Long-Term Use of Antiplatelet Therapy in Real-World Patients with Acute Myocardial Infarction: Insights from the PIPER Study.
The aim of this study was to assess long-term drug adherence and prognosis in real-world patients discharged on dual-antiplatelet therapy (DAPT) after acute myocardial infarction (AMI). A retrospective cohort analysis using administrative databases kept by eight local health units was performed. DAPT exposure (defined as ≥ 2 prescriptions), adherence, and the occurrence of major adverse events (MACE) were analyzed during a 36-month follow-up. The analysis included 11,101 patients who were discharged alive with a primary diagnosis of AMI. Of these, 5,919 patients (53.31%) were discharged on DAPT without a diagnosis of cancer or anemia, without transient DAPT discontinuation, and represented the study population. DAPT discontinuation occurred in 2,200 patients (37.2%) and in 1,995 (33.7%) after the first 6 and 12 months, respectively, whereas 423 patients (7.1%) were still on DAPT after 36 months. Patients who maintained DAPT up to 12 months had a significantly lower overall mortality, compared with patients who discontinued DAPT after 6 months. Exposure to DAPT at 3 years was associated with reduced all-cause mortality (hazard ratio [HR]: 0.067, 95% confidence interval [CI]: 0.027-0.162, p < 0.001) and reduced recurrent AMI (HR: 0.02, 95% CI: 0.003-0.173, p < 0.001). In conclusion, this study shows that prolonged DAPT over 12 months is maintained in a relevant number of patients after AMI. However, adherence to antiplatelet therapy in first 12 months after AMI is still unsatisfactory and efforts to enhance patients' compliance are warranted. Exposure to prolonged DAPT at 3 years seems to be associated with a significant reduction in all-cause mortality and AMI.


Diet and blood pressure in children.
The prevalence of hypertension among children in the US is increasing in concert with rising obesity rates. Leading health organizations agree that elevated blood pressure should be managed in children; however, data on the relation between diet and lifestyle and blood pressure in this age group are sparse and controversial. The purpose of this review is to summarize the current evidence regarding nutrients, foods, and dietary patterns and their role in blood pressure elevation and in the treatment of pediatric hypertension. There is clear evidence that avoidance of excess weight gain in early life is important for the prevention of future hypertension and that weight reduction is an important therapeutic intervention for the prevention and treatment of hypertension in overweight children. Similarly, reduction in dietary sodium may be beneficial for children who are salt sensitive, but this trait cannot be easily measured. Children who were breast-fed or consume a diet rich in fruits, vegetables, and dairy foods tend to have lower blood pressure in adolescence. How these foods lower blood pressure is unclear. Data supporting the efficacy of dietary interventions for preventing or treating high blood pressure are limited. Future studies should emphasize adequate sample size, adjustment for confounding factors, use of standardized blood pressure techniques, and random assignment of children in intervention trials. Additionally, because adherence to dietary interventions may be particularly problematic among children, innovative nutrition intervention approaches are needed that address the unique needs and circumstances of this age group.


Growth rate trades off with enzymatic investment in soil filamentous fungi.
Saprobic soil fungi drive many important ecosystem processes, including decomposition, and many of their effects are related to growth rate and enzymatic ability. In mycology, there has long been the implicit assumption of a trade-off between growth and enzymatic investment, which we test here using a set of filamentous fungi from the same soil. For these fungi we measured growth rate (as colony radial extension) and enzymatic repertoire (activities of four enzymes: laccase, cellobiohydrolase, leucine aminopeptidase and acid phosphatase), and explored the interaction between the traits based on phylogenetically corrected methods. Our results support the existence of a trade-off, however only for the enzymes presumably representing a larger metabolic cost (laccase and cellobiohydrolase). Our study offers new insights into potential functional complementarity within the soil fungal community in ecosystem processes, and experimentally supports an enzymatic investment/growth rate trade-off underpinning phenomena including substrate succession.


Remodeling of the arterial wall: Response to restoration of normal blood flow after flow reduction.
Although many studies have shown that arteries change diameter in response to chronic change in blood flow (BF), keeping wall shear stress (WSS) at physiologically normal levels, relatively little is known about the effects of flow restoration after flow reduction and also the role of vascular smooth muscle (VSM) during such a remodeling process. To elucidate the biomechanical responses of the arterial wall to the restoration of normal BF after flow reduction and compare the results with our previous results observed in response to decreased BF alone. Carotid artery BF in the Wistar rat was decreased by ligation and then restored to normal levels by release of the ligation. The effects of BF changes on the biomechanical properties of the carotid arterial wall were determined from measurements of diameters and pressures of excised artery segments. During BF reduction and restoration, WSS was maintained at physiological levels by changes in the internal diameter. No significant changes in the incremental elastic modulus were found in response to changes in BF. VSM tone was significantly enhanced during the changes in BF. Arteries change diameters in response to BF reduction and also flow restoration to normal after flow reduction, keeping WSS at physiologically normal levels. The lack of changes in vascular elasticity suggests that there were no significant changes in major wall constituents, such as elastin and collagen. VSM may play the dominant role in observed arterial remodeling and adaptation.


Refinement of the stress-enhanced fear learning model of post-traumatic stress disorder: a behavioral and molecular analysis.
Post-traumatic stress disorder (PTSD) is a debilitating mental health condition for which current treatments have long-term efficacy in 50% of patients. There is a clear need for better understanding of the mechanisms underlying PTSD and the development of new treatment approaches. Analog trauma procedures in animals, such as the stress-enhanced fear learning (SEFL) procedure, can be used to produce behavioral and neurobiological changes that have validity in modeling PTSD. However, by necessity, the modeling of PTSD in animals requires them to potentially experience pain and suffering. Consistent with the '3Rs' (reduction, refinement and replacement) of animal research, this study aimed to determine whether the SEFL procedure can be refined to reduce potential animal pain and suffering while retaining the same behavioral and neurobiological changes. Here we showed that PTSD-relevant changes could be produced in both behavior and the brain of rats that were group- rather than single-housed and that received lower-magnitude electric shocks in the 'trauma analog' session. We also varied the number of shock exposures in the trauma analog session, finding SEFL-susceptible and SEFL-resilient populations at all levels of shock exposure, but with greater levels of shock increasing the proportion of rats showing the SEFL-susceptible phenotype. These data demonstrate that the SEFL procedure can be used as an animal analog of PTSD with reduced potential pain and suffering to the animals and that variations in the procedure could be used to generate specific proportions of SEFL-susceptible and SEFL-resilient animals in future studies.


Development of a model for functional studies of ABCG2 (breast cancer resistance protein) efflux employing a standard BeWo clone (B24).
Human choriocarcinoma-derived BeWo cells express high levels of breast cancer resistance protein (BCRP/ABCG2) with no functional P-glycoprotein (P-gp) (ABCB1) activity, making them a potential model to study bidirectional ABCG2-mediated drug transport. However, the original BeWo clone (B24) available to researchers does not form confluent monolayers with tight junctions required by the model. Our aim was to adapt culture conditions to attempt to generate confluent BeWo monolayers for drug transport studies using the standard B24 clone. BeWo cells (B24; American Type Culture collection [ATCC]) were cultured in six-well plates or polycarbonate millicell inserts in a number of media formulations, growth supplements, and basement membrane substitutes. Cells were examined for confluence by microscopy, and transepithelial electrical resistance (TEER) was measured daily; monolayer permeability was assessed when TEER had stabilized. Optimal growth rates were achieved in culture conditions consisting of Medium 199 (M199) supplemented with epidermal growth factor (EGF; 20 ng/mL), vitamin supplements, and 10% fetal calf serum (FCS) with collagen coating. A TEER of 170 Ω in 0.6 cm(2) inserts was achieved 2 weeks after seeding under optimal conditions. The cell-impermeable diffusion marker 5(6) carboxy-2,7dichlorodihydrofluorescein (C-DCDHF) had a permeability coefficient of 3.5×10(-6) cm/s, indicative of minimal paracellular permeability. ABCG2 expression, as determined by immunoblotting, remained unaffected by confluency. In conclusion, we describe culture conditions for the B24 BeWo clone that facilitate the formation of monolayers with tighter junctions and reduced paracellular transport compared to previously published models. These growth conditions provide a good model of ABCG2-mediated drug transport in a human placental cell line.


The First Genomic Resources for Phymatotrichopsis omnivora, a Soilborne Pezizomycete Pathogen with a Broad Host Range.
Phymatotrichopsis omnivora is a destructive plant pathogen causing root rot disease of alfalfa, cotton, pecan, grape, and many other important dicotyledonous species. A member of the family Rhizinaceae, in the class Pezizomycetes, P. omnivora is a soilborne ascomycete fungus that is difficult to maintain in culture, currently genetically intractable, and for which there are no publicly available genomic resources. We have generated draft genome sequences of four P. omnivora isolates obtained from cotton and alfalfa, growing in Texas and Oklahoma. These genome sequences will provide new insights into the biology of the fungus, including the factors responsible for its broad host range and pathogenicity.


[Autoimmune liver diseases and their overlap syndromes].
Autoimmune diseases of the liver are chronic inflammatory diseases leading to an etiologically undefined immune-mediated attack aimed at the hepatocyte, small microscopic bile ducts, and the entire biliary system detectable by cholangiography, respectively. From the standpoint of clinical disease three entities can be distinguished: autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). These are not only different regarding their clinical profile but also differ in diagnostic strategy, therapeutic regimen and probability of remission, as well as their association with other immune-mediated diseases and cancer. PBC and PSC are cholestatic diseases. PBC is most often diagnosed in women. The diagnosis is readily reached by the detection of specific antimitochondrial autoantibodies directed against pyruvate dehydrogenase (PDH-E2), is associated with an array of rheumatological extrahepatic syndromes and responds unsatisfactorily to immunosuppressive drugs. Ursodeoxycholic acid leads to biochemical and possibly histological benefits. In contrast, PSC affects younger men who suffer from inflammatory bowel disease in 75% of cases. PSC is not characterized by specific serum autoantibodies. The diagnosis is reached by histology and typical findings upon cholangiography. In 10-20% PSC is associated with cholangiocarcinoma and also with colon cancer. PSC also does not respond well to immunosuppression. Therapeutic interventions include mechanical endoscopic manipulation of the bile ducts, treatment of cholangitis and ursodeoxycholic acid. AIH is a classical autoimmune disease with a female predisposition, circulating autoantibodies, elevated immunoglobulins, the association of other extrahepatic autoimmune diseases, and a dramatic response to immunosuppression with normalization of the patient's prognosis upon remission and prevention of cirrhosis. However, the diagnosis is only reached by the exclusion of other liver diseases also characterized by biochemical, histological and clinical features of chronic hepatitis. In this light, the precise diagnosis is essential. In spite of the clear distinctions of the three diseases overlapping syndromes do exist. These can be characterized as the coexistence of serological parameters of PBC and AIH, of cholestasis and hepatitis, of autoantibodies and viral markers, or the consecutive manifestation of PBC and AIH, or AIH and PSC. However, the overlap of genuine autoimmune diseases is rare. This is relevant regarding therapy and must lead to the precise clinical and diagnostic discrimination of serological autoimmunity (autoantibodies) and genuine autoimmune disease (i.e. AIH) for the initiation of efficatious therapeutic measures. AIH, PBC and PSC are well established indications for liver transplantation with good results. Transplantation is required when cirrhosis is progressive despite therapy and is likely to lead to liver failure.


