Weakened functional connectivity in patients with psychogenic non-epileptic seizures (PNES) converges on basal ganglia.
Psychogenic non-epileptic seizures (PNES) are involuntary paroxysmal events that are unaccompanied by epileptiform EEG discharges. We hypothesised that PNES are a disorder of distributed brain networks resulting from their functional disconnection.The disconnection may underlie a dissociation mechanism that weakens the influence of unconsciously presented traumatising information but exerts maladaptive effects leading to episodic failures of behavioural control manifested by psychogenic 'seizures'. To test this hypothesis, we compared functional connectivity (FC) derived from resting state high-density EEGs of 18 patients with PNES and 18 age-matched and gender-matched controls. To this end, the EEGs were transformed into source space using the local autoregressive average inverse solution. FC was estimated with a multivariate measure of lagged synchronisation in the θ, α and β frequency bands for 66 brain sites clustered into 18 regions. A multiple comparison permutation test was applied to deduce significant between-group differences in inter-regional and intraregional FC. The significant effect of PNES-a decrease in lagged FC between the basal ganglia and limbic, prefrontal, temporal, parietal and occipital regions-was found in the α band. We believe that this finding reveals a possible neurobiological substrate of PNES, which explains both attenuation of the effect of potentially disturbing mental representations and the occurrence of PNES episodes. By improving understanding of the aetiology of this condition, our results suggest a potential refinement of diagnostic criteria and management principles.


Regulation of murine oocyte meiosis: evidence for a gonadotropin-induced, cAMP-dependent reduction in a maturation inhibitor.
We have developed an assay that can detect relative changes in the amount of a non-cAMP inhibitor of maturation present in cumulus cells (Eppig et al., 1983, Dev. Biol., 100:39-49). Using this assay in which accelerated maturation of a group of treated cumulus cell-oocyte complexes relative to untreated complexes indicates a decrease in the amount of inhibitor, results of the experiments described here suggest a possible relationship between elevation of cAMP levels and subsequent decreased amounts of a non-cAMP inhibitor. Mouse oocytes obtained from cumulus cell-oocyte complexes treated with luteinizing hormone (LH) resumed meiosis prior to oocytes obtained from untreated complexes; the degree of acceleration of maturation was dependent on LH concentration. A similar result was obtained with follicle-stimulating hormone (FSH). Correlated with LH- or FSH-acceleration of maturation was an LH- or FSH-induced elevation of cumulus cell cAMP levels. Inhibiting LH-induced elevation of cumulus cell cAMP levels inhibited LH-induced acceleration of maturation. An initial incubation of complexes in medium containing dibutyryl cAMP (dbcAMP) also promoted acceleration of maturation. In contrast, maturation of denuded oocytes was not altered by treatment with either LH, FSH, or dbcAMP. Complexes initially incubated in dbcAMP-containing medium still demonstrated acceleration of maturation after a subsequent 2 h incubation in dbcAMP-free medium. Relative to untreated complexes, none of these treatments disrupted intercellular communication between cumulus cells and the oocyte. Elevating follicle cAMP levels with cholera toxin induced maturation of follicle-enclosed oocytes when cumulus cell-oocyte coupling was still fully maintained. These results are interpreted to indicate that gonadotropin-mediated acceleration of maturation is via a cAMP-dependent reduction in the level of a maturation inhibitor present in granulosa/cumulus cells.


Epidemiology of COVID-19
It seems that coronaviruses take an important place in the 21th century history. Five of seven human coronavirus was isolated in this century. Unfortunately, last three of them entered our life with a fear of outbreak, pandemic or death. Last human coronavirus which emerged world from Wuhan China, SARS CoV-2 and its clinical expression, Coronavirus disease (COVID-19) recently taken a significant place in our daily practice. Initial reports showed that, its origin was bats. It transmitted human to human by droplet and contact routes, but some doubt about airborne, fecal or intrauterine transmission also should be removed. Its R0 value is 2.3 but it could be as high as 5.7. Its case fatality rate was 6.3, but it was different in different ages and counties, and it could be over 15%. According to early models total 10–12 weeks is required to control an outbreak in the community. While different countries show different daily case numbers, total number of case, case mortality rates or R0, it seems they show a similar epidemic curve. Every day we learn new data about the current outbreak. Since the outbreak is not over yet, every detail should be evaluated carefully and the updates should be followed closely to monitor the epidemiological properties of COVID-19.


HPV16 viral characteristics in primary, recurrent and metastatic vulvar carcinoma.
Vulvar carcinoma is the fourth most common gynecological malignancy. Two separate carcinogenic pathways are suggested, where one is associated with the human papillomavirus (HPV) and HPV16 the most common genotype. The aim of this study was to evaluate HPV-markers in a set of primary tumors, metastases and recurrent lesions of vulvar squamous cell carcinomas (VSCC). Ten HPV16-positive VSCC with metastatic regional lymph nodes, distant lymphoid/hematogenous metastases or local recurrent lesions were investigated for HPV genotype, HPV16 variant, HPV16 viral load, HPV16 integration and HPV16 E2BS3 and 4 methylation. In all 10 analyzed case series, the same HPV genotype (HPV16), HPV16 variant and level of viral load were detected in all lesions within a patient case. Primary tumors with a high E2/E6 ratio were found to have fewer vulvar recurrences and/or metastases after diagnosis and treatment. Also, a significantly lower viral load was evident in regional lymph nodes compared to primary tumors. The data presented strengthens the evidence for a clonal HPV-induced pathway for vulvar carcinoma.


Disease patterns in a rural black population.
Epidemiological information concerning disease patterns among blacks in southern Africa is scanty and a plea has been made for greater research. Between September 1968 and January 1970, patients admitted to the medical wards of Jane Furse Hospital in Lebowa were studied; 14 years later the study was repeated and the results compared. The increasing incidence of asthma, hypertension and diabetes, well recognized in urban blacks, seems to be reflected in the rural setting of Jane Furse Hospital. Tuberculosis remains a common problem and a cause for concern.


Preliminary investigation of economics issues in hospitalized patients with stroke.
The study of economics is important in Iranian stroke patients, because it is one of the costly diseases that could be linked to disability, mortality, and morbidity. The aim of this preliminary study was to investigate total treatment costs of hospitalized patients with stroke. A cross-sectional study of 24 patients conducted to Isfahan Neurosciences Research Centre was carried out between April 1, 2012 and September 31, 2012. Demographic (sex, age) and economic variables (Raise tariffs, accumulated surplus, the total amount, of patients', patients' paid, and home insurance contribution) were extracted from the patients' profiles. All information recorded and processed using Excel. The mean age of patients was 71 years (ranged; 40-93 years old). Preliminary analysis of available costs issues could be described as: Raise tariffs (mean: 3500256 Rial, ranged: 504460-9775455 Rial), accumulated surplus (mean: 565578 Rial, ranged: 56700-2343664 Rial), the total amount (mean: 4045556 Rial, ranged: 715460-12219119 Rial), of patients' (mean: 756037 Rial, ranged: 0-8365447 Rial), patients' paid (mean: 1307762 Rial, ranged: 45300-9193000 Rial), and home insurance contribution (mean: 3070713 Rial, ranged 0-8887907 Rial). The cost disparity within this study after stroke could be mainly connected to variations in duration of hospital stay. Inspecting agenda towards this direction could reduce the economic cost of stroke significantly. Therefore, further assessment correlated to attain strategies in order to reduce costs associated to patients' paid and home insurance contribution could be much more advantageous.


Effects of Mind⁻Body Movements on Balance Function in Stroke Survivors: A Meta-Analysis of Randomized Controlled Trials.
Objective: We performed a systematic review with meta-analysis and meta-regression to determine if mind⁻body movements (MBM) could be effective in rehabilitating balance function among stroke survivors. Methods: A literature search was conducted using major Chinese and English electronic databases from an inception until January 2018. Randomized controlled studies were included in our meta-analysis. Data was independently extracted by two review authors using a pre-developed table and confirmed by a third party to reach a consensus. Pooled effect size (Hedge’s g) was computed while the random-effect model was set. Results: The meta-analytic results showed a significant benefit of the MBM intervention on increased balance function compared to the control groups (Hedge’s g = 1.59, CI 0.98 to 2.19, p < 0.001, I² = 94.95%). Additionally, the meta-regression indicated that the total number of sessions (β = 0.00142, 95% CI 0.0039 to 0.0244, p = 0.0067) and dose of weekly training (β = 0.00776, 95% CI 0.00579 to 0.00972, p = 0.00) had significantly positive effects on balance function. Conclusions: The study encouraging findings indicate the rehabilitative effect of a MBM intervention for balance function in stroke survivors. However, there were significant limitations in the design among several of the included trials. Additional studies with more robust methodologies are needed to provide a more definitive conclusion.


Mechanisms of arm paresis in middle cerebral artery distribution stroke: pilot study.
The development of effective neurobiological adjuvants to rehabilitation of paresis caused by stroke will depend on understanding mechanisms of paresis. Our objective was to determine the extent to which upper-limb (UL) paresis after nonlacunar ischemic middle cerebral artery (MCA) distribution stroke is caused by infarction of posterior periventricular white matter (PVWM), where corticospinal fibers serving movement descend, and caused by infarction of the arm-hand region of precentral gyrus (ahPCG). We conducted a blinded, retrospective analysis of computed tomography and magnetic resonance imaging from a convenience sample of 64 prospectively evaluated subjects with UL paresis resulting from MCA distribution stroke. Of the subjects, 96.5% had PVWM involvement while 53% had minimal or no ahPCG involvement. Even in subjects with no UL function, 56% had very minimal infarction (<25%) of the ahPCG. Degree of paresis was statistically associated with presence or absence of detectable posterior PVWM damage but not with extent of ahPCG involvement. These preliminary findings suggest that posterior PVWM involvement may be a major, if not the principal, determinant of paresis in all hemispheric ischemic strokes and motivate further prospective studies of this problem.


Assessment of barriers to bone marrow donation by unrelated African-American potential donors.
African Americans have a lower registration rate for becoming potential bone marrow and stem cell donors. The same attitudes and behaviors are exhibited in regard to solid organ and blood donations, causing a serious under-representation of the African-American population in the donor pool. In our efforts to increase donor availability for African Americans through a project funded by the Medical University of South Carolina, we used a survey to determine the reasons African Americans do not participate as donors for bone marrow. We surveyed 589 African Americans, a great majority of whom were women. Our survey identified major barriers to donation to be the lack of awareness that transplantation can save lives, the cost of donation, and the lack of opportunities to donate. The most effective interventions in increasing donation have been to provide both educational programs preceding marrow drives and the opportunity to donate. Through these efforts, the number of potential African-American donors has increased from 768 (accrued over a period of 12 years) to 1977 in less than 2 years. We conclude that a minority recruitment program targeting African-American volunteers for the National Marrow Donor Program (NMDP) should include an education component addressing the most common barriers before drives.


