Mechanisms of salt tolerance conferred by overexpression of the HAL1 gene in Saccharomyces cerevisiae.
Overexpression of the HAL1 gene improves the tolerance of Saccharomyces cerevisiae to NaCl by increasing intracellular K+ and decreasing intracellular Na+. The effect of HAL1 on intracellular Na+ was mediated by the PMR2/ENA1 gene, corresponding to a major Na+ efflux system. The expression level of ENA1 was dependent on the gene dosage of HAL1 and overexpression of HAL1 suppressed the salt sensitivity of null mutants in calcineurin and Hal3p, other known regulators of ENA1 expression. The effect of HAL1 on intracellular K+ was independent of the TRK1 and TOK1 genes, corresponding to a major K+ uptake system and to a K+ efflux system activated by depolarization, respectively. Overexpression of HAL1 reduces K+ loss from the cells upon salt stress, a phenomenon mediated by an unidentified K+ efflux system. Overexpression of HAL1 did not increase NaCl tolerance in galactose medium. NaCl poses two types of stress, osmotic and ionic, counteracted by glycerol synthesis and sodium extrusion, respectively. As compared to glucose, with galactose as carbon source glycerol synthesis is reduced and the expression of ENA1 is increased. As a consequence, osmotic adjustment through glycerolsynthesis, a process not affected by HAL1, is the limiting factor for growth on galactose under NaCl stressed.


Reproducibility of wax interocclusal records on different articulators.
The construction of a dental prosthesis needs the duplication of intermaxillary relationships of the patient on the articulator. This procedure is normally fulfilled using interocclusal records to program the articulator according to the patient's condylar inclinations. Wax is a popular recording material used for this purpose but has proven to suffer from inaccuracies due to its dimensional variation over time. This study intends to test the reproducibility of eccentric interocclusal wax records over time. Thirteen dental students aged between 18 and 30 years participated in this study. Maxillary and mandibular casts of the participants were mounted on two types of articulators; wax lateral and protrusive interocclusal records were used to program these articulators. Horizontal and lateral condylar inclinations were obtained for each participant. The interocclusal records were stored for 10 days and the casts of each participant were remounted on the articulators. The interocclusal records were reused to obtain new condylar inclinations of each participant. The initial and the delayed condylar inclinations were compared to evaluate the impact of storage time on wax records. Paired Student's t-test was used for this comparison. No significant difference (0.38 < P < 0.92) was found between initial and delayed condylar inclinations for both articulators. An interclass correlation coefficient analysis was used to test the reproducibility of measures, and the correlation was significantly elevated (intraclass correlation coefficient >0.600). The use of wax interocclusal records for articulator programing was shown to be acceptable even with delayed intervals, without concerns of possible variations of condylar settings due to storage time.


Inflammatory response associated with pulmonary complications in non-HIV immunocompromised patients.
A study was undertaken to evaluate the local and systemic inflammatory response associated with pulmonary complications in immunocompromised patients and potential implications regarding severity and prognosis. Levels of different inflammatory mediators were measured in the bronchoalveolar lavage (BAL) fluid and serum on days 1 and 4 after the identification of the pulmonary complication in 127 patients with different immunosuppressive conditions. Pulmonary complications were characterised by a high percentage of neutrophils and increased levels of tumour necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-8 and IL-10 in the BAL fluid and high serum levels of TNF-alpha, IL-6, and plasma C-reactive protein (CRP). The inflammatory response was similar in the different groups of immunocompromised patients evaluated. The levels of proinflammatory cytokines were higher in patients with pulmonary infections, particularly those of bacterial aetiology. Patients with a more severe pulmonary infection had a more intense local and systemic inflammatory response. A BAL fluid IL-6 level of >40 pg/ml was an independent predictor of mortality (OR 4.65, 95% CI 1.3 to 16.1), together with a need for mechanical ventilation (OR 13.5, 95% CI 3.2 to 57.3). Patients who died had persistently high levels of CRP on day 4. The evaluation of the inflammatory response, particularly the determination of IL-6 levels in the BAL fluid and CRP in the serum, may be useful for deciding the appropriate management of pulmonary complications in immunocompromised patients.


Politics, Personality, and Impulsivity Can Color People's Perceptions of-and Responses to-Hurricane Threats of Varying Severity.
Theory and research suggest that objective features of a threatening situation and individual differences influence threat responses. We examine three ways individual traits may relate to a threat response: (a) directly and independent of objective threat features, (b) indirectly through relationships with threat perception, or (c) as moderators of the relationship between objective threat features and responses. Using integrative data analysis (IDA), we aggregated data across three studies examining hurricane preparation intentions. Analysis supported two of the potential pathways. Supporting the first path, both openness and extraversion had direct, positive relationships with preparation likelihood. Supporting the second path, agreeableness, conscientiousness, and social conservatism positively related to preparation likelihood through a positive relationship with threat perception, whereas impulsivity and sensation-seeking negatively related to preparation likelihood through a negative relationship with threat perception. This work shows the pivotal role individual differences play regarding responses to uncertain threats.


Synthetic cationic antimicrobial peptides bind with their hydrophobic parts to drug site II of human serum albumin.
Many biologically active compounds bind to plasma transport proteins, and this binding can be either advantageous or disadvantageous from a drug design perspective. Human serum albumin (HSA) is one of the most important transport proteins in the cardiovascular system due to its great binding capacity and high physiological concentration. HSA has a preference for accommodating neutral lipophilic and acidic drug-like ligands, but is also surprisingly able to bind positively charged peptides. Understanding of how short cationic antimicrobial peptides interact with human serum albumin is of importance for developing such compounds into the clinics. The binding of a selection of short synthetic cationic antimicrobial peptides (CAPs) to human albumin with binding affinities in the μM range is described. Competitive isothermal titration calorimetry (ITC) and NMR WaterLOGSY experiments mapped the binding site of the CAPs to the well-known drug site II within subdomain IIIA of HSA. Thermodynamic and structural analysis revealed that the binding is exclusively driven by interactions with the hydrophobic moieties of the peptides, and is independent of the cationic residues that are vital for antimicrobial activity. Both of the hydrophobic moieties comprising the peptides were detected to interact with drug site II by NMR saturation transfer difference (STD) group epitope mapping (GEM) and INPHARMA experiments. Molecular models of the complexes between the peptides and albumin were constructed using docking experiments, and support the binding hypothesis and confirm the overall binding affinities of the CAPs. The biophysical and structural characterizations of albumin-peptide complexes reported here provide detailed insight into how albumin can bind short cationic peptides. The hydrophobic elements of the peptides studied here are responsible for the main interaction with HSA. We suggest that albumin binding should be taken into careful consideration in antimicrobial peptide studies, as the systemic distribution can be significantly affected by HSA interactions.


"The Cooties Effect": Amygdala Reactivity to Opposite- versus Same-sex Faces Declines from Childhood to Adolescence.
One of the most important social identities that children learn to define themselves and others by is sex, becoming a salient social category by early childhood. Although older children begin to show greater flexibility in their gendered behaviors and attitudes, gender rigidity intensifies again around the time of puberty. In the current study, we assessed behavioral and neural biases to sex across a wide age group. Ninety-three youth (ages 7-17 years) provided behavioral rating of same- and opposite-sex attitudes, and 52 youth (ages 4-18 years) underwent an fMRI scan as they matched the emotion of same- and opposite-sex faces. We demonstrate significant age-related behavioral biases of sex that are mediated by differential amygdala response to opposite-sex relative to same-sex faces in children, an effect that completely attenuates by the teenage years. Moreover, we find a second peak in amygdala sensitivity to opposite-sex faces around the time of puberty. Thus, the amygdala codes for developmentally dependent and motivationally relevant social identification across development.


Evasion of host defenses by measles virus: wild-type measles virus infection interferes with induction of Alpha/Beta interferon production.
Measles is a highly contagious disease currently responsible for over one million childhood deaths, particularly in the developing world. Since alpha/beta interferons (IFNs) are pivotal players both in nonspecific antiviral immunity and in specific cellular responses, their induction or suppression by measles virus (MV) could influence the outcome of a viral infection. In this study we compare the IFN induction and sensitivity of laboratory-passaged attenuated MV strains Edmonston and Moraten with those of recent wild-type viruses isolated and passaged solely on human peripheral blood mononuclear cells (PBMC) or on the B958 marmoset B-cell line. We report that two PBMC-grown wild-type measles isolates and two B958-grown strains of MV induce 10- to 80-fold-lower production of IFN by phytohemagglutinin-stimulated peripheral blood lymphocytes (PBL) compared to Edmonston and Moraten strains of measles. Preinfection of PBL with these non-IFN-inducing MV isolates prevents Edmonston-induced but not double-stranded-RNA-induced IFN production. This suggests that the wild-type viruses can actively inhibit Edmonston-induced IFN synthesis and that this is not occurring by double-stranded RNA. Furthermore, the wild-type MV is more sensitive than Edmonston MV to the effect of IFN. MV is thus able to suppress the synthesis of the earliest mediator of antiviral immunity, IFN-alpha/beta. This could have important implications in the virulence and spread of MV.


Roles of reactive oxygen species and mitochondria in cadmium-induced injury of liver cells.
The roles of reactive oxygen species (ROS) and mitochondrial damage in the cadmium (Cd)-induced injury of liver cells were studied by using N-acetyl-L-cysteine (NAC) and acetyl-L-carnitine hydrochloride (ALCAR). After exposure of experimental rats to cadmium (Cd) for 16 h, mitochondrial membrane potential (MMP), ROS production, glutathione peroxidase (GSH-Px) activity, glutathione (GSH) content, malondialdehyde (MDA) content and DNA single-strand break (DNA-SSB) were analyzed. Loss of MMP, increase of ROS production, inhibition of GSH-Px activity, elevation of GSH content, rise of MDA content and DNA-SSB level suggest the participation of ROS and mitochondrion in Cd-induced injury of liver cell. NAC pretreatment attenuated oxidative stress, reversed the decline in GSH-Px activity and reduced GSH and MDA levels significantly. However, Cd-induced loss in MMP was significantly exacerbated by NAC. For another, ALCAR did not perform as well as NAC in terms of reducing ROS production, restoring GSH-Px activity and reducing GSH content. Nevertheless, it significantly improved the recovery of MMP and reduction of MDA content. In addition, conspicuous DNA damage was observed in the samples treated with NAC or ALCAR, indicating Cd could attack DNA through other pathways. These results suggest that oxidative stress or mitochondrial impairment plays a main role in different injuries respectively.


