Chitinophaga ginsengisegetis sp. nov. and Chitinophaga ginsengisoli sp. nov., isolated from soil of a ginseng field in South Korea.
Two novel strains belonging to the phylum Bacteroidetes [formerly the Cytophaga-Flexibacter-Bacteroides (CFB) group], designated Gsoil 040(T) and Gsoil 052(T), were isolated from the soil of a ginseng field in Pocheon province, South Korea. A polyphasic approach was used to characterize the taxonomic position of the novel strains. Both strains were Gram-negative, aerobic, non-motile, non-spore-forming and rod-shaped. Phylogenetic analysis based on 16S rRNA gene sequences indicated that the novel isolates belong to the genus Chitinophaga but are clearly separated from the recognized species of this genus; gene sequence similarities between the novel isolates and type strains of recognized species ranged from 91.2 to 96.5 %. One exception was found; strain Gsoil 052(T) and the type strain of Chitinophaga filiformis had a gene sequence similarity of 99.6 % but had a DNA-DNA relatedness value of 38 %. Phenotypic and chemotaxonomic data (major menaquinone, MK-7; major fatty acids, iso-C(15 : 0) and C(16 : 1)omega5c; major hydroxy fatty acid, iso-C(17 : 0) 3-OH and major polyamine, homospermidine) supported the affiliation of both strains Gsoil 040(T) and Gsoil 052(T) to the genus Chitinophaga. The results of physiological and biochemical tests enabled the genotypic and phenotypic differentiation of the novel strains from the other recognized species of the genus Chitinophaga. Therefore, it is suggested that the new isolates represent two novel species, for which the names Chitinophaga ginsengisoli [corrected] sp. nov. [type strain Gsoil 040(T) (=KCTC 12654(T)=DSM 18108(T))] and Chitinophaga ginsengisoli sp. nov. [type strain Gsoil 052(T) (=KCTC 12592(T)=DSM 18017(T))] are proposed.


Comparative characterisation of two nitroreductases from Giardia lamblia as potential activators of nitro compounds.
Giardia lamblia is a protozoan parasite that causes giardiasis, a diarrhoeal disease affecting humans and various animal species. Nitro drugs such as the nitroimidazole metronidazole and the nitrothiazolide nitazoxanide are used for treatment of giardiasis. Nitroreductases such as GlNR1 and GlNR2 may play a role in activation or inactivation of these drugs. The aim of this work is to characterise these two enyzmes using functional assays. For respective analyses recombinant analogues from GlNR1 and GlNR2 were produced in Escherichia coli. E. coli expressing GlNR1 and GlNR2 alone or together were grown in the presence of nitro compounds. Furthermore, pull-down assays were performed using HA-tagged GlNR1 and GlNR2 as baits. As expected, E. coli expressing GlNR1 were more susceptible to metronidazole under aerobic and semi-aerobic and to nitazoxanide under semi-aerobic growth conditions whereas E. coli expressing GlNR2 were susceptible to neither drug. Interestingly, expression of both nitroreductases gave the same results as expression of GlNR2 alone. In functional assays, both nitroreductases had their strongest activities on the quinone menadione (vitamin K3) and FAD, but reduction of nitro compounds including the nitro drugs metronidazole and nitazoxanide was clearly detected. Full reduction of 7-nitrocoumarin to 7-aminocoumarin was preferentially achieved with GlNR2. Pull-down assays revealed that GlNR1 and GlNR2 interacted in vivo forming a multienzyme complex. These findings suggest that both nitroreductases are multifunctional. Their main biological role may reside in the reduction of vitamin K analogues and FAD. Activation by GlNR1 or inactivation by GlNR2 of nitro drugs may be the consequence of a secondary enzymatic activity either yielding (GlNR1) or eliminating (GlNR2) toxic intermediates after reduction of these compounds.


Antioxidant potential, cytotoxic activity and total phenolic content of Alpinia pahangensis rhizomes.
Alpinia pahangensis, a wild ginger distributed in the lowlands of Pahang, Malaysia, is used by the locals to treat flatulence. In this study, the antioxidant and cytotoxic activities of the crude aqueous methanol and fractionated extracts of Alpinia pahangensis against five different cancer and one normal cell lines were investigated. The total phenolic content of each extract and its fractions were also quantified. This is the first report on the antioxidant and cytotoxic activities of Alpinia pahangensis extract. In the current study, the crude methanol and fractionated extract of the rhizomes of Alpinia pahangensis were investigated for their antioxidant activity using four different assays namely, the DPPH scavenging activity, superoxide anion scavenging, β-carotene bleaching and reducing power assays whilst their phenolic contents were measured by the Folin-Ciocalteu's method.In vitro neutral red cytotoxicity assay was employed to evaluate the cytotoxic activity against five different cancer cell lines, colon cancer (HCT 116 and HT-29), cervical cancer (Ca Ski), breast cancer (MCF7) and lung cancer (A549) cell lines, and one normal cell line (MRC-5). The extract that showed high cytotoxic activity was further investigated for its chemical constituents by GC-MS (gas chromatography-mass spectrometry) analysis. The ethyl acetate fraction showed the strongest DPPH radical scavenging (0.35 ± 0.094 mg/ml) and SOD activities (51.77 ± 4.9%) whilst the methanol extract showed the highest reducing power and also the strongest antioxidant activity in the β-carotene bleaching assays in comparison to other fractions. The highest phenolic content was found in the ethyl acetate fraction, followed by the crude methanol extract, hexane and water fractions. The results showed a positive correlation between total phenolic content with DPPH radical scavenging capacities and SOD activities. The hexane fraction showed potent cytotoxic effect against KB, Ca Ski and HCT 116 cell lines with IC₅₀ of 5.8 ± 0.1 and 9.1 ± 2.0 ug/ml, respectively. The major components of hexane fraction analysed by GC-MS analysis were mostly methyl esters. The current study suggests that the methanol extract and ethyl acetate fraction of A. pahangensis is a potential source of natural antioxidant for protective as well as prevention of life-threatening diseases. The hexane fraction of A. pahangensis may have the potential to be developed into therapeutic option for treating cancer.


SF 36 health survey questionnaire: II. Responsiveness to changes in health status in four common clinical conditions.
To assess the responsiveness of the SF 36 health survey questionnaire to changes in health status over time for four common clinical conditions. Postal questionnaires at baseline and after one year's follow up, with two reminders at two week intervals if necessary. Clinics and four training general practices in Grampian region in the north east of Scotland. More than 1,700 patients aged 16 to 86 years with one of four conditions: low back pain, menorrhagia, suspected peptic ulcer, and varicose veins; and a random sample of 900 members of the local general population for comparison. A transition question measuring change in health and the eight scales of the SF 36 health survey questionnaire; standardised response means (mean change in score for a scale divided by the standard deviation of the change in scores) used to quantify the instrument's responsiveness to changes in perceived health status, and comparison of patient scores at baseline and follow up with those of the general population. The response rate exceeded 75% in a patient population. Changes across the SF 36 questionnaire were associated with self reported changes in health, as measured by the transition question. The questionnaire showed significant improvements in health status for all four clinical conditions, whether in referred or non-referred patients. For patients with suspected peptic ulcer and varicose veins the SF 36 profiles at one year approximate to the general population. These results provide the first evidence of the responsiveness of the SF 36 questionnaire to changes in perceived health status in a patient population in the United Kingdom.


Induction of candidal vaginitis in diabetic mice and attempts to prevent the infection.
In the present study on the induction and prevention of candidal vaginal infection in diabetic mice, ICR female mice were rendered diabetic by intraperitoneal injections of 160 mg kg-1 streptozotocin (SZ) which induced a stable non-lethal diabetic state apparent 2-7 days post-SZ injection. Diabetic mice and non-diabetic controls were inoculated intravaginally with 10(7)-10(10) Candida albicans yeasts. Infection was evaluated by the number of infected mice 3 days post-inoculation and the rate of clearance of infection during a 35-day follow-up. All C. albicans doses investigated induced vaginal infection in the diabetic mice, while in the non-diabetic controls only 40% of those inoculated with the lower (10(7) CFU) dose developed infection. The yeast load in the diabetic mice was 10-fold higher than in the controls and the duration of infection was longer. In an attempt to prevent infection intravaginal treatment with 5-40 mg of a chitin derivative (CSE) mouse-1 was given prior and pre- and post-inoculation with C. albicans. The optimal CSE treatment regimen was both pre- and post-administration of 10 or 20 mg CSE mouse-1 which significantly reduced the number of infected animals and also the duration of infection.


Processes for Trauma Care at Six Level I Trauma Centers During the COVID-19 Pandemic.
As the COVID-19 pandemic spread, patient care guidelines were published and elective surgeries postponed. However, trauma admissions are not scheduled and cannot be postponed. There is a paucity of information available on continuing trauma care during the pandemic. The study purpose was to describe multicenter trauma care process changes made during the COVID-19 pandemic. This descriptive survey summarized the response to the COVID-19 pandemic at six Level I trauma centers. The survey was completed in 05/2020. Questions were asked about personal protective equipment, ventilators, intensive care unit (ICU) beds, and negative pressure rooms. Data were summarized as proportions. The survey took an average of 5 days. Sixty-seven percent reused N-95 respirators; 50% sanitized them with 25% using ultraviolet light. One hospital (17%) had regional resources impacted. Thirty-three percent created ventilator allocation protocols. Most hospitals (83%) designated more beds to the ICU; 50% of hospitals designated an ICU for COVID-19 patients. COVID-19 patients were isolated in negative pressure rooms at all hospitals. In response to the COVID-19 pandemic, Level I trauma centers created processes to provide optimal trauma patient care and still protect providers. Other centers can use the processes described to continue care of trauma patients during the COVID-19 pandemic.


