Tuberculosis chemoprophylaxis using a liquid isoniazid-methadone admixture for drug users in methadone maintenance.
Tuberculosis is common in drug users, although compliance with therapy may be difficult in this population. To evaluate an approach to enhancing compliance with tuberculosis chemoprophylaxis in drug users enrolled on methadone maintenance utilizing an isoniazid (INH)-methadone admixture. A prospective cohort study. A drug treatment program in New Haven, Connecticut, USA. Opioid-dependent drug users enrolled in methadone maintenance. Liquid isoniazid was mixed into subjects' daily dose of methadone. Vitamin B6 was given to subjects for self-administration. Number of eligible subjects, reasons for not starting therapy, number starting therapy, proportion completing therapy and median duration of INH therapy were calculated. Thirty-nine subjects were eligible for INH chemoprophylaxis: 34 (87%) received INH mixed directly in their methadone and five (13%) had their INH consumption supervised by a nurse. Among these subjects, 72% (28/39) completed therapy. Among the 11 subjects who discontinued INH, discharge from the methadone maintenance program was the most common reason--73% (8/11). Thus, among the 31 subjects who were not discharged from methadone maintenance, 90% (28/31) successfully completed INH prophylaxis. The median duration of therapy was 182 days. Tuberculosis chemoprophylaxis using a liquid isoniazid-methadone admixture appears to be an effective approach to enhancing compliance with this therapy in methadone-maintained drug users.


Analysis of observational studies in the presence of treatment selection bias: effects of invasive cardiac management on AMI survival using propensity score and instrumental variable methods.
Comparisons of outcomes between patients treated and untreated in observational studies may be biased due to differences in patient prognosis between groups, often because of unobserved treatment selection biases. To compare 4 analytic methods for removing the effects of selection bias in observational studies: multivariable model risk adjustment, propensity score risk adjustment, propensity-based matching, and instrumental variable analysis. A national cohort of 122,124 patients who were elderly (aged 65-84 years), receiving Medicare, and hospitalized with acute myocardial infarction (AMI) in 1994-1995, and who were eligible for cardiac catheterization. Baseline chart reviews were taken from the Cooperative Cardiovascular Project and linked to Medicare health administrative data to provide a rich set of prognostic variables. Patients were followed up for 7 years through December 31, 2001, to assess the association between long-term survival and cardiac catheterization within 30 days of hospital admission. Risk-adjusted relative mortality rate using each of the analytic methods. Patients who received cardiac catheterization (n = 73 238) were younger and had lower AMI severity than those who did not. After adjustment for prognostic factors by using standard statistical risk-adjustment methods, cardiac catheterization was associated with a 50% relative decrease in mortality (for multivariable model risk adjustment: adjusted relative risk [RR], 0.51; 95% confidence interval [CI], 0.50-0.52; for propensity score risk adjustment: adjusted RR, 0.54; 95% CI, 0.53-0.55; and for propensity-based matching: adjusted RR, 0.54; 95% CI, 0.52-0.56). Using regional catheterization rate as an instrument, instrumental variable analysis showed a 16% relative decrease in mortality (adjusted RR, 0.84; 95% CI, 0.79-0.90). The survival benefits of routine invasive care from randomized clinical trials are between 8% and 21%. Estimates of the observational association of cardiac catheterization with long-term AMI mortality are highly sensitive to analytic method. All standard risk-adjustment methods have the same limitations regarding removal of unmeasured treatment selection biases. Compared with standard modeling, instrumental variable analysis may produce less biased estimates of treatment effects, but is more suited to answering policy questions than specific clinical questions.


Substance-Induced Psychosis.
Intoxication and withdrawal from a variety of central nervous system depressants and stimulants may induce hallucinations or delusions, which, when unaccompanied by insight, are the hallmarks of psychosis. A substance-induced psychosis may, in many instances, present as an organic psychosis or as an independent mental disorder (eg, schizophrenia), complicating diagnostic efforts. Ramifications of a misdiagnosed psychotic illness are potentially long-lasting and harmful to a patient. It is, therefore, crucial that health care providers be aware of the complex relationship between substance abuse, psychotic symptoms, and independent psychotic disorders. This report addresses substance-induced psychosis, by describing those psychotic symptoms most commonly associated with the abuse of specific drugs and alcohol, detailing useful diagnostic techniques and outlining treatment recommendations.


[The administered activity of radionuclides in nuclear medicine--rational reduction of medical radiation exposure].
A survey of 104 hospitals was conducted to determine the administered activity of radionuclides. Eighty-five hospitals responded, and reported a total of 119,614 examinations in one year. The examinations included: bone scintigraphy, 26.4%; Thallium-201 (201Tl) myocardial scintigraphy, 15.5%; Gallium-67 (67Ga) scintigraphy, 13.3%; N-isopropyl-p-[123I]iodoamphetamine (IMP) brain perfusion scintigraphy, 7.0%. The administered activity was corrected by body weight only for children at more than 80% of the responding hospitals. The number of hospitals that reported over-administration of radionuclide varied according to the type of scintigraphy performed: bone, 76%; inflammatory (67Ga), 93%; myocardial (201Tl), 89.2%; brain (IMP), 8.5%. The administered activity of IMP was closer to the upper limits specified in the Recommendations on Standardization of Radionuclide Imaging by the Japan Radioisotope Association (1987), because IMP is very expensive and is supplied as single vials. The highest average effective dose was for myocardial scintigraphy, the second-highest for inflammatory scintigraphy, and the third-highest for bone scintigraphy. In 201Tl and 67Ga scintigraphy, the entire contents of the vial may be administered two days before the expiration date, because the ratio of (true patient administered activity) to (declared patient administered activity) is similar to the ratio of (radioactivity on the day of supply) to (radioactivity on the day of expiration). The factors that influence administered activity are throughput, price of the radionuclide, and whether the radionuclide is sold as a single vial. In order to decrease the effective dose, it is necessary to establish a close cooperation between medical personnel, the makers of radiopharmaceuticals, and manufacturers of gammacameras.


Radiation hardening techniques for Er/Yb doped optical fibers and amplifiers for space application.
We investigated the efficiencies of two different approaches to increase the radiation hardness of optical amplifiers through development of improved rare-earth (RE) doped optical fibers. We demonstrated the efficiency of codoping with Cerium the core of Erbium/Ytterbium doped optical fibers to improve their radiation tolerance. We compared the γ-rays induced degradation of two amplifiers with comparable pre-irradiation characteristics (~19 dB gain for an input power of ~10 dBm): first one is made with the standard core composition whereas the second one is Ce codoped. The radiation tolerance of the Ce-codoped fiber based amplifier is strongly enhanced. Its output gain decrease is limited to ~1.5 dB after a dose of ~900 Gy, independently of the pump power used, which authorizes the use of such fiber-based systems for challenging space missions associated with high total doses. We also showed that the responses of the two amplifiers with or without Ce-codoping can be further improved by another technique: the pre-loading of these fibers with hydrogen. In this case, the gain degradation is limited to 0.4 dB for the amplifier designed with the standard composition fiber whereas 0.2 dB are reported for the one made with Ce-codoped fiber after a cumulated dose of ~900 Gy. The mechanisms explaining the positive influences of these two treatments are discussed.


Imaging of Plasmodium liver stages to drive next-generation antimalarial drug discovery.
Most malaria drug development focuses on parasite stages detected in red blood cells, even though, to achieve eradication, next-generation drugs active against both erythrocytic and exo-erythrocytic forms would be preferable. We applied a multifactorial approach to a set of >4000 commercially available compounds with previously demonstrated blood-stage activity (median inhibitory concentration < 1 micromolar) and identified chemical scaffolds with potent activity against both forms. From this screen, we identified an imidazolopiperazine scaffold series that was highly enriched among compounds active against Plasmodium liver stages. The orally bioavailable lead imidazolopiperazine confers complete causal prophylactic protection (15 milligrams/kilogram) in rodent models of malaria and shows potent in vivo blood-stage therapeutic activity. The open-source chemical tools resulting from our effort provide starting points for future drug discovery programs, as well as opportunities for researchers to investigate the biology of exo-erythrocytic forms.


Language and Reading Progress of Young Deaf and Hard-of-Hearing Children.
We examined the language and reading progress of 336 young DHH children in kindergarten, first and second grades. Trained assessors tested children's language, reading, and spoken and fingerspelled phonological awareness in the fall and spring of the school year. Children were divided into groups based on their auditory access and classroom communication: a spoken-only group (n = 101), a sign-only group (n = 131), and a bimodal group (n = 104). Overall, children showed delays in language and reading compared to norms established for hearing children. For language, vocabulary standard scores were higher than for English syntax. Although delayed in language, children made expected gains based on hearing norms from kindergarten to second grade. Reading scores declined from kindergarten to second grade. Spoken-only and bimodal children had similar word reading and reading comprehension abilities and higher scores than sign-only children. Spoken-only children had better spoken phonological awareness and nonword reading skills than the other two groups. The sign-only and bimodal groups made similar and significant gains in ASL syntax and fingerspelling phonological awareness.


Gene targeting demonstrates that the Plasmodium berghei subtilisin PbSUB2 is essential for red cell invasion and reveals spontaneous genetic recombination events.
The Plasmodium merozoite proteases involved in the crucial process of erythrocyte invasion are promising targets for novel malaria control strategies. We report here the characterization of the subtilisin-like protease SUB2 from the rodent parasites Plasmodium berghei and Plasmodium yoelii, leading the way to in vivo functional studies of this enzyme. The kinetics of expression and subcellular localization imply a central role for SUB2 in erythrocyte invasion. Through the use of gene targeting strategies, we assessed the relevance of P. berghei SUB2 for the intraerythrocytic cycle. The selection of recombinant Pbsub2-TrimycDuoXpress-tagged parasites and the proper expression of the modified coding region demonstrate that the Pbsub2 locus is accessible to genetic modifications. However, Pbsub2 knock-out parasites were not recovered, confirming the importance of PbSUB2 for P. berghei merozoite stages, and supporting the fact that its Plasmodium falciparum SUB2 orthologue is an attractive drug target candidate. Finally, we identify revertant parasites that have lost the integrated selection cassette while conserving a Pbsub2-tagged gene. These spontaneous reversion events should overcome the scarcity of selectable markers available for this parasite, giving access to multiple gene tagging strategies, which, together with the validation of a TrimycDuoXpress tag, would represent valuable new tools for studying the biology of P. berghei.


