Ruptured abdominal aortic aneurysm.
A total of 131 surgically treated ruptured abdominal aortic aneurysms have been reviewed. Factors affecting morbidity and mortality rates have been analyzed. In our experience very little improvement has occurred in the last 10 years and the question is raised whether a plateau has been reached in the management of this catastrophic disease. Patient selection is not considered to be the key to better results, since some operated patients inevitably die. Improved technique with better, more rapid control of blood loss, especially from venous tears, will continue to yield better results. Eighty-six nonoperative cases have been studied. Diagnostic accuracy is lower than it should be, often leading to delayed surgery or death.


Structure-Activity Relationships Reveal Key Features of 8-Oxoguanine: A Mismatch Detection by the MutY Glycosylase.
Base excision repair glycosylases locate and remove damaged bases in DNA with remarkable specificity. The MutY glycosylases, unusual for their excision of undamaged adenines mispaired to the oxidized base 8-oxoguanine (OG), must recognize both bases of the mispair in order to prevent promutagenic activity. Moreover, MutY must effectively find OG:A mismatches within the context of highly abundant and structurally similar T:A base pairs. Very little is known about the factors that initiate MutY's interaction with the substrate when it first encounters an intrahelical OG:A mispair, or about the order of recognition checkpoints. Here, we used structure-activity relationships (SAR) to investigate the features that influence the in vitro measured parameters of mismatch affinity and adenine base excision efficiency by E. coli MutY. We also evaluated the impacts of the same substrate alterations on MutY-mediated repair in a cellular context. Our results show that MutY relies strongly on the presence of the OG base and recognizes multiple structural features at different stages of recognition and catalysis to ensure that only inappropriately mispaired adenines are excised. Notably, some OG modifications resulted in more dramatic reductions in cellular repair than in the in vitro kinetic parameters, indicating their importance for initial recognition events needed to locate the mismatch within DNA. Indeed, the initial encounter of MutY with its target base pair may rely on specific interactions with the 2-amino group of OG in the major groove, a feature that distinguishes OG:A from T:A base pairs. These results furthermore suggest that inefficient substrate location in human MutY homologue variants may prove predictive for the early onset colorectal cancer phenotype known as MUTYH-Associated Polyposis, or MAP.


Important therapeutic targets in chronic myelogenous leukemia.
Review the state-of-art knowledge of the biology and therapy of chronic myelogenous leukemia (CML). A review of the literature was undertaken to summarize current information on the pathophysiology of CML and to update data of imatinib mesylate therapy, mechanisms of resistance, and in vitro and clinical data with the new tyrosine kinase inhibitors. Imatinib, which targets the ABL kinase activity of BCR-ABL, has prolonged survival in CML. Despite the efficacy of imatinib, some patients in chronic phase and more in advanced phases of CML develop resistance, frequently as a result of BCR-ABL tyrosine kinase domain mutants that impair imatinib binding but retain enzymatic activity. New tyrosine kinase inhibitors inhibit BCR-ABL more potently than imatinib and maintain activity against an array of imatinib-resistant BCR-ABL mutants. The IC(50) values of nilotinib and dasatinib are at least 10- to 100-fold lower for BCR-ABL compared with imatinib. Phase I-II trials of nilotinib and dasatinib showed high activity in imatinib-resistant CML and Philadelphia chromosome-positive ALL. Dasatinib also inhibits members of the Src family of kinases (SFKs); nilotinib does not. Whether SFKs have a critical role in imatinib resistance or BCR-ABL-mediated oncogenesis is unresolved. Agents that target signals downstream of BCR-ABL (e.g. Ras/Raf and phosphatidylinositol 3-kinase) are under investigation. Understanding the pathophysiology of CML and mechanisms of resistance has produced effective targeted strategies for imatinib-resistant CML.


Reported childhood trauma, attempted suicide and self-mutilative behavior among women in the general population.
This study attempted to determine the prevalence of childhood trauma among women in the general population as assessed in a representative sample from a city in central Turkey. The Dissociative Experiences Scale (DES) was administered to 628 women in 500 homes. They were also asked for childhood abuse and/or neglect. DES was administered to 251 probands. Mean age of the probands was 34.8+/- 11.5 years (range 18-65). Sixteen women (2.5%) reported sexual abuse, 56 women (8.9%) physical abuse, and 56 women (8.9%) emotional abuse in childhood. The most frequently reported childhood trauma was neglect (n= 213, 33.9%). The prevalence of suicide attempts was 4.5% (n= 28). Fourteen probands (2.2%) reported self-mutilative behavior.


[Cellular therapy in amyotrophic lateral sclerosis].
The possible role of stem cells transplantation in therapy for traumatic lesions or for diseases has been outlined in recent years. Amyotrophic lateral sclerosis (ALS) is one of the diseases where cellular therapy may be useful. The authors make an analytic review of the studies carried out in humans with ALS and in G93A transgenic rodent model of ALS to evaluate the effect of stem cell transplantation. They also review cellular responses from NSC-EZ cells in the spinal cord. Research on the potential uses of cellular therapy for ALS is on-going, however, the different studies are not homogeneous. Thus, many questions need to be answered, such as which is the most appropriate type of cells or which should be the volume of cells to implant, which is the best method for the transplantation and in the case of spinal cord implant which is the best target for the implant, or if it is necessary to administer concomitant substances, such as immunosuppressant drugs.


Genetic polymorphism and expression of a highly potent scorpion depressant toxin enable refinement of the effects on insect Na channels and illuminate the key role of Asn-58.
We isolated from the venom of the scorpion Leiurus quinquestriatus hebraeus an extremely active anti-insect selective depressant toxin, Lqh-dprIT(3). Cloning of Lqh-dprIT(3) revealed a gene family encoding eight putative polypeptide variants (a-h) differing at three positions (37A/G, 50D/E, and 58N/D). All eight toxin variants were expressed in a functional form, and their toxicity to blowfly larvae, binding affinity for cockroach neuronal membranes, and CD spectra were compared. This analysis links Asn-58, which appears in variants a-d, to a toxin conformation associated with high binding affinity for insect sodium channels. Variants e-h, bearing Asp-58, exhibit a different conformation and are less potent. The importance of Asn-58, which is conserved in other depressant toxins, was further validated by construction and analysis of an N58D mutant of the well-characterized depressant toxin, LqhIT(2). Current and voltage clamp assays using the cockroach giant axon have shown that despite the vast difference in potency, the two types of Lqh-dprIT(3) variants (represented by Lqh-dprIT(3)-a and Lqh-dprIT(3)-e) are capable of blocking the action potentials (manifested as flaccid paralysis in blowfly larvae) and shift the voltage dependence of activation to more negative values, which typify the action of beta-toxins. Moreover, the stronger and faster shift in voltage dependence of activation and lack of tail currents observed in the presence of Lqh-dprIT(3)-a suggest an extremely efficient trapping of the voltage sensor compared to that of Lqh-dprIT(3)-e. The current clamp assays revealed that repetitive firing of the axon, which is reflected in contraction paralysis of blowfly larvae, can be obtained with either the less potent Lqh-dprIT(3)-e or the highly potent Lqh-dprIT(3)-a at more negative membrane potentials. Thus, the contraction symptoms in flies are likely to be dominated by the resting potential of neuronal membranes. This study clarifies the electrophysiological basis of the complex symptoms induced by scorpion depressant toxins in insects, and highlights for the first time molecular features involved in their activity.


Antimicrobial Consumption among 66 Acute Care Hospitals in Catalonia: Impact of the COVID-19 Pandemic.
Antimicrobials have been widely used during the COVID-19 pandemic. This study aimed to analyze the impact of the COVID-19 pandemic on the antimicrobial consumption of 66 hospitals in Catalonia. Adult antibacterial and antimycotic consumption was calculated as defined daily doses (DDD)/100 bed-days and DDD/100 discharges. Firstly, overall and ICU consumption in 2019 and 2020 were compared. Secondly, observed ICU 2020 consumptions were compared with non-COVID-19 2020 estimated consumptions (based on the trend from 2008-2019). Overall, antibacterial consumption increased by 2.31% and 4.15% DDD/100 bed-days and DDD/100 discharges, respectively. Azithromycin (105.4% and 109.08% DDD/100 bed-days and DDD/100 discharges, respectively) and ceftriaxone (25.72% and 27.97% DDD/100 bed-days and DDD/100 discharges, respectively) mainly accounted for this finding. Likewise, antifungal consumption increased by 10.25% DDD/100 bed-days and 12.22% DDD/100 discharges, mainly due to echinocandins or amphotericin B. ICU antibacterial and antimycotic consumption decreased by 1.28% and 4.35% DDD/100 bed-days, respectively. On the contrary, antibacterial and antifungal use, expressed in DDD/100 discharges, increased by 23.42% and 19.58%. Azithromycin (275.09%), ceftriaxone (55.11%), cefepime (106.35%), vancomycin (29.81%), linezolid (31.28%), amphotericin B (87.98%), and voriconazole (96.17%) use changed the most. Observed consumption of amphotericin B, azithromycin, caspofungin, ceftriaxone, vancomycin, and voriconazole were higher than estimated values. The consumption indicators for most antimicrobials deviated from the expected trend pattern. A worrisome increase in antibacterial and antifungal consumption was observed in ICUs in Catalonia.


Pan-antiviral effects of a PIKfyve inhibitor on respiratory virus infection in human nasal epithelium and mice.
Endocytosis, or internalization through endosomes, is a major cell entry mechanism used by respiratory viruses. Phosphoinositide 5-kinase (PIKfyve) is a critical enzyme for the synthesis of phosphatidylinositol (3, 5)biphosphate (PtdIns (3, 5)P2) and has been implicated in virus trafficking via the endocytic pathway. In fact, antiviral effects of PIKfyve inhibitors against SARS-CoV-2 and Ebola have been reported, but there is little evidence regarding other respiratory viruses. In this study, we demonstrated the antiviral effects of PIKfyve inhibitors on influenza virus and respiratory syncytial virus in vitro and in vivo. PIKfyve inhibitors Apilimod mesylate (AM) and YM201636 concentration-dependently inhibited several influenza strains in an MDCK cell-cytopathic assay. AM also reduced the viral load and cytokine release, while improving the cell integrity of human nasal air-liquid interface cultured epithelium infected with influenza PR8. In PR8-infected mice, AM (2 mg/mL), when intranasally treated, exhibited a significant reduction of viral load and inflammation and inhibited weight loss caused by influenza infection, with effects being similar to oral oseltamivir (10 mg/kg). In addition, AM demonstrated antiviral effects in RSV A2-infected human nasal epithelium in vitro and mouse in vivo, with an equivalent effect to that of ribavirin. AM also showed antiviral effects against human rhinovirus and seasonal coronavirus in vitro. Thus, PIKfyve is found to be involved in influenza and RSV infection, and PIKfyve inhibitor is a promising molecule for a pan-viral approach against respiratory viruses.