α-synuclein reactive antibodies as diagnostic biomarkers in blood sera of Parkinson's disease patients.
Auto-antibodies with specificity to self-antigens have been implicated in a wide variety of neurological diseases, including Parkinson's (PD) and Alzheimer's diseases, being sensitive indicators of neurodegeneration and focus for disease prevention. Of particular interest are the studies focused on the auto-immune responses to amyloidogenic proteins associated with diseases and their applications in therapeutic treatments such as vaccination with amyloid antigens and antibodies in PD, Alzheimer's disease and potentially other neurodegeneration ailments. Generated auto-antibodies towards the major amyloidogenic protein involved in PD Lewy bodies--α-synuclein and its amyloid oligomers and fibrils were measured in the blood sera of early and late PD patients and controls by using ELISA, Western blot and Biacore surface plasmon resonance. We found significantly higher antibody levels towards monomeric α-synuclein in the blood sera of PD patients compared to controls, though the responses decreased with PD progression (P<0.0001). This indicates potential protective role of autoimmunity in maintaining the body homeostasis and clearing protein species whose disbalance may lead to amyloid assembly. There were no noticeable immune responses towards amyloid oligomers, but substantially increased levels of IgGs towards α-synuclein amyloid fibrils both in PD patients and controls, which subsided with the disease progression (P<0.0001). Pooled IgGs from PD patients and controls interacted also with the amyloid fibrils of Aβ (1-40) and hen lysozyme, however the latter were recognized with lower affinity. This suggests that IgGs bind to the generic amyloid conformational epitope, displaying higher specificity towards human amyloid species associated with neurodegeneration. Our findings may suggest the protective role of autoimmunity in PD and therefore immune reactions towards PD major amyloid protein--α-synuclein can be of value in the development of treatment and diagnostic strategies, especially during the early disease stages.


Differential expression of human cytochrome P450 enzymes from the CYP3A subfamily in the brains of alcoholic subjects and drug-free controls.
Cytochrome P450 enzymes are responsible for the metabolism of most commonly used drugs. Among these enzymes, CYP3A forms mediate the clearance of around 40-50% of drugs and may also play roles in the biotransformation of endogenous compounds. CYP3A forms are expressed both in the liver and extrahepatically. However, little is known about the expression of CYP3A proteins in specific regions of the human brain. In this study, form-selective antibodies raised to CYP3A4 and CYP3A5 were used to characterize the expression of these forms in the human brain. Both CYP3A4 and CYP3A5 immunoreactivity were found to varying extents in the microsomal fractions of cortex, hippocampus, basal ganglia, amygdala, and cerebellum. However, only CYP3A4 expression was observed in the mitochondrial fractions of these brain regions. N-terminal sequencing confirmed the principal antigen detected by the anti-CYP3A4 antibody in cortical microsomes to be CYP3A4. Immunohistochemical analysis revealed that CYP3A4 and CYP3A5 expression was primarily localized in the soma and axonal hillock of neurons and varied according to cell type and cell layer within brain regions. Finally, analysis of the frontal cortex of chronic alcohol abusers revealed elevated expression of CYP3A4 in microsomal but not mitochondrial fractions; CYP3A5 expression was unchanged. The site-specific expression of CYP3A4 and CYP3A5 in the human brain may have implications for the role of these enzymes in both normal brain physiology and the response to drugs.


Porous multishelled NiO hollow microspheres encapsulated within three-dimensional graphene as flexible free-standing electrodes for high-performance supercapacitors.
Exploration of electrode materials with well-defined nanostructures and good flexibility is an efficient approach for achieving high-performance and flexible energy storage systems. However, it is still challenging to well integrate active materials into flexible electrodes and simultaneously maintain satisfactory electrochemical performance. Herein, we successfully synthesize novel three-dimensional graphene (3DG)-encapsulated porous multishelled NiO hollow microsphere (3DG/pMS-NiO) composite aerogels via a modified self-templating method and a dopamine (DA)-assisted self-assembly route. The well-designed highly interconnected porous 3DG network and the close contact NiO-graphene structure of the 3DG/pMS-NiO composite aerogels offer multiple advantages such as high porosity and accessible area, improved conductivity, enhanced electrolyte diffusion and a simple electrode preparation process. Thus, the as-prepared flexible 3DG/pMS-NiO electrodes showed significantly improved specific capacitance of 710.4 F g-1 at 0.5 A g-1 and excellent rate capability with an ultrahigh capacitance retention of 92.5% at 10 A g-1. In addition, the fabricated asymmetric supercapacitors (3DG/pMS-NiO//AC) showed a high specific capacitance of 34.4 F g-1 at 1 A g-1 with a voltage window of 0-1.6 V, a large energy density of 12.3 W h kg-1 at a power density of 815.3 W kg-1, and a decent cycling stability. This work profoundly enlightens the material design and electrode preparation, and even opens up an avenue for the development of high-performance and flexible energy storage systems.


Histological and histomorphometrical alterations of the periodontal ligament in gerbils submitted to teeth extraction.
This study verified the effect of unilateral teeth extraction on the periodontal ligament in gerbils (Meriones unguiculatus). Ten adult male gerbils weighing about 50 g had induced occlusal alterations by upper left molar extractions while the other ten animals, only submitted to surgical stress, were considered as controls. The periodontal ligament was characterized by qualitative and quantitative analysis, histological description and histomorphometric quantification. Significant alterations were observed on the left side of the experimental group (P < 0.05), the hypofunctional region, when it was compared with the contralateral side and the corresponding region of the control group. Two months after occlusal alterations induced by unilateral teeth extraction, atrophic histological alterations and a decrease in the periodontal space on the ipsilateral side characterized the periodontal ligament. In this study it was possible to conclude that the gerbil can be used in experimental models attempting to correlate the periodontium's biological response to various mechanical stresses, as the periodontal ligament was shown to be highly sensitive to occlusal alterations.


Divergent responses of ras-transfected and non-ras-transfected human keratinocytes to extracellular calcium.
Raising extracellular calcium (Ca(o)) induces terminal differentiation in cultured epidermal keratinocytes. The introduction of the ras oncogene into keratinocytes results in resistance to Ca(o)-mediated differentiation. To understand the signaling mechanism involved, we examined the Ca(o)-induced formation of inositol triphosphate (IP3) and changes in intracellular Ca2+ (Ca(i)) concentration in non-ras-transfected and ras-transfected HaCaT lines of human keratinocytes. When switched from 0.05- to 1.5-mM Ca(o) medium, the non-ras HaCaT line showed a rapid twofold increase in IP3 formation, whereas the IP3 level in the ras-transfected I-7 line was slightly affected. G-protein-coupled activation of phospholipase was intact in both lines, as evidenced by the generation of similar amounts of IP3 in response to addition of bradykinin or guanosine 5'-[gamma-thio]-triphosphate. Addition of 1.0 mM Ca(o) evoked similar Ca(i) responses in both non-ras- and ras-transfected cells: a transient elevation, followed by a sustained lower plateau. However, the two lines differed in their later responses: after being maintained in 1.0 mM Ca2+ for 24 h, the Ca(i) level was significantly lower in ras-transfected cells than in non-ras-transfected HaCaT cells. The Ca(o)-induced increase in Ca(i) in both lines was inhibited by the Ca2+ entry blocker SK&F 96365 or depolarization in high K+ bathing solution, demonstrating its dependence of calcium influx. The results suggest fundamental differences in the early signal that are generated in response to an increase in Ca(o) in ras-transfected keratinocytes, with the absence of a Ca(o)-induced rise in IP3--a signaling pathway defect that may play a role in the differentiation block the cells exhibit. In addition, the inability of ras-transfected cells to sustain a prolonged Ca(i) plateau may also contribute to their inability to differentiate in response to the Ca(o) signal.


Stress-induced mutagenesis: Stress diversity facilitates the persistence of mutator genes.
Mutator strains are expected to evolve when the availability and effect of beneficial mutations are high enough to counteract the disadvantage from deleterious mutations that will inevitably accumulate. As the population becomes more adapted to its environment, both availability and effect of beneficial mutations necessarily decrease and mutation rates are predicted to decrease. It has been shown that certain molecular mechanisms can lead to increased mutation rates when the organism finds itself in a stressful environment. While this may be a correlated response to other functions, it could also be an adaptive mechanism, raising mutation rates only when it is most advantageous. Here, we use a mathematical model to investigate the plausibility of the adaptive hypothesis. We show that such a mechanism can be mantained if the population is subjected to diverse stresses. By simulating various antibiotic treatment schemes, we find that combination treatments can reduce the effectiveness of second-order selection on stress-induced mutagenesis. We discuss the implications of our results to strategies of antibiotic therapy.


Initiation of antibody responses by different classes of lymphocytes. I. Types of thoracic duct lymphocytes involved in primary antibody responses of rats.
Thoracic duct cells and spleen cells were tested for their ability to restore the primary antibody response of X-irradiated rats to bovine serum albumin (BSA), sheep red blood cells (SRBC), horse spleen femtin (HSF), and Salmonella typhi flagella. Spleen cells were at least as efficient as thoracic duct cells in restoring the response to BSA, HSF, and Salmonella typhi flagella. In further experiments thoracic duct cells lacking large dividing lymphocytes were tested for their ability to restore the primary response. Large lymphocytes were eliminated by the in vitro incubation of thoracic duct cells for 24 hr at 37 degrees C or by treatment of thoracic duct cell donors with the mitotic inhibitor vinblastine sulfate 24 hr prior to cannulation of the thoracic duct. Experiments with SRBC show that incubated cells and cells from vinblastine-treated donors are as efficient as normal cells in restoring the primary antibody response. On the other hand, experiments with HSF and Salmonella typhi flagella show that incubated cells and cells from vinblastine-treated donors are about five times less efficient than normal cells in restoring the response. Normal thoracic duct cells were more efficient than incubated cells but less efficient than cells from vinblastine-treated donors in restoring the early response to BSA. The experimental findings indicate that the classes of thoracic duct lymphocytes which initiate the primary antibody response to SRBC differ from the classes which initiate the response to HSF and Salmonella typhi flagella, or BSA.


Nicotine 5'-oxidation and methyl oxidation by P450 2A enzymes.
In smokers, the primary pathway of nicotine metabolism is P450 2A6-catalyzed 5'-oxidation. The nicotine Delta(5'(1'))-iminium ion product of this reaction is further metabolized to cotinine by aldehyde oxidase. Previous investigators have reported kinetic parameters for cotinine formation using human liver cytosol as a source of aldehyde oxidase. Using [5-(3)H]nicotine and radioflow high-performance liquid chromatography analysis, we determined kinetic parameters for nicotine 5'-oxidation by P450 2A6 and the closely related human extrahepatic P450 2A13 as well as the rodent P450s 2A3, 2A4, and 2A5. The formation of both cotinine and nicotine Delta(5'(1'))-iminium ion was monitored. The K(m) and V(max) values for P450 2A6 were 144 +/- 15 muM and 1.30 +/- 0.05 pmol/min/pmol, respectively. Previously reported K(m) values for cotinine formation by P450 2A6 in the presence of cytosol were much lower, ranging from 11 to 45 muM. P450 2A13 was a somewhat better catalyst of nicotine Delta(5'(1'))-iminium formation, with 2-fold lower K(m) and 2-fold higher V(max) values than P450 2A6. The rat P450 2A3 and the mouse P450 2A5, which are 85 and 84% identical to P450 2A6, were much more efficient catalysts of nicotine 5'-oxidation. P450 2A4 was not an efficient catalyst of nicotine metabolism. Whereas 5'-oxidation was the major pathway of nicotine metabolism for all five P450 2A enzymes, these enzymes also catalyzed methyl oxidation. Nornicotine, the product of this reaction was detected as 5 to 15% of the total nicotine metabolites. Nornicotine is the amine precursor to the esophageal carcinogen N'-nitrosonornicotine. Therefore, methyl oxidation of nicotine by P450 2A6 or P450 2A13 followed by nitrosation of nornicotine are possible endogenous pathways of N'-nitrosonornicotine formation.