Medullary projection of nonaugmenting inspiratory neurons of the ventrolateral medulla in the cat.
In Nembutal-anesthetized, immobilized, and artificially ventilated cats, we studied the morphological characteristics of inspiratory neurons with nonaugmenting firing patterns. HRP was injected intracellularly into a total of 22 neurons of the Bötzinger complex (BOT) and the ventral respiratory group (VRG). In 20 cases somata with their axonal trajectories were stained, and in two cases only axons were stained. None of the neurons stained could be antidromically activated by stimulation of the cervical cord. The somata of 20 neurons were located in the vicinity of the nucleus ambiguus or the retrofacial nucleus (RFN) between 600 microns and 2,800 microns caudal to the rostral end of the RFN. Their axons could be traced for a distance of several millimeters on the side of the somata, and showed various projection patterns. According to these projection patterns, the 20 neurons were tentatively classified into four groups: A (8/20), B (4/20), C (6/20), and motoneurons (2/20). Group A neurons gave off extensive axon collaterals that arborized and distributed boutons predominantly in the BOT and the VRG areas. Group B neurons had less extensive axon collaterals with various projection patterns, projecting rarely to the BOT or the VRG area. Group C neurons sent their stem axons, without issuing any axonal collaterals, to the contralateral side in five cases and to the ipsilateral pons in one case. The two motoneurons had axons leaving the brainstem without any intramedullary collaterals. Thus, the nonaugmenting inspiratory neurons showed morphological variations, which may play different roles in neural control of respiration.


Transpupillary thermotherapy for choroidal melanoma: tumor control and visual results in 100 consecutive cases.
The authors evaluated the results of primary transpupillary thermotherapy for choroidal melanoma in 100 cases. Prospective nonrandomized analysis of treatment method. One hundred patients with choroidal melanoma were studied. Tumor response, ocular side effects, and visual results. Of 100 consecutive patients with choroidal melanoma treated with transpupillary thermotherapy, the mean tumor basal diameter was 7.1 mm and tumor thickness was 2.8 mm. The tumor margin touched the optic disc in 34 eyes (34%) and was beneath the fovea in 42 eyes (42%). Documented growth was present in 64 eyes (64%), and known clinical risks for growth were present in all of the remaining 36 eyes (36%), with an average of 4 of 5 statistical risk factors for growth per tumor. After a mean of three treatment sessions and 14 months of follow-up, the mean tumor thickness was reduced to 1.4 mm. Treatment was successful in 94 eyes (94%) and failed in 6 eyes (6%). Three patients with amelanotic tumors showed no initial response to thermotherapy, but subsequent intravenous indocyanine green administration during thermotherapy resulted in improved heat absorption and tumor regression to a flat scar. The six eyes classified as treatment failures included four eyes with tumors that showed partial or no response to thermotherapy, thus requiring plaque radiotherapy or enucleation, and two eyes with recurrence, subsequently controlled with additional thermotherapy. After treatment, the visual acuity was the same (within 1 line) or better than the pretreatment visual acuity in 58 eyes (58%) and worse in 42 eyes (42%). The main reasons for poorer vision included treatment through the foveola for subfoveal tumor (25 eyes), retinal traction (10 eyes), retinal vascular obstruction (5 eyes), optic disc edema (1 eye), and unrelated ocular ischemia (1 eye). Temporal location (versus nasal and superior, P = 0.02) and greater distance from the optic disc (P = 0.04) were risks for retinal traction. Transpupillary thermotherapy may be an effective treatment for small posterior choroidal melanoma, especially those near the optic disc and fovea. Despite satisfactory local tumor control, ocular side effects can result in decreased vision. Longer follow-up will be necessary to assess the impact of thermotherapy on ultimate local tumor control and metastatic disease.


Synthesis and biological activity of 5-(2,2-difluorovinyl)-2'-deoxyuridine.
5-(2,2-Difluorovinyl)uracil (IV) was synthesized from 2,4-dimethoxy-5-bromopyrimidine by sequential formylation, difluoromethylenation, and removal of the 2- and 4-methyl groups. Condensation of the trimethylsilyl derivative of IV with protected D-erythro-pentofuranosyl chloride followed by separation of anomers and deblocking gave 5-(2,2-difluorovinyl)-2'-deoxyuridine (V). Compound V was active against herpes simplex virus type 1 (HSV-1) infection as well as tumor cells transformed by the HSV-1 thymidine kinase gene.


[Long-term survival metastatic ovarian cancer elderly patient].
Ovarian cancer is the sixth diagnosed cancer among women worldwide, it has a high mortality and in most cases it's diagnosed in advanced stage (stage III-IV). Combination platinum-paclitaxel chemotherapy administered every 3 weeks is considered the gold standard for first-line treatment of patients with advanced ovarian cancer. Elderly patients with ovarian cancer represents a subgroup with poor prognosis because they are often treated less radically for comorbidities and age. In the present article, we report a case of a 85 year old woman who was diagnosed with stage IV ovarian carcinoma for the presence of peritoneal carcinomatosis ab initio, not radically debulked and then treated with weekly schedule platinum-based and paclitaxel. Despite not being able to complete the chemotherapy, the patient achieved excellent results and represents a case of long survival.


Laboratory Study of the Influence of Substrate Type and Temperature on the Exploratory Tunneling by Formosan Subterranean Termite.
Using two-dimensional foraging arenas, laboratory tests were conducted to investigate the effect of soil type, soil moisture level and ambient temperature on the exploratory tunneling by Coptotermes formosanus Shiraki. In choice arenas consisting of two substrate types having two moisture levels each, and conducted at a constant temperature of 22 °C, a significantly greater proportion of termites aggregated in sand than in sandy loam. Similarly, the length of excavated tunnels was also increased in sand. In a given substrate, termite aggregation or tunnel length did not differ between 5% and 15% moisture levels. In no-choice tests, where three different substrates (sand, sandy loam and silt loam) were tested at two temperatures (22 °C and 28 °C), excavations were significantly greater in sand than either sandy loam or silt loam at 22 °C. Fewer primary tunnels were constructed in sandy loam than in sand and fewer branched tunnels than either in sand or silt loam. No significant difference in either tunnel length or number of primary or branched tunnels was found between these two temperatures.


EMT and stem cell-like properties associated with HIF-2α are involved in arsenite-induced transformation of human bronchial epithelial cells.
Arsenic is well-established as a human carcinogen, but the molecular mechanisms leading to arsenic-induced carcinogenesis are complex and elusive. It is not been determined if the epithelial-mesenchymal transition (EMT) and stem cell-like properties contribute in causing to carcinogen-induced malignant transformation and subsequent tumor formation. To investigate the molecular mechanisms underlying EMT and the emergence of cancer stem cell-like properties during neoplastic transformation of human bronchial epithelial (HBE) cells induced by chronic exposure to arsenite. HBE cells were continuously exposed to arsenite. Spheroid formation assays and analyses of side populations (SPs) were performed to confirm that arsenite induces the acquired EMT and cancer stem cell-like phenotype. Treated HBE cells were molecularly characterized by RT-PCR, Western blots, immunofluorescence, Southwestern assays, reporter assays, and chromatin immunoprecipitation. With chronic exposure to arsenite, HBE cells undergo an EMT and then acquire a malignant cancer stem cell-like phenotype. Twist1 and Bmi1 are involved in arsenite-induced EMT. The process is directly regulated by HIF-2α. The self-renewal genes, Oct4, Bmi1, and ALDH1, are necessary for arsenite-mediated maintenance of stem cells. EMT, regulated by HIF-2α, and the development of a cancer stem cell-like phenotype are associated with arsenite-induced transformation of HBE cells.


Direct, sensitive determination of trace amounts of dissolved ferric iron in natural water by light absorption ratio variation spectrometry.
The chromophore eriochrome cyanine R (ECR) was used to sensitively coordinate Al(II) and Fe(II) in the presence of cetylpyridinium chloride (CPC) at pH 4.8. Trace amounts of Fe(III) can displace Al(III) from the Al(ECR)(CPC) ternary complex to form the Fe(ECR)(CPC) complex. The composition of the complexes was determined by the break point approach. The competitive displacement complexation was sensitive and highly selective, even if no masking reagent was added. An ongoing novel spectrophotometry, named the light-absorption ratio variation approach, was applied to the direct determination of Fe(III) in natural water with recovery between 92.5 and 106%. The detection limit was only 9 ng/mL Fe(III).


A deletion mutation in nfxB of in vitro-induced moxifloxacin-resistant Pseudomonas aeruginosa confers multidrug resistance.
The modulation of efflux pump functions under fluoroquinolone (FQ) exposure is of great concern as it could result in occurrence of multidrug-resistant (MDR) bacterial strains. In this study, MDR mechanism in Pseudomonas aeruginosa induced via moxifloxacin (MOX) pressure was investigated. After serial MOX [concentration of 0.5 × the minimum inhibitory concentration (MIC)] exposure, the fully susceptible P. aeruginosa ATCC 9027 strain has increased its MIC not only toward MOX (1→128 mg/L) but also to other antibiotics. Furthermore, this MOX-exposed strain did not revert to antibiotic-sensitive phenotype when being cultured in antibiotic-free medium for 12 days. No mutation was observed for FQ-target (gyrA and parC) or most investigated efflux regulatory genes (mexT, mexR, and nalC) except nfxB in which a 100-bp deletion was found. This associated with the elevated expression of multidrug efflux pump operon (mexCD-oprJ) which could directly result in MDR phenotype.


