Curative-intent radical en bloc resection using a minimum of a 3 cm margin in feline injection-site sarcomas: a retrospective analysis of 131 cases.
Objectives Owing to its highly infiltrative growth, feline injection-site sarcoma (FISS) carries a significant risk of local tumour recurrence. Parameters of possible prognostic significance (eg, tumour size and location, resection of de novo vs recurrent tumours, and achievement of tumour-free surgical margins) were examined with regard to their influence on recurrence rate (RR), disease-free interval (DFI) and survival time (ST). Methods This was a retrospective analysis of cats with FISSs located on the chest or abdominal wall or the interscapular region treated in a single institution using a standardised radical resection technique with 3 cm lateral margins and full-thickness body wall resection (tumours over chest/abdominal wall) or a minimum of two fascial planes (interscapular tumours). Results Median postoperative DFI and ST of 131 cats with FISSs was 21 and 24 months, respectively. Patients operated on for recurrent tumours were significantly more likely to die from tumour-related reasons compared with patients with de novo tumours ( P <0.001). RR and DFI in the different tumour locations were comparable ( P = 0.544 and P = 0.17, respectively). Local tumour recurrence occurred in 38.1% of the cats. Cats operated on for tumour recurrences had a significantly higher chance of another recurrence (RR 55.5% vs 33.3%; P = 0.005). Completeness of excision was determined by taking tumour bed biopsies. Tumour bed biopsies that did not contain tumour cells were associated with a significantly lower RR compared with those with tumour cells (30.5% vs 76.2%). Conclusions and relevance Depending on prognostic factors such as surgery for primary vs recurrent tumour, tumour-free resection margins and tumour location, the RR in FISS ranges from 33-55%, despite curative intent radical surgery. This study may help in identifying patients at risk for recurrence.


Swallowing disorders: proposal of a method for forensic medicine assessment.
For a correct classification of dysphagia, morphologic instrumental investigations capable of analysing the anatomical structures of the digestive tract, are undoubtedly essential, but the most important investigations are the functional investigations, such as videofluoroscopy, fiberoptic endoscopic evaluation of swallowing, oro-pharyngo-oesophageal scintigraphy, manometry and pH-metry. Results of these examinations enable us to identify, in patients with dysphagia, the extent of permanent damage, as a consequence of injury to the structures designated to swallowing, must be such that it at least minimally impairs and decreases the relative function, but to a degree that can be detected and, in some manner, measured. From a legal point of view, alterations in swallowing, caused by damage to structures belonging to the respiratory-digestive tract, can be found in crimes against persons and particularly in those involving body injury. In the case of civil, but also in private or social insurance proceedings, it is necessary to distinguish which parameters are to be used as reference for evaluating and quantifying the injury in terms of reimbursement. With the introduction of complete biological well-being, injury is considered as an impairment of the worth and right to enjoy psychological-physical integrity as a quality of life. The criteria currently used internationally take into account the conception of psychological-physical efficiency; nevertheless, in Italian forensic medicine, there is no table that offers a thorough quantification of swallowing modifications, if one excludes oesophageal disorders. Herewith, an evaluation table, dividing oro-pharyngo-oesophageal dysphagia into five, progressively serious classes, is proposed.


Natural History of Lung Hernias.
Lung herniation has been described in case reports or series. There are scare data in the form of original research studies to systematically evaluate this condition. Our aim was to evaluate lung hernias with a focus on their natural history. This is a retrospective study at our institution of patients who were found to have lung herniation on imaging between September 2010 and November 2022. Electronic medical record review was performed to extract clinical information regarding patients. Computed tomographic imaging was used to evaluate hernia size and size progression over time with a median follow-up time of 3.8 years. Thirty-eight patients were eligible for analysis. Majority of patients were overweight or obese (31/38), smokers (31/38), had prior thoracic surgery (30/38), and were asymptomatic (33/38). Twenty of 38 patients had stability in hernia size, 12 of 38 patients had hernia size progression, and 6 of 38 patients showed hernia size regression. Younger age was found to be predictive of hernia size progression with age of 60 years being the cut-off for its prediction. Lung hernias typically either remain stable in size or show size progression. Younger age (60 years cut-off) was found to be predictive of size progression. This is the largest systematic investigation at a medical institution to the best of our knowledge of lung hernias which used computed tomographic imaging to follow up lung hernias. Further information could be given to patients with this condition and to clinicians for potential management guidance.


Corticosterone response to gestational stress and postpartum memory function in mice.
Maternal stress is a common adversity during pregnancy. Gestational corticosterone alternations are thought to contribute to the etiology of postpartum behavioral disturbances. However, the impact of stress during pregnancy, in particular noise exposure, on gestational corticosterone fluctuations and spatial cognition in postpartum mice has not been fully understood yet. We hypothesized that noise exposure during pregnancy negatively affects gestational corticosterone levels and postpartum memory function in the dams similar to the physical stressors. Pregnant C57BL/6 mice were randomly assigned to either one of two stress conditions or a control condition. The noise stress (NS) was induced by presenting a loud intermittent 3000 Hz frequency on gestational days (GDs) 12, 14, and 16 for 24 hours, whereas the physical stress (PS) consisted of restraint and exposure to an elevated platform on GDs 12-16. Plasma corticosterone level was collected on GDs 11 and 17, and Morris water task (MWT) was carried out 30 days after parturition. Compared to the control group, the level of corticosterone in the stressed groups was significantly increased on GD17 relative to GD11. Significantly longer swim time and lower swim speed were observed in both stressed groups relative to the control group. Probe time was significantly shorter in the NS group than the other groups. The delta corticosterone level was significantly correlated with the swim time as well as the probe time in the three groups. Given the results, the adverse effects of gestational noise exposure on the hypothalamic pituitary-adrenal (HPA) axis activation and postpartum spatial learning and memory function were as large as/ or a bit stronger than the physical stresses. The findings suggest the significance of conservation against loud noise exposure in daily living, as well as need to further notice to the different aspects of gestational stress in mothers' behavior like offspring.


Healing Donor Defect States in CVD-Grown MoS2 Field-Effect Transistors Using Oxygen Plasma with a Channel-Protecting Barrier.
Molybdenum disulfide (MoS2 ), a metal dichalcogenide, is a promising channel material for highly integrated scalable transistors. However, intrinsic donor defect states, such as sulfur vacancies (Vs ), can degrade the channel properties and lead to undesired n-doping. A method for healing the donor defect states in monolayer MoS2 is proposed using oxygen plasma, with an aluminum oxide (Al2 O3 ) barrier layer that protects the MoS2 channel from damage by plasma treatment. Successful healing of donor defect states in MoS2 by oxygen atoms, even in the presence of an Al2 O3 barrier layer, is confirmed by X-ray photoelectron spectroscopy, photoluminescence, and Raman spectroscopy. Despite the decrease in 2D sheet carrier concentration (Δn2D = -3.82×1012 cm-2 ), the proposed approach increases the on-current and mobility by 18% and 44% under optimal conditions, respectively. Metal-insulator transition occurs at electron concentrations of 5.7×1012 cm-2 and reflects improved channel quality. Finally, the activation energy (Ea ) reduces at all the gate voltages (VG ) owing to a decrease in Vs , which act as a localized state after the oxygen plasma treatment. This study demonstrates the feasibility of plasma-assisted healing of defects in 2D materials and electrical property enhancement and paves the way for the development of next-generation electronic devices.


Determination of the critical absolute blood volume for intradialytic morbid events.
The reduction of blood volume below a critical threshold is assumed to trigger intradialytic morbid events (IME). Recently, we presented a simple method to determine the absolute blood volume during routine hemodialysis (HD) carried out without blood sampling and without injection of dyes or radiolabeled markers. Such information could be used to detect excessive volume reduction during HD and to prevent IME. Therefore, we performed a pilot study in IME-prone patients to identify the absolute blood volume at which they developed clinical symptoms. A volume of 240 mL of ultrapure dialysate was automatically infused into the extracorporeal circulation using the bolus function of a commercial online hemodiafiltration machine incorporating a blood volume monitor (BVM). The increase in relative blood volume (RBV) caused by the infusion was measured and used to determine the absolute blood volume at that time. The blood volume per kilogram body mass at the time of symptomatic IME was also determined. All IME-prone patients of a single-dialysis center were included in the study. Ten out of 12 patients became symptomatic at a specific blood volume between 65 and 56 mL/kg (mean 62 mL/kg) whereas RBV showed a wide scatter (82-97%). A specific blood volume of 65 mL/kg seems to represent the threshold for IME by this method. The technique could be completely automated without altering the hardware of the dialysis device. Present feedback systems for automated blood volume-controlled ultrafiltration could be adapted to maintain absolute blood volume above this critical volume to safely prevent volume-dependent IME.


Selective expression of HSP70-1 gene in the adrenal cortex but not in the medulla of thermally stressed rats.
The heat shock protein 70 (HSP70) gene expression in rat adrenal glands was investigated. In situ hybridization and Northern blotting revealed a marked increase of inducible HSP70 (HSP70-1) gene expression in the adrenal cortex, but not in the medulla, after whole body hyperthermia. In vivo footprinting assay of HSP70-1 promoter region suggested a possible involvement of other factor(s) in addition to the heat shock factor (HSF). We also detected significant increases of both ACTH and corticosterone in the plasma of the hyperthermic rats. These results suggested some physiological factors other than HSF may also participate in the tissue-specific induction of HSP70-1 gene in vivo.


The pathway of leukemic cell death caused by glucocorticoid receptor fragment 465*.
The truncated glucocorticoid receptor mutant gene 465* codes for a protein that is interrupted by a frame-shift mutation in the second zinc finger of the natural DNA binding domain. Thus, 465* represents the natural amino acid sequence 1-465 followed by 21 novel amino acids starting at position 466. The entire ligand binding domain is missing. Prior studies have shown that transient transfection of the glucocorticoid-resistant leukemic T-cell clone ICR-27 with a plasmid expressing 465* rapidly reduces the number of viable cells. This response does not require activation by a steroid, and a hybrid protein consisting of green fluorescent protein fused to 465* is found primarily in the cytoplasm. In the present study, we present evidence that the decrease in cell number is due to a form of cell death that bears many of the classic characteristics of apoptosis. Expression of the 465* protein can be detected a few hours after electroporation and is followed by activation of caspase-3 as well as reduction of the mitochondrial inner transmembrane potential. The caspase-3 inhibitor ZVAD-fmk blocks 465*-dependent cell death when added acutely after electroporation, but fails to do so later. We conclude that the novel 465* gene causes cell death by apoptosis.


