Characterization of molecular mechanisms underlying mutations in dystrophic epidermolysis bullosa using site-directed mutagenesis.
Type VII collagen (C7) is a major component of anchoring fibrils, structures that mediate epidermal-dermal adherence. Mutations in gene COL7A1 encoding for C7 cause dystrophic epidermolysis bullosa (DEB), a genetic mechano-bullous disease. The biological consequences of specific COL7A1 mutations and the molecular mechanisms leading to DEB clinical phenotypes are unknown. In an attempt to establish genotype-phenotype relationships, we generated four individual substitution mutations that have been associated with recessive DEB, G2049E, R2063W, G2569R, and G2575R, and purified the recombinant mutant proteins. All mutant proteins were synthesized and secreted as a 290-kDa mutant C7 alpha chain at levels similar to wild type C7. The G2569R and G2575R glycine substitution mutations resulted in mutant C7 with increased sensitivity to protease degradation and decreased ability to form trimers. Limited proteolytic digestion of mutant G2049E and R2063W proteins yielded aberrant fragments and a triple helix with reduced stability. These two mutations next to the 39-amino acid helical interruption hinge region caused local destabilization of the triple-helix that exposed an additional highly sensitive proteolytic site within the region of the mutation. Our functional studies demonstrated that C7 is a potent pro-motility matrix for skin human keratinocyte migration and that this activity resides within the triple helical domain. Furthermore, G2049E and R2063W mutations reduced the ability of C7 to support fibroblast adhesion and keratinocyte migration. We conclude that known recessive DEB C7 mutations perturb critical functions of the C7 molecule and likely contribute to the clinical phenotypes of DEB patients.


Activin A Inhibits MPTP and LPS-Induced Increases in Inflammatory Cell Populations and Loss of Dopamine Neurons in the Mouse Midbrain In Vivo.
Parkinson's disease is a chronic neurodegenerative disease characterized by a significant loss of dopaminergic neurons within the substantia nigra pars compacta region and a subsequent loss of dopamine within the striatum. A promising avenue of research has been the administration of growth factors to promote the survival of remaining midbrain neurons, although the mechanism by which they provide neuroprotection is not understood. Activin A, a member of the transforming growth factor β superfamily, has been shown to be a potent anti-inflammatory following acute brain injury and has been demonstrated to play a role in the neuroprotection of midbrain neurons against MPP+-induced degeneration in vitro. We hypothesized that activin A may offer similar anti-inflammatory and neuroprotective effects in in vivo mouse models of Parkinson's disease. We found that activin A significantly attenuated the inflammatory response induced by both MPTP and intranigral administration of lipopolysaccharide in C57BL/6 mice. We found that administration of activin A promoted survival of dopaminergic and total neuron populations in the pars compacta region both 8 days and 8 weeks after MPTP-induced degeneration. Surprisingly, no corresponding protection of striatal dopamine levels was found. Furthermore, activin A failed to protect against loss of striatal dopamine transporter expression in the striatum, suggesting the neuroprotective action of activin A may be localized to the substantia nigra. Together, these results provide the first evidence that activin A exerts potent neuroprotection and anti-inflammatory effects in the MPTP and lipopolysaccharide mouse models of Parkinson's disease.


The Cognition and Flow Study: A Feasibility Randomized Controlled Trial of the Effects of Cognitive Training on Cerebral Blood Flow.
Cognitive training (CT) has demonstrated benefits for healthy older adults (HG) and mild cognitive impairment (MCI), but the effects on vascular function are unknown. This is a feasibility trial investigating the effects of CT on cerebral blood flow velocity (CBFv). Twenty HG, 24 with Alzheimer's disease (AD), and 12 with MCI were randomized to 12 weeks of multi-domain CT or control. Outcomes included: cognition (Addenbrooke's Cognitive Examination III), mood, quality of life (QoL), physical, and neurovascular function (transcranial Doppler ultrasonography measured task activation of CBFv responses). Data are presented as mean difference (MD) and 95% confidence interval (CI). 47 participants completed the trial. There were three dropouts from the training arm in the AD group, and one in the HG group. The intervention was acceptable and feasible to the majority of participants with a high completion rate (89%). The dropout rate was higher among participants with dementia. Few changes were identified on secondary analyses, but QoL was significantly improved in HG post-training (MD: 4.83 [95% CI: 1.13, 8.54]). CBFv response rate was not significantly different in HG (MD: 1.84 [95% CI: -4.81, 1.12]), but a significant increase was seen in the patient group (MD: 1.79 [95% CI: 0.005, 3.58]), requiring sample sizes of 56 and 84 participants respectively for a fully-powered trial. A 12-week CT program was acceptable and feasible in HG, AD, and MCI. CT may be associated with alterations in vascular physiology which require further investigation in an appropriately powered randomized controlled trial.


Role of the JNK signaling pathway in downregulation of connexin43 by TNF-α in human corneal fibroblasts.
Proinflammatory cytokines such as tumor necrosis factor (TNF)-α contribute to corneal inflammation. Corneal stromal fibroblasts are connected to each other via gap junctions. We have now examined the role of mitogen-activated protein kinase (MAPK) signaling pathways in TNF-α-induced downregulation of the gap junction protein connexin43 (Cx43) in human corneal fibroblasts. Cultured human corneal fibroblasts were exposed to TNF-α in the absence or presence of inhibitors of MAPK signaling pathways. Expression of Cx43 was evaluated by immunofluorescence and immunoblot analyses. Gap-junctional intercellular communication (GJIC) was measured with a dye-coupling assay. TNF-α reduced the abundance of Cx43 in human corneal fibroblasts (as revealed by immunoblot analysis) as well as induced the loss of specific staining for this protein (as revealed by immunofluorescence analysis). These effects of TNF-α were attenuated by an inhibitor of c-Jun NH₂-terminal kinase (JNK inhibitor II) but not by inhibitors of signaling by extracellular signal-regulated kinase (PD98059) or by p38 MAPK (SB203580). JNK inhibitor II also attenuated the inhibitory effect of TNF-α on GJIC. The inhibitory effects of TNF-α on Cx43 expression and GJIC in human corneal fibroblasts are mediated, at least in part, by the JNK signaling pathway, which therefore likely plays a role in corneal inflammation.


[Chronic sports injuries of the knee joint].
Chronic sports injuries of the knee joint are common and mainly caused by repetitive (micro) trauma and exertion. Chronic insertion tendinopathies and avulsion fractures and symptoms related to entrapment, friction and impingement can be pathophysiologically distinguished in athletes. In this review, we depict the characteristic magnetic resonance imaging (MRI) findings of the most commonly occurring pathologies.


New insights into the role of the maize ameiotic1 locus.
In maize the am1-1 mutant allele results in both the male and female meiocytes undergoing mitosis in place of the meiotic divisions. A second mutant allele am1-praI enables both the male and female meiocytes to proceed to the early zygotene stage of meiotic prophase I before being blocked. Here we report on three new alleles that allow all male meiocytes to undergo mitosis but in female meiocytes approximately one quarter (am1-2), one half (am1-485), or all (am1-489) of them are blocked at an abnormal interphase stage. Previous analysis has shown that am1-praI is dominant to am1-1 in male meiocytes. Cytological analysis of heteroallelic combinations in female meiocytes now indicates a dominance relationship of am1-praI > am1-1 > am1-2/am1-485 > am1-489. The evidence provided by the female phenotypes of the new mutant alleles suggest that, whereas the normal am1 allele is required for the meiocytes to proceed through meiosis, a partially functional allele may be required for their diversion into a mitotic division. The partial or complete blockage of mitosis in female meiocytes carrying the new am1 alleles rules out the possibility that the mitotic division of mutant meiocytes reflects a simple default pathway for cells that cannot initiate meiosis. This locus may have a dual function.


Influence of Gamma Irradiation on Electric Cables Models: Study of Additive Effects by Mid-Infrared Spectroscopy.
Cables, especially their insulation and jacket materials made of polymers, are vulnerable to ageing degradation during normal operation. However, they must remain functional for the entire life of a nuclear power plant, or even in the event of an accident for cables with a safety requirement. This study focuses on models of crosslinked polyethylene (XLPE)-based insulation of cables and deals with the structure modification and the behavior of XLPE for nuclear applications due to the effect of additives. Various additives are added to the polymer formulation to evaluate their impact on ageing. The samples are irradiated at room temperature by several gamma doses, up to 374 kGy, with two dose rates (40 Gy/h and 300 Gy/h) and compared with a non-irradiated sample used as reference. To understand the impact of gamma irradiation on the materials, the principal component analysis (PCA) method is applied on spectra recorded through attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy. The results highlight the effects of ageing depending on the dose rate and on the formulation of the materials, with the identification of different degradation products. A curve resolution study compares the effects of different additives on polymer oxidation and shows that the low dose rate leads to a higher degradation than the high dose rate.


Prospective randomized double-blind trial of neurolytic coeliac plexus block in patients with pancreatic cancer.
In a randomized double-blind study the efficacy of neurolytic coeliac plexus block (NCPB) was compared with pharmacological therapy in the treatment of pain from pancreatic cancer. Twenty-four patients were divided into two groups: 12 patients underwent NCPB (group 1) and 12 were treated with pharmacological therapy (group 2). Immediate and long-term efficacy, mean analgesic consumption, mortality and morbidity were evaluated at follow-up. Statistical analysis was performed with the unpaired t test, Mann-Whitney U test and Fisher's exact test. Immediately after the block, patients in group 1 reported significant pain relief compared with those in group 2 (P < 0.05), but long-term results did not differ between the groups. Mean analgesic consumption was lower in group 1. There were no deaths. Complications related to NCPB were transient diarrhoea and hypotension (P not significant between groups). Drug-related adverse effects were constipation (five of 12 patients in group 1 versus 12 of 12 in group 2), nausea and/or vomiting (four of 12 patients in group 1 versus 12 of 12 in group 2) (P < 0.05), one gastric ulcer and one gluteal abscess in group 2. NCPB was associated with a reduction in analgesic drug administration and drug-related adverse effects, representing an effective tool in the treatment of pancreatic cancer pain.