Global health diplomacy: a solution to meet the needs of disabled people in Yemen.
People with disabilities (PWD) are one of the most vulnerable groups in society during armed conflicts. According to the statistics, four million persons with disability live in Yemen. Lack of access and the use of rehabilitation services make PWD unable to retrieve their social and economic roles, which would have substantial negative impacts both on their families and community. The conflict escalation, an increase in the number the of displaced, COVID-19 pandemic, an increase in non-communicable diseases, and the exacerbation of poverty and malnutrition have rapidly enhanced the population at risk of disability in Yemen. Accordingly, effective and comprehensive approaches such as global health diplomacy (GHD) should be considered to meet the emerged needs. GHD seeks to address the common challenges in the global health system by involving all key stakeholders and establishing negotiations and diplomatic dialogue among official actors. Given the presence of various regional and international actors in Yemen and the examples of the successful use of GHD under conflict and post-conflict conditions in Iraq and Afghanistan, the use of diplomacy is crucial to respond to the needs of PWD in this war-torn country appropriately.


Engineering chimeric human and mouse major histocompatibility complex (MHC) class I tetramers for the production of T-cell receptor (TCR) mimic antibodies.
Therapeutic monoclonal antibodies targeting cell surface or secreted antigens are among the most effective classes of novel immunotherapies. However, the majority of human proteins and established cancer biomarkers are intracellular. Peptides derived from these intracellular proteins are presented on the cell surface by major histocompatibility complex class I (MHC-I) and can be targeted by a novel class of T-cell receptor mimic (TCRm) antibodies that recognise similar epitopes to T-cell receptors. Humoural immune responses to MHC-I tetramers rarely generate TCRm antibodies and many antibodies recognise the α3 domain of MHC-I and β2 microglobulin (β2m) that are not directly involved in presenting the target peptide. Here we describe the production of functional chimeric human-murine HLA-A2-H2Dd tetramers and modifications that increase their bacterial expression and refolding efficiency. These chimeric tetramers were successfully used to generate TCRm antibodies against two epitopes derived from wild type tumour suppressor p53 (RMPEAAPPV and GLAPPQHLIRV) that have been used in vaccination studies. Immunisation with chimeric tetramers yielded no antibodies recognising the human α3 domain and β2m and generated TCRm antibodies capable of specifically recognising the target peptide/MHC-I complex in fully human tetramers and on the cell surface of peptide pulsed T2 cells. Chimeric tetramers represent novel immunogens for TCRm antibody production and may also improve the yield of tetramers for groups using these reagents to monitor CD8 T-cell immune responses in HLA-A2 transgenic mouse models of immunotherapy.


Osteoclast-derived exosomal miR-212-3p suppressed the anabolism and accelerated the catabolism of chondrocytes in osteoarthritis by targeting TGF-β1/Smad2 signaling.
Osteoarthritis (OA) is a common aging-related disease affecting entire joint structures, encompassing articular cartilage and subchondral bone. Although senescence and dysfunction of chondrocytes are considered crucial factors in the occurrence of OA, the exact pathogenesis remains to be investigated. In our study, chondrocytes were incubated with a conditioned medium obtained from osteoclasts at different differentiation stages, suggesting that osteoclasts and osteoclast precursors suppressed anabolism and promoted the catabolism of chondrocytes in vitro. In contrast, the function of osteoclasts was more significant than osteoclast precursors. Further blocking of osteoclast exosome secretion by using GW4869 abolished the effect of osteoclasts on chondrocytes. Functionally, exosomal transfer of osteoclast-derived miR-212-3p inhibited Smad2 to mediate chondrocyte dysfunction, thus accelerating cartilage matrix degradation in OA via TGF-β1/Smad2 signaling. The mechanism was also confirmed within the articular cartilage in OA patients and surgery-induced OA mice. Our study provides new information on intercellular interactions in the bone microenvironment within articular cartilage and subchondral bone during OA progression. The miR-212-3p/Smad2 axis is a potential target for the prevention and therapy of OA.


Ethnic disparities in liver transplantation.
End-stage liver disease is a major cause of morbidity and mortality among ethnic minorities. In the United States, ethnic minorities comprise approximately 30% of all adult liver transplantations performed annually. Several studies have suggested that ethnic populations differ with respect to access and outcomes in the pre- and post-transplantation setting. This paper will review the existing literature on ethnic variations in the adult liver transplantation population.


The construction and evaluation of a device for mechanomyography in anaesthetized Göttingen minipigs.
To devise a method for assessing evoked muscle strength on nerve stimulation [mechanomyography (MMG)] in the anaesthetized minipig. Prospective observational. Sixty male Göttingen minipigs weighing 10.5-26.0 kg. After cadaveric studies, a limb fixation device was constructed which allowed the twitch responses of the pelvic limb digital extensor muscles to be measured by force-displacement transduction in response to supramaximal train-of-four (TOF) stimulation of the common peroneal nerve. The device was tested in 60 minipigs weighing 10.5-26.0 kg positioned in dorsal recumbency. The technique recorded the MMG of the common peroneal-pelvic limb digital extensor nerve-muscle unit for up to 12 hours during which twitch height remained constant in 18 animals in which single twitch duration was <300-500 ms. In 42, in which twitch duration was >300-500 ms, 2 Hz nerve stimulation caused progressive baseline elevation (reverse fade) necessitating a modified signal capture method for TOF ratio (TOFR) computation. However, T1 was unaffected. The mean (range) of the TOFR in pigs with reverse fade was 1.2 (1.1-1.3). The technique allowed MMG recording in unparalysed pigs in response to TOF nerve stimulation and revealed a hitherto unreported complication of MMG monitoring using TOF in animals: reverse fade. This complicated TOFR calculation.


Early detection of consciousness in patients with acute severe traumatic brain injury.
See Schiff (doi:10.1093/awx209) for a scientific commentary on this article. Patients with acute severe traumatic brain injury may recover consciousness before self-expression. Without behavioural evidence of consciousness at the bedside, clinicians may render an inaccurate prognosis, increasing the likelihood of withholding life-sustaining therapies or denying rehabilitative services. Task-based functional magnetic resonance imaging and electroencephalography techniques have revealed covert consciousness in the chronic setting, but these techniques have not been tested in the intensive care unit. We prospectively enrolled 16 patients admitted to the intensive care unit for acute severe traumatic brain injury to test two hypotheses: (i) in patients who lack behavioural evidence of language expression and comprehension, functional magnetic resonance imaging and electroencephalography detect command-following during a motor imagery task (i.e. cognitive motor dissociation) and association cortex responses during language and music stimuli (i.e. higher-order cortex motor dissociation); and (ii) early responses to these paradigms are associated with better 6-month outcomes on the Glasgow Outcome Scale-Extended. Patients underwent functional magnetic resonance imaging on post-injury Day 9.2 ± 5.0 and electroencephalography on Day 9.8 ± 4.6. At the time of imaging, behavioural evaluation with the Coma Recovery Scale-Revised indicated coma (n = 2), vegetative state (n = 3), minimally conscious state without language (n = 3), minimally conscious state with language (n = 4) or post-traumatic confusional state (n = 4). Cognitive motor dissociation was identified in four patients, including three whose behavioural diagnosis suggested a vegetative state. Higher-order cortex motor dissociation was identified in two additional patients. Complete absence of responses to language, music and motor imagery was only observed in coma patients. In patients with behavioural evidence of language function, responses to language and music were more frequently observed than responses to motor imagery (62.5-80% versus 33.3-42.9%). Similarly, in 16 matched healthy subjects, responses to language and music were more frequently observed than responses to motor imagery (87.5-100% versus 68.8-75.0%). Except for one patient who died in the intensive care unit, all patients with cognitive motor dissociation and higher-order cortex motor dissociation recovered beyond a confusional state by 6 months. However, 6-month outcomes were not associated with early functional magnetic resonance imaging and electroencephalography responses for the entire cohort. These observations suggest that functional magnetic resonance imaging and electroencephalography can detect command-following and higher-order cortical function in patients with acute severe traumatic brain injury. Early detection of covert consciousness and cortical responses in the intensive care unit could alter time-sensitive decisions about withholding life-sustaining therapies.


Anodal transcranial patterned stimulation of the motor cortex during gait can induce activity-dependent corticospinal plasticity to alter human gait.
The corticospinal system and local spinal circuits control human bipedal locomotion. The primary motor cortex is phase-dependently activated during gait; this cortical input is critical for foot flexor activity during the swing phase. We investigated whether gait-combined rhythmic brain stimulation can induce neuroplasticity in the foot area of the motor cortex and alter gait parameters. Twenty-one healthy subjects participated in the single-blinded, cross-over study. Each subject received anodal transcranial patterned direct current stimulation over the foot area of the right motor cortex during gait, sham stimulation during gait, and anodal transcranial patterned direct current stimulation during rest in a random order. Six subjects were excluded due to a failure in the experimental recording procedure. Complete-case analysis was performed using the data from the remaining 15 subjects. Self-paced gait speed and left leg stride length were significantly increased after the stimulation during gait, but not after the sham stimulation during gait or the stimulation during rest. In addition, a significant increase was found in the excitability of the corticospinal pathway of the left tibialis anterior muscle 30 min after stimulation during gait. Anodal transcranial patterned direct current stimulation during gait entrained the gait cycle to enhance motor cortical activity in some subjects. These findings suggest that the stimulation during gait induced neuroplasticity in corticospinal pathways driving flexor muscles during gait.