High nuclear RBM3 expression is associated with an improved prognosis in colorectal cancer.
In this study, we investigated the prognostic impact of human RBM3 expression in colorectal cancer using tissue microarray-based immunohistochemical analysis. One polyclonal antibody and four monoclonal anti-RBM3 antibodies were generated and epitope mapped using two different methods. Bacterial display revealed five distinct epitopes for the polyclonal antibody, while the four mouse monoclonal antibodies were found to bind to three of the five epitopes. A peptide suspension bead array assay confirmed the five epitopes of the polyclonal antibody, while only one of the monoclonal antibodies could be mapped using this approach. Antibody specificity was confirmed by Western blotting and immunohistochemistry, including siRNA-mediated knock-down. Two of the antibodies (polyclonal and monoclonal) were subsequently used to analyze RBM3 expression in tumor samples from two independent colorectal cancer cohorts, one consecutive cohort (n=270) and one prospectively collected cohort of patients with cancer of the sigmoid colon (n=305). RBM3-expression was detected, with high correlation between both antibodies (R=0.81, p<0.001). In both cohorts, tumors with high nuclear RBM3 staining had significantly prolonged the overall survival. This was also confirmed in multivariate analysis, adjusted for established prognostic factors. These data demonstrate that high tumor-specific nuclear expression of RBM3 is an independent predictor of good prognosis in colorectal cancer.


Deficiency of CCAAT/enhancer binding protein family DNA binding prevents malignant conversion of adenoma to carcinoma in NNK-induced lung carcinogenesis in the mouse.
The CCAAT/enhancer binding proteins (C/EBPs) play important roles in carcinogenesis of many tumors including the lung. Since multiple C/EBPs are expressed in lung, the combinatorial expression of these C/EBPs on lung carcinogenesis is not known. A transgenic mouse line expressing a dominant negative A-C/EBP under the promoter of lung epithelial Clara cell secretory protein (CCSP) gene in doxycycline dependent fashion was subjected to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung carcinogenesis bioassay in the presence and absence of doxycycline, and the effect of abolition of DNA binding activities of C/EBPs on lung carcinogenesis was examined. A-C/EBP expression was found not to interfere with tumor development; however, it suppressed the malignant conversion of adenoma to carcinoma during NNK-induced lung carcinogenesis. The results suggested that Ki67 may be used as a marker for lung carcinomas in mouse. The DNA binding of C/EBP family members can be used as a potential molecular target for lung cancer therapy.


A macrocyclic receptor containing two viologen species connected by conjugated terphenyl groups.
A macrocyclic receptor molecule containing two viologen species connected by conjugated terphenyl groups has been designed and synthesised. The single-crystal X-ray structure shows that the two viologen residues have a transannular NN separation of ca. 7.4 Å. Thus, the internal cavity dimensions are suitable for the inclusion of π-electron-rich species. The macrocycle is redox active, and can accept electrons from suitable donor species including triethylamine, resulting in a dramatic colour change from pale yellow to dark green as a consequence of the formation of a paramagnetic bis(radical cationic) species. Cyclic voltammetry shows that the macrocycle can undergo two sequential and reversible reduction processes (E1/2 = -0.65 and -0.97 V vs. Fc/Fc+). DFT and TD-DFT studies accurately replicate the structure of the tetracationic macrocycle and the electronic absorption spectra of the three major redox states of the system. These calculations also showed that during electrochemical reduction, the unpaired electron density of the radical cations remained relatively localised within the heterocyclic rings. The ability of the macrocycle to form supramolecular complexes was confirmed by the formation of a pseudorotaxane with a guest molecule containing a π-electron-rich 1,5-dihydroxynaphthalene derivative. Threading and dethreading of the pseudorotaxane was fast on the NMR timescale, and the complex exhibited an association constant of 150 M-1 (±30 M-1) as calculated from 1H NMR titration studies.


MRI and clinical syndrome in dura mater-related Creutzfeldt-Jakob disease.
Iatrogenic Creutzfeldt-Jakob disease (iCJD) is mainly associated with dura mater (DM) grafts and administration of human growth hormones (hGH). Data on disease course in DM-CJD are limited. We describe the clinical and diagnostic findings in this patient group with special emphasis on MRI signal alterations. Ten DM-CJD patients were studied for their clinical symptoms and diagnostic findings. The MRIs were evaluated for signal increase of the cortical and subcortical structures. DM-CJD patients had a median incubation time of 18 years and median disease duration of 7 months. The majority of patients were MM homozygous at codon 129 of the prion protein gene (PRNP) and presented with gait ataxia and psychiatric symptoms. No correlation between the graft site and the initial disease course was found. The MRI showed cortical and basal ganglia signal increase each in eight out of ten patients and thalamic hyperintensity in five out of ten cases. Of interest, patients with thalamic signal increase were homozygous for methionine. The MRI findings in DM-CJD largely resemble those seen in sporadic CJD, as the cortex and basal ganglia are mainly affected.


Effect of insulin and its combination with resveratrol or curcumin in attenuation of diabetic neuropathic pain: participation of nitric oxide and TNF-alpha.
Diabetic neuropathic pain, an important microvascular complication in diabetes mellitus, is recognized as one of the most difficult types of pain to treat. The underlying mechanisms of painful symptoms may be closely associated with hyperglycaemia but a lack of the understanding of its proper aetiology, inadequate relief, development of tolerance and potential toxicity of classical antinociceptives warrant the investigation of newer agents to relieve this pain. The aim of the present study was to explore the antinociceptive effect of insulin and its combinations with resveratrol and curcumin in attenuating diabetic neuropathic pain. The study also aimed to examine the effect of these combinations on tumour necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) levels in streptozotocin (STZ) induced diabetic mice. Four weeks after a single intraperitoneal injection of streptozotocin (200 mg/kg), mice were tested in the tail immersion and hot-plate assays. Diabetic mice exhibited significant hyperalgesia along with increased plasma glucose and decreased body weights compared with control mice. Chronic treatment with insulin (10 IU/kg/day, s.c.) and its combinations with antioxidants (resveratrol 20 mg/kg or curcumin 60 mg/kg, p.o.) for 4 weeks starting from the 4th week of STZ injection significantly attenuated thermal hyperalgesia and the hot-plate latencies. There was a significant inhibition of TNF-alpha and NO levels when these drugs were given in combination compared with their effects per se. These results indicate an antinociceptive activity of resveratrol and curcumin and point towards the beneficial effect of these combinations with insulin in attenuating diabetic neuropathic pain, possibly through the participation of NO and TNF-alpha.


Digital Fourier optics.
Analog Fourier optical processing systems can perform important classes of signal processing operations in parallel, but suffer from limited accuracy. Digital-optical equivalents of such systems could be built that share many features of the analog systems while allowing greater accuracy. We show that the digital equivalent of any system consisting of an arbitrary number of lenses, niters, spatial light modulators, and sections of free space can be constructed. There are many possible applications for such systems as well as many alternative technologies for constructing them; this paper stresses the potential of free-space interconnected active-device-plane-based optoelectronic architectures as a digital signal processing environment. Implementation of the active-device planes through hybridization of optoelectronic components with silicon electronics should allow the realization of systems whose performance exceeds that of purely electronic systems.


Measurement error correction and sensitivity analysis in longitudinal dietary intervention studies using an external validation study.
In lifestyle intervention trials, where the goal is to change a participant's weight or modify their eating behavior, self-reported diet is a longitudinal outcome variable that is subject to measurement error. We propose a statistical framework for correcting for measurement error in longitudinal self-reported dietary data by combining intervention data with auxiliary data from an external biomarker validation study where both self-reported and recovery biomarkers of dietary intake are available. In this setting, dietary intake measured without error in the intervention trial is missing data and multiple imputation is used to fill in the missing measurements. Since most validation studies are cross-sectional, they do not contain information on whether the nature of the measurement error changes over time or differs between treatment and control groups. We use sensitivity analyses to address the influence of these unverifiable assumptions involving the measurement error process and how they affect inferences regarding the effect of treatment. We apply our methods to self-reported sodium intake from the PREMIER study, a multi-component lifestyle intervention trial.


Identity of SMCT1 (SLC5A8) as a neuron-specific Na+-coupled transporter for active uptake of L-lactate and ketone bodies in the brain.
SMCT1 is a sodium-coupled (Na(+)-coupled) transporter for l-lactate and short-chain fatty acids. Here, we show that the ketone bodies, beta-d-hydroxybutyrate and acetoacetate, and the branched-chain ketoacid, alpha-ketoisocaproate, are also substrates for the transporter. The transport of these compounds via human SMCT1 is Na(+)-coupled and electrogenic. The Michaelis constant is 1.4 +/- 0.1 mm for beta-d-hydroxybutyrate, 0.21 +/- 0.04 mm for acetoacetate and 0.21 +/- 0.03 mm for alpha-ketoisocaproate. The Na(+) : substrate stoichiometry is 2 : 1. As l-lactate and ketone bodies constitute primary energy substrates for neurons, we investigated the expression pattern of this transporter in the brain. In situ hybridization studies demonstrate widespread expression of SMCT1 mRNA in mouse brain. Immunofluorescence analysis shows that SMCT1 protein is expressed exclusively in neurons. SMCT1 protein co-localizes with MCT2, a neuron-specific Na(+)-independent monocarboxylate transporter. In contrast, there was no overlap of signals for SMCT1 and MCT1, the latter being expressed only in non-neuronal cells. We also demonstrate the neuron-specific expression of SMCT1 in mixed cultures of rat cortical neurons and astrocytes. This represents the first report of an Na(+)-coupled transport system for a major group of energy substrates in neurons. These findings suggest that SMCT1 may play a critical role in the entry of l-lactate and ketone bodies into neurons by a process driven by an electrochemical Na(+) gradient and hence, contribute to the maintenance of the energy status and function of neurons.