In vitro studies on human cervical epithelium, benign and neoplastic.
The early neoplastic lesions of the cervix offer an excellent model to study the neoplastic process in the human; In vitro studies indicate that these lesions are intermediate between normal epithelium and invasive carcinoma in many aspects. More recent studies show that the in vitro cells retain many of the characteristics of their in vivo counterparts. The techniques are available for short-term culture of normal and CIN cells, but no cell lines have been established. Spontaneous transformation of normal cervical epithelial cells in culture has been rare, but planned transformation with chemical carcinogens and HSV-2 has not been successful. Even though much preliminary work has been done, the establishment of a cell line from the human cervix and methods for transforming normal cell in vitro are needed. Studies toward these objectives are continuing in this laboratory.


Association Between NR4A2 Gene Polymorphism and Depressive Symptoms and Antidepressant Effect.
Although the pathogenesis of major depressive disorder (MDD) is still unclear, studies have shown that the dopaminergic system of depressed patients is defective, and that NR4A2 is an important transcription factor affecting the development and maintenance of dopaminergic neurons. As such, NR4A2 levels affected by NR4A2 single nucleotide polymorphisms (SNPs) may be associated with MDD. This study examined whether NR4A2 SNPs are associated with depressive symptoms and antidepressant efficacy. A total of 441 patients with first-episode depression were enrolled in this study. We analysed three SNPs of NR4A2, using the 17-item Hamilton Depression Rating Scale (HAM-D) and its four factors to obtain scores at baseline and at the end of 6 weeks. UNPHASED software was employed for quantitative character analysis, and SPSS software was adopted for antidepressant efficacy analysis. Patients with rs12803-A exhibited higher scores of retardation symptoms. Patients with the rs834834-C allele and rs834834-CC genotype had higher retardation symptom scores. Patients with rs3769340 exhibited greater antidepressant efficacy. NR4A2 gene polymorphisms are associated with retardation symptoms, somatic symptoms (gastro-intestinal), anxiety-based somatic symptoms, insight, and weight loss in patients with MDD. Additionally, rs3769340 may be a predictor of antidepressant efficacy in patients with major depressive disorder.


Time-weighted vs. conventional quantification of 24-h average systolic and diastolic ambulatory blood pressures.
Conventional calculation of mean 24-h ambulatory blood pressure (BP), SBP and DBP based on the average of all BP readings disregards the fact that a larger number of measurements is usually scheduled during the daytime than at night, an imbalance possibly leading to an overestimation of 24-h average BP. The aim of our study was to quantify this possible bias and to explore its determinants. Four hundred and fifty untreated individuals were subdivided into three groups (150 individuals each) with three different ambulatory blood pressure measurement schedules for day/night: group I, four (day)/two (night) readings/h; group II, four (day)/three (night) readings/h; and group III, with BP readings every 30 min throughout 24 h. Hourly and 24-h averages were computed. The conventional 24-h averages of all SBP and DBP values were compared with the averages of hourly SBP and DBP mean values (time-weighted quantification). The difference between 24-h conventional and 24-h time-weighted BP was computed in each group and related to the degree of nocturnal BP dip and to the ratio between the number of readings of day and night. In the three groups, 24-h conventional and 24-h time-weighted BP values were highly correlated (r > 0.99), 24-h conventional SBP and DBP being significantly higher (P < 0.01) than the corresponding 24-h time-weighted values in groups I and II but not in group III (Bland-Altman analysis). The bias magnitude was related to the day/night ratio in number of readings and to nocturnal BP dip in groups I and II (P < 0.01) but not in group III. The higher number of readings/h during daytime leads to an overestimation of conventional 24-h average BP, particularly in individuals with preserved nocturnal BP dipping. This can be avoided either by scheduling the same number of readings/h throughout 24 h or by performing a time-weighted quantification of 24-h BP. The clinical implications of these different approaches deserve further investigation.


Clonal analysis via barcoding reveals diverse growth and differentiation of transplanted mouse and human mammary stem cells.
Cellular barcoding offers a powerful approach to characterize the growth and differentiation activity of large numbers of cotransplanted stem cells. Here, we describe a lentiviral genomic-barcoding and analysis strategy and its use to compare the clonal outputs of transplants of purified mouse and human basal mammary epithelial cells. We found that both sources of transplanted cells produced many bilineage mammary epithelial clones in primary recipients, although primary clones containing only one detectable mammary lineage were also common. Interestingly, regardless of the species of origin, many clones evident in secondary recipients were not detected in the primary hosts, and others that were changed from appearing luminal-restricted to appearing bilineage. This barcoding methodology has thus revealed conservation between mice and humans of a previously unknown diversity in the growth and differentiation activities of their basal mammary epithelial cells stimulated to grow in transplanted hosts.


On intermittency in sheared granular systems.
We consider a system of granular particles, modeled by two dimensional frictional soft elastic disks, that is exposed to externally applied time-dependent shear stress in a planar Couette geometry. We concentrate on the external forcing that produces intermittent dynamics of stick-slip type. In this regime, the top wall remains almost at rest until the applied stress becomes sufficiently large, and then it slips. We focus on the evolution of the system as it approaches a slip event. Our main finding is that there are two distinct groups of measures describing system behavior before a slip event. The first group consists of global measures defined as system-wide averages at a fixed time. Typical examples of measures in this group are averages of the normal or tangent forces acting between the particles, system size and number of contacts between the particles. These measures do not seem to be sensitive to an approaching slip event. On average, they tend to increase linearly with the force pulling the spring. The second group consists of the time-dependent measures that quantify the evolution of the system on a micro (particle) or mesoscale. Measures in this group first quantify the temporal differences between two states and only then aggregate them to a single number. For example, Wasserstein distance quantitatively measures the changes of the force network as it evolves in time while the number of broken contacts quantifies the evolution of the contact network. The behavior of the measures in the second group changes dramatically before a slip event starts. They increase rapidly as a slip event approaches, indicating a significant increase in fluctuations of the system before a slip event is triggered.


What works in coping with HIV? A meta-analysis with implications for coping with serious illness.
Knowledge of effective ways of coping with HIV is critical to help individuals with HIV maintain the best possible psychological and physical well-being. The purpose of the present article is to determine, through meta-analysis, the strength of the evidence regarding 2 questions: (a) Which types of coping are related to psychological and physical well-being among people with HIV? and (b) Do contextual (pre?post introduction of highly active antiretroviral therapies [HAART]; time since diagnosis), measurement (HIV-related event vs. generic prompts for coping measurement), or individual (gender) variables affect the extent to which coping is related to physical and psychological well-being? The authors' analysis demonstrates that Direct Action and Positive Reappraisal were consistently associated with better outcomes in people coping with HIV across affective, health behavior, and physical health categories. In contrast, disengagement forms of coping, such as Behavioral Disengagement and Use of Alcohol or Drugs to Cope, were consistently associated with poorer outcomes. The findings also indicate that in some cases, coping effectiveness was dependent on contextual factors, including time since diagnosis and the advent of HAART.


Esophageal candidiasis. Managing an increasingly prevalent infection.
Esophageal candidiasis is an opportunistic infection that is being recognized increasingly often in certain patients, including those who have a neoplastic disease, are undergoing protracted antibiotic therapy, or hae acquired immunodeficiency syndrome (AIDS). Impaired cell-mediated immunity may predispose the patient to esophageal mucosal colonization, whereas chemotherapy-induced granulocytopenia may predispose to disseminated candidiasis. Esophageal candidiasis should be suspected in susceptible patients with complaints of substernal odynophagia or dysphagia. The diagnosis is confirmed by endoscopically directed mucosal biopsy. Esophagitis from other causes (eg. herpes simplex virus, cytomegalovirus, or bacterial infection) may develop concomitantly with esophageal candidiasis. Treatment is determined by the clinical and immune status of the patient. Amphotericin B (Fungizone) is administered to immunocompromised patients at risk for disseminated or deeply invasive candidiasis and is indicated in nongranulocytopenic patients whose symptoms prevent reliable administration of oral antifungal agents. Ketoconazole (Nizoral) may be administered to clinically stable nongranulocytopenic patients with esophageal candidiasis limited to the mucosa. Patients with AIDS and a history of esophageal candidiasis usually benefit from long-term suppression with an oral antifungal agent.


Radiosensitivity of small-cell lung cancer xenografts compared with activity of c-myc, N-myc, L-myc, c-raf-1 and K-ras proto-oncogenes.
Oncogenes of the myc family c-raf-1 and K-ras have been reported to modulate radiosensitivity. We examined the possible relationship between in vivo radiosensitivity to single-dose irradiation with 3-10 Gy, and activity of these proto-oncogenes in 2 sets of small-cell lung cancer (SCLC) xenografts, the CPH and the GLC series. CPH-54A and CPH-54B are in vitro-derived subclones of a SCLC cell line, while the GLC tumours were established as cell lines from a patient during longitudinal follow-up. Both tumours were later transferred into nude mice. CPH-54A was more sensitive to single-dose irradiation than CPH-54B, while, with respect to the 3 GLC tumours examined, GLC-16 was most sensitive, followed by GLC-14 and GLC-19. The CPH tumours expressed similar amounts of c-myc and c-raf-1 mRNA, and neither expressed N-myc or L-myc. GLC-14 expressed N-myc and c-raf-1 mRNA but no c-myc. GLC-16 and GLC-19 expressed identical amounts of c-raf-1 and high levels of c-myc mRNA, but neither expressed N-myc or L-myc. None of the tumours was mutated at codon 12 or K-ras. Our results show that SCLC xenografts with different radiosensitivity may express identical amounts of some of the proto-oncogenes reported to modulate radiosensitivity. Thus, factors other than activation of the examined proto-oncogenes must be involved in causing the differences in radiosensitivity found in the SCLC xenografts. Possible long-term effects of irradiation on proto-oncogene expression was examined in xenografts of GLC-16, following regrowth after single-dose irradiation. No long-term difference in expression of c-raf-1 or c-myc mRNA was detected between control tumours and tumours irradiated with 5 or 10 Gy.


Graft fixation in cruciate ligament reconstruction.
Cruciate ligament reconstruction has progressed dramatically in the last 20 years. Anatomic placement of ligament substitutes has fostered rehabilitation efforts that stress immediate and full range of motion, immediate weightbearing, neuromuscular strength and coordination, and early return to athletic competition (3 months). This has placed extreme importance on secure graft fixation at the time of ligament reconstruction. Current ligament substitutes require a bony or soft tissue component to be fixed within a bone tunnel or on the periosteum at a distance from the normal ligament attachment site. Fixation devices have progressed from metal to biodegradable and from far to near-normal native ligament attachment sites. Ideally, the biomechanical properties of the entire graft construct would approach those of the native ligament and facilitate biologic incorporation of the graft. Fixation should be done at the normal anatomic attachment site of the native ligament (aperture fixation) and, over time, allow the biologic return of the histologic transition zone from ligament to fibrocartilage, to calcified fibrocartilage, to bone. The purpose of this article is to review current fixation devices and techniques in cruciate ligament surgery.


