Effect of morphine on the electroencephalogram and other physiological and other physiological and behavioral parameters.
A double-blind, crossover, placebo-controlled study was carried out in 10 healthy male volunteers to investigate the effects of subcutaneously administered single doses of 4 and 8 mg morphine and 2.5 and 5 mg of a new centrally acting analgesic with a benzomorphane structure. After an adaptation session, each subject received all five treatments in a random sequence at intervals of 1 week. Quantified EEG, cardiovascular and behavioral parameters, quantitative respiratory measurements, body temperature, symptom reports, pain threshold estimates, and blood drug assays were used to assess the effects of the drugs. The measurement battery was completed before injection and after 30, 60, 120, 240 and 360 min. In addition, EEG, blood samples and respiratory signals were also taken during/after the first 5, 10, 15, 20 and 25 min. As the new compound did not show any obvious advantages over morphine, only the results with the latter substance are reported here. As the main effects of morphine on the EEG a dose-dependent slowing and monorhythmization of alpha and an increase of the average frequency of fast beta activity were observed. Slow EEG waves tended to decrease. Heart rate and body temperature decreased, whereas there was no discernible effect on blood pressure. Subjects reported feelings of drowsiness, muzziness, lethargy and mental slowness. The pain threshold increased. All these effects had a maximum between min 120 and 240, although the highest blood levels of the parent drug were measured 10-25 min after drug administration. An explanation for this delay might be that the pharmacological effects are due not to free morphine but to one of its metabolites.


Macrophage EP4 deficiency increases apoptosis and suppresses early atherosclerosis.
Prostaglandin (PG) E(2), a major product of activated macrophages, has been implicated in atherosclerosis and plaque rupture. The PGE(2) receptors, EP2 and EP4, are expressed in atherosclerotic lesions and are known to inhibit apoptosis in cancer cells. To examine the roles of macrophage EP4 and EP2 in apoptosis and early atherosclerosis, fetal liver cell transplantation was used to generate LDLR(-/-) mice chimeric for EP2(-/-) or EP4(-/-) hematopoietic cells. After 8 weeks on a Western diet, EP4(-/-) --> LDLR(-/-) mice, but not EP2(-/-) --> LDLR(-/-) mice, had significantly reduced aortic atherosclerosis with increased apoptotic cells in the lesions. EP4(-/-) peritoneal macrophages had increased sensitivity to proapoptotic stimuli, including palmitic acid and free cholesterol loading, which was accompanied by suppression of activity of p-Akt, p-Bad, and NF-kappaB-regulated genes. Thus, EP4 deficiency inhibits the PI3K/Akt and NF-kappaB pathways compromising macrophage survival and suppressing early atherosclerosis, identifying macrophage EP4-signaling pathways as molecular targets for modulating the development of atherosclerosis.


The complexity of mitochondrial tRNA import.
Import of nucleus-encoded, cytoplasmic tRNAs into mitochondria to compensate evolutionary loss of the corresponding mitochondrial genes has been documented in a large number of species. Although the phenomenon has been known for more than 25 years, it was only recently that the mechanism of tRNA import started receiving the sustained attention of workers investigating yeast, protozoal and higher plant systems. The purpose of this review is to summarize recent developments that shed new light on the selectivity of the process, the identity of the import apparatus and the nature of the bioenergetic transactions leading to tRNA translocation, and to build a working model of the import complex suggested by these observations.


GSK-3β controls autophagy by modulating LKB1-AMPK pathway in prostate cancer cells.
Glycogen synthase kinase 3β (GSK3B, GSK-3β) is a multi-functional protein kinase involved in various cellular processes and its activity elevates after serum deprivation. We have shown that inhibition of GSK-3β activity triggered a profound autophagic response and subsequent necrotic cell death after serum deprivation in prostate cancer cells. In this study, we dissected the mechanisms involved in GSK-3β inhibition-triggered autophagy. Prostate cancer PC-3 and DU145 cells were used in the study. Multiple GSK-3β specific inhibitors were used including small chemicals TDZD8, Tideglusib, TWS119, and peptide L803-mts. Western blot assay coupled with phospho-specific antibodies were used in detecting signal pathway activation. ATP levels were assessed with ATPLite kit and HPLC methods. Autophagy response was determined by evaluating Microtubule-associated proteins 1A/1B light chain 3B (LC3B) processing and p62 protein stability in Western blot assays. Immunofluorescent microscopy was used to detect LKB1 translocation. Inhibition of GSK-3β activity resulted in a significant decline of cellular ATP production, leading to a significant increase of AMP/ATP ratio, a strong trigger of AMP-activated protein kinase (AMPK) activation in prostate cancer PC-3 cells. In parallel with increased LC-3B biosynthesis and p62 protein reduction, the classical sign of autophagy induction, AMPK was activated after inhibition of GSK-3β activity. Further analysis revealed that Liver kinase B1 (LKB1) but not Calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ) is involved in AMPK activation and autophagy induction triggered by GSK-3β inhibition. Meanwhile, GSK-3β inhibition promoted LKB1 translocation from nuclear to cytoplasmic compartment and enhanced LKB1 interaction with its regulatory partners Mouse protein-25 (MO25) and STE20-related adaptor (STRAD). In conclusion, our data suggest that GSK-3β plays an important role in controlling autophagy induction by modulating the activation of LKB1-AMPK pathway after serum deprivation.


A new Prenylated Flavonoid induces G0/G1 arrest and apoptosis through p38/JNK MAPK pathways in Human Hepatocellular Carcinoma cells.
Prenylated flavonoids have been demonstrated to possess diverse bioactivities including antitumor effects. One new, daphnegiravone D (1), and four known (2-5) prenylated flavonoids were isolated from Daphne giraldii. Their cytotoxic activities revealed that daphnegiravone D markedly inhibited the proliferation of cancer cells, but had no apparent cytotoxicity on human normal cells. Mechanistically, daphnegiravone D induced G0/G1 arrest and apoptosis, reduced the expression of cyclin E1, CDK2 and CDK4, and promoted the cleavage of caspase 3 and PARP in Hep3B and HepG2 cells. Meanwhile, daphnegiravone D increased the level of phosphorylated p38 and attenuated phosphorylated JNK. Further studies indicated that SB203580 partially reversed daphnegiravone D-induced G0/G1 arrest and apoptosis. The addition of SP600125 to both cell lines increased the cleavage of caspase 3 and PARP, but did not affect the G0/G1 arrest. Besides, in vivo studies demonstrated that daphnegiravone D obviously inhibited tumor growth in a nude mouse xenograft model through suppressing the proliferation of tumor cells, without significant effect on body weight or pathology characteristics. Taken together, the new compound selectively inhibited the proliferation of hepatoma cells via p38 and JNK MAPK pathways, suggesting its potential as a novel natural anti-hepatocellular carcinoma agent.


Monoclonal antibodies to tick-borne encephalitis (TBE) virus: their use for differentiation of the TBE complex viruses.
Monoclonal antibodies (MoAbs) to Central European tick-borne encephalitis virus (strain Hypr) were used for differentiation of eight viruses of the TBE complex by indirect immunofluorescence. MoAb 11/B3 (in Western blot recognizing 52 and 70 kD polypeptides) reacted with five out of the eight TBE complex viruses, MoAb 13/E5 (anti-52 kD protein) reacted with the western or eastern subtype of TBE virus only, while MoAb 12/G4 (anti-70 kD protein) distinguished the western subtype of TBE virus from the rest of the TBE complex. These three MoAbs were able to differentiate the virulent strain Hypr from attenuated strains Skalica and Hy-HK-18-"3". MoAb 2/10C (anti-56 and 70 kD proteins) which reacted with all viruses of the TBE complex, recognized both virulent and attenuated strains of TBE virus.


Design of a magnetic shielding system for the time of flight enhanced diagnostics neutron spectrometer at Experimental Advanced Superconducting Tokamak.
The novel neutron spectrometer TOFED (Time of Flight Enhanced Diagnostics), comprising 90 individual photomultiplier tubes coupled with 85 plastic scintillation detectors through light guides, has been constructed and installed at Experimental Advanced Superconducting Tokamak. A dedicated magnetic shielding system has been constructed for TOFED, and is designed to guarantee the normal operation of photomultiplier tubes in the stray magnetic field leaking from the tokamak device. Experimental measurements and numerical simulations carried out employing the finite element method are combined to optimize the design of the magnetic shielding system. The system allows detectors to work properly in an external magnetic field of 200 G.


Follow-up intervals in patients with Cushing's disease: recommendations from a panel of experienced pituitary clinicians.
Follow-up guidelines are needed to assess quality of care and to ensure best long-term outcomes for patients with Cushing's disease (CD). The purpose of this study was to assess agreement by experts on recommended follow-up intervals for CD patients at different phases in their treatment course. The RAND/UCLA modified Delphi process was used to assess expert consensus. Eleven clinicians who regularly manage CD patients rated 79 hypothetical patient scenarios before and after ("second round") an in-person panel discussion to clarify definitions. Scenarios described CD patients at various time points after treatment. For each scenario, panelists recommended follow-up intervals in weeks. Panel consensus was assigned as follows: "agreement" if no more than two responses were outside a 2 week window around the median response; "disagreement" if more than two responses were outside a 2 week window around the median response. Recommendations were developed based on second round results. Panel agreement was 65.9% before and 88.6% after the in-person discussion. The panel recommended follow-up within 8 weeks for patients in remission on glucocorticoid replacement and within 1 year of surgery; within 4 weeks for patients with uncontrolled persistent or recurrent disease; within 8-24 weeks in post-radiotherapy patients controlled on medical therapy; and within 24 weeks in asymptomatic patients with stable plasma ACTH concentrations after bilateral adrenalectomy. With a high level of consensus using the Delphi process, panelists recommended regular follow-up in most patient scenarios for this chronic condition. These recommendations may be useful for assessment of CD care both in research and clinical practice.


Mandibular ameloblastoma: analysis of surgical treatment carried out in 60 patients between 1977 and 1998.
Ameloblastoma, a benign tumor of odontogenic type, represents 10% of all tumors of the jawbone. It is localized in the mandible in 80% of cases and in the upper jaw in the remaining 20%. In every case, the selection of the surgical treatment to be applied must consider some fundamental elements, including the age and general state of health of the patient, the clinicopathological variant, and the localization and extent of the tumor. In addition, it is necessary to evaluate whether the neoplasm to be treated is a primitive lesion or a recurrence. Although ameloblastoma has relative histological characteristics of benignity, this neoplasm has a high percentage of local recurrence and possible malignant development when treated inadequately. The aim of this study was to carry out a follow-up of 60 patients treated for ameloblastoma of the mandible between 1977 and 1998, analyzing the problems faced in removing this benign neoplasm and those concerning reconstruction of the surgical defect.


