Interpretation of the à ← X[combining tilde] transition of hydrated protons in aqueous solutions observed in the far-UV region with quantum chemical calculations.
Far-ultraviolet spectra (wavelength: 140-200 nm) of group I, II, and XIII cation nitrate electrolyte aqueous solutions show that the first electronic transition (à ← X[combining tilde]) energies of water hydrating the cations are linearly dependent on the hydration energies of the cations. However, deviations from these linear relations have been observed only for electrolyte solutions of small cations, i.e., H+, Li+, and Be2+ (T. Goto, A. Ikehata, Y. Morisawa, N. Higashi and Y. Ozaki, Phys. Chem. Chem. Phys., 2012, 14, 8097-8104). In this study, the à ← X[combining tilde] transitions of group I cation-water clusters holding the first and second shell water molecules around the cations (M+(H2O)6, M+: H+, Li+, Na+, and K+) were studied with quantum chemical calculations to elucidate the cation size effects on the electronic states of each shell water molecule. The calculation results show that the à ← X[combining tilde] transitions of the small cation clusters, especially H+, are more intensely split than those of the larger cation clusters, because of the difference in the à ← X[combining tilde] transition of each shell and the asymmetric structure of H+(H2O)6. Specifically, the à ← X[combining tilde] transitions of the first shell water molecules are mostly ascribed to the charge transfer transition of the nonbonding electrons to the central cations, while those of the second shell water molecules are ascribed to the transition to the σ* orbitals of the second shell water molecules. Moreover, the condensed and distorted structure of H+(H2O)6 causes an asymmetrically delocalized electronic distribution in the excited state, as well as the ground state, because the electronic interference from the second shell water molecules weakens the exciton-hole interaction of the first shell. These interpretations based on calculations provide a detailed explanation concerning the substantial blue-shift of the à ← X[combining tilde] band of aqueous sulfuric acid solutions.


Ten outcome measures in forensic mental health: A survey of clinician views on comprehensiveness, ease of use and relevance.
Measurement of outcomes in forensic mental health services is essential to ensure that these services are delivering good quality care and treatment. Instruments for outcome measurement should cover all important domains, be easy to implement in a routine clinical context and facilitate transfer of relevant information between clinicians as the patient progresses along a recovery and rehabilitation pathway. We sought the views of clinicians on 10 common instruments used as outcome measures in forensic mental health services, especially on their perceived comprehensiveness and ease of use. An online survey was used to gather the views of clinicians from a range of professional backgrounds working in forensic mental health services in the United Kingdom. The selected instruments were identified from a previous systematic review of instruments for measuring outcomes in this context. Questions covered comprehensiveness, ease of use, patient involvement, relevance and use for progressing tracking and care planning. Complete responses were received from 229 individuals. The range of respondents either agreeing or strongly agreeing that individual instruments were comprehensive was 6-39%; easy to use 19%-69%; relevant 31%-78%; useful to measure progress 7-70%; and useful for care planning 33-81%. Respondents reported that, for each of the 10 instruments, full involvement of patients varied between 3% and 22%; partial involvement 12-45%, patients informed, but not involved 11%-28%; and patients not involved or informed 21%-64%. The Health of the Nation Outcome Scale Secure, the only instrument designed as an outcome measure, is not regarded by clinicians as useful in that respect and the majority of clinicians do not inform patients they are using it. Clinicians appear most familiar with the Historical Clinical Risk 20 (HCR-20), which some respondents considered potentially useful as a progress measure but with limited patient involvement. Most respondents did not think that the HCR-20 is comprehensive. There is a need for outcome measures that are comprehensive, easy to use and have adequate patient involvement in their development and rating.


Retrospective comparison of bortezomib-containing regimens with vincristine-doxorubicin-dexamethasone (VAD) as induction treatment prior to autologous stem cell transplantation for multiple myeloma.
Patients with multiple myeloma (MM) achieving high-quality responses, defined as a complete response (CR) and a very good partial response (VGPR) after transplant, benefit from high-dose therapy followed by autologous stem cell transplantation (ASCT). Induction pre-transplantation treatment with vincristine, doxorubicin and dexamethasone (VAD) is currently being replaced by new targeted agents with high anti-myeloma activity. The use of these novel agents may increase the CR + VGPR rate before ASCT, which may improve post-transplantation responses and survival. We performed a retrospective analysis of 69 patients with MM who received bortezomib-containing regimens (n = 30) or VAD (n = 39) before collection of peripheral blood stem cells and ASCT. Objective response rate (at least a partial response) prior to ASCT was documented in 27 (90%) of 30 and 31 (81.6%) of evaluable 38 patients with bortezomib-containing regimens and VAD, respectively. The difference between the two groups was not significant (P = 0.494). However, the high-quality response rate with VGPR or more in the bortezomib group was significantly higher compared with the VAD group (66.7% vs. 34.2%, respectively, P = 0.006). The superiority of bortezomib-containing regimens in the high-quality response rate remained significant for only the newly diagnosed patients (n = 16, P = 0.008). The engraftment data as well as stem cell harvesting were comparable between the two groups. The major bortezomib-related toxicities were thrombocytopenias and peripheral neuropathies; toxicities of VAD were hematologic and infectious. After ASCT, the difference between the two groups did not reach the level of statistical significance with respect to progression-free survival and overall survival (P = 0.498 and 0.835, respectively). The results of this retrospective comparison of bortezomib-containing regimens with the VAD as induction treatment prior to ASCT for MM provided a demonstration of the superiority of bortezomib therapy in terms of achieving a high-quality response. However, survivals following ASCT did not differ according to the induction regimens.


Relation between CT axial cross-sectional area of the oropharynx and obstructive sleep apnea syndrome in adults.
To look for correlation between obstructive sleep apnea syndrome (OSAS) and axial cross-sectional area of the narrowed oropharyngeal lumen. Thirty-six men with OSAS and 10 control subjects underwent polysomnography with registration of oxygen saturation and number of sleep apnea episodes and their duration. Nine of them underwent uvulopalatopharyngoplasty and repeated polysomnography. Each polysomnography was followed by high-resolution CT scan with reconstructions in sagittal and coronal planes. Measurements of the axial cross-sectional area of the oropharyngeal lumen were taken at the level of the narrowing. Twenty-seven patients with severe OSAS (high number and prolonged episodes of OSAS and 22% or greater decrease in oxygen saturation) had a narrowed oropharyngeal cross-sectional area less than 50 mm2 wide. The control subjects and 6 patients who had uvulopalatopharyngoplasty without OSAS had a minimal pharyngeal cross-sectional area of 110 mm2. Eight patients with moderate OSAS and 3 patients who had uvulopalatopharyngoplasty and diagnoses of OSAS had intermediate values of the narrowest pharyngeal level--between 60 mm2 and 100 mm2. The measurement of the axial cross-sectional area of the pharyngeal lumen can play an important role in evaluation of OSAS and indications for surgery.


Asiatic acid and corosolic acid enhance the susceptibility of Pseudomonas aeruginosa biofilms to tobramycin.
Asiatic acid and corosolic acid are two natural products identified as biofilm inhibitors in a biofilm inhibition assay. We evaluated the activities of these two compounds on Pseudomonas aeruginosa biofilms grown in rotating disk reactors (RDRs) in combination with tobramycin and ciprofloxacin. To determine the ruggedness of our systems, the antibiotic susceptibilities of these biofilms were assessed with tobramycin and ciprofloxacin. The biofilm bacteria produced in the RDR were shown to display remarkable tolerance to 10 mug/ml of ciprofloxacin, thus mimicking the tolerance observed in recalcitrant bacterial infections. These studies further demonstrate that a nonmucoid strain of P. aeruginosa can form a biofilm that tolerates ciprofloxacin at clinically relevant concentrations. Neither asiatic acid nor corosolic acid reduced the viable cell density of P. aeruginosa biofilms. However, both compounds increased the susceptibility of biofilm bacteria to subsequent treatment with tobramycin, suggesting asiatic acid and corosolic acid to be compounds that potentiate the activity of antibiotics. A similar statistical interaction was observed between ciprofloxacin and subsequent treatment with tobramycin.


Visualization technology in medical education.
Visualization technology offers the possibility of profoundly changing the way in which osteopathic medical students assimilate basic osteopathic principles by giving them the ability to interactively explore biomechanical components of the musculoskeletal system, and to investigate the effects that changes in physical properties can have on functionality. The authors are developing a multiple-volume series of computer-assisted learning modules that use three-dimensional, visualization technology to enhance the acquisition of knowledge and skills necessary for clinical evaluation and treatment of the lumbar and cervical spines. These materials, designed to serve as an adjunct to teaching strategies that faculty are currently using, are available to students on campus through the Kobiljak Resource Center at Michigan State University College of Osteopathic Medicine (MSUCOM) and via the Internet (http://hal.bim.msu.edu/EdTech) to individuals and groups who are physically removed from the Michigan State University campus. In addition to addressing needs in undergraduate and graduate medical education, these osteopathic materials, delivered to users via CD-ROM, have been approved for obtaining Category 1-B CME credits (http://hal.bim.msu.edu/cme). It is anticipated that the use of these materials will facilitate understanding of static and dynamic relationships among physical components of the musculoskeletal system, thus contributing to ongoing efforts to develop and maintain physician, faculty, and student expertise in areas that are uniquely osteopathic. Although initial efforts were restricted to the cervical and lumbar spines, future modules will include other regions of the body. The ultimate goal is to enable students to visualize the effects of pathologic processes as they interactively control an articulation in three-dimensional space.


In vitro contracture test results and anaesthetic management of a patient with emery-dreifuss muscular dystrophy for cardiac transplantation.
Emery-Dreifuss muscular dystrophy (EDMD) is a hereditary neuromuscular disorder characterized by slowly progressive muscle weakness, early contractures, and dilated cardiomyopathy. We reported an uneventful general anaesthesia using total intravenous anaesthesia (TIVA) for cardiac transplantation in a 19-year-old woman suffering from EDMD. In vitro contracture test results of two pectoralis major muscle bundles of the patient suggest that exposition to triggering agents does not induce a pathological sarcoplasmic calcium release in the lamin A/C phenotype. However, due to the lack of evidence in the literature, we would recommend TIVA for patients with EDMD if general anaesthesia is required.


