Development and validation of a patient-reported outcome in systemic sclerosis: the Hand scleroDerma lived Experience (HAnDE) scale.
Hand involvement in systemic sclerosis (SSc) is at the core of the disease, with a substantial impact on both functional aspects and quality of life. There is no patient-reported outcome (PRO) scale globally assessing hand involvement in SSc. To develop and validate a PRO scale, the Hand scleroDerma lived Experience (HAnDE) scale, to assess the lived experience of hand involvement in patients with SSc. This was an exploratory sequential mixed-methods study with two phases: (i) PRO development through an inductive process to analyse the structure of lived experience, involving 21 patients with SSc; and (ii) PRO validation by assessing the psychometric properties of the scale among 105 patients with SSc. Phase 1 enabled us to generate the 18-item provisional scale. From Phase 2, the mean (SD) total score of the scale was 29·16 (16·15). The item reduction process retained 16 items with five levels of answers (range 0-64). Internal consistency of the 16-item version was excellent (Cronbach's alpha = 0·946). Construct validity was very good, principal component analysis pointing towards a unidimensional instrument, with one factor explaining 56% of the variance, and concurrent validity being confirmed: Cochin Hand Function Scale r = 0·66; Health Assessment Questionnaire - Disability index r = 0·58; Hospital Anxiety and Depression Scale, anxiety r = 0·51, depression r = 0·4; Mouth Handicap in Systemic Sclerosis scale r = 0·61; 36-Item Short Form Health Survey, physical component r = -0·48, mental component r = -0·46; and Kapandji score r = -0·46. The correlations were statistically significant (P < 0·05). We propose, for future trials and clinical practice in SSc, a new PRO, the HAnDE scale, that assesses all the dimensions - functional, aesthetic, relational, existential and emotional - of the lived experience of hand involvement in SSc.


Recent advances on nanoparticle-based therapies for cardiovascular diseases.
Nanoparticles are exclusively suitable for studying and developing potential therapies against cardiovascular diseases (CVD) because of their size, fine-tunable properties, and ability to incorporate therapeutic and imaging modalities. Recent advancements in nanomaterials open new avenues for treating CVD. In cardiology, the use of nanoparticles and nanocarriers has gathered significant consideration owing to characteristic features such as active and passive targeting to the cardiac tissues, greater target specificity, and sensitivity. It has been reported that through the use of nanotechnology, more than 50% of CVDs can be treated efficiently. Heart-targeted nano carrier-based drug delivery is an effective and efficient approach for treating cardiac-related disorders such as atherosclerosis, hypertension, and myocardial infarction. In this review, the authors focus on nanoparticle-based therapies used in CVD and provide an outline of essential knowledge and critical concerns on polymer-based nanomaterials in treating CVD.


Rapid and selective effects of thyrotropin on [35S]methionine incorporation into cytoplasmic and nuclear proteins in calf thyroid tissue slices.
Previous studies have indicated that thyrotropin may induce general increases in RNA and protein synthesis in calf thyroid tissue slices. In this report, we show that thyrotropin selectively stimulates [35S]methionine incorporation into small numbers of specific cytoplasmic and nuclear proteins. We provide data on the time course of stimulation and on relative molecular masses and isoelectric points of hormone-response proteins. Calf thyroid tissue slices were incubated for 3 h, 6 h or 9 h in the presence or absence of thyrotropin (50 mU/ml); [35S]methionine (50-75 microCi/ml) was added for the final 3 h of incubation. Cytoplasmic and nuclear fractions were then prepared, and analyzed by two-dimensional polyacrylamide gel electrophoresis and fluorography. Thyrotropin increased [35S]methionine incorporation into two cytoplasmic and four nuclear proteins within 3 h; hormonal effects on the labeling of five of these six proteins were transient, and no longer evident after 6-9 h. In contrast, a second group of two cytoplasmic and four nuclear proteins exhibited increased labeling after a delay of 6-9 h. Our results suggest that thyrotropin selectively stimulates the synthesis of specific cytoplasmic and nuclear proteins in calf thyroid tissue slices, and that stimulation involves at least two mechanisms (one rapid, the other delayed).


Exploiting the systematic review protocol for classification of medical abstracts.
To determine whether the automatic classification of documents can be useful in systematic reviews on medical topics, and specifically if the performance of the automatic classification can be enhanced by using the particular protocol of questions employed by the human reviewers to create multiple classifiers. The test collection is the data used in large-scale systematic review on the topic of the dissemination strategy of health care services for elderly people. From a group of 47,274 abstracts marked by human reviewers to be included in or excluded from further screening, we randomly selected 20,000 as a training set, with the remaining 27,274 becoming a separate test set. As a machine learning algorithm we used complement naïve Bayes. We tested both a global classification method, where a single classifier is trained on instances of abstracts and their classification (i.e., included or excluded), and a novel per-question classification method that trains multiple classifiers for each abstract, exploiting the specific protocol (questions) of the systematic review. For the per-question method we tested four ways of combining the results of the classifiers trained for the individual questions. As evaluation measures, we calculated precision and recall for several settings of the two methods. It is most important not to exclude any relevant documents (i.e., to attain high recall for the class of interest) but also desirable to exclude most of the non-relevant documents (i.e., to attain high precision on the class of interest) in order to reduce human workload. For the global method, the highest recall was 67.8% and the highest precision was 37.9%. For the per-question method, the highest recall was 99.2%, and the highest precision was 63%. The human-machine workflow proposed in this paper achieved a recall value of 99.6%, and a precision value of 17.8%. The per-question method that combines classifiers following the specific protocol of the review leads to better results than the global method in terms of recall. Because neither method is efficient enough to classify abstracts reliably by itself, the technology should be applied in a semi-automatic way, with a human expert still involved. When the workflow includes one human expert and the trained automatic classifier, recall improves to an acceptable level, showing that automatic classification techniques can reduce the human workload in the process of building a systematic review.


Use of allogeneic scaffold-free chondrocyte pellet in repair of osteochondral defect in a rabbit model.
Cell-based therapies are currently being used in treating osteochondral defect (OCD), but technical advances are needed to tackle the problems of scaffold and grafting technique. This study aimed to test the potential of allogeneic scaffold-free bioengineered chondrocyte pellet (BCP) in treating OCD. BCP was fabricated from rabbit costal cartilage and implanted into 3 mm × 3 mm OCD in medial femoral condyle of 20 rabbits. Samples were harvested at 2, 4, 8, and 16 weeks for histology, histological scoring and histomorphometric analysis. At treated side, cartilage score was significantly better at week 4 (p = 0.027), and cartilage thickness measured in histomorphometric analysis was significantly thicker at week 4 (p = 0.028) and week 16 (p = 0.028) compared to the empty controls. At treated side, bone score remained significantly lower from week 8 onwards (p = 0.024 at week 8, p = 0.02 at week 16) whereas bone area was significantly smaller from week 4 onwards compared to the empty controls (p = 0.028 at week 4, 8, 16). No immunorejection was observed throughout the experiment. The results demonstrated that the BCP enhanced cartilage repair at early stage. Press-fitting of allogeneic BCP was a simple method for OCD repair without immunorejection. Further optimization of the treatment is required before clinical application.


Initial evaluation of an Internet intervention to improve the sleep of cancer survivors with insomnia.
Insomnia is a common complaint among cancer survivors. Fortunately, cognitive-behavioral therapy for insomnia (CBT-I) has been shown to be an effective treatment in this population. However, it is rarely implemented given its limited availability. To address this barrier, we examined the ability of an easily accessible online CBT-I program to improve insomnia symptoms in cancer survivors. Twenty-eight cancer survivors with insomnia were randomly assigned to either an Internet insomnia intervention (n = 14) or to a waitlist control group (n = 14). The online program, Sleep Healthy Using The Internet, delivers the primary components of CBT-I (sleep restriction, stimulus control, cognitive restructuring, sleep hygiene, and relapse prevention). Pre- and post-assessment data were collected via online questionnaires and daily sleep diaries. Participants in the Internet group showed significant improvements at post-assessment compared with those in the control group in overall insomnia severity (F(1,26) = 22.8; p<0.001), sleep efficiency (F(1,24) = 11.45; P = 0.002), sleep onset latency (F(1,24) = 5.18; P = 0.03), soundness of sleep (F(1,24) = 9.34; P = 0.005), restored feeling upon awakening (F(1,24) = 11.95; P = 0.002), and general fatigue (F(1,26) = 13.88; P = 0.001). Although other group × time interactions were not significant, overall adjusted effect sizes for all sleep variables as well as for fatigue, depression, anxiety, and quality of life ranged from small to large. CBT-I delivered through an interactive, individually tailored Internet intervention may be a viable treatment option for cancer survivors experiencing insomnia.


Medial transposition of a split lateral rectus muscle in synergistic divergence.
Synergistic divergence is a rare congenital ocular motility disorder characterized by paradoxical abduction during attempted horizontal gaze to the contralateral side. It is generally unilateral and associated with limited adduction of the affected eye and large-angle exotropia in primary position. Various surgical techniques have been used to manage this condition, with limited success. We describe our experience using splitting and medial transposition of the lateral rectus muscle on the affected side to treat an 18-month-old girl with synergistic divergence. Postoperative improved motor alignment remained stable through 6 months' follow-up.


Direct qualitative and quantitative determination methodology for massive screening of DON in wheat flour based on multi-molecular infrared spectroscopy (MM-IR) with 2T-2DCOS.
Deoxynivalenol (DON) contamination in wheat flour induces a number of adverse health effects to consumers and livestock, even at very low concentrations. Direct detection methods for massive screening of DON in wheat flour is still lacking. A new methodology integrating multi-molecular infrared spectroscopy (MM-IR) with two-trace two-dimensional correlation spectroscopy (2T-2DCOS) was developed for in-situ qualitative and quantitative determination of DON in wheat flour as a whole. Typical spectral variation of wheat flour samples with diverse concentration of DON were stepwise characterized by MM-IR and tiny spectral profile differences resulting from concentration variation of DON were visually disclosed by 2T-2DCOS. Based on the obtained key spectral features of DON, 180 of wheat flour samples with DON higher and lower than 1.00 mg/kg were undoubtedly classified by Principal Component Analysis (PCA) and Support Vector Machines (SVM) with an accuracy rate up to 100% (for Second derivative spectra consisted of selected bands, SD-SS). Furthermore, a robust quantitative prediction model was established based on partial least squares (PLS) of SD-SS (Rc: 0.998, RMSEC: 0.135; Rp: 0.968, RMSEP: 0.421), and its excellent predictive capacity of model was validated by both residual prediction deviation (RPD) value of 3.2 and t-test. It was demonstrated that the developed methodology was applicable for screening and quantitative detection of DON in wheat flour based on the novel correlation analysis methods (SD-2DCOS-IR and 2T-2DCOS-IR) with chemometrics tools, which could be utilized both at laboratory and industrial level for quality control purposes of a large wheat flour sample set.