Enzyme-Catalyzed Bottom-Up Synthesis of Mechanically and Physicochemically Stable Cellulose Hydrogels for Spatial Immobilization of Functional Colloidal Particles.
The dispersion stabilization of colloidal particles and subsequent construction of functional materials are of great interest in areas ranging from colloid chemistry to materials science. A promising strategy is the spatial immobilization of colloidal particles within gel scaffolds. However, conventional gels readily deform and even collapse when changes in environmental conditions occur. Herein, we describe the enzyme-catalyzed bottom-up synthesis of mechanically and physicochemically stable nanoribbon network hydrogels composed of crystalline cellulose oligomers in which cellulose nanocrystals (CNCs) as model colloidal particles are immobilized spatially. The stiffness of the hydrogels increased with the amount of CNCs incorporated. Filling the void space of the hydrogels with hydrophobic polymers resulted in polymer nanocomposites with excellent mechanical properties. The nanoribbon networks will be useful for demonstrating the potential functions of colloidal particles.


BK polyoma virus allograft nephropathy: ultrastructural features from viral cell entry to lysis.
BK virions must enter the host cell and target their genome to the nucleus in order to complete their life cycle. The mechanisms by which the virions accomplish these tasks are not known. In this morphological study we found that BK virions localized beneath the host cell cytoplasmic membrane in 60-70-nm, smooth (non-coated) monopinocytotic vesicles similar to, or consistent with, caveolae. In the cytoplasm, the monopinocytotic vesicles carrying virions appeared to fuse with a system of smooth, vesicles and tubules that communicated with the rough endoplasmic reticulum and was continuous with the Golgi system. Membrane-bound single virions and large tubulo-reticular complexes loaded with virions accumulated in paranuclear locations. Occasional nuclei displayed virions within the perinuclear cisterna in association to the perinuclear viral accumulations. Tubular cells with mature productive infection had large nuclei, distended by daughter virions, whereas they lacked significant numbers of cytoplasmic virions. In addition to virally induced cell necrosis, there was extensive tubular cell damage (apoptosis and necrosis) in morphologically non-infected tubules. The observed ultrastructural interactions between the BK virions and host cells are remarkably similar to viral cell entry and nuclear targeting described for SV40 virus.


The effects of exercise and cold exposure on mitochondrial biogenesis in skeletal muscle and white adipose tissue.
The purpose of this study was to determine whether exercise or/and cold exposure regulate mitochondria biogenesis-related gene expression in soleus and inguinal adipose tissue of mice. Forty ICR 5-week old male mice were divided into four groups: thermoneutrality-untrained (23 ± 1 °C in room temperature, n=10), cold-water immersion (24 ± 1 °C, n=10), exercise in neutral temperature (34 ± 1 °C, n=10), and exercise in cold temperature (24 ± 1 °C, n=10). The mice performed swimming exercise (30 min to 60 min, 5 times) for 8 weeks. After 8 weeks, we confirmed mitochondrial biogenesis-related gene expression changes for peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), nuclear respiratory factors 1 (NRF1), and mitochondrial transcription factor A (Tfam) in soleus muscle and inguinal adipose tissue, and the related protein expression in soleus muscle. In soleus muscle, PGC-1α expression significantly increased in response to cold exposure (p = 0.006) and exercise (p = 0.05). There was also significant interaction between exercise and cold exposure (p = 0.005). Only exercise had a significant effect on NRF1 relative expression (p=0.001). Neither cold exposure nor the interaction showed significant effects (p = 0.1222 and p = 0.875, respectively). Relative Tfam expression did not show any significant effect from exercise. In inguinal adipose tissue, relative PGC-1α expression did not significantly change in any group. NRF1 expression showed a significant change from exercise (p = 0.01) and cold exposure (p = 0.011). There was also a significant interaction between exercise and cold exposure (p = 0.000). Tfam mRNA expression showed a significant effect from exercise (p=0.000) and an interaction between exercise and cold exposure (p=0.001). Only temperature significantly affected PGC-1α protein levels (p=0.045). Neither exercise nor the interaction were significant (p = 0.397 and p = 0.292, respectively). NRF1 protein levels did not show a significant effect in any experimental treatments. Tfam protein levels showed a significant effect in the exercise group (p=0.012), but effects of neither cold exposure nor the interaction were significant (p = 0.085 and p=0.374, respectively). Exercise and cold exposure promoted increased expression of mitochondrial biogenesis- related genes in soleus muscle. Only cold exposure had a significant effect on PGC-1α protein expression and only exercise had a significant effect on Tfam protein expression. In inguinal adipose tissue, there was interaction between exercise and cold exposure in expression of mitochondrial biogenesis-related genes.


Antinociceptive effect of clinical analgesics in a nonhuman primate model of knee osteoarthritis.
A number of potential analgesic pharmacotherapies developed in preclinical osteoarthritis animal models have failed clinical trials. A possible basis for the lack of translation of preclinical findings to clinical efficacy is the use of a preclinical species that is distinct from that of humans. The current study tested clinical analgesics in a nonhuman primate model of knee osteoarthritis. Following a medial meniscectomy, the animals developed a robust ipsilateral reduction in knee pressure threshold (hyperalgesia) and an ipsilateral reduction in weight bearing (resting pain). The serotonin-noradrenalin reuptake inhibitor duloxetine and opioid morphine increased ipsilateral pressure threshold and weight bearing. By contrast, the anticonvulsant pregabalin did not affect either pressure hyperalgesia or resting pain. The current findings in the nonhuman primate model of osteoarthritis parallel clinical findings, in that duloxetine and opioids are used in the management of osteoarthritis pain whereas pregabalin is not. The current findings also suggest the possible differentiation of pharmacotherapeutics in a nonhuman primate model, of distinguishing potential clinically useful analgesics for the management of osteoarthritic pain from those that are not.


Multiple introduction of Asian H5N1 avian influenza virus in Croatia by wild birds during 2005-2006 and isolation of the virus from apparently healthy black-headed gulls (Larus ridibundus).
This study describes the introduction and spread of avian influenza A (H5N1) subtype in Croatia. Seventeen isolates were identified during the period from October 2005 to March 2006, all originating from wild birds. The full-length nucleotide sequence analysis of the hemagglutinin (HA) gene of seven representative isolates revealed that three distinct genetic strains involved in the outbreaks, implicating at least three independent introductions of the virus into Croatia during a relatively short period of time. All three genetic strains belonged to clade 2.2 (Qinghai-like viruses) and each strain displayed significant similarity to concurrent H5N1 viruses from other European countries. The dominant strain of the virus was present in all four affected areas and in all three bird species (mute swan, mallard, and black-headed gull), indicating cross-species transmission of the virus. Two other genetic strains were found, together with the dominant strain, only in a marsh at the Adriatic coast during late February and early March 2006, which could be associated with frozen water surfaces in the continental part of Croatia as well as in Eastern Europe in early 2006 and the movement of birds toward warmer areas. This is also the first isolation of highly pathogenic avian influenza virus of H5N1 subtype from apparently healthy black-headed gulls.


Cure of Oligometastatic Classic Biphasic Pulmonary Blastoma Using Aggressive Tri-modality Treatment: Case Series and Review of the Literature.
Pulmonary blastoma is a rare lung cancer classified into three subtypes: classic biphasic pulmonary blastoma (CBPB), well-differentiated fetal adenocarcinoma (WDFA), and pleuropulmonary blastoma (PPB) of childhood. Compared to the other subtypes, CPPB is an aggressive tumor with an overall five-year survival of 16% across all stages. We present two cases of biopsy-proven metastatic CBPB, who have been disease-free for over 10 years since treatment completion. Both patients were treated with surgery to the primary tumor followed by an adjuvant cisplatin-based chemotherapy for four cycles and thoracic radiation. One patient relapsed shortly after the completion of thoracic radiation with brain metastases and underwent craniotomy, gamma knife radiosurgery (GKRS), and whole brain radiation therapy. The other patient presented with synchronous pelvic metastases and underwent metastasectomy after the completion of chemotherapy but before the initiation of thoracic radiation. We review the literature regarding surgical, chemotherapeutic, and radiation treatment for patients with metastatic pulmonary blastoma. Based on our experience and review of the existing case reports, aggressive tri-modality treatment including surgery, chemotherapy with a cisplatin backbone, and a definitive treatment of oligometastatic lesions amenable to local therapy including resection or radiosurgery is reasonable to consider for medically fit patients with CBPB.


Role of Chondroitin Sulfate Proteoglycan 5 in Steroid-Induced Cataract.
Steroid-induced cataracts (SIC) are defined as cataracts associated with the administration of corticosteroids. Long-term glucocorticoid treatment for inflammatory diseases reportedly increases the risk of SIC, and steroids can induce cataracts by disrupting ocular growth factor balance or homeostasis. In this study, we verified the effect of chondroitin sulfate proteoglycan 5 (CSPG5) using dexamethasone (dexa)-treated human lens epithelial (HLE-B3) cells and the lens epithelium from the anterior capsule of SIC patients obtained during cataract surgery. CSPG5 expression increased in the lens epithelium of SIC patients. The downregulation of CSPG5 suppressed the dexa-induced epithelial-mesenchymal transition (EMT)-related protein expression and motility in HLE-B3 cells. The disruption of the transcription factors EZH2 and B-Myb downregulated CSPG5, dexa-induced fibronectin expression, and cell migration in HLE-B3 cells, reaffirming that CSPG5 expression regulates EMT in lens epithelial cells. Taken together, these results indicate that the steroid-induced effects on lens epithelial cells are mediated via alterations in CSPG5 expression. Therefore, our study emphasizes the potential of CSPG5 as a therapeutic target for the prevention and treatment of SIC.