A Novel Motion-on-Color Paradigm for Isolating Magnocellular Pathway Function in Preperimetric Glaucoma.
This study investigated a novel motion-on-color paradigm to functionally isolate the magnocellular pathway and evaluate its diagnostic value in preperimetric glaucoma patients. Thirty patients with preperimetric primary open-angle glaucoma and 30 controls participated in this study. They were tested in both the foveal and peripheral locations. Contrast sensitivity was assessed for the direction discrimination of a moving luminance-modulated grating presented on top of a red/green isoluminant grating. The moving test grating was designed to target the magnocellular pathway, while the background red/green isoluminant grating was designed to saturate the parvocellular pathway. The luminance-modulated grating was presented at spatial frequency of 0.5 cyc/deg, moving horizontally at four temporal frequencies (3 Hz, 8 Hz, 15 Hz, 25 Hz). Participants were asked to indicate the direction of motion for the luminance grating. As a comparison condition, frequency-doubling stimuli were also presented in the periphery and participants were asked to detect the occurrence of the frequency-doubled pattern. Two-way repeated-measures analysis of variance was performed with temporal frequency modulations as within-subject factor and group as between-subject factor, while contrast sensitivity was the dependent variable. Receiver operating characteristic (ROC) analysis was used to characterize diagnostic performance of the new procedure in comparison with the frequency-doubling tests for preperimetric glaucoma. The contrast sensitivity function in both the fovea and the periphery showed an inverted "V" shape with highest sensitivity in the intermediate temporal frequencies, consistent with physiological properties of the magnocellular pathway. At the fovea, compared to the control group, the sensitivity for the glaucoma patients was slightly but not significantly reduced (P > 0.05), and there was no significant interaction between groups and temporal frequency (P > 0.05). In the periphery, patients' sensitivity was significantly lower (P < 0.001) than that of normal participants, especially in high temporal frequencies, as supported by a statistically significant interaction between groups and temporal frequency (P < 0.001). The areas under ROC curves (AUROC) obtained for the motion-on-color paradigm in the periphery were 0.957 (25 Hz), 0.870 (15 Hz), 0.758 (8 Hz), and 0.561 (3 Hz) and were 0.761 for the traditional frequency-doubling test. The motion-on-color paradigm revealed a loss of contrast sensitivity in the peripheral visual field in preperimetric glaucoma. When applied with stimuli at high temporal frequency, the new paradigm had higher diagnostic sensitivity and specificity than the traditional frequency-doubling test. The findings also support the viewpoint that selective evaluation of magnocellular pathway function could facilitate the earlier detection of functional defects in glaucoma before visual field defects by standard perimetry.


State of Cancer Control in Rwanda: Past, Present, and Future Opportunities.
Rwanda is a densely populated low-income country in East Africa. Previously considered a failed state after the genocide against the Tutsi in 1994, Rwanda has seen remarkable growth over the past 2 decades. Health care in Rwanda is predominantly delivered through public hospitals and is emerging in the private sector. More than 80% of patients are covered by community-based health insurance (Mutuelle de Santé). The cancer unit at the Rwanda Biomedical Center (a branch of the Ministry of Health) is responsible for setting and implementing cancer care policy. Rwanda has made progress with human papillomavirus (HPV) and hepatitis B vaccination. Recently, the cancer unit at the Rwanda Biomedical Center launched the country's 5-year National Cancer Control Plan. Over the past decade, patients with cancer have been able to receive chemotherapy at Butaro Cancer Center, and recently, the Rwanda Cancer Center was launched with 2 linear accelerator radiotherapy machines, which greatly reduced the number of referrals for treatment abroad. Palliative care services are increasing in Rwanda. A cancer registry has now been strengthened, and more clinicians are becoming active in cancer research. Despite these advances, there is still substantial work to be done and there are many outstanding challenges, including the need to build capacity in cancer awareness among the general population (and shift toward earlier diagnosis), cancer care workforce (more in-country training programs are needed), and research.


A form of muscular dystrophy associated with pathogenic variants in JAG2.
JAG2 encodes the Notch ligand Jagged2. The conserved Notch signaling pathway contributes to the development and homeostasis of multiple tissues, including skeletal muscle. We studied an international cohort of 23 individuals with genetically unsolved muscular dystrophy from 13 unrelated families. Whole-exome sequencing identified rare homozygous or compound heterozygous JAG2 variants in all 13 families. The identified bi-allelic variants include 10 missense variants that disrupt highly conserved amino acids, a nonsense variant, two frameshift variants, an in-frame deletion, and a microdeletion encompassing JAG2. Onset of muscle weakness occurred from infancy to young adulthood. Serum creatine kinase (CK) levels were normal or mildly elevated. Muscle histology was primarily dystrophic. MRI of the lower extremities revealed a distinct, slightly asymmetric pattern of muscle involvement with cores of preserved and affected muscles in quadriceps and tibialis anterior, in some cases resembling patterns seen in POGLUT1-associated muscular dystrophy. Transcriptome analysis of muscle tissue from two participants suggested misregulation of genes involved in myogenesis, including PAX7. In complementary studies, Jag2 downregulation in murine myoblasts led to downregulation of multiple components of the Notch pathway, including Megf10. Investigations in Drosophila suggested an interaction between Serrate and Drpr, the fly orthologs of JAG1/JAG2 and MEGF10, respectively. In silico analysis predicted that many Jagged2 missense variants are associated with structural changes and protein misfolding. In summary, we describe a muscular dystrophy associated with pathogenic variants in JAG2 and evidence suggests a disease mechanism related to Notch pathway dysfunction.


T(H)17 cytokines in autoimmune neuro-inflammation.
It has been firmly established that IL-23 polarized T(H)17 cells are potent effectors in the pathogenesis of experimental autoimmune encephalitomyelitis (EAE). However, the relative importance of these cells in comparison to other encephalitogenic T(H) subsets, and the mechanisms that they employ to effect inflammatory demyelination, are topics of continuing investigation. Interestingly, deletion of individual 'T(H)17 cytokines', such as IL-17A, IL-17F, IL-22 and IL-21, does not phenocopy the complete EAE-resistance of IL-23-deficient mice. The instability of T(H)17 cells in vivo introduces an additional layer of complexity to their role in the context of relapsing or chronic disease. Recent data indicate that IL-23 drives the production of myeloid activating factors, such as GM-CSF, by myelin-reactive T cells and facilitates their accumulation in the CNS. This review discusses the above issues in relation to the use of T(H)17 cells and related factors as potential therapeutic targets and biomarkers in CNS autoimmune diseases such as multiple sclerosis (MS).


Abundance and molecular diversity of thraustochytrids in coastal waters of southern China.
Thraustochytrids are unicellular fungi-like (heterotrophic) marine protists that have long been considered to play an important role in the biogeochemical cycles of the coastal oceans. However, the significance of their ecological functions and their diversity in marine ecosystems remain largely unknown. In this report, we examined the spatial and temporal variations of planktonic thraustochytrids, their relationship with other environmental factors, and their diversity in the subtropical coastal waters of China. The abundance of planktonic thraustochytrids ranged from 2.56 × 105 to 17.57 × 105 cells L-1 with highest abundance detected in polluted coastal water in the Spring (March) season. The thraustochytrid biomass was greater than the bacterial biomass in most seawater samples, ranging from 32.29 to 359.51% that of bacterioplankton. The abundance of thraustochytrids appeared to be largely related to that of bacterioplankton and to chemical oxygen demand in water columns. High-throughput sequencing analyses revealed a total of 105 OTUs (97% similarity), which were members of genera Thraustochytrium, Aplanochytrium, Oblongichytrium, Ulkenia, Labyrinthula and undescribed novel phylotypes. Results of this study indicated unprecedented high diversity of labyrinthulomycetes as well as the presence of novel labyrinthulomycete and thraustochytrid lineages, and also provided new information on the significant role of thraustochytrids in microbial food webs in a coastal marine ecosystem.


Brazilian green propolis and its constituent, Artepillin C inhibits allogeneic activated human CD4 T cells expansion and activation.
Propolis has long been used as a popular folk medicine by various ethnic groups due to its wide spectrum of alleged biological and pharmaceutical properties including anti-microbial, anti-cancer and anti-inflammatory functions. All these can be linked to the modulation of immune function. Therefore, it will be relevant for us to find out whether there is any novel compound that can account for such action and the mechanism involved. We investigated the immune modulating effect of Brazilian green propolis (PBrazil) and its constituent Artepillin C (Art-C) by using mixed leukocytes reaction. The cytotoxic effect of Art-C on non-tumorigenic human liver cell line miHA and non-tumorigenic human kidney cell line HK-2 as well as human peripheral blood mononuclear cells (PBMCs) were measured by XTT cell proliferation assay. The effect of PBrazil and Art-C on T cell proliferation and activation were determined by using carboxyfluorescein succinimidyl ester (CFSE) and by CD25 expression, respectively. Cytokines including tumor necrosis factor-α (TNF-α), interferon-gamma (IFN-γ), interleukins such as IL-2, IL-17 were measured by intracellular cytokine staining and IL-10 was measured by ELISA. The effect of PBrazil and Art-C on regulatory T cells (Treg) induction was determined by the Foxp3 expression. The apoptotic effect of these compounds on CFSE labeled alloreactive T cells was measured by using Annexin V. Using mixed leukocytes reaction we demonstrated for the first time that both Art-C and PBrazil significantly inhibited the alloreactive CD4 T cell proliferation, activation, and suppressed the expressions of IL-2, IFN-γ and IL-17 in these alloreactive CD4 T cells. The inhibitions of Art-C and PBrazil on CD4 T cells were not due to direct cytotoxic effect on PBMC or inducing regulatory T cells differentiation. Both Art-C and PBrazil were found to selectively induce apoptosis in proliferating T cells. The anti-proliferative effect of Art-C and PBrazil were reversible and were also applied to the activated T cells. In conclusion, our results indicated that Art-C and PBrazil can suppress alloreactive CD4 T cell responses in vitro, suggesting that Art-C could be used as a potential immunosuppressant, either solely or as adjunct agent in treating graft versus host disease.


