Measurement of fluorescein and fluorescein monoglucuronide in the living human eye.
Fluorescein monoglucuronide is a fluorescent metabolite of fluorescein, and is 1/3 to 1/34 as fluorescent as fluorescein, depending on the wavelength of excitation. After systemic administration, fluorescein glucuronide reaches concentrations many times greater than fluorescein. In order to study the effect of fluorescein glucuronide on the measurement of ocular dynamics, we devised a technique to measure fluorescein and fluorescein glucuronide in the anterior segment of the living human eye. Concentrations of each fluorophore were determined by differential spectrofluorophotometry from measurements at excitation wavelengths of 457.9 nm and 488.0 nm. Measurements were made on normal volunteers after oral and intravenous administration of fluorescein. Fluorescein was the dominant fluorophore during the first hour, while fluorescein glucuronide became dominant after 3 hours. By 6 hours there was 10 to 30 times more fluorescein glucuronide than fluorescein in the anterior chamber after oral administration, and three to ten times more after intravenous administration. The blood aqueous diffusion coefficient kd estimated from the apparent concentration of fluorescein measured at 457.9 nm was consistently greater than kd estimated from measurements at 488.0 nm. Estimates of kd, which were made on the basis of concentrations of fluorescein determined from measurements at both wavelengths, were lower than estimates based on measurements at either wavelength. These results indicate that wavelength of excitation may influence the determination of ocular parameters when systemic fluorescein is used. Care must be taken in the interpretation of measurements when metabolites of a fluorophore can interfere with measurement of the fluorophore itself.


The depolarized Raman 2ν3 overtone of CO2: a line-mixing shape analysis.
In a recent article we showed that the 2ν(3) transition of CO(2) gives rise to a Raman spectrum that is almost entirely depolarized [M. Chrysos, I. A. Verzhbitskiy, F. Rachet, and A. P. Kouzov, J. Chem. Phys. 134, 044318 (2011)]. In the present article, we go further forward in the study of this overtone by reporting a first-principles shape analysis of its depolarized spectrum at room temperature. As a first step in our analysis, a model assuming isolated Lorentzian line shapes was applied, which at low gas densities turns out to be sufficient for qualitative conclusions. As the next step, a sophisticated approach was developed on the basis of the extended strong-collision model in order to properly account for the heavy line mixing between rotational lines. Whereas a marked deviation between model and measured spectra was observed upon application of the simpler model, striking agreement even at the highest CO(2) density was found on applying the sophisticated one. Accurate calculated data were used for the rotational line broadening coefficients without resort to arbitrary parameters. Values for the vibrational shift scaling linearly with the density of the gas are given.


Science, religion, and society: the problem of evolution in America.
American resistance to accepting evolution is uniquely high among First World countries. This is due largely to the extreme religiosity of the United States, which is much higher than that of comparably advanced nations, and to the resistance of many religious people to the facts and supposed implications of evolution. The prevalence of religious belief in the United States suggests that outreach by scientists alone will not have a huge effect in increasing the acceptance of evolution, nor will the strategy of trying to convince the faithful that evolution is compatible with their religion. Because creationism is a symptom of religion, another strategy to promote evolution involves loosening the grip of faith on America. This is easier said than done, for recent sociological surveys show that religion is highly correlated with the dysfunctionality of a society, and various measures of societal health show that the United States is one of the most socially dysfunctional First World countries. Widespread acceptance of evolution in America, then, may have to await profound social change.


Understanding self-reported importance of religion/spirituality in a North American sample of individuals at risk for familial depression: A principal component analysis.
Several studies have shown protective effects between health outcomes and subjective reports of religious/spiritual (R/S) importance, as measured by a single self-report item. In a 3-generation study of individuals at high or low familial risk for depression, R/S importance was found to be protective against depression, as indicated by clinical and neurobiological outcomes. The psychological components underlying these protective effects, however, remain little understood. Hence, to clarify the meaning of answering the R/S importance item, we employed a comprehensive set of validated scales assessing religious beliefs and experiences and exploratory factor analysis to uncover latent R/S constructs that strongly and independently correlated with the single-item measure of R/S importance. A Varimax-rotated principal component analysis (PCA) resulted in a 23-factor solution (Eigenvalue > 1; 71.5% explained variance) with 8 factors that, respectively, accounted for at least 3% of the total variance. The first factor (15.8%) was directly related to the R/S importance item (r = .819), as well as personal relationship with the Divine, forgiveness by God, religious activities, and religious coping, while precluding gratitude, altruism, and social support, among other survey subscales. The corresponding factor scores were greater in older individuals and those at low familial risk. Moreover, Spearman rank-order correlations between the R/S importance item and other subscales revealed relative consistency across generations and risk groups. Taken together, the single R/S importance item constituted a robust measure of what may be generally conceived of as "religious importance," ranking highest among a diverse latent factor structure of R/S. As this suggests adequate single-item construct validity, it may be adequate for use in health studies lacking the resources for more extensive measures. Nonetheless, given that this single item accounted for only a small fraction of the total survey variance, results based on the item should be interpreted and applied with caution.


Erratum.
In the report "Size of the chloroplast genome in Codium fragile" by M. F. Hedberg et al. (24 July, p. 445), measurements in the legend to Fig. Ia are mistakenly reported. The correct value of the contour length of the chloroplast DNA is 26.1 micrometers (54 x 10(6) daltons) and that of the scale is 5 microm.


The occurrence of polyenoic very long chain fatty acids with greater than 32 carbon atoms in molecular species of phosphatidylcholine in normal and peroxisome-deficient (Zellweger's syndrome) brain.
The n-6 tetra- and pentaenoic fatty acids with carbon chain lengths greater than 32 found in normal brain are located predominantly in a separable species of phosphatidylcholine. A similar phospholipid is found in increased amounts in the brain of peroxisome-deficient (Zellweger's syndrome) patients, but the fatty acid composition differs in that penta- and hexaenoic derivatives predominate. Our data strongly suggest that the polyenoic very long chain fatty acids are confined to the sn-1 position of the glycerol moiety, while the sn-2 position is enriched in saturated, monounsaturated and polyunsaturated fatty acids with less than 24 carbon atoms. It is postulated that these unusual molecular species of phosphatidylcholine may play some, as yet undefined, role in brain physiology.


Zinc oxide nanowire arrays for silicon core/shell solar cells.
The optics of core / shell nanowire solar cells was investigated. The optical wave propagation was studied by finite difference time domain simulations using realistic interface morphologies. The interface morphologies were determined by a 3D surface coverage algorithm, which provides a realistic film formation of amorphous silicon films on zinc oxide nanowire arrays. The influence of the nanowire dimensions on the interface morphology and light trapping was investigated and optimal dimensions of the zinc oxide nanowire were derived.


Evidence for de novo synthesis of lysophosphatidic acid in the spinal cord through phospholipase A2 and autotaxin in nerve injury-induced neuropathic pain.
We previously reported that lysophosphatidic acid (LPA) initiates nerve injury-induced neuropathic pain and its underlying mechanisms. In addition, we recently demonstrated that intrathecal injection of LPA induces de novo LPA production through the action of autotaxin (ATX), which converts lysophosphatidylcholine to LPA. Here, we examined nerve injury-induced de novo LPA production by using a highly sensitive biological titration assay with B103 cells expressing LPA1 receptors. Nerve injury caused high levels of LPA production in the ipsilateral sides of the spinal dorsal horn and dorsal roots, but not in the dorsal root ganglion, spinal nerve, or sciatic nerve. Nerve injury-induced LPA production reached its maximum at 3 h after injury, followed by a rapid decline by 6 h. The LPA production was significantly attenuated in ATX heterozygous mutant mice, whereas the concentration and activity of ATX in cerebrospinal fluid were not affected by nerve injury. On the other hand, the activities of cytosolic phospholipase A2 (cPLA2) and calcium-independent phospholipase A2 (iPLA2) were enhanced, with peaks at 1 h after injury. Both de novo LPA production and neuropathic pain-like behaviors were substantially abolished by intrathecal injection of arachidonyl trifluoromethyl ketone, a mixed inhibitor of cPLA2 and iPLA2, or bromoenol lactone, an iPLA2 inhibitor, at 1 h after injury. However, administration of these inhibitors at 6 h after injury had no significant effect on neuropathic pain. These findings provide evidence that PLA2- and ATX-mediated de novo LPA production in the early phase is involved in nerve injury-induced neuropathic pain.