Prevalence of objective eye manifestations in people working in office buildings with different prevalences of the sick building syndrome compared with the general population.
A cross-sectional clinical epidemiological study was carried out among 169 office workers in four Copenhagen town halls with different prevalences of the sick building syndrome. The results were compared with those in 112 subjects randomly selected from the general population. Biomicroscopic eye manifestations, such as premature break-up of the precorneal tear film, absence of foam at the inner eye canthus and epithelial damage of the bulbar conjunctiva, were investigated together with self-reported eye complaints. Although intercorrelated, the objective eye manifestations independently were statistically associated with self-reported eye complaints in office workers. The prevalence of the objective eye manifestations was significantly elevated in office workers compared with the general population and most pronounced for the buildings with a high prevalence of the sick building syndrome (P < 0.001). In the general population, subjects with a non-industrial occupation, including office workers, had a significantly higher prevalence of objective eye manifestations than those with an industrial occupation (P = 0.03), but the prevalence was still significantly lower than that among the office workers in buildings with a high prevalence of the sick building syndrome (P < 0.001). Since possible confounders were found not to explain the difference in prevalence of objective eye manifestations and complaints among the two populations, it is concluded that the office environment (buildings and/or type of office work) promotes these objective changes accompanied by self-reported complaints.


Diagnosis of pulmonary embolism.
Pulmonary embolism (PE) is often unrecognized or misdiagnosed because of the lack of specificity of clinical signs and symptoms. PE shares many of the clinical features of pneumonia and is therefore often unrecognized in elderly patients who present with low-grade fever, modest leukocytosis, and pulmonary infiltrates. Assessment of clinical risk factors increases the usefulness of diagnostic tests. The accuracy of diagnosis is improved if specific tests are performed. Ventilation-perfusion lung scans, noninvasive or contrast venography, and pulmonary angiography increase the likelihood of correct diagnosis. Since pulmonary angiography is a relatively low-risk procedure, it should be performed in most patients suspected of having PE who have nondiagnostic lung scans and negative lower extremity venous studies.


Treatment for glioblastoma multiforme: current guidelines and Canadian practice.
Our survey aimed to document variability in the practice patterns of Canadian radiation oncologists treating high-grade brain tumours. A 20-question survey was developed to address various aspects of treatment: Guidelines usedTypes of fusion protocols usedNumber of treatment phasesMargins for volume delineationDose constraintsThe survey was sent to Canadian radiation oncologists currently treating the central nervous system (cns) as one of their primary sites. We attained a 56% response rate from radiation oncologists across Canada treating cns sites. In their practice, 14% of respondents reported following guidelines from the European Organisation for Research and Treatment of Cancer; 32%, from the Radiation Therapy Oncology Group; and 56%, centre-specific guidelines. Single-phase treatment was reported by 60% of clinicians, and two-phase or multi-phase treatments, by 37%. For clinicians treating in single phase, margins from the gross treatment volume (gtv) to the planning treatment volume (ptv) included 0.5 cm (6%), 1 cm (6%), 1.5 cm (25%), 2.0 cm (56%), 2.5 cm (25%), and 3 cm (12.5%), with some respondents selecting more than one standard margin. For clinicians treating in multiple phases, margins from gtv to ptv in phase 2 included 1 cm (10%), 2.0 cm (40%), 2.5 cm (30%), and 3.0 cm (20%). Variability was also observed in dose constraints to critical structures. All respondents trimmed their margins to bony structures. Our survey shows considerable variation in the current treatment by Canadian radiation oncologists of high-grade brain tumours, especially with respect to guidelines followed, number of phases, and overall volume treated. Further studies are thus required to establish the evidence for optimal radiation volumes and phases, especially as brain tumour treatments evolve in the age of mr imaging and chemotherapy.


Lhermitte-Duclos and Cowden diseases: breast cancer as an unusual initial presentation of these overlapping conditions.
The authors report the case of a woman presenting with breast cancer who subsequently developed neck pain and ataxia. She had a family history of breast cancer and Cowden disease. A MRI study of the brain revealed a lesion in the cerebellum consistent with Lhermitte-Duclos disease (LDD) and a lesion consistent with a meningioma in the temporal lobe. This case emphasises the importance of awareness of the overlap between LDD and Cowden disease.


Antibacterial metabolites from the beetle-associated fungus Penicillium chrysogenum.
The antibacterial secondary metabolites of the fungus Penicillium chrysogenum associated with the beetle Aspongopus chinensis were investigated through chromatographic fractionation methods of ethyl acetate extracts of the fungal cultures. Five compounds were isolated, and their structures were determined as emodin, 4-(methoxymethyl)benzoic acid, isoochracinic acid, secalonic acid D, and dicerandrol A using mass spectroscopy and nuclear magnetic resonance spectroscopic analyses. Emodin exhibited strong antimicrobial activity, especially against Staphylococcus aureus even when growing on cooked pork, with a minimal inhibitory concentration (MIC) of 6.3 μg/mL. Dimeric tetrahydroxanthones, such as secalonic acid D and dicerandrol A, also exhibited potent activity, with MIC values ranging from 9.5 to 28.5 μg/mL. In summary, P. chrysogenum was isolated as a symbiotic fungus of the beetle A. chinensis for the first time and this strain could generate antibacterial secondary metabolites, which could potently inhibit gram-positive bacteria growth in vitro.


Beyond 'cure' and 'treatment success': quality of life of patients with multidrug-resistant tuberculosis.
Two drug-resistant tuberculosis (DR-TB) sites (MSF Clinic, Jupiter Hospital) in Mumbai, India. To assess health-related quality of life (HRQoL) and associated factors among DR-TB patients and explore their perspectives about HRQoL. We used a mixed-methods design: a quantitative cross-sectional questionnaire (the World Health Organization's Quality of Life Brief Questionnaire [WHOQoL-BREF]); and qualitative in-depth interviews for purposively selected patients. Assessments were conducted between April and November 2016. Ninety-five patients completed WHOQoL-BREF; 12 were interviewed. The psychological and physical health domains were the most affected (mean scores 56.2 ± standard deviation [SD] 18.3, and 56.5 ± SD 15.1, respectively; maximum 100). The social relations and environmental domains mean scores were respectively 68.6 (SD ±21.1) and 60.3 (SD ±15.9). Loss of jobs due to TB adversely affected the social relations and environmental domains. Qualitative analysis showed that support was the most important theme affecting quality of life. Other themes were physical factors (e.g., treatment adverse events), psychological factors (e.g., depression), social functioning (e.g., fear of stigmatisation) and environmental factors (e.g., health systems). HRQoL was lower among study participants, but not as low as previously reported among TB patients. Support was the main factor that positively affected HRQoL, although both disease and treatment were physically and socially challenging.


Efficient in planta production of amidated antimicrobial peptides that are active against drug-resistant ESKAPE pathogens.
Antimicrobial peptides (AMPs) are promising next-generation antibiotics that can be used to combat drug-resistant pathogens. However, the high cost involved in AMP synthesis and their short plasma half-life render their clinical translation a challenge. To address these shortcomings, we report efficient production of bioactive amidated AMPs by transient expression of glycine-extended AMPs in Nicotiana benthamiana line expressing the mammalian enzyme peptidylglycine α-amidating mono-oxygenase (PAM). Cationic AMPs accumulate to substantial levels in PAM transgenic plants compare to nontransgenic N. benthamiana. Moreover, AMPs purified from plants exhibit robust killing activity against six highly virulent and antibiotic resistant ESKAPE pathogens, prevent their biofilm formation, analogous to their synthetic counterparts and synergize with antibiotics. We also perform a base case techno-economic analysis of our platform, demonstrating the potential economic advantages and scalability for industrial use. Taken together, our experimental data and techno-economic analysis demonstrate the potential use of plant chassis for large-scale production of clinical-grade AMPs.


Vitamin D status in Greenland is influenced by diet and ethnicity: a population-based survey in an Arctic society in transition.
Vitamin D status as measured by plasma 25-hydroxyvitamin D (25(OH)D) is important to human health. Circumpolar people rely on dietary sources and societal changes in the Arctic are having profound dietary effects. The objective of the present study was to determine plasma 25(OH)D status and factors important to plasma 25(OH)D in populations in Greenland. Inuit and non-Inuit aged 50-69 years in the capital in West Greenland (latitude 64°15'N) and in a major town and remote settlements in East Greenland (latitude 65°35'N) were surveyed. Supplement use and lifestyle factors were determined by questionnaires. Inuit food scores were computed from a FFQ of seven traditional Inuit and seven imported food items. 25(OH)D₂ and 25(OH)D₃ levels were measured in the plasma. We invited 1 % of the population of Greenland, and 95 % participated. 25(OH)D₃ contributed 99·7 % of total plasma 25(OH)D. Non-Inuit had the lowest median plasma 25(OH)D of 41 (25th-75th percentile 23-53) nmol/l compared with 64 (25th-75th percentile 51-81) nmol/l in Inuit (P< 0·001). Plasma 25(OH)D was below 20 and 50 nmol/l in 13·8 and 60·1 % of participants, respectively, with Inuit food item scores below 40 % (P< 0·001), and in 0·2 and 25·0 % of participants, respectively, with higher scores (P< 0·001). The Inuit diet was an important determinant of plasma 25(OH)D (P< 0·001) and its effect was modified by ethnicity (P= 0·005). Seal (P= 0·005) and whale (P= 0·015) were major contributors to plasma 25(OH)D. In conclusion, a decrease in the intake of the traditional Inuit diet was associated with a decrease in plasma 25(OH)D levels, which may be influenced by ethnicity. The risk of plasma 25(OH)D deficiency in Arctic populations rises with the dietary transition of societies in Greenland. Vitamin D intake and plasma 25(OH)D status should be monitored.


Prescribing motivations and patients' characteristics related to the use of biologic drugs in adult-onset Still's disease: analysis of a multicentre "real-life" cohort.
A growing body of evidence suggests the usability of biologic disease-modifying anti-rheumatic drugs (bDMARDs) in treating adult-onset Still's disease (AOSD). In a multicentre "real-life" cohort, the physicians' prescribing motivations and patients' predictive characteristics of being treated with bDMARDs were assessed. Patients with AOSD, who were included in GIRRCS (Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale) cohort and treated with bDMARDs, were retrospectively assessed. Relevant data were collected by a review of clinical charts. Forty-four patients treated with bDMARDs were analysed, with slight male preponderance (52.3%) and a mean age of 39.3 ± 15.2 years. All patients were treated with corticosteroids (CCSs) (38.6% with low dosage) and 93.2% were treated with synthetic DMARDs (sDMARDs). Regarding the effectiveness of the first-line bDMARD, 65.6% of patients experienced a complete remission, defined as complete disappearance of both systemic and joint symptoms and normalisation of laboratory evidence of disease. The physicians' prescribing motivations for bDMARDs were inadequate response to CCSs and/or sDMARDs, CCS-sparing effect and occurrence of macrophage activation syndrome (MAS). Analysing patients' characteristics, chronic disease course (OR 3.09; 95%CI 1.22-7.80, p = 0.017), defined as disease with persistent symptoms, was predictive of being treated with bDMARDs, whereas age (OR 0.97, 95%CI 0.93-0.99, p = 0.048) was negatively associated, suggesting younger age as a further predictive factor. Patients with AOSD were treated with bDMARDs for inadequate response to CCSs and/or sDMARDs, CCS-sparing effect and MAS occurrence. Younger age and chronic disease course were patients' predictive characteristics of being treated with bDMARDs.