Oxidative lipidomics of apoptosis: redox catalytic interactions of cytochrome c with cardiolipin and phosphatidylserine.
The primary life-supporting function of cytochrome c (cyt c) is control of cellular energetic metabolism as a mobile shuttle in the electron transport chain of mitochondria. Recently, cyt c's equally important life-terminating function as a trigger and regulator of apoptosis was identified. This dreadful role is realized through the relocalization of mitochondrial cyt c to the cytoplasm where it interacts with Apaf-1 in forming apoptosomes and mediating caspase-9 activation. Although the presence of heme moiety of cyt c is essential for the latter function, cyt c's redox catalytic features are not required. Lately, two other essential functions of cyt c in apoptosis, that may rely heavily on its redox activity have been suggested. Both functions are directed toward oxidation of two negatively charged phospholipids, cardiolipin (CL) in the mitochondria and phosphatidylserine (PS) in the plasma membrane. In both cases, oxidized phospholipids seem to be essential for the transduction of two distinctive apoptotic signals: one is participation of oxidized CL in the formation of the mitochondrial permeability transition pore that facilitates release of cyt c into the cytosol and the other is the contribution of oxidized PS to the externalization and recognition of PS (and possibly oxidized PS) on the cell surface by specialized receptors of phagocytes. In this review, we present a new concept that cyt c actuates both of these oxidative roles through a uniform mechanism: its specific interactions with each of these phospholipids result in the conversion and activation of cyt c, transforming it from an innocuous electron transporter into a calamitous peroxidase capable of oxidizing the activating phospholipids. We also show that this new concept is compatible with a leading role for reactive oxygen species in the execution of the apoptotic program, with cyt c as the main executioner.


XBMP-1B (Xtld), a Xenopus homolog of dorso-ventral polarity gene in Drosophila, modifies tissue phenotypes of ventral explants.
Previously we have isolated a Xenopus cDNA homolog of bone morphogenetic protein-1 (XBMP-1A). In the present report we describe a new cDNA clone called XBMP-1B (or Xtld) from a Xenopus embryonic library. Sequence analysis indicates that these two clones share an indentical N-terminal sequence, including a region of metalloprotease domain, three copies of a repeat first found in complement proteins C1r/s and an epidermal growth factor (EGF)-like sequence. XBMP-1B protein has an additional copy of an EGF-like sequence followed by two copies of complement 1 r/s repeat in the C-terminus. The overall protein structure predicted from the XBMP-1B sequence reveals that it encodes a protein homologous to Drosophila tolloid. Three XBMP-1 transcripts (2.9, 5.2 and 6.6 kb) were detected by northern blot analysis. However, the 2.9 kb transcript hybridized specifically with XBMP-1A and the 5.2 and 6.6 kb transcripts hybridized with XBMP-1B. In Drosophila, a major function of tolloid is to augment the activity of the decapentaplegic gene product, a close relative of tumor growth factor (TGF)-beta superfamily members, BMP-2/4. Although XBMP-1 and XBMP-4 are detected in various adult tissues of Xenopus, the expression pattern of these two genes was not tightly correlated. In the embryo, the expression of XBMP-1 increased gradually from the morula to the swimming tadpole stages. Injection of XBMP-1B RNA into the ventral blastomeres at the 4-cell stage caused an elongation of the ventral marginal zone explants and converted globin-positive blood cells to mesenchymal and muscle tissues at later stages. It was shown that XBMP-1A was less active and a 1A mutant lacking the signal sequence was inactive. Further studies revealed that injection of XBMP-1B RNA into the ventral marginal zone induced up-regulation of dorsal marginal zone markers, such as goosecoid and chordin, at the gastrulation stage. These data indicate that XBMP-1 may have a role in determining dorso-ventral patterning in Xenopus, but in a different way from the dpp/tolloid system demonstrated in Drosophila.


Prosthesis-guided implant restoration of an auricular defect using computed tomography and 3-dimensional photographic imaging technologies: a clinical report.
The concept of prosthesis-guided implantation has been widely accepted for intraoral implant placement, although clinicians do not fully appreciate its use for facial defect restoration. In this clinical report, multiple digital technologies were used to restore a facial defect with prosthesis-guided implantation. A simulation surgery was performed to remove the residual auricular tissue and to ensure the correct position of the mirrored contralateral ear model. The combined application of computed tomography and 3-dimensional photography preserved the position of the mirrored model and facilitated the definitive implant-retained auricular prosthesis.


Thermo-TRP channels are involved in BAT thermoregulation in cold-acclimated Brandt's voles.
Transient receptor potential (TRP) channels, which can sense temperature, pressure and mechanical stimuli, were involved in many physiological and biochemical reactions. Whether thermosensitive TRP channels (Thermo-TRPs) are involved in thermoregulation in small mammals is still not clear. We measured the changes of thermo-TRPs at 4 °C, 23 °C and 30 °C in Brandt's voles (Lasiopodomys brandtii) to test the hypothesis that Thermo-TRPs are involved in cold-induced thermogenesis of brown adipose tissue (BAT) in small mammals. Results showed that air temperatures had no effect on body mass and rectal temperature, but the food intake and basal metabolic rate (BMR) in the 4 °C group were significantly higher than in the 30 °C group. Compared with 30 °C group, the protein contents of uncoupling protein 1(UCP1), TRP vanilloid 2 (TRPV2), TRP ankyrin 1 (TRPA1), TRP melastatin 2 (TRPM2), silent Information Regulator T1 (SIRT1), AMP-activated protein kinase (AMPK) and Calcium/calmodulin-dependent protein kinase II (CaMKII) in BAT increased significantly in 4 °C group, but there was no significant difference in the protein content of Thermo-TRPs in the hypothalamus among groups. Further, the expression of PRDM16 (PR domain containing 16) in inguinal white adipose tissue (iWAT) at 4 °C was significantly higher than that at 30 °C, but no difference was observed in the expression of other browning-related genes or TRPV2. In conclusion, TRP channels may participate in BAT thermoregulation through the CaMKII, AMPK, SIRT1 and UCP1 pathway in cold-acclimated Brandt's voles.


Considerations for bioanalytical characterization and batch release of COVID-19 vaccines.
The COVID-19 pandemic has prompted hundreds of laboratories around the world to employ traditional as well as novel technologies to develop vaccines against SARS-CoV-2. The hallmarks of a successful vaccine are safety and efficacy. Analytical evaluation methods, that can ensure the high quality of the products and that can be executed speedily, must be in place as an integral component of Chemistry, Manufacturing, and Control (CMC). These methods or assays are developed to quantitatively test for critical quality attributes (CQAs) of a vaccine product. While clinical (human) efficacy of a vaccine can never be predicted from pre-clinical evaluation of CQA, precise and accurate measurements of antigen content and a relevant biological activity (termed "potency") elicited by the antigen allow selection of potentially safe and immunogenic doses for entry into clinical trials. All available vaccine technology platforms, novel and traditional, are being utilized by different developers to produce vaccines against SARS-CoV-2. It took less than a year from the publication of SARS-CoV-2 gene sequence to Emergency Use Authorization (EUA) of the first vaccine, setting a record for speed in the history of vaccine development. The largest ever global demand for vaccines has prompted some vaccine developers to enter multiple manufacturing partnerships in different countries in addition to implementing unprecedented scale-up plans. Quantitative, robust, and rapid analytical testing for CQA of a product is essential in ensuring smooth technology transfer between partners and allowing analytical bridging between vaccine batches used in different clinical phases leading up to regulatory approvals and commercialization. We discuss here opportunities to improve the speed and quality of the critical batch release and characterization assays.


A review of sleep-promoting medications used in pregnancy.
Approximately 4% of adults who have symptoms of insomnia resort to various hypnotic or sedating medications for acute symptom relief. Although typically a common practice for nonpregnant adults, this is not the case for the thousands of pregnant women who also report substantial sleep issues. Unfortunately, a paucity of randomized controlled trials in this population, scant empiric evidence regarding the appropriateness of prescribing options, and the concern of subsequent teratogenicity restricts the ability of clinicians to make informed decisions. We synthesized the current research regarding hypnotics and sedating medications used (both on- and off-label) during pregnancy and their association with adverse outcomes. Medications that we investigated included benzodiazepines, hypnotic benzodiazepine receptor agonists, antidepressants, and antihistamines. Overall, the examined studies showed no correlation of increased risk of congenital malformations. However, benzodiazepines and hypnotic benzodiazepine receptor agonists may increase rates of preterm birth, low birthweight, and/or small-for-gestational-age infants. The small number of studies and the small number of subjects prohibit any definitive interpretation regarding the consequences of the use of hypnotic or sedating medications in pregnancy. Additional case reports, randomized clinical trials, and epidemiologic studies are needed urgently.


Electrical stimulation of a small brain area reversibly disrupts consciousness.
The neural mechanisms that underlie consciousness are not fully understood. We describe a region in the human brain where electrical stimulation reproducibly disrupted consciousness. A 54-year-old woman with intractable epilepsy underwent depth electrode implantation and electrical stimulation mapping. The electrode whose stimulation disrupted consciousness was between the left claustrum and anterior-dorsal insula. Stimulation of electrodes within 5mm did not affect consciousness. We studied the interdependencies among depth recording signals as a function of time by nonlinear regression analysis (h(2) coefficient) during stimulations that altered consciousness and stimulations of the same electrode at lower current intensities that were asymptomatic. Stimulation of the claustral electrode reproducibly resulted in a complete arrest of volitional behavior, unresponsiveness, and amnesia without negative motor symptoms or mere aphasia. The disruption of consciousness did not outlast the stimulation and occurred without any epileptiform discharges. We found a significant increase in correlation for interactions affecting medial parietal and posterior frontal channels during stimulations that disrupted consciousness compared with those that did not. Our findings suggest that the left claustrum/anterior insula is an important part of a network that subserves consciousness and that disruption of consciousness is related to increased EEG signal synchrony within frontal-parietal networks.