Molecular dynamics simulation of cation-phospholipid clustering in phospholipid bilayers: possible role in stalk formation during membrane fusion.
In this study, we performed all-atom long-timescale molecular dynamics simulations of phospholipid bilayers incorporating three different proportions of negatively charged lipids in the presence of K(+), Mg(2+), and Ca(2+) ions to systemically determine how membrane properties are affected by cations and lipid compositions. Our simulations revealed that the binding affinity of Ca(2+) ions with lipids is significantly stronger than that of K(+) and Mg(2+) ions, regardless of the composition of the lipid bilayer. The binding of Ca(2+) ions to the lipids resulted in bilayers having smaller lateral areas, greater thicknesses, greater order, and slower rotation of their lipid head groups, relative to those of corresponding K(+)- and Mg(2+)-containing systems. The Ca(2+) ions bind preferentially to the phosphate groups of the lipids. The complexes formed between the cations and the lipids further assembled to form various multiple-cation-centered clusters in the presence of anionic lipids and at higher ionic strength-most notably for Ca(2+). The formation of cation-lipid complexes and clusters dehydrated and neutralized the anionic lipids, creating a more-hydrophobic environment suitable for membrane aggregation. We propose that the formation of Ca(2+)-phospholipid clusters across apposed lipid bilayers can work as a "cation glue" to adhere apposed membranes together, providing an adequate configuration for stalk formation during membrane fusion.


The need for improved contrast media. Ioxilan: updating design theory.
Because of computed tomography (CT) and digital subtraction angiography (DSA), other diagnostic procedures assisted by urovascular contrast media (CM) have decreased, but the annual total remains at 10 to 11 million procedures since 1980. This trend, expected to continue, suggests that CM will remain vital to medical imaging. The current nonionic CM are not universally affordable, and may elicit pain in peripheral angiography. The author and co-workers explored conversion of ionic into nonionic CM, and have arrived at Ioxilan, 5-(N-2,3-dihydroxypropylacetamido)-2,4,6-triiodo-N-(2-hydroxyethyl )-N'-(2,3- dihydroxypropyl)-isophthalamide; a stable, water-soluble and well-tolerated CM. Ioxilan has unexpectedly low osmolality (570 mOsm at 300 mgI/mL), attributable to the region of double-methylenes that, by hydrophobic bonding, transiently associates the Ioxilan molecules. The high overall hydrophilicity, and thus good biological tolerance, of Ioxilan is accomplished by masking the hydrophobic region with a hydrophilic group. The author suggests that improved urovascular nonionic CM can be designed using this principle.


Study on integration of the National Leprosy Eradication Programme into primary health care services: a pilot project.
The Central Leprosy Training and Research Institute, Chengalpattu, Tamil Nadu, undertook an interventional study, as a pilot project, on integration of the National Leprosy Eradication Programme (NLEP) vertical activities into the PHC system in two selected districts of Visakhapatnam and Krishna of Andhra Pradesh, between September 1997 and March 1999. The objective of the study was to assess the various operational aspects and implications of integrated implementation of the activities of the NLEP through the PHC system. 1,304,163 people (239,142 in the study group and 1,065,020 in the control group) were enrolled in the study. The methodology employed in carrying out the pilot project in the two selected districts is described. MDT was in operation for more than 5 years in these two districts through vertical approach. Prevalence has declined from >50/10000 at the start of MDT to about 3/10000 at the start of the project. During the implementation phase, 1459 new leprosy cases were detected (NCDR 5.39/10000 person-years) and 1458 cases were released from treatment (RFT rate: 93.04%) and towards the end of the project 450 cases were under treatment (PR 1.66/10000). Simple rates, ratios and proportions were used in the analysis of data and results were compared. The interventional study was designed to assess the implications and impact of implementation of NLEP activities through PHC staff. The study design, rationale, data collection, data processing, quality control methods employed in the study project and the results are discussed. The results of the study indicate that integrated implementation of the NLEP by PHC staff is feasible, if proper support is provided.


A Mixed Methods Analysis of Care Coordination Needs and Desirable Features of an M-Health Application to Support Caregivers of Children With Down Syndrome.
Care coordination is critical for the management of health care needs of children with Down syndrome by encompassing management of health information and linking of providers. This study was designed to identify caregiver and health care provider experiences of care coordination to inform the development of an m-health application. In this mixed methods study, caregivers completed survey materials addressing the child's health care needs, m-health use, and care coordination experiences. A sample of caregivers and health care providers were interviewed to further understanding. Most caregivers reported having a primary health care provider but wanted increased communication and help with care coordination. Interview data identified themes related to care coordination challenges, including information management, information sharing, use of health care guidelines, tracking health data, resources, technology use, previous application use, and coordination of schedules. Qualitative themes were linked to desired features of an m-health application to aid in development.


Early 18F-FDG PET Flare-up Phenomenon After CAR T-Cell Therapy in Lymphoma.
18F-FDG PET/CT imaging series were acquired on a 64-year-old woman with refractory diffuse large B lymphoma to monitor chimeric antigen receptor (CAR) T-cell therapy. Because of a clinical deterioration, 18F-FDG PET/CT performed 8 days after CAR T-cell therapy suggested an early flare-up phenomenon with new lymph node involvement, lymph node progression while a decrease in metabolic tumor volume. The 18F-FDG PET/CT 1 month after CAR T-cell therapy confirmed this hypothesis. Pseudoprogression in solid tumors treated by immunotherapy has generally been reported later after treatment.


[A case of pancreatic and duodenal fistula after total gastrectomy successfully treated with coagulation factor XIII].
Pancreatic fistula( PF) is a challenging postoperative complication. We report a case of PF following gastrectomy successfully treated using intravenous coagulation factor XIII( FXIII).A 78-year-old man with early gastric cancer underwent total gastrectomy with Roux-en-Y reconstruction. PF developed postoperatively, following which, leakage from the duodenal stump was observed. Percutaneous drainage and re-operative surgery were performed. A somatostatin analogue, antibiotic drugs, and gabexate mesilate were administrated along with nutritional support. The pancreatic and duodenal fistula had been producing duodenal juice for over 30 days since the re-operative surgery. As suspected, reduced FXIII activity was confirmed in the patient. After administering FXIII for 5 days, the amount of duodenal juice from the fistula markedly reduced, and the fistula closed immediately afterwards. The results of our study suggest that administration of FXIII could be a reasonable and effective treatment for patients with pancreatic or/and enterocutaneous fistula who are resistant to standard treatments.


Medial Femoral Trochlea Osteochondral Flap: Applications for Scaphoid and Lunate Reconstruction.
Vascularized osteochondral flaps are a new technique described for the reconstruction of challenging articular defects of the carpus. The medial femoral trochlea osteochondral flap is supplied by the descending geniculate artery. This osteochondral flap has shown promise in the treatment of recalcitrant scaphoid proximal pole nonunions and advanced avascular necrosis of the lunate. The anatomy, surgical technique, and results are discussed, with clinical cases provided.


[The case of immunologic vasculitis which was treated as a hypochondriac disorder].
The long and difficult diagnostic and therapeutic process in a 21 year old patient with hypochondriac disorder was presented. In the past he had the streptococcal throat infection and during 5 years he was diagnosed and treated because of headache, heart, muscles and joints pains. His blood pressure was occasionally high. He had tonsillectomy and his ASO index was high (from 405 IU/ml to 2500 IU/ml). His cranial CT, EEG, ECG were normal. Finally he was diagnosed as having hypochondriac disorder and began psychiatric treatment. Because of lacking improvement in the out-patient therapy he was admitted to the Neurotic Ward of Medical Academy in Gdańsk. The results of cerebral SPECT showed hypoperfusion in different regions (prefrontal, frontal, temporal, parietal, about medial from 5-22%). The antibodies ABA type II/20/, ACA/ CA/ type III /10/, MSA /ASMA/++/ were found. The level of thrombomodulin was 36.64 ng/ ml. Psychological tests (Benton, Bender, MMPI) were normal. In result of the above findings and observation the diagnosis was changed from hypochondriac disorder to secondary immunologic vasculitis. The patient received probably the possibility to be properly treated.


The role of viral infection in pulmonary exacerbations of bronchiectasis in adults: a prospective study.
Although viral infections are a major cause of exacerbations in patients with chronic airway diseases, their roles in triggering bronchiectasis exacerbations in adults remain unclear. Therefore, we prospectively investigated the incidence and clinical impacts of viral infection in adults with bronchiectasis exacerbations. The study cohort of 119 adults with bronchiectasis was followed up prospectively for 12 months. Nasopharyngeal swabs and sputum samples were assayed for 16 respiratory viruses, using polymerase chain reaction assays. Symptoms, spirometry, quality of life, bacterial cultures, and inflammatory markers were assessed during steady-state bronchiectasis and exacerbations. A total of 100 exacerbations were captured from 58 patients during 1-year follow-up. Respiratory viruses were found more frequently in nasopharyngeal swabs and sputum during bronchiectasis exacerbations (49 of 100, 49.0%) than during steady state (11 of 58, 18.9%; P < .001). The most common viruses found in patients experiencing exacerbations were coronavirus (19 of 65, 39.2%), rhinovirus (16 of 65, 24.6%), and influenza A/B viruses (16 of 65, 24.6%). Virus-positive exacerbations were associated with a greater increase in markers of systemic and airway inflammation (serum IL-6 and tumor necrosis factor-α; sputum IL-1β and tumor necrosis factor-α) compared with virus-negative exacerbations, but the differences in spirometric indexes, quality of life, and bacterial density were unremarkable. In receiver operating characteristics analysis, serum interferon-γ-induced protein 10 yielded an area under curve of 0.67 (95% CI, 0.53-0.77; P = .018). Furthermore, a greater proportion of patients with virus-positive exacerbations received IV antibiotics. Prevalence of viral infections, detected by polymerase chain reaction assay, is higher in cases of bronchiectasis exacerbations than in steady-state bronchiectasis, suggesting that respiratory viruses play crucial roles in triggering bronchiectasis exacerbations. The potential mechanisms of virus-induced bronchiectasis exacerbations merit further investigations. ClinicalTrials.gov; No.: NCT01801657; www.clinicaltrials.gov.