Vitamin E-added Highly Cross-Linked Polyethylene Decreases the Risk of Osteolysis in an In Vivo Arthroplasty Model.
Introduction Aseptic loosening is one of the most important complications of arthroplasty surgery. It is known that immune response against particles plays role in the pathogenesis of aseptic loosening. Polyethylene (PE) has an important place in these particles. There are limited in vivo studies examining aseptic loosening caused by PE residues. Objective The aim of the present study is to evaluate the aseptic loosening created by highly cross-linked PE (HXLPE) and vitamin E-added PE particles in an in vivo knee prosthesis model. Materials and methods Thirty-nine male Sprague-Dawley rats, which were randomized into three groups, were included in the study. After surgical exposure of knee joints of rats, femoral intramedullary canals were drilled and instilled with isolated saline solution and saline solution that contained standard PE or vitamin E-added PE particles according to their groups. Afterwards, a titanium implant was placed on the femoral articular surface of each animal. Rats received intraarticular injections weekly of the same solution, which was initially instilled into their femoral canal. The rats were sacrificed at the end of the third week and then underwent radiological and histopathological evaluations. Result In histopathological evaluation, periprosthetic membrane formation, inflammatory cell change, and cellular damage of cartilage and bone tissue around the implant were assessed. There was a statistically lesser amount of cellular damage and periprosthetic membrane formation in the vitamin-E/HXLPE group compared to the HXLPE group (p=0.04, p=0.001). No significant difference was found between the PE groups with respect to inflammatory cells (p=0.715). Conclusions HXLPE caused more significant osteolysis compared to VE-HXLPE. Antioxidants in PE could provide a reduction in osteolysis and aseptic loosening.


Estrogen induces nitric oxide production via activation of constitutive nitric oxide synthases in human neuroblastoma cells.
Although it is becoming increasingly evident that nitric oxide (NO) mediates some of estrogen's actions in the brain, the effects of estrogen on NO production through NO synthases (NOS) in neuronal cells have not yet been identified. Here we assessed changes in NO production induced by 17beta-estradiol (E2) in cells of neuronal origin using human SK-N-SH neuroblastoma cells, which we show express all three isoforms of NOS. Involvement of NOS isoforms in E2-induced NO production was examined using isoform-specific NOS inhibitors. E2 (10(-10)-10(-6) m) induced rapid increases in NO release and changes in endothelial NOS (eNOS) expression, which were blocked by ICI 182,780, an antagonist of estrogen receptors. Increased levels of NO release and NOS activity induced by E2 were blocked by N5-(1-Imino-3-butenyl)-L-ornithine, a neuronal NOS inhibitor, and N(5)-(1-Iminoethyl)-L-ornithine, an eNOS inhibitor, but not by 1400W, an inducible NOS inhibitor. These results demonstrate that E2-stimulated NO production occurs via estrogen receptor-mediated activation of the constitutive NOSs, neuronal NOS and eNOS. The E2-induced NO increase was abolished when extracellular Ca2+ was removed from the medium or after the addition of nifedipine, an L-type channel blocker, and was partially inhibited using 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester, an intracellular Ca2+ chelator. However, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester itself also caused an increase in NO release that was blocked by 1400W, suggesting that inducible NOS mediates this response. Together these data reveal that constitutive NOS activities are responsible for E2-induced NO production in neuroblastoma cells and that differential activation of NOS isoforms in these cells occurs in response to different treatments.


Modulation of Mechanical Stress Mitigates Anti-Dsg3 Antibody-Induced Dissociation of Cell-Cell Adhesion.
It is becoming increasingly clear that mechanical stress in adhesive junctions plays a significant role in dictating the fate of cell-cell attachment under physiological conditions. Targeted disruption of cell-cell junctions leads to multiple pathological conditions, among them the life-threatening autoimmune blistering disease pemphigus vulgaris (PV). The dissociation of cell-cell junctions by autoantibodies is the hallmark of PV, however, the detailed mechanisms that result in tissue destruction remain unclear. Thus far, research and therapy in PV have focused primarily on immune mechanisms upstream of autoantibody binding, while the biophysical aspects of the cell-cell dissociation process leading to acantholysis are less well studied. In work aimed at illuminating the cellular consequences of autoantibody attachment, it is reported that externally applied mechanical stress mitigates antibody-induced monolayer fragmentation and inhibits p38 MAPK phosphorylation activated by anti-Dsg3 antibody. Further, it is demonstrated that mechanical stress applied externally to cell monolayers enhances cell contractility via RhoA activation and promotes the strengthening of cortical actin, which ultimately mitigates antibody-induced cell-cell dissociation. The study elevates understanding of the mechanism of acantholysis in PV and shifts the paradigm of PV disease development from a focus solely on immune pathways to highlight the key role of physical transformations at the target cell.


Human Subjects Protection and Cancer Surveillance Research: Revised Regulations, Expanded Opportunities.
On January 19, 2017, the United States federal government issued revisions to the Common Rule under which scientists who receive federal funding conduct research involving human subjects. The revised Common Rule expressly addresses public health surveillance in relation to scientific research and the protection of human subjects, and its impacts are anticipated to contribute to the efficiency of activities, including cancer registration and surveillance, and research that uses cancer registry data. Cancer Res; 77(12); 3140-3. ©2017 AACR.


Using modified fish scale waste from Sardinella brasiliensis as a low-cost adsorbent to remove dyes from textile effluents.
Textile industry wastewater has become a cause of concern to environmentalists due to its toxic composition and the difficulty of breaking down certain dyes. In this study, modified fish scales of Sardinella brasiliensis (SSb) were used as an alternative for a low-cost adsorbent to remove dyes from textile wastewaters. Adsorption efficiency was assessed by measuring the general, kinetic, and thermodynamic physico-chemical parameters of adsorption isotherms, using Reactive Turquoise Blue 15 (RTB15) and Reactive Red 120 (RR120) dyes as adsorbate models, as local textile industries commonly use these dyes. The isothermal data from the batch experiments were inserted in the Langmuir, Freundlich, and Langmuir-Freundlich (SIPS) equations; the Langmuir isotherm equation showed the most appropriate. The thermodynamic parameters showed that adsorption of dyes by the modified SSb adsorbent was an endothermic yet spontaneous process in the case of RR120. Sorbent-based on SSb material was concluded as adsorbing both of the tested dyes. Because of its abundant availability, and the small amount of activation needed to turn it into an adsorbent, this biowaste can be employed as a low-cost alternative for removal of dyes in the treatment of textile wastewater.


Influence of child-rearing on aggressive behavior in a transcultural perspective.
The aim of this paper is to summarize the literature and exemplify the author's research findings concerning the influence of different systems of child-rearing across cultures on aggressive behavior by using an individual-environment interaction approach. The question is whether a restrictive environment (e.g., China), foster children with lower levels of and less variation in aggression than children in a more permissive environment (e.g., Sweden). The main results involve 290 primary school children, mean age 10.3, their mothers and teachers in Beijing. The children showed distinct individual differences in aggression, though at a lower level and with less variation than Scandinavian children. Aggression was meaningfully related to other selfreport dimensions, such as positive attitude to school and negative relations with parents, findings similar to those in the Western literature. In line with the literature, sex differences in terms of aggression was also found among the Chinese children, namely, that girls seem better able to control aggression than boys. Chinese mothers in comparison to Swedish mothers, seemed to be more in control of their children. Children preferred their mothers, shame was the most frequent disciplinary method used, followed by reasoning. Both parents made decisions concerning the child. Finally, theoretical and practical implications are concluded in the paper.


[Not Available].
The diagnostical process is dealt with considering it a specific case of manifestation of cognition. Attention is drawn to the relationship existing between the various forms of manifestation of the "alive contemplation" and those of abstract thinking in the course of establishing the diagnosis in individual patients. Upon clarifying the link existing between the logical and the historical, it is established that the logical in the diagnostical process reproduces in a peculiar way the historical. It is furthermore underlined that the forms of abstract thinking in the diagnostical process should not be considered separately one from another, which is characteristic for formal logic, but rather originating one from another; not coordinated, but rather subordinated.


Relationship between animal health and livestock farmers' wellbeing in Ghana: beyond zoonoses.
Livestock production is a key livelihood source for many people in developing countries. Poor control of livestock diseases hamper livestock productivity, threatening farmers' wellbeing and food security. This study estimates the effect of livestock mortalities attributable to disease on the wellbeing of livestock farmers. Overall, 350 ruminant livestock farmers were randomly selected from three districts located in the north, middle and southern belts of Ghana. Mixed-effect linear regression models were used to estimate the relationship between animal health and farmer wellbeing. Farmer wellbeing was assessed using the WHOQOL-BREF tool, as the mean quality-of-life in four domains (physical, psychological, social, and environmental). Animal health was assessed as annual livestock mortalities to diseases adjusted for herd size, and standardized in tropical livestock units to account for different ruminant livestock species. We adjusted for the potential confounding effect of farmers' age, sex, educational attainment, farmland size, socio-economic status, perception of disease risk to herd, satisfaction with health, previous experience of disease outbreaks in herds, and social support availability by including these as fixed effects, and community as random effects, in a pre-specified model. Our results showed that farmers had a median score of 65.5 out of 100 (IQR: 56.6 to 73.2) on the wellbeing scale. The farmers' reported on average (median) 10% (IQR: 0 to 23) annual herd mortalities to diseases. There was a significantly negative relationship between increasing level of animal disease-induced mortality in herds and farmers' wellbeing. Specifically, our model predicted an expected difference in farmers' wellbeing score of 7.9 (95%CI 1.50 to 14.39) between a farmer without any herd mortalities to diseases compared to a (hypothetical) farmer with 100% of herd mortalities caused by diseases in a farming year. Thus, there is a reduction of approximately 0.8 wellbeing points of farmers, for the average of 10% disease-induced herd mortalities experienced. Disease-induced livestock mortalities have a significant negative effect on farmers' wellbeing, particularly in the physical and psychological domains. This suggests that veterinary service policies addressing disease risks in livestock, could contribute to improving the wellbeing of livestock dependent populations, and public food security.


