Ohio strains of a virus pathogenic for infant mice, Coxsackie group; simultaneous occurrence with poliomyelitis virus in patients with summer grippe.
Further evidence for the widespread occurrence of Coxsackie or C virus is presented in this paper. This virus is characterized by paralysis and myositis produced in infant mice. An epidemic of mild illnesses diagnosed as "non-paralytic poliomyelitis" and as "summer grippe" occurred during the summer of 1947 in Akron and Cincinnati, Ohio. From the pooled feces of such patients both poliomyelitis virus and C virus were obtained. From the samples of single patients, 3 immunologically related strains of C virus were isolated. One patient from whom virus was isolated had an illness which was diagnosed as non-paralytic poliomyelitis (with pleocytosis). Although poliomyelitis virus could not be isolated from this patient, previous tests (5) from similar non-paralytic patients in the same area revealed that 9 of 23 were infected with poliomyelitis virus. C virus could not be recovered from the stools of 3 of these poliomyelitis virus-infected patients. Four patients with an illness diagnosed as "summer grippe" were tested. Two harbored poliomyelitis virus of low virulence (4) as well as C virus, and two harbored poliomyelitis virus without any evidence of infection with C virus, either by virus isolation or by serological tests. The patients from whom C virus was isolated developed complement-fixing antibodies 4 weeks after onset. Neutralizing antibodies appeared within the first 5 days of disease (before complement-fixing antibodies) and increased in titer during the next 3 to 4 weeks. The patients from whom C virus could not be recovered failed to develop either neutralizing or complement-fixing antibodies. Other patients in the area were infected with C virus as indicated by their serological response to the agent.


Recovery from hypoxemia and Hypercapnia following noninvasive pressure support ventilation in a patient with statin-associated necrotizing myopathy: a case report.
Statin-associated necrotizing myopathy (SANM) is a rare autoimmune disorder caused by administration of statins. SANM is characterized by weakness due to necrosis and regeneration of myofibers. Here we report the first case of SANM with acute respiratory failure treated with noninvasive pressure support ventilation in addition to immunosuppressants. A 59-year-old woman who had been treated with 2.5 mg/day of rosuvastatin calcium for 5 years stopped taking the drug 4 months before admission to our hospital due to elevation of creatine kinase (CK). Withdrawal of rosuvastatin for 1 month did not decrease the level of CK, and she was admitted to our hospital due to the development of muscle weakness of her neck and bilateral upper extremities. Anti-3-hydroxy-3-methylglutaryl coenzyme A reductase antibodies were positive. Magnetic resonance imaging showed myositis, and muscle biopsy from the right biceps brachii muscle showed muscle fiber necrosis and regeneration without inflammatory cell infiltration, suggesting SANM. After the diagnosis, she received methylprednisolone pulse therapy (mPSL, 1 g/day × 3 days, twice) and subsequent oral prednisolone therapy (PSL, 30 mg/day for 1 month, 25 mg/day for 1 month and 22.5 mg/day for 1 month), leading to improvement of her muscle weakness. One month after the PSL tapering to 20 mg/day, her muscle weakness deteriorated with oxygen desaturation (SpO2: 93% at room air) due to hypoventilation caused by weakness of respiratory muscles. BIPAP was used for the management of acute respiratory failure in combination with IVIG (20 g/day × 5 days) followed by mPSL pulse therapy (1 g/day × 3 days), oral PSL (30 mg/day × 3 weeks, then tapered to 25 mg/day) and tacrolimus (3 mg/day). Twenty-seven days after the start of BIPAP, she was weaned from BIPAP with improvement of muscle weakness, hypoxemia and hypercapnia. After she achieved remission with improvement of muscle weakness and reduction of serum CK level to a normal level, the dose of oral prednisolone was gradually tapered to 12.5 mg/day without relapse for 3 months. Our report provides new insights into the role of immunosuppressants and biphasic positive airway pressure for induction of remission in patients with SANM.


Opioid-induced bowel dysfunction: pathophysiology and potential new therapies.
Opioid treatment for postoperative or chronic pain is frequently associated with adverse effects, the most common being dose-limiting and debilitating bowel dysfunction. Postoperative ileus, although attributable to surgical procedures, is often exacerbated by opioid use during and following surgery. Postoperative ileus is marked by increased inhibitory neural input, heightened inflammatory responses, decreased propulsive movements and increased fluid absorption in the gastrointestinal tract. The use of opioids for chronic pain is characterised by a constellation of symptoms including hard dry stools, straining, incomplete evacuation, bloating, abdominal distension and increased gastroesophageal reflux. The current management of opioid-induced bowel dysfunction among patients receiving opioid analgesics consists primarily of nonspecific ameliorative measures. Intensive investigations into the mode of action of opioids have characterised three opioid receptor classes -mu, delta and kappa- that mediate the myriad of peripheral and central actions of opioids. Activation of mu-opioid receptors in the gastrointestinal tract is responsible for inhibition of gut motility, whereas receptors in the central nervous system mediate the analgesic actions of opioids. Blocking peripheral opioid receptors in the gut is therefore a logical therapeutic target for managing opioid-induced bowel dysfunction. Available opioid antagonists such as naloxone are of limited use because they are readily absorbed, cross the blood-brain barrier, and act at central opioid receptors to reverse analgesia and elicit opioid withdrawal. Methylnaltrexone and alvimopan are recently developed opioid antagonists with activity that is restricted to peripheral receptors. Both have recently shown the ability to reverse opioid-induced bowel dysfunction without reversing analgesia or precipitating central nervous system withdrawal signs in non-surgical patients receiving opioids for chronic pain. In addition, recent clinical studies with alvimopan suggest that it may normalise bowel function without blocking opioid analgesia in abdominal laparotomy patients with opioid-related postoperative ileus.


Barriers of HIPAA regulation to implementation of health services research.
Although many perspectives on the impact of the Health Insurance Portability and Accountability Act of 1996 (HIPAA) on health services research have been wide spread, little empirical evidence has been reported about HIPAA-related barriers during the implementation of research projects. Using three cases of health services research projects, this study examined practical barriers created by HIPAA regulation. During the stage of implementation of the three projects, we experienced some HIPAA-related concerns, previously raised in the field of health services research. We found that technically complicated consent forms and privacy protection forms as well as socially-sensitive clinical conditions make patients less willing to participate in research projects; concerns about safety of patient medical information makes health organizations more hesitant to let researchers have access to the patient's information, especially through electronic transfer; more restrictive IRB processes and challenging patient recruiting processes make health services researchers reluctant to go through the process; and as a result, they may compromise with the scientific soundness of the project. Overall, HIPAA complicates the research process and requires more resources and longer time to conduct research.


Digital PBL-CBL teaching method improves students' performance in learning complex implant cases in atrophic anterior maxilla.
The clinical teaching of esthetic implant-supported restoration of the atrophic maxilla is challenging due to the complexity and unpredictability of bone and soft tissue augmentation. The traditional problem-based learning and case-based learning method (PBL-CBL method) with a full digital workflow (digital PBL-CBL method) provides the students a chance to view clinical cases in a more accurate and measurable way. The aim is to evaluate the effectiveness of the new digital PBL-CBL method in teaching complex implant cases in esthetic area. A full digital workflow of dental implant therapy was established for patients with severely atrophic anterior maxilla. The digital data of cases done in the new workflow was used as teaching materials in digital PBL-CBL teaching. Fifty-four postgraduate students were randomly selected and divided into three groups, including traditional PBL-CBL group (students taught in a PBL-CBL method with no digital cases), digital PBL-CBL group (students taught in a PBL-CBL method with full digital cases) and control group (students taught in didactic teacher-centered method). After training for three months, a study of the students' opinions on the corresponding teaching method was carried out through a feedback questionnaire. A theory test was used to evaluate students' mastery of knowledge about tissue augmentation and esthetic implant restoration. A case analysis was used to determine whether students could apply the knowledge to problem solving. The digital PBL-CBL method resulted in a higher rate of satisfaction than the traditional PBL-CBL method and the didactic teacher-centered method in all items except for "This approach decreases extracurricular work". Case analysis scores of the digital PBL-CBL group were significantly higher than that of the traditional PBL-CBL group and the control group. For the theory test, the digital PBL-CBL group (61.00 ± 6.80) but not traditional PBL-CBL group (55.22 ± 9.86) obtained a significant higher score than the control group (45.11 ± 12.76), although no significant difference was found between the digital PBL-CBL group and the traditional PBL-CBL group. Compared with other methods, students taught with the digital PBL-CBL method showed higher satisfaction and better performance in acquisition of academic knowledge and ability in solving practical clinical problems. The digital PBL-CBL method provided a promising alternative for teaching complex implant cases at the anterior maxilla.


[Smoking prevalence and associated factors among public high school students in Santa Maria, Rio Grande do Sul, Brazil, 2002].
Smoking is the second cause of death in the world. It currently accounts for one out of ten deaths in adults worldwide (5 million per year). If current patterns persist, smoking will cause 10 million deaths a year by 2020 according to the World Health Organization. A prevalence study on smoking habits was conducted in 2002 among 459 students from eight public high schools in Santa Maria, Rio Grande do Sul State, Brazil. This study aimed to measure smoking prevalence and related factors by multivariate logistic regression. The overall smoking prevalence rate in the sample was 18% (95%CI: 14.6-21.7), and the students had begun smoking at a mean age of 14 years. Students from public high schools had begun smoking early, influenced by friends who smoked (OR = 4.37; p = 0.000), family income (OR = 2.04; p = 0.013), and age (OR = 1.86; p = 0.031). It is thus crucial to adopt measures to prevent adolescents' access to smoking.


An anatomical landmark for the supplementary eye fields in human revealed with functional magnetic resonance imaging.
Together with the frontal and parietal eye fields, the supplementary eye field (SEF) is involved in the performance and control of voluntary and reflexive saccades and of ocular pursuit. This region was first described in non-human primates and is rather well localized on the dorsal surface of the medial frontal cortex. In humans the site of the SEF is still ill-defined. Functional imaging techniques have allowed investigation of the location and function of the SEF. However, there is great variability with regard to the published standardized coordinates of this area. We used here the spatial precision of functional magnetic resonance imaging (fMRI) in order to better localize the SEF in individuals. We identified as the SEF a region on the medial wall that was significantly activated when subjects executed self-paced horizontal saccades in darkness as compared to rest. This region appeared to be predominantly activated in the left hemisphere. We found that, despite a discrepancy of >2 cm found in the standardized Talairach coordinates, the location of this SEF-region could be precisely and reliably described by referring to a sulcal landmark found in each individual: the upper part of the paracentral sulcus.


