Targeting KRASp.G12C Mutation in Advanced Non-Small Cell Lung Cancer: a New Era Has Begun.
KRASp.G12C mutation occurs in 12% of newly diagnosed advanced NSCLC and has recently emerged as a positive predictive biomarker for the selection of advanced NSCLC patients who may respond to novel KRASp.G12C inhibitors. The recent discovery of a new binding pocket under the effector region of KRAS G12C oncoprotein has made direct pharmacological inhibition of the KRASp.G12 mutation possible, leading to the clinical development of a new series of direct selective inhibitors, with a potential major impact on patients' survival and quality of life. Promising efficacy and tolerability data emerging from the early phase CodeBreak trial have already supported the regulatory approval of sotorasib as first in class targeted treatment for the second-line treatment of KRASp.G12C-positive NSCLC population, following immunotherapy-based first-line therapies, while the randomized phase III CodeBreak 200 clinical study has recently confirmed a significant superiority of sotorasib over docetaxel in terms of progression-free survival and quality of life. However, KRAS mutant NSCLC is a high heterogeneous disease characterized by a high rate of co-mutations, most frequently involving P53, STK11, and KEAP1 genes, which significantly modulate the composition of the tumor microenvironment and consequently affect clinical responses to both immunotherapy and targeted inhibitors now available in clinical practice. Both pre-clinical and clinical translational series have recently revealed a wide spectrum of resistance mechanisms occurring under selective KRASG12C inhibitors, including both on-target and off-target molecular alterations as well as morphological switching, negatively affecting the antitumor activity of these drugs when used as single agent therapies. The understanding of such biological background along with the emergence of pre-clinical data provided a strong rational to investigate different combination strategies, including the inhibition of SHP2, SOS1, and KRAS G12C downstream effectors, as well as the addition of immunotherapy and/or chemotherapy to targeted therapy. The preliminary results of these trials have recently suggested a promising activity of SHP2 inhibitors in the front-line setting, while toxicity issues limited the concurrent administration of immune-checkpoint inhibitors and sotorasib. The identification of predictive genomic/immunological biomarkers will be crucial to understand how to optimally sequencing/combining different drugs and ultimately personalize treatment strategies under clinical investigation, to definitively increase the survival outcomes of KRASp.G12C mutant advanced NSCLC patients.


Expression of prostate-specific membrane antigen in renal cortical tumors.
Prostate-specific membrane antigen is a type II membrane glycoprotein that is expressed in benign and neoplastic prostatic tissue and has been recently shown to be also expressed in the neovasculature of various solid malignant tumors including renal cell carcinoma. Renal cell carcinoma is a heterogeneous group of tumors with distinct morphologic and genetic characteristics and clinical behaviors. We performed immunohistochemical studies on formalin-fixed, paraffin-embedded archival material from 75 nephrectomies, using antibodies 13D6 against prostate-specific membrane antigen and CD31 against endothelial cells. The study included 30 clear cell renal cell carcinomas, and 15 of each of papillary and chromophobe renal cell carcinoma and oncocytoma. The extent and intensity of staining were assessed semiquantitatively. In all cases, immunoreactivity was detected only in the tumor-associated neovasculature and not in tumor cells. Clear cell renal cell carcinoma showed the most diffuse staining pattern, where 24/30 cases or 80% had >50% reactive vessels, followed by chromophobe renal cell carcinoma (9/15; 60%) and oncocytoma (5/15, 33%). No diffuse staining was detected in any of the papillary renal cell carcinomas and only focal staining was detected in 11 cases (11/15; 73%). Staining intensity was the strongest in clear cell renal cell carcinoma (25/30; 83%) followed by chromophobe renal cell carcinoma (9/15; 60%), oncocytoma (8/15, 53%) and papillary renal cell carcinoma (5/15; 33%). In summary, prostate-specific membrane antigen is expressed in tumor-associated neovasculature of the majority of renal cortical tumors and is most diffusely and intensely expressed in clear cell renal cell carcinoma and least in papillary renal cell carcinoma. The differences in the expression of prostate-specific membrane antigen in renal cell carcinoma subtypes provide further evidence of the biological diversity of these tumors, and diagnostic and therapeutic applications of such expression can be expanded to include subtypes of renal cell carcinoma.


Effect of dexamethasone on binding activity of transcription factors nuclear factor-kappaB and activator protein-1 in SW982 human synovial sarcoma cells.
Previously, we showed that dexamethasone (DEX) inhibited the expression of inflammatory cytokines, matrix metalloproteinase-1, and cyclooxygenase-2 messenger ribonucleic acid in SW982 cells. In this study, the effect of DEX on the transcription factors nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) was examined in SW982 cells by electrophoretic mobility shift assay (EMSA). Both NF-kappaB and AP-1 deoxyribonucleic acid binding activities were detectable in SW982 cells by EMSA, and they were induced by interleukin-1beta treatment. DEX inhibited NF-kappaB binding activity at 10 microM as well as at 100 microM, although the inhibition was only partial. However, DEX had little effect on AP-1 activity. These results suggest that DEX reduces the expression of inflammatory cytokines and other proteins in SW982 cells by inhibiting NF-kappaB.


Muscleblind participates in RNA toxicity of expanded CAG and CUG repeats in Caenorhabditis elegans.
We have utilized Caenorhabditis elegans as a model to investigate the toxicity and underlying mechanism of untranslated CAG repeats in comparison to CUG repeats. Our results indicate that CAG repeats can be toxic at the RNA level in a length-dependent manner, similar to that of CUG repeats. Both CAG and CUG repeats of toxic length form nuclear foci and co-localize with C. elegans muscleblind (CeMBL), implying that CeMBL may play a role in repeat RNA toxicity. Consistently, the phenotypes of worms expressing toxic CAG and CUG repeats, including shortened life span and reduced motility rate, were partially reversed by CeMbl over-expression. These results provide the first experimental evidence to show that the RNA toxicity induced by expanded CAG and CUG repeats can be mediated, at least in part, through the functional alteration of muscleblind in worms.


The cremasteric reflex: a useful but imperfect sign in testicular torsion.
The cremaster reflex has been reported to be absent in 100% of cases of testicular torsion, making it a useful sign in this difficult diagnosis. The authors report a case of surgically confirmed testicular torsion in which the cremasteric reflex clearly was present at presentation. The background of this sign and its utility in the evaluation of the acute scrotum are discussed.


Percutaneous initiation of cardiopulmonary bypass.
Improved technology has allowed us to develop support pumps that can be applied rapidly and safely. A system utilizing thin-walled (4 mm inner diameter) percutaneously inserted sheaths has been designed for rapid bedside arterial and central venous cannulation to establish femoral arterial and venous cardiopulmonary bypass. The system utilizes two 30-cm-long large-bore, thin-walled (end and side holes) venous cannulas and a single 15-cm-long (end hole) arterial reperfusion cannula, which is connected to a pediatric oxygenator and a vortex pump head. Five patients with refractory cardiac arrest who could not be resuscitated by conventional means were revived with this system. Application time was approximately five minutes. This system appears to be an easily applied and reliable short-term mechanical support device.


Excitatory amino acids and drugs of abuse: a role for N-methyl-D-aspartate receptors in drug tolerance, sensitization and physical dependence.
N-methyl-D-aspartate (NMDA) receptors have been implicated in several types of neural and behavioral plasticity ranging from development to learning. The present paper reviews evidence suggesting that these receptors might also be involved in the neural and behavioral changes resulting from chronic administration of drugs of abuse. NMDA receptor antagonists have been found to interfere with tolerance, sensitization, physical dependence and conditioning to a variety of self-administered drugs, including psychomotor stimulants, opiates, ethanol and nicotine. The results indicate a broad role for NMDA receptors in drug-induced neural and behavioral plasticity, including changes in the brain and behavior that may lead to compulsive drug use, and suggest that drugs acting at the NMDA receptor complex may be clinically useful.


The BDNF-TrkB signaling pathway in the rostral anterior cingulate cortex is involved in the development of pain aversion in rats with bone cancer via NR2B and ERK-CREB signaling.
Patients with bone cancer pain (BCP) are more prone to aversion. which not only causes mental distress but also aggravates BCP. However, the mechanism of BCP-related aversion is still unclear. Previous studies have demonstrated that the brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling pathway of the rostral anterior cingulate cortex (rACC) plays an important role in the regulation of emotions related to chronic pain, such as neuropathic pain or inflammatory pain; however, few studies have investigated the role of this pathway in cancer pain. This study explored the role of BDNF in cancer pain-related aversion in the rACC and to determine whether N-methyl D-aspartate receptor subtype 2B (NR2B) and extracellular signal-regulated kinase (ERK)-cAMP response element-binding (CREB) signaling are involved in cancer pain-related aversion. A Sprague-Dawley rat model of BCP (one of the classic BCP models) was established, and the changes in pain aversion were detected by mechanical stimulation-induced conditioned place avoidance. Our findings confirmed that rats with BCP exhibited intense pain aversion accompanied by the up-regulated BDNF expression in the rACC. Additionally, the pain aversion of BCP rats was reduced while blocking the BDNF-TrkB. Furthermore, the expression of NR2B and phosphorylated ERK (pERK)/phosphorylated CREB (pCREB) were up-regulated with the development of pain aversion, whereas the use of NR2B blocker Ro25-6981, or ERK inhibitor U0126 could reduce the pain aversion. The expression of NR2B and pERK/pCREB were up-regulated after exogenous BDNF was injected into the rACC, whereas the expression levels of NR2B and pERK/pCREB were down-regulated after blocking the BDNF-TrkB signaling. In conclusion, the BDNF-TrkB signaling in the rACC mediates the generation of aversion in rats with BCP, which requires the involvement of NR2B and the ERK-CREB signaling pathway.


Global Trends in Ocean Noise.
This ongoing work provides information about sound level trends from three ocean regions to compare with those of the North Pacific to determine whether increasing sound levels are a global phenomenon. Here the term soundscape is used to describe a measured physical property that can be selectively decomposed by frequency and sound level is used to provide insight relating to conditions ranging from the quietest conditions (sound floor) to the most extreme acoustic events. Acoustic time series from the Indian, South Atlantic, and Equatorial Pacific Oceans were used to quantify the rate and direction of low-frequency change over the past decade.