[Role of demotivation and affective disorders in apathy in patients with Parkinson's disease without dementia and depression].
to assess the role of demotivation and various affective factors in apathy in patients with Parkinson's disease (PD) without dementia and depression. 20 patients and 20 control subjects matched with age, education level, and genre. apathy was assessed by the Apathy evaluation scale (AES) and by a specific scale including a quantitative evaluation of 32 intentional activities and a qualitative assessment of the causes of attribution of restricted activities by a semi-structured interview (GDAS). Four causal attributions were distinguished: E = related to external factors, M = disease symptoms related, C = affective disturbances with preservation of motivation, and D = demotivation. The results were compared to a battery of tests including cognitive evaluation (mini-mental state and Mattis dementia rating scale for global evaluation, selecting reminding test for memory; Stroop test for inhibition, and six element test for planification); affective evaluation (Montgomery & Asberg and Hamilton depression rating scales for depression, emotional disturbances by the Abrams and Taylor scale, the Depression mood scale, and the International picture system), premorbid personality (NEOPI-R), and defensive psychological mechanisms (DSQ-40); functional assessment by a combined scale including the Self-maintenance physical scale and the Instrumental activities of daily living (Lawton) and the Social activities scale (Katz & Lyerly), the Disability assessment scale, and the UPDRS. apathy was found in 25% of the patients according to the AES, but only in 15% according to the GDAS. Scores on cognitive and affective evaluation were higher in patients than in controls but only emotional blunting was correlated to apathy. Some results coud be interpreted in favor of a premorbid personality disorder in patients with PD, but were not correlated to apathy. Causal attribution was M in 38% of cases of reduced activities, D in 30%, E in 22%, and C in 10%. emotional blunting was the main correlate of apathy in PD patients without dementia and depression. Demotivation was the causal mechanism in only 30% of the patients with apathy.


Establishing long-term survival and cure in young patients with Ewing's sarcoma.
This paper investigates the potential for long-term survivorship for young patients diagnosed with Ewing's sarcoma. Data are examined from two successive UKCCSG Ewing's Tumour studies (ET-1 and ET-2). Patients have been followed for up to 20 years. These studies had suggested that better 5-year survival with ET-2 over the earlier ET-1 was achieved by replacing cyclophosphamide by ifosfamide and increasing the dose of doxorubicin in a four-drug chemotherapy regimen. The updated hazard ratio, stratified for metastatic status at diagnosis, of 0.39 (95% confidence interval 0.12-0.61) confirmed the advantage of the ET-2 regimen in terms of overall survival. Cure models, based on the Weibull distribution, suggested that factors for long-term survival in addition to presence of metastases were age, primary site of tumour and study. Modelling identified the proportion cured with the ET-2 protocol as best at 70% in those who are under 10 years with a nonpelvic primary site and without metastatic disease. This contrasts to only 13% cure in those with the corresponding adverse prognostic indicators. Additionally, the risk of death remains greatest but relatively constant over the first 2 years postdiagnosis, and then declines to a lower but constant value for the next 3 years before reaching the 'cure plateau' at about 5 years. This investigation suggests that 'cure' is possible for patients with Ewing's sarcoma. This is established at approximately 5 years post diagnosis and the proportion cured depends on the presence of metastases, pelvic site and age at diagnosis.


Potential impact of N-terminal pro-BNP testing on the emergency department evaluation of acute dyspnea.
Measurement of the serum B-type natriuretic peptide (BNP) level and more recently its precursor, N-terminal proBNP (NT-proBNP), has been advocated to facilitate the diagnosis of heart failure in the emergency department (ED). We sought to determine the potential impact of adding NT-proBNP testing to the routine evaluation of emergency patients with acute dyspnea. This prospective cohort study enrolled a convenience sample of acutely dyspneic patients at a tertiary care ED. We excluded trauma patients and those under 30 years of age. Patients underwent standard evaluation, including radiography when indicated. At the point of final diagnosis and blinded to the NT-proBNP result, physicians documented the likelihood that heart failure accounted for the patient's acute dyspnea on a 7-point Likert scale, the data from which was subsequently collapsed to 3 categories for analysis purposes. The primary outcome was the agreement between clinical impression and the NT-proBNP assay classified using manufacturer-recommended, age-specific cut-offs. Newly proposed cut-offs from a recent study were also evaluated. One hundred and twenty-nine patients making 139 ED visits were enrolled (median age 76 years; 59% admitted). The serum NT-proBNP assay was positive in 119 (86%, 95% confidence interval [CI] 80%-91%) cases, including 75% (43/57, 95% CI 62%-86%) of the cases that the treating physician felt were not caused by heart failure, and 86% (25/29, 95% CI 68%-96%) where the treating physician was unsure. The median NT-proBNP concentration was higher in patients clinically believed to have heart failure rather than pneumonia or chronic obstructive pulmonary disease; however, the ranges of these values overlapped extensively (median 4361 pg/mL; interquartile range [IQR] 2386-10877 v. 1651 pg/mL; IQR 370-4745, respectively). There is high discordance between the clinical impression of treating physicians and NT-proBNP concentrations, notably in patients who are believed not to have heart failure. Although the reference standard of ED diagnosis is imperfect, the broad overlap in NT-proBNP concentrations suggests poor specificity in this target patient population. The introduction of routine ED NT-proBNP testing using the current cut-offs would be expected to result in substantial indirect costs from further diagnostic testing. It remains unclear whether the introduction of this diagnostic test would have a positive impact on clinically relevant patient outcomes.


Nutrient-Dependent Trade-Offs between Ribosomes and Division Protein Synthesis Control Bacterial Cell Size and Growth.
Cell size control emerges from a regulated balance between the rates of cell growth and division. In bacteria, simple quantitative laws connect cellular growth rate to ribosome abundance. However, it remains poorly understood how translation regulates bacterial cell size and shape under growth perturbations. Here, we develop a whole-cell model for growth dynamics of rod-shaped bacteria that links ribosomal abundance with cell geometry, division control, and the extracellular environment. Our study reveals that cell size maintenance under nutrient perturbations requires a balanced trade-off between ribosomes and division protein synthesis. Deviations from this trade-off relationship are predicted under translation inhibition, leading to distinct modes of cell morphological changes, in agreement with single-cell experimental data on Escherichia coli. Furthermore, by calibrating our model with experimental data, we predict how combinations of nutrient-, translational-, and shape perturbations can be chosen to optimize bacterial growth fitness and antibiotic resistance.


Rabeximod reduces arthritis severity in mice by decreasing activation of inflammatory cells.
The novel small molecule 9-chloro-2,3-dimethyl-6-(N,N-dimethylaminoethylamino-2-oxoethyl)-6H-indolo[2,3-b] quinoxaline (Rabeximod) reduces severity of arthritis in rodent models of rheumatoid arthritis (RA) and multiple sclerosis (MS). This study aimed to investigate the cellular target in vivo. Collagen antibody-induced arthritis (CAIA) is induced by monoclonal collagen type II antibodies and enhanced by lipopolysaccharide. It was investigated how and when Rabeximod operates on inflammatory cells after stimulation of either Toll-like receptor (TLR)4 (lipopolysaccharide) or TLR2 (lipomannan) in mice lacking functional signalling through TLR4 due to a spontaneous deletion of the Tlr4 gene. Rabeximod efficiently prevented arthritis during the time window when TLR2 or TLR4 ligands activate inflammatory macrophages. The effect operated downstream of TLR activation as Rabeximod was highly therapeutic in CAIA enhanced through TLR2 stimuli in TLR4 deficient mice. In addition, it was found that the arthritis ameliorating effect of Rabeximod was time dependent, since inhibition of tumour necrosis factor alpha production from macrophages in vitro was more pronounced if administered close to stimulation. Rabeximod suppresses arthritis by preventing activation of inflammatory cells, most likely macrophages, in a time dependent fashion, downstream of TLR2 and TLR4 stimulation.


The MoxFo initiative-Mechanisms of action: Biomarkers in multiple sclerosis exercise studies.
As exercise exerts neurobiological and immunomodulatory effects, it might also act as a disease-modifying intervention in MS. However, a clear mechanistic link between exercise and disease-modifying effects in MS has yet to be established. Establish recommendations for future mechanistic exercise studies in MS. In regular meetings, members of the mechanisms of action group within the MoXFo (Moving eXercise research Forward in MS) initiative evaluated gaps of knowledge and discussed unmet needs in mechanistic MS research. We concluded that biomarkers assessed in translational studies in humans and animals are essential to decipher the underlying mechanisms of exercise in MS. Consequently, we defined clear definitions of different types of biomarkers examined in MS exercise studies and operationalized their use to align with the research question and optimal testing time points. Furthermore, we provide key considerations to improve the rigor of translational studies and defined minimal reporting criteria for animal studies. The resulting recommendations are intended to improve the quality of future mechanistic exercise studies in MS and consequently lead to a better understanding of therapeutic approaches.


A clinical study on bing gan ling oral liquid for treatment of hepatitis C.
Based on the principles of cooling the blood to expel the pathogenic toxins and regulating the function of liver and activating the spleen in traditional Chinese medicine, 60 cases of chronic hepatitis C were treated with Bing Gan Ling (BGL), an oral liquid, which is composed mainly of Shuiniujiao (Cornu Bubali), Huzhang (Rhizoma Polygoni Cuspidati), Chishao (Radix Paeoniae Rubra), and Huangqi (Radix Astragali), etc. The total effective rate was 86.7%, which is considerably better than that of the control group (P < 0.01). The animal experiments and pathological studies suggest that the above-mentioned prescription has marked action of protecting the liver and lowering the activity of enzymes; and that it can ameliorate the acute liver injury induced by D-galactosamine.