Evidence for the involvement of an oxidative stress in the initiation of infection of pear by Erwinia amylovora.
Involvement of an oxidative burst, usually related to incompatible plant/pathogen interactions leading to hypersensitive reactions, was investigated with Erwinia amylovora, the causal agent of fire blight of Maloideae subfamily of Rosaceae, in interaction with pear (Pyrus communis; compatible situation) and tobacco (Nicotiana tabacum; incompatible situation). As expected, this necrogenic bacterium induced in tobacco a sustained production of superoxide anion, lipid peroxidation, electrolyte leakage, and concomitant increases of several antioxidative enzymes (ascorbate peroxidases, glutathion reductases, glutathion-S-transferases, and peroxidases), in contrast to the compatible pathogen Pseudomonas syringae pv tabaci, which did not cause such reactions. In pear leaves, however, inoculations with both the disease- and the hypersensitive reaction-inducing bacteria (E. amylovora and P. syringae pv tabaci, respectively) resulted in superoxide accumulation, lipid peroxidation, electrolyte leakage, and enzyme induction at similar rates and according to equivalent time courses. The unexpected ability of E. amylovora to generate an oxidative stress even in compatible situation was linked to its functional hrp (for hypersensitive reaction and pathogenicity) cluster because an Hrp secretion mutant of the bacteria did not induce any plant response. It is suggested that E. amylovora uses the production of reactive oxygen species as a tool to provoke host cell death during pathogenesis to invade plant tissues. The bacterial exopolysaccharide could protect this pathogen against the toxic effects of oxygen species since a non-capsular mutant of E. amylovora induced locally the same responses than the wild type but was unable to further colonize the plant.


Essential role of heparan sulfates in axon navigation and targeting in the developing visual system.
Heparan sulfate (HS) is abundant in the developing brain and is a required co-factor for many types of fibroblast growth factor (FGF) signaling in vitro. We report that some HSs, when added exogenously to the developing Xenopus optic pathway, severely disrupt target recognition causing axons from the retina to bypass their primary target, the optic tectum. Significantly, HS sidechains from a neuroepithelial perlecan variant that preferentially bind FGF-2, HS(FGF-2), cause aberrant targeting, whereas those that preferentially bind FGF-1 do not. Charge-matched fragments of HS(FGF-2) show that the mistargeting activity associates with the FGF-binding fragments. Heparitinase removal of native HSs at the beginning of optic tract formation retards retinal axon elongation; addition of FGF-2 restores axon extension but axons lose directionality. Late HS removal, after axons have extended through the tract, elicits a tectal bypass phenotype indicating a growth promoting and guidance function for native HSs. Our results demonstrate that different HS sidechains from the same core protein differentially affect axon growth in vivo, possibly due to their distinct FGF-binding preferences, and suggest that growth factors and HSs are important partners in regulating axon growth and guidance in the developing visual system.


Normalisation of EMG amplitude: an evaluation and comparison of old and new methods.
The purpose of this study was to evaluate and compare four different methods of normalising the amplitude of electromyograms (EMGs), from the biceps brachii. Five males performed isotonic contractions of the elbow flexors with an external force of 50 N, 100 N, 150 N and 200 N. These were followed by a single isometric maximal voluntary contraction (MVC) and ten isokinetic MVCs at 0.35 rad s(-1) intervals between 0.35 rad s(-1) and 3.50 rad s(-1). The processed EMGs recorded from the isotonic contractions were normalised by expressing them as a percentage of: (i) the mean (Dynamic Mean Method) and (ii) the peak EMG from the same contraction (Dynamic Peak Method), (iii) the EMG from the isometric MVC (Isometric MVC Method), and (iv) the EMG from an isokinetic MVC at the same elbow angle and angular velocity (Isokinetic MVC Method). The root mean square difference (RMSD) between the outputs of the Isokinetic MVC and Dynamic Mean methods was significantly greater (P<0.05) than between the Isokinetic MVC method and the Dynamic Peak and the Isometric MVC methods. The small (10%) difference between the Isokinetic MVC and the Isometric MVC Methods was a consequence, firstly, of the lack of difference in EMG recorded from the isometric and isokinetic MVCs and, secondly, the consistency in EMG over the range of motion and at different angular velocities of isokinetic MVC. We conclude that only the Isometric and Isokinetic MVC methods should be used to normalise the amplitude of EMGs from the biceps brachii.


Drug-drug interaction between methotrexate and levetiracetam resulting in delayed methotrexate elimination.
To report a case of delayed methotrexate (MTX) elimination while receiving concomitant levetiracetam. A 46-year-old man with relapsed osteosarcoma of the base of the skull receiving high-dose MTX tolerated his first cycle of MTX with elimination to nontoxic MTX levels (≤0.1 µmol/L) within 90 hours. After hospital discharge, the patient experienced seizures secondary to brain metastasis and started on levetiracetam, which was continued as maintenance therapy. The patient experienced delayed MTX elimination during cycles 2, 3, and 4 while receiving levetiracetam. On average, elimination to nontoxic MTX levels took 130 hours (106-144 hours). Before the fifth cycle of MTX, lorazepam was substituted for the levetiracetam. MTX was eliminated to nontoxic levels within 95 hours. During all cycles, the patient received standard supportive care and serum creatinine remained stable. No other drugs known to interact with MTX were administered. This possible drug interaction has only been reported once in the pediatric population. With a score of 6 on the Drug Interaction Probability Scale for evaluating causation of drug interactions, it is probable that the delayed MTX elimination was caused by an interaction with levetiracetam. Coadministration of levetiracetam and MTX may result in delayed elimination of MTX, increasing the likelihood of toxicity. Consideration should be given to temporarily switching from levetiracetam to another antiepileptic (ie, lorazepam) to prevent this interaction. This is particularly important in those experiencing delayed elimination with prior cycles of concomitant MTX and levetiracetam or those at greater risk for MTX toxicity.


Immunodetection of the proteins encoded by grapevine chrome mosaic nepovirus RNA2.
Fragments of the putative non-structural proteins (44K and 46K) encoded by RNA2 of grapevine chrome mosaic nepovirus (GCMV) were expressed as fusion proteins in Escherichia coli and used to raise specific antisera. All three proteins encoded by GCMV RNA2 (viral coat protein, and the 44K and 46K proteins) were detected by immunoblotting in subcellular fractions prepared from the leaves of infected Chenopodium quinoa plants, confirming a previously proposed model of the GCMV RNA2-encoded polyprotein. In addition to the 44K protein, one of the antisera detected a 90K protein presumably representing a precursor of the 44K and 46K proteins. Whereas the 44K and coat proteins could be detected in both soluble and membrane fractions, the 46K protein was found to be specific to the membrane fraction. Analysis of the kinetics of accumulation of the proteins showed that the 44K and 46K proteins were very transient whereas the coat protein was more stable and could be detected up to 21 days after inoculation. These results provide the first direct in vivo data supporting the maturation map of the GCMV RNA2 polyprotein deduced from in vitro experiments.


[The correlations between changes in coronary vascular tonus and eicosanoid formation during an immune action on the heart].
Activation of the lipoxygenase way of the arachidone acid metabolism was shown to play a major role in development of pathological processes in the heart. The data on interrelationship between the formation of eucosanoids and the character of the heart immune response to inhibition of lipoxygenase, were obtained. A correlation was found between the increase in the LTS4 in the blood and the development of prolonged constrictor responses of the coronary vessels.