Investigating dormant-season application of pheromone in citrus to control overwintering and spring populations of Phyllocnistis citrella (Lepidoptera: Gracillariidae).
The leafminer, Phyllocnistis citrella Stainton, reproduces on leaf flush during winter. Deployment of pheromone during winter could suppress moth populations in spring and summer more than a spring application alone. We tested the primary pheromone component of P. citrella, (Z,Z,E)-7,11,13-hexadecatrienal, released gradually over several months from elastomeric dispensers in a citrus grove in 6.4 ha main plots in winter and/or 3.2 ha subplots in spring (834 mg triene ha(-1) ) and evaluated moth catch and leaf mining. After winter treatment, dispensers provided >85% disruption of male moth catch in traps for 37 weeks, and after spring treatment they provided >92% disruption for 26 weeks, but there was only a 12% reduction in leaf infestation in spring. Two applications were no better than only a single application in spring. Disruption of moth catch was weaker in treated plots where traps were placed high (3.1 m) rather than low (1.6 m) in the tree canopy. Dispensers provided effective and persistent disruption of male catch in pheromone-baited monitoring traps but were minimally effective in reducing leaf infestation by P. citrella. Winter application of pheromone did not reduce leaf mining in spring compared with spring application alone. Tops of trees may have provided a refuge for mating. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.


Estetrol: a unique steroid in human pregnancy.
Estetrol (E(4)) is an estrogenic steroid molecule synthesized exclusively by the fetal liver during human pregnancy and reaching the maternal circulation through the placenta. Its function is presently unknown. After its discovery in the mid-1960s, E(4) research revealed rather unique properties of this steroid and spawned a large body of state-of-the art publications. Nevertheless, 20 years later experimental work was virtually abandoned. In recent years based on new data, E(4) has experienced a vita nova, a revival of preclinical and clinical research activities with the goal to elucidate its physiological function and explore its potential for therapeutic use in humans. This review is intended to offer an historical account of the discovery of E(4) and the preclinical studies conducted during the heyday of E(4) research that ended in the mid-1980s.


Isolation and characterization of a bacteriophage specific for Sphaerotilus natans which contain an unusual base in its deoxyribonucleic acid.
A bacteriophage was isolated specific for Sphaerotilus natans, an organism for which bacteriophages have not been previously described. This phage (designated SN1) was found to infect both the single-cell (S-type) and filamentous (R-type) forms of the host, although the sheath appeared to provide R-type cells with a degree of physical protection from infection. SN1 had a hexagonal head and a long flexible tail resembling most closely the phages in Bradley's group B. The nucleic acid was found to be deoxyribonucleic acid and contained an unusual base which substituted for 35% of the guanine. Deoxyribonucleic acid base composition was 56% cytosine plus guanine.


Ten years' experience with the Björk-Shiley tilting disc valve.
More than 10 years of clinical experience with 1,800 consecutive valve replacements with the Björk-Shiley tilting disc valve were focused on improving its durability, flow dynamics, thromboresistance, and in vivo functional control. Although the original Delrin disc functions excellently after 10 years in the human circulation, the durability of the prosthetic valve was further prolonged by the introduction of pyrolytic carbon as disc material. The opening mechanism was also reinforced by integrating the bearing struts with the valve ring. No other presently available heart valve prosthesis shows such a low resistance to flow for a given tissue diameter. The disc was equipped with a ring-shaped radiopaque marker that permitted noninvasive functional control. The 5 year survival rates were 82% after aortic, 66% after mitral, and 66% after mitral and aortic valve replacements, including the operative mortality rates. The incidence of systemic emboli was 0.7% per year after aortic, 4.2% per year after mitral, and 2.2% per year after mitral and aortic valve replacements with anticoagulation treatment. The incidence of obstruction by thrombosis was 0.3% per year for aortic, 1.3% per year for mitral, and 2.3% per year tricuspid prostheses. The new convex-concave model decreases the stagnation zone behind the disc, decreases emboli from 4.2% to 1.2% per year after mitral valve replacement, and has a lower gradient.


Magnetic-graphene based molecularly imprinted polymer nanocomposite for the recognition of bovine hemoglobin.
The protein imprinted technique combining surface imprinting and nanomaterials has been an attractive strategy for recognition and rapid separation of proteins. In this work, magnetic-graphene (MG) was chosen as the supporting substrate for the magnetic nanomaterials, which served to absorb the targeting imprinting molecules, bovine hemoglobin (BHb). Acryl amide (AAm) with a high affinity to BHb and N,N'- methylenebisacrylamide (MBA) were selected as the functional monomer and cross-linking agent, respectively. After in-situ polymerization, the proposed magnetic-graphene based molecularly imprinted polymer (MG-MIP) was obtained with a further extraction step of imprinted BHb. Fourier transform infrared (FT-IR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), raman spectroscopy(RS), X-ray diffraction (XRD) and vibrating sample magnetometer (VSM) were employed to characterize the resulted MG-MIP. The maximum adsorption capability (Qmax) was determined by Langmuir Isotherm Plots and was 186.73 mg/g for imprinted nanomaterials (MIP) with an imprinting factor of 1.96. The selectivity of MG-MIP was investigated by using several proteins that are different in molecular mass and isoelectric points as the reference. The results showed that the shape memory effect of imprinted cavities, the size of proteins and the charge effect of proteins were the major factors for the selective recognition. The proposed method was also employed to specifically capture BHb from a binary protein mixture.


Core stability exercise in chronic low back pain.
In conclusion, core stability exercise is an evolving process, and refinement of the clinical rehabilitation strategies is ongoing. Two major foci are addressed in contemporary core stability programs: motor control and muscle capacity. Both of these factors have considerable foundation in the literature and can be seen as a progression of exercise rather than conflicting approaches. Importantly, the clinical efficacy of these approaches is being realized in clinical trials. Further work is required, however, to refine and validate the approach, particularly with reference to contemporary understanding of the neurobiology of chronic pain.


The prediction of relapse after drug treatment of Graves' disease by assay of long acting thyroid stimulator-protector (LATS-P).
In a study of fifty-two patients with Graves' disease followed for 1 year after stopping antithyroid drugs, a strong relationship has been found between serum LATS-P and relapse. In those with serum LATS-P activity on stopping therapy, twenty-one (88%) out of twenty-four relapsed. In those with no LATS-P activity on stopping antithyroid drugs only eight (29%) out of twenty-eight relapsed and in five LATS-P was detectable at relapse. The overall prevalence of positive assays for LATS-P at relapse (90%) was similar to that seen in untreated Graves' disease.


Haemodynamic and renal effects of felodipine in young and elderly subjects.
To study the influence of age on renal and haemodynamic effects of the calcium antagonist felodipine. Eight young (mean age 27 years) and eight elderly (mean age 75 years) healthy normotensive subjects were given felodipine intravenously for 120 min aiming at close to therapeutic plasma level concentration. Renal blood flow (RBF) and renal vascular resistance (RVR) was estimated from para-aminohippuric acid (PAH) clearance 51CrEDTA clearance was used to measure glomerular filtration rate (GFR) and used in the calculations of fractional excretion (FE) of electrolytes. Impedance cardiography was performed to assess stroke volume and for the calculation of cardiac output and ejection fraction. At the end of felodipine infusion, the concentration of felodipine was on average 10.0 nmol x l(-1) in young and 12.0 nmol x l(-1) in elderly subjects (NS). During felodipine infusion blood pressure (BP) decreased from 138/76 to 120/68 in elderly subjects. The BP in young subjects was 126/74 at basal and 125/70 after infusion of felodipine. The systemic and renal vascular resistance decreased to a similar extent in young and elderly subjects after felodipine infusion. Felodipine caused a decrease in systemic vascular resistance from 25.6 to 23.3 in elderly and from 23.8 to 21.8 in the young subjects. Mean values for RVR at baseline and during infusion of felodipine were significantly higher in the elderly (10.1-15.1) than in the young subjects (5.4-6.7). Felodipine reduced RVR by 10% in the young and by 12% in the elderly at the end of infusion. The young subjects had 31% higher GFR than the elderly subjects at the start of infusion. Felodipine infusion did not affect GFR. There were no effects on stroke volume and ejection fraction. An initial natriuretic effect was found after infusion of felodipine in the young subjects. The fractional excretion of all electrolytes tended to increase after both felodipine and placebo, more in the elderly than in the young subjects. The effects of felodipine on central and renal haemodynamics previously observed in young and middle-aged subjects also seem to exist in the elderly. Volume expansion seems to increase the excretion of electrolytes more in elderly than in young people, and therefore the effect of felodipine on natriuresis is more evident in young subjects.


Replication of a Prospective Randomized Controlled Trial of Resource Facilitation to Improve Return to Work and School After Brain Injury.
To determine the extent to which previous findings on the effectiveness of resource facilitation to impact return to work and school could be replicated. Randomized controlled trial. Outpatient rehabilitation clinic. Outpatients with acquired brain injury (N=44). Fifteen months of resource facilitation services. A revised version of the Vocational Independence Scale and the Mayo-Portland Adaptability Inventory-4 Participation Index. Participants randomized to the resource facilitation group demonstrated a significant advantage in terms of rate and timing of return to productive community-based work relative to control participants. When examining only return to competitive work (and not return to school), 69% of the resource facilitation group was able to return compared with 50% of the control participants. Analyses of measures of participation in household and community activities revealed that both groups improved significantly over the 15-month study period, but no significant advantage for either group was demonstrated. This study replicates the positive impact of resource facilitation in improving productive community-based activity, including competitive employment and volunteering in the community.


Electronic health records and electronic prescribing: promise and pitfalls.
Health information technology (health IT), especially technology related to electronic health records (EHRs) and electronic prescription (e-prescribing) systems, is believed to be the cornerstone for improvements in quality of care, patient safety, and efficiencies, all leading to cost benefits. With increasing requirements for quality reporting and with new pay-for-performance programs being initiated by insurers, many physicians are asking if it is time to invest in health IT. However, as those who have already made this decision have found, adopting EHRs and e-prescribing systems is not an easy task: Our colleagues resist their use, they are costly, the case for a return on investment for an ambulatory practice has not been well established, incentives to use are misaligned, implementations may be difficult, and often such systems disrupt or inhibit workflow.


[Advances in Double Mutations of EGFR and ALK Gene in Non-small Cell Lung Cancer].
Molecular target therapy is one of the most popular field of non-small cell lung cancer (NSCLC) treatmnet. Epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearragement are the most important two oncogenic drivers in NSCLC, early studies suggested that EGFR mutations and ALK rearrangements are mutually exclusive, but isolated cases or small sample research with concomitant EGFR and ALK alterations have been constantly reported. The co-occurrence of EGFR mutations and anaplastic lymphoma kinase (ALK) rearrangements constitutes a rare molecular, the frequency of EGFR/ALK co-alterations was about 1%, however, little has been known about clinicopathologic feature and treatment. This review summarized published case report, EGFR and ALK alterations are common in female, Asian origin, never smoker, IV stage, and denocarcinomas. First-line treatment can choose EGFR or ALK tyrosine kinase inhibitors (TKIs). However, studies about the origin and resistance mechanism in EGFR/ALK co-alterations are little, require more experimental and clinical research. .