Healthcare Stereotype Threat and Health Outcomes Among LGB Individuals.
Health disparities between sexual minorities and heterosexuals are well documented and have been explained by differential access to healthcare as well as exposure to discrimination. The current research examines the role that healthcare stereotype threat, or the fear of being judged by healthcare providers based on negative group stereotypes, plays in the health of LGB individuals. LGB individuals (N = 1507) in three age cohorts were recruited via random digit dialing to participate in a larger study on sexual minority health. Participants completed measures assessing healthcare stereotype threat, lifetime health diagnoses, life satisfaction, and number of bad physical health days and personal distress in the past 30 days. Healthcare stereotype threat was associated with higher psychological distress and number of reported bad physical health days. Additionally, the Younger and Middle cohorts reported more stereotype threat than the Older cohort, but reported significantly higher levels of life satisfaction in the face of this threat than those in the Older cohort. Healthcare stereotype threat was related to poorer mental and physical health among LGB individuals; this was true when these outcomes were assessed over the past 30 days but not when they were assessed in general. Cohort differences in healthcare stereotype threat suggest potential important within group variation that needs further investigating. The research broadens the contexts to which stereotype threat is relevant and establishes a stressor related to LGB health.


Molecular understanding of anthocyanin biosynthesis activated by PAP1 and regulated by 2, 4-dichlorophenoxyacetic acid in engineered red Artemisia annua cells.
Eight promoters were cloned, from which AC and G-box cis-elements were identified. PAP1 enhanced the promoter activity. 2,4-D reduced the anthocyanin biosynthesis via downregulating the expression of the PAP1 transgene. Artemisia annua is an effective antimalarial medicinal crop. We have established anthocyanin-producing red cell cultures from this plant with the overexpression of Production of Anthocyanin Pigment 1 (PAP1) encoding a R2R3MYB transcription factor. To understand the molecular mechanism by which PAP1 activated the entire anthocyanin pathway, we mined the genomic sequences of A. annua and obtained eight promoters of the anthocyanin pathway genes. Sequence analysis identified four types of AC cis-elements from six promoters, the MYB response elements (MRE) bound by PAP1. In addition, six promoters were determined to have at least one G-box cis-element. Eight promoters were cloned for activity analysis. Dual luciferase assays showed that PAP1 significantly enhanced the promoting activity of seven promoters, indicating that PAP1 turned on the biosynthesis of anthocyanins via the activation of these pathway gene expression. To understand how 2,4-dichlorophenoxyacetic acid (2,4-D), an auxin, regulates the PAP1-activated anthocyanin biosynthesis, five different concentrations (0, 0.05, 0.5, 2.5, and 5 µM) were tested to characterize anthocyanin production and profiles. The resulting data showed that the concentrations tested decreased the fresh weight of callus growth, anthocyanin levels, and the production of anthocyanins per Petri dish. HPLC-qTOF-MS/MS-based profiling showed that these concentrations did not alter anthocyanin profiles. Real-time RT-PCR was completed to characterize the expression PAP1 and four representative pathway genes. The results showed that the five concentrations reduced the expression levels of the constitutive PAP1 transgene and three pathway genes significantly and eliminated the expression of the chalcone synthase gene either significantly or slightly. These data indicate that the constitutive PAP1 expression depends on gradients added in the medium. Based on these findings, the regulation of 2,4-D is discussed for anthocyanin engineering in red cells of A. annua.


Holographic vibration analysis of the ossicular chain.
The mechanics of movement of the ossicular chain has been investigated on human temporal bone preparations by means of time average holography. The malleus and incus moved like a lever around an axis, which position was somewhat dependent upon frequency. Simulation of contraction of the muscles of the middle ear gave as result a change in the pattern of movement of the ossicular chain. The position of the rotatory axis was changed, and the amplitudes of vibration were reduced. This should be a protecting mechanism.


Suppressive effects of interferon on cell fusion by Sendai virus.
Suppressive effects of human IFN-alpha, IFN-beta and mouse-IFN on syncytium formation in human and mouse transformed cells have been studied using u.v.-irradiated Sendai virus (UV-Sendai virus). After treatment of human RSa cells with 500 units/ml human IFN-alpha for 16 h, the syncytium formation induced by UV-Sendai virus was reduced to less than 10% of controls. The suppressive effect was dependent on the amount of interferon added, and it was blocked by the addition of cycloheximide. Suppression of syncytium formation was also observed on human IFr cells, which are partially resistant to the anticellular effect of interferon but are sensitive to the antiviral effect of interferon. Human IFN-beta also had a suppressive effect on syncytium formation in human transformed cells, and human IFN-alpha, IFN-beta and mouse IFN showed species specificity in their effect on fusion. This anti-cell fusion activity was developed in IFr cells from about 5 h after addition, of IFN-alpha and when the cells were treated with IFN-alpha for 16 h, the resistant state of cell continued for over 20 h after removal of IFN-alpha.


Nox-4 and progressive kidney disease.
Nox-4 is a member of the NADPH oxidase (Nox) family of enzymes implicated in reactive oxygen species generation. Nox-4 is distributed in many tissues; however, its physiological functions remain poorly understood. In contrast to other Nox isoforms, it is unique in that it produces large amounts of hydrogen peroxide constitutively and does not require other cytosolic oxidase components for its activation. This review highlights the recent developments in Nox-4 research and progressive kidney disease as well as the potential of new Nox-4 inhibitors to reduce renal damage. Recently, Nox-4 was shown to be implicated in kidney diseases such as diabetic nephropathy. Nox-4 has been identified as playing a role in damage to the kidney induced by hyperglycaemia and other major pathways of renal damage, including advanced glycation end-products, the renin-angiotensin system, TGF-β and protein kinase C. The role of Nox-4 as a target for renoprotection remains controversial, although recent positive preclinical data have stimulated increased interest in inhibiting the enzyme in clinical trials of renal disease.


Pediatric lung transplantation.
Lung transplantation is an accepted therapy for selected pediatric patients with severe end-stage vascular or parenchymal lung disease. Collaboration between the patients' primary care physicians, the lung transplant team, patients, and patients' families is essential. The challenges of this treatment include the limited availability of suitable donor organs, the toxicity of immunosuppressive medications needed to prevent rejection, the prevention and treatment of obliterative bronchiolitis, and maximizing growth, development, and quality of life of the recipients. This article describes the current status of pediatric lung transplantation, indications for listing, evaluation of recipient and donor, updates on the operative procedure,graft dysfunction, and the risk factors, outcomes, and future directions.


Pain in elderly patients: a neglected phenomenon?
The assessment and control of pain in elderly patients present unique problems. Old people are likely to experience more pain, both chronic and acute, than their younger counterparts. Demographic changes mean that larger numbers of older patients will require effective and efficient control of pain in order to optimize their quality of life. Relatively little research has focused on this potentially huge problem. This paper discusses issues specific to pain in elderly people, and suggests that wide ranging and careful assessments are needed. Benefits can be achieved not only from the appropriate use of analgesic drugs, but also physical and psychological therapies.


Growth and substrate consumption of Nitrobacter agilis cells immobilized in carrageenan: part 2. Model evaluation.
A dynamic model that predicts substrate and biomass concentration profiles across gel beads and from that the overall substrate consumption rate by the gel beads containing growing cells was evaluated with immobilized Nitrobacter agilis cells in an airlift loop reactor with oxygen as the limiting substrate. The model predictions agreed well with the observed oxygen consumption rates at three different liquid phase oxygen concentrations. Image analysis showed that 90% of the immobilized cells after 42 days of cultivation was situated in the outer shells in a film of 140 mum, while the bead radius was about 1 mm. The maximum biomass concentration in the outmost film of 56 mum was 11 kg . m(-3) gel.


The EBV early gene product EB2 transforms rodent cells through a signalling pathway involving c-Myc.
Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus associated with several neoplasia. We present evidence here that the protein EB2, an EBV posttranscriptional activator, has transforming properties not only when expressed in established cell lines such as Rat1 or NIH3T3 but also in primary rat fibroblasts (REF). EB2 transformation in Rat1 cells correlates with an increase in the steady-state level of the cellular oncogenic protein c-Myc, and cotransfection of a plasmid expressing Max suppresses the transformation. These results implicate c-Myc in EB2-mediated cell transformation and help define the pathway by which this EBV early protein causes transformation.


Airway occlusion pressure and diaphragm global electromyogram analysis for evaluation of inspiratory muscle drive and neuromechanical coupling in cattle.
Although healthy and diseased bovine respiratory tracts have been intensively studied during the last years, to the authors' knowledge, there have been no attempts to objectively examine the inspiratory drive from the brain to the nerves and muscles and its transformation in pressure. Such technique would be useful in assessing the possibility of altered ventilatory drive or inspiratory muscle fatigue in the context of an animal with ventilatory failure. The relation among ventilation, airway opening occlusion pressure generated 100 milliseconds after onset of inspiration (Pawo100ms) and 6 indexes describing diaphragmatic electromyographic activity (EMGdi) recorded via implanted fishhooks was evaluated during free and impeded CO2 rebreathing in 6 young bulls. The best significant linear correlations (r > 0.8) with inspiratory center afferent stimulation, as judged by end-tidal CO2 concentration in expired air, were found for Pawo100ms, peak moving time average or variance EMGdi, and mean integrated EMGdi, whatever had been the respiratory impedance. However, with an inspiratory load, Pawo100ms responses systematically had greater increase for a given change in the driving EMGdi, implying dependence of the former not only on neural input, but also on configurational factors that determine inspiratory muscle excitation-pressure generation couplings. The reproducibility of EMGdi absolute values and changes was satisfactory up to 10 hours, but could not be repeated from one day to the other. It was concluded that, provided the constancy of the electrical coupling of the recording system to the tissue being studied is ensured, specific EMGdi and Pawo100ms values correlate reliably with amount of CO2 during free and loaded breathing.(ABSTRACT TRUNCATED AT 250 WORDS)


Relationships Between Working Alliance and Outcomes in Group Therapy for People Diagnosed with Schizophrenia.
Working alliance (WA) is an important predictor of treatment outcomes in therapy. Forming a strong WA can be challenging with people diagnosed with schizophrenia, and differences between client-rated and clinician-rated WA have been found in this population. This project examined WA in people diagnosed with schizophrenia who completed a skills training and attention shaping group intervention. Paired samples t-tests revealed differences between client and clinician ratings on the Working Alliance Inventory Short Form (WAI-S). Clinician-rated WAI-S scores were related to symptom severity, cognitive functioning, and attention during group sessions. Yet, the primary hypothesis was not supported as WAI-S scores were unrelated to clients' treatment response. Clinician-rated WAI-S was found to partially mediate the relationship between negative symptoms and overall attention. Client-rated WAI-S scores were associated with client measures of self-efficacy and mastery. Results reinforce the importance of working alliance in the treatment of those diagnosed with schizophrenia and indicate clinical and functional factors that may influence the quality of WA.


