Neonatal Facial Coding System for assessing postoperative pain in infants: item reduction is valid and feasible.
The objectives of this study were to: (1). evaluate the validity of the Neonatal Facial Coding System (NFCS) for assessment of postoperative pain and (2). explore whether the number of NFCS facial actions could be reduced for assessing postoperative pain. Prospective, observational study. Thirty-seven children (0-18 months old) undergoing major abdominal or thoracic surgery. The outcome measures were the NFCS, COMFORT "behavior" scale, and a Visual Analog Scale (VAS), as well as heart rate, blood pressure, and catecholamine and morphine plasma concentrations. At 3-hour intervals during the first 24 hours after surgery, nurses recorded the children's heart rates and blood pressures and assigned COMFORT "behavior" and VAS scores. Simultaneously we videotaped the children's faces for NFCS coding. Plasma concentrations of catecholamine, morphine, and its metabolite M6G were determined just after surgery, and at 6, 12, and 24 hours postoperatively. All 10 NFCS items were combined into a single index of pain. This index was significantly associated with COMFORT "behavior" and VAS scores, and with heart rate and blood pressure, but not with catecholamine, morphine, or M6G plasma concentrations. Multidimensional scaling revealed that brow bulge, eye squeeze, nasolabial furrow, horizontal mouth stretch, and taut tongue could be combined into a reduced measure of pain. The remaining items were not interrelated. This reduced NFCS measure was also significantly associated with COMFORT "behavior" and VAS scores, and with heart rate and blood pressure, but not with the catecholamine, morphine, or M6G plasma concentrations. This study demonstrates that the NFCS is a reliable, feasible, and valid tool for assessing postoperative pain. The reduction of the NFCS to 5 items increases the specificity for pain assessment without reducing the sensitivity and validity for detecting changes in pain.


Vapor-liquid equilibrium of ethanol by molecular dynamics simulation and Voronoi tessellation.
Explicit atom simulations of ethanol were performed by molecular dynamics using the OPLS-AA potential. The phase densities were determined self-consistently by comparing the distribution of Voronoi volumes from two-phase and single-phase simulations. This is the first demonstration of the use of Voronoi tessellation in two-phase molecular dynamics simulation of polyatomic fluids. This technique removes all arbitrary determination of the phase diagram by using single-phase simulations to self-consistently validate the probability distribution of Voronoi volumes of the liquid and vapor phases extracted from the two-phase molecular dynamics simulations. Properties from the two phase simulations include critical temperature, critical density, critical pressure, phase diagram, surface tension, and molecule orientation at the interface. The simulations were performed from 375 to 472 K. Also investigated were the vapor pressure and hydrogen bonding along the two phase envelope. The phase envelope agrees extremely well with literature values from GEMC at lower temperatures. The combined use of two-phase molecular dynamics simulation and Voronoi tessellation allows us to extend the phase diagram toward the critical point.


The involvement of the nuclear lamina in human and rodent spermiogenesis: a systematic review.
The nuclear lamina (NL) is a filamentous protein meshwork, composed essentially of lamins, situated between the inner nuclear membrane and the chromatin. The NL is a component of the nuclear envelope, interacts with a wide range of proteins and is required for normal nuclear structure and physiological development. During spermiogenesis the spermatid nucleus is elongated, and dramatically reduced in size with protamines replacing histones to produce a highly compacted chromatin. There is mounting evidence from studies in human and rodent, that the NL plays an important role in mammalian spermatid differentiation during spermiogenesis. In this review, we summarize and discuss the data available in the literature regarding the involvement of lamins and their direct or indirect partners in normal and abnormal human spermiogenesis.


SK Channels Regulate Resting Properties and Signaling Reliability of a Developing Fast-Spiking Neuron.
Reliable and precise signal transmission is essential in circuits of the auditory brainstem to encode timing with submillisecond accuracy. Globular bushy cells reliably and faithfully transfer spike signals to the principal neurons of the medial nucleus of the trapezoid body (MNTB) through the giant glutamatergic synapse, the calyx of Held. Thus, the MNTB works as a relay nucleus that preserves the temporal pattern of firing at high frequency. Using whole-cell patch-clamp recordings, we observed a K+ conductance mediated by small-conductance calcium-activated potassium (SK) channels in the MNTB neurons from rats of either sex. SK channels were activated by intracellular Ca2+ sparks and mediated spontaneous transient outward currents in developing MNTB neurons. SK channels were also activated by Ca2+ influx through voltage-gated Ca2+ channels and synaptically activated NMDA receptors. Blocking SK channels with apamin depolarized the resting membrane potential, reduced resting conductance, and affected the responsiveness of MNTB neurons to signal inputs. Moreover, SK channels were activated by action potentials and affected the spike afterhyperpolarization. Blocking SK channels disrupted the one-to-one signal transmission from presynaptic calyces to postsynaptic MNTB neurons and induced extra postsynaptic action potentials in response to presynaptic firing. These data reveal that SK channels play crucial roles in regulating the resting properties and maintaining reliable signal transmission of MNTB neurons.SIGNIFICANCE STATEMENT Reliable and precise signal transmission is required in auditory brainstem circuits to localize the sound source. The calyx of Held synapse in the mammalian medial nucleus of the trapezoid body (MNTB) plays an important role in sound localization. We investigated the potassium channels that shape the reliability of signal transfer across the calyceal synapse and observed a potassium conductance mediated by small-conductance calcium-activated potassium (SK) channels in rat MNTB principal neurons. We found that SK channels are tonically activated and contribute to the resting membrane properties of MNTB neurons. Interestingly, SK channels are transiently activated by calcium sparks and calcium influx during action potentials and control the one-to-one signal transmission from presynaptic calyces to postsynaptic MNTB neurons.


Factors Associated with Mortality in Patients with a Solid Malignancy Admitted to the Intensive Care Unit - A Prospective Observational Study.
Several studies show conflicting results regarding the prognosis and predictors of the outcome of critically ill patients with a solid malignancy. This study aims to determine the outcome of critically ill patients, admitted to a hospital, with a solid malignancy and the factors associated with the outcomes. All patients with a solid malignancy admitted to an intensive care unit (ICU) at a tertiary academic medical center were enrolled. Clinical data upon admission and during ICU stay were collected. Hospital, ICU, and six months outcomes were documented. There were 252 patients with a solid malignancy during the study period. Urogenital malignancies were the most common (26.3%) followed by lung cancer (23.5%). Acute respiratory failure was the most common ICU diagnosis (51.6%) followed by sepsis in 46%. ICU mortality and hospital mortality were 21.8% and 34.3%. Six months mortality was 38.4%. Using multivariate analysis, acute kidney injury, OR 2.82, 95% CI 1.50-5.32 and P=0.001, use of mechanical ventilation, OR 2.67 95% CI 1.37 - 5.19 and P=0.004 and performance status of ≥2 with OR of 3.05, 95% CI of 1.5-6.2 and P= 0.002 were associated with hospital mortality. There were no differences in outcome between African American patients (53% of all patients) and other races. This study reports encouraging survival rates in patients with a solid malignancy who are admitted to ICU. Patients with a poor baseline performance status require mechanical ventilation or develop acute renal failure have worse outcomes.


Factors Contributing to Diagnostic Discordance Between Store-and-Forward Teledermatology Consultations and In-Person Visits: Case Series.
Use of asynchronous store-and-forward (SAF) teledermatology can improve access to timely and cost-effective dermatologic care and has increased during the COVID-19 pandemic. Previous research has found high diagnostic concordance rates between SAF teledermatology and face-to-face clinical diagnosis, but to our knowledge, none have used specific cases to illustrate factors contributing to diagnostic discordance. To identify and illustrate characteristics that may have contributed to diagnostic discordance between store-and-forward teledermatology and in-person clinical diagnosis in a series of patients. We identified 7 cases of diagnostic discordance between teledermatology and in-person visits where the favored diagnosis of the in-person dermatologist was not included in the differential diagnosis formulated by the teledermatologist. Cases were identified from a previously published retrospective chart review of 340 SAF teledermatology consultations, which was previously performed at an academic community health care system in the greater Boston area, Massachusetts, from January 1, 2014, through December 31, 2017. Of 99 patients who completed an in-person dermatology appointment after their teledermatology consultation, 7 had diagnostic disagreement between the teledermatologist and in-person dermatologist where the diagnosis in the in-person consultation was not included in the differential diagnosis in the original teledermatology consult. These 7 cases were examined by 2 author reviewers to identify factors that may have contributed to diagnostic discordance. Factors contributing to diagnostic discordance between SAF teledermatology consultations and in-person visits included poor image quality, inadequate history or diagnostic workup, inability to evaluate textural characteristics, diagnostic uncertainty due to atypical presentations, and evolution in appearance of skin conditions over time. We identified multiple factors that contributed to diagnostic discordance. Recognition and mitigation of these factors, when possible, may help to improve diagnostic accuracy and reduce the likelihood of misdiagnosis. Continuing education of referring providers and implementation of standardized guidelines for referrals may also be helpful in reducing the risk of misdiagnosis due to inherent limitations of teledermatology services.


Isolated Pyogenic Pancreatic Abscess Successfully Treated via Endoscopic Ultrasound-guided Drainage.
An isolated pyogenic pancreatic abscess (IPPA) without pancreatitis is extremely rare but can occur in patients with uncontrolled diabetes. This pathologic condition poses a clinical challenge in diagnosis and management because it can be confused easily with a malignancy. Endoscopic ultrasound (EUS) may be a useful diagnostic modality for indeterminate pancreatic lesions and IPPA. Here, we report two cases with elevated carbohydrate antigen 19-9 levels and pancreatic masses on cross sectional imaging. The patients were subsequently diagnosed with IPPA by EUS. EUS-guided drainage was performed successfully and the patients' clinical symptoms and radiologic findings improved. In our experience, EUS and EUS-guided drainage are crucial steps for the diagnosis and management of patients with an indeterminate pancreatic lesion. In addition, EUS-guided drainage has excellent technical and clinical outcomes for the treatment of IPPA.