Selection of micronutrients used along with DMSA in the treatment of moderately lead intoxicated mice.
The objective of this study was to explore the optimum combination of micronutrients used with 2,3-dimercaptosuccinic acid (DMSA) in the treatment of moderately lead-intoxicated mice. Experiment was carried out based on the orthogonal design L(8)(2(7)) setting six factors with two different levels of each, and eight groups of mice were needed. Mice were exposed to lead by drinking water contaminated with 0.1% lead acetate for four consecutive weeks, and then supplemented by gavage with different combinations of micronutrients with and without DMSA as designed in the orthogonal table. Lead levels in blood, liver, kidney, brain and bone and activities of blood delta-aminolevulinic acid dehydratase (ALAD) were analyzed after cessation of supplementation. The results suggested that DMSA was the only factor which could decrease significantly lead levels in blood, liver, kidney and bone; calcium and ascorbic acid were the notable factors decreasing lead levels in blood, liver, kidney, bone and brain; zinc and calcium were the notable factors reversing the lead-inhibited activities of blood ALAD; taurine was the notable factor decreasing lead levels in kidney and brain; and thiamine was the notable factor decreasing lead levels in brain. The lowest lead level in blood, liver, kidney and bone was shown in the mice supplemented with combination of calcium and ascorbic acid along with DMSA. In conclusion, the optimum combination of micronutrients used with DMSA suggested in present study was calcium and ascorbic acid, which seemed to potentiate the chelating efficacy of DMSA in the treatment of moderately lead intoxicated mice.


The role of leptin in progression of non-alcoholic fatty liver disease.
Since non-alchoholic steatohepatitis (NASH) is often accompanied with metabolic syndrome comprising obesity, type-2 diabetes and hypertension, it is hypothesized that adipocytokines, insulin resistance and autonomic nervous system play crucial roles in disease progression of NASH. On the other hand, hepatic stellate cells (HSCs) have been shown to produce leptin when they get activated during hepatic fibrogenesis. Therefore, we investigated the role of leptin in fibrogenesis in the liver. Xenobiotics-induced liver fibrosis was extremely diminished in ob/ob mice and Zucker (fa/fa) rats, an inborn leptin- and leptin receptor (Ob-R)-deficient animal, respectively. Further, leptin increased transforming growth factor (TGF)-beta mRNA in isolated sinusoidal endothelial cells and Kupffer cells, suggesting that leptin promotes hepatic fibrogenesis through up-regulation of TGF-beta in the liver. Moreover, leptin augmented PDGF-dependent proliferation of HSCs by enhancing downstream intracellular signaling pathways via mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3 kinase (PI3K)/Akt. Taken together, it is postulated that leptin acts as a profibrogenic cytokine in sinusoidal microenvironment. These findings indicate that leptin is one of the key regulators for inflammation and progression of fibrosis in various chronic liver diseases including NASH.


Homograft failure in mycotic aortic aneurysm caused by Streptococcus pneumoniae.
Treatment of a rare Streptococcus pneumoniae mycotic aneurysm by homograft replacement failed in a 59-year-old patient because of persistent lobar pneumonia. Despite reoperation with replacement of the infected homograft by a fresh one, he finally died of septicemia. This case illustrates that homograft tissue may be infected per continuum and that extensive debridement of periaortic tissue-including major lung resection-and the use of muscle flaps may be necessary in certain circumstances.


Brain responses to erotic and other emotional stimuli in breast cancer survivors with and without distress about low sexual desire: a preliminary fMRI study.
Many breast cancer survivors report a loss of sexual desire and arousability, consonant with the new DSM-V category of female sexual interest/arousal disorder. The cause of decreased sexual desire and pleasure after treatment for cancer is unknown. One possibility is that cancer, or treatment for cancer, damages brain circuits that are involved in reward-seeking. To test the hypothesis that brain reward systems are involved in decreased sexual desire in breast cancer survivors, we used functional magnetic resonance imaging (fMRI) to compare brain responses to erotica and other emotional stimuli in two groups of women previously treated for breast cancer with chemotherapy: those who were distressed about a perceived loss of sexual desire and those who may have had low desire, but were not distressed about it. Women distressed about their desire had reduced brain responses to erotica in the anterior cingulate and dorsolateral prefrontal cortex, which are part of the brain reward system. This study is the first to demonstrate, in cancer survivors, that problems with sexual desire/arousability are associated with blunted brain responses to erotica in reward systems. Future research is necessary to determine whether brain responses differ as a result of chemotherapy, hormone therapy, and menopausal status. This may contribute to the development of new, evidence-based interventions for one of the most prevalent and enduring side effects of cancer treatment.


Stimulation and inhibition of pancreatic phospholipase A2 by local anesthetics as a result of their interaction with the substrate.
1. At low concentrations the local anesthetic dibucaine stimulates hydrolysis by pancreatic phospholipase A2 of phospholipids extracted from rat liver mitochondria or microsomes, whereas at higher concentrations it inhibits. The action of this enzyme towards membrane-bound substrates is barely influenced by low, but inhibited by high concentrations of dibucaine. 2. Butacaine, which is a weaker anesthetic, stimulates hydrolysis of extracted phospholipids and inhibits that of membrane-bound substrates, both actions being concentration dependent. 3. The inhibitory potency of dibucaine is several times higher in NaCl than in sucrose solutions and strongly increases with decreasing pH. Neither one of these two effects is the result of a change in binding efficiency of the anesthetic to the substrates. 4. Extracted total membrane lipids bind considerably less anesthetic than an equivalent amount of native membrane. Liver phosphatidylethanolamine is more effective in binding of dibucaine than liver phosphatidylcholine. 5. Binding of dibucaine to the phospholipase, as studied by equilibrium dialysis is at the lower level of detectability. According to the same method dibucaine is unable to displace 45Ca2+ bound to the enzyme. 6. These results are interpreted as to support the view that local anesthetics interfere with pancreatic phospholipase activity by means of interaction with the substrate rather than with the enzyme.


Evidence that puriified liver microsomal cytochrome P-450 is a one-electron acceptor.
Two forms of highly purified liver microsomal cytochrome P-450, P-450LM2, and P-450LM4, have been titrated with standardized solutions of sodium dithionite under anaerobic conditions. Only 1 electron was consumed per hemin molecule, and reoxidation of the reduced heme is accompanied by the transfer of 1 electron to oxidizing agents such as cytochrome c, cytochrome b5, or potassium ferricyanide. The present results are in disagreement with earlier dithionite titrations and reoxidation experiments which indicate that liver microsomal cytochrome P-450 is a 2-electron acceptor, but are in accord with previous potentimetric titrations and product yield data which indicate that this hemeprotein is a 1-electron acceptor. The cause for the discrepancy between the present and previous results is not fully understood.


Cholesteryl sulphate and phosphate in the solid state and in aqueous systems.
Cholesteryl sodium sulphate (CS) crystallizes as the dihydrate, the crystal structure of which is known. On heating the dihydrate, solid state phase transitions are observed at 65 degrees C and 95 degrees C and melting occurs at 165 degrees C. The structure of the high temperature phase has not been determined. Cholesteryl dihydrogen phosphate (CP) is not isostructural with any phases of CS. It undergoes a phase transition at 50 degrees C and melts at 190 degrees C. In systems with water CS is unstable whereas it was possible to determine the phase diagram of CP. In most of the composition range a crystalline hydrate is in equilibrium with a gel-phase. The latter has remarkable properties in that lamellar order exists with the 46 A lipid bilayer interleaved with water layers up to 1000 A. The monofilm behaviour of CS and CP at different pH levels is also reported.


Incidence, predisposing factors, and outcome of engraftment syndrome in pediatric allogeneic stem cell transplant recipients.
Engraftment syndrome (ES) has been recognized as an inflammatory condition during neutrophil recovery after hematopoietic stem cell transplantation (HSCT) characterized by noninfectious fever and skin rash. It has been reported to occur frequently after autologous HSCT in children and adults, and has been shown to be an independent risk factor for increased transplant-related mortality (TRM). However, virtually no data exist on its occurrence after allogeneic HSCT in children. To determine incidence, predisposing factors for, and complications of ES in a pediatric transplant cohort, we analyzed 61 consecutive recipients of a myeloablative allogeneic HSCT for the occurrence of ES. Diagnosis of ES was established when children presented with > or =2 of the following symptoms within 7 days before engraftment: (1) fever >38.0 degrees C, (2) skin rash, (3) weight gain and albumin drop, or (4) dyspnea, hypoxia, and pulmonary infiltrates. Incidence of ES in this cohort was 48% (29 of 61). In a univariate analysis, posttransplant granulocyte-colony stimulating factor (G-CSF) administration (P = .02), and high mononuclear cell count (MNC) (P = .002) were identified as significant risk factors predisposing for the development of ES. In a multiple logistic regression analysis, amphotericin B therapy (P = .009) and high MNC (P = .004) were significant explanatory variables for ES risk. There was a slight trend toward a higher rate of chronic GVHD (cGVHD) in patients with ES (P = .11). However, after a median follow-up of 9.5 years overall survival (OS) (P = .53) and TRM (P = .65) did not differ between the 2 groups. ES presenting with fever, rash, weight gain, and pulmonary symptoms should be recognized as a frequent complication of allogeneic HSCT after myeloablative conditioning in children. Treatment with G-CSF, amphotericin B, and a high nucleated cell count of the graft predisposed for the development of ES in this study. OS and TRM in this cohort were not affected by the occurrence of ES.