Stage-dependent skeletal malformations induced by valproic acid in rat.
In this work we study the skeletal teratogenic response in rats exposed to NaVP at different embryonic stages. Crl:CD female rats were treated subcutaneously with 400 mg/Kg b.w. NaVP at presomitic stage (group II) or nearly at 2, 6, 10, 14, 18 or 22 somites (groups III-VIII). The females on group I were treated with saline and served as controls. No treatment-related effects were observed at the level of resorptions, live fetuses and fetal or placental weight. The skeletal examination showed characteristic patterns of malformations strictly related to the period of treatment. In particular, groups II and III showed a significant increase of alterations of cervical vertebrae (mainly 1st to 3rd segment) and a decrease of the frequency of extra lumbar ribs in comparison to control. Group IV showed severe abnormalities localized at the 4th to 7th cervical segment and at the level of the 1st and 2nd thoracic segments, including duplications of thoracic segments 1, 2 or 3. The fetuses of group V were characterized by several alterations of the thoracic segments distributed without a clear specificity. In group VI, the thoracic region was also affected with some specificity at the level of the segments 4th to 9th; in group VII, last thoracic and lumbar segments were affected (mainly duplications) and in group VIII only lumbo-sacral abnormalities were recorded. These results confirm the specific effect of NaVP at the level of the axial skeleton and suggest a possible interaction with the expression of genes identifying the vertebral segments.


Individualized risks of first adverse events in patients with Fanconi anemia.
Fanconi anemia (FA) is an autosomal recessive condition associated with bone marrow failure (BMF) leading to death or hematopoietic stem cell transplantation, acute myeloid leukemia (AML), and solid tumors (STs). It is unclear which patients are most likely to develop each outcome. From a cohort of 144 North American patients with FA, we calculated individualized risks of each outcome, given the presence or absence of readily diagnosed congenital abnormalities that occur frequently in FA. Abnormal radii and a 5-item congenital abnormality score were significant risk factors for BMF. The cumulative incidence of BMF by age 10 years varied from 18% in the lowest BMF risk group to 83% in the highest. Because of competing risks, patients in the lowest BMF risk group were most likely to live long enough to develop AML or ST, and, conversely, patients in the highest BMF risk group were least likely to live long enough to develop AML or ST. By age 40, the cumulative incidence of ST ranged from 0.6% to 29% in the highest and lowest BMF risk groups, respectively. Abnormal radii are the strongest predictor of early BMF in FA; a congenital abnormality score separates patients with normal radii into distinct prognostic groups.


Body Composition and Metabolic Syndrome Components on Lipodystrophy Different Subtypes Associated with HIV.
HIV-associated lipodystrophy syndrome (HALS) is characterized by body fat redistribution as a consequence of the antiretroviral therapy (ART) introduction, associated with an increased risk of cardiovascular disease development. Subjective diagnosis, classified between three subtypes according to the body region on which fat is lost and/or accumulated, named lipoatrophy, lipohypertrophy, and mixed lipodystrophy, is possibly accompanied with metabolic alterations. Forty people living with HIV/AIDS (PLHA), with clinical diagnosis of HALS and from both genders, were assessed. They performed ambulatorial follow-up and used ART regularly. The main findings were greater lipid profile alterations among women, while no metabolic profile differences were found between the HALS subtypes. The lipohypertrophy group showed major alterations, with higher values for total body fat percent, visceral fat area (VFA), body mass index (BMI), and abdominal and neck circumferences when compared to the other groups. Lean body mass was superior only compared to the mixed lipodystrophy group, and fat mass only compared to the lipoatrophy group. BMI showed strong correlation with the VFA. In conclusion, despite anthropometric alterations related to HALS these individuals present, those are not accompanied with metabolic alterations. Strategies, as behavioral changes and disorders prevention, are important to decrease the risk of cardiovascular disease development.


Advances in inline quantification of co-eluting proteins in chromatography: Process-data-based model calibration and application towards real-life separation issues.
Pooling decisions in preparative liquid chromatography for protein purification are usually based on univariate UV absorption measurements that are not able to differentiate between product and co-eluting contaminants. This can result in inconsistent pool purities or yields, if there is a batch-to-batch variability of the feedstock. To overcome this analytical bottleneck, a tool for selective inline quantification of co-eluting model proteins using mid-UV absorption spectra and Partial Least Squares Regression (PLS) was presented in a previous study and applied for real-time pooling decisions. In this paper, a process-data-based method for the PLS model calibration will be introduced that allows the application of the tool towards chromatography steps of real-life processes. The process-data-based calibration method uses recorded inline mid-UV absorption spectra that are correlated with offline fraction analytics to calibrate PLS models. In order to generate average spectra from the inline data, a Visual Basic for Application macro was successfully developed. The process-data-based model calibration was established using a ternary model protein system. Afterwards, it was successfully demonstrated in two case studies that the calibration method is applicable towards real-life separation issues. The calibrated PLS models allowed a successful quantification of the co-eluting species in a cation-exchange-based aggregate and fraction removal during the purification of monoclonal antibodies and of co-eluting serum proteins in an anion-exchange-based purification of Cohn supernatant I. Consequently, the presented process-data-based PLS model calibration in combination with the tool for selective inline quantification has a great potential for the monitoring of future chromatography steps and may contribute to manage batch-to-batch variability by real-time pooling decisions.


Distribution of the snail Biomphalaria glabrata, intermediate host of Schistosoma mansoni, within a St Lucian field habitat.
A total of 6360 mud samples were obtained, in 62 collections made with an exhaustive sampling device, from banana drains on the West Indian island of St Lucia during fortnightly samplings over a 2(1/2)-year period. Analysis of counts of the snail Biomphalaria glabrata from these samples showed that this species had a contagious distribution. This finding is consistent with other evidence that banana drains form a rigorous habitat for B. glabrata. Its distribution was more contagious than that of Oncomelania quadrasi in certain Philippine habitats and several species of aquatic snail in various African irrigation canals. The exact transformation for normalizing the snail counts for standard statistical techniques was z = x(0.287) but the more convenient cube root transformation is probably adequate. However, if too few snails are collected (15 or fewer per 100 samples) or if the frequency distribution of snail counts is discontinuous, with too many widely separated high frequency counts, neither transformation will be entirely satisfactory.


Aged Mice Exhibit Severe Exacerbations of Dry Eye Disease with an Amplified Memory Th17 Cell Response.
The prevalence as well as the severity of dry eye disease increase with age. Memory T helper 17 (Th17) cells (CD4+IL-17A+CD44+) drive the chronic and relapsing course of dry eye disease. Here, we investigated the contribution of memory Th17 cells to age-related dry eye disease, and evaluated memory Th17 cell depletion with anti-IL-15 antibody as a strategy to abrogate the severe exacerbations of dry eye disease observed in aged mice. After initial exposure to desiccating stress, aged mice maintained higher frequencies of memory Th17 cells in the draining lymph nodes relative to young mice. Upon secondary exposure to desiccating stress, aged mice developed more severe corneal epitheliopathy than young mice, which is associated with increased local frequencies of Th17 cells (CD4+IL-17A+). Treatment with anti-IL-15 antibody decreased the enlarged memory Th17 pool in aged mice to frequencies comparable with young mice. Furthermore, anti-IL-15-treated mice showed significantly reduced conjunctival infiltration of Th17 cells and lower corneal fluorescein staining scores compared with saline-treated control mice. Our data suggest that age-related increases in the memory Th17 compartment predispose aged mice toward the development of severe corneal epithelial disease after exposure to a dry environment. Selectively targeting memory Th17 cells may be a viable therapeutic approach in the treatment of age-related dry eye disease.


Evidence That Artificial Light at Night Induces Structure-Specific Changes in Brain Plasticity in a Diurnal Bird.
We recently reported that artificial light at night (ALAN), at ecologically relevant intensities (1.5, 5 lux), increases cell proliferation in the ventricular zone and recruitment of new neurons in several forebrain regions of female zebra finches (Taeniopygia guttata), along with a decrease of total neuronal densities in some of these regions (indicating possible neuronal death). In the present study, we exposed male zebra finches to the same ALAN intensities, treated them with 5'-bromo-2'-deoxyuridine, quantified cell proliferation and neuronal recruitment in several forebrain regions, and compared them to controls that were kept under dark nights. ALAN increased cell proliferation in the ventricular zone, similar to our previous findings in females. We also found, for the first time, that ALAN increased new neuronal recruitment in HVC and Area X, which are part of the song system in the brain and are male-specific. In other brain regions, such as the medial striatum, nidopallium caudale, and hippocampus, we recorded an increased neuronal recruitment only in the medial striatum (unlike our previous findings in females), and relative to the controls this increase was less prominent than in females. Moreover, the effect of ALAN duration on total neuronal densities in the studied regions varied between the sexes, supporting the suggestion that males are more resilient to ALAN than females. Suppression of nocturnal melatonin levels after ALAN exhibited a light intensity-dependent decrease in males in contrast to females, another indication that males might be less affected by ALAN. Taken together, our study emphasizes the importance of studying both sexes when considering ALAN effects on brain plasticity.


The effects of overexpression of histamine releasing factor (HRF) in a transgenic mouse model.
Asthma is a disease that affects all ages, races and ethnic groups. Its incidence is increasing both in Westernized countries and underdeveloped countries. It involves inflammation, genetics and environment and therefore, proteins that exacerbate the asthmatic, allergic phenotype are important. Our laboratory purified and cloned a histamine releasing factor (HRF) that was a complete stimulus for histamine and IL-4 secretion from a subpopulation of allergic donors' basophils. Throughout the course of studying HRF, it was uncovered that HRF enhances or primes histamine release and IL-13 production from all anti-IgE antibody stimulated basophils. In order to further delineate the biology of HRF, we generated a mouse model. We constructed an inducible transgenic mouse model with HRF targeted to lung epithelial cells, via the Clara cells. In antigen naïve mice, overproduction of HRF yielded increases in BAL macrophages and statistical increases in mRNA levels for MCP-1 in the HRF transgenic mice compared to littermate controls. In addition to demonstrating intracellular HRF in the lung epithelial cells, we have also been able to document HRF's presence extracellularly in the BAL fluid of these transgenic mice. Furthermore, in the OVA challenged model, we show that HRF exacerbates the allergic, asthmatic responses. We found statistically significant increases in serum and BAL IgE, IL-4 protein and eosinophils in transgenic mice compared to controls. This mouse model demonstrates that HRF expression enhances allergic, asthmatic inflammation and can now be used as a tool to further dissect the biology of HRF.