Neonatal mortality and prevalence of practices for newborn care in a squatter settlement of Karachi, Pakistan: a cross-sectional study.
During the past two decades there has been a sustained decline in child and infant mortality, however neonatal mortality has remained relatively unchanged. Almost all neonatal deaths (99%) occur in developing countries, where the majority are delivered at homes. Evidence suggests that these deaths could be prevented by simple, inexpensive practices and interventions during the pregnancy, delivery and postnatal period. In Pakistan over the last decade extensive efforts have been made by the international donors and government to implement these practices. However, limited attempts have been made to explore if these efforts have made a difference at the grass root level. This study assessed the burden of neonatal mortality and prevalence of practices for newborn care in a squatter settlement of Karachi, Pakistan. A community based cross-sectional study was performed. A pre-tested structured questionnaire was administered to 565 women who had recently delivered. Information was collected on neonatal morbidity, mortality and practices of women regarding care during pregnancy, child birth and for newborn, till 28th day of birth. Although 70% of women mentioned receiving antenatal care by a skilled provider, only 54.5% had four or more visits. Tetanus toxoid was received by 79% of women while only 56% delivered at a health care facility by a skilled attendant. Newborn care practices like bathing the baby immediately after birth (56%), giving pre-lacteals (79.5%), late initiation of breast feeding (80.3%), application of substances on umbilical cord (58%) and body massage (89%) were common. Most neonates (81.1%) received BCG injection and polio drops after birth. Neonatal mortality rate was 27/1000 live births with the majority of deaths occurring during the first three days of life. Even after years of efforts by government and nongovernmental sector to reduce newborn morbidity and mortality, inadequate antenatal care, home deliveries and unhealthy newborn care practices are highly prevalent. This leads us to important questions of why practices and behaviors have not changed. Who is responsible and what strategies are needed to bring this change?


D-dimer and C-reactive Protein Blood Levels Over Time Used to Predict Pulmonary Embolism in Two COVID-19 Patients.
The diagnosis of pulmonary embolism is challenging in symptomatic COVID-19 patients since shortness of breath, chest pain, tachycardia, tachypnoea, fever, oxygen desaturation and high D-dimer blood levels might be features of both diseases. We present two COVID-19 patients in whom pulmonary embolism was suspected (and diagnosed) due to a discrepancy between an increase in D-dimer blood levels and a decrease in C-reactive protein blood levels over time. We believe that an opposite change in the blood levels of both biomarkers over time may be used as a novel method to predict pulmonary embolism in COVID-19 patients. The diagnosis of pulmonary embolism is challenging in COVID-19 patients since symptoms, signs and high D-dimer blood levels might be similar in both diseases.An increase in D-dimer blood levels and a decrease in C-reactive protein blood levels over time may be used as a novel method to predict pulmonary embolism in COVID-19 patients.


Efficient near-infrared quantum cutting in NaYF4: Ho3+, Yb3+ for solar photovoltaics.
Quantum cutting converting a ultraviolet photon into two near-infrared photons has been demonstrated by spectroscopic measurements in NaYF4:Ho3+,Yb3+ synthesized by hydrothermal method. Evidence is provided to confirm the occurrence of quantum cutting. Upon excitation of Ho3+ 5G4 level, near-infrared quantum cutting could occur through a two-step resonance energy transfer from Ho3+ to Yb3+ by cross relaxation, with a maximum quantum efficiency of 155.2%. This result reveals the possibility of violet to near-infrared quantum cutting with a quantum efficiency larger than 100% in Ho3+/Yb3+ codoped fluorides, suggesting the possible application in modifying the solar spectrum to enhance the efficiency of silicon solar cells.


Operational sex ratio and density do not affect directional selection on male sexual ornaments and behavior.
Demographic parameters including operational sex ratio (OSR) and population density may influence the opportunity for, and strength of sexual selection. Traditionally, male-biased OSRs and high population densities have been thought to increase the opportunity for sexual selection on male sexual traits due to increased male competition for mates. Recent experimental evidence, however, suggests that male-biased OSRs might reduce the opportunity for sexual selection due to increased sexual coercion experienced by females. How OSR, density, and any resultant changes in the opportunity for sexual selection actually affect selection on male sexual traits is unclear. In this study, we independently manipulated OSR and density in the guppy (Poecilia reticulata) without altering the number of males present. We recorded male and female behavior and used DNA microsatellite data to assign paternity to offspring and estimate male reproductive success. We then used linear selection analyses to examine the effects of OSR and density on directional sexual selection on male behavioral and morphological traits. We found that females were pursued more by males in male-biased treatments, despite no change in individual male behavior. There were no differences in sexual behavior experienced by females or performed by males in relation to density. Neither OSR nor density significantly altered the opportunity for sexual selection. Also, Although there was significant multivariate linear selection operating on males, neither OSR nor density altered the pattern of sexual selection on male traits. Our results suggest that differences in either OSR or density (independent of the number of males present) are unlikely to alter directional evolutionary change in male sexual traits.


A biphasic change in ribosomal conformation during transneuronal degeneration is altered by inhibition of mitochondrial, but not cytoplasmic protein synthesis.
Following loss of eighth nerve input, 20-40% of neurons in the neonatal chick cochlear nucleus, nucleus magnocellularis (NM), undergo cell death. Intracellular changes that precede the death of NM neurons include increased oxidative metabolism and mitochondrial volume, decreased cytoplasmic protein synthesis, and destruction of ribosomes. Six hours following afferent deprivation, dying NM neurons demonstrate complete loss of ribosomes and cessation of protein synthesis, suggesting that the rapid destruction of ribosomes leads to neuronal death. Increased NM neuron death occurs when mitochondrial upregulation is prevented by chloramphenicol, a mitochondrial protein synthesis inhibitor. This finding suggests that increased oxidative capacity is required for neuronal survival following loss of afferent input. To study changes in the ribosomes of afferent-deprived NM neurons, we obtained a monoclonal antibody to ribosomal RNA. This monoclonal antibody, Y10B, labels ribosomes of all NM neurons receiving normal synaptic activity. Following removal of afferent input, NM neurons demonstrate a biphasic change in their pattern of Y10B label. During the initial phase, there is a uniform decrease in the density of Y10B label. In the second phase, some NM neurons recover the capacity to bind the Y10B antibody while others remain unlabeled. During this second phase, NM neurons putatively destined to die, based on their failure to synthesize protein, are unlabeled by the Y10B antibody. New gene expression is not necessary to initiate the change in ribosomal immunoreactivity that leads deafferented NM neurons toward cell death. Blocking cytoplasmic protein synthesis with cycloheximide had no effect on the biphasic change in Y10B labeling of afferent-deprived NM neurons. Treating chicks with chloramphenicol, however, prevented the recovery of Y10B immunoreactivity in NM neurons during the second phase of the response to afferent deprivation.


Enzymatic Synthesis of 7',5'-Bicyclo-DNA Oligonucleotides.
The selection of artificial genetic polymers with tailor-made properties for their application in synthetic biology requires the exploration of new nucleosidic scaffolds that can be used in selection experiments. Herein, we describe the synthesis of a bicyclo-DNA triphosphate (i.e., 7',5'-bc-TTP) and show its potential to serve for the generation of new xenonucleic acids (XNAs) based on this scaffold. 7',5'-bc-TTP is a good substrate for Therminator DNA polymerase, and up to seven modified units can be incorporated into a growing DNA chain. In addition, this scaffold sustains XNA-dependent DNA synthesis and potentially also XNA-dependent XNA synthesis. However, DNA-dependent XNA synthesis on longer templates is hampered by competitive misincorporation of deoxyadenosine triphosphate (dATP) caused by the slow rate of incorporation of 7',5'-bc-TTP.


Pharmacological Analysis and Structure Determination of 7-Methylcyanopindolol-Bound β1-Adrenergic Receptor.
Comparisons between structures of the β1-adrenergic receptor (AR) bound to either agonists, partial agonists, or weak partial agonists led to the proposal that rotamer changes of Ser(5.46), coupled to a contraction of the binding pocket, are sufficient to increase the probability of receptor activation. (RS)-4-[3-(tert-butylamino)-2-hydroxypropoxy]-1H-indole-2-carbonitrile (cyanopindolol) is a weak partial agonist of β1AR and, based on the hypothesis above, we predicted that the addition of a methyl group to form 4-[(2S)-3-(tert-butylamino)-2-hydroxypropoxy]-7-methyl-1H-indole-2-carbonitrile (7-methylcyanopindolol) would dramatically reduce its efficacy. An eight-step synthesis of 7-methylcyanopindolol was developed and its pharmacology was analyzed. 7-Methylcyanopindolol bound with similar affinity to cyanopindolol to both β1AR and β2AR. As predicted, the efficacy of 7-methylcyanopindolol was reduced significantly compared with cyanopindolol, acting as a very weak partial agonist of turkey β1AR and an inverse agonist of human β2AR. The structure of 7-methylcyanopindolol-bound β1AR was determined to 2.4-Å resolution and found to be virtually identical to the structure of cyanopindolol-bound β1AR. The major differences in the orthosteric binding pocket are that it has expanded by 0.3 Å in 7-methylcyanopindolol-bound β1AR and the hydroxyl group of Ser(5.46) is positioned 0.8 Å further from the ligand, with respect to the position of the Ser(5.46) side chain in cyanopindolol-bound β1AR. Thus, the molecular basis for the reduction in efficacy of 7-methylcyanopindolol compared with cyanopindolol may be regarded as the opposite of the mechanism proposed for the increase in efficacy of agonists compared with antagonists.


Sulfonyl fluorides as privileged warheads in chemical biology.
Sulfonyl fluoride electrophiles have found significant utility as reactive probes in chemical biology and molecular pharmacology. As warheads they possess the right balance of biocompatibility (including aqueous stability) and protein reactivity. Their functionality is privileged in this regard as they are known to modify not only reactive serines (resulting in their common use as protease inhibitors), but also context-specific threonine, lysine, tyrosine, cysteine and histidine residues. This review describes the application of sulfonyl fluoride probes across various areas of research and explores new approaches that could further enhance the chemical biology toolkit. We believe that sulfonyl fluoride probes will find greater utility in areas such as covalent enzyme inhibition, target identification and validation, and the mapping of enzyme binding sites, substrates and protein-protein interactions.


Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci.
We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10⁻⁸). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease.


Assessment of CYP1A2 enzyme activity in relation to type-2 diabetes and habitual caffeine intake.
Coffee consumption is a known inducer of cytochrome P450 1A2 (CYP1A2) enzyme activity. We recently observed that a group of type-2 diabetes patients consumed more caffeine (coffee) on a daily basis than non-type-2 diabetes controls. Here, we investigated whether type-2 diabetes cases may metabolize caffeine faster than non-type-2 diabetes controls. To estimate CYP1A2 enzyme activity, an established marker of caffeine metabolism, we quantified the paraxanthine/caffeine concentration ratio in saliva in 57 type-2 diabetes and 146 non-type-2 diabetes participants in a case-control field study. All participants completed validated questionnaires regarding demographic status, health and habitual caffeine intake, and were genotyped for the functional -163C > A polymorphism of the CYP1A2 gene. In the diabetes group, we found a larger proportion of participants with the highly inducible CYP1A2 genotype. Furthermore, the paraxanthine/caffeine ratio, time-corrected to mitigate the impact of different saliva sampling times with respect to the last caffeine intake, was higher than in the control group. Participants who reported habitually consuming more caffeine than the population average showed higher CYP1A2 activity than participants with lower than average caffeine consumption. Multiple regression analyses revealed that higher caffeine intake was potentially an important mediator of higher CYP1A2 activity. Estimated CYP1A2 enzyme activity, and thus speed of caffeine metabolism, was higher in our type-2 diabetes group; this was possibly due to higher intake of caffeine, a known inducer of CYP1A2 enzyme activity. Given the fairly small sample sizes, the results need to be considered as preliminary and require validation in larger populations.


Compensation for time fluctuations of phase modulation in a liquid-crystal-on-silicon display by process synchronization in laser materials processing.
We demonstrate the adverse influence of temporal fluctuations of the phase modulation of a spatial light modulator (SLM) display device on nanosecond laser micromachining. We show that active cooling of the display reduces the amplitude of these fluctuations, and we demonstrate a process synchronization technique developed to compensate for these fluctuations when applying the SLM to laser materials processing. For alternative SLM devices developed specifically for laser wavefront control (which do not exhibit such flickering problems), we show that our process synchronization approach is also beneficial to avoid machining glitches when switching quickly between different phase profiles (and hence beam patterns).


Octapeptide repeat insertions in the prion protein gene and early onset dementia.
The most common familial early onset dementia mutations are found in the genes involved in Alzheimer's disease; the amyloid precursor protein (APP) and the presenilin 1 and 2 (PSEN1 and 2) genes; the prion protein gene (PRNP) may be involved. Following identification of a two-octapeptide repeat insertion in PRNP, we conducted a meta-analysis to investigate the relation of number of PRNP octapeptide repeats with age at disease onset and duration of illness; identifying 55 patients with PRNP octapeptide repeat insertions. We used a linear mixed effects model to assess the relation of number of repeats with age at disease onset, and studied the effect of the number of inserted octapeptide repeats on disease duration with a Cox proportional hazards regression analysis. We found an increasing number of repeats associated with younger age at onset (p < 0.001). Duration of the disease decreased significantly with the length of the octapeptide repeat (p < 0.001) when adjusting for age at onset. Our findings show significant inverse associations of the length of the PRNP octapeptide repeat with age at disease onset and disease duration in the spongiform encephalopathies.


Analysis of optical waveguides with ultra-thin metal film based on the multidomain pseudospectral frequency-domain method.
Analysis of optical waveguides with thin metal films is studied by the multidomain pseudospectral frequency-domain (PSFD) method. Calculated results for both guiding and leaky modes are precise by means of the PSFD based on Chebyshev-Lagrange interpolating polynomials with modified perfectly matched layer (MPML). By introducing a suitable boundary condition for the dielectric-metallic interface, the stability and the spectrum convergence characteristic of the PSFD-MPML method can be sustained. The comparison of exact solutions of highly sensitive surface plasmon modes in 1D dielectric-metal waveguides and those calculated by our PSFD-MPML demonstrates the validity and usefulness of the proposed method. We also apply the method to calculate the effective refractive indices of an integrated optical waveguide with deposition of the finite gold metal layer which induces the hybrid surface plasmon modes. Furthermore, the 2-D optical structures with gold films are investigated to exhibit hybrid surface plasmon modes of wide variations. We then apply hybrid surface plasmon modes to design novel optical components-mode selective devices and the polarizing beam splitter.


Intestinal CD103+, but not CX3CR1+, antigen sampling cells migrate in lymph and serve classical dendritic cell functions.
Chemokine receptor CX3CR1(+) dendritic cells (DCs) have been suggested to sample intestinal antigens by extending transepithelial dendrites into the gut lumen. Other studies identified CD103(+) DCs in the mucosa, which, through their ability to synthesize retinoic acid (RA), appear to be capable of generating typical signatures of intestinal adaptive immune responses. We report that CD103 and CX3CR1 phenotypically and functionally characterize distinct subsets of lamina propria cells. In contrast to CD103(+) DC, CX3CR1(+) cells represent a nonmigratory gut-resident population with slow turnover rates and poor responses to FLT-3L and granulocyte/macrophage colony-stimulating factor. Direct visualization of cells in lymph vessels and flow cytometry of mouse intestinal lymph revealed that CD103(+) DCs, but not CX3CR1-expressing cells, migrate into the gut draining mesenteric lymph nodes (LNs) under steady-state and inflammatory conditions. Moreover, CX3CR1(+) cells displayed poor T cell stimulatory capacity in vitro and in vivo after direct injection of cells into intestinal lymphatics and appeared to be less efficient at generating RA compared with CD103(+) DC. These findings indicate that selectively CD103(+) DCs serve classical DC functions and initiate adaptive immune responses in local LNs, whereas CX3CR1(+) populations might modulate immune responses directly in the mucosa and serve as first line barrier against invading enteropathogens.


Vitamin D and risk of cognitive decline in elderly persons.
To our knowledge, no prospective study has examined the association between vitamin D and cognitive decline or dementia. We determined whether low levels of serum 25-hydroxyvitamin D (25[OH]D) were associated with an increased risk of substantial cognitive decline in the InCHIANTI population-based study conducted in Italy between 1998 and 2006 with follow-up assessments every 3 years. A total of 858 adults 65 years or older completed interviews, cognitive assessments, and medical examinations and provided blood samples. Cognitive decline was assessed using the Mini-Mental State Examination (MMSE), and substantial decline was defined as 3 or more points. The Trail-Making Tests A and B were also used, and substantial decline was defined as the worst 10% of the distribution of decline or as discontinued testing. The multivariate adjusted relative risk (95% confidence interval [CI]) of substantial cognitive decline on the MMSE in participants who were severely serum 25(OH)D deficient (levels <25 nmol/L) in comparison with those with sufficient levels of 25(OH)D (>/=75 nmol/L) was 1.60 (95% CI, 1.19-2.00). Multivariate adjusted random-effects models demonstrated that the scores of participants who were severely 25(OH)D deficient declined by an additional 0.3 MMSE points per year more than those with sufficient levels of 25(OH)D. The relative risk for substantial decline on Trail-Making Test B was 1.31 (95% CI, 1.03-1.51) among those who were severely 25(OH)D deficient compared with those with sufficient levels of 25(OH)D. No significant association was observed for Trail-Making Test A. Low levels of vitamin D were associated with substantial cognitive decline in the elderly population studied over a 6-year period, which raises important new possibilities for treatment and prevention.


Human diseases through the lens of network biology.
One of the challenges raised by next generation sequencing (NGS) is the identification of clinically relevant mutations among all the genetic variation found in an individual. Network biology has emerged as an integrative and systems-level approach for the interpretation of genome data in the context of health and disease. Network biology can provide insightful models for genetic phenomena such as penetrance, epistasis, and modes of inheritance, all of which are integral aspects of Mendelian and complex diseases. Moreover, it can shed light on disease mechanisms via the identification of modules perturbed in those diseases. Current challenges include understanding disease as a result of the interplay between environmental and genetic perturbations and assessing the impact of personal sequence variations in the context of networks. Full realization of the potential of personal genomics will benefit from network biology approaches that aim to uncover the mechanisms underlying disease pathogenesis, identify new biomarkers, and guide personalized therapeutic interventions.


Differentially expressed genes in pancreatic ductal adenocarcinomas identified through serial analysis of gene expression.
Serial analysis of gene expression (SAGE) is a powerful tool for the discovery of novel tumor markers. The publicly available online SAGE libraries of normal and neoplastic tissues (http://www.ncbi.nlm.nih.gov/SAGE/) have recently been expanded; in addition, a more complete annotation of the human genome and better biocomputational techniques have substantially improved the assignment of differentially expressed SAGE "tags" to human genes. These improvements have provided us with an opportunity to re-evaluate global gene expression in pancreatic cancer using existing SAGE libraries. SAGE libraries generated from six pancreatic cancers were compared to SAGE libraries generated from 11 non-neoplastic tissues. Compared to normal tissue libraries, we identified 453 SAGE tags as differentially expressed in pancreatic cancer, including 395 that mapped to known genes and 58 "uncharacterized" tags. Of the 395 SAGE tags assigned to known genes, 223 were overexpressed in pancreatic cancer, and 172 were underexpressed. In order to map the 58 uncharacterized differentially expressed SAGE tags to genes, we used a newly developed resource called TAGmapper (http://tagmapper.ibioinformatics.org), to identify 16 additional differentially expressed genes. The differential expression of seven genes, involved in multiple cellular processes such as signal transduction (MIC-1), differentiation (DMBT1 and Neugrin), immune response (CD74), inflammation (CXCL2), cell cycle (CEB1) and enzymatic activity (Kallikrein 6), was confirmed by either immunohistochemical labeling of tissue microarrays (Kallikrein 6, CD74 and DMBT1) or by RT-PCR (CEB1, Neugrin, MIC1 and CXCL2). Of note, Neugrin was one of the genes whose previously uncharacterized SAGE tag was correctly assigned using TAGmapper, validating the utility of this program. Novel differentially expressed genes in a cancer type can be identified by revisiting updated and expanded SAGE databases. TAGmapper should prove to be a powerful tool for the discovery of novel tumor markers through assignment of uncharacterized SAGE tags.