Biophysical Mechanisms of Membrane-Thickness-Dependent MscL Gating: An All-Atom Molecular Dynamics Study.
The bacterial mechanosensitive channel, MscL, is activated by membrane tension, acting as a safety valve to prevent cell lysis against hypotonic challenge. It has been established that its activation threshold decreases with membrane thickness, while the underlying mechanism remains to be solved. We performed all-atom molecular dynamics (MD) simulations for the initial opening process of MscL embedded in four different types of lipid bilayers with different thicknesses: 1,2-dilauroyl- sn-glycero-3-phosphocholine (DLPC)), 1,2-dimyristoyl-glycero-3-phosphorylcholine (DMPC), 1,2-dipalmitoyl- sn-glycero-3-phosphocholine (DPPC), and 1,2-distearoyl- sn-glycero-3-phosphocholine (DSPC). In response to membrane stretching, channel opening occurred only in the thinner membranes (DLPC and DMPC) in a thickness-dependent way. We found that the MscL opening was governed by the rate and degree of membrane thinning and that the channel opening was tightly associated with the tilting of transmembrane (TM) helices of MscL toward the membrane plane. Upon membrane stretching, the order parameter of acyl chains of thinner membranes (DLPC and DMPC) became smaller, whereas other thicker membranes (DPPC and DSPC) showed interdigitation with little changes in the order parameter. The decreased order parameter contributed much more to membrane thinning than did interdigitation. We conclude that the membrane-thickness-dependent MscL opening mainly arises from structural changes in MscL to match the altered membrane thickness by stretching.


Association between Drinking Patterns and Incident Hypertension in Southwest China.
Based on a prospective cohort study of adults from southwest China with heterogeneity in their demographical characteristics and lifestyles, we aimed to explore the association between drinking patterns and incident hypertension under the interaction of these confounding factors. The Cox proportional hazard model was used to estimate the hazard ratios (HR) and 95% confidence intervals (95% CI). Subgroup analysis was performed according to sex, ethnicity, area, occupation, smoking, and exercise to compare the differences in the association between drinking patterns and the incidence of hypertension. Blood pressure was higher in participants with a high drinking frequency than those with a low drinking frequency (p < 0.001). We found that total drinking frequency, liquor drinking frequency, rice wine drinking frequency, and alcohol consumption were significantly associated with an increased risk of hypertension. Compared with the non-drinking group, a heavy drinking pattern was positively correlated with hypertension. Drinking can increase the risk of hypertension, especially heavy drinking patterns, with a high frequency of alcohol intake and high alcohol consumption. From the analysis results of the longitudinal data, drinking alcohol is still an important risk factor for hypertension among Chinese subjects, especially for men, the rural population, the employed, the Han nationality, smokers, and certain exercise populations.


Modified Allergens for Immunotherapy.
During the past few decades, modified allergens have been developed for use in allergen-specific immunotherapy (AIT) with the aim to improve efficacy and reduce adverse effects. This review aims to provide an overview of the different types of modified allergens, their mechanism of action and their potential for improving AIT. In-depth research in the field of allergen modifications as well as the advance of recombinant DNA technology have paved the way for improved diagnosis and research on human allergic diseases. A wide range of structurally modified allergens has been generated including allergen peptides, chemically altered allergoids, adjuvant-coupled allergens, and nanoparticle-based allergy vaccines. These modified allergens show promise for the development of AIT regimens with improved safety and long-term efficacy. Certain modifications ensure reduced IgE reactivity and retained T cell reactivity, which facilities induction of immune tolerance to the allergen. To date, multiple clinical trials have been performed using modified allergens. Promising results were obtained for the modified cat, grass and birch pollen, and house dust mite allergens. The use of modified allergens holds promise for improving AIT efficacy and safety. There is however a need for larger clinical studies to reliably assess the added benefit for the patient of using modified allergens for AIT.


The longitudinal assessment of congenitally infected infants.
Infants with congenital infections are at high risk for developmental disabilities. Because of this increased-risk status, they require comprehensive, longitudinal follow-up that should begin in the neonatal period with sensory, developmental, and neuromotor assessments as well as neuroradiological imaging. Reassessments of general development, sensory function, neuromotor abilities, and emerging language should be done during the early years, with cognitive, preacademic, and phonologic-awareness skills assessed during the preschool years. Serial evaluations of cognitive, academic, language, attention, neuromotor and sensory functions are needed through adolescence. Such surveillance of children with congenital infections is required to identify specific disabilities, to determine educational/intervention needs, and to investigate the total effects of congenital infection.


"Brace Technology" Thematic Series - The ScoliOlogiC® Chêneau light™ brace in the treatment of scoliosis.
Bracing concepts in use today for the treatment of scoliosis include symmetric and asymmetric hard braces usually made of polyethylene (PE) and soft braces. The plaster cast method worldwide seems to be the most practiced technique for the construction of hard braces at the moment. CAD (Computer Aided Design) systems are available which allow brace adjustments without plaster. Another possibility is the use of the ScoliOlogiC™ off the shelf system enabling the Certified Prosthetist and Orthotist (CPO) to construct a light brace for scoliosis correction from a variety of pattern specific shells to be connected to an anterior and a posterior upright. This Chêneau light™ brace, developed according to the Chêneau principles, promises a reduced impediment of quality of life in the brace. The correction effects of the first 81 patients (main diagnosis Adolescent Idiopathic Scoliosis (AIS) [n = 64] or Early Onset Scoliosis (EOS) [n = 15]), treated according to the principles of the Chêneau light™ brace have shown a satisfactory in-brace correction exceeding 50% of the initial Cobb angle. The ScoliOlogiC® off the shelf bracing system enables the CPO to construct a light brace for scoliosis correction from a variety of pattern specific shells to be connected to an anterior and a posterior upright. This brace, when finally adjusted is called Chêneau light™ brace. The advantage of this new bracing system is that the brace is available immediately, is easily adjustable and that it can also be easily modified. This avoids construction periods of sometimes more than 6 weeks, where the curve may drastically increase during periods of fast growth. The disadvantage of this bracing system is that there is a wide variability of possibilities to arrange the different shells during adjustment. The Cobb angle in the whole group was reduced by an average of 16,4°, which corresponds to a correction effect of 51%. The differences were highly significant in the T-test (T = 17,4; p < 0,001). The best correction effects achieved with Chêneau braces reported in literature so far are about 40% in two different studies. The correction effect was highest in lumbar and thoracolumbar curve patterns (62%; n = 18). In thoracic scoliosis the correction effect was 36% (n = 41) and in double major curve patterns 50% (n = 22). The correction effect was affected in a slightly negative way due to age (r = -0,24; p = 0,014), negatively with the Risser stage (-0,29; p = 0,0096) and correlated negatively with the Cobb angle measured before treatment (r = -0,43; p < 0,0001). The use of the Chêneau light™ brace leads to correction effects above average when compared to correction effects of other braces described in literature. The reduction of material seems to increase patient's comfort and reduces the stress patients may suffer from whilst in the brace.80% of the adolescent population of scoliosis patients can be braced with the Chêneau light™ brace. In certain patterns of curvature and in the younger population with an age of less than 11 years, other approaches have to be used, such as plaster based bracing or the application of CAD/CAM based orthoses.


Oral health-related quality of life of periodontal patients.
The purpose of this study was to assess the oral health-related quality of life of patients presenting to a periodontal specialist by means of six questions, and to assess the perceived oral health by means of one question. Self-assessments of oral health were associated with clinical characteristics. Logistic regression models were used to associate self-assessments with clinical characteristics in a cross-sectional study. On the six-item questionnaire, close to 20% (295/1480) of the patients reported that teeth, gums or dentures had an impact fairly often or very often on one or more items (eating, relaxing, avoiding going out, feeling self-conscious, pain or discomfort). On the single question requesting a self-assessment of oral health, 42% (628/1468) rated their oral health as fair or poor. Both common oral health-related quality of life problems and worse perceived oral health were associated with having more than eight teeth with>5 mm periodontal pockets (odds ratio=1.45, 95% confidence interval=1.01-2.08; and odds ratio=2.83, 95% confidence interval=2.08-3.84, respectively), compared with patients who had fewer than three teeth with>5 mm periodontal pockets. Oral health-related problems in patients presenting to a periodontal specialist office negatively affect their quality of life. If some of the findings of this study can be confirmed in other studies, it could change the perception of chronic periodontitis as a silent disease.


Multifunctional phase-change hollow mesoporous Prussian blue nanoparticles as a NIR light responsive drug co-delivery system to overcome cancer therapeutic resistance.
Developing novel stimuli-responsive systems to optimize the co-delivery and concurrent controlled release of different anticancer drugs is highly pursued for reducing the probability of evolution of therapeutic resistance, which is the major cause of cancer mortality. In this work, we report a novel NIR light responsive drug co-delivery system based on hollow mesoporous Prussian blue nanoparticles (HMPBs) and a phase change material (PCM, such as 1-tetradecanol which has a melting point around 38 °C). The fabrication of this PCM@HMPB system simply involves filling the hollow interior and mesoporous shell of the HMPBs with PCM molecules, which acted as both a thermosensitive gatekeeper and a medium for loading both hydrophilic and hydrophobic anticancer drugs. The photothermal effect of the HMPBs under NIR light irradiation would induce the PCM to go through processes of melting and escaping from the HMPBs, concurrently releasing the encapsulated anticancer drugs into the surrounding medium. Notably, the as-prepared (PCM + drugs)@HMPB system could achieve near "zero release" of both hydrophilic doxorubicin hydrochloride (DOX) and hydrophobic camptothecin (CPT), as well as precise "on" or "off" drug delivery with various NIR light treatments in vitro to efficiently induce cell apoptosis. More importantly, according to the phenomenon that generated heat could improve drug absorption by increasing the cell metabolism and membrane fluidity, the (PCM + drugs)@HMPB system revealed significant photothermal-chemo synergistic effects against HeLa cancer cells. Therefore, the as-prepared (PCM + drugs)@HMPB system has good potential as a versatile NIR light responsive co-delivery platform of both hydrophobic and hydrophilic anticancer drugs for targeting adaptive therapeutic resistance as well as synergistic photothermal-chemo cancer treatment.


Ear wax.
Ear wax only becomes a problem if it causes a hearing impairment or other ear-related symptoms. Ear wax is more likely to accumulate and cause a hearing impairment when normal extrusion is prevented; for example, by the use of hearing aids, or by the use of cotton buds to clean the ears. Ear wax can visually obscure the ear drum, and may need to be removed for diagnostic purposes. We conducted a systematic review and aimed to answer the following clinical question: What are the effects of methods to remove ear wax? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2014 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We found nine studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. In this systematic review we present information relating to the effectiveness and safety of the following interventions: ear irrigation (syringing); manual removal (other than ear irrigation); wax softeners prior to irrigation; and wax softeners alone.