Novel Levetiracetam Derivatives That Are Effective against the Alzheimer-like Phenotype in Mice: Synthesis, in Vitro, ex Vivo, and in Vivo Efficacy Studies.
We have synthesized a series of heptamethylene-linked levetiracetam-huprine and levetiracetam-(6-chloro)tacrine hybrids to hit amyloid, tau, and cholinergic pathologies as well as β-amyloid (Aβ)-induced epileptiform activity, some of the mechanisms that eventually lead to cognitive deficits in Alzheimer's disease patients. These hybrids are potent inhibitors of human acetylcholinesterase and butyrylcholinesterase in vitro and moderately potent Aβ42 and tau antiaggregating agents in a simple E. coli model of amyloid aggregation. Ex vivo determination of the brain acetylcholinesterase inhibitory activity of these compounds after intraperitoneal injection to C57BL6J mice has demonstrated their ability to enter the brain. The levetiracetam-huprine hybrid 10 significantly reduced the incidence of epileptic seizures, cortical amyloid burden, and neuroinflammation in APP/PS1 mice after a 4-week treatment with a 5 mg/kg dose. Moreover, the hybrid 10 rescued transgenic mice from cognitive deficits, thereby emerging as an interesting disease-modifying anti-Alzheimer drug candidate.


Noncardiac chest pain of esophageal origin in patients with and without coronary artery disease.
Non-cardiac chest pain is a frequent finding in patients admitted to emergency departments, and it has been shown that many of these patients may have an esophageal cause for their pain. However, little data are available on patients primarily referred to the cardiology unit, and especially those with coronary artery disease. The purpose of this study was to assess the role of esophageal dysfunction in chest pain patients with and without coronary artery disease. Eighty-one patients referred from a cardiology unit for chest pain and no myocardial infarction entered the study. Sixty-one patients had no evidence of coronary artery disease, whereas 20 had coronary artery disease with chest pain at rest. After the cardiological evaluation, the patients underwent esophageal function testing by means of upper endoscopy, manometry, and 24-hour pH-monitoring. Overall, 10% of patients (2.5% in the coronary artery disease group) had evidence of endoscopic esophagitis, 46% of esophageal motor disorders (12% in the coronary artery disease group), and 10% abnormal pH-monitoring (1% in the coronary artery disease group). We report that the esophagus might be responsible for non-cardiac chest pain in patients with and without coronary artery disease. In our experience, esophageal motor disorders, and not an increased acid reflux, are the abnormalities most commonly found in these patients.


Loss of TGF-beta signaling contributes to autoimmune pancreatitis.
Recent observations suggest that immune response is involved in the development of pancreatitis. However, the exact pathogenesis underlying this immune-mediated response is still under debate. TGF-beta has been known to be an important regulating factor in maintaining immune homeostasis. To determine the role of TGF-beta in the initiation or progression of pancreatitis, TGF-beta signaling was inactivated in mouse pancreata by overexpressing a dominant-negative mutant form of TGF-beta type II receptor in the pancreas, under control of the pS2 mouse trefoil peptide promoter. Transgenic mice showed marked increases in MHC class II molecules and matrix metalloproteinase expression in pancreatic acinar cells. These mice also showed increased susceptibility to cerulein-induced pancreatitis. This pancreatitis was characterized by severe pancreatic edema, inflammatory cell infiltration, T- and B-cell hyperactivation, IgG-type autoantibodies against pancreatic acinar cells, and IgM-type autoantibodies against pancreatic ductal epithelial cells. Therefore, TGF-beta signaling seems to be essential either in maintaining the normal immune homeostasis and suppressing autoimmunity or in preserving the integrity of pancreatic acinar cells.


Estimation of free energy barriers in the cytoplasmic and mitochondrial aspartate aminotransferase reactions probed by hydrogen-exchange kinetics of C alpha-labeled amino acids with solvent.
The existence of the postulated quinonoid intermediate in the cytoplasmic aspartate amino-transferase catalyzed transamination of aspartate to oxaloacetate was probed by determining the extent of transfer of tritium from the C alpha position of tritiated L-aspartate to pyridoxamine 5'-phosphate in single turnover experiments in which washout from the back-reaction was obviated by product trapping. The maximum amount of transferred tritium observed was 0.7%, consistent either with a mechanism in which a fraction of the net transamination reaction proceeds through a quinonoid intermediate or with a mechanism in which this intermediate is formed off the main reaction pathway. It is shown that transfer of labeled hydrogen from the amino acid to cofactor cannot be used to differentiate a stepwise from a concerted transamination mechanism. The amount of tritium transferred is a function of the rate constant for torsional equilibration about the epsilon-amino group of Lys-258, the presumptive abstractor of the C alpha proton; the relative rate constants for hydrogen exchange with solvent versus cofactor protonation; and the tritium isotope effect on this ratio. The free energy barriers facing the covalent intermediate between aldimine and keto acid product (i.e., ketimine and possibly quinonoid) were evaluated relatively by comparing the rates of C alpha-hydrogen exchange in starting amino acid with the rates of keto acid formation. The value of theta (= kexge/kprod) was found to be 2.6 for the reaction of cytoplasmic isozyme with aspartate and ca. 0.5 for that of the mitochondrial form with glutamate.


Endoscopic endonasal clipping of an unsecured superior hypophyseal artery aneurysm. Technical note.
Paraclinoidal aneurysms, especially superior hypophyseal artery (SHA) aneurysms (with medial projection), can be challenging to access via a pterional craniotomy and damage to the optic nerve can occur during surgery. The authors have previously reported on endonasal clipping and aneurysmorrhaphy of a vertebral artery aneurysm following proximal and distal protection of the aneurysm using partial coil embolization. To the best of the authors' knowledge no unprotected aneurysm has been clipped using an endonasal approach. The 56-year-old woman in this report was found to have two unruptured aneurysms: an anterior communicating artery (ACoA) aneurysm and an SHA aneurysm. An endoscopic endonasal, transplanar-transsellar approach was used to successfully clip the SHA aneurysm. Proximal and distal control was obtained endonasally prior to successful clip occlusion of the aneurysm. The ACoA aneurysm was clipped via a pterional craniotomy during the same anesthetic session. This report shows that it is possible to successfully clip a medially projecting, paraclinoidal aneurysm using an endonasal approach. Such cases must be chosen with extreme caution and only performed by surgeons with significant experience with both endoscopic endonasal approaches and neurovascular surgery.


GfsA is a β1,5-galactofuranosyltransferase involved in the biosynthesis of the galactofuran side chain of fungal-type galactomannan in Aspergillus fumigatus.
Previously, we reported that GfsA is a novel galactofuranosyltransferase involved in the biosynthesis of O-glycan, the proper maintenance of fungal morphology, the formation of conidia and anti-fungal resistance in Aspergillus nidulans and A. fumigatus (Komachi Y et al., 2013. GfsA encodes a novel galactofuranosyltransferase involved in biosynthesis of galactofuranose antigen of O-glycan in Aspergillus nidulans and Aspergillus fumigatus. Mol. Microbiol. 90:1054-1073). In the present paper, to gain an in depth-understanding of the enzymatic functions of GfsA in A. fumigatus (AfGfsA), we established an in vitro assay to measure galactofuranosyltransferase activity using purified AfGfsA, UDP-α-d-galactofuranose as a sugar donor, and p-nitrophenyl-β-d-galactofuranoside as an acceptor substrate. LC/MS, 1H-NMR and methylation analyses of the enzymatic products of AfGfsA revealed that this protein has the ability to transfer galactofuranose to the C-5 position of the β-galactofuranose residue via a β-linkage. AfGfsA requires a divalent cation of manganese for maximal activity and consumes UDP-α-d-galactofuranose as a sugar donor. Its optimal pH range is 6.5-7.5 and its optimal temperature range is 20-30°C. 1H-NMR, 13C-NMR and methylation analyses of fungal-type galactomannan extracted from the ∆AfgfsA strain revealed that AfGfsA is responsible for the biosynthesis of β1,5-galactofuranose in the galactofuran side chain of fungal-type galactomannan. Based on these results, we conclude that AfGfsA acts as a UDP-α-d-galactofuranose: β-d-galactofuranoside β1,5-galactofuranosyltransferase in the biosynthetic pathway of galactomannans.


Metagenome-assembled genomes from particle-associated microbial communities in the mesopelagic zone of the Pacific Ocean.
We report 10 particle-associated metagenome-assembled genomes (MAGs) from the mesopelagic zone of Pacific Ocean seawaters. MAGs comprise members of Flavobacteria Halomonas, Blastomonas, Brevundimonas, Alteromonas, Shingomonas, Sphingopyxis, Tabrizicola, Proteobacteria, and Gammaproteobacteria. Functional annotation suggests that these bacteria are involved in central particulate organic carbon conversion, nitrogen cycling, and phosphorus cycling.


Low-Ceiling-Temperature Polymer Microcapsules with Hydrophobic Payloads via Rapid Emulsion-Solvent Evaporation.
We report a microencapsulation procedure based on rapid solvent evaporation to prepare microcapsules with hydrophobic core materials and low-ceiling-temperature polymer shell wall of cyclic poly(phthalaldehyde) (cPPA). We use and compare microfluidic and bulk emulsions. In both methods, rapid solvent evaporation following emulsification resulted in kinetically trapped core-shell microcapsules, whereas slow evaporation resulted in acorn morphology. Through the systematic variation of encapsulation parameters, we found that polymer-to-core weight ratios higher than 1 and polymer concentrations higher than 4.5 wt % in the oil phase were required to obtain a core-shell structure. This microencapsulation procedure enabled the fabrication of microcapsules with high core loading, controlled size, morphology, and stability. This procedure is versatile, allowing for the encapsulation of other hydrophobic core materials, i.e., mineral oil and organotin catalyst, or using an alternative low-ceiling-temperature polymer shell wall, poly(vinyl tert-butyl carbonate sulfone).