Consciousness: here, there and everywhere?
The science of consciousness has made great strides by focusing on the behavioural and neuronal correlates of experience. However, while such correlates are important for progress to occur, they are not enough if we are to understand even basic facts, for example, why the cerebral cortex gives rise to consciousness but the cerebellum does not, though it has even more neurons and appears to be just as complicated. Moreover, correlates are of little help in many instances where we would like to know if consciousness is present: patients with a few remaining islands of functioning cortex, preterm infants, non-mammalian species and machines that are rapidly outperforming people at driving, recognizing faces and objects, and answering difficult questions. To address these issues, we need not only more data but also a theory of consciousness-one that says what experience is and what type of physical systems can have it. Integrated information theory (IIT) does so by starting from experience itself via five phenomenological axioms: intrinsic existence, composition, information, integration and exclusion. From these it derives five postulates about the properties required of physical mechanisms to support consciousness. The theory provides a principled account of both the quantity and the quality of an individual experience (a quale), and a calculus to evaluate whether or not a particular physical system is conscious and of what. Moreover, IIT can explain a range of clinical and laboratory findings, makes a number of testable predictions and extrapolates to a number of problematic conditions. The theory holds that consciousness is a fundamental property possessed by physical systems having specific causal properties. It predicts that consciousness is graded, is common among biological organisms and can occur in some very simple systems. Conversely, it predicts that feed-forward networks, even complex ones, are not conscious, nor are aggregates such as groups of individuals or heaps of sand. Also, in sharp contrast to widespread functionalist beliefs, IIT implies that digital computers, even if their behaviour were to be functionally equivalent to ours, and even if they were to run faithful simulations of the human brain, would experience next to nothing.


ChromoHub V2: cancer genomics.
Cancer genomics data produced by next-generation sequencing support the notion that epigenetic mechanisms play a central role in cancer. We have previously developed Chromohub, an open access online interface where users can map chemical, structural and biological data from public repositories on phylogenetic trees of protein families involved in chromatin mediated-signaling. Here, we describe a cancer genomics interface that was recently added to Chromohub; the frequency of mutation, amplification and change in expression of chromatin factors across large cohorts of cancer patients is regularly extracted from The Cancer Genome Atlas and the International Cancer Genome Consortium and can now be mapped on phylogenetic trees of epigenetic protein families. Explorators of chromatin signaling can now easily navigate the cancer genomics landscape of writers, readers and erasers of histone marks, chromatin remodeling complexes, histones and their chaperones. http://www.thesgc.org/chromohub/.


Team cohesiveness, team size and team performance in team-based learning teams.
The purpose of this study was to explore the relationships among variables associated with teams in team-based learning (TBL) settings and team outcomes. We administered the National Board of Medical Examiners (NBME) Psychiatry Subject Test first to individuals and then to teams of Year three students at four medical schools that used TBL in their psychiatry core clerkships. Team cohesion was analysed using the Team Performance Scale (TPS). Bivariate correlation and linear regression analysis were used to analyse the relationships among team-level variables (mean individual TPS scores for each team, mean individual NBME scores of teams, team size, rotation and gender make-up) and team NBME test scores. A hierarchical linear model was used to test the effects of individual TPS and individual NBME test scores within each team, as well as the effects of the team-level variables of team size, team rotation and gender on team NBME test scores. Individual NBME test and TPS scores were nested within teams and treated as subsampling units. Individual NBME test scores and individual TPS scores were positively and statistically significantly (p < 0.01) associated with team NBME test scores, when team rotation, team size and gender make-up were controlled for. Higher team NBME test scores were associated with teams rotating later in the year and larger teams (p < 0.01). Gender make-up was not significantly associated. The results of an NBME Psychiatry Subject Test administered to TBL teams at four medical schools suggest that larger teams on later rotations score higher on a team NBME test. Individual NBME test scores and team cohesion were positively and significantly associated with team NBME test scores. These results suggest the need for additional studies focusing on team outcomes, team cohesion, team size, rotation and other factors as they relate to the effective and efficient performance of TBL teams in health science education.


Effects of soil erosion and anoxic-euxinic ocean in the Permian-Triassic marine crisis.
The largest mass extinction of biota in the Earth's history occurred during the Permian-Triassic transition and included two extinctions, one each at the latest Permian (first phase) and earliest Triassic (second phase). High seawater temperature in the surface water accompanied by euxinic deep-intermediate water, intrusion of the euxinic water to the surface water, a decrease in pH, and hypercapnia have been proposed as direct causes of the marine crisis. For the first-phase extinction, we here add a causal mechanism beginning from massive soil and rock erosion and leading to algal blooms, release of toxic components, asphyxiation, and oxygen-depleted nearshore bottom water that created environmental stress for nearshore marine animals. For the second-phase extinction, we show that a soil and rock erosion/algal bloom event did not occur, but culmination of anoxia-euxinia in intermediate waters did occur, spanning the second-phase extinction. We investigated sedimentary organic molecules, and the results indicated a peak of a massive soil erosion proxy followed by peaks of marine productivity proxy. Anoxic proxies of surface sediments and water occurred in the shallow nearshore sea at the eastern and western margins of the Paleotethys at the first-phase extinction horizon, but not at the second-phase extinction horizon. Our reconstruction of ocean redox structure at low latitudes indicates that a gradual increase in temperature spanning the two extinctions could have induced a gradual change from a well-mixed oxic to a stratified euxinic ocean beginning immediately prior to the first-phase extinction, followed by culmination of anoxia in nearshore surface waters and of anoxia and euxinia in the shallow-intermediate waters at the second-phase extinction over a period of approximately one million years or more. Enhanced global warming, ocean acidification, and hypercapnia could have caused the second-phase extinction approximately 60 kyr after the first-phase extinction. The causes of the first-phase extinction were not only those environmental stresses but also environmental stresses caused by the soil and rock erosion/algal bloom event.


Translocation of 'Candidatus Liberibacter solanacearum', the Zebra Chip pathogen, in potato and tomato.
Zebra Chip disease is a serious threat to potato production. The pathogen, the phloem-limited bacterium 'Candidatus Liberibacter solanacearum,' is vectored by the potato and tomato psyllid Bactericerca cockerelli to potato and tomato. Patterns of pathogen translocation through phloem in potato and tomato plants were examined to determine whether rate or direction of translocation vary by host species or potato cultivars. Two insects were given a 7-day inoculation access period on a single leaf. Weekly, leaves from upper-, middle-, and lower-tier branches were tested for the presence of 'Ca. L. solanacearum' by polymerase chain reaction (PCR). In tomato and potato, 'Ca. L. solanacearum' was detected 2 to 3 weeks after infestation, most frequently in upper- and middle-tier leaves. In potato, the pathogen was detected in leaves on a second, noninfested stem when the stems remained joined via the tuber. Although rates of pathogen movement were similar among potato cultivars, symptoms developed earlier in more susceptible cultivars. Quantitative PCR indicated that bacterial titers were frequently low in tomato and potato samples (<20 genome units per nanogram of DNA). Results establish that, for improved detection, samples should include newly developing leaves and consider that, under low insect pressure, the pathogen may be undetectable by PCR until 3 weeks after infestation.


Preschool morphological training produces long-term improvements in reading comprehension.
We evaluated the effect of morphological awareness training delivered in preschool (8 months before school entry) on reading ability at the end of grade 1 and 5 years later (in Grade 6). In preschool, one group of children received morphological awareness training, while a second group received phonological awareness training. A control group followed the ordinary preschool curriculum. The comparison between each training condition and the control condition is quasi experimental, whereas the comparison between the morphological and phonological treatments is randomized at group level. In Grade 1 children in the morphological awareness training group had significantly higher scores than children in the control group on both word reading and text reading measures, but no differences were found between the experimental groups. In Grade 6 children in the morphological awareness training group had significantly higher scores compared with the control group on a latent measure of reading comprehension, whereas the children in the phonological awareness training group did not differ from the controls; although the experimental groups did not differ significantly from each other. The results suggest that early training in morphological awareness can have long-term effects on children's literacy skills.


Nurse-based antenatal and child health care in rural India, implementation and effects - an Indian-Swedish collaboration.
Improving maternal and child health care are two of the Millennium Development Goals of the World Health Organization. India is one of the countries worldwide most burdened by maternal and child deaths. The aim of the study was to describe how families participate in nurse-based antenatal and child health care, and the effect of this in relation to referrals to specialist care, institutional deliveries and mortality. The intervention took place in a remote rural area in India and was influenced by Swedish nurse-based health care. A baseline survey was performed before the intervention commenced. The intervention included education program for staff members with a model called Training of Trainers and the establishment of clinics as both primary health centers and mobile clinics. Health records and manuals, and informational and educational materials were produced and the clinics were equipped with easily handled instruments. The study period was between 2006 and 2009. Data were collected from antenatal care and child healthcare records. The Chi-square test was used to analyze mortality differences between years. A focus group discussion and a content analysis were performed. Families' participation increased which led to more check-ups of pregnant women and small children. Antenatal visits before 16 weeks among pregnant women increased from 32 to 62% during the period. Women having at least three check-ups during pregnancy increased from 30 to 60%. Maternal mortality decreased from 478 to 121 per 100 000 live births. The total numbers of children examined in the project increased from approximately 6000 to 18 500 children. Infant mortality decreased from 80 to 43 per 1000 live births. Women and children referred to specialist care increased considerably and institutional deliveries increased from 47 to 74%. These results suggest that it is possible in a rural and remote area to influence peoples' awareness of the value of preventive health care. The results also indicate that this might decrease maternal and child mortality. The education led to a more patient-friendly encounter between health professionals and patients.