Load-induced deformation of the tibia and its effect on implant loosening detection.
CT imaging under external valgus and varus loading conditions and consecutive image analysis can be used to detect tibial implant loosening after total knee arthroplasty. However, the applied load causes the tibia to deform, which could result in an overestimation of implant displacement. This research evaluates the extent of tibia deformation and its effect on measuring implant displacement. Ten cadaver specimen with TKA were CT-scanned under valgus/varus loading (20 Nm), first implanted without bone cement fixation (mimicking a loose implant) and subsequently with bone cement fixation (mimicking a fixed implant). By means of image analysis, three relative displacements were assessed: (1) between the proximal and distal tibia (measure of deformation), (2) between the implant and the whole tibia (including potential deformation effect) and (3) between the implant and the proximal tibia (reduced deformation effect). Relative displacements were quantified in terms of translations along, and rotations about the axes of a local coordinate system. As a measure of deformation, the proximal tibia moved relative to the distal tibia by, on average 1.27 mm (± 0.50 mm) and 0.64° (± 0.25°). Deformation caused an overestimation of implant displacement in the cemented implant. The implant displaced with respect to the whole tibia by 0.45 mm (± 0.22 mm) and 0.79° (± 0.38°). Relative to the proximal tibia, the implant moved by 0.23 mm (± 0.10 mm) and 0.62° (± 0.34°). The differentiation between loose and fixed implants improved when tibia deformation was compensated for by using the proximal tibia rather than the whole tibia.


Functional Connectivity Between Default Mode and Ventral Attention Networks Mediates the Effects of Chronotype on Daily Physical Activity.
Daily physical activity (dPA) is closely related to circadian rhythm and chronotype. The functional connectivity (FC) within or between the default mode (DMN) and ventral attention network (vAN) were associated with dPA and chronotype. DMN-vAN FC was investigated for its role in chronotype and dPA. 153 participants completed the reduced version of the Morningness-Eveningness Questionnaire (rMEQ), dPA was measured via actigraphy (5-day), and then resting-state fMRI scans were performed. rMEQ scores and steps recorded by the actigraphic devices (with each hour as the time window to calculate steps for five consecutive days per hour, subsequently yielding the maximum number of steps and its corresponding time, ie, SM and SMT) represent chronotype and dPA respectively. The results found that the rMEQ scores were significantly negatively correlated with SMT. The positive correlation between the rMEQ scores and the DMN-vAN FC was significant. There were also significant positive correlations between SMT and DMN-vAN FC. Further analysis revealed that DMN-vAN mediates the relationship between chronotype and SMT. The FC of DMN-vAN may be the underlying neural mechanism through which chronotype influences dPA. These findings could support the development of reasonable activity schedules or specific intervention programs to improve physical health.


Body mass index trajectories in young adulthood predict non-alcoholic fatty liver disease in middle age: The CARDIA cohort study.
Non-alcoholic fatty liver disease is an epidemic. Identifying modifiable risk factors for non-alcoholic fatty liver disease development is essential to design effective prevention programmes. We tested whether 25-year patterns of body mass index change are associated with midlife non-alcoholic fatty liver disease. In all, 4423 participants from Coronary Artery Risk Development in Young Adults, a prospective population-based biracial cohort (age 18-30), underwent body mass index measurement at baseline (1985-1986) and 3 or more times over 25 years. At Year 25, 3115 had liver fat assessed by non-contrast computed tomography. Non-alcoholic fatty liver disease was defined as liver attenuation ≤40 Hounsfield Units after exclusions. Latent mixture modelling identified 25-year trajectories in body mass index per cent change (%Δ) from baseline. We identified four distinct trajectories of BMI%Δ: stable (26.2% of cohort, 25-year BMI %Δ = 3.1%), moderate increase (46.0%, BMI%Δ = 21.7%), high increase (20.9%, BMI%Δ = 41.9%) and extreme increase (6.9%, BMI%Δ = 65.9%). Y25 non-alcoholic fatty liver disease prevalence was higher in groups with greater BMI %Δ: 4.1%, 9.3%, 13.0%, and 17.6%, respectively (P-trend <.0001). In multivariable analyses, participants with increasing BMI%Δ had increasingly greater odds of non-alcoholic fatty liver disease compared to the stable group: OR: 3.35 (95% CI: 2.07-5.42), 7.80 (4.60-13.23) and 12.68 (6.68-24.09) for moderate, high and extreme body mass index increase, respectively. Associations were only moderately attenuated when adjusted for baseline or Y25 body mass index. Trajectories of weight gain during young adulthood are associated with greater non-alcoholic fatty liver disease prevalence in midlife independent of metabolic covariates and baseline or concurrent body mass index highlighting the importance of weight maintenance throughout adulthood as a target for primary non-alcoholic fatty liver disease prevention.


Epithelium-mesenchyme interactions control the activity of peroxisome proliferator-activated receptor beta/delta during hair follicle development.
Hair follicle morphogenesis depends on a delicate balance between cell proliferation and apoptosis, which involves epithelium-mesenchyme interactions. We show that peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) and Akt1 are highly expressed in follicular keratinocytes throughout hair follicle development. Interestingly, PPARbeta/delta- and Akt1-deficient mice exhibit similar retardation of postnatal hair follicle morphogenesis, particularly at the hair peg stage, revealing a new important function for both factors in the growth of early hair follicles. We demonstrate that a time-regulated activation of the PPARbeta/delta protein in follicular keratinocytes involves the up-regulation of the cyclooxygenase 2 enzyme by a mesenchymal paracrine factor, the hepatocyte growth factor. Subsequent PPARbeta/delta-mediated temporal activation of the antiapoptotic Akt1 pathway in vivo protects keratinocytes from hair pegs against apoptosis, which is required for normal hair follicle development. Together, these results demonstrate that epithelium-mesenchyme interactions in the skin regulate the activity of PPARbeta/delta during hair follicle development via the control of ligand production and provide important new insights into the molecular biology of hair growth.


Molecular characterization of two badnavirus genomes associated with Canna yellow mottle disease.
Members of the genus Badnavirus have a single non-covalently closed circular double-stranded DNA genome of 7.2-9.2kb. The genome encodes three open reading frames (ORFs) on the positive DNA strand. Canna yellow mottle virus (CaYMV) is a badnavirus that has been described as the etiological cause of yellow mottle disease in canna, although only a 565bp fragment of the genome has been previously reported from cannas. In this report, concentrated virions were recovered from infected canna plants and nucleic acids were extracted. Two full-length sequences represent two badnavirus genomes were recovered and were determined to be 6966bp and 7385bp in length. These DNAs represent a virus strain belonging to Canna yellow mottle virus and a novel species tentatively termed Canna yellow mottle associated virus. Phylogenetic analysis indicates that these two viruses are closely related to sugarcane bacilliform GD virus, pineapple bacilliform comosus virus, banana streak MY virus, and cycad leaf necrosis virus. We also showed naturally grown canna plants to be frequently co-infected by these two badnaviruses along with a potyvirus, Canna yellow streak virus.


Absorption and distribution of selenium in animals consuming canola grown for selenium phytoremediation.
Canola (Brassica napus) grown as a selected plant species for field phytoremediation of selenium (Se) may be harvested and utilized as Se-enriched forage for marginally Se-deficient lambs and cows. Two field studies were conducted under controlled conditions to evaluate the accumulation of Se into different animal tissues, including blood, excreta, and milk. In Study 1, treatments consisted of feeding lambs freshly cut Se-enriched canola (containing approximately 4 mg Se kg(-1) DM) or control canola (containing <0.1 mg Se kg(-1) DM), respectively, for 64 days. In Study 2, treatments consisted of feeding cows dried Se-enriched canola (containing approximately 3.5 mg Se kg(-1) DM) as part of their daily ration for 20 days. In Study 1 at postmortem, Se concentrations were significantly greater in all tested tissues and in excreta from lambs fed Se-enriched canola. In Study 2, Se values were slightly higher in blood and excreta, but not significantly higher in milk from cows sampled throughout the study. Significant differences in total live animal weight were not observed between treatments in either study. Based on these results, canola plants (not including seeds) used for field phytoremediation of Se may be harvested and safely fed to lambs and cows to help meet normal Se intake requirements.


When chronic obstructive pulmonary disease meets small cell lung cancer: an unusual case report of rapid progression.
Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease and a risk factor for lung cancer. Small cell lung cancer is a neuroendocrine tumor with a high degree of malignancy and an overall five-year survival rate of less than 7%. Herein, we report the case of an 68-year-old male presented to the respiratory department with cough, sputum, and dyspnea. He was diagnosed as community acquired pneumonia and treated with intravenous anti-infection. Previous pulmonary function was definitively diagnosed as COPD. About 7 months after discharge, the patient returned to the hospital for cough and dyspnea. After diagnosis of the tumor, cisplatin, etoposide and durvalumab were administered. Finally the patient died of respiratory failure approximately 9 months after his diagnosis. For COPD patients with immunocompromised manifestations, it is necessary to be alert to complications and shorten the follow-up interval of chest CT. COPD may accelerate the formation and progression of SCLC.


The trans action of HMRa in mating type interconversion.
HML and HMR are the sites of cryptic mating type genes in the yeast Saccharomyces cerevisiae. In the presence of the HO gene, the information from HML or HMR (an a or alpha cassette) is transferred to the mating type locus (MAT). HML, HMR, and MAT are located on chromosome III, yet are widely separated. Similarly, in other yeasts, at least some of the genes involved in mating typing interconversion are linked to the mating type locus. We demonstrate here that a cassette donor (HMR) and the cassette target (MAT) need not be physically linked for successful mating type interconversion. In particular, we show that HMRa on one chromosome can donate an a cassette to the mating type locus on a homologous chromosome III.


Dislocations at the cervicothoracic junction.
Dislocations of the cervicothoracic junction are frequently missed. Experience of this rare injury over 27 years at the Spinal Injuries Unit in Sheffield confirms that nearly two-thirds were not properly diagnosed on admission. Only two of the 14 dislocations studied were reduced by conservative methods and these were both associated with fractures of the posterior bony elements. Open reduction is necessary to replace pure dislocations at the C7-T1 level. It seems likely that the spinal cord lesion is not influenced by reduction of the displacement. The three patients who had an incomplete lesion of the spinal cord made excellent neurological recoveries although none of the dislocations was reduced. It is concluded that on theoretical grounds it is justified to embark on operative reduction of displacements at this spinal level only if the cord lesion is incomplete, nerve root recovery therefore possible, and if the operation can be brought about soon after the injury.