Presence of epidermal growth factor, platelet-derived growth factor, and their receptors in human myometrial tissue and smooth muscle cells: their action in smooth muscle cells in vitro.
Immunohistochemical observations indicate that human myometrial smooth muscle cells express epidermal growth factor (EGF) and platelet-derived growth factor (PDGF)-AB and contain EGF and PDGF-beta receptors with no variation in intensity with phases of the menstrual cycle. Furthermore, immunofluorescent microscopic studies revealed that primary myometrial smooth muscle cell cultures also express EGF, PDGF-AB, and contain EGF and PDGF-beta, but not alpha-receptor. Incubation of subconfluent smooth muscle cells in serum-free medium leads to quiescence within 48 h as demonstrated by 3H-thymidine incorporation and labeling index. Exposure of quiescent cells to 10% fetal bovine serum stimulates resumption of DNA synthesis and proliferation in a time-dependent manner with a doubling time of 41.6 h. EGF (1.5-50 ng/ml) and PDGF-AB (1-10 ng/ml) in a dose- and time-dependent manner significantly stimulated 3H-thymidine incorporation by quiescent myometrial smooth muscle cells (P less than 0.05). Combinations of EGF (15 ng/ml) and PDGF-AB (10 ng/ml) significantly increased 3H-thymidine incorporation induced by either growth factor alone (P less than 0.05). PDGF-BB at 10 ng/ml also stimulated 3H-thymidine incorporation and its effect was similar to that induced by PDGF-AB at the same concentration. 17 beta-Estradiol (E2) at 1 microM inhibited 3H-thymidine incorporation by the smooth muscle cells (P less than 0.05). E2 also reduced the stimulatory effect of EGF (15 ng/ml) and PDGF (3 ng/ml). Progesterone at 1 microM either alone or in combination with E2 did not have any effect on 3H-thymidine incorporation or alter the mitogenic action of EGF and PDGF. The effect of EGF and PDGF on cell growth and 3H-thymidine incorporation by myometrial smooth muscle cells was independent of phases of the menstrual cycle. In summary, the results of present studies indicate that human myometrial tissue and myometrial smooth muscle cells in primary culture locally produce EGF and PDGF-AB and contain EGF and PDGF-beta, but not alpha-receptors. Moreover, the myometrial smooth muscle cells in culture respond to the mitogenic action of EGF and PDGF.


An Automated Draft Report Generator for Peripheral Blood Smear Examinations Based on Complete Blood Count Parameters.
Complete blood count (CBC) results play an important role in peripheral blood smear (PBS) examinations. Many descriptions in PBS reports may simply be translated from CBC parameters. We developed a computer program that automatically generates a PBS draft report based on CBC parameters and age- and sex-matched reference ranges. The Java programming language was used to develop a computer program that supports a graphical user interface. Four hematology analyzers from three different laboratories were tested: Sysmex XE-5000 (Sysmex, Kobe, Japan), Sysmex XN-9000 (Sysmex), DxH800 (Beckman Coulter, Brea, CA, USA), and ADVIA 2120i (Siemens Healthcare Diagnostics, Eschborn, Germany). Input data files containing 862 CBC results were generated from hematology analyzers, middlewares, or laboratory information systems. The draft reports were compared with the content of input data files. We developed a computer program that reads CBC results from a data file and automatically writes a draft PBS report. Age- and sex-matched reference ranges can be automatically applied. After examining PBS, users can modify the draft report based on microscopic findings. Recommendations such as suggestions for further evaluations are also provided based on morphological findings, and they can be modified by users. The program was compatible with all four hematology analyzers tested. Our program is expected to reduce the time required to manually incorporate CBC results into PBS reports. Systematic inclusion of CBC results could help improve the reliability and sensitivity of PBS examinations.


Central Sensitization in Knee Osteoarthritis: Relating Presurgical Brainstem Neuroimaging and PainDETECT-Based Patient Stratification to Arthroplasty Outcome.
The neural mechanisms of pain in knee osteoarthritis (OA) are not fully understood, and some patients have neuropathic-like pain associated with central sensitization. To address this, we undertook the present study in order to identify central sensitization using neuroimaging and PainDETECT and to relate it to postarthroplasty outcome. Patients awaiting arthroplasty underwent quantitative sensory testing, psychological assessment, and functional magnetic resonance imaging (fMRI). Neuroimaging (fMRI) was conducted during punctate stimulation (n = 24) and cold stimulation (n = 20) to the affected knee. The postoperative outcome was measured using the Oxford Knee Score, patient-reported moderate-to-severe long-term pain postarthroplasty, and a range of pain-related questionnaires. Patients with neuropathic-like pain presurgery (identified using PainDETECT; n = 14) reported significantly higher pain in response to punctate stimuli and cold stimuli near the affected joint (P < 0.05). Neural activity in these patients, compared to those without neuropathic-like pain, was significantly lower in the rostral anterior cingulate cortex (P < 0.05) and higher in the rostral ventromedial medulla (RVM) during punctate stimulation (P < 0.05), with significant functional connectivity between these two areas (r = 0.49, P = 0.018). Preoperative neuropathic-like pain and higher neural activity in the RVM were associated with moderate-to-severe long-term pain after arthroplasty (P = 0.0356). The psychophysical and neuroimaging data suggest that a subset of OA patients have centrally mediated pain sensitization. This was likely due to supraspinally mediated reductions in inhibition and increases in facilitation of nociceptive signaling, and was associated with a worse outcome following arthroplasty. The neurobiologic confirmation of central sensitization in patients with features of neuropathic pain, identified using PainDETECT, provides further support for the investigation of such bedside measures for patient stratification, to better predict postsurgical outcomes.


Novel predictors of overt nephropathy in subjects with type 1 diabetes. A nested case control study from the Pittsburgh Epidemiology of Diabetes Complications cohort.
Predictors of diabetic nephropathy are only partly known and traditional risk factors do not adequately explain disease risk. We thus examined novel risk factors for overt nephropathy (ON) in type 1 diabetes. The EDC is a prospective study of childhood-onset type 1 diabetes. When first seen (1986-1988), mean age was 28 and diabetes duration 19 years. In the subsequent 10 years, 56 of 485 subjects without ON in 1986-88 developed ON. An age, duration (+/-3 years), and sex-matched control was identified for 47 cases. Forty-two matched pairs had available stored plasma samples obtained prior to ON onset in cases, and complete standard risk factor data. Cases had a higher baseline albumin excretion rate (AER), HbA1, pulse rate, non-HDL cholesterol, fibrinogen, small LDL and lower eGDR and LDL particle size compared to controls (all P values<0.05). Multiple measures of immune complexes were increased in cases (P<0.05), whereas borderline elevations were seen for total antioxidant reserve (P=0.06) and retinol (P=0.08). Multivariably, other than AER, LDL particle size and IgG-IC were predictive beyond the standard predictors. Besides AER, the immunecomplexes and lipoprotein subclasses may provide additional information in the assessment of ON risk in type 1 diabetes.


Colloids versus crystalloids for fluid resuscitation in critically ill patients.
Colloid solutions are widely used in fluid resuscitation of critically ill patients. There are several choices of colloid, and there is ongoing debate about the relative effectiveness of colloids compared to crystalloid fluids. To assess the effects of colloids compared to crystalloids for fluid resuscitation in critically ill patients. We searched the Cochrane Injuries Group Specialised Register (17 October 2012), the Cochrane Central Register of Controlled Trials (The Cochrane Library) (Issue 10, 2012), MEDLINE (Ovid) 1946 to October 2012, EMBASE (Ovid) 1980 to October 2012, ISI Web of Science: Science Citation Index Expanded (1970 to October 2012), ISI Web of Science: Conference Proceedings Citation Index-Science (1990 to October 2012), PubMed (October 2012), www.clinical trials.gov and www.controlled-trials.com. We also searched the bibliographies of relevant studies and review articles. Randomised controlled trials (RCTs) of colloids compared to crystalloids, in patients requiring volume replacement. We excluded cross-over trials and trials involving pregnant women and neonates. Two review authors independently extracted data and rated quality of allocation concealment. We analysed trials with a 'double-intervention', such as those comparing colloid in hypertonic crystalloid to isotonic crystalloid, separately. We stratified the analysis according to colloid type and quality of allocation concealment. We identified 78 eligible trials; 70 of these presented mortality data.COLLOIDS COMPARED TO CRYSTALLOIDS: Albumin or plasma protein fraction - 24 trials reported data on mortality, including a total of 9920 patients. The pooled risk ratio (RR) from these trials was 1.01 (95% confidence interval (CI) 0.93 to 1.10). When we excluded the trial with poor-quality allocation concealment, pooled RR was 1.00 (95% CI 0.92 to 1.09). Hydroxyethyl starch - 25 trials compared hydroxyethyl starch with crystalloids and included 9147 patients. The pooled RR was 1.10 (95% CI 1.02 to 1.19). Modified gelatin - 11 trials compared modified gelatin with crystalloid and included 506 patients. The pooled RR was 0.91 (95% CI 0.49 to 1.72). (When the trials by Boldt et al were removed from the three preceding analyses, the results were unchanged.) Dextran - nine trials compared dextran with a crystalloid and included 834 patients. The pooled RR was 1.24 (95% CI 0.94 to 1.65). COLLOIDS IN HYPERTONIC CRYSTALLOID COMPARED TO ISOTONIC CRYSTALLOID: Nine trials compared dextran in hypertonic crystalloid with isotonic crystalloid, including 1985 randomised participants. Pooled RR for mortality was 0.91 (95% CI 0.71 to 1.06). There is no evidence from randomised controlled trials that resuscitation with colloids reduces the risk of death, compared to resuscitation with crystalloids, in patients with trauma, burns or following surgery. Furthermore, the use of hydroxyethyl starch might increase mortality. As colloids are not associated with an improvement in survival and are considerably more expensive than crystalloids, it is hard to see how their continued use in clinical practice can be justified.


Effectiveness of MP29-02 for the treatment of allergic rhinitis in real-life: results from a noninterventional study.
The efficacy of MP29-02 (a novel intranasal formulation of azelastine hydrochloride and fluticasone propionate in an advanced delivery system) has been well established in controlled clinical trials. This study was designed to assess the use of MP29-02 and its effectiveness in routine clinical practice. This was a German multicenter, prospective, noninterventional study, including 1781 allergic rhinitis (AR) patients. Eligible patients (i.e., acute AR symptoms and visual analog scale [VAS] score >50 mm) were included, assigned MP29-02 at baseline, and reassessed after ∼14 days. Patients assessed symptom control using a VAS from 0 (not at all bothersome) to 100 mm (very bothersome) in the morning before MP29-02 use, on days 0, 1, 3, and 7 and after ∼ 14 days. Patients' perceived levels of disease control were assessed on day 3. The Youden index determined patient-reported VAS score cutoffs on day 3 for "well controlled" and "partly controlled." MP29-02 reduced the VAS score from 75.4 mm (SD = 17.2) at baseline to 21.3 mm (SD = 18.3) by the last visit, a shift of 54.1 mm (SD = 24.6). One in every two patients felt their symptoms were well controlled at day 3. This perception of well-controlled symptoms at day 3 corresponded to an optimal VAS cutoff of 36 mm. On average, patients treated with MP29-02 crossed this well-controlled VAS cutoff by last visit. Similar results were found in adolescents, adults, and older adults, in those with perennial AR (PAR), seasonal AR (SAR), or PAR + SAR and in those with more and less severe disease. MP29-02 provides effective and rapid symptom control across all age groups in a real-life setting with responder rates higher than those observed in controlled clinical trials, supporting MP29-02's position as the drug of choice for the treatment for AR.