Longitudinal regret and information satisfaction after deciding on treatment for localized prostate cancer with or without a decision aid. Results at one-year follow-up in the PCPCC trial.
To investigate the effect of including an online decision aid (DA) during prostate cancer treatment counseling on decisional regret and information satisfaction in a one-year follow-up. Within a cluster RCT, 18 Dutch hospitals were randomized to DA counseling or care-as-usual, patients (n = 382) initially completed questionnaires directly after treatment decision making. Six and twelve months later regret (Decisional Regret Scale) and information satisfaction (SCIP-B) were assessed. Anxious and depressive symptoms (HADS) was included as possible covariate. After 12 months, 43 participants (15%) regretted their treatment choice and 105 participants (36%) were dissatisfied with the information that was received at the time of decision-making, regardless of being exposed to the DA. Anxious and depressive symptoms at follow-up were associated with regret and information dissatisfaction. No long-term benefical effects emerged from DA usage compared to patients who underwent standard counseling. During PCa treatment counseling, healthcare providers should be aware of anxious and depressive symptoms.


Calcineurin inhibitor effects on growth and phenotype of human airway epithelial cells in vitro.
Calcineurin inhibitors (CIs) cyclosporin and tacrolimus form the basis for immunosuppression in lung transplantation, yet also exert biological effects on nonlymphoid tissue. With the advent of inhaled cyclosporin, we hypothesize that the airway epithelium is also subject to CI effects at high doses. The aim of this study was to identify human tracheobronchial epithelial cell (hTBEC) calcineurin gene expression and quantify effects of CIs on hTBEC growth, interleukin-1-beta stimulated IL-8 production and hTBEC phenotype. Cyclophillin B and FK-associated binding protein, calcineurin A (alpha and beta), and NFATC3 and NFAT5 were detected in hTBEC cultures by RT-PCR. Acute and chronic cyclosporine treatment 1000 ng/mL significantly inhibited hTBEC proliferation, while tacrolimus did not (range of 10 ng/mL to 1000 ng/mL for acute treatment, 50 ng/mL for chronic treatment). Cyclosporin at 10,000 ng/mL significantly increased LDH release by well-differentiated hTBEC cultures (n = 6) and trended towards significance at 1000 ng/mL. IL1-beta stimulated IL-8 production was significantly increased in rapidly growing hTBEC cultures (n = 8) treated with cyclosporin (p = 0.049). Prolonged treatment of well-differentiated hTBECs at air-liquid-interface (ALI) with cyclosporin 1000 ng/mL significantly reduced intact multilayered mucociliary epithelium (p = 0.009). Inhibition of hTBEC growth, stimulation of IL-8 production and long-term effects on mucociliary phenotype and intact multi-layered epithelium suggest that cyclosporin may have a direct toxic effect on airway epithelium after transplantation.


Therapeutic potential of TNFR2 agonists: a mechanistic perspective.
TNFR2 agonists have been investigated as potential therapies for inflammatory diseases due to their ability to activate and expand immunosuppressive CD4+Foxp3+ Treg cells and myeloid-derived suppressor cells (MDSCs). Despite TNFR2 being predominantly expressed in Treg cells at high levels, activated effector T cells also exhibit a certain degree of TNFR2 expression. Consequently, the role of TNFR2 signaling in coordinating immune or inflammatory responses under different pathological conditions is complex. In this review article, we analyze possible factors that may determine the therapeutic outcomes of TNFR2 agonism, including the levels of TNFR2 expression on different cell types, the biological properties of TNFR2 agonists, and disease status. Based on recent progress in the understanding of TNFR2 biology and the study of TNFR2 agonistic agents, we discuss the future direction of developing TNFR2 agonists as a therapeutic agents.


Root dentine and endodontic instrumentation: cutting edge microscopic imaging.
Cutting of the dental hard tissues is an integral part of restorative dentistry. Cutting of the root dentine is also needed in preparation prior to endodontic treatment, with significant commercial investment for the development of flexible cutting instruments based around nickel titanium (NiTi) alloys. This paper describes the evolution of endodontic cutting instruments, both in materials used, e.g. the transition from stainless steel to NiTi, and the design of the actual instruments themselves and their method of activation-by hand or motor driven. We have been examining tooth-cutting interactions microscopically for over 25 years using a variety of microscopic techniques; in particular, video-rate confocal microscopy. This has given a unique insight into how many of the procedures that we take for granted are achieved in clinical practice, by showing microscopic video images of the cutting as it occurs within the tooth. This technology has now been extended to allow imaging of the endodontic instrument and the root canal wall for the first time. We are able to image dentine distortion and crack propagation during endodontic filing of the root canal space. We are also able to visualize the often claimed, but seldom seen action of contemporary endodontic instruments.


Developmental exposure to bisphenol A modulates innate but not adaptive immune responses to influenza A virus infection.
Bisphenol A (BPA) is used in numerous products, such as plastic bottles and food containers, from which it frequently leaches out and is consumed by humans. There is a growing public concern that BPA exposure may pose a significant threat to human health. Moreover, due to the widespread and constant nature of BPA exposure, not only adults but fetuses and neonates are also exposed to BPA. There is mounting evidence that developmental exposures to chemicals from our environment, including BPA, contribute to diseases late in life; yet, studies of how early life exposures specifically alter the immune system are limited. Herein we report an examination of how maternal exposure to a low, environmentally relevant dose of BPA affects the immune response to infection with influenza A virus. We exposed female mice during pregnancy and through lactation to the oral reference dose for BPA listed by the US Environmental Protection Agency, and comprehensively examined immune parameters directly linked to disease outcomes in adult offspring following infection with influenza A virus. We found that developmental exposure to BPA did not compromise disease-specific adaptive immunity against virus infection, or reduce the host's ability to clear the virus from the infected lung. However, maternal exposure to BPA transiently reduced the extent of infection-associated pulmonary inflammation and anti-viral gene expression in lung tissue. From these observations, we conclude that maternal exposure to BPA slightly modulates innate immunity in adult offspring, but does not impair the anti-viral adaptive immune response, which is critical for virus clearance and survival following influenza virus infection.


Disaster mental health in higher education: A review.
Disaster mental health (DMH), also referred to as disaster behavioral health, and crisis intervention more broadly, is a significant, yet relatively nonstandardized response system in the United States. Higher education can play a critical role in shifting understanding of DMH, its place within emergency management, and skills building among students. With the increased need for qualified DMH practitioners growing, the academy is uniquely positioned to train students as they become our future responders. Movement toward standardized curriculum and certification programs within schools of social work and emergency management can alleviate lack of knowledge and training as well as better prepare emergency managers and behavioral health professionals to respond to the emotional and mental wellbeing of those impacted by disasters (natural or human-caused).


Ex vivo 1H MR spectroscopy and histology after experimental chronic spinal cord compression.
Proton magnetic resonance imaging (MRS) is used increasingly to image the spinal cord in compressive cervical myelopathy (CSM). However, detailed analyses of the underlying histomorphological changes leading to MRS alterations are still lacking. The aim of our study was to correlate neuroimaging and neuropathologic alterations in a rabbit myelopathy model. Chronic spinal cord compression was induced in a rabbit model (n=16) allowing for a gradual 270° compression of the spinal cord. Spinal cord compression core areas were divided into two samples for (A) 1H MRS and (B) histopathological analyses. Postoperatively the animals underwent a neurological examination twice a day and outcome was categorized in pattern of injury and amount of recovery. Three groups were observed and categorized: (I) animals with severe deficits and no or minimal recovery; (II) animals with severe deficits and complete or almost complete recovery; (III) animals with mild to moderate deficits and a complete recovery. Significant differences in the lesioned spinal cords between the different recovery groups were found for N-acetyl-aspartate and choline. NAA/Cr was detected significantly (P<0.001, ANOVA) less in the group that did show permanent neurological deficits. To the contrary, choline was detected significantly (P<0.001, ANOVA) more in the group that did show permanent neurological deficits. Histologically the first group showed more apoptosis and necrosis than the second and third group. MR spectroscopy (MRS) may be helpful for clinicians in improving the prognostic accuracy in cervical myelopathies since this method nicely reflects the extent and severity of spinal cord damage.


Stabilization of posture by precision contact of the index finger.
Postural sway during quiet stance increases if sight of the surroundings is denied. We studied how sensory-motor information about body displacement provided by contact of the index finger with a stationary bar can be used to stabilize balance in the absence of vision. Stabilization equivalent to the contribution conferred by vision was achieved at contact force levels less than 1 N. This value is much below that necessary to provide significant physical stabilization of the body. We interpret our findings in relation to tactile thresholds for motion detection, "precision grip," and proprioceptive and sensory-motor information about the configuration of the arm to the torso. In conditions allowing higher force levels at the fingertip (5-8 N), subjects assumed a passively stable state to stabilize their stance.


Histopathological outcome in 167 patients operated on with radical retropubic prostatectomy.
To evaluate the histopathological outcome in patients with prostate cancer operated on with radical retropubic prostatectomy. A total of 167 patients with clinically organ-localized prostate cancer treated with open radical retropubic prostatectomy between 1996 and 2001 were divided into three equally sized consecutive cohorts (cohorts I-III). The prostatectomy specimens were re-examined by two pathologists with respect to pathological tumour stage, tumour grade and surgical tumour margins. The mean preoperative prostate-specific antigen (PSA) value was statistically significantly higher in cohort I compared to cohorts II and III: 13.2, 9.0 and 8.5 ng/ml, respectively (p<0.05). The incidence of locally advanced (pT3a-3b) tumours was 44% in cohort I and 20% in both cohorts II and III (p<0.05). The incidence of positive tumour margins was 58% in cohort I, compared to 30% in cohort II and 13% in cohort III (p<0.05). The incidence of positive intracapsular tumour margins was 55% in cohort I, compared to 25% in cohort II and 8.9% in cohort III (p<0.05). The incidence of positive tumour margins in the pT2 tumours in cohorts I-III was 57%, 26% and 8.9%, respectively (p<0.05). Cohort III had significantly more low-grade tumours (Gleason score 4-6; 58.9%) compared to cohorts I (31.5%) and II (34%). There was a higher incidence of Gleason score >or=7 in the pT3 tumours compared to the pT2 tumours (80% vs 46%) and in margin-positive compared to -negative tumours (69.6% vs 48.6%) (p<0.05). The decline in pT3 tumours and positive tumour margins between cohorts I-III is probably due to a gradually more strict selection of patients for radical retropubic prostatectomy. The successive reduction in positive intracapsular tumour margins is most likely due to an improved surgical technique.