Spontaneous recurrent seizures after pilocarpine-induced status epilepticus activate calbindin-immunoreactive hilar cells of the rat dentate gyrus.
Although it is now established that neurogenesis of dentate gyrus granule cells increases after experimental seizures, little is currently known about the function of the new granule cells. One question is whether they become integrated into the network around them. Recent experiments that focused on the newly born granule cells in the hilus showed that indeed the new cells appear to become synchronized with host hippocampal neurons [Scharfman et al. (2000) J. Neurosci. 20, 6144-6158]. To address this issue further, we asked whether the new hilar granule cells were active during spontaneous limbic seizures that follow status epilepticus induced by pilocarpine injection. Thus, we perfused rats after spontaneous seizures and stained sections using antibodies to c-fos, a marker of neural activity, and calbindin, a marker of the newly born hilar granule cells [Scharfman et al. (2000) J. Neurosci. 20, 6144-6158]. We asked whether calbindin-immunoreactive hilar neurons were also c-fos-immunoreactive.C-fos was highly expressed in calbindin-immunoreactive hilar neurons. Approximately 23% of hilar cells that expressed c-fos were double-labeled for calbindin. In addition, other types of hilar neurons, i.e. those expressing parvalbumin or neuropeptide Y, also expressed c-fos. Yet other hippocampal neurons, including granule cells and pyramidal cells, had weak expression of c-fos at the latency after the seizure that hilar neuron expression occurred. In controls, there was very little c-fos or calbindin expression in the hilus.These results indicate that calbindin-immunoreactive hilar cells are activated by spontaneous seizures. Based on the evidence that many of these cells are likely to be newly born, the data indicate that new cells can become functionally integrated into limbic circuits involved in recurrent seizure generation. Furthermore, they appear to do so in a manner similar to many neighboring hilar neurons, apparently assimilating into the local environment. Finally, the results show that a number of hilar cell types are activated during chronic recurrent seizures in the pilocarpine model, a surprising result given that many hilar neurons are thought to be damaged soon after pilocarpine-induced status epilepticus.


Beta-catenin siRNA inhibits ischemia-induced striatal neurogenesis in adult rat brain following a transient middle cerebral artery occlusion.
Beta-catenin, a protein that functions in both cell adhesion and Wnt signaling, plays vital roles in mammalian neural development. To investigate the roles of beta-catenin in stroke-induced neurogenesis, we injected beta-catenin siRNA into ipsilateral ischemic lateral ventricle. We found that inactivation of beta-catenin by siRNA caused the decline of beta-catenin in the ischemic striatum, enlarged stroke-induced infarct volume, reduced SVZ expansion, and inhibited striatal neurogenesis in adult rat brain following a transient middle cerebral artery occlusion (tMCAO). These results show that beta-catenin-mediated transcriptional activation functions in the decision of subventricular zone precursors to proliferate or differentiate during stroke-induced striatal neurogenesis, and suggest that the signaling activity of beta-catenin may control the production of newborn neurons and thus regulate the autonomous repair in the striatum after ischemia.


Influence of Mg doping on the structural, morphological, optical, thermal, and visible-light responsive antibacterial properties of ZnO nanoparticles synthesized via co-precipitation.
Mg-doped zinc oxide (Zn1-xMgxO, where x = 0.000, 0.001, 0.003, 0.005, and 0.010 M) nanoparticles (MgZnO NPs) were synthesized via a co-precipitation method and subjected to various analyses for application as functional additives in food packaging. The MgZnO NPs were successfully formed at approximately 360 °C and showed an increase in the optical band gap with respect to the increase in the concentration of Mg doping. The X-ray diffraction and scanning electron microscopy analyses of MgZnO NPs confirmed the formation of hexagonal wurtzite structure and rod-like morphology. X-ray photoelectron spectra revealed that the Mg (1s) peaks centered at 1303.35 and 1303.38 eV were ascribed to the presence of Mg2+ replacing Zn2+. Transmission electron microscopy images showed rod shapes with the length of 208-650nm and width of 84-142 nm. Various concentrations of synthesized MgZnO NPs were investigated against a gram-negative (Escherichia coli - DH5α) bacterial strain under light and dark conditions. Among the studied samples, 0.010 M MgZnO NPs of concentration 3 mg/mL showed the best antibacterial activity under the light condition. MgZnO NPs revealed uneven ridges on the outer surface, which promote the diffusion ability of Zn2+ and increased production of reactive oxygen species, and consequently lead to bacterial lysis. Furthermore, this study demonstrates excellent feasibility for the application of MgZnO NPs as fillers with good antibacterial activity, especially in antimicrobial food packaging applications.


Migration and health impact assessment.
Government policies, programmes and projects can have a significant impact on health. Health impact assessments (HIAs) seek to estimate this impact, but they often do so by measuring intermediate or proxy indicators and factors that act to determine health. These measures frequently assume a static population. However, regeneration policies can work hard for several years to no apparent effect. One explanation could be migration. Families who have benefited move from the area and other, perhaps more deprived, families move in. Conversely, healthy, prosperous families may move into an improved area, giving the impression that the health of the population has changed, when in fact it is the actual population that has changed. Census data in England and Wales show that a positive correlation exists between migration within wards and deprivation scores. This paper explores the possible implications of migration for HIA. The census, NHS central register, electoral register, labour force survey, central index of the Department of Social Security, council tax database and other data sources are examined to identify what migration data are available at a local level. Factors that determine rates of migration at a local level have been reviewed, with special reference to the differences between population subgroups. The paper concludes with recommendations to take account of residential mobility and changes in migration patterns when carrying out HIAs.


Blocking noise but not music lowers bispectral index scores during sedation in noisy operating rooms.
To determine whether playing music or blocking noise can reduce bispectral index (BIS) values during propofol sedation. Prospective, randomized, single-blinded study. Operating room. 63 ASA physical status I and II patients, aged 55 to 75 years, undergoing total knee replacement. Patients were divided into three groups: noise, silence, and music. After induction of combined spinal-epidural anesthesia, sedation was begun with 1.2 mug/mL of propofol in a target-controlled infusion. In the silence group, patients' ears were packed tightly to block ambient noise, whereas patient-selected music was applied to patients in the music group. Patients in the noise group were exposed to ambient operating room noise. Bispectral index measurement was recorded 7 times during operation. Ambient room noise was recorded at the same time sequence. Sound level was highest when the saw (T3, 80.25 dB) and the impact device (T4, 80.98 dB) were in use. Bispectral index scores in the silence group during those times (T3, 68.5 vs 76.9, P = 0.025, and T4, 67.6 vs 78, P = 0.005) were lower than in the noise group. However, BIS scores were similar in the noise and music groups. Preoperative anxiety level, postoperative comfort level, and pain scores were similar in all groups. Blocking noise is more effective than playing music in reducing BIS scores during propofol sedation in a noisy environment.


Naphthol-based fluorescent sensors for aluminium ion and application to bioimaging.
Three naphthol Schiff base-type fluorescent sensors, 1,3-Bis(2-hydroxy-1-naphthylideneamino)propane (L1), 1,3-Bis(1-naphthylideneamino)-2-hydroxypropane (L2) and 1,3-Bis(2-hydroxy-1-naphthylideneamino)-2-hydroxypropane (L3), have been synthesized. Their recognition abilities for Al(3+) are studied by fluorescence spectra. Coordination with Al(3+) inhibited the CN isomerization of Schiff base which intensely increase the fluorescence of L1-L3. Possessing a suitable space coordination structure, L3 is a best selective probe for Al(3+) over other metal ions in MeOH-HEPES buffer (3/7, V/V, pH=6.6, 25°C, λem=435nm). A turn-on ratio over 140-fold is triggered with the addition of 1.0 equiv. Al(3+) to L3. The binding constant Ka of L3-Al(3+) is found to be 1.01×10(6.5)M(-1) in a 1:1 complex mode. The detection limit for Al(3+) is 0.05μM. Theoretical calculations have also been included in support of the configuration of the L3-Al(3+) complex. Importantly, the probe L3 has been successfully used for fluorescence imaging in colon cancer SW480 cells.


Retrospective long-term evaluation of autotransplantation of premolars to the central incisor region.
This retrospective case-series study aimed to examine the long-term outcomes of autogenously transplanted premolars. Twelve patients in whom donor premolars were used to replace maxillary central incisors lost by trauma were clinically and radiologically monitored. Standardized clinical and radiographic records were systematically obtained during the follow-up period of 14 years, to determine the influence of specific clinical criteria on the overall success rate of transplantation. The success rate of premolar autotransplantation in the maxillary central incisor area was 80% after 14 years follow-up. The highest success rate occurred in those teeth transplanted with two-thirds of full root development. Complete pulp obliteration was positively related to autotransplant viability, followed by root formation in the bony crypt. Autotransplantation of donor teeth, at the stage of ½ to ¾ of their expected root length, can provide a successful treatment solution for over 14 years.


The coagulant response in sepsis.
Sepsis is often associated with systemic intravascular activation of coagulation, potentially leading to widespread microvascular deposits of fibrin, and thereby contributing to multiple organ dysfunction. A complex interaction exists between activation of inflammatory systems and the initiating and regulating pathways of coagulation. A diagnosis of sepsis-associated disseminated intravascular coagulation can be made by a combination of routinely available laboratory tests, for which simple diagnostic algorithms have become available. Strategies to inhibit coagulation activation may theoretically be justified and are being evaluated in clinical studies.


Application of the 2006 WHO growth standard from birth to 4 years to Pacific Island children.
Pacific adults and children have very high rates of obesity. Body size at birth, 2- and 4 years for the whole cohort, compliant (not smoking and breastfed) and non-compliant children was compared to the 2006 World Health Organization (WHO) growth standard using z-scores. Longitudinal data (n=659) from the 2000 Pacific Island family birth cohort study of weight at birth and weight and height at 2- and 4 years was analysed. At birth the average child was 3.673+/-0.501 kg; z-score 0.605 units higher (P<0.000001) than the WHO standard. At 2- and 4 years, average z-scores for weight and body mass index (BMI) were significantly different from 0 (mean z-scores for weight +1.062 and +1.688, for BMI +1.701 and +1.969 respectively, P<0.000001). Mean height was significantly lower (P<0.000001) z-score=-0.232 at 2 years but higher (P<0.000001) at 4 years, z-score=+0.626. Over 4 years, the daily weight gain was 11.2 g day(-1) compared with 8.9 g day(-1) for the WHO child. Compliant (n=287) compared to non-compliant (n=372) weighed less and were slightly shorter at 2- and 4 years measurement points. Non-compliant children categorized as non-smoking (n=229) weighed more than smoking mothers' (n=143) children at birth, 2- and 4 years. Pacific children are born heavy, over 4 years increase in weight is faster and between 2- and 4 years increase in height is faster than the reference breastfed child, independent of pre- and postnatal factors. Smoking decreases the rate of weight gain and children who are not breastfed gain weight faster. Interventions to limit weight gain need to start with the family before conception.