In vitro effects of peroxynitrite on human spermatozoa.
In the present study, the in vitro effects of peroxynitrite on sperm motility, lipid peroxidation and sulfhydryl content were examined. Sperm percentage motility and movement characteristics were assessed by a computer-assisted system. Lipid peroxidation was measured by determining malondialdehyde levels using the thiobarbituric acid (TBA) method. Sperm sulfhydryl content was measured by a spectrophotometric method based on reduction of 5,5'-dithiobis-(2-nitrobenzoic acid) by sulfhydryl groups. Percentage motility, movement characteristics and sulfhydryl content decreased significantly in peroxynitrite-treated samples compared to decomposed peroxynitrite-treated samples. Lipid peroxidation in peroxynitrite-treated samples was significantly higher than in decomposed peroxynitrite-treated samples. These results indicate that peroxynitrite anion may cause sperm dysfunction through lipid peroxidation stimulation and total SH depletion.


[Nineteen cases of school-aged children with degenerative or metabolic neurological disorders initially presenting with learning difficulty and/or behavior disturbance].
We reported 19 cases of school-aged children. They were initially judged to have learning difficulty or school maladaptation because of attention deficits, hyperactive behaviors or poor school performance, followed by the diagnosis such as degenerative or metabolic neurological diseases. The patients consisted of 4 cases of adrenoleukodystrophy, 5 cases of dentatorubral-pallidoluysian atrophy, 3 cases of Sanfilippo syndrome, 3 cases of subacute sclerosing panencephalitis, and each one case of juvenile Gaucher disease, juvenile Huntington disease, juvenile metachromatic leukodystrophy and Leigh disease. They had markedly poor school performance, and/or abnormal behaviors, followed by seizures, character disorders or psychomotor regression. The diagnostic clues included brain CT scan and/or MRI, peculiar facial appearance and notable family histories. When the children were indicated to have learning difficulty or maladjustment to school life, we should make deliberate differential diagnoses before concluding that they have a learning disorder and/or attention-deficit/hyperactivity disorder. Instead they should be recommended to visit child neurologists, when they present with any problems as aforesaid.


The "Inferior Temporal Numeral Area" distinguishes numerals from other character categories during passive viewing: A representational similarity analysis.
A region in the posterior inferior temporal gyrus (pITG) is thought to be specialized for processing Arabic numerals, but fMRI studies that compared passive viewing of numerals to other character types (e.g., letters and novel characters) have not found evidence of numeral preference in the pITG. However, recent studies showed that the engagement of the pITG is modulated by attention and task contexts, suggesting that passive viewing paradigms may be ill-suited for examining numeral specialization in the pITG. It is possible, however, that even if the strengths of responses to different category types are similar, the distributed response patterns (i.e., neural representations) in a candidate numeral-preferring pITG region ("pITG-numerals") may reveal categorical distinctions, even during passive viewing. Using representational similarity analyses with three datasets that share the same task paradigm and stimulus sets (total N = 88), we tested whether the neural representations of digits, letters, and novel characters in pITG-numerals were organized according to visual form and/or conceptual categories (e.g., familiar versus novel, numbers versus others). Small-scale frequentist and Bayesian meta-analyses of our dataset-specific findings revealed that the organization of neural representations in pITG-numerals is unlikely to be described by differences in abstract shape, but can be described by a categorical "digits versus letters" distinction, or even a "digits versus others" distinction (suggesting greater numeral sensitivity). Evidence of greater numeral sensitivity during passive viewing suggest that pITG-numerals is likely part of a neural pathway that has been developed for automatic processing of objects with potential numerical relevance. Given that numerals and letters do not differ categorically in terms of shape, categorical distinction in pITG-numerals during passive viewing must reflect ontogenetic differentiation of symbol set representations based on repeated usage of numbers and letters in differing task contexts.


At least two regions of the viral genome determine the oncogenic potential of avian leukosis viruses.
Recombinants of oncogenic and nononcogenic avian leukosis viruses were tested for their oncogenic potential in chickens. The results indicate that at least two regions of the viral genome determine the oncogenic potential of these viruses. The first region contains sequences that control viral mRNA synthesis. These sequences determine the potential of a virus to induce a low incidence of lymphomas, carcinomas, chondrosarcomas, fibrosarcomas, and osteopetrosis. The second region lies outside the sequences that control viral mRNAs synthesis. These sequences determine the ability of a virus to induce a high incidence of lymphomas or osteopetrosis.


High efficiency green OLEDs based on homoleptic iridium complexes with steric phenylpyridazine ligands.
A series of steric phenylpyridazine based homoleptic iridium(iii) complexes (1-3) have been synthesized with novel one-pot methods. Single X-ray structural analyses are conducted on complexes 1 and 2 to reveal their coordination arrangement. These complexes exhibit a very strong green phosphorescence emission with high quantum yields of over 64%. The relationship between photophysical properties and the substituent nature of the complexes is discussed by density functional theory (DFT) and time-dependent DFT. Self-quenching is significantly reduced for these complexes in solid even at very high concentrations because the sterically hindered bicyclo [2.2.2] oct-2-ene and m-substituted CF3 spacers in the phosphor molecules lead to minimum bimolecular interactions. Accordingly, the electroluminescence device based on complex 3 exhibits a maximum luminous efficiency of 64.1 cd A-1 with a high EQE of 25.2% at a high doping concentration of 15 wt%. Meanwhile, when neat 3 was adopted as the emitting layer, the non-doped green device gives a state-of-the-art EQE as high as 15.2% (40.1 cd A-1) along with CIE coordinates of (0.346, 0.599).


Hypoxia imaging in brain tumors.
Assessment of the oxygenation status of brain tumors has been studied increasingly with imaging techniques in light of recent advances in oncology. Tumor oxygen tension is a critical factor influencing the effectiveness of radiation and chemotherapy and malignant progression. Hypoxic tumors are resistant to treatment, and prognostic value of tumor oxygen status is shown in head and neck tumors. Strategies increasing the tumor oxygenation are being investigated to overcome the compromising [figure: see text] effect of hypoxia on tumor treatment. Administration of nicotinamide and inhalation of various high oxygen concentrations have been implemented. Existing methods for assessment of tissue oxygen level are either invasive or insufficient. Accurate and noninvasive means to measure tumor oxygenation are needed for treatment planning, identification of patients who might benefit from oxygenation strategies, and assessing the efficacy of interventions aimed to increase the radiosensitivity of tumors. Of the various imaging techniques used to assess tissue oxygenation, MR spectroscopy and MR imaging are widely available, noninvasive, and clinically applicable techniques. Tumor hypoxia is related closely to insufficient blood flow through chaotic and partially nonfunctional tumor vasculature and the distance between the capillaries and the tumor cells. Information on characteristics of tumor vasculature such as blood volume, perfusion, and increased capillary permeability can be provided with MR imaging. MR imaging techniques can provide a measure of capillary permeability based on contrast enhancement and relative cerebral blood volume estimates using dynamic susceptibility MR imaging. Blood oxygen level dependent contrast MR imaging using gradient echo sequence is intrinsically sensitive to changes in blood oxygen level. Animal models using blood oxygen level-dependent contrast imaging reveal the different responses of normal and tumor vasculature under hyperoxia. Normobaric hyperoxia is used in MR studies as a method to produce MR contrast in tissues. Increased T2* signal intensity of brain tissue has been observed using blood oxygen level-dependent contrast MR imaging. Dynamic blood oxygen level-dependent contrast MR imaging during hyperoxia is suggested to image tumor oxygenation. Quantification of cerebral oxygen saturation using blood oxygen level-dependent MR imaging also has been reported. Quantification of cerebral blood oxygen saturation using MR imaging has promising clinical applications; however, technical difficulties have to be resolved. Blood oxygen level dependent MR imaging is an emerging technique to evaluate the cerebral blood oxygen saturation, and it has the potential and versatility to assess oxygenation status of brain tumors. Upon improvement and validation of current MR techniques, better diagnostic, prognostic, and treatment monitoring capabilities can be provided for patients with brain tumors.


Transcatheter Closure of Patent Ductus Arteriosus: The Penang Hospital's Experience.
Transcatheter closure of small and moderate sizes of Patent Ductus Arteriosus (PDA) is a standard and well accepted form of treatment. The aim of this study is to describe the experience of transcatheter closure of PDA in Penang Hospital. All patients who underwent transcatheter closure of PDA at our institution between 20th January 2006 and 27th June 2008 were retrospectively identified and studied. There were a total of 66 patients who had undergone transcatheter closure of PDA during this period which comprised of 24 male and 42 female. The PDA was closed by Amplatzer Duct Occluder (ADO) in 31 patients, Gianturco coil in 29 patients and other types of devices in 6 patients. There were 4 patients (6%) who had developed acute complication during the procedure (3 of them developed coil embolization and 1 had bleeding from puncture site). The PDA was successfully close in 95.5% of the study population without any residual PDA shunting. All the patients were alive but 5 of them (4.5%) have some abnormalities (2 has mild left pulmonary stenosis, 3 has small residual). Comparison between ADO and Gianturco coil revealed no significant difference in the outcome. Transcatheter closure of PDA has proven to be safe and effective with good midterm outcome. There was no significant difference between Amplatzer Ductal Occluder and Gianturco coil in term of the outcome.


Sleep apnea in Machado-Joseph disease: a clinical and polysomnographic evaluation.
Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is the most common type of autosomal dominant spinocerebellar ataxia (SCA). Sleep disorders have been described as frequent non-motor symptoms in MJD, and with marked impairment on quality of life. However, few studies have evaluated the frequency and characteristics of sleep apnea in MJD. This study analyzed the prevalence of sleep apnea in 47 patients with MJD by using polysomnography. Clinical variables such as age, age at onset of symptoms, duration of symptoms (at time of evaluation), body index mass, ataxia scales severity and CAG repeat length were compared with polysomnographic findings. Thirty four percent of MJD patients had OSAS, and 42.5% had excessive daytime somnolence. There were no differences considering ataxia severity, CAG repetition length or other clinical variable. Patients with MJD have high frequency of obstructive sleep apnea, and this sleep disorder is not correlated with ataxia severity, CAG repetition length or other clinical variable.


