since there is a possibility that clearance may spontaneously increase at very low plasma glucose levels.


Pulmonary tuberculosis in patients with rheumatoid arthritis (four case reports).
Pulmonary involvement is one of the most common extra-articular manifestations of rheumatoid arthritis (RA). We studied four smear-positivepulmonary tuberculosis patients who had had RA for 2.5-12 years. Three of them were using corticosteroids at the time of diagnosis. The clinical, radiological and bacteriological features of all the patients were examined. We conclude that when patients with RA have symptoms related to pulmonary involvement, tuberculosis should be considered, particularly in developing countries.


Pinhole single-photon emission computed tomography for myocardial perfusion imaging of mice.
Although transgenic mice have emerged as powerful experimental models of cardiovascular disease, methods for in vivo phenotypic assessment and characterization remain limited, motivating the development of new instruments for biologic measurement. We have developed a single-photon emission computed tomography system with a pinhole collimator (pinhole SPECT) for high-resolution cardiovascular imaging of mice. In this study, we describe a protocol for myocardial perfusion imaging of mice using technetium-99m ((99m)Tc)-sestamibi and demonstrate the feasibility for measurement of perfusion defect size from pinhole SPECT images. Mice were anesthetized and injected with 370 MBq (10 mCi) of (99m)Tc-sestamibi. Tomographic projection images were acquired by rotating each mouse in a vertical axis in front of a stationary clinical scintillation camera equipped with a pinhole collimator. BALB/c mice (n = 15) were imaged after the permanent ligation of the left anterior descending coronary artery. The resulting defect size was measured from circumferential profiles of short-axis images. After imaging, the hearts were excised and sectioned to obtain ultra-high resolution digital autoradiographs of (99m)Tc-sestamibi, from which the actual infarct size was determined. Reconstructed image quality was equivalent to that obtained for clinical myocardial perfusion imaging. Linear regression analysis produced a correlation coefficient of 0.83 (p < 0.001) between the measured and actual values of the defect size. These results demonstrate that myocardial perfusion can be characterized qualitatively and quantitatively in mice using pinhole SPECT.


Benchmarking federated strategies in Peer-to-Peer Federated learning for biomedical data.
The increasing requirements for data protection and privacy have attracted a huge research interest on distributed artificial intelligence and specifically on federated learning, an emerging machine learning approach that allows the construction of a model between several participants who hold their own private data. In the initial proposal of federated learning the architecture was centralised and the aggregation was done with federated averaging, meaning that a central server will orchestrate the federation using the most straightforward averaging strategy. This research is focused on testing different federated strategies in a peer-to-peer environment. The authors propose various aggregation strategies for federated learning, including weighted averaging aggregation, using different factors and strategies based on participant contribution. The strategies are tested with varying data sizes to identify the most robust ones. This research tests the strategies with several biomedical datasets and the results of the experiments show that the accuracy-based weighted average outperforms the classical federated averaging method.


Use of an analytical model to study limitations on net photosynthesis in Arbutus unedo under field conditions.
From field gas-exchange measurements on Arbutus unedo growing in Portugal, parameter values necessary to apply an analytical, physiologicallybased model of C 3 photosynthesis were obtained. The model successfully simulated measured diurnal photosynthetic responses in Arbutus during periods without water stress, under both natural and CO2-saturating conditions. The model was used to analyze those factors limiting primary productivity during each of the experimental days. Due to a large investment in ribulose bisphosphate (RuBP) regeneration capacity, irradiance was rarely limiting, even during cloudy periods, but the limitation imposed by stomatal conductance was quite large, averaging over 30%. The fact that experimental leaves were maintained in a horizontal position is at least partially responsible for these results. Possible other reasons for this apparent excess of RuBP regeneration capacity visa-vis RuBP carboxylase-oxygenase concentration are discussed.


High occurrence of various Clostridium difficile PCR ribotypes in pigs arriving at the slaughterhouse.
Clostridium difficile is recognized as an important cause of nosocomial diarrhoea in humans, especially in association with the administration of antibiotics. Furthermore, C. difficile can not only cause neonatal enteritis in pigs but can also be found in pigs without any clinical disease symptoms. Clostridium difficile had been found on pork samples destined for human consumption. However, little is known about the risk of food-borne transmission. To elaborate the risk of food-borne transmission of C. difficile via pigs. The occurrence of C. difficile was assessed in pigs arriving at a slaughterhouse in the Netherlands. Rectal faecal samples from 50 pigs originating from 10 different farms were taken just after the pigs were stunned and bled. These samples were examined using a real-time PCR (BD GeneOhm™ Cdiff Assay) combined with culturing following enrichment. Using real-time PCR, none of the faecal samples were found positive for C. difficile while after culturing following enrichment, 14 out of 50 samples (28%) contained C. difficile. The positive samples were derived from nine different farms and encompassed seven different PCR ribotypes (015 predominant). All isolated C. difficile strains were positive for the toxin A and B genes. These results indicate that C. difficile can be found in faecal samples obtained from pigs after they were stunned and bled in a slaughterhouse. The potential risk of these findings on food-borne transmission via pigs and associated impact on human health cannot be excluded and needs further study.


Application of principal component and discriminant analyses to morpho-structural indices of indigenous and exotic chickens raised under intensive management system.
The objectives of this study were to investigate the relationships between body weight and morpho-structural indices to predict body weight from their orthogonal body shape characters using principal component analysis and to morphologically classify the chicken genotypes using multivariate discriminant analysis. Data used were from 273 randomly selected 12-weeks-old indigenous chickens of normal-feathered (NF), frizzle-feathered (FF), naked-neck (NN) and Anak Titan (AT) genotypes. Phenotypic correlation among body weight and most biometric traits ranged from 0.227-0.876, -0.7-0.901, 0.034-0.968 and -0.207-0.849 for NF, NN and AT chickens, respectively. Factor analysis with varimax rotation of interrelated traits revealed three principal components which accounted for 83.1%, 74.4%, 78.8% and 76.5% of the total variance in NF, FF, NN and AT chickens in the order listed. Breast girth, keel length, thigh length, shank length and wing length were found to be the most discriminating variables to separate the chicken genotypes. The longest distance (72.54) occurred between AT and NF genotypes while the shortest distance (4.27) was recorded for FF and NN genotypes. Classification results showed that 85.2% of AT genotype was correctly classified into their source population. However, 22.7% of NF was misclassified as NN, while 33.3% of NN was misclassified as NF chickens. These results suggest that there is high rate of gene flow between these two indigenous chicken genotypes. Information obtained from this study may be considered useful in breed improvement programmes for selection, characterization, conservation and better management of Nigerian indigenous chickens.


Assays to Assess Arenaviral Glycoprotein Function.
Arenaviruses, such as Lassa virus (LASV) and Pichindé virus (PICV), are enveloped viruses with a bi-segmented ambisense RNA genome. The large (L) genomic segment encodes the Z matrix protein and the L RNA-dependent RNA polymerase, whereas the small (S) genomic segment encodes the nucleoprotein (NP) and the glycoprotein precursor complex (GPC). GPC is processed by signal peptidase in the endoplasmic reticulum into the stable signal peptide (SSP) and GP1/GP2, which is further cleaved by the Golgi-resident subtilisin kexin isozyme-1 (SKI-1)/site-1 protease (S1P) into the cellular receptor-recognition subunit GP1 and the transmembrane subunit GP2, which helps promote the membrane fusion reaction to allow virus entry into the cell. This article describes assays to assess PICV GPC expression, proteolytic processing, fusion function, and GPC-mediated virus-like particle (VLP) entry into cells under tissue-culture conditions.