Prognostic factors and outcome of children with severe head injury: an 8-year experience.
Our aim was to analyze prognostic factors and their association with outcome among children with severe head injury. We conducted a retrospective study among children with severe head injury admitted to our Pediatric Intensive Care Unit (PICU) from November 1992 to December 2000. The patients were immediately evaluated for the severity of head injury (Glasgow Coma Score, GCS), clinical presentation, cerebral axial tomography, early complications (hypoxia and hypotension), metabolic and hematological alterations and early post-traumatic seizures. Six months after injury we applied the Glasgow Outcome Score (GOS). Correlations with GOS were evaluated using univariate and multivariate logistic models. In all, 122 children with severe head injury were identified. The patients presented the following scores: 18 (14.7.0%) children had a GOS of 1; 2 had a GOS of 2 (1.6%); 27 (22.2%) a GOS of 3 and 75 (61.5%) a GOS of 4 or 5. A low GOS was significantly and independently associated with low GCS, multiple trauma, the presence of hypoxia and hypotension, disseminated intravascular coagulation (DIC), hyperglycemia and early post-traumatic seizures. Hematological alterations (white blood cells) were also associated with a low GOS, though not significantly. In addition to GCS, types of trauma and brain lesion, hypoxia and hypotension, hemocoagulative disorders (DIC), hyperglycemia and early post-traumatic seizures are predictors of GOS. A knowledge of these prognostic factors and the correct management of children with severe head injury helps clinicians to improve outcome and to reduce morbidity and mortality.


Age and the Trying Out of New Ideas.
The aging of the scientific workforce and graying of grant recipients are central policy concerns in biomedicine. These trends are potentially important because older scientists are often seen as less open to new ideas than younger scientists. In this paper, we put this hypothesis to an empirical test. Using a measure of new ideas derived from the text of nearly all biomedical scientific articles published since 1946, we compare the tendency of younger and older researchers to try out new ideas in their work. We find that papers published in biomedicine by younger researchers are more likely to build on new ideas. Collaboration with an experienced researcher matters as well. Papers with a young first author and a more experienced last author are more likely to try out newer ideas than papers published by other team configurations. Given the crucial role that the trying out of new ideas plays in the advancement of science, our results buttress the case for funding scientific work by young researchers but also provide a caution against unconditional idolatry of youth over experience.


Lead poisoning prevention for preschool settings: a program template.
Lead is a naturally occurring metal that has been linked to neurological impairments and insanity since ancient times. It has been used in many products such as paint, pipes, and ceramics and still remains a public hazard. Young children between the ages of 6 months and 6 years with lead-contaminated housing are at the greatest risk for cognitive, neurological, and behavioral health problems. Briefly, lead exposure is around us and it correlates with learning deficits and violent behaviors as these children become adults. It also can cause anemia, abdominal pain, seizure, and death.


[Radionuclide study of cutaneous melanomas with 99m Tc-HMPAO: visualization of metastases and recurrence].
Malignant cutaneous melanoma (MCM) is a very aggressive disease that becomes in a true problem of health because of the increase in the last 5 years. In the present paper, authors report the detection of the tumor, metastases and recurrences mean 99mTc HMPAO. We presented 5 cases of MCM patients and observed the radiopharmaceutical uptake in skin, nodules and recurrent tumor lesions. Because of the number of patients was limited, authors recommended the research with a lot of patients. The gammagraphic studies could be very important for the staging of the disease and early detection of metastases and recurrent lesions.


A novel sustained-release formulation of recombinant human growth hormone and its pharmacokinetic, pharmacodynamic and safety profiles.
An effective and safe formulation of sustained-release rhGH for two months using poly(monomethoxypolyethylene glycol-co-D,L-lactide) (mPEG-PLA, PELA) microspheres was developed to reduce the frequency of medication. The rhGH-loaded PELA microspheres with a narrow size distribution were successfully prepared by a double emulsion method combined with a premix membrane emulsification technique without any exogenous stabilizing excipients. The narrow size distribution of the microspheres would guarantee repeatable productivity and release behavior. Moreover, the amphiphilic PELA improved the bioactivity retention of protein drugs since it prevented protein contact with the oil/water interface and the hydrophobic network, and modulated diffusion of acidic degradation products from the carrier system. These PELA microspheres were compared in vivo with commercial rhGH solution, conventional poly(D,L-lactic acid) (PLA) and poly(D,L-lactic-co-glycolic acid) (PLGA) microspheres. Administration of rhGH-PELA could extend the duration of rhGH release (for up to 56 days) and increase area under the curve (AUC) compared to rhGH solution, PLA or PLGA microspheres in Sprague-Dawley (SD) rats. In addition, rhGH-PELA microspheres induced a greater response in total insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) than other rhGH formulations. With a hypophysectomized SD rat model, the pharmacological efficacy of rhGH-PELA microspheres was shown to be better than that from daily administration of rhGH solutions over 6 days based on body weight gain and width of the tibial growth plate. Histological examination of the injection sites indicated a significantly milder inflammatory response than that observed after injection of PLA and PLGA microspheres. Neither anti-rhGH antibodies nor the toxic effects on heart, liver and kidney were detectable after administration of rhGH-PELA microspheres in SD rats. These results suggest that rhGH-PELA microspheres have the potential to be clinically effective and safe when administered only once every two months, a dose regimen for better patient acceptance and compliance.


Comparative measurements of left ventricular ejection time by mechano-, echo- and electrical impedance cardiography.
Several electrical impedance cardiographic and mechanocardiographic methods for assessing left ventricular ejection time (LVET) were compared with the aortic valve LVET echogram to determine whether values from an impedance method allow an exact measurement of LVET. From seven healthy subjects, tracings of signals from the ECG, phonocardiogram, carotid pulse, and electrical impedance cardiography were inscribed simultaneously with M-mode aortic valve echograms which recorded the separation and closure of the aortic valves. LVETs were measured from each cycle according to several established techniques. To yield variations in the LVET, heart rate was increased using injections of atropine 0.25 mg i.v. every 10 min until the rate reached 100 to 110 beats/min. Using biometrical methods with different sensitivities to extreme values, individual regression analyses compared the LVET from carotid and from impedance tracings to the "real" value measured from the echogram. The results showed the carotid pulse values underestimate and the conventional impedance methods over- and underestimate the real LVET. A modified approach identified LVET onset at the crossing of the dZ/dt line from the impedance cardiogram with baseline or, when a presystolic wave appeared at higher heart rates, the first turning point in the dZ/dt curve before this wave, and the LVET termination as the initial signal from the second heart sound. This combination of impedance cardiography and phonocardiography offers a precise estimation of LVET in noninvasive cardiology.


[Boutonneuse Mediterranean fever (author's transl)].
Authors report six cases of boutonneuse Mediterranean fever seen in the last two years. All of them presented fever, malaise, generalised maculopapulous rash and a typical black spot or inoculation canker. Diagnosis was done by a positive Weil-Félix test. The treatment used was tetracycline with good results. Incidence of this disease is increasing in our country.


Changes in heart rate, heart rate variability, and atrioventricular block during withholding of food in Thoroughbreds.
To determine whether withholding of food affects autonomic nervous system balance by analysis of heart rate (HR), HR variability (HRV), and frequency of second-degree atrioventricular block in horses. 5 healthy Thoroughbreds. For two 24-hour periods in a crossover study, food was withheld from horses or horses were maintained on their regular feeding schedule (control conditions) in their stalls and Holter monitor ECG recordings were obtained. The ECGs were analyzed by use of fast-Fourier transformation, and power spectrum densities were calculated for low-frequency (0.01 to 0.07 Hz) and high-frequency (0.07 to 0.6 Hz) variations in HR. Serum cortisol and plasma ACTH, norepinephrine, and glucose concentrations were measured at predetermined time points. Withholding of food resulted in significantly lower HR and more frequent second-degree atrioventricular block (the frequency of which was inversely related to the HR), compared with findings for control conditions. Circadian rhythms were similar during food-withholding and control conditions; peak HR was detected from 7:00 pm to 8:00 pm, and the lowest HR was detected in the early morning. During food-withholding conditions, the low-frequency and high-frequency components of HRV were significantly higher, and the low-frequency-to-high-frequency ratio was lower than during control conditions. Serum cortisol concentration was higher and plasma glucose concentration was lower at 6:00 pm in horses when food was withheld, compared with findings during control conditions. Indices of HRV seemed to be sensitive to changes in autonomic nervous activity and may be useful as clinical indices of the neuroendocrine response to stressors in horses.


Anti-TNF in rheumatoid arthritis: an overview.
Since the introduction of tumor necrosis factor (TNF)-α inhibitors, the treatment of rheumatoid arthritis (RA) has been revolutionized. The approach of targeting TNF-α has considerably improved the success in the treatment of RA. Over the last 3 decades five different TNF-α inhibitors have been administered: infliximab, etanercept, adalimumab, golimumab, and certolizumab-pegol. All of them show excellent efficacy with similar rates of clinical response and prevention of radiographic disease progression. With improved therapies, treatment strategies have also changed, with the aims now being to achieve and maintain remission. Most recently, the discussion expands to the issue of treatment reduction in patients who have achieved sustained remission; here, the discontinuation of TNF-α inhibitor therapy has become an area of interest, given obvious economic and risk-benefit evaluations. However, only little is known if "biologic free" remission is possible in patients with sustained remission following intensive TNF-α inhibitor therapy.


Winter climate change and the poleward range expansion of a tropical invasive tree (Brazilian pepper-Schinus terebinthifolius).
Winter climate change is expected to lead to the tropicalization of temperate ecosystems, where tropical species expand poleward in response to a decrease in the intensity and duration of winter temperature extremes (i.e., freeze events). In the southeastern United States, freezing temperatures control the northern range limits of many invasive nonnative species. Here, we examine the influence of freezing temperatures and winter climate change on the northern range limits of an invasive nonnative tree-Schinus terebinthifolius (Brazilian pepper). Since introduction in the 1800s, Brazilian pepper has invaded ecosystems throughout south and central Florida to become the state's most widespread nonnative plant species. Although Brazilian pepper is sensitive to freezing temperatures, temperature controls on its northern distribution have not been adequately quantified. We used temperature and plant occurrence data to quantify the sensitivity of Brazilian pepper to freezing temperatures. Then, we examined the potential for range expansion under three alternative future climate scenarios (+2°C, +4°C, and +6°C). Our analyses identify a strong nonlinear sigmoidal relationship between minimum temperature and Brazilian pepper presence, with a discrete threshold temperature occurring near -11°C. Our future scenario analyses indicate that, in response to warming winter temperatures, Brazilian pepper is expected to expand northward and transform ecosystems in north Florida and across much of the Gulf of Mexico and south Atlantic coasts of the United States. These results underscore the importance of early detection and rapid response efforts to identify and manage the northward invasion of Brazilian pepper in response to climate change. Looking more broadly, our work highlights the need to anticipate and prepare for the tropicalization of temperate ecosystems by tropical invasive species.