Restoration of hamstring function following sciatic nerve resection at the greater sciatic foramen with reconstruction involving acellular nerve allograft and vascularized sural nerve autograft: A case report.
Segmental loss of the sciatic nerve secondary to oncologic resection or trauma is detrimental to hamstring and leg function. The diameter of this nerve and the length of its axons spanning the lower extremity create significant challenges in reconstruction and optimizing return of sensory or motor function. The purpose of this report is to describe outcomes of a free vascularized sural nerve graft to preserve hamstring function in a large proximal sciatic nerve defect beginning at the greater sciatic foramen. A 44-year-old female underwent neoadjuvant chemotherapy and radiation for treatment of a left sciatic nerve synovial cell sarcoma. The patient underwent R0 resection of the proximal left sciatic nerve resulting in a 15 cm defect. An ipsilateral vascularized sural nerve graft was used to reconstruct the medial aspect of the sciatic nerve, prioritizing the tibial division, in an effort to restore hamstring function and plantar sensation. A 5 cm allograft nerve was added to the cutaneous branches of the sural nerve graft to better span the large defect and reconstruct the lateral aspect of the nerve. The patient's postoperative course was uneventful. At 1-year follow-up, the patient showed MRC grade 4/5 strength with knee flexion and steady gait pattern with a left ankle-foot orthosis. Outcomes support the use of a single vascularized nerve graft alongside acellular nerve allograft to restore motor function in large diameter and large defect mixed nerve injuries.


Effectiveness of Pharmacological Interventions for Symptoms of Behavioral Variant Frontotemporal Dementia: A Systematic Review.
Clinical guidance on the symptomatic treatment of behavioral variant frontotemporal dementia (bvFTD) is limited. To provide a systematic review of pharmacological interventions for symptomatic treatment of bvFTD, based on the International bvFTD Criteria Consortium clinical diagnostic criteria: apathy, disinhibition, lack of empathy or sympathy, hyperorality, stereotypical behavior, and executive dysfunction. We systematically searched the PubMed, Embase, and PsycINFO databases for reports on pharmacological interventions for individuals with bvFTD, published between 1970 and 2018, using key indicators and relevant terms. Studies were included if the efficacy of the intervention in alleviating bvFTD symptoms was provided as an outcome. Due to the high prevalence of depressive symptoms in individuals with bvFTD, we also evaluated the effect of the interventions on depression. We included 23 studies-11 randomized controlled trials, eight open-label studies, one proof-of-concept study, and three case series-reporting on a total of 573 individuals. Of the 23 studies, 16 used pharmacological interventions that improved bvFTD symptoms. Based on the Neuropsychiatric Inventory, trazodone had the greatest significant reductive effect on the symptoms of bvFTD. Overall, citalopram, rivastigmine, paroxetine, and trazodone all reduced multiple symptoms, including disinhibition, hyperorality, and depression. This review provides an overview of the pharmacological interventions that can be used to treat the main bvFTD symptoms as well as a guideline for managing bvFTD. More research is needed to investigate the efficacy of pharmacological interventions for bvFTD through use of a validated outcome and a focus on the specific behavioral problems associated with bvFTD.


Instability of the metacarpophalangeal joint of the thumb. Reconstruction of the collateral ligaments using the extensor pollicis brevis tendon.
Reconstruction of the collateral ligaments of the metacarpophalangeal joint of the thumb was performed for fourteen ruptures of the ulnar and two ruptures of the radial collateral ligament, one to eighteen months after injury. The extensor pollicis brevis tendon was used to reinforce the resutured ligament. Symptoms were relieved in all cases after follow-ups ranging from one to seven years, even in two thumbs with mild degenerative arthritis of the metacarpophalangeal joint.


Rapid time-gated polarimetric Stokes imaging using photoelastic modulators.
We report a rapid time-gated full Stokes imaging approach without mechanically moving parts, which is well-suited for biomedical applications, using two photoelastic modulators (PEMs). A charge-coupled device (CCD) with microsecond time-gating capability was used to acquire the images. To synchronize the CCD with the PEMs, thus gaining signal-to-noise ratio advantage, a field programmable gate array was employed. After calibration, an evolutionary algorithm was used to select four time points from which the full Stokes vector can be recovered. Using the images taken by the camera at these four times (in ~80 ms), the images of the full Stokes vectors of different incident polarization states were accurately derived.


Impact of increased ventilation on indoor temperature and malaria mosquito density: an experimental study in The Gambia.
In sub-Saharan Africa, cooler houses would increase the coverage of insecticide-treated bednets, the primary malaria control tool. We examined whether improved ventilation, using windows screened with netting, cools houses at night and reduces malaria mosquito house entry in The Gambia. Identical houses were constructed, with badly fitting doors the only mosquito entry points. Two men slept in each house and mosquitoes captured using light traps. First, temperature and mosquito density were compared in four houses with 0, 1, 2 and 3 screened windows. Second, carbon dioxide (CO2), a major mosquito attractant, was measured in houses with (i) no windows, (ii) screened windows and (iii) screened windows and screened doors. Computational fluid dynamic modelling captured the spatial movement of CO2. Increasing ventilation made houses cooler, more comfortable and reduced malaria mosquito house entry; with three windows reducing mosquito densities by 95% (95%CI = 90-98%). Screened windows and doors reduced the indoor temperature by 0.6°C (95%CI = 0.5-0.7°C), indoor CO2 concentrations by 31% between 21.00 and 00.00 h and malaria mosquito entry by 76% (95%CI = 69-82%). Modelling shows screening reduces CO2 plumes from houses. Under our experimental conditions, cross-ventilation not only reduced indoor temperature, but reduced the density of house-entering malaria mosquitoes, by weakening CO2 plumes emanating from houses.


Single chloride channels from Torpedo electroplax. Activation by protons.
Single-channel fluctuations of a chloride-specific channel from Torpedo californica electroplax were studied with high current and time resolution. Channels were incorporated into virtually solvent-free planar bilayer membranes formed from phospholipid monolayers, and the substructure of the open channel was analyzed. The single channel displays three well-defined substates of conductances 0, 10, and 20 pS in 200 mM Cl-. These three substates are interpreted in terms of a dimeric channel complex composed of two identical "protochannels" gating independently in parallel on a time scale of milliseconds, but coupled together by a bursting process on a time scale of seconds. The probability of forming an open protochannel is voltage dependent and is increased strongly as aqueous pH is lowered. Variations of pH are effective only on the same side of the bilayer as the addition of electroplax vesicles. The dependence of single-channel kinetics on pH and voltage lead to a minimal four-state model in which both open and closed states can be protonated on a residue that changes its pK from 6 to 9 upon opening of the protochannel.


Interventions for helping patients to follow prescriptions for medications.
People who are prescribed self-administered medications typically take less than half the prescribed doses. Efforts to assist patients with adherence to medications might improve the benefits and efficiency of health care, but also might increase its adverse effects. To update a review summarising the results of randomised controlled trials (RCTs) of interventions to help patients follow prescriptions for medications for medical problems, focusing on trials that measured both adherence and clinical outcomes. Computerised searches to August 2001 in MEDLINE, CINAHL, The Cochrane Library, International Pharmaceutical Abstracts (IPA) PsychInfo, and Sociofile; bibliographies in articles on patient adherence; articles in the reviewers' personal collections; and contact with authors of original and review articles on the topic. Articles were selected if they reported an unconfounded RCT of an intervention to improve adherence with prescribed medications, measuring both medication adherence and treatment outcome, with at least 80% follow-up of each group studied and, for long-term treatments, at least six months follow-up for studies with positive initial findings. Information on study design features, interventions and controls, and results were extracted by one reviewer and confirmed by at least one other reviewer. The studies were too disparate to warrant meta-analysis. For short-term treatments, one of three interventions reported in three RCTs showed an effect on both adherence and clinical outcome. Eighteen of 36 interventions for long-term treatments reported in 30 RCTs were associated with improvements in adherence, but only 16 interventions led to improvements in treatment outcomes. Almost all of the interventions that were effective for long-term care were complex, including combinations of more convenient care, information, reminders, self-monitoring, reinforcement, counselling, family therapy, and other forms of additional supervision or attention by a health care provider (physician, nurse, pharmacist or other). Even the most effective interventions did not lead to large improvements in adherence and treatment outcomes. Two studies showed that telling patients about adverse effects of treatment did not affect their adherence. The full benefits of medications cannot be realised at currently achievable levels of adherence. Current methods of improving adherence for chronic health problems are mostly complex and not very effective. Innovations to assist patients to follow medication prescriptions are needed.