Risk prediction models for cancer-specific survival following cytoreductive nephrectomy in the contemporary era.
To develop a risk-stratification model for cancer-specific survival (CSS) following cytoreductive nephrectomy (CN) in the contemporary era. A retrospective review was performed of 313 patients who underwent CN for M1 renal cell carcinoma (RCC) from 1990 to 2010. To account for the introduction of targeted therapies, timing of surgery was classified as immunotherapy era (1990-2004) or contemporary era (2005-2010). Risk scores were developed to predict CSS using Cox proportional hazards regression models. A total of 215 (69%) and 98 (31%) patients were treated in the immunotherapy and contemporary eras, respectively. Median follow-up among survivors was 9.6 years, during which time 291 patients died, including 279 from RCC. On multivariable analysis limited to preoperative features, age ≥ 75, (hazard ratio [HR] 1.9), female sex (HR 1.9), constitutional symptoms (HR 1.61), radiographic lymphadenopathy (HR 1.59), and IVC tumor thrombus (HR 1.65) were significantly associated with CSS. On multivariable analysis including pathologic features, the features above as well as coagulative necrosis (HR 1.51) and sarcomatoid differentiation (HR 1.44) were significantly associated with CSS (all P < 0.05). Risk scores were developed for each model and used to predict CSS according to era. Decision curve analysis revealed that the preoperative risk score conferred a net benefit over a treat-all or treat-none approach beyond a 1-year cancer-specific mortality threshold of 25%. We developed risk scores to predict CSS for patients treated with CN in the contemporary era. Patients with poor predicted survival may consider avoiding CN as initial management.


High-normal serum homocysteine concentrations are associated with an increased risk of early atherosclerotic carotid artery wall lesions in healthy subjects.
Moderate hyperhomocysteinaemia is common in the general population and has been linked with systemic atherosclerotic vascular disease. We studied the relation of sonographically determined carotid intima-media wall thickness to serum homocysteine concentrations in asymptomatic, healthy subjects. Seventy-five male and female untreated subjects (mean age 49 years, range 22-75) with normal serum folate concentrations were included. High-resolution duplex sonography was used to determine intima-media thickness of the common carotid artery. Serum homocysteine concentration was measured by high-performance liquid chromotography with fluorescence detection. Mean intima-media thickness (+/- SD) was 0.78 +/- 0.19 mm (range 0.5-1.35) and mean serum homocysteine concentration was 10.5 +/- 2.81 micromol/l (range 5.7-19.6). In stepwise regression models, statistically significant predictors of intima-media thickness included age, body mass index, LDL cholesterol and homocysteine (R2 = 0.51). Homocysteine concentration was independently associated with intima-media thickness after adjustment for the other variables (P < 0.001) and explained an additional 18% of the variation of intima-media thickness. In healthy subjects, high-normal serum homocysteine concentrations are associated with an increased prevalence of carotid artery wall thickening. The significance of the contribution of homocysteine to the variation of carotid intima-media thickness, even at concentrations previously believed to be normal, suggests a role for homocysteine as an independent risk factor for early carotid artery atherosclerosis in the asymptomatic subjects.


Pre-transplant cytomegalovirus (CMV) serostatus remains the most important determinant of CMV reactivation after allogeneic hematopoietic stem cell transplantation in the era of surveillance and preemptive therapy.
Between January 2001 and June 2008, 315 adult patients (median age 43 years, range 16-65) including 203 males and 112 females undergoing hematopoietic stem cell transplantation (HSCT) had serial monitoring for cytomegalovirus (CMV) followed by initiation of preemptive therapy. The majority (62.1%) had a conventional myeloablative transplant with 116 (36.9%) having a reduced-intensity conditioning (RIC) transplant, using either matched sibling/family (63.3%) or unrelated donors (36.7%). Graft source was peripheral blood stem cells in 257 (81.5%), bone marrow in 41 (13.1%), and cord blood in 16 (5.4%). T-cell depletion with anti-thymocyte globulin or alemtuzumab was used in 35%. Based upon CMV serostatus, patients were classified into low risk (donor [D]-/recipient [R]-), intermediate risk (D+/R-), or high risk (D-/R+ or D+/R+). Serial weekly monitoring for CMV viremia was performed using a qualitative polymerase chain reaction (PCR) and when positive, quantification was done using either pp65 antigen or a quantitative PCR. CMV reactivation was seen in 123 patients (39.1%) at a median of 50 days post HSCT (range 22-1978). CMV serostatus was the most important risk factor with incidence of 53% in the high-risk group (53.3%) compared with 10.2% in the intermediate risk and 0% in the low-risk group (P<0.0001). Other significant risk factors identified included use of alemtuzumab during conditioning (P=0.03), RIC transplants (P=0.06), and the presence of acute graft-versus-host disease (GVHD) (P<0.0001). On a multivariate analysis, CMV serostatus, RIC transplants, and acute GVHD remained independent predictors of CMV reactivation. All were treated with antiviral therapy with responses seen in 109 (88.6%). Sixteen patients (13%) developed CMV disease at a median of 59 days post HSCT (range 26 days-46 months), 8 of whom died. At a median follow up of 43 months (range 6-93), 166 patients (52.6%) are alive with a significantly higher survival among patients without CMV reactivation (57.2%) as compared with patients with CMV reactivation (45.5%; P=0.049). CMV reactivation and disease remains a major problem in high-risk patients undergoing allogeneic HSCT. Novel prophylactic measures such as immunotherapy and drug prophylaxis need to be considered in this specific group of patients.


Stress and associated risk factors among the elderly: a cross-sectional study from rural Thailand.
Background. Stress is a common mental health problem of the elderly population that affects their quality of life. The objective of this study was to determine the level of stress and associated factors among the elderly living in rural areas of Thailand. Methods. This was a cross-sectional study conducted in two sub-districts of rural Thailand and interviewed 403 elderly persons. We used simple random sampling technique from a list of registered elderly individuals and conducted face-to-face interviews using a questionnaire. The questionnaire were piloted, validated and pretested beforehand. Multiple linear regression was applied for data analysis. This study was approved by the Ethical Review Committee of the University of Phayao, Thailand. Results. The mean age of the participants was 68 and two thirds (67%) were female. Less than 43% of the participants had moderate, and one third (34%) had high levels of stress. More than half of participants had low level stress management. Stress was significantly associated with alcohol and illness with a predictive power of 3.0% [(R = 0.173, R Square = 0.030) (p<0.05)]. Conclusion. We conclude that risk factors such as alcohol and illness affect elderly population living in rural areas of Thailand to a major extent in terms of stress.


Blood Transcriptomic Analyses Reveal Functional Pathways Associated with Thermotolerance in Pregnant Ewes Exposed to Environmental Heat Stress.
Environmental heat stress triggers a series of compensatory mechanisms in sheep that are dependent on their genetic regulation of thermotolerance. Our objective was to identify genes and regulatory pathways associated with thermotolerance in ewes exposed to heat stress. We performed next-generation RNA sequencing on blood collected from 16 pregnant ewes, which were grouped as tolerant and non-tolerant to heat stress according to a physiological indicator. Additional samples were collected to measure complete blood count. A total of 358 differentially expressed genes were identified after applying selection criteria. Gene expression analysis detected 46 GO terms and 52 KEGG functional pathways. The top-three signaling pathways were p53, RIG-I-like receptor and FoxO, which suggested gene participation in biological processes such as apoptosis, cell signaling and immune response to external stressors. Network analysis revealed ATM, ISG15, IRF7, MDM4, DHX58 and TGFβR1 as over-expressed genes with high regulatory potential. A co-expression network involving the immune-related genes ISG15, IRF7 and DXH58 was detected in lymphocytes and monocytes, which was consistent with hematological findings. In conclusion, transcriptomic analysis revealed a non-viral immune mechanism involving apoptosis, which is induced by external stressors and appears to play an important role in the molecular regulation of heat stress tolerance in ewes.


Antibodies to gliadin, endomysium, and tissue transglutaminase for the diagnosis of celiac disease.
Tissue transglutaminase has recently been identified as the main autoantigen recognized by antiendomysial antibodies in celiac disease. Serum immunoglobulin (Ig)A antibodies to tissue transglutaminase (tTG-ab) determined by an enzyme-linked immunosorbent assay (ELISA) technique have been reported to correlate closely with IgA antiendomysial antibodies (EMA). The purpose of this study was to assess the sensitivity, specificity, and predictive value of tTG-ab measured by a commercially available ELISA technique, compared with those of EMA and IgA antigliadin antibodies (AGA) for the diagnosis of celiac disease. Twenty-seven serum samples were obtained from patients with untreated celiac disease, 37 from patients who had had gluten withdrawn from their diets for varying time spans, and 34 from control subjects without celiac disease. All were younger than 14 years. Presence of tTG-ab and AGA was determined by ELISA and of EMA by indirect immunofluorescence. Twenty-six of 27 serum samples obtained from patients at the time of diagnosis of celiac disease were AGA positive. All 27 (concordance rate 100%) were positive for EMA and tTG-ab. Of the 34 control subjects, 1 was for AGA and 2 for tTG-ab. All 34 were negative for EMA. Sensitivity, specificity, positive predictive value, and negative predictive value within this group were, for tTG-ab: 100%, 94%, 93%, and 100%, respectively; for EMA: all four indexes were 100%; and for AGA: 96%, 97%, 96%, and 97%, respectively. Of the 37 with treated celiac disease, 2 were AGA positive, 9 were EMA positive, and 6 were tTG-ab positive. The concordance rate between EMA and tTG-ab was 100% in the group with untreated celiac disease, 94% in the control subjects, and 76% in the group with treated celiac disease. Immunoglobulin A antibodies to tissue transglutaminase are new, highly sensitive, and specific markers of celiac disease. They can be determined easily by an accurate, comparatively cheap technique and thereby may advantageously replace the EMA marker traditionally used.


Onabotulinum toxin A in the treatment of chronic migraine: patient selection and special considerations.
Discovered by serendipity, onabotulinum toxin A (BoNT-A) is the only US Food and Drug Administration-approved treatment for the prevention of chronic migraine (CM), one of the most disabling and burdensome human conditions. Its efficacy, safety and tolerability, proved by the largest and longest migraine therapeutic trial (the Phase III Research Evaluating Migraine Prophylaxis Therapy program [PREEMPT]), have been replicated by various real-life studies also in the presence of medication overuse. The benefit of BoNT-A prophylaxis is likely due to its ability to counteract peripheral and central nociceptive sensitization through reversible chemical denervation of pericranial sensitive afferents. Its efficacy increases considerably over time during long-term treatments, significantly varying among patients. The present review focuses on the state-of-the art of current knowledge on putative instrumental, biochemical and clinical predictors of BoNT-A responsiveness, outlining the need for a thorough characterization of the full phenotypic migraine picture when trying to predict good responders. Available evidence suggests that disentangling the BoNT-A responsiveness puzzle requires 1) a reappraisal of easy-obtainable clinical details (eg, site and quality of pain, presence of cranial autonomic symptoms), 2) a proper stratification of patients with CM according to their headache frequency, 3) the evaluation of potential synergistic effects of concomitant prophylaxis/treatment and 4) a detailed assessment of modifiable risk factors evolution during treatment.