Western population-based study of oncologic surgical quality and outcomes of laparoscopic versus open gastrectomy for gastric adenocarcinoma.
While studies have reported improved morbidity of laparoscopic (LG) compared with open gastrectomy (OG), it remains unclear whether comparable oncologic outcomes can be achieved. This study aims at comparing not only short-term outcomes, including 30- and 90-day mortality, but also survival of LG vs OG. The National Cancer Database was searched for adult patients with histologically proven gastric cancer and complete information regarding M0 disease, tumor size, differentiation grade, T stage, nodal status, comorbidities, type of hospital, hospital stay, type of surgery, oncological treatment and survival data were included. Logistic regression analyses were performed to analyze margin status, 30- and 90-day mortality, and 30-day re-admission rate. Linear regression was performed for length of hospital stay and lymph node yield. Kaplan-Meier survival analyses were performed to evaluate median survival. Cox multivariable regression models were created to correct for confounders and identify factors affecting survival. A query of the National Cancer Database identified 13,538 patients with complete dataset. A significant regression equation favoring LG for lymph node yield, hospital stay, and unplanned re-admission rate was identified. There was no significant effect of surgical approach on R1 margin rate, 30-day mortality, or 90-day mortality. Median survival was comparable between LG and OG (44.8 vs 40.2 months, p = 0.804). LG offers a safe surgical approach to gastric cancer with shorter hospital stay and lower re-admission rates than OG, and also similar and sometimes improved operative oncologic quality parameters (margin, lymph node yield). More importantly, this Western series demonstrates that equivalent long-term outcomes of LG vs. OG are being achieved.


Efficacy, safety and variability in pharmacotherapy for adults with attention deficit hyperactivity disorder: a meta-analysis and meta-regression in over 9000 patients.
The factors underlying the variability in the results of randomized, placebo-controlled clinical trials (RPCCT) assessing pharmacological interventions for adults with attention deficit hyperactivity disorder (ADHD) are not fully understood. A systematic review and meta-analysis of RPCCT comparing pharmacological treatment and placebo in adults with ADHD was carried out. The study outcomes were all-cause treatment discontinuation, efficacy on ADHD symptoms, and safety. Patient-, intervention-, and study design-related covariates were collected. Meta-regression methods were applied. Forty-four studies involving 9952 patients were included. All-cause treatment discontinuation was slightly higher with pharmacological treatment than with placebo (odds ratio (OR) = 1.18; 95 % confidence interval (CI) 1.02, 1.36; p = 0.003). A better outcome on all-cause treatment discontinuation was observed in studies that provided concomitant psychotherapy when compared to those that did not (rate of OR (ROR) = 0.68, p = 0.048). Pharmacological treatment was efficacious for reducing ADHD symptoms (standardized mean difference (SMD) = 0.45; 95 % CI 0.37, 0.52; p < 0.00001), with stronger intervention effects found in studies investigating stimulant drugs (difference of SMD (Diff SMD) = 0.18, p = 0.017), in shorter studies (Diff SMD = -0.01, p = 0.044), and when clinician-rated scales were used (Diff SMD = 0.44, p < 0.0001). Pharmacological treatment was associated with more frequent adverse events (AEs) (OR = 2.29; 95 % CI 1.97, 2.66; p = 0.006). Studies with a lead-in phase and with a higher proportion of patients previously treated with stimulants were associated with a better safety outcome (ROR = 0.59, p = 0.017; ROR = 0.98, p = 0.036, respectively). Pharmacological treatment provides mild symptom improvement but is associated with frequent AEs and higher treatment discontinuation than placebo, particularly when no concomitant psychotherapy is administered. Stimulants appear more efficacious than non-stimulant drugs and the former should be preferred over the latter. The efficacy of pharmacological treatment should be monitored over time because it may decrease progressively.


Anatomic Dissection of Arachnoid Membranes Encircling the Pituitary Stalk on Fresh, Non-Formalin-Fixed Specimens: Anatomoradiologic Correlations and Clinical Applications in Craniopharyngioma Surgery.
The anatomy of the arachnoid membranes and cisternal spaces around the pituitary stalk has not been yet exhaustively described and understood. In this study, we performed a detailed anatomic study on fresh, non-formalin-fixed cadavers of the arachnoid membranes encircling the pituitary stalk and correlate our anatomic findings with magnetic resonance imaging (MRI). Ten fresh, non-formalin-fixed, non-silicon-injected adult cadaveric heads were analyzed in this study. The membrane and cisterns that were studied for our study were as follows: 1) the diaphragma sellae and its dural components; 2) the basal arachnoid membrane; 3) the Liliequist membrane with its diencephalic and mesencephalic portion; 4) the medial carotid membrane; 5) the chiasmatic cistern; and 6) the pituitary stalk. MRI examinations of the sellar region were performed in 15 healthy volunteers (9 men, mean age 40 years; and 6 women mean age, 37 years) to visualize the arachnoid membrane encircling the pituitary stalk. MRI examinations were performed with a 3-T unit. A 3-dimensional constructive interference in steady state pulse magnetic resonance sequence was used. All the membranes examined were visualized clearly in all the dissections performed. Their 3-dimensional organization around the pituitary stalk was clarified and confirmed by MRI. Our study gives a detailed description of the pituitary stalk arachnoid sheets on fresh, non-formalin-fixed cadavers. This technique allowed us to clearly identify a funnel-shaped arachnoid collar encircling the pituitary stalk and delimiting a distinct cisternal space belonging to the stalk itself.


Influence of phosphate chelators on white efflorescence formation in dry fermented sausages with co-extruded alginate casings.
The aim of the study was to investigate the effect of different condensed phosphates on the white efflorescence formation on dry fermented sausages with calcium alginate casings. The efflorescence formation is induced by the complexation of the divalent cations magnesium and calcium with lactate on the surface of the product. Phosphates are known to complex divalent cations like magnesium and calcium, which are responsible for the efflorescence formation with lactate. To treat the surface of the raw fermented sausages a mixture of di- and polyphosphates and a polyphosphate were used. The sausages were dipped in 5% solutions of the phosphates. The mixture of di- and polyphosphate showed the best results in reducing the white efflorescence formation, the amount of efflorescences on the surface was 18.12% after 8 weeks of storage. The diffusion of magnesium was significantly reduced by ~40% after 8 weeks of storage compared to the control for both phosphates. However, the crystals formed during storage had a different structure and size compared to the control. Isothermal titration calorimetry measurements showed that the divalent calcium ions and the polyphosphates from aggregates caused the crystal formation on the surface, whereas this effect was not seen in combination with magnesium. The surface treatment with the phosphates did not inhibit the white efflorescence formation. However, the extent was reduced but different kind of crystals were formed on the surface during the storage.


A long and winding sTORy.
This year's Albert Lasker Basic Medical Research Award honoured Michael Hall for his work on the TOR proteins. We congratulate the new Lasker laureate and take this opportunity to revisit the history of this fundamental signalling pathway.


Pnictogen Interactions with Nitrogen Acceptors.
Stabilizing nitrogen pnictogen bond interactions were measured using molecular rotors. Intramolecular C=O⋅⋅⋅N interactions were formed in the bond rotation transition states which lowered the rotational barriers and increased the rates of rotation, as measured by EXSY NMR. The pnictogen interaction energies show a very strong correlation with the positive electrostatic potential on nitrogen, which was consistent with a strong electrostatic component. In contrast, the NBO perturbation and pyramidalization analyses show no correlation, suggesting that the orbital-orbital component is minor. The strongest C=O⋅⋅⋅N pnictogen interactions were comparable to C=O⋅⋅⋅C=O interactions and were stronger than C=O⋅⋅⋅Ph interactions, when measured using the same N-phenylimide rotor system. The ability of the nitrogen pnictogen interactions to stabilize transition states and enhance kinetic processes demonstrates their potential in catalysis and reaction design.


First international workshop on human endogenous retroviruses and diseases, HERVs & disease 2015.
The First International Scientific Conference on Human Endogenous Retroviruses (HERVs) and Disease, Lyon-France, May 26-27th 2015, brought together scientific and medical specialists from around the world investigating the involvement of human endogenous retroviruses (HERVs) in complex human diseases.


Pain does not explain reduced teres major co-contraction during abduction in patients with Subacromial Pain Syndrome.
Patients with Subacromial Pain Syndrome show reduced co-contraction of the teres major during abduction. Consequent insufficient humeral depressor function may contribute to painful irritation of subacromial tissues and offers a potential target for therapy. A crucial gap in knowledge is whether the degree of teres major co-contraction in these patients is influenced by pain itself. To gain insight into this matter, we assessed whether relief of subacromial pain with local analgesics leads to increased adductor co-contraction in 34 patients with subacromial pain. In a single-arm interventional study with 34 patients, electromyographic activity of the latissimus dorsi, pectoralis major, teres major and deltoid was assessed during isometric force tasks in 24 directions before and after subacromial Lidocaine injection. Co-contraction was quantified using the activation ratio; range [-1 (sole antagonistic activation, i.e. co-contraction) to 1 (sole agonistic activation)]. There were no changes in activation ratio of the teres major after the intervention (Z-score: -0.6, p = 0.569). The activation ratio of the latissimus dorsi increased to 0.38 (quartiles: 0.13-0.76), indicating decreased co-contraction (Z-score: -2.0, p = 0.045). Subacromial analgesics led to a decrease in co-contraction of the latissimus dorsi, whereas no change in the degree of teres major co-contraction was observed. This study shows that decreased teres major co-contraction in patients with subacromial pain, likely is not the consequence of pain itself, opening a window for physical therapy with training of teres major co-contraction to reduce subacromial irritation and pain. Level II treatment study.


Suitable, fit, competent and safe to practice nursing? Assessing nursing students' personal qualities in clinical placement-An integrative review.
This study aims to explore, describe, and synthesize the personal requirements student nurses are assessed in their clinical placement to be suitable, fit, competent, and safe for the nursing profession. There are different terms and concepts used when describing what nursing students are assessed by regarding personal requirements needed to be eligible to enter the nursing profession. This is regulated and enforced mainly by different standards and guidelines. An integrative review using Whittmore and Knafl's (2005) methodology. Searches were systematically conducted in CINAHL, Education Source, ERIC, Academic Source Elite, MEDLINE and EMBASE, NORART, SveMed+, and Bibliotek.dk. The PRISMA checklist for systematic reviews was used. Eighteen studies were included in the review. The results present various factors student nurses are assessed by in clinical placements, which were categorized into three themes: attitude and personal characteristics, behavior, and basic knowledge. Assessing students is a complex and subjective endeavor, and decisions are based on a holistic assessment of several different aspects of the student's performance and behavior CONCLUSIONS: The personal requirements to be deemed suited for det nursing profession are complex and composed of several different components. Assessments are often based more on assessors' subjective standards and intuition than on the provided guidelines and standards. There is no universal understanding of which characteristics or qualities are considered necessary for a student to be deemed suited for the nursing profession. This study points at challenges with the assessment of nursing students today as there are no clear standards or understanding of the requirements needed.