Electron, Hole, Singlet, and Triplet Energy Transfer in Photoexcited Porphyrin-Naphthalenediimide Dyads.
The excited-state dynamics of two molecular dyads, consisting of zinc (1) and free-base (2) porphyrin connected via a peptide linker to a core-substituted naphthalenediimide (NDI) have been investigated using optical spectroscopy. These dyads exhibit rich photophysics because of the large number of electronic excited states below 3 eV. In the case of 1 in apolar solvents, excitation energy transfer from the vibrationally hot singlet excited porphyrin to the NDI takes place with a 500 fs time constant. Electronic energy ends up in the NDI-localized triplet state, which decays to the ground state on a microsecond timescale. In polar solvents, ground-state recovery is faster by 5 orders of magnitude because of the occurrence of charge separation followed by recombination. On the other hand, excitation energy transfer in 2 takes place in the opposite direction, namely from the NDI to the porphyrin, which then undergoes intersystem crossing to the triplet state, followed by triplet energy transfer back to the NDI. Therefore, four distinct local electronic excited states are consecutively populated after excitation of the NDI unit of 2, with the energy shuttling between the two ends of the dyad.


Central pattern generator based on self-sustained oscillator coupled to a chain of oscillatory circuits.
We have proposed and studied both numerically and experimentally a multistable system based on a self-sustained Van der Pol oscillator coupled to passive oscillatory circuits. The number of passive oscillators determines the number of multistable oscillatory regimes coexisting in the proposed system. It is shown that our system can be used in robotics applications as a simple model for a central pattern generator (CPG). In this case, the amplitude and phase relations between the active and passive oscillators control a gait, which can be adjusted by changing the system control parameters. Variation of the active oscillator's natural frequency leads to hard switching between the regimes characterized by different phase shifts between the oscillators. In contrast, the external forcing can change the frequency and amplitudes of oscillations, preserving the phase shifts. Therefore, the frequency of the external signal can serve as a control parameter of the model regime and realize a feedback in the proposed CPG depending on the environmental conditions. In particular, it allows one to switch the regime and change the velocity of the robot's gate and tune the gait to the environment. We have also shown that the studied oscillatory regimes in the proposed system are robust and not affected by external noise or fluctuations of the system parameters. Moreover, using the proposed scheme, we simulated the type of bipedal locomotion, including walking and running.


Sertoli cell proliferation during prepubertal development in the rhesus monkey (Macaca mulatta) is maximal during infancy when gonadotropin secretion is robust.
Although a marked pubertal increase in Sertoli cell number is a hallmark of testicular development in the rhesus monkey, the ontogeny of this somatic cell type before puberty is less clear. To clarify this issue, groups (n = 4) of neonate (1-2 d old), infant (4-5 months old), juvenile (14-17 months old), and adult male rhesus monkeys were injected with 5-bromo-2'-deoxyuridine (BrdU) 2 h before castration. Tissue was fixed in Bouin's fluid, and the percentage of BrdU-labeled Sertoli cells at each developmental stage was calculated. In addition to the labeling index, Sertoli cell number per testis for the neonate and infant groups was enumerated using standard histomorphometry and compared with that previously reported by this laboratory for juvenile and adult rhesus monkeys. The number of Sertoli cells per testis in infants (156 +/- 49 x 10(6), mean +/- SD) was 4-fold greater than that in neonates (42 +/- 12 x 10(6)). The previously established value for this parameter in juvenile monkeys was 286 +/- 121 x 10(6). Incorporation of BrdU into nuclei of Sertoli cells indicated that these cells were mitotically active at all three stages of prepubertal development. The labeling index in the neonate and infant groups (1.33% in both cases), however, was significantly greater than that in juveniles (0.25%). From the foregoing results, we conclude that Sertoli cell proliferation during prepubertal development in the rhesus monkey occurs predominantly during infancy, when gonadotropin secretion is elevated, and to a lesser extent during the juvenile phase of development, when circulating gonadotropin concentrations are undetectable.


Stability of spray-dried tuna oil emulsions encapsulated with two-layered interfacial membranes.
omega-3 Fatty acids have numerous health benefits, but their addition to foods is limited by oxidative rancidity. Spray-drying tuna oil-in-water emulsion droplets with a coating of lecithin and chitosan multilayer system could produce emulsion droplet interfacial membranes that are cationic and thick, both factors that can help control lipid oxidation. Physicochemical and oxidative stability of the spray-dried emulsions were determined as a function of storage temperature and relative humidity (RH). The combination of ethylenediaminetetraacetic acid (EDTA) and mixed tocopherols was able to increase the oxidative stability of dried emulsions. Lipid oxidation was more rapid during storage at low relative humidity (11% and 33% compared to 52% RH). At high moisture, physical modifications in the sample were observed, including reduced dispersibility and formation of brown pigments. Sugar crystallization or Maillard products produced at the higher humidities may have inhibited oxidation. Overall, spray-dried tuna oil-in-water emulsions stabilized by lecithin-chitosan membranes were more oxidatively stable than bulk oils and thus have excellent potential as an omega-3 fatty acid ingredient for functional foods.


Population-based evaluation of retinal nerve fiber layer, retinal ganglion cell layer, and inner plexiform layer as a diagnostic tool for glaucoma.
We determined the glaucoma screening performance of regional optical coherence tomography (OCT) layer thickness measurements in the peripapillary and macular region, in a population-based setting. Subjects (n = 1224) in the Rotterdam Study underwent visual field testing (Humphrey Field Analyzer) and OCT of the macula and optic nerve head (Topcon 3-D OCT-1000). We determined the mean thicknesses of the retinal nerve fiber layer (RNFL), retinal ganglion cell layer (RGCL), and inner plexiform layer for regions-of-interest; thus, defining a series of OCT parameters, using the Iowa Reference Algorithms. Reference standard was the presence of glaucomatous visual field loss (GVFL); controls were subjects without GVFL, an intraocular pressure (IOP) of 21 mm Hg or less, and no positive family history for glaucoma. We calculated the area under the receiver operating characteristics curve (AUCs) and the sensitivity at 97.5% specificity for each parameter. After excluding 23 subjects with an IOP > 21 mm Hg and 73 subjects with a positive family history for glaucoma, there were 1087 controls and 41 glaucoma cases. Mean RGCL thickness in the inferior half of the macular region showed the highest AUC (0.85; 95% confidence interval [CI] 0.77-0.92) and sensitivity (53.7%; 95% CI, 38.7-68.0%). The mean thickness of the peripapillary RNFL had an AUC of 0.77 (95% CI, 0.69-0.85) and a sensitivity of 24.4% (95% CI, 13.7-39.5%). Macular RGCL loss is at least as common as peripapillary RNFL abnormalities in population-based glaucoma cases. Screening for glaucoma using OCT-derived regional thickness identifies approximately half of those cases of glaucoma as diagnosed by perimetry.


Energetics and hierarchical interactions of metal-phthalocyanines adsorbed on graphene/Ir(111).
The adsorption of metal-phthalocyanine (MPc) layers (M = Fe, Co, Cu) assembled on graphene/Ir(111) is studied by means of temperature-programmed X-ray photoemission spectroscopy (XPS) and near-edge X-ray absorption fine structure (NEXAFS). The balance between interaction forces among the organometallic molecules and the underlying graphene gives rise to flat-lying molecular layers, weakly interacting with the underlying graphene. Further MPc layers pile up face-on onto the first layer, up to a few nanometers thickness, as deduced by NEXAFS. The FePc, CoPc, and CuPc multilayers present comparable desorption temperatures, compatible with molecule-molecule interactions dominated by van der Waals forces between the π-conjugated macrocycles. The MPc single layers desorb from graphene/Ir at higher temperatures. The CuPc single layer desorbs at lower temperature than the FePc and CoPc single layers, suggesting a higher adsorption energy of the FePc and CoPc single layers on graphene/Ir with respect to CuPc, with increasing molecule-substrate interaction in the order E(CuPc) < E(FePc) ~ E(CoPc).


Facilitating cells in tolerance induction for kidney transplantation.
To describe the clinical outcomes and science behind a CD8/TCR facilitating cell-based hematopoietic stem cell transplant approach (termed FCRx) to induce tolerance to renal allografts without graft-versus-host disease (GVHD) and avoidance of long-term immunosuppressant drugs in living donor kidney transplant recipients. Successful solid organ transplantation currently requires the life-long use of medications to suppress the immune system to prevent transplant rejection. Drug-based immunosuppression significantly increases the risk of infection and cancer, as well as being very costly. Development of new therapies to minimize or eliminate entirely the need for antirejection drugs is of great interest to the transplant community. Therapeutic cell transfer for the control of the human immune system represents a compelling approach to reduce or eliminate the need for antirejection drugs. Establishment of durable hematopoietic macrochimerism under nonmyeloablative conditioning is achievable in mismatched recipients using facilitating cells and stem cells obtained from donor mobilized peripheral blood mononuclear cells. Persistently chimeric recipients developed donor-specific tolerance and were weaned off of immunosuppressive drugs over 12 months. They maintained stable renal function without development of acute or chronic GVHD.


[Intratympanic dexamethasone for refractory sudden deafness].
To observe the clinical efficacy of intratympanic dexamethasone (IT-DEX) for sudden deafness (SD) which were inefficient and contraindicant for systemic steroid. Thirty-four patients who were inefficient and contraindicant for systemic steroid were treated by IT-DEX (5 g/L) for 4 times within 12 days. The improvement of audits, tinnitus and stuffy were observed. And the results between the different influencing factor such as age, sex and course of disease were compared by statistical analysis. 1) For total patients, the effective power of audits, tinnitus and stuffy were 52.9%, 58.8% and 82.4% respectively. And the patients who treated within 2 weeks result in higher effective power of audits and tinnitus than those having been treated for more than 2 weeks, but there was no significant difference between these two groups (P >0.05). 2) For the patients who were inefficient and contraindicant for systemic steroid, the audible effective power of them were 44.4% and 62.5% respectively. IT-DEX can treat refractory SD effectively and safely. It is an effective treatment for the patients who were contraindicant for systemic steroid, and it could be used for salvage for the patients who were inefficient for systemic steroid.