Slipping through the cracks: a qualitative study to explore pathways of HIV care and treatment amongst hospitalised patients with advanced HIV in Kenya and the Democratic Republic of the Congo.
Advanced HIV causes substantial mortality in sub-Saharan Africa despite widespread antiretroviral therapy coverage. This paper explores pathways of care amongst hospitalised patients with advanced HIV in rural Kenya and urban Democratic Republic of the Congo, with a view to understanding their care-seeking trajectories and poor health outcomes. Thirty in-depth interviews were conducted with hospitalised patients with advanced HIV who had previously initiated first-line antiretroviral therapy, covering their experiences of living with HIV and care-seeking. Interviews were audio-recorded, transcribed and translated before being coded inductively and analysed thematically. In both settings, participants' health journeys were defined by recurrent, severe symptoms and complex pathways of care before hospitalisation. Patients were often hospitalised after multiple failed attempts to obtain adequate care at health centres. Most participants managed their ill-health with limited support networks, lived in fragile economic situations and often experienced stress and other mental health concerns. Treatment-taking was sometimes undermined by strict messaging around adherence that was delivered in health facilities. These findings reveal a group of patients who had "slipped through the cracks" of health systems and social support structures, indicating both missed opportunities for timely management of advanced HIV and the need for interventions beyond hospital and clinical settings.


Hamiltonian Analysis of Subcritical Stochastic Epidemic Dynamics.
We extend a technique of approximation of the long-term behavior of a supercritical stochastic epidemic model, using the WKB approximation and a Hamiltonian phase space, to the subcritical case. The limiting behavior of the model and approximation are qualitatively different in the subcritical case, requiring a novel analysis of the limiting behavior of the Hamiltonian system away from its deterministic subsystem. This yields a novel, general technique of approximation of the quasistationary distribution of stochastic epidemic and birth-death models and may lead to techniques for analysis of these models beyond the quasistationary distribution. For a classic SIS model, the approximation found for the quasistationary distribution is very similar to published approximations but not identical. For a birth-death process without depletion of susceptibles, the approximation is exact. Dynamics on the phase plane similar to those predicted by the Hamiltonian analysis are demonstrated in cross-sectional data from trachoma treatment trials in Ethiopia, in which declining prevalences are consistent with subcritical epidemic dynamics.


Diagnostic Accuracy of Zero-Echo Time MRI for the Evaluation of Cervical Neural Foraminal Stenosis.
A cohort study. The aim of this study was to evaluate the clinical utility of Zero-Echo-Time (ZTE) magnetic resonance imaging (MRI) for the assessment of cervical neural foraminal stenosis (CNFS) through the comparison of inter-modality [computed tomography (CT) and ZTE-MRI] CNFS grade severity agreements. Conventional MRI limited in its ability to provide direct visualization of cortical bone. The highly organized tissue structure of cortical bone results in very short T2 values that preclude acquisition of sufficient signal intensity and positive image contrast. ZTE imaging permits visualization of tissues with very short transverse relaxation times, and is capable of displaying images with CT-like contrast. Thirty-four subjects were recruited from a clinical cohort of patients undergoing standard of care MRI and CT imaging for evaluation of CNFS. Standard of care CT imaging studies were obtained on all subjects within 6 months of their ZTE-MRI acquisition (mean time interval: 25.3 ± 54.1 days; median: 0 days). ZTE-MRI and CT imaging studies were evaluated and severity of CNFS was graded on a scale from 0 to 5 (0 = none; 5 = severe). Weighted-kappa statistics were used to assess agreement between ZTE and CT grades of CNFS on both sides (right and left) of each motion segment. Ordinal logistic mixed-effects regression analyses evaluated the effects of inter-modality position differences (flexion-extension curvature) on inter-modality differences in CNFS grade. Substantial agreement (κ = 0.72) was found between ZTE- and CT-based grades of CNFS. Significant inter-modality differences in cervical spine curvature were found for all motion segments, except C2-3 and C3-4 (P < 0.05). However, no significant relationship was found between inter-modality differences in curvature, and inter-modality differences in CNFS grade for any motion segment (P = 0.28). Results of the current study suggest that ZTE-MRI is well-suited for the evaluation of CNFS and may have the potential to obviate the need for concurrent CT scans in some cases. 2.


Enhancing contrast of fingerprints on plastic tape.
Many of the currently available fingerprinting methods have limited ability to visualize fingerprints on plastic tape without expensive equipment or significant handling of the sample. This is especially true for visualizing fingerprints on black electrical tape. This study sought a hands-off method to produce easy visualization of fingerprints on different types of plastic tape, including black electrical tape, without the need for expensive equipment. The methods selected were to sublime disperse dyes into the tape, both with and without the fuming of cyanoacrylate, everywhere except for where the fingerprint was applied. The resulting color contrasts provided enough differentiation to visualize fingerprints on plastic tape under ambient light. Sequential fuming with cyanoacrylate followed by disperse dyes provided the best visualizations on all tapes, and cyanoacrylate followed by disperse yellow 211 clearly visualized fingerprints on black electrical tape.


Somatic and dendritic small-conductance calcium-activated potassium channels regulate the output of cerebellar Purkinje neurons.
Cerebellar Purkinje neurons provide the sole output of the cerebellar cortex and play a crucial role in motor coordination and maintenance of balance. They are spontaneously active, and it is thought that they encode timing signals in the rate and pattern of their activity. An understanding of factors that control their excitability is important for delineating their computational role in the cerebellum. We evaluated the role of small-conductance calcium-activated potassium (SK) channels in the regulation of activity of mouse and rat Purkinje neurons. We find that somatic SK channels effectively limit the maximum firing rate of Purkinje neurons; when SK channels are blocked by the specific antagonists apamin or scyllatoxin, cells fire spontaneously at rates as high as 500 spikes per second. Dendritic SK channels, however, control primarily the extent to which dendrites contribute to the firing rate of Purkinje cells. Given their presence in the dendrites, it is likely that SK channels in the proximal dendrites govern the efficacy of dendrosomatic electrical coupling. When studied under physiological conditions, it is found that SK channels play the same role in controlling the excitability of adult Purkinje neurons as they do in young cells.


Bioenergetic actions of beta-bungarotoxin, dendrotoxin and bee-venom phospholipase A2 on guinea-pig synaptosomes.
Low concentrations of beta-bungarotoxin or bee-venom phospholipase A2 cause a progressive Ca2+-dependent increase in the proton permeability of the mitochondria within the synaptosomal cytosol, manifested as an increase in oligomycin-insensitive respiration and a partial depolarization of the mitochondrial membrane potential. This uncoupling appears to be a consequence of fatty acids liberated by phospholipase A2 activity at the plasma membrane, since it can be mimicked by the addition of oleate-albumin complexes, in which case there is no requirement for external Ca2+. Dendrotoxin does not affect the mitochondrial proton permeability in situ, but protects partially against the uncoupling action of beta-bungarotoxin. In contrast, this effect of bee-venom phospholipase A2 is unaffected by dendrotoxin. beta-Bungarotoxin, but not bee-venom phospholipase A2, induces a slow progressive depolarization of the plasma membrane. The action of beta-bungarotoxin at the plasma membrane appears not to be related to fatty acid production, since it is augmented rather than inhibited by raising albumin concentrations in the medium. It is concluded that beta-bungarotoxin has at least two actions on intact synaptosomes, both of which may involve interaction at the plasma membrane with a site common to dendrotoxin: first, a mitochondrial uncoupling mediated by fatty acids and, secondly, a depolarization at the plasma membrane.


Effects related to indomethacin prolonged survival and decreased tumor-growth in a mouse-tumor model with cytokine dependent cancer cachexia.
Tumor-bearing mice with two different locally growing malignant tumors (epithelial like, MCG 101; malignant melanoma, K1735-M2) were used to evaluate the putative role of prostaglandins for survival and local tumor growth in experimental cancer. Daily systemic injections of indomethacin (1 mu g/g bw) were used to block prostaglandin production in normal and T-cell deficient tumor-bearing nude mice. Tumor progression was determined by measurements of tumor weight, DNA-synthesis, cell cycle kinetics in vivo and in vitro (flow cytometry), tumor tissue concentrations of polyamines (putrescine, spermidine, spermine) and tumor tissue gene expression of growth regulating factors (IL-1 alpha, IL-6, TNF alpha, A,B-PDGF, EGF, VEGF, bFGF, TGF beta(3), angiogenin and transferrin receptor). Tumor tissue content of von Willebrandt factor VIII was estimated by immunohistochemistry. Indomethacin had no effect on survival, host nutritional state or local tumor growth in mice bearing the malignant melanoma with low PGE(2) production. In contrast, indomethacin prolonged survival, improved cachexia and decreased tumor growth in mice bearing the MCG 101 tumor with hundredfold higher prostaglandin tumor production, leading to elevated liver and muscle tissue as well as plasma concentrations of PGE(2). Indomethacin inhibited almost completely the high tumor PGE(2) production in MCG tumors, leading to prolonged potential doubling time for tumor growth in vivo, and a trend to decreased tumor tissue concentration of polyamines (spermidine). Indomethacin had no inhibitory effect on tumor cell proliferation in vitro, although PGE(2) production was decreased by 75%. The effect of indomethacin in vivo was independent of T-cells and was observed with similar magnitude irrespective of the number of MCG cells (10(4)-10(6)) implanted or the site of implantation (s.c., i.p., liver, lung, skeletal muscles). Tumor growth inhibition by indomethacin was not intrinsically transferable by tumor cells from indomethacin treated tumor-animals. Tumor expression of mRNA for several growth regulating factors were either increased (IL-6, TNF alpha, GM-CSF, TGF beta(3)) unchanged (EGF, VEGF, PDGF A,B, IL-1 alpha, transferrin receptor) or decreased (b-FGF and angiogenin) (p<0.05) by indomethacin treatment of MCG mice. Decreased tumor content of von Willebrandt factor VIII in combination with an attenuated tumor vasculature were associated with decreased tumor growth (p<0.05). Our results confirm that high tumor production of prostaglandins was related to reduced survival. Tumor prostaglandins probably promote local tumor growth by stimulation of tumor surrounding cells to produce growth factor(s) for tumor angiogenesis including tumor and matrix cell proliferation unrelated to immune cells.