Factors predicting endocrine late effects in childhood cancer survivors from a Japanese hospital.
We retrospectively analyzed endocrine late effects in 81 childhood cancer survivor (CCS) patients who had been referred to our endocrinology department in Chiba Children's Hospital between January 1, 2008 and December 31, 2016. Among 69 eligible patients (33 male, 36 female), endocrine late effects were identified in 56 patients (81.1%). The median age at the last visit to our endocrinology department was 17.4 years (range: 7.1-35.3 years). The most common primary cancer was acute lymphoblastic leukemia (22 patients, 31.8%). Forty-four patients (64%) were treated using radiation therapy. A primary brain tumor and high doses (≥6 g/m2) of cyclophosphamide were significantly associated with growth hormone deficiency (GHD). Our present study suggests that high doses of cyclophosphamide is a risk factor for GHD. Adult heights and pubertal growth spurts of patients treated with radiation therapy were significantly lower than patients not treated with radiation therapy. Our retrospective study reconfirmed that hematopoietic stem cell transplantation and chronic graft versus host disease (GVHD) were associated with elevated risks of primary hypothyroidism. However, it is unclear whether GVHD induces thyroid dysfunction. Gonadal radiation and busulfan were associated with primary hypogonadism as reported in previous studies. We found high doses of cyclophosphamide to be involved in pituitary disorders. We suggest that pediatric endocrinologists should discuss the potential effects of radiation therapy on adult height and pubertal growth spurt in CCS patients. Moreover, patients who have been treated with high doses of cyclophosphamide or have chronic GVHD require long-term follow-up for endocrine late effects.


Quality and Microbiome Analysis of Pickled Swimming Crabs (Portunus trituberculatus) during Storage at Two Alternative Temperatures.
The storage quality and microbiome analysis of pickled swimming crabs (Portunus trituberculatus) stored at 20 and 4 °C were investigated. It showed that samples stored at 4 °C had a longer shelf life, lower total viable count (TVC), pH, and total volatile base nitrogen (TVB-N) contents than those stored at 20 °C. The biogenic amine (BA) results demonstrated that tyramine (tyr), putrescine (put), and cadaverine (cad) were the dominant amines in all samples, and samples stored at 4 °C had lower BA contents. A microbiome analysis indicated that a salt-alcohol water mixture significantly inhibited the growth of Tenericutes. Firmicutes, Proteobacteria, Bacteroidetes, Acidobacteria, Actinobacteria, and Cyanobacteria were the dominant bacteria of stored pickled crabs, and storage at 4 °C significantly inhibited the growth of dominant bacteria, more than that of 20 °C. In conclusion, 4 °C storage guaranteed the quality of samples by inhibiting changes in biochemical properties and the growth of dominant bacteria, thereby prolonging its shelf life.


Phase 1 study of marizomib in relapsed or relapsed and refractory multiple myeloma: NPI-0052-101 Part 1.
Marizomib (MRZ) is a novel, irreversible proteasome inhibitor in clinical development for the treatment of relapsed or relapsed and refractory multiple myeloma (RRMM). MRZ inhibits the 3 proteolytic activities of the 20S proteasome with specificity distinct from bortezomib and carfilzomib. Study NPI-0052-101 Part 1 enrolled relapsed or RRMM patients into an open-label, dose-escalation design to determine the maximum tolerated dose and recommended phase 2 dose (RP2D) of MRZ administered intravenously on 2 different schedules: schedule A (0.025-0.7 mg/m(2) once weekly on days 1, 8, and 15 of 4-week cycles) and schedule B (0.15-0.6 mg/m(2) twice weekly on days 1, 4, 8, and 11 of 3-week cycles; concomitant dexamethasone was allowed with schedule B). Patients had received an average of 4.9 and 7.3 prior treatment regimens (schedules A and B, respectively). MRZ schedule A was administered to 32 patients, and the RP2D was established as 0.7 mg/m(2) infused over 10 minutes. Schedule B was administered to 36 patients, and the RP2D was determined to be 0.5 mg/m(2) infused over 2 hours. The most common (>20% of patients) related adverse events were fatigue, headache, nausea, diarrhea, dizziness, and vomiting. Six patients achieved clinical benefit responses (defined as minimal response or better), including 5 partial responses (1 patient on schedule A and 4 on schedule B; 3 of these 4 patients received concomitant dexamethasone). MRZ was generally well tolerated, and results suggest activity in previously treated RRMM patients. Combination studies using pomalidomide and dexamethasone are now underway. The trial was registered at www.clinicaltrials.gov as #NCT00461045.


Do pericardial bioprostheses improve outcome of elderly patients undergoing aortic valve replacement?
Pericardial bioprostheses have favorable echocardiographic hemodynamics in the aortic position compared with porcine valves; however, there are few data comparing clinical outcomes. Our objective was to assess the late results of the two valve types. We reviewed 2,979 patients aged 65 years or older undergoing aortic valve replacement with pericardial (n=1,976) or porcine (n=1,003) prostheses between January 1993 and December 2007. The most common pericardial prostheses were Carpentier-Edwards Perimount and Mitroflow, and the most common porcine valves were Medtronic Mosaic, Carpentier-Edwards, Hancock modified orifice, and St. Jude Biocor. Follow-up extended to a maximum of 16 years (mean, 5.2±3.5 years). Survival at 5, 10 and 12 years was, respectively, 68%, 33%, and 21% overall, was 68%, 30%, and 16% for patients with pericardial bioprosthesis, and was 69%, 38% and 27% for the porcine group. In a multivariate model, long-term survival was reduced in patients with diabetes, renal failure, prior myocardial infarction, congestive heart failure, and older age, but late survival was not higher in the pericardial valve group. Overall freedom from reoperation was 96%, 92%, and 90% at 5, 10, and 12 years, and freedom from explant was 98%, 96%, and 94% during the same period. The reason for explant was structural valve deterioration in 50 patients (2%). Despite the better hemodynamic performance documented in prior investigations, pericardial valves do not confer any survival advantage over porcine valves in patients aged 65 years or older undergoing aortic valve replacement.


Preoperative carbohydrate drink in fast-track primary total knee arthroplasty: a randomized controlled trial of 168 patients.
A key component in fast-track total knee arthroplasty (TKA) is early mobilization. Preoperative fasting might cause orthostatic hypotension and -intolerance which both can interfere with early mobilization. It was hypothesized that consuming a carbohydrate drink 2-3 hours prior to surgery is a viable option to reduce orthostatic hypotension, and as a result, improve rehabilitation. In this randomized controlled trial, all consecutive unilateral primary TKA patients were reviewed for eligibility. Exclusion criteria were American Society of Anesthesiologists (ASA) class above 3, older than 80 years of age, Diabetes Mellitus, and an insufficient comment of Dutch language. Patients were distributed in two groups. The control group was allowed to eat till 6 hours and drink clear fluids till 2 hours before surgery (standard treatment). The intervention group consumed, additionally to the standard treatment, a carbohydrate drink 2-3 hours before surgery. Blood pressure was measured both lying and standing as a measure for orthostatic hypotension during first time postoperative mobilization on day of surgery. A total of 168 patients were included. Prevalence of orthostatic hypotension in the control- and intervention group was 24 patients (34%) and 14 patients (19%) respectively, (p=0.05). Prevalence of orthostatic intolerance was 13 patients (19%) in the control group and 9 patients (13%) in the intervention group (p=0.32). No drink related adverse events occurred. In conclusion, taking a carbohydrate drink 2-3 hours before TKA significantly lowers the number of patients with orthostatic hypotension in early mobilization. However, the clinical relevance of the carbohydrate drink has to be studied further.


Diurnal variation in neuroendocrine response to stress in rats: plasma ACTH, beta-endorphin, beta-LPH, corticosterone, prolactin and pituitary cyclic AMP responses.
The effects of restraint stress applied at different times of the day on levels of five stress-responsive plasma hormones (ACTH, beta-endorphin, beta-LPH, corticosterone and prolactin) and pituitary cyclic AMP levels were assessed. Different groups of rats were subjected to 15 min of restraint stress at 2-hour intervals over a 24-hour period. Rats were sacrificed immediately upon removal from their home cage (controls) or immediately following restraint (stressed). The time of day of stress exposure markedly affected the stress responses measured. Generally, responses to stress applied at the beginning of the dark cycle (18:00) were less than those seen following stress applied at the beginning of the light cycle (06:00). Stress at 06:00 increased levels of pituitary cyclic AMP 10-fold, while stress applied at 18:00 did not significantly increase pituitary cyclic AMP levels. In stressed rats, high correlations were seen among levels of hormones derived from the common precursor, proopiomelanocortin (ACTH, beta-endorphin, beta-LPH) and between these hormones and levels of pituitary cyclic AMP. These findings support the hypothesis that pituitary cyclic AMP is involved in the stress-induced release or synthesis of the pituitary hormones ACTH, beta-endorphin, and beta-LPH.


Atypical familial juvenile hyperuricemic nephropathy associated with a hepatocyte nuclear factor-1beta gene mutation.
Familial juvenile hyperuricemic nephropathy (FJHN) is a dominantly inherited condition characterized by young-onset hyperuricemia, gout, and renal disease. The etiologic genes are unknown, although a locus on chromosome 16 has been identified in some kindreds. Mutations in the gene encoding hepatocyte nuclear factor (HNF)-1beta have been associated with dominant inheritance of a variety of disorders of renal development, particularly renal cystic disease and early onset diabetes; hyperuricemia has been reported in some kindreds. To assess a possible role for the HNF-1beta gene in some FJHN kindreds we sequenced the HNF-1beta gene in subjects from three unrelated FJHN families with atypical features of renal cysts or abnormalities of renal development. We also compared serum urate levels in subjects with HNF-1beta mutations with populations of controls, type 2 diabetic subjects, and subjects with mild chronic renal failure without HNF-1beta mutations. A splice-site mutation in intron 2, designated IVS2+1G>T, showed complete co-segregation with FJHN in one family with diabetes. Serum urate levels were significantly higher in the HNF-1beta subjects compared with the normal control subjects (384 micromol/L vs. 264 micromol/L, P = 0.002) and the type 2 diabetic subjects (397 micromol/L vs. 271 micromol/L, P = 0.01). Comparison of serum urate levels in the HNF-1beta subjects with gender-matched subjects with renal impairment of other causes did not reach significance (402 micromol/L vs. 352 micromol/L, P = 0.2). Hyperuricemia and young-onset gout are consistent features of the phenotype associated with HNF-1beta mutations, but the mechanism is uncertain. Families with HNF-1beta mutations may fit diagnostic criteria for FJHN. Identification of HNF-1beta patients by recognizing the features of diabetes and disorders of renal development is important in resolving the genetic heterogeneity in FJHN.