Generation of two human induced pluripotent stem cell lines (MHHi017-A, MHHi017-B) from a patient with primary ciliary dyskinesia carrying a homozygous mutation (c.7915C > T [p.Arg2639*]) in the DNAH5 gene.
Dynein axonemal heavy chain 5 (DNAH5) is part of a microtubule-associated protein complex found within the cilia of the lung. Mutations in the DNAH5 gene lead to impaired ciliary function and are linked to primary ciliary dyskinesia (PCD), a rare autosomal recessive disorder. We established two human induced pluripotent stem cell (hiPSC) lines generated from a patient with PCD and homozygous mutation in the corresponding DNAH5 gene. These cell lines represent an excellent tool for modeling the ciliary dysfunction in PCD.


Isolation and identification of unique marker compounds from the Tasmanian poppy Papaver somniferum N. Implications for the identification of illicit heroin of Tasmanian origin.
Tasmanian opium accounts for 25% of the world's legal supply of opium straw, and in 1998-99 sufficient numbers of flower pods (66,013) to manufacture ca 500 kg of heroin were stolen. Whilst the heroin signature program has been developed to determine the origin of heroin from other key producers, no such signature currently exists for Tasmanian derived heroin. Tasmanian poppies contain a unique alkaloid, oripavine, which is the source of 'marker' impurities in illicit heroin produced from Tasmanian poppy straw. Treatment of oripavine (500mg) under Thiboumery and Mohr heroin processing conditions, followed by simple evaporative workup afforded 613 mg of a dark orange residue, which upon extensive chromatographic purification yielded oripavine 3-acetate (2) 22 mg; 3-acetyl-N-acetyldesthebaine (3) 35 mg; 3-acetyl-6-methoxy-4,5-epoxyphenanthrene (4) 5.8 mg; 3,4-diacetyl-6-methoxyphenanthrene (5) 27 mg; and 3,4,6-methoxy-5-[2(N-methylacetamido)]ethylphenanthrene (6) 52 mg. Compounds (2-6) are derived from oripavine and are unique to heroin derived from the Tasmanian poppy Papaver somniferum N. Analysis of illicit heroin samples seized from Turkey, Pakistan, Columbia and Myanmar did not reveal any of the aforementioned marker compounds. We have, however, identified four of these marker compounds (3-6) in seized heroin samples from Australia suggesting that they are of Tasmanian origin. Complete details of the isolation and identification of these compounds are provided.


Splenic artery embolization versus splenectomy: Analysis for early in-hospital infectious complications and outcomes.
Splenic artery embolization (SAE) has gained increasing acceptance as an important adjunct in the treatment of splenic injuries. Residual immunologic function of the spleen after embolization and its consequences on early infectious complications still remain intensely debated. The purpose of this study was to compare SAE and splenectomy (SP) in terms of early in-hospital infectious complications and outcomes. Two-year retrospective Trauma Quality Improvement Program database prognostic study. Patients with grade IV to V splenic injury requiring SAE or SP were included in the final analysis. Examined variables were demographics, mechanism of injury, Abbreviated Injury Scale (AIS), Injury Severity Score, Organ Injury Scale, admission vital signs, blood transfusion in the first 24 hours, early infectious complications, and outcomes. Multivariate analysis adjusted for patient and injury-related variables was used to identify independent predictors for infectious complication and mortality. During the study period, 4,063 patients with a grade IV to V splenic injury managed with SAE or SP were included in the study. SAE was performed in 461 (11.3%) patients. The early infectious complication rate was 23.1% in the SP group and 11.7% in the SAE group (p < 0.001). Stepwise logistic regression analysis identified age 65 years or older, Glasgow Coma Scale (GCS) score less than 9, Head AIS score of 3 or greater, SP, and blood transfusion in the first 24 hours as independent predictors for early infectious complications. The unadjusted overall mortality was 12.7% in the SP group and 5.4% in the SAE group (p < 0.001). Age 65 years or older, GCS score less than 9, hypotension, head AIS score of 3 or greater, and blood transfusion in the first 24 hours were independent risk factor for mortality. SP was not an independent risk factor in terms of mortality. Subgroup analysis in patients with isolated splenic injury showed age 65 years or older, GCS score less than 9, and blood transfusion in the first 24 hours as independent factors associated with early infection. Our study supports the effectiveness of SAE in hemodynamically stable patients with a grade IV to V splenic injury. SP is associated with an increased risk of early infectious complications but is not an independent risk for mortality. Therapeutic study, level IV.


The Effect of a Global, Subject, and Device-Specific Model on a Noninvasive Glucose Monitoring Multisensor System.
We study here the influence of different patients and the influence of different devices with the same patients on the signals and modeling of data from measurements from a noninvasive Multisensor glucose monitoring system in patients with type 1 diabetes. The Multisensor includes several sensors for biophysical monitoring of skin and underlying tissue integrated on a single substrate. Two Multisensors were worn simultaneously, 1 on the upper left and 1 on the upper right arm by 4 patients during 16 study visits. Glucose was administered orally to induce 2 consecutive hyperglycemic excursions. For the analysis, global (valid for a population of patients), personal (tailored to a specific patient), and device-specific multiple linear regression models were derived. We find that adjustments of the model to the patients improves the performance of the glucose estimation with an MARD of 17.8% for personalized model versus a MARD of 21.1% for the global model. At the same time the effect of the measurement side is negligible. The device can equally well measure on the left or right arm. We also see that devices are equal in the linear modeling. Thus hardware calibration of the sensors is seen to be sufficient to eliminate interdevice differences in the measured signals. We demonstrate that the hardware of the 2 devices worn on the left and right arms are consistent yielding similar measured signals and thus glucose estimation results with a global model. The 2 devices also return similar values of glucose errors. These errors are mainly due to nonstationarities in the measured signals that are not solved by the linear model, thus suggesting for more sophisticated modeling approaches.


Haplotype effects on matrix metalloproteinase-1 gene promoter activity in cancer cells.
Increased expression of matrix metalloproteinase-1 (MMP1) is associated with poor prognosis in cancers. Several single nucleotide polymorphisms (-1607GG>G, -839G>A, -755G>T, -519A>G, -422T>A, -340C>T, and 320C>T) in the MMP1 gene promoter have recently been identified. In this study, we assessed the functional effects of these polymorphisms on MMP1 gene promoter activity in cell lines of melanoma (A2058 and A375), breast cancer (MCF7 and MDA-MB-231), lung cancer (A549 and H69), and colorectal cancer (HT-29, SW-620) by comparing the promoter strengths of 10 most common haplotypes deriving from these polymorphisms. In A2058 cells, the GG-G-G-A-T-T-T and GG-G-G-A-C-T haplotypes had 2-fold higher promoter activity than the GG-G-T-A-T-T-C, GG-G-G-A-A-T-T, GG-G-G-A-T-T-C, and GG-G-G-A-A-C-T haplotypes, which in turn, had 3-fold higher promoter activity than the G-G-T-A-A-C-T, G-A-T-G-T-T-T, G-A-T-G-A-C-T, and G-A-T-G-A-T-G haplotypes. In A375 and MDA-MB-231 cells, high expression haplotypes include not only the -1607GG-bearing haplotypes but also the G-A-T-G-A-T-T haplotype containing the -1607G allele. A similar trend was detected in A549 cells. In addition, in A549 cells, the GG-G-G-A-T-T-T haplotype had >2-fold higher promoter activity than several other -1607GG-bearing haplotypes. In MCF7 cells, the GG-G-G-A-T-T-T and G-G-T-A-A-C-T haplotypes had 1.5- to 4-fold higher promoter activity than the other haplotypes. These results suggest that the polymorphisms exert haplotype effects on the transcriptional regulation of the MMP1 gene in cancer cells, and indicate a need to examine haplotypes rather than any single polymorphism in genetic epidemiologic studies of the MMP1 gene in cancers.


Basal Tryptase High Levels Associated with a History of Arterial Hypertension and Hypercholesterolemia Represent Risk Factors for Severe Anaphylaxis in Hymenoptera Venom-Allergic Subjects over 50 Years Old.
Allergy to Hymenoptera venom (HV) may lead to life-threatening anaphylaxis. Some of the factors influencing the symptom's severity are still undetermined. The aim of this study was to identify the clinical aspects associated with the most severe reactions in a population with HV allergy, by comparing clinical and immunochemical biomarkers between patients with previous local large reactions (LLRs) and systemic reactions (SRs). We selected adult patients with a history of HV allergy, with positive diagnostic tests and a correlation with one single Hymenoptera species. Age, gender, atopy, serum basal tryptase (sBT) value, total IgE, venom-specific IgE, history of hypertension, cardiovascular diseases, and hypercholesterolemia were compared between patients with previous LLRs and SRs. 460 adult patients (381 SRs, 79 LLRs) were included. Age (p = 0.0097), male gender (p < 0.0001), arterial hypertension (p = 0.046), hypercholesterolemia (p = 0.009), and higher sBT levels (p = 0.0004) were significantly associated with severe reactions as independent variables. Moreover, considering the previous variables as risk factors, there was a significant and progressive increase in the odds of being Mueller III + IV as the number of positive variables increased. Patients with sBT ≥6.4 ng/mL adjusted for any of the positive variables had increased the risk of Mueller grade IV reaction (p < 0.0001). According to our results, older age, male gender, arterial hypertension, hypercholesterolemia, and increased levels of sBT ≥6.4 ng/mL are risk factors for severe anaphylaxis to HV in adults. Atopy and allergic asthma do not increase the risk of HV-induced SRs.