Health beliefs and behaviors of livestock industry workers regarding Crimean-Congo hemorrhagic fever in Northwest of Iran.
Crimean-Congo hemorrhagic fever (CCHF) is an acute, feverous disease that is caused by tick bites or humans' direct contact with the blood and tissues of infected livestock and humans. The transmission of the disease is also possible via human-to-human contacts and nosocomial transmission is well described. The majority of patients suffering from this disease are slaughterhouse workers (including butchers), farmers, veterinarians and hospital staff. Thus, this study aimed to investigate the health behaviors of butchers regarding CCHF and study factors affecting such behaviors based on the health belief model. This is a descriptive cross-sectional study conducted on 500 butchers in Ardabil Province in 2020 by a multistage sampling method. The participants of the study completed the researcher-made questionnaire of health belief model and health behaviors model relevant to CCHF. The collected data were then analyzed by descriptive statistical tests and linear regression analysis. The mean (SD) age of the participants was 44.4 (10.5) years, and 96% were males. Only 11.1% of the participants displayed acceptable disease-preventive behaviors. The validity and reliability of the developed questionnaire were confirmed. The results of the exploratory factor analysis showed that the constructs of the model explained 84% of the total variance. The results of the study revealed that among the variables of the health belief model, perceived susceptibility (p-value = 0.006, β = 0.152) and perceived barriers (p-value = 0.023, β = 0.14) were the strongest factors predicting disease-preventive behaviors regarding CCHF. The results of the study showed that the health belief model can predict preventive behaviors for CCHF. Therefore, designing and executing interventions based on the results of this study may encourage such preventive behaviors in butchers.


Flecainide acetate for treatment of tachyarrhythmias in children: review of world literature on efficacy, safety, and dosing.
A review of all published experience with flecainide in infants, children, and fetuses was performed to evaluate the appropriate place of the drug in pediatric practice and to determine dosing guidelines. A total of 704 case references was generated. Flecainide appeared to be safe (no deaths with usual oral dosing, < 1% serious proarrhythmia) and effective (73% to 100% control, depending on mechanism) in children with supraventricular tachycardia. The drug was very effective for treatment of fetal tachyarrhythmias. Flecainide may not be safe for children who have structurally abnormal hearts and atrial flutter or ventricular arrhythmias. The safety of flecainide for patients with ventricular arrhythmias and normal hearts requires further investigation. Pharmacokinetic data reveal an age-dependent change in elimination half-life. Patients younger than 1 year of age have a plasma elimination half-life that is similar to that in children older than 12 years (i.e., 11 to 12 hours). Children aged 1 to 12 years have a mean elimination half-life of 8 hours. The effective flecainide dose is 100 to 200 mg/m2/day or 1 to 8 mg/kg/day. Toxicity may occur with doses in excess of these ranges, especially when high doses are accompanied by low serum trough levels. Milk blocks flecainide absorption, and toxicity may become manifest when milk products are removed from the diet.


[Profiles of medical malpractice in the prophylaxis of pulmonary thromboembolism].
Deaths caused by pulmonary thromboembolism (PTE) are often of forensic interest, due to the frequent preexistence of a traumatic event the suddeness of death, and possible professional responsibility. Early diagnosis of vein thromboembolism is often difficult. Fatal PTE usually presents itself on an unexpected and large scale, chronologically occurring shortly before death and thus irreconcilable with any consequent efficacious therapy. Pharmacological prophylaxis, aiming at reducing the state of blood hypercoagulability, is the elective therapeutic strategy for vein thromboembolism. These are the premises for this work which, after a brief pharmacological and clinical description of heparin prophylaxis and a review of data emerging from a sample of 24 deaths due to PTE, makes some considerations regarding professional responsibility.


Azithromycin-loaded liposomes for enhanced topical treatment of methicillin-resistant Staphyloccocus aureus (MRSA) infections.
Antibiotic delivery via liposomal encapsulation represents a promising approach for the efficient topical treatment of skin infections. The present study aimed to investigate the potential of using different types of azithromycin (AZT)-loaded liposomes to locally treat skin infections caused by methicillin-resistant Staphylococcus aureus (MRSA) strains. Conventional liposomes (CLs), deformable liposomes (DLs), propylene glycol-containing liposomes (PGLs) and cationic liposomes (CATLs) encapsulating AZT were prepared, and their physical characteristics, drug release profiles, ex vivo skin penetration/deposition abilities, in vitro anti-MRSA activities (planktonic bacteria and biofilm) and cell biocompatibilities were assessed. The (phospho)lipid composition and presence of surfactant or propylene glycol affected the physical characteristics of the liposomes, the release profile of AZT, its deposition inside the skin, as well as in vitro antibacterial efficacy and tolerability with the skin cells. All the liposomes retained AZT inside the skin more efficiently than did the control and were biocompatible with keratinocytes and fibroblasts. CATLs, DLs and PGLs efficiently inhibited MRSA strain growth and were superior to free AZT in preventing biofilm formation, exhibiting minimal inhibitory concentrations and minimal biofilm inhibitory concentrations up to 32-fold lower than those of AZT solution, thus confirming their potential for improved topical treatment of MRSA-caused skin infections.


Acute effects of haemodialysis on biochemical modulators of endothelial function.
To assess the acute effects of haemodialysis (HD) on biochemical factors modulating endothelial function. Academic medical centre. Forty patients (age 63.5 +/- 2.2 years, mean +/- SEM) undergoing HD. Folic acid (F), homocysteine (tHcy), asymmetric dimethylarginine (ADMA), high-sensitivity C-reactive protein (CRP) and malondialdehyde (MDA) were measured pre-HD, 1 h after commencing HD and within the last hour of HD (end-HD). Endothelium-dependent and -independent vasodilatation were measured by applanation tonometry (changes in augmentation index, AIx, postinhaled salbutamol and postsublingual nitroglycerin) in conjunction with biochemical measurements. Marked reductions in serum F (616 +/- 73 vs. 273 +/- 30 nmol L(-1), P < 0.001), tHcy (16.3 +/- 0.7 vs. 11.2 +/- 0.5 micromol L(-1), P < 0.001) and ADMA (0.64 +/- 0.02 vs. 0.47 +/- 0.02 micromol L(-1), P < 0.001) occurred end-HD, whereas CRP and MDA levels did not significantly change. There was no significant change in endothelium-dependent vasodilatation, whereas endothelium-independent vasodilatation improved end-HD (-23.1 +/- 1.9 vs. -17.3 +/- 1.3%, P = 0.018). Regression analysis showed that both higher ADMA (P = 0.029) and lower F levels (P = 0.040) end-HD were determinants of reduced endothelium-dependent vasodilatation end-HD (R(2) = 0.23). HD is associated with significant reductions in F, tHcy and ADMA serum concentrations. The lack of significant effects of HD on endothelium-dependent vasodilatation could be secondary to the concomitant loss of factors either enhancing (F) or impairing (ADMA) endothelial function.


Nucleic acid carrier composed of a branched fatty acid lysine conjugate-Interaction studies with blood components.
For the development of gene therapeutics for systemic administration several hurdles have to be overcome. In this article we screen the branched fatty acid lysine conjugate T14diLys, a newly designed cationic lipid for lipofection, regarding this problem. The structure and particle size of lipoplexes, prepared with lipid formulations which are based on these lipid as nucleic acid complexing agent, are investigated in absence and presence of serum. Nuclease digestion assays were performed to evaluate the protective characteristics of the lipid formulation for the complexed nucleic acid. Furthermore, the lipid formulation is investigated regarding the interaction with different serum proteins to get first insights into the protein corona formation. Another focus is set on the hemocompatibility using in vitro assays for hemolysis and complement activation and the irritation test at the chorion allantois membrane of the chicken embryo as in vivo model. Finally, preliminary transfection efficiency studies with cell culture models for cells which are assessable via systemic administration are performed to evaluate possibilities for future therapeutic applications of the new lipid formulations. Summarizing, T14diLys with the co-lipid DOPE can be used to prepare a lipoplex formulation which can be applied systemically and can be used to develop gene therapeutics for targeting endothelial cells, macrophages, or leucocytes.


Importance of the irradiation timing within a chemoradiotherapy sequence including cisplatin and 5-FU-folinic acid. Experimental results.
The objective of the present in vitro study was to determine an optimal timing of the irradiation in the combination cisplatin (CDDP) and 5-fluorouracil-folinic-acid (5-FU-FA) allowing a maximal cytotoxic effect on a human cell line derived from a head and neck carcinoma (CAL 27 cells). The various tested chemoradiotherapy sequences were applied in parallel to human keratinocytes in culture (SVK 14 cells). This was done in order to define the best sequence allowing the achievement of an optimal selectivity of the cytotoxic effects. The drug sequence was: CDDP over 2 h then fresh medium was added including the tandem 5-FU-d,I FA applied 6 h after CDDP, for 5 days. Irradiation was applied only once and at various times within the drug sequence. The cytotoxicity effects of the different chemoradiotherapy combinations were assessed by the MTT semi-automated test. The part taken by the 5-FU-FA combinations in the overall cytotoxicity was examined; an effect was apparent on CAL 27 cells only. The evolution of the radiation effect (RE = cell survival after drugs/cell survival after drugs plus irradiation) was analysed as a function of the different times of irradiation within the given drug sequence. Clearly, the RE values were dependent upon time at which the radiation dose in the chemoradiotherapy regimen was administered. For CAL 27 cells, irradiation effects were maximal at the first irradiation time tested after the end of the CDDP exposure (i.e. t = 3.5 h). In contrast, this optimal chemoradiotherapy timing for better cytotoxicity on CAL 27 cells did not correspond to that of SVK 14 cells. Consequently, it was possible to establish that the best time for the selectivity index was located shortly after the CDDP exposure.


Urban-rural differences in multimorbidity and associated factors in China and Korea: A population-based survey study.
To analyze differences in multimorbidity rates and associated factors between urban and rural regions of Korea and China. Data were drawn from the Gateway to Global Aging Datasets. We describe multimorbidity patterns across rural and urban settings in each of the countries. Multivariate regression was used to identify factors associated with multimorbidity in each of the countries by region. In China, 31% of the sample had multimorbidity, with significantly higher proportions in the cities. In Korea, 24% had multimorbidity, with higher proportions in rural areas. However, multivariate analyses showed that rurality was associated with a lower risk of multimorbidity in both countries. Also, although there was significant socioeconomic disparity regarding multimorbidity in both rural and urban China, the disparity was focused around urban areas for Korea. Multimorbidity rates and associated socioeconomic factors varied by country and region. The concentration of socioeconomic disparities associated with multimorbidity in urban regions call to attention the vulnerability of "urban poor" in East Asia against chronic conditions. Geriatr Gerontol Int 2019; 19: 1157-1164.