Hyperthermic chemotherapy intra-abdominal laparoscopic approach: development of a laparoscopic model using CO2 recirculation system and clinical translation in peritoneal carcinomatosis.
Hyperthermic intraperitoneal chemotherapy (HIPEC) is an effective treatment for peritoneal carcinomatosis (PC). Laparoscopic surgery is performed in the treatment of colorectal and appendiceal cancer, and PC from diverse origin in selected patients. HIPEC management by laparoscopic approach after cytoreductive surgery (CRS) completed locoregional treatment of PC, and may be feasible and safe after appropriate patient selection. Development of an experimental model of HIPEC by laparoscopic approach, with CO2 recirculation. Clinical translation in two patients with PC and low peritoneal cancer index. We performed CRS in a porcine model of 5 pigs (35-38 kg) by laparoscopic approach. Laparoscopic HIPEC by CO2 recirculation system was performed; laparoscopic access was used for catheter input and output placement (Paclitaxel 175 mg/m2 for 60 min at 42 °C). The experimental variables were: blood gases, haemodynamic and intra-abdominal and central temperature. Clinical model application was performed in three cases with PC from colorectal origin. No statistically significant differences was found in blood gases, haemodynamic or temperature in the experimental study. In clinical study, there were no technical complications during laparoscopic-HIPEC approach, and we observed no changes in haemodynamic variables during the procedure. CRS and HIPEC laparoscopic model by CO2 recirculation system is safe and feasible technique in selected patients, that include low PC index, local and accessible tumour recurrences or high-risk of PC tumours.


Genetic risk for schizophrenia is associated with substance use in emerging adulthood: an event-level polygenic prediction model.
Emerging adulthood is a peak period of risk for alcohol and illicit drug use. Recent advances in psychiatric genetics suggest that the co-occurrence of substance use and psychopathology arises, in part, from a shared genetic etiology. We sought to extend this research by investigating the influence of genetic risk for schizophrenia on trajectories of four substance use behaviors as they occurred across emerging adulthood. Young adult participants of non-Hispanic European descent provided DNA samples and completed daily reports of substance use for 1 month per year across 4 years (N = 30 085 observations of N = 342 participants). A schizophrenia polygenic score was included in two-level hierarchical linear models designed to test associations between genetic risk for schizophrenia, participant age, and four substance use phenotypes. Participants with a greater schizophrenia polygenic score experienced greater age-related increases in the likelihood of using substances across emerging adulthood (p < 0.005). Additionally, our results suggest that the polygenic score was positively associated with participants' overall likelihood to engage in illicit drug use but not alcohol-related substance use. This study used a novel combination of polygenic prediction and intensive longitudinal methods to characterize the influence of genetic risk for schizophrenia on patterns of age-related change in substance use across emerging adulthood. Results suggest that genetic risk for schizophrenia has developmentally specific effects on substance use behaviors in a non-clinical population of young adults.


Estimation of the prevalence of injection drug use in greater Boston in 1993.
This article is a report on different methods of estimation of the number of injection drug users (IDUs) in the Boston standard metropolitan statistical area (SMSA) in 1993. Because the sharing of needles is a means of transmission for HIV, an estimate of the prevalence of injection drug use is essential for acquired immunodeficiency syndrome (AIDS) prevention programs. The data for this study come from the Massachusetts Department of Public Health Bureau of Substance Abuse, the Massachusetts AIDS Surveillance Unit, the Drug Abuse Warning Network (DAWN), the National Household Survey on Drug Abuse: Population Estimates 1993, and the Massachusetts State Police Crime Reporting Unit. The estimates in this study can be assessed with regard to the different time frames that are involved, noting that some estimates are useful only to establish upper or lower bounds. The estimate that best meshes with the findings of this report is that there were between 13,500-16,500 injection drug users in greater Boston and 45,000-60,000 IDUs in Massachusetts in 1993.


Determination of organophosphorus pesticides in foods using an accelerated solvent extraction system.
Residual organophosphorus pesticides in foods were determined by accelerated solvent extraction (ASE), gel permeation chromatography and GC-FPD. Pesticides were extracted at 100 degrees C under 1500 psi pressure in less than 20 min. Wet samples were extracted after mixing with Extrelut drying agent. Four foods were spiked with 19 pesticides at 0.1 ppm or less. The average recoveries of these pesticides were 80-90% and the precision was < 10%. Both methamidophos and acephate gave 37-50% recoveries and 6-40% precision. These results suggested that ASE can be used to extract residues of organophosphorus pesticides in foods.


Complete genome sequence and comparative genome analysis of Klebsiella oxytoca HKOPL1 isolated from giant panda feces.
The giant panda (Ailuropoda melanoleuca) is an endangered species well-known for ingesting bamboo as a major part of their diet despite the fact that it belongs to order Carnivora. However, the giant panda's draft genome shows no direct evidence of enzymatic genes responsible for cellulose digestion. To explore this phenomenon, we study the giant panda's gut microbiota using genomic approaches in order to better understand their physiological processes as well as any potential microbial cellulose digestion processes. A complete genome of isolated Klebsiella oxytoca HKOPL1 of 5.9 Mb has been successfully sequenced, closed and comprehensively annotated against various databases. Genome comparisons within the Klebsiella genus and K. oxytoca species have also been performed. A total of 5,772 genes were predicted, and among them, 211 potential virulence genes, 35 pathogenicity island-like regions, 1,615 potential horizontal transferring genes, 23 potential antibiotics resistant genes, a potential prophage integrated region, 8 genes in 2,3-Butanediol production pathway and 3 genes in the cellulose degradation pathway could be identified and discussed based on the comparative genomic studies between the complete genome sequence of K. oxytoca HKOPL1 and other Klebsiella strains. A functional study shows that K. oxytoca HKOPL1 can degrade cellulose within 72 hours. Phylogenomic studies indicate that K. oxytoca HKOPL1 is clustered with K. oxytoca strains 1686 and E718. K. oxytoca HKOPL1 is a gram-negative bacterium able to degrade cellulose. We report here the first complete genome sequence of K. oxytoca isolated from giant panda feces. These studies have provided further insight into the role of gut microbiota in giant panda digestive physiology. In addition, K. oxytoca HKOPL1 has the potential for biofuel application in terms of cellulose degradation and potential for the production of 2,3-Butanediol (an important industrial raw material).


Effect of dual delivery of antibiotics (vancomycin and cefazolin) and BMP-7 from chitosan microparticles on Staphylococcus epidermidis and pre-osteoblasts in vitro.
The main aims of this manuscript are to: i) determine the effect of commonly used antibiotics to treat osteoarticular infections on osteoblast viability, ii) study the dual release of the growth factor (BMP-7) and antibiotics (vancomycin and cefazolin) from chitosan microparticles iii) demonstrate the bioactivity of the antibiotics released in vitro on Staphylococcus epidermidis. The novelty of this work is dual delivery of growth factor and antibiotic from the chitosan microparticles in a controlled manner without affecting their bioactivity. Cefazolin and vancomycin have different therapeutic concentrations for their action in vivo and therefore, two different concentrations of the drugs were used. Osteoblast cytotoxicity test concluded that cefazolin concentrations of 50 and 100μg/ml were found to have positive influence on osteoblast proliferation. A significant increase in osteoblast proliferation was observed in the presence of cefazolin and BMP-7 in comparison with BMP-7 alone group; indicating cefazolin might play a role in osteoblast proliferation. On the other hand, vancomycin concentration of 1000μg/ml was found to significantly reduce (p<0.01) osteoblast proliferation in comparison with controls. The microbial study indicated that cefazolin at a minimum concentration of 21.5μg/ml could inhibit ~85% growth of S. epidermidis, whereas vancomycin at a concentration of 30μg/ml was found to inhibit ~80% bacterial growth.


Adherence to cardioprotective medications and mortality among patients with diabetes and ischemic heart disease.
Patients with diabetes and ischemic heart disease (IHD) are at high risk for adverse cardiac outcomes. Clinical practice guidelines recommend multiple cardioprotective medications to reduce recurrent events. We evaluated the association between cardioprotective medication adherence and mortality among patients with diabetes and IHD. In a retrospective cohort study of 3,998 patients with diabetes and IHD, we evaluated use of ACE inhibitors or angiotensin receptor blockers, beta-blockers, and statin medications. Receipt of cardioprotective medications was based on filled prescriptions. Medication adherence was calculated as the proportion of days covered (PDC) for filled prescriptions. The primary outcome of interest was all-cause mortality. The majority of patients (92.8%) received at least 1 cardioprotective medication. Patients receiving any medications had lower unadjusted mortality rates compared to patients not receiving any medications (7.9% vs. 11.5%; p = 0.03). In multivariable analysis, receipt of any cardioprotective medication remained associated with lower all-cause mortality (OR 0.65; 95% CI 0.43-0.99). Among patients receiving cardioprotective medications, the majority (80.3%) were adherent (PDC > or = 0.80). Adherent patients had lower unadjusted mortality rates (6.7% vs. 12.1%; p < 0.01). In multivariable analysis, medication adherence remained associated with lower all-cause mortality (OR 0.52; 95% CI 0.39-0.69) compared to non-adherence. In contrast, there was no mortality difference between patients receiving cardioprotective medications who were non-adherent compared to patients not receiving any medications (OR 1.01; 95% CI 0.64-1.61). In conclusion, medication adherence is associated with improved outcomes among patients with diabetes and IHD. Quality improvement interventions are needed to increase medication adherence in order for patients to maximize the benefit of cardioprotective medications.


Clinical utility of ixekizumab in the treatment of moderate-to-severe plaque psoriasis.
Psoriasis vulgaris is a chronic, immune-mediated systemic disease that affectŝ7.5 million people in the US. It can be treated with many therapies, often in combination, which include topicals, phototherapy, oral systemics, and biologics. Biologic agents target specific components of the immune system involved in the pathogenesis of psoriasis including TNF-alpha, IL-12, IL-17, and IL-23. The biologic ixekizumab, approved for the treatment of moderate-severe plaque psoriasis in the US, targets IL-17. This review describes the role of IL-17 in psoriasis, the mechanism by which ixekizumab targets this cytokine, and the clinical utility of ixekizumab.