Ochratoxin A in brewer's yeast used as food supplement.
Brewer's yeasts are rich in vitamins of the B-group and contain other nutritive factors; therefore, they are recommended as valuable food supplements for people with special dietary requirements like pregnant women, children, and adolescents, or for people with high physical activity. Additionally, certain strains of brewer's yeast are known to be capable of adsorbing xenobiotics such as mycotoxins. Because of that, these yeasts are regarded as having positive effects in food, beverage, and feed technology. Their potential to bind mycotoxins such as ochratoxin A (OTA), however, can subsequently lead to a contamination of such brewer's yeasts used as food supplements. In the present study, we analyzed 46 samples of brewer's yeasts for the occurrence of OTA by HPLC with fluorescence detector (HPLC-FLD) and for confirmatory measurements by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Nearly 90% of the samples were contaminated with OTA, the levels ranging from the limit of detection (LOD, 0.01 μg/kg) to 4.2 μg/kg. The mean and median levels of contamination were 0.49 and 0.27 μg/kg, respectively. Based on these results, the additional weekly OTA exposure by regularly consuming such supplements was assessed. Depending on different subpopulations (adults, children) and levels of contamination used for calculation, the additional OTA intake via brewer's yeast products ranged from 9.3% (mean case) to 114% (worst case) of the published mean weekly OTA intake in Germany (adults 279.3 ng, children 195.3 ng). At present, maximum levels for OTA in nutritional supplements like brewer's yeast do not exist. Based on our results, however, it is recommended that producers of these dietary supplements should include mycotoxin analyses in ongoing and future self-monitoring programs and in product quality checks.


Immune diffuse alveolar hemorrhage: Clinical presentation and outcome.
Diffuse alveolar haemorrhage (DAH) is a manifestation of several immune and nonimmune diseases. The objective of this study was to characterize the clinical characteristics and short-term outcomes of patients with immune-mediated DAH requiring hospital admission. A retrospective study from December 2010 to December 2015, was conducted by analyzing the clinical records of 39 patients with DAH with a proven immunological origin. The diagnosis of individual collagen vascular diseases (CVD) was made according to the criteria of the corresponding societies. Thirty-nine patients were included (median age 44.8 years, range 16-76). The main causes of DAH were ANCA-related vasculitis (74.3%) mainly granulomatosis with polyangiitis (n = 14) and microscopic polyangiitis (n = 13). Thirty patients (76.9%) had hemoptysis. An alveolar airspace filling pattern was found in most of patients (59%). All the patients had a drop in hemoglobin level that ranged from 1.0 to 3.0 g/dL. BAL fluid was macroscopically bloody in 43.6% of patients (n = 17) and showed siderophagic alveolitis on BAL cytology in 100%. All patients received high doses of corticosteroids. Other additional treatments were antibiotics (53,8%, n = 21), intravenous cyclophosphamide (87.2%, n = 34), plasma exchange (35.9%, n = 14); intravenous immunoglobulin (12.8%, n = 5) and rituximab in 5 patients (12.8%). Mortality rate was higher amongst patients who required dialysis (50.0 vs 15.4%, p = 0.045), with SaO2 <90% at admission (50.0 vs 5.3%, p = 0.003) or those who required mechanical ventilation (76.9 vs 6.8%, p = < 0.001). DAH may present without hemoptysis and requires an early bronchoscopy to confirm the diagnosis and exclude infection. Other characteristics could be included in the abstract which are relevant to the paper. (relation between mortality, dialysis, ventilation, etc.).


Finite Element Modelling of a Synthetic Paediatric Spine for Biomechanical Investigation.
Studies on paediatric spines commonly use human adult or immature porcine spines as specimens, because it is difficult to obtain actual paediatric specimens. There are quite obvious differences, such as geometry, size, bone morphology, and orientation of facet joint for these specimens, compared to paediatric spine. Hence, development of synthetic models that can behave similarly to actual paediatric spines, particularly in term of range of motion (ROM), could provide a significant contribution for paediatric spine research. This study aims to develop a synthetic paediatric spine using finite element modelling and evaluate the reliability of the model by comparing it with the experimental data under certain load conditions. The ROM of the paediatric spine was measured using a validated FE model at ±0.5 Nm moment in order to determine the moment required by the synthetic spine to achieve the same ROM. The results showed that the synthetic spine required two moments, ±2 Nm for lateral-bending and axial rotation, and ±3 Nm for flexion-extension, to obtain the paediatric ROM. The synthetic spine was shown to be stiffer in flexion-extension but more flexible in lateral bending than the paediatric FE model, possibly as a result of the intervertebral disc's simplified shape and the disc's weak bonding with the vertebrae. Nevertheless, the synthetic paediatric spine has promising potential in the future as an alternative paediatric spine model for biomechanical investigation of paediatric cases.


Acceleration element for femtosecond electron pulse compression.
An acceleration element is proposed for compressing the electron pulse duration in a femtosecond photoelectron gun. The element is a compact metal cavity with curved-shaped walls. An external voltage is applied to the cavity where a special electric field forms in such a way that the slow electrons in the electron pulse front are accelerated more than the fast electrons, and consequently the electron pulse duration will be compressed. The distribution of the electric field inside the acceleration cavity is analyzed for the geometry of the cavity. The electron dynamics in this acceleration cavity is also investigated numerically. Numerical results show that the electron pulse front and pulse duration can be improved by compensating for the effects of space charge and the initial energy spread of photoelectrons with a Lambertian angular distribution. Depending on the design parameters and the shape of the electron pulse, for a femtosecond electron gun with an electron energy of 30 keV, 10(3) electrons per pulse, and an electron drift length of 40 cm, the electron pulse duration can be reduced from 550 to 200 fs when using a compensating cavity with an average radius of 1.7 and 5.6 cm in length. Electron pulses shorter than 200 fs can be achieved if the length of the drift region is reduced.


Pan-Sarbecovirus Neutralizing Antibodies in BNT162b2-Immunized SARS-CoV-1 Survivors.
Emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern pose a challenge to the effectiveness of current vaccines. A vaccine that could prevent infection caused by known and future variants of concern as well as infection with pre-emergent sarbecoviruses (i.e., those with potential to cause disease in humans in the future) would be ideal. Here we provide data showing that potent cross-clade pan-sarbecovirus neutralizing antibodies are induced in survivors of severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) infection who have been immunized with the BNT162b2 messenger RNA (mRNA) vaccine. The antibodies are high-level and broad-spectrum, capable of neutralizing not only known variants of concern but also sarbecoviruses that have been identified in bats and pangolins and that have the potential to cause human infection. These findings show the feasibility of a pan-sarbecovirus vaccine strategy. (Funded by the Singapore National Research Foundation and National Medical Research Council.).


High-Capacity and Ultrafast Na-Ion Storage of a Self-Supported 3D Porous Antimony Persulfide-Graphene Foam Architecture.
The key challenge for high-performance sodium-ion batteries is the exploitation of appropriate electrode materials with a long cycling stability and high rate capability. Here, we report Sb2S5 nanoparticles (∼5 nm) uniformly encapsulated in three-dimensional (3D) porous graphene foam, which were fabricated by a facile hydrothermal coassembly strategy, as a high-performance anode material for sodium-ion batteries. The as-prepared composite can be directly used as electrodes without adding a binder or current collector, exhibiting outstanding electrochemical performance with a high reversible capacity (845 mA h g-1 at 0.1 A g-1), ultralong cycling life (91.6% capacity retention after 300 cycles at 0.2 A g-1), and exceptional rate capability (525 mA h g-1 at 10.0 A g-1). This is attributed to fast Na+ ion diffusion from the ultrasmall nanoparticles and excellent electric transport between the active material and 3D porous graphene, which also provide an effective strategy for anchoring the nanoparticles. Experimental results show that the Sb2S5 undergoes a reversible reaction of Sb2S5 + 16Na ↔ 5Na2S + 2Na3Sb during sodiation/desodiation. Moreover, a full cell with Na3(VO0.5)2(PO4)2F2/C cathode and the as-prepared composite anode was assembled, displaying high output voltage (∼2.2 V) with a stable capacity of 828 mA h g-1 for anode material (with 100 cycles at 0.1 A g-1), showing the potential for practical application.


Sensitivity of intracellular signals responsible for cell cycle progression to cyclosporine.
Within the cascade of intracellular activation signals triggering T lymphocyte effector response to alloantigen is a cytoplasmic protein, ADR, that activates DNA replication in isolated nuclei. Quantitative changes in ADR (exclusive to activated cells) regulate cell cycle progression and may indicate changes in intracellular proliferative control. The present communication documents that inhibition of ADR activity reflects the in vitro immunosuppressive effects of Cyclosporine. CsA inhibition of both proliferation and generation of ADR was concentration-dependent and occurred only in the G0 phase of the cell cycle. Drug addition did not affect G1 cells. ADR generation was inhibited both by CsA and by PGE2 alpha, possibly via effects on calcium-dependent activation pathways confined to G0/G1 transition. On the other hand, ADR generation was not inhibited by the immunosuppressive agents 6-mercaptopurine, Enisoprost (a PGE1 analog), or FK506. ADR activity was sensitive to aprotinin, which typically inhibits serine proteases. Using an enzymatic assay to quantitate serine protease activity (SPA) following PHA stimulation revealed that ADR content inversely correlated with SPA: ADR was only present in activated cells; SPA was highest in resting cells and decreased after PHA stimulation. The PHA-induced fall in SPA activity was inhibited by CsA, consistent with the failure to generate ADR. Like ADR, SPA was sensitive to PGE2 alpha and quantitatively unaffected by 6-mercaptopurine, Enisoprost, or FK506. Thus, ADR and SPA may represent opposing components of a cytoplasmic signaling cascade the balance of which reflects the level of immunosuppression, and thus represents a focus for in vitro evaluation of the immunologic response of allografted patients to cyclosporine.


Intraoperative neurophysiological monitoring during resection of intradural extramedullary spinal cord tumors: experience with 100 cases.
Intradural-extramedullary spinal cord tumor surgery is common. Unlike intramedullary spinal cord tumor surgery, where intraoperative neurophysiological monitoring (IONM) has been described extensively, the application of IONM has not been described in this context, and its relevance has not been investigated. From 2001 to 2012, 100 patients underwent intradural-extramedullary spinal cord tumor resection with IONM. Preoperative and postoperative clinical evaluations were completed retrospectively, using a modified McCormick grading scale and correlated with IONM monitorability and dynamics. IONM consisted of transcranial motor evoked potentials (tcMEP), spinal (D wave) and muscle generators, somatosensory evoked potentials (SSEP), and electromyography (EMG). Both short-term and long-term clinical evaluations were performed. Patient demographics, tumor type, span, location, and morphologic complexity were analyzed. Surgeries were performed for resection of schwannomas (33 %), meningiomas (22 %), ependymomas (12 %), and other pathologies (20 %); pathology was unknown in 13 % of patients. Tumor locations were cervical in 21 %, thoracic in 46 %, thoracolumbar in 7 %, lumbar 20 %, and not specified in 6 %. Tumors spanned an average of 2.2 spinal levels. Monitorability was 97 and 67 % with tcMEP and SSEP modalities respectively. D waves were monitorable in 73 % of attempts. Intraoperative tcMEP changes were reported in 29 cases with 14 resolved intraoperatively, There were one false-negative outcome and five true-positive outcomes. For SSEP, 13 changes were noted and three resolved; there were three false-negative results and one true-positive result. For D wave monitoring there were two intraoperative changes with none resolved leading to one false negative and one true positive result. With a multimodality approach incorporating any change in evoked potential, IONM demonstrated sensitivity of 0.82, specificity of 0.95, positive predictive value of 0.82, and a negative predictive value of 0.95. IONM is feasible and useful in the context of intradural-extramedullary spinal cord surgery for identifying iatrogenic injury to the spinal cord.