Ultrasonography as a diagnostic tool for posteromedial corner pathologies: a pictorial essay.
The posteromedial corner (PMC) is a common location for knee joint pain, and accurate diagnosis is essential for appropriate treatment. The frequent causes of pain in the PMC include pathologies of the posterior part of the medial meniscus, damage to articular cartilage, popliteal cysts and the semimembranosus tendinopathy.Currently, magnetic resonance imaging is the gold standard for assessing knee joint disorders, but its availability and cost can limit its use in some cases. In this pictorial essay, we presented the use of ultrasonography as an alternative method for assessing PMC.We present a series of images to demonstrate the value of ultrasonography and describe the methods used for assessing PMC with a particular focus on semimembranosus tendinopathy.


The diversity of phytoseiid mite communities in the Maghreb comparisons with the fauna of one of the Canary Islands.
Phytoseiid mite diversity was surveyed on wild and cultivated plants in Morocco and Tunisia from 1994 to 2003. Results were associated with those obtained in previous surveys conducted by other authors in Algeria and in one of the Canary Islands (Gran Canaria). They showed, 21 species are known from Tunisia (1 was known before), 53 from Algeria, 41 from Morocco (15 were known before) and 23 from the Canary Island. Eight were known from all these islands before the data published in 2003 concerning only Gran Canaria, which represent a very small area compared to the three large countries, above all to Algeria. Ten species were common to all the four countries, 4 to Morocco, Algeria and Tunisia, 1 to Algeria and Tunisia. One species was in Tunisia and Morocco, suggesting that this species might also be present in Algeria, 1 was present in Morocco, Algeria and in the Canary Island. Nine species were found in Algeria and Morocco and one species in Algeria and the Canary Island. The authors detected a new genus and a new species in Tunisia, 8 new species in Morocco, and published data mentioned 6 new species in the Canary Island. The considerations on biogeography were also given.


Identification and genes expression analysis of ATP-dependent phosphofructokinase family members among three Saccharum species.
Sugarcane contributes ~80% of sugar production in the world and is an established biofuel crop. In working towards understanding the molecular basis of high sucrose accumulation, we have annotated and analysed the ATP-dependent phosphofructokinase (PFK) gene family that catalyses the phosphorylation of D-fructose 6-phosphate to D-fructose 1,6-bisphosphate. PFKs play an essential role in sucrose metabolism in plants and their expression patterns are unknown in sugarcane. In this study, based on the sorghum genome and sugarcane EST database, 10 PFK gene members were annotated and further verified by PCR using sugarcane genomic DNA. An unrooted phylogenetic tree was constructed with the deduced protein sequences of PFKs that were from the assembly of cDNA library of sugarcane and other plants. The results showed that gene duplication events and the retention rate after genome wide or segmental duplications occurred in higher frequency in monocots than in dicots and the genes in subgroup II of group III were likely originated from recent duplication events. Quantitative RT-PCR was performed to investigate the gene expression of 10 PFK genes in five tissues of three Saccharum species, including two developmental stages in leaves and three in culms. Of the PFK family members in sugarcane, ScPFK6, 7 and 8 appeared to be the primary isoforms based on the highly abundant expression of these three genes. ScPFK7 showed high expression level in the leaves, suggesting a potential role in sucrose metabolism. ScPFK8 had lower expression level in Saccharum officinarum L. than in the other two species, suggesting negative regulation of sucrose metabolism, which might have contributed to the high sugar content of S. officinarum. The genes in monocot specific subgroup II of group III, PFK7, 8 and 9, showed variation among the three Saccharum species, suggesting potential functional redundancy. Our results provide detailed annotation and analysis of the PFK gene family in sugarcane. Further elucidation of the role of ScPFK8 in the domestication process of sugarcane would be useful.


Insulin treatment ameliorates impaired corneal reepithelialization in diabetic rats.
Patients with diabetes are at an increased risk for developing corneal disorders, often as a result of surgical and nonsurgical trauma. This study investigated whether intensive treatment of diabetes with the goal of maintaining blood glucose concentrations close to the normal range could ameliorate the delayed corneal wound healing found in animals with uncontrolled diabetes. Diabetes was induced with streptozotocin, and rats were divided into groups based on the degree of blood glucose control: 1) not treated with insulin implants (DB group), 2) receiving insulin implants and determined to be normoglycemic (DB-IN group), and 3) normal, nondiabetic animals serving as controls. Immediately before wounding at 9 or 11 weeks after the induction of the diabetic state, corneal thickness and corneal sensitivity of the DB and DB-IN groups were comparable with controls. DB, but not DB-IN, rats exhibited subnormal intraocular pressure. At 9 and 11 weeks after the onset of diabetes, the corneas of the right and left eyes, respectively, were abraded by mechanical scraping. The DB rats had residual corneal epithelial defects that ranged from 23% to 5.6-fold larger compared with the control group and a rate of healing that was 19% slower than control animals. The DB-IN group had healing characteristics similar to the control group. DNA synthesis in the peripheral cornea and conjunctiva, but not the limbus, of DB animals was reduced 50 and 91%, respectively, from control levels. Cell proliferation in the DB-IN group was comparable with the control group, with the exception of a 72% increase in the peripheral cornea in the DB-IN group. These results indicate that intensive therapy with insulin, which establishes normoglycemia in rats with diabetes, prevents the delay in wound healing of ocular surface epithelium observed in poorly controlled diabetic animals.


Estimating the in vitro cytotoxicity of the newly emerged zinc oxide (ZnO) doped chromium nanoparticles using the human fetal lung fibroblast cells (WI38 cells).
Advances in nanotechnology have been increased for more smart applications and getting the highest level of benefits, recently modification of the surface characters of nanoparticles is a new trend to get the optimal benefits, one of these modification is doping of zinc oxide with chromium nanoparticles (ZnO doped Cr NPs), the present study aimed to identify the surface characters of doped ZnO and their possible cytotoxic effects. The doped NPs were characterized by X-ray diffraction (XRD), Fourier transform infrared (FTIR), Field emission scanning electron microscope (FESEM), and Electromagnetic Data Exchange (EDX). Human fetal lung fibroblast cells (WI38 Cells) was treated with variable concentrations of pure ZnO and ZnO doped Cr (0.01 %, 0.02 %, 0.03 % and 0.04 %) for 24 hr at 37 °C followed by the MTT assay. The cells treated with the obtained half-maximal inhibitory concentration (IC50). The supernatant and cells were collected for oxidant/anti-oxidant and molecular analysis.The observed FESEM features are in line with the reported XRD analysis confirming the hexagonal crystal symmetry of all samples. The findings revealed that pure ZnO exhibited potent cytotoxic effects followed by (0.03 % and 0.04 %). All tested NPs produce lipid peroxidation significantly (0.03 % and 0.04 %). The significant up regulation of Bcl-2-associated X protein (BAX) and apoptotic Caspase (Cas-3) transcription level were reported in ZnO and 0.03 % and 0.04 % in contrast the anti apoptitic B-cell lymphoma 2 (Bcl-2) is elevated in 0.01 % and 0.02 %. Doping of ZnO with Cr causing significant morphological changes which effect on their toxicity especially with 0.03 % and 0.04 %.


Axitinib dose titration: analyses of exposure, blood pressure and clinical response from a randomized phase II study in metastatic renal cell carcinoma.
In a randomized, double-blind phase II trial in patients with metastatic renal cell carcinoma (mRCC), axitinib versus placebo titration yielded a significantly higher objective response rate. We evaluated pharmacokinetic and blood pressure (BP) data from this study to elucidate relationships among axitinib exposure, BP change, and efficacy. Patients received axitinib 5 mg twice daily during a lead-in period. Patients who met dose-titration criteria were randomized 1:1 to stepwise dose increases with axitinib or placebo. Patients ineligible for randomization continued without dose increases. Serial 6-h and sparse pharmacokinetic sampling were carried out; BP was measured at clinic visits and at home in all patients, and by 24-h ambulatory BP monitoring (ABPM) in a subset of patients. Area under the plasma concentration-time curve from 0 to 24 h throughout the course of treatment (AUCstudy) was higher in patients with complete or partial responses than those with stable or progressive disease in the axitinib-titration arm, but comparable between these groups in the placebo-titration and nonrandomized arms. In the overall population, AUCstudy and efficacy outcomes were not strongly correlated. Mean BP across the population was similar when measured in clinic, at home, or by 24-h ABPM. Weak correlations were observed between axitinib steady-state exposure and diastolic BP. When grouped by change in diastolic BP from baseline, patients in the ≥10 and ≥15 mmHg groups had longer progression-free survival. Optimal axitinib exposure may differ among patients with mRCC. Pharmacokinetic or BP measurements cannot be used exclusively to guide axitinib dosing. Individualization of treatment with vascular endothelial growth factor receptor tyrosine kinase inhibitors, including axitinib, is thus more complex than anticipated and cannot be limited to a single clinical factor.


Evaluation of natural colonisation of cementitious materials: effect of bioreceptivity and environmental conditions.
Incorporation of living organisms, such as photosynthetic organisms, on the structure envelope has become a priority in the area of architecture and construction due to aesthetical, economic and ecological advantages. Important research efforts are made to achieve further improvements, such as for the development of cementitious materials with an enhanced bioreceptivity to stimulate biological growth. Previously, the study of the bioreceptivity of cementitious materials has been carried out mainly under laboratory conditions although field-scale experiments may present different results. This work aims at analysing the colonisation of cementitious materials with different levels of bioreceptivity by placing them in three different environmental conditions. Specimens did not present visual colonisation, which indicates that environmental conditions have a greater impact than intrinsic properties of the material at this stage. Therefore, it appears that in addition to an optimized bioreceptivity of the concrete (i.e., composition, porosity and roughness), extra measures are indispensable for a rapid development of biological growth on concrete surfaces. An analysis of the colonisation in terms of genus and quantity of the most representative microorganisms found on the specimens for each location was carried out and related to weather conditions, such as monthly average temperature and total precipitation, and air quality in terms of NOx, SO2, CO and O3. OPC-based specimens presented a higher colonisation regarding both biodiversity and quantity. However, results obtained in a previous experimental programme under laboratory conditions suggested a higher suitability of Magnesium Phosphate Cement-based (MPC-based) specimens for algal growth. Consequently, carefully considering the environment and the relationships between the different organisms present in an environment is vital for successfully using a cementitious material as a substrate for biological growth.