Dual Axl/MerTK inhibitor INCB081776 creates a proinflammatory tumor immune microenvironment and enhances anti-PDL1 efficacy in head and neck cancer.
The tyrosine kinase receptors Axl and MerTK are highly overexpressed in head and neck cancer (HNC) cells, where they are critical drivers of survival, proliferation, metastasis, and therapeutic resistance. We investigated the role of Axl and MerTK in creating an immunologically "cold" tumor immune microenvironment (TIME) by targeting both receptors simultaneously with a small molecule inhibitor of Axl and MerTK (INCB081776). Effects of INCB081776 and/or anti-PDL1 on mouse oral cancer (MOC) cell growth and on the TIME were evaluated. Targeting Axl and MerTK can reduce M2 and induce M1 macrophage polarization. In vivo, INCB081776 treatment alone or with anti-PDL1 appears to slow MOC tumor growth, increase proinflammatory immune infiltration, and decrease anti-inflammatory immune infiltration. This data indicates that simultaneous targeting of Axl and MerTK with INCB081776, either alone or in combination with anti-PDL1, slows tumor growth and creates a proinflammatory TIME in mouse models of HNC.


Annual lung function changes in young patients with chronic lung disease.
Reference equations for ventilatory function that use different statistical models may introduce artifacts that affect the estimated change of lung function during growth in young subjects. The effect of differently modelled reference equations on the estimated annual change of forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) in young patients with chronic lung disease was assessed. Four frequently used reference equations were used to describe the longitudinal changes of FEV1 and FVC in 52 patients (23 females) with cystic fibrosis (CF) during a mean follow-up of 3.9 yrs. Choice of reference equations directly affected value and, most importantly, estimated annual change of FVC and FEV1. Mean+/-SD annual change of FEV1 varied from 2.2+/-6.2 to -2.2+/-3.6% of predicted. For two reference equations the estimated individual changes of FEV1 and FVC in CF were positively correlated with mean individual age. This probably reflects underestimation of deteriorating lung function. Variability of annual change was independent of age only when reference equations that were designed to accurately predict lung function during the pubertal growth spurt were used. These findings have implications for patient care and clinical research.


Mechanism-based protein cross-linking probes to investigate carrier protein-mediated biosynthesis.
Fatty acid, polyketide, and nonribosomal peptide biosynthetic enzymes perform structural modifications upon small molecules that remain tethered to a carrier protein. This manuscript details the design and analysis of cross-linking substrates that are selective for acyl carrier proteins and their cognate condensing enzymes. These inactivators are engineered through a covalent linkage to fatty acid acyl carrier protein via post-translational modification to contain a reactive probe that traps the active site cysteine residue of ketosynthase domains. These proteomic tools are applied to Escherichia coli fatty acid synthase enzymes, where KASI and KASII selectively cross-link ACP-bound epoxide and chloroacrylate moieties. These mechanism-based, protein-protein fusion reagents also demonstrated cross-linking of KASI to type II polyketide ACPs, while nonribosomal peptide carrier proteins showed no reactivity. Similar investigations into protein-protein interactions, proximity effects, and substrate specificities will be required to complete the mechanistic understanding of these pathways.


Association of MSX1 and TGF-β1 genetic polymorphisms with hypodontia: meta-analysis.
We conducted a comprehensive meta-analysis of 4 case-control studies to explore the association between polymorphisms of Msh homeobox 1 (MSX1) and transforming growth factor-β1 (TGF-β1) genes and hypodontia. A total of 643 tooth agenesis cases and 733 healthy controls were included in this study. The meta-analysis results showed that the T allele and T carrier (CT + TT) of rs1095 in the MSX1 gene were positively associated with hypodontia susceptibility. However, the T allele and T carrier (TC + CC) of rs12532 and rs8670 showed no association with cancer susceptibility. In addition, there were no strong associations between the T allele and T carrier (CT + TT) of C509T and the A allele and A carrier (AG + AA) of G800A in the TGF-β1 gene polymorphisms between patients with tooth agenesis and healthy subjects. In conclusion, these meta-analysis results demonstrated that polymorphisms in the rs1095 region of the MSX1 gene may influence the transcriptional activity of this gene and are associated with hypodontia in humans. However, the association between the TGF-β1 gene and sporadic tooth agenesis is not well understood, and further studies are required to explore the correlation between the TGF-β1 gene and hypodontia.


Coordinated transcription of ANRIL and P16 genes is silenced by P16 DNA methylation.
To investigate the relationship between the transcription of ANRIL, P15, P14 and P16 at the same locus and the regulation mechanism of ANRIL. Publicly available database of Cancer Cell Line Encyclopedia (CCLE) was used in bioinformatic analyses. Methylation of CpG islands was detected by denaturing high performance liquid chromatography (DHPLC). Gene transcript levels were determined using quantitative real-time polymerase chain reaction (qRT-PCR) assays. An engineered P16-specific transcription factor and DNA methyltransferase were used to induce P16-specific DNA demethylation and methylation. The expression level of ANRIL was positively and significantly correlated with that of P16 but not with that of P15 in the CCLE database. This was confirmed in human cell lines and patient colon tissue samples. In addition, ANRIL was significantly upregulated in colon cancer tissues. Transcription of ANRIL and P16 was observed only in cell lines in which the P16 alleles were unmethylated and not in cell lines with fully methylated P16 alleles. Notably, P16-specific methylation significantly decreased transcription of P16 and ANRIL in BGC823 and GES1 cells. In contrast, P16-specific demethylation re-activated transcription of ANRIL and P16 in H1299 cells (P<0.001). Alteration ofANRIL expression was not induced by P16 expression changes. ANRIL and P16 are coordinately transcribed in human cells and regulated by the methylation status of the P16 CpG islands around the transcription start site.


Intensity modulation of TMS-induced cortical excitation: primary motor cortex.
The intensity dependence of the local and remote effects of transcranial magnetic stimulation (TMS) on human motor cortex was characterized using positron-emission tomography (PET) measurements of regional blood flow (BF) and concurrent electromyographic (EMG) measurements of the motor-evoked potential (MEP). Twelve normal volunteers were studied by applying 3 Hz TMS to the hand region of primary motor cortex (M1(hand)). Three stimulation intensities were used: 75%, 100%, and 125% of the motor threshold (MT). MEP amplitude increased nonlinearly with increasing stimulus intensity. The rate of rise in MEP amplitude was greater above MT than below. The hemodynamic response in M1(hand) was an increase in BF. Hemodynamic variables quantified for M1(hand) included value-normalized counts (VNC), intensity (z-score), and extent (mm(3)). All three hemodynamic response variables increased nonlinearly with stimulus intensity, closely mirroring the MEP intensity-response function. VNC was the hemodynamic response variable which showed the most significant effect of TMS intensity. VNC correlated strongly with MEP amplitude, both within and between subjects. Remote regions showed varying patterns of intensity response, which we interpret as reflecting varying levels of neuronal excitability and/or functional coupling in the conditions studied.


The Pauson-Khand reaction of medium sized trans-cycloalkenes.
Medium sized trans-cycloalkenes are unusually reactive in the intermolecular Pauson-Khand reaction (PKR) with regard to typical monocyclic alkenes. This is due to the ring strain imparted by the E stereochemistry. The PKR of these alkenes offers a modular, regioselective and straightforward entry to trans fused [n.3.0] bicyclic scaffolds (n = 6-8).


Hypertrophic osteoarthropathy, cutaneous vasculitis, and mixed-type cryoglobulinemia in a patient with nasopharyngeal carcinoma.
We describe a 27-year-old woman with a primary nasopharyngeal carcinoma who developed hypertrophic osteoarthropathy and cutaneous vasculitis. Her serum contained antibodies to Epstein-Barr virus and U1 RNP antigens. Cryoproteins isolated from her serum contained antibodies to U1 RNP and a protein with a molecular weight of 32 kd which reacted specifically with antibodies to U1 RNP. HLA typing revealed HLA-B7 and DR1; these have been reported to be increased in Japanese patients with rheumatic diseases who have autoantibodies to U1 RNP. These findings indicate that some features of the paraneoplastic syndrome in this patient might have been caused by immune complexes, part of which were formed by specific autoantibodies produced under genetically controlled conditions of immune responsiveness.


Two techniques for the preparation of cell-scaffold constructs suitable for sinus augmentation: steps into clinical application.
The objective of this clinical trial was the analysis of 2 methods for engineering of autologous bone grafts for maxillary sinus augmentation with secondary implant placement. Group 1 (8 patients, 12 sinuses): cells of mandibular periosteum were cultured in a good manufacturing practice laboratory (2 weeks) with autologous serum and then transferred onto a collagen matrix. After another week, these composites were transplanted into the sinuses. In group 2A (2 patients, 3 sinuses), cells of maxillary bone were cultivated with autologous serum for 2 weeks, seeded onto natural bone mineral (NBM, diameter [Ø] = 8 mm) blocks, and cultivated for another 1.5 months. These composites were transplanted into the sinuses. Group 2B (control, 3 patients, 5 sinuses) received NBM blocks alone. In the course of implant placement 6 (group 1) and 8 (group 2) months later, core biopsy were taken. Clinical follow-up period was 1 to 2.5 years in group 1 and approximately 7 years in groups 2A and 2B. New vital bone was found in all cases at median densities of 38% (n = 12) in group 1, 32% in group 2A (n = 3), and 25% in group 2B (n = 5). Differences between group 1 and 2B as well as 2A and 2B were statistically significant ( p = 0.025). No adverse effects were seen. All methods described were capable of creating new bone tissue with sufficient stability for successful implant placement.