Intra-arterial thrombolysis in acute basilar artery thromboembolism: the initial Mayo Clinic experience.
To investigate the feasibility of intra-arterial thrombolysis in acute basilar artery thrombosis. We reviewed a consecutive series of patients in whom intra-arterial thrombolysis was performed during the period from 1994 to 1996. Intra-arterial thrombolysis with urokinase was done in an attempt to recanalize the basilar artery in a series of nine patients with basilar artery thrombosis admitted to the neurologic intensive care unit. At the time of initial assessment, all nine patients had major neurologic deficits attributable to brain-stem ischemia, including two patients with locked-in syndrome. Recanalization of the basilar artery system was successful in seven of the nine patients (a range of 2 to 13 hours after the ictus). Failure to recanalize the basilar artery occurred in two patients, who died after progressing to coma. Complete recovery or only minimal neurologic deficits were demonstrated in five of the nine patients. Despite recanalization of the basilar artery, two patients had no major change in their neurologic function, and both ultimately had severe ataxia and were fully dependent on others. A cerebellar hemorrhage occurred in one patient but without clinical worsening. Two patients had a retroperitoneal hematoma. Intra-arterial thrombolysis with urokinase in acute basilar artery occlusion resulted in recanalization in seven of the nine patients (78%). Five of the nine patients recovered fully, including two patients who had had locked-in syndrome. In light of the devastating natural course of acute basilar artery occlusion, these initial results are encouraging and indicate that intra-arterial thrombolysis may be a useful emergency treatment, even in patients with prolonged symptoms of ischemia (up to 12 hours).


Vasopressin and oxytocin responses to acute and chronic osmotic stimuli in man.
The regulation of both arginine vasopressin (AVP) and oxytocin secretion was studied during rapid and prolonged osmotic stimuli in normal adult volunteers. In five subjects given an intravenous infusion of 0.85 mol NaCl at 0.05 ml/kg per min over 2 h there was a significant (P less than 0.05) rise only in plasma AVP, with no significant change in plasma levels of oxytocin. In six further subjects 5 days of restriction to 500 ml fluid daily resulted in significant increases of both plasma and 24-h urinary AVP, whereas there was no change in corresponding oxytocin levels. During another 5-day period in which the same subjects were given an additional 200 mmol sodium as well as having their fluid intake restricted to 1000 ml daily, there were again significant rises in plasma and 24 h urinary AVP with no change in corresponding oxytocin levels. We conclude that, in man, AVP is selectively secreted in response to both dehydration and high sodium intake, whilst even after the stimulus of rapidly increasing plasma osmolality during intravenous infusion of hypertonic saline the rise in oxytocin is not statistically significant. It therefore appears unlikely that oxytocin has a significant role in the physiological control of fluid balance in man.


The interobserver and test-retest variability of the dysphonia severity index.
The purpose of this study was to investigate the interobserver variability and the test-retest variability of the Dysphonia Severity Index (DSI), a multiparametric instrument to assess voice quality. The DSI was measured in 30 nonsmoking volunteers without voice complaints or voice disorders by two speech pathologists. The subjects were measured on 3 different days, with an interval of 1 week. The difference in DSI between two observers (interobserver difference) was not significant. The intraclass correlation coefficient for the DSI was 0.79. The standard deviation of the difference between two duplicate measurements by different observers was 1.27. Differences in measurements between different observers were not significant. The intraclass correlation coefficient of the DSI was 0.79, which is to be considered good. Differences in DSI within one patient need to be larger than 2.49 to be significant.


Promoting faculty professionalism: a case-based approach.
Professionalism is a key attribute for health professionals. Yet, it is unknown how much faculty development is directed toward skills and behaviours of faculty professionalism. Faculty professionalism includes boundaries in teacher-student relationships, self-reflection, assuring one's own fitness for duty, and maintaining confidentiality when appropriate. For five years, we have incorporated faculty professionalism as a routine agenda item for the monthly Physician Assistant Programme faculty meetings, allowing faculty members to introduce issues they are comfortable sharing or have questions about. We also have case discussions of faculty professionalism within faculty meetings every three months. Faculty professionalism is important in the daily work lives of faculty members and including this as part of routine agendas verifies its importance. A faculty survey showed that a majority look forward to the quarterly faculty professionalism case discussions. These have included attempted influence in the admissions process, student/faculty social boundaries, civic professionalism, students requesting medical advice, and self-disclosure. A preventive approach works better than a reactionary approach to faculty missteps in professionalism. Routine discussion of faculty professionalism normalizes the topic and is helpful to both new and experienced faculty members. We recommend incorporation of faculty professionalism as a regular agenda item in faculty meetings.


The Stability and Validity of Automated Indices of Vocal Development in Infants With Autistic and Non-Autistic Siblings.
This study evaluates the extent to which automated indices of vocal development are stable and valid for predicting language in infants at increased familial likelihood for autism and/or language impairment and relatively lower likelihood infants. A group of infants with autistic siblings (Sibs-autism; 20 infants) and a comparison group of infants with non-autistic siblings (Sibs-NA; 20 infants) wore Language ENvironment Analysis (LENA) recording devices for 16 hr on 2 days within a 1-week period. Extant software was used to derive several putative indices of vocal development from these recordings. Stability of these variables was examined across and within groups. Expressive and receptive language aggregates were calculated for each participant. Multiple regression analyses were used to (a) evaluate zero-order correlations for variables derived from LENA recordings with concurrent and future language and (b) test whether those associations were moderated by group status. Both stability and validity differed by variable and group status. All variables reached acceptable stability in the Sibs-autism group within two to three observations, whereas stability of most variables was attenuated in the Sibs-NA group. No variables were associated with concurrent language in the theoretically motivated direction across groups, but two variables were strongly associated with concurrent expressive language in only the Sibs-NA group. Additionally, two variables were associated with later expressive language, though these correlations were again stronger in the Sibs-NA versus Sibs-autism group. Although selected automated indices of vocal development were stable in Sibs-autism and/or valid for predicting expressive language within Sibs-NA, no scores showed strong, theoretically motivated associations with language within the Sibs-autism group. Automated indices of vocal development may, thus, have limited validity or clinical utility for predicting language development in infants at elevated familial likelihood for autism. https://doi.org/10.23641/asha.24415735.


Prediction of wave-front sensor slope measurements with artificial neural networks.
For adaptive optical systems to compensate for atmospheric turbulence effects, the wave-front perturbation must be measured with a wave-front sensor (WFS) and corrected with a deformable mirror. One limitation in this process is the time delay between the measurement of the aberrated wave front and implementation of the proper correction. Statistical techniques exist for predicting the atmospheric aberrations at the time of correction based on the present and past measured wave fronts. However, for the statistical techniques to be effective, key parameters of the atmosphere and the adaptive optical system must be known. These parameters include the Fried coherence length r(0), the atmospheric wind-speed profile, and the WFS slope measurement error. Neural networks provide nonlinear solutions to adaptive optical problems while offering the possibility to function under changing seeing conditions without actual knowledge of the current state of the key parameters. We address the use of neural networks for WFS slope measurement prediction with only the noisy WFS measurements as inputs. Where appropriate, we compare with classical statistical-based methods to determine if neural networks offer true benefits in performance.


A leadership program in an undergraduate nursing course in Western Australia: building leaders in our midst.
This paper discusses a leadership program implemented in the School of Nursing at Edith Cowan University to develop leadership in fourth semester nursing students enrolled in a three year undergraduate nursing degree to prepare them for the dynamic 'changing world' environment of healthcare. Students were invited to apply to undertake the program in extracurricular time. Nineteen students applied to the program and ten were chosen to participate in the program. The numbers were limited to ten to equal selected industry leader mentors. The leadership program is based on the belief that leadership is a function of knowing oneself, having a vision that is well communicated, building trust among colleagues, and taking effective action to realize one's own potential. It is asserted that within the complexity of health care it is vital that nurses enter the clinical setting with leadership capabilities because graduate nurses must take the lead to act autonomously, make decisions at the point of service, and develop a professional vision that fits with organizational and professional goals Thus, the more practice students have with leadership skills, the more prepared they will be to enter the workforce. The program consists of three components: leadership knowledge, leadership skills and leadership-in-action. The leadership program focuses on the student-participant's ability to be self reflective on personal leadership qualities, critically appraise, and work within a team as well as to take responsibility for ensuring the achievement of team goals as leader. The program is practical and is reliant on the involvement of leader mentors who hold positions of leadership with the health industry in Western Australia. Students completed a pre and post program questionnaire related to abilities and skills in leadership. This paper discusses pre and post evaluation data against program outcomes. The findings demonstrate that participants of the program increased their ability to influence, persuade and motivate others; to effectively communicate; to team build and work collaboratively; to develop problem solving and perseverance skills to overcome obstacles; and to serve as agents for positive change.


Effects of Ultrasound-Guided Administration of Botulinum Toxin (IncobotulinumtoxinA) in Patients with Lateral Epicondylitis.
How effective and safe are incobotulinumtoxinA injections in adult patients with lateral epicondylitis refractory to other treatments? In this experimental study, ultrasound-guided incobotulinumtoxinA 10⁻30 U/muscle was injected into extensor carpi ulnaris, extensor digiti minimi, extensor digitorum longus and extensor carpi radialis brevis muscles. Pain (visual analogue scale [VAS], 0 to 10 [no pain to severe pain]) and upper-limb functionality (QuickDASH scale, 0 to 100 [best to worst]), assessed at baseline, 1, 3 and 6 months post-treatment, were analysed using repeated-measures analysis of variance (ANOVA) and Tukey post-hoc tests. Secondary analyses stratifying patient population by sex and baseline VAS were performed. Adverse events were reported. Twenty-four patients (mean [standard deviation] age 46.8 years) were included. Compared with baseline, mean VAS and QuickDASH scores improved at all follow-ups (p < 0.001 and p = 0.001, respectively; repeated-measures ANOVA). Secondary analyses revealed significant differences between baseline and all follow-ups in the group with baseline VAS ≥ 6 and in males and females (all p < 0.05, Tukey post-hoc test). No adverse events, except for the expected third finger weakness, were reported. In conclusion, ultrasound-guided incobotulinumtoxinA injections may be an effective treatment for lateral epicondylitis in the appropriate patient population.