Comparison of Ketamine- Versus Nonketamine-Based Sedation on Delirium and Coma in the Intensive Care Unit.
At this time, there are no studies evaluating the risk of delirium or coma with the use of ketamine in mechanically ventilated adult patients, compared to conventional therapies such as propofol or dexmedetomidine. The objective of this study was to evaluate the number of days alive without delirium or coma in mechanically ventilated patients in the intensive care unit receiving analgosedation infusions with ketamine versus without ketamine. This was a retrospective cohort study conducted at an academic medical center in the United States. Consecutive mechanically ventilated adult patients between November 2015 and April 2017 were evaluated. Patients were divided into 2 groups based on the sedative regimen used: ketamine based or nonketamine based. The primary outcome was the number of days alive without delirium or coma. The secondary outcomes were incidence of delirium, incidence of coma, and ventilator-free days at day 28. The study cohort consisted of 79 patients, of which 39 received ketamine- and 40 received nonketamine-based sedation. The number of days alive without delirium or coma was 6 days (interquartile range [IQR]: 2-9 days) with ketamine and 4 days (IQR: 3-7 days) with nonketamine (P = .351). Delirium occurred in 29 (74%) of 39 patients with ketamine and 34 (85%) of 40 patients with nonketamine (P = .274). Coma occurred in 16 (41%) of 39 patients with ketamine and 6 (15%) of 40 patients with nonketamine (P = .013). The median ventilator-free days were 13 days (IQR: 0-23 days) with ketamine and 21 days (0-25 days) with nonketamine (P = .229). Sustained ketamine-based sedation in mechanically ventilated patients may be associated with a higher rate of observed coma but similar delirium- and coma-free days compared nonketamine-based regimens.


Learning Similar Actions by Reinforcement or Sensory-Prediction Errors Rely on Distinct Physiological Mechanisms.
Humans can acquire knowledge of new motor behavior via different forms of learning. The two forms most commonly studied have been the development of internal models based on sensory-prediction errors (error-based learning) and success-based feedback (reinforcement learning). Human behavioral studies suggest these are distinct learning processes, though the neurophysiological mechanisms that are involved have not been characterized. Here, we evaluated physiological markers from the cerebellum and the primary motor cortex (M1) using noninvasive brain stimulations while healthy participants trained finger-reaching tasks. We manipulated the extent to which subjects rely on error-based or reinforcement by providing either vector or binary feedback about task performance. Our results demonstrated a double dissociation where learning the task mainly via error-based mechanisms leads to cerebellar plasticity modifications but not long-term potentiation (LTP)-like plasticity changes in M1; while learning a similar action via reinforcement mechanisms elicited M1 LTP-like plasticity but not cerebellar plasticity changes. Our findings indicate that learning complex motor behavior is mediated by the interplay of different forms of learning, weighing distinct neural mechanisms in M1 and the cerebellum. Our study provides insights for designing effective interventions to enhance human motor learning.


Radiation shielding design for a hot repair facility.
A new repair and decontamination area is being built to support operations at the demonstration fuel cycle facility for the Integral Fast Reactor program at Argonne National Laboratory's site at the Idaho National Engineering Laboratory. Provisions are made for remote, glove wall, and contact maintenance on equipment removed from hot cells where spent fuel will be electrochemically processed and recycled to the Experimental Breeder Reactor-II. The source for the shielding design is contamination from a mix of fission and activation products present on items removed from the hot cells. The repair facility also serves as a transfer path for radioactive waste produced by processing operations. Radiation shields are designed to limit dose rates to no more than 5 microSv h-1 (0.5 mrem h-1) in normally occupied areas. Point kernel calculations with buildup factors have been used to design the shielding and to position radiation monitors within the area.


The rich get richer, the poor get even: Perceived socioeconomic position influences micro-social distributions of wealth.
Economic inequality has a robust negative effect on a range of important societal outcomes, including health, wellbeing, and education. Yet, it remains insufficiently understood why, how, and by whom unequal systems tend to be perpetuated. In two studies we examine whether psychological mindsets adopted by the wealthy and the poor in their micro-social transactions act to perpetuate or challenge inequality. We hypothesized that occupying a wealthier socioeconomic position promotes the pursuit of self-interest and contributes to inequality maintenance; poorer socioeconomic position, on the other hand, should promote the pursuit of fairness and equality restoration. In Study 1, participants completed an ultimatum game as proposers after being primed to believe they are wealthier or poorer, offering money to either poor or wealthy responders. As expected, the wealthy pursued their self-interest and the net effect of this behavior contributes to the maintenance of inequality. Conversely, the poor pursued fairness and the net effect of this behavior challenges inequality. In Study 2, participants were responders deciding whether to accept or reject unfair distributions. Compared to the wealthier, the poorer challenged inequality by rejecting unequal offers. The links between micro-social processes and macro-societal inequality are discussed.


[Genetic counseling and prognosis of the development of complications in patients with syndromes of hereditary polyposis of the colon].
Physical examinations, genealogic analysis and genetic consulting were done for 14 probands and their family members with most frequent syndromes of hereditary polyposis of large bowel during 4 generations. These syndromes include familial adenomatous polyposis, Gardner syndrome and Peutz-Jeghers syndrome. 46 relatives of probands with the same pathology were affected (from 1 to 9 of affected relatives within families). We have found the congenital abnormalities in 13 (28.2%) patients with syndromes of hereditary polyposis. 29 (63%) patients have malignant neoplasia. In families with high risk for hereditary polyposis we recommend regular medical and genetic consultation for early prophylaxis of illness and for genetic risk of possible complications in their members.


Feedback regulation of the spc operon in Escherichia coli: translational coupling and mRNA processing.
The spc operon of Escherichia coli encodes 10 ribosomal proteins in the order L14, L24, L5, S14, S8, L6, L18, S5, L30, and L15. This operon is feedback regulated by S8, which binds near the translation start site of L5 and inhibits translation of L5 directly and that of the distal genes indirectly. We constructed plasmids carrying a major portion of the spc operon genes under lac transcriptional control. The plasmids carried a point mutation in the S8 target site which abolished regulation and resulted in overproduction of plasmid-encoded ribosomal proteins upon induction. We showed that alteration of the AUG start codon of L5 to UAG decreased the synthesis rates of plasmid-encoded distal proteins, as well as L5, by approximately 20-fold, with a much smaller (if any) effect on mRNA synthesis rates, indicating coupling of the distal cistrons' translation with the translation of L5. This conclusion was also supported by experiments in which S8 was overproduced in trans. In this case, there was a threefold reduction in the synthesis rates of chromosome-encoded L5 and the distal spc operon proteins, but no decrease in the mRNA synthesis rate. These observations also suggest that transcription from ribosomal protein promoters may be special, perhaps able to overcome transcription termination signals. We also analyzed the state of ribosomal protein mRNA after overproduction of S8 in these experiments and found that repression of ribosomal protein synthesis was accompanied by stimulation of processing (and degradation) of spc operon mRNA. The possible role of mRNA degradation in tightening the regulation is discussed.


Diurnal expression of Dnmt3b mRNA in mouse liver is regulated by feeding and hepatic clockwork.
DNA methyltransferase 3B (DNMT3B) is critically involved in de novo DNA methylation and genomic stability, while the regulatory mechanism in liver is largely unknown. We previously reported that diurnal variation occurs in the mRNA expression of Dnmt3b in adult mouse liver. The aim of this study was to determine the mechanism underlying the diurnal expression pattern. The highest level and the lowest level of Dnmt3b mRNA expression were confirmed to occur at dawn and in the afternoon, respectively, and the expression pattern of Dnmt3b closely coincided with that of Bmal1. Since the diurnal pattern of Dnmt3b mRNA expression developed at weaning and scheduled feeding to separate the feeding cycle from the light/dark cycle led to a phase-shift in the expression, it could be assumed that feeding plays a critical role as an entrainment signal. In liver-specific Bmal1 knockout (L-Bmal1 KO) mice, L-Bmal1 deficiency resulted in significantly higher levels of Dnmt3b at all measured time points, and the time when the expression was the lowest in wild-type mice was shifted to earlier. Investigation of global DNA methylation revealed a temporal decrease of 5-methyl-cytosine percentage in the genome of wild-type mice in late afternoon. By contrast, no such decrease in 5-methyl-cytosine percentage was detected in L-Bmal1 KO mice, suggesting that altered Dnmt3b expression affects the DNA methylation state. Taken together, the results suggest that the feeding and hepatic clockwork generated by the clock genes, including Bmal1, regulate the diurnal variation in Dnmt3b mRNA expression and the consequent dynamic changes in global DNA methylation.


Molecular catalysis science: Perspective on unifying the fields of catalysis.
Colloidal chemistry is used to control the size, shape, morphology, and composition of metal nanoparticles. Model catalysts as such are applied to catalytic transformations in the three types of catalysts: heterogeneous, homogeneous, and enzymatic. Real-time dynamics of oxidation state, coordination, and bonding of nanoparticle catalysts are put under the microscope using surface techniques such as sum-frequency generation vibrational spectroscopy and ambient pressure X-ray photoelectron spectroscopy under catalytically relevant conditions. It was demonstrated that catalytic behavior and trends are strongly tied to oxidation state, the coordination number and crystallographic orientation of metal sites, and bonding and orientation of surface adsorbates. It was also found that catalytic performance can be tuned by carefully designing and fabricating catalysts from the bottom up. Homogeneous and heterogeneous catalysts, and likely enzymes, behave similarly at the molecular level. Unifying the fields of catalysis is the key to achieving the goal of 100% selectivity in catalysis.


Let there be light: zebrafish neurobiology and the optogenetic revolution.
Optogenetics has revolutionized the toolbox arsenal that neuroscientists now possess to investigate neuronal circuit function in intact and living animals. With a combination of light emitting 'sensors' and light activated 'actuators', we can monitor and control neuronal activity with minimal perturbation and unprecedented spatiotemporal resolution. Zebrafish neuronal circuits represent an ideal system to apply an optogenetic based analysis owing to its transparency, relatively small size and amenability to genetic manipulation. In this review, we describe some of the most recent advances in the development and applications of optogenetic sensors (i.e., genetically encoded calcium indicators and voltage sensors) and actuators (i.e., light activated ion channels and ion pumps). We focus mostly on the tools that have already been successfully applied in zebrafish and on those that show the greatest potential for the future. We also describe crucial technical aspects to implement optogenetics in zebrafish including strategies to drive a high level of transgene expression in defined neuronal populations, and recent optical advances that allow the precise spatiotemporal control of sample illumination.