Spontaneous regression of cancer or misdiagnosis? Four case reports.
Four case reports regarding possible spontaneous regression of cancer are given. This is a rare but previously documented occurrence, with the literature suggesting possible causal factors for cancer regression or an indefinite period of dormancy. These include genetic, hormonal, immunological and psychological factors. However, the literature makes no reference to potential misdiagnosis, either clinically or histologically. The effect of being diagnosed as having terminal cancer is profound and even after regression or resolution of the disease, there are inevitable psychological sequelae.


Transcription factor KLF11 integrates progesterone receptor signaling and proliferation in uterine leiomyoma cells.
Uterine leiomyoma is the most common tumor of the female genital tract and the leading cause of hysterectomy. Although progesterone stimulates the proliferation of uterine leiomyoma cells, the mechanism of progesterone action is not well understood. We used chromatin immunoprecipitation (ChIP)-cloning approach to identify progesterone receptor (PR) target genes in primary uterine leiomyoma smooth muscle cells. We identified 18 novel PR-binding sites, one of which was located 20.5 kb upstream of the transcriptional start site of the Krüppel-like transcription factor 11 (KLF11) gene. KLF11 mRNA levels were minimally downregulated by progesterone but robustly upregulated by the progesterone antagonist RU486. Luciferase reporter assays showed significant baseline and RU486-inducible promoter activity in the KLF11 basal promoter or distal PR-binding region, both of which contained multiple Sp1-binding sequences but lacked classic progesterone response elements. RU486 stimulated recruitment of Sp1, RNA polymerase II, PR, and the coactivators SRC-1 and SRC-2 to the distal region and basal promoter. siRNA knockdown of PR increased KLF11 expression, whereas knockdown of KLF11 increased leiomyoma cell proliferation and abolished the antiproliferative effect of RU486. In vivo, KLF11 expression was significantly lower in leiomyoma tissues compared with adjacent myometrial tissues. Taken together, using a ChIP-cloning approach, we uncovered KLF11 as an integrator of PR signaling and proliferation in uterine leiomyoma cells.


Use of radiologic modalities in coccidioidal meningitis.
The diagnostic utility of pentetate indium trisodium in 111 CSF studies, technetium Tc 99m brain scans, and computerized tomographic (CT) scans was evaluated in eight patients in whom coccidioidal meningitis developed following a dust storm in the Central Valley of California. The 111In flow studies and the CT scans demonstrated hydrocephalus in five patients with clinical findings suggesting this complication. Ventriculitis has not previously been diagnosed before death in patients with coccidioidal meningitis; however, it was demonstrated in two patients by the technetium Tc 99m brain scan. Basal meningitis, which is indicative of fungal infection, is also detectable on contrast-enhanced CT scan. The finding that communicating hydrocephalus occurs early in meningitis and interferes with CSF flow into infected basilar regions has important therapeutic implications in that antifungal agents injected into the lumbar subarachnoid space may not reach these regions.


Effect of the addition of basil essential oil on the degradation of palm olein during repeated deep frying of French fries.
The potential antioxidant power of basil essential oil under frying conditions was explored. Two concentrations (200 or 500 ppm) were added to palm olein (PO) to evaluate their effect on fat oxidation/degradation during repeated frying of French fries at 180 °C. A higher oxidative stability index was detected for PO with basil essential oil at 200 ppm. Both concentrations showed lower p-anisidine values than PO without basil essential oil after 5 d of frying. Addition at 500 ppm resulted in the lowest total polar compounds and free fatty acids contents. Thus, the addition of basil essential oil improved the performance of PO during repeated frying of French fries.


Olive baboons' (Papio anubis) response towards crowned eagles (Stephanoaetus coronatus) at Lake Manyara National Park.
In this paper we report on two encounters between olive baboons (Papio anubis) and crowned eagles (Stephanoaetus coronatus) at Lake Manyara National Park, northern Tanzania. During these encounters olive baboons responded by giving alarm calls and all infants and juveniles rushed down from trees seeking cover under bushes or close proximity to adult conspecifics. In one of the events, alarm calls from banded mongoose (Mungos mungo) and rock hyraxes (Procavia capensis) most likely triggered alarm calling of vervet monkeys (Chlorocebus pygerythrus) which in turn prompted baboons to respond with alarm calls as well. In both observations, adult male baboons took the lead in climbing trees, threatening the eagle (staring, yawning, ground slapping) and chasing it away. The reaction of the baboons suggests that crowned eagles pose a threat at least for juvenile baboons at Lake Manyara National Park.


Study on the acute toxicity of trichlorfon and its breakdown product dichlorvos to goldfish (Carassius auratus) based on 1H NMR metabonomics.
Trichlorfon, one of the most widely used organophosphate insecticides, is commonly employed in aquaculture and agriculture to combat parasitic infestations. However, its inherent instability leads to rapid decomposition into dichlorvos (DDVP), increasing its toxicity by eightfold. Therefore, the environmental effects of trichlorfon in real-world scenarios involve the combined effects of trichlorfon and its degradation product, DDVP. In this study, we systematically investigated the degradation of trichlorfon in tap water over time using HPLC and LC-MS/MS analysis. Subsequently, an experiment was conducted to assess the acute toxicity of trichlorfon and DDVP on goldfish (Carassius auratus), employing a 1H NMR-based metabolic approach in conjunction with serum biochemistry, histopathological inspection, and correlation network analysis. Exposure to trichlorfon and its degradation product DDVP leads to increased lipid peroxidation, reduced antioxidant activity, and severe hepatotoxicity and nephrotoxicity in goldfish. Based on the observed pathological changes and metabolite alterations, short-term exposure to trichlorfon significantly affected the liver and kidney functions of goldfish, while exerting minimal influence on the brain, potentially due to the presence of the blood-brain barrier. The changes in the metabolic profile indicated that trichlorfon and DDVP influenced several pathways, including oxidative stress, protein synthesis, energy metabolism, and nucleic acid metabolism. This study demonstrated the applicability and potential of 1H NMR-based metabonomics in pesticide environmental risk assessment, providing a feasible method for the comprehensive study of pesticide toxicity in water environments.


Molecular cytological characterization of two novel durum--Thinopyrum intermedium partial amphiploids with resistance to leaf rust, stem rust and Fusarium head blight.
Thinopyrum intermedium, a wild relative of wheat, is an excellent source of disease resistance. Two novel partial amphiploids, 08-47-50 and 08-53-55 (2n = 6x = 42), were developed from wide crosses between durum wheat and Th. intermedium. Meiotic analysis showed that pollen mother cells of the two partial amphiploids formed an average 20.49 bivalents for 08-47-50 and 20.67 bivalents for 08-53-55, indicating that they are basically cytologically stable. GISH analysis revealed that the two partial amphiploids carried different chromosome compositions. 08-47-50 had fourteen chromosomes from Th. intermedium and its alien chromosomes included six St-, four E(e) - and four E(e)-St translocated chromosomes, whereas 08-53-55 had four St- and ten E(e)-St translocated chromosomes. Fungal disease evaluation indicated that both partial amphiploids had a high level of resistance to FHB, leaf rust and stem rust race Ug99. These two novel partial amphiploids with multiple disease resistance could be used as a new source of multiple disease resistance in bread wheat and durum wheat breeding programs.


Do MOOCs encourage corporate social responsibility or are they simply a marketing opportunity?
This paper explores institutional drivers for developing MOOCs by juxtaposing them against the original drivers for generating MOOCs: to offer open access education. However, the original impetus for MOOC development may be shifting towards a business oriented model. Therefore, instead of contributing to corporate social responsibility and inclusivity agendas facilitating open access to education, MOOCs are akin to an institution's shop window allowing the pseudo 'purchaser' the opportunity to glimpse behind the scenes. Hence, we ask: are MOOCs merely a sophisticated form of window dressing, showing pseudo 'purchasers' what institutions want them to see enticing them to purchase more lucrative products? Notwithstanding the motivation for developing MOOCs participants must first access them. Therefore the paper examines what MOOCs actually offer participants who are likely to access them and concludes by examining how MOOCs can be developed to facilitate better completion rates and encourage wider participation from hard to access groups.


And then there were acyl coenzyme A:cholesterol acyl transferase inhibitors.
The reputation of acyl coenzyme A:cholesterol acyltransferase (ACAT) inhibitors has changed profoundly from promising new drugs for cardiovascular prevention to drugs without clinical benefits or possibly even with adverse effects. ACAT inhibitors decrease the intracellular conversion of free cholesterol into cholesteryl ester in a number of tissues, including intestine, liver and macrophages. In contrast to promising results in experimental animal models, all subsequent clinical studies in humans with ACAT inhibitors failed to show lipid profile changes as well as reductions in surrogate markers for coronary artery disease. In fact, there was even a tendency towards an increase in atheroma burden in the most recent and well executed clinical trials. In addition, the inhibition of this pivotal enzyme in cholesterol esterification may interfere with reverse cholesterol transport. In our opinion, the consistent negative findings in recent clinical trials have virtually eliminated the chances for this class of drugs to be introduced for cardiovascular prevention. Possible strategies focused on selective ACAT 2 inhibition or the combination of ACAT inhibitors with compounds that stimulate reverse cholesterol transport may prove to have clinical benefit. This will have to await further clinical research in humans, however, as, obviously, rodent models cannot provide reliable data as to the efficacy of this class of drugs in humans.


Theoretical simulation of temperature elevations in a joint wear simulator during rotations.
The objective of this study is to develop a theoretical model to simulate temperature fields in a joint simulator for various bearing conditions using finite element analyses. The frictional heat generation rate at the interface between a moving pin and a stationary base is modeled as a boundary heat source. Both the heat source and the pin are rotating on the base. We are able to conduct a theoretical study to show the feasibility of using the COMSOL software package to simulate heat transfer in a domain with moving components and a moving boundary source term. The finite element model for temperature changes agrees in general trends with experimental data. Heat conduction occurs primarily in the highly conductive base component, and high temperature elevation is confined to the vicinity of the interface in the pin. Thirty rotations of a polyethylene pin on a cobalt-chrome base for 60 s generate more than 2.26 °C in the temperature elevation from its initial temperature of 25 °C at the interface in a baseline model with a rotation frequency of 0.5 Hz. A higher heat generation rate is the direct result of a faster rotation frequency associated with intensity of exercise, and it results in doubling the temperature elevations when the frequency is increased by100%. Temperature elevations of more than 7.5 °C occur at the interface when the friction force is tripled from that in the baseline model. The theoretical modeling approach developed in this study can be used in the future to test different materials, different material compositions, and different heat generation rates at the interface under various body and environmental conditions.