Distances between 3' ends of ribosomal ribonucleic acids reassembled into Escherichia coli ribosomes.
The three ribonucleic acids (RNAs) from Escherichia coli ribosomes were isolated and then labeled at their 3' ends by oxidation with periodate followed by reaction with thiosemicarbazides of fluorescein or eosin. Ribosomal subunits reconstituted with the labeled RNAs were active for polyphenylalanine synthesis. The distances between the 3' ends of the RNAs in 70S ribosomes were estimated by nonradiative energy transfer from fluorescein to eosin. The percentage of energy transfer was calculated from the decrease in fluorescence lifetime of fluorescein in the quenched sample compared to the unquenched sample. Fluorescence lifetime was measured in real time by using a mode-locked laser for excitation and a high-speed electrostatic photomultiplier tube for detection of fluorescence. The distances between fluorophores attached to the 3' ends of 16S RNA and 5S RNA or 23S RNA were estimated to be about 55 and 71 A, respectively. The corresponding distance between the 5S RNA and 23S RNA was too large to be measured reliably with the available probes but was estimated to be greater than 65 A. Comparison of the quantum yields of the labeled RNAs free in solution and reconstituted into ribosomal subunits suggests that the 3' end of 16S RNA does not interact appreciably with other ribosomal components and may be in a relatively exposed position, whereas the 3' ends of the 5S RNA and 23S RNA may be buried in the 70S ribosomal subunit.


First line anti-tuberculosis induced hepatotoxicity: incidence and risk factors.
In our days, tuberculosis, whet ever its localization, became a curable disease. The cornerstone is a 6 month course of isoniazid, rifampicine and pyrazinamide. All of the three first line antituberculosis drugs may induce hepatic damage which may have negative consequences for treatment outcome. Several risk factors were associated with the development of antituberculosis- drug-induced hepatotoxicity (ATDH). A retrospective study was conducted from July 2014 to March 2015 regarding all therapeutic drug-monitoring requests sent to the Laboratory of Poison Control and Pharmacovigilance Centre of Morocco. 142 patients diagnosed with active tuberculosis were included in study. Plasma peak levels of isoniazid, rifampicin and pyrazinamide were analyzed in plasma samples after 2 to 3 hours of administration of anti-tuberculosis treatment. Logistic regression was used to identify the ATDH risk factors. The incidence of ATDH was found 24.6% (35 patients out of 142). Intergroup differences in the plasma levels were statistically significant for isoniazid (p=0.036). ATDH was found to be associated with combined form of anti-TB drugs (p=0.002, COR=13.1, AOR= 13.5) and plasma concentration of INH superior to 2mg/l (p=0.045, COR=1.3, AOR= 1.4).age, gender, alcohol intake and smoking status were not significantly associated with ATDH. The finding of 24.6% incidence of hepatotoxicity is extremely high. Many factors can be associated with the development of ATDH such as genetic factors, combined forms of treatment and plasma peak levels.


Sensory innervation of the ovotestis in the snail Helix aspersa.
Because oviposition in the land snail Helix aspersa is a metabolically expensive process coupled to a high fixed cost, one expects oviposition to occur only when the clutch size surpasses a minimum value at which the reproductive benefit exceeds the cost. We propose that neural innervation of the gonad allows H. aspersa to monitor oocyte production and ensure an adequate supply of gametes prior to ovulation. The ovotestis is innervated by a branch of the intestinal nerve in which the majority of axon fibres measure <0.2 microm in diameter. We found a strong positive correlation between the number of mature oocytes in the ovotestis and the frequency of spontaneous afferent spikes in the nerve branch. Tactile stimulation of the ovotestis resulted in a 20-fold increase in afferent spikes and an efferent reflex directed towards the ovotestis and the pericardium. Afferent activity also increased 10-fold after an experimentally induced increase in the volume of the ovotestis. These results suggest that the growing oocytes expand the walls of the acini and trigger action potentials in the mechanosensitive nerve terminals that lie within the acinar walls. We hypothesize that the resulting tonic signal is permissive for ovulation. In addition, a phasic sensory signal may occur during ovulation to trigger CNS motor output related to oviposition.


Protein transport machineries for precursor translocation across the inner mitochondrial membrane.
The mitochondrial inner membrane has a central function for the energy metabolism of the cell. The respiratory chain generates a proton gradient across the inner mitochondrial membrane, which is used to produce ATP by the F1Fo-ATPase. To maintain the electrochemical gradient, the inner membrane represents an efficient permeability barrier for small molecules. Nevertheless, metabolites as well as polypeptide chains need to be transported across the inner membrane while the electrochemical gradient is retained. While specialized metabolite carrier proteins mediate the transport of small molecules, dedicated protein translocation machineries in the inner mitochondrial membrane (so called TIM complexes) transport precursor proteins across the inner membrane. Here we describe the organization of the TIM complexes and discuss the current models as to how they mediate the posttranslational import of proteins across and into the inner mitochondrial membrane.


[Postoperative pyoderma gangrenosum and cancer of the breast. Apropos of a case].
Pyoderma gangrenosum (PG) consists of extensive necrotic ulceration with bluish and purplish red margins. This disease is often associated with ulcerative colitis, systemic, hematologic or rheumatic diseases. However post-surgical idiopathic PG can occur. One post-mastectomy case is reported. PG can first be suspected on clinical appearance and the lack of a specific etiology. PG is a diagnosis of exclusion that is made only after other possibilities have been ruled out. The treatment is surgical excision and systemic corticosteroids.


Effect of the pH-zero point of charge relationship on the interaction of ionic compounds and polyols with aluminum hydroxide gel.
The adsorption of magnesium nitrate, docusate sodium, and mannitol by chloride-containing aluminum hydroxide gel or aluminum hydroxycarbonate gel can be directly related to the surface charge characteristics of the aluminum hydroxide gel as determined by the pH-zero point of charge (ZPC) relationship. Magnesium cation is completely adsorbed under pH conditions where the gel has a negative surface charge, i.e. when the pH is above the ZPC. Docusate sodium is more strongly adsorbed when the pH-ZPC relationship causes the surface charge of aluminum when the pH-ZPC relationship causes the surface charge of aluminum hydroxycarbonate gel to be positive indicating adsorption of the docusate anion. However, adsorption also occurred when the pH was above the ZPC suggesting that adsorption of the hydrophobic portion of docusate anion by van der Waals forces also contributes to the overall adsorption mechanism. Mannitol is adsorbed under all pH conditions. However, greater adsorption occurs when the pH is above the ZPC. Maximum hydrogen bonding is believed to occur when mannitol acts as the proton donor and the negative aluminum hydroxycarbonate gel surface serves as the proton acceptor.


Reference structure tomography.
Reference structure tomography (RST) uses multidimensional modulations to encode mappings between radiating objects and measurements. RST may be used to image source-density distributions, estimate source parameters, or classify sources. The RST paradigm permits scan-free multidimensional imaging, data-efficient and computation-efficient source analysis, and direct abstraction of physical features. We introduce the basic concepts of RST and illustrate the use of RST for multidimensional imaging based on a geometric radiation model.


Knowing what to measure.
When the Barger Clinic in Eugene, Ore., implemented an electronic medical record, it found that true return on investment is measured not only in financial terms but also in terms of greater clinical value for patients. Within two years of implementing the system, the organization was able to significantly reduce the amount of paper filed in patient records, improve provider productivity and efficiency, reduce the potential for adverse drug events by automating prescriptions, and improve patient and provider satisfaction.


GLP1 and cancer: friend or foe?
The new incretin-based therapies, dipeptidyl peptidase-4 (DPP4) inhibitors and glucagon like peptide 1 (GLP1) receptor agonists are widely used for the treatment of type 2 diabetes because of their glucose-lowering capacity with low risk of hypoglycemia. As they are weight neutral or induce weight loss in this mostly overweight population, they are popular among clinicians and patients alike. Nonetheless, concerns have been raised about GLP1's trophic effects. While increased β cell mass observed in rodents sounds appealing for treatment of diabetes, there was also an increased incidence of medullary thyroid cancer (MTC) in some species. We reviewed literature available in the Medline database until March 2012. Safety signals have emerged for MTC and pancreatic carcinoma from adverse event databases in the United States and Europe. Considering the relatively short duration of these studies, it is more likely that premalignant lesions are stimulated in presence of GLP1, rather than new neoplasms induced. Moreover, interpreting results of animal studies is difficult because of species-specific differences in presence and density of GLP1 receptors. Furthermore, data are emerging suggesting beneficial effects of GLP1 on colon and breast cancer. In conclusion, presently, the benefits of using DPP4 inhibitors or GLP1 receptor agonists for treatment of type 2 diabetes outweigh the risks. Nonetheless, their safety profile should be monitored and their indications should be widened cautiously. At present they remain contra-indicated in patients with a personal or family history of MTC or multiple endocrine neoplasia type 2.


To what extent are specific psychotherapies for borderline personality disorders efficacious? A systematic review of published randomised controlled trials.
Over the past 20 years, several studies have established the efficacy of different forms of psychotherapy for borderline personality disorders (BPD). However, existing research has used a wide range of outcomes measures which makes it difficult to quantify data and to compare interventions. This review has been designed to analyse the evidence from randomized controlled trials (RCT) through a qualitative approach. A systematic review of published RCT on specific psychotherapies for BPD has been undertaken to find relevant literature from online PsycINFO, ISI Web of Knowledge and Medline databases. An analysis of variability in primary outcomes, dropout patients and those who do not enter treatment has been conducted to assess if a wide range of variation could show any potential bias. There is a substantial variation between the studies in primary outcomes, such as suicide attempts (7.4- 33.9%), and specially in dropout patients (6.7-47.4%) and those who do not enter treatment (17.6-63.6%). Globally, specific psychotherapy for BPD, at least in a 40% of patients who demand treatment, would not be efficacious. The overall efficacy of specific therapies for BPD is promising. However, the variability of results raise questions about potential bias. Future studies should investigate new therapeutic approaches to allow the management of more severe and refractory patients.