Clofarabine and Treosulfan as Conditioning for Matched Related and Unrelated Hematopoietic Stem Cell Transplantation: Results from the Clo3o Phase II Trial.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be curative for patients with hematologic malignancies. The ideal conditioning regimen before allo-HSCT has not been established. We conducted a Phase II study to evaluate the tolerability and efficacy of clofarabine and treosulfan as conditioning regimen before allo-HSCT. The primary objective was to evaluate the cumulative incidence of nonrelapse mortality (NRM) on day +100. Forty-four patients (36 with acute myelogenous leukemia, 5 with acute lymphoblastic leukemia, 3 with myelodysplastic syndromes) were enrolled. The median patient age was 47 years, and the median duration of follow-up was 27 months. The conditioning regimen was based on clofarabine 40 mg/m2 (days -6 to -2) and treosulfan 14 g/m2 (days -6 to -4). Allogeneic hematopoietic stem cells were derived from a sibling (n = 22) or a well-matched unrelated donor (n = 22). Graft-versus-host disease (GVHD) prophylaxis consisted of antithymocyte globulin, rituximab, cyclosporine, and a short-course of methotrexate. The regimen allowed for rapid engraftment and a 100-day NRM of 18%, due mainly to bacterial infections. The incidences of grade II-IV acute GVHD and chronic GVHD were 16% and 19%, respectively. The rates of overall survival (OS), progression-free survival, and relapse at 2 years were 51%, 31%, and 50%, respectively. Significantly different outcomes were observed between patients with low-intermediate and patients with high-very high Disease Risk Index (DRI) scores (1-year OS, 78% and 24%, respectively). Our findings show that the use of treosulfan and clofarabine as a conditioning regimen for allo-HSCT is feasible, with a 78% 1-year OS in patients with a low-intermediate DRI score. However, 1-year NRM was 18%, and despite the intensified conditioning regimen, relapse incidence remains a major issue in patients with poor prognostic risk factors.


A longitudinal study of the relationship between empowerment and burnout among registered and assistant nurses.
The relation between empowerment and burnout was investigated using a two-wave and two-variable panel model. A questionnaire was completed on two occasions, one year apart, by 1,356 nurses. The paths in the model were estimated using regression analyses and the following results were obtained: (a) empowerment is a stable state; (b) higher levels of empowerment are related to lower levels of burnout, when empowerment and burnout are studied at the same point in time; (c) higher prior levels of empowerment can be associated with higher later levels of burnout, when empowerment and burnout are studied at different points in time; (d) for assistant nurses, but not for registered nurses, prior higher levels of burnout resulted in lower later levels of empowerment, indicating a reciprocal relation between the two concepts. The results imply that what is a protective factor from a cross-sectional perspective may be a risk factor from a longitudinal perspective.


Nedd4 family interacting protein 1 (Ndfip1) is required for ubiquitination and nuclear trafficking of BRCA1-associated ATM activator 1 (BRAT1) during the DNA damage response.
During injury, cells are vulnerable to apoptosis from a variety of stress conditions including DNA damage causing double-stranded breaks. Without repair, these breaks lead to aberrations in DNA replication and transcription, leading to apoptosis. A major response to DNA damage is provided by the protein kinase ATM (ataxia telangiectasia mutated) that is capable of commanding a plethora of signaling networks for DNA repair, cell cycle arrest, and even apoptosis. A key element in the DNA damage response is the mobilization of activating proteins into the cell nucleus to repair damaged DNA. BRAT1 is one of these proteins, and it functions as an activator of ATM by maintaining its phosphorylated status while also keeping other phosphatases at bay. However, it is unknown how BRAT1 is trafficked into the cell nucleus to maintain ATM phosphorylation. Here we demonstrate that Ndfip1-mediated ubiquitination of BRAT1 leads to BRAT1 trafficking into the cell nucleus. Without Ndfip1, BRAT1 failed to translocate to the nucleus. Under genotoxic stress, cells showed increased expression of both Ndfip1 and phosphorylated ATM. Following brain injury, neurons show increased expression of Ndfip1 and nuclear translocation of BRAT1. These results point to Ndfip1 as a sensor protein during cell injury and Ndfip1 up-regulation as a cue for BRAT1 ubiquitination by Nedd4 E3 ligases, followed by nuclear translocation of BRAT1.


The Cellular Behavior and SEM Evaluation of ProRoot and Root MTAs on Fibroblast L929.
Mineral trioxide aggregate is being widely used for root end filling, pulp capping, perforation repair, and other endodontic procedures. Recently, a material similar to ProRoot mineral trioxide aggregate (PMTA) was developed in Iran named Root mineral trioxide aggregate (RMTA) with the claim of having the exact result of original MTA. The purpose of this study was to compare the amount of cell cytotoxicity of RMTA with PMTA at three different time periods using scanning electron microscopy (SEM) as well as the amount of cell viability at the above mentioned period. Three culture plates in each group were packed with a homogenous layer of PMTA and RMTA prepared according to manufacturers instruction. A plate of media without any material was used as control in each group. The material set for 72 h in CO2 incubator and 2x10 of fibroblast L929 was added to each plate. SEM evaluation with x800-3000 magnification and cell viability counting using trepan blue counting method were done after 48, 72, and 168 hours. There was no significant difference between cell viability of PMTA and RMTA, although the amount of cells remained viable in PMTA group was higher at 48 and 168 hours while for RMTA, it was higher after 72 hours. The SEM evaluation showed that PMTA compared with RMTA has less porosity, but relatively similar amount of cell coverage was detected for both materials after 168 hours. ProRoot and Root MTAs showed comparative biocompatibility while evaluated in vitro. The results suggest that RMTA can be used as an alternative for PMTA in clinical trials.


High prevalence of multiple drug resistant enteric bacteria: Evidence from a teaching hospital in Southwest Nigeria.
The development and evolution of antimicrobial resistance (AMR) in pathogens has been reported to be one of the major issues confronting the global health community. The aim of this study was to examine the period prevalence of antibiotic resistance, as well as the trends and patterns in sensitivity profile of enteric bacteria isolated from urine samples of patients with UTIs in a teaching Hospital in south west Nigeria. Urine samples were collected from 77 patients with UTIs from February 2017 to October 2018. Standard laboratory methods were used for urine sample culture and bacterial identification. The Kirby-Bauer disk diffusion method was used to evaluate antimicrobial sensitivity. Predominant enteric bacteria isolates were Escherichia coli (24, 39.3%), Salmonella species (12, 19.7%), Klebsiella species (4, 6.6%), Providencia species (6, 9.8%), Proteus species (8, 13.1%), Serratia species (2, 3.3%), Yersinia species (1, 1.6%) and Morganella species (4, 6.6%). A large proportion (90.2%) of isolates obtained were multi-drug resistant. High resistance in amoxycillin-clavulanate (98%), cefuroxime (92%), erythromycin (90%) and ceftazidime (84%) were recorded. These results emphasize the importance of continuous screening and surveillance programmes for detection of AMR in enteric bacteria of public health importance.


The Pan-University Network for Global Health: framework for collaboration and review of global health needs.
In the current United Nations efforts to plan for post 2015-Millennium Development Goals, global partnership to address non-communicable diseases (NCDs) has become a critical goal to effectively respond to the complex global challenges of which inequity in health remains a persistent challenge. Building capacity in terms of well-equipped local researchers and service providers is a key to bridging the inequity in global health. Launched by Penn State University in 2014, the Pan University Network for Global Health responds to this need by bridging researchers at more than 10 universities across the globe. In this paper we outline our framework for international and interdisciplinary collaboration, as well the rationale for our research areas, including a review of these two themes. After its initial meeting, the network has established two central thematic priorities: 1) urbanization and health and 2) the intersection of infectious diseases and NCDs. The urban population in the global south will nearly double in 25 years (approx. 2 billion today to over 3.5 billion by 2040). Urban population growth will have a direct impact on global health, and this growth will be burdened with uneven development and the persistence of urban spatial inequality, including health disparities. The NCD burden, which includes conditions such as hypertension, stroke, and diabetes, is outstripping infectious disease in countries in the global south that are considered to be disproportionately burdened by infectious diseases. Addressing these two priorities demands an interdisciplinary and multi-institutional model to stimulate innovation and synergy that will influence the overall framing of research questions as well as the integration and coordination of research.


Ab initio and direct dynamics study of the reaction of Cl atoms with HOCO.
The reaction of Cl with HOCO has been examined using the coupled-cluster method to locate and optimize the critical points on the ground-state potential energy surface. The results show that the reaction produces the HCl and CO(2) products as experimentally observed. The reaction occurs via a HOC(O)Cl intermediate with an estimated heat of formation of -97.8+/-2.0 kcal/mol. A direct ab initio dynamics method has been used to provide insight into the reaction mechanisms and to determine the thermal rate coefficients in the temperature range of 200-600 K. At room temperature, the thermal rate coefficient is predicted to be 3.0x10(-11) cm(3) molecule(-1) s(-1) with an activation energy of -0.2 kcal/mol. Two kinds of reactive trajectories are found. One kind proceeds through short-lived HOC(O)Cl complexes with a lifetime of 310 fs while the other kind occurs via longer-lived intermediates with a lifetime of 1.9 ps.


Differential effects of type I IFN and IFN-gamma on the binding of tumor necrosis factor to receptors in two human cell lines.
The effect of IFN-alpha and IFN-beta on the expression of cell surface receptors for tumor necrosis factor (TNF) was examined in two human cell lines. In HeLa cells, IFN-alpha and IFN-beta increased 125I-TNF binding, whereas in HT-29 cells these two IFN either slightly decreased or had no effect on 125I-TNF binding. In contrast, IFN-gamma increased 125I-TNF binding in both cell lines. Both IFN-alpha and IFN-beta exerted an antagonistic effect on IFN-gamma-induced stimulation of TNF receptor expression in HT-29 cells, but did not inhibit TNF receptor induction by IFN-gamma in HeLa cells. IFN-gamma and, to a lesser extent, IFN-beta were synergistic with TNF in producing cytotoxic/cytostatic activity in HT-29 cells. Despite the inhibitory effect of IFN-beta on the IFN-gamma-induced stimulation of TNF receptor expression, IFN-beta did not inhibit the synergistic enhancement of TNF cytotoxicity by IFN-gamma in HT-29 cells. The dissociation between the effects of IFN-beta on TNF receptor expression and on the cytotoxic activity of TNF in HT-29 cells suggests that TNF receptor modulation is not a major mechanism of synergism between IFN and TNF.