Estrogen receptor 1 modulates circadian rhythms in adult female mice.
Estradiol influences the level and distribution of daily activity, the duration of the free-running period, and the behavioral phase response to light pulses. However, the mechanisms by which estradiol regulates daily and circadian rhythms are not fully understood. We tested the hypothesis that estrogens modulate daily activity patterns via both classical and "non-classical" actions at the estrogen receptor subtype 1 (ESR1). We used female transgenic mice with mutations in their estrogen response pathways; ESR1 knock-out (ERKO) mice and "non-classical" estrogen receptor knock-in (NERKI) mice. NERKI mice have an ESR1 receptor with a mutation in the estrogen-response-element binding domain, allowing only actions via "non-classical" genomic and second messenger pathways. Ovariectomized female NERKI, ERKO, and wildtype (WT) mice were given a subcutaneous capsule with low- or high-dose estradiol and compared with counterparts with no hormone replacement. We measured wheel-running activity in a light:dark cycle and constant darkness, and the behavioral phase response to light pulses given at different points during the subjective day and night. Estradiol increased average daily wheel-running, consolidated activity to the dark phase, and shortened the endogenous period in WT, but not NERKI and ERKO mice. The timing of activity onset during entrainment was advanced in all estradiol-treated animals regardless of genotype suggesting an ESR1-independent mechanism. We propose that estradiol modifies period, activity level, and distribution of activity via classical actions of ESR1 whereas an ESR1 independent mechanism regulates the phase of rhythms.


Local hypothyroidism favors the progression of preneoplastic lesions to hepatocellular carcinoma in rats.
Thyroid hormone receptors (TRs) are ligand-dependent transcription factors that mediate most of the effects elicited by the thyroid hormone, 3,5,3'-L-triiodothyronine (T3). TRs have been implicated in tumorigenesis, although it is unclear whether they act as oncogenes or tumor suppressors, and at which stage of tumorigenesis their dysregulation occurs. Using the resistant-hepatocyte rat model (R-H model), we found down-regulation of TRβ1 and TRα1 and their target genes in early preneoplastic lesions and hepatocellular carcinoma (HCCs), suggesting that a hypothyroid status favors the onset and progression of preneoplastic lesions to HCC. Notably, TRβ1 and, to a lesser extent, TRα1 down-regulation was observed only in preneoplastic lesions positive for the progenitor cell marker, cytokeratin-19 (Krt-19) and characterized by a higher proliferative activity, compared to the Krt-19 negative ones. TRβ1 down-regulation was observed also in the vast majority of the analyzed human HCCs, compared to the matched peritumorous liver or to normal liver. Hyperthyroidism induced by T3 treatment caused up-regulation of TRβ1 and of its target genes in Krt-19(+) preneoplastic rat lesions and was associated with nodule regression. In HCC, TRβ1 down-regulation was not the result of hypermethylation of its promoter, but was associated with an increased expression of TRβ1-targeting microRNAs ([miR]-27a, -181a, and -204). An inverse correlation between TRβ1 and miR-181a was also found in human cirrhotic peritumoral tissue, compared to normal liver. Down-regulation of TRs, especially TRβ1, is an early and relevant event in liver cancer development and is species and etiology independent. The results also suggest that a hypothyroid status of preneoplastic lesions may contribute to their progression to HCC and that the reversion of this condition may represent a possible therapeutic goal to interfere with the development of this tumor.


Probing the microRNA and small interfering RNA pathways with virus-encoded suppressors of RNA silencing.
In plants, small interfering RNAs (siRNAs) and microRNAs (miRNAs) are effectors of RNA silencing, a process involved in defense through RNA interference (RNAi) and in development. Plant viruses are natural targets of RNA silencing, and as a counterdefensive strategy, they have evolved highly diverse silencing suppressor proteins. Although viral suppressors are usually thought to act at distinct steps of the silencing machinery, there had been no consensus system so far that allowed a strict side-by-side analysis of those factors. We have set up such a system in Arabidopsis thaliana and used it to compare the effects of five unrelated viral silencing suppressors on the siRNA and miRNA pathways. Although all the suppressors inhibited RNAi, only three of them induced developmental defects, indicating that the two pathways are only partially overlapping. These developmental defects were remarkably similar, and their penetrance correlated with inhibition of miRNA-guided cleavage of endogenous transcripts and not with altered miRNA accumulation per se. Among the suppressors investigated, the tombusviral P19 protein coimmunoprecipitated with siRNA duplexes and miRNA duplexes corresponding to the primary cleavage products of miRNA precursors. Thus, it is likely that P19 prevents RNA silencing by sequestering both classes of small RNAs. Moreover, the finding here that P19 binds siRNAs and suppresses RNAi in Hela cells also suggests that this factor may be useful to dissect the RNA silencing pathways in animals. Finally, the differential effects of the silencing suppressors tested here upon other types of Arabidopsis silencing-related small RNAs revealed a surprising variety of biosynthetic and, presumably, functional pathways for those molecules. Therefore, silencing suppressors are valuable probes of the complexity of RNA silencing.


[Combined effect of benzylpenicillin, furagin and bile acids on staphylococci].
The results of the study of the effect of benzylpenicillin or furagin in combination with bile acids, such as cholic, glycocholic and desoxycholic on the collection cultures of staphylococci are presented. The study showed that the subbacteriostatic doses of the bile acids increased the bacteriostatic and bactericidal effects of benzylpenicillin and furagin by tens and hundreds times. The highest potentiation effect was attained with the use of the furagin combination and desoxycholic acid.


Effect of simvastatin on endothelium-dependent vaso-relaxation and endogenous nitric oxide synthase inhibitor.
To investigate the effect of simvastatin on endothelium-dependent vasorelaxation and endogenous nitric oxide synthesis inhibitor asymmetric dimethylarginine (ADMA) in rats and cultured ECV304 cells. Endothelial injury was induced by a single injection of low density lipoprotein (LDL) (4 mg/kg, 48 h) in rats or incubation with LDL (300 mg/L) or oxidative-modified LDL (100 mg/L) in cultured ECV304 cells, and vasodilator responses to acetylcholine (ACh) in the aortic rings and the level of ADMA, nitrite/nitrate (NO) and tumor necrosis factor-alpha (TNF-alpha) in the serum or cultured medium were determined. And the adhesion of the monocytes to endothelial cells and the activity of dimethylarginine dimethylaminohydrolase (DDAH) in the cultured ECV304 cells were measured. A single injection of LDL decreased endothelium-dependent relaxation to ACh, markedly increased the serum level of endogenous ADMA and TNF-alpha, and reduced serum level of NO. Pretreatment with simvastatin (30 or 60 mg/kg) markedly attenuated inhibition of vasodilator responses to ACh, the increased level of TNF-alpha and the decreased level of NO by LDL, but no effect on serum concentration of endogenous ADMA. In cultured ECV304 cells, LDL or ox-LDL markedly increased the level of ADMA and TNF-alpha and potentiated the adhesion of monocytes to endothelial cells, concomitantly with a significantly decrease in the activity of DDAH and serum level of NO. Pretreatment with simvastatin (0.1, 0.5, or 2.5 micromol/L) markedly decreased the level of TNF-alpha and the adhesion of monocytes to endothelial cells, but did not affect the concentration of endogenous ADMA and the activity of DDAH. Simvastatin protect the vascular endothelium against the damages induced by LDL or ox-LDL in rats or cultured ECV304 cells, and the beneficial effects of simvastatin may be related to the reduction of inflammatory cytokine TNF-alpha level.


Influence of endotracheal tube diameter on forced deflation flow-volume curves in rhesus monkeys.
The forced deflation (FD) technique is the recommended gold standard to generate forced expiratory vital capacity (FVC) curves and to measure maximum expiratory flow-volume (MEFV) relationships in intubated infants and children. However, the influence of the endotracheal tube (ETT) on the site of flow limitation, the shape and the analysis of the resultant MEFV curves have not been defined. Nine anaesthetized (thiopentone, 8 mg x kg(-1) x h(-1)) rhesus monkeys (mean weight (+/-SEM) 10+/-1 kg) were intubated consecutively with ETTs of different internal diameters (ID 3.0-5.5 mm, at intervals of 0.5 mm); the largest representing the appropriate ETT size for the animal. Quadruplicate MEFV curves were generated by FD using the standard +40 cmH2Oinsp/-40 cmH2Oexp pressures and recorded at each ETT diameter. The effect of the different ETT diameters on the FD flow-volume curve was analysed by comparing maximum expiratory flows at isovolume points at 50, 25 and 10% FVC (MEF50, MEF25 and MEF10, respectively). The shape of the resulting MEFV curves could be divided into an initial horizontal part (tube-dependent), and a final descending slope (airway-dependent). No difference in FVC occurred irrespective of the ETT size (p>0.05 by analysis of variance (ANOVA)). MEF50 increased with increasing tube diameter (p<0.05). MEF25 remained unchanged using ETTs which were less than 1.5 mm smaller than the largest ETT. Smaller ETTs resulted in significantly reduced MEF25 (p<0.05). MEF10 was not influenced by the ETT size. We conclude that maximum expiratory flows measured by the forced deflation technique are not influenced by an appropriately sized endotracheal tube at lung volumes below 25% forced vital capacity in our monkey model with normal lungs. We postulate that the effect of endotracheal tubes on maximum expiratory flow volume curves in intubated infants might be of similar or even smaller magnitude, which remains to be established.


Degradation of phenol by Pseudomonas putida ATCC 11172 in continuous culture at different ratios of biofilm surface to culture volume.
Pseudomonas putida ATCC 11172 was grown in continuous culture with phenol as the only carbon and energy source; a culture practically without biofilm was compared with biofilm cultures of differing surface area/volume ratios. The biofilm did not significantly affect the maximal suspended cell concentration in the effluent, but it increased the maximal phenol reduction rate from 0.23 g/liter per h (without biofilm) to 0.72 g/liter per h at the highest biofilm level (5.5 cm2 of biofilm surface per ml of reactor volume). The increase in phenol reduction rate was linear up to the surface area/volume ratio of 1.4 cm2/ml. The continuous cultures with biofilms could tolerate a higher phenol concentration of the medium (3.0 g/liter) than the nonbiofilm system (2.5 g/liter). At higher dilution rates an intermediate product, 2-hydroxymuconic semialdehyde, accumulated in the culture. When the biomass of the effluent started to decrease, the concentration of 2-hydroxymuconic semialdehyde reached a peak value. We conclude that biofilms in continuous culture have the potential to enhance the aerobic degradation of aromatic compounds.