Development of a Case-based Reading Curriculum and Its Effect on Resident Reading.
Textbook reading plays a foundational role in a resident's knowledge base. Many residency programs place residents on identical reading schedules, regardless of the clinical work or rotation the resident is doing. We sought to develop a reading curriculum that takes into account the clinical work a resident is doing so their reading curriculum corresponds with their clinical work. Preliminary data suggests an increased amount of resident reading and an increased interest in reading as a result of this change to their reading curriculum.


Surgical treatment of piles: prospective, randomized study of Parks vs. Milligan-Morgan hemorrhoidectomy.
The present prospective, randomized clinical trial compares the outcome of surgical hemorrhoidectomy according to Parks and Milligan-Morgan in terms of hospital stay, duration of incapacity to work, symptom relief, length of morbidity, and patient convenience. Thirty-four consecutive patients with third or fourth degree internal hemorrhoids were randomly allocated to the two groups. Before surgery, all patients were interviewed using a standard questionnaire, followed by rectal examination. All patients underwent a follow-up interview and examinations 1, 2, 4, 8, and 12 weeks after the operation. No serious postoperative complications were seen. Length of hospital stay (3.2 days for Parks hemorrhoidectomy vs. 4.6 days for Milligan-Morgan hemorrhoidectomy; 95 percent confidence interval, 0.2 and 2.6, respectively; P = 0.02) and mean duration of incapacity to work (12.3 days for Parks hemorrhoidectomy vs. 20.2 days for Milligan-Morgan hemorrhoidectomy; 95 percent confidence interval, 5.7 and 10.2, respectively; P < 0.001) differed significantly between the Milligan-Morgan and Parks patients. Until two weeks after the operation, Milligan-Morgan hemorrhoidectomy patients experienced significantly more pain. Our study confirms that both operations are safe, easy to perform, and lead to satisfactory results. However, the Parks procedure is the preferred option, because it minimizes patients' postoperative discomfort, is more economic, has a significantly reduced hospital stay, and has a shorter time for return to work.


Perception of ischaemic heart disease, knowledge of and attitude to reduction of its risk factors.
To assess the perception of ischaemic heart disease (heart attack) as a cause of mortality and determine the current knowledge of its risk factors as well as the level of adoption of preventive strategies among Nigerians working in a tertiary institution. Cross-sectional study. University of Calabar, Calabar, Nigeria. Five hundred randomly selected University workers both senior and junior staff. Assessment of the awareness of ischaemic heart disease as a cause of morbidity and mortality, knowledge of risk factors and degree of adoption of lifestyle modification strategies. Only 136 (27.7%) of respondents considered ischaemic heart disease (heart attack) as the leading cause of death in their environment while 201 (40.2%) thought it was hypertension. Smoking was readily identified by 70.6% as a risk factor, excessive alcohol use by 52.8% and 41.6% of respondents identified obesity. Sedentary life-style and oral contraceptive use were least identified with only 16.6% and 6.4% of respondents respectively identifying them. This knowledge was significantly influenced by the educational status and cadre of the subjects. The senior staff who were also better educated demonstrated more knowledge. Two point two percent of respondents were smokers and smoked ten sticks of cigarettes or less per day. All expressed willingness to stop. One hundred and fifty eight admitted taking alcohol, most taking less than ten units a week and of these, only 64 were willing to quit. Fifty three point four percent (29.2% of senior and 24.2% of junior undertook some exercise while only 45.6% checked their body weights regularly. Only 25% of all the respondents visited the hospital or clinic for routine medical check-up. No statistically significant difference was found between the senior/better educated and the junior/less educated members of staff in the adoption of these life style modification measures. Sixty four point four percent got medical information from doctors and other health workers. Level of awareness of ishaemic heart disease as a leading cause of death is poor even in an academic environment. Knowledge of risk factors is also poor and is influenced by the level of educational attainment. Life style modification strategies are still not widely accepted irrespective of educational status. A concerted public health response is advocated to improve the present level of knowledge and establish behavioural changes.


Incarcerated mothers' contact with children, perceived family relationships, and depressive symptoms.
Concurrent relations among contact with children, perceived family relationships, early experiences of relationship disconnection and trauma, and maternal depressive symptoms were examined in 94 incarcerated mothers with children between the ages of 2 and 7 years. Qualitative analysis revealed that most mothers experienced intense distress when initially separated from their children, although many women currently viewed the situation in a more balanced way. Quantitative findings indicated that fewer visits from children and early experiences of relationship disconnection and trauma were associated with elevated maternal depressive symptoms. Mother-child relationships were more positive when mothers had more frequent telephone contact with older children. Moreover, conflicted relationships with caregivers related to less contact between mothers and their children. Results highlight the need for mental health services for incarcerated women and suggest that interventions aimed at increasing contact between imprisoned mothers and their children should consider the quality of the mother-caregiver relationship.


Neisseria cinerea Expresses a Functional Factor H Binding Protein Which Is Recognized by Immune Responses Elicited by Meningococcal Vaccines.
Neisseria meningitidis is a major cause of bacterial meningitis and sepsis worldwide. Capsular polysaccharide vaccines are available against meningococcal serogroups A, C, W, and Y. More recently two protein-based vaccines, Bexsero and Trumenba, against meningococcal serogroup B strains have been licensed; both vaccines contain meningococcal factor H binding protein (fHbp). fHbp is a surface-exposed lipoprotein that binds the negative complement regulator complement factor H (CFH), thereby inhibiting the alternative pathway of complement activation. Recent analysis of available genomes has indicated that some commensal Neisseria species also contain genes that potentially encode fHbp, although the functions of these genes and how immunization with fHbp-containing vaccines could affect the commensal flora have yet to be established. Here, we show that the commensal species Neisseria cinerea expresses functional fHbp on its surface and that it is responsible for recruitment of CFH by the bacterium. N. cinerea fHbp binds CFH with affinity similar to that of meningococcal fHbp and promotes survival of N. cinerea in human serum. We examined the potential impact of fHbp-containing vaccines on N. cinerea We found that immunization with Bexsero elicits serum bactericidal activity against N. cinerea, which is primarily directed against fHbp. The shared function of fHbp in N. cinerea and N. meningitidis and cross-reactive responses elicited by Bexsero suggest that the introduction of fHbp-containing vaccines has the potential to affect carriage of N. cinerea and other commensal species.


Naphtho[1,2-b]furan-4,5-dione induces apoptosis of oral squamous cell carcinoma: involvement of EGF receptor/PI3K/Akt signaling pathway.
Naphtho[1,2-b]furan-4,5-dione (NFD), prepared from 2-hydroxy-1,4-naphthoquinone and chloroacetaldehyde in an efficient one-pot reaction, exerts an anti-tumor effect. This study was performed to elucidate whether the epidermal growth factor (EGF) receptor and phosphatidylinositol-3-kinase (PI3K) signaling pathways are involved in NFD-induced apoptosis of oral squamous cell carcinoma (OSCC). Immunoblot showed that NFD suppressed the phosphorylation of EGF receptor and activation of PI3K/Akt, downstream molecules of EGF receptor signaling pathway, in Ca9-22 cells. The levels of downstream targets of Akt, including phospho-glycogen synthase kinase-3beta (p-GSK-3beta), GSK-3beta, forkhead transcription factor (FKHR), and cyclin D1, were also reduced after NFD treatment. Moreover, inactivation of nuclear factor-kappaB (NF kappaB), modulation of I kappa K beta and I kappaB alpha, up-regulation of Bad, and down-regulation of anti-apoptotic proteins including phospho-Bad, Bcl-X(L), myeloid cell leukemia-1(Mcl-1), and XIAP were found in NFD-treated cells. In addition, NFD treatment disrupted mitochondrial membrane potential (Delta Psi m), resulted in release of cytochrome c, and activation of both caspases-9 and caspase-3. Taken together, these results indicate that NFD induces apoptosis in Ca9-22 cells via inactivation of the EGF receptor-mediated survival pathway.


Panniculitis in childhood-onset systemic lupus erythematosus: a multicentric cohort study.
To evaluate prevalence, clinical manifestations, laboratory abnormalities, treatment and outcome in a multicenter cohort of childhood-onset systemic lupus erythematosus (cSLE) patients with and without panniculitis. Panniculitis was diagnosed due to painful subcutaneous nodules and/or plaques in deep dermis/subcutaneous tissues and lobular/mixed panniculitis with lymphocytic lobular inflammatory infiltrate in skin biopsy. Statistical analysis was performed using Bonferroni correction(p < 0.004). Panniculitis was observed in 6/847(0.7%) cSLE. Painful subcutaneous erythematosus and indurated nodules were observed in 6/6 panniculitis patients and painful subcutaneous plaques in 4/6. Generalized distribution was evidenced in 3/6 and localized in upper limbs in 2/6 and face in 1/6. Cutaneous hyperpigmentation and/or cutaneous atrophy occurred in 5/6. Histopathology features showed lobular panniculitis without vasculitis in 5/6(one of them had concomitant obliterative vasculopathy due to antiphospholipid syndrome) and panniculitis with vasculitis in 1/6. Comparison between cSLE with panniculitis and 60 cSLE without panniculitis with same disease duration [2.75(0-11.4) vs. 2.83(0-11.8) years,p = 0.297], showed higher frequencies of constitutional involvement (67% vs. 10%,p = 0.003) and leukopenia (67% vs. 7%,p = 0.002). Cutaneous atrophy and hyperpigmentation occurred in 83% of patients. Panniculitis is a rare skin manifestation of cSLE occurring in the first three years of disease with considerable sequelae. The majority of patients have concomitant mild lupus manifestations.