Effect of replacing conventional feeds with tropical agricultural by-products on the growth performance, nutrient digestibility and ruminal microbiota of water buffaloes.
This study investigated the effect of replacing corn grain, soybean meal and wheat bran with tropical agricultural by-products, such as palm kernel cake (PKC), cassava residue and dried distiller's grain with solubles (DDGS), on the dry matter intake (DMI), growth performance, apparent nutrient digestibility, ruminal short-chain fatty acids (SCFA) and ruminal microbial communities of water buffaloes. Thirty healthy 15-month-old crossbred water buffaloes with a similar initial body weight of 353.1 ± 23.7 kg were randomly allocated into three dietary experimental groups, and they were fed with same forage but three different concentrates for 50 days fattening. The dietary treatments were as following: typical concentrate (TC, 65% corn + 15% wheat bran + 15% soybean meal), partial replacement concentrate Ⅰ (PRC I, 50% corn + 22.5% corn gluten + 22.5% PKC) and partial replacement concentrate Ⅱ (PRC II, 50% corn + 22.5% cassava residue + 22.5% DDGS). The results showed that the average daily gain of the PRC II group was the highest, and the DMI, acid detergent fibre digestibility and neutral detergent fibre digestibility value of the three groups were different and in the following order: PRC II group > TC group > PRC I group. The crude protein digestibility of PRC II was higher than that of the TC and PRC I groups (p < .05). The ruminal concentrations of total SCFA, acetate, propionate and butyrate of TC group were higher than the other two groups (p < .05). The PRC I group had the highest Bacteroidetes-to-Firmicutes ratio (B/F) and relative abundance of the genus Prevotella, while the PRC II group had the lowest B/F and relative abundance of Prevotella. In conclusion, using PKC and corn gluten to completely replace common feed ingredients in the buffalo concentrate ration decreased, while using cassava residue and DDGS increased animal growth performance, mainly due to the different combination influenced nutrient digestibility and ruminal microbial community composition was shifted.


[Bilateral necrobiotic xanthogranuloma of the eyelids with associated paraproteinemia: Case report and review of literature].
Necrobiotic xanthogranuloma is a rare disorder which predominantly affects the periorbital region and is frequently associated with paraproteinemia and lymphoproliferative diseases. A 49-year old woman presented with bilateral, yellowish, subcutaneous lesions involving all four eyelids. These lesions have developed over the last year. Additionally, similar skin lesions developed on the trunk and the lower extremities. Two years ago, the patient had a bilateral episcleritis. An incisional biopsy was taken form the lesion. In addition, we reviewed the literature concerning similar cases. Histologic examination revealed a granulomatous process consisting of histiocytes, foamy cells, multinucleated giant cells (touton- and foreign body-type) and associated with necrobiotic collagen and cholesterol clefts. General examination revealed the presence of a paraproteinemia of the IgG-typ associated with a hyperlipidemia. The patient was treated with a low dose chemotherapy which resulted in improvement of signs and symptoms. We could identify in the literature 75 similar cases. The mean age of those patients was 53 years. The clinical and histologic findings in our patient were typical for a necrobiotic xanthogranuloma with associated paraproteinemia. The most favorable treatment response has been reported with low doses of systemic administered chemotherapeutic agents in combination with radiation therapy; however, the mortality due to underlying diseases is high.


Proximal femoral changes related to obesity: an analysis of slipped capital femoral epiphysis pathoanatomy.
Recent research has revealed the importance of the femoral epiphyseal tubercle and cupping height in the stability of the physis and its association with capital femoral slippage. To better understand the connection between the pathogenesis of slipped capital femoral epiphysis and obesity, we performed a retrospective analysis of proximal femur and acetabular anatomies using computed tomography (CT) scans in the hips of normal weight and obese pediatric patients. We measured morphologic characteristics of the proximal femur and acetabulum in developing hips of 31 obese adolescent patients and age-matched and sex-matched control group using pelvic CT scans. Measurements included physeal diameter, tubercle height, width, and volume, cupping height, acetabular rotation and inclination, and metaphyseal bone density. Measurements were performed on true coronal and sagittal views through the center of the epiphysis using previously described and validated techniques. Statistical analysis was performed to compare the measurements between obese and nonobese adolescents. The epiphyseal tubercle volume and average cupping size were similar between the two groups. Acetabular inclination and metaphyseal bone density were significantly different between the cohorts. Metaphyseal bone density was lower among obese patients. Obesity does not appear to cause morphologic changes to the capital femoral physis, though it is associated with a decreased metaphyseal bone mineral density which could indicate physeal instability. This could suggest increased metabolic activity in the metaphyseal bone in obese adolescents. Therefore, metabolic factors associated with obesity, rather than anatomical changes, may be responsible for physeal instability seen in obese adolescents.


[Percutaneous endourologic treatment of obstructive ureteral lithiasis in renal transplant].
Donor graft lithiasis is a unusual complication of renal transplantation, however, it is associated to a high morbidity. This pathology is due to several causes such us: metabolic factors, infectious disease, drugs, foreign bodies or transferred in the donor graft. The objective of the treatment is to remove the lithiasis without damaging the renal unit. We report the successful percutaneous anterograde treatment of an ureteral obstructive hard calculi, in renal allograft.


Validation of the Center for Medicare and Medicaid Services algorithm for eligibility for dialysis.
The Center for Medicaid and Medicare Services (CMS) has recently revised their end-stage renal disease (ESRD) Medical Evidence Report, Medicare Entitlement, and Patient Registration CMS 2728 Form. The modified algorithm calls for the use of formulae to estimate glomerular filtration rate (GFR). The new criterion is defined as estimated GFR of less than 20 ml/min per 1.73 m(2). GFR is either estimated by Schwartz formula (C(SCH)) in children or Modification of Diet in Renal Disease formula (C(MDRD)) in adults. The purpose of this communication is to test the validity of the new CMS GFR algorithm in detecting children who need renal replacement therapy. We evaluated two cohorts of children. Group I included single-center data from 626 (125)I-iothalamate clearance studies (C(IO)) that were compared with the simultaneous estimation of GFR by C(SCH). Group II included data on 659 children from the patient incidence registry obtained from the ESRD Network of Texas between February 1996 and October 2003. In group I there were 76 children (76 C(IO)) with C(SCH) less than 20 ml/min per 1.73 m(2) of whom 50 (67%) had C(IO) less than 15 ml/min per 1.73 m(2). Of children with C(IO) less than 15 ml/min per 1.73 m(2), 62% had a C(SCH) less than 20 ml/min per 1.73 m(2). The ability of C(SCH) greater than 20 ml/min per 1.73 m(2 ) to predict C(IO) greater than 15 ml/min per 1.73 m(2 )(negative predictive value) is 0.95. The number of children who were started on dialysis in Texas within the study period was 659 (group II). The mean C(SCH)+/-SD was 10.8+/-7.7 ml/min per 1.73 m(2). Of the patients who were initiated on dialysis, 94% had C(SCH) less than 20 ml/min per 1.73 m(2). The results were sustained when race, gender, age range, and type of diagnosis were considered. The new CMS algorithm provides a good negative predictive estimate of GFR less than 15 ml/min per 1.73 m(2).


Ultrastructure of the synovial membrane.
The normal synovial membrane as seen by electron microscopy is bordered by one to three layers of lining cells that include some with phagocytic function, others rich in endoplasmic reticulum for protein synthesis and additional cells with mixed properties. Lining cells with prominent Golgi apparatus probably produce the synovial hyaluronic acid. The synovial matrix contains collagen and mucopolysaccharide. It offers little barrier to diffusion of most materials. Superficial capillaries and venules are fenestrated and presumably allow rapid exchange of fluid and electrolytes. Deeper venules have thick endothelium that can separate at intracellular junctions and can phagocytize circulating particles. Other identified synovial structures are fibrocytes, macrophages, lymphatics, mast cells, non-myelinated nerves and fat.


Family Functioning and School Success in At-Risk, Inner-City Adolescents.
The relation between family functioning and school success was examined in 211 at risk, African American, inner city adolescents attending middle school (grades 6-8). Interviews with adolescents and caregivers yielded data on family cohesion, parental monitoring, and school engagement; school records provided data on grade point average. Results showed that both family cohesion and parental monitoring predicted school engagement, but neither family characteristic predicted GPA. Important gender differences also emerged. For boys only, the relation between family cohesion and school engagement was stronger when parental monitoring was high. For girls only, the effects of cohesion and monitoring on school engagement were additive: girls with both high family cohesion and high parental monitoring were most likely to be engaged in school. These findings extend the research base on family protective factors for antisocial behavior in young adolescents. Implications for future examination of family process characteristics in high-risk adolescents are discussed.


Young People's Experiences and Perceptions of YouTuber-Produced Health Content: Implications for Health Promotion.
The growing diversity and uptake of social media has increased the sources of health information available to young people. YouTube is one of the most popular social media platforms for young people in the United Kingdom, and YouTubers are the most important influencers on the platform producing diverse health content. They are increasingly recognized by popular media and public health organizations as a potentially influential source of health information for young people. This study aimed to qualitatively explore young people's experiences and perceptions of YouTuber health content. Focus groups (November 2017 to January 2018) with 85 young people (13-18 years) were recruited from schools in a single county in North West England. The findings suggest young people's engagement with YouTuber health content is dependent on how they encounter it, YouTubers' motivations for producing it, and the perceived relatability, sincerity, and generalization present in this content. The study confirms YouTuber health content was one of the many sources of health information used by young people and was most frequently encountered during young people's routine viewing. Collaboration between public health organizations and YouTubers could be promising in communicating health messages to young people already engaged with these YouTubers, as part of wider campaigns or interventions. These messages could be particularly effective if they focused on experiences and norms rather than advice, remained consistent with YouTubers' existing health content, incorporate clear indicators of accuracy into their narrative, and state their intention to benefit young people.