Hydrologic variability governs population dynamics of a vulnerable amphibian in an arid environment.
Dynamics of many amphibian populations are governed by the distribution and availability of water. Therefore, understanding the hydrological mechanisms that explain spatial and temporal variation in occupancy and abundance will improve our ability to conserve and recover populations of vulnerable amphibians. We used 16 years of survey data from intermittent mountain streams in the Sonoran Desert to evaluate how availability of surface water affected survival and adult recruitment of a threatened amphibian, the lowland leopard frog (Lithobates yavapaiensis). Across the entire study period, monthly survival of adults ranged from 0.72 to 0.99 during summer and 0.59 to 0.94 during winter and increased with availability of surface water (Z = 7.66; P < 0.01). Recruitment of frogs into the adult age class occurred primarily during winter and ranged from 1.9 to 3.8 individuals/season/pool; like survival, recruitment increased with availability of surface water (Z = 3.67; P < 0.01). Although abundance of frogs varied across seasons and years, we found no evidence of a systematic trend during the 16-year study period. Given the strong influence of surface water on population dynamics of leopard frogs, conservation of many riparian obligates in this and similar arid regions likely depends critically on minimizing threats to structures and ecosystem processes that maintain surface waters. Understanding the influence of surface-water availability on riparian organisms is particularly important because climate change is likely to decrease precipitation and increase ambient temperatures in desert riparian systems, both of which have the potential to alter fundamentally the hydrology of these systems.


Three-dimensional object visualization and detection in low light illumination using integral imaging.
Conventional two-dimensional (2D) imaging systems that operate in the visible spectrum may perform poorly in environments under low light illumination. In this work, we present the potential of passive three-dimensional (3D) integral imaging (II) to perform 3D imaging of a scene under low light conditions in the visible spectrum and without the need for a photon counting or cooled CCD camera. Using dedicated algorithms, we demonstrate that the reconstructed 3D integral image is naturally optimum in a maximum likelihood sense in low light levels and in the presence of detector noise enabling object visualization in the scene. The conventional 2D imaging fails due to the limited number of photons. Using 3D imaging, we demonstrate the potential for 3D detection of objects behind occlusion in a photon-starved scene. To the best of our knowledge, this is the first report of experimentally using II sensing under low illumination conditions for 3D visualization and 3D object detection in the presence of obscurations with a conventional image sensor.


Prevalence and predictors of home and automobile smoking bans and child environmental tobacco smoke exposure: a cross-sectional study of U.S.- and Mexico-born Hispanic women with young children.
Detrimental effects of environmental tobacco smoke (ETS) exposure on child health are well documented. Because young children's primary exposure to ETS occurs in homes and automobiles, voluntary smoking restrictions can substantially reduce exposure. We assessed the prevalence of home and automobile smoking bans among U.S.- and Mexico-born Hispanics in the southwestern United States, and examined the influence of mother's country of birth and smoking practices on voluntary smoking bans and on child ETS exposure. U.S.- and Mexico-born Hispanic mothers of children aged 2 through 12 years were systematically sampled from health clinics in Albuquerque, New Mexico. In-person interviews were conducted with 269 mothers (75.4% response rate) to obtain information on main study outcomes (complete versus no/partial home and automobile smoking bans; child room and automobile ETS exposure) and risk factors (mother's country of birth, maternal and household smoking behaviors). Data were analyzed with chi square tests and logistic regression models. Three-fourths (74-77%) of U.S.-born and 90-95% of Mexico-born mothers reported complete automobile and home smoking bans. In multivariate analyses, mother's U.S nativity, mother's current smoking, and presence of other adult smokers in the home were associated with significantly increased odds of not having a complete home or automobile smoking ban. Mother's smoking was associated with child ETS exposure both indoors (odds ratio [OR] = 3.31) and in automobiles (OR = 2.97). Children of U.S.-born mothers had increased odds of exposure to ETS indoors (OR = 3.24; 95% confidence interval [CI]: 1.37-7.69), but not in automobiles. Having complete smoking bans was associated with substantially reduced odds of child ETS exposure both indoors (OR = 0.10; 95% CI: 0.04-0.27) and in automobiles (OR = 0.14; 95% CI: 0.05-0.36). This study of Hispanic mothers in the southwestern U.S. indicates that there are substantial differences between U.S.- and Mexico-born mothers in the prevalence of home and automobile smoking bans, and resulting child ETS exposure. Tobacco interventions to increase smoke-free environments for U.S. Hispanic children should focus on both home and automobile smoking practices, especially among U.S.-born mothers, and utilize strategies that impact smoking practices of all household members.


Cerebrospinal fluid-based kinetic biomarkers of axonal transport in monitoring neurodegeneration.
Progress in neurodegenerative disease research is hampered by the lack of biomarkers of neuronal dysfunction. We here identified a class of cerebrospinal fluid-based (CSF-based) kinetic biomarkers that reflect altered neuronal transport of protein cargo, a common feature of neurodegeneration. After a pulse administration of heavy water (2H2O), distinct, newly synthesized 2H-labeled neuronal proteins were transported to nerve terminals and secreted, and then appeared in CSF. In 3 mouse models of neurodegeneration, distinct 2H-cargo proteins displayed delayed appearance and disappearance kinetics in the CSF, suggestive of aberrant transport kinetics. Microtubule-modulating pharmacotherapy normalized CSF-based kinetics of affected 2H-cargo proteins and ameliorated neurodegenerative symptoms in mice. After 2H2O labeling, similar neuronal transport deficits were observed in CSF of patients with Parkinson's disease (PD) compared with non-PD control subjects, which indicates that these biomarkers are translatable and relevant to human disease. Measurement of transport kinetics may provide a sensitive method to monitor progression of neurodegeneration and treatment effects.


Parental separation and child aggressive and internalizing behavior: an event history calendar analysis.
This study investigated the relationship between parental separation and aggressive and internalizing behavior in a large sample of Swiss children drawn from the ongoing Zurich Project on the Social Development of Children and Youths. Parents retrospectively reported life events and problem behavior for the first 7 years of the child's life on a quarterly basis (N = 995; 28,096 time points) using an Event History Calendar. The time sequences of separation and child problem behavior were analyzed. Parental separation affected both aggressive and internalizing behavior even when maternal depression, financial difficulties, and parental conflict were included. Parental separation exerted a direct effect on child problem behavior as well as an indirect effect via maternal depression.


Human and mouse skeletal muscle stem cells: convergent and divergent mechanisms of myogenesis.
Satellite cells are the chief contributor to skeletal muscle growth and regeneration. The study of mouse satellite cells has accelerated in recent years due to technical advancements in the isolation of these cells. The study of human satellite cells has lagged and thus little is known about how the biology of mouse and human satellite cells compare. We developed a flow cytometry-based method to prospectively isolate human skeletal muscle progenitors from the satellite cell pool using positive and negative selection markers. Results show that this pool is enriched in PAX7 expressing cells that possess robust myogenic potential including the ability to give rise to de novo muscle in vivo. We compared mouse and human satellite cells in culture and identify differences in the elaboration of the myogenic genetic program and in the sensitivity of the cells to cytokine stimulation. These results indicate that not all mechanisms regulating mouse satellite cell activation are conserved in human satellite cells and that such differences may impact the clinical translation of therapeutics validated in mouse models. Thus, the findings of this study are relevant to developing therapies to combat muscle disease.


Astaxanthin pretreatment attenuates acetaminophen-induced liver injury in mice.
Acetaminophen (APAP) is a conventional drug widely used in the clinic because of its antipyretic-analgesic effects. However, accidental or intentional APAP overdoses induce liver injury and even acute liver failure (ALF). Astaxanthin (ASX) is the strongest antioxidant in nature that shows preventive and therapeutic properties, such as ocular protection, anti-tumor, anti-diabetes, anti-inflammatory, and immunomodulatory effects. The aim of present study was to determine whether ASX pretreatment provides protection against APAP-induced liver failure. Male C57BL/6 mice were randomly divided into 7 groups, including control, oil, ASX (30mg/kg or 60mg/kg), APAP and APAP+ASX (30mg/kg or 60mg/kg) groups. Saline, olive oil and ASX were administered for 14days. The APAP and APAP+ASX groups were given a peritoneal injection of 700mg/kg or 300mg/kg APAP to determine the 5-day survival rate and for further observation, respectively. Blood and liver samples were collected to detect alanine transaminase (ALT), aspartate transaminase (AST), inflammation, oxidative stress and antioxidant systems, and to observe histopathologic changes and key proteins in the mitogen-activated protein kinase (MAPK) family. ASX pretreatment before APAP increased the 5-day survival rate in a dose-dependent manner and reduced the ALT, AST, hepatic necrosis, reactive oxygen species (ROS) generation, lipid peroxidation (LPO), oxidative stress and pro-inflammatory factors. ASX protected against APAP toxicity by inhibiting the depletion of glutathione (GSH) and superoxide dismutase (SOD). Administration of ASX did not change the expression of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and P38. However, phosphorylation of JNK, ERK and P38 was reduced, consistent with the level of tumor necrosis factor alpha (TNF-α) and TNF receptor-associated factor 2 (TRAF2). ASX provided protection for the liver against APAP hepatotoxicity by alleviating hepatocyte necrosis, blocking ROS generation, inhibiting oxidative stress, and reducing apoptosis by inhibiting the TNF-α-mediated JNK signal pathway and by phosphorylation of ERK and P38, which made sense in preventing and treating liver damage.