Immediate anaphylactic death following antibiotics injection: splenic eosinophilia easily revealed by pagoda red stain.
The comparison of 4 cases of immediate anaphylactic death following the intramuscular injection of antibiotics (different types of penicillin or cephalosporins) with 4 cases of immediate non-anaphylactic death (induced by different causes) recognized splenic eosinophilia, as the main feature for the differential diagnosis, in agreement with isolated previous studies. The use of a stain (pagoda red) little known and seldom employed in Pathology and in Forensic Medicine, showed the concomitant massive presence (immunohistochemically confirmed) of mast cells and degranulated mast cells, the latter mainly located in splenic sinuses. The whole of our findings led us to consider the spleen as the possible shock organ in man. Waiting for further judgment on our hypothesis, we seized the opportunity to remark the employment of the pagoda red stain when the contemporary demonstration of eosinophils, mast cells and degranulated mast cells is required.


Meta-analyses using real-world data to generate clinical and epidemiological evidence: a systematic literature review of existing recommendations.
To identify existing guidelines, key recommendations, and existing limitations regarding the evaluation and use of real-world evidence (RWE) in meta-analyses (MAs) to generate clinical and epidemiological evidence: a systematic review of existing recommendations. A literature search was performed in April 2017 in MEDLINE and Embase using the Ovid platform, the Cochrane Library, and other sources. No specific inclusion and exclusion criteria were applied, and no restrictions in timeframe, language, or geographical scope were imposed. The search strategy identified 1681 citations; 12 references were included in this review. Recommendations within the literature regarding the use of RWE in MAs are: (1) it may be useful to extract and analyze adjusted results because confounding is expected; (2) testing heterogeneity in the MA of RWE is important as it may minimize the potential for bias and generate hypotheses for future research; (3) limiting a search ≤2 bibliographic databases when conducting MAs of RWE will not provide a thorough summary of existing literature; and (4) the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) checklist is a 35-item checklist developed to allow for more standardized reporting of MAs of RWE and address their limitations. (1) No formal guidelines were found regarding the use of RWE in MAs; (2) no consensus was found on a preferred instrument for the assessment of RWE; and (3) critical appraisal of RWE is often omitted from Health Technology Assessment submissions. The inclusion of RWE in MAs may facilitate the confirmation of conclusions drawn from randomized controlled trials and, thus, reassure decision-makers that findings can be extrapolated to real-world populations. However, qualitative and quantitative bias may co-exist in MAs of RWE. Reviewers should select the most appropriate tools that match the study designs identified in a particular systematic review.


An effective live attenuated vaccine against Streptococcus agalactiae infection in farmed Nile tilapia (Oreochromis niloticus).
Streptococcus agalactiae is an important pathogen associated with various aquatic animals, especially tilapia. Streptococcosis has greatly limited the healthy development of tilapia aquaculture in recent times. The development of novel effective vaccines is important for the prevention and control of streptococcosis in fish. We previously constructed a non-encapsulated S. agalactiae strain △cps by the in-frame deletion method. Here, we evaluated whether this mutant △cps is safe for tilapia and suitable for protection against streptococcosis. We observed that the △cps strain was non-pathogenic to tilapia, and there was no reversion of virulence when it was passaged in tilapia. Moreover, the △cps strain survived for at least 11 d in the main immune organs of tilapia. The tilapia vaccinated via intraperitoneal (IP) injection with △cps strain induced a high antibody titer, and the IgM antibody levels were significantly higher in the vaccinated group than in the control group. The vaccination protected tilapia against the S. agalactiae challenge with a relative percent survival of 90.47%. In addition, tilapia immunized with the △cps strain showed significantly higher expression level of IFN-γ, IL-1β, MyD88, IgM, and MHC-Iα in the head kidney than those in the control during the entire observation period. The expression of MHC-IIβ was inhibited during 1-7 d of immunization. These results revealed that the △cps strain is able to induce humoral and cell-mediated immune response in tilapia. Therefore, the strain △cps has a broad application prospect as a target for attenuation in vaccine development.


Polaprezinc reduces paclitaxel-induced peripheral neuropathy in rats without affecting anti-tumor activity.
Paclitaxel, an anticancer drug, frequently causes painful peripheral neuropathy. In this study, we investigated the preventive effect of polaprezinc on paclitaxel-induced peripheral neuropathy in rats. Polaprezinc (3 mg/kg, p.o., once daily) inhibited the development of mechanical allodynia induced by paclitaxel (4 mg/kg, i.p., on days 1, 3, 5 and 7) and suppressed the paclitaxel-induced increase in macrophage migration in dorsal root ganglion cells. In addition, polaprezinc did not affect the anti-tumor activity of paclitaxel in cultured cell lines or tumor-bearing mice. These results suggest a clinical indication for polaprezinc in the prevention of paclitaxel-induced neuropathy.


An evaluation of three methods of in-hospital cardiac arrest educational debriefing: The cardiopulmonary resuscitation debriefing study.
The use of cardiac arrest educational debriefing has been associated with improvements in cardiopulmonary resuscitation (CPR) quality and patient outcome. The practical challenges associated with delivering some debriefing approaches may not be generalisable to the UK health setting. The aim of this study was to evaluate the deliverability and effectiveness of three cardiac arrest debriefing approaches that were tailored to UK working practice. We undertook a before/after study at three hospital sites. During the post-intervention period of the study, three cardiac arrest educational debriefing models were implemented at study hospitals (one model per hospital). To evaluate the effectiveness of the interventions, CPR quality and patient outcome data were collected from consecutive adult cardiac arrest events attended by the hospital cardiac arrest team. The primary outcome was chest compression depth. Between November 2011 and July 2014, 1198 cardiac arrest events were eligible for study inclusion (782 pre-intervention; 416 post-intervention). The quality of CPR was high at baseline. During the post-intervention period, cardiac arrest debriefing interventions were delivered to 191 clinicians on 344 occasions. Debriefing interventions were deliverable in practice, but were not associated with a clinically important improvement in CPR quality. The interventions had no effect on patient outcome. The delivery of these cardiac arrest educational debriefing strategies was feasible, but did not have a large effect on CPR quality. This may be attributable to the high-quality of CPR being delivered in study hospitals at baseline. ISRCTN39758339.


A controlled study comparing cimetidine treatment to an intensive antacid regimen in the therapy of uncomplicated duodenal ulcer.
The authors report the results of a randomized study in which comparison was made between two different kinds of treatment in patients affected by uncomplicated duodenal ulcer endoscopically diagnosed. The first group was treated with 1 g of cimetidine per day, during a period of four weeks (200 mg three times a day and 400 mg at bedtime); the second with a liquid Al-Mg antacid compound, 210 ml/day 30 ml, 1 and 3 hr after meals and 30 ml before bedtime) for four weeks. Fity-one patients were studied, 27 treated with cimetidine, 24 with antacids. At the end of the four-week period, 21 patients (77.7%) in the cimetidine group and 18 patients (75%) in the antacid group were completely healed. Benign side effects were remarked in both types of treatment, none of which made it necessary to suspend treatment. No significant variation of the basal and peak acid output before and after each kind of treatment was observed, while a slight but significant increase in fasting serum gastrin concentration was noted after treatment in the antacid group.


Pseudomonas aeruginosa: an antibiotic resilient pathogen with environmental origin.
Pseudomonas aeruginosa, a bacterium characterized for its low antibiotics' susceptibility, is one of the most relevant opportunistic pathogens, causing infections at hospitals and in cystic fibrosis patients. Besides its relevance for human health, P. aeruginosa colonizes environmental ecosystems; therefore the elements driving its infectivity and antibiotic resistance must be analyzed from a One-Health perspective. Although some epidemic clones have been described, there are not specific lineages linked to infections, suggesting that P. aeruginosa virulence and antibiotic resistance determinants evolved in nature to play functions other than infecting the human host and avoiding antimicrobial treatment. Herein, we review current information on the population structure of P. aeruginosa and on the functional role that its resistance and virulence determinants have in non-clinical ecosystems.


Time course of locomotor recovery and functional regeneration in spinal-transected lamprey: kinematics and electromyography.
The time course of recovery of locomotor function was examined with kinematic analysis and muscle recordings in larval lampreys 2-32 weeks after rostral spinal cord transection at the level of the third gill (approximately 10% of body length, BL). Animals began to recover locomotor movements within 2-4 weeks of spinal cord transection, but the amplitude of locomotor movements in the tail region was less than in normal animals. At 2 weeks post-transection, locomotor activity was limited to 20% BL, and at 3 weeks after spinal transection activity could be recorded at least as far as 40% BL. At 4 weeks after spinal transection, well-coordinated locomotor muscle activity was often present as far as 60% BL. At 8 weeks of recovery and longer, well-coordinated locomotor activity was present consistently at least as far as 60% BL, and the amplitudes of locomotor movements were restored to normal values. At each recovery time examined the ranges of locomotor parameters (cycle time, burst proportion, and intersegmental phase lag) overlapped with those in normal animals. Thus, the gradual recovery of the amplitude of locomotor movements in the caudal body is associated with the gradual return of coordinated muscle activity at progressively more caudal levels along the body. The mechanisms responsible for this gradual recovery of locomotor function are discussed in relation to our recent anatomical and in vitro studies.


Catheter Ablation for Ventricular Tachycardia Involving the His-Purkinje System: Fascicular and Bundle Branch Reentrant Ventricular Tachycardia.
The Purkinje system has been found to mediate several monomorphic ventricular tachycardias (VTs). These include fascicular VTs and bundle branch reentrant (BBR) VTs. Previous studies have revealed that VTs involving the His-Purkinje system are composed of multiple discrete subtypes that are best differentiated by their mechanism, drug effect, VT morphology, and successful ablation site. Recognition of the heterogeneity of these VTs and their unique characteristics should facilitate the appropriate diagnosis and therapy and help guide catheter ablation therapy. In this article, we focus on the latest updates of the mechanisms underlying left ventricle fascicular VTs and BBR-VTs as well as the latest catheter ablation techniques.


The mechanobiology of mitral valve function, degeneration, and repair.
In degenerative valve disease, the highly organized mitral valve leaflet matrix stratification is progressively destroyed and replaced with proteoglycan rich, mechanically inadequate tissue. This is driven by the actions of originally quiescent valve interstitial cells that become active contractile and migratory myofibroblasts. While treatment for myxomatous mitral valve disease in humans ranges from repair to total replacement, therapies in dogs focus on treating the consequences of the resulting mitral regurgitation. The fundamental gap in our understanding is how the resident valve cells respond to altered mechanical signals to drive tissue remodeling. Despite the pathological similarities and high clinical occurrence, surprisingly little mechanistic insight has been gleaned from the dog. This review presents what is known about mitral valve mechanobiology from clinical, in vivo, and in vitro data. There are a number of experimental strategies already available to pursue this significant opportunity, but success requires the collaboration between veterinary clinicians, scientists, and engineers.