[Reimplantation lesion in the postoperative period of lung transplantation. Incidence, predictive factors, prognosis and outcome. The Lung Transplantation Group of Vall d'Hebron University General Hospital].
Reimplantation disease (RD) is a postoperative complication in lung transplantation. It is defined as hypoxemia (PaO2/FiO2 ratio < 150 mmHg), radiologic infiltrates and decrease of lung compliance. The aim of the study was to analyze the incidence, predictive factors, prognosis and outcome of the patients with RD. 49 patients submitted to lung transplantation (June 1991-December 1996) were admitted in our intensive care unit (ICU). Donor and recipient conditions, surgical parameters and outcome in ICU were analyzed. Mann-Whitney, Kruskall-Wallis, Fisher, Pearson and ANOVA-Friedman tests were used for statistical analysis according to the different variables. 49% of the patients (29/49) developed RD, which was influenced neither by lung disease, nor by the kind of transplantation or by ischemia time. All patients with a long surgical time developed RD, versus only 41% in those where surgery was undertaken in a shorter period of time, OR: 2.8 (1.5-5.7; p = 0.0016). The patients with RD improved showing a PaO2/FiO2 ratio of 176 and 235 mmHg at 24 and 48 h respectively (ANOVA, p < 0.00001). The patients with RD needed 14 days of mechanical ventilation versus 7 days in those without RD (p = 0.013). There were no statistically significant differences in stay and mortality in ICU. RD is a common complication in the postoperative phase of lung transplantation. It is present in almost all the patients with long surgical time. Almost all of them improve, with the same survival but a longer period of mechanical ventilation.


Analysis of gene expression profiles reveals novel correlations with the clinical course of colorectal cancer.
In order to discover potential markers of prognosis in colorectal cancer (CRC) we have determined gene expression profiles, using cDNA microarrays in CRC samples obtained from 19 patients in Dukes stages C and D, with favorable clinical course (Dukes C patients, survival >5 years after surgery, group A, n=7) or unfavorable clinical course (Dukes stage C and D patients, survival <5 years after surgery, group B, n=12). Gene expression was measured in RNA from each tumor, using a pool of equal amounts of RNA from all tumors as a reference. To identify and rank differentially expressed genes we used three different analytical methods: (i) Significance Analysis of Microarrays (SAM), (ii) Cox's Proportional Hazard Model, and (iii) Trend Filter (a mathematical method for the assessment of numerical trends). The level of expression of a gene in an individual tumor was regarded as of interest when that gene was identified as differentially expressed by at least two of these three methods. By these stringent criteria we identified eight genes (ITGB2, MRPS11, NPR1, TXNL2, PHF10, PRSS8, KCNK3, JAK3) that were correlated with prolonged survival after surgery. Pathway analysis showed that patients with favorable prognosis had several activated metabolic pathways (carbon metabolism, transcription, amino acid and nitrogen metabolism, signaling and fibroblast growth factor receptor pathways). To further validate individual gene expression findings, the RNA level of each gene identified as a marker with microarrays was measured by real-time RT-PCR in CRC samples from an independent group of 55 patients. In this set of patients the Cox Proportional Hazard Model analysis demonstrated a significant association between increased patient survival and low expression of ITGB2 (p = 0.011) and NPR1 (p = 0.023) genes.


Engineering entropy in soft matter: the bad, the ugly and the good.
The role of entropic interactions, often subtle and sometimes crucial, on the structure and properties of soft matter has a well-recognized place in the classic and modern scientific literature. However, the lessons learned from many of those studies do not always form part of the standard arsenal of strategies that are taught or used for de novo studies relevant to the engineering of new materials. Fortunately, a growing number of examples exist where entropic effects have been designed a priori to achieve a desired or new outcome. This tutorial review describes some recent such examples, selected to illustrate the potential benefits of a more pro-active approach to harnessing the often overlooked power of entropy.


Workplace monitoring of occupational exposure to refractory ceramic fiber--a 17-year retrospective.
This article presents a 17-year (1990-2006) retrospective summary of ongoing studies of occupational exposure to refractory ceramic fiber (RCF) in the United States. Beginning in 1990, RCF producers integrated and harmonized individual workplace monitoring programs to provide data useful for various longitudinal and cross-sectional analyses, benchmarking, and various technical analyses. For 10 of these 17 years, the program has been conducted in partnership with government agencies, first a 5-year (1993-1998) program with the U.S. Environmental Protection Agency and later another 5-year (2002-2006) program with the Occupational Safety and Health Administration and the National Institute for Occupational Safety and Health. This article updates earlier published studies and provides lessons to be learned in the design of industrial hygiene monitoring and control programs.


RNA immunoprecipitation and microarray analysis show a chloroplast Pentatricopeptide repeat protein to be associated with the 5' region of mRNAs whose translation it activates.
Plant nuclear genomes encode hundreds of predicted organellar RNA binding proteins, few of which have been connected with their physiological RNA substrates and functions. In fact, among the largest family of putative RNA binding proteins in plants, the pentatricopeptide repeat (PPR) family, no physiologically relevant RNA ligands have been firmly established. We used the chloroplast-splicing factor CAF1 to demonstrate the fidelity of a microarray-based method for identifying RNAs associated with specific proteins in chloroplast extract. We then used the same method to identify RNAs associated with the maize (Zea mays) PPR protein CRP1. Two mRNAs whose translation is CRP1-dependent were strongly and specifically enriched in CRP1 coimmunoprecipitations. These interactions establish CRP1 as a translational regulator by showing that the translation defects in crp1 mutants are a direct consequence of the absence of CRP1. Additional experiments localized these interactions to the 5' untranslated regions and suggested a possible CRP1 interaction motif. These results enhance understanding of the PPR protein family by showing that a PPR protein influences gene expression through association with specific mRNAs in vivo, suggesting an unusual mode of RNA binding for PPR proteins, and highlighting the possibility that translational regulation may be a particularly common function of PPR proteins. Analogous methods should have broad application for the study of native RNA-protein interactions in both mitochondria and chloroplasts.


Pesticide usage and occupational hazards among farmers working in small-scale tomato farms in Cameroon.
Agriculture is undoubtedly the backbone of the Cameroonian economy, and other economic activities thrive only if production in this sector is assured. It has been estimated that approximately 25 million agricultural workers worldwide experience unintentional pesticide poisoning yearly. Unfortunately, limited information exists about the health and safety of the farmers. The aim of this study was to describe the occupational health and safety (OHS) conditions of farmers working on small-scale tomato farms in the western region of Cameroon. A cross-sectional research method was used to collect data from tomato farmers in May 2017, using a questionnaire developed by the research team. A total of 104 tomato farmers from small-scale farms participated in the study. The analysis revealed that the occupation is male-dominated (86.5%). The training and use of personal protective equipment (PPE) among farmers were rare (35.6%), and farmers were mostly exposed to chemical hazards. The farmers reported the following work-related health problems: skin irritation, backache, impairment of the central nervous system (CNS), visual problems, and respiratory difficulties. The OHS conditions on small-scale tomato farms are mostly poor, thus predisposing farmers to the risk of work-related health problems. Exposure to occupational hazards can be significantly reduced if the required PPE are available and efficiently used.


Malignancy-induced lactic acidosis in adult lymphoma.
Malignancy-induced lactic acidosis (MILA), a rare paraneoplastic phenomenon, is mostly described with hematologic malignancies (lymphomas and leukemias) but has also been reported with solid tumors. It is a subset of type B lactic acidosis being mediated without evidence of tissue hypoperfusion. Lymphoma-induced lactic acidosis is often considered an oncologic emergency and is associated with an increased risk of mortality and poor prognosis. It has a complex pathophysiology centered in the "Warburg effect," i.e., the programming of cancer cells to depend on aerobic glycolysis for promotion of their proliferation and anabolic growth. The treatment of lymphoma-induced lactic acidosis is focused on prompt administration of chemotherapy. The role of alkali therapy in this setting is controversial and has limited proven benefit with a potential for worsening the lactic acidosis. If alkali therapy is used in the presence of severe acidemia to optimize cardiovascular status, it should be administered judiciously.


Prevalence of anxiety and depression in people with different types of cancer or haematologic malignancies: a cross-sectional study.
Cancer patients often present with psychological symptoms that affect their quality of life, physical health outcomes and survival. Two of the most frequent psychiatric comorbidities are anxiety and depression. However, the prevalence of these disorders among cancer patients remains unclear, as studies frequently report varying rates. In the present study, we aimed to provide robust point estimates for the prevalence of anxiety and depression for both a mixed cancer sample and for 13 cancer types separately, considering confounding variables. In a sample of 7509 cancer outpatients (51.4% female), we used the Hospital Anxiety and Depression Scale to assess rates of anxiety and depression. Applying ordinal logistic regression models, we compared the prevalence of anxiety and depression between different cancer types, controlling for age and gender. About one third of our sample showed symptoms of anxiety (35.2%) or depression (27.9%), and every sixth patient had a very likely psychiatric condition, with women being more frequently affected. Elderly patients more often showed signs of depression. The prevalence of anxiety and depression was significantly higher in lung and brain cancer patients, than in other cancer patients. Lowest depression rates were found in breast cancer patients. The prevalence of anxiety and depression is high in cancer patients. Type of cancer is an important predictor for anxiety and depressive symptoms, with lung and brain cancer patients being highly burdened. Considering a personalised medicine approach, physicians should take into account the high prevalence of psychiatric comorbidities and include psychiatric consultations in the treatment plan.


Assessment of the Mode of Action Underlying the Effects of GenX in Mouse Liver and Implications for Assessing Human Health Risks.
GenX is an alternative to environmentally persistent long-chain perfluoroalkyl and polyfluoroalkyl substances. Mice exposed to GenX exhibit liver hypertrophy, elevated peroxisomal enzyme activity, and other apical endpoints consistent with peroxisome proliferators. To investigate the potential role of peroxisome proliferator-activated receptor alpha (PPARα) activation in mice, and other molecular signals potentially related to observed liver changes, RNA sequencing was conducted on paraffin-embedded liver sections from a 90-day subchronic toxicity study of GenX conducted in mice. Differentially expressed genes were identified for each treatment group, and gene set enrichment analysis was conducted using gene sets that represent biological processes and known canonical pathways. Peroxisome signaling and fatty acid metabolism were among the most significantly enriched gene sets in both sexes at 0.5 and 5 mg/kg GenX; no pathways were enriched at 0.1 mg/kg. Gene sets specific to the PPARα subtype were significantly enriched. These findings were phenotypically anchored to histopathological changes in the same tissue blocks: hypertrophy, mitoses, and apoptosis. In vitro PPARα transactivation assays indicated that GenX activates mouse PPARα. These results indicate that the liver changes observed in GenX-treated mice occur via a mode of action (MOA) involving PPARα, an important finding for human health risk assessment as this MOA has limited relevance to humans.