Traditional healers and provision of mental health services in cosmopolitan informal settlements in Nairobi, Kenya.
The study aimed to investigate the types of mental illnesses treated by traditional healers, and their methods of identifying and treating mental illnesses in their patients. In urban informal settlements of Kibera, Kangemi and Kawangware in Nairobi, Kenya, we used opportunistic sampling until the required number of traditional healers was reached, trying as much as possible to represent the different communities of Kenya. Focus group discussions were held with traditional healers in each site and later an in-depth interview was conducted with each traditional healer. An in-depth interview with each patient of the traditional healer was conducted and thereafter the MINIPLUS was administered to check the mental illness diagnoses arrived at or missed by the traditional healers. Quantitative analysis was performed using SPSS while focus group discussions and in-depth interviews were analysed for emerging themes. Traditional healers are consulted for mental disorders by members of the community. They are able to recognize some mental disorders, particularly those relating to psychosis. However, they are limited especially for common mental disorders. There is a need to educate healers on how to recognize different types of mental disorders and make referrals when patients are not responding to their treatments.


In vivo imaging models of bone and brain metastases and pleural carcinomatosis with a novel human EML4-ALK lung cancer cell line.
EML4-ALK lung cancer accounts for approximately 3-7% of non-small-cell lung cancer cases. To investigate the molecular mechanism underlying tumor progression and targeted drug sensitivity/resistance in EML4-ALK lung cancer, clinically relevant animal models are indispensable. In this study, we found that the lung adenocarcinoma cell line A925L expresses an EML4-ALK gene fusion (variant 5a, E2:A20) and is sensitive to the ALK inhibitors crizotinib and alectinib. We further established highly tumorigenic A925LPE3 cells, which also have the EML4-ALK gene fusion (variant 5a) and are sensitive to ALK inhibitors. By using A925LPE3 cells with luciferase gene transfection, we established in vivo imaging models for pleural carcinomatosis, bone metastasis, and brain metastasis, all of which are significant clinical concerns of advanced EML4-ALK lung cancer. Interestingly, crizotinib caused tumors to shrink in the pleural carcinomatosis model, but not in bone and brain metastasis models, whereas alectinib showed remarkable efficacy in all three models, indicative of the clinical efficacy of these ALK inhibitors. Our in vivo imaging models of multiple organ sites may provide useful resources to analyze further the pathogenesis of EML4-ALK lung cancer and its response and resistance to ALK inhibitors in various organ microenvironments.


Cost-effectiveness of enzyme replacement therapy with alglucosidase alfa in adult patients with Pompe disease.
Pompe disease is a rare, progressive, metabolic disease, and the first treatable inheritable muscle disorder. Enzyme replacement therapy (ERT) with alglucosidase alfa is disease specific and the only medicinal product authorized for the treatment of Pompe disease. Costs of ERT are very high as for most orphan drugs. This study investigates the cost-effectiveness of ERT compared to supportive treatment in adult patients with Pompe disease. Survival probabilities were estimated from an international observational dataset (n = 283) using a time-dependent Cox model. Quality of life was estimated on a Dutch observational dataset using a previously developed conceptual model which links clinical factors to quality of life. Costs included costs of ERT, costs of drug administration and other healthcare costs. Cost-effectiveness was estimated using a patient-level simulation model (n = 90), synthesising the information from underlying models for survival, quality of life and costs. The cost-effectiveness model estimated the (difference in) lifetime effects and costs for both treatments. Two scenarios were modelled: (1) a worse case scenario with no extrapolation of the survival gain due to ERT beyond the observed period (i.e. from 10 years onwards); and (2) a best case scenario with lifetime extrapolation of the survival gain due to ERT. Effects were expressed in (quality adjusted) life years (QALYs). Costs were discounted at 4.0% and effects at 1.5%. Substantial increases in survival were estimated - discounted incremental life years of ERT ranged from 1.9 years to 5.4 years in the scenarios without and with extrapolation of survival gains beyond the observed period. Quality of life was also significantly better for patients receiving ERT. Incremental costs were considerable and primarily consisted of the costs of ERT. Incremental costs per QALY were €3.2 million for scenario 1 and €1.8 million for scenario 2. The availability of extended, prospectively collected, longitudinal observational data on the most important input parameters required to construct a cost-effectiveness model is quite exceptional for orphan diseases. The cost-effectiveness model showed substantial survival gains from ERT. Despite these substantial gains, ERT was not cost-effective in the treatment of adult Pompe disease because of the high cost of treatment.


Squid beak inspired water processable chitosan composites with tunable mechanical properties.
Natural biological composites often couple light weight with tunable and spatially controlled mechanical properties including stiffness, toughness, and hardness. Examples include the toughness of seashells, the hardness of the chiton tooth, and the stiffness gradient of the squid beak. While seashells and the chiton tooth have a mineralized inorganic component, the squid beak is entirely organic. The squid beak is known as one of the hardest fully organic materials. The hydrated squid beak has a large stiffness gradient from soft, at the interface with the squid mouth, to hard at the tip. This gradient occurs from the spatially controlled cross-linking of chitin nanofibers with a protein matrix aided by catecholamines. Here, we introduce a water processable deacetylated chitin composite with tunable mechanical properties from spatially controlled cross-linking assisted by catecholamines. Given the natural abundance of chitin and the ease of water processing, this composite can find applications for bridging mechanically mismatched materials.


Text-mining analysis of mHealth research.
In recent years, because of the advancements in communication and networking technologies, mobile technologies have been developing at an unprecedented rate. mHealth, the use of mobile technologies in medicine, and the related research has also surged parallel to these technological advancements. Although there have been several attempts to review mHealth research through manual processes such as systematic reviews, the sheer magnitude of the number of studies published in recent years makes this task very challenging. The most recent developments in machine learning and text mining offer some potential solutions to address this challenge by allowing analyses of large volumes of texts through semi-automated processes. The objective of this study is to analyze the evolution of mHealth research by utilizing text-mining and natural language processing (NLP) analyses. The study sample included abstracts of 5,644 mHealth research articles, which were gathered from five academic search engines by using search terms such as mobile health, and mHealth. The analysis used the Text Explorer module of JMP Pro 13 and an iterative semi-automated process involving tokenizing, phrasing, and terming. After developing the document term matrix (DTM) analyses such as single value decomposition (SVD), topic, and hierarchical document clustering were performed, along with the topic-informed document clustering approach. The results were presented in the form of word-clouds and trend analyses. There were several major findings regarding research clusters and trends. First, our results confirmed time-dependent nature of terminology use in mHealth research. For example, in earlier versus recent years the use of terminology changed from "mobile phone" to "smartphone" and from "applications" to "apps". Second, ten clusters for mHealth research were identified including (I) Clinical Research on Lifestyle Management, (II) Community Health, (III) Literature Review, (IV) Medical Interventions, (V) Research Design, (VI) Infrastructure, (VII) Applications, (VIII) Research and Innovation in Health Technologies, (IX) Sensor-based Devices and Measurement Algorithms, (X) Survey-based Research. Third, the trend analyses indicated the infrastructure cluster as the highest percentage researched area until 2014. The Research and Innovation in Health Technologies cluster experienced the largest increase in numbers of publications in recent years, especially after 2014. This study is unique because it is the only known study utilizing text-mining analyses to reveal the streams and trends for mHealth research. The fast growth in mobile technologies is expected to lead to higher numbers of studies focusing on mHealth and its implications for various healthcare outcomes. Findings of this study can be utilized by researchers in identifying areas for future studies.


EHMT1 and EHMT2 inhibition induces fetal hemoglobin expression.
Fetal hemoglobin (HbF, α2γ2) induction is a well-validated strategy for sickle cell disease (SCD) treatment. Using a small-molecule screen, we found that UNC0638, a selective inhibitor of EHMT1 and EHMT2 histone methyltransferases, induces γ-globin expression. EHMT1/2 catalyze mono- and dimethylation of lysine 9 on histone 3 (H3K9), raising the possibility that H3K9Me2, a repressive chromatin mark, plays a role in silencing γ-globin expression. In primary human adult erythroid cells, UNC0638 and EHMT1 or EHMT2 short hairpin RNA-mediated knockdown significantly increased γ-globin expression, HbF synthesis, and the percentage of cells expressing HbF. At effective concentrations, UNC0638 did not alter cell morphology, proliferation, or erythroid differentiation of primary human CD34(+) hematopoietic stem and progenitor cells in culture ex vivo. In murine erythroleukemia cells, UNC0638 and Ehmt2 CRISPR/Cas9-mediated knockout both led to a marked increase in expression of embryonic β-globin genes Hbb-εy and Hbb-βh1. In primary human adult erythroblasts, chromatin immunoprecipitation followed by sequencing analysis revealed that UNC0638 treatment leads to genome-wide depletion in H3K9Me2 and a concomitant increase in the activating mark H3K9Ac, which was especially pronounced at the γ-globin gene region. In RNA-sequencing analysis of erythroblasts, γ-globin genes were among the most significantly upregulated genes by UNC0638. Further increase in γ-globin expression in primary human adult erythroid cells was achieved by combining EHMT1/2 inhibition with the histone deacetylase inhibitor entinostat or hypomethylating agent decitabine. Our data provide genetic and pharmacologic evidence that EHMT1 and EHMT2 are epigenetic regulators involved in γ-globin repression and represent a novel therapeutic target for SCD.


Human ventilatory response to acute hyperoxia during and after 8 h of both isocapnic and poikilocapnic hypoxia.
During 8 h of either isocapnic or poikilocapnic hypoxia, there may be a rise in ventilation (VE) that cannot be rapidly reversed with a return to higher PO2 (L. S. G. E. Howard and P. A. Robbins. J. Appl. Physiol. 78:1098-1107, 1995). To investigate this further, three protocols were compared: 1) 8-h isocapnic hypoxia [end-tidal PCO2 (PETCO2) held at prestudy value, end-tidal PO2 (PETO2) = 55 Torr], followed by 8-h isocapnic euoxia (PETO2 = 100 Torr); 2) 8-h poikilocapnic hypoxia followed by 8-h poikilocapnic euoxia; and 3) 16-h air-breathing control. Before and at intervals throughout each protocol, the VE response to eucapnic hyperoxia (PETCO2 held 1-2 Torr above prestudy value, PETO2 = 300 Torr) was determined. There was a significant rise in hyperoxic VE over 8 h during both forms of hypoxia (P < 0.05, analysis of variance) that persisted during the subsequent 8-h euoxic period (P < 0.05, analysis of variance). These results support the notion that an 8-h period of hypoxia increases subsequent hyperoxic VE, even if acid-base changes have been minimized through maintenance of isocapnia during the hypoxic period.