Postreceptor modulation of action of VIP and secretin on pancreatic enzyme secretion by secretagogues that mobilize cellular calcium.
In dispersed acini from rat pancreas, secretagogues that act through or mimic the action of AMP [vasoactive intestinal peptide (VIP), secretin, or 8-bromo-AMP] caused a twofold increase in amylase secretion. Secretagogues that mobilize cellular calcium (carbamylcholine, C-terminal octapeptide of cholecystokinin, bombesin, or A23187) caused a sevenfold augmentation of the actions of VIP, secretin, or 8-bromo-cAMP on enzyme secretion. Carbamylcholine and the C-terminal octapeptide of cholecystokinin also augmented the action of VIP on amylase secretion from mouse pancreatic acini. Secretagogues that mobilize cellular calcium did not alter binding of 125I-VIP, cellular cAMP, or the increase in cellular cAMP caused by VIP or secretin. Similarly, secretagogues that increase cellular cAMP did not alter 45Ca outflux or the increase in 45Ca outflux caused by carbamylcholine, C-terminal octapeptide of cholecystokinin, bombesin, or A23187. These results indicate that in dispersed acini from rat pancreas there is postreceptor modulation of the actions of VIP and secretin on enzyme secretion by secretagogues that mobilize cellular calcium and that this modulation is a major determinant of the magnitude of the effect of VIP and secretin on enzyme secretion. This modulation, in turn, reflects the ability of cellular calcium, mobilized from intracellular stores, to amplify the action of cellular cAMP on the enzyme secretory process.


Four new species, taxonomic, and nomenclatural notes in Hammatoderus Gemminger & Harold, 1873 (Coleoptera, Cerambycidae, Lamiinae).
Plagiohammus Dillon & Dillon, 1941 is considered a junior synonym of Hammatoderus Gemminger & Harold, 1873. Four new species are described: Hammatoderus juliae, from Colombia; H. migueli and H. antonkozlovi, from Ecuador; and H. lingafelteri, from Mexico. Hammoderus spinipennis Thomson, 1860, and Hammoderus quadriplagiatus Breuning, 1943 are placed as junior synonyms of Hammoderus thoracicus White, 1858 (= Hammatoderus thoracicus). Consequently, Hammatoderus jacobyi Nonfried, 1894, synonym of H. spinipennis, is also a junior synonym of H. thoracicus. The synonymy between Hammoderus strandi Breuning, 1943 and Plagiohammus olivescens Dillon & Dillon, 1941 is formally established. Plagiohammus mexicanus Breuning, 1950 is provisionally transferred to Monochamus Dejean, 1821, and the type locality is questioned. Eight types are figured for the first time: Plagiohammus strandi; Plagiohammus mexicanus; Plagiohammus confusor Dillon & Dillon, 1941; Hammoderus spinipennis; Hammoderus quadriplagiatus; Hammoderus inermis (Thomson, 1857); Hammoderus sallei (Thomson, 1860); Hammoderus lacordairei (Thomson, 1860).


Insufficient Acidification of Autophagosomes Facilitates Group A Streptococcus Survival and Growth in Endothelial Cells.
Group A streptococcus (GAS) is an important human pathogen, and its invasion via blood vessels is critically important in serious events such as bacteremia or multiorgan failure. Although GAS was identified as an extracellular bacterium, the internalization of GAS into nonphagocytic cells may provide a strategy to escape from immune surveillance and antibiotic killing. However, GAS has also been reported to induce autophagy and is efficiently killed within lysosome-fused autophagosomes in epithelial cells. In this study, we show that GAS can replicate in endothelial cells and that streptolysin O is required for GAS growth. Bacterial replication can be suppressed by altering GAS gene expression in an acidic medium before internalization into endothelial cells. The inhibitory effect on GAS replication can be reversed by treatment with bafilomycin A1, a specific inhibitor of vacuolar-type H(+)-ATPase. Compared with epithelial cells in which acidification causes autophagy-mediated clearance of GAS, there was a defect in acidification of GAS-containing vesicles in endothelial cells. Consequently, endothelial cells fail to maintain low pH in GAS-containing autophagosomes, thereby permitting GAS replication inside LAMP-1- and LC3-positive vesicles. Furthermore, treatment of epithelial cells with bafilomycin A1 resulted in defective GAS clearance by autophagy, with subsequent bacterial growth intracellularly. Therefore, low pH is a key factor for autophagy-mediated suppression of GAS growth inside epithelial cells, while defective acidification of GAS-containing vesicles results in bacterial growth in endothelial cells. Previous reports showed that GAS can induce autophagy and is efficiently killed within lysosome-fused autophagosomes in epithelial cells. In endothelial cells, in contrast, induction of autophagy is not sufficient for GAS killing. In this study, we provide the first evidence that low pH is required to prevent intracellular growth of GAS in epithelial cells and that this mechanism is defective in endothelial cells. Treatment of GAS with low pH altered GAS growth rate and gene expression of virulence factors and resulted in enhanced susceptibility of GAS to intracellular lysosomal killing. Our findings reveal the existence of different mechanisms of host defense against GAS invasion between epithelial and endothelial cells.


Excess Mortality in Kidney and Kidney-Pancreas Transplant Recipients in the COVID-19 Pandemic in Portugal-A Cohort Study.
The COVID-19 pandemic increased morbidity and mortality worldwide, particularly in the Kidney and Kidney-Pancreas Transplant Recipient (KTR/KPTR) population. Aiming at assessing the absolute and relative excess mortality (EM) in a Portuguese KTR/KPTR cohort, we conducted a retrospective observational study of two KTR/KPTRs cohorts: cohort 1 (P1; n = 2,179) between September/2012 and March/2020; cohort 2 (P2; n = 2067) between March/2020, and August/2022. A correlation between relative and absolute EM and age, sex, time from transplantation and cause of death was explored. A total of 145 and 84 deaths by all causes were observed in P1 and P2, respectively. The absolute EM in P2 versus P1 was 19.2 deaths (observed/expected mortality ratio 1.30, p = 0.006), and the relative EM was 1.47/1,000 person-months (95% CI 1.11-1.93, p = 0.006). Compared to the same period in the general population, the standardized mortality rate by age in P2 was 3.86 (95% CI 2.40-5.31), with a peak at 9.00 (95% CI 4.84-13.16) in P2C. The higher EM identified in this population was associated, mainly, with COVID-19 infection, with much higher values during the second seasonal COVID-19 peak when compared to the general population, despite generalized vaccination. These highlight the need for further preventive measures and improved therapies in these patients.


Mucopolysaccharidosis type VII: characterization of mutations and molecular heterogeneity.
We identified two different exonic point mutations causing beta-glucuronidase (beta G1) deficiency in two Japanese patients with mucopolysaccharidosis type VII (MPSVII). Enzyme assay of lysates of the lymphocytes and cultured fibroblasts showed little residual activity. The beta G1-specific mRNA levels were normal, as determined by northern blot analysis. Mutated cDNA clones, including the entire coding sequence, were isolated using the polymerase chain reaction (PCR) products derived from beta G1-deficient fibroblasts. Sequence analysis of the full-length mutated cDNAs showed C----T transitions, which resulted in a single Ala619----Val change (case 1, a 24-year-old male) and a Arg382----Cys change (case 2, a 7-year-old female). The former change was revealed by a loss of the cleavage site for the Fnu4HI in the mutated cDNA. On the basis of the loss of Fnu4HI restriction site, the patient (case 1) was a homozygote with this mutation. The mutational change in patient 2 was confirmed by direct sequencing and by demonstrating heterozygosity for the mutation in her parents. The Ala619----Val and Arg382----Cys mutations each disrupt a different domain which is highly conserved among human, rat, and Escherichia coli beta G1s. Each of these two amino acid changes reduced the beta G1 activity of the corresponding mutant beta G1 expressed following transfection of COS cells with expression vectors harboring the mutated cDNAs.


Ethics tries handling inner conflicts scientifically/spiritually.
"Ethic: from ethos, character, L ethos, adopted by English especially in sense of 'character and spirit of a people'. Intimately akin to Gr ethos, custom, Skt. sva-dha one's own doing or action; sva self (cf suicide) + dha to self." "Sva-dha:self-position, self-power, inherent power, custom, rule, ease, comfort, according to one's habit or pleasure, spontaneously, willingly, easily, freely, undisturbedly, wantonly, sportively." Words reveal their meanings to those who establish intimacy with them, as the bride unveils her face only to the beloved one.


[Spinal navigation with intra-operative 3D-imaging modality in lumbar pedicle screw fixation].
To evaluate the efficacy and safety of spinal navigation with intra-operative 3D-imaging modality in lumbar pedicle screw fixation. 401 patients with lumbar degenerative disorders or fracture were randomly divided into 2 groups: Group A, undergoing pedicle screw fixation by spinal navigation with intra-operative 3D-imaging system, and Group B undergoing pedicle screw fixation by traditional method. The position of pedicle screw was assessed by intra-operative 3D-imaging system. The excellent rate of pedicle screw position, mean time of pedicle screw implantation, operating time, blood loss, and post-operative complication were compared. The excellent rate of pedicle screw position was higher Group A was 95.3%, significantly higher than that of Group B (84.1%, P < 0.001). The mean time of pedicle screw implantation and operating time of Group A were (3.70 +/- 0. 65) min, significantly shorter than that of Group B [(7.83 +/- 2.32) min, P < 0.001]. The blood loss amount of Group A was (272 +/- 153) ml, significantly less than that of Group B [(455 +/- 289) ml, P < 0.05]. However, the total operating time of Group A was (134 +/- 48) min, not significantly different from that of Group B [(179 +/- 62) min, P > 0.05]. With spinal navigation combined with the intra-operative 3D-imaging modality, implantation of lumbar pedicle screw is more simplified, more accurate, safer, and with shorter operating time.


Import of frog prepropeptide GLa into microsomes requires ATP but does not involve docking protein or ribosomes.
Frog prepropeptide GLa, a precursor to a secretory protein containing 64 amino acids, was processed and imported by dog pancreas microsomes. These events did not depend on either docking protein or on the presence of ribosomes. A hybrid protein between the first 60 amino acids of prepropeptide GLa and an unrelated peptide of 49 amino acids fused to the carboxy terminus, however, behaved like a typical secretory protein precursor with regard to docking protein dependence. This suggests that independence of the need for docking protein, in the case of prepropeptide GLa, can be attributed to the size of the precursor protein. Processing and import of prepropeptide GLa by microsomes were ATP dependent. Therefore, import of proteins into the endoplasmic reticulum (ER) includes an ATP-requiring step not involving a ribosome/ribosome receptor or signal recognition particle (SRP)/docking protein interaction.