Leukocytes are required for increased lung microvascular permeability after microembolization in sheep.
We studied the effects of uneven pulmonary artery obstruction by microemboli on steady state transvascular fluid and protein exchange in normal and leukopenic sheep. We measured pulmonary artery and left atrial pressures, cardiac output, lung lymph flow, and lymph plasma protein concentrations. Sheep were made profoundly leukopenic by administration of intra-arterial mechlorethamine hydrochloride (0.4 mg/kg, two doses) and colchicine (0.1-0.2 mg/kg, anesthetized sheep only). In anesthetized sheep, we injected glass beads 200 micrometers in diameter via the right atrium to raise pulmonary vascular resistance to 2-3 times baseline values. With normal levels of circulating leukocytes, sheep developed an increased protein-rich lymph flow from the lung characteristic of increased permeability edema. Leukopenic sheep had a significantly attenuated response after embolization for equivalent degrees of vascular obstruction. In unanesthetized sheep, we continuously infused air bubbles 1 mm in diameter via the right atrium to raise pulmonary vascular resistance to about 2 times baseline values. Each sheep served as its own control. With normal circulating leukocyte levels, there was an increase in protein-rich lymph flow from the lung during embolization. When the air infusion ended, the sheep recovered to the baseline condition in 24 hours. We induced emboli with the same amount of air when the sheep were profoundly leukopenic; lymph and protein flow from the lung were significantly less for equivalent degrees of obstruction. We conclude that circulating leukocytes are essential for the microvascular injury that results in increased permeability in the lungs of sheep after microembolization.


Pleuroparenchymal fibroelastosis in systemic sclerosis: prevalence and prognostic impact.
Interstitial lung disease (ILD) in systemic sclerosis (SSc) is a major cause of morbidity and mortality, mostly presenting as non-specific interstitial pneumonia. Little is known about the prevalence of pleuroparenchymal fibroelastosis (PPFE), a specific entity affecting the visceral pleura and subpleural parenchyma. We set out to estimate PPFE prevalence in two large cohorts of SSc patients and to assess its impact on survival and functional decline.A total of 359 SSc patients, derived from two referral centres in two different countries (UK and Italy), were included. The first available high-resolution computed tomography scan was independently evaluated by two radiologists blind to clinical information, to quantify ILD extent, freestanding bronchial abnormalities, and lobar percentage involvement of PPFE on a four-point categorical scale. Discordant scores were adjudicated by a third scorer. PPFE extent was further classified as limited (≤2/18) or extensive (>2/18). Results were evaluated against functional decline and mortality.The overall prevalence of PPFE in the combined SSc population was 18% (11% with extensive PPFE), with no substantial difference between the two cohorts. PPFE was significantly linked to free-standing bronchial abnormalities (61% versus 25% in PPFE versus no PPFE; p<0.0001) and to worse survival, independently of ILD severity or short-term lung function changes (HR 1.89, 95% CI 1.10-3.25; p=0.005).In the current study, we provide an exhaustive description of PPFE prevalence and clinical impact in the largest cohort of SSc subjects published so far. PPFE presence should be carefully considered, due to its significant prognostic implications.


Outcome of nonerosive gastro-esophageal reflux disease patients with pathological acid exposure.
To assess the management and outcome of nonerosive gastro-esophageal reflux disease (NERD) patients who were identified retrospectively, after a 5-year follow-up. We included patients with gastro-esophageal reflux disease (GERD) symptoms who had a negative endoscopy result and pathological 24-h esophageal pH-monitoring while off therapy. We interviewed them after an average period of 5 years (range 3.5-7 years) by means of a structured questionnaire to assess presence of GERD symptoms, related therapy, updated endoscopic data and other features. We assessed predictors of esophagitis development by means of univariate and multivariate statistical analysis. 260 patients (137 women) were included. Predominant GERD symptoms were heartburn and regurgitation in 103/260 (40%). 70% received a maintenance treatment, which was proton pump inhibitor (PPI) in 55% of cases. An average number of 1.5 symptomatic relapses per patient/year of follow-up were observed. A progression to erosive gastro-esophageal reflux disease (ERD) was found in 58/193 (30.0%) of patients undergoing repeat endoscopy; 72% of these were Los Angeles grade A-B. This study shows that progression to ERD occurs in about 5% of NERD cases per year, despite therapy. Only two factors consistently and independently influence progression: smoking and absence of PPI therapy.


Evaluation of common variants in the six known maturity-onset diabetes of the young (MODY) genes for association with type 2 diabetes.
An important question in human genetics is the extent to which genes causing monogenic forms of disease harbor common variants that may contribute to the more typical form of that disease. We aimed to comprehensively evaluate the extent to which common variation in the six known maturity-onset diabetes of the young (MODY) genes, which cause a monogenic form of type 2 diabetes, is associated with type 2 diabetes. Specifically, we determined patterns of common sequence variation in the genes encoding Gck, Ipf1, Tcf2, and NeuroD1 (MODY2 and MODY4-MODY6, respectively), selected a comprehensive set of 107 tag single nucleotide polymorphisms (SNPs) that captured common variation, and genotyped each in 4,206 patients and control subjects from Sweden, Finland, and Canada (including family-based studies and unrelated case-control subjects). All SNPs with a nominal P value <0.1 for association to type 2 diabetes in this initial screen were then genotyped in an additional 4,470 subjects from North America and Poland. Of 30 nominally significant SNPs from the initial sample, 8 achieved consistent results in the replication sample. We found the strongest effect at rs757210 in intron 2 of TCF2, with corrected P values <0.01 for an odds ratio (OR) of 1.13. This association was observed again in an independent sample of 5,891 unrelated case and control subjects and 500 families from the U.K., for an overall OR of 1.12 and a P value <10(-6) in >15,000 samples. We combined these results with our previous studies on HNF4alpha and TCF1 and explicitly tested for gene-gene interactions among these variants and with several known type 2 diabetes susceptibility loci, and we found no genetic interactions between these six genes. We conclude that although rare variants in these six genes explain most cases of MODY, common variants in these same genes contribute very modestly, if at all, to the common form of type 2 diabetes.


Programmed symptoms: disparate effects united by purpose.
Central sensitivity syndromes (CSS) share features of similar multiple symptoms, virtually unknown mechanisms and lack of effective treatments. The CSS nomenclature was chosen over alternatives because it focused on a putative physiological mechanism of central sensitization common to disorders such as fibromyalgia, irritable bowel syndrome, vulvodynia and temporomandibular disorder. Increasing evidence from multiple biological systems suggests a further development. In this new model central sensitization is part of a ensemble that includes also the symptoms of widespread pain, fatigue, unrefreshing sleep and dyscognition. The main feature is an intrinsic program that produces this ensemble to guide behavior to restore normal function in conditions that threaten survival. The well known "illness response" is a classic example that is triggered in response to the specific threat of viral infection. The major leap for this model in the context of CSS is that the symptom complex is not a reactive result of pathology, but a purposeful feeling state enlisted to combat pathology. Once triggered, this state is produced by potential mechanisms that likely include contributions of the peripheral and central immune systems, as well as stress response systems such as the autonomic system and the hypothalamic-pituitary-adrenal (HPA) axis. These act in concert to alter behavior in a beneficial direction. This concept explains similar symptoms for many triggering conditions, the poorly understood pathology, and the resistance to treatment.


Perovskite R{\bar 3}c phase AgCuF3: multiple Dirac cones, 100% spin polarization and its thermodynamic properties.
Very recently, experimentally synthesized R{\bar 3}c phase LaCuO3 was studied by Zhang, Jiao, Kou, Liao & Du [J. Mater. Chem. C (2018), 6, 6132-6137], and they found that this material exhibits multiple Dirac cones in its non-spin-polarized electronic structure. Motivated by this study, the focus here is on a new R{\bar 3}c phase material, AgCuF3, which has a combination of multiple Dirac cones and 100% spin polarization properties. Compared to the non-spin-polarized system LaCuO3, the spin-polarized Dirac behavior in AgCuF3 is intrinsic. The effects of on-site Coulomb interaction, uniform strain and spin-orbit coupling were added to examine the stability of its multiple Dirac cones and half-metallic behavior. Moreover, the thermodynamic properties under different temperatures and pressures were investigated, including the normalized volume, thermal volume expansion coefficient, heat capacity at constant volume and Debye temperature. The thermal stability and the phase stability of this material were also studied via ab initio molecular dynamic simulations and the formation energy of the material, respectively.


Scales of gravity in head injury.
From the head injury onward the victim loses control over his own existence and starts a long journey through the various fields of forces determining his destiny until he can reassume control. Scales of gravity applied at different points in time vary and sometimes contradict each other. The vital scale is an immediate emergency scale, determined by the need to save a life, observe and treat a coma, and detect early complications, and the criteria are those of intensive care, surgery, and neurosurgery. The neurological and neuropsychological scale established towards the end of the first hospitalisation, assesses brain damage by neurological investigations, ophthalmological and otological tests and a neuropsychological evaluation. First individual psychiatric reactions appear at this stage. The psychosocial scale should consider information provided by previous scales, but also evaluate pre- and post-traumatic personality, family setting, social, legal, administrative and economic realities, residual skills, previous profession, possibilities of reinstatement and above all, motivation. Probably the neurological and neuropsychological scale provide the best common point of reference for a global assessment. These scales of gravity are examined in their relationship to traditional clinical thinking in different countries. A prospective and descriptive system of a "European" cofification as proposed within the framework of the European Communities is described.