Driving Structure-Based Drug Discovery through Cosolvent Molecular Dynamics.
Identifying binding hotspots on protein surfaces is of prime interest in structure-based drug discovery, either to assess the tractability of pursuing a protein target or to drive improved potency of lead compounds. Computational approaches to detect such regions have traditionally relied on energy minimization of probe molecules onto static protein conformations in the absence of the natural aqueous environment. Advances in high performance computing now allow us to assess hotspots using molecular dynamics (MD) simulations. MD simulations integrate protein flexibility and the complicated role of water, thereby providing a more realistic assessment of the complex kinetics and thermodynamics at play. In this review, we describe the evolution of various cosolvent-based MD techniques and highlight a myriad of potential applications for such technologies in computational drug development.


Nanoparticle Biomolecular Corona-Based Enrichment of Plasma Glycoproteins for N-Glycan Profiling and Application in Biomarker Discovery.
Biomolecular corona formation has emerged as a recurring and important phenomenon in nanomedicine that has been investigated for potential applications in disease diagnosis. In this study, we have combined the "personalized protein corona" with the N-glycosylation profiling that has recently gained considerable interest in human plasma biomarker discovery as a powerful early warning diagnostic and patient stratification tool. We envisioned that the protein corona formation could be exploited as an enrichment step that is critically important in both proteomic and proteoglycomic workflows. By using silica nanoparticles, plasma fibrinogen was enriched to a level in which its proteomic and glycomic "fingerprints" could be traced with confidence. Despite being a more simplified glycan profile compared to full plasma, the corona glycan profile revealed a fibrinogen-derived glycan peak that was found to potentially distinguish lung cancer patients from controls in a pilot study.


Gas Chromatography-Mass Spectrometry Analysis of Constituent Oil from Lingzhi or Reishi Medicinal Mushroom, Ganoderma lucidum (Agaricomycetes), from Nigeria.
Gas chromatography-mass spectrometry analysis of constituent oil from dried Ganoderma lucidum was carried out. Fresh G. lucidum obtained from its natural environment was thoroughly washed with distilled water and air-dried for 2 weeks and the component oils were extracted and analyzed. Four predominant components identified were pentadecanoic acid, 14-methyl-ester (retention time [RT] = 19.752 minutes; percentage total = 25.489), 9,12-octadecadienoic acid (Z,Z)- (RT = 21.629 minutes and 21.663 minutes; percentage total = 25.054), n-hexadecanoic acid (RT = 20.153 minutes; percentage total = 24.275), and 9-octadecenoic acid (Z)-, methyl ester (RT = 21.297 minutes; percentage total = 13.027). The two minor oils identified were 9,12-octadecadienoic acid, methyl ester, (E,E)- and octadecanoic acid, methyl ester (RT = 21.246 minutes and 21.503 minutes; percentage total = 7.057 and 5.097, respectively).


DNA replication origin interference increases the spacing between initiation events in human cells.
Mammalian DNA replication origins localize to sites that range from base pairs to tens of kilobases. A regular distribution of initiations in individual cell cycles suggests that only a limited number of these numerous potential start sites are converted into activated origins. Origin interference can silence redundant origins; however, it is currently unknown whether interference participates in spacing functional human initiation events. By using a novel hybridization strategy, genomic Morse code, on single combed DNA molecules from primary keratinocytes, we report the initiation sites present on 1.5 Mb of human chromosome 14q11.2. We confirm that initiation zones are widespread in human cells, map to intergenic regions, and contain sequence motifs found at other mammalian initiation zones. Origins used per cell cycle are less abundant than the potential sites of initiation, and their limited use increases the spacing between initiation events. Between-zone interference decreases in proportion to the distance from the active origin, whereas within-zone interference is 100% efficient. These results identify a hierarchical organization of origin activity in human cells. Functional origins govern the probability that nearby origins will fire in the context of multiple potential start sites of DNA replication, and this is mediated by origin interference.


Gallbladder visualization in adrenal scanning: case report.
A patient suspected of having adrenal hyperfunction was scanned with 131I-iodocholesterol. Intense gallbladder activity persisted for several days and was eliminated by a fatty meal. The possibility of confusion with unilateral adrenal localization is discussed.


Highly Enantioselective Synthesis of Pharmaceuticals at Chiral-Encoded Metal Surfaces.
Invited for the cover of this issue are the groups of Chularat Wattanakit and Alexander Kuhn at the Vidyasirimedhi Institute of Science and Technology and the University of Bordeaux. The two tunnels in the image illustrate the entrance into a porous heterogeneous catalyst for the stereoselective transformation of adrenalone into the desired epinephrine stereoisomer. Read the full text of the article at 10.1002/chem.202302054.


[Chilaiditi's syndrome: a rare cause of abdominal pain in the differential diagnosis of the abdominal perforation. Case report].
A case of a 92-years-old patient with abdominal pain and constipation is presented. He reported a recent traumatic fracture of the upper limb. Traditional diagnostic work-up for patient with abdominal pain was started up. He was submitted to abdominal film that demonstrated air underneath the diaphragm suggestive for perforation. This hallmark is opposed to clinical condition of patient, so differential diagnosis for rare Chilaiditi's syndrome was considered, because this syndrome is frequent in old patient. Diagnostic work-up was completed with upper abdominal CT that excluded intestinal perforation and confirmed the diagnosis of Chilaiditi's syndrome showing hepatodiaphragmatic interposition of the dilated colon. Therefore it was decided in favour of medical therapy. In the our case, in spite of negative clinical examination, the uncertain radiological hallmark obliged us to exclude diagnosis of abdominal perforative syndrome that needs emergency operation. Although the Chilaiditi's syndrome is rare, it must be considerated in differential diagnosis of perforative abdominal syndrome, when there are doubts about the subdiaphragmatic air in abdominal film.


Personality factors in chronic gastric and duodenal ulcers: a controlled study.
The personality profiles, as evaluated with Cattell's 16 personality factors test (16 PF), were compared in 25 subjects with gastric ulcer, 25 with duodenal ulcer and 25 healthy controls. Subjects were matched for sex, age, education, geographical area of living and duration of illness (only for patients). The profiles of the gastric and duodenal ulcer patients were substantially similar and characterized by greater anxiety, dependence, introversion, low ego strength and greater adaptability as compared to the controls. Patients with gastric ulcer, however, seemed to be slightly more disturbed than those with duodenal ulcer.


The transcriptional regulator CzcR modulates antibiotic resistance and quorum sensing in Pseudomonas aeruginosa.
The opportunistic pathogen Pseudomonas aeruginosa responds to zinc, cadmium and cobalt by way of the CzcRS two-component system. In presence of these metals the regulatory protein CzcR induces the expression of the CzcCBA efflux pump, expelling and thereby inducing resistance to Zn, Cd and Co. Importantly, CzcR co-regulates carbapenem antibiotic resistance by repressing the expression of the OprD porin, the route of entry for these antibiotics. This unexpected co-regulation led us to address the role of CzcR in other cellular processes unrelated to the metal response. We found that CzcR affected the expression of numerous genes directly involved in the virulence of P. aeruginosa even in the absence of the inducible metals. Notably the full expression of quorum sensing 3-oxo-C12-HSL and C4-HSL autoinducer molecules is impaired in the absence of CzcR. In agreement with this, the virulence of the czcRS deletion mutant is affected in a C. elegans animal killing assay. Additionally, chromosome immunoprecipitation experiments allowed us to localize CzcR on the promoter of several regulated genes, suggesting a direct control of target genes such as oprD, phzA1 and lasI. All together our data identify CzcR as a novel regulator involved in the control of several key genes for P. aeruginosa virulence processes.


Development of a new resistant liposome coated with polysaccharide film for cosmetic application.
The aim of our study was to elaborate a resistant liposome that can be used in cosmetic formulations containing high amounts of surfactants and electrolytes. The stability of liposomes was increased via hydrophobized polysaccharide (Stearoyl Inulin) by anchoring its stearic acid tail into liposome bilayer. Coated and noncoated liposomes were prepared under the same conditions and their morphology, size, and resistance to surfactants and electrolytes were evaluated. We established that coated lipbsomes were more resistant to surfactants and electrolytes. It seems that a coating of polysaccharides prevents liposome destabilization in the presence of high amounts of surfactants and electrolytes. Moreover, the ability of coated liposomes to improve the skin delivery of active molecules was evaluated. Coated liposomes increased the efficacy of magnesium chloride by improving its skin availability.


Loss of split thickness skin grafts due to non-group A beta-haemolytic streptococci.
Over a 17-month period 77 patients requiring a split skin graft for a burn injury have suffered loss of previously well taken graft due to the growth of a beta-haemolytic streptococcus. Of these only 42 were streptococci of Lancefield group A (Streptococcus pyogenes); 16 were group B, 3 group C and 16 group G. Some strains of groups B, C and G produce cytopathic and spreading factors capable of destroying the new skin graft and regenerating epithelium. We suggest that the non-group A streptococci may be more pathogenic than previously recognised in this particular respect.


Dental fluorosis in the Blue Mountains and Hawkesbury, New South Wales, Australia: policy implications.
The aim of the present study was to determine whether the adjustment of the fluoride concentration to 1 ppm in the drinking water supplied to the Blue Mountains, New South Wales, Australia in 1993 was associated with fluorosis incidence. In 2003, children attending schools in the Blue Mountains and a control region (fluoridated in 1967) that had been randomly selected at baseline in 1992 were examined for dental fluorosis (maxillary central incisors only) using Dean's index. A fluoride history for each child was obtained by questionnaire. Associations between fluorosis and 58 potential explanatory variables were explored. The response rate was 63%. A total of 1138 children aged from 7 to 11 years with erupted permanent central incisors were examined for dental fluorosis. Fluorosis prevalence was the same in both regions. The Community Index of Dental Fluorosis values were slightly different, but were both above 0.6, indicative of public health concern. For the group as a whole, we concluded that: (a) fluorosis prevalence (0.39) in both regions was similar; and (b) the higher-than-expected prevalence and severity of fluorosis was due mainly to two factors: (a) the higher-than-optimal fluoride level in drinking water; and (b) swallowing of fluoride toothpaste in early childhood.