[The bactericidal power of antibiotic combinations. Application in the treatment of osteo-articular infections due to Staphylococcus aureus (author's transl)].
Study of the bactericidal power of antibiotic combinations against 18 strains of staphylococcus aureus causing osteoarthritis showed that the combinations most often synergistic or indifferent were: rifampicin + lincomycin or synergistine, rifampicin + fusidic acid, synergistine + fusidic acid or trimethoprim-sulphamethoxazole, cephalosporins + gentamycin, rifampicin or fusidic acid + gentamycin, trimethoprim-sulphamethoxazole + rifampicin or fusidic acid. Study of the antibiotic therapy used here was based upon the inhibitory power of serum and the measurement of antibiotic concentrations in healthy bone. Combinations which are synergistic or indifferent in vitro endow the serum with a high level of bactericidal activity. Certain antagonisms (cephalosporins or penicillin M + rifampicin) found in vitro may be reflected neither clinically nor in study of the inhibitory power of the serum.


Immunity to intracellular pathogens as a complex genetic trait.
Although the role of host heredity in susceptibility to infectious diseases is significant, the genetic control of immunity to infection remains poorly understood. Advances in experimental and epidemiological analyses of complex genetic traits have led to the discoveries of novel genetic determinants of host resistance. New loci that control susceptibility to a number of intracellular pathogens have been identified using mouse models of infectious diseases. The contributions of individual loci, however, vary in quantitative and qualitative manner, depending on mechanisms of pathogen virulence and genetic background of the host. In this review, we discuss how genetic analysis of host resistance contributes to further understanding of host immunity and pathogenesis of intracellular infections.


Protocols for Efficient Chemical Synthesis of N2 -Modified Guanosine Phosphate Derivatives: Versatile Probes for mRNA Labeling.
A facile, reliable, and efficient method for the synthesis of N2 -modified guanosine nucleotides such as N2 -[benzyl-N-(propyl)carbamate]-guanosine-5'-O-monophosphate, N2 -[benzyl-N-(propyl)carbamate]-guanosine-5'-O-diphosphate, N2 -[benzyl-N-(propyl)carbamate]-guanosine-5'-O-triphosphate, and N2 -[benzyl-N-(propyl)carbamate]-N7 -methyl-guanosine-5'-O-diphosphate, starting from the corresponding nucleotide is described. The general process entails condensation between the exocyclic amine of guanosine nucleotide and 3-[(benzyloxycarbonyl)amino]propionaldehyde in aqueous methanol, followed by reduction using sodium cyanoborohydride to furnish the corresponding N2 -modified guanosine nucleotide in moderate yield with high purity (>99.5%). © 2023 Wiley Periodicals LLC. Basic Protocol: Synthesis of N2 -modified guanosine derivatives.


Functional analysis of mutations in the human carnitine/acylcarnitine translocase in Aspergillus nidulans.
Deficiency of the carnitine/acylcarnitine translocase (CACT), the most severe disorder of fatty acid beta-oxidation, is usually lethal in both humans and animals, precluding the development of animal models of the disease. In contrast, CACT deficiency is conditionally lethal in the fungus Aspergillus nidulans, since loss-of-function mutations in acuH, the translocase structural gene, do not prevent growth on carbon sources other than ketogenic compounds, such as fatty acids. Here, we describe the molecular characterization of extant acuH alleles and the development of a fungal model for CACT deficiency based on the ability of human CACT to fully complement, when expressed at physiological levels, the growth defect of an A. nidulans DeltaacuH strain on acetate and long-chain fatty acids. By using growth tests and in vitro assays this model enabled us to carry out a functional characterization of human CACT mutations showing that it may be useful for distinguishing potentially pathogenic human CACT missense mutations from neutral, single residue substitution-causing polymorphisms.


New and Potential Treatments for Atopic Dermatitis: Biologicals and Small Molecules.
An update on new therapies currently approved or potentially useful in the future for the management of patients suffering moderate-to-severe atopic dermatitis. New pathogenic mechanisms involved in atopic dermatitis have permitted to propose novel therapeutic approaches devised to control the inflammatory process observed in involved cutaneous tissues by neutralizing mediators, cytokines, and their receptors. Recent research findings have disclosed important and previously unrecognized pathogenic mechanisms that have resulted in innovative targeted therapies, such as dupilumab, and potentially other biologicals and small molecules. Further studies should permit the sub-classification of patients according to the relevance of different mediators and inflammatory cells. It can be concluded that the treatment of atopic dermatitis has entered into the era of personalized/precision medicine.


Effect of permanganate oxidation on the photoreactivity of dissolved organic matter for photodegradation of typical pharmaceuticals.
Permanganate has been widely used in the remediation of contaminated water due to its relatively strong oxidation properties and ease of use. The ubiquitous dissolved organic matter (DOM) in natural waters causes a significant sink of permanganate in treatments, which further impacts the photoformation of reactive species and the removal of trace pollutants by DOM. Significantly, the effect of permanganate oxidation on the photoreactivity of DOM remains unknown. The present paper investigated for the first time the photophysical and photochemical properties variation of DOM from different sources after permanganate oxidation. Results showed that the permanganate oxidation caused a decrease in UV absorbance, fluorescence intensity, aromaticity, and molecular weight for all tested DOM samples, as well as photoformation rate of DOM triplet states (3DOM⁎), singlet oxygen (1O2), and hydroxyl radical (OH) under simulated sunlight. Quantum yield of 1O2 showed positively linear correlations with both triplet quantum yield coefficient (fTMP) and E2/E3 (ratio of absorbance at 254 and 365 nm) for all the DOM samples before and after permanganate oxidation. The quantum yield of OH exhibited no significant correlation with fTMP or E2/E3. Permanganate oxidation inhibited the DOM-photosensitized indirect photodegradation of pollutants that do not absorb sunlight (e.g., decreased by 15-29%). For the tested pollutants that undergo direct photolysis under sunlight, their photodegradation was promoted (e.g., increased by 1-19%) in the permanganate oxidized DOM solutions due to the decrease of light-screening effect by DOM. These findings suggest that permanganate oxidation affects the photoreactivity of DOM and the corresponding photochemical fate of organic pollutants in natural waters.


Reversal of advanced left ventricular dysfunction following aortic valve replacement for aortic stenosis.
A series of 12 consecutive patients who underwent aortic valve replacement (AVR) for aortic stenosis complicated by severe left ventricular dysfunction was reviewed. Ventricular dysfunction was reflected by pulmonary congestion, edema, renal and hepatic dysfunction, and by severely depressed ejection fractions (mean, 13%; range equal to 0-20%). Aortic valve replacement was accompanied by mitral commissurotomy in 1 patient and aortocoronary bypass in 5. Three of 5 patients with greater than 50% coronary obstruction died without reversal of heart failure, and 1 of the 5 died after a stroke. The 1 survivor of this group has done well. All 7 patients with minimal or no coronary disease survived operation and are now in New York Heart Association Class I or II. Postoperative catheterization (2 to 12 months) in 6 patients showed improved cardiac index and filling pressures. Left ventricular diastolic volume fell from 159 to 82 ml/m2, and ejection fraction rose from 13 to 45%. We conclude that left ventricular dysfunction owing to aortic stenosis alone is reversible and that AVR results in great clinical improvement. When coronary disease is present, survival may be accompanied by great improvement but the operative mortality is much higher.