Sarcopenia affects the clinical efficacy of immune checkpoint inhibitors in patients with gastrointestinal cancers.
The impact of sarcopenia on the efficacy of immune checkpoint inhibitors (ICI) in gastrointestinal cancer (GIC) patients remains uncertain in clinical practice. Hence, this study aims to investigate the potential correlation between sarcopenia and the clinical outcomes of GIC patients treated with ICIs. To gather pertinent studies, a systematic literature search was implemented across multiple databases, including PubMed, Embase, the Cochrane Library, and Google Scholar. The primary outcomes of interest were overall survival (OS) and progression-free survival (PFS), measured with the hazard ratio (HR). And the secondary outcomes, including disease control rate (DCR), overall response rate (ORR), and adverse events (AE), were evaluated with the odd ratio (OR). A total of 13 articles involving 1294 patients were collected for this analysis. The pooled results revealed that GIC patients with sarcopenia had significantly poorer OS (HR = 1.697, 95% CI = 1.367-2.106, p < 0.001) and PFS (HR: 1.551, 95% CI: 1.312-1.833, p < 0.001), and lower ORR (OR = 0.594, 95% CI = 0.388-0.909, p = 0.016) and DCR (OR: 0.553, 95% CI: 0.360-0.850, p = 0.007) compared to those without sarcopenia. However, sarcopenia did not increase the incidence of treatment-related adverse events compared with non-sarcopenia (OR = 1.377, 95% CI = 0.693-2.737, p = 0.361). According to subgroup analysis, the association between sarcopenia and the therapeutic effect of ICI on patients with primary liver cancer or gastric cancer was consistent with the above findings. Sarcopenia is significantly correlated with poorer treatment response and worse long-term efficacy in GIC patients treated with ICIs. Moreover, sarcopenia does not increase the incidence of adverse events.


Uptake of aggregated immunoglobulin by the mouse kidney. II. Effect of hydrocortisone.
The uptake of radiolabelled (125I) aggregated human IgG (AggIgG) by the renal cortex, liver, spleen and lung was evaluated quantitatively in mice treated with hydrocortisone (HC) (25 mg) 72 h previously. AggIgG was administered in a dose of 1.5 or 3.5 mg/g body wt i.v.; tissue and blood were obtained at 1, 4 and 24 h. Renal cortical and mesangial uptake of AggIgG was significantly increased in HC animals. A rise in blood level was also observed in association with decreased splenic uptake, normal or slightly increased hepatic uptake and unchanged lung uptake. A significant increase in the kidney:lung and kidney:spleen ratios of AggIgG was induced by hydrocortisone, suggesting a relatively greater rate of loss from the spleen and liver than the renal cortex. The increased mesangial uptake may be a consequence of higher blood levels of AggIgG, as well as a direct effect of HC on the mesangium.


The safety of herbal medicinal products derived from Echinacea species: a systematic review.
Echinacea spp. are native to North America and were traditionally used by the Indian tribes for a variety of ailments, including mouth sores, colds and snake-bites. The three most commonly used Echinacea spp. are E. angustifolia, E. pallida and E. purpurea. Systematic literature searches were conducted in six electronic databases and the reference lists of all of the papers located were checked for further relevant publications. Information was also sought from the spontaneous reporting programmes of the WHO and national drug safety bodies. Twenty-three manufacturers of echinacea were contacted and asked for data held on file. Finally our own departmental files were searched. No language restrictions were imposed. Combination products and homeopathic preparations were excluded. Data from clinical studies and spontaneous reporting programmes suggest that adverse events with echinacea are not commonly reported. Gastrointestinal upsets and rashes occur most frequently. However, in rare cases, echinacea can be associated with allergic reactions that may be severe. Although there is a large amount of data that investigates the efficacy of echinacea, safety issues and the monitoring of adverse events have not been focused on. Short-term use of echinacea is associated with a relatively good safety profile, with a slight risk of transient, reversible, adverse events. The association of echinacea with allergic reactions is supported by the present evaluation. While these reactions are likely to be rare, patients with allergy or asthma should carefully consider their use of echinacea. The use of echinacea products during pregnancy and lactation would appear to be ill-advised in light of the paucity of data in this area.


Perioperative Management of a Patient With Tongue Cancer Who Developed Pneumomediastinum Following Tracheostomy Performed to Secure the Airway.
Prior to a scheduled operation for a 45-year-old male patient with tongue cancer, a tracheotomy performed under intravenous sedation to prevent asphyxia due to extensive bleeding resulted in pneumomediastinum and subcutaneous emphysema. The planned operations were postponed until reduction of the pneumomediastinum was confirmed. During operation, airway pressure was kept low to prevent tension pneumomediastinum along with a sufficient depth of anesthesia, controlled analgesia, and continuous administration of muscle relaxants. Postoperatively, sedation was used to avoid stress and complications with the vascular anastomosis site. In this case, air leakage into the soft tissues was one of the possible causes of the event associated with increased airway pressure. Although the incidence of such complications is relatively low, caution should be exercised after tracheostomy.


A computer-based education intervention to enhance surrogates' informed consent for genomics research.
Many research studies conducted today in critical care have a genomics component. Patients' surrogates asked to authorize participation in genomics research for a loved one in the intensive care unit may not be prepared to make informed decisions about a patient's participation in the research. To examine the effectiveness of a new, computer-based education module on surrogates' understanding of the process of informed consent for genomics research. A pilot study was conducted with visitors in the waiting rooms of 2 intensive care units in a Midwestern tertiary care medical center. Visitors were randomly assigned to the experimental (education module plus a sample genomics consent form; n = 65) or the control (sample genomics consent form only; n = 69) group. Participants later completed a test on informed genomics consent. Understanding the process of informed consent was greater (P = .001) in the experimental group than in the control group. Specifically, compared with the control group, the experimental group had a greater understanding of 8 of 13 elements of informed consent: intended benefits of research (P = .02), definition of surrogate consenter (P= .001), withdrawal from the study (P = .001), explanation of risk (P = .002), purpose of the institutional review board (P = .001), definition of substituted judgment (P = .03), compensation for harm (P = .001), and alternative treatments (P = .004). Computer-based education modules may be an important addition to conventional approaches for obtaining informed consent in the intensive care unit. Preparing patients' family members who may consider serving as surrogate consenters is critical to facilitating genomics research in critical care.


Fetal exposure to maternal inflammation interrupts murine intestinal development and increases susceptibility to neonatal intestinal injury.
Fetal exposure to chorioamnionitis can impact the outcomes of the developing fetus both at the time of birth and in the subsequent neonatal period. Infants exposed to chorioamnionitis have a higher incidence of gastrointestinal (GI) pathology, including necrotizing enterocolitis (NEC); however, the mechanism remains undefined. To simulate the fetal exposure to maternal inflammation (FEMI) induced by chorioamnionitis, pregnant mice (C57BL/6J, IL-6-/-, RAG-/- or TNFR1-/-) were injected intraperitoneally on embryonic day (E)15.5 with lipopolysaccharide (LPS; 100 µg/kg body weight). Pups were delivered at term, and reared to postnatal day (P)0, P7, P14, P28 or P56. Serum and intestinal tissue samples were collected to quantify growth, inflammatory markers, histological intestinal injury, and goblet and Paneth cells. To determine whether FEMI increased subsequent susceptibility to intestinal injury, a secondary dose of LPS (100 µg/kg body weight) was given on P5, prior to tissue harvesting on P7. FEMI had no effect on growth of the offspring or their small intestine. FEMI significantly decreased both goblet and Paneth cell numbers while simultaneously increasing serum levels of IL-1β, IL-10, KC/GRO (CXCL1 and CXCL2), TNF and IL-6. These alterations were IL-6 dependent and, importantly, increased susceptibility to LPS-induced intestinal injury later in life. Our data show that FEMI impairs normal intestinal development by decreasing components of innate immunity and simultaneously increasing markers of inflammation. These changes increase susceptibility to intestinal injury later in life and provide novel mechanistic data to potentially explain why preterm infants exposed to chorioamnionitis prior to birth have a higher incidence of NEC and other GI disorders.


Low prevalence of oral and nasal human papillomavirus in employees performing CO2-laser evaporation of genital warts or loop electrode excision procedure of cervical dysplasia.
Risk of human papillomavirus (HPV) transmission during laser vaporisation of genital warts or loop electrode excision procedure is controversial. An oral rinse, a nasal swabs, history of HPV related diseases and data on HPV exposure were collected from 287 employees at departments of dermato-venerology and gynaecology in Denmark. A mucosal HPV type was found among 5.8% of employees with experience of laser treatment of genital warts as compared to 1.7% of those with no experience (p = 0.12). HPV prevalence was not higher in employees participating in electrosurgical treatment or cryotherapy of genital warts, or loop electrode excision procedure compared with those who did not. HPV 6 or 11 were not detected in any samples. Hand warts after the age of 24 years was more common among dermatology than among non-dermatology personnel (18% vs. 8.0%, p = 0.03). Mucosal HPV types are infrequent in the oral and nasal cavity of health care personnel, however, employees at departments of dermato-venereology are at risk of acquiring hand warts.


Comparison of Root Surface Wear and Roughness Resulted from Different Ultrasonic Scalers and Polishing Devices Applied on Human Teeth: An In-Vitro Study.
The aim of the present study was to compare the root surface wear and roughness, resulted from the professional dental hygiene instruments, including ultrasonic dental scalers, rubber prophy cups, and nylon bristle brushes, on the extracted human mandibular incisor teeth. Teeth (n = 80) were randomly assigned into eight groups according to the applied scaler type (Ma = Magnetostrictive, Pi = Piezoelectric), degree of power (M = Medium, F = Full), and angulation (0° and 45°). In the second stage, the specimens (n = 40) were further divided into two groups according to the applied polishing device (nylon bristle brush or rubber prophy cup). Laser scanner and contact profilometer devices were used for the surface analysis. Both ultrasonic instruments tested in our study produced rougher surfaces when full power was used at a 0° angle (p < 0.01). The highest wear (0.82 ± 0.07 mm3) and roughness values (0.30 ± 0.01 µm) were detected in the PiF0 group. Polishing performed with a rubber prophy cup resulted in almost twice the wear as well as a smoother surface when compared to polishing performed with a nylon bristle brush (p < 0.001). Variations in the application parameters of ultrasonic scalers and the type of polishing instrument might lead to significantly different root-surface characteristics.