Quality of life before and after endovascular and open repair of asymptomatic AAAs: a prospective study.
To assess how patients perceive health-related quality of life (HRQOL) after endovascular and open abdominal aortic aneurysm (AAA) repair. Forty-two consecutive patients (33 men; mean age 74 years, range 46-81) were assessed prospectively before and after elective endovascular (n = 21) and open (n = 21) AAA repair. Aneurysm morphology dictated the type of repair. The two patient groups were similar regarding age, gender, comorbidities, and cardiopulmonary function. Data concerning surgical trauma were compiled. The Nottingham Health Profile (NHP) score was used to assess the perceived HRQOL (criteria: pain, mobility, sleep, emotion, energy, and isolation) preoperatively and at 5, 30, and 90 days postoperatively. Specific treatment perception questions were added. One patient from each group died, leaving 40 patients to complete the study. Two patients with open repair and 1 patient with endovascular repair were unfit to answer the questionnaire on day 5. The HRQOL improved at 3 months compared with the preoperative values (p < 0.05). No significant difference was found at any time between the open and endovascular groups regarding the NHP score, although the operative time, blood loss, analgesic use, and hospital stay were significantly in favor of endovascular repair. Reinterventions were required in 5 patients with endovascular and 2 patients with open repair. In general, 3 months after AAA repair, the perceived HRQOL seems better than before treatment. Perceived HRQOL is similar after endovascular and open AAA repair despite greater surgical trauma in open surgery. This may reflect the higher number of reinterventions following endovascular repair but also difficulties in defining HRQOL.


Recompression of JPEG images by requantization.
In this paper, we report a novel heuristic for requantizing JPEG images. The resulting images are generally smaller and often have improved perceptual image quality over a "blind" requantization approach, that is, one that does not consider the properties of the quantization matrices. The heuristic is supported by a detailed mathematical treatment which incorporates the well-known Laplacian distribution of the AC discrete cosine transform (DCT) coefficients with an analysis of the error introduced by requantization. We note that the technique is applicable to any image compression method which employs discrete cosine transforms and quantization.


The state of harm reduction in the Middle East and North Africa: A focus on Iran and Morocco.
HIV/AIDS and hepatitis C among people who inject drugs are on the rise in the Middle East and North Africa (MENA) region. But the regional response to the epidemic falls short both in terms of the quality and scale of response. From the threat of the death sentence for drug offenses to the burden of refugees fleeing conflict, there are many legal, political and social barriers that hinder the introduction and expansion of harm reduction in the region. However Iran and Morocco are two pioneering countries and over the last decade they have been providing evidence that harm reduction is feasible and acceptable in MENA. Using different approaches, these two countries have overcome various obstacles and encouraged discussion and collaboration among stakeholders, including government, health professionals, civil society and community-based organizations. In so doing they have created an enabling environment to endorse a national harm strategy.


Bifidobacterium castoris strains isolated from wild mice show evidence of frequent host switching and diverse carbohydrate metabolism potential.
Members of the gut microbiota genus Bifidobacterium are widely distributed human and animal symbionts believed to exert beneficial effects on their hosts. However, in-depth genomic analyses of animal-associated species and strains are somewhat lacking, particularly in wild animal populations. Here, to examine patterns of host specificity and carbohydrate metabolism capacity, we sequenced whole genomes of Bifidobacterium isolated from wild-caught small mammals from two European countries (UK and Lithuania). Members of Bifidobacterium castoris, Bifidobacterium animalis and Bifodobacterium pseudolongum were detected in wild mice (Apodemus sylvaticus, Apodemus agrarius and Apodemus flavicollis), but not voles or shrews. B. castoris constituted the most commonly recovered Bifidobacterium (78% of all isolates), with the majority of strains only detected in a single population, although populations frequently harboured multiple co-circulating strains. Phylogenetic analysis revealed that the mouse-associated B. castoris clades were not specific to a particular location or host species, and their distribution across the host phylogeny was consistent with regular host shifts rather than host-microbe codiversification. Functional analysis, including in vitro growth assays, suggested that mouse-derived B. castoris strains encoded an extensive arsenal of carbohydrate-active enzymes, including putative novel glycosyl hydrolases such as chitosanases, along with genes encoding putative exopolysaccharides, some of which may have been acquired via horizontal gene transfer. Overall, these results provide a rare genome-level analysis of host specificity and genomic capacity among important gut symbionts of wild animals, and reveal that Bifidobacterium has a labile relationship with its host over evolutionary time scales.


Ascending projection of jaw-closing muscle-proprioception to the intralaminar thalamic nuclei in rats.
An invasive intralaminar thalamic stimulation and a non-invasive application of oral splint are both effective in treating tic symptoms of patients with Tourette syndrome (TS). Therefore, these two treatments may exert some influence on the same brain region in TS patients. We thus hypothesized that the proprioceptive input arising from the muscle spindles of jaw-closing muscles (JCMSs), known to be increased by the application of oral splint, is transmitted to the intralaminar thalamic nuclei. To test this issue, we morphologically and electrophysiologically examined the thalamic projections of proprioceptive input from the JCMSs to the intralaminar thalamic nuclei of rats. We first injected an anterograde tracer, biotinylated dextranamine, into the electrophysiologically identified supratrigeminal nucleus, which is known to receive proprioceptive inputs from the JCMSs via the trigeminal mesencephalic neurons. A moderate number of biotinylated dextranamine-labeled axon terminals were bilaterally distributed in the oval paracentral nucleus (OPC) of the intralaminar thalamic nuclei. We also detected electrophysiological responses to the electrical stimulation of bilateral masseter nerves and to sustained jaw-opening in the OPC. After injection of retrograde tracer (cholera toxin B subunit or Fluorogold) into the OPC, neuronal cell bodies were retrogradely labeled in the rostrodorsal portion of the bilateral supratrigeminal nucleus. Here, we show that proprioceptive inputs from the JCMSs are conveyed to the OPC in the intralaminar nuclei via the supratrigeminal nucleus. This study can help to understand previously unrecognized pathways of proprioception ascending inputs from the brainstem to the thalamus, which may contribute to treatments of TS patients.


Awareness of hepatitis B virus among undergraduate medical and non-medical students.
To investigate the awareness of Omani medical and non-medical students of hepatitis-B virus (HBV) infection. A structured questionnaire of 31 different statements concerning basic knowledge of HBV, its modes of transmission, diagnosis, risk behaviors, prevention, treatment, beliefs as well as attitudes towards patients with HBV infection were distributed to 280 students (154 females and 126 males). Of these 138 were pre-clinical medical students and 142 were non-medical students. The study was conducted at Sultan Qaboos University, Muscat, Sultanate of Oman during the period of 2001 to 2003. The majority of the students (75%) were aware that HBV is a common cause of hepatitis and 50.7% of them think that HBV infection is preventable. Availability of vaccine is a fact appreciated more by medical (65.2%) than by non-medical (35.2%) students (p<0.05). Approximately 70% of the cohort believed that screening blood for HBV renders blood safe for transfusion. Hepatitis B virus infected student or colleague in the same classroom or working place was accepted by 58% of medical and 46.5% of non-medical students. However, the majority of students (63.2%) hesitate to take care of a HBV infected patient. The majority of students showed some knowledge regarding HBV transmission, risk behaviors and prevention. However, there are still misconceptions regarding the attitudes, which reflect a false perception of the disease among students. This calls for well-structured health education programs stressing on such misconceptions.


Retrospective analysis of formulary restriction demonstrates significant cost savings.
Concurrent and retrospective analyses of drug use may be needed to ensure that formulary conversions are achieving the desired results. The department of pharmaceutical services at Botsford General Hospital, a 325-bed community teaching hospital in Farmington Hills, Mich., analyzed the impact of a formulary H2-receptor antagonist conversion and demonstrated that quality of care was maintained with significant cost savings achieved.


A 16-channel dual-row transmit array in combination with a 31-element receive array for human brain imaging at 9.4 T.
Arranging transmit array elements in multiple rows provides an additional degree of freedom to correct B1 (+) field inhomogeneities and to achieve whole-brain excitation at ultrahigh field strengths. Receive arrays shaped to the contours of the anatomy increase the signal-to-noise ratio of the image. In this work, the advantages offered by the transmit and receive array techniques are combined for human brain imaging at 9.4 T. A 16-element dual-row transmit array and a 31-element receive array were developed. Based on an accurate numerical model of the transmit array, the deposited power was calculated for different head sizes and positions. The influence of the receive array on the transmit field was characterized. Parallel imaging performance and signal-to-noise ratio of the receive array were evaluated. On average, a two fold increase in signal-to-noise ratio was observed in the whole-brain volume when compared with a 16-channel elliptic microstrip transceiver array. The benefits of combining the two arrays, B1 (+) shimming in three directions and high receive sensitivity, are demonstrated with high-resolution in vivo images. The dual-row transmit array provides whole-brain coverage at 9.4 T, which, in combination with the helmet-shaped receive array, is a valuable radio frequency configuration for ultra-high field magnetic resonance imaging of the human brain.


Automatic RBG-depth-pressure anthropometric analysis and individualised sleep solution prescription.
Sleep surfaces must adapt to individual somatotypic features to maintain a comfortable, convenient and healthy sleep, preventing diseases and injuries. Individually determining the most adequate rest surface can often be a complex and subjective question. To design and validate an automatic multimodal somatotype determination model to automatically recommend an individually designed mattress-topper-pillow combination. Design and validation of an automated prescription model for an individualised sleep system is performed through a single-image 2 D-3 D analysis and body pressure distribution, to objectively determine optimal individual sleep surfaces combining five different mattress densities, three different toppers and three cervical pillows. A final study (n = 151) and re-analysis (n = 117) defined and validated the model, showing high correlations between calculated and real data (>85% in height and body circumferences, 89.9% in weight, 80.4% in body mass index and more than 70% in morphotype categorisation). Somatotype determination model can accurately prescribe an individualised sleep solution. This can be useful for healthy people and for health centres that need to adapt sleep surfaces to people with special needs. Next steps will increase model's accuracy and analise, if this prescribed individualised sleep solution can improve sleep quantity and quality; additionally, future studies will adapt the model to mattresses with technological improvements, tailor-made production and will define interfaces for people with special needs.