Clarifying the arrhythmogenic substrate for Brugada syndrome.
The right ventricular outflow tract (RVOT) is considered the arrhythmogenic region that gives rise to Brugada syndrome. To obtain a better understanding of this substrate, we performed electroanatomic mapping of the right ventricle (RV) in patients with Brugada syndrome. The RV was mapped electroanatomically with the CARTO system in 11 patients with asymptomatic Brugada syndrome but in whom ventricular fibrillation was induced by programmed ventricular stimulation, and in 5 control patients. The low voltage zone area (< 1.5 mV) was larger (16.1% versus 7.8%, P < 0.01) and the bipolar electrogram duration was greater (81.6 ± 7.8 ms versus 53.4 ± 5.6 ms, P < 0.01) in the patients with Brugada syndrome versus the control patients; the bipolar electrogram duration was greater in the septal portion and free wall of the RVOT. Our data suggest that regional endocardial conduction slowing based on structural abnormalities exists at the RVOT in Brugada syndrome.


Dominance of the forward compression wave in determining pulsatile components of blood pressure: similarities between inotropic stimulation and essential hypertension.
Pulsatile components of blood pressure may arise from forward (ventricular generated) or backward wave travel in the arterial tree. The objective of this study was to determine the relative contributions of forward and backward waves to pulsatility. We used wave intensity and wave separation analysis to determine pulsatile components of blood pressure during inotropic and vasopressor stimulation by dobutamine and norepinephrine in normotensive subjects and compared pulse pressure components in hypertensive (mean±SD, 48.8±11.3 years; 165±26.6/99±14.2 mm Hg) and normotensive subjects (52.2±12.6 years; 120±14.2/71±8.2 mm Hg). Dobutamine (7.5 μg/kg per minute) increased the forward compression wave generated by the ventricle and increased pulse pressure from 36.8±3.7 to 59.0±3.4 mm Hg (mean±SE) but had no significant effect on mean arterial pressure or the midsystolic backward compression wave. By contrast, norepinephrine (50 ng/kg per minute) had no significant effect on the forward compression wave but increased the midsystolic backward compression wave. Despite this increase in the backward compression wave, and an increase in mean arterial pressure, norepinephrine increased central pulse pressure less than dobutamine (increases of 22.1±3.8 and 7.2±2.8 mm Hg for dobutamine and norepinephrine, respectively; P<0.02). An elevated forward wave component (mean±SE, 50.4±3.4 versus 35.2±1.8 mm Hg, in hypertensive and normotensive subjects, respectively; P<0.001) accounted for approximately two thirds of the total difference in central pulse pressures between hypertensive and normotensive subjects. Increased central pulse pressure during inotropic stimulation and in essential hypertension results primarily from the forward compression wave.


Characterization of immunosuppressive myeloid cells in Merkel cell carcinoma: correlation with resistance to PD-1 pathway blockade.
Merkel cell carcinoma (MCC) is a highly immunogenic skin cancer. Although essentially all MCCs are antigenic through viral antigens or high tumor mutation burden, MCC has a response rate of only ~50% to PD-(L)1 blockade suggesting barriers to T cell responses. Prior studies of MCC immunobiology have focused on CD8 T-cell infiltration and their exhaustion status, while the role of innate immunity, particularly myeloid cells, in MCC remains underexplored. We utilized single cell transcriptomics from 9 MCC patients and multiplex-immunohistochemistry staining of 54 patients' pre-immunotherapy tumors, to identify myeloid cells and evaluate association with immunotherapy response. Single cell transcriptomics identified tumor-associated macrophages (TAMs) as the dominant myeloid component within MCC tumors. These TAMs express an immunosuppressive gene signature characteristic of monocytic myeloid derived suppressor cells and importantly express several targetable immune checkpoint molecules, including PD-L1 and LILRB receptors, that are not present on tumor cells. Analysis of 54 pre-immunotherapy tumor samples showed that a subset of TAMs (CD163+, CD14+, S100A8+) selectively infiltrated tumors that had significant CD8 T-cells. Indeed, higher TAM prevalence was associated with resistance to PD-1 blockade. While spatial interactions between TAMs and CD8 T cells were not associated with response, myeloid transcriptomic data showed evidence for cytokine signaling and expression of LILRB receptors, suggesting potential immunosuppressive mechanisms. This study further characterizes TAMs in MCC tumors and provides insights into their possible immunosuppressive mechanism. TAMs may reduce the likelihood of treatment response in MCC by counteracting the benefit of CD8 T-cell infiltration.


Tuning characteristics of low-frequency EEG to positions and velocities in visuomotor and oculomotor tracking tasks.
Movement decoders exploit the tuning of neural activity to various movement parameters with the ultimate goal of controlling end-effector action. Invasive approaches, typically relying on spiking activity, have demonstrated feasibility. Results of recent functional neuroimaging studies suggest that information about movement parameters is even accessible non-invasively in the form of low-frequency brain signals. However, their spatiotemporal tuning characteristics to single movement parameters are still unclear. Here, we extend the current understanding of low-frequency electroencephalography (EEG) tuning to position and velocity signals. We recorded EEG from 15 healthy participants while they performed visuomotor and oculomotor pursuit tracking tasks. Linear decoders, fitted to EEG signals in the frequency range of the tracking movements, predicted positions and velocities with moderate correlations (0.2-0.4; above chance level) in both tasks. Predictive activity in terms of decoder patterns was significant in superior parietal and parieto-occipital areas in both tasks. By contrasting the two tracking tasks, we found that predictive activity in contralateral primary sensorimotor and premotor areas exhibited significantly larger tuning to end-effector velocity when the visuomotor tracking task was performed.


Membrane continuities involving chloroplasts and other organelles in plant cells.
Plant cell membranes were examined in thin sections by electron microscopy. Numerous membrane continuities appeared between chloroplasts and other organelles of the fern Pteris vittata L., and occasionally in the leaves of the tomato Lycopersicon esculentum Mill. A number of these continuities had not been reported earlier or had been seen only infrequently.


User experiences and perspectives of a driving simulator intervention for individuals with acquired brain injury: A qualitative study.
Driving a motor vehicle is a common rehabilitation goal following acquired brain injury (ABI). There is increasing interest in the use of driving simulators for driver rehabilitation post-ABI; however, there is still limited research demonstrating efficacy and acceptability. This study sought to examine the user experience of a driving simulator intervention for ABI survivors. Semi-structured interviews were conducted with 14 individuals, including 12 ABI survivors (42% male; Mean age = 53.92 years, SD age = 17.63) who completed the intervention, and 2 occupational therapist driver assessors who facilitated the intervention. Thematic analysis was adopted to analyse interview data. Findings suggest that individual differences (e.g., anxiety, previous experience) influenced participant response to training. The intervention allowed participants to practise various driving skills, re-familiarize themselves with the task of driving, and prepare for return to on-road driving within a safe environment. The intervention was perceived to be useful for enhancing driver self-awareness, autonomy, confidence and patience. Fidelity and simulator sickness were considered limitations of the simulator technology. Subjective accounts of the appropriateness of intervention components are also documented. Overall, the simulator intervention was reported to be a positive experience for participants. Themes emerging from this study can inform future driving simulator interventions for ABI survivors.


Intensity-based adaptive optics with sequential optimization for laser communications.
Wavefront distortions of optical waves propagating through the turbulent atmosphere are responsible for phase and amplitude fluctuations, causing random fading in the signal coupled into single-mode optical fibers. Wavefront aberrations can be confronted, in principle, with adaptive optics technology that compensates the incoming optical signal by the phase conjugation principle and mitigates the likeliness of fading. However, real-time adaptive optics requires phase wavefront measurements, which are generally difficult under typical propagation conditions for communication scenarios. As an alternative to the conventional adaptive optics approach, here, we discuss a novel phase-retrieval technique that indirectly determines the unknown phase wavefront from focal-plane intensity measurements. The adaptation approach is based on sequential optimization of the speckle pattern in the focal plane and works by iteratively updating the phases of individual speckles to maximize the received power. We found in our analysis that this technique can compensate the distorted phasefront and increase the signal coupled with a significant reduction in the required number of iterations, resulting in a loop bandwidth utilization well within the capacity of commercially available deformable mirrors.


The probiotic Bifidobacteria infantis: An assessment of potential antidepressant properties in the rat.
It is becoming increasingly apparent that probiotics are important to the health of the host. The absence of probiotic bacteria in the gut can have adverse effects not only locally in the gut, but has also been shown to affect central HPA and monoaminergic activity, features that have been implicated in the aetiology of depression. To evaluate the potential antidepressant properties of probiotics, we tested rats chronically treated with Bifidobacteria infantis in the forced swim test, and also assessed the effects on immune, neuroendocrine and central monoaminergic activity. Sprague-Dawley rats were treated for 14 days with B. infantis. Probiotic administration in naive rats had no effect on swim behaviours on day 3 or day 14 following the commencement of treatment. However, there was a significant attenuation of IFN-gamma, TNF-alpha and IL-6 cytokines following mitogen stimulation (p<0.05) in probiotic-treated rats relative to controls. Furthermore, there was a marked increase in plasma concentrations of tryptophan (p<0.005) and kynurenic acid (p<0.05) in the bifidobacteria-treated rats when compared to controls. Bifidobacteria treatment also resulted in a reduced 5-HIAA concentration in the frontal cortex and a decrease in DOPAC in the amygdaloid cortex. The attenuation of pro-inflammatory immune responses, and the elevation of the serotonergic precursor, tryptophan by bifidobacteria treatment, provides encouraging evidence in support of the proposition that this probiotic may possess antidepressant properties. However, these findings are preliminary and further investigation into the precise mechanisms involved, is warranted.


Chemical constitution of the host-specific toxin of Helminthosporium carbonum.
The host-specific toxin of Helminthosporium carbonum Ullstrup has a molecular formula approximating C(32)H(50)N(6)O(10). The compound has been crystallized and a crystalline hydrochloride derivative has been produced. The molecular weight, as determined by chromatography on Sephadex G-10, is slightly less than 700. The toxin appears to be a cyclic peptide, since, although it does not react with ninhydrin or dinitrofluorobenzene, it yields, on hydrolysis, compounds which react to these reagents. It is unstable in dilute acids, yielding ninhydrin-reacting products. Complete acid hydrolysis yields alanine, proline, and three other ninhydrin-reacting components. The infrared spectrum of the toxin reveals an ester band in addition to amide absorption. Its ultraviolet spectrum reveals the presence of unsaturation in the molecule. The toxin is relatively unstable and loses its specific toxicity. This loss of activity appears to be associated with loss of nitrogen and with decreased solubility in water.