The Case for Animal Privacy in the Design of Technologically Supported Environments.
Privacy is an essential consideration when designing interactive systems for humans. However, at a time when interactive technologies are increasingly targeted at non-human animals and deployed within multispecies contexts, the question arises as to whether we should extend privacy considerations to other animals. To address this question, we revisited early scholarly work on privacy, which examines privacy dynamics in non-human animals (henceforth "animals"). Then, we analysed animal behaviour literature describing privacy-related behaviours in different species. We found that animals use a variety of separation and information management mechanisms, whose function is to secure their own and their assets' safety, as well as negotiate social interactions. In light of our findings, we question tacit assumptions and ordinary practises that involve human technology and that affect animal privacy. Finally, we draw implications for the design of interactive systems informed by animals' privacy requirements and, more broadly, for the development of privacy-aware multispecies interaction design.


Feasibility of self-reflection as a tool to balance clinical reasoning strategies.
Clinicians are believed to use two predominant reasoning strategies: system 1 based pattern recognition, and system 2 based analytical reasoning. Balancing these cognitive reasoning strategies is widely believed to reduce diagnostic error. However, clinicians approach different problems with different reasoning strategies. This study explores whether clinicians have insight into their problem specific reasoning strategy, and whether this insight can be used to balance their reasoning and reduce diagnostic error. In Experiment 1, six medical residents interpreted eight ECGs and self-reported their predominant reasoning strategy using a four point scale (4S). Self-assessed reasoning strategy correlated with objective assessment by two clinical experts using a post hoc talk-aloud protocol (ρ = 0.69, p < 0.0001). Reporting an analytic strategy was also associated with 40% longer interpretation times (p = 0.01). In Experiment 2, twenty-four residents were asked to reinterpret eight ECGs with instructions customized to their 4S. Half of the ECGs were reinterpreted with instructions to use the opposite reasoning strategy to that reported, and half with instructions to use the same reasoning strategy. ECG reinterpretation scores did not differ with potentiating compared to balancing reasoning instructions (F(1,188) = 0.22, p = 0.64). However, analytic instructions were associated with improved scores (F(1,188) = 15, p < 0.0001). These data suggest that clinicians are able to recognize their reasoning strategies. However, attempting to balance reasoning strategies through customizable instructions did not result in a reduction in diagnostic errors. This suggests important limitations to the widespread belief in balancing reasoning strategies to reduce diagnostic error.


Nevus spilus.
Nevus spilus (NS), also known as speckled lentiginous nevus (SLN), is a relatively common cutaneous lesion that is characterized by multiple pigmented macules or papules within a pigmented patch. It may be congenital or acquired; however, its etiology remains unknown. NS deserves its own place in the spectrum of classification of important melanocytic nevi; as a lentigo and melanocytic nevus, it has the slight potential to develop into melanoma. Accordingly, we recommend consideration of punch excisions of the speckles alone if excision of the entire NS is declined.


CUDC-907 displays potent antitumor activity against human pancreatic adenocarcinoma in vitro and in vivo through inhibition of HDAC6 to downregulate c-Myc expression.
Pancreatic adenocarcinoma is a highly malignant cancer that often involves a deregulation of c-Myc. It has been shown that c-Myc plays a pivotal role in the regulation of a variety of physiological processes and is involved in early neoplastic development, resulting in poor progression. Hence, suppression of c-Myc overexpression is a potential strategy for pancreatic cancer therapy. CUDC-907 is a novel dual-acting inhibitor of phosphoinositide 3-kinase (PI3K) and histone deacetylase (HDAC). It has shown potential efficiency in patients with lymphoma, multiple myeloma, or thyroid cancer, as well as in solid tumors with c-Myc alterations, but the evidence is lacking for how CUDC-907 regulates c-Myc. In this study, we investigated the effect of CUDC-907 on human pancreatic cancer cells in vitro and in vivo. Our results showed that CUDC-907 potently inhibited the proliferation of 9 pancreatic cancer cell lines in vitro with IC50 values ranging from 6.7 to 54.5 nM. Furthermore, we revealed the antitumor mechanism of CUDC-907 in Aspc-1, PANC-1, and Capan-1 pancreatic cancer cells: it suppressed the HDAC6 subunit, thus downregulating c-Myc protein levels, which was a mode of action distinct from the existing mechanisms. Consistently, the extraordinary antitumor activity of CUDC-907 accompanied by downregulation of c-Myc and Ki67 expression in tumor tissue was observed in a human pancreatic cancer Aspc-1 xenograft nude mouse model in vivo. Our results suggest that CUDC-907 can be a valuable therapeutic option for treating pancreatic adenocarcinoma.


Helper T cells induced by a purified 28-kilodalton antigen of Schistosoma mansoni protect rats against infection.
Schistosoma mansoni adult worm 28-kilodalton (kDa) proteins were separated on polyacrylamide slab gels, recovered by electrophoretic elution, and used to immunize Fischer rats. After the second or third injection, inguinal lymph node T lymphocytes were propagated in vitro for 4 weeks in the presence of syngeneic antigen-presenting cells and adult worm antigens in medium containing interleukin-2. After this period of culture, 99% of the cells expressed the W3/13+ surface phenotype and 93% of the cells expressed the W3/25+ surface phenotype. These cells were then tested for their in vivo functional activity after transfer to Fischer rats that had been either infected with S. mansoni cercariae or immunized with the 28-kDa purified protein. In each case, an increase of S. mansoni-specific antibodies was observed. Whereas anti-28-kDa antibodies were only detectable at day 40 postinfection in controls injected with normal T lymphocytes, they appeared as early as day 13 postinfection when the animals received 28-kDa protein-specific T lymphocytes. This led to an effective protection of infected rats (45 to 85%) which correlated with the increase in S. mansoni-specific antibodies. These results therefore demonstrate that the 28-kDa protein possesses epitopes capable of activating helper T cells, which confer a strong protective immunity by enhancing the production of cytotoxic antibodies. The stimulation of the 28-kDa-specific T cells with recombinant proteins suggests that the major epitopes are located toward the carboxylic end of the molecule.


Molecular dynamics study of heparin based coatings.
Heparin based surface coatings can be used to improve the biocompatibility of metallic surfaces such as vascular stents. Here, we report molecular dynamics simulations of a macromolecular conjugate of heparin used to prepare such surfaces. The structural properties of the heparin conjugate are investigated for different degrees of hydration, to allow comparison with spectroscopic results. The simulations show that the polymer becomes more compact with an increasing degree of inter-chain interactions as the hydration increases. This is also accompanied by changes in the interaction patterns among the heparin chains, where counter ions become looser associated with the disaccharide units and their strong interactions can be partly replaced by water molecules and heparin hydroxyl groups. The structural information that can be obtained from computer simulations of this type of coatings can be very valuable for understanding and further development of functional interfaces, since very little is known experimentally regarding their detailed structural properties.


Familial Hypercholesterolemia-Risk-Score: A New Score Predicting Cardiovascular Events and Cardiovascular Mortality in Familial Hypercholesterolemia.
Objective: Familial hypercholesterolemia (FH) is associated with a high risk of premature atherosclerotic cardiovascular disease (ASCVD). However, this risk is highly heterogeneous and current risk prediction algorithms for FH suffer from limitations. The primary objective of this study was to develop a score predicting incident ASCVD events over 10 years in a large multinational FH cohort. The secondary objective was to investigate the prediction of major adverse cardiovascular events and cardiovascular mortality using this score. Approach and Results: We prospectively followed 3881 patients with adult heterozygous FH with no prior history of ASCVD (32 361 person-years of follow-up) from 5 registries in Europe and North America. The FH-Risk-Score incorporates 7 clinical variables: sex, age, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, hypertension, smoking, and lipoprotein (a) (Lp(a)) with a Harrell C-index for 10-year ASCVD event of 0.75, which was superior to the SAFEHEART-RE (Spanish Familial Hypercholesterolemia Cohort; 0.69). Subjects with an elevated FH-Risk-Score had decreases in 10-year ASCVD-free survival, 10-year major adverse cardiovascular event-free survival, and 30-year survival for CV mortality compared with the low-risk group, with hazard ratios of 5.52 (3.94-7.73), 4.64 (2.66-8.11), and 10.73 (2.51-45.79), respectively. The FH-Risk-Score showed a similar performance in subjects with and without an FH-causing mutation. Conclusions: The FH-Risk-Score is a stronger predictor of future ASCVD than the SAFEHEART-RE and was developed in FH subjects with no prior cardiovascular event. Furthermore, the FH-Risk-Score is the first score to predict CV death and could offer personalized cardiovascular risk assessment and treatment for patients with FH. Future studies are required to validate the FH-Risk-Score in different ethnic groups.


Interleaving cerebral CT perfusion with neck CT angiography. Part II: clinical implementation and image quality.
Feasibility evaluation of the One-Step Stroke Protocol, which is an interleaved cerebral computed tomography perfusion (CTP) and neck volumetric computed tomography angiography (vCTA) scanning technique using wide-detector computed tomography, and to assess the image quality of vCTA. Twenty patients with suspicion of acute ischaemic stroke were prospectively scanned and evaluated with a head and neck CTA and with the One-Step Stroke Protocol. Arterial enhancement and contrast-to-noise ratio (CNR) in the carotid arteries was assessed. Three observers scored artefacts and image quality of the cervical arteries. The total z-coverage was evaluated. Mean enhancement in the carotid bifurcation was rated higher in the vCTA (595 ± 164 HU) than CTA (441 ± 117 HU). CNR was rated higher in vCTA. Image quality scores showed no significant difference in the region of the carotid bifurcation between vCTA and CTA. Lower neck image quality scores were slightly lower for vCTA due to artefacts, although not rated as diagnostically relevant. In ten patients, the origin of the left common carotid artery was missed by 1.6 ± 0.8 cm. Mean patient height was 1.8 ± 0.09 m. Carotid bifurcation and origin of vertebral arteries were covered in all patients. The One-Step Stroke Protocol is feasible with good diagnostic image quality of vCTA, although full z-coverage is limited in tall patients. • Interleaving cerebral CTP with neck CTA (One-Step Stroke Protocol) is feasible • Diagnostic quality of One-Step Stroke Protocol neck CTA is similar to conventional CTA • One-Step Stroke Protocol neck CTA suffers from streak artefacts in the lower neck • A limitation of One-Step Stroke Protocol CTA is lack of coverage in tall patients • Precise planning of One-Step Stroke Protocol neck CTA is necessary in tall patients.