Study of recent and future trends in place of death in Belgium using death certificate data: a shift from hospitals to care homes.
Since most patients prefer out-of-hospital death, place of death can be considered an indicator of end-of-life care quality. The study of trends in place of death is necessary to examine causes of shifts, to evaluate efforts to alter place of death and develop future policies. This study aims to examine past trends and future projections of place of death. Analysis of death certificates (decedents aged ≥ 1 year) in Belgium (Flanders and Brussels Capital region) 1998-2007. Trends in place of death were adjusted for cause of death, sociodemographic characteristics, environmental factors, numbers of hospital beds, and residential and skilled nursing beds in care homes. Future trends were based on age- and sex-specific mortality prognoses. Hospital deaths decreased from 55.1% to 51.7% and care home deaths rose from 18.3% to 22.6%. The percentage of home deaths remained stable. The odds of dying in a care home versus hospital increased steadily and was 1.65 (95%CI:1.53-1.78) in 2007 compared to 1998. This increase could be attributed to the replacement of residential beds by skilled nursing beds. Continuation of these trends would result in the more than doubling of deaths in care homes and a decrease in deaths at home and in hospital by 2040. Additional end-of-life care resources in care homes largely explain the decrease in hospital deaths. Care homes will become the main locus of end-of-life care in the future. Governments should provide sufficient skilled nursing resources in care homes to fulfil the end-of-life care preferences and needs of patients.


Activation of v-Myb avian myeloblastosis viral oncogene homolog-like2 (MYBL2)-LIN9 complex contributes to human hepatocarcinogenesis and identifies a subset of hepatocellular carcinoma with mutant p53.
Up-regulation of the v-Myb avian myeloblastosis viral oncogene homolog-like2 B-Myb (MYBL2) gene occurs in human hepatocellular carcinoma (HCC) and is associated with faster progression of rodent hepatocarcinogenesis. We evaluated, in distinct human HCC prognostic subtypes (as defined by patient survival length), activation of MYBL2 and MYBL2-related genes, and relationships of p53 status with MYBL2 activity. Highest total and phosphorylated protein levels of MYBL2, E2F1-DP1, inactivated retinoblastoma protein (pRB), and cyclin B1 occurred in HCC with poorer outcome (HCCP), compared to HCC with better outcome (HCCB). In HCCP, highest LIN9-MYBL2 complex (LINC) and lowest inactive LIN9-p130 complex levels occurred. MYBL2 positively correlated with HCC genomic instability, proliferation, and microvessel density, and negatively with apoptosis. Higher MYBL2/LINC activation in HCC with mutated p53 was in contrast with LINC inactivation in HCC harboring wildtype p53. Small interfering RNA (siRNA)-mediated MYBL2/LINC silencing reduced proliferation, induced apoptosis, and DNA damage at similar levels in HCC cell lines, irrespective of p53 status. However, association of MYBL2/LINC silencing with doxorubicin-induced DNA damage caused stronger growth restraint in p53(-/-) Huh7 and Hep3B cells than in p53(+/+) Huh6 and HepG2 cells. Doxorubicin triggered LIN9 dissociation from MYBL2 in p53(+/+) cell lines and increased MYBL2-LIN9 complexes in p53(-/-) cells. Doxorubicin-induced MYBL2 dissociation from LIN9 led to p21(WAF1) up-regulation in p53(+/+) but not in p53(-/-) cell lines. Suppression of p53 or p21(WAF1) genes abolished DNA damage response, enhanced apoptosis, and inhibited growth in doxorubicin-treated cells harboring p53(+/+) . We show that MYBL2 activation is crucial for human HCC progression. In particular, our data indicate that MYBL2-LIN9 complex integrity contributes to survival of DNA damaged p53(-/-) cells. Thus, MYBL2 inhibition could represent a valuable adjuvant for treatments against human HCC with mutated p53.


Isavuconazole Kinetic Exploration for Clinical Practice.
Isavuconazole is a new antifungal prodrug for the treatment of invasive aspergillosis and mucormycosis. As no clear pharmacokinetic-pharmacodynamic relationship has been established for patients, therapeutic drug monitoring is not currently required. However, as isavuconazole is a new drug, clinicians are sometimes sceptical about the exposure achieved in their patients and seek pharmacokinetic exploration. A minimal response consists of determining that the patient's pharmacokinetic profile agrees with profiles reported by Desai et al. using concentrations from the SECURE study. Based on one concentration and Desai et al.'s population-pharmacokinetic model, it is possible to estimate a patient's most likely pharmacokinetic profile. If a patient's pharmacokinetic profile is close to the profiles reported by Desai et al., therapeutic drug monitoring is not required. In contrast, when the pharmacokinetic profile differs from the Desai et al. profiles, isavuconazole concentration monitoring and pharmacokinetic profile modeling are the only methods for obtaining information on a patient's exposure and the efficacy of isavuconazole. Four patients presented with surprising pharmacokinetic profiles, unexplained by drug interactions or cytochrome P450 3A4/5 polymorphisms. For two of them, a drug dosage adjustment was proposed and applied by clinicians, together with a check for a new pharmacokinetic profile a few days later. Collecting one blood sample just before the first maintenance dose to make an early estimation of the patient's most likely pharmacokinetic profile is one method of identifying patients with outlier pharmacokinetic behavior.


Application of the Threedimensional CT Scan to the Reconstruction of Craniofacial Deformities.
New developments in computerised tomography (CT) imaging technology have paralleled advances in craniofacial surgical techniques. The ability to reconstruct congenital, neoplastic, and traumatic deformities is dependent upon good pre-operative assessment. Understanding the spatial relationship of a given deformity is limited with conventional two-dimensional CT scans. A more precise, reproducible portrayal of the craniofacial problem has been' made possible with the development of three-dimensional CT scan capabilities.


Expression pattern of MRPS18 family genes in malignantly transformed b-cells.
To compare expression patterns of proteins of a family of mitochondrial ribosomal protein S18 (MRPS18) in tumor cell lines of the B-cell origin. The study has been performed on different subsets of tonsil B-cells and tumor cell lines of the B-cell origin using quantitative polymerase chain reaction analysis, western blot analysis, immunohistochemistry, bioinformatic analysis of the publicly available data bases on expression. We have found that genes of the MRPS18 family (1-3) show different expression patterns in tumor cell lines of the B-cell origin. The highest levels of expression were shown for MRPS18-3, the lowest - for MRPS18-1. MRPS18-2 was expressed at the highest levels in germinal center cells, Burkitt lymphoma and Hodgkin lymphoma cell lines. At the protein levels, MRPS18-2 showed the highest expression in Burkitt lymphoma and B-cell precursor acute lymphoblastic leukemia cell lines. In lymphoblastoid cell lines, and in germinal center B-cells MRPS18-2 levels were somewhat lower, but higher than in memory and plasma B-cells. The differential expression pattern of the MRPS18 family proteins suggests that they play various roles in cellular processes.


Novel methods for discriminating behavioral differences between stickleback individuals and populations in a laboratory shoaling assay.
Threespine sticklebacks (Gasterosteus aculeatus) from different habitats have been observed to differ in shoaling behavior, both in the wild and in laboratory studies. In the present study, we surveyed the shoaling behavior of sticklebacks from a variety of marine, lake, and stream habitats throughout the Pacific Northwest. We tested the shoaling tendencies of 113 wild-caught sticklebacks from 13 populations using a laboratory assay that was based on other published shoaling assays in sticklebacks. Using traditional behavioral measures for this assay, such as time spent shoaling and mean position in the tank, we were unable to find population differences in shoaling behavior. However, simple plotting techniques revealed differences in spatial distributions during the assay. When we collapsed individual trials into population-level data sets and applied information theoretic measurements, we found significant behavioral differences between populations. For example, entropy estimates confirm that populations display differences in the extent of clustering at various tank positions. Using log-likelihood analysis, we show that these population-level observations reflect consistent differences in individual behavioral patterns that can be difficult to discriminate using standard measures. The analytical techniques we describe may help improve the detection of potential behavioral differences between fish groups in future studies.


New intermediate phenotype between MED and DD caused by compound heterozygous mutations in the DTDST gene.
DTDST mutations cause a spectrum of diastrophic dysplasia disorders characterized by defects of proteoglycans sulfation. Reduction of sulfate/chloride antiporter activity is manifested by lower sulfate uptake and depends on a combination of mutations in DTDST. We analyzed a family with an autosomal recessive form of bone dysplasia. Three affected brothers from this family are compound heterozygotes for C653S/A715V mutations. We classified their phenotype as a new intermediate form between diastrophic dysplasia and multiple epiphyseal dysplasia, manifested by shortening of stature, metatarsus adductus/club foot, mild brachydactyly, proximally placed thumbs and clinodactyly of the fifth fingers. Radiographs document platyspondyly most marked in the lower thoracic and upper lumbar spine, epiphyseal dysplasia affecting predominantly the femoral heads, widening of the metaphyses, narrow growth cartilage and multilayered patellae. Exaggerated lesser trochanters of femur, that is, "monkey wrench" sign, elevated greater trochanters, thin upper pubic rami, grossly normal carpal/tarsal bones and severe, early onset osteoarthritis were other notable features.


Comparison of the direct and indirect reduction techniques during the surgical management of posterior malleolar fractures.
The optimal method for the reduction and fixation of posterior malleolar fracture (PMF) remains inconclusive. Currently, both of the indirect and direct reduction techniques are widely used. We aimed to compare the reduction quality and clinical outcome of posterior malleolar fracture managed with the direct reduction technique through posterolateral approach or the indirect reduction technique using ligamentotaxis. Patients with a PMF involving over 25% of the articular surface were recruited and assigned to the direct reduction (DR) group or the indirect reduction (IR) group. Following reduction and fixation of the fracture, the quality of fracture reduction was evaluated in post-operative CT images. Clinical and radiological follow-ups were performed at 6 weeks, 3 months, 6 months, 12 months, and then at 6 month-intervals postoperatively. Functional outcome (AOFAS score), ankle range of motion, and Visual Analog Scale (VAS) were evaluated at the last follow-up. Statistical differences were compared between the DR and IR groups considering the patient demographics, quality of fracture reduction, AOFAS score, and VAS. Totally 116 patients were included, wherein 64 cases were assigned to the DR group and 52 cases were assigned to the IR group. The quality of fracture reduction was significant higher in the DR group (P = 0.038). In the patients who completed a minimum of 12 months' follow-up, a median AOFAS score of 87 was recorded in the DR group, which was significantly higher than that recorded in the IR group (a median score of 80). The ankle range of motion was slightly better in the DR group, with the mean dorsiflexion restriction recorded to be 5.2° and 6.1° in the DR and IR group respectively (P = 0.331). Similar VAS score was observed in the two groups (P = 0.419). The direct reduction technique through a posterolateral approach provide better quality of fracture reduction and functional outcome in the management of PMF over 25% of articular surface, as compared with the indirect reduction technique using ligamentotaxis. NCT02801474 (retrospectively registered, June 2016, ClinicalTrails.gov).