Why do patients with neurodegenerative frontal syndrome fail to answer: 'In what way are an orange and a banana alike?'.
Concept formation is the ability to create an abstract link between dissimilar objects or thoughts and is crucial for abstract and creative thinking. This process is related to the integrity of the prefrontal cortex, given the altered performances reported in patients with frontal damage, particularly those suffering from the behavioural variant of frontotemporal dementia. However, the cognitive mechanisms and neural bases of verbal concept formation are not clearly understood. The present study was aimed at addressing the following unresolved issues regarding concept formation in the field of neurology and cognitive neuroscience: (i) Are alterations in concept formation specific to frontotemporal dementia or are they also present in other cortical neurodegenerative disorders such as Alzheimer's disease? (ii) Is impaired performance in concept formation due to cortical lesions specific to frontotemporal dementia or to a cortico-subcortical frontal syndrome? and (iii) What are the cognitive mechanisms and neural bases underlying concept formation? To address these questions, we designed the Verbal Concept Formation Task, an experimental paradigm based on the similarities test. Patients presenting with severe frontal dysfunction (frontotemporal dementia, n = 18, and the Richardson form of progressive supranuclear palsy, n = 21) or with medial temporal pathology (amnestic mild cognitive impairment or Alzheimer's disease, n = 14) and healthy participants (n = 18) were given the Verbal Concept Formation Task and a large battery of neuropsychological tests. In addition, all participants underwent 3D T1-weighted MRI to analyse grey matter volume using voxel-based morphometry. Frontal patients were significantly impaired on the Verbal Concept Formation Task as compared to non-frontal participants (P = 0.00001). Global performance score was positively correlated with scores in cognitive tasks assessing executive functions and with grey matter volume in several areas, mostly in the frontal-basal-ganglion network. Two types of errors were observed in frontal patients. The most frequent was discriminating instead of grouping items ('linking deficit'). Patients also linked items on a concrete instead of an abstract basis ('abstraction deficit'). Linking and abstraction deficits were related to partially different areas: the linking deficit to the dorsal anterior cingulate cortex, right middle frontal gyrus and both inferior parietal lobules and the abstraction deficit to the head of the caudate nuclei and the left superior frontal gyrus. These data suggest that verbal concept formation requires the integrity of the prefrontal-basal-ganglion functional network. In addition, it can be divided into two distinct cognitive processes, which are underlain by two partially different neural networks.


Prospective, randomized, controlled comparison of SYSTANE UD eye drops versus VISINE INTENSIV 1% EDO eye drops for the treatment of moderate dry eye.
The aim of this prospective, randomized, clinical, single-center study was to compare the safety and efficacy of 2 ocular surface lubricant eye drops: preservative-free hydroxypropyl (HP)-Guar (SYSTANE UD(®)) eye drops versus preservative-free Tamarindus indica seed polysaccharide (TSP) 1% (VISINE INTENSIV 1% EDO(®)) eye drops. Fifty-six eyes of 28 patients with moderate keratoconjunctivitis sicca (DEWS severity level 2) were enrolled in the trial. Patients were randomized for 2 treatment groups (SYSTANE UD eye drops vs. VISINE INTENSIV 1% EDO eye drops). The eye drops in both groups were applied 5 times per day for 3 months. Statistical analyses were performed using Statistica™ software (Mann-Whitney U-test and Wilcoxon test). P-Values<0.05 were considered significant. After 3 months of treatment the patients of both groups had subjective benefit in the relief of symptoms of dry eye disease evaluated by the Ocular Surface Disease Index (OSDI) questionnaire score. Patients treated with HP-Guar and TSP showed improvements in tear film stability measured by tear break-up time (TBUT), which are statistically significant in the HP-Guar group (P=0.02). The results of this clinical trial show improvements of symptoms and signs in patients with moderate dry eye after the consistent use of preservative-free HP-Guar and TSP lubricant eye drops. Both artificial tear formulations produce amelioration in tear film stability improving eye conditions and patient quality of life. HP-Guar seems to be slightly more effective in improving ocular surface protection by decreasing tear film evaporation.


Challenges in Stratifying the Molecular Variability of Patient-Derived Colon Tumor Xenografts.
Colorectal cancer (CRC) is the second most common cancer in Europe and a leading cause of death worldwide. Patient-derived xenograft (PDX) models maintain complex intratumoral biology and heterogeneity and therefore remain the platform of choice for translational drug discovery. In this study, we implanted 37 primary CRC tumors and five CRC cell lines into NU/J mice to develop xenograft models. Primary tumors and established xenografts were histologically assessed and surveyed for genetic variants and gene expression using a panel of 409 cancer-related genes and RNA-seq, respectively. More than half of CRC tumors (20 out of 37, 54%) developed into a PDX. Histological assessment confirmed that PDX grading, stromal components, inflammation, and budding were consistent with those of the primary tumors. DNA sequencing identified an average of 0.14 variants per gene per sample. The percentage of mutated variants in PDXs increased with successive passages, indicating a decrease in clonal heterogeneity. Gene Ontology analyses of 4180 differentially expressed transcripts (adj. p value < 0.05) revealed overrepresentation of genes involved in cell division and catabolic processes among the transcripts upregulated in PDXs; downregulated transcripts were associated with GO terms related to extracellular matrix organization, immune responses, and angiogenesis. Neither a transcriptome-based consensus molecular subtype (CMS) classifier nor three other predictors reliably matched PDX molecular subtypes with those of the primary tumors. In sum, both genetic and transcriptomic profiles differed between donor tumors and PDXs, likely as a consequence of subclonal evolution at the early phase of xenograft development, making molecular stratification of PDXs challenging.


Pathology review of cases presenting to a multidisciplinary pigmented lesion clinic.
To determine if pathology review, within the context of a multidisciplinary pigmented lesion clinic, results in changes in diagnosis of melanocytic lesions and to ascertain if the change in diagnosis altered clinical management and outcome. Retrospective review of pathology reports, progress notes, and diagnoses entered in the University of Pennsylvania (Philadelphia) Pigmented Lesion Clinic database. A total of 5136 primary melanocytic lesions from patients referred to the pigmented lesion clinic between 1991 and 1999 were reviewed by a single pathologist. Of these, 559 (11%) had diagnoses that were changed significantly from the submitting diagnosis, with 120 (2.3%) undergoing a "critical" revision, 63 (1.2%) defined as a change from malignant to benign, and 57 (1.1%) from benign to malignant; 171 (3.3%) remained within the same category (benign or malignant) but had a downgrade in diagnosis (less severe) that would have a significant impact on treatment, prognosis, and research. Likewise, 268 (5.2%) remained within the same category but had an upgrade in diagnosis (more severe) that would have a significant impact on the same parameters. In addition, 257 reexcisions of melanocytic lesions were reviewed, of which 15 (5.8%) were changed from clear to involved margins, while another 16 (6.2%) were changed from involved to clear margins, for a total of 12%. Of the lesions with a critical revision, follow-up was obtained in 98 (83%). The patients in the malignant-to-benign category were followed up for an average of 2.6 years while those in the benign-to-malignant category were followed up for an average of 4.2 years. The change of diagnosis from malignant to benign resulted in 9 patients (17%) being spared a reexcision while 12 patients (23%) were downgraded from a radical to moderate reexcision. The change in diagnosis from benign to malignant resulted in 45 patients (98%) requiring a reexcision after review. Twenty-five of these patients were found to have residual disease in their reexcision specimens or had already had recurrence at the excision site. Furthermore, 7 patients (15%) underwent lymph node dissection or sentinel lymph node biopsy after review. However, none of the nodes were positive for metastatic disease. During this time, 8 patients (17%) in the benign-to-malignant category, and 1 patient (1.9%) in the malignant-to-benign category (who had previously had 4 primary melanomas) developed metastatic disease. Pathology review of primary melanocytic lesions, within the context of a multidisciplinary pigmented lesion clinic, results in changes in diagnosis in a significant proportion of cases. These changes have important implications for clinical decision making, patient outcome, and research data collection.


Factors influencing job satisfaction of new graduate nurses participating in nurse residency programs: a systematic review.
Nurse residency programs are designed to increase competence and skill, and ease the transition from student to new graduate nurse. These programs also offer the possibility to positively influence the job satisfaction of new graduate nurses, which could decrease poor nursing outcomes. However, little is known about the impact of participation in a nurse residency program on new graduate nurses' satisfaction. This review examines factors that influence job satisfaction of nurse residency program participants. Eleven studies were selected for inclusion, and seven domains influencing new graduate nurses' satisfaction during participation in nurse residency programs were identified: extrinsic rewards, scheduling, interactions and support, praise and recognition, professional opportunities, work environment, and hospital system. Within these domains, the evidence for improved satisfaction with nurse residency program participation was mixed. Further research is necessary to understand how nurse residency programs can be designed to improve satisfaction and increase positive nurse outcomes.


The Role of Peroxiredoxins in the Transduction of H2O2 Signals.
Hydrogen peroxide (H2O2) is produced on stimulation of many cell surface receptors and serves as an intracellular messenger in the regulation of diverse physiological events, mostly by oxidizing cysteine residues of effector proteins. Mammalian cells express multiple H2O2-eliminating enzymes, including catalase, glutathione peroxidase (GPx), and peroxiredoxin (Prx). A conserved cysteine in Prx family members is the site of oxidation by H2O2. Peroxiredoxins possess a high-affinity binding site for H2O2 that is lacking in catalase and GPx and which renders the catalytic cysteine highly susceptible to oxidation, with a rate constant several orders of magnitude greater than that for oxidation of cysteine in most H2O2 effector proteins. Moreover, Prxs are abundant and present in all subcellular compartments. The cysteines of most H2O2 effectors are therefore at a competitive disadvantage for reaction with H2O2. Recent Advances: Here we review intracellular sources of H2O2 as well as H2O2 target proteins classified according to biochemical and cellular function. We then highlight two strategies implemented by cells to overcome the kinetic disadvantage of most target proteins with regard to H2O2-mediated oxidation: transient inactivation of local Prx molecules via phosphorylation, and indirect oxidation of target cysteines via oxidized Prx. Critical Issues and Future Directions: Recent studies suggest that only a small fraction of the total pools of Prxs and H2O2 effector proteins localized in specific subcellular compartments participates in H2O2 signaling. Development of sensitive tools to selectively detect phosphorylated Prxs and oxidized effector proteins is needed to provide further insight into H2O2 signaling. Antioxid. Redox Signal. 28, 537-557.