Diagnostic accuracy and linkage analysis: how useful are schizophrenia spectrum phenotypes?
Numerous studies suggest that the nonschizophrenic relatives of schizophrenic patients exhibit psychiatric and other features that discriminate them from normal comparison subjects. These features have been put forth as "spectrum" phenotypes that may be variant manifestations of the schizophrenia genotype. However, most of these studies do not address a key measurement question: does the diagnostic accuracy of these spectrum classifications warrant their use in genetic linkage studies of schizophrenia? The authors reviewed 30 studies of putative indicators of the schizophrenic genotype: schizotypal personality disorder, eye tracking dysfunction, attentional impairment, auditory evoked potentials, neurological signs, neuropsychological impairment, and allusive thinking. Although each of 42 measures of these indicators discriminated the relatives of schizophrenic patients from the normal comparison subjects, a diagnostic accuracy analysis suggested that only six of these would improve the informativeness of genetic linkage data. Many proposed spectrum phenotypes for schizophrenia may not be useful for linkage analysis because of high false positive rates (poor specificity). Future work aimed at describing and developing phenotypes for linkage analysis should assess the diagnostic accuracy of proposed measures.


Limbic and brainstem afferents to thalamic mediodorsal nucleus: a horseradish peroxidase study.
Subcortical ipsilateral afferents to mediodorsal (MD) thalamic nucleus were investigated by retrograde transport of horseradish peroxidase (HRP). HRP was injected into the rostral and caudal part of MD following both a vertical and an oblique stereotaxic approach. We have identified MD afferents from the following structures: area septalis, amygdaloid complex, hypothalamus, mamillary bodies, tuberculum olfactorium, claustrum, ventral tegmental area, zona incerta, substantia nigra, griseum centralis, formatio reticularis mesencephali and pontis oralis. The projections from hypothalamus, amygdaloid nuclei and area septalis and reticular formation are in agreement with the integrative function of sensory afferents of this thalamic nucleus.


Towards valid and reusable reference alignments - ten basic quality checks for ontology alignments and their application to three different reference data sets.
Identifying relationships between hitherto unrelated entities in different ontologies is the key task of ontology alignment. An alignment is either manually created by domain experts or automatically by an alignment system. In recent years, several alignment systems have been made available, each using its own set of methods for relation detection. To evaluate and compare these systems, typically a manually created alignment is used, the so-called reference alignment. Based on our experience with several of these reference alignments we derived requirements and translated them into simple quality checks to ensure the alignments' validity and also their reusability. In this article, these quality checks are applied to a standard reference alignment in the biomedical domain, the Ontology Alignment Evaluation Initiative Anatomy track reference alignment, and two more recent data sets covering multiple domains, including but not restricted to anatomy and biology.


Ballistic and Collisional Flow Contributions to Anti-Fourier Heat Transfer in Rarefied Cavity Flow.
This paper investigates anti-Fourier heat transfer phenomenon in a rarefied gas confined within a lid-driven cavity using a novel flow decomposition technique in the direct simulation Monte Carlo (DSMC) method proposed by Stefanov and co-workers. An isothermal cavity with different degrees of flow rarefaction from near continuum to mid transition regimes was considered to investigate cold-to-hot heat transfer from ballistic/collision flow decomposition viewpoint. A new cold-to-hot heat transfer indicator in the form of a scalar product of normalized heat flow vector and normalized temperature gradient vector has been introduced for the overall, ballistic and collision parts of these vectors. Using the new indicator, contributions of ballistic and collision flow parts to temperature and heat flux components was investigated with a specific emphasis on the cold-to-hot heat transfer phenomenon. We demonstrated that both ballistic and collision flow parts contribute to the occurrence of cold-to-hot heat transfer. However, it was found out that considered separately both ballistic and collision parts of heat transfer, when related to corresponding ballistic and collision temperature fields, they are ever hot-to-cold for all degrees of flow rarefaction. Thus, cold-to-hot heat transfer is a result of a subtle interplay between ballistic and collision parts in the slip and transition Knudsen regimes.


A small-molecule organic ferroelectric with piezoelectric voltage coefficient larger than that of lead zirconate titanate and polyvinylidene difluoride.
Piezoelectric materials that generate electricity when deforming are ideal for many implantable medical sensing devices. In modern piezoelectric materials, inorganic ceramics and polymers are two important branches, represented by lead zirconate titanate (PZT) and polyvinylidene difluoride (PVDF). However, PVDF is a nondegradable plastic with poor crystallinity and a large coercive field, and PZT suffers from high sintering temperature and toxic heavy element. Here, we successfully design a metal-free small-molecule ferroelectric, 3,3-difluorocyclobutanammonium hydrochloride ((3,3-DFCBA)Cl), which has high piezoelectric voltage coefficients g 33 (437.2 × 10-3 V m N-1) and g 31 (586.2 × 10-3 V m N-1), a large electrostriction coefficient Q 33 (about 4.29 m4 C-2) and low acoustic impedance z 0 (2.25 × 106 kg s-1 m-2), significantly outperforming PZT (g 33 = 34 × 10-3 V m N-1 and z 0 = 2.54 × 107 kg s-1 m-2) and PVDF (g 33 = 286.7 × 10-3 V m N-1, g 31 = 185.9 × 10-3 V m N-1, Q 33 = 1.3 m4 C-2, and z 0 = 3.69 × 106 kg s-1 m-2). Such a low acoustic impedance matches that of the body (1.38-1.99 × 106 kg s-1 m-2) reasonably well, making it attractive as next-generation biocompatible piezoelectric devices for health monitoring and "disposable" invasive medical ultrasound imaging.


Helenalin and 11 alpha,13-dihydrohelenalin, two constituents from Arnica montana L., inhibit human platelet function via thiol-dependent pathways.
This study investigates the effect on human platelet function of two sesquiterpene lactones from Arnica montana L., helenalin (H) and 11 alpha,13-dihydrohelenalin (DH). Both compounds inhibited collagen-induced platelet aggregation, thromboxane formation and 5-hydroxytryptamine secretion in a concentration-dependent manner at 3-300 microM. When arachidonic acid was used as stimulus, thromboxane formation remained unaffected despite of inhibition of platelet aggregation. Both H and DH reduced the number of acid-soluble sulfhydryl groups in platelets, by up to 78% at anti-aggregatory concentrations. Moreover, H- and DH-induced platelet inhibition could be prevented by the thiol containing amino acid cysteine. It is concluded that H and DH inhibit platelet function via interaction with platelet sulfhydryl groups, probably associated with reduced phospholipase A2 activity.


Function of PHEX mutations p.Glu145* and p.Trp749Arg in families with X-linked hypophosphatemic rickets by the negative regulation mechanism on FGF23 promoter transcription.
X-linked hypophosphatemic rickets (XLH) is characterized by increased circulating fibroblast growth factor 23 (FGF23) concentration caused by PHEX (NM_000444.5) mutations. Renal tubular resorption of phosphate is impaired, resulting in rickets and impaired bone mineralization. By phenotypic-genetic linkage analysis, two PHEX pathogenic mutations were found in two XLH families: c.433 G > T, p.Glu145* in exon 4 and c.2245 T > C, p.Trp749Arg in exon 22. Immunofluorescence showed that the localization of p.Glu145* and p.Trp749Arg mutant and secretory PHEX (secPHEX) changed, with decreased expression. In a HEK293T cell model co-transfected with PHEX, secPHEX, and FGF23, wild-type PHEX, secPHEX, and FGF23 proteins were distributed in the cell membrane or endoplasmic reticulum, while the mutant was located in the nuclear membrane and cytoplasm. qPCR of p.Glu145* revealed decreased PHEX and secPHEX mRNA expression in cells, with no difference in mRNA expression of p.Trp749Arg. Both mutations decreased intracellular PHEX endopeptidase activity. Western blot analysis showed decrease in mutant and secPHEX protein expression and no FGF23 protein expression in single-transfected PHEX and secPHEX cells. In cells co-transfected with FGF23, PHEX and secPHEX mutation promoted FGF23 expression. Dual-luciferase reporter gene was used to detect the effect of PHEX on FGF23 promoter. The dual-luciferase reporter gene showed that after PHEX overexpression, the activity of mutant firefly luciferase was significantly higher than that of wild type. The regulatory mechanism between PHEX and FGF23 is still unclear, but we found that PHEX is a direct transcriptional inhibitor of FGF23 and affects the expression of FGF23. This study verified the pathogenicity of the two variants and revealed the possible regulatory mechanism between PHEX and FGF23.


A newborn with chylous ascites caused by intestinal malrotation associated with heterotaxia syndrome.
Chylous ascites is a rare entity in infants. An uncommon cause of chylous ascites is intestinal malrotation. We report a case of a neonate with heterotaxia-polysplenia syndrome and intestinal malrotation who presented with chylous ascites and subsequently developed duodenal obstruction from midgut volvulus. He was successfully treated with peritoneal drainage, surgical intervention, and nutritional support. A brief overview of the association of chylous ascites, intestinal rotational anomalies and heterotaxia syndromes is discussed.


Molecular epizootiology of equine arteritis virus isolates from Poland.
Phylogenetic analysis was performed on the sequences of 44 Polish isolates of equine arteritis virus that were isolated from the semen of stallions from national and private studs, collected during 2001--2005. These sequences were also compared with 41 reference strains previously described and commonly used in phylogenesis. On the basis of the nucleotide sequence analysis of the ORF5 gene, encoding the glycoprotein GP5, it was demonstrated that the Polish EAV isolates belonged to two subgroups and showed the closest relationship to the European strains. Similar results were obtained using the nucleotide sequences of the ORF7 gene. The nucleotide identity between the ORF5 and ORF7 sequences of all Polish isolates was in the range of 80.1-99.0% and 93.6-100%, respectively. The analysis of genetic diversity within the ORF5 sequences enabled a retrospective epizootic investigation. This study suggested that some of the EAV shedding stallions were probably infected before they were moved to Poland.


Blunt cardiac injury in the elderly trauma patient.
Elderly patients are at significant risk for development of complications after a traumatic event as a result of the aging process. This case discusses the diagnosis and sequelae of blunt cardiac injury, as well as the needs and approaches for an elderly patient. Nursing care interventions are provided.