Endoscopic management of duodenal levodopa-carbidopa therapy of advanced Parkinson's disease.
treatment of intraduodenal levodopa using percutaneous endoscopic gastrostomy is an alternative therapy in patients with advanced Parkinson's disease. There are few studies that have evaluated the endoscopic aspects of this technique. to describe our experience and adverse events regarding this technique in advanced Parkinson's disease. a retrospective study was performed from January 2007 to January 2019 in a tertiary healthcare center. thirty-seven patients aged 65.1 ± 10.3 years were included in the study, 21 were male and the disease duration was ten years (1-26). The median follow-up was 16 months (1-144). The device was successfully placed in all cases. The persistence rate with the PEG-D at the end of follow-up was 62.2%. The system was removed in 14 patients, seven due to neurological impairment, four because of the decision of the patient and three due to related events. Fifty-nine adverse events occurred in 23 patients (62.2%, 0.63 per patient-year), four of which were severe (8.1%, 0.05 per patient-year). Minor adverse events included 14 (37.8%) related to the stoma, six (16.2%) to the gastric tube and 15 (40.5%) to the duodenal tube. Forty-four system replacements were performed in 20 patients (54.1%, 0.52 per patient-year). Male sex, age over 70 and a higher comorbidity index were associated with a greater likelihood of persistence of the system (OR: 0.14, 95% CI: 0.03-0.62; OR: 0.52, 95% CI: 0.32-0.86; OR: 0.16, 95% CI: 0.03-0.99, respectively). No predictors of adverse events associated with PEG-D were identified. percutaneous endoscopic gastrostomy for the continuous delivery of duodenal levodopa is a highly effective technique. Adverse events are common, although most are resolved by endoscopy.


HIV and hepatitis B and C incidence rates in US correctional populations and high risk groups: a systematic review and meta-analysis.
High Human Immunodeficiency Virus (HIV) prevalence and high risk behaviors have been well documented within United States (US) correctional systems. However, uncertainty remains regarding the extent to which placing people in prison or jail increases their risk of HIV infection, and regarding which inmate populations experience an increased incidence of HIV. Describing these dynamics more clearly is essential to understanding how inmates and former detainees may be a source for further spread of HIV to the general US population. The authors conducted a systematic review and meta-analysis of studies describing HIV incidence in US correctional facility residents and, for comparison, in high risk groups for HIV infection, such as non-incarcerated intravenous drug users (IVDU) and men who have sex with men (MSM) in the US. HIV incidence rates were further compared with Hepatitis B and Hepatitis C Virus rates in these same populations. Thirty-six predominantly prospective cohort studies were included. Across all infection outcomes, continuously incarcerated inmates and treatment recruited IVDU showed the lowest incidence, while MSM and street recruited IVDU showed the highest. HIV incidence was highest among inmates released and re-incarcerated. Possible sources of heterogeneity identified among HIV studies were risk population and race. Although important literature gaps were found, current evidence suggests that policies and interventions for HIV prevention in correctional populations should prioritize curtailing risk of infection during the post-release period. Future research should evaluate HIV incidence rates in inmate populations, accounting for proportion of high risk sub-groups.


Facial paralysis in the newborn.
A group of 95 patients with facial paralysis in the neonatal period are presented. In 74 patients it was believed to be secondary to trauma associated with pregnancy and delivery, and in 21 to be secondary to congenital lesions. The cause, extent, and clinical course of the paralyses are discussed. A classification is outlined to help in organizing a logical and systematic evaluation plan for these patients. Patients may be divided into four groups based on the time they are seen after birth, whether the nerve is stimulable, or whether the nerve loses its stimulability. On the basis of this classification, electromyogram studies, and roentgenographic findings, a presumptive diagnosis may be made and a treatment plan formulated. The treatment plan is based on the diagnosis, facial nerve excitability testing, and degree of deformity present. If there is evidence of facial nerve disruption, a facial nerve exploration is indicated. In congenital cases, reanimation procedures may be necessary.


Recent advances in autoimmune autonomic ganglionopathy.
This review highlights recent advances in our understanding of autoimmune autonomic ganglionopathy (AAG) including serological diagnosis, clinical observations, pathophysiology, and treatment. Classical AAG is a subacute disorder associated with antibodies against ganglionic acetylcholine receptors. Recent observations demonstrate that these antibodies cause a specific inhibition of synaptic transmission in autonomic ganglia and antibody levels correlate in a predictable way with severity of autonomic failure. Ganglionic acetylcholine receptor antibodies can be associated with other neurological disorders including chronic or restricted forms of autonomic dysfunction and with neurological or paraneoplastic disorders unrelated to the autonomic nervous system. Treatment of AAG is based on case reports. It is clear that AAG patients respond to immunomodulatory treatments but combination immunotherapy may be required to achieve a clinical response. Recently, additional clinical observations indicate that AAG patients may also show signs of treatment-responsive cognitive impairment. The pathophysiology and varied clinical presentation of AAG are becoming more clear. AAG is a treatable antibody-mediated disorder of autonomic ganglionic synaptic transmission. Future studies will continue to define the optimal diagnostic and therapeutic approach to autoimmune autonomic disorders.


Neurotrauma research in Taiwan.
Because of the rapid industrial and economic growth, Taiwan and other developing countries have faced an enormous increase in the number of motorcycles, which has subsequently caused a rapid increase of the motorcycle-related traumatic brain injuries (TBI). In order to tackle this serious problem, stepwise approaches for TBI were implemented in Taiwan from 1991 to 2007. Step 1 was to do a nationwide TBI registry in order to identify the risk factors and determinants. We found that the major cause of TBI in Taiwan was motorcycle-related injury, and very few motorcyclists wore a helmet. Step 2 was to launch the implementation of the helmet use law on June 1, 1997. A rapid decline of TBI hospitalizations and deaths was demonstrated soon thereafter. Step 3 was to enroll into international collaborations with the Global Spine and Head Injury Prevention Project (Global SHIP Project) groups for TBI. The comparative results thus obtained could be used to develop prevention strategies for developing countries. Step 4 was to implement clinical researches for TBI, which included a Propofol study, hyperbaric oxygen therapy (HBOT), brain parenchymal oxygen (PbtO2) monitoring, etc. Step 5 was to develop guidelines for the management of severe TBI in Taiwan. Through a 2-year period of review, discussion, and integration, a 9-chapter guideline was published in June 2007. In summary, our experience and process for management of TBI in Taiwan can be used as a reference for other developing countries.


Ginsenoside Rg3 induces apoptosis in the U87MG human glioblastoma cell line through the MEK signaling pathway and reactive oxygen species.
Ginsenoside is known to have potential cancer-preventive activities. The major active components in red ginseng consist of a variety of ginsenosides including Rg3, Rg5 and Rk1, each of which has different pharmacological activities. Among these, Rg3 has been reported to exert anticancer activities through inhibition of angiogenesis and cell proliferation. However, the effects of Rg3 and its molecular mechanism on glioblastoma multiforme (GBM) remain unclear. Therefore, it is essential to develop a greater understanding of this novel compound. In the present study, we investigated the effects of Rg3 on a human glioblastoma cell line and its molecular signaling mechanism. The mechanisms of apoptosis by ginsenoside Rg3 were related with the MEK signaling pathway and reactive oxygen species. Our data suggest that ginsenoside Rg3 is a novel agent for the chemotherapy of GBM.


Significance of PELP1 in ER-negative breast cancer metastasis.
Breast cancer metastasis is a major clinical problem. The molecular basis of breast cancer progression to metastasis remains poorly understood. PELP1 is an estrogen receptor (ER) coregulator that has been implicated as a proto-oncogene whose expression is deregulated in metastatic breast tumors and whose expression is retained in ER-negative tumors. We examined the mechanism and significance of PELP1-mediated signaling in ER-negative breast cancer progression using two ER-negative model cells (MDA-MB-231 and 4T1 cells) that stably express PELP1-shRNA. These model cells had reduced PELP1 expression (75% of endogenous levels) and exhibited less propensity to proliferate in growth assays in vitro. PELP1 downregulation substantially affected migration of ER-negative cells in Boyden chamber and invasion assays. Using mechanistic studies, we found that PELP1 modulated expression of several genes involved in the epithelial mesenchymal transition (EMT), including MMPs, SNAIL, TWIST, and ZEB. In addition, PELP1 knockdown reduced the in vivo metastatic potential of ER-negative breast cancer cells and significantly reduced lung metastatic nodules in a xenograft assay. These results implicate PELP1 as having a role in ER-negative breast cancer metastasis, reveal novel mechanism of coregulator regulation of metastasis via promoting cell motility/EMT by modulating expression of genes, and suggest PELP1 may be a potential therapeutic target for metastatic ER-negative breast cancer.


A spatial database of health facilities managed by the public health sector in sub Saharan Africa.
Health facilities form a central component of health systems, providing curative and preventative services and structured to allow referral through a pyramid of increasingly complex service provision. Access to health care is a complex and multidimensional concept, however, in its most narrow sense, it refers to geographic availability. Linking health facilities to populations has been a traditional per capita index of heath care coverage, however, with locations of health facilities and higher resolution population data, Geographic Information Systems allow for a more refined metric of health access, define geographic inequalities in service provision and inform planning. Maximizing the value of spatial heath access requires a complete census of providers and their locations. To-date there has not been a single, geo-referenced and comprehensive public health facility database for sub-Saharan Africa. We have assembled national master health facility lists from a variety of government and non-government sources from 50 countries and islands in sub Saharan Africa and used multiple geocoding methods to provide a comprehensive spatial inventory of 98,745 public health facilities.


Electroconvulsive seizures stimulate glial proliferation and reduce expression of Sprouty2 within the prefrontal cortex of rats.
Reductions in cell number are found within the medial prefrontal cortex (PFC) in major depression and bipolar disorder, conditions for which electroconvulsive therapy (ECT) is a highly effective treatment. We investigated whether electroconvulsive seizure (ECS) in rats stimulates cellular proliferation in the PFC immediately and four weeks after the treatments. In parallel, we examined if ECS also alters the expression of Sprouty2 (SPRY2), an inhibitor of cell proliferation. Sprague-Dawley rats received 10 days of ECS treatments and bromodeoxyuridine (BrdU) injections. After a four week survival period, we estimated the density and number of BrdU-, proliferating cell nuclear antigen (PCNA)-, and SPRY2-immunoreactive cells in the medial (infralimbic) PFC (ILPFC). We also determined the percentage of BrdU-labeled cells that were immunoreactive for markers specific to oligodendrocytes, astrocytes, endothelial cells and neurons. ECS dramatically enhanced the proliferation of new cells in the infralimbic PFC, and this effect persisted four weeks following the treatments. The percentage of new cells expressing oligodendrocyte precursor cell markers increased slightly following ECS. In contrast, ECS dramatically reduced the number of cells expressing SPRY2. ECS stimulates long-lasting increases in glial proliferation within the ILPFC. ECS also decreases SPRY2 expression in the same region, an effect that might contribute to increased glial proliferation.