Ultrasound in twin pregnancies.
To review the literature with respect to the use of diagnostic ultrasound in the management of twin pregnancies. To make recommendations for the best use of ultrasound in twin pregnancies. Reduction in perinatal mortality and morbidity and short- and long-term neonatal morbidity in twin pregnancies. Optimization of ultrasound use in twin pregnancies. Published literature was retrieved through searches of PubMed and the Cochrane Library in 2008 and 2009 using appropriate controlled vocabulary (e.g., twin, ultrasound, cervix, prematurity) and key words (e.g., acardiac, twin, reversed arterial perfusion, twin-to-twin transfusion syndrome, amniotic fluid). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date restrictions. Studies were restricted to those with available English or French abstracts or text. Searches were updated on a regular basis and incorporated into the guideline to September 2009. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. The evidence collected was reviewed by the Diagnostic Imaging Committee of the Society of Obstetricians and Gynaecologists of Canada, with input from members of the Maternal Fetal Medicine Committee and the Genetics Committee of the SOGC. The recommendations were made according to the guidelines developed by The Canadian Task Force on Preventive Health Care (Table 1). The benefit expected from this guideline is facilitation and optimization of the use of ultrasound in twin pregnancy. SUMMARY STATEMENTS: 1. There are insufficient data to make recommendations on repeat anatomical assessments in twin pregnancies. Therefore, a complete anatomical survey at each scan may not be needed following a complete and normal assessment. (III) 2. There are insufficient data to recommend a routine preterm labour surveillance protocol in terms of frequency, timing, and optimal cervical length thresholds. (II-2) 3. Singleton growth curves currently provide the best predictors of adverse outcome in twins and may be used for evaluating growth abnormalities. (III) 4. It is suggested that growth discordance be defined using either a difference (20 mm) in absolute measurement in abdominal circumference or a difference of 20% in ultrasound-derived estimated fetal weight. (II-2) 5. Although there is insufficient evidence to recommend a specific schedule for ultrasound assessment of twin gestation, most experts recommend serial ultrasound assessment every 2 to 3 weeks, starting at 16 weeks of gestation for monochorionic pregnancies and every 3 to 4 weeks, starting from the anatomy scan (18 to 22 weeks) for dichorionic pregnancies. (II-1) 6. Umbilical artery Doppler may be useful in the surveillance of twin gestations when there are complications involving the placental circulation or fetal hemodynamic physiology. (II-2) 7. Although many methods of evaluating the level of amniotic fluid in twins (deepest vertical pocket, single pocket, amniotic fluid index) have been described, there is not enough evidence to suggest that one method is more predictive than the others of adverse pregnancy outcome. (II-3) 8. Referral to an appropriate high-risk pregnancy centre is indicated when complications unique to twins are suspected on ultrasound. (II-2) These complications include: 1. Twin-to-twin transfusion syndrome 2. Monoamniotic twins gestation 3. Conjoined twins 4. Twin reversed arterial perfusion sequence 5. Single fetal death in the second or third trimester 6. Growth discordance in monochorionic twins. Recommendations 1. All patients who are suspected to have a twin pregnancy on first trimester physical examination or who are at risk (e.g., pregnancies resulting from assisted reproductive technologies) should have first trimester ultrasound performed. (II-2A) 2. Every attempt should be made to determine and report amnionicity and chorionicity when a twin pregnancy is identified. (II-2A) 3. Although the accuracy in confirmation of gestational age at the first and second trimester is comparable, dating should be done with first trimester ultrasound. (II-2A) 4. Beyond the first trimester, it is suggested that a combination of parameters rather than a single parameter should be used to confirm gestational age. (II-2C) 5. When twin pregnancy is the result of in vitro fertilization, accurate determination of gestational age should be made from the date of embryo transfer. (II-1A) 6. There is insufficient evidence to make a recommendation of which fetus (when discordant for size) to use to date a twin pregnancy. However, to avoid missing a situation of early intrauterine growth restriction in one twin, most experts agree that the clinician may consider dating pregnancy using the larger fetus. (III-C) 7. In twin pregnancies, aneuploidy screening using nuchal transluscency measurements should be offered. (II-2B) 8. Detailed ultrasound examination to screen for fetal anomalies should be offered, preferably between 18 and 22 weeks' gestation, in all twin pregnancies. (II-2B) 9. When ultrasound is used to screen for preterm birth in a twin gestation, endovaginal ultrasound measurement of the cervical length should be performed. (II-2A) 10. Increased fetal surveillance should be considered when there is either growth restriction diagnosed in one twin or significant growth discordance. (II-2A) 11. Umbilical artery Doppler should not be routinely offered in uncomplicated twin pregnancies. (I-E) 12. For defining oligohydramnios and polyhydramnios, the ultrasonographer should use the deepest vertical pocket in either sac: oligohydramnios when < 2 cm and polyhydramnios when > 8 cm. (II-2B).


Characterization of biofilm formed by human-derived nanoparticles.
Microbial biofilm matrix contains polysaccharides and proteins and can require extracellular nucleic acids for initial formation. Experiments were designed to identify infectious pathogens in human aneurysms and to characterize biofilm formed by calcified human arterial-derived nanoparticles. A total of 26 different microbial pathogens were isolated from 48 inflammatory aneurysms. Consistent amounts (0.49 McFarland units) of nanoparticles derived from similar tissue were seeded into 24-well plates and cultured for 21 days in the absence (control) or presence of RNase, tetracycline or gentamicin. Control biofilm developed within 14 days, as detected by concanavalin A and BacLight Green staining. The formation of biofilm in wells treated with RNase was not different from the control; however, gentamicin partially inhibited and tetracycline completely inhibited biofilm formation. Therefore, nanoparticle biofilm retains some characteristics of conventional bacterial biofilm and requires protein-calcium interactions, although extracellular RNA is not required. This model system may also allow study of nanosized vesicles derived from donor tissue, including any microbes present, and could provide a useful tool for in vitro investigation of nanoparticle biofilm formation.


The relationship between the diameter of chemically-functionalized multi-walled carbon nanotubes and their organ biodistribution profiles in vivo.
Carbon nanotubes (CNTs) exhibit unique properties which have led to their applications in the biomedical field as novel delivery systems for diagnosis and therapy purposes. We have previously reported that the degree of functionalization of CNTs is a key factor determining their biological behaviour. The present study broadens the spectrum by investigating the impact of the diameter of CNTs using two series of multi-walled CNTs (MWNTs) with distinct differences in their diameters. Both MWNTs were doubly functionalized by 1,3-dipolar cycloaddition and amidation reactions, allowing the appended functional groups to be further conjugated with radionuclide chelating moieties and antibodies or antibody fragments. All constructs possessed comparable degree of functionalization and were characterized by thermogravimetric analysis, transmission electron microscopy, gel electrophoresis and surface plasmon resonance. The MWNT conjugates were radio-labelled with indium-111, which thereby enabled in vivo single photon emission computed tomography/computed tomography (SPECT/CT) imaging and organ biodistribution study using γ-scintigraphy. The narrow MWNTs (average diameter: 9.2 nm) demonstrated enhanced tissue affinity including non-reticular endothelial tissues compared to the wider MWNTs (average diameter: 39.5 nm). The results indicate that the higher aspect ratio of narrow MWNTs may be beneficial for their future biological applications due to higher tissue accumulation.


Generation of iC3 at the interface between blood and gas.
Earlier studies have shown that C3 can be denatured when blood comes in contact with a polystyrene surface. This study was undertaken to see if similar denaturation of C3 occurs at the gas-plasma interface which is found in all kinds of oxygenator used during cardio-pulmonary operations. An in vitro system consisting of gas bubbling through human blood, serum or plasma was used. The generation of C3a, as an indicator of complement activation, and iC3 and iC3 fragments were monitored. Both C3a and iC3/iC3 fragments levels were increased during bubbling. In contrast to the C3a level, no reduction in iC3/iC3 fragments formation was seen in the presence of EDTA, indicating that it was independent of complement activation. The rate of iC3/iC3 fragments generation was unaffected by the composition of the gas (pure oxygen, pure nitrogen or air), suggesting that the denaturation of C3 indeed occurred at the serum-gas interface. C3 and iC3/iC3 fragments were isolated from bubbled EDTA-chelated serum by PEG precipitation and chromatography on FPLC, using a Mono S column and detected by two ELISAs, specific for native C3 and iC3/iC3 fragments. After 240 min approximately 20% of the total amount of C3 consisted of intact iC3 and it was confirmed that this population bound to human erythrocytes.