DNA EVOLUTION AND COLONIZATION SEQUENCE OF ISLAND LIZARDS IN RELATION TO GEOLOGICAL HISTORY: MTDNA RFLP, CYTOCHROME B, CYTOCHROME OXIDASE, 12S RRNA SEQUENCE, AND NUCLEAR RAPD ANALYSIS.
A novel source of nuclear DNA information from random amplified polymorphisms (RAPD) and a wide-range mitochondrial DNA information (cytochrome b, cytochrome oxidase, and 12s rRNA sequence, RFLP from 4-base and 6-base recognition endonucleases) are used to reconstruct the population phylogeny of the western Canary Island lizard, Gallotia galloti, which, for geological reasons, has been subject to dispersal but not vicariance. Interpretation of DNA phylogenies in terms of colonization sequence indicates that G. galloti arose in Tenerife and dispersed westward in two independent pathways: north from north Tenerife to La Palma, and south from south Tenerife to Gomera to Hierro. The direction and timing of colonization by DNA divergence is entirely compatible with geological time and sequence of island origin.


Eosinophilic ulcer of the tongue.
A 76-year-old woman presented with a 1-month history of a rapidly expanding painful ulcerated nodule on her tongue following tooth extraction. Triamcinolone acetonide ointment was applied twice daily for 1 month without any benefit. The histopathology of the excision specimen was consistent with an eosinophilic ulcer of the oral mucosa. There has been no recurrence 12 months later.


Primary immune responsiveness and other observations in mice given oral dimethyl sulfoxide.
Mice were allowed to drink 5% DMSO in their drinking water ad libitum for a period of six weeks, during which time a number of variables were compared with age-, weight-, and sex-matched control mice given ordinary tap water. The amount of DMSO consumed increased from a daily average of 27 g/kg/mouse during the first week to 52 g/kg/mouse by the end of the third week. Significant decreases were observed in the treated animals for total body weight, percent spleen weight relative to total body weight, and serum volume, while serum immunoglobulin concentrations remained unchanged. Mice given 4.4 g/kg DMSO intraperitoneally for 7 days, however, revealed significant losses in serum IgG and IgA, but not IgM. The effect of DMSO on the primary humoral response was assessed following immunization of mice with sheep red blood cells either 16 days or 8 weeks after the start of DMSO. Compared with similarly immunized controls, test animals demonstrated moderate, but significant, reductions in both spontaneous and facilitated plaque-forming cells, hemagglutination titres, and serum concentrations of IgG1. Based on a comparison of the two DMSO-treated groups, the degree of immune inhibition increased and the peak of the response was delayed relative to the length of time of DMSO ingestion prior to immunization.


Ectomycorrhiza succession patterns in Pinus sylvestris forests after stand-replacing fire in the Central Alps.
Fires shape fundamental properties of many forest ecosystems and climate change will increase their relevance in regions where fires occur infrequently today. In ecosystems that are not adapted to fire, post-fire tree recruitment is often sparse, a fact that might be attributed to a transient lack of mycorrhizae. Ectomycorrhizal (EcM) fungi play an important role for recruitment by enhancing nutrient and water uptake of their hosts. The questions arise whether and for how long the EcM community is transformed by fire. We investigated the resistance and resilience of EcM fungal communities on a chronosequence of 12 Pinus sylvestris stands in Valais (Switzerland) and Val d'Aosta (Italy) affected by fire between 1990 and 2006. Soil samples from burnt and non-burnt forests were analyzed with respect to EcM fungi by means of a bioassay. The number of EcM species was significantly lower in samples from recently (2-5 years) burnt sites than non-burnt forest, and increased with time since fire reaching levels of adjacent forests after 15-18 years. Community composition changed after fire but did not converge to that of non-burnt sites over the 18 year period. Only Rhizopogon roseolus and Cenococcum geophilum were abundant in both burnt sites and adjacent forest. Our data indicate fire resistance of some EcM fungal species as well as rapid resilience in terms of species number, but not in species composition. As long as the function of different EcM species for seedling establishment is unknown, the consequences of long-term shifts in EcM community composition for tree recruitment remain unclear.


An investigation of satellite hemodialysis fallbacks in the province of Ontario.
In Ontario, Canada, hemodialysis services are organized in a "hub and spoke" model comprised of regional centers (hubs), satellites, and independent health facilities (IHFs; spokes). Rarely is a nephrologist on site when dialysis treatments take place at satellite units or IHFs. Situations occur that require transfer of the patient back ("fallbacks") to the regional center that necessitate either in- or outpatient care. Growth in the satellite dialysis population has led to an increased burden on the regional centers. This study was carried out to determine the incidence, nature, and outcome of such fallbacks to aid resource planning. Data were collected on 565 patients from five regional centers over 1 yr. These regional centers controlled 19 satellite dialysis centers including 7 IHFs. There were 681 fallbacks in 328 patients: 1.21 incidents per patient or 2.1 incidents per patient year. Multiple fallbacks occurred in 170 patients. Fallback episodes lasted a mean of 10.3 d, requiring 4.6 dialysis treatments. Forty-five percent of fallbacks required hospitalization with a mean stay of 16.7 d. Access-related problems (33%) and nondialysis medical causes (32%) were the major causes of fallback. Resolution of the problem occurred in 87.8%, with the patient returning to the satellite. By the end of the study 77.3% were still satellite patients, 10.8% died, 3.8% returned to the regional center, 3.4% were transplanted, and 4.7% were transferred to other treatment modalities. Fallbacks are common, yet the model operates well.


Synthesis of cationic magnetic nanoparticles and evaluation of their gene delivery efficacy in Hep G2 cells.
Well-defined cationic polymers were synthesized via the reversible addition fragmentation chain transfer polymerization and were subsequently used as stabilizer for the synthesis of cationic iron-oxide magnetic nanoparticles via the coprecipitation method. The surface-coated iron-oxide nanoparticles made stable suspension in water and were characterized by a range of techniques such as dynamic light scattering, transmission electron microscopy, and thermogravimetric analysis. The presence of protonated amine and carbohydrate residues onto the surface of the nanoparticles allowed their facile complexation with DNA and the resulting nanocomplexes were then studied for their efficacy as DNA carriers in Hep G2 cells.


Insights into the structure of Escherichia coli outer membrane as the target for engineering microbial cell factories.
Escherichia coli is generally used as model bacteria to define microbial cell factories for many products and to investigate regulation mechanisms. E. coli exhibits phospholipids, lipopolysaccharides, colanic acid, flagella and type I fimbriae on the outer membrane which is a self-protective barrier and closely related to cellular morphology, growth, phenotypes and stress adaptation. However, these outer membrane associated molecules could also lead to potential contamination and insecurity for fermentation products and consume lots of nutrients and energy sources. Therefore, understanding critical insights of these membrane associated molecules is necessary for building better microbial producers. Here the biosynthesis, function, influences, and current membrane engineering applications of these outer membrane associated molecules were reviewed from the perspective of synthetic biology, and the potential and effective engineering strategies on the outer membrane to improve fermentation features for microbial cell factories were suggested.


Image Analysis in Plant Sciences: Publish Then Perish.
Image analysis has become a powerful technique for most plant scientists. In recent years dozens of image analysis tools have been published in plant science journals. These tools cover the full spectrum of plant scales, from single cells to organs and canopies. However, the field of plant image analysis remains in its infancy. It still has to overcome important challenges, such as the lack of robust validation practices or the absence of long-term support. In this Opinion article, I: (i) present the current state of the field, based on data from the plant-image-analysis.org database; (ii) identify the challenges faced by its community; and (iii) propose workable ways of improvement.


Simian varicella virus open reading frame 63/70 expression is required for efficient virus replication in culture.
Simian varicella virus (SVV) open reading frame (ORF) 63, duplicated in the virus genome as ORF 70, is homologous to varicella zoster virus ORF 63/70. Transfection of bacterial artificial chromosome clones containing the wild-type SVV genome and mutants with stop codons in ORF 70, in both ORFs 63 and 70 and the repaired virus DNA sequences into Vero cells produced a cytopathic effect (CPE). The onset of CPE was much slower with the double-mutant transfectants (10 days vs. 3 days) and plaques were smaller. While SVV ORF 63 is not required for replication in culture, its expression leads to robust virus replication.


On-Treatment Albumin-Bilirubin Grade: Predictor of Response and Outcome of Sorafenib-Regorafenib Sequential Therapy in Patients with Unresectable Hepatocellular Carcinoma.
In the RESORCE study, regorafenib after sorafenib therapy improved survival in patients with advanced hepatocellular carcinoma (HCC). In total, 88 patients with unresectable HCC who received sorafenib-regorafenib sequential therapy were enrolled. The objective response rate and disease control rate were 19.3% and 48.9%, respectively, for regorafenib therapy (median duration: 8.1 months). Median progression-free survival (PFS) after regorafenib therapy was 4.2 months (95% CI: 3.2-5.1). The median overall survival (OS; from initiation of either sorafenib or regorafenib) was not reached in this cohort. According to multivariate Cox regression analyses, albumin-bilirubin (ALBI) grade at the initiation of regorafenib therapy is an independent predictor of disease control, PFS, and OS. Moreover, the combination of ALBI grade 2 and an alpha-fetoprotein (AFP) level of ≥20 ng/mL was an independent predictor of PFS (hazard ratio (HR): 3.088, 95% CI: 1.704-5.595; p < 0.001) for regorafenib therapy, and OS for both regorafenib (HR: 3.783, 95% CI: 1.316-10.88; p = 0.014) and sorafenib-regorafenib sequential (HR: 4.603, 95% CI: 1.386-15.29; p = 0.013) therapy. A combination of ALBI grade and AFP level can be used to stratify patients with unresectable HCC by PFS and OS probability for sorafenib-regorafenib sequential therapy.


Predictors of well-being and functioning in older Mexican Americans and Anglos: an eight-year follow-up.
Using longitudinal data on older Mexican Americans and Anglos, we examined predictors of functioning and well-being over an eight-year period. Mean declines in measures of activity, health, and psychological well-being were observed in the 254 subjects followed-up, but these declines were not large. Residualized multiple regression analysis showed that Time 2 values of our dependent variables were significantly predicted by their Time 1 values. Age predicted declines in activity levels, while less educated subjects and those reporting lower levels of functional health were more likely to report declines in self-rated health. Less educated subjects were also more likely to report increased psychological distress. Finally, declines in life satisfaction were associated with higher initial levels of psychological distress. These findings are generally in agreement with those found by Palmore et al. (1985) in a different population of older people.