Effect of tDCS on well-being and autonomic function in professional male players after official soccer matches.
This study aimed to examine the effect of transcranial direct current stimulation (tDCS) used as a recovery strategy, on heart rate (HR) measures and perceived well-being in 12 male professional soccer players. tDCS was applied in the days after official matches targeting the left dorsolateral prefrontal cortex (DLPFC) with 2 mA for 20 min (F3-F4 montage). Participants were randomly assigned to anodal tDCS (a-tDCS) or sham tDCS sessions. Players completed the Well-Being Questionnaire (WBQ) and performed the Submaximal Running Test (SRT) before and after tDCS. HR during exercise (HRex) was determined during the last 30 s of SRT. HR recovery (HRR) was recorded at 60 s after SRT. The HRR index was calculated from the absolute difference between HRex and HRR. A significant increase was observed for WBQ (effect of time; p<0.001; ηp2=0.417) with no effect for condition or interaction. A decrease in HRR (p = 0.014; ηp2=0.241), and an increase in HRR index were observed (p = 0.045; ηp2=0.168), with no effect for condition or interaction. No change for HRex was evident (p>0.05). These results suggest that a-tDCS over the DLPFC may have a positive effect on enhancing well-being and parasympathetic autonomic markers, which opens up a possibility for testing tDCS as a promising recovery-enhancing strategy targeting the brain in soccer players. The findings suggest that brain areas related to emotional and autonomic control might be involved in these changes with a possible interaction effect of tDCS by placebo-related effects, but more research is needed to verify this effect.


Interactions between climate change, urban infrastructure and mobility are driving dengue emergence in Vietnam.
Dengue is expanding globally, but how dengue emergence is shaped locally by interactions between climatic and socio-environmental factors is not well understood. Here, we investigate the drivers of dengue incidence and emergence in Vietnam, through analysing 23 years of district-level case data spanning a period of significant socioeconomic change (1998-2020). We show that urban infrastructure factors (sanitation, water supply, long-term urban growth) predict local spatial patterns of dengue incidence, while human mobility is a more influential driver in subtropical northern regions than the endemic south. Temperature is the dominant factor shaping dengue's distribution and dynamics, and using long-term reanalysis temperature data we show that warming since 1950 has expanded transmission risk throughout Vietnam, and most strongly in current dengue emergence hotspots (e.g., southern central regions, Ha Noi). In contrast, effects of hydrometeorology are complex, multi-scalar and dependent on local context: risk increases under either short-term precipitation excess or long-term drought, but improvements in water supply mitigate drought-associated risks except under extreme conditions. Our findings challenge the assumption that dengue is an urban disease, instead suggesting that incidence peaks in transitional landscapes with intermediate infrastructure provision, and provide evidence that interactions between recent climate change and mobility are contributing to dengue's expansion throughout Vietnam.


Measures of the effects of vaccination in a randomly mixing population.
Vaccine efficacy in the field is often derived from the relative attack rates in the vaccinated and unvaccinated after an outbreak. In this paper, vaccine efficacy is defined in terms of the probability that the infectious agent is transmitted from an infected to a susceptible person, and a method for estimating it from the usual attack rate data is given. We explore two mechanisms of vaccine action defined by Smith et al, but include an underlying dynamic epidemic model of an acute directly transmitted disease. We show analytically that under the model in which the vaccine mechanism reduces the probability of infection given a certain exposure, vaccine efficacy based on the relative attack rates underestimates the protective effect of the vaccine based on the relative transmission probabilities. Under the other model in which the vaccine mechanism offers complete protection to a certain proportion of those vaccinated, and no protection to the other vaccinated proportion, the vaccine efficacy based on the relative attack rates will equal that based on the transmission probabilities. Parameters for the effectiveness of a vaccination programme are defined in terms of the direct and indirect benefit to a single person as well as the total and average benefit to the entire population, and derived from the dynamic model for an outbreak of an acute directly transmitted disease. These effects can also be estimated without an actual separate unvaccinated population, independent of assumptions about the vaccine mechanism. The variation of these measures as functions of the fraction of vaccinated people in the population is explored numerically.


Scoping review of brucellosis in Cameroon: Where do we stand, and where are we going?
Brucellosis is a zoonotic disease known to be endemic to parts of western and sub-Saharan Africa. However, the epidemiology for humans and animals remains largely unknown in many of these countries with Cameroon being a typical example. Despite common knowledge that brucellosis affects livestock, the actual number of infected animals remains unknown. Through a scoping review, the current known status of the disease is described. The aim is to ascertain relevant and publicly accessible research and knowledge of human and animal brucellosis in the country, and to provide an overview of the factors associated with its known persistence. Seroprevalence has been estimated and published in 12 separate instances (1 human; 9 cattle; 1 human and cattle; and 1 that includes cattle, pigs, and small ruminants), between 1982 and 2020, in 9 of the country's 10 geopolitical regions. In 1983, Brucella abortus and B. melitensis were isolated in cattle, but no further bacterial isolation has been published since. The seroprevalence from 196 total humans has ranged between 5.6% and 28.1%, and between 3.0% and 30.8% for 14,044 total cattle. As there is no ongoing surveillance program, it is not currently possible to identify the specific Brucella spp. that are endemic to the country and its regions. There are sufficient agricultural systems of cattle, pigs, goats, and sheep to sustain the presence of multiple Brucella spp. Surveillance information is the cornerstone of epidemiologic decision making, and is needed to direct policy makers, public health authorities, and veterinary services to appropriate actions. A combination of serological and molecular based diagnostics for surveillance is necessary to identify, quantify, and direct the appropriate public health interventions. Cameroon has an opportunity to build public and animal health infrastructure, leading the way for central Africa in the management and future eradication of brucellosis.


Peripancreatic tuberculosis.
Peripancreatic tuberculosis (PTB) is a very rare variant of tuberculosis and its clinical and radiological findings are similar to those of pancreatic malignancy. Diagnosis of PTB is usually incidental and is made after surgical resection. We are presenting a male patient who had complaints of prolonged fever, significant weight loss and yellowish discolouration of eyes and dark-coloured urine. Investigations revealed that there was a pancreatic mass causing obstructive jaundice. However, the aetiology of the mass, whether tubercular or malignant, was not clear. Hence, the patient was planned for endoscopic ultrasound-guided fine needle aspiration cytology. Cytology and aspirate were sent for a cartridge-based nucleic acid amplification test which revealed the presence of Mycobacterium tuberculosis, sensitive to rifampicin. The patient improved completely after treatment with antitubercular therapy.


Pornographic Content and Real-Life Sexual Experiences: Findings From a Survey of German University Students.
The aim of this study was to explore liked pornographic content and real-life experience with the depicted sexual activities in a nationwide sample of 1,197 German university students. The results indicate that there is a positive, content-specific association. Generally, the link was stronger for less conventional (less widespread) practices. However, a considerable proportion of participants had no interest to experience activities they liked in pornography and this was especially the case for the unconventional activities. This indicates that pornography use may constitute a distinct form of sexuality and may create an "intimate space" for sexual fantasies.


The Role of Autologous Stem Cell Transplantation in Amyloidosis.
Autologous stem cell transplantation (ASCT) has been an essential part of the treatment armamentarium in light chain (AL) amyloidosis for several decades. Patients who achieve a complete hematologic response following ASCT have a long overall survival. However, only 1 randomized controlled trial compared ASCT with the standard of care used at the time, which was melphalan and dexamethasone, and the results did not support the use of ASCT in AL amyloidosis. These results are of limited significance due to the unexpected high transplant-related mortality (TRM) (24%). TRM is a major concern in AL amyloidosis, but its incidence can be lessened by better patient selection and by patients receiving ASCT in specialized centers. ASCT in AL amyloidosis is performed only in selected patients; approximately 20% of patients with AL amyloidosis are transplant eligible up front or after bortezomib (Velcade) based conditioning. The introduction of newer agents such as bortezomib and daratumumab (Darzalex), which lead to deep responses and have good safety profiles, encourage revisiting the benefit and timing of ASCT in the modern era. This review provides a comprehensive assessment of eligibility criteria for ASCT in AL amyloidosis, conditioning dosing, efficacy in terms of hematologic and organ response, and future areas of research.


The role of endoscopic ultrasound in the management of intraductal papillary mucinous neoplasms: a systematic update.
The widespread use of cross-sectional imaging has led to an increased frequency of incidentally detected pancreatic cysts. Neoplastic cysts such as mucinous lesions and solid pseudo-papillary neoplasms have malignant potential and therefore the early detection of these lesions presents an opportunity for prevention or early detection and management of pancreatic adenocarcinoma. Serous neoplastic lesions and non-neoplastic pancreatic cysts such as pseudocysts or walled off pancreatic necrosis and are not associated with malignant potential. It is important to identify those mucinous lesions with the highest potential of malignancy in order to direct management either towards surveillance or resection. The preoperative diagnosis of these cysts is a challenge as cross-sectional imaging alone is often inadequate at making the diagnosis. Endoscopic ultrasound (EUS) with or without fine-needle aspiration (FNA) can assess the morphology of cysts including identification of high risk characteristics of cysts as well as allowing aspiration of cyst fluid, which can be analyzed for cytology, mucin, tumor markers, amylase and molecular markers. Intraductal papillary mucinous neoplasms (IPMN) have three main subtypes; main duct IPMNs (MD-IPMN), branch duct IPMNs (BD-IPMN) and mixed type IPMNs which have feature of both the aforementioned. MD-IPMNs have the highest malignant potential and are often easier to identify on cross-sectional imaging due to the involvement of the main pancreatic duct. Current guidelines suggest that these lesions should generally be considered for resection without further evaluation. Several guidelines exist for the investigation and management of BD-IPMNs, which have a lower malignant potential and there has been much interest in more clearly defining the role of EUS and EUS-FNA in this group of patients. In this review article we discuss the role of EUS in the diagnosis, risk stratification and management of these lesions.


Recovery-oriented policy and care systems in the UK and USA.
The concept of recovery has been an influence on addicted individuals for many decades. But only in the past 15 years has the concept had a purchase in the world of public policy. In the USA, federal and state officials have promulgated policies intended to foster 'recovery-oriented systems of care' and have ratified recovery-supportive laws and regulations. Though of more recent vintage and therefore less developed, recovery policy initiatives are also being implemented in the UK. The present paper describes recovery-oriented policy in both countries and highlights key evaluations of the recovery-oriented interventions.