An evaluation of microleakage of various glass ionomer based restorative materials in deciduous and permanent teeth: An in vitro study.
To evaluate the microleakage of recently available glass ionomer based restorative materials (GC Fuji IX GP, GC Fuji VII, and Dyract) and compare their microleakage with the previously existing glass ionomer restorative materials (GC Fuji II LC) in primary and permanent teeth. One hundred and fifty (75 + 75) non-carious deciduous and permanent teeth were restored with glass ionomer based restorative materials after making class I cavities. Samples were subjected to thermocycling after storing in distilled water for 24 h. Two coats of nail polish were applied 1 mm short of restorative margins and samples sectioned buccolingually after storing in methylene blue dye for 24 h. Microleakage was assessed using stereomicroscope. Significant differences (P < 0.05) were found when inter group comparisons were done. Except when GC Fuji VII (Group III) was compared with GC Fuji II LC (Group II) and Dyract (Group IV), non-significant differences (P > 0.05) were observed. It was found that there was no statistically significant difference when the means of microleakage of primary teeth were compared with those of permanent teeth. GC Fuji IX GP showed maximum microleakage and GC Fuji VII showed least microleakage.


Catecholamine stimulation and the response to behavioral challenge in Wistar rats.
Male Wistar rats were injected with CH-38083, an alpha 2-adrenoceptor blocker, after which they were challenged by a size-matched Wistar or Long-Evans opponent. In residents facing low-aggression opponents, the alpha 2-adrenoceptor blockade significantly reduced aggressiveness, whereas in those facing highly aggressive opponents the treatment significantly increased aggression scores compared to saline-treated controls, irrespective of the strain of the intruder. When the animals were treated with CH-38083, the frequency of biting attacks correlated significantly with the aggressiveness of the opponent in residents fighting with Wistar and Long-Evans rats. Similar correlations were not found in control (saline-injected) rats. The results suggest that the catecholaminergic activation caused by the alpha 2 receptor antagonist elicits a more efficient adaptation to the behavioral actions of the opponent. Plasma corticosterone levels were not influenced by the treatment, but this variable seemed to be correlated with the defensive behavior performed by the intruder.


Measles virus infection induces interleukin-8 release in human pulmonary epithelial cells.
Measles virus (MV) infection primarily targets epithelial cells of the respiratory tract, which have the potential to synthesize a variety of cytokines. In this report, we studied the effect of MV infection on the production of interleukin (IL)-8 by the pulmonary epithelial cells. A549 cells, a lower airway epithelial cell line, produced IL-8 after MV inoculation in a dose- and time-dependent manner. The IL-8 production was little affected by UV-inactivation of MV and scarcely suppressed by cycloheximide treatment. These results indicated that MV particle binding to and/or incorporation into cells stimulated IL-8 expression in A549 cells.


Multifaceted Barriers to Rapid Roll-out of HIV Pre-exposure Prophylaxis in China: A Qualitative Study Among Men Who Have Sex with Men.
Oral pre-exposure prophylaxis (PrEP) as a safe and effective antiretroviral medicine-based prevention against HIV has not been widely adopted by gay, bisexual, and other men who have sex with men (MSM) in China. A deeper understanding of barriers and facilitators to PrEP uptake is needed to inform the development of effective interventions. During July-August 2020, we conducted one-on-one semi-structured interviews with 31 Chinese MSM with varied PrEP use experiences (PrEP-naïve, former, and current PrEP users). Interviews were digitally recorded and transcribed in Chinese. Informed by the Information-Motivation-Behavioral Skills Model (IMB), we analyzed the data using a thematic analysis approach to identify the barriers and facilitators to PrEP uptake among Chinese MSM. Major barriers to PrEP uptake among MSM in the sample included uncertainty about PrEP efficacy and lack of PrEP education (information), concerns over potential side effects and cost (motivation), and difficulties in identifying authentic PrEP medications and managing PrEP care (behavioral skills). Facilitators include the perceived benefit of PrEP in improving the quality of sex life and control over health. At the contextual level, we also identified barriers to PrEP access from a thriving informal PrEP market and stressors related to being MSM. Our findings identified a need to invest in non-discriminatory public health messaging of PrEP, explore options for MSM-friendly provision of PrEP outside of traditional HIV care settings, and be attentive to the unique context of an established informal PrEP market in future PrEP initiatives.


An image-based guidewire navigation method for robot-assisted intravascular interventions.
This paper aims at using a newly developed robotic system to automatically deliver guidewires or catheters to the target site on percutaneous coronary interventions (PCIs) or electrophysiology interventions. An autonomous delivery strategy using electromagnetic tracking technology is introduced and phantom experiments are performed to validate this strategy. In order to advance the guidewire into the planned branch, the strategy classifies this branch selection problem into three cases according to the width of the vessels and employs an image-based algorithm for the first and second cases. Another image-based algorithm specifically designed for the third case is also presented.


Factors associated with the transition from abuse to dependence among substance abusers: implications for a measure of addictive liability.
This study was conducted to test the validity of a measure that has potential to bridge research on the addictive liability of drugs and on individuals' liability to addiction, which to date have evolved in largely parallel arenas. The length of time between onset of abuse and dependence (LOTAD) has evolved from recent findings on transitions through levels of addiction; it was hypothesized that shorter LOTAD is indicative of greater addictive liability. Hypotheses were based on animal studies and human studies. Retrospective data from the DSM-IV Substance Use Disorders Work Group were reanalyzed using configural frequency analysis, survival curves, bivariate Kendall's tau associations, and linear regression. The sample consisted of participants recruited from community and clinical settings. The measure was the Composite International Diagnostic Interview-Substance Abuse Module (CIDI-SAM). The shortest LOTADs were observed for disorders related to use of cocaine and opiates, followed by cannabis and then alcohol regardless of the subsample that was analyzed. As hypothesized, females and early initiators of drug use had shorter LOTADs compared to men and other initiators of drug use; no consistent differences in LOTAD were observed between African-Americans and Caucasians. None of the LOTAD variance associated with differences between drugs could be accounted for by gender, early use of the drug, or ethnicity. Specific areas of research where LOTAD might be useful as well as how LOTAD might be improved are discussed.


A systematic review of the research progress of traditional Chinese medicine against pulmonary fibrosis: from a pharmacological perspective.
Pulmonary fibrosis is a chronic progressive interstitial lung disease caused by a variety of etiologies. The disease can eventually lead to irreversible damage to the lung tissue structure, severely affecting respiratory function and posing a serious threat to human health. Currently, glucocorticoids and immunosuppressants are the main drugs used in the clinical treatment of pulmonary fibrosis, but their efficacy is limited and they can cause serious adverse effects. Traditional Chinese medicines have important research value and potential for clinical application in anti-pulmonary fibrosis. In recent years, more and more scientific researches have been conducted on the use of traditional Chinese medicine to improve or reduce pulmonary fibrosis, and some important breakthroughs have been made. This review paper systematically summarized the research progress of pharmacological mechanism of traditional Chinese medicines and their active compounds in improving or reducing pulmonary fibrosis. We conducted a systematic search in several main scientific databases, including PubMed, Web of Science, and Google Scholar, using keywords such as idiopathic pulmonary fibrosis, pulmonary fibrosis, interstitial pneumonia, natural products, herbal medicine, and therapeutic methods. Ultimately, 252 articles were included and systematically evaluated in this analysis. The anti-fibrotic mechanisms of these traditional Chinese medicine studies can be roughly categorized into 5 main aspects, including inhibition of epithelial-mesenchymal transition, anti-inflammatory and antioxidant effects, improvement of extracellular matrix deposition, mediation of apoptosis and autophagy, and inhibition of endoplasmic reticulum stress. The purpose of this article is to provide pharmaceutical researchers with information on the progress of scientific research on improving or reducing Pulmonary fibrosis with traditional Chinese medicine, and to provide reference for further pharmacological research.