[Clinical and genetic manifestations of immunodeficiency, centromeric instability, and facial anomalies syndrome: a case report and literature review].
Objective: To analyze the clinical and genetic features of immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome with a case report and literature review. Methods: The clinical data and genetic test of a girl diagnosed with ICF syndrome in the Department of Nephrology and Immunology in Qingdao Women and Children's Hospital in December 2016 were extracted and analyzed. "ICF syndrome" "immunodeficiency, centromeric instability and facial anomalies syndrome" "ICF syndrome and DNMT3B" were used as key words to search Chinese databases and Pubmed for literature until March 2018, and the literature was reviewed. Results: A female patient aged 22 months old with ocular hypertelorism and low-set ears was admitted due to recurrent infection over one year. Laboratory tests showed humoral immune deficiency with IgG<1.34 g/L, IgA<0.060 g/L, and IgM<0.179 g/L, but normal cellular immunity (total T lymphocyte 0.503, hepler T lymphocyte 0.328, cytotoxic T lymphocyte 0.166, natural killer cell 0.184, total B lymphocyte 0.276). Whole-exome sequencing revealed a de novo heterozygous splice site mutation c.922-2A>G in intron 8, and a de novo heterozygous missense mutation c.2477G>A in exon 23 of DNMT3B gene. Chromosome karyotype analysis showed 46, XX, with 64 out of 100 karyotypes showing centromere instability in chromosome 1. Five papers were found which were all in English, with total of 29 patients. Forty-three mutations were reported, including 34 missense, 2 deletion, 1 insertion, 6 splice site mutations. Eleven patients had complex heterozygosis mutations. All patients had centromere instability, humoral immune deficiency and facial dysplasia which were mainly ocular hypertelorism and low-set ears. Most patients had language and motor development delay, and a few were combined with mental retardation. Conclusions: ICF syndrome is a rare autosomal recessive primary immunodeficiency with classic clinical triad manifestations. De novo mutation of DNMT3B gene is one of etiologies according to genetic test.


Serendipitous passage of a common duct stone following ampullary cannulation.
A transduodenal endoscopic pancreatocholangiography dislodged a distal common duct stone. The conclusion that the stone was disimpacted by the manipulation was reached by (1) demonstration of a negative shadow representing a stone in the distal part of the common duct on roentgenograms following injection of contrast material after successful ampullary cannulation, (2) the clinical sequence of events that followed ampullary cannulation, and (3) the operative finding of a grossly dilated common duct without the presence of a stone and normal intraoperative and postoperative T-tube cholangiograms.


HSP47: a potential target for fibrotic diseases and implications for therapy.
Introduction: Chronic fibrotic disorders are challenging clinical problems. The major challenge is the identification of specific targets expressed selectively in fibrotic tissues. Collagen accumulation is the hallmark fibrosis. HSP47 is a collagen-specific chaperon with critical role in collagen folding. This review discusses the anti-fibrotic potential of HSP47. Areas covered: This review compiles data retrieved from the PubMed database with keywords 'HSP47+fibrosis' from 01/2005 to 06/2020. We examined 1) collagen biology and its role in fibrotic diseases, 2) HSP47 role in fibrosis, 3) HSP47 inhibition strategies and 4) clinical investigations. The identification of the HSP47-collagen binding site led to the development of methods to screen HSP47 inhibitors with anti-fibrotic potential. Specific in vivo delivery systems of HSP47 siRNA to fibrotic tissue reduced collagen production/secretion associated with fibrosis inhibition in preclinical models. This strategy is about to be tested in clinical trials. Expert opinion: As a collagen-specific chaperon, HSP47 is a promising therapeutic target in fibrosis. Preclinical models have shown encouraging anti-fibrotic results. Anti-HSP47 strategies need to be further evaluated in clinical trials. The increase in circulating-HSP47 in lung fibrosis patients highlights the potential of HSP47 as a noninvasive biomarker and may represent an important step toward personalized medicine in fibrotic disorders.


[Ultrasound study and computerized tomography in the diagnosis of choledocholithiasis].
A comparative analysis of the results of using the ultrasonic investigation and computed tomography in differential diagnosis of jaundice was made in 205 patients. The reliability of USI in diagnosis of cholelithiasis was 54.3%, and that of standard CT was 55.9%. The authors have developed and used computed tomocholangiography (direct and indirect) in 187 patients with pronounced bilirubinemia. Indirect tomocholangiography was used in patients with bilirubinemia not more than 157 mkm/l. Contrasted main bile ducts were noted in 95% of the patients. When the content of bilirubin in blood plasma was higher than the figures shown, the authors used the direct contrast of the bile ducts in combination with computed tomography. When using more perfect X-ray devices (CT) with the greater resolving power for diagnosis in jaundice patients, it was possible to get the overwhelming information about the state of the bile ducts.


Comparison of Routine Replacement With Clinically Indicated Replacement of Peripheral Intravenous Catheters.
Peripheral intravenous catheters (PVCs) are the most frequently used indwelling devices in hospitals worldwide. Peripheral intravenous catheter bloodstream infections (PVC-BSIs) are rare, but severe and preventable, adverse events. To investigate the incidence of PVC-BSIs after changing the policy of routine PVC replacement every 96 hours to clinically indicated replacement. This institution-wide, observational cohort study evaluated all patients hospitalized at a large university-affiliated hospital with 10 sites in Western Switzerland with a PVC insertion between January 1, 2016, and February 29, 2020. Peripheral intravenous catheters were routinely replaced every 96 hours until March 31, 2018 (baseline period). Between April 1, 2018, and October 15, 2019, PVCs were replaced if clinically indicated (intervention period). From October 16, 2019, PVCs were again routinely replaced every 96 hours (reversion period). The PVC-BSI rates and PVC-BSI incidence rate ratios (IRRs) during each period. A total of 412 631 PVCs with documented catheter duration were included (164 331 patients; median [interquartile range] patient age, 51 [33-72] years; 88 928 [54.1%] female): 241 432 PVCs at baseline, 130 779 at intervention, and 40 420 at reversion. Eleven PVC-BSIs were observed during the baseline period, 46 during the intervention, and 4 during the reversion period. Although the monthly number of PVC-days remained stable during all study periods, the number of monthly inserted PVCs decreased during the intervention period. The number of PVCs still in place more than 4 or more than 7 days was higher during the intervention period compared with the baseline and reversion periods. A significantly increased IRR of PVC-BSIs was observed for the intervention period (IRR, 7.20; 95% CI, 3.65-14.22; P < .001) compared with baseline, whereas during the reversion period there was no significant increase (IRR, 1.35; 95% CI, 0.30 6.17; P = .69). The results of this cohort study using a large, prospective surveillance database suggest that replacement of PVCs only when clinically indicated may be associated with an increased risk of PVC-BSI compared with routine replacement. Even if PVC-associated BSI is a rare event, the use of PVCs in most patients makes this outcome relevant.


Epinephrine- and norepinephrine-evoked potential changes of frog primary afferent terminals: pharmacological characterization of alpha and beta components.
The effects of superfused epinephrine (E) and norepinephrine (NE) on the membrane potential of primary afferent fibers of the isolated frog spinal cord were studied by sucrose gap recordings from the dorsal root. In all preparations both E and NE, applied in concentrations ranging from 0.1 microM to 1.0 mM, produced a hyperpolarization of afferent terminals. In many instances this was followed by a slow depolarization and, in a small number of cords, a small depolarization preceded the increase in membrane potential. E- and NE-induced hyperpolarizations were blocked by the selective alpha 2-antagonists yohimbine and piperoxan, but not by the selective alpha 1-antagonists prazosin and corynanthine or by the beta-blockers propranolol and sotalol. The alpha 2-agonists clonidine, alpha-methylnorepinephrine and guanabenz also hyperpolarized terminals, causing a change in potential that was reduced by yohimbine and piperoxan. Taken together, these results suggest that alpha 2-receptors mediate the hyperpolarizing effects of E and NE. The beta-agonist isoproterenol evoked a slow depolarization similar to that produced by E and NE. The isoproterenol-depolarization was antagonized by propranolol. Sometimes, application of E and NE after superfusion with yohimbine produced only a depolarization of the dorsal root and this depolarization was sensitive to propranolol. It would appear therefore that the late depolarization seen after the application of E and NE is produced by activation of beta-receptors. In contrast, the alpha 1-agonist phenylephrine elicited a short latency, short duration depolarization similar to those seen preceding approximately 10% of the E- and NE-hyperpolarizations. Such short-latency depolarizations were blocked by prazosin and corynanthine. The major component of the response to both E and NE is indirectly mediated through a synaptic process: application of Mn2+, Mg2+, procaine or tetrodotoxin in concentrations sufficient to block synaptic transmission substantially reduced, but never eliminated, the actions of the catecholamines. Interneurons are probably involved because mephenesin, which reduces interneuronal transmission, significantly decreased the E and NE effects. Furthermore, interneurons which secrete excitatory amino acids and/or GABA may mediate the indirect effects of the catecholamines on afferent terminals because (-)baclofen and D.L-alpha-aminoadipate decrease, and picrotoxin and bicuculline increase, the dorsal root (DR) effects of E and NE.(ABSTRACT TRUNCATED AT 400 WORDS)


HEV-associated dendritic cells are observed in metastatic tumor-draining lymph nodes of cutaneous melanoma patients with longer distant metastasis-free survival after adjuvant immunotherapy.
Tissue biomarkers that aid in identifying cutaneous melanoma (CM) patients who will benefit from adjuvant immunotherapy are of crucial interest. Metastatic tumor-draining lymph nodes (mTDLN) are the first encounter site between the metastatic CM cells and an organized immune structure. Therefore, their study may reveal mechanisms that could influence patients´ outcomes. Twenty-nine stage-III CM patients enrolled in clinical trials to study the vaccine VACCIMEL were included in this retrospective study. After radical mTDLN dissection, patients were treated with VACCIMEL (n=22) or IFNα-2b (n=6), unless rapid progression (n=1). Distant Metastasis-Free Survival (DMFS) was selected as an end-point. Two cohorts of patients were selected: one with a good outcome (GO) (n=17; median DMFS 130.0 months), and another with a bad outcome (BO) (n=12; median DMFS 8.5 months). We analyzed by immunohistochemistry and immunofluorescence the expression of relevant biomarkers to tumor-cell biology and immune cells and structures in mTDLN, both in the tumor and peritumoral areas. In BO patients, highly replicating Ki-67+ tumor cells, low tumor HLA-I expression and abundant FoxP3+ lymphocytes were found (p=0.037; p=0.056 and p=0.021). In GO patients, the most favorable biomarkers for prolonged DMFS were the abundance of peri- and intra-tumoral CD11c+ cells (p=0.0002 and p=0.001), peri-tumoral DC-LAMP+ dendritic cells (DCs) (p=0.001), and PNAd+ High Endothelial Venules (HEVs) (p=0.004). Most strikingly, we describe in GO patients a peculiar, heterogeneous structure that we named FAPS (Favoring Antigen-Presenting Structure), a triad composed of DC, HEV and CD62L+ naïve lymphocytes, whose postulated role would be to favor tumor antigen (Ag) priming of incoming naïve lymphocytes. We also found in GO patients a preferential tumor infiltration of CD8+ and CD20+ lymphocytes (p=0.004 and p=0.027), as well as peritumoral CD20+ aggregates, with no CD21+ follicular dendritic cells detected (p=0.023). Heterogeneous infiltration with CD64+CD68-CD163-, CD64+CD68+CD163- and CD64+CD68+CD163+ macrophages were observed in both cohorts. The analysis of mTDLN in GO and BO patients revealed marked differences. This work highlights the importance of analyzing resected mTDLN from CM patients and suggests a correlation between tumor and immune characteristics that may be associated with a spontaneous or vaccine-induced long DMFS. These results should be confirmed in prospective studies.