Pathways of acetylcholine synthesis, transport and release as targets for treatment of adult-onset cognitive dysfunction.
Acetylcholine (ACh) is a neurotransmitter widely diffused in central, peripheral, autonomic and enteric nervous system. This paper has reviewed the main mechanisms of ACh synthesis, storage, and release. Presynaptic choline transport supports ACh production and release, and cholinergic terminals express a unique transporter critical for neurotransmitter release. Neurons cannot synthesize choline, which is ultimately derived from the diet and is delivered through the blood stream. ACh released from cholinergic synapses is hydrolyzed by acetylcholinesterase into choline and acetyl coenzyme A and almost 50% of choline derived from ACh hydrolysis is recovered by a high-affinity choline transporter. Parallel with the development of cholinergic hypothesis of geriatric memory dysfunction, cholinergic precursor loading strategy was tried for treating cognitive impairment occurring in Alzheimer's disease. Controlled clinical studies denied clinical usefulness of choline and lecithin (phosphatidylcholine), whereas for other phospholipids involved in choline biosynthetic pathways such as cytidine 5'-diphosphocholine (CDP-choline) or alpha-glyceryl-phosphorylcholine (choline alphoscerate) a modest improvement of cognitive dysfunction in adult-onset dementia disorders is documented. These inconsistencies have probably a metabolic explanation. Free choline administration increases brain choline availability but it does not increase ACh synthesis/or release. Cholinergic precursors to serve for ACh biosynthesis should be incorporate and stored into phospholipids in brain. It is probable that appropriate ACh precursors and other correlated molecules (natural or synthesized) could represent a tool for developing therapeutic strategies by revisiting and updating treatments/supplementations coming out from this therapeutic stalemate.


Mycoremediation of heavy metal (Cd and Cr)-polluted soil through indigenous metallotolerant fungal isolates.
Remediation of heavy metals, other than microbial bioleaching method, is expensive and unsuitable for large contaminated areas. The current study was aimed to isolate, identify, and test the potential of indigenous fungal strains for heavy metal removal from contaminated soil. A total of three metallotolerant fungal strains, i.e., Aspergillus niger (M1DGR), Aspergillus fumigatus (M3Ai), and Penicillium rubens (M2Aii), were isolated and identified by phenotyping and genotyping from heavy metal-contaminated soil of Hattar Industrial Estate, Pakistan. A. niger was found to be the most successful strain for the removal of heavy metals from the contaminated soil with maximum bioaccumulation efficiency of 98% (Cd) and 43% (Cr). In contrast, A. fumigatus showed comparatively low but still considerable bioleaching potential, i.e., 79% and 69% for Cd and Cr removal, respectively. Maximum metal uptake efficiency, i.e., 0.580 mg g-1 and 0.152 mg g-1 by A. niger strain was noticed for Cd and Cr with Czapek yeast extract (CYE) and Sabouraud dextrose broth (SDB) media, respectively. A. fumigatus (M3Ai) exhibited the maximum bioleaching capacity (0.40 mg g-1) for Cr with CYE medium. The results reveal that A. niger M1DGR and A. fumigatus M3Ai could be used to develop new strategies to remediate soil contaminated with heavy metals (Cd and Cr) through either in situ or ex situ mycoremediation.


GLIPR1-ΔTM synergizes with docetaxel in cell death and suppresses resistance to docetaxel in prostate cancer cells.
Docetaxel is the first chemotherapy agent approved for treatment of metastatic castration-resistant prostate cancer (mCRPC). The limited survival benefit associated with the quick emergence of resistance and systemic toxicity diminished its efficacy. JNK-mediated apoptosis is one of the mechanisms of docetaxel activity whereas ERK1/2-c-Myc-CXCR4 signaling is implicated in the development of resistance and induction of migration. The aim of this study was to evaluate the hypothesis that the combination treatment with docetaxel and GLIPR1-ΔTM will synergistically induce greater cell death and inhibit the emergence of resistance and development of metastatic potential in prostate cancer (PCa) cells. The synergistic effects of the docetaxel and GLIPR1-ΔTM were evaluated with DNA fragmentation, DAPI staining and MTS using paired t-test and isobologram study. The effects of the drugs on JNK and ERK1/2-c-Myc-CXCR4 signaling were evaluated with Western blot, DNA fragmentation, and MTS assays using the JNK inhibitor SP600125, and CXCR4 siRNA. The results of docetaxel and GLIPR1-ΔTM combination on migration were examined with scratch assay using the CXCR4 inhibitor AMD3100 while our hypothesis was examined in vivo using VCaP orthotopic xenograft model. We found that GLIPR1-ΔΤΜ synergized with docetaxel to induce apoptosis in VCaP and PC-3 PCa cells through induction of JNK signaling and concomitant inhibition of ERK1/2-c-Myc-CXCR4 signaling. We showed that JNK activation mediates the apoptotic effects of the drug combination and that CXCR4 knockdown increases its efficacy. We also found that the addition of GLIPR1-ΔΤΜ to docetaxel decreases the migration of VCaP and PC-3 cells. The combination treatment with docetaxel and GLIPR1-ΔTM inhibited tumor growth and decreased metastatic potential in VCaP xenografts more than single agents did. Our data suggested that addition of GLIPR1-ΔTM treatment in PCa cells increases the efficacy of docetaxel and may inhibit the emergence of drug resistance; potentially permitting a decrease of docetaxel dose for patients with mCRPC eliminating its systemic toxicities.


A Latent Growth Mixture Modeling Approach to PTSD Symptoms in Rape Victims.
The research literature has suggested that longitudinal changes in posttraumatic stress disorder (PTSD) could be adequately described in terms of one universal trajectory, with individual differences in baseline levels (intercept) and rate of change (slope) being negligible. However, not everyone who has experienced a trauma is diagnosed with PTSD, and symptom severity levels differ between individuals exposed to similar traumas. The current study employed the latent growth mixture modeling technique to test for multiple trajectories using data from a sample of Danish rape victims (N = 255). In addition, the analysis aimed to determine whether a number of explanatory variables could differentiate between the trajectories (age, acute stress disorder [ASD], and perceived social support). Results concluded the existence of two PTSD trajectories. ASD was found to be the only significant predictor of one trajectory characterized by high initial levels of PTSD symptomatology. The present findings confirmed the existence of multiple trajectories with regard to PTSD symptomatology in a way that may be useful to clinicians working with this population.


Contrasting outcomes of older versus middle-aged and younger adult chemical dependency patients in a managed care program.
This study examined how well older chemical dependency patients succeed in treatment relative to middle-aged and younger patients in a mixed-age private HMO outpatient program. To predict successful outcome, we tested a model incorporating age group differences in individual, treatment and extratreatment factors. The sample included 89 patients aged 55 and over, 379 patients aged 40 to 54, and 736 patients aged 18-39 (N = 1,204). Baseline measures included DSM-IV substance misuse diagnoses, Addiction Severity Index (ASI), psychiatric symptom checklist, sources of suggestion to enter treatment, treatment history and motivation. Outcome measures were abstinence rates and ASI score 6 months posttreatment. At baseline, older adults showed higher levels of alcohol dependence, lower rates of drug dependence and lower psychiatric symptoms relative to younger individuals. Source of suggestions to enter treatment differed by age. Older and middle-aged patients were more likely to have an abstinence goal and to stay in treatment longer than younger adults. At 6 months posttreatment, 55% of older adults reported abstinence in the preceding 30 days, versus 59% of middle-aged adults and 50% of younger adults (p = .035). Lower rates of dependence and hostility, and greater abstinence motivation and length of stay in treatment--all of which were associated with greater age--positively affect prognosis of older adults in treatment.


Biochemical assay-based selectivity profiling of clinically relevant kinase inhibitors on mutant forms of EGF receptor.
Gefitinib and erlotinib are potent EGFR tyrosine kinase inhibitors (potentially) useful for the treatment of non-small-cell lung cancer (NSCLC). Clinical responses, however, in NSCLC patients have been linked to the presence of certain activating mutations of EGFR. We used an ELISA-based biochemical assay to confirm the selective inhibitory efficacy of gefitinib and erlotinib on the activated mutant receptor. Our results are in line with the clinical observations providing evidence for the predictive power of the kinase assay. Four additional compounds were also investigated: CI-1033 and EKB-569 had dramatic inhibitory effects on all EGFR forms, whereas PD153035 and AG1478 were active on wild-type and activating mutant protein. In docking simulations with wild-type EGFR, our inhibitory data are in good agreement with the binding scores. These data confirm that anilinoquinazolines are good starting structures for the next generation of selective drugs against mutant EGFR, whereas CI-1033 and EKB-569 may represent advances for patients with both wild-type and anilinoquinazoline-resistant mutant tumors.


Characterization of initial events in bacterial surface colonization by two Pseudomonas species using image analysis.
The processes leading to bacterial colonization on solid-water interfaces are adsorption, desorption, growth, and erosion. These processes have been measured individually in situ in a flowing system in real time using image analysis. Four different substrata (copper, silicon, 316 stainless-steel and glass) and 2 different bacterial species (Pseudomonas aeruginosa and Pseudomonas fluorescens) were used in the experiments. The flow was laminar (Re = 1.4) and the shear stress was kept constant during all experiments at 0.75 N m(-2). The surface roughness varied among the substrata from 0.002 microm (for silicon) to 0.015 microm (for copper). Surface free energies varied from 25.1 dynes cm(-1) for silicon to 31.2 dynes cm(-1) for copper. Cell curface hydrophobicity, reported as hydrocarbon partitioning values, ranged from 0.67 for Ps. fluorescens to 0.97 for Ps. aeruginosa.The adsorption rate coefficient varied by as much as a factor of 10 among the combinations of bacterial strain and substratum material, and was positively correlated with surface free energy, the surface roughness of the substratum, and the hydrophobicity of the cells. The probability of desorption decreased with increasing surface free energy and surface roughness of the substratum. Cell growth was inhibited on copper, but replication of cells overlying an initial cell layer was observed with increased exposure time to the cell-containing bulk water. A mathematical model describing cell accumulation on a substratum is presented.