Health services for women in outpatient substance abuse treatment.
To evaluate how a sample of outpatient substance abuse treatment units respond to organizational and environmental influences by adopting and implementing treatment services for women. The National Drug Abuse Treatment System Survey from 1995 and 2000, a national survey of outpatient substance abuse treatment units. Health services for women are the dependent variables. The predictors include organizational and environmental factors that represent resource dependence and institutional pressures for the treatment unit. Logistic regression and Heckman selection models were used to test hypotheses. Program directors and clinical supervisors at each treatment unit were interviewed by telephone in 1995 and 2000. Units that depended on specific funding for women's programs and that depended on government funds were more likely to adopt, but not necessarily implement, women's services. Methadone units and units that train more staff to work with women were more likely to adopt as well as implement women's services. Private not-for-profit units were more likely to adopt some services, while for-profit units were less so. However, in general, neither for-profit nor not-for-profit units significantly implemented services. There was evidence that the odds of adopting services were greater in 2000 than 1995 for two services, but were otherwise stable. There is considerable variation in the adoption and implementation of women's services. In addition, not all adopted services were significantly implemented, which could reflect limited organizational resources and/or conflicting expectations. This also suggests that referral mechanisms to these services, and therefore access, may not be adequate. Government funds and specific funds for women's programs are important resources for the provision of these services. Women's services appear more available in methadone units, suggesting that regulation has been influential and that the recent methadone accreditation system should be evaluated. Staff training may be one strategy to encourage implementation of these services. For the most part, the adoption of services for women did not change between 1995 and 2000.


Regulation of cytokine gene expression in the central nervous system by glucocorticoids: mechanisms and functional consequences.
The proinflammatory cytokines which are released by activated accessory immune cells during the course of an infection have profound effects on the brain. These effects include activation of the hypothalamic-pituitary-adrenal axis, fever and behavioral depression. They are mediated by cytokines which are synthesized and released in the brain, in response to peripherally released cytokines. Glucocorticoids have potent regulatory effects on the synthesis of cytokines by activated macrophages and monocytes. These hormones are also able to regulate the synthesis and action of cytokines in the brain, as demonstrated by the sensitizing effects of adrenalectomy and the depressing effects of stress on the increased cytokine and interleukin-1 beta converting enzyme gene expression that occurs in response to lipopolysaccharide in mice. Preliminary experiments indicate that another way glucocorticoids can contribute to down regulation of the IL-1 system is by increasing the expression of the type II IL-1 receptor in the brain. The regulatory effects of glucocorticoids on cytokine expression in the brain have functional consequences, as demonstrated by the enhanced sensitivity of adrenalectomized animals to the behavioral actions of centrally administered LPS and IL-1. The effects of adrenalectomy are inhibited by compensation with a corticosterone implant and they are mimicked by administration of the type II glucocorticoid receptor, RU 38486. The regulatory role of glucocorticoids on the expression and action of cytokines in the brain makes these hormones and their mechanisms of action key targets for therapeutic interventions in psychopathology and neuropathology.


Obesity and associated complications in patients with severe mental illnesses: a cross-sectional survey.
This naturalistic cross-sectional survey of patients with severe mental illnesses explores the association between important variables and obesity, extreme obesity, diabetes mellitus type 2, hypertension, and hyperlipidemia in the clinical environment. Weight and height were obtained from 560 patients with severe mental illnesses (including DSM-IV schizophrenia, schizoaffective disorder, bipolar disorder, and major depressive disorder) at central Kentucky inpatient and outpatient facilities to estimate their body mass index (BMI). Chart diagnoses of diabetes mellitus, hypertension, and hyperlipidemia were obtained. When comparing the patients with severe mental illnesses with Kentucky adults from the general population, the odds ratio (OR) of obesity (BMI > or = 30 kg/m(2)) was 2.6 (95% confidence interval [CI] = 2.2 to 3.0), and the OR of diabetes mellitus was 2.9 (95% CI = 2.3 to 3.6). Female gender, African American race, early start of psychiatric medication, and long psychiatric medication duration were significantly associated with obesity. Current alcohol and nicotine use exhibited significant ORs of obesity lower than 1, particularly in males. Obesity was closely associated with hypertension, type 2 diabetes mellitus, and hyperlipidemia. These complications were closely associated with each other and may indicate a further progression of obesity after aging. These results suggest a complex pattern of variables that may influence the development of obesity and its complications in patients with severe mental illnesses, but they need replication. The major factors associated with obesity appear to be a long-term illness or treatment duration and substance use. The former may be more important in females, while the latter may be more important in males. Clinical diagnoses (schizophrenic or mood disorders) or current treatment did not appear to be fundamental factors.


Sea Snakes: An Unusual Salt Gland under the Tongue.
The posterior sublingual gland of sea snakes is a salt gland. It secretes a fluid surpassing seawater in sodium chloride concentration. The gland lies on the ventrolateral surfaces of the tongue sheath and empties through multiple ducts into the sheath. Fluid is expelled from the sheath when the tongue is extended. For freshly captured Pelamis, the plasma concentrations of sodium, chloride, and potassium were 210, 167, and 8 millimoles per liter, respectively. Injections of sodium chloride led to a rise in its concentration in the plasma and to an increase in the rate and concentration of fluid secreted by the sublingual gland. The ultrastructure of this gland is similar to that of other reptilian salt glands. However, the gland is not homologous with any other salt gland. The sublingual gland in Pelamis is larger than that in Laticauda, and the rate of electrolyte excretion from the larger gland is greater.


E-mentoring for violence and injury prevention: early lessons from a global programme.
To address the growing burden of violence and injuries, especially in low- and middle-income countries, in 2007 the World Health Organization launched MENTOR-VIP, a global violence and injury prevention (VIP)-mentoring programme. The programme aims to develop human resource capacity through 12-month mentoring arrangements between individual VIP experts (mentors) and less-experienced injury practitioners (mentees). In this paper, we review the first five years of the programme (2007-2011) using a systems analysis and SWOT (Strengths, Weaknesses, Opportunities and Threats) frameworks, discuss programme findings and make recommendations. A well-defined programme with clear instructions, successful matching of mentorship pairs with similar interests and language, a formal accord agreement, institutional support and effective communication were identified as programme strengths. Overambitious projects, lack of funds and difficulties with communications were identified as programme weaknesses. Mentorship projects that require institutional permissions or resources could be potential threats to the success of mentorship. The study resulted in the four following recommendations to strengthen the programme: (1) institute additional steps in selection and matching mentor-mentee pair; (2) train mentors on e-mentoring; (3) conduct special orientation for mentees to the programme; and (4) maintain effective and open communication throughout the programme.


Patient recall 6 weeks after surgical consent for midurethral sling using mesh.
We aimed to determine patient recall of specific surgical risks and benefits discussed during consent for midurethral sling (MUS) surgery immediately after consent and at 6 weeks follow-up. Specifically we sought to determine whether or not women recalled specific risks related to the placement of mesh. Surgeons consented patients for MUS in their usual fashion during audio recorded consent sessions. After consent and again at 6 weeks postoperatively, women completed a checklist of risks, benefits, alternatives, and general procedural items covered during consent. In addition, women completed the Decision Regret Scale for Pelvic Floor Disorders (DRS-PFD). Audio files were used to verify specific risks, benefits, alternatives, and procedural items discussed at consent. Recall of specific risks, benefits, and alternatives were correlated with DRS-PFD scores. Sixty-three women completed checklists immediately post consent and at 6 weeks postoperatively. Six-week recall of benefits, alternatives, and description of the operation did not change. Surgical risk recall as measured by the patient checklist deteriorated from 92 % immediately post consent to 72 % at 6 weeks postoperatively (p < .001). Recall of the risk for mesh erosion declined from 91 to 64 % (p < .001). Recall that mesh was placed during the MUS procedure declined from 98 to 84 % (p = .01). DRS-PFD scores were correlated with poorer surgical risk recall and surgical complications (r = .31, p = .02). Recall of MUS surgery risks deteriorated over time. Specifically, women forgot that mesh was placed or might erode. Further investigations into methods and measures of adequate consent that promote recall of long-term surgical risks are needed.


Biosynthesis of glutamic acid in Saccharomyces: accumulation of tricarboxylic acid cycle intermediates in a glutamate auxotroph.
Aconitaseless glutamic acid auxotroph MO-1-9B of Saccharomyces grew in glutamic acid-supplemented minimal medium, but failed to grow when glutamic acid was substituted by proline, arginine, ornithine, or glutamine. This mutant was also unable to utilize lactate or glycerol as a carbon source. Under a glutamic acid-limiting condition, by using acetate-1-(14)C as tracer, the mutant accumulated rather large amounts of (14)C-citric acid and (14)C-succinic acid when compared with the wild-type strain. Under excess glutamic acid supplementation, accumulation of citric acid and succinic acid was considerably reduced. When (14)C-glutamic acid-(U) was used as tracer, (14)C-alpha-ketoglutaric acid, (14)C-citric acid, and (14)C-succinic acid were accumulated in the mutant. The citric acid peak was the largest, followed by alpha-ketoglutaric acid and succinic acid. In the wild-type strain under similar conditions, only small amounts of (14)C-citric acid and (14)C-succinic acid and no (14)C-alpha-ketoglutaric acid were accumulated.


Combinatorial regulation of the balance between dynein microtubule end accumulation and initiation of directed motility.
Cytoplasmic dynein is involved in a multitude of essential cellular functions. Dynein's activity is controlled by the combinatorial action of several regulatory proteins. The molecular mechanism of this regulation is still poorly understood. Using purified proteins, we reconstitute the regulation of the human dynein complex by three prominent regulators on dynamic microtubules in the presence of end binding proteins (EBs). We find that dynein can be in biochemically and functionally distinct pools: either tracking dynamic microtubule plus-ends in an EB-dependent manner or moving processively towards minus ends in an adaptor protein-dependent manner. Whereas both dynein pools share the dynactin complex, they have opposite preferences for binding other regulators, either the adaptor protein Bicaudal-D2 (BicD2) or the multifunctional regulator Lissencephaly-1 (Lis1). BicD2 and Lis1 together control the overall efficiency of motility initiation. Remarkably, dynactin can bias motility initiation locally from microtubule plus ends by autonomous plus-end recognition. This bias is further enhanced by EBs and Lis1. Our study provides insight into the mechanism of dynein regulation by dissecting the distinct functional contributions of the individual members of a dynein regulatory network.