Exploring visuomotor priming following biological and non-biological stimuli.
Observation of human actions influences the observer's own motor system, termed visuomotor priming, and is believed to be caused by automatic activation of mirror neurons. Evidence suggests that priming effects are larger for biological (human) as opposed to non-biological (object) stimuli and enhanced when viewing stimuli in mirror compared to anatomical orientation. However, there is conflicting evidence concerning the extent of differences between biological and non-biological stimuli, which may be due to stimulus related confounds. Over three experiments, we compared how visuomotor priming for biological and non-biological stimuli was affected over views, over time and when attention to the moving stimulus was manipulated. The results indicated that the strength of priming for the two stimulus types was dependent on attentional location and load. This highlights that visuomotor priming is not an automatic process and provides a possible explanation for conflicting evidence regarding the differential effects of biological and non-biological stimuli.


A precise radioimmunochemical method for determination of free insulin and insulin bound to serum proteins, including antibodies.
Polyethyleneglycol precipitation of insulin antibodies and insulin-antibody complexes is associated with co-precipitation of part of the free insulin. The recovery of free insulin was found to depend both on the quantity and quality of the antibodies and varied between 94% and 40%. Thus, the concentrations of free and total insulin may be lowered up to 2.5-fold in different sera containing endogenous antibodies. A critical evaluation of these results led to the development of a more reliable method for the assay of total and free insulin, based on individual radioisotopic determinations of the recovery of insulin extracted by PEG. The recovery of insulin added to sera containing antibodies as determined by the present method is within the range of 100 +/1 2.5%. In sera not containing antibodies total insulin concentration was found to be up to 5-times higher than that of IRI and to reach values above 250 muU/ml whereas whereas indirect IRI (i-IRI) may increase over 25 times with age.


Foamy virus vectors.
Gene therapy is a promising novel treatment for a variety of human diseases. Successful application of gene therapy requires the availability of vehicles with the ability to efficiently deliver and express genes. Viral vectors are efficient means of transferring a gene of interest into target cells. Current available vehicles for gene transfer are either inefficient or potentially unsafe for human gene therapy applications. Foamy viruses offer a fresh alternative vector system for gene transfer with the potential to overcome the concerns of the current vectors. Foamy viruses are nonpathogenic and have a broad host range with the ability to infect various types of cells from different species. Foamy virus replication is distinct and may provide an edge for foamy virus vector usage over other retroviral vectors. These features offer the foamy vectors unique opportunities to deliver several genes into a number of different cell types in vivo safely and efficiently. The principal problems for the design of foamy virus vectors have been solved, and several foamy virus vectors that efficiently transduce a variety of cell types are available. This chapter reviews specific features of foamy virus vector systems and recent advances in the development and use of these vectors.


Auditory elicitation of the P300 event-related evoked potential in the rat.
Auditory stimuli were used to elicit a P300 event-related evoked potential (ERP) in rat. Test conditions were comparable to those for eliciting ERP's in humans. A train of background tones with a randomly inserted target tone at a ten to one ratio were presented individually to ten unrestrained subjects in a baseline, a novel, and a trained condition. In the novel condition EEG's were averaged from subjects hearing both background and target stimuli for the first time. In the trained condition, subjects were previously trained using footshock in a shuttle box to discriminate the target tone. A statistical comparison of an ERP peak elicited at approximately 300 msec in both the novel and target condition compared with the baseline demonstrated the presence of the P300 in the rat.


Preserved acetazolamide reactivity in lacunar patients with severe white-matter lesions: 15O-labeled gas and H2O positron emission tomography studies.
Limited evidence exists on the relationships between severity of white-matter lesions (WMLs) and cerebral hemodynamics in patients without major cerebral artery disease. To examine changes of cerebral blood flow (CBF), oxygen metabolism, and vascular reserve capacity associated with severity of WML in patients with lacunar stroke, we used a positron emission tomography (PET). Eighteen lacunar patients were divided into two groups according to the severity of WMLs, assessed by Fazekas classification; grades 0 to 1 as mild WML group and grades 2 to 3 as severe WML group. Rapid dual autoradiography was performed with (15)O-labeled gas-PET followed by (15)O-labeled water-PET with acetazolamide (ACZ) challenge. Compared with the mild WML group, the severe WML group showed lower CBF (20.6±4.4 versus 29.9±8.2 mL/100 g per minute, P=0.008), higher oxygen extraction fraction (OEF) (55.2±7.4 versus 46.7±5.3%, P=0.013), and lower cerebral metabolic rate of oxygen (CMRO(2)) (1.95±0.41 versus 2.44±0.42 mL/100 g per minute, P=0.025) in the centrum semiovale. There were no significant differences in the ACZ reactivity between the two groups (48.6±22.6% versus 42.5±17.2%, P=0.524). Lacunar patients with severe WMLs exhibited reduced CBF and CMRO(2), and increased OEF in the centrum semiovale. The ACZ reactivity was preserved in both patients with severe and mild WMLs in each site of the brain.


[Boundary cap cells--a nest of neural stem cells in the peripheral nervous system].
The peripheral nervous system (PNS) is formed by neural crest cells (NCC) that migrate out of the neural tube in early mid-gestation. NCC give rise to most components of the PNS, including sensory neurons, glial satellite cells and Schwann cells. Neural crest cells also give rise to another type of PNS cell population named boundary cap (BC) cells, that form clusters at the surface of the neural tube, at entry and exit points of peripheral nerve roots. Using various genetic tools we were able to trace BC cell progeny during development and to ablate them in vivo. This revealed a previously unsuspected function of BC cells: they are required to maintain the integrity of the spinal cord motor column as, in their absence, motor neurons translocate their cell bodies along their axons into the periphery. In addition, we found that trunk BC-derived cells migrated along peripheral axons and colonized spinal nerve roots and dorsal root ganglia (DRG). All Schwann cell precursors occupying the dorsal roots were derived from BC cells. In the DRG, BC-derived cells were the progenitors of both neurons (mainly nociceptive afferents) and satellite cells. These unexpected observations indicate that BC cells constitute a source of peripheral nervous system (PNS) components that, after the major neural crest ventrolateral migratory stream, feed a secondary wave of migration to the PNS.


B-cell lymphomas morphologically resembling T-cell lymphomas.
Seven cases of B-cell lymphoma that morphologically resembled T-cell lymphoma are described. These cases are of four morphologic types: atypical poorly differentiated lymphocytic lymphoma (PDLL) with convoluted nuclei, "Lennert's" lymphoma, mixed lymphocytic-"histiocytic" lymphoma with large variation in size of abnormal cells, and "histiocytic" lymphoma with large multilobed nuclei. These cases add further support to the belief that morphologic criteria alone are not sufficient for accurate immunologic classification of the malignant lymphomas since they may represent a distinct clinicopathologic entity.