Design of recombinant stem cell factor-macrophage colony stimulating factor fusion proteins and their biological activity in vitro.
Stem cell factor (SCF) and macrophage colony stimulating factor (M-CSF) can act in synergistic way to promote the growth of mononuclear phagocytes. SCF-M-CSF fusion proteins were designed on the computer using the Homology and Biopolymer modules of the software packages InsightII. Several existing crystal structures were used as templates to generate models of the complexes of receptor with fusion protein. The structure rationality of the fusion protein incorporated a series of flexible linker peptide was analyzed on InsightII system. Then, a suitable peptide GGGGSGGGGSGG was chosen for the fusion protein. Two recombinant SCF-M-CSF fusion proteins were generated by construction of a plasmid in which the coding regions of human SCF (1-165aa) and M-CSF (1-149aa) cDNA were connected by this linker peptide coding sequence followed by subsequent expression in insect cell. The results of Western blot and activity analysis showed that these two recombinant fusion proteins existed as a dimer with a molecular weight of approximately 84 KD under non-reducing conditions and a monomer of approximately 42 KD at reducing condition. The results of cell proliferation assays showed that each fusion protein induced a dose-dependent proliferative response. At equimolar concentration, SCF/M-CSF was about 20 times more potent than the standard monomeric SCF in stimulating TF-1 cell line growth, while M-CSF/SCF was 10 times of monomeric SCF. No activity difference of M-CSF/SCF or SCF/M-CSF to M-CSF (at same molar) was found in stimulating the HL-60 cell linear growth. The synergistic effect of SCF and M-CSF moieties in the fusion proteins was demonstrated by the result of clonogenic assay performed with human bone mononuclear, in which both SCF/M-CSF and M-CSF/SCF induced much higher number of CFU-M than equimolar amount of SCF or M-CSF or that of two cytokines mixture.


MRI of intracranial vertebral artery dissection: evaluation of intramural haematoma using a black blood, variable-flip-angle 3D turbo spin-echo sequence.
We investigated the efficacy of three-dimensional black blood T1-weighted imaging (3D-BB-T1WI) using a variable refocusing flip angle turbo spin-echo sequence in the diagnosis of intracranial vertebral artery dissection (VAD). Sixteen consecutive patients diagnosed with intracranial VAD underwent magnetic resonance imaging that included 3D time-of-flight-MRA, axial spin-echo T1-weighted images (SE-T1WI) and oblique coronal 3D-BB-T1WI sequences. The visualization, morphology and extent of intramural haematomas were assessed and compared among the sequences. Results obtained by digital subtraction angiography (DSA), 3D-angiography and/or 3D-CT angiography (CTA) were used as standards of reference. 3D-BB-T1WI revealed intramural haematomas in all cases, whereas SE-T1WI and magnetic resonance angiography (MRA) failed to reveal a haematoma in one case and three cases, respectively. The mean visualization grading score for the intramural haematoma was the highest for 3D-BB-T1WI, and there was a statistically significant difference among the sequences (p < 0.001). At least a portion of the intramural haematoma was distinguishable from the lumen on 3D-BB-T1WI, whereas the haematomas were entirely indistinguishable from intraluminal signals on MRA in two cases (12.5%) and on SE-T1WI in one case (6.3%). 3D-BB-T1WI revealed the characteristic crescent shape of the intramural haematoma in 14 cases (87.5%), whereas SE-T1WI and MRA revealed a crescent shape in only 7 cases (43.8%) and 8 cases (50%), respectively. In a consensus reading, 3D-BB-T1WI was considered the most consistent sequence in representing the extent and morphology of the lesion in 14 cases (87.5%), compared to DSA and CTA. 3D-BB-T1WI is a promising method to evaluate intramural haematoma in patients with suspected intracranial VAD.


Normative diameters and effects of aging on the cochlear and facial nerves in normal-hearing Korean ears using 3.0-tesla magnetic resonance imaging.
To assess the normative size of the cochlear nerve (CN) and facial nerve (FN) in normal-hearing ears and to determine whether nerve size varies with age. Cross-sectional. We included 169 ears with normal hearing between 2005 and 2010. The height, width, and cross-sectional area (CSA) of the CN and FN in the middle of the internal auditory canal were measured on oblique sagittal images of 3.0-T magnetic resonance imaging. Results were compared by age. Young subjects were divided into three age groups, 0-5, 6-10, and 11-15 years. Subjects over age 40 years were divided into groups at 10-year intervals. Mean age was 32.6 years (range, 0.75-79 years). We found that the CN had significantly greater vertical (1.10 ± 0.21 mm vs. 0.95 ± 0.21 mm) and horizontal (1.11 ± 0.20 mm vs. 1.03 ± 0.22 mm) diameters than the FN. The CSA of the CN was larger than that of the FN (0.98 ± 0.33 mm(2) vs. 0.79 ± 0.31 mm(2) ). Except for the CN vertical diameter, there were no significant differences between right and left ears. Sex did not affect the nerve size. Although the CN was not affected by age, the FN vertical diameter and CSA of children <5 years were significantly smaller than those of children aged >5 years. The size of the two nerves did not differ among groups over age 40 years. The CN is not affected by age in normal-hearing ears. The FN vertical diameter and CSA of children <5 years are smaller than those of older children.


Immunogenicity and safety of heterologous mRNA-1273/MVC-COV1901 vaccination versus homologous mRNA1273 vaccination: A randomized, double-blind controlled study.
MVC-COV1901 is a protein vaccine based on the same SARS-CoV-2 strain used in mRNA vaccine mRNA-1273. Data are lacking on immunogenicity and safety of MVC-COV1901 as heterologous boost for people already received one dose of mRNA-1273. This is a randomized, double-blind trial that recruited adults aged 20-70 years who previously received a single dose of mRNA-1273 vaccine and were randomly assigned in a 1:1 ratio to receive a second dose with the homologous vaccine or protein-based MVC-COV1901 8-12 weeks after the first dose. The primary outcome was neutralizing antibody titers in terms of the geometric mean titer (GMT) 14 days after the second dose. Safety was assessed in all participants who received a dose of the study vaccine. The study is registered with ClinicalTrials.gov (NCT05079633). From September 30 to November 5, 2021, 144 participants were enrolled and randomly assigned to the MVC-COV1901 boost group (n = 72) or the mRNA-1273 boost group (n = 72). The neutralizing antibodies on Day 15 and the anti-SARS-CoV-2 IgG titers on Day 15 and 29 of homologous mRNA-1273 were significantly higher than those of heterologous mRNA-1273/MVC-COV1901. Cellular immune responses were comparable in both groups. However, adverse events were much more frequent after the mRNA-1273 boost than after the MVC-COV1901 boost. Our results show that heterologous boost with MVC-COV1901 yielded an inferior immunogenicity but significantly fewer adverse events, compared with homologous boost with mRNA-1273. In people experienced severe adverse events after prime dose of mRNA-1273, as well as in periods when the supply of mRNA-1273 is limited, MVC-COV1901 could serve as an acceptable alternative heterologous boost.


Screening for hemochromatosis and iron overload: satisfaction with results notification and understanding of mailed results in unaffected participants of the HEIRS study.
The purpose of this study was to assess the level of satisfaction and understanding of test results, by a sample of non-C282Y homozygous participants in the hemochromatosis and iron overload screening (HEIRS) study, who received serum ferritin (SF), transferrin saturation (TS), and HFE gene test results by mail. Approximately 1 month after receiving test results by mail, participants were surveyed about understanding of and satisfaction with results notification. Overall, participants were satisfied with receiving test results by mail. Participants receiving results with one or two HFE mutations or TS and/or SF levels outside the normal range (an "alert value") were less likely to be satisfied with this method of notification. Participants with normal HFE test results understood their results and recommendations better than those with one or two mutations. Although all participants received results letters in their native language, English-speaking participants had higher mean understanding scores than Mandarin, Vietnamese, or Spanish-speaking participants. Participants were satisfied with receiving test results by mail. However, the level of understanding of the results was not sufficient for this mode of results notification to stand alone, especially for non-English speaking participants, and all participants with one or more test results outside the normal range.


Intravenous flumazenil for Parkinson's disease: a single dose, double blind, placebo controlled, cross-over trial.
Flumazenil is a short-acting intravenously administered gamma-aminobutyric acid (GABA) antagonist used to reverse the effects of benzodiazepines. Based upon current basal ganglion models in Parkinson's disease (PD), flumazenil could normalize neuronal signaling at several different locations. We conducted a double-blind, placebo controlled, single dose, cross-over trial of flumazenil and placebo in 16 subjects with PD. Subjects were primarily assessed with serial tapping tests (1 minute for each hand) at 15-minute intervals for 90 minutes after infusion. Secondary assessments included the Unified Parkinson's Disease Rating Scale (UPDRS) Motor part at baseline and 45 minutes after infusion, and global impressions. Subjects then underwent a 90-minute washout and entered the opposite arm of the cross-over. Change in tapping speed compared to baseline improved throughout the 90-minute period (P < 0.0001) and at each individual time (P < 0.01), except for 15 minutes status after infusion, with flumazenil compared to placebo. UPDRS scores tended to improve more on drug, but this finding was not significant. The medication was well tolerated. The most common adverse event on drug was a sense of "light-headedness" or "dizziness." GABA antagonists represent a novel potential treatment class for PD.


Antibacterial activities and antiproliferative assays over a tumor cells panel of a silver complex with 4-aminobenzoic acid: Studies in vitro of sustained release using bacterial cellulose membranes as support.
The aims of this work were to evaluate the antibacterial and antiproliferative potential in vitro of the metal complex with 4-aminobenzoic acid (Ag-pABA) and a drug delivery system based on bacterial cellulose (BC-Ag-pABA). The Ag-pABA complex was characterized by elemental analysis, high resolution mass spectrometry and single-crystal X-ray diffraction techniques, which indicated a 1:2 metal/pABA composition plus a nitrate ion coordinated to silver by the oxygen atom, with the coordination formula [Ag (C7H7NO2)2(NO3)]. The coordination of pABA to the silver ion occurred by the nitrogen atom. The in vitro antibacterial activity of the complex evaluated by minimum inhibitory concentration assays demonstrated the effective growth inhibitory activity against Gram-positive, Gram-negative biofilm producers and acid-alcohol resistant Bacillus. The antiproliferative activities against a panel of eight tumor cells demonstrated the activity of the complex with a significant selectivity index (SI). The DNA interaction capacity and the Ames Test indicated the absence of mutagenicity. The BC-Ag-pABA composite showed an effective capacity of sustained release of Ag-pABA. The observed results validate further studies on its mechanisms of action and the conditions that mediate the in vivo biological effects using animal models to confirm its safety and effectiveness for treatment of skin and soft tissues infected by bacterial pathogens, urinary tract infections and cancer.