Complications of ERCP: ethical obligations and legal consequences.
Endoscopic retrograde cholangiopancreatography (ERCP) is a skill and technique demanding high-risk procedure with an overall complication rate of about 5-10%. Pancreatitis remains the most common complication of ERCP, however, bleeding after sphincterotomies, infections and cardiopulmonary complications as well as perforations may also occur. Patient- and procedure-related risk factors of ERCP complications are mainly predictable so that ERCP often can be avoided and substituted for alternative imaging techniques, especially in high-risk patients. Written consent should be obtained for any ERCP to provide documentary evidence that explanation of the proposed procedure and endoscopic treatment was given and that consent was sought and obtained. The investigating doctor remains responsible for ensuring sufficient time for the patient's questions and to make informed decision before the start of any procedure. The most common legal consequence of an ERCP complication is a civil negligence claim for compensation, however, a clinician may in rare cases be faced with criminal proceedings where there is evidence of gross negligence. Analysis of claims against gastroenterologists suggests the conclusion that ERCP should be done for good indications, by trained endoscopists with standard techniques, with good, documented, patient-informed consent and communication before and after the procedure.


Dietary energy density predicts women's weight change over 6 y.
Dietary energy density (ED) is positively associated with energy intake, but little is known about long-term effects on weight change. We assessed whether dietary ED predicts weight change over 6 y among a sample of non-Hispanic, white women. Participants were part of a 6-y longitudinal study (n = 186), assessed at baseline and biennially. ED (in kcal/g) was calculated from the energy content of all foods (excluding beverages) with the use of three 24-h recalls. Height and weight were measured in triplicate to calculate body mass index (BMI; in kg/m(2)). Repeated measures (PROC MIXED) were used to examine the influence of ED on weight change, before and after adjusting for initial weight status. Food choices were examined among subjects consuming low-, medium-, and high-ED diets at study entry. ED did not change across time for a subject. ED was positively associated with weight gain and higher BMI over time; this association did not vary by BMI classification. Food group data showed that, compared with women consuming higher-ED diets, women consuming lower-ED diets reported significantly lower total energy intakes and consumed fewer servings of baked desserts, refined grains, and fried vegetables and more servings of vegetables, fruit, and cereal. Women consuming lower-ED diets ate more meals at the table and fewer meals in front of the television. Findings indicate that consumption of a lower-ED diet moderates weight gain, which may promote weight maintenance. Consuming lower ED diets can be achieved by consuming more servings of fruit and vegetables and limiting intake of high-fat foods.


Vision-threatening thyroid orbital disease--the clinical features.
Thyroid orbital disease may threaten sight when acute proptosis causes corneal exposure or when enlarged extraocular muscles cause compressive optic neuropathy. The early clinical signs of thyroid optic neuropathy include loss of colour perception and visual field defects. The onset of thyroid optic neuropathy is difficult to predict and these clinical tests should be included in the routine examination of patients with thyroid orbital disease.


Cleft palate, arachnoid cyst and posterior urethral valve.
A 5-month-old infant presented with cleft palate, febrile urinary tract infection and abnormal movements. His urinary stream was poor and investigations revealed posterior urethral valve and grade V vesicoureteric reflux. This baby was investigated for seizure activity and on MRI of the brain was found to have a large arachnoid cyst, splaying the occipital horns and compressing the posterior aspect of third ventricle leading to dilatation of the ventricles. This seems to be a very unusual coexistence of three abnormalities in one patient for which no plausible explanation can be given. It appears to be a chance finding.


New Advances in Targeting the Resolution of Inflammation: Implications for Specialized Pro-Resolving Mediator GPCR Drug Discovery.
Chronic inflammation is a component of numerous diseases including autoimmune, metabolic, neurodegenerative, and cancer. The discovery and characterization of specialized pro-resolving mediators (SPMs) critical to the resolution of inflammation, and their cognate G protein-coupled receptors (GPCRs) has led to a significant increase in the understanding of this physiological process. Approximately 20 ligands, including lipoxins, resolvins, maresins, and protectins, and 6 receptors (FPR2/ALX, GPR32, GPR18, chemerin1, BLT1, and GPR37) have been identified highlighting the complex and multilayered nature of resolution. Therapeutic efforts in targeting these receptors have proved challenging, with very few ligands apparently progressing through to preclinical or clinical development. To date, some knowledge gaps remain in the understanding of how the activation of these receptors, and their downstream signaling, results in efficient resolution via apoptosis, phagocytosis, and efferocytosis of polymorphonuclear leukocytes (mainly neutrophils) and macrophages. SPMs bind and activate multiple receptors (ligand poly-pharmacology), while most receptors are activated by multiple ligands (receptor pleiotropy). In addition, allosteric binding sites have been identified signifying the capacity of more than one ligand to bind simultaneously. These fundamental characteristics of SPM receptors enable alternative targeting strategies to be considered, including biased signaling and allosteric modulation. This review describes those ligands and receptors involved in the resolution of inflammation, and highlights the most recent clinical trial results. Furthermore, we describe alternative mechanisms by which these SPM receptors could be targeted, paving the way for the identification of new therapeutics, perhaps with greater efficacy and fidelity.


Proteomic analysis of the metabolic adaptation of the biocontrol agent Pseudozyma flocculosa leading to glycolipid production.
The yeast-like epiphytic fungus Pseudozyma flocculosa is known to antagonize powdery mildew fungi through proliferation on colonies presumably preceded by the release of an antifungal glycolipid (flocculosin). In culture conditions, P. flocculosa can be induced to produce or not flocculosin through manipulation of the culture medium nutrients. In order to characterize and understand the metabolic changes in P. flocculosa linked to glycolipid production, we conducted a 2-DE proteomic analysis and compared the proteomic profile of P. flocculosa growing under conditions favoring the development of the fungus (control) or conducive to flocculosin synthesis (stress). A large number of protein spots (771) were detected in protein extracts of the control treatment compared to only 435 matched protein spots in extracts of the stress cultures, which clearly suggests an important metabolic reorganization in slow-growing cells producing flocculosin. From the latter treatment, we were able to identify 21 protein spots that were either specific to the treatment or up-regulated significantly (2-fold increase). All of them were identified based on similarity between predicted ORF of the newly sequenced genome of P. flocculosa with Ustilago maydis' available annotated sequences. These proteins were associated with the carbon and fatty acid metabolism, and also with the filamentous change of the fungus leading to flocculosin production. This first look into the proteome of P. flocculosa suggests that flocculosin synthesis is elicited in response to specific stress or limiting conditions.


Multilevel analysis in public health research.
Over the past few years there has been growing interest in considering factors defined at multiple levels in public health research. Multilevel analysis has emerged as one analytical strategy that may partly address this need, by allowing the simultaneous examination of group-level and individual-level factors. This paper reviews the rationale for using multilevel analysis in public health research, summarizes the statistical methodology, and highlights some of the research questions that have been addressed using these methods. The advantages and disadvantages of multilevel analysis compared with standard methods are reviewed. The use of multilevel analysis raises theoretical and methodological issues related to the theoretical model being tested, the conceptual distinction between group- and individual-level variables, the ability to differentiate "independent" effects, the reciprocal relationships between factors at different levels, and the increased complexity that these models imply. The potentialities and limitations of multilevel analysis, within the broader context of understanding the role of factors defined at multiple levels in shaping health outcomes, are discussed.


Studies on the kinetics of the erythroid colony-forming cell.
The appearance, rate of formation, and morphologic characteristics of the erythroid colony-forming cell (CFU-E) was studied in control, exhypoxic polycythemic, and anemic mice. Polycythemia resulted in a significant reduction in CFU-E number and a lag time of approximately 8 h before colonies were visible in culture. Thereafter, the rate of formation of colonies, as assessed by the slope of the increase in their number, was identical to the control. The slower appearance of CFU-E in polycythemia was corrected by the injection of erythropoietin (Ep) 8 h prior to sacrifice, but an absolute increase in colony number only occurred when Ep was injected 24 h previously. Polycythemia also slowed the rate of colony maturation, so that at later culture times the colonies more frequently contained fewer cells and consisted of basophilic normoblasts. Anemia did not shorten the time of first appearance of colonies, but their rate of maturation was significantly more rapid than the control. These findings are best explained by a redistribution of CFU-E in various phases of the cell cycle when erythropoiesis is manipulated. Unit-gravity sedimentation studies suggested a greater fraction of CFU-E in long G1 or G0 in polycythemia. In addition, the kinetics of CFU-E development were identical to polycythemia in mice in which S and post-S-phase CFU-E were removed by hydroxyurea injection. It is likely that Ep stimulates CFU-E in all phases of the cell cycle. After stimulation by Ep, however, CFU-E in long G1 must move through the cell cycle prior to commencing cell division. This transit time of 8 h, which is unaffected by the Ep concentration in the medium, results in a lag in appearance and maturation of colonies derived from these cells. These results demonstrate that cellular variables are important in CFU-E kinetics in vitro and provide insights into factors affecting the regulation of normal erythropoiesis.


The changing paradigm of sexually transmitted disease control in the era of managed health care.
Several trends in sexually transmitted diseases (STDs) have laid the foundation for a new paradigm for STD treatment and prevention that encompasses a community-wide, population-oriented approach. Public health STD programs, in partnership with a wide variety of community collaborators, will need to carry out the essential functions of public health-assessment, policy development, and assurance-by developing resources for community organizing and planning, enhanced information systems, and comprehensive training programs for professional staff and community partners. Community providers (particularly practicing clinicians and community and hospital clinics) will need to deliver primary prevention (community health promotion and clinical preventive services) and secondary prevention (screening and treatment) services while categorical STD clinics focus on providing care for high-risk, high-frequency STD transmitters who serve as the reservoir for much of a community's bacterial STDs. Managed care organizations and public health STD programs will need to formalize collaborative arrangements and capitalize on the strengths of each organization in order to have a population-level impact on STD transmission.