Interferon-inducible p202 in the susceptibility to systemic lupus.
Systemic lupus erythematosus (SLE) is the prototype systemic autoimmune disease, which has potential to involve multiple organ systems. Studies in human SLE patients and murine models of lupus have indicated that genetic predisposition plays a crucial role in the development of this disease. To identify the genetic basis of human lupus and to understand the molecular mechanisms, mouse models of SLE have been studied. Generation of mice congenic for the Nba2 locus on the C57BL/6 genetic background, coupled with gene expression profiling, recently identified the interferon-activatable Ifi202 gene (encodes the protein p202) as a candidate lupus-susceptibility gene. The protein p202 is a member of the 200-protein family. The family includes structurally and functionally related mouse and human interferon-inducible proteins. The protein p202 (52-kDa) is a relatively well-characterized phosphoprotein in the family with demonstrated ability to control cell-signaling pathways regulating cell proliferation, survival, and differentiation. Here, we review what is known about the gene Ifi202 and the protein it encodes. Moreover, we discuss how an understanding of the role of p202 in cell growth regulation, particularly in cells of the immune system, will help elucidate the molecular mechanisms contributing to the development of lupus.


Development and validation of a transitions-of-care pharmacist tool to predict potentially avoidable 30-day readmissions.
A practical tool for predicting the risk of 30-day readmissions using data readily available to pharmacists before hospital discharge is described. A retrospective cohort study to identify predictors of potentially avoidable 30-day readmissions was conducted using transitions-of-care pharmacy notes and electronic medical record data from a large health system. Through univariate and multivariable logistic regression analyses of factors associated with unplanned readmissions in the study cohort (n = 690) over a 22-month period, a risk prediction tool was developed. The tool's discriminative ability was assessed using the C statistic; its calibration was assessed using the Hosmer-Lemeshow goodness-of-fit test. Three factors predictive of readmission risk were identified; these variables-medication count, comobidity count, and health insurance status at discharge-form the 3-predictor MEDCOINS score. Among patients identified as being at high risk for readmission using the MEDCOINS tool, the estimated readmission risk was 22.5%, as compared with an observed readmission rate of 21.9%. The discriminatory performance of MEDCOINS scoring was fair (C statistic = 0.65 [95% confidence interval, 0.60-0.70]), with good calibration (Hosmer-Lemeshow p = 0.99). Among a cohort of patients who were seen by a transitions-of-care pharmacist during an inpatient hospitalization, comorbidity burden, number of medications, and health insurance coverage were most predictive of 30-day readmission. The MEDCOINS tool was found to have fair discriminative ability and good calibration.


Expression of claudin 1, 4 and 7 in thyroid neoplasms.
The distinction of thyroid carcinoma from benign thyroid neoplasm, as well as the subtyping of papillary carcinoma (PC) and follicular carcinoma (FC), may be performed histopathologically in the majority of cases. However, in certain cases, it is difficult to histopathologically distinguish between PC and FC, as well as follicular adenoma (FA), FC and the dominant nodule of multinodular goiter (MNG-DN). The present study aimed to determine the roles of the expression levels of the tight junction proteins claudin 1, 4 and 7 in the differential diagnosis of PC, FC, FA, MNG-DN, medullary carcinoma (MC) and anaplastic carcinoma (AC). The current study included 114 cases of histopathologically diagnosed thyroid neoplasia, which were distributed as follows: 29 FA, 18 MNG-DN, 47 PC, 10 FC, 5 MC and 5 AC. The expression levels of claudin 1, 4 and 7 were examined using immunohistochemical methods. The results revealed a significant difference in claudin 1 expression between malignant and benign thyroid neoplasms (P<0.001). Claudin 1 expression was not detected in any of the MNG-DN cases, and no significant difference in claudin 1 expression levels was identified between FA and FC (P=0.653). However, a statistically significant difference was observed between FC and PC (P<0.001). Claudin 4 expression did not differ between malignant and benign thyroid neoplasms, neither between MNG-DN, FA and FC, nor between FC and PC (P=0.068, P=0.502 and P=0.481, respectively). Claudin 7 exhibited positive immunohistochemical staining in 107 patients (94%); however, no significant difference in claudin 7 expression §levels was identified between malignant and benign thyroid neoplasms among MNG-DN, FA and FC (malignant, P=0.135; benign, P=0.470). Claudin 7 exhibited positive staining in all PC and FC cases. Therefore, claudin 1 expression levels may be useful in distinguishing cases of FC and PC with overlapping histopathological features, and provide a novel immunohistochemical marker for the subtyping of thyroid carcinoma.


A Conversation with ASTMH Past President Regina Rabinovich.
At the 2018 ASTMH Annual Meeting, October 28 through November 1, N. Regina Rabinovich, MD, FASTMH, wrapped up her term as ASTMH President. She recently talked with science writer Matthew Davis about the highlights of her year, the current state of the fight against major threats, including malaria and Ebola, and her advice for the new Society president, Chandy C. John, MD, MS, FASTMH.


Multistimuli-Responsive Luminescence Switching of Pyrazine Derivative Based Donor-Acceptor-Donor Luminophores.
Three symmetrical donor-acceptor-donor (D-A-D) luminophores (C1, C2, and C3) with pyrazine derivatives as electron-withdrawing groups have been developed for multistimuli-responsive luminescence switching. For comparison, reference compounds R1 and R2 without the pyrazine moiety have also been synthesized. Intramolecular charge transfer (ICT) interactions can be found for all D-A-D luminophores owing to the electron-withdrawing properties of the two imine nitrogen atoms in the pyrazine ring and the electron-donating properties of the other two amine nitrogen atoms in the two triphenylamine units. Moreover, luminophores C1, C2, and C3 exhibit "on-off-on" luminescence switching properties in mixtures of water/tetrahydrofuran with increasing water content, which is different from the "on-off" switching for typical aggregation-caused quenching (ACQ) materials and "off-on" switching for traditional aggregation-induced emission (AIE) materials. Additionally, upon grinding the pristine samples, luminophores C1, C2, and C3 display bathochromically shifted photoluminescence maxima that can be recovered by either solvent fuming or thermal annealing treatments. The piezofluorochromic (PFC) properties are more pronounced than those for reference compounds R1 and R2, which indicates that D-A molecules have the ability to amplify the PFC effect by tuning the ICT interactions upon tiny structural changes under pressure. Furthermore, the target luminophores demonstrate acid-responsive photoluminescence spectra that can be recovered in either basic or ambient environments. These results suggest that D-A complexes are potential candidates for multistimuli-responsive luminescence switching because their ICT profiles can be facilely tuned with tiny external stimuli.


Antioxidant and Adaptative Response Mediated by Nrf2 during Physical Exercise.
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a powerful nuclear transcription factor that coordinates an antioxidant cytoprotector system complex stimulated by the increase in inoxidative stress (OS). In the present manuscript, we conduct a review on the evidence that shows the effect different modalities of physical exercise exert on the antioxidant metabolic response directed by Nrf2. During physical exercise, the reactive oxygen species (ROS) are increased; therefore, if the endogenous and exogenous antioxidant defenses are unable to control the elevation of ROS, the resulting OS triggers the activation of the transcriptional factor Nrf2 to induce the antioxidant response. On a molecular basis related to physical exercise, hormesis maintenance (exercise preconditioning) and adaptative changes in training are supported by a growing body of evidence, which is important for detailing the health benefits that involve greater resistance to environmental aggressions, better tolerance to constant changes, and increasing the regenerative capacity of the cells in such a way that it may be used as a tool to support the prevention or treatment of diseases. This may have clinical implications for future investigations regarding physical exercise in terms of understanding adaptations in high-performance athletes but also as a therapeutic model in several diseases.


Interaction of fibroblast growth factor and C-natriuretic peptide signaling in regulation of chondrocyte proliferation and extracellular matrix homeostasis.
Overexpression of C-natriuretic peptide (CNP) in cartilage partially rescues achondroplasia in the mouse. Here, we studied the interaction of fibroblast growth factor (FGF) and CNP signaling in chondrocytes. CNP antagonized FGF2-induced growth arrest of rat chondrosarcoma (RCS) chondrocytes by inhibition of the Erk mitogen activated protein kinase pathway. This effect of CNP was protein kinase G-dependent and was mimicked by the cGMP analog pCPT-cGMP. FGF2-mediated activation of both MEK and Raf-1 but not Ras or FRS2 was abolished by CNP demonstrating that CNP blocks the Erk pathway at the level of Raf-1. CNP also counteracted the FGF2-mediated degradation of RCS extracellular matrix. CNP partially antagonized FGF2-induced expression, release and activation of several matrix-remodeling molecules including matrix metalloproteinase 2 (MMP2), MMP3, MMP9, MMP10 and MMP13. In addition, CNP compensated for FGF2-mediated matrix loss by upregulation of matrix production independent of its interference with FGF signaling. We conclude that CNP utilizes both direct and indirect ways to counteract the effects of FGF signaling in a chondrocyte environment.


Helminths of Wild Boar ( Sus scrofa) in the Calabrian Region of Southern Italy.
In Calabria, as in other Italian regions, the wild boar (Sus scrofa) population has increased considerably in the last few years. The presence of this wild ungulate, a huntable species, was detected throughout this region. Wild boars are a host for many endoparasites, some of which are zoonotic. Our aim was to acquire data on the prevalence endoparasites in wild boar in the region of Calabria, Italy, where such information is limited. We used 60 wild boars culled during the 2014-15 hunting season. We used FLOTAC dual techniques for fecal microscopic exams, as well as qualitative and quantitative microscopic examination with a sensitivity level of 2 eggs/g of feces. The research has underlined the remarkable diffusion of gastrointestinal helminths, particularly Ascaris suum, in wild boar of the areas of Sila and Presila in the province of Catanzaro, Calabria.


Xerostomia is associated with old age and poor appetite in patients on chronic hemodialysis.
The objective of this study was to assess variables associated with xerostomia in patients on chronic hemodialysis (HD). This was a cross-sectional study of 75 HD patients at an outpatient HD service. Demographic, clinical (renal disease, HD regimen/duration, Charlson comorbidity index, activities of daily living, instrumental activities of daily living [IADL], body mass index), and laboratory (hemoglobin, albumin, interleukin-6 [IL-6], and parathyroid hormone) parameters were recorded. We assessed the appetite through the Hemodialysis Study Appetite questionnaire and xerostomia through the Xerostomia Inventory (XI). A single question ("How often does your mouth feel dry?"; never = Class 1, almost never = Class 2, occasionally = Class 3, often = Class 4, very often = Class 5) was also included in the study questionnaire. The main outcome measure was factors correlated with XI. The median XI score was 18 (min-max = 11-33). Forty patients had an XI score of 18 or less (Group 1) and between 18 and 35 (Group 2). In Group 2, age, Charlson comorbidity index score, and number of patients with poor/very poor appetite were significantly higher. At the univariate analysis, the score of the XI was significantly associated with age, appetite, IADL, Charlson comorbidity index, and serum IL-6 levels. Multiple linear regression analysis showed that the XI was independently associated with age and appetite. Thirty-one patients were in Class 1 to 2, 23 were in Class 3, and 21 were in Class 4 to 5. In Classes 4 to 5, age and the number of patients with poor/very poor appetite were higher (P = .012 and .09, respectively). Xerostomia is associated with old age and poor appetite in patients on chronic HD.