A tool for filtering information in complex systems.
We introduce a technique to filter out complex data sets by extracting a subgraph of representative links. Such a filtering can be tuned up to any desired level by controlling the genus of the resulting graph. We show that this technique is especially suitable for correlation-based graphs, giving filtered graphs that preserve the hierarchical organization of the minimum spanning tree but containing a larger amount of information in their internal structure. In particular in the case of planar filtered graphs (genus equal to 0), triangular loops and four-element cliques are formed. The application of this filtering procedure to 100 stocks in the U.S. equity markets shows that such loops and cliques have important and significant relationships with the market structure and properties.


Accessing ART in Malawi while living in South Africa - a thematic analysis of qualitative data from undocumented Malawian migrants.
The majority of international migrants from Malawi to South Africa are undocumented, and some of them are on ART. This study explored how these migrants manage to access ART. Qualitative data were collected using open-ended questions in semi-structured interviews. 23 returned undocumented Malawian migrants from South Africa participated in the study. Also, key informant discussions were held with three health workers. Data collection took place in April and May 2015 at a rural village of Namwera in Mangochi district in southern Malawi. Interviews were audio-recorded, transcribed and translated into English for thematic analysis. The guardians collected ART from health facilities in Malawi on behalf of the migrants. The guardians sent ART through truck and bus drivers to the migrants in South Africa. The migrants shared their ART. Others bought ART from the 'street pharmacies'. Others accessed ART from South African health facilities through the help of their South African friends. There are risks to dispensing ART to the migrants who do not themselves present at health facilities. There is value to more regular contacts between clients and health service system that is compromised by alternative strategies. It is better to deliver ART services in South Africa to the undocumented migrants.


Analysis of promoter targets for Escherichia coli transcription elongation factor GreA in vivo and in vitro.
Transcription elongation factor GreA induces nucleolytic activity of bacterial RNA polymerase (RNAP). In vitro, transcript cleavage by GreA contributes to transcription efficiency by (i) suppressing pauses and arrests, (ii) stimulating RNAP promoter escape, and (iii) enhancing transcription fidelity. However, it is unclear which of these functions is (are) most relevant in vivo. By comparing global gene expression profiles of Escherichia coli strains lacking Gre factors and strains expressing either the wild type (wt) or a functionally inactive GreA mutant, we identified genes that are potential targets of GreA action. Data analysis revealed that in the presence of chromosomally expressed GreA, 19 genes are upregulated; an additional 105 genes are activated upon overexpression of the wt but not the mutant GreA. Primer extension reactions with selected transcription units confirmed the gene array data. The most prominent stimulatory effect (threefold to about sixfold) of GreA was observed for genes of ribosomal protein operons and the tna operon, suggesting that transcript cleavage by GreA contributes to optimal expression levels of these genes in vivo. In vitro transcription assays indicated that the stimulatory effect of GreA upon the transcription of these genes is mostly due to increased RNAP recycling due to facilitated promoter escape. We propose that transcript cleavage during early stages of initiation is thus the main in vivo function of GreA. Surprisingly, the presence of the wt GreA also led to the decreased transcription of many genes. The mechanism of this effect is unknown and may be indirect.


How patients want to engage with their personal health record: a qualitative study.
To assess factors related to use and non-use of a sophisticated interactive preventive health record (IPHR) designed to promote uptake of 18 recommended clinical preventive services; little is known about how patients want to use or be engaged by such advanced information tools. Descriptive and interpretive qualitative analysis of transcripts and field notes from focus groups of the IPHR users and of patients who were invited but did not use the IPHR (non-users). Grounded theory techniques were then applied via an editing approach for key emergent themes. Primary care patients in eight practices of the Virginia Ambulatory Care Outcomes Research Network (ACORN). Three focus groups involved a total of 14 IPHR users and two groups of non-users totalled 14 participants. For themes identified (relevance, trust and functionality) participants indicated that endorsement and use of the IPHR by their personal clinician was vital. In particular, participants' comments linked the IPHR use to: (1) integrating the IPHR into current care, (2) promoting effective patient-clinician encounters and communication and (3) their confidence in the accuracy, security and privacy of the information. In addition to patients' stated desires for advanced functionality and information accuracy and privacy, successful adoption of the IPHRs by primary care patients depends on such technology's relevance, and on its promotion via integration with primary care practices' processes and the patient-clinician relationship. Accordingly, models of technological success and adoption, when applied to primary care, may need to include the patient-clinician relationship and practice workflow. These findings are important for healthcare providers, the information technology industry and policymakers who share an interest in encouraging patients to use personal health records. Clinicaltrials.gov identifier: NCT00589173.


Management of metastatic germ cell tumors.
Germ cell tumors are the most common solid malignancies to affect young adult men and incidence is increasing worldwide. The introduction of cisplatin-based combination chemotherapy in the late 1970s resulted in a dramatic improvement in the prognosis of patients with metastatic germ cell tumors, and overall cure rates in this group now exceed 80%. Randomized clinical trials and prognostic factors have guided treatment strategies over the last two decades. Clinical research for most advanced adult malignant diseases is driven by the need to improve response rates and prolong survival. The remarkable chemotherapy sensitivity of testicular germ cell cancers has revolutionized treatment results in the last 20 years, substantially altering the landscape in these tumors with greater than 80% cure rates routinely achievable. Furthermore, it seems unlikely that modifications in dose or scheduling of currently available drugs will improve the outlook for the small minority of poor-prognosis metastatic disease cases. Failing this there are real changes in our approach to these tumors that could enhance outcomes, including better supportive care, better service delivery and better public education. The choice of different platinum, and total dose of etoposide and bleomycin and their impact on the clinical outcome in context of various trials is discussed in detail in this review.


Brain Connectivity Measures Improve Modeling of Functional Outcome After Acute Ischemic Stroke.
Background and Purpose- The ability to model long-term functional outcomes after acute ischemic stroke represents a major clinical challenge. One approach to potentially improve prediction modeling involves the analysis of connectomics. The field of connectomics represents the brain's connectivity as a graph, whose topological properties have helped uncover underlying mechanisms of brain function in health and disease. Specifically, we assessed the impact of stroke lesions on rich club organization, a high capacity backbone system of brain function. Methods- In a hospital-based cohort of 41 acute ischemic stroke patients, we investigated the effect of acute infarcts on the brain's prestroke rich club backbone and poststroke functional connectomes with respect to poststroke outcome. Functional connectomes were created using 3 anatomic atlases, and characteristic path-length (L) was calculated for each connectome. The number of rich club regions affected were manually determined using each patient's diffusion weighted image. We investigated differences in L with respect to outcome (modified Rankin Scale score; 90 days) and the National Institutes of Health Stroke Scale (NIHSS; early: 2-5 days; late: 90-day follow-up). Furthermore, we assessed the effect of including number of rich club regions and L in outcome models, using linear regression and assessing the explained variance (R2). Results- Of 41 patients (mean age [range]: 70 [45-89] years), 61% were male. Lower L was generally associated with better outcome. Including number of rich club regions in the backward selection models of outcome, R2 increased between 1.3- and 2.6-fold beyond that of traditional markers (age and acute lesion volume) for NIHSS and modified Rankin Scale score. Conclusions- In this proof-of-concept study, we showed that information on network topology can be leveraged to improve modeling of poststroke functional outcome. Future studies are warranted to validate this approach in larger prospective studies of outcome prediction in stroke.


Interface Engineering of Flexible Piezoresistive Sensors via Near-Field Electrospinning Processed Spacer Layers.
The interface contact between the active material and its neighboring metal electrodes dominates the sensing response of mainstream high-sensitivity piezoresistive pressure sensors. However, the properties of such interface are often difficult to control and preserve owing to the limited strategies to precisely engineer the surface structure and mechanical property of the active material. Here, a top-down fabrication method to create a grid-like polyurethane fiber-based spacer layer at the interface between a piezoresistive layer and its contact electrodes is proposed. The tuning of the period and thickness of the spacer layer is conveniently achieved by a programmable near-field electrospinning process, and the influence of the spacer structure on the sensing performance is systematically investigated. The sensor with the optimized spacer layer shows a widened sensing range (230 kPa) while maintaining a high sensitivity (1.91 kPa-1 ). Furthermore, the output current fluctuation of the sensors during a 74 000-cycle test is drastically reduced from 14.28% (without a spacer) to 3.63% (with a spacer), demonstrating greatly enhanced long-term reliability. The new near-field electrospinning-based strategy is capable of tuning sensor responses without changing the active material, providing a universal and scalable path to engineer the performances of contact-dominant sensors.