Genetic basis of ethylene perception and signal transduction in Arabidopsis.
Ethylene is a simple gaseous hormone in plants. It plays important roles in plant development and stress tolerance. In the presence of ethylene treatment, all ethylene receptors are in an activated form, which can physically interact with CTR1 and consequently recruit CTR1 protein to endoplasmic reticulum membraneto activate it. Activated CTR1 suppresses the downstream signal transduction by an unknown mechanism. Upon binding to its receptors, ethylene will inactivate the receptor/CTR1 module and in turn alleviate their inhibitory effect on two positive regulators acting downstream of CTR1: EIN2 and EIN3. Genetic study reveals that EIN2 is an essential component in the ethylene signaling pathway but its biochemical function remains a mystery. EIN3 is a plant-specific transcription factor and its protein abundance in the nucleus is rapidly induced upon ethylene treatment. In the absence of ethylene signal, EIN3 protein is degraded by an SCF complex containing one of the two F-box proteins EBF1/EBF2 in a 26S proteasome-dependent manner. EIN3 can bind to the promoter sequences of a number of downstream components, such as ERFs, which in turn bind to a GCC box, a cis-element found in many ethylene-regulated defense genes. Ethylene has been shown to also regulate many other hormones' signaling pathways including auxin, abscisic acid and jasmonic acid, implying the existence of complicated signaling networks in the growth, development and defense responses of various plants.


Stem cell therapy in stroke: a review literature.
Stroke is an important cause of death in the world and disability world-wide especially in developed countries. Following acute phase of stroke, some procedures and medical treatment such as thrombolytic agents has been recommended; nevertheless many patients have enduring deficits. Thus, there is a realistic need to develop treatment strategies for reducing neurological deficits. However, the stem cell (SC) therapy could arrange an alternative intervention for disease modifying therapy. In this article, we present a brief review of different methods of SC therapy in stroke patients and discuss the results with different cell types and routes of administration.


A survey of job satisfaction, sources of stress and psychological symptoms among general practitioners in Leeds.
The past seven years have seen rapid changes in general practice in the United Kingdom (UK), commencing with the 1990 contract. During the same period, concern about the health and morale of general practitioners (GPs) has increased and a recruitment crisis has developed. To determine levels of psychological symptoms, job satisfaction, and subjective ill health in GPs and their relationship to practice characteristics, and to compare levels of job satisfaction since the introduction of the 1990 GP contract with those found before 1990. Postal questionnaire survey of all GP principals on the Leeds Health Authority list. The main outcome measures included quantitative measures of practice characteristics, job satisfaction, mental health (General Health Questionnaire), and general physical health. Qualitative statements about work conditions, job satisfaction, and mental health were collected. A total of 285/406 GPs (70%) returned the questionnaires. One hundred and forty-eight (52%) scored 3 or more on the General Health Questionnaire (GHQ-12), which indicates a high level of psychological symptoms. One hundred and sixty GPs (56%) felt that work had affected their recent physical health. Significant associations were found between GHQ-12 scores, total job satisfaction scores, and GPs' perceptions that work had affected their physical health. Problems with physical and mental health were associated with several aspects of workload, including list size, number of sessions worked per week, amount of time spent on call, and use of deputizing services. In the qualitative part of the survey, GPs reported overwork and excessive hours, paperwork and administration, recent National Health Service (NHS) changes, and the 1990 GP contract as the most stressful aspects of their work. Fifty-two per cent of GPs in Leeds who responded showed high levels of psychological symptoms. Job satisfaction was lower than in a national survey conducted in 1987, and GPs expressed the least satisfaction with their hours, recognition for their work, and rates of pay. Nearly 60% felt that their physical health had been affected by their work. These results point to a need to improve working conditions in primary care and for further research to determine the effect of any such changes.


Social Anxiety Disorder Among Undergraduate Students of Hawassa University, College of Medicine and Health Sciences, Ethiopia.
Social anxiety disorder (SAD), also called social phobia, is an uncontrollable fear of social situations, which involve fear of observation or making contact with strangers. So, helping individuals with social anxiety, which is among the factors affecting mental health, can significantly influence a students' mental health and prevent other problems. The study aimed at assessing the magnitude of SAD and its determinants among undergraduate students of Hawassa University, College of Medicine and Health Sciences. An institution based cross-sectional study was conducted from April 1 to May 30, 2018, in Hawassa University, College of Medicine and Health Sciences. We selected participants by a stratified random sampling method, and we collected data independently from each stratum (department) using a 17 item self-rating Social Phobia Inventory (SPIN) scale to assess SAD. We performed multiple logistic regression analysis to find factors associated with SAD. Out of 304 students, 293 completed the questionnaire, with a response rate of 96.3%. The mean age of the participants was 22.13 years with a standard deviation of ± 2.176, and 172 (58.7%) were males. The prevalence of SAD was 32.8%. Family history of mental illness (AOR=4.72, 95% CI (1.25, 17.74)), being a 3rd-year student (AOR=0.178, 95% CI (0.055, 0.57)) and being a 4th year student (AOR=0.15, 95% CI (0.049, 0.49)) were significantly associated with SAD. This study showed a high prevalence of SAD among medicine and health science students of Hawassa University. Therefore, the Ethiopian Ministry of Higher Education and university officials need to draw up a plan to reduce social phobia.


Design and evaluation of antibacterials crosslinked chitosan nanoparticle as a novel carrier for the delivery of metronidazole to treat bacterial vaginosis.
Bacterial vaginosis (BV) is a recurring, chronic infection that is difficult to treat due to the limited bioavailability of antimicrobials within vaginal epithelial cells. Vaginal administration, because of lower dosing and systemic exposure offers a viable option for treating vaginal infections. In this study, Metronidazole-loaded chitosan nanoparticles were synthesised employing borax (BX) or tannic acid (TA) as an antimicrobial crosslinking agent for treating BV. The prepared NPs were characterized for various physical, physicochemical, pharmaceutical, thermal and antibacterial properties. Morphological investigation revealed that nanoparticles prepared from 0.5 % w/v chitosan, 1.2 % w/v BX, and 0.4 % w/v metronidazole (MTZ) were non-spherical, with particle sizes of 377.4 ± 37.3 nm and a zeta potential of 34 ± 2.1 mV. The optimised formulation has MIC values of 24 ± 0.5 and 59 ± 0.5 μg/mL, against Escherichia coli (E.coli) and Candida albicans (C.albicans) respectively. The results of DSC and XRD demonstrated no change in the physical state of the drug in the finished formulation. Under simulated vaginal fluid, the optimised formulation demonstrates a cumulative drug release of about 90 % within 6h. The prepared borax crosslinked NPs exhibit anti-fungal activities by inhibiting ergosterol synthesis. The in-vivo antibacterial data indicated a comparable reduction in bacterial count compared to the marketed formulation in female Swiss albino mice treated with optimised nanoparticles. According to histopathological findings, the prepared nanoparticle was safe for vaginal use. Based on the experimental findings, it was concluded that MBCSNPs, due to their good physiochemical and antimicrobial properties, could serve as a potential topical alternative for treating BV and reducing fungal infection.


Valid publication of the names Caecibacterium and Caecibacterium sporoformans.
Descriptions of the genus Caecibacterium and its proposed type species Caecibacterium sporoformans were published in the IJSEM by Onrust et al. (Int J Syst Evol Microbiol 2017;67:4589-4594). The type strain was deposited as LMG 27730 and DSM 26959. DSM 26959 is a patent strain, and therefore the names were effectively, but not validly, published based on Rule 30(4) of the International Code of Nomenclature of Prokaryotes. The type strain of C. sporoformans is now available from the Deutsche Sammlung von Mikroorganismen und Zellkulturen as DSM 103070 and no restrictions have been placed on its distribution. We here present new descriptions of the genus and its type species so that the names can be validly published.


Diffusion tensor imaging of white matter tracts in the dog brain.
Diffusion weighted imaging sequences are now widely available on Magnetic Resonance Imaging (MRI) scanners. Diffusion Tensor Imaging (DTI) of the brain is able to show white matter tracts and is now commonly used in human medicine to study brain anatomy, tumors, structural pathways,… The purpose of this study was to show the interest of DTI to reveal the white matter fibers in the dogs' brain. DTI MR Images for this study were obtained with a 3 T system of 4 dogs euthanized for other reasons than neurological disorders. Combined fractional anisotropic (FA) and directional maps were obtained in the first 2 hours after death. The heads were amputated immediately after scanning and stored in 10% formalin until preparation for dissection. An experienced anatomist tracked white matter tracts with clinical relevance using the scanner software. The selected tracts were REFVIDume rendered and correlated with gross dissection. Using DTI we were able to track relevant neurological connections, such as the corticospinal tract, the optic and the cerebellar tract. The three dimensional anatomy is better presented using modern visualization techniques. DTI seems to be a valuable tool in order to present clinically relevant white matter tracts to neurological clinicians and researchers.


Test of incremental respiratory endurance as home-based, stand-alone therapy in chronic obstructive pulmonary disease: A case report.
The prevalence of chronic obstructive pulmonary disease (COPD) is increasing worldwide, and at the same time it is associated with increased mortality and reduced quality of life. Efforts to build sustainable rehabilitation approaches to COPD treatment and prevention are crucial. The system of long-term pulmonary rehabilitation care is insufficient. The main reasons for the absence of these outpatient programs are the lack of experience, the lack of interest of insurance companies in secondary prevention programs, and the lack of healthcare facilities in large geographical areas. The possibility of at-home pulmonary rehabilitation models (telemonitoring and telecoaching) could solve this problem. A 71-year-old man with severe COPD, Global Initiative for Obstructive Lung Diseases stage 3 underwent an 8-wk remotely monitored inspiratory muscle training with a device based on the test of incremental respiratory endurance method. Spirometry, body plethysmography, test of incremental respiratory endurance examination, 6-min walking test, body mass index, airflow obstruction, dyspnea, exercise capacity index, and subjective perception of dyspnea were performed as part of the initial and final examination. The patient performed training at home, and the physiotherapist monitored the patient remotely through a web application that allowed the physiotherapist to evaluate all training parameters in real-time and respond to any problems. After 8 wk of home training, there was a significant increase in all monitored values: maximal inspiratory pressure, a novel parameter sustained maximal inspiratory pressure, forced expiratory volume in 1 s, total lung capacity, forced vital capacity, peak expiratory flow, and inspiratory capacity. There was also an improvement in the perception of dyspnea according to the COPD Assessment Test and a modified Medical Research Council Breathlessness Scale, an increase in exercise tolerance according to the 6-min walking test, and a decrease in the exercise capacity index as a predictor of prognosis. Respiratory telerehabilitation was greatly beneficial in a cooperative patient with COPD and may represent an alternative therapeutic approach to the increasing incidence of all lung diseases.