A Study of Global Quality Scale and Reliability Scores for Chest Pain: An Instagram-Post Analysis.
Utilized in the healthcare sector, social media offers numerous benefits. However, its drawbacks encompass the variable quality of unregulated and unsupervised content. Thus, we aimed to evaluate the information in content related to chest pain found across Instagram and analyze the quality and reliability of chest pain-related content via Instagram posts. Instagram posts with content related to chest pain were analyzed with the help of a structured questionnaire that included the Global Quality Scale (GQS) and DISCERN score (DS). To collect Instagram posts, several distinct hashtags were employed: #chestpain, #chestpains, #angina, #anginatreatment, #heartattack, #heartattacksurvivor, #heartattackprevention. A total of 262 posts were included, of which 29.7% of the total posts (n=78) contained information that describes the etiology of the disease. 27.8% of the total posts (n = 73) enclosed promotional content. Posts were found to be uploaded by doctors (18.7%), hospitals (15.6%), patients (17.9%), dieticians (11.1%), healthcare organizations (9.2%), and others (27.5%). Both Global Quality and DISCERN scores were statistically significant with a p-value of 0.001. The findings of this study revealed that most of the Instagram content on chest pain posted via physicians were highly reliable and had a better global quality score. Information regarding various causes, symptoms and preventive measures on Instagram can be considered as an acceptable source for patients to surf on. A major limitation is that only English content was analyzed. In the future, the use of higher quality posts produced by healthcare professionals could potentially contribute to enhancing patient education via Instagram.


Identification of QTL with large effect on seed weight in a selective population of soybean with genome-wide association and fixation index analyses.
Soybean seed weight is not only a yield component, but also a critical trait for various soybean food products such as sprouts, edamame, soy nuts, natto and miso. Linkage analysis and genome-wide association study (GWAS) are two complementary and powerful tools to connect phenotypic differences to the underlying contributing loci. Linkage analysis is based on progeny derived from two parents, given sufficient sample size and biological replication, it usually has high statistical power to map alleles with relatively small effect on phenotype, however, linkage analysis of the bi-parental population can't detect quantitative trait loci (QTL) that are fixed in the two parents. Because of the small seed weight difference between the two parents in most families of previous studies, these populations are not suitable to detect QTL that have considerable effects on seed weight. GWAS is based on unrelated individuals to detect alleles associated with the trait under investigation. The ability of GWAS to capture major seed weight QTL depends on the frequency of the accessions with small and large seed weight in the population being investigated. Our objective was to identify QTL that had a pronounced effect on seed weight using a selective population of soybean germplasm accessions and the approach of GWAS and fixation index analysis. We selected 166 accessions from the USDA Soybean Germplasm Collection with either large or small seed weight and could typically grow in the same location. The accessions were evaluated for seed weight in the field for two years and genotyped with the SoySNP50K BeadChip containing >42,000 SNPs. Of the 17 SNPs on six chromosomes that were significantly associated with seed weight in two years based on a GWAS of the selective population, eight on chromosome 4 or chromosome 17 had significant Fst values between the large and small seed weight sub-populations. The seed weight difference of the two alleles of these eight significant SNPs varied from 8.1 g to 11.7 g/100 seeds in two years. We also identified haplotypes in three haplotype blocks with significant effects on seed weight. These findings were validated in a panel with 3753 accessions from the USDA Soybean Germplasm Collection. This study highlighted the usefulness of selective genotyping populations coupled with GWAS and fixation index analysis for the identification of QTL with substantial effects on seed weight in soybean. This approach may help geneticists and breeders to more efficiently identify major QTL controlling other traits. The major regions and haplotypes we have identified that control seed weight differences in soybean will facilitate the identification of genes regulating this important trait.


Best practices in Web-based courses: generational differences across undergraduate and graduate nursing students.
The demand for online courses is greatly increasing across all levels of the curriculum in higher education. With this change in teaching and learning strategies comes the need for quality control to determine best practices in online learning communities. This study examines the differences in student perceptions of the use of technology, educational practices, and outcomes between undergraduate and graduate students enrolled in Web-based courses. The multisite study uses the benchmarking process and the Flashlight Program Evaluating Educational Uses of the Web in Nursing survey instrument to study best practices and examine generational differences between the two groups of students. The outcomes of the study establish benchmarks for quality improvement in online learning. The results support the educational model for online learning and postulates about generational differences for future study.


Ground-State Distortion in N-Acyl-tert-butyl-carbamates (Boc) and N-Acyl-tosylamides (Ts): Twisted Amides of Relevance to Amide N-C Cross-Coupling.
Amide N-C(O) bonds are generally unreactive in cross-coupling reactions employing low-valent transition metals due to nN → π*C═O resonance. Herein we demonstrate that N-acyl-tert-butyl-carbamates (Boc) and N-acyl-tosylamides (Ts), two classes of acyclic amides that have recently enabled the development of elusive amide bond N-C cross-coupling reactions with organometallic reagents, are intrinsically twisted around the N-C(O) axis. The data have important implications for the design of new amide cross-coupling reactions with the N-C(O) amide bond cleavage as a key step.


Does response facilitation to visuo-tactile stimuli around a remote-controlled hand avatar reflect peripersonal space or attentional bias?
People react faster to visuo-tactile stimuli presented near the body (i.e., in peripersonal space) than to tactile stimuli presented alone. This multi-sensory facilitation effect has been used as a measurement of peripersonal space. Previous research has reported that peripersonal space representations can be modulated by actively using hand-held tools or disconnected hand avatars. However, previous research has ignored the possibility that the attentional effect of active tool use could affect multi-sensory facilitation. In the present study, we delivered tactile stimuli to participants' left or right hand concurrently with visual stimuli presented near a virtual hand avatar operated by the movements of participants' left or right hand, which was shown far in a virtual environment and disconnected from the body. Participants reacted to tactile stimuli while ignoring the visual stimuli. The results indicated a multi-sensory facilitation effect when tactile stimuli were delivered to the hand used to operate the hand avatar. In contrast, the facilitation was not observed when the tactile stimuli were delivered to the hand that is not operating the hand avatar. These results suggest that the strength of the multi-sensory facilitation effect differed across conditions, even though the visual attention captured around the hand avatar was controlled across conditions. We concluded that the modulation of peripersonal space resulting from using tools or avatars is nearly independent of visual attention captured around tools or avatars.


Appendicovesicostomy as an Alternative Procedure for Patients with Complex Urethral Distraction Defect.
Surgical repair of post-traumatic complex urethral stricture poses a major challenge to urologists. Here, we report six patients with irreparable urethral strictures who were successfully treated by using the appendix as conduit for urinary diversion. Six patients who had underwent urinary diversion using an appendix during 2015 to 2019 were included in our study. All patients had a history of one or more failed attempts of urethral reconstruction in the past. Mean follow-up for patients was 29 months. Continency was defined as being completely dry for at least 3 hours. Mean age of patients was 40.1 years old (range: 20-70 years). Intermittent catheterization through the conduit was easily performed for every patient without any stomal stenosis. Mild stomal incontinence only occurred in one case which was resolved after a few months. All patients were continent during day and night. Based on the results of our study, Mitrofanoff's technique is a valuable procedure for managing patients with serious complicated urethral strictures who cannot be treated with common standard approaches.


Hallucinatory experiences in a community sample of Japanese children.
Hallucinatory experiences in children are often thought to indicate serious psychopathology. However, they have also been reported in normally developing children and in association with temporary psychological reactions to acute stress. The aim of this study was to investigate the prevalence of hallucinatory experiences in a nonclinical population of children and to examine the relationship between the modality and content of hallucinations and psychopathology. Seven hundred sixty-one Japanese children, 11 to 12 years old, completed a battery of four measures: (1) a questionnaire about the type of hallucinatory experience, (2) the Children's Depression Inventory, (3) the State-Trait Anxiety Inventory for Children, and (4) the Adolescent Dissociative Experiences Scale. Approximately 21% of the subjects had experienced hallucinations. Subjects who had experienced hallucinations, in particular, hallucinations characterized by combined modalities, closely self-related auditory content, or concrete visual content, had more significant psychopathology than did those who had never experienced hallucinations. Therapeutic intervention should be considered for children who experience hallucinations in association with depression, anxiety, or dissociation.


A far-upstream (-70 kb) enhancer mediates Sox9 auto-regulation in somatic tissues during development and adult regeneration.
SOX9 encodes a transcription factor that presides over the specification and differentiation of numerous progenitor and differentiated cell types, and although SOX9 haploinsufficiency and overexpression cause severe diseases in humans, including campomelic dysplasia, sex reversal and cancer, the mechanisms underlying SOX9 transcription remain largely unsolved. We identify here an evolutionarily conserved enhancer located 70-kb upstream of mouse Sox9 and call it SOM because it specifically activates a Sox9 promoter reporter in most Sox9-expressing somatic tissues in transgenic mice. Moreover, SOM-null fetuses and pups reduce Sox9 expression by 18-37% in the pancreas, lung, kidney, salivary gland, gut and liver. Weanlings exhibit half-size pancreatic islets and underproduce insulin and glucagon, and adults slowly recover from acute pancreatitis due to a 2-fold impairment in Sox9 upregulation. Molecular and genetic experiments reveal that Sox9 protein dimers bind to multiple recognition sites in the SOM sequence and are thereby both necessary and sufficient for enhancer activity. These findings thus uncover that Sox9 directly enhances its functions in somatic tissue development and adult regeneration through SOM-mediated positive auto-regulation. They provide thereby novel insights on molecular mechanisms controlling developmental and disease processes and suggest new strategies to improve disease treatments.


Manganese(I)-Catalyzed C-H Aminocarbonylation of Heteroarenes.
A versatile manganese(I) catalyst was employed in C-H aminocarbonylation reactions of heteroarenes with aryl as well as with alkyl isocyanates using a removable directing group approach. Detailed experimental mechanistic studies were suggestive of an organometallic C-H manganesation step, followed by a rate-determining migratory insertion.


Isolation of an Escherichia coli mutant deficient in glutathione synthesis.
A mutant of Escherichia coli that contains essentially no detectable glutathione has been isolated. The mutant contains a very low level of the enzyme glutathione synthetase and accumulates lambda-glutamyl cysteine at a concentration approximately equal to the level of glutathione found in its parent. No significant differences in growth were observed between the mutant and its parent. However, the activity of at least one enzyme was found to be affected by the absence of glutathione; the specific activity of the B1 subunit of ribonucleoside diphosphate reductase was greatly reduced. The possibility that the decreased B1 activity is due to a mutation in the structural gene coding for B1 or its regulatory gene could be eliminated. This suggests that one role of glutathione in the cell is to maintain at least this one protein in an active state. We propose the designation gshB for the gene coding for glutathione synthetase.