Marmoricola aequoreus sp. nov., a novel actinobacterium isolated from marine sediment.
A yellow-coloured, marine actinobacterium, designated SST-45(T), was isolated from sandy sediment under the surface of a beach and taxonomically characterized by physiological, chemotaxonomic and phylogenetic methods. The cells of the isolate were Gram-positive, aerobic, non-sporulating, non-motile, spherical cells that occurred singly, in pairs, in clusters or as short chains. The isolate grew at 10-37 degrees C, an initial pH 5.1-12.1 and in the presence of 5 % (w/v) NaCl. The organism possessed LL-2,6-diaminopimelic acid as the diagnostic diamino acid in the cell wall, MK-8(H(4)) as the major menaquinone, a polar lipid profile including diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol and an unknown phospholipid, C(18 : 1) and C(16 : 0) as the major fatty acids, and a DNA G+C content of 72.4 mol%. A phylogenetic analysis based on 16S rRNA gene sequences showed that the organism was related to members of the genera Marmoricola and Nocardioides. The closest neighbours were Marmoricola aurantiacus DSM 12652(T) (97.0 % sequence similarity) and Nocardioides jensenii KCTC 9134(T) (96.7 %). The combination of morphological and chemotaxonomic characters supported the assignment of the isolate to the genus Marmoricola. However, the organism is clearly distinguished phenotypically from the single described species of this genus, Marmoricola aurantiacus. Based on the data obtained, the organism has been assigned as a novel species, for which the name Marmoricola aequoreus sp. nov. is proposed. The type strain is strain SST-45(T) (=JCM 13812(T)=NRRL B-24464(T)).


Techniques and benefits of multiple internal mammary artery bypass at 20 years of follow-up.
In patients with multivessel coronary artery disease, performing multiple internal mammary artery (MIMA) grafts to two coronary systems during coronary artery bypass grafting (CABG) improves clinical outcome. Few databases have decades of follow-up, however, and the optimal configuration is still in question. The purpose of this study was to assess 20-year clinical benefits of MIMA grafting and to evaluate the possible effects of two different MIMA configurations. From 1984 to 1986, 867 patients with multivessel coronary disease underwent CABG. Single (SIMA) IMA grafts were used in 490 and multiple (MIMA) IMA grafts in 377, along with concomitant saphenous veins. Generally, MIMAs were placed to the two largest coronary systems. Among baseline characteristics, only smoking, diabetes, and hypertension were significantly higher for MIMA versus SIMA. Multivariable Cox model analysis was used to assess outcome differences between groups. During a median follow-up of 20 years, the composite of mortality, myocardial infarction, percutaneous coronary intervention, and redo CABG was significantly reduced after MIMA versus SIMA (p = 0.013). Event-free survival was extended by almost 1 year (p = 0.018), and redo CABG was reduced by 59% (p = 0.005). A comparison within the MIMA group was made between 235 patients receiving IMA grafts to left anterior descending/left circumflex territories versus 122 with grafts to left anterior descending/right coronary artery systems. No significant difference in composite outcome was observed between these configurations (p = 0.88). These data confirm the clinical benefits of MIMA grafting in multivessel coronary disease to 20 years of follow-up. As long as MIMAs are placed to the two largest coronary systems, no significant differences in long-term results are evident between left anterior descending/left circumflex and left anterior descending/right coronary artery configurations.


An evaluation of eating disorders among a group of Turkish university students.
The prevalence of eating disorders has been increasing in the last 20 years, not only in developed countries, but also in less developed countries such as Turkey. This study was conducted among 610 university students, 338 males and 272 females who are between 17 and 23 years old, in Ankara, the capital of Turkey, to determine eating disorders among the young. The data regarding the eating disorders and self-evaluation were assessed according to the EAT-40 test and the Body Cathexis Scale. The scores received from the eating attitudes test were low among the underweight (18.9+/-9.7) and higher among the overweight (21.6+/-15.9). Eating disorders risks are more prevalent among females compared to males (P<0.001). 17.2% of the underweight and 21.2% of the overweight are at higher risk of eating disorders. There was a positive correlation between the eating attitudes test scores and young people's body weight, BMI, mid-upper arm and waist circumferences, while a negative correlation was determined between the body cathexis scores and these variables. The authors believe that educating young people about healthy nutrition and monitoring them through longitudinal research studies will be helpful to prevent eating disorders, which are significant in terms of public health.


Advances on photosystem II investigation by measurement of delayed chlorophyll fluorescence by a phosphoroscopic methods.
A method for data acquisition based on recording of light signal from a conventional phophoroscope fluorometer with high-speed digitalization is proposed to extract more information from a delayed chlorophyll a fluorescence (DF) signal. During the signal processing from all points registered by the fluorometer, we obtain simultaneously a large number of induction curves of DF decaying at different time ranges. In addition, it is possible to register a series of dark relaxation kinetics of DF, recorded at different moments during the induction period or at different temperatures. This allows the evaluation of the contribution of DF kinetic components during the induction period or at different temperatures and the comparison between DF signals registered with different phophoroscopes. With the phosphoroscope system used in this study, we have shown that the contribution of the millisecond components (with lifetimes 0.6 and 2-4 ms) predominates during the first second of the induction period. After 1 s of illumination, the amplitudes of the 0.6 ms and 2-4 ms components and of the slower one (with lifetime more than 10 ms) become approximately equal. The change in lifetime of the different components during the induction and during gradual heating is also observed. It is shown that all registered DF kinetic components have different temperature dependences.


Phase II trial of irinotecan and carboplatin for extensive or relapsed small-cell lung cancer.
The regimens of weekly irinotecan with platinum have been used for treatment of metastatic small-cell lung cancer (SCLC). We conducted a multi-institution phase II trial to evaluate a novel 21-day schedule of irinotecan and carboplatin in patients with relapsed or extensive SCLC. Eighty patients were enrolled with the following characteristics: 39 male patients, 41 female patients; median age, 65 years; and Zubrod performance status, 0 to 1 in 85% and 2 in 15% of patients. Dosing schemas were based on the maximum-tolerated dose derived in a previous phase I study. Chemotherapy-naive patients with extensive SCLC were treated with irinotecan 200 mg/m(2) and carboplatin area under the curve (AUC) of 5 (arm A). Patients, who had previously been treated with chemotherapy and had relapsed disease received irinotecan 150 mg/m(2) and carboplatin AUC of 5 (arm B). In each study arm, the treatment was given every 21 days for up to six cycles. The most common grade 3 to 4 toxicities included neutropenia (54%), thrombocytopenia (22%), anemia (13%), diarrhea (22%), and nausea/emesis (11%) in both study arms. There were three treatment-related deaths owing to neutropenic sepsis. Among 72 assessable patients, response rates of 65% and 50% were observed, respectively, for arm A and arm B. The median survival for both study arms was identical at 10 months (95% CI, 6 to 14 months). A response rate of 65% was observed in the intracranial disease of 14 patients with known brain metastases. This 21-day regimen of irinotecan and carboplatin seems promising for the treatment of relapsed SCLC.


Evaluation of self-combustion risk in tire derived aggregate fills.
Lightweight tire derived aggregate (TDA) fills are a proven recycling outlet for waste tires, requiring relatively low cost waste processing and being competitively priced against other lightweight fill alternatives. However its value has been marred as several TDA fills have self-combusted during the early applications of this technique. An empirical review of these cases led to prescriptive guidelines from the ASTM aimed at avoiding this problem. This approach has been successful in avoiding further incidents of self-combustion. However, at present there remains no rational method available to quantify self-combustion risk in TDA fills. This means that it is not clear which aspects of the ASTM guidelines are essential and which are accessory. This hinders the practical use of TDA fills despite their inherent advantages as lightweight fill. Here a quantitative approach to self-combustion risk evaluation is developed and illustrated with a parametric analysis of an embankment case. This is later particularized to model a reported field self-combustion case. The approach is based on the available experimental observations and incorporates well-tested methodological (ISO corrosion evaluation) and theoretical tools (finite element analysis of coupled heat and mass flow). The results obtained offer clear insights into the critical aspects of the problem, allowing already some meaningful recommendations for guideline revision.


Gating motions in voltage-gated potassium channels revealed by coarse-grained molecular dynamics simulations.
Voltage-gated potassium (Kv) channels are ubiquitous transmembrane proteins involved in electric signaling of excitable tissues. A fundamental property of these channels is the ability to open or close in response to changes in the membrane potential. To date, their structure-based activation mechanism remains unclear, and there is a large controversy on how these gates function at the molecular level, in particular, how movements of the voltage sensor domain are coupled to channel gating. So far, all mechanisms proposed for this coupling are based on the crystal structure of the open voltage-gated Kv1.2 channel and structural models of the closed form based on electrophysiology experiments. Here, we use coarse-grain (CG) molecular dynamics simulations that allow conformational changes from the open to the closed form of the channel (embedded in its membrane environment) to be followed. Despite the low specificity of the CG force field, the obtained closed structure satisfies several experimental constraints. The overall results suggest a gating mechanism in which a lateral displacement the S4-S5 linker leads to a closing of the gate. Only a small up-down movement of the S4 helices is noticed. Additionally, the study suggests a peculiar upward motion of the intracellular tetramerization domain of the channel, hence providing a molecular view on how this domain may further regulate conduction in Kv channels.


Preparation of megabase-sized tomato DNA and separation of large restriction fragments by field inversion gel electrophoresis (FIGE).
The Schwartz and Cantor technique for releasing and fractionating megabase-sized DNA from agarose-embedded cells is beginning to bridge the gap in resoluation between classical genetics and current molecular DNA techniques, particularly in mammalian systems. As yet no conditions have been described for preparing plant DNA that is of sufficient length to allow similar long-range restriction mapping experiments in plant systems. In this report, we describe the application of the Schwartz and Cantor technique for preparing high molecular weight DNA from embedded tomato leaf protoplasts, as well as conditions for generating and fractionating large restriction fragments, by field inversion gel electrophoresis (FIGE). The bulk of DNA released from lysed protoplasts was at least 2 Mb in size and amenable to restriction digestion as shown by hybridizing Southern blots with, among others, a probe for the Adh-2 gene of tomato. Restriction fragments as large as 700 kb were detected. Chloroplast DNA is isolated intact, amenable to restriction analysis and, in its native form, not mobile in FIGE.