Recovery in mammalian cells irradiated with a beam of pi--mesons.
HeLa cells have been irradiated in a beam of pi--mesons using fractionated exposures. The response-time curve for cells irradiated in the peak and in the plateau regions showed evidence of recovery. For cells irradiated in the post-peak position recovery was either absent or delayed.


Recent biomonitoring reports on phosphate ester flame retardants: a short review.
Organophosphate triesters (PEFRs) are used increasingly as flame retardants and plasticizers in a variety of applications, such as building materials, textiles, and electric and electronic equipment. They have been proposed as alternatives to brominated flame retardants. This updated review shows that biomonitoring has gained incrementally greater importance in evaluating human exposure to PEFRs, and it holds the advantage of taking into account the multiple potential sources and various intake pathways of PEFRs. Simultaneous and extensive internal exposure to a broad range of PEFRs have been reported worldwide. Their metabolites, mainly dialkyl or diaryl diesters, have been used as biomarkers of exposure and have been ubiquitously detected in the urine of adults and children in the general population. Concentrations and profiles of PEFR urinary metabolites are seen to be variable and are highly dependent on individual and environmental factors, including age, country regulation of flame retardants, and types and quantities of emissions in microenvironments, as well as analytical procedures. Additional large biomonitoring studies, using a broad range of urinary diesters and hydroxylated metabolites, would be useful to improve the validity of the biomarkers and to refine assessments of human exposure to PEFRs.


Detection of Escherichia coli O157:H7, Salmonella typhimurium, and Legionella pneumophila in water using a flow-through chemiluminescence microarray readout system.
Fast, sensitive, and especially, multianalyte test systems are currently of high interest for the monitoring and quality control of drinking water, since traditional microbiological methods are labor intensive and can take days until a response is achieved. In this study, the first flow-through chemiluminescence microarray was developed and characterized for the rapid and simultaneous detection of Escherichia coli O157:H7, Salmonella typhimurium, and Legionella pneumophila in water samples using a semiautomated readout system. Therefore, antibody microarrays were produced on poly(ethylene glycol)-modified glass substrates by means of a contact arrayer. For capturing bacteria, species-specific polyclonal antibodies were used. Cell recognition was carried out by binding of species-specific biotinylated antibodies. Chemiluminescence detection was accomplished by a streptavidin-horseradish peroxidase (HRP) catalyzed reaction of luminol and hydrogen peroxide. The chemiluminescence reaction that occurred was recorded by a sensitive charge-coupled device (CCD) camera. The overall assay time was 13 min, enabling a fast sample analysis. In multianalyte experiments, the detection limits were 3 x 10(6), 1 x 10(5), and 3 x 10(3) cells/mL for S. typhimurium, L. pneumophila, and E. coli O157:H7, respectively. Quantification of samples was possible in a wide concentration range with good recoveries. The presented system is well suited for quick and automatic water analysis.


Identification of retinal neurons in a regressive rodent eye (the naked mole-rat).
The retina consists of many parallel circuits designed to maximize the gathering of important information from the environment. Each of these circuits is comprised of a number of different cell types combined in modules that tile the retina. To a subterranean animal, vision is of relatively less importance. Knowledge of how circuits and their elements are altered in response to the subterranean environment is useful both in understanding processes of regressive evolution and in retinal processing itself. We examined common cell types in the retina of the naked mole-rat, Heterocephalus glaber with immunocytochemical markers and retrograde staining of ganglion cells from optic nerve injections. The stains used show that the naked mole-rat eye has retained multiple ganglion cell types, 1-2 types of horizontal cell, rod bipolar and multiple types of cone bipolar cells, and several types of common amacrine cells. However, no labeling was found with antibodies to the dopamine-synthesizing enzyme, tyrosine hydroxylase. Although most of the well-characterized mammalian cell types are present in the regressive mole-rat eye, their structural organization is considerably less regular than in more sighted mammals. We found less precision of depth of stratification in the inner plexiform layer and also less precision in their lateral coverage of the retina. The results suggest that image formation is not very important in these animals, but that circuits beyond those required for circadian entrainment remain in place.


A seamless phase IIB/III adaptive outcome trial: design rationale and implementation challenges.
The licensed four-valent prophylactic human papillomavirus vaccine is highly efficacious in preventing cervical, vulvar, vaginal, and anal cancers and related precancers caused by human papillomavirus types 6, 11, 16, and 18. These four types account for approximately 70% of cervical cancers. A nine-valent human papillomavirus vaccine, including the four original types (6, 11, 16, and 18) plus the next five most prevalent types in cervical cancer (31, 33, 45, 52, and 58) could provide approximately 90% overall cervical cancer coverage. To expedite the nine-valent human papillomavirus vaccine clinical development, an adaptive, seamless Phase IIB/III outcome trial with ∼ 15,000 subjects was conducted to facilitate dose formulation selection and provide pivotal evidence of safety and efficacy for regulatory registrations. We discuss the design rationale and implementation challenges of the outcome trial, focusing on the adaptive feature of the seamless Phase IIB/III design. Subjects were enrolled in two parts (Part A and Part B). Approximately 1240 women, 16-26 years of age, were enrolled in Part A for Phase IIB evaluation and equally randomized to one of three dose formulations of the nine-valent human papillomavirus vaccine or the four-valent human papillomavirus vaccine (active control). Based on an interim analysis of immunogenicity and safety, one dose formulation of the nine-valent human papillomavirus vaccine was selected for evaluation in the Phase III part of the study. Subjects enrolled in Part A who received the selected dose formulation of the nine-valent human papillomavirus vaccine or four-valent human papillomavirus vaccine continued to be followed up and contributed to the final efficacy and safety analyses. In addition, ∼ 13,400 women 16-26 years of age were enrolled in Part B, randomized to nine-valent human papillomavirus vaccine at the selected dose formulation or four-valent human papillomavirus vaccine, and followed for immunogenicity, efficacy, and safety. A seamless Phase IIB/III design was justified by the extensive pre-existing knowledge of the licensed four-valent human papillomavirus vaccine and the development objectives for the nine-valent human papillomavirus vaccine. Subjects enrolled in Part A who received either the selected nine-valent human papillomavirus formulation or four-valent human papillomavirus vaccine contributed ∼ 10% of person-years of follow-up due to its earlier start-thereby maximizing the overall efficiency of the trial. Some of the challenges encountered in the implementation of the adaptive design included practical considerations during Phase IIB formulation selection by internal and external committees, End-of-Phase II discussion with health authorities and managing changes in the assay for immunological endpoints. Application of the experience and lesson learned from this seamless adaptive design to other clinical programs may depend on case-by-case consideration. A seamless Phase IIB/III adaptive design was successfully implemented in this large outcome study. The development time of the second-generation nine-valent human papillomavirus vaccine was shortened due to improved statistical efficiency.


Organocatalytic Enantioselective Michael Addition between 3-(3-hydroxy-1H-pyrazol-1-yl)Oxindole and β-Nitrostyrene for the Preparation of Chiral Disubstituted Oxindoles.
A new enantioselective Michael addition between 3-(3-hydroxy-1H-pyrazol-1-yl)oxindole, a new synthon generated from isatin N,N'-cyclic azomethine imine 1,3-dipole, and β-nitrostyrene has been disclosed. A series of chiral 3-(3-oxo-2,3-dihydro-1H-pyrazol-1-yl) disubstituted oxindoles were obtained in excellent results (up to 97% yield, up to 94% ee) with moderate to good diastereoselectivities (up to 4.3:1 dr).


Weak and Strong Gels and the Emergence of the Amorphous Solid State.
Gels are amorphous solids whose macroscopic viscoelastic response derives from constraints in the material that serve to localize the constituent molecules or particles about their average positions in space. These constraints may either be local in nature, as in chemical cross-linking and direct physical associations, or non-local, as in case of topological "entanglement" interactions between highly extended fiber or sheet structures in the fluid. Either of these interactions, or both combined, can lead to "gelation" or "amorphous solidification". While gels are often considered to be inherently non-equilibrium materials, and correspondingly termed "soft glassy matter", this is not generally the case. For example, the formation of vulcanized rubbers by cross-linking macromolecules can be exactly described as a second order phase transition from an equilibrium fluid to an equilibrium solid state, and amorphous solidification also arises in diverse physical gels in which molecular and particle localization occurs predominantly through transient molecuar associations, or even topological interactions. As equilibrium, or near equilibrium systems, such gels can be expected to exhibit universal linear and non-linear viscoelastic properties, especially near the "critical" conditions at which the gel state first emerges. In particular, a power-law viscoelastic response is frequently observed in gel materials near their "gelation" or "amorphous solidification" transition. Another basic property of physical gels of both theoretical and practical interest is their response to large stresses at constant shear rate or under a fixed macrocopic strain. In particular, these materials are often quite sensitive to applied stresses that can cause the self-assembled structure to progressively break down under flow or deformation. This disintegration of gel structure can lead to "yield" of the gel material, i.e., a fluidization transition, followed by shear thinning of the resulting heterogeneous "jelly-like" fluid. When the stress is removed, however, the material can relax back to its former equilibrium gel state, i.e., gel rejuvenation. In constrast, a non-equilibrium material will simply change its form and properties in a way that depends on processing history. Physical gels are thus unique self-healing materials in which the existence of equilibrium ensures their eventual recovery. The existence of equilibrium also has implications for the nature of both the linear and non-linear rheological response of gel materials, and the present paper explores this phenomenon based on simple scaling arguments of the kind frequently used in describing phase transitions and the properties of polymer solutions.


Smectic liquid crystals from supramolecular guanidinium alkylbenzenesulfonates.
A homologous series of guanidinium alkylbenzenesulfonates from ethyl to tetradecyl were synthesized and characterised. Their thermotropic polymorphism was investigated by polarizing optical microscopy, differential scanning calorimetry, and dilatometry. The structure of the smectic liquid crystal phases obtained at high temperature with the compounds from octyl to tetradecyl was analysed by X-ray diffraction. The supramolecular assembling of the ionic species inside the smectic layers was investigated by infrared spectroscopy.