[Pure lower motoneurone syndrome in a series of six patients].
Lower motoneurone syndromes (SMNI) have been defined by their clinical pattern, anomalies in nerve conduction and the presence of antiglycolipid antibodies. The possible response to immunotherapy is another characteristic which makes these syndromes interesting. We studied the clinical and electrophysiological data, clinical progress and response to treatment of a series of six patients, with a pure lower motoneurone syndrome, with a follow up period of between 5 and 13 years. The clinical phenotype of our patients was: male, middle aged, the clinical topography showed only lower motoneurone involvement, predominantly or exclusively limited to the upper limbs, asymmetrical, distal rather than proximal, with a chronic course progressing initially but later becoming stable. From the electrophysiological point of view some of our cases were of SMNI. In these the conduction block was not permanent although there were signs of axon loss and multifocal demyelination. Response to treatment with intravenous immunoglobulins was seen in patients with anti GMI antibodies of IgM type and recent signs of clinical deterioration, whether there were conduction blocks present or not. In the cases which responded to this treatment there was tolerance and dependence following repeated transfusions of IV IgG.


Derived woodiness and annual habit evolved in African umbellifers as alternative solutions for coping with drought.
One of the major trends in angiosperm evolution was the shift from woody to herbaceous habit. However, reversals known as derived woodiness have also been reported in numerous, distantly related clades. Among theories evoked to explain the factors promoting the evolution of derived woodiness are moderate climate theory and cavitation theory. The first assumes that woody habit evolves in response to mild climate allowing for prolonged life span, which in turn leads to bigger and woodier bodies. The second sees woodiness as a result of natural selection for higher cavitation resistance in seasonally dry environments. Here, we compare climatic niches of woody and herbaceous, mostly southern African, umbellifers from the Lefebvrea clade to assess whether woody taxa in fact occur in markedly drier habitats. We also calibrate their phylogeny to estimate when derived woodiness evolved. Finally, we describe the wood anatomy of selected woody and herbaceous taxa to see if life forms are linked to any particular wood traits. The evolution of derived woodiness in chamaephytes and phanerophytes as well as the shifts to short-lived annual therophytes in the Lefebvrea clade took place at roughly the same time: in the Late Miocene during a trend of global climate aridification. Climatic niches of woody and herbaceous genera from the Cape Floristic Region overlap. There are only two genera with distinctly different climatic preferences: they are herbaceous and occur outside of the Cape Floristic Region. Therefore, studied herbs have an overall climatic niche wider than their woody cousins. Woody and herbaceous species do not differ in qualitative wood anatomy, which is more affected by stem architecture and, probably, reproductive strategy than by habit. Palaeodrought was likely a stimulus for the evolution of derived woodiness in the Lefebvrea clade, supporting the cavitation theory. The concurrent evolution of short-lived annuals withering before summer exemplifies an alternative solution to the same problem of drought-induced cavitation. Changes of the life form were most likely neither spurred nor precluded by any qualitative wood traits, which in turn are more affected by internode length and probably also reproductive strategy.


Long-Term Impairment of Sound Processing in the Auditory Midbrain by Daily Short-Term Exposure to Moderate Noise.
Most citizen people are exposed daily to environmental noise at moderate levels with a short duration. The aim of the present study was to determine the effects of daily short-term exposure to moderate noise on sound level processing in the auditory midbrain. Sound processing properties of auditory midbrain neurons were recorded in anesthetized mice exposed to moderate noise (80 dB SPL, 2 h/d for 6 weeks) and were compared with those from age-matched controls. Neurons in exposed mice had a higher minimum threshold and maximum response intensity, a longer first spike latency, and a higher slope and narrower dynamic range for rate level function. However, these observed changes were greater in neurons with the best frequency within the noise exposure frequency range compared with those outside the frequency range. These sound processing properties also remained abnormal after a 12-week period of recovery in a quiet laboratory environment after completion of noise exposure. In conclusion, even daily short-term exposure to moderate noise can cause long-term impairment of sound level processing in a frequency-specific manner in auditory midbrain neurons.


Radioimmunoelectrophoretic analysis of proteins binding 3, 3', 5'-triiodothyronine in human serum.
The binding of purified 131I-3, 3', 5'-triiodothyronine (reverse T3) (rT3) to normal human serum components was investigated by a radioimmunoelectrophoretic technique. When anti-whole human serum was used, five distinct arcs of radioactivity were observed. Evidence was obtained that five of these radioactive arcs were not artifacts, but were due to components binding rT3. From the radioimmunoelectrophoretic patterns with specific antisera, five of these components were identified as thyroxine binding prealbumin, albumin, thyroxine binding globulin (TBG) and alpha 1-and beta-lipoproteins. No radioactive arc of TBG was detected in serum from a patient with TBG deficiency.


OxyContin and neonatal abstinence syndrome.
Opioids are a commonly abused class of drugs. OxyContin abuse, a long-acting oxycodone derivative, has been increasingly identified as a potent narcotic resulting in drug dependence, overdose and even death. Use during pregnancy may result in withdrawal symptoms in the neonate. However, detection of the drug and its metabolites needs special methods in order to initiate appropriate therapy.


Maternal lipid profiles vs. fetal growth and cord blood hematopoietic cells: weak associations in healthy Korean newborn-mother pairs.
We aimed to define the maternal lipid profiles that are associated with fetal growth and cord blood (CB) hematopoietic cells in healthy Korean full-term newborns. A total of 608 fetal-maternal pairs were enrolled; mothers voluntarily donated CB with informed consent. We analyzed birth weight (BW) as a marker of fetal growth, and we examined total nucleated cells (TNCs) and CD34+ cell concentrations of CB as markers of hematopoietic progenitor cell (HPC) contents. We also analyzed maternal lipid levels and investigated their associations with BW, TNCs and CD34+ cells. Maternal triglycerides (TG) showed a significant positive association with BW and CD34+ cells, and low-density lipoprotein (LDL) showed a negative association with BW and CD34+ cells. Though not statistically significant, higher maternal TG showed a tendency toward higher levels of TNCs. Maternal TG was independently and positively correlated with BW, and maternal LDL was independently and negatively correlated with CD34+ cells, although the impacts were not as strong, as indicated by small beta coefficients (0.157 and -0.226, respectively). We were able to investigate the association of maternal lipid profiles with BW and CB HPCs in healthy Korean newborn-mother pairs in this study. Both BW and the HPC contents showed independent associations with maternal TG and LDL, although the effect of maternal lipid levels on fetal growth and HPCs was not strong in the normal healthy population. Because maternal lipid levels were assessed once in the healthy fetal-maternal pairs, we could not investigate those associations across pregnancy.


Total Ankle Replacement in a Military Jet Pilot.
INTRODUCTION: A total ankle replacement in a jet pilot after an open, high-energy foot and ankle fracture and dislocation with talar extrusion in a plane crash was carefully evaluated before considering fitness to fly.CASE REPORT: A 33-yr-old male test pilot of the Italian Air Force was involved in a plane crash and reported an open high-energy fracture/dislocation of the right ankle, with the expulsion of the right talus due to the impact, and other fractures. A titanium replica was inserted inside the ankle. However, the patient suffered from intolerable pain and developed arthritic changes in the cartilage of the tibial plafond. For these reasons, a decision was made to perform a custom-made total ankle replacement.DISCUSSION: The 2-yr follow-up after the last operation and the evaluation of the pilot's fitness to fly are reported in this case study. The pilot was assessed fit to fly, including high performance military aircrafts.Verde P, Guardigli S, Morgagni F, Roberts S, Monopoli D, Scala A. Total ankle replacement in a military jet pilot. Aerosp Med Hum Perform. 2020; 91(7):597-603.


Comparison of the non-absorbable polymer clips, knot-tying, and loop ligature appendiceal stump closure methods in laparoscopic appendectomy.
In laparoscopic appendectomy (LA), closure of the appendix stump is important. This method must be safe and easy-to-use as well as an economical one. We compared three methods of the appendix stump closure in terms of safety, easiness, and financial cost. Three-hundred and ten LA patients operated between January 2011 and December 2019 and appendix stump was closed using one of the three methods, namely, non-absorbable polymeric clips (Group 1, n = 126), knot-tying group (Group 2, n = 101), and laparoscopic loop ligature group (Group 3, n = 83) were retrospectively analyzed in terms of stump leakage, infection, operation, and hospital stay duration. There were 148 female and 162 male patients. The mean age was 33.57 ± 12.60 years. There was not any appendiceal stump leakage nor intra-abdominal infection in none of the groups. Local trocar site infection in 11 patients was medically treated. Surgical site infection and hospital stay period did not show statistically important difference among the groups. The operation duration in Group 1 was found to be shorter compared to the other groups. All three techniques are safe in LA. Non-absorbable polymer clips provide a shorter operation time. Extracorporeal knot-tying with knot-pusher provides the cheapest closure of the stump.


[Evaluation of intestinal pathogenicity of Yersinia spp. strains isolated from human feces].
Yersinia enterocolitica is a human pathogen which an acts on the intestine by basically enteroinvasive mechanism. Its virulence has been related with the presence of a plasmid of 40-50 MD which codes a series of properties. There are strains of Y. enterocolitica and of other species assimilated to the Y. enterocolitica group which lack the virulence plasmid. In these cases there is a problem in evaluating the pathogenic ability on the intestine of these bacterias when isolated in faeces. A study of 30 Yersinia spp. strains including growth in a magnesium oxalate medium, Reg-Congo and agar (CR-MOX), sculine hydrolisis (Sc), pyrazinamidase activity (Pyz) and salicine fermentation (Sal) was performed. In addition, the presence of virulence plasmid (VP) was determined. Twenty-two strains identified as Y. enterocolitica presented the virulence pattern (CR-MOX+, Pyz-, Sal/Sc-) and 21 were VP+. Seven strains isolated were CR-MOX-, Pyz+, Sal/Sc+ and VP- being typed as Y. fredericksenii (6) and Y. kristensenii (1). The remaining strain was CR-MOX- and VP- but Pyz, Sal/Sc were also negative, being identified as Y. enterocolitica. By the tests referred the authors were able to identify and evaluate the pathogenicity of Yersinia spp. isolated in faeces. These techniques may be used in the microbiology laboratory as a method which aids to evaluate the diagnosis of intestinal infections caused by Yersinia spp.