Epidermal barrier formation and recovery in skin disorders.
Skin is at the interface between the complex physiology of the body and the external, often hostile, environment, and the semipermeable epidermal barrier prevents both the escape of moisture and the entry of infectious or toxic substances. Newborns with rare congenital barrier defects underscore the skin's essential role in a terrestrial environment and demonstrate the compensatory responses evoked ex utero to reestablish a barrier. Common inflammatory skin disorders such as atopic dermatitis and psoriasis exhibit decreased barrier function, and recent studies suggest that the complex response of epidermal cells to barrier disruption may aggravate, maintain, or even initiate such conditions. Either aiding barrier reestablishment or dampening the epidermal stress response may improve the treatment of these disorders. This Review discusses the molecular regulation of the epidermal barrier as well as causes and potential treatments for defects of barrier formation and proposes that medical management of barrier disruption may positively affect the course of common skin disorders.


Transduction and expression of the human carcinoembryonic antigen gene in a murine colon carcinoma cell line.
A cell line derived from the mouse colon adenocarcinoma, MC-38, has been transduced with a retroviral construct containing complementary DNA encoding the human carcinoembryonic antigen (CEA) gene. MC-38, which forms tumors in syngeneic C57BL/6 mice, has been extensively studied as a target for active immunotherapy. Individual transduced clones that express high levels of cell surface CEA were isolated, and two clones, termed MC-38-ceal and MC-38-cea2, were extensively characterized. The levels of CEA found on the surface of these clones were considerably higher than that found in a moderately differentiated human colon carcinoma cell line (WiDr) and were comparable to those found on the human colon carcinoma cell lines GEO and CBS (among the highest CEA-expressing cells reported). Further analysis demonstrated that the CEA expressed in the MC-38-cea1 clone had a similar molecular weight to native CEA (Mr 180,000), but the MC-38-cea2 cell line expressed a single Mr 70,000 glycosylated immunoreactive product. Seven anti-CEA monoclonal antibodies were found to react with both clones. The CEA gene present in the MC-38-cea2 clone was partially sequenced and was found to contain a deletion of two of the three repeated domains present in CEA. These results provide a basis for future studies to map immunodominant epitopes of CEA and to develop a syngeneic model system that may aid in the design of reagents and protocols to study active and passive immunotherapy directed against a carcinoma expressing human CEA.


Neuroleptic-induced decrease in plasma homovanillic acid and antipsychotic activity in schizophrenic patients.
Plasma-free homovanillic acid, a major metabolite of dopamine, was measured in chronically ill schizophrenic patients both before and during treatment with the antipsychotic phenothiazine, fluphenazine. Neuroleptic treatment was associated with a significant time-dependent decrease in plasma homovanillic acid from pretreatment values, which were significantly elevated when compared with those of age- and sex-matched healthy control subjects. Further, both the absolute concentrations as well as the neuroleptic-induced reductions in plasma homovanillic acid determined over 5 weeks of neuroleptic treatment were statistically significantly correlated with ratings of psychosis and improvement in psychosis, respectively. These findings suggest that the delayed effects of neuroleptic agents on presynaptic dopamine activity may more closely parallel their therapeutic actions than do their immediate effects in blocking postsynaptic dopamine receptors and that a decrease in dopamine "turnover" may be responsible for their antipsychotic effects.


Ficolins do not alter host immune responses to lipopolysaccharide-induced inflammation in vivo.
Ficolins are a family of pattern recognition molecules that are capable of activating the lectin pathway of complement. A limited number of reports have demonstrated a protective role of ficolins in animal models of infection. In addition, an immune modulatory role of ficolins has been suggested. Yet, the contribution of ficolins to inflammatory disease processes remains elusive. To address this, we investigated ficolin deficient mice during a lipopolysaccharide (LPS)-induced model of systemic inflammation. Although murine serum ficolin was shown to bind LPS in vitro, there was no difference between wildtype and ficolin deficient mice in morbidity and mortality by LPS-induced inflammation. Moreover, there was no difference between wildtype and ficolin deficient mice in the inflammatory cytokine profiles after LPS challenge. These findings were substantiated by microarray analysis revealing an unaltered spleen transcriptome profile in ficolin deficient mice compared to wildtype mice. Collectively, results from this study demonstrate that ficolins are not involved in host response to LPS-induced systemic inflammation.


Improvement of serum alkaline phosphatase to <1.5 upper limit of normal predicts better outcome and reduced risk of cholangiocarcinoma in primary sclerosing cholangitis.
Normalization of serum alkaline phosphatase (SAP) was recently shown to correlate with better prognosis in Primary Sclerosing Cholangitis (PSC). We aimed at evaluating the impact of SAP improvement to below 1.5 the upper limit of normal (ULN) on the prognosis of this cholestatic liver disease. Oxford PSC database was screened for cases diagnosed between 1980 and 2004. Cases which met the inclusion criteria were retrospectively examined for clinical parameters, laboratory values, and clinical end points (liver decompensation, liver transplantation, and liver-related deaths including cholangiocarcinoma). Cases were followed-up to 31/12/2010. 139 patients were included, (87 males). Improvement of SAP to below 1.5 ULN was achieved by 55 (40%) patients in a median time of 2 years, compared to 84 (60%) who did not. 3/55 (6%) patients with SAP improvement reached an end point compared to 32/84 (38%) patients with no SAP improvement (p <0.0001). 13/84 (15%) patients with no SAP improvement developed cholangiocarcinoma compared to no cholangiocarcinoma in the group with SAP improvement (p = 0.002). The end point free survival was significantly longer in patients with SAP improvement (p <0.0001). The significance of SAP improvement as a predictor of prognosis persisted after controlling for other clinical and laboratory variables. Improvement of SAP to below 1.5 ULN was comparable to complete normalization of SAP in terms of prognosis. Improvement in SAP to below 1.5 ULN is associated with better outcome and reduced risk of CCA in PSC. This was comparable to the achievement of complete normalization of SAP.


Connexin36 mediates gap junctional coupling of alpha-ganglion cells in mouse retina.
Alpha-ganglion cells are present in all vertebrate retinae and are subdivided into ON and OFF types according to their level of dendritic ramification within the inner plexiform layer. They have large dendritic fields and usually a good responsiveness to moving stimuli. They were the first ganglion cells in which tracer coupling was observed, suggesting the presence of gap junctions composed of unknown connexins. Here we show that ON-alpha-ganglion cells in the mouse retina are coupled to amacrine cells, whereas OFF-alpha-ganglion cells are coupled to other OFF-alpha-ganglion cells and to amacrine cells. These tracer coupling patterns were completely absent in mice deficient in connexin36 (Cx36). The expression of Cx36 protein in alpha-ganglion cells but not in coupled amacrine cells was confirmed in mice in which the Cx36 coding DNA was replaced by the lacZ reporter gene. The dendritic localization and the distribution pattern of Cx36 patches, analyzed in mice in which the enhanced green fluorescent protein (EGFP) was linked to the C-terminal region of the Cx36 protein, revealed a rather small number of fluorescent plaques and different patterns for ON- and OFF-alpha-ganglion cells. Furthermore, tracer coupling between OFF-alpha-ganglion cells could be inhibited by quinine, a gap junctional blocker with a slight preference for gap junctions formed by Cx36. These data strongly suggest that Cx36 gap junction channels are functional not only in interneurons but also in output neurons of the retina and are responsible for distinct coupling patterns of ganglion cells.


Simplified flow cytometric immunophenotyping panel for multiple myeloma, CD56/CD19/CD138(CD38)/CD45, to differentiate neoplastic myeloma cells from reactive plasma cells.
Flow cytometric immunophenotyping has been used to identify neoplastic plasma cell populations in patients with multiple myeloma (MM). Previous reports have described the use of several antigens, including CD38, CD138, CD56, CD117, CD52, CD19 and CD45, to distinguish distinct populations of plasma cells. The aim of this study was to evaluate a simplified immunophenotyping panel for MM analysis. A total of 70 patients were enrolled in the study, 62 of which were newly diagnosed with MM (untreated), whereas the remaining 8 were undergoing bone marrow assessment as part of follow-up after treatment (treated). Treated cases included 3 patients with relapse and 5 patients with persistence of MM. Multiparametric flow cytometric immunophenotyping was performed using monoclonal antibodies against CD56, CD19, CD138 (CD38), and CD45. In differential counts, plasma cells in bone marrow (BM) accounted for 3.6-93.2% of the total nucleated cell count. The positive expression rates of CD56, CD19, CD138, and CD45 in neoplastic myeloma cells were 83.9%, 0%, 98.4%, and 37.1%, respectively, among the 62 untreated cases, and 75.0%, 0%, 87.5%, and 37.5%, respectively, among the 8 treated cases. CD19 expression of neoplastic plasma cells was negative in both untreated and treated cases. The simplified immunophenotyping panel, CD56/CD19/CD138(CD38)/CD45, is useful for distinguishing neoplastic myeloma cells from reactive plasma cells in clinical practice. In addition, CD19 represents the most valuable antigen for identifying neoplastic myeloma cells in patients with MM.


β-Adrenergic stimulation does not activate p38 MAP kinase or induce PGC-1α in skeletal muscle.
There are reports that the β-adrenergic agonist clenbuterol induces a large increase in peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in skeletal muscle. This has led to the hypothesis that the increases in PGC-1α and mitochondrial biogenesis induced in muscle by endurance exercise are mediated by catecholamines. In the present study, we evaluated this possibility and found that injecting rats with clenbuterol or norepinephrine induced large increases in PGC-1α and mitochondrial proteins in brown adipose tissue but had no effect on PGC-1α expression or mitochondrial biogenesis in skeletal muscle. In brown adipocytes, the increase in PGC-1α expression induced by β-adrenergic stimulation is mediated by activation of p38 mitogen-activated protein kinase (p38 MAPK), which phosphorylates and activates the cAMP response element binding protein (CREB) family member activating transcription factor 2 (ATF2), which binds to a cyclic AMP response element (CRE) in the PGC-1α promoter and mediates the increase in PGC-1α transcription. Phospho-CREB does not have this effect. Our results show that the reason for the lack of effect of β-adrenergic stimulation on PGC-1α expression in muscle is that catecholamines do not activate p38 or increase ATF2 phosphorylation in muscle.


Effectiveness of dry needling versus a classical physiotherapy program in patients with chronic low-back pain: a single-blind, randomized, controlled trial.
[Purpose] We compared the effectiveness of dry needling with a classical physiotherapy program in patients with chronic low-back pain caused by lumbar disc hernia (LHNP). [Subjects and Methods] In total, 34 subjects were allocated randomly to the study (n=18) and control groups (n=16). In the study group, dry needling was applied using acupuncture needles. The control group performed a home exercise program in addition to hot pack, TENS, and ultrasound applications. Pain was assessed with the short form of the McGill Pain Questionnaire. The number of trigger points and their pressure sensitivity were evaluated with a physical examination (palpation). The Beck Depression Inventory was used to assess depression. The Tampa Kinesiophobia Scale was used to assess fear of movement. [Results] In the study group, the calculated Cohen's effect sizes were bigger than those in the control group in terms of pain, trigger point-related variables, and fear of movement. Effect sizes for reducing depressive symptoms were similar in both groups. [Conclusion] These results suggest that dry needling can be an effective treatment for reducing pain, number of trigger points, sensitivity, and kinesiophobia in patients with chronic low-back pain caused by lumbar disc hernia.