6-Methoxymellein Isolated from Carrot (Daucus carota L.) Targets Breast Cancer Stem Cells by Regulating NF-κB Signaling.
The presence of breast cancer stem cells (BCSCs) induces the aggressive progression and recurrence of breast cancer. These cells are drug resistant, have the capacity to self-renew and differentiate and are involved in recurrence and metastasis, suggesting that targeting BCSCs may improve treatment efficacy. In this report, methanol extracts of carrot root were purified by means of silica gel, Sephadex LH-20, and preparative high-performance liquid chromatography to isolate a compound targeting mammosphere formation. We isolated the compound 6-methoxymellein, which inhibits the proliferation and migration of breast cancer cells, reduces mammosphere growth, decreases the proportion of CD44+/CD24- cells in breast cancer cells and decreases the expression of stemness-associated proteins c-Myc, Sox-2 and Oct4. 6-Methoxymellein reduces the nuclear localization of nuclear factor-κB (NF-κB) subunit p65 and p50. Subsequently, 6-methoxymellein decreases the mRNA transcription and secretion of IL-6 and IL-8. Our data suggest that 6-methoxymellein may be an anticancer agent that inhibits BCSCs via NF-κB/IL-6 and IL-8 regulation.


The unexpected roles of σ and π orbitals in electron donor and acceptor group effects on the 13C NMR chemical shifts in substituted benzenes.
Effects of electron-donating (R = NH2) and electron-withdrawing (R = NO2) groups on 13C NMR chemical shifts in R-substituted benzene are investigated by molecular orbital analyses. The 13C shift substituent effect in ortho, meta, and para position is determined by the σ bonding orbitals in the aryl ring. The π orbitals do not explain the substituent effects in the NMR spectrum as conventionally suggested in textbooks. The familiar electron donating and withdrawing effects on the π system by NH2 and NO2 substituents induce changes in the σ orbital framework, and the 13C chemical shifts follow the trends induced in the σ orbitals. There is an implicit dependence of the σ orbital NMR shift contributions on the π framework, via unoccupied π* orbitals, due to the fact that the nuclear shielding is a response property.


Comparing National Institutes of Health funding of emergency medicine to four medical specialties.
The purpose of this study was to compare National Institutes of Health (NIH) funding received in 2008 by emergency medicine (EM) to the specialties of internal medicine, pediatrics, anesthesiology, and family medicine. The hypothesis was that EM would receive fewer NIH awards and less funding dollars per active physician and per medical school faculty member compared to the other four specialties. Research Portfolio Online Reporting Tools (RePORT) were used to identify NIH-funded grants to 125 of the 133 U.S. allopathic medical schools for fiscal year 2008 (the most recent year with all grant funding information). Eight medical schools were excluded because six were not open in 2008, one did not have a website, and one did not have funding data available by medical specialty. From RePORT, all grants awarded to EM, internal medicine, family medicine, anesthesiology, and pediatric departments of each medical school were identified for fiscal year 2008. The authors extracted the project number, project title, dollars awarded, and name of the principal investigator for each grant. Funds awarded to faculty in divisions of EM were accounted for by identifying the department of the EM division and searching for all grants awarded to EM faculty within those departments using the name of the principal investigator. The total number of active physicians per medical specialty was acquired from the Association of American Medical Colleges' 2008 Physician Specialty report. The total number of faculty per medical specialty was collected by two research assistants who independently counted the faculty listed on each medical school website. The authors compared the total number of NIH awards and total funding per 1,000 active physicians and per 1,000 faculty members by medical specialty. Of the 125 medical schools included in the study, 84 had departments of EM (67%). In 2008, NIH awarded over 9,000 grants and approximately $4 billion to the five medical specialties of interest. Less than 1% of the grants and funds were awarded to EM. EM had the second-lowest number of awards and funding per active physician, and the lowest number of awards and funding per faculty member. A higher percentage of grants awarded to EM were career development awards (26%, vs. a range of 11% to 19% for the other specialties) and cooperative agreements (26%, vs. 2% to 10%). In 2008, EM was the only specialty of the five not to have a fellowship or T32 training grant. EM had the lowest proportion of research project awards (42%, vs. 58% to 73%). Compared to internal medicine, pediatrics, anesthesiology, and family medicine, EM received the least amount of NIH support per active faculty member and ranked next to last for NIH support by active physician. Given the many benefits of research both for the specialty and for society, EM needs to continue to develop and support an adequate cohort of independent investigators.


Complexities of care: Common components of models of care in geriatrics.
As people age, they are more likely to have an increasing number of medical diagnoses and medications, as well as healthcare providers who care for those conditions. Health professionals caring for older adults understand that medical issues are not the sole factors in the phenomenon of this "care complexity." Socioeconomic, cognitive, functional, and organizational factors play a significant role. Care complexity also affects family caregivers, providers, and healthcare systems and therefore society at large. The American Geriatrics Society (AGS) created a work group to review care to identify the most common components of existing healthcare models that address care complexity in older adults. This article, a product of that work group, defines care complexity in older adults, reviews healthcare models and those most common components within them and identifies potential gaps that require attention to reduce the burden of care complexity in older adults.


Synthesis, Plasmodium falciparum Inhibitory Activity, Cytotoxicity and Solubility of N2 ,N4 -Disubstituted Quinazoline-2,4-diamines.
Despite the development of extensive control strategies and treatment options, approximately 200 million malaria cases, leading to approximately 450,000 deaths, were reported in 2015. Due to issue of disease resistance, additional drug development efforts are needed to produce new, more effective treatments. Quinazoline-2,4-diamines were identified as antiparasitic compounds over three decades ago and have remained of interest to date in industry and academia. An anti-malarial SAR evaluation of previously unreported N2 ,N4 -disubstituted quinazoline- 2,4-diamines have been undertaken in this study. We have synthesized and evaluated new derivatives against P. falciparum in our attempt to better characterize their biological activity and overall physical properties. The synthesis of N2 ,N4 -disubstituted quinazoline-2,4-diamines inhibitors is reported along with activities in a radioactive labeled hypoxanthine incorporation assay against the f Plasmodium falciparum (Pf.) K1 strain. In addition, cytotoxicity was determined in the A549 and Vero cell lines using an MTT based. The aqueous solubility of key compounds was assessed at pH 7.4 using a shake flask-based approach. We identified compounds 1 and 6p as sub µM inhibitors of P. falciparum, having equivalent anti-malarial activity to Chloroquine. Compounds 1 and 6m are low µM inhibitors of P. falciparum with improved cytotoxicity profiles. Compound 6m displayed the best balance between P. falciparum Inhibitory activity (2 µM) and cytotoxicity, displaying >49 fold selectivity over A549 and Vero cell lines. Twenty one N2 ,N4 -Disubstituted Quinazoline-2,4-diamines have been prepared in our group and characterized in terms of their antimalarial activity, cytotoxicity and physical properties. Compounds with good activity and reasonable selectivity over mammalian cell lines have been identified. SAR analyses suggest further exploration is are necessary to improve the balance of P. falciparum Inhibitory activity, cytotoxicity and solubility.


Participatory Video on Menstrual Hygiene: A Skills-Based Health Education Approach for Adolescents in Nepal.
School adolescents who are in the formative years of their lives are in stark need of appropriate and innovative skills-based health education and information. In this paper, we aim to explain how the participatory video (PV) approach was used in exploring the issues concerning adolescent reproductive health, particularly on menstrual hygiene among school adolescents in Chitwan district of Nepal. The students were engaged in the PV process for more than 6 months. They were given smart android phones with a 15-megapixel camera to shoot the video. The school adolescents regarded PV as an innovative and participatory medium for developing their critical thinking skills, collaborative skills, communication skills, and creative skills, which are required in the twenty-first century.


Clinical utility of plasma miR-371a-3p in germ cell tumors.
Germ cell tumours predominantly of the testis ((T)GCTs) are remarkably chemotherapy sensitive. However, a small proportion of patients fail to be cured with cisplatin-based combination chemotherapy. miR-371a-3p is a new liquid biopsy biomarker for (T)GCTs. The aim of this study was to evaluate clinical utility of plasma miR-371a-3p level in patients starting systemic chemotherapy. Patients were included before the first cycle (N = 180) and second cycle (N = 101) of systemic first line chemotherapy, treated between July 2010 and May 2017. Plasma miR-371a-3p levels were measured with the ampTSmiR test and compared to disease characteristics and outcome. Pretreatment plasma miR-371a-3p levels were increased in 51.7% of cases and associated with number of metastatic sites, presence of lung, retroperitoneal, and mediastinal lymph node metastases, S - stage, IGCCCG risk group, and response to therapy. Patients with a negative pretreatment plasma level had better progression-free survival (PFS) and overall survival (OS) compared to patients being positive for miR-371a-3p (hazard ratio [HR] = 0.26, 95% confidence interval [CI] 0.09-0.71, P = 0.02 for PFS and HR = 0.21, 95% CI 0.07-0.67, P = 0.03 for OS, respectively). Patients negative for miR-371a-3p in both samples had a superior PFS (HR = 0.10, 95% CI 0.01-21.49, P = 0.02) and OS (HR = 0.08, 95% CI 0.01-27.81, P = 0.008) compared to patients with miR-371a-3p positive in both samples (multivariate analyses were non-significant). In total 68% of the patients were S0. This study demonstrates clinical value of plasma miR-371a-3p level in chemotherapy naïve (T)GCT patients starting first line of chemotherapy to predict prognosis.


Haemophilia B in a female caused by skewed inactivation of the normal X-chromosome.
Hemophilia B (factor IX deficiency) is an X-linked recessive disorder with a prevalence of 1:30,000 male births, which rarely affects females. A missense mutation T38R (6488C>G) of the factor IX (FIX) gene was characterized in a young female with moderate-to-severe hemophilia B. She is heterozygous for this mutation, which she inherited from her carrier mother. Analysis of the methyl-sensitive HpaII sites in the first exon of the human androgen-receptor locus indicated a de novo skewed X-chromosomal inactivation. This indicates that the paternal X-chromosome carrying her normal FIX gene is the inactive one, which has led to the phenotypic expression of hemophilia B in this patient.