The design of a decision aid about diabetes medications for use during the consultation with patients with type 2 diabetes.
To describe the process used to develop a medication choice decision aid (DA) for patients with type 2 diabetes. We developed the DA through active collaboration with patients, clinicians, and designers, direct observations of clinical encounters, literature review, and collaborative development of design criteria. Insights from these processes informed the iterative creation of prototypes that were reviewed and field tested in actual consultations. The goal of the DA was to facilitate a conversation between the clinician and the patient about diabetes medication options. Four iterations of the DA were developed and field-tested before arriving at issue cards that organized the data for five medications around glucose control, hypoglycemia, weight changes, daily routine, self-monitoring and side effects. These cards successfully generated conversations during consultations. An ongoing clinical trial will determine if this DA affects patient adherence and outcomes. A collaboratively developed DA designed to create a conversation about diabetes medications may lead to more patient-centered treatment choices. If effective, this DA could replace disease-centered treatment algorithms for patient-centered conversations that enhance the management of patients with type 2 diabetes.


[Work capacity evaluation within Social Security].
Incapacity for work is not a medical but an economic concept. The difference between the earnings somebody could have had without health problems, and the possible earnings with health problems determine the degree of incapacity for work. Social security physicians and vocational experts together judge the degree of incapacity for work in discussion with the client. The physician judges the general possibilities of the client. The vocational expert selects possible jobs the client should be able to do. The disability allowances are relatively low. Treating physicians should take into account this and other negative aspects of incapacity for work.


The relative sensitivity of sperm, eggs and embryos to copper in the blue mussel (Mytilus trossulus).
Copper, an essential element, is toxic at elevated concentrations, and as a result of anthropogenic activities is becoming increasingly prevalent in marine environments. In this study, we examined the effects of copper on early life stages of the blue mussel, Mytilus trossulus. We assessed the impacts of increasing copper concentrations on embryo development, egg viability, sperm fertilization capacity and, in particular, on sperm swimming speed using computer-assisted sperm analysis. Sensitivity to copper followed the pattern: embryos > sperm > eggs. A dramatic increase in abnormal embryo development was observed following exposure to copper concentrations exceeding 10 microg/L. Sperm swimming speeds decreased significantly when exposed to 100 microg/L of copper, but lower doses did not influence sperm swimming speed. Copper exposure (at any tested concentration) did not affect sperm flagellum length, or alter egg viability. Based on our results, we suggest that exposure of sperm to copper may interfere with mitochondrial activity, which reduces sperm swimming speed during the extended duration of sperm motility in blue mussel.


Automated correction of room location errors in anesthesia information management systems.
Anesthesia information management systems (AIMS) and operating room information management systems (ORIMS) are both used in operating rooms (OR). Anesthesia providers use AIMS to document their care in near real-time, including milestone events, and these systems automatically record vital signs from patient monitors. Circulating nurses use ORIMS primarily to document procedural information. Because of automatic documentation, AIMS would be ideal platforms for OR managerial decision support if the correct locations of cases in progress were known accurately. Trust is diminished if recommendations are poor. We compiled room location error rates from prior analyses of ORIMS data. Data from 24 consecutive 4-wk periods (45,459 cases) were analyzed from one hospital where both ORIMS and AIMS data were available. The actual location of cases was inferred from the physical location of the workstation recording the majority of pulse oximetry saturations. These were compared to the listed location in the AIMS and the final corrected location in the ORIMS. The scheduled and final ORIMS locations were compared to determine how often location changes were updated before the start of anesthesia. The location of cases was inferred in near real-time by using the identifier of the AIMS workstation transmitting pulse oximetry saturated electrocardiogram heart rate, and end-tidal CO(2) partial pressures. Location error rates ranged from 0% to 7.5% at 42 hospitals. The error rate at the studied hospital was just 0.4%, showing that the hospital was suitable for investigation. The 0.4% error rate was based on cases listed as overlapping in the same OR, and thus under-estimated the actual error rate in the ORIMS (1.0%). With education, there was a decrease in the moved cases in the ORIMS whose location was not changed before the start of anesthesia (9.3%-2.0%, P < 10(-5)). Despite the significant improvement (P < 10(-5)) in the error rate between the AIMS listed and actual locations, the residual AIMS real-time error rate was 4.1% of cases. Use of vital sign data reduced errors to <0.1%. Education can only modestly improve the accuracy of OR locations in ORIMS and AIMS data. The actual location can be inferred, either in near real-time or afterwards, from the AIMS workstation transmitting vital sign data. This addresses the fundamental problem of cases having more than one location during the course of anesthetic care (e.g., holding area, block room, OR, and postanesthesia care unit), which cannot be determined from scheduled ORIMS or listed AIMS locations.


Patient engagement and prescription opioid use in perioperative pain management.
To examine (1) patient perceptions regarding their engagement and the engagement of their families in perioperative pain management, (2) demographic and clinical characteristics associated with perceived patient and family engagement, and (3) the association between perceived patient and family engagement and patient outcomes. A prospective, observational study. The Personalized Pain Program (PPP) at the Johns Hopkins Hospital in Baltimore, Maryland. Patients having more than one visit to the PPP. n/a. Since the inception of the PPP, patients were surveyed prior to each clinic visit to assess their pain severity and interference using the Brief Pain Inventory. Starting August 22, 2018, two additional questions were added to the survey to assess patient perceptions of their engagement and the engagement of their families in perioperative pain management. In addition, electronic medical records were reviewed to collect data on daily opioid consumption during the first and last PPP visits presurgery and post-surgery. The final analysis included 511 survey responses from 155 patients. Perceived engagement of the patient in perioperative pain management improved over time (p < .001) and was significantly associated with reduction in prescription opioid consumption after surgery (coef = 12.7, SE = 5.8, p = .031). Surgical patients and their family members should be actively engaged in perioperative pain management to improve prescription opioid use and the quality and safety of perioperative care.


[Pharmacological correction of low cardiac output syndrome in hemofiltration].
Low cardiac output was corrected by catecholamines in the course of hemofiltration (HF) administered to 37 patients with multiple organ failure after surgery. Catecholamines (adrenaline hydrochloride, noradrenaline hydrotartrate, dopamine hydrochloride, and dobutamine hydrochloride) were used as monotherapy or in various combinations (two, three, or four drugs). Ninety percent of patients with low cardiac output subjected to HF were administered combined catecholamine therapy. Catecholamines provided the hemodynamic stability of HF in patients with low cardiac output. The frequency of noradrenaline administrations and its mean doses were reliably decreased in the course of HF, whereas the mean doses of adrenaline, dopamine, and dobutamine remained virtually the same.


Electrically evoked cubic distortion product otoacoustic emissions from gerbil cochlea.
It has been demonstrated that electrical stimulation of the cochlear partition results in basilar membrane vibration and otoacoustic emissions. Electromotility of stimulated outer hair cells (OHCs) elicits the electrically evoked otoacoustic emissions (EEOAEs). Although electrically evoked upper and lower sideband distortion products (DPs) have been reported, electrically evoked cubic DP has not been investigated. Since the acoustically evoked cubic DP is the most commonly used otoacoustic measure of cochlear nonlinearity, this study tested whether electrical stimuli evoke a cubic DP otoacoustic emission. An electrical current containing the frequency component f1 and f2 (f1 < f2) was delivered to the round window niche of the gerbil, and electrically induced sound pressure change in the external ear canal was measured with a microphone. It was found that, in addition to f1 and f2 EEOAEs, cubic DP (2f1-f2) and other emissions at 3f1-2f2, 2f2-f1 and f2-f1 frequencies are electrically evoked. The electrically evoked cubic DP growth is similar to that of an acoustically evoked cubic DP. An electrical stimulus at f1 or f2 and an acoustic stimulus at f2 or f1 produce an identical cubic DP to that evoked by two electrical stimuli and/or two acoustic stimuli at f1 and f2 frequencies. An acoustic suppressor at a frequency near f2 can completely suppress an electrically evoked cubic DP emission. These data demonstrate that DPs can be provoked by a complex two frequency electrical current delivered to the round window niche. These stimuli elicit mechanical vibrations, from stimulated OHCs near the round window, which propagate apically toward their characteristic frequency places on the basilar membrane, and produce combination DPs. Electrically evoked cubic DPs appear to be produced by the same nonlinear mechanism that generates acoustically evoked DPs.