High field proton NMR investigations of the metabolic profiles of multidrug-sensitive and -resistant leukaemic cell lines: evidence for diminished taurine levels in multidrug-resistant cells.
High field proton (1H) nuclear magnetic resonance (NMR) spectroscopy has for the first time been employed to investigate and compare the metabolic profiles of vinblastine-sensitive and -resistant T-lymphoid leukaemic cell lines (CCRF-CEM and CEM/VLB100 respectively) and evidence is presented for a significantly lower taurine content in the CEM/VLB100 resistant subline when expressed relative to that of its drug-sensitive parental counterpart. These data suggest differences in the nature and relative involvements of taurine biosynthetic pathways between the two cell lines, a phenomenon that may be related to their differing sensitivities towards chemotherapeutic agents such as adriamycin which promote the generation of cytotoxic reactive oxygen species (ROS) in vivo. However, the 1H NMR data obtained provided no evidence for an increased metabolic consumption of hypotaurine (a metabolic precursor of taurine with powerful .OH radical scavenging properties) in CCRF-CEM cells since differences observed in the hypotaurine: taurine concentration ratio between the drug-sensitive and -resistant cell lines were not statistically significant. Furthermore, hypotaurine is unlikely to compete with alternative endogenous .OH radical scavengers present such as lactate since its level in either of the two cell lines investigated (ca. 6.0 x 10(-8) mol./10(8) cells) is insufficient for it to act as an antioxidant in this context. The biochemical and therapeutic significance of these results are discussed.


A conserved Tyr residue is required for sugar selectivity in a Pol alpha DNA polymerase.
Many DNA polymerases select their natural substrates, deoxy- as opposed to ribonucleoside triphosphates, with a selectivity greater than 10000-fold. The function of a highly conserved residue, Tyr416, in the palm domain of the parental enzyme, an exo(-) derivative of RB69 DNA polymerase (gp43), a member of the pol alpha DNA polymerase family, was examined for its role in helping the polymerase discriminate between ribo-, dideoxyribo-, and deoxyribonucleoside triphosphates. The parental enzyme selected dNTPs vs rNTPs with about the same preference as dNTPs vs ddNTPs. Pre-steady-state kinetic analysis was carried out with the parental enzyme and two mutants, Y416A and Y416F. The Y416A mutant incorporated ribonucleotide residues much more efficiently than the parental enzyme, whereas the Y416F mutant was more permissive toward ddNTP vs rNTP utilization than either the Y416A mutant or the parental enzyme. We also found that both dCDP and rCDP inhibited dCTP incorporation by the Y416A mutant, while only dCDP but not rCDP inhibited dCTP incorporation by the parental enzyme and the Y416F mutant. The parental enzyme and the Y416A and Y416F mutants were all able to add araCTP (1-beta-D-arabinofuranosylcytosine-5'-triphosphate) to a primer but with reduced efficiency relative to dCTP. Based on our kinetic results, interpreted in the context of the crystal structure of the RB69 gp43 ternary complex, we suggest that sugar discrimination is provided mainly by the Tyr416 side chain which can sterically block the 2'-OH group of an incoming rNTP.


Do physicians judge a study by its cover? An investigation of journal attribution bias.
The effect of a journal's prestige on readers' impressions of an article is unknown. Two hypotheses were tested: first, that attribution of a study to a "high" prestige journal would be associated with improved impressions and attribution to a "low" prestige journal would be associated with diminished impressions; and second, that formal training in epidemiology and biostatistics would mitigate the effects of this journal attribution bias. The study was designed as a trial among a random sample of 264 internists. Participants were asked to read an article and an abstract from either the Southern Medical Journal (SMJ) or the New England Journal of Medicine (NEJM). Questionnaires were constructed that either attributed the article or abstract to its source or presented it as unattributed. After each article or abstract, respondents were asked to rate the quality of the study, the appropriateness of the methodology employed, the significance of the findings, and its likely effects on their practice. A 20-point impression score was created based on responses to these statements. The effect of attribution to a specific journal and formal epidemiology training on impression scores were assessed using linear regression. Of the 399 eligible participants, 264 questionnaires were returned (response rate 66%). Differences in impression scores associated with attribution of an article or abstract to the NEJM were.71 [95% C.I. (-.44-1.87)] and.50 [95% C.I. (-.87-1.87)] respectively; differences in impression scores associated with attribution of an article or abstract to the SMJ were -.12 [95% C.I. (-1.53-1.30)] and -.95 [95% C.I. (-2.41-.52)]. A stratified analysis demonstrated that epidemiology training did not meaningfully alter the effect of journal attribution on participants' impression scores. If journal attribution bias exists, it is likely to exert small and clinically insignificant effects when physicians read articles carefully. Formal training in epidemiology and biostatistics does not appear to alter these results.


High serum IFN-alpha activity is a heritable risk factor for systemic lupus erythematosus.
Interferon alpha (IFN-alpha) levels are elevated in many patients with systemic lupus erythematosus (SLE); however it is not known whether high serum IFN-alpha activity is a cause or a result of the disease. We studied 266 SLE patients and 405 of their healthy relatives, and frequently found high serum IFN-alpha activity in both patients and healthy relatives as compared to healthy unrelated individuals. High IFN-alpha activity was clustered in specific families in both SLE patients and their healthy first-degree relatives, suggesting a heritable trait. Heritability was also supported by quantitative familial correlation of IFN-alpha activity, concordance in affected sib pairs and frequent transmission of the high IFN-alpha activity trait from parents to offspring. Autoantibodies to RNA-binding proteins and double-stranded DNA were associated with high IFN-alpha activity in SLE patients; however these autoantibodies were very uncommon in healthy family members and did not explain the observed familial correlations. The frequency of high IFN-alpha activity was similar across all studied ethnic backgrounds. These data suggest that high serum IFN-alpha activity is a complex heritable trait, which plays a primary role in SLE pathogenesis.


Pharmacogenetics of risperidone: a systematic review of the clinical effects of CYP2D6 polymorphisms.
To summarize and evaluate the pharmacogenetic literature pertaining to the effects of CYP2D6 polymorphism on clinical outcomes of risperidone therapy. A systematic literature search was performed using the search terms risperidone, pharmacogenetics, cytochrome P-450 enzyme system, cytochrome P-450 CYP2D6, and polymorphism (genetic) in MEDLINE (1946-October 2012), EMBASE (1980-October 2012), PubMed (1947-October 2012), International Pharmaceutical Abstracts (1970-October 2012), and Google Scholar. Identified articles were included if they measured the association between CYP2D6 genetic polymorphisms and clinical outcomes in at least 2 patients taking risperidone. The data elements extracted from these articles consisted of study design, number of subjects, indication for risperidone therapy, CYP2D6 phenotype status, mean daily dose of risperidone, and effects on clinical outcomes. The identified citations consisted of 10 prospective nonrandomized, uncontrolled cohort studies, 1 retrospective cohort study, 1 prospective case-control study, and 1 retrospective case series. Studies were of variable quality and none provided high-quality evidence; they included heterogeneous patient populations with varying clinical diagnoses and drug therapy regimens. Most studies reported nonsignificant trends but were limited by power to detect statistical significance and short trial duration. However, increased risk of adverse effects (including QT interval prolongation) was observed in patients with inactive alleles. While there were trends toward increased adverse effects in poor metabolizers, most outcomes were not significant. As such, routine genotyping should not be used for screening. Future usefulness cannot be ruled out, as many studies had significant limitations that preclude determination of clinical relevance. Adequately powered clinical and epidemiologic studies are warranted to clarify the role of CYP2D6 genotyping in practice.


Crumbs interacts with moesin and beta(Heavy)-spectrin in the apical membrane skeleton of Drosophila.
The apical transmembrane protein Crumbs is necessary for both cell polarization and the assembly of the zonula adherens (ZA) in Drosophila epithelia. The apical spectrin-based membrane skeleton (SBMS) is a protein network that is essential for epithelial morphogenesis and ZA integrity, and exhibits close colocalization with Crumbs and the ZA in fly epithelia. These observations suggest that Crumbs may stabilize the ZA by recruiting the SBMS to the junctional region. Consistent with this hypothesis, we report that Crumbs is necessary for the organization of the apical SBMS in embryos and Schneider 2 cells, whereas the localization of Crumbs is not affected in karst mutants that eliminate the apical SBMS. Our data indicate that it is specifically the 4.1 protein/ezrin/radixin/moesin (FERM) domain binding consensus, and in particular, an arginine at position 7 in the cytoplasmic tail of Crumbs that is essential to efficiently recruit both the apical SBMS and the FERM domain protein, DMoesin. Crumbs, Discs lost, betaHeavy-spectrin, and DMoesin are all coimmunoprecipitated from embryos, confirming the existence of a multimolecular complex. We propose that Crumbs stabilizes the apical SBMS via DMoesin and actin, leading to reinforcement of the ZA and effectively coupling epithelial morphogenesis and cell polarity.


Cardiorespiratory Fitness and White Matter Neuronal Fiber Integrity in Mild Cognitive Impairment.
Mounting evidence showed the self-reported levels of physical activity are positively associated with white matter (WM) integrity and cognitive performance in normal adults and patients with mild cognitive impairment (MCI). However, the objective measure of cardiorespiratory fitness (CRF) was not used in these studies. To determine the associations of CRF measured by maximal oxygen uptake (VO2max) with WM fiber integrity and neurocognitive performance in older adults with MCI. Eighty-one participants (age = 65±7 years, 43 women), including 26 cognitively normal older adults and 55 amnestic MCI patients, underwent VO2max test to measure CRF, diffusion tensor imaging (DTI) to assess WM fiber integrity, and neurocognitive assessment focused on memory and executive function. DTI data were analyzed by the tract-based spatial statistics and region-of-interest approach. Cognitively normal older adults and MCI patients were not different in global WM fiber integrity and VO2max. VO2max was associated positively with DTI metrics of fractional anisotropy in ∼54% WM fiber tracts, and negatively with mean and radial diffusivities in ∼46% and ∼56% of the WM fiber tracts. The associations of VO2max with DTI metrics remained statistically significant after adjustment of age, sex, body mass index, WM lesion burden, and MCI status. The DTI metrics obtained from the area that correlated to VO2max were associated with executive function performance in MCI patients. Higher levels of CRF are associated with better WM fiber integrity, which in turn is correlated with better executive function performance in MCI patients.