Inhibition of vascular endothelial growth factor expression in HEC1A endometrial cancer cells through interactions of estrogen receptor alpha and Sp3 proteins.
Treatment of HEC1A endometrial cancer cells with 10 nm 17beta-estradiol (E2) resulted in decreased vascular endothelial growth factor (VEGF) mRNA expression, and a similar response was observed using a construct, pVEGF1, containing a VEGF gene promoter insert from -2018 to +50. In HEC1A cells transiently transfected with pVEGF1 and a series of deletion plasmids, it was shown that E2-dependent down-regulation was dependent on wild-type estrogen receptor alpha (ERalpha) and reversed by the anti-estrogen ICI 182, 780, and this response was not affected by progestins. Deletion analysis of the VEGF gene promoter identified an overlapping G/GC-rich site between -66 to -47 that was required for decreased transactivation by E2. Protein-DNA binding studies using electrophoretic mobility shift and DNA footprinting assays showed that both Sp1 and Sp3 proteins bound this region of the VEGF promoter. Coimmunoprecipitation and pull-down assays demonstrated that Sp3 and ERalpha proteins physically interact, and the interacting domains of both proteins are different from those previously observed for interactions between Sp1 and ERalpha proteins. Using a dominant negative form of Sp3 and transcriptional activation assays in Schneider SL-2 insect cells, it was confirmed that ERalpha-Sp3 interactions define a pathway for E2-mediated inhibition of gene expression, and this represents a new mechanism for decreased gene expression by E2.


inv(2)(p23q13)/RAN-binding protein 2 (RANBP2)-ALK fusion gene in myeloid leukemia that developed in an elderly woman.
A 75-year-old woman presented with marked leukocytosis; the white cell count was 143.6 × 10³/μL with 38.6 % monocytes and 13.6 % immature granulocytes, including blasts. Bone marrow (BM) aspirate smears showed >90 % cellularity with hyperplasia of myeloid-lineage cells, 14.6 % monocytes, and 32.1 % blasts. The granulocyte series showed a range of dysplastic morphologies. The rate of peroxidase positivity was 51.5 %. CD36+ cells with monocytic differentiation comprised 64.6 % mononuclear cells. Metaphase spreads obtained from the BM revealed an aneuploid karyotype with -7 and a submetacentric marker chromosome derived from chromosome 2, which was determined to be inv(2)(p23q13) by fluorescence in situ hybridization using the Vysis ALK probe. RAN-binding protein 2 (RANBP2)-ALK fusion mRNA was confirmed by reverse transcriptase-mediated polymerase chain reaction and nucleotide sequencing. High-sensitivity anti-ALK immunohistochemistry of a BM biopsy specimen demonstrated nuclear membrane staining of leukemia cells. As the leukemia showed features of chronic myelomonocytic leukemia, the patient was treated with standard daunorubicin-cytarabine followed by azacitidine, leading to the durable suppression of leukemia progression. These findings suggest that inv(2)(p23q13)/RABBP2-ALK defines a small subset of myeloid leukemia characterized by differentiation to monocytes and sharing features of myelodysplastic syndrome/myeloproliferative neoplasm.


CyNetSVM: A Cytoscape App for Cancer Biomarker Identification Using Network Constrained Support Vector Machines.
One of the important tasks in cancer research is to identify biomarkers and build classification models for clinical outcome prediction. In this paper, we develop a CyNetSVM software package, implemented in Java and integrated with Cytoscape as an app, to identify network biomarkers using network-constrained support vector machines (NetSVM). The Cytoscape app of NetSVM is specifically designed to improve the usability of NetSVM with the following enhancements: (1) user-friendly graphical user interface (GUI), (2) computationally efficient core program and (3) convenient network visualization capability. The CyNetSVM app has been used to analyze breast cancer data to identify network genes associated with breast cancer recurrence. The biological function of these network genes is enriched in signaling pathways associated with breast cancer progression, showing the effectiveness of CyNetSVM for cancer biomarker identification. The CyNetSVM package is available at Cytoscape App Store and http://sourceforge.net/projects/netsvmjava; a sample data set is also provided at sourceforge.net.


New and Recurrent Colorectal Cancers After Resection: a Systematic Review and Meta-analysis of Endoscopic Surveillance Studies.
Outcomes of endoscopic surveillance after surgery for colorectal cancer (CRC) vary with the incidence and timing of CRC detection at anastomoses or non-anastomoses in the colorectum. We performed a systematic review and meta-analysis to evaluate the incidence of CRCs identified during surveillance colonoscopies of patients who have already undergone surgery for this cancer. We searched PubMed, EMBASE, SCOPUS, and the Cochrane Central Register of Clinical Trials through January 1, 2018 to identify studies investigating rates of CRCs at anastomoses or other locations in the colorectum after curative surgery for primary CRC. We collected data from published randomized controlled, prospective, and retrospective cohort studies. Data were analyzed by multivariate meta-analytic models. From 2373 citations, we selected 27 studies with data on 15,803 index CRCs for analysis (89% of patients with stage I-III CRC). Overall, 296 CRCs at non-anastomotic locations were reported over time periods of more than 16 years (cumulative incidence, 2.2% of CRCs; 95% confidence interval [CI], 1.8%-2.9%). The risk of CRC at a non-anastomotic location was significantly reduced more than 36 months after resection compared with before this time point (odds ratio for non-anastomotic CRCs at 36-48 months vs 6-12 months after surgery, 0.61; 95% CI, 0.37-0.98; P = .031); 53.7% of all non-anastomotic CRCs were detected within 36 months of surgery. One hundred and fifty-eight CRCs were detected at anastomoses (cumulative incidence of 2.7%; 95% CI, 1.9%-3.9%). The risk of CRCs at anastomoses was significantly lower 24 months after resection than before (odds ratio for CRCs at anastomoses at 25-36 months after surgery vs 6-12 months, 0.56; 95% CI, 0.32-0.98; P = .036); 90.8% of all CRCs at anastomoses were detected within 36 months of surgery. After surgery for CRC, the highest risk of CRCs at anastomoses and at other locations in the colorectum is highest during 36 months after surgery-risk decreases thereafter. Patients who have undergone CRC resection should be evaluated by colonoscopy more closely during this time period. Longer intervals may be considered thereafter.


The effect of consequent exposure of stress and dermal application of low doses of chlorpyrifos on the expression of glial fibrillary acidic protein in the hippocampus of adult mice.
Chlorpyrifos (CPF), a commonly used pesticide worldwide, has been reported to produce neurobehavioural changes. Dermal exposure to CPF is common in industries and agriculture. This study estimates changes in glial fibrillary acidic protein (GFAP) expression in hippocampal regions and correlates with histomorphometry of neurons and serum cholinesterase levels following dermal exposure to low doses of CPF with or without swim stress. Male albino mice were separated into control, stress control and four treatment groups (n = 6). CPF was applied dermally over the tails under occlusive bandage (6 hours/day) at doses of 1/10th (CPF 0.1) and 1/5th dermal LD50 (CPF 0.2) for seven days. Consequent treatment of swim stress followed by CPF was also applied. Serum cholinesterase levels were estimated using spectroflurometric methods. Paraffin sections of the left hippocampal regions were stained with 0.2% thionin followed by the counting of neuronal density. Right hippocampal sections were treated with Dako Envision GFAP antibodies. CPF application in 1/10th LD50 did not produce significant changes in serum cholinesterase levels and neuronal density, but increased GFAP expression significantly (p < 0.001). Swim stress with CPF 0.1 group did not show increase in astrocytic density compared to CPF 0.1 alone but decreased neuronal density. Findings suggest GFAP expression is upregulated with dermal exposure to low dose of CPF. Stress combined with sub-toxic dermal CPF exposure can produce neurotoxicity.


The RNF168 paralog RNF169 defines a new class of ubiquitylated histone reader involved in the response to DNA damage.
Site-specific histone ubiquitylation plays a central role in orchestrating the response to DNA double-strand breaks (DSBs). DSBs elicit a cascade of events controlled by the ubiquitin ligase RNF168, which promotes the accumulation of repair factors such as 53BP1 and BRCA1 on the chromatin flanking the break site. RNF168 also promotes its own accumulation, and that of its paralog RNF169, but how they recognize ubiquitylated chromatin is unknown. Using methyl-TROSY solution NMR spectroscopy and molecular dynamics simulations, we present an atomic resolution model of human RNF169 binding to a ubiquitylated nucleosome, and validate it by electron cryomicroscopy. We establish that RNF169 binds to ubiquitylated H2A-Lys13/Lys15 in a manner that involves its canonical ubiquitin-binding helix and a pair of arginine-rich motifs that interact with the nucleosome acidic patch. This three-pronged interaction mechanism is distinct from that by which 53BP1 binds to ubiquitylated H2A-Lys15 highlighting the diversity in site-specific recognition of ubiquitylated nucleosomes.


Canadian Cancer Trials Group IND197: a phase II study of foretinib in patients with estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2-negative recurrent or metastatic breast cancer.
In murine models, overexpression of the MET receptor transgene induces tumors with human basal gene expression characteristics supporting MET inhibition as a treatment strategy for triple-negative breast cancer (TNBC). Foretinib is an oral multi-kinase inhibitor of MET, RON, AXL, TIE-2, and VEGF receptors with anti-tumor activity in advanced HCC and papillary renal cell cancer. Patients with centrally reviewed primary TNBC and 0-1 prior regimens for metastatic disease received daily foretinib 60 mg po in a 2-stage single-arm trial. Primary endpoints were objective response and early progression rates per RECIST 1.1. In stage 2, correlative studies of MET, PTEN, EGFR, and p53 on archival and fresh tumor specimens were performed along with enumeration of CTCs. 45 patients were enrolled with 37 patients having response evaluable and centrally confirmed primary TNBC (cTNBC). There were 2 partial responses (ITT 4.7 % response evaluable cTNBC 5.4 %) with a median duration of 4.4 months (range 3.7-5 m) and 15 patients had stable disease (ITT 33 %, response evaluable cTNBC 40.5 %) with a median duration of 5.4 months (range 2.3-9.7 m). The most common toxicities (all grades/grade 3) were nausea (64/4 %), fatigue (60/4 %), hypertension (58/49 %), and diarrhea (40/7 %). Six serious adverse events were considered possibly related to foretinib and 4 patients went off study due to adverse events. There was no correlation between MET positivity and response nor between response and PTEN, EGFR, p53, or MET expression in CTCs. Although CCTG IND 197 did not meet its primary endpoint, the observation of a clinical benefit rate of 46 % in this cTNBC population suggests that foretinib may have clinical activity as a single, non-cytotoxic agent in TNBC (ClinicalTrials.gov number, NCT01147484).