An efficient peak assignment algorithm for two-dimensional NMR correlation spectra of framework structures.
An algorithm is described for efficiently assigning the resonances in NMR spectra to the inequivalent atoms in the structure under study based on the information in two-dimensional NMR correlation experiments and the 'connectivities' known from the structure. The algorithm, which is based on basic graph theory concepts, finds all possible assignments sets which are consistent with the experimentally observed correlations and known connectivities in a very efficient manner. It is designed to deal with less than ideal experimental data in which there may be overlapping peaks and uncertainty about the presence or absence of correlation peaks. The algorithm was primarily developed for assigning the peaks in the high-resolution solid-state 29Si MAS NMR spectra of highly siliceous zeolites based on two-dimensional 29Si INADEQUATE spectra and is described using the zeolites ZSM-12 and ZSM-5 as working examples. Peak assignment for zeolite frameworks is particularly challenging since there is often little or no information to distinguish peaks from one another such as characteristic chemical shifts, relative intensities, or different relaxation times. The algorithm may be a useful tool for easily, reliably, and efficiently working out peak assignments from other types of correlation experiments on other types of systems and further examples are provided in the Supplementary material.


Sox9 sustains chondrocyte survival and hypertrophy in part through Pik3ca-Akt pathways.
During endochondral bone formation, Sox9 expression starts in mesenchymal progenitors, continues in the round and flat chondrocyte stages at high levels, and ceases just prior to the hypertrophic chondrocyte stage. Sox9 is important in mesenchymal progenitors for their differentiation into chondrocytes, but its functions post-differentiation have not been determined. To investigate Sox9 function in chondrocytes, we deleted mouse Sox9 at two different steps after chondrocyte differentiation. Sox9 inactivation in round chondrocytes resulted in a loss of Col2a1 expression and in apoptosis. Sox9 inactivation in flat chondrocytes caused immediate terminal maturation without hypertrophy and with excessive apoptosis. Inactivation of Sox9 in the last few cell layers resulted in the absence of Col10a1 expression, suggesting that continued expression of Sox9 just prior to hypertrophy is necessary for chondrocyte hypertrophy. SOX9 knockdown also caused apoptosis of human chondrosarcoma SW1353 cells. These phenotypes were associated with reduced Akt phosphorylation. Forced phosphorylation of Akt by Pten inactivation partially restored Col10a1 expression and cell survival in Sox9(floxdel/floxdel) mouse chondrocytes, suggesting that phosphorylated Akt mediates chondrocyte survival and hypertrophy induced by Sox9. When the molecular mechanism of Sox9-induced Akt phosphorylation was examined, we found that expression of the PI3K subunit Pik3ca (p110α) was decreased in Sox9(floxdel/floxdel) mouse chondrocytes. Sox9 binds to the promoter and enhances the transcriptional activities of Pik3ca. Thus, continued expression of Sox9 in differentiated chondrocytes is essential for subsequent hypertrophy and sustains chondrocyte-specific survival mechanisms by binding to the Pik3ca promoter, inducing Akt phosphorylation.


Nanostructured lipid carriers (NLC) based controlled release topical gel of clobetasol propionate: design and in vivo characterization.
Nanostructured lipid carrier (NLC)-based gel was developed as a potential topical system for clobetasol propionate (CP) topical delivery for the treatment of eczema. The characterizations of the prepared NLC formulation for topical application on the skin were assessed by means of morphology (SEM), particle size distribution, zeta potential analysis, drug entrapment efficiency, and in vitro drug release studies to select the optimized NLC formulation. The optimized NLC formulation encompasses particle size of 137.9 nm with -20.5 mV zeta potential and 0.224 polydispersity index which indicates good stability of NLC dispersion. NLC formulation showed a good entrapment efficiency of 78.5 % ± 0.03 with cumulative in vitro release 85.42 % up to 24 h. The optimized NLC formulation was suitably gelled and characterized for rheology, drug content, ex vivo drug permeation studies, and drug release kinetics studies. The permeation study revealed that the permeability parameters like steady-state flux (Jss), permeability coefficient (Kp), and enhancement ratio were significantly higher for NLC-based gel formulation as compared to marketed formulation of clobetasol propionate. The value of r (2) (Korsmeyer-Peppas equation) indicated good linearity showing anomalous (non-Fickian) diffusion viz. drug release is controlled by more than one process, i.e., superposition of both phenomenon, the diffusion controlled as well as swelling controlled release. The anti-inflammatory activity of NLC gel via paw oedema technique showed a rapid onset of action, as well as a prolonged duration of action as compared with the marketed gel.


Activation and binding of peroxisome proliferator-activated receptor gamma by synthetic cannabinoid ajulemic acid.
Ajulemic acid (AJA) is a synthetic analog of the tetrahydrocannabinol (THC) metabolite THC-11-oic acid; THC is a major active ingredient of the drug marijuana derived from the plant cannabis. AJA has potent analgesic and anti-inflammatory activity without the psychotropic action of THC. Unlike the nonsteroidal anti-inflammatory drugs, AJA is not ulcerogenic at therapeutic doses, making it a promising anti-inflammatory drug. However, the mechanism of AJA action remains unknown. Here we report that AJA binds directly and specifically to the peroxisome proliferator-activated receptor gamma (PPARgamma), a pharmacologically important member of the nuclear receptor superfamily. Functional assay indicates that AJA activates the transcriptional activity of both human and mouse PPARgamma at pharmacological concentrations. Activation of PPARgamma by AJA requires the AF-2 helix of the receptor, suggesting that AJA activates PPARgamma through the ligand-dependent AF-2 function. AJA binding consistently enables PPARgamma to recruit nuclear receptor coactivators. In addition, we show that AJA inhibits interleukin-8 promoter activity in a PPARgamma-dependent manner, suggesting a link between the anti-inflammatory action of AJA and the activation of PPARgamma. Finally, we find that AJA treatment induces differentiation of 3T3 L1 fibroblasts into adipocytes, a process mediated by PPARgamma. Together, these data indicate that PPARgamma may be a molecular target for AJA, providing a potential mechanism for the anti-inflammatory action of AJA, and possibly other cannabinoids. These studies also implicate other potential therapeutic actions of AJA through PPARgamma activation in multiple signaling pathways.


Spinal Cord Injury and Autonomic Dysreflexia: A Case Report on an Overlooked Complication of Spinal Cord Injury.
Autonomic dysreflexia (AD) is a life-threatening condition that affects patients with spinal cord injuries (SCI) at the sixth thoracic vertebrae (T6) and above due to a noxious stimulus below the level of spinal cord injury. This is a case report of a 48-year-old man with a history of paraplegia T1 (American Spinal Injury Association Impairment Scale - ASIA A) spinal cord injury due to a road traffic accident 16 years ago who presented with recurrent episodes of hypertension, sweating, bradycardia, and hypothermia. Previous hospitalizations suggested that his symptoms were caused by sepsis from a urinary tract infection; however, further assessment revealed that his symptoms were consistent with untreated and undiagnosed autonomic dysreflexia. This case report provides an overview of AD, including its distinctive presentation, etiology, pathophysiology, and management. Autonomic dysreflexia can be a life-threatening condition associated with spinal cord injury patients at the T6 level and above due to various noxious stimuli below the neurological level of injury. Bladder distension appears to be the trigger in most of the cases reported. AD can be easily missed by medical staff unfamiliar with this condition. Patient and healthcare provider education and a thorough evaluation are essential for diagnosis and management.