Predicting the UV-vis spectra of Tetraarylcyclopentadienones: Using DFT molecular orbital energies to model electronic transitions of organic materials.
Tetraphenylcyclopentadienone, due to its intrinsically low HOMO-LUMO gap, has been suggested as a valuable repeat unit in conducting polymers for nanoscale electronics. The HOMO and LUMO of tetraphenylcyclopentadienone appear to be associated with the relevant pi orbitals of unsubstituted cyclopentadienone. Using previously developed carbonylative coupling reactions, a series of tetraarylcyclopentadienones was synthesized, accessing a range of substituents not previously available. The UV-vis spectra of these molecules were compared to their calculated wave functions and predicted transitions. A quantitative structure-activity relationship was discovered that may greatly simplify prediction of band gaps for oligomers and polymers built from these tetraarylcyclopentadienones.


Norovirus Narita 104 virus-like particles expressed in Nicotiana benthamiana induce serum and mucosal immune responses.
Narita 104 virus is a human pathogen belonging to the norovirus (family Caliciviridae) genogroup II. Noroviruses cause epidemic gastroenteritis worldwide. To explore the potential of developing a plant-based vaccine, a plant optimized gene encoding Narita 104 virus capsid protein (NaVCP) was expressed transiently in Nicotiana benthamiana using a tobacco mosaic virus expression system. NaVCP accumulated up to approximately 0.3 mg/g fresh weight of leaf at 4 days postinfection. Initiation of hypersensitive response-like symptoms followed by tissue necrosis necessitated a brief infection time and was a significant factor limiting expression. Transmission electron microscopy of plant-derived NaVCP confirmed the presence of fully assembled virus-like particles (VLPs). In this study, an optimized method to express and partially purify NaVCP is described. Further, partially purified NaVCP was used to immunize mice by intranasal delivery and generated significant mucosal and serum antibody responses. Thus, plant-derived Narita 104 VLPs have potential for use as a candidate subunit vaccine or as a component of a multivalent subunit vaccine, along with other genotype-specific plant-derived VLPs.


Speed is not everything: Identifying patients who may benefit from helicopter transport despite faster ground transport.
Helicopter emergency medical services (HEMS) have demonstrated survival benefits over ground emergency medical services (GEMS) for trauma patient transport. While HEMS speed is often-cited, factors such as provider experience and level of care may also play a role. Our objective was to identify patient groups that may benefit from HEMS even when prehospital time for helicopter utilization is longer than GEMS transport. Adult patients transported by HEMS or GEMS from the scene of injury in the Pennsylvania State Trauma Registry were included. Propensity score matching was used to match HEMS and GEMS patients for likelihood of HEMS, keeping only pairs in which the HEMS patient had longer total prehospital time than the matched GEMS patient. Mixed-effects logistic regression evaluated the effect of transport mode on survival while controlling for demographics, admission physiology, transfusions, and procedures. Interaction testing between transport mode and existing trauma triage criteria was conducted and models stratified across significant interactions to determine which criteria identify patients with a significant survival benefit when transported by HEMS even when slower than GEMS. From 153,729 eligible patients, 8,307 pairs were matched. Helicopter emergency medical services total prehospital time was a median of 13 minutes (interquartile range, 6-22) longer than GEMS. Patients with abnormal respiratory rate (odds ratio [OR], 2.39; 95% confidence interval [CI], 1.26-4.55; p = 0.01), Glasgow Coma Scale score of 8 or less (OR, 1.61; 95% CI, 1.16-2.22; p < 0.01), and hemo/pneumothorax (OR, 2.25; 95% CI, 1.06-4.78; p = 0.03) had a significant survival advantage when transported by HEMS even with longer prehospital time than GEMS. Conversely, there was no association between transport mode and survival in patients without these factors (p > 0.05). Patients with abnormal respiratory rate, Glasgow Coma Scale score of 8 or less, and hemo/pneumothorax benefit from HEMS transport even when GEMS transport was faster. This may indicate that these patients benefit primarily from HEMS care, such as advanced airway and chest trauma management, rather than simply faster transport to a trauma center. Therapeutic, level III.


Common polymorphisms in FMO1 are associated with nicotine dependence.
Cigarette smoking and other forms of tobacco use are the leading cause of preventable mortality in the world. A better understanding of the etiology of nicotine addiction may help to increase the success rate of cessation and to decrease the massive morbidity and mortality associated with smoking. To identify genetic polymorphisms that contribute to nicotine dependence, our group undertook a genetic association study including three enzyme families that potentially influence nicotine metabolism: cytochrome P450 enzymes, flavin monooxygenases (FMOs), and UDP-glucuronosyl transferases. Several polymorphisms in FMO1 showed association in a discovery sample, and were tested in an independent replication sample. One polymorphism, rs10912765, showed an association that remained significant after Bonferroni correction (nominal P=0.0067, corrected P=0.0134). Several additional polymorphisms in linkage disequilibrium with this single nucleotide polymorphism also showed association. Subsequent in-vitro experiments characterized FMO1 as a more efficient catalyst of nicotine N-oxidation than FMO3. In adult humans, FMO1 is primarily expressed in the kidney and is likely to be a major contributor to the renal metabolism and clearance of therapeutic drugs. FMO1 is also expressed in the brain and could contribute to the nicotine concentration in this tissue. These findings suggest that polymorphisms in FMO1 are significant risk factors in the development of nicotine dependence and that the mechanism may involve variation in nicotine pharmacology.


Ubiquitin control of S phase: a new role for the ubiquitin conjugating enzyme, UbcH7.
Events within and transitions between the phases of the eukaryotic cell cycle are tightly controlled by transcriptional and post-translational processes. Prominent among them is a profound role for the ubiquitin proteasome proteolytic pathway. The timely degradation of proteins balances the increases in gene products dictated by changes in transcription. Of the dozens of ubiquitin conjugating enzymes, or E2s, functions in control of the cell cycle have been defined for only UbcH10 and Ubc3/Cdc34. Each of these E2s works primarily with one ubiquitin ligase or E3. Here we show that another E2, UbcH7 is a regulator of S phase of the cell cycle. Over-expression of UbcH7 delays entry into S phase whereas depletion of UbcH7 increases the length of S phase and decreases cell proliferation. Additionally, the level of the checkpoint kinase Chk1 increases upon UbcH7 depletion while the level of phosphorylated PTEN decreases. Taken together, these data indicate that the length of S phase is controlled in part by UbcH7 through a PTEN/Akt/Chk1 pathway. Potential mechanisms by which UbcH7 controls Chk1 levels both directly and indirectly, as well as the length of S phase are discussed and additional functions for UbcH7 are reviewed.


Analysis of the receiver response in lidar measurements.
We report on the calculation of the effective telescope area in lidar applications by a ray-tracing approach. This method allows one to consider the true experimental working conditions and hence to obtain accurate values of the effective telescope area as a function of the height. This in turn allows the retrieval of the signal from the ranges where the overlap function is not constant (e.g., lower ranges), thus increasing the useful range interval. Moreover, we show that the spherical mirrors are more appropriate than the parabolic ones for most of the lidar measurements, although a particular alignment procedure, such as the one we describe, must be used.


Mindfulness-Based Group Cognitive Behavior Therapy for Provoked Localized Vulvodynia: A Randomized Controlled Trial.
The aim of the study was to compare the effectiveness of mindfulness-based group cognitive behavior therapy (M-gCBT) versus education support group therapy for the pain and distress associated with provoked localized vulvodynia. Participants were randomized to M-gCBT or education support group therapy. Mindfulness-based group cognitive behavior participants attended 8 weekly sessions. Education support group participants received 8 weeks of online education with 3 in-person group visits. Vaginal insertion pain (tampon test) was the primary outcome. Secondary outcomes (Generalized Anxiety Disorder 7, Beck's Depression Index, Female Sexual Distress Scale, Female Sexual Function Index, and Pain Catastrophizing) were administered before intervention and at the completion of the study period, 3 months, and 6 months. Sample size was based on the ideal number for group dynamics of 6 to 12 participants per group. Participants were enrolled from August 1, 2016, to January 30, 2017. Thirty-two participants were enrolled and 31 were randomized: 14 to M-gCBT and 17 to education support. Baseline characteristics did not differ significantly. Vaginal insertion pain decreased in both groups but was not statistically different between groups (difference of 1.23; 95% CI = -0.52 to 2.98). At 6 months, participants in the M-gCBT group showed statistically significant improvement in the Female Sexual Function Index, Generalized Anxiety Disorder 7, and Beck's Depression Index compared with the education support group. Mindfulness-based group cognitive behavior and education support group therapy are effective in reducing pain and distress. However, women in the M-gCBT program showed greater improvement in certain secondary outcomes, indicating that M-gCBT may offer some advantages in reducing distress associated with provoked localized vulvodynia.


Regulation of AGR2 expression via 3'UTR shortening.
One recently discussed general mechanism affecting gene expression is 3'-untranslated region (3'UTR) length. Events such as shortening, translocation or loss of 3'UTRs are observed within oncogenes and are proposed to associate with increased expression. Thus, increased efforts are being made to understand constitutive and differential transcript 3'end formation. Investigation of AGR2 mRNA revealed a direct impact of its 3'UTR length on AGR2 expression. In silico analyses identified several regulatory sequences within the distal part of AGR2 mRNA that may regulate 3'UTR length and associated protein levels. Short 3'UTRs were observed in a panel of AGR2-positive cancer cell lines and in human breast cancer specimens, in which more extensive 3'UTR shortening correlated with increased AGR2 protein levels. AGR2 is an important member of PI3K/AKT signalling pathway, which along with the proposed involvement of mTOR in the regulation of alternative polyadenylation, prompted us to study the role of mTOR in relation to AGR2 mRNA 3'UTR shortening. A direct impact of mTOR signalling on AGR2 3'UTR shortening associated with increased protein synthesis was found, which led to the identification of a novel molecular mechanism involved in upregulation of AGR2 levels in mTOR-activated cells via modulating the 3'UTR length of AGR2 mRNA.