Delineation of supernumerary marker chromosomes in 38 patients.
We present cytogenetic and clinical data on 38 patients with supernumerary marker chromosomes (SMCs). SMCs were characterized using a strategy combining classical banding techniques and molecular cytogenetic studies. Cases were ascertained prenatally, postnatally, and after fetal death. In 26 patients (68%), the SMC originated entirely from acrocentric chromosomes. Among these, most patients carried a der(15). In 11 patients (29%), they were of nonacrocentric origin, including 9 autosomal and 2 gonosomal marker chromosomes. In 1 patient the SMC was of partially acrocentric origin. Patients with small derivatives of chromosome 15 [der(15)] had a normal phenotype. Those with a larger der(15) showed phenotypical abnormalities. Patients with supernumerary marker chromosomes derived from chromosomes 13 or 21, and 14 appeared to have a low risk of abnormalities. Out of this group only 1 patient who carried an additional r(21) had physical anomalies. Patients with an SMC originating from chromosome 22 showed physical abnormalities in 2 out of 6 cases. Supernumerary marker chromosomes identified as i(9p), i(12p), and der(18) were all associated with an abnormal phenotype. Two of the derivatives of chromosome 20 analyzed were correlated with a normal phenotype, while the carrier of the third one showed physical anomalies and motor retardation. Of 2 patients with an extra der(X), 1 was normal and 1 showed an abnormal phenotype.


Early changes in clinical, functional, and laboratory biomarkers in workers at risk of indium lung disease.
Occupational exposure to indium compounds, including indium-tin oxide, can result in potentially fatal indium lung disease. However, the early effects of exposure on the lungs are not well understood. To determine the relationship between short-term occupational exposures to indium compounds and the development of early lung abnormalities. Among indium-tin oxide production and reclamation facility workers, we measured plasma indium, respiratory symptoms, pulmonary function, chest computed tomography, and serum biomarkers of lung disease. Relationships between plasma indium concentration and health outcome variables were evaluated using restricted cubic spline and linear regression models. Eighty-seven (93%) of 94 indium-tin oxide facility workers (median tenure, 2 yr; median plasma indium, 1.0 μg/l) participated in the study. Spirometric abnormalities were not increased compared with the general population, and few subjects had radiographic evidence of alveolar proteinosis (n = 0), fibrosis (n = 2), or emphysema (n = 4). However, in internal comparisons, participants with plasma indium concentrations ≥ 1.0 μg/l had more dyspnea, lower mean FEV1 and FVC, and higher median serum Krebs von den Lungen-6 and surfactant protein-D levels. Spline regression demonstrated nonlinear exposure response, with significant differences occurring at plasma indium concentrations as low as 1.0 μg/l compared with the reference. Associations between health outcomes and the natural log of plasma indium concentration were evident in linear regression models. Associations were not explained by age, smoking status, facility tenure, or prior occupational exposures. In indium-tin oxide facility workers with short-term, low-level exposure, plasma indium concentrations lower than previously reported were associated with lung symptoms, decreased spirometric parameters, and increased serum biomarkers of lung disease.


Paraneoplastic endocrine syndromes.
The majority of neoplasms are responsible for symptoms caused by mass effects to surrounding tissues and/or through the development of metastases. However, occasionally neoplasms, with or without endocrine differentiation, acquire the ability to secrete a variety of bioactive substances or induce immune cross-reactivity with the normal tissues that can lead to the development of characteristic clinical syndromes. These syndromes are named endocrine paraneoplastic syndromes when the specific secretory components (hormones, peptides or cytokines) are unrelated to the anticipated tissue or organ of origin. Endocrine paraneoplastic syndromes can complicate the patient's clinical course, response to treatment, impact prognosis and even be confused as metastatic spread. These syndromes can precede, occur concomitantly or present at a later stage of tumour development, and along with the secreted substances constitute the biological 'fingerprint' of the tumour. Their detection can facilitate early diagnosis of the underlying neoplasia, monitor response to treatment and/or detect early recurrences following successful initial management. Although when associated with tumours of low malignant potential they usually do not affect long-term outcome, in cases of highly malignant tumours, endocrine paraneoplastic syndromes are usually associated with poorer survival outcomes. Recent medical advances have not only improved our understanding of paraneoplastic syndrome pathogenesis in general but also enhanced their diagnosis and treatment. Yet, given the rarity of endocrine paraneoplastic syndromes, there is a paucity of prospective clinical trials to guide management. The development of well-designed prospective multicentre trials remains a priority in the field in order to fully characterise these syndromes and provide evidence-based diagnostic and therapeutic protocols.


The use of carba(dethia)-coenzyme A (CH2CoA) derivatives for mechanistic investigations.
A novel class of acyl-coenzyme A analogues has been synthesized in which the sulphur atom is replaced by methylene. In contrast to their natural thiolester counterparts these acyl-CH2CoA analogues are stable to hydrolysis. They are good substrates for several enzymes that do not attack the thiolester group (carboxylases, mutases, dehydrogenases, epimerases, etc.) and potent inhibitors for most enzymes that do so. Some of the new insights gained by the use of acyl-CH2CoA are discussed in terms of enzymatic mechanisms.


Ethylene is required for elicitin-induced oxidative burst but not for cell death induction in tobacco cell suspension cultures.
The signal compound ethylene and its relationships with oxidative burst and cell death were analyzed in cultured tobacco cells treated with the proteinaceous elicitor quercinin. Quercinin belongs to the protein family of elicitins and was isolated from the soil-born oak pathogen Phytophthora quercina. It was shown to induce a dose-dependent oxidative burst in tobacco cell culture in concentrations from 0.05 to 0.5 nM, and subsequently, cell death. The characteristics of quercinin-induced cell death included both membrane damage and DNA fragmentation in tobacco cell culture. At higher quercinin concentrations (2 nM), H(2)O(2) formation and ethylene biosynthesis were inhibited. Ethylene at low concentrations proved to be necessary for induction and maintenance of H(2)O(2) production in tobacco cells treated with quercinin. It was demonstrated that external addition of inhibitors of ethylene biosynthesis such as alpha-amino-oxy-acetic acid (AOA) and CoCl(2) also decreased or even inhibited the quercinin-induced oxidative burst, but did not influence cell death induction. These results demonstrate evidence for a requirement of the plant hormone ethylene for the onset of the quercinin-induced oxidative burst.


The relation between progressive osteoarthritis of the knee and long term progression of osteoarthritis of the hand, hip, and lumbar spine.
The association between progression of knee osteoarthritis and progression of osteoarthritis at sites distant from the knee is unclear because of a lack of multisite longitudinal progression data. To examine the association between radiological progression of knee osteoarthritis and osteoarthritis of the hands, hips, and lumbar spine in a population based cohort. 914 women had knee x rays taken 10 years apart, which were read for the presence of osteophytes and joint space narrowing (JSN). Progression status was available for hand, hip, and lumbar spine x rays over the same 8 to 10 year period. The association between progression of knee osteoarthritis and osteoarthritis at other sites was analysed using odds ratios (OR) and 95% confidence intervals (CI) in logistic regression models. 89 of 133 women had progression of knee osteoarthritis based on osteophytes, and 51 of 148 based on JSN definition. Progression of JSN in the knee was predicted by progression in lumbar spine disc space narrowing (OR = 2.9 (95% CI 1.2 to 7.5)) and hip JSN (OR = 2.0 (1.0 to 4.2)). No consistent effects were seen for hand osteoarthritis. The associations remained after adjustment for age and body mass index. Progression of knee osteoarthritis is associated with progression of lumbar spine and hip osteoarthritis. This may have implications for trial methodology, the selection of patients for osteoarthritis research, and advice for patients on prognosis of osteoarthritis.


Investigation of Methylenetetrahydrofolate Reductase C677T Polymorphism and Human Papilloma Virus Genotypes in Iranian Breast Cancer.
Breast cancer (BC) is the leading cause of death among Iranian women. Development of BC is a multistep process, arising from genetic changes such as methylenetetrahydrofolate reductase (MTHFR) polymorphism and infection with human papillomavirus (HPV). In this study, we investigated HPV genotypes associated with BCs and its relation with MTHFR C677T polymorphism for early detection of familial BCs. A total of 84 archival BC samples from Iran were collected. Verification of each cancer reported in a relative was sought through the pathology reports of the hospital records. Then, DNA was extracted from all samples by standard methods and HPV genotypes and MTHFR C677T polymorphism genotypes were analyzed using multiplex polymerase chain reaction (PCR) and amplification-refractory mutation system (ARMS)-PCR. Finally, data analysis was performed using version 7 of the Epi Info™ 2012 software and test chi-square (x2) for trend. The frequencies of the CC, TC, and TT genotypes of MTHFR (C677T) were 0.53, 0.38, and 0.09 in familial BC patients, and 0.46, 0.51, and 0.03, respectively, in nonfamilial BC patients. Furthermore, HPV DNA typing identified 29 infections and C677T TT genotype was significantly associated with an increased risk of familial BC in the study population. Our results demonstrate that infection with HPV was prevalent among Iranian women with familial BC. Finally, the testing of C677T GG genotype in combination with HPV genotyping as molecular markers can be helpful in the early diagnosis of Iranian familial BCs by PCR.


Individualized high-dose cabergoline therapy for hyperprolactinemic infertility in women with micro- and macroprolactinomas.
Cabergoline is effective for hyperprolactinemic hypogonadism. However, the rate of cabergoline-induced pregnancy in women with prolactinoma remains unknown. Also unknown is whether cabergoline can control tumor growth and thereby achieve successful pregnancy in patients with macroprolactinomas. Eighty-five women with macroprolactinomas (n = 29) or microprolactinomas (n = 56) received prospective, high-dose cabergoline therapy for infertility based on individual prolactin suppression and/or tumor shrinkage. The patients included 31 bromocriptine-resistant, 32 bromocriptine-intolerant, and 22 previously untreated women. Conception was withheld until three regular cycles returned in women with microadenoma and until tumors shrank below 1.0 cm in height in women with macroadenoma. Cabergoline was withdrawn at the fourth gestational week. Cabergoline normalized hyperprolactinemia and recovered the ovulatory cycle in all patients. All adenomas contracted, and 11 macroadenomas and 29 microadenomas disappeared. Eighty patients (94%) conceived 95 pregnancies, two of which were cabergoline-free second pregnancies. The dose of cabergoline at the first pregnancy was 0.25-9 mg/wk overall and 2-9 mg/wk in the resistant patients. Of the 93 pregnancies achieved on cabergoline, 86 resulted in 83 single live births, one stillbirth, and two abortions; the remaining seven were ongoing. All babies were born healthy, without any malformations. No mothers experienced impaired vision or headache suggestive of abnormal tumor reexpansion throughout pregnancy. Cabergoline achieved a high pregnancy rate with uneventful outcomes in infertile women with prolactinoma, independent of tumor size and bromocriptine resistance or intolerance. Cabergoline monotherapy could substitute for the conventional combination therapy of pregestational surgery or irradiation plus bromocriptine in macroprolactinomas.