Role of seed coat in imbibing soybean seeds observed by micro-magnetic resonance imaging.
Imbibition of Japanese soybean (Glycine max) cultivars was studied using micro-magnetic resonance imaging (MRI) in order to elucidate the mechanism of soaking injury and the protective role of the seed coat. Time-lapse images during water uptake were acquired by the single-point imaging (SPI) method at 15-min intervals, for 20 h in the dry seed with seed coat, and for 2 h in seeds with the seed coat removed. The technique visualized water migration within the testa and demonstrated the distortion associated with cotyledon swelling during the very early stages of water uptake. Water soon appeared in the testa and went around the dorsal surface of the seed from near the raphe, then migrated to the hilum region. An obvious protrusion was noted when water reached the hypocotyl and the radicle, followed by swelling of the cotyledons. A convex area was observed around the raphe with the enlargement of the seed. Water was always incorporated into the cotyledons from the abaxial surfaces, leading to swelling and generating a large air space between the adaxial surfaces. Water uptake greatly slowed, and the internal structures, veins and oil-accumulating tissues in the cotyledons developed after the seed stopped expanding. When the testa was removed from the dry seeds before imbibition, the cotyledons were severely damaged within 1.5 h of water uptake. The activation of the water channel seemed unnecessary for water entry into soybean seeds, and the testa rapidly swelled with steeping in water. However, the testa did not regulate the water incorporation in itself, but rather the rate at which water encountered the hypocotyl, the radicle, and the cotyledons through the inner layer of the seed coat, and thus prevented the destruction of the seed tissues at the beginning of imbibition.


A novel continuous-time neural network for realizing associative memory.
A novel neural network is proposed in this paper for realizing associative memory. The main advantage of the neural network is that each prototype pattern is stored if and only if as an asymptotically stable equilibrium point. Furthermore, the basin of attraction of each desired memory pattern is distributed reasonably (in the Hamming distance sense), and an equilibrium point that is not asymptotically stable is really the state that cannot be recognized. The proposed network also has a high storage as well as the capability of learning and forgetting, and all its components can be implemented. The network considered is a very simple linear system with a projection on a closed convex set spanned by the prototype patterns. The advanced performance of the proposed network is demonstrated by means of simulation of a numerical example.


[Post-infarction left ventricular free wall rupture].
We report four cases of subacute left ventricular free wall rupture after myocardial infarction successfully treated with emergency surgery. Some aspects dealing with clinical presentation, diagnosis and treatment are discussed.


Writing and reading methodology for biochips with sub-100-nm chemical patterns based on near-field scanning optical microscopy.
This paper demonstrates a writing and reading methodology, which allows both to create and to detect sub-100-nm carboxyl-terminated patterns on light-transmissive quartz substrates by the same instrumental system. Such a technique, capable of creating carboxyl-terminated nanopatterns, offers several benefits for the miniaturization of biochips, since the carboxyl-terminated nanopatterns allow the easy immobilization of biomolecules by amide bond formation. As a consequence, increasingly miniaturized biochips require suitable analytical methods for the detection of nanopatterns. In our approach, carboxyl-terminated nanopatterns of down to 80 nm width were created using a photolabile silane coupling agent and a UV laser coupled to a near-field scanning optical microscope (NSOM). The same NSOM system was then used in a next step to detect the fabricated carboxyl-terminated nanopatterns after modification with a fluorescent label. Furthermore, as a first step towards biochip applications, the successful immobilization of several biomolecules, such as streptavidin, IgG and DNA on carboxyl-terminated nanopatterns was demonstrated. We have shown that our approach has the potential to lead to a new bioanalytical method, which enables one to write and to read biochips on a sub-100-nm scale by the same system.


[Regulation of alkaline exoprotease and cephalosporin C synthesis in Acremonium chrysogenum by different carbon and nitrogen sources].
The synthesis of exoproteases and cephalosporin C in Acremonium chrysogenum is repressed by easily assimilated forms of nitrogen and carbon according to the type of nitrogen metabolism repression and catabolism inhibition. Glucose and ammonium salts inhibited the mycelium fragmentation and prevented formation of conidia. Amino acids had a diverse effect on the synthesis of the proteases and antibiotic. Methionine played the role of an inductor of the synthesis of alkaline exoproteases, cephalosporin C and the mycelium fragmentation into arthrospores.


Strong species differences in life history do not predict oxidative stress physiology or sensitivity to an environmental oxidant.
Species typically align along a fast-slow life-history continuum, yet it is not clear to what extent oxidative stress physiology can be integrated with this continuum to form a 'pace-of-life syndrome', especially so in invertebrates. This is important, given the assumed role of oxidative stress in mediating life-history trade-offs, and the prediction that species with a faster pace should be more vulnerable to oxidative stress. We tested whether a species' life-history pace, here represented by its growth rate, can predict species-level differentiation in physiology and sensitivity to oxidative stress. Therefore, we exposed four species of Ischnura damselflies that strongly align along a fast-slow life-history continuum to different levels of ultraviolet (UV) radiation. We measured an extended set of physiological traits linked to the pace-of-life: standard metabolic rate, oxidative stress physiology (antioxidant enzymes and oxidative damage) and defence/condition traits (investment in immune function, energy storage and structural defence). Despite strong species differences in growth rate and physiology, growth rate did not predict species-level differentiation in physiology. Hence there was no support for the integration of metabolic rate, oxidative stress physiology or defence/condition traits into a species-level syndrome. Ultraviolet exposure affected nearly all traits: it reduced growth rate and increased metabolic rate, affected all oxidative stress physiology traits and increased the two defence traits (immune function, and melanin content). Nevertheless, the pace-of-life based on growth rate did not predict sensitivity to UV. Instead, the observed pattern of investment in structural UV defence (melanin) might have reduced the need for enzymatic antioxidant defence, this way potentially decoupling the covariation between the life-history pace and oxidative stress physiology. The absence of an integrated axis of life-history and physiological variation indicates no major constraints for the evolution of these traits among the studied damselfly species. Our study highlights that ecological differences between species may decouple covariation between species' life-history pace and their physiology, as well as their sensitivity to environmental stressors.


EXPLORING SPIRITUAL WELL-BEING AMONG SURVIVORS OF COLORECTAL AND LUNG CANCER.
This descriptive, exploratory study is part of a larger observational study of the quality of cancer care delivered to population-based cohorts of newly-diagnosed patients with lung and colorectal cancer. The current study explores the role of spiritual well-being in adjustment to life after the cancer diagnosis, utilizing the Functional Assessment of Chronic Illness Therapy - Spiritual Well-being - Expanded (FACIT-Sp-Ex) Scale. Survey data collected from 304 newly-diagnosed cancer survivors were analyzed to explore important aspects of spirituality, such as sense of meaning in one's life, harmony, peacefulness, and a sense of strength and comfort from one's faith. Spiritual well-being scores, particularly meaning/peace, were statistically significant for African Americans, women and colorectal cancer survivors. These findings amplify a need for oncology social workers and other practitioners to assess spiritual well-being in cancer survivors in an effort to strengthen psychosocial treatment plans. Implications for social work practice and research are discussed.


Biogeography of bacterioplankton in the tropical seawaters of Singapore.
Knowledge about the biogeography of marine bacterioplankton on the global scale in general and in Southeast Asia in particular has been scarce. This study investigated the biogeography of bacterioplankton community in Singapore seawaters. Twelve stations around Singapore island were sampled on different schedules over 1 year. Using PCR-DNA fingerprinting, DNA cloning and sequencing, and microarray hybridization of the 16S rRNA genes, we observed clear spatial variations of bacterioplankton diversity within the small area of the Singapore seas. Water samples collected from the Singapore Strait (south) throughout the year were dominated by DNA sequences affiliated with Cyanobacteria and Alphaproteobacteria that were believed to be associated with the influx of water from the open seas in Southeast Asia. On the contrary, water in the relatively polluted Johor Strait (north) were dominated by Betaproteobacteria, Gammaproteobacteria, and Bacteroidetes and that were presumably associated with river discharge and the relatively eutrophic conditions of the waterway. Bacterioplankton diversity was temporally stable, except for the episodic surge of Pseudoalteromonas, associated with algal blooms. Overall, these results provide valuable insights into the diversity of bacterioplankton communities in Singapore seas and the possible influences of hydrological conditions and anthropogenic activities on the dynamics of the communities.