Sentinel node imaging via a nonparticulate receptor-binding radiotracer.
Technetium-99m-labeled polydiethylenetriamine pentaacetic acid polymannosyl polylysine (DTPA-man-PL) was synthesized and tested for lymph node scintigraphy by subcutaneous administration. The agent was designed for receptor-mediated uptake by mannosebinding protein, which resides on the plasma membrane of reticuloendothelial cells. Subcutaneous injections of a 99mTc-labeled agent having 18 DTPA and 82 mannosyl groups attached to a polylysine of 100 units ([99mTc]DTPA18-man82-PL100) were made at the level of the metacarpus and metatarsus of three healthy rabbits. Images were acquired at 1, 6, 12 and 24 hr. Popliteal and axillary nodes were then assayed for percent of injected dose (%ID). A negative control study was performed in three normal rabbits with [99mTc]DTPA18-PL100. Significant differences in mean 24-hr %ID between the receptor specific and nonspecific agents were observed for both the popliteal (p < 0.006) and axillary (p < 0.012) nodes. Popliteal percent injected dose at 24 hr was 3.00 +/- 0.72% for [99mTc]DTPA-man-PL and 0.13 +/- 0.08% for [99mTc] DTPA-polylysine. Axillary accumulation at 24 hr was 2.84 +/- 0.83% for [99mTc]DTPA-mannosyl-polylysine and 0.22 +/- 0.12% for [99mTc] DTPA-polylysine. Percent injected dose of the receptor-specific agent was highest (4%) during the 6-hr scan. Accumulation of the nonspecific agent by the popliteal and axillary nodes at 6-hr postinjection was approximately 0.5%. This study provides proof of principle for lymphoscintigraphy by receptor-mediated delivery of a nonparticulate imaging agent.


Computational fluid dynamics modeling of the upper airway of children with obstructive sleep apnea syndrome in steady flow.
Computational fluid dynamic (CFD) analysis was used to model the effect of airway geometry on internal pressure in the upper airway of three children with obstructive sleep apnea syndrome (OSAS), and three controls. Model geometry was reconstructed from magnetic resonance images obtained during quiet tidal breathing, meshed with an unstructured grid, and solved at normative peak resting flow. The unsteady Reynolds-averaged Navier-Stokes equations were solved with steady flow boundary conditions in inspiration and expiration, using a two-equation low-Reynolds number turbulence model. Model results were validated using an in-vitro scale model, unsteady flow simulation, and reported nasal resistance measurements in children. Pharynx pressure drop strongly correlated to airway area restriction. Inspiratory pressure drop was primarily proportional to the square of flow, consistent with pressure losses due to convective acceleration caused by area restriction. On inspiration, in OSAS pressure drop occurred primarily between the choanae and the region where the adenoids overlap the tonsils (overlap region) due to airway narrowing, rather than in the nasal passages; in controls the majority of pressure drop was in the nasal passages. On expiration, in OSAS the majority of pressure drop occurred between the oropharynx (posterior to the tongue) and overlap region, and local minimum pressure in the overlap region was near atmospheric due to pressure recovery in the anterior nasopharynx. The results suggest that pharyngeal airway shape in children with OSAS significantly affects internal pressure distribution compared to nasal resistance. The model may also help explain regional dynamic airway narrowing during expiration.


In-site and solvent-free exfoliation of porous graphene oxide from pencil lead fiber for solid-phase microextraction of cadmium ion before GF-AAS determination.
Graphene oxide (GO)-functionalized pencil lead fiber was prepared for the first time by in situ oxidation and exfoliation of graphite contained in pencil lead fiber to porous graphene oxide structure via a one-step solvent-free dielectric barrier discharge (DBD) microplasma treatment. This new fiber was demonstrated as a highly efficient and low-cost solid-phase microextraction (SPME) fiber for the determination of toxic metal ions. The fiber extraction performance was evaluated by using cadmium as a model analyte in a direct immersing SPME mode. Unlike most commercially available and other lab-built fibers, the preparation of the graphene oxidized pencil lead fiber is environmentally friendly, low cost, and non-toxic without using any organic solvents. The fiber is robust due to its coating-free configuration. Furthermore, high extraction efficiency and high sensitivity for cadmium can be obtained due to the abundant oxygen-containing functional groups on the surface of the novel fiber. After extraction, the cadmium adsorbed on the fiber was desorbed to 150-μL solution. Graphite furnace atomic absorption spectrometry (GF-AAS) with low sample consumption was used to determine cadmium. The calibration curve for cadmium ions was linear in a range 0.04-0.26 μg L-1 with a detection limit of 0.005 μg L-1. A relative standard deviation (RSD, n = 5) of 2.1% was obtained at 0.1 μg L-1 of cadmium. The sensitivity enhancement factor (EF) value of the proposed SPME method was 25. The SPME fiber was successfully applied to determine cadmium in tap water, river water, and pond water with spike recoveries ranging from 94 to 105%. Pipe network water samples were also analyzed to evaluate the cadmium release to drinking water due to the corrosion of tubes.


Dysfunctional distracter inhibition and facilitation for sad faces in depressed individuals.
Depression is a commonly occurring mental disorder, which is characterized by dysfunctional inhibition and facilitation for emotional stimuli. The aim of the present study was to investigate distracter inhibition and facilitation for emotional faces in depressed individuals in a negative affective priming task. Control participants who had never suffered from depression (NC), sub-clinically depressed participants, and participants diagnosed with a current major depressive disorder (MDD), Anxiety Inventory, the Hamilton Depression Rating Score were recruited using the Beck Depression Inventory, the Beck and DSM-IV as tools. Twenty-four participants in each group completed a negative affective priming task. The main finding was that there were no significant differences among the three groups in the positive and negative priming effects of happy faces. However, there were significant differences for positive and negative priming effects of sad faces between each pair of groups, with the effects being lowest for MDD and highest for NC participants. It can be concluded that depressed individuals are characterized by enhanced facilitation and deficient inhibition for negative materials, which is a stable cognitive vulnerability risk, possibly associated with the occurrence of depression. There are differences in the cognitive dysfunction for negative stimuli between clinically depressed and sub-clinically depressed individuals.


A Phase II Trial of Melphalan Based Reduced-Intensity Conditioning for Transplantation of T-Replete HLA-Haploidentical Peripheral Blood Stem Cells with Posttransplant Cyclophosphamide in Patients with Hematologic Malignancies.
T-replete haploidentical donor transplants using posttransplant cyclophosphamide (haplo) have greatly expanded donor availability and are increasingly utilized. Haplo were originally performed using truly nonmyeloablative conditioning and a bone marrow graft. We have also developed myeloablative conditioning and peripheral blood stem cell (PBSC) grafts for use with haplo. However, some patients may not tolerate myeloablative conditioning but may still benefit from a more dose-intensified preparative regimen to control malignancy and diminish graft rejection. To this end, we enrolled 25 patients on a prospective phase II trial utilizing a regimen of fludarabine 30 mg/m2/day × 5 days and Melphalan 140 mg/m2 on day -1 (flu/Mel) followed by infusion of unmanipulated PBSC graft from a haploidentical donor. GVHD prophylaxis included cyclophosphamide 50 mg/kg/day on days 3 and 4, mycophenolate mofetil on day 35, and tacrolimus on day 180. Median age was 57 years (range from 35 to 68). Transplantation diagnosis included AML (n = 11), ALL (n = 4), MDS/MPD (n = 6), NHL/CLL (n = 3), and MM (n = 1). Using the refined Disease Risk Index (DRI), patients were low (n = 1), intermediate (n = 13), and high/very high (n = 11). 22 out of 25 patients engrafted with a median time to neutrophil and platelet engraftment of 18 days and 36 days, respectively. All engrafting patients achieved full peripheral blood T-lymphocyte and myeloid donor chimerism at day 30. The 180-day cumulative incidence for acute GVHD grades II-IV and III-IV was seen in 20% (95% CI 8%-37%) and 8% (95% CI 2%-22%), respectively. The 2-year cumulative incidence of chronic GVHD was 16% (95% CI 5%-33%) (moderate-severe 12% (95% CI 3%-27%)). After a median follow-up of 28.3 months, the estimated 2-year OS, DFS, NRM, and relapse were 56% (95%CI 33-74%), 44% (95%CI 23%-64%), 20% (95% CI 8%-37%), and 36% (95% CI 17%-55%), respectively. Among patients with high/very high risk DRI, 2-year OS was 53% compared to 69% for low/intermediate DRI. When compared with a contemporaneous cohort of patients at our center receiving haploidentical transplant with nonablative fludarabine, Cytoxan, and total body irradiation flu/Cy/TBI regimen, the outcomes were statistically similar to the 2-year OS at 56% vs. 63% p=0.75 and DFS at 44% vs. 46% p=0.65.


Surgical procedures for carcinoma of the rectum. A historical review.
A review of the development of surgical procedures for the treatment of carcinoma of the rectum is presented. There have been very few truly new techniques offered in recent years; instead many of the older methods have been revived. This brief review of some of the important contributions made in this field may be of interest to today's surgeons. This discussion will concern the various approaches including perineal, abdominoperineal, abdominal, sacral, abdominosacral, abdominoanal, and vaginal approaches and local resections.


Flow of long chain hydrocarbons through carbon nanotubes (CNTs).
The pressure-driven flow of long-chain hydrocarbons in nanosized pores is important in energy, environmental, biological, and pharmaceutical applications. This paper examines the flow of hexane, heptane, and decane in carbon nanotubes (CNTs) of pore diameters 1-8 nm using molecular dynamic simulations. Enhancement of water flow in CNTs in comparison to rates predicted by continuum models has been well established in the literature. Our work was intended to observe if molecular dynamic simulations of hydrocarbon flow in CNTs produced similar enhancements. We used the OPLS-AA force field to simulate the hydrocarbons and the CNTs. Our simulations predicted the bulk densities of the hydrocarbons to be within 3% of the literature values. Molecular sizes and shapes of the hydrocarbon molecules compared to the pore size create interesting density patterns for smaller sized CNTs. We observed moderate flow enhancements for all the hydrocarbons (1-100) flowing through small-sized CNTs. For very small CNTs the larger hydrocarbons were forced to flow in a cork-screw fashion. As a result of this flow orientation, the larger molecules flowed as effectively (similar enhancements) as the smaller hydrocarbons.