Prospective bidirectional relations between depression and metabolic health: 30-year follow-up from the National Heart, Lung, and Blood Institute (NHLBI) Coronary Artery Disease in Young Adults (CARDIA) study.
This study investigated prospective bidirectional relationships between depressive symptoms and metabolic syndrome (MetS) and the moderating effects of race, sex, and health behaviors in a diverse cohort followed for 30 years. Data were analyzed from the National Heart, Lung, and Blood Institute (NHLBI) Coronary Artery Disease in Young Adults (CARDIA) study, a 30-year prospective study of young adults (N = 5,113; Mage = 24.76 [SD = 3.63] at baseline; 45% male) who were tested every 5 years between 1985 and 2015. Measures included biological assessments of MetS components and self-reported depressive symptoms based on the Center for Epidemiologic Studies Depression (CESD) scale. Data analyses included bidirectional general estimating equations analyses of time-lagged associations between depressive symptoms and MetS. There was a consistent, bidirectional relationship between depressive symptoms and MetS over time. Individuals with more CESD depressive symptoms were more likely to develop MetS over time compared to those reporting fewer symptoms, Wald χ²(1) = 7.09, p < .008, and MetS was similarly predictive of CESD. MetS more consistently predicted CESD scores at each 5-year exam than CESD predicted MetS. Race and sex moderated these relationships, with White females, White individuals overall, and females overall demonstrating significant relationships between CESD depressive symptoms and MetS. Health behaviors were not related to associations between CESD and MetS. In a diverse young adult population prospectively followed into late middle age, MetS more consistently predicted depressive symptoms over time than depressive symptoms predicted MetS. The relation between MetS and depressive symptoms was moderated by race and sex, but not health behaviors. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Association of Lipoprotein(a) Levels With Myocardial Fibrosis in the Multi-Ethnic Study of Atherosclerosis.
Lipoprotein(a) (Lp[a]) has been identified as an emerging risk factor for adverse cardiovascular (CV) outcomes, including heart failure. However, the connections among Lp(a), myocardial fibrosis (interstitial and replacement), and cardiac remodeling as pathways to CV diseases remains unclear. This study investigated the relationship between Lp(a) levels and myocardial fibrosis by cardiac magnetic resonance (CMR) T1 mapping and late gadolinium enhancement, as well as cardiac remodeling by cine CMR, in the MESA (Multi-Ethnic Study of Atherosclerosis) cohort. The study included 2,040 participants with baseline Lp(a) measurements and T1 mapping for interstitial myocardial fibrosis (IMF) evaluation in 2010. Lp(a) was analyzed as a continuous variable (per log unit) and using clinical cutoff values of 30 and 50 mg/dL. Multivariate linear and logistic regression were used to assess the associations of Lp(a) with CMR measures of extracellular volume (ECV fraction [ECV%]), native T1 time, and myocardial scar, as well as parameters of cardiac remodeling, in 2,826 participants. Higher Lp(a) levels were associated with increased ECV% (per log-unit Lp[a]; β = 0.2%; P = 0.007) and native T1 time (per log-unit Lp[a]; β = 4%; P < 0.001). Similar relationships were observed between elevated Lp(a) levels and a higher risk of clinically significant IMF defined by prognostic thresholds per log-unit Lp(a) of ECV% (OR: 1.20; 95% CI: 1.04-1.43) and native T1 (OR: 1.2; 95% CI: 1.1-1.4) equal to 30% and 955 ms, respectively. Clinically used Lp(a) cutoffs (30 and 50 mg/dL) were associated with greater prevalence of myocardial scar (OR: 1.85; 95% CI: 1.1-3.2 and OR: 1.9; 95% CI: 1.1-3.4, respectively). Finally, higher Lp(a) levels were associated with left atrial enlargement and dysfunction. Elevated Lp(a) levels are linked to greater subclinical IMF, increased myocardial scar prevalence, and left atrial remodeling.


Naturally occurring mutations in the canine CFTR gene.
Naturally occurring cystic fibrosis (CF)-causing mutations in the CFTR gene have not been identified in any nonhuman animal species. Since domestic dogs are known to develop medical conditions associated with atypical CF in humans (e.g., bronchiectasis and pancreatitis), we hypothesized that dogs with these disorders likely have a higher expression rate of CFTR mutations than the at-large population. Temporal temperature-gradient gel electrophoresis (TTGE) was used to screen canine CFTR in 400 animals: 203 dogs diagnosed with pancreatitis, 23 dogs diagnosed with bronchiectasis, and 174 dogs admitted to clinics for any illness (at-large dogs). Twenty-eight dogs were identified with one of four CFTR missense mutations. P1281T and P1464H mutations occur in relatively unconserved residues. R1456W is analogous to the human R1453W mutation, which has approximately 20% of normal CFTR function and is associated with pancreatitis and panbronchiolitis. R812W disrupts a highly conserved protein kinase A recognition site within the regulatory domain. We conclude that naturally occurring CFTR mutations are relatively common in domestic dogs and can be detected with TTGE. No substantive differences in mutation frequency were observed between the at-large, pancreatitis, and bronchiectasis dogs.


New antibiotics: carbapenems, monobactams and quinolones.
New beta lactams and the quinolone class of antibiotics represent major improvements in the therapy of moderate to severe infections. These newer antibiotics have an extended spectrum of antimicrobial activity, excellent pharmacokinetic properties and low toxicity. The beta lactams include carbapenems, represented by imipenem-cilastatin, and monobactams, represented by aztreonam. Norfloxacin and ciprofloxacin are potent quinolones.


Ribcage kinematics during exercise justifies thoracoscopic versus postero-lateral thoracotomy lobectomy prompt recovery.
The video-assisted thoracic surgery (VATS) approach is encouraged over postero-lateral thoracotomy (PLT) for lobectomy in lung cancer. We compare the ribcage kinematics during exercise before and after both procedures, assuming that VATS, being minimally invasive, could better preserve ribcage expansion. Thirty-one patients undergoing lobectomy by means of VATS (n = 20) or PLT (n = 11) were compared presurgery, after chest drainage removal (T1) and 2 months post-surgery (T2) during quiet breathing and incremental exercise. Spirometry, chest pain, ventilatory pattern and expansions of the ribcage (ΔVRC) and abdomen were measured. Furthermore, the expansion of the ribcage and abdomen in the operated (ΔVRC-OP and ΔVAB-OP, respectively) and non-operated (ΔVRC-NO and ΔVAB-NO, respectively) sides was also considered. At T1, in both groups, spirometry worsened and chest pain increased, being higher after PLT. Tidal volume (VT) decreased after PLT because the ribcage expanded less due to reduced ΔVRC-OP. Contrary to this, in VATS, there were no changes in VT and ΔVRC, although ΔVRC-OP was lower, because ΔVRC-NO increased at high level of exercise. At T2, ΔVRC-OP was completely restored after VATS. At high levels of exercise following PLT, although patients still showed reduced ΔVRC and ΔVRC-OP, VT was restored owing to increased ΔVAB-NO. We demonstrate VATS to have a reduced impact on ribcage kinematics while PLT induced restriction more markedly during exercise and still present 2 months after surgery. Patients adopt 2 different compensatory mechanisms, by shifting the expansion toward the contralateral ribcage after VATS and toward the abdomen after PLT. Our study justifies thoracoscopic lobectomy prompt recovery. clinicaltrials.gov (NCT02910453).


Life meaning and feelings of ineffectiveness as transdiagnostic factors in eating disorder and comorbid internalizing symptomatology - A combined undirected and causal network approach.
The field of eating disorders is facing problems ranging from a suboptimal classification system to low long-term success rates of treatments. There is evidence supporting a transdiagnostic approach to explain the development and maintenance of eating disorders. Meaning in life has been proposed as a promising key transdiagnostic factor that could potentially not only bridge between the different eating disorder subtypes but also explain frequent co-occurrence with symptoms of comorbid psychopathology, such as anxiety and depression. The present study used self-report data from 501 participants to construct networks of eating disorder and comorbid internalizing symptomatology, including factors related to meaning in life, i.e., presence of life meaning, perceived ineffectiveness, and satisfaction with basic psychological needs. In an undirected network model, it was found that ineffectiveness is a central node, also bridging between eating disorder and other psychological symptoms. A directed network model displayed evidence for a causal effect of presence of life meaning both on the core symptomatology of eating disorders and depressive symptoms via ineffectiveness. These results support the notion of meaning in life and feelings of ineffectiveness as transdiagnostic factors within eating disorder symptomatology in the general population.


Head impact exposure measured in a single youth football team during practice drills.
OBJECTIVE This study evaluated the frequency, magnitude, and location of head impacts in practice drills within a youth football team to determine how head impact exposure varies among different types of drills. METHODS On-field head impact data were collected from athletes participating in a youth football team for a single season. Each athlete wore a helmet instrumented with a Head Impact Telemetry (HIT) System head acceleration measurement device during all preseason, regular season, and playoff practices. Video was recorded for all practices, and video analysis was performed to verify head impacts and assign each head impact to a specific drill. Eleven drills were identified: dummy/sled tackling, install, special teams, Oklahoma, one-on-one, open-field tackling, passing, position skill work, multiplayer tackle, scrimmage, and tackling drill stations. Generalized linear models were fitted to log-transformed data, and Wald tests were used to assess differences in head accelerations and impact rates. RESULTS A total of 2125 impacts were measured during 30 contact practices in 9 athletes (mean age 11.1 ± 0.6 years, mean mass 44.9 ± 4.1 kg). Open-field tackling had the highest median and 95th percentile linear accelerations (24.7 g and 97.8 g, respectively) and resulted in significantly higher mean head accelerations than several other drills. The multiplayer tackle drill resulted in the highest head impact frequency, with an average of 0.59 impacts per minute per athlete, but the lowest 95th percentile linear accelerations of all drills. The front of the head was the most common impact location for all drills except dummy/sled tackling. CONCLUSIONS Head impact exposure varies significantly in youth football practice drills, with several drills exposing athletes to high-magnitude and/or high-frequency head impacts. These data suggest that further study of practice drills is an important step in developing evidence-based recommendations for modifying or eliminating certain high-intensity drills to reduce head impact exposure and injury risk for all levels of play.


Transcription factor EGR-1 inhibits growth of hepatocellular carcinoma and esophageal carcinoma cell lines.
The transcription factor EGR-1 (early growth response gene-1) plays an important role in cell growth, differentiation and development. It has identified that EGR-1 has significant transformation suppression activity in some neoplasms, such as fibrosarcoma, breast carcinoma. This experiment was designed to investigate the role of egr-1 in the cancerous process of hepatocellular carcinoma (HCC) and esophageal carcinoma (EC), and then to appraise the effects of EGR-1 on the growth of these tumor cells. Firstly, the transcription and expression of egr-1 in HCC and EC, paracancerous tissues and their normal counterpart parts were detected by in situ hybridization and immunohistochemistry, with normal human breast and mouse brain tissues as positive controls. Egr-1 gene was then transfected into HCC (HHCC, SMMC7721) and EC (ECa109) cell lines in which no egr-1 transcription and expression were present. The cell growth speed, FCM cell cycle, plate clone formation and tumorigenicity in nude mice were observed and the controls were the cell lines transfected with vector only. Little or no egr-1 transcription and expression were detected in HCC, EC and normal liver tissues. The expression of egr-1 were found higher in hepatocellular paracancerous tissue (transcription level P=0.000; expression level P=0.143, probably because fewer in number of cases) and dysplastic tissue of esophageal cancer (transcription level P=0.000; expression level P=0.001). The growth rate of egr-1-transfected HHCC (HCC cell line) cells and ECa109 (EC cell line) cells was much slower than that of the controls. The proportion of S phase cell, clone formation and tumorigenicity were significantly lower than these of the controls' (decreased 45.5% in HHCC cells and 34.1% in ECa109 cells; 46.6% and 41.8%; 80.4% and 72.6% respectively). There were no obvious differences between SMMC7721 (HCC) egr-1-transfected cells and the controls with regard to the above items. The decreased expression of egr-1 might play a role in the dysregulation of normal growth in the cancerous process of HCC and EC. Egr-1 gene of transfected HHCC and ECa109 cells showed obvious suppression of the cell growth and malignant phenotypes, but no suppression in SMMC7721 (HCC cell line) cells.