Mulberrofuran G, a Mulberry Component, Prevents SARS-CoV-2 Infection by Blocking the Interaction between SARS-CoV-2 Spike Protein S1 Receptor-Binding Domain and Human Angiotensin-Converting Enzyme 2 Receptor.
Despite the recent development of RNA replication-targeted COVID-19 drugs by global pharmaceutical companies, their prescription in clinical practice is limited by certain factors, including drug interaction, reproductive toxicity, and drug resistance. COVID-19 drugs with multiple targets for the SARS-CoV-2 life cycle may lead to a successful reduction in drug resistance as well as enhanced therapeutic efficacy, and natural products are a potential source of molecules with therapeutic effects against COVID-19. In this study, we investigated the inhibitory efficacy of mulberrofuran G (MG), a component of Morus alba L., also known as mulberry, which has been used as food and traditional medicine, on the binding of the spike S1 receptor-binding domain (RBD) protein to the angiotensin-converting enzyme 2 (ACE2) receptor, which is the initial stage of the SARS-CoV-2 infection. In competitive enzyme-linked immunosorbent assays, MG effectively blocked the spike S1 RBD: ACE2 receptor molecular binding, and investigations using the BLItz system and in silico modeling revealed that MG has high affinity for both proteins. Finally, we confirmed that MG inhibits the entry of SARS-CoV-2 spike pseudotyped virus and a clinical isolate of SARS-CoV-2 into cells, suggesting that MG might be a promising therapeutic candidate for preventing SARS-CoV-2 binding to the cell surface during early infection.


Inhibition of circulating exosomes release with GW4869 mitigates severe acute pancreatitis-stimulated intestinal barrier damage through suppressing NLRP3 inflammasome-mediated pyroptosis.
Intestinal barrier dysfunction frequently occurs as a complication in cases of severe acute pancreatitis (SAP); however, no effective therapeutic methods are available because the precise mechanism remains obscure. Recent research has elucidated the role of circulating exosomes in the progression of SAP. Therefore, the present study explored whether inhibiting circulating exosomes release would improve intestinal barrier injury triggered via SAP and investigated the possible underlying mechanism. In vivo, we found that circulating exosomes release exhibited a considerable increase in SAP rats than in SO rats, and GW4869, a suppressor of exosomes release, significantly decreased exosomes release in SAP rats. We also observed that GW4869 suppressed NLRP3 inflammasome-mediated pyroptosis within the intestine and alleviated intestinal barrier injury within SAP. Moreover, the inflammatory response and remote organ (kidney and lung) injury associated with SAP improved after GW4869 treatment. In vitro, we confirmed that depletion of exosomes with GW4869 could partially abolish the destructive effects of SAP rat plasma on the viability and barrier function of IEC-6 cells. In summary, our findings show that the suppression of the release of circulating exosomes effectively inhibits the process of pyroptosis mediated by the NOD-like receptor protein 3 (NLRP3) inflammasome and, therefore, mitigates intestinal barrier dysfunction in SAP, suggesting that circulating exosomes may be a potential target for treating SAP.


Predicting Dynamic Embedding Trajectory in Temporal Interaction Networks.
Modeling sequential interactions between users and items/products is crucial in domains such as e-commerce, social networking, and education. Representation learning presents an attractive opportunity to model the dynamic evolution of users and items, where each user/item can be embedded in a Euclidean space and its evolution can be modeled by an embedding trajectory in this space. However, existing dynamic embedding methods generate embeddings only when users take actions and do not explicitly model the future trajectory of the user/item in the embedding space. Here we propose JODIE, a coupled recurrent neural network model that learns the embedding trajectories of users and items. JODIE employs two recurrent neural networks to update the embedding of a user and an item at every interaction. Crucially, JODIE also models the future embedding trajectory of a user/item. To this end, it introduces a novel projection operator that learns to estimate the embedding of the user at any time in the future. These estimated embeddings are then used to predict future user-item interactions. To make the method scalable, we develop a t-Batch algorithm that creates time-consistent batches and leads to 9× faster training. We conduct six experiments to validate JODIE on two prediction tasks- future interaction prediction and state change prediction-using four real-world datasets. We show that JODIE outperforms six state-of-the-art algorithms in these tasks by at least 20% in predicting future interactions and 12% in state change prediction.


In Vitro and In Vivo Antimicrobial Activities of Vancomycin and Rifampin against Elizabethkingia anophelis.
Elizabethkingia anophelis has emerged as a critical human pathogen, and a number of isolated reports have described the successful treatment of Elizabethkingia infections with vancomycin, a drug that is typically used to target Gram-positive bacteria. This study employed in vitro broth microdilution checkerboard and time-kill assays, as well as in vivo zebrafish animal models to evaluate the individual and combination antimicrobial effects of vancomycin and rifampin against E. anophelis. The minimum inhibitory concentration ranges of vancomycin and rifampin against 167 isolates of E. anophelis were 16-256 mg/L and 0.06-128 mg/L, respectively. The checkerboard assay results revealed a synergistic effect between vancomycin and rifampin in 16.8% (28/167) of the isolates. Time-kill assays were implemented for 66 isolates, and the two-drug combination had a synergistic interaction in 57 (86.4%) isolates. In vivo zebrafish studies revealed that treatment with vancomycin monotherapy, rifampin monotherapy, or vancomycin-rifampin combination therapy yielded a higher survival rate than the control group treatment with 0.9% saline. The results of this study support the use of vancomycin to treat E. anophelis infections.


Identification of alpha6beta1 integrin positive cells in synovial lining layer as type B synoviocytes.
In rheumatoid arthritis (RA) the synovial lining is responsible for cartilage destruction. Laminin is one of the major matrix molecules surrounding the lining cells. We investigated the laminin adhesion mechanism of synovial lining cells by analyzing the presence of its receptor, alpha6beta1 integrin, on type A and type B synoviocytes. The alpha6 integrin subunit and a macrophage marker were simultaneously localized by immunohistochemistry in 29 RA derived, 6 osteoarthritis derived, and 2 healthy synovial samples by light and electron microscopy. We also used enzyme treatments to release cells from synovial tissue samples and localized the same antigens on adherent cells. The alpha6beta1 integrin positive cells were localized in basal areas of the lining layer and many of them were negative for the macrophage markers. By immunolabeling electron microscopy the alpha6 integrin positive cells were confirmed to represent the fibroblast-like type B cells. Further, in freshly isolated synoviocyte cultures the type B cells were positive for alpha6 integrin, whereas all other cell types were negative for this laminin receptor. Integrin alpha6beta1 is known to be a laminin receptor of endothelial cells, adipocytes, and macrophages, not usually expressed on fibroblasts. However, in synovial lining layer it is expressed on fibroblastic type B cells, but the macrophage population is negative. The unique characteristics of synovial lining cells distinguish them from other connective tissue cells and must be taken into account in all considerations of the pathogenic mechanisms of rheumatoid disease.


Latitudinal gradients in body size and sexual size dimorphism in fleas: males drive Bergmann's pattern.
We tested for the effects of latitude and geographic range size (GRS) on body size, leg length, and sexual size dimorphism (SSD) across 103 species of fleas, taking into account phylogenetic between-species relationships. When the data on body size were combined for males and females, the positive correlation between body size and latitude, but not GRS, was revealed. When the analysis was restricted to one sex only, the effect of latitude appeared to be non-significant for females, whereas male body size increased with an increase in latitude. Intraspecific body size variation was not associated with either the latitude or the latitudinal span of the geographic range, independently of which data subset was analyzed. No evidence of association between size-independent tibia length and latitude was found for either females, males, or both sexes combined. The degree of SSD decreased with a decrease in latitude but was not affected by GRS. We conclude that macroecological patterns might be manifested differently in males and females. This should be kept in mind while searching for these patterns.


Comparative study of a 15-MHz focused ultrasonic transducer and a 15-MHz unfocused ultrasonic transducer for clinical in-vivo skin-thickness measurements in human subjects.
A commercial focused 15-MHz immersion ultrasonic transducer and a commercial unfocused 15-MHz thickness-gaging ultrasonic transducer were evaluated for invivo skin-thickness measurements in humans. The unfocused transducer produced thicker skin measurements than did the focused transducer but both measurements were generally within previously reported ranges. The differences in the determined thicknesses may have been a result of the uneven nature of the dermissubcutaneous tissue interface and the ability of the focused transducer to better follow this interface.


Kinetic characteristics of a solid photochromic film.
Analytical or numerical solutions are given for the kinetic equations describing the time behavior of a solid photochromic film for the cases of photocoloration, photobleaching, and thermal bleaching. A procedure to evaluate relative quantum yields and absorption cross sections from the comparison of experimental results with theoretical solutions is demonstrated by an example using 6-nitro-8 piperidinomethyl-1', 3', 3'-trimethylspiro-[1H-benzopyran-2, 2'-indoline] as a photochromic compound. The theoretical results are presented in a suitably normalized form to be applicable to a broad range of experimental situations. The agreement between calculated and measured results is good as long as strictly first-order reaction mechanisms are obeyed.


Molecular characterization of NbPAF encoding the alpha6 subunit of the 20S proteasome in Nicotiana benthamiana.
The 26S proteasome involved in degradation of proteins covalently modified with polyubiquitin consists of the 20S proteasome and 19S regulatory complex. The NbPAF gene encoding the alpha6 subunit of the 20S proteasome was identified from Nicotiana benthamiana. NbPAF exhibits high sequence homology with the corresponding genes from Arabidopsis, human and yeast. The deduced amino acid sequence of NbPAF reveals that this protein contains the proteasome alpha-type subunits signature and nuclear localization signal at the N-terminus. The genomic Southern blot analysis suggests that the N. benthamiana genome contains one copy of NbPAF. The NbPAF mRNA was detected abundantly in flowers and weakly in roots and stems, but it was almost undetectable in mature leaves. In response to stresses, accumulation of the NbPAF mRNA was stimulated by methyl jasmonate, NaCl and salicylic acid, but not by abscisic acid and cold treatment in leaves. The NbPAF-GFP fusion protein was localized in the cytoplasm and nucleus.


Heart regeneration: Past, present and future.
The heart has been considered a post-mitotic organ without regenerative capacity for most of the last century. We review the evidence that led to this hypothesis in the early 1900s and how it was progressively modified, culminating with the report that we renew 50% of our cardiomyocytes during our lifetime. The future of cardiac regenerative therapies is discussed, presenting the difficulties to overcome before repair of the diseased heart can come into clinical practice.