Fabrication of 3D freeform porous tubular constructs with mechanical flexibility mimicking that of soft vascular tissue.
Three-dimensional (3D) printing, with its capability for producing arbitrary shapes, has been extensively studied for tissue engineering applications. However, clinical applications, especially for soft tissues, have been limited due to mechanical mismatch between the 3D-printed artificial tissues and the native tissues. Here, we suggest an integrative method of 3D printing, dip coating, and salt leaching for the fabrication of soft 3D freeform porous tubes, which are expected to be applied to the engineering of vascular tissues. Owing to their porous morphology and controlled wall thickness, the processed tubular constructs had flexible properties comparable to those of native soft tissues with a modulus range of several MPa. When thermoplastic polyurethane (TPU) was used as the dip-coating material, the porous tube exhibited a low tensile modulus from 1.47 to 2.47 MPa and a high elongation limit of over 400%. These flexible properties, which were clearly differentiated from the stiffness of 3D-printed samples with moduli of tens or hundreds of MPa, were confirmed to mimic the mechanical properties of native tissues. Furthermore, by varying the material composition in the dip-coating process, the flexibility of the tube could be modulated when stiffer polycaprolactone (PCL) layers were combined. In addition, such a combination using biocompatible materials could be expected to provide safer interaction at surgical interfaces. Synergistically with the mechanical flexibility, since the proposed method was based on a 3D-printed template, the resulting construct would have extensive applicability in patient-specific tissue engineering.


Down-modulation of receptors for granulocyte colony-stimulating factor on human neutrophils by granulocyte-activating agents.
Purified human blood neutrophils were able to bind radioiodinated murine granulocyte-colony-stimulating factor (G-CSF) in a specific manner. This factor has previously been shown to stimulate functional activities of human and murine neutrophilic granulocytes and to be functionally analogous to human-derived CSF beta. The binding of 125I G-CSF to human neutrophils was competed for equally by unlabeled G-CSF and CSF beta but not by other CSF's. Saturation analysis indicated that human neutrophils displayed about 700-1,500 receptors for G-CSF/CSF beta per cell. Three other agents (N-formyl-methionine-leucine phenylalanine, bacterial lipopolysaccharide, and human CSF alpha) known to activate neutrophils did not compete directly for G-CSF binding sites but, in preincubation experiments at 37 degrees C, were able to down-modulate the expression of G-CSF receptors on human neutrophils in a dose- and time-dependent manner. This effect was specific since the same agents have been shown elsewhere to up-regulate the expression of other granulocyte surface antigens and other agents were much less effective at down-modulating G-CSF receptors. Since the granulocyte-activating agents increase the sensitivity of human neutrophils to G-CSF/CSF beta and mimic some of the actions of G-CSF on neutrophils, it is suggested that G-CSF receptor down-modulation might be a mechanism whereby these agents activate G-CSF receptors and thereby exert some of their effects.


Local intramuscular transplantation of autologous bone marrow mononuclear cells for critical lower limb ischaemia.
Peripheral arterial disease is a major health problem, and in about 1% to 2% of patients, the disease progresses to critical limb ischaemia (CLI), also known as critical limb-threatening ischaemia. In a substantial number of individuals with CLI, no effective treatment options other than amputation are available, with around a quarter of these patients requiring a major amputation during the following year. This is the second update of a review first published in 2011. To evaluate the benefits and harms of local intramuscular transplantation of autologous adult bone marrow mononuclear cells (BMMNCs) as a treatment for CLI. We used standard, extensive Cochrane search methods. The latest search date was 8 November 2021. We included all randomised controlled trials (RCTs) of CLI in which participants were randomly allocated to intramuscular administration of autologous adult BMMNCs or control (either no intervention, conventional conservative therapy, or placebo). We used standard Cochrane methods. Our primary outcomes of interest were all-cause mortality, pain, and amputation. Our secondary outcomes were angiographic analysis, ankle-brachial index (ABI), pain-free walking distance, side effects and complications. We assessed the certainty of the evidence using the GRADE approach. We included four RCTs involving a total of 176 participants with a clinical diagnosis of CLI. Participants were randomised to receive either intramuscular cell implantation of BMMNCs or control. The control arms varied between studies, and included conventional therapy, diluted autologous peripheral blood, and saline. There was no clear evidence of an effect on mortality related to the administration of BMMNCs compared to control (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.15 to 6.63; 3 studies, 123 participants; very low-certainty evidence). All trials assessed changes in pain severity, but the trials used different forms of pain assessment tools, so we were unable to pool data. Three studies individually reported that no differences in pain reduction were observed between the BMMNC and control groups. One study reported that reduction in rest pain was greater in the BMMNC group compared to the control group (very low-certainty evidence). All four trials reported the rate of amputation at the end of the study period. We are uncertain if amputations were reduced in the BMMNC group compared to the control group, as a possible small effect (RR 0.52, 95% CI 0.27 to 0.99; 4 studies, 176 participants; very low-certainty evidence) was lost after undertaking sensitivity analysis (RR 0.52, 95% CI 0.19 to 1.39; 2 studies, 89 participants). None of the included studies reported any angiographic analysis. Ankle-brachial index was reported differently by each study, so we were not able to pool the data. Three studies reported no changes between groups, and one study reported greater improvement in ABI (as haemodynamic improvement) in the BMMNC group compared to the control group (very low-certainty evidence). One study reported pain-free walking distance, finding no clear difference between BMMNC and control groups (low-certainty evidence). We pooled the data for side effects reported during the follow-up, and this did not show any clear difference between BMMNC and control groups (RR 2.13, 95% CI 0.50 to 8.97; 4 studies, 176 participants; very low-certainty evidence). We downgraded the certainty of the evidence due to the concerns about risk of bias, imprecision, and inconsistency. We identified a small number of studies that met our inclusion criteria, and these differed in the controls they used and how they measured important outcomes. Limited data from these trials provide very low- to low-certainty evidence, and we are unable to draw conclusions to support the use of local intramuscular transplantation of BMMNC for improving clinical outcomes in people with CLI. Evidence from larger RCTs is needed in order to provide adequate statistical power to assess the role of this procedure.


A growing bacterial colony in two dimensions as an active nematic.
How a single bacterium becomes a colony of many thousand cells is important in biomedicine and food safety. Much is known about the molecular and genetic bases of this process, but less about the underlying physical mechanisms. Here we study the growth of single-layer micro-colonies of rod-shaped Escherichia coli bacteria confined to just under the surface of soft agarose by a glass slide. Analysing this system as a liquid crystal, we find that growth-induced activity fragments the colony into microdomains of well-defined size, whilst the associated flow orients it tangentially at the boundary. Topological defect pairs with charges [Formula: see text] are produced at a constant rate, with the [Formula: see text] defects being propelled to the periphery. Theoretical modelling suggests that these phenomena have different physical origins from similar observations in other extensile active nematics, and a growing bacterial colony belongs to a new universality class, with features reminiscent of the expanding universe.


Structural neuroimaging in mild traumatic brain injury: A chronic effects of neurotrauma consortium study.
The chronic effects of neurotrauma consortium (CENC) observational study is a multisite investigation designed to examine the long-term longitudinal effects of mild traumatic brain injury (mTBI). All participants in this initial CENC cohort had a history of deployment in Operation Enduring Freedom (Afghanistan), Operation Iraqi Freedom (Iraq), and/or their follow-on conflicts (Operation Freedom's Sentinel). All participants undergo extensive medical, neuropsychological, and neuroimaging assessments and either meet criteria for any lifetime mTBI or not. These assessments are integrated into six CENC core studies-Biorepository, Biostatistics, Data and Study Management, Neuroimaging, and Neuropathology. The current study outlines the quantitative neuroimaging methods managed by the Neuroimaging Core using FreeSurfer automated software for image quantification. At this writing, 319 participants from the CENC observational study have completed all baseline assessments including the imaging protocol and tertiary data quality assurance procedures. The preliminary findings of this initial cohort are reported to describe how the Neuroimaging Core manages neuroimaging quantification for CENC studies.


[Cases of devascularization of the liver in hepatic metastases of carcinoid tumors. Two cases (author's transl)].
The authors report two cases of hepatic artery's ligature in patients suffering from pan-hepatic metastases in carcinoid tumor of the bowels. They have come to believe that the hepatic devascularization (by removing the carcinoid syndrome and associated hepatalgia) offers a more comfortable chance of survival to the patient, giving him often the illusion that he is cured.


Effect of metabolic syndrome on pathologic features of prostate cancer.
The prevalence of metabolic syndrome has been increasing worldwide, however its association with prostate cancer (CaP) is unclear. We reviewed patients undergoing robot assisted radical prostatectomy (RARP) to evaluate if those with metabolic syndrome had more aggressive disease. A prospective database of patients undergoing RARP between January 2005 and December 2008 (n = 2756) was queried for components of metabolic syndrome (BMI ≥ 30 and ≥ 2 of the following: hypertension, diabetes or elevated blood glucose, and dyslipidemia; n = 357). Patients with no components of metabolic syndrome were used as controls (n = 694). Biopsy and final pathology were compared between the 2 groups using all controls, and using best-matched controls (n = 357) based on greedy matching by propensity score. Compared with unmatched controls, metabolic syndrome patients had higher pathology Gleason grade (≥ 7: 78% vs. 64%, P < 0.001) and higher pathologic stage (≥ T3 disease: 43% vs. 31%, P < 0.001). After controlling for confounders, those with metabolic syndrome when compared with best-matched controls had maintained the greater pathology Gleason grade (≥ 7: 78% vs. 64%, P < 0.001) and pathologic stage (≥ T3 disease: 43% vs. 32%, P < 0.001). They also had significantly greater pathologic upgrading of Gleason grade 6 adenocarcinoma found on biopsy compared with best-matched controls (63% vs. 45%, P < 0.001). On pathology, a 2-fold increase in Gleason 8 and greater was noted between patients with metabolic syndrome and best-matched controls (15% vs. 8%). After controlling for confounders, patients with metabolic syndrome were found to have higher Gleason grade and tumor stage on final pathology and were more likely to have upgrading.