Effects of ochratoxin A on DNA evaluatedin vitro with the single cell gel electrophoresis (Comet assay).
In cell cultures of Madin Darby canine kidney (MDCK) cells, the mycotoxin ochratoxin A (OTA) induced single strand breaks (ssb) in a concentration dependent manner detected with the single cell gel electrophoresis (Comet assay). When an external metabolizing enzyme system (S9-mix from rat liver) was added, this genotoxic effect was significantly stronger. By addition of methotrexate (MT), a substrate of the hepatic organic anion transporter, the effect of OTA can be completely blocked at concentrations >100 μM methotrexate.When DNA repair was inhibited by addition of cytosine arabinose (araC) and hydroxyurea (HU), the tail length in the Comet assay increased dramatically and all treated cells showed ssb. A further culture of the damaged cells in the absence of any supplement resulted in a complete repair of the damaged DNA within three hours.Compared with MDCK cells, primary cultured porcine urinary bladder epithelial cells (PUBECs) showed weaker effects in the Comet assay if treated with OTA. The presence of S9-mix did not significantly enhance the response. Methotrexate only partially reduced the OTA-induced effects, because in PUBECs methotrexate induced ssb at high concentrations. If DNA repair was inhibited, also in PUBECs clearly more ssb were induced by OTA, an effect which was reversible.These results demonstrate that OTA induces single strand breaks in vitro. The damaged DNA can be repaired more effectively in primary cultured epithelial cells (PUBECs) compared to cells of a cell line (MDCK cells). By competitive inhibition of OTA uptake, DNA damage can be prevented with suitable substrates.


Comparative nanoindentation study of biogenic and geological calcite.
Biogenic minerals are often reported to be harder and tougher than their geological counterparts. However, quantitative comparison of their mechanical properties, particularly fracture toughness, is still limited. Here we provide a systematic comparison of geological and biogenic calcite (mollusk shell Atrina rigida prisms and Placuna placenta laths) through nanoindentation under both dry and 90% relative humidity conditions. Berkovich nanoindentation is used to reveal the mechanical anisotropy of geological calcite when loaded on different crystallographic planes, i.e., reduced modulus Er{104} ≥ Er{108} > Er{001} and hardness H{001} ≥ H{104} ≥ H{108}, and biogenic calcite has comparable modulus but increased hardness than geological calcite. Based on conical nanoindentation, we elucidate that plastic deformation is activated in geological calcite at the low-load regime (<20 mN), involving r{104} and f{012} dislocation slips as well as e{018} twinning, while cleavage fracture dominates under higher loads by cracking along {104} planes. In comparison, biogenic calcite tends to undergo fracture, while the intercrystalline organic interfaces contribute to damage confinement. In addition, increased humidity does not show a significant influence on the properties of geological calcite and the single-crystal A. rigida prisms, however, the laminate composite of P. placenta laths (layer thickness, ∼250-300 nm) exhibits increased toughness and decreased hardness and modulus. We believe the results of this study can provide a benchmark for future investigations on biominerals and bio-inspired materials.


Low HDL-C: a secondary target of dyslipidemia therapy.
Current guidelines for the prevention of coronary heart disease (CHD) focus on lowering low-density lipoprotein cholesterol (LDL-C) as the primary target of lipid-modifying therapy. However, there is increasing interest in high-density lipoprotein cholesterol (HDL-C) as a secondary target of therapy. A wealth of epidemiologic data demonstrate that low levels of HDL-C are associated with an increased risk of CHD events, and data from large-scale clinical trials with statins and fibrates indicate that observed clinical benefits are related, at least in part, to improvements in HDL-C levels. Raising HDL-C levels with therapeutic lifestyle changes and pharmacologic intervention might afford opportunities to further reduce the risk of CHD beyond LDL-C lowering. Statins are first-line pharmacotherapy for dyslipidemia and can also improve HDL-C levels, although the extent to which they modify HDL-C varies. Combining a fibrate or niacin with statin therapy raises HDL-C more than a statin alone but might be associated with reduced tolerability and increased adverse reactions. Several new therapeutic approaches to raising HDL-C are in development, including an HDL mimetic and inhibitors of cholesteryl ester transfer protein. Although lowering LDL-C remains the primary target of lipid-modifying therapy, dyslipidemia therapies that are efficacious for both LDL-C reduction and raising HDL-C might offer further improvements in CHD risk reduction.


femtoPro: virtual-reality interactive training simulator of an ultrafast laser laboratory.
The huge field of optics and photonics research and development is in constant demand of well-trained experts. However, it is challenging to teach efficiently the setup process of complicated optical experiments due to limited hardware availability and eye-safety concerns, in particular, in the case of femtosecond lasers. We have developed an interactive simulation of an ultrafast laser laboratory ("femtoPro") for teaching and training, implementing physical models for the calculation and visualization of Gaussian laser beam propagation, ultrashort optical pulses, their modulation by typical optical elements, and linear as well as nonlinear light-matter interaction. This facilitates the setup and simulated measurement procedure, in virtual reality (VR) and at real-time speeds, of various typical optical arrangements and spectroscopy schemes such as telescopes, interferometers, or pulse characterization. femtoPro can be employed to supplement academic teaching in connection with regular courses in optics or spectroscopy, to train future scientists and engineers in the field of (ultrafast) optics in practical skills, to communicate to other researchers how to set up and align a particular experiment, to "test-build" and simulate new designs of optical setups, to simulate ultrafast spectroscopy data, to offer practical exercises to high-school students, and to reach out to the general public.


Integrated lecithin-bile salt nanovesicles as a promising approach for effective skin delivery of luteolin to improve UV-induced skin damage in Wistar Albino rats.
The present study improved the effectiveness of a poorly water-soluble drug, luteolin (LUT), by encapsulating it in lecithin-bile salt-integrated system called bilosomes (BLs). Such a delivery system offers the benefits of mimicking the skin's biological structure and being a prominent tool to circumvent skin delivery obstacles. The prepared BLs underwent complete in vitro assessment. The developed BLs showed enhanced characteristics compared to free luteolin suspension (P < 0.05). Optimized BLs attained good entrapment efficiency (78.60% ± 0.88%), small particle size (226.1 ± 2.45 nm), and sustained drug-release pattern. The study also showed that both blank and LUT-loaded BLs preparations were safe to the skin with a primary irritancy index of < 2 based on the Draize test. In vivo tests were conducted to study the effect of the bile salt-based nanovesicles compared with the free LUT suspension. The photoprotective effect was evaluated according to the visual examination and biochemical analyses of antioxidant, anti-inflammatory, and anti-wrinkling markers after ultraviolet B irradiation. Results of biochemical markers and histopathological examination demonstrated that the LUT-BLs effect was superior than the LUT suspension (P < 0.05). Consequently, the current study proves that novel LUT-loaded BLs is a promising nanoplatform that overcome LUT delivery obstacles and, hence, alleviate UV-induced skin damage.