Multiple testing for gene sets from microarray experiments.
A key objective in many microarray association studies is the identification of individual genes associated with clinical outcome. It is often of additional interest to identify sets of genes, known a priori to have similar biologic function, associated with the outcome. In this paper, we propose a general permutation-based framework for gene set testing that controls the false discovery rate (FDR) while accounting for the dependency among the genes within and across each gene set. The application of the proposed method is demonstrated using three public microarray data sets. The performance of our proposed method is contrasted to two other existing Gene Set Enrichment Analysis (GSEA) and Gene Set Analysis (GSA) methods. Our simulations show that the proposed method controls the FDR at the desired level. Through simulations and case studies, we observe that our method performs better than GSEA and GSA, especially when the number of prognostic gene sets is large.


Conceptualisation of patient satisfaction: a systematic narrative literature review.
Patient satisfaction concept is widely measured due to its appropriateness to health service; however, evidence suggests that it is a poorly developed concept. This article is a first part of a two-part series of research with a goal to review a current conceptual framework of patient satisfaction and to bring the concept for further operationalisation procedures. The current article aimed to review a theoretical framework that helps the next article to review determinants of patient satisfaction for designing a measurement system. The study used a systematic review method, meta-narrative review, based on the RAMESES guideline with the phases of screening evidence, appraisal evidence, data extraction and synthesis. Patient satisfaction theoretical articles were searched on the two databases MEDLINE and CINAHL. Inclusion criteria were articles published between 1980 and 2014, and English language papers only. There were 36 articles selected for the synthesis. Results showed that most of the patient satisfaction theories and formulations are based on marketing theories and defined as how well health service fulfils patient expectations. However, review demonstrated that a relationship between expectation and satisfaction is unclear and the concept expectation itself is not distinctly theorised as well. Researchers brought satisfaction theories from other fields to the current healthcare literature without much adaptation. Thus, there is a need to attempt to define the patient satisfaction concept from other perspectives or to learn how patients evaluate the care rather than struggling to describe it by consumerist theories.


Effects of retrovirus protein on the feline one-way mixed leukocyte reaction.
The objective of this study was to evaluate the effects of feline retrovirus protein on cat lymphocyte recognition of allogeneic cells in the mixed leukocyte reaction (MLR), using u.v.-inactivated feline leukaemia virus (FeLV) and a non-disease-producing endogenous cat virus (RD-114). Twenty micrograms of u.v.-inactivated virus protein from each virus were added to mixed leukocyte cultures. FeLV induced significant suppression of the MLR (P less than 0.005) whereas no significant suppression was found using RD-114. Since feline leukaemia infection is associated with immunosuppression, the retrovirus proteins may be interfering with the response of immunocompetent cells when they are confronted with an altered host cell.


Upregulation of CXC chemokine receptor 4-CXC chemokine ligand 12 axis ininvasive breast carcinoma: A potent biomarker predicting lymph node metastasis.
Breast cancer is considered as a heterogeneous disease, characterized by different biological and phenotypic features which make its diagnosis and treatment challenging. The CXC chemokine receptor 4 (CXCR4) expression was found to be correlated with poor overall survival in invasive breast carcinoma patients. Here, we sought to investigate the expression levels of the CXCR4-CXC chemokine ligand 12 (CXCL12) chemokine axis and their association with clinicopathologic features and lymph node metastasis in invasive breast carcinoma. The expression of the CXCR4-CXCL12 chemokine axis and metastasis-related genes (E-cadherin and matrix metalloproteinase 2 [MMP2]) was measured by quantitative real-time-polymerase chain reaction. The correlation with various clinicopathologic parameters was analyzed. We found upregulation of the CXCR4-CXCL12 chemokine axis in invasive breast carcinoma samples compared with normal adjacent tissues. Moreover, we observed that upregulation of this chemokine axis was correlated with tumor stages and lymph node metastasis of breast tumors. Interestingly, this correlation was affected by the expression of human epidermal growth factor receptor 2/neu. There is also a significant correlation between the expression levels of CXCR4-CXCL12 axis and metastasis-related genes (E-cadherin and MMP2) in tumor samples with advanced stages of metastasis. These results suggest a key role for the CXCR4-CXCL12 chemokine axis in breast cancer progression and highlight the prognostic importance of this chemokine axis for breast cancer survival.


Ultrasonography of the nuchal translucency of healthy and abnormal English Bulldog fetuses.
The aim of this study was to measure the nuchal translucency (NT) of canine fetuses to establish reference values for healthy gestational processes and to verify its effectiveness in the diagnosis of congenital abnormalities. On day 34 of gestation, the NT of three fetuses from each of the 26 English bulldog female dogs was measured. The first fetus was the one located immediately cranial to the bladder, the second was selected from the left side of the abdomen, and the third from the right side. The reference values for healthy animals were offset using descriptive statistics. The diagnostic ability of the test to identify fetal malformations was studied using receiver operating characteristic curve analysis. Of the 26 litters, only 18 had healthy fetuses, 4 had fetuses with anasarca, 3 had fetuses with abdominal wall defects, and 1 had both types of abnormalities. The NT was higher in canine fetuses that presented anasarca in the litter than in normal litters (1.8 ± 0.77 mm vs. 1.4 ± 0.48 mm; P = 0.0249), with a cut-off value of NT > 1.45 mm (sensitivity = 61.54%, specificity = 70.18%). NT greater than 1.45 mm seems to be a diagnostic tool for the identification of anasarca during gestation of bulldogs. Considering the unprecedented use of this parameter in canine species and the limitations found during the study, further studies will be needed in order to use it on clinical practice.


An evolutionarily conserved positively charged amino acid in the putative membrane-spanning domain of the foamy virus envelope protein controls fusion activity.
Foamy viruses (FVs) are highly fusogenic, and their replication induces massive syncytium formation in infected cell cultures which is believed to be mediated by expression of the envelope (Env) protein. The FV Env is essential for virus particle egress. The unusually long putative membrane-spanning domain (MSD) of the transmembrane subunit carries dispersed charged amino acids and has an important function for particle envelopment. To better understand the capsid-envelope interaction and Env-mediated cell fusion, we generated a variety of FV MSD mutations. C-terminal deletions revealed the cytoplasmic domain to be dispensable but the full-length MSD to be required for fusogenic activity. The N-terminal 15 amino acids of the MSD were found to be sufficient for membrane anchorage and promotion of FV particle release. Expression of wild-type Env protein rarely induced syncytia due to intracellular retention. Coexpression with FV Gag-Pol resulted in particle export and a dramatic increase in fusion activity. A nonconservative mutation of K(959) in the middle of the putative MSD resulted in increased fusogenic activity of Env in the absence of Gag-Pol due to enhanced cell surface expression as well as structural changes in the mutant proteins. Coexpression with Gag-Pol resulted in a further increase in the fusion activity of mutant FV Env proteins. Our results suggest that an interaction between the viral capsid and Env is required for FV-induced giant-cell formation and that the positive charge in the MSD is an important determinant controlling intracellular transport and fusogenic activity of the FV Env protein.


Activation in vivo of retroperitoneal fibromatosis-associated herpesvirus, a simian homologue of human herpesvirus-8.
Retroperitoneal fibromatosis-associated herpesvirus of rhesus macaques (RFHVMm) is a gammaherpesvirus closely related to human herpesvirus-8 (HHV-8), which is thought to be a necessary cofactor for the development of Kaposi's sarcoma (KS) in humans. Here, RFHVMm infection of rhesus macaques exposed to the D-type retrovirus simian retrovirus-2 (SRV-2) is described. Development of SRV-2 viraemia, infection with simian immunodeficiency virus or administration of cyclosporin A could result in persistent RFHVMm viraemia. From this, it is concluded that productive retrovirus infection or otherwise-induced immune suppression has the ability to activate this herpesvirus in vivo. Elevated levels of circulating interleukin-6, a cytokine that plays a central role in KS, were found in RFHVMm-viraemic animals. In viraemic animals, RFHVMm was found in tissues that are common sites for the development of AIDS-associated KS, especially the oral cavity. Together, these data suggest a common biology between RFHVMm infection of macaques and HHV-8 infection and pathogenesis in humans.


Impact of Pt additives on the surface reactions between SnO2, water vapour, CO and H2; an operando investigation.
The impact of Pt doping on the surface reactions between tin dioxide, water vapour, CO and H2 was investigated by a combination of simultaneously performed operando DRIFT (Diffuse Reflectance Infrared Fourier Transform) spectroscopy, DC resistance measurements and analysis of the reaction products by using a MS (Mass Spectrometer). Both undoped and Pt doped tin dioxide sensors were exposed to different test gases in synthetic air or in N2 backgrounds. The approach made it possible to identify the differences between the two materials with respect to their surface chemistry and their impact on the gas sensing performance. The main finding is that the presence of Pt changes the reaction partners' nature for water vapour and H2 on the one hand, and CO on the other hand when the sensors are operated in air. In this way the cross interference effect of humidity, which is responsible for the loss of CO sensing performance for the sensors based on undoped SnO2, is reversed.


Caregivers' Difficulty Rating Scale: Development and Initial Validation of a Tool to Identify the Unmet Needs of Indian Caregivers.
Caring for a cancer patient is debilitating for caregivers, especially among Indian population, as culturally people prefer to care at home than at nursing home. Unavailability of palliative care services and professional caregivers adds to the family burden. Caregiving difficulties need assessment, but cancer-specific burden instruments are rare in the Indian context. This article presents development and initial validation of Caregiver's Difficulty Rating Scale (CDRS) and highlights the nature of caregiving burden on primary caregivers. A total of 108 items were prepared in English after case interviews and reviewing the existing scales for face validity. Experts judged the items for content validity, of which 54 items with 100% agreement were retained. Forward-backward policy was used for Hindi translation. Reliability analysis was performed with thirty respondents. The final scale was administered to 100 caregivers of head-and-neck cancer patients for internal consistency and item-scale statistics. For construct validity, know-group comparison was made using EORTCQOL instrument with caregiver-patients dyads. High correlation among the three translated versions (r > 0.76, P < 0.01), Cronbach's alpha (0.948), and spilt-half coefficient (0.965) suggested translation reliability and scale consistency. Caregiver's burden had significant negative correlation with global quality of life of patients (-0.514**). Help for food arrangement, managing work-life, and treatment cost were the highly rated difficulties. CDRS had fifty items under four dimensions - physical, emotional, social, and financial. The scale requires further work on convergent and divergent validity and sensitivity to change which are underway. The study has implications for respite care. Community engagements and caregivers' support group may work as sources of emotional and social support.