Identification of hypoxia-regulated proteins using MALDI-mass spectrometry imaging combined with quantitative proteomics.
Hypoxia is present in most solid tumors and is clinically correlated with increased metastasis and poor patient survival. While studies have demonstrated the role of hypoxia and hypoxia-regulated proteins in cancer progression, no attempts have been made to identify hypoxia-regulated proteins using quantitative proteomics combined with MALDI-mass spectrometry imaging (MALDI-MSI). Here we present a comprehensive hypoxic proteome study and are the first to investigate changes in situ using tumor samples. In vitro quantitative mass spectrometry analysis of the hypoxic proteome was performed on breast cancer cells using stable isotope labeling with amino acids in cell culture (SILAC). MS analyses were performed on laser-capture microdissected samples isolated from normoxic and hypoxic regions from tumors derived from the same cells used in vitro. MALDI-MSI was used in combination to investigate hypoxia-regulated protein localization within tumor sections. Here we identified more than 100 proteins, both novel and previously reported, that were associated with hypoxia. Several proteins were localized in hypoxic regions, as identified by MALDI-MSI. Visualization and data extrapolation methods for the in vitro SILAC data were also developed, and computational mapping of MALDI-MSI data to IHC results was applied for data validation. The results and limitations of the methodologies described are discussed.


Prospecting and dispersal: their eco-evolutionary dynamics and implications for population patterns.
Dispersal is not a blind process, and evidence is accumulating that individual dispersal strategies are informed in most, if not all, organisms. The acquisition and use of information are traits that may evolve across space and time as a function of the balance between costs and benefits of informed dispersal. If information is available, individuals can potentially use it in making better decisions, thereby increasing their fitness. However, prospecting for and using information probably entail costs that may constrain the evolution of informed dispersal, potentially with population-level consequences. By using individual-based, spatially explicit simulations, we detected clear coevolutionary dynamics between prospecting and dispersal movement strategies that differed in sign and magnitude depending on their respective costs. More specifically, we found that informed dispersal strategies evolve when the costs of information acquisition during prospecting are low but only if there are mortality costs associated with dispersal movements. That is, selection favours informed dispersal strategies when the acquisition and use processes themselves were not too expensive. When non-informed dispersal strategies evolve, they do so jointly with the evolution of long dispersal distance because this maximizes the sampling area. In some cases, selection produces dispersal rules different from those that would be 'optimal' (i.e. the best possible population performance--in our context quantitatively measured as population density and patch occupancy--among all possible individual movement rules) for the population. That is, on the one hand, informed dispersal strategies led to population performance below its highest possible level. On the other hand, un- and poorly informed individuals nearly optimized population performance, both in terms of density and patch occupancy.


Primary tracheal tumours: a national survey.
Primary tracheal tumours are rare, so few physicians have extensive experience of their management. No direct comparisons have been made of surgical and radiotherapy treatment. A postal survey of cases presenting in the last 10 years in the United Kingdom was conducted. Results were expressed as cumulative survival and survival curves were compared by the log rank test. Three hundred and twenty one patients were recruited. Overall five year survival rates were 25% for squamous cell carcinomas, and 80% for adenoid cystic carcinoma; 62% received radiotherapy but only 10% underwent surgery. Small cell carcinoma was more common than expected with an incidence of 6%. In patients with squamous carcinoma improved survival was seen in those with tumour in the upper trachea. High dose radiotherapy was more effective than low dose only in tumours of the upper trachea and in squamous carcinoma. In adenoid cystic carcinoma no significant difference in survival rate was seen between treatment with radiotherapy and surgery. No histological diagnosis was made in 44 patients, the most common reason being fear over the safety of fibreoptic bronchoscopy; however, this group had a cumulative survival at five years of 46%. Survival may be somewhat better in cases with tracheal tumours than in those with bronchial tumours. Small cell carcinoma is less rare than was previously thought. Upper tracheal tumours may merit more aggressive therapy. It is important to make a histological diagnosis even if rigid bronchoscopy is necessary, and referral to specialist centres is recommended. A larger prospective study is required to compare the value of surgery and radiotherapy.


Plasmodium falciparum exploits CD44 as a co-receptor for erythrocyte invasion.
The malaria parasite Plasmodium falciparum invades and replicates asexually within human erythrocytes. CD44 expressed on erythrocytes was previously identified as an important host factor for P. falciparum infection through a forward genetic screen, but little is known about its regulation or function in these cells, nor how it may be utilized by the parasite. We found that CD44 can be efficiently deleted from primary human hematopoietic stem cells using CRISPR/Cas9 genome editing, and that the efficiency of ex-vivo erythropoiesis to enucleated cultured red blood cells (cRBCs) is not impacted by lack of CD44. However, the rate of P. falciparum invasion was substantially reduced in CD44-null cRBCs relative to isogenic wild-type (WT) control cells, validating CD44 as an important host factor for this parasite. We identified two P. falciparum invasion ligands as binding partners for CD44, Erythrocyte Binding Antigen-175 (EBA-175) and EBA-140, and demonstrated that their ability to bind to human erythrocytes relies primarily on their canonical receptors-glycophorin A and glycophorin C, respectively. We further show that EBA-175 induces phosphorylation of erythrocyte cytoskeletal proteins in a CD44-dependent manner. Our findings support a model where P. falciparum exploits CD44 as a co-receptor during invasion of human erythrocytes, stimulating CD44-dependent phosphorylation of host cytoskeletal proteins that alter host cell deformability and facilitate parasite entry.


[The use of medication in the perception of users Hiperdia Program].
This article discusses the question of access to medication as a social right, investigating how users registered in the Hiperdia program perceive their access to medication. To achieve this, the process of "medicalization" experienced by Brazilian society today was assessed, highlighting the influence that this process has on access to medication, prejudicing the achievement of universal and equalitarian access. Using a technique recommended by qualitative research, focal groups with Hiperdia users in the basic health service of Juiz de Fora, Minas Gerais, Brazil, were set up. The survey emphasizes the perception that these users have with respect to their rights related to essential medication. In this process, their beliefs, knowledge, attitudes, difficulties, fears, doubts and anxieties concerning the use of essential medication are investigated, as well as their viewpoints on the disease(s) they suffer from. Among the results obtained, it was revealed that the majority of the users of basic health units do not consider that they have rights and that access to medication as a constitutionally-assured social right is far from being implemented in the Brazilian public health service today.


A randomised phase II trial to examine feasibility of standardised, early palliative (STEP) care for patients with advanced cancer and their families [ACTRN12617000534381]: a research protocol.
Current international consensus is that 'early' referral to palliative care services improves cancer patient and family carer outcomes; however, in practice, these referrals are not routine. Uncertainty about the 'best time' to refer has been highlighted as contributing to care variation. Previous work has identified clear disease-specific transition points in the cancer illness which heralded subsequent poor prognosis (less than 6 months) and which, we contest, represent times when palliative care should be routinely introduced as a standardised approach, if not already in place, to maximise patient and carer benefit. This protocol details a trial that will test the feasibility of a novel standardised outpatient model of early palliative care [Standardised Early Palliative Care (STEP Care)] for advanced cancer patients and their family carers, with referrals occurring at the defined disease-specific evidence-based transition points.The aims of this study are to (1) determine the feasibility of conducting a definitive phase 3 randomised trial, which evaluates effectiveness of STEP Care (compared to usual best practice cancer care) for patients with advanced breast or prostate cancer or high grade glioma; (2) examine preliminary efficacy of STEP Care on patient/family caregiver outcomes, including quality of life, mood, symptoms, illness understanding and overall survival; (3) document the impact of STEP Care on quality of end-of-life care; and (4) evaluate the timing of palliative care introduction according to patients, families and health care professionals. Phase 2, multicenter, open-label, parallel-arm, randomised controlled trial (RCT) of STEP Care plus standard best practice cancer care versus standard best practice cancer care alone. The research will test the feasibility of standardised palliative care introduction based on illness transitions and provide guidance on subsequent development of phase 3 studies of integration. This will directly address the current uncertainty about palliative care timing. Australian New Zealand Clinical Trials Registry ACTRN12617000534381.


Children's thinking in the wake of Challenger.
The Challenger spacecraft explosion in 1986 offered an opportunity to study the thinking of normal children after a sudden and distant disaster, differences in thinking among children of different levels of emotional concern and different ages, and changes in their thinking over time. The authors studied six thinking patterns known to characterize childhood posttraumatic stress disorder and four additional hypothesized patterns in 153 randomly selected children of Concord, N.H. (who watched the explosion on television) and Porterville, Calif. (who heard about it later). They compared the structured-interview responses of the more involved (East Coast) and less involved (West Coast) children, of the latency-age children and the adolescents, and of the children initially (5-7 weeks after the explosion) and 14 months later. The children exhibited the 10 predictable thinking patterns. They initially defended themselves, denying the reality of the explosion. They later fantasized about it. They tried to cope by seeking additional information on their own, at home, and at school. Most children talked about Challenger, but a minority of the latency-age youngsters avoided related talk and thoughts. The adolescents experienced more paranormal thinking, philosophical changes, and negative attitudes. Over the year, omens, paranormal experiences, and Challenger-based fantasies tended to disappear, but negative views about institutions and the world's future held steady or increased. The children's thinking followed predictable patterns. A higher degree of emotional involvement (East Coast children) was strongly linked to these thinking patterns, as was being an adolescent. Distant disasters appear to set up commonalities of thought that might come to characterize certain generations of children.