Nardilysin in human brain diseases: both friend and foe.
Nardilysin is a metalloprotease that cleaves peptides, such as dynorphin-A, α-neoendorphin, and glucagon, at the N-terminus of arginine and lysine residues in dibasic moieties. It has various functionally important molecular interaction partners (heparin-binding epidermal growth factor-like growth factor, tumour necrosis factor-α-converting enzyme, neuregulin 1, beta-secretase 1, malate dehydrogenase, P42(IP4)/centaurin-α1, the histone H3 dimethyl Lys4, and others) and is involved in a plethora of normal brain functions. Less is known about possible implications of nardilysin for brain diseases. This review, which includes some of our own recent findings, attempts to summarize the current knowledge on possible roles of nardilysin in Alzheimer disease, Down syndrome, schizophrenia, mood disorders, alcohol abuse, heroin addiction, and cancer. We herein show that nardilysin is a Janus-faced enzyme with regard to brain pathology, being probably neuropathogenic in some diseases, but neuroprotective in others.


Biodiversity of entomopathogenic nematodes in Italy.
An investigation was carried out on the distribution and biodiversity of steinernematid and heterorhabdtid entomopathogenic nematodes (EPN) in nine regions of Italy in the period 1990-2010. More than 2000 samples were collected from 580 localities and 133 of them yielded EPN specimens. A mapping of EPN distribution in Italy showed 133 indigenous EPN strains belonging to 12 species: 43 isolates of Heterorhabditis bacteriophora, 1 of H. downesi, 1 of H. megidis, 51 of Steinernema feltiae, 12 of S. affine, 4 of S. kraussei, 8 of S. apuliae, 5 of S. ichnusae, 3 of S. carpocapsae, 1 of S. vulcanicum, 3 of Steinernema 'isolate S.sp.MY7' of 'S. intermedium group' and 1 of S. arenarium. Steinernematids are more widespread than heterorhabditids and S. feltiae and H. bacteriophora are the most commonly encountered species. Sampling sites were grouped into 11 habitats: uncultivated land, orchard, field, sea coast, pinewood, broadleaf wood, grasslands, river and lake borders, caves, salt pan and moist zones; the soil texture of each site was defined and the preferences of habitat and soil texture of each species was assessed. Except for the two dominant species, S. feltiae and H. bacteriophora, EPN occurrence tends to be correlated with a specific vegetation habitat. Steinernema kraussei, H. downesi and H. megidis were collected only in Sicily and three of the species recently described - S. apuliae, S. ichnusae and S. vulcanicum - are known only from Italy and seem to be endemic.


Randomized Controlled Clinical Trial of Bivalent Oral Poliovirus Vaccine and Inactivated Poliovirus Vaccine in Nigerian Children.
We conducted a trial in Nigeria to assess the immunogenicity of the new bivalent oral poliovirus vaccine + inactivated poliovirus vaccine (bOPV+IPV) immunization schedule and gains in type 2 immunity with addition of second dose of IPV. The trial was conducted in August 2016-March 2017, well past the trivalent OPV-bOPV switch in April 2016. This was an open-label, 2-arm, noninferiority, multicenter, randomized, controlled trial. We enrolled 572 infants aged ≤14 days and randomized them into 2 arms. Arm A received bOPV at birth, 6, and 10 weeks, bOPV+IPV at week 14, and IPV at week 18. Arm B received IPV each at 6, 10, and 14 weeks and bOPV at 18 weeks of age. Seroconversion rates for poliovirus types 1 and 3, respectively, were 98.9% (95% confidence interval [CI], 96.7-99.8) and 98.1% (95% CI, 88.2-94.8) in Arm A and 89.6% (95% CI, 85.4-93.0) and 98.5% (95% CI, 96.3-99.6) in Arm B. Type 2 seroconversion with 1 dose IPV in Arm A was 72.0% (95% CI, 66.2-77.3), which increased significantly with addition of second dose to 95.9% (95% CI, 92.8-97.9). This first trial on the new Expanded Program on Immunization (EPI) schedule in a sub-Saharan African country demonstrated excellent immunogenicity against poliovirus types 1 and 3 and substantial/enhanced immunogenicity against poliovirus type 2 after 1 to 2 doses of IPV, respectively.


Microcarrier culture: A different approach to granulosa cell cultivation.
Granulosa cells (GC) are steroid secreting and hormone responsive cells synthesizing increased amounts of progesterone (P(4)) under the influence of gonadotropins. Up to now these cells have been cultivated as monolayers. However, in this system, cells dedifferentiate early and cease to respond to stimulation. GC are a good model for studying hormonal regulation of ovarian cell function. In this study, microcarrier culture was tested for the first time to see whether it would be a good system in which GC would grow and give a stronger responsivity to gonadotropins. Cells were grown in stationary culture on microcarriers Cytodex 3 (C3) coated with collagen and on pure gelatin beads. Only C3 cultures were successful. Cells proliferated better on C3 microcarriers and on day 4 of culture secreted more P(4) under the influence of FSH and LH than comparative monolayer cultures.


Cellular IL-10 is more effective than viral IL-10 in decreasing venous thrombosis.
Systemic administration of cellular interleukin-10 (cIL-10) and gene transfection of viral interleukin-10 (vIL-10) at thrombus induction decreases vein wall inflammation. Only cIL-10, despite sharing an 84% amino acid sequence homology with vIL-10, decreases thrombosis through mechanisms yet to be determined. C57BL/6 mice (Mus musculus, n99) were studied. Inferior vena caval thrombosis was created by inferior vena caval ligation and the animals were sacrificed and evaluated at days 2 and 6 after ligation. At thrombus induction groups received intravenous 0.25 microg of cIL-10, 0.25 microg of vIL-10, or saline (untreated controls). Evaluations included thrombus mass and vein wall leukocyte counts, protein levels, and reverse-transcription polymerase chain reaction mRNA levels of P- and E-selectin, monocyte chemotactic protein-1, and IL-10. Groups were compared by analysis of variance and t tests. Less thrombus was noted at both days 2 and 6 in animals treated with cIL-10. At day 2 only, vein wall leukocyte counts revealed a significant decrease in neutrophils in cIL-10 animals versus controls, with no significant differences for vIL-10 animals. In cIL-10-treated animals, P-selectin protein levels were decreased at day 6, along with a decreased thrombus mass, without significant differences in E-selectin, monocyte chemotactic protein-1, or IL-10 protein levels. vIL-10 treated animals showed increased E-selectin mRNA and thrombus mass versus controls on day 6. cIL-10 is more antithrombotic/anti-inflammatory than vIL-10. This may be the result of cIL-10 decreasing P-selectin protein expression and vIL-10 increasing E-selectin mRNA levels.


Head and neck epithelioid sarcoma in a child: diagnostic dilemma and anterolateral thigh free flap reconstruction.
The diagnostic dilemma is discussed of a child who presented with a granulomatous process of the external ear that was originally considered granuloma annulare and was later diagnosed as epithelioid sarcoma. We present the surgical treatment and the first report of reconstruction of a lateral skull base and cheek defect with an anterolateral thigh (ALT) free flap in a pediatric patient.