Social organization and movement influence the incidence of bovine tuberculosis in an undisturbed high-density badger Meles meles population.
1. The culling of European badgers Meles meles has been a central part of attempts to control bovine tuberculosis (TB) in British cattle for many years. Recent results, however, indicate that this approach could in practice enhance disease spread. 2. This paper looks at the relationship between TB incidence and badger ecology in a high-density population in south-west England, which has been the subject of a long-term intensive study. The principal aims were to relate the probability of TB incidence, as detected by culture of clinical samples (i.e. excretion of bacilli), at the level of the individual and of the social group to demographic processes, movement, social organization and disease dynamics. 3. The probability of an individual being an incident case was greater in groups where TB was already present, although this was less influential in groups that were subject to some instability in numbers. Both individuals and groups were more likely to be incident cases where the social group was diminishing in size, although no relationship was observed with group size itself. This suggests that the process of group size reduction rather than group size per se has most influence on disease dynamics. The likelihood that either an individual or a group was an incident case was positively correlated with both individual and group-level movement. When the proportion of females in a social group was high, the positive association between movement and incidence was found to be more pronounced and there was a significantly higher probability of incident cases among males. 4. These relationships highlight the importance of social structure in driving TB transmission dynamics in this stable, high-density badger population. The results support the idea that a stable social structure mitigates against new incident cases of disease, and are consistent with the contention that badger culling may create the social circumstances for enhanced transmission of TB.


Expression of cyclooxygenase 2 in human malignant melanoma.
Cyclooxygenase (COX)-2 is an inducible enzyme involved in production of prostaglandins in inflammatory processes. There is now increasing evidence that a constitutive expression of COX-2 plays a role in development and progression of malignant epithelial tumors. In the present study we investigated expression and function of COX-2 in malignant melanoma. Expression of COX-2 was determined by immunohistochemistry in 28 cases of primary skin melanoma and 4 benign nevi. We show that COX-2 was expressed in 26 cases (93%) of melanomas, with a moderate to strong expression in 19 cases (68%). Benign nevi as well as normal epithelium were negative in all cases. A constitutive expression of COX-2 mRNA and protein was found in five melanoma cell lines (A375, MeWo, SK-Mel-13, SK-Mel-28, and IGR-37) by using Northern blot as well as immunoblotting. All melanoma cell lines produced prostaglandin (PG) E2 between 468 and 3500 pg/ml as determined by ELISA. Treatment with NS-398 (50 microM), a specific inhibitor of COX-2, suppressed PGE2 production of all melanoma cell lines by 50-96%. The IC50 for inhibition of PGE2 production by NS-398 was determined as 4 microM, indicating that NS-398 acts via inhibition of the COX-2 isoenzyme. We could show that proliferation of melanoma cell lines was not influenced by treatment with NS-398 in concentrations up to 100 microM. However, NS-398 reduced Matrigel invasion of all five malignant melanoma cell lines by 50-68%. Our results indicate that COX-2 is expressed in malignant melanomas and may be involved in regulation of melanoma invasion. It remains to be investigated whether selective inhibitors of COX-2 might be useful for prevention or treatment of malignant melanoma.


Conventional management of maternal red cell alloimmunization compared with management by Doppler assessment of middle cerebral artery peak systolic velocity.
This study was undertaken to compare management of red blood cell alloimmunization by Doppler measurement of middle cerebral artery peak systolic velocity (MCA-PSV) to conventional management with amniocentesis. A historical cohort of 28 fetuses at risk for anemia caused by red blood cell alloimmunization was followed between 1999 and 2002 at a single institution. The decision to perform percutaneous umbilical cord blood sampling (PUBS) was based on conventional management. MCA-PSV Doppler was measured before amniocentesis or PUBS but not used clinically. Twenty-eight fetuses were followed up: 4 had severe anemia, 1 had moderate anemia, 3 had mild anemia, and 20 were nonanemic. Conventional management had a sensitivity and positive predictive value for moderate-to-severe anemia of 80% and 44%, with a false-positive rate of 56%. In the same patients, MCA-PSV Doppler had a sensitivity and positive predictive value for moderate-to-severe anemia of 100% and 71%, with a false-positive rate of 28%. Compared with conventional management, MCA-PSV Doppler may have a better predictive accuracy for moderate-to-severe fetal anemia in red blood cell alloimmunization. Management by MCA-PSV Doppler may eliminate the need for amniocentesis and reduce the number of PUBS performed in red blood cell-alloimmunized pregnancies.


Myocardial matrix metalloproteinase activity and abundance with congestive heart failure.
The left ventricular (LV) myocardial collagen matrix has been proposed to participate in the maintenance of LV geometry. Thus alterations in the composition of the LV myocardial collagen matrix may influence LV function. The matrix metalloproteinases (MMPs) are a family of enzymes that contribute to extracellular remodeling in several disease states. However, the types of MMPs expressed in the normal and congestive heart failure (CHF) state and the relation to MMP activity remained unclear. Accordingly, after 3 wk of pacing (240 beats/min), changes in LV function, substrate-specific MMP activity, and MMP subclass abundance were measured in comparison with control pigs (n = 6). Changes in LV function and geometry were measured by echocardiography; LV end-diastolic dimension increased (3.6 +/- 0.1 vs. 6.0 +/- 0.1 cm, P < 0.05) and LV fractional shortening decreased (47 +/- 1 vs. 15 +/- 1%, P < 0.05) compared with controls. Degradation of fibrillar collagen is achieved through the combined action of interstitial collagenase (MMP-1), gelatinase A (MMP-2), and stromelysin (MMP-3) (He, C., S. Wilheilm, A. Pentland, B. Marmer, G. Grant, A. Eisen, and G. Goldberg. Proc. Natl. Acad. Sci. USA 86:2632-2636, 1989; Woessner, J. FASEB J. 5: 2145-2154, 1991). Accordingly, the relative abundance of specific MMPs (MMP-1, MMP-2, and MMP-3) was examined by immunoblotting. With pacing CHF, the relative abundance for MMP-1 increased to 319 +/- 94%, MMP-2 increased to 194 +/- 31%, and MMP-3 increased to 493 +/- 159% (all P < 0.05). With pacing CHF, LV myocardial zymographic activity for the substrate gelatin increased by 119% (P < 0.05) and for the substrate collagen III by 153% (P < 0.05) over controls. Caseinolytic activity also increased with pacing CHF by 139% (P < 0.05) over controls. In conclusion, LV myocardial MMP activity and abundance increased with pacing-induced CHF. These findings demonstrate that pacing-induced CHF leads to changes in myocardial MMP activity and expression that may be responsible for LV remodeling in CHF.


Distinct age-related brain activity patterns in the prefrontal cortex when increasing cognitive load: A functional near-infrared spectroscopy study.
Researchers have long observed distinct brain activity patterns in older adults compared with younger adults that correlate with cognitive performance. Mainly, older adults tend to show over-recruitment of bilateral brain regions during lower task loads and improved performance interpreted as compensation, but not observed at higher loads. However, there are discrepancies about whether increases in activity are compensatory and whether older adults can show compensation at higher loads. Our aim was to examine age-related differences in prefrontal cortex (PFC) activity and cognitive performance using functional near-infrared spectroscopy (fNIRS) during single and dual N-back tasks. Twenty-seven young adults (18-27 years) and 31 older adults (64-84 yrs) took part in the study. We used a robust fNIRS data methodology consisting of channel and region of interest analyses. Results showed differences in performance between task load conditions and age-related differences in reaction times but no age-group effects for accuracy. Older adults exhibited more bilateral PFC activation compared with young adults across all tasks and showed increases in brain activity in high compared to low load conditions. Our findings further support previous reports showing that older adults use compensatory recruitment of additional brain regions in PFC to maintain cognitive performance but go against the notion that such compensation is not present at higher cognitive loads. Additionally, our results indicate that fNIRS is a sensitive tool that can characterize adaptive cortical changes in healthy aging.


A two-dimensional electrophoresis map of Chinese hamster ovary cell proteins based on fluorescence staining.
We report on the development of a detailed two-dimensional electrophoresis map of Chinese hamster ovary (CHO) cell proteins based on fluorescence staining and tandem time-of-flight (TOF/TOF)-mass spectrometry. We observed a 71% success rate in the identification of proteins even though the CHO genome is not sequenced. The map consists of 224 protein identifications present in 274 two-dimensional gel electrophoresis (2-DE) gel spots. We have also initiated a study of the phosphoproteome using a commercially available phosphoprotein-specific fluorescent stain. Using this stain, we observe 672 phosphorylated proteins, including many proteins known to be phosphorylated, which is 36% of the proteins we visualized with a total protein stain and consistent with expectations.


Antitumor activity of a novel antiestrogen (Analog II) on human breast cancer cells.
Analog II (1,1-dichloro-cis-2,3-diarylcyclopropane), previously shown to be a pure antiestrogen in mice, was examined for potential antitumor activity on human breast cancer cells in culture. In this study, Analog II produced a dose-related antiproliferative effect on the growth of estrogen receptor (ER)-positive MCF-7 human breast cancer cells over a concentration range of 10(-11) to 10(-5) M. Analog II increased the fraction of MCF-7 cells in the G2/M phase of the cell cycle. Further, this compound inhibited the growth of ER-negative MDA-MB-231 human breast cancer cells over a concentration range of 10(-9) to 10(-6) M. Using scanning electron microscopy to evaluate drug-induced changes in cellular morphology, it was observed that Analog II decreased the length and density of microvilli on both MCF-7 and MDA-MB-231 cells. The effects of Analog II on MCF-7 and MDA-MB-231 cell proliferation and morphology were not reversed in the presence of estradiol. In addition, the induction of estrogen-dependent genes in MCF-7 cells was not reversed by Analog II. It was observed that non-specific cytotoxicity may be responsible for part of the Analog II-induced inhibition on MCF-7 and MDA-MB-231 cell proliferation. However, the antitumor activity of this compound was found to be specific to human breast cancer cells since it did not alter the proliferation or viability of non-breast A-549 human lung cancer cells. In conclusion, these results indicate that Analog II is a potent antitumor agent, has a unique antitumor mechanism in breast cancer cells and may be effective in the treatment of breast cancer.