The Relationship between Anxiety, Subjective and Objective Sleep, Chronotype and Circadian Rhythms with Depressive Symptoms in Insomnia Disorder.
Insomnia is a highly prevalent sleep disorder with strong bidirectional associations with depressive symptoms. The circadian preference for eveningness has been shown to be associated with depressive symptoms in insomnia and other mental health conditions. However, there is a lack of studies in insomnia investigating whether objective measures, such as dim light melatonin onset (DLMO) or polysomnographic (PSG) sleep, are associated with depressive symptoms. Therefore, we investigated the associations between subjective measures (questionnaires assessing anxiety, sleep quality and circadian preference, and sleep diary) and depressive symptoms and whether the addition of objective measures (DLMO, PSG parameters) would strengthen the associations with depressive symptoms. In 115 insomnia disorder patients we found that anxiety was strongly associated with depressive symptoms in a model including circadian preference, dysfunctional beliefs of sleep, and self-reported previous depressive symptoms (R2 = 0.496, p < 0.001). The addition of sleep diary measures did not strengthen the model. We also found that the addition of objective measures (DLMO, PSG parameters) did not improve the subjective associations with depressive symptoms. Our data suggest that objective circadian markers are less important in the prediction of depressive symptoms in insomnia compared to subjective measures.


Anti-inflammatory and anti-allergic effects and underlying mechanisms of Huang-Lian-Jie-Du extract: Implication for atopic dermatitis treatment.
Huang-Lian-Jie-Du Decoction (HLJDD), a well-known Chinese herbal formula recorded in the Tang dynasty, is composed of Coptidis rhizoma (Huang-Lian), Scutellariae radix (Huang-Qin), Phellodendri Chinensis cortex (Huang-Bai) and Gardenia fructus (Zhi-Zi). It has clinical efficacy of purging fire for removing toxin and is commonly used for the treatment of disease including Alzheimer's disease, stroke and gastrointestinal disorders. HLJDD is also frequently applied for the treatment of various skin diseases, such as atopic dermatitis (AD) and various types of eczema. The aim of this study is to investigate the anti-inflammatory and anti-allergic actions of Huang-Lian-Jie-Du ethanolic extract (HLJDE) and to elucidate underlying molecular mechanisms of action using relevant in vitro experimental models. The anti-inflammatory effects of HLJDE were investigated through evaluating the change of nitric oxide (NO) and the production of several cytokines and chemokines in lipopolysaccharide (LPS)-stimulated RAW264.7 cell line. Expression of mitogen-activated protein kinases (MAPKs), NF-κB p65 phosphorylation, inhibitor-κBα (IκBα) degradation were further investigated to elucidate its anti-inflammatory molecular mechanisms. Meanwhile, the anti-allergic activities of HLJDE was also evaluated using antigen-induced RBL-2H3 cell line. β-hexosaminidase and histamine release and selected cytokines and chemokines were measured to evaluate the anti-allergic activities of HLJDE. In addition, intracellular Ca(2+)level, MAPKs and Lyn phosphorylation were further investigated to reveal its anti-allergic molecular mechanisms. HLJDE could significantly suppress the secretion of NO, IL-1β, IL-4, MCP-1 and GM-CSF in RAW264.7 cells in a dose-dependent manner. In addition, HLJDE also markedly reduced the phosphorylation of MAPKs, and inhibited the transcriptional activity of NF-κB and IκBα degradation. Furthermore, HLJDE exerted marked anti-allergic activity through inhibiting the release of β-hexosaminidase and histamine. The release of cytokines and chemokines (IL-4, TNF-α, MCP-1) from activated RBL-2H3 cells were also attenuated by pretreatment with HLJDE. The inhibitory effects on intracellular Ca(2+)level, and reduced phosphorylation of MAPKs and Lyn are believed to be the anti-allergic mechanisms. HLJDE exerted significant anti-inflammatory and anti-allergic effects through suppressing the production of allergic and inflammatory mediators via the NF-κB and MAPKs inactivation and IκBα degradation in the LPS-stimulated RAW24.7 cells, inactivation of MAPKs and Lyn pathway in antigen-induced RBL-2H3 cells. The present study provides in vitro experimental evidence to support the use of HLJDE for the clinical treatment of AD.


Plasmodium falciparum-Specific Memory B-Cell and Antibody Responses Are Associated With Immunity in Children Living in an Endemic Area of Kenya.
Identifying the mechanism of naturally acquired immunity against Plasmodium falciparum malaria could contribute to the design of effective malaria vaccines. Using a recently developed multiplexed FluoroSpot assay, we assessed cross-sectional pre-existing memory B-cells (MBCs) and antibody responses against six well known P. falciparum antigens (MSP-119, MSP-2 (3D7), MSP-2 (FC27), MSP-3, AMA-1 and CSP) and measured their associations with previous infections and time to clinical malaria in the ensuing malaria season in Kenyan children. These children were under active weekly surveillance for malaria as part of a long-term longitudinal malaria immunology cohort study, where they are recruited from birth. After performing Cox regression analysis, we found that children with a breadth of three or more antigen-specific MBC or antibody responses at the baseline had a reduced risk for malaria in the ensuing P. falciparum transmission season. Specifically, MBC responses against AMA-1, MSP-2 (3D7) and MSP-3, as well as antibody responses to MSP-2 (3D7) and MSP-3 were prospectively associated with a reduced risk for malaria. The magnitude or breadth of MBC responses were however not correlated with the cumulative number of malaria episodes since birth. We conclude that increased breadth for merozoite antigen-specific MBC and antibody responses is associated with protection against malaria.


A review of the effectiveness and acceptability of the female condom for dual protection.
The female condom remains the sole female-initiated method of dual protection against unintended pregnancy and sexually transmissible infections (STIs), including HIV. We reviewed published data on the effectiveness and acceptability of the female condom for protection against pregnancy and infection. Overall, use of the female condom is low and several barriers hinder the wider adoption of the use of the method. Research on effectiveness has focussed on pregnancy, STIs and biological markers of semen exposure. Although the data available suggest that female condoms (or a mixture of female and male condoms) may provide similar degrees of protection against pregnancy and STIs as do latex male condoms alone, this conclusion has not been demonstrated and thus comparative research is urgently needed.


Synthesis and structure-activity relationship of a novel class of 15-membered macrolide antibiotics known as '11a-azalides'.
Macrolide antibiotics are widely prescribed for the treatment of respiratory tract infections; however, the increasing prevalence of macrolide-resistant pathogens is a public health concern. Therefore, the development of new macrolide scaffolds with activities against resistant pathogens is urgently needed. An efficient method for reconstructing the erythromycin A macrolactone skeleton has been established. Based on this methodology, novel 15-membered macrolides, known as '11a-azalides', with substituents at the C12, C13, or C4″ positions were synthesized and their antibacterial activities were evaluated. These derivatives showed promising antibacterial activities against erythromycin-resistant Streptococcus pneumoniae. Among them, the C4″ substituted derivatives had the most potent activity against erythromycin-resistant S. pneumoniae.


Performance evaluation of an IMDD optical OFDM-CDMA system.
In this paper, we propose a modulation technique for passive optical networks that harnesses two-dimensional prime hop system optical code division multiplexing access (OCDMA) and optical orthogonal frequency-division multiplexing (OFDM) for intensity modulation with direct-detection (IMDD) to enhance users' signal capacity in a cost-effective manner. The theoretical analysis is built from an analytical formula that takes into account both multiple-access interference and photodetector noise. Results show that OFDM-OCDMA with multiple users has similar performance to single-user conventional OOFDM for low transmitted powers.


Mutational hierarchies in myelodysplastic syndromes dynamically adapt and evolve upon therapy response and failure.
Clonal evolution is believed to be a main driver for progression of various types of cancer and implicated in facilitating resistance to drugs. However, the hierarchical organization of malignant clones in the hematopoiesis of myelodysplastic syndromes (MDS) and its impact on response to drug therapy remain poorly understood. Using high-throughput sequencing of patient and xenografted cells, we evaluated the intratumoral heterogeneity (n= 54) and reconstructed mutational trajectories (n = 39) in patients suffering from MDS (n = 52) and chronic myelomonocytic leukemia-1 (n = 2). We identified linear and also branching evolution paths and confirmed on a patient-specific level that somatic mutations in epigenetic regulators and RNA splicing genes frequently constitute isolated disease-initiating events. Using high-throughput exome- and/or deep-sequencing, we analyzed 103 chronologically acquired samples from 22 patients covering a cumulative observation time of 75 years MDS disease progression. Our data revealed highly dynamic shaping of complex oligoclonal architectures, specifically upon treatment with lenalidomide and other drugs. Despite initial clinical response to treatment, patients' marrow persistently remained clonal with rapid outgrowth of founder-, sub-, or even fully independent clones, indicating an increased dynamic rate of clonal turnover. The emergence and disappearance of specific clones frequently correlated with changes of clinical parameters, highlighting their distinct and far-reaching functional properties. Intriguingly, increasingly complex mutational trajectories are frequently accompanied by clinical progression during the course of disease. These data substantiate a need for regular broad molecular monitoring to guide clinical treatment decisions in MDS.


Kinetics of microbial translocation markers in patients on efavirenz or lopinavir/r based antiretroviral therapy.
We investigated whether there are differences in the effects on microbial translocation (MT) and enterocyte damage by different antiretroviral therapy (ART) regimens after 1.5 years and whether antibiotic use has impact on MT. In a randomized clinical trial (NCT01445223) on first line ART, patients started either lopinavir/r (LPV/r) (n = 34) or efavirenz (EFV) containing ART (n = 37). Lipopolysaccharide (LPS), sCD14, anti-flagellin antibodies and intestinal fatty acid binding protein (I-FABP) levels were determined in plasma at baseline (BL) and week 72 (w72). The levels of LPS and sCD14 were reduced from BL to w72 (157.5 pg/ml vs. 140.0 pg/ml, p = 0.0003; 3.13 ug/ml vs. 2.85 ug/ml, p = 0.005, respectively). The levels of anti-flagellin antibodies had decreased at w72 (0.35 vs 0.31 [OD]; p<0.0004), although significantly only in the LPV/r arm. I-FABP levels increased at w72 (2.26 ng/ml vs 3.13 ng/ml; p<0.0001), although significantly in EFV treated patients only. Patients given antibiotics at BL had lower sCD14 levels at w72 as revealed by ANCOVA compared to those who did not receive (Δ = -0.47 µg/ml; p = 0.015). Markers of MT and enterocyte damage are elevated in untreated HIV-1 infected patients. Long-term ART reduces the levels, except for I-FABP which role as a marker of MT is questionable in ART-experienced patients. Why the enterocyte damage seems to persist remains to be established. Also antibiotic usage may influence the kinetics of the markers of MT. ClinicalTrials.gov NCT01445223.