Calbindin-D28k and calretinin as markers of retinal neurons in the anuran amphibian Rana perezi.
In the present study we have analyzed the distribution of the calcium binding proteins calbindin-D28k (CB) and calretinin (CR) immunoreactive cells in the retina of the anuran Rana perezi using poly- and mono-clonal antibodies that were proven to be specific in the amphibian brain, without cross-reactivity. Double immunohistofluorescence techniques were used to demonstrate colocalization of both proteins in the same retinal cells. In addition, retrograde tracing experiments from the optic nerve were conducted to labeled ganglion cells and these were observed in combination with CB and/or CR immunohistochemistry. Cells containing CB were identified as all cones, scattered bipolar and amacrine cells together with cells in the ganglion cell layer. The pattern of CR immunoreactivity was strikingly different. Abundant cells contained CR in the inner retinal layers including horizontal, bipolar and amacrine cells, and cells in the ganglion cell layer. By means of double immunohistochemistry it was found that only subpopulations of amacrine cells and cells in the ganglion cell layer contained both CB and CR. Tracing from the optic nerve revealed retrogradely labeled ganglion cells with different morphologies and most of them contained CB and/or CR. All these data taken together suggest that in amphibians CB and CR are distinctly and precisely distributed in retinal neurons showing, however, peculiar features not observed previously in other vertebrates.


Successful management of two heart transplant recipients with mycobacterial pulmonary infections.
We report two cases of pulmonary tuberculosis in heart transplant recipients: a 46-year-old man with pulmonary tuberculosis due to Mycobacterium tuberculosis and a 64-year-old man with nontuberculous mycobacterial infection with pulmonary infiltrates due to Mycobacterium xenopi. The time intervals from transplantation to diagnosis were 3 and 4 years, respectively. The patient with tuberculosis underwent standard treatment with isoniazid, rifampin, ethambutol, and pyrazinamide. The patient with the nontuberculous mycobacterial infection received treatment with clarithromycin and ciprofloxacin for 18 months in addition to rifampin for the first 3 months. Both patients responded well to treatment. No recurrences were observed during follow-up. The interactions between antibiotic treatment and cyclosporine therapy should be observed closely in organ transplant recipients, requiring frequent level determinations and dosing changes.


The cocaine "body stuffer" syndrome: a fatal case.
Body stuffer, sometimes called "mini packer", is the definition of someone who admits to or is strongly suspected of ingesting illegal drugs in order to escape detection by authorities, and not for recreational purposes or to transport the drug across borders. Cocaine is the drug most commonly involved in the body stuffer syndrome. Reported cases of body stuffer deaths are rare, however a fatality related to the ingestion of a plastic bag containing cocaine is described regarding a 17-year-old dealer. The authors describe how the cocaine body stuffer syndrome differs from the usual body packer. Histological and toxicological findings are examined and discussed for a better definition of this unique syndrome.


Introduction of a Polyethylene Glycol Linker Improves Uptake of 67Cu-NOTA-Conjugated Lactam-Cyclized Alpha-Melanocyte-Stimulating Hormone Peptide in Melanoma.
The aim of this study was to evaluate the effect of linker on tumor targeting and biodistribution of 67Cu-NOTA-PEG2Nle-CycMSHhex {67Cu-1,4,7-triazacyclononane-1,4,7-triyl-triacetic acid-polyethylene glycol-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-CONH2} and 67Cu-NOTA-GGNle-CycMSHhex {67Cu-NOTA-GlyGlyNle-CycMSHhex} on melanoma-bearing mice. NOTA-PEG2Nle-CycMSHhex and NOTA-GGNle-CycMSHhex were synthesized and purified by HPLC. The biodistribution of 67Cu-NOTA-PEG2Nle-CycMSHhex and 67Cu-NOTA-GGNle-CycMSHhex was determined in B16/F10 melanoma-bearing C57 mice. The melanoma imaging property of 67Cu-NOTA-PEG2Nle-CycMSHhex was further examined in B16/F10 melanoma-bearing C57 mice. 67Cu-NOTA-PEG2Nle-CycMSHhex exhibited higher tumor uptake than 67Cu-NOTA-GGNle-CycMSHhex at 2, 4, and 24 h post-injection. The tumor uptake of 67Cu-NOTA-PEG2Nle-CycMSHhex was 27.97 ± 1.98, 24.10 ± 1.83, and 9.13 ± 1.66% ID/g at 2, 4, and 24 h post-injection, respectively. Normal organ uptake of 67Cu-NOTA-PEG2Nle-CycMSHhex was lower than 2.6% ID/g at 4 h post-injection, except for kidney uptake. The renal uptake of 67Cu-NOTA-PEG2Nle-CycMSHhex was 6.43 ± 1.31, 2.60 ± 0.79, and 0.90 ± 0.18% ID/g at 2, 4, and 24 h post-injection, respectively. 67Cu-NOTA-PEG2Nle-CycMSHhex showed high tumor to normal organ uptake ratios after 2 h post-injection. The B16/F10 melanoma lesions could be clearly visualized by single photon emission computed tomography (SPECT) using 67Cu-NOTA-PEG2Nle-CycMSHhex as an imaging probe at 4 h post-injection. The favorable tumor targeting and biodistribution properties of 67Cu-NOTA-PEG2Nle-CycMSHhex underscored its potential as an MC1R-targeted therapeutic peptide for melanoma treatment.


Association of intravenous thrombolysis and pre-interventional reperfusion: a post hoc analysis of the SWIFT DIRECT trial.
A potential benefit of intravenous thrombolysis (IVT) before mechanical thrombectomy (MT) is pre-interventional reperfusion. Currently, there are few data on the occurrence of pre-interventional reperfusion in patients randomized to IVT or no IVT before MT. SWIFT DIRECT (Solitaire With the Intention For Thrombectomy Plus Intravenous t-PA vs DIRECT Solitaire Stent-retriever Thrombectomy in Acute Anterior Circulation Stroke) was a randomized controlled trial including acute ischemic stroke IVT eligible patients being directly admitted to a comprehensive stroke center, with allocation to IVT with MT versus MT alone. The primary endpoint of this analysis was the occurrence of pre-interventional reperfusion, defined as a pre-interventional expanded Thrombolysis in Cerebral Infarction score of ≥2a. The effect of IVT and potential treatment effect heterogeneity were analyzed using logistic regression analyses. Of 396 patients, pre-interventional reperfusion occurred in 20 (10.0%) patients randomized to IVT with MT, and in 7 (3.6%) patients randomized to MT alone. Receiving IVT favored the occurrence of pre-interventional reperfusion (adjusted OR 2.91, 95% CI 1.23 to 6.87). There was no IVT treatment effect heterogeneity on the occurrence of pre-interventional reperfusion with different strata of Randomization-to-Groin-Puncture time (p for interaction=0.33), although the effect tended to be stronger in patients with a Randomization-to-Groin-Puncture time >28 min (adjusted OR 4.65, 95% CI 1.16 to 18.68). There were no significant differences in rates of functional outcomes between patients with and without pre-interventional reperfusion. Even for patients with proximal large vessel occlusions and direct access to MT, IVT resulted in an absolute increase of 6% in rates of pre-interventional reperfusion. The influence of time strata on the occurrence of pre-interventional reperfusion should be studied further in an individual patient data meta-analysis of comparable trials. clinicaltrials.gov NCT03192332.