Effects of chronic stress on depressive-like behaviors and JMJD3 expression in the prefrontal cortex and hippocampus of C57BL/6 and ob/ob mice.
Depression is a psychiatric disorder which is accompanied by neuroinflammatory responses. Obesity is considered as a low-grade inflammatory state. Studies have found that obese individuals are more likely to suffer from depression, but its possible mechanism has not been specifically illuminated. The Jumonji domain protein 3 (JMJD3) is a specific histone demethylase of trimethylation at lysine 27 of histone-H3 (H3K27me3). Over-expressions of JMJD3 induces the demethylation of H3K27me3 and results in the expression of pro-inflammatory genes, while its upregulation may be limited by adiponectin (APN). However, the role of JMJD3 in susceptibility to neuroinflammation and depression in obesity has not been clarified. Chronic unpredictable mild stress (CUMS) was selected to build depression model in C57BL/6 and ob/ob mice. Sucrose preference test, tail suspension test, open field test and Morris water maze test were used to detect depressive-like behaviors and memory impairment. Microglial activation, pro-inflammatory cytokines, APN, NF-ĸB, JMJD3 and H3K27me3 expressions in the serum, prefrontal cortex (PFC) and hippocampus (HIP) were examined in C57BL/6 and ob/ob mice. Meanwhile, GSK-J4 was used to inhibit JMJD3 expression. CUMS led to depressive-like behaviors and memory impairment, microglial activation, increased expressions of pro-inflammatory cytokines, NF-κB and JMJD3, decreased expression of H3K27me3 in the PFC and HIP in C57BL/6 and ob/ob mice. Meanwhile, ob/ob mice showed worse behavioral injury and memory impairment, microglial excessively activation, over-expression of pro-inflammatory cytokines and NF-ĸB and decreased H3K27me3 levels than C57BL/6 mice. CUMS also decreased the APN levels in the serum and brain tissues in ob/ob mice compared to C57BL/6 mice. But GSK-J4 could relieve these alterations. JMJD3 might be involved in the susceptibility to depressive-like behaviors and neuroinflammation of obese mice by the demethylation of H3K27me3, and decreased levels of APN could reduce Enhancer of zeste homolog 2 (EZH2) binding with H3K27me3. The role of JMJD3 in severer inflammatory state in the comorbidity of obesity and depression was considered.


Redescription of Paradiplozoon opsariichthydis (Jiang, Wu et Wang 1984) Jiang, Wu et Wang, 1989 (Monogenea, Diplozoidae).
Paradiplozoon opsariichthydis (Jiang, Wu et Wang, 1984) Jiang, Wu et Wang, 1989 (Platyhelminthes, Monogenea, Diplozoidae) is blood-feeding parasite from the gills of Asian cyprinid fish Opsariichthys bidens Günther, 1873. In this study, we present a morphological redescription of P. opsariichthydis neotype main morphological features e.g. size of body and clamps due to the fact that the type material is missing. We decided to supplement morphological descriptions by the relevant molecular data (internal transcribed spacer - ITS2) related to P. opsariichthydis adult worm isolates and other representatives of genus Paradiplozoon to cross verify our findings. In addition to that, this study also brings an attention to the host identification. Thus, parasite data were complemented by the determinant cytochrome oxidase b (cytb) sequences of its hosts. All novel sequences are deposited in GenBank. This combination of the morphological and molecular data related to both the parasite and its host seems to be the optimal approach to the general process of (re)description of highly host-specific parasitic organisms, which can then lead to a meaningful phylogenetic analysis.


Differentiating between active and latent tuberculosis with chest computed tomography.
The purpose of this study was to evaluate the capabilities of chest computed tomography (CT) in distinguishing between active and latent tuberculosis in patients positive for interferon-gamma release assay (IGRA) testing, and to compare the performance of CT with that of quantitative IGRA testing in a low incidence setting. Patients with latent or active tuberculosis define by an IGRA positive test were retrospectively recruited. Sensitivity, specificity and accuracy were determined for CT variables and quantitative IGRA results. Final diagnosis of active tuberculosis was based on clinical data and microbiological culture. Univariable and multivariable analyses were performed using logistic regression model to identify CT variables associated with the diagnosis of active tuberculosis. A total of 92 patients with positive IGRA results who underwent CT examination were included. There were 54 men and 38 women with a mean age of 53.5±18 (SD) years (range: 40-68 years). Of them, 22 patients (24%) had positive Mycobacterium tuberculosis culture and 70 (76%) had latent tuberculosis. Among CT variables, consolidation had the greatest sensitivity (77%; 95%CI: 60-95%) and "tree-in-bud" the greatest specificity (97%; 95% CI: 93-100%) for the diagnosis of active tuberculosis. At univariable analysis "tree-in-bud", splenic calcification and non-calcified lung nodules were the significant variables independently associated with active tuberculosis. At multivariable analysis, the adjusted odds ratio of "tree-in-bud" was 42.91 (95% CI: 5.62-327.42). Using an optimal threshold of 51 spots, quantitative IGRA yielded 64% sensitivity (95% CI: 44-84%) and 61% specificity (95% CI: 50-73%) for the diagnosis of active tuberculosis. In a low incidence setting, chest CT, especially when "tree-in-bud" pattern is present, is superior to quantitative IGRA testing to identify patients with active tuberculosis among those with positive IGRA testing.


Proteins and the intracellular exchange of lipids. I. Stimulation of phospholipid exchange between mitochondria and microsomal fractions by proteins isolated from potato tuber.
1. An active fraction which stimulates the exchange of phospholipids between microsomal fractions and mitochondria was isolated by gel filtration from potato tuber homogenates. 2. This fraction is probably a protein since the stimulatory factor is nondialyzable and temperature-sensitive. The molecular weight of the active fraction is approximatively 22 000. 3. The addition of the stimulatory fraction increases essentially the exchange of the main phospholipids of the potato tuber organelles; phosphatidyl-inositol, phosphatidylcholine and phosphatidylethanolamine. 4. Inhibiting factors, probably lipid-degrading enzymes, are present in the total supernatant fraction and are responsible for the inhibiting effect on the exchange of lipids when the crude supernatant fraction is used. The "inhibition effect" is rather a degradation of the exchangeable phospholipid pools.


Association Between Statin Medication and Asthma/Asthma Exacerbation in a National Health Screening Cohort.
Statins, which are a type of 3-hydroxy-3-methylglutaryl-CoA inhibitor, have multiple therapeutic effects, including anti-inflammatory and immunomodulatory properties. Despite positive preclinical data on statin use in patients with asthma, clinical trials and epidemiological studies have yielded conflicting results. To evaluate the association between statin use and an asthma diagnosis in all participants and the effects of statins on asthma-related outcomes among patients with asthma using a national health screening cohort. Patients with asthma and control participants matched for age group, sex, income, and region of residence were selected from the Korean National Health Insurance Service-Health Screening Cohort data. This case-control study comprised 88,780 people with asthma and the same number of control participants. Asthma exacerbation (AE) was defined as an emergency department visit, a history of hospitalization due to asthma, or the use of systemic steroids for 2 weeks. Conditional and unconditional logistic regression analyses were used to evaluate the effect of the previous use of statins on an asthma diagnosis or AE after adjusting for multiple covariates. A significant association between a statin prescription and an asthma diagnosis was not observed in this cohort (adjusted odds ratio, 1.01; 95% CI, 0.98-1.03; P = .633 for 1 year of statin prescription). Among the patients with asthma, 16.54% (n = 14,687) were categorized into the AE group and the others (n = 74,093) were categorized into the no AE group. A statin prescription was associated with fewer AEs in patients with asthma (adjusted odds ratio, 0.89; 95% CI, 0.84-0.93; P < .001 for 1 year of statin prescription). Statin use was associated with a reduced risk of asthma-related emergency department visits, hospitalizations, and systemic steroid use in patients with asthma in this cohort study.


Access to Reperfusion Therapy and Mortality in Women with ST-Segment-Elevation Myocardial Infarction: VICTIM Register.
Myocardial reperfusion is a fundamental part of the treatment for ST elevation myocardial infarction (STEMI) and is responsible for reducing morbidity and mortality in affected patients. However, reperfusion rates are usually lower and mortality rates higher in women compared to men. To evaluate the prevalence of the use of reperfusion therapies among women and men with STEMI in hospitals where percutaneous coronary intervention (PCI) is available in the state of Sergipe. This is a cross-sectional study that used data from the VICTIM Register. Patients diagnosed with STEMI admitted to the four hospitals (one public and three private) where PCI is available in the state of Sergipe were evaluated, from December 2014 to June 2018. A multivariate analysis with adjusted model using mortality as a dependent variable was made. In all analyses, the level of significance adopted was 5% (p < 0.05). A total of 878 volunteers with a confirmed diagnosis of STEMI, of which 33.4% were women, were included in the study. Only 53.3% of the patients underwent myocardial reperfusion (134 women versus 334 men). Fibrinolysis was performed only in 2.3% of all patients (1.7% of women versus 2.6% of men; p = 0.422). The rate of primary PCI was lower (44% versus 54.5%; p = 0.003) and hospital mortality was higher (16.1% versus 6.7%; p < 0.001) in women than in men. Women have significantly lower rates of primary PCI and higher hospital mortality. Reperfusion rates were low in both sexes and there was a clear underutilization of thrombolytic agents.


Multiple extracranial arterial lesions following closed craniocervical trauma.
Lesions of the cervical carotid and vertebral arteries resulting from closed craniocervical trauma are being recognized with increasing frequency. This paper describes a patient with severe stenosis and aneurysm formation of both distal internal carotid arteries and stenosis of the left vertebral artery, who presented with only head noise. A multiple vessel angiographic examination is necessary to demonstrate the extent of vascular injury and complications and the collateral circulation.


A Systematic Degradation Kinetics Study of Dalbavancin Hydrochloride Injection Solutions.
The degradation kinetics of the glycopeptide antibiotic dalbavancin in solution are systematically evaluated over the pH range 1-12 at 70°C. The decomposition rate of dalbavancin was measured as a function of pH, buffer composition, temperature, ionic strength, and drug concentration. A pH-rate profile was constructed using pseudo first-order kinetics at 70°C after correcting for buffer effects; the observed pH-rate profile could be fitted with standard pseudo first order rate laws. The degradation reactions of dalbavancin were found to be strongly dependent on pH and were catalyzed by protons or hydroxyl groups at extreme pH values. Dalbavancin shows maximum stability in the pH region 4-5. Based on the Arrhenius equation, dalbavancin solution at pH 4.5 is predicted to have a maximum stability of thirteen years under refrigerated conditions, eight months at room temperature and one month at 40°C. Mannosyl Aglycone (MAG), the major thermal and acid degradation product, and DB-R6, an additional acid degradation product, were formed in dalbavancin solutions at 70°C due to hydrolytic cleavage at the anomeric carbons of the sugars. Through deamination and hydrolytic cleavage of dalbavancin, a small amount of DB-Iso-DP2 (RRT-1.22) degradation product was also formed under thermal stress at 70°C. A greater amount of the base degradation product DB-R2 forms under basic conditions at 70°C due to epimerization of the alpha carbon of phenylglycine residue 3.