Cancer Diagnosis Using Deep Learning: A Bibliographic Review.
In this paper, we first describe the basics of the field of cancer diagnosis, which includes steps of cancer diagnosis followed by the typical classification methods used by doctors, providing a historical idea of cancer classification techniques to the readers. These methods include Asymmetry, Border, Color and Diameter (ABCD) method, seven-point detection method, Menzies method, and pattern analysis. They are used regularly by doctors for cancer diagnosis, although they are not considered very efficient for obtaining better performance. Moreover, considering all types of audience, the basic evaluation criteria are also discussed. The criteria include the receiver operating characteristic curve (ROC curve), Area under the ROC curve (AUC), F1 score, accuracy, specificity, sensitivity, precision, dice-coefficient, average accuracy, and Jaccard index. Previously used methods are considered inefficient, asking for better and smarter methods for cancer diagnosis. Artificial intelligence and cancer diagnosis are gaining attention as a way to define better diagnostic tools. In particular, deep neural networks can be successfully used for intelligent image analysis. The basic framework of how this machine learning works on medical imaging is provided in this study, i.e., pre-processing, image segmentation and post-processing. The second part of this manuscript describes the different deep learning techniques, such as convolutional neural networks (CNNs), generative adversarial models (GANs), deep autoencoders (DANs), restricted Boltzmann's machine (RBM), stacked autoencoders (SAE), convolutional autoencoders (CAE), recurrent neural networks (RNNs), long short-term memory (LTSM), multi-scale convolutional neural network (M-CNN), multi-instance learning convolutional neural network (MIL-CNN). For each technique, we provide Python codes, to allow interested readers to experiment with the cited algorithms on their own diagnostic problems. The third part of this manuscript compiles the successfully applied deep learning models for different types of cancers. Considering the length of the manuscript, we restrict ourselves to the discussion of breast cancer, lung cancer, brain cancer, and skin cancer. The purpose of this bibliographic review is to provide researchers opting to work in implementing deep learning and artificial neural networks for cancer diagnosis a knowledge from scratch of the state-of-the-art achievements.


[The density of lymphocyte beta 2-adrenoreceptors and blood plasma catecholamines in patients with dilated cardiomyopathy].
27 patients with dilated cardiomyopathy (DCM) complicated by heart failure (HF) of stages I-IIB were studied. The density of lymphocyte beta 2-adrenoceptors decreased significantly as HF progressed. The level of circulating catecholamines (epinephrine, norepinephrine) was significantly higher in patients were severe HF, which probably caused more evident decrease in lymphocyte beta 2-adrenoceptors density in these patients. This point of view was confirmed by the data of correlation-regression analysis between the general beta 2-adrenoceptors density and hemodynamics data. The identified changes in the number of adrenoceptors reflect the process of cellular receptors desensitization. They should be considered as a possible mechanism of HF development on a molecular level that cause development of refractoriness to routine therapy.


Effects of exposure to ultrafine carbon particles in healthy subjects and subjects with asthma.
Increased levels of particulate air pollution are associated with increased respiratory and cardiovascular mortality and morbidity as well as worsening of asthma. Ultrafine particles (UFP; less than 0.1 microm in aerodynamic diameter) may contribute to the health effects of particulate matter (PM) for a number of reasons. Compared with larger particles on a mass basis, UFP have a higher predicted pulmonary deposition, greater potential to induce pulmonary inflammation, larger surface area, and enhanced oxidant capacity. UFP also have the potential to cross the epithelium and enter the systemic circulation. We hypothesized that exposure to UFP causes airway inflammation in susceptible humans with activation of circulating leukocytes and vascular endothelium, a systemic acute phase response, and transient hypercoagulability. We further hypothesized that in people with asthma, UFP deposition would be increased and underlying airway inflammation enhanced. Our objectives were: to develop a system for controlled exposures of humans to UFP; to measure the pulmonary fractional deposition of UFP; to assess the effects of UFP exposure on blood leukocyte and endothelial adhesion molecule expression and activation, on airway nitric oxide (NO) production, on the systemic acute phase response, on blood coagulability, and on cardiac electrical activity and repolarization; and to evaluate these responses in both healthy subjects and people with asthma. We developed and validated a mouthpiece exposure system for human studies of carbon UFP and then conducted three clinical exposure studies: healthy subjects breathing filtered air and UFP (10 microg/m3) at rest (UPREST); healthy subjects breathing air and UFP (10 and 25 microg/m3) with intermittent exercise (UPDOSE); and subjects with mild asthma breathing air and UFP (10 microg/m3) with intermittent exercise (UPASTHMA). All exposures were for 2 hours on the mouthpiece system. Exposures were separated by at least 2 (UPREST and UPDOSE) or 3 (UPASTHMA) weeks. Prior to and at intervals after each exposure, we assessed symptoms, pulmonary function, blood markers of inflammation and coagulation, and airway NO production. Sputum inflammatory cells were assessed 21 hours after exposure. Continuous 12-lead electrocardiography (ECG) recordings were analyzed for changes in heart rate variability, repolarization, and arrhythmias. For healthy subjects, the fractional deposition of UFP at rest was 0.66 +/- 0.11 (mean +/- SD) by particle number, confirming the high deposition for UFP predicted by models. Deposition further increased during exercise (0.83 +/- 0.04). Asthmatic subjects showed higher UFP deposition than did healthy subjects when breathing at rest (0.76 +/- 0.05). During the UPREST protocol, there were no convincing effects for any outcome measures. Breathing 25 microg/m3 UFP with exercise (UPDOSE) was associated with reductions in blood monocytes and activation of T lymphocytes in healthy females. In asthmatic subjects (UPASTHMA), breathing 10 microg/m3 UFP was associated with reduced numbers of blood eosinophils and CD4+ T lymphocytes. In the UPDOSE group, monocyte expression of intercellular adhesion molecule-1 (ICAM-1) was reduced in a concentration-related manner (P = 0.001). In the UPASTHMA group, CD11b expression was reduced on monocytes and eosinophils, and ICAM-1 expression was reduced on polymorphonuclear leukocytes (PMNs). ECG analyses of UPDOSE subjects showed transient reductions in parasympathetic influence on heart rate variability and a reduced repolarization (QT) interval. In UPASTHMA subjects, ECG analyses showed decreased QT variability, but no effect on the QT interval. There were no significant effects in any of the studies on symptoms, pulmonary function, or markers of airway inflammation. We found no increases in soluble markers of systemic inflammation or coagulation. Our hypothesis that inhalation of carbon UFP causes pulmonary inflammation and an acute phase response was not confirmed. However, the observed subtle changes in leukocyte subsets and adhesion molecule expression are consistent with effects on vascular endothelial function. We also found effects on heart rate variability and on cardiac repolarization in healthy subjects. If confirmed, the finding that very low mass concentrations of particles have cardiovascular effects would have important implications for future PM regulatory strategies.


Length of residence and risk of developing hyperemesis gravidarum among first generation immigrants to Norway.
To estimate the risk of hyperemesis gravidarum (HG) among first generation immigrants to Norway by length of residence. A cross-sectional study. The sample consisted of first generation immigrants with a prevalence of HG exceeding ethnic Norwegians by 50%, registered in the Medical Birth Registry of Norway (MBRN). The women were born in Turkey, Middle East, North Africa, Other Africa, Iran, Pakistan, India and Sri Lanka and Central and South America, the total sample size is 50,904. MBRN data on HG, age, parity, plurality and sex of the baby were linked to information on country of birth, maternal education and duration of stay obtained from Statistics Norway. Independent associations were studied for each immigrant group and adjusted for potential confounders. To account for dependencies in the sample, a generalized estimating equations (GEE) approach was used. For women from Central and South America, adjusted analysis showed a decrease in the risk of HG by longer residency (P for trend = 0.026). A similar but not significant trend was observed for women born in the Middle East (P for trend = 0.097). Women born in Turkey who had been living in Norway for 6-8 years had a higher risk of HG than newcomers, though no trend was observed (P for trend = 0.127). Women born in Iran and North Africa who lived longer in Norway tended to have a higher risk of developing HG than newcomers (P for trend = 0.083 and 0.118, respectively) Associations between HG and duration of residence in Norway did not show a universal pattern across immigrant groups. Women born in Central and South America had a lower risk of HG with increasing length of residence. Some evidence to the contrary was found for women born in Iran, North Africa and Turkey.


Alarming Trends in Mortality from Firearms Among United States Schoolchildren.
Mortality from firearms among US schoolchildren is an increasingly major clinical and public health crisis. We explored temporal trends in mortality from firearms among US schoolchildren from 1999 to 2017 by age and race. We used the Multiple Cause of Death Files of the United States National Center for Health Statistics; PubMed searches, and joinpoint regressions for trend analyses and calculated mortality rates and 95% confidence limits. From 1999 to 2017, the 38,942 deaths due to firearms in school-age children ranged from 340 per year at ages 5-14 to 2050 at 15-18 years. One epidemic among 5- to 14-year-olds began in 2009 and another among 15- to 18-year-olds began in 2014. The listed intents were 61% assault, 32% suicide, 5% accidental, and 2% undetermined. Blacks accounted for 41% of overall deaths, but only 17% of the school-age deaths. 86% of all deaths were boys. Mortality from firearms in US schoolchildren is increasing at alarming rates, especially among blacks and those aged 15-18 years. To the best of our knowledge, this is the first report to quantify these recent epidemics. Although federal laws prohibited them until recently, analytic studies designed a priori to do so are necessary to test the hypotheses generated by these descriptive data. We believe that combatting the epidemic of mortality from firearms among US schoolchildren without addressing firearms is analogous to combatting the epidemic of mortality from lung cancer from cigarettes without addressing cigarettes.


The effect of a second-generation 3D endoscope on the laparoscopic precision of novices and experienced surgeons.
Endoscopic surgeons rely on visual feedback to control their movements but lack stereopsis, an important depth cue. Previous three-dimensional (3D) systems alternated images on a two-dimensional (2D) screen, which was uncomfortable for surgeons. A second-generation 3D system provides continuous stereoscopic images on a monitor suspended at arm's length. We studied its effect on the laparoscopic precision of novices and experienced surgeons. Experienced laparoscopic surgeons (n = 12) and novices (n = 16) performed a total of 672 tasks in 2D, 3D, and under direct vision. Precision was assessed using the Imperial College Surgical Assessment Device (ICSAD), which generates objective scores of performance by analyzing the movements of surgical instruments. We found that 2D endoscopic vision impaired performance by 35-100% when compared with direct vision, whereas 3D reduced this endoscopic handicap by 41-53% in novices and experienced surgeons (p < 0.03). No side effects were reported with the new 3D system. Even in 2D, novices performed better with an image at arm's length (p < 0. 03). Second-generation 3D significantly improved the laparoscopic precision of novices and experienced surgeons, without the side effects reported from previous systems. This technology is expected to improve the ease and safety of laparoscopic surgery.