Serum dextromethorphan/dextrorphan metabolic ratio for CYP2D6 phenotyping in clinical practice.
Accurate prediction of actual CYP2D6 metabolic activity may prevent some adverse drug reactions and improve therapeutic response in patients receiving CYP2D6 substrates. Dextromethorphan-to-dextrorphan metabolic ratio (MR(DEM/DOR)) is well established as a marker of CYP2D6 metabolizer status. The relationship between urine and plasma or serum MR(DEM/DOR) is not well established nor is there evidence of antimode for separation of intermediate and especially poor metabolizers (PM) from extensive metabolizers (EM). This study addressed whether CYP2D6 phenotyping using molar metabolic ratio of dextromethorphan to dextrorphan (MR(DEM/DOR)) in serum is usable and reliable in clinical practice as urinary MR(DEM/DOR). We measured MR(DEM/DOR) in serum and CYP2D6 genotype in 51 drug-naive patients and 30 volunteers. Receiver-operator characteristic (ROC) analysis was used for the evaluation of optimum cut-off value for discriminating between extensive, intermediate and PM. In addition, we studied the correlation of serum MR(DEM/DOR) with urine MR(DEM/DOR) in the 30 healthy volunteers. A trimodal distribution of log MR(DEM/DOR) in serum was observed, with substantial overlap between extensive and intermediate metabolizer groups. We obtained an acceptable cut-off serum MR(DEM/DOR) value to discriminate between PM and either extensive or extensive + intermediate metabolizers. Using serum MR(DEM/DOR), it seems to be unreliable to discriminate EM from intermediate metabolizers (IM). A strong correlation between serum MR(DEM/DOR) and urine MR(DEM/DOR) was found. Serum MR(DEM/DOR) (3 h) correlated with MR(DEM/DOR) in urine (0-8 h). Serum MR(DEM/DOR) discriminated between extensive and PM and between extensive + intermediate and PM. Our CYP2D6 phenotyping using serum dextromethorphan/dextrorphan molar ratio appears reliable but requires independent validation.


Using Latent Class Analysis to Model Preference Heterogeneity in Health: A Systematic Review.
Latent class analysis (LCA) has been increasingly used to explore preference heterogeneity, but the literature has not been systematically explored and hence best practices are not understood. We sought to document all applications of LCA in the stated-preference literature in health and to inform future studies by identifying current norms in published applications. We conducted a systematic review of the MEDLINE, EMBASE, EconLit, Web of Science, and PsycINFO databases. We included stated-preference studies that used LCA to explore preference heterogeneity in healthcare or public health. Two co-authors independently evaluated titles, abstracts, and full-text articles. Abstracted key outcomes included segmentation methods, preference elicitation methods, number of attributes and levels, sample size, model selection criteria, number of classes reported, and hypotheses tests. Study data quality and validity were assessed with the Purpose, Respondents, Explanation, Findings, and Significance (PREFS) quality checklist. We identified 2560 titles, 99 of which met the inclusion criteria for the review. Two-thirds of the studies focused on the preferences of patients and the general population. In total, 80% of the studies used discrete choice experiments. Studies used between three and 20 attributes, most commonly four to six. Sample size in LCAs ranged from 47 to 2068, with one-third between 100 and 300. Over 90% of the studies used latent class logit models for segmentation. Bayesian information criterion (BIC), Akaike information criterion (AIC), and log-likelihood (LL) were commonly used for model selection, and class size and interpretability were also considered in some studies. About 80% of studies reported two to three classes. The number of classes reported was not correlated with any study characteristics or study population characteristics (p > 0.05). Only 30% of the studies reported using statistical tests to detect significant variations in preferences between classes. Less than half of the studies reported that individual characteristics were included in the segmentation models, and 30% reported that post-estimation analyses were conducted to examine class characteristics. While a higher percentage of studies discussed clinical implications of the segmentation results, an increasing number of studies proposed policy recommendations based on segmentation results since 2010. LCA is increasingly used to study preference heterogeneity in health and support decision-making. However, there is little consensus on best practices as its application in health is relatively new. With an increasing demand to study preference heterogeneity, guidance is needed to improve the quality of applications of segmentation methods in health to support policy development and clinical practice.


Developmental profiles of protective mechanisms of heart against peroxidative injury.
The developmental profiles of the protective mechanisms of heart against peroxidative injury during neonatal growth was examined in the pigs of three different age groups. Lipid peroxidation expressed in terms of malonaldehyde formation was considerably higher in the pig hearts of the 8-10 day age group compared to that either by newborn or adult age groups. The four principal antioxidative enzymes, superoxide dismutase, glutathione peroxidase, glutathione reductase, and glucose-6-phosphate dehydrogenase (G6PD), were enhanced during early neonatal growth and, with the exception of G6PD, all other enzymes were further enhanced during further growth to adulthood. G6PD activity dropped significantly in adult heart. The phospholipid contents of myocardial membrane between newborn and week-old pigs did not vary significantly. Total phospholipids and phosphatidylcholine contents were significantly higher in adult heart compared to those in neonatal heart. The enzymes of phospholipid synthesis and degradation, fatty acyl CoA synthetase (FACS), phospholipase A2 (PLA2), lysophospholipase (LPL), and lysophophatidylcholine acyltransferase (LPCAT) increased during early neonatal growth. During further growth to adulthood, FACS decreased, PLA2 did not change, whereas both LPL and LPCAT increased significantly. Analysis of free fatty acids showed that palmitic and stearic acids decreased during the first week of growth, but increased during further growth to adulthood. Oleic acid did not change with aging, but arachidonic acid dropped in adult heart compared to that in neonatal heart. Linoleic, palmitoleic and free fatty acids increased dramatically during the first week of neonatal growth, but dropped thereafter. These results suggest that the unusual peroxidative status of the week-old pig heart is related to the presence of high concentrations of polyunsaturated fatty acids in the membrane phospholipids and not with the antioxidative defense system.


[Sarcoidosis associated with hypothyroidism due to thyrotropin-receptor blocking antibodies].
The association of sarcoidosis and auto-immune thyroid disease has been reported. We report a 29-year-old woman, treated for hypothyroidism caused by thyrotropin-receptor blocking antibodies, who developed a sarcoidosis (Löfgren's syndrome). Auto-immune thyroid diseases and sarcoidosis could share common pathogenic mechanisms.


What Happens After a Stop the Bleed Class? The Contrast Between Theory and Practice.
The Department of Homeland Security launched the Stop the Bleed initiative, a campaign intended to teach bystanders hemorrhage control strategies. Despite the program's popularity, little is known about actions taken by participants afterwards. We sought to determine how often participants acquired the equipment that is necessary in applying the skills taught. A standardized survey instrument was distributed to all American College of Surgeons Bleeding Control Basic (B-Con) class participants from 05/2017 to 01/2018. The instrument queried about the likelihood of applying skills and obtaining materials. A web-based survey was administered one month later inquiring whether materials were obtained and barriers that would prohibit acquisition. Academic, urban, Level I trauma center. Healthcare and nonhealthcare personnel. There were 336 and 183 participants who completed the initial and subsequent web-based survey, respectively. Participants indicated a high likelihood of applying a tourniquet (95.5%), applying pressure (97.9%), and packing a wound (96.4%), if required. Additionally, 74.7% and 76.2% reported a high likelihood of obtaining a tourniquet and packing material, respectively. However, only 21.3% and 50.8% obtained a tourniquet and packing material, respectively, 1 month later. Cost, time, and accessibility of items during a time of need were cited to be common reasons for not obtaining these materials. Despite reporting a high likelihood of utilizing hemorrhage control skills upon completion of the B-Con class, few went on to acquire the materials needed to apply these skills among those who responded. These results may be impacted by loss of follow up and response bias. Developing strategies that allow for easy access to materials is imperative and may lead to both better implementation of the purposes of the program and improved dissemination of its principles within the community.