Methods for identifying lipoxygenase producing microorganisms on agar plates.
Plate assays for lipoxygenase producing microorganisms on agar plates have been developed. Both potassium iodide-starch and indamine dye formation methods were effective for detecting soybean lipoxygenase activity on agar plates. A positive result was also achieved using the β-carotene bleaching method, but the sensitivity of this method was lower than the other two methods. The potassium iodide-starch and indamine dye formation methods were also applied for detecting lipoxygenase production by Trichoderma reesei and Pichia pastoris transformants expressing the lipoxygenase gene of the fungus Gaeumannomyces graminis. In both cases lipoxygenase production in the transformants could be identified. For detection of the G. graminis lipoxygenase produced by Aspergillus nidulans the potassium iodide-starch method was successful. When Escherichia coli was grown on agar and soybean lipoxygenase was applied on the culture lipoxygenase activity could clearly be detected by the indamine dye formation method. This suggests that the method has potential for screening of metagenomic libraries in E. coli for lipoxygenase activity.


Fast and robust fixed-point algorithms for independent component analysis.
Independent component analysis (ICA) is a statistical method for transforming an observed multidimensional random vector into components that are statistically as independent from each other as possible. In this paper, we use a combination of two different approaches for linear ICA: Comon's information-theoretic approach and the projection pursuit approach. Using maximum entropy approximations of differential entropy, we introduce a family of new contrast (objective) functions for ICA. These contrast functions enable both the estimation of the whole decomposition by minimizing mutual information, and estimation of individual independent components as projection pursuit directions. The statistical properties of the estimators based on such contrast functions are analyzed under the assumption of the linear mixture model, and it is shown how to choose contrast functions that are robust and/or of minimum variance. Finally, we introduce simple fixed-point algorithms for practical optimization of the contrast functions. These algorithms optimize the contrast functions very fast and reliably.


Silicate-based bioceramics regulating osteoblast differentiation through a BMP2 signalling pathway.
Bioactive materials with osteostimulation properties have the potential to promote bone regeneration. We have found that silicate-based biomaterials have the osteostimulation ability for regeneration of large bone defects; however, the corresponding mechanism is unclear. In this study, we set out to elucidate the potential mechanism of silicate-based biomaterials with osteostimulation ability. A model silicate bioceramic, nagelschmidtite (NAGEL, Ca7P2Si2O16), was applied to study their ionic products on the effect of the Bone morphogenic protein (BMP) signaling pathway for osteoblast MC3T3-E1 as NAGEL has been previously shown to have excellent in vitro and in vivo bone-forming activity. BMP signaling, especially BMP2, is involved in bone formation during mammalian development and exhibits versatile regulatory functions in the body. It is found that NAGEL bioceramics significantly enhance the migration and osteoblastic differentiation of MC3T3-E1. mRNA and protein expression of BMP2 is enhanced by NAGEL bioceramics in a dose-dependent manner. Moreover, NAGEL bioceramics activate the Smad-dependent BMP signaling pathway and induce the activation of the BMP downstream cascade (OCN, OPN and Runx2). The accumulation of phosphorylated-Smad1/5 is induced by NAGEL bioceramics in the MC3T3-E1 cell nucleus. It is further found that NAGEL bioceramic-mediated migration, osteoblastic differentiation and the activation of the BMP downstream cascade are significantly downregulated by inhibition of BMP2 activity. Our results suggest that silicate-based NAGEL bioceramics possess excellent in vitro osteostimulation properties and the possible mechanism of silicate-based biomaterials with distinct osteostimulation may be directly related to the activation of the BMP2 signaling pathway of osteoblasts by release of Si-containing bioactive ionic products.


Twelve Tips for Students in Longitudinal Integrated Clerkships.
This article was migrated. The article was marked as recommended. Longitudinal integrated clerkships (LICs) are a curricular structure for medical clerkships grounded in continuity across learning environments and experiences. There has yet to be a peer-reviewed article directly advising students in LIC programs. Twelve tips were created based on a comprehensive literature review of LICs and supported by the cumulative experience of the authors. They are ordered in four sequential groups: The first three tips discuss the importance of the relationships that are built between students and their patients (Tip 1), preceptors (Tip 2), and peers (Tip 3). Next we cover health systems, and offer advice on how students can integrate their learning (Tip 4), use technology to their advantage (Tip 5), and practice systems thinking (Tip 6). We then discuss the educational benefits when students take an active role in patient care (Tip 7), their own learning (Tip 8), and the feedback process (Tip 9). Finally, we cover the importance of self-care (Tip 10), reflection (Tip 11) and patience (Tip 12) during a LIC. These tips are designed to help students understand the pedagogical theory that underpins LICs, take an active role in their education, and maximize learning and wellness during their clerkship.


Barriers to patient-clinician collaboration in asthma management: the patient experience.
To describe what adult patients with asthma report about their experiences with their own self-management behavior and working with their clinicians to control asthma. The study sample consisted of 104 patients with persistent asthma participating in a clinical trial on asthma monitoring. All subjects were seen by primary care clinicians of a large, academic medical center. This qualitative post hoc analysis examined the views of adults with asthma about their asthma-related health care. Patients attended monthly visits as part of their study participation, during which data were derived from semistructured interviews. All patients included in this analysis participated in the study for 1 year. At the end of study participation, patients were asked to complete an evaluation of their clinician's communication behavior. All study clinicians were also asked to complete a self-evaluation of their own communication behavior. Five major themes of barriers to successful self-management were identified, including personal constraints, social constraints, communication failures, medication issues, and health care system barriers to collaboration with their clinicians. Patients most frequently reported lack of communication surrounding issues relating to day-to-day management of asthma (31%) and home management of asthma (24%). Clinicians generally rated themselves well for consistency in showing nonverbal attentiveness (89%) and maintaining interactive conversations (93%). However, only 30% of clinicians reported consistency in helping patients make decisions about asthma management and only 33% of clinicians reported consistency in tailoring medication schedules to the patient's routines. These findings emphasize the difficulties of establishing and maintaining a therapeutic partnership between patients and clinicians. The results underscore the need for system-wide interventions that promote the success of a therapeutic patient-clinician relationship in order to achieve long-term success in chronic disease management.


Effect on water resources from upstream water diversion in the Ganges basin.
Bangladesh faces at least 30 upstream water diversion constructions of which Farakka Barrage is the major one. The effects of Farakka Barrage on water resources, socioeconomy, and culture have been investigated downstream in the basins of the Ganges and its distributaries. A diversion of up to 60% of the Ganges water over 25 yr has caused (i) reduction of water in surface water resources, (ii) increased dependence on ground water, (iii) destruction of the breeding and raising grounds for 109 species of Gangetic fishes and other aquatic species and amphibians, (iv) increased malnutrition, (v) deficiency in soil organic matter content, (vi) change in the agricultural practices, (vii) eradication of inland navigable routes, (viii) outbreak of waterborne diseases, (ix) loss of professions, and (x) obstruction to religious observances and pastimes. Further, arsenopyrites buried in the prebarrage water table have come in contact with air and formed water-soluble compounds of arsenic. Inadequate recharging of ground water hinders the natural cleansing of arsenic, and threatens about 75,000,000 lives who are likely to use water contaminated with up to 2 mg/L of arsenic. Furthermore, the depletion of surface water resources has caused environmental heating and cooling effects. Apart from these effects, sudden releases of water by the barrage during the flood season cause devestating floods. In consideration of such a heavy toll for the areas downstream, strict international rules have to be laid down to preserve the riparian ecosystems.


Neuroimaging and the search for a cure for Alzheimer disease.
As radiologists, our role in the workup of the dementia patient has long been limited by the sensitivity of our imaging tools and lack of effective treatment options. Over the past 30 years, we have made tremendous strides in understanding the genetic, molecular, and cellular basis of Alzheimer disease (AD). We now know that the pathologic features of AD are present 1 to 2 decades prior to development of symptoms, though currently approved symptomatic therapies are administered much later in the disease course. The search for true disease-modifying therapy continues and many clinical trials are underway. Current outcome measures, based on cognitive tests, are relatively insensitive to pathologic disease progression, requiring long, expensive trials with large numbers of participants. Biomarkers, including neuroimaging, have great potential to increase the power of trials by matching imaging methodology with therapeutic mechanism. One of the most important advances over the past decade has been the development of in vivo imaging probes targeted to amyloid beta protein, and one agent is already available for clinical use. Additional advances include automated volumetric imaging methods to quantitate cerebral volume loss. Use of such techniques in small, early phase trials are expected to significantly increase the number and quality of candidate drugs for testing in larger trials. In addition to a critical role in trials, structural, molecular, and functional imaging techniques can give us a window on the etiology of AD and other neurodegenerative diseases. This combination of developments has potential to bring diagnostic radiology to the forefront in AD research, therapeutic trials, and patient care.


Guidelines for operative vaginal birth.
To provide guidelines for operative vaginal birth in the management of the second stage of labour. Non-operative techniques, episiotomy, and Caesarean section are compared to operative vaginal birth. outcome: Reduced fetal and maternal morbidity and mortality. MEDLINE and Cochrane databases were searched using the key words 'vacuum' and 'birth' as well as 'forceps' and 'birth' for literature published in English from January 1970 to June 2004. The level of evidence and quality of recommendations made are described using the Evaluation of Evidence from the Canadian Task Force on the Periodic Health Examination. 1. Non-operative interventions such as one-to-one support, partogram use, oxytocin use, and delayed pushing in women using epidurals will decrease need for operative birth. (I-A) 2. Manual rotation may be used alone or in conjunction with instrumental birth with little or no increased risk to the pregnant woman or to the fetus. (III-B) 3. Routine episiotomy is not necessary for an assisted vaginal birth. (II-1E) 4. When operative intervention in the second stage of labour is required, the options, risks, and benefits of vacuum, forceps, and Caesarean section must be considered. The choice of intervention needs to be individualized, as one is not clearly safer or more effective than the other. (II-B) 5. Failure of the chosen method, vacuum and/or forceps, to achieve delivery of the fetus in a reasonable time should be considered an indication for abandonment of the method. (III-C) 6. Adequate clinical experience and appropriate training of the operator are essential to the safe performance of operative deliveries. Hospital credentialing boards should grant privileges for performing these techniques only to an appropriately trained individual who demonstrates adequate skills. (III-C). The Clinical Practice Obstetrics Committee and Executive and Council of the Society of Obstetricians and Gynaecologists of Canada approved these guidelines.