Green Analysis: High Throughput Analysis of Emerging Pollutants in Plant Sap by Freeze-Thaw-Centrifugal Membrane Filtration Sample Preparation-HPLC-MS/MS Analysis.
Emerging and fugitive contaminants (EFCs) released to our biosphere have caused a legacy and continuing threat to human and ecological health, contaminating air, water, and soil. Polluted media are closely linked to food security through plants, especially agricultural crops. However, measuring EFCs in plant tissues remains difficult, and high-throughput screening is a greater challenge. A novel rapid freeze-thaw/centrifugation extraction followed by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) analysis was developed for high-throughput quantification of 11 EFCs with diverse chemical properties, including estriol, codeine, oxazepam, 2,4-dinitrotoluene, 1,3,5-trinitroperhydro-1,3,5-triazine, bisphenol A, triclosan, caffeine, carbamazepine, lincomycin, and DEET, in three representative crops, corn, tomato, and wheat. The internal aqueous solution, i.e., sap, is liberated via a freeze/thaw cycle, and separated from macromolecules utilizing molecular weight cutoff membrane centrifugal filtration. Detection limits ranged from 0.01 μg L-1 to 2.0 μg L-1. Recoveries of spiked analytes in three species ranged from 83.7% to 109%. Developed methods can rapidly screen EFCs in agriculture crops and can assess pollutant distribution at contaminated sites and gain insight on EFCs transport in plants to assess transmembrane migration in vascular organisms. The findings contribute significantly to environmental research, food security, and human health, as it assesses the first step of potential entry into the food chain, that being transmembrane migration and plant uptake, the primary barrier between polluted waters or soils and our food.


2-Acetylpyridine thiosemicarbazones and Mycobacterium leprae.
Four 2-acetylpyridine thiosemicarbazones were tested in mice against Mycobacterium leprae by the kinetic method and found to be nearly inactive in a dosage of 0.05% in the diet. At the same dosage, thiacetazone, as a positive control, exhibited its expected activity.


Haptic search is more efficient when the stimulus can be interpreted as consisting of fewer items.
In a typical haptic search task, separate items are presented to individual fingertips. The time to find a specific item generally increases with the number of items, but is it the number of items or the number of fingers that determines search time? To find out, we conducted haptic search experiments in which horizontal lines made of swell paper were presented to either two, four or six of the participants' fingertips. The task for the participant was to lift the finger under which they did not feel (part of) a line. In one of the conditions separate non-aligned lines were presented to the fingertips so that the number of items increased with the number of fingers used. In two other conditions the participants had to find an interruption in a single straight line under one of the fingertips. These conditions differed in the size of the gap. If only the number of items in the tactile display were important, search times would increase with the number of fingers in the first condition, but not depend on the number of fingers used in the other two conditions. In all conditions we found that the search time increased with the number of fingers used. However, this increase was smaller in the single line condition in which the gap was large enough for one finger to not make any contact with the line. Thus, the number of fingers involved determines the haptic search time, but search is more efficient when the stimulus can be interpreted as consisting of fewer items.


Proton Compared to X-Irradiation Induces Different Protein Profiles in Oral Cancer Cells and Their Derived Extracellular Vesicles.
Extracellular vesicles (EVs) are membrane-bound particles released from cells, and their cargo can alter the function of recipient cells. EVs from X-irradiated cells have been shown to play a likely role in non-targeted effects. However, EVs derived from proton irradiated cells have not yet been studied. We aimed to investigate the proteome of EVs and their cell of origin after proton or X-irradiation. The EVs were derived from a human oral squamous cell carcinoma (OSCC) cell line exposed to 0, 4, or 8 Gy from either protons or X-rays. The EVs and irradiated OSCC cells underwent liquid chromatography-mass spectrometry for protein identification. Interestingly, we found different protein profiles both in the EVs and in the OSCC cells after proton irradiation compared to X-irradiation. In the EVs, we found that protons cause a downregulation of proteins involved in cell growth and DNA damage response compared to X-rays. In the OSCC cells, proton and X-irradiation induced dissimilar cell death pathways and distinct DNA damage repair systems. These results are of potential importance for understanding how non-targeted effects in normal tissue can be limited and for future implementation of proton therapy in the clinic.


Association of Zika Virus Exposure in Utero with Ocular Phenotypes in a Group of Newborns in Puerto Rico Exposure with ocular phenotypes in newborns in Puerto Rico.
After the outbreak in January 2016, researchers in Brazil reported the first cases of ophthalmic abnormalities in infants with microcephaly and presumed Zika virus (ZIKV) intrauterine infection. Screening for ocular lesions in all newborns exposed to ZIKV prenatally has been emphasized because of a chorioretinal macular scar found in a number normocephalic patient exposed to ZIKV. A retrospective review of the medical records of infants born to mothers found to be ZIKV-positive during their pregnancies (January 2016-July 2017) was performed. We included all newborns and infants admitted to the NICU and/or receiving ambulatory care at the high-risk clinics at the University Pediatric Hospital, San Juan, Puerto Rico. The creation of this database was approved by the IRB of the University of Puerto Rico, Medical Sciences Campus. Records from 234 newborns born to Zika-positive mothers were identified. The ophthalmic evaluations of 95 patients were available. Sixty-three of them had normal findings (66%). Twelve of the 95 patients had microcephaly (12.6% of the cohort). Of the microcephalic group, half had normal ophthalmological findings. Of the normocephalic group (83/95), almost 31% had ocular findings: a small optic nerve in 3%, a double-ring sign in 10%, macular stippling in 8%, mottling in 4%, an oval optic nerve in 2%, a tilted nerve in 1%, and blunted foveal reflex in 1%. We report herein ZIKV associated ophthalmologic findings, similar to those published, in 34% of the infants with suspected/confirmed ZIKV fetal exposure. These data underline the importance of ocular examination in patients with suspected congenital Zika but without other findings on physical exam.


Consumption of fructose and high fructose corn syrup increase postprandial triglycerides, LDL-cholesterol, and apolipoprotein-B in young men and women.
The American Heart Association Nutrition Committee recommends women and men consume no more than 100 and 150 kcal of added sugar per day, respectively, whereas the Dietary Guidelines for Americans, 2010, suggests a maximal added sugar intake of 25% or less of total energy. To address this discrepancy, we compared the effects of consuming glucose, fructose, or high-fructose corn syrup (HFCS) at 25% of energy requirements (E) on risk factors for cardiovascular disease. PARTICIPANTS, DESIGN AND SETTING, AND INTERVENTION: Forty-eight adults (aged 18-40 yr; body mass index 18-35 kg/m(2)) resided at the Clinical Research Center for 3.5 d of baseline testing while consuming energy-balanced diets containing 55% E complex carbohydrate. For 12 outpatient days, they consumed usual ad libitum diets along with three servings per day of glucose, fructose, or HFCS-sweetened beverages (n = 16/group), which provided 25% E requirements. Subjects then consumed energy-balanced diets containing 25% E sugar-sweetened beverages/30% E complex carbohydrate during 3.5 d of inpatient intervention testing. Twenty-four-hour triglyceride area under the curve, fasting plasma low-density lipoprotein (LDL), and apolipoprotein B (apoB) concentrations were measured. Twenty-four-hour triglyceride area under the curve was increased compared with baseline during consumption of fructose (+4.7 ± 1.2 mmol/liter × 24 h, P = 0.0032) and HFCS (+1.8 ± 1.4 mmol/liter × 24 h, P = 0.035) but not glucose (-1.9 ± 0.9 mmol/liter × 24 h, P = 0.14). Fasting LDL and apoB concentrations were increased during consumption of fructose (LDL: +0.29 ± 0.082 mmol/liter, P = 0.0023; apoB: +0.093 ± 0.022 g/liter, P = 0.0005) and HFCS (LDL: +0.42 ± 0.11 mmol/liter, P < 0.0001; apoB: +0.12 ± 0.031 g/liter, P < 0.0001) but not glucose (LDL: +0.012 ± 0.071 mmol/liter, P = 0.86; apoB: +0.0097 ± 0.019 g/liter, P = 0.90). Consumption of HFCS-sweetened beverages for 2 wk at 25% E increased risk factors for cardiovascular disease comparably with fructose and more than glucose in young adults.


Pruritus in primary myelofibrosis: management options in the era of JAK inhibitors.
Primary myelofibrosis (PMF)-associated pruritus is often severe and requires treatment. Fifty-one patients with bone marrow-proven PMF with associated pruritus were identified from a primary cohort of patients with PMF (n = 566) seen at our institution. We conducted a retrospective review of the clinical characteristics, severity of pruritus, type of treatment, and response of these patients. Thirty-two out of 51 patients (63 %) reported severe PMF-associated pruritus and required a total of 108 treatment episodes, with complete response (CR), partial response (PR) and no response (NR) observed in 22, 23, and 55 % of episodes, respectively. The most common treatment categories included JAK inhibitors (n = 19), anti-depressants (n = 18), and antihistamines (n = 17). Highest CR rates were observed in patients treated with a JAK inhibitor (53 %) and immunomodulatory drugs (IMiDS (50 %)). Emerging targeted therapies may result in better symptom control and higher response rates in patients suffering from severe PMF-associated pruritus.


[Research methods in dentistry 2. Methods for determining the flow rate of saliva].
For patients with complaints of either hyposalivation or hypersalivation, or saliva with altered properties, the secretory flow rate can be determined in an easy way to study whether abnormalities are detectable. It is most simple to measure the flow rate of whole saliva. After collection of saliva the oral fluid can be analyzed on rheological properties, such as viscosity and elasticity and also on pH and its chemical composition. Oral fluid is the combined fluid in the oral cavity mainly composed of glandular salivas, and in addition crevicular fluid and serum exsudate. For collection of oral fluid it is of crucial importance to standardize the conditions. The diverse collection methods and their application for patient research with oral complaints are described.


Neuroprotection of reduced thyroid hormone with increased estrogen and progestogen in postpartum depression.
Background: Postpartum depression (PPD) is a common serious mental health problem. Recent studies have demonstrated that hormone therapy serves as a promising therapeutic approach in managing PPD. The present study aims at exploring the role of thyroid hormone (TH), estrogen and progestogen in patients with PPD.Methods: Initially, PPD patients were enrolled and a PPD mouse model was established. The serum levels of estradiol (E2), progesterone (P), triiodothyronine (T3), thyroxine (T4), free triiodothyronine (FT3), free thyroxine (FT4), and thyroid-stimulating hormone (TSH) were subsequently measured. Next, in order to identify the effects of TH, estrogen and progestogen on PPD progression, mice were administrated with E2, P, contraceptives (CA), Euthyrox and methimazole (MMI). Besides, the body weight, activities, basolateral amygdala (BLA) neuron cell structure and the related gene expression of mice were analyzed.Results: The PPD patients and the mice showed elevated serum levels of T3, T4, FT3 and FT4 along with diminished E2, P and TSH levels. In the mice administered with a combination of E2, P, and MMI, decreased TH and increased estrogen and progestogen were detected, which resulted in increased body weight, normal activities, and BLA neuron cell structure. Moreover, brain-derived neurotrophic factor (BDNF) and cAMP-responsive element-binding protein (CREB) were both up-regulated in PPD mice administrated with a combination of E2, P, and MMI, which was accompanied by decreased TH and elevated estrogen and progestogen.Conclusion: Taken together, reduced TH combined with enhanced estrogen and progestogen confers neuroprotection in PPD, highlighting a potential target in prevention and treatment of PPD.