Simulating the self-assembly of gemini (dimeric) surfactants.
The morphologies and dynamics of aggregates formed by surfactant molecules are known to influence strongly performance properties spanning biology, household cleaning, and soil cleanup. Molecular dynamics simulations were used to investigate the morphology and dynamics of a class of surfactants, the gemini or dimeric surfactants, that are of potential importance in several industrial applications. Simulation results show that these surfactants form structures and have dynamic properties that are drastically different from those of single-chain surfactants. At the same weight fraction, single-chain surfactants form spherical micelles whereas gemini surfactants, whose two head groups are coupled by a short hydrophobic spacer, form thread-like micelles. Simulations at different surfactant concentrations indicate the formation of various structures, suggesting an alternative explanation for the unexpected viscosity behavior of gemini surfactants.


Molecular analysis of argininosuccinate synthetase deficiency in human fibroblasts.
We have analyzed cultured skin fibroblasts derived from patients with argininosuccinate synthetase deficiency for alterations in gene structure, mRNA content, and protein structure. Genomic DNA was digested with the endonucleases EcoRI or HindIII, and the fragments were analyzed by Southern blotting and hybridization with a cDNA probe for argininosuccinate synthetase. The blot pattern is complex because there are at least 10 copies of argininosuccinate synthetase-like genes scattered over multiple human chromosomes. All nine patients studied showed patterns of DNA fragments that were indistinguishable from the normal control cell lines, and despite the possibility that the complexity could mask some changes, major deletions of the active gene(s) were not present. Blot hybridization of RNA indicated the presence of hybridizable mRNA of approximately normal size in seven of seven individuals examined with a suggestion of some heterogeneity. Analysis of enzyme antigen by protein transfer from NaDodSO4 containing polyacrylamide gels revealed considerable heterogeneity. This analysis revealed no cross-reacting material (CRM) in nine cell lines, CRM of normal molecular weight in one cell line, and CRM of reduced molecular weight in one cell line. These findings suggest that the genes for argininosuccinate synthetase in most citrullinemia patients are transcribed and produce stable mRNA. These mRNA either are not translated, or the translation product (enzyme) is rapidly degraded or is immunologically nonreactive. Defective gene expression in this disorder appears to involve abnormal mRNA, which may be altered by point mutations, frame shift mutations, deletions, insertions or particularly by abnormal RNA processing.


What works best for ensuring treatment adherence. Lessons from a social support program for people treated for tuberculosis in Ukraine.
Worldwide, TB is one of the top 10 causes of death and the leading cause from a single infectious agent. Ukraine is one of 30 countries with the highest burden of multidrug-resistant tuberculosis. Global literature shows that social support (SS) is important in improving TB treatment adherence, reducing lost to follow up rates and improving treatment outcomes. There are several models of SS available, and the literature provides little information on what aspects of SS are most important to TB patients in improving their adherence. We used qualitative data collected through in-depth interviews (IDI) with 21 TB patients and 15 SS providers and coordinators in Ukraine in August-September 2016 to understand how the SS program promoted treatment adherence among patients. We examined the aspects of outpatient TB treatment that made adherence particularly difficult for patients in at-risk groups and aspects of the SS programs that worked best for addressing those barriers. Interviews were transcribed and analysis was performed to derive emergent themes. Main barriers included side effects from medicine, the amount of time required daily for transportation and waiting in lines at the health facility, transportation expenses, risks of being identified when visiting a TB facility and lack of motivation to seek treatment. Features of the SS program most valued by patients were convenience of not having to visit facility and support provided by nurses. These two features directly addressed most of the barriers identified. The commitment and qualities of the nurses that provided the SS was an important element of the program. This qualitative study suggests that the SS program in Ukraine was successful in reducing treatment default among patients at high risk of default because it directly addressed most of the major barriers they faced to treatment adherence.


Ocular Histopathologic Features of Congenital Zika Syndrome.
Congenital Zika syndrome (CZS) is known to be associated with severe malformations in newborns. Although microcephaly is the hallmark of this disease, the ocular findings are important given the severe visual impairment that has been observed in these patients. Regardless of the increased number of CZS cases reported, to date, no studies have described the ocular histopathologic findings of this entity. To evaluate the presence of Zika virus (ZIKV) antigens and describe the associated ocular histopathologic features of 4 cases of CZS. In this observational case series performed from June 19, 2015, through April 30, 2017, ocular tissue samples from 4 deceased fetuses with a diagnosis of CZS from the National Institute of Health in Colombia were sent to the Florida Lions Ocular Pathology Laboratory for evaluation. The microscopic features of each specimen were described, and immunostaining was performed using a ZIKV NS2B protein antibody. Ocular tissue samples from the 4 deceased fetuses (2 female, 2 male) ranging from 21.5 to 29 weeks' gestation with a diagnosis of CZS were studied. The 4 eyes manifested with pupillary membranes, immature anterior chamber angles, loss of pigment and thinning of the retinal pigment epithelium, choroidal thinning, undifferentiated nuclear layers of the retina, and a perivascular inflammatory infiltrate within the choroid. The optic nerve, present in 2 of the eyes, demonstrated atrophy. Expression of ZIKV antigen was present in the iris in cases 1, 3, and 4; the neural retina and choroid in case 1; and in the optic nerve in case 4. Loss of retinal pigment epithelium, the presence of a thin choroid, a perivascular choroidal inflammatory infiltrate, and atrophic changes within the optic nerve were consistently present. These findings may be attributed to ZIKV infection and warrant further study.


A usability study of a mobile monitoring system for congestive heart failure patients.
Sensor-based monitoring of congestive heart-failure (CHF) patients living at home can improve quality of care, detect exacerbations of disease at an earlier stage and motivate the patient for better self care. This paper reports on a usability study of the ESUMS system that provides continuous measurements of heart rate, activity, upper body posture and skin temperature via a sensor belt and a smartphone as patient terminal. Five CHF patients were included in the trial, all recently discharged from hospital. The nurses experienced continuous heart rate, activity and posture monitoring as useful and objective tools that helped them in their daily assessment of patient health. They also saw the system as an important educational tool to help patients gain insight into their own condition. Three patients liked that they could have a view of their own physiological and activity data, however the smartphones used in the study turned out to be too complicated for the patients to operate. A smartphone is built to be a multi-purpose device, and this may (conceptually and practically) be incompatible with the patients' demands for ease of use.


Low birth weight and home intervention strategies: preterm infants.
We investigated the effects of a 1-year home intervention on premature infants with low (less than 1500 g) and higher (1500-2000 g) birth weights. Infants from each weight condition were block randomly assigned to a control or to one of two treatment groups. One treatment group focused on the development of the infant; the other treatment group focused on the parent-infant interaction. The low birth weight infants obtained significantly lower Bayley mental and motor scores, and were more passive and less intense than the higher birth weight infants. However, the low birth weight infants and their parents were more responsive to the home intervention than were the higher birth weight infants, as demonstrated by changes in the Bayley mental scores and the Home Observation for Measurement of the Environment (HOME) inventory. These findings exemplify the reciprocal relationship between the child's characteristics and parental responding. The importance of selecting the most high-risk premature infants for early home intervention is outlined.


Climate, altitude, and blood pressure.
The effects of climate and altitude on casual blood pressure are examined from the perspectives of initial exposure, acclimatization, long-term residence, and birthplace. Hot arid and hot humid climates seem to have little effect on blood pressure, although a slight reduction may be found in some naturally acclimatized groups. Exposure of the total body to mild cold likewise has little apparent effect. Local exposure of the extremities to severe cold occasions significant increases in blood pressure during exposure but not at other times. Acclimatization reduces but does not eliminate that response. The effects of altitude on blood pressure are variable. There is initial hypertension, followed by gradual normalization. After years of residence at high altitude blood pressure may actually be lower than that observed among residents at sea level.


Integrative multi-omics analysis reveals different metabolic phenotypes based on molecular characteristics in thyroid cancer.
Thyroid cancer (TC) metabolic characteristics vary depending on the molecular subtype determined by mutational status. We aimed to investigate the molecular subtype-specific metabolic characteristics of TCs. An integrative multi-omics analysis was conducted, incorporating transcriptomics, metabolomics, and proteomics data obtained from human tissues representing distinct molecular characteristics of TCs; BRAF-like (papillary TC with BRAFV600E mutation; PTC-B), RAS-like (follicular TC with RAS mutation; FTC-R), and ATC-like (anaplastic TC with BRAFV600E or RAS mutation; ATC-B or ATC-R). To validate our findings, we employed tissue microarray of human TC tissues and performed in vitro analyses of cancer cell phenotypes and metabolomic assays after inducing genetic knockdown. Metabolic properties differed between differentiated TCs of PTC-B and FTC-R, but were similar in de-differentiated TCs of ATC-B/R, regardless of their mutational status. Tricarboxylic acid (TCA) intermediates and branched-chain amino acids (BCAA) were enriched with the activation of TCA cycle only in FTC-R, whereas one-carbon metabolism and pyrimidine metabolism increased in both PTC-B and FTC-R and to a great extent in ATC-B/R. However, the protein expression levels of the BCAA transporter (SLC7A5) and a key enzyme in one-carbon metabolism (SHMT2) increased in all TCs and were particularly high in ATC-B/R. Knockdown of SLC7A5 or SHMT2 inhibited the migration and proliferation of TC cell lines differently, depending on the mutational status. These findings define the metabolic properties of each molecular subtype of TCs and identify metabolic vulnerabilities, providing a rationale for therapies targeting its altered metabolic pathways in advanced TC.


[Can drugs, especially calcium antagonists, bring about regression of atherosclerosis, especially coronary sclerosis?].
The feasibility of true regression of human atherosclerotic plaques (reduction in volume) through drug therapy is still debated; the increase in coronary artery diameter, especially eccentric stenoses during massive reduction of serum cholesterol, can also be due to stabilization of endothelial function and improvement of the abnormally raised basal coronary tone. Today, there are two groups of substances with anti-atherosclerotic properties: lipid-lowering drugs, and calcium-entry blockers. As evidenced both from animal experiments and prospective studies in man by quantitated coronary angiography (QCA), the latter act mainly by retarding the evolution of new plaques, and possibly even of fatty streaks. In man, four studies with calcium-entry blockers so far exist, all demonstrating a significant reduction (average -46%) of new lesions (stenoses and occlusions) in previously angiographically normal segments. To what extent these favourable anatomical results will lead to an improvement of cardiac events caused by plaque rupture (unstable angina, myocardial infarction) later on is still an open question. The slow anatomical progression of coronary artery disease, as evidenced by prospective repeated QCA, calls for studies with long-term follow-ups (10 and more years) and large numbers of patients.