[Seasonal incidence of alcoholic psychoses].
Analysis of the incidence of alcoholic psychoses in Moscow in 1982-1993 revealed a considerable increase of their number during the period from March till July-August and a decrease by October-November. It was found that such increase resulted from low-concentration atmospheric oxygen in spring-summer period. Hypoxia as a factor provoking alcoholic psychosis is responsible for 10-12% of the cases. The highest sensitivity to hypoxia occurred in the last days of the abuse.


How Did School Meal Access Change during the COVID-19 Pandemic? A Two-Step Floating Catchment Area Analysis of a Large Metropolitan Area.
SARS-CoV-2 (COVID-19) resulted in school closures and contingencies across the U.S. that limited access to school meals for students. While some schools attempted to provide alternative meal access points where students or parents could pick up meals, many students-especially those in low-income households-lacked adequate transportation to these access points. Thus, physical proximity to meal access points was particularly important during the pandemic. In this study, we explore how school meal access changed during the COVID-19 pandemic, especially as it relates to race/ethnicity and socio-economic status. Taking into account both the "supply" (meal access points) and the "demand" (low-income students) for free meals, we employed a two-step floating catchment area analysis to compare meal accessibility in St. Louis, Missouri before and during the pandemic in the spring and summer of 2019 and 2020. Overall, while school meal access decreased during the spring of 2020 during the early months of the pandemic, it increased during the summer of 2020. Moreover, increased access was greatest in low-income areas and areas with a higher proportion of Black residents. Thus, continuing new policies that expanded access to school meals-especially for summer meal programs-could lead to positive long-term impacts on children's health and well-being.


The relationship between sentence meaning and word order: evidence from structural priming in German.
Most theories of human language production assume that generating a sentence involves several stages, including an initial stage where the prelinguistic message is determined and a subsequent stage of grammatical encoding. However, it is contentious whether grammatical encoding involves separate stages of grammatical-function assignment and linearization. To address this question, we examined the mapping between the message level and grammatical encoding in two structural priming experiments in which German speakers choose between three different structures expressing ditransitive events. Although speakers showed a tendency to repeat the order of constituents (noun phrase-prepositional phrase, NP-PP, vs. NP-NP), they were additionally primed to repeat the order of thematic roles when constituent structure was constant (NPRECIPIENT-NPTHEME vs. NPTHEME-NPRECIPIENT). Experiment 2 found that the latter effect could not be due to persistence of the order of phrases referring to animate and inanimate entities. These results suggest a direct mapping of thematic roles to word order, consistent with a model in which the message is mapped onto syntactic structure in a single stage.


[Cartography of epidemiologic data. The principal methods of making continuous data discrete and their importance in cartographic representation].
The cartographic representation of continuous quantitative data is often required in studies of the spatial distribution of health indicators. It imposes a succession of choices which directly affect the result obtained. The conversion of continuous data to discrete data is one of the most important steps in the development of epidemiological maps. This article presents the methods currently used to make data discrete, discusses the advantages and disadvantages of each method and assesses their appropriateness for various situations. As an example, and for comparison purposes, we mapped the same series of statistics (relative rates of avoidable male deaths, "associated with the health care system", for "employment zones" in France from 1988 to 1992), using each of the methods discussed.


Growth associated exopolysaccharide expression in Lactococcus lactis subspecies cremoris Ropy352.
A natural lactococcal isolate, Lactococcus lactis ssp. cremoris Ropy352, has been previously shown to express two phenotypically distinct exopolysaccharides (ropy and mucoid). This natural isolate was cultured on various media to explore the carbon requirements for exopolysaccharide expression. Ropy exopolysaccharide expression was optimal when grown in defined media rather than on M17-based media. Ropy352 was examined for inducible lysogenic phages. No lytic burst was observed in Ropy352 with ultraviolet light or mitomycin C for phage induction. The sugar compositions of the two phenotypically distinct exopolysaccharides were determined. The ropy exopolysaccharide is composed of galactose and glucose in the molar percents of 42 and 58%, respectively. The mucoid exopolysaccharide is composed of galactose, glucose, and mannose in the molar percents of 58, 29, and 13%, respectively. Mutational analysis revealed that mutations impairing ropy exopolysaccharide expression but not affecting mucoid exopolysaccharide expression could be isolated.


ERP investigation of study-test background mismatch during face recognition in schizophrenia.
Old/new effects on event-related potentials (ERP) were explored in 20 patients with schizophrenia and 20 paired comparison subjects during unfamiliar face recognition. Extrinsic perceptual changes - which influence the overall familiarity of an item while retaining face-intrinsic features for use in structural face encoding - were manipulated between the study phase and the test. The question raised here concerns whether these perceptual incongruities would have a different effect on the sense of familiarity and the corresponding behavioral and ERP measures in the two groups. The results showed that schizophrenia patients were more inclined to consider old faces shown against a new background as distractors. This drop in face familiarity was accompanied by the disappearance of ERP old/new effects in this condition, i.e., FN400 and parietal old/new effects. Indeed, while ERP old/new recognition effects were found in both groups when the picture of the face was physically identical to the one presented for study, the ERP correlates of recognition disappeared among patients when the background behind the face was different. This difficulty in disregarding a background change suggests that recognition among patients with schizophrenia is based on a global perceptual matching strategy rather than on the extraction of configural information from the face. The correlations observed between FN400 amplitude, the rejection of faces with a different background, and the reality-distortion scores support the idea that the recognition deficit found in schizophrenia results from early anomalies that are carried over onto the parietal ERP old/new effect. Face-extrinsic perceptual variations provide an opportune situation for gaining insight into the social difficulties that patients encounter throughout their lives.


Evidence of degradation process of sucrase-isomaltase in jejunum of adult rats.
To evaluate degradation processes of sucrase-isomaltase in adult rat jejunum, we determined enzymic activity of sucrase and isomaltase and compared it with the amount of immunoreactive sucrase-isomaltase. In rats fed or starved for 18h, killed at 10:00 h or 22:00 h, sucrase activity (expressed on the basis of total protein or of immunoreactive sucrase-isomaltase) was significantly (P less than 0.02) lower in the lower jejunum than in the upper jejunum; isomaltase activity was similar in both segments. Crossed immunoelectrophoresis demonstrated the existence of a second sucrase-isomaltase antigen reacting with anti-(sucrase-isomaltase) serum. This antigen was present in larger amounts in the lower jejunum than in the upper jejunum, exhibited immunological partial identity with the intact sucrase-isomaltase, and had isomaltase activity but no sucrase activity. Results suggest that this antigen is a degradation product of sucrase-isomaltase in which the sucrase active site has been broken down. To examine the role of pancreatic enzymes in degradation of sucrase-isomaltase, common pancreatico-biliary ducts were ligated. Within 18 h after the operation, the difference of sucrase activity between the upper and the lower jejunum disappeared and the amount of the second sucrase-isomaltase antigen markedly decreased in the lower jejunum. Our results indicate that, during the degradation of intestinal sucrase-isomaltase by the pancreatic proteinases, degradation of the sucrase active site precedes that of the isomaltase active site.


Study on nanobubble generation: saline solution/water exchange method.
In a recently introduced method for nanobubble generation, water is replaced with NaCl solution. It has the same mechanism as alcohol/water exchange: a liquid of higher gas solubility is used to replace one of lower gas solubility. Herein, the opposite process is realized by replacement of saline solutions with water. Interestingly, nanobubbles are also observed by AFM when different concentrations and valences of saline liquids are employed.


Number of supervised studies required to reach competence in advanced critical care transesophageal echocardiography.
To determine the minimum number of supervised transesophageal echocardiography (TEE) that intensivists should perform to reach competence in performing and interpreting a comprehensive hemodynamic assessment in ventilated intensive care unit patients. Prospective and multicentric study. Skills of 41 intensivists (trainees) with no (level 0) or little (level 1) experience in echocardiography was evaluated over a 6-month period, using a previously validated skills assessment score (/40 points). Trainees were evaluated at 1 (M1), 3 (M3) and 6 months (M6) by their tutor while performing 2 TEE examinations in ventilated patients. Competence was a priori defined by a skills assessment score >35/40 points. No difference in the score was observed between level 0 and level 1, except at M1 (22.2 ± 6.2 vs. 25.9 ± 4.4 points, p = 0.03). After 6 months, trainees performed a mean of 31 ± 9 supervised TEE. The score gradually increased from M1 to M6 (24 ± 6, 32 ± 3, and 35 ± 3 points, p < 0.001), regardless of trainees' initial level. A correlation was found between the number of supervised TEE and the skills assessment score (r (2) = 0.60; p < 0.001). The number of supervised TEE examinations which best predicted a score >35/40 points was 25, with a sensitivity of 81 % and a specificity of 93 % (area under the ROC curve: 0.91 ± 0.04). A number of 31 supervised TEE examinations predicted a score >35/40 points with a specificity close to 100 %. The performance of at least 31 supervised examinations over 6 months is required to reach competence in TEE driven hemodynamic evaluation of ventilated patient.