Vesicular calcium channels as regulators of the exocytotic post-fusion phase.
Regulated secretion is a fundamental cellular process in many different types of eukaryotic cells with Ca2(+-)triggered exocytosis taking centre stage. Elevations of the cytoplasmic Ca(2+) concentration ([Ca(2+)](c)) regulate multiple steps from vesicle fusion with the plasma membrane to fusion pore dilation and subsequent retrieval of spent vesicles. The general view is that the rise in [Ca(2+)](c) initiates during the pre-fusion stage and either results from Ca(2+)-influx via Ca(2+) channels in the plasma membrane or from release from intracellular Ca(2+)-stores. However, there is increasing evidence that exocytosis of secretory vesicles triggers additional, localised Ca(2+) signals via insertion of vesicle-associated Ca(2+) channels into the cell surface. These restricted Ca(2+) signals following fusion are ideally suited for regulating the post-fusion fate of individual secretory vesicles. In invertebrates they have been shown to trigger compensatory endocytosis. Recently we have reported that exocytosis of lamellar bodies in alveolar type II epithelial cells results in a localized Ca(2+)-influx via vesicular P2X(4) receptors which regulates fusion pore expansion and vesicle content release. This finding expands the emerging picture that post-fusion Ca(2+) entry via vesicle-associated Ca(2+) channels plays a central role for regulated exocytosis.


Middle ratings rise regardless of grammatical construction: Testing syntactic variability in a repeated exposure paradigm.
People perceive sentences more favourably after hearing or reading them many times. A prominent approach in linguistic theory argues that these types of exposure effects (satiation effects) show direct evidence of a generative approach to linguistic knowledge: only some sentences improve under repeated exposure, and which sentences do improve can be predicted by a model of linguistic competence that yields natural syntactic classes. However, replications of the original findings have been inconsistent, and it remains unclear whether satiation effects can be reliably induced in an experimental setting at all. Here we report four findings regarding satiation effects in wh-questions across German and English. First, the effects pertain to zone of well-formedness rather than syntactic class: all intermediate ratings, including calibrated fillers, increase at the beginning of the experimental session regardless of syntactic construction. Second, though there is satiation, ratings asymptote below maximum acceptability. Third, these effects are consistent across judgments of superiority effects in English and German. Fourth, wh-questions appear to show similar profiles in English and German, despite these languages being traditionally considered to differ strongly in whether they show effects on movement: violations of the superiority condition can be modulated to a similar degree in both languages by manipulating subject-object initiality and animacy congruency of the wh-phrase. We improve on classic satiation methods by distinguishing between two crucial tests, namely whether exposure selectively targets certain grammatical constructions or whether there is a general repeated exposure effect. We conclude that exposure effects can be reliably induced in rating experiments but exposure does not appear to selectively target certain grammatical constructions. Instead, they appear to be a phenomenon of intermediate gradient judgments.


Role of interleukin-6 in regulation of immune responses to remodeling after myocardial infarction.
Myocardial remodeling following myocardial infarction (MI) is emerging as key causes of chronic infarct mortality. Interleukin-6 is a classic pro-inflammatory cytokine needed to mount an effective immune response. It seems that interleukin-6 acts as an important role in the dynamic and superbly orchestrated process of innate immunity after MI. Interleukin-6 timely suppresses of innate immune signals to prevent the catastrophic consequences of uncontrolled inflammation on cardiac geometry and function, and thus tunes myocardial remodeling. A comprehensive understanding of biological processes of interleukin-6 in innate immunity leading to inflammatory response and disease-related ventricular remodeling is helpful to find the solution of chronic heart failure. To accomplish this, we reviewed the articles of interleukin-6 regard to inflammation, innate immunity, and cardiac remodeling. This review focuses on the role of interleukin-6 that dominates cell-mediated immunity, especially on neutrophils, monocytes, macrophages, and fibroblasts. In addition, we will also briefly discuss other inflammatory cytokines involved in this process within the paper.


Water regulation in weanling hypodipsic dorsomedial hypothalamic-lesioned rats.
Weanling rats with dorsomedial hypothalamic nuclei lesions (DMN-L) are hypodipsic and hypophagic when compared to sham-operated rats. When tested for interdependence of food and water intake (WI) the DMN-L rats drank in the absence of food and ate in the absence of water. The data suggest DMN-L rats are not prandial drinkers. On testing for intracellular thirst (5.8 or 5.4% NaCl, 1 ml/100 g body wt), extracellular thirst [polyethylene glycol (PG), 25% wt/vol, 0.5 ml/35 g body wt], or a combination of both thirsts, the DMN-L rats responded as well or better than the control animals when the test data were expressed as a percentage of the rat's base-line WI. Both groups were more responsive to PG when tested in the light phase. When injected with angiotensin II (200 micrograms/100 g body wt) both groups responded similarly. Therefore, whereas the DMN-L rats were hypodipsic in comparison to controls, they respond as well or better than control animals when classical thirst testing procedures are utilized. It is suggested that DMN-L may have "reset" WI similarly to the previously proposed reset for body weight and food intake.


An overview of pathophysiology and treatment options of osteonecrosis of femoral head in sickle cell disease.
Osteonecrosis of the femoral head (ONFH) is the most prevalent musculoskeletal pathologic manifestation of sickle cell disease (SCD) resulting in an osteonecrotic event. This review aimed to summarize mechanisms involved in pathophysiology of ONFH and treatment options available in Saudi Arabia to treat SCD patients with complication of osteonecrotic event. The pathophysiology of ONFH include genetic and micro particles involvement. The progression of osteonecrosis involves reduced levels of bioactive compounds in peripheral blood mononuclear cells and elevated CD4+T circulating levels to stimulate pro-inflammatory cytokines contributing to inflammation at target site. Initial treatment approach is pharmacological agents use to mitigate risk. Further, bone morphogenetic protein stimulation initiate bone formation and treatment can be improved with the use of bone morphogenetic protein, total hip arthroplasty and cell therapies. This review provides baseline information for future studies to be carried out in Saudi Arabia to improve treatment options in SCD patients with ONFH.


[Effect of the extents of surgical resection in total laryngectomy on esophageal voice and speech rehabilitation].
The study of functional results of total laryngectomy cannot be separated from articulation of esophageal voice and speech. To achieve success of phoniatric rehabilitation in laringectomized patients, it is necessary to be well aware of pathological sequelae of the very operation, long-term adverse effect of oncological risk factors as well as postoperative anatomo-physiological changes. Anatomic results of total laryngectomy depend on the type of surgical intervention and probable radiotherapy. The extent of surgical procedure, primary dictated by oncological indications, has the essential effect to articulation of esophageal voice and speech. If possible for oncological reasons, hyoid bone should be particularly left intact. Extensive surgical interventions of hypopharynx and the base of the tongue during laryngectomy, neck dissection--especially the radical one, and subsequent radiotherapy, all of them significantly reduce the possibility to produce esophageal voice and speech. Total laryngectomy eliminates the creator of voice and vibrations, which are acoustically perceived as esophageal voice, proceeding at the level of pharyngoesophageal junction. For this reason, the quality of newly created vibrating narrowing is especially important.


Cleavage maps for human cytomegalovirus DNA strain AD169 for restriction endonucleases EcoRI, BglII, and HindIII.
We have used cloned EcoRI fragments of the human CMV (HCMV) genome, strain AD169, to prepare restriction endonuclease maps of the DNA. Individual 32P-labeled cloned fragments were hybridized to Southern blots of HCMV DNA cleaved to completion with the restriction endonucleases BglII and HindIII and cleaved partially with EcoRI. By determining which EcoRI fragments hybridized to the same band on a Southern blot, we were able to establish linkage groups. This information coupled with the data derived from digestion of the cloned fragments with the enzymes BglII and HindIII (Tamashiro et al., J. Virol. 42:547-557, 1982) provided the basis for the construction of detailed maps for the enzymes EcoRI, BglII, and HindIII. We also identified the EcoRI fragments derived from the termini of this genome and mapped them with respect to the BglII and HindIII terminal fragments. From our mapping data, we conclude that the genome of HCMV is approximately 240 kilobases in length and is divided into long (198 kilobases) and short (42 kilobases) regions. Both regions consist of a unique sequence bounded by inverted repeats (11 to 12 kilobases for the long region and 2 to 3 kilobases for the short region). Furthermore, the long and short regions can invert relative to each other.


Antifibrotic properties of hyaluronic acid crosslinked polyisocyanide hydrogels.
Fibrosis is characterized by the formation of fibrous connective tissue in response to primary injury. As a result, an affected organ may lose part of its functionality due to chronic, organ-specific tissue damage. Since fibrosis is a leading cause of death worldwide, targeting fibrotic diseases with antifibrotic hydrogels can be a lifesaving therapeutic strategy. This study developed a novel hybrid antifibrotic hydrogel by combining the synthetic polyisocyanide (PIC) with hyaluronic acid (HA). Gels of PIC are highly tailorable, thermosensitive, and strongly biomimetic in architecture and mechanical properties, whereas HA is known to promote non-fibrotic fetal wound healing and inhibits inflammatory signaling. The developed HA-PIC hybrids were biocompatible with physical properties comparable to those of the PIC gels. The antifibrotic nature of the gels was assessed by 3D cultures of human foreskin fibroblasts in the presence (or absence as control) of TGFβ1 that promotes differentiation into myofibroblasts, a critical step in fibrosis. Proliferation and macroscopic contraction assays and studies on the formation of stress fibers and characteristic fibrosis markers all indicate a strong antifibrotic nature of HA-PIC hydrogel. We showed that these effects originate from both the lightly crosslinked architecture and the presence of HA itself. The hybrid displaying both these effects shows the strongest antifibrotic nature and is a promising candidate for use as in vivo treatment for skin fibrosis.