Mutations of KIF5C cause a neurodevelopmental disorder of infantile-onset epilepsy, absent language, and distinctive malformations of cortical development.
The clinical diagnosis of malformations of cortical development (MCDs) is often challenging due to the complexity of the brain malformation by neuroimaging, the rarity of individual malformation syndromes, and the rapidly evolving genetic landscape of these disorders facilitated with the use of Next Generation Sequencing (NGS) methods. While the clinical and molecular diagnosis of severe cortical malformations, such as classic lissencephaly, is often straightforward, the diagnosis of more subtle and complex types of cortical malformations, such as pachygyria and polymicrogyria (PMG), can be more challenging due to limited knowledge regarding their genetic etiologies. Here, we report two individuals with the same de novo KIF5C mutation who present with subtle MCDs, early onset epilepsy and significant neurodevelopmental and behavioral issues including absent language. Our data, combined with the limited literature on KIF5C mutations, to date, support that KIF5C mutations are associated with a neurodevelopmental disorder characterized by infantile onset epilepsy, and subtle but recognizable types of brain malformations. We also show that the spectrum of KIF5C mutations is narrow, as five out of the six identified individuals have mutations affecting amino acid Glu237. Therefore, the identification of the clinical and neuroimaging features of this disorder may strongly facilitate rapid and efficient molecular diagnosis.


Comparison of two preoperative medical management strategies for laparoscopic resection of pheochromocytoma.
To compare the intraoperative and postoperative course of patients undergoing laparoscopic pheochromocytoma resection at 2 institutions (Mayo Clinic and Cleveland Clinic) with differing approaches to preoperative preparation. Patients undergoing adrenalectomy for pheochromocytoma typically undergo a preoperative preparation to normalize their blood pressure and intravascular volume. However, no consensus has been reached regarding the best preoperative preparation regimen. A retrospective chart review was performed of 50 Mayo Clinic patients and 37 Cleveland Clinic patients who had undergone laparoscopic pheochromocytoma resection. Mayo Clinic predominantly used the long-lasting nonselective alpha(1,2) antagonist phenoxybenzamine, and Cleveland Clinic predominately used selective alpha(1) blockade. Data regarding the intraoperative hemodynamics and postoperative complications were collected. Almost all patients at Mayo Clinic received phenoxybenzamine (98%). At Cleveland Clinic, the predominant treatment (65%) was selective alpha(1) blockade (doxazosin, terazosin, or prazosin). Intraoperatively, patients at Cleveland Clinic had a greater maximal systolic blood pressure (209 +/- 44 mm Hg versus 187 +/- 30 mm Hg, P = .011) and had received a greater amount of intravenous crystalloid (median 5000, interquartile range 3400-6400, versus median 2977, interquartile range 2000-3139; P <.010) and colloid (median 1000, interquartile range 500-1000, versus median 0, interquartile range 0-0; P <.001). At Mayo Clinic, more patients had received phenylephrine (56.0% versus 27.0%, P = .009). No differences were found in the postoperative surgical outcomes, and the hospital stay was comparable between the 2 groups. Differences in the preoperative preparation and intraoperative management were associated with differences in intraoperative hemodynamics but not with clinically significant outcomes in patients undergoing laparoscopic adrenalectomy for pheochromocytoma at 2 large tertiary care centers.


Intrinsic protein disorder and protein-protein interactions.
Intrinsically disordered proteins often bind to more than one partner. In this study, we focused on 11 sets of complexes in which the same disordered segment becomes bound to two or more distinct partners. For this collection of protein complexes, two or more partners of each disordered segment were selected to have less than 25% amino acid identity at structurally aligned positions. As it turned out that most of the examples so selected had similar 3D structure, the studied set was reduced to just these similar-fold cases. Based on the analyses of the interacting partners, the average sequence identity of the partners' binding regions showed substantially higher conservation as compared to the nonbinding regions: The residue identities, averaged over the 11 sets of partner proteins, were as follows: binding residues, 42 ± 6%; nonbinding residues 20 ± 3%; nonbinding buried residues 26 ± 5%; and nonbinding surface residues 16 ± 3%. The higher sequence identity of the binding residues compared to the other sets of residues provides evidence that these observed interactions are likely to be meaningful biological interactions, not artifacts. Since many of the features of the various interactions indicate that the disordered binding segments were likely to have been disordered before binding, these results also add further weight to the existence and function of intrinsically disordered regions inside cells.


Interleukin-32 induces the differentiation of monocytes into macrophage-like cells.
After emigration from the bone marrow to the peripheral blood, monocytes enter tissues and differentiate into macrophages, the prototype scavenger of the immune system. By ingesting and killing microorganisms and removing cellular debris, macrophages also process antigens as a first step in mounting a specific immune response. IL-32 is a cytokine inducing proinflammatory cytokines and chemokines via p38-MAPK and NF-kappaB. In the present study, we demonstrate that IL-32 induces differentiation of human blood monocytes as well as THP-1 leukemic cells into macrophage-like cells with functional phagocytic activity for live bacteria. Muramyl dipepide (MDP), the ligand for the intracellular nuclear oligomerization domain (NOD) 2 receptor, has no effect on differentiation alone but augments the monocyte-to-macrophage differentiation by IL-32. Unexpectedly, IL-32 reversed GM-CSF/IL-4-induced dendritic cell differentiation to macrophage-like cells. Whereas the induction of TNFalpha, IL-1beta, and IL-6 by IL-32 is mediated by p38-MAPK, IL-32-induced monocyte-to-macrophage differentiation is mediated through nonapoptotic, caspase-3-dependent mechanisms. Thus, IL-32 not only contributes to host responses through the induction of proinflammatory cytokines but also directly affects specific immunity by differentiating monocytes into macrophage-like cells.


Efficacy of Precordial Percussion Pacing Assessed in a Cardiac Standstill Microminipig Model.
Potential cardiovascular benefits of precordial percussion pacing (PPP) during cardiac standstill are unknown.Methods and Results:A cardiac standstill model in amicrominipigwas created by inducing complete atrioventricular block with a catheter ablation technique (n=7). Next, the efficacy of cardiopulmonary resuscitation by standard chest compressions (S-CPR), PPP and ventricular electrical pacing in this model were analyzed in series (n=4). To assess the mechanism of PPP, a non-selective, stretch-activated channel blocker, amiloride, was administered during PPP (n=3). Peak systolic and diastolic arterial pressures during S-CPR, PPP and ventricular electrical pacing were statistically similar. However, the duration of developed arterial pressure with PPP was comparable to that with ventricular electrical pacing, and significantly greater than that with S-CPR. Amiloride decreased the induction rate of ventricular electrical activity by PPP in a dose-related manner. Each animal survived without any neurological deficit at 24, 48 h and 1 week, even with up to 2 h of continuous PPP. In amicrominipigmodel of cardiac standstill, PPP can become a novel means to significantly improve physiological outcomes after cardiac standstill or symptomatic bradyarrhythmias in the absence of cardiac pacing. Activation of the non-selective stretch-activated channels may mediate some of the mechanophysiological effects of PPP. Further study of PPP by itself and together with S-CPR is warranted using cardiac arrest models of atrioventricular block and asystole.


Retrobulbar optic nerve cysticercosis. Case report.
The authors report a first case of intraoptic neurocysticercosis in a 12-year-old boy living on Reunion Island. Cysticercosis of the retrobulbar portion of the optic nerve is rare. Because of the patient's age and disturbances in both visual acuity and visual field, it was initially believed to be an optic nerve tumor. Computerized tomography scans and surgical aspects were confirmed by pathological findings. A conservative removal using en bloc orbitotomy showed good functional and aesthetic results.


Rouxiella chamberiensis gen. nov., sp. nov., a member of the family Enterobacteriaceae isolated from parenteral nutrition bags.
Parenteral nutrition bags for newborns were found contaminated by a previously undescribed member of the family Enterobacteriaceae. The six isolates studied by rrs gene (encoding 16S rRNA) sequence analysis and multi-locus sequence analysis (MLSA) formed a discrete branch close to the genera Ewingella, Rahnella, Yersinia,Hafnia and Serratia. Phenotypically, the new taxon was distinct from these five genera. The new taxon gave positive results in Voges-Proskauer, Simmons citrate and o-nitrophenyl-β-galactoside hydrolysis tests; fermented d-glucose, d-mannitol, l-rhamnose, melibiose, l-arabinose and d-xylose; hydrolysed aesculin; and did not ferment maltose, trehalose, raffinose, d-sorbitol, sucrose or cellobiose. Tests for motility, gas production, urease, gelatinase and nitrate reduction were also negative. All isolates failed to grow at 37 °C. The DNA G+C content of strain 130333T was 53 mol%. On the basis of data obtained in this study, the six isolates represent a novel species of a new genus in the family Enterobacteriaceae, named Rouxiella chamberiensis gen. nov., sp. nov. The type strain of the type species is 130333T ( = CIP 110714T = DSM 28324T).


Crystal Structure-Based Exploration of Arginine-Containing Peptide Binding in the ADP-Ribosyltransferase Domain of the Type III Effector XopAI Protein.
Plant pathogens secrete proteins called effectors into the cells of their host to modulate the host immune response against colonization. Effectors can either modify or arrest host target proteins to sabotage the signaling pathway, and therefore are considered potential drug targets for crop disease control. In earlier research, the Xanthomonas type III effector XopAI was predicted to be a member of the arginine-specific mono-ADP-ribosyltransferase family. However, the crystal structure of XopAI revealed an altered active site that is unsuitable to bind the cofactor NAD+, but with the capability to capture an arginine-containing peptide from XopAI itself. The arginine peptide consists of residues 60 through 69 of XopAI, and residue 62 (R62) is key to determining the protein-peptide interaction. The crystal structure and the molecular dynamics simulation results indicate that specific arginine recognition is mediated by hydrogen bonds provided by the backbone oxygen atoms from residues W154, T155, and T156, and a salt bridge provided by the E265 sidechain. In addition, a protruding loop of XopAI adopts dynamic conformations in response to arginine peptide binding and is probably involved in target protein recognition. These data suggest that XopAI binds to its target protein by the peptide-binding ability, and therefore, it promotes disease progression. Our findings reveal an unexpected and intriguing function of XopAI and pave the way for further investigation on the role of XopAI in pathogen invasion.