Susceptibility of the endangered frog Dendropsophus meridensis to the pathogenic fungus Batrachochytrium dendrobatidis.
Chytridiomycosis is an emerging disease that has driven some amphibian species to extinction while leaving others apparently unharmed. Its causative agent, Batrachochytrium dendrobatidis (Bd), now persists endemically in many amphibian communities. Understanding host species response to Bd infection is critical for managing chytridiomycosis because the epidemiology of this disease is host-specific. Dendropsophus meridensis is an endangered hylid frog endemic to the Venezuelan Andes. This species is sympatric with the American bullfrog Lithobates catesbeianus, an introduced species known to act as a reservoir for Bd. High prevalence of infection and high zoospore burdens in wild populations of D. meridensis in the Venezuelan Andes suggested some tolerance for Bd. However, experimental exposure of post-metamorphic frogs resulted in 53% mortality, a value that represents a 14-fold increase in the odds of dying compared to control frogs. Repeated diagnostics using real-time polymerase chain reaction assays demonstrated that individuals that died accumulated a higher number of zoospores than those that survived, although this value was lower than the mean zoospore burdens observed in natural populations. Given the susceptibility of D. meridensis to a strain of Bd isolated from a nearby population of bullfrogs, we emphasize the need to limit the dispersion of this invasive species.


c-Myc Sustains Transformed Phenotype and Promotes Radioresistance of Embryonal Rhabdomyosarcoma Cell Lines.
We have previously reported that the MEK/ERK pathway sustains in vitro and in vivo transformed phenotype and radioresistance of embryonal rhabdomyosarcoma (ERMS) cell lines. Furthermore, we found that aberrant MEK/ERK signaling activation promotes c-Myc oncoprotein accumulation. In this study, the role of c-Myc in sustaining the ERMS transformed and radioresistant phenotype is characterized. RD and TE671 cell lines conditionally expressing MadMyc chimera protein, c-Myc-dominant negative and shRNA directed to c-Myc were used. Targeting c-Myc counteracted in vitro ERMS adherence and in suspension, growth motility and the expression of pro-angiogenic factors. c-Myc depletion decreased MMP-9, MMP-2, u-PA gelatinolytic activity, neural cell adhesion molecule sialylation status, HIF-1α, VEGF and increased TSP-1 protein expression levels. Rapid but not sustained targeting c-Myc radiosensitized ERMS cells by radiation-induced apoptosis, DNA damage and impairing the expression of DNA repair proteins RAD51 and DNA-PKcs, thereby silencing affected ERMS radioresistance. c-Myc sustains ERMS transformed phenotype and radioresistance by protecting cancer cells from radiation-induced apoptosis and DNA damage, while promoting radiation-induced DNA repair. This data suggest that c-Myc targeting can be tested as a promising treatment in cancer therapy.


Potent Fc Receptor Signaling by IgA Leads to Superior Killing of Cancer Cells by Neutrophils Compared to IgG.
Antibody therapy of cancer is increasingly used in the clinic and has improved patient's life expectancy. Except for immune checkpoint inhibition, the mode of action of many antibodies is to recognize overexpressed or specific tumor antigens and initiate either direct F(ab')2-mediated tumor cell killing, or Fc-mediated effects such as complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity/phagocytosis (ADCC/P) after binding to activating Fc receptors. All antibodies used in the clinic are of the IgG isotype. The IgA isotype can, however, also elicit powerful anti-tumor responses through engagement of the activating Fc receptor for monomeric IgA (FcαRI). In addition to monocytes, macrophages and eosinophils as FcαRI expressing immune cells, neutrophils are especially vigorous in eliminating IgA opsonized tumor cells. However, with IgG as single agent it appears almost impossible to activate neutrophils efficiently, as we have visualized by live cell imaging of tumor cell killing. In this study, we investigated Fc receptor expression, binding and signaling to clarify why triggering of neutrophils by IgA is more efficient than by IgG. FcαRI expression on neutrophils is ~2 times and ~20 times lower than that of Fcγ receptors FcγRIIa and FcγRIIIb, but still, binding of neutrophils to IgA- or IgG-coated surfaces was similar. In addition, our data suggest that IgA-mediated binding of neutrophils is more stable compared to IgG. IgA engagement of neutrophils elicited stronger Fc receptor signaling than IgG as indicated by measuring the p-ERK signaling molecule. We propose that the higher stoichiometry of IgA to the FcαR/FcRγ-chain complex, activating four ITAMs (Immunoreceptor Tyrosine-based Activating Motifs) compared to a single ITAM for FcγRIIa, combined with a possible decoy role of the highly expressed FcγRIIIb, explains why IgA is much better than IgG at triggering tumor cell killing by neutrophils. We anticipate that harnessing the vast population of neutrophils by the use of IgA monoclonal antibodies can be a valuable addition to the growing arsenal of antibody-based therapeutics for cancer treatment.


The anatomy of language: a review of 100 fMRI studies published in 2009.
In this review of 100 fMRI studies of speech comprehension and production, published in 2009, activation is reported for: prelexical speech perception in bilateral superior temporal gyri; meaningful speech in middle and inferior temporal cortex; semantic retrieval in the left angular gyrus and pars orbitalis; and sentence comprehension in bilateral superior temporal sulci. For incomprehensible sentences, activation increases in four inferior frontal regions, posterior planum temporale, and ventral supramarginal gyrus. These effects are associated with the use of prior knowledge of semantic associations, word sequences, and articulation that predict the content of the sentence. Speech production activates the same set of regions as speech comprehension but in addition, activation is reported for: word retrieval in left middle frontal cortex; articulatory planning in the left anterior insula; the initiation and execution of speech in left putamen, pre-SMA, SMA, and motor cortex; and for suppressing unintended responses in the anterior cingulate and bilateral head of caudate nuclei. Anatomical and functional connectivity studies are now required to identify the processing pathways that integrate these areas to support language.


Pediatric Non-Rhabdomyosarcoma Soft Tissue Sarcomas: Standard of Care and Treatment Recommendations from the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG).
This paper describes the standard of care for patients with non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) and the therapeutic recommendations developed by the European paediatric Soft tissue sarcoma Study Group (EpSSG). NRSTS form a very mixed group of mesenchymal extraskeletal malignancies. Their rarity, heterogeneity, and aggressiveness make the management of children and adolescents with these tumors complex and challenging. The overall cure rate for patients with NRSTS is around 70%, but survival depends on several prognostic variables, such as histotype and tumor grade, extent of disease and stage, tumor size, and tumor site. While surgery remains the mainstay of treatment for most of these tumors, a multimodal therapeutic approach including radiotherapy and chemotherapy is required in many cases. The EpSSG NRSTS 2005 study was the first prospective protocol tailored specifically to NRSTS. Together with the ARST0332 study developed by the North-American Soft Tissue Sarcoma Committee of the Children's Oncology Group (COG), the EpSSG NRSTS 2005 study currently represents the benchmark for these tumors, establishing risk-adapted standards of care. The EpSSG has developed common treatment recommendations for the large group of adult-type NRSTS (including synovial sarcoma), and specific treatment recommendations for other particular adult-type histologies (ie, alveolar soft-part sarcoma, clear cell sarcoma and dermatofibrosarcoma protuberans); other highly malignant tumors with a biology and clinical behavior differing from those of adult-type NRSTS (ie, rhabdoid tumors and desmoplastic small round cell tumor); and soft tissue tumors of intermediate malignancy (ie desmoid-type fibromatosis, inflammatory myofibroblastic tumors, and infantile fibrosarcoma). New effective drugs are needed for patients whose NRSTS carries the worst prognosis, ie, those with unresectable tumors, metastases at diagnosis, or relapsing disease. Progress in this area relies on our ability to develop international integrated prospective collaborations, both within existing pediatric oncology networks and, importantly, between the communities of specialists treating pediatric and adult sarcoma.


Protease-activated receptor (PAR), a novel family of G protein-coupled seven trans-membrane domain receptors: activation mechanisms and physiological roles.
The protease-activated receptor (PAR) belongs to the large superfamily of G-protein-coupled seven trans-membrane domain receptors. The activation of PARs is achieved by proteolytic unmasking of the cryptic N-terminal receptor-activating sequence that binds to the body of the same receptor molecule. PARs-1, -3 and -4 are activated by thrombin, while PAR-2 is activated by trypsin or mast cell tryptase, but not by thrombin. PARs are widely distributed to a variety of tissues and participate in a number of physiological or pathophysiological phenomena such as platelet aggregation, inflammation and cardiovascular, digestive or respiratory functions. Thus, PARs are of physiological importance and also of pharmacological interest as the novel target for drug development.


Assessing molecular interactions with biophysical methods using the validation cross.
There are numerous methods for studying molecular interactions. However, each method gives rise to false negative- or false positive binding results, stemming from artifacts of the scientific equipment or from shortcomings of the experimental format. To validate an initial positive binding result, additional methods need to be applied to cover the shortcomings of the primary experiment. The aim of such a validation procedure is to exclude as many artifacts as possible to confirm that there is a true molecular interaction that meets the standards for publishing or is worth investing considerable resources for follow-up activities in a drug discovery project. To simplify this validation process, a graphical scheme - the validation cross - can be used. This simple graphic is a powerful tool for identifying blind spots of a binding hypothesis, for selecting the most informative combination of methods to reveal artifacts and, in general, for understanding more thoroughly the nature of a validation process. The concept of the validation cross was originally introduced for the validation of protein-ligand interactions by NMR in drug discovery. Here, an attempt is made to expand the concept to further biophysical methods and to generalize it for binary molecular interactions.


[Evaluating oronasal flow with temperature (thermistor) and obstructive pressure (prongs)].
The measurement of oronasal flow during sleep studies using thermistors is internationally well accepted. As an alternative the possibility exists to measure the pressure at the nose by means of nasal prongs. Our objective was to compare and evaluate the methods to detect respiratory events in clinical routine, namely O2-saturation by pulse oxymetry oronasal flow by thermistors thoraco-abdominal effort by belts oronasal flow by prongs, 8 consecutive patients suspected of sleep apnoea syndrome (7 m, 1 f), mean age 56.5 +/- 9.5 years, height 173 +/- 6.4 cm, BMI 28.7 +/- 2.6 kg/m2, Epworth sleepiness scale score 9.1 +/- 3.2, AHI 24.9 +/- 13.7 h-1, lowest SaO2 86 +/- 4.9%, were examined. Between nose and mouth we fixed an oronasal 3-point thermistor and oronasal prongs (2 openings at the mouth and 2 openings at the mouth applying a common tube). During breathing the resulting pressure was registered with a pressure transducer parallel to the signal of the thermistors and the other polysomnographic data. We defined a respiratory event if at least one of the 4 signals met the criteria of a respiratory disturbance (for exact definitions see method). The detection rate of the 4 signals was calculated in relation to the sum of all events. Of the 1824 events (100%) only 52.3% were detected by an O2-desaturation of more than 4%, but 61.0% by thermistors. An acceptable detection rate was found measuring effort with 83.4%, only nasal prongs detected 95.1% of all events. We conclude that with regard to the detection rate of respiratory events the measurement of pressure by nasal prongs is superior to the use of thermistors.