Application of the EU-SILC 2011 data module "intergenerational transmission of disadvantage" to robust analysis of inequality of opportunity.
This data article describes the original data, the sample selection process and the variables used in Andreoli and Fusco (Andreoli and Fusco, 2019) to estimate gap curves for a sample of European countries. Raw data are from 2011 roaster of EU-SILC, cross-sectional sample of module "intergenerational transmission of disadvantage". This article reports descriptive statistics of the using sample. It also discusses the algorithm adopted to estimate the main effects and details the content of additional Stata files stored on the online repository. These additional files contain raw estimates from bootstrapped samples, which form the basis for estimating gap curves and their variance-covariance matrices. The data article also reports representations of gap curves for all 16 selected countries.


Variation in outpatient procedure rates in Canadian teaching hospitals.
To determine the variation in the rate at which specific procedures are performed on an outpatient basis in Canadian teaching hospitals. An index of outpatient activity was developed using the ratio of expected-to-actual performance, with the expected performance representing empirical, exogenous criteria. Canadian teaching hospitals. The index indicated whether the hospital, or group of hospitals, of interest is equally, more, or less active than the comparison group. The results show that Canadian teaching hospitals were 3% less active than Canadian nonteaching hospitals and Alberta teaching hospitals were 22% less active than all Canadian teaching hospitals. Individual teaching hospitals in Alberta were 21% more, 40% less, 9% less, 44% less, 8% less, 39% less, 20% less, and 2% less active than all other Alberta teaching hospitals. If variation in the use of less costly treatment modalities represents variation in quality as in Donabedian's unifying model, the results show considerable variation in quality across the generally accepted leaders in the medical care field. By comparing teaching hospitals with other teaching hospitals the difference in the patient severity level is minimized. The decision regarding the delivery modality represents only one decision in the complex decision matrix faced by physicians in the treatment episode. Given the considerable variation demonstrated in this study, the task of developing protocol, standards, or guidelines in order to reduce variation over the total treatment episode will be enormous.


[Variability of heat resistance of frog muscle tissue in Ringer's solution].
The variability in the initial level of heat resistance of muscles was found to decrease with increase in the duration of keeping the frogs in vivarium. However, the variability in the resistance of isolated muscles kept in Ringer's solution during 90 min. is independent of this factor and lesser than the initial one. The data obtained suggest that the narrowing of the variability in the resistance of muscles kept in Ringer's solution is determined by the dispersion of the initial level of the resistance. This phenomenon is only observed when the individual variability in the resistance of muscles is sufficiently high immediately after their isolation.


Elucidating the cellular determinants of targeted membrane protein degradation by lysosome-targeting chimeras.
Targeted protein degradation can provide advantages over inhibition approaches in the development of therapeutic strategies. Lysosome-targeting chimeras (LYTACs) harness receptors, such as the cation-independent mannose 6-phosphate receptor (CI-M6PR), to direct extracellular proteins to lysosomes. In this work, we used a genome-wide CRISPR knockout approach to identify modulators of LYTAC-mediated membrane protein degradation in human cells. We found that disrupting retromer genes improved target degradation by reducing LYTAC recycling to the plasma membrane. Neddylated cullin-3 facilitated LYTAC-complex lysosomal maturation and was a predictive marker for LYTAC efficacy. A substantial fraction of cell surface CI-M6PR remains occupied by endogenous M6P-modified glycoproteins. Thus, inhibition of M6P biosynthesis increased the internalization of LYTAC-target complexes. Our findings inform design strategies for next-generation LYTACs and elucidate aspects of cell surface receptor occupancy and trafficking.


Hybrid ICA-Seed-Based Methods for fMRI Functional Connectivity Assessment: A Feasibility Study.
Brain functional connectivity (FC) is often assessed from fMRI data using seed-based methods, such as those of detecting temporal correlation between a predefined region (seed) and all other regions in the brain; or using multivariate methods, such as independent component analysis (ICA). ICA is a useful data-driven tool, but reproducibility issues complicate group inferences based on FC maps derived with ICA. These reproducibility issues can be circumvented with hybrid methods that use information from ICA-derived spatial maps as seeds to produce seed-based FC maps. We report results from five experiments to demonstrate the potential advantages of hybrid ICA-seed-based FC methods, comparing results from regressing fMRI data against task-related a priori time courses, with "back-reconstruction" from a group ICA, and with five hybrid ICA-seed-based FC methods: ROI-based with (1) single-voxel, (2) few-voxel, and (3) many-voxel seed; and dual-regression-based with (4) single ICA map and (5) multiple ICA map seed.


Stereoselective synthesis of acyclic amino alcohols via von Braun ring opening of chiral piperidines.
Multisubstituted piperidines containing a phenyl group at C-2 can be opened regio- and stereoselectively with cyanogen bromide. The ring-opened products contain useful cyanamide and benzylic bromide functional groups. This methodology is useful for the stereoselective synthesis of uniquely substituted alkylamine derivatives containing multiple chiral centers and various functionality.


Contrast-Induced Nephropathy and Long-Term Clinical Outcomes Following Percutaneous Coronary Intervention in Patients With Advanced Renal Dysfunction (Estimated Glomerular Filtration Rate <30 ml/min/1.73 m2).
The incidence of contrast-induced nephropathy (CIN) increases with the progression of renal dysfunction. Recent reports have shown that percutaneous coronary intervention (PCI) can be safely performed even in patients with advanced renal dysfunction by appropriate CIN-prevention strategies. However, data are limited regarding the occurrence and prognostic influence of CIN in patients with advanced renal dysfunction. We examined the data obtained from 323 consecutive patients with advanced renal dysfunction (eGFR <30 ml/min/1.73 m2) who underwent PCI at 5 hospitals. CIN was defined as a ≥25% increase in baseline serum creatinine levels and/or a ≥0.5 mg/dl increase in absolute serum creatinine levels within 72 hours after PCI. Incidence of all-cause death and the initiation of permanent dialysis were examined during follow-up. The prevalence of emergency/urgent PCI was 53.3%. Intravascular ultrasound was used in 266 patients (82.4%), and the volume of contrast used was 71.7 ± 57.2 ml. CIN was observed in 31 patients (9.7%). The median follow-up duration was 656 days (interquartile range 257-1143 days). The cumulative rates of all-cause death or the initiation of permanent dialysis, all-cause death, and the initiation of permanent dialysis were 38.1%, 25.9%, and 18.2%, respectively, at 2 years. A comparison between patients with and without CIN showed no significant intergroup differences in the occurrence of the aforementioned events. In conclusion, the incidence of CIN was not high in Japanese patients with advanced renal dysfunction in routine clinical practice. Whereas, the long-term prognosis following PCI is observed to be poor in this studied population, and CIN did not show a significant prognostic influence.


Work-related non-crash heavy vehicle driver fatalities in Australia, 2000-9.
The objective of this study was to describe the nature and mechanisms of a case series of Australian work-related non-crash heavy vehicle driver fatalities. The study used existing population-based mortality data on non-crash work-related heavy vehicle (gross vehicle mass >4.5 t) driver fatalities reported to Australian coroners between 2000 and 2009. There were 47 fatalities with a mean age of 46.5 years. Available toxicology detected that six of 16 drivers consumed illegal drugs or alcohol. The most frequent task was attending to cargo (n=22, 47%); 31 (66%) fatalities occurred when the driver was working alone. Brake issues (n=21, 45%) were the most frequent contributing factor, and crushing the most common mechanism (n=33, 70%), particularly between the vehicle and another object (n=22, 47%). Fatalities occurred in most jurisdictions averaging 4.7 per year overall. A large number of truck drivers die performing non-driving tasks. Crushing following vehicle rolling accounts for almost 50% of fatalities. Considering this pathway may provide prevention opportunities.


Neurologic Compromise in COVID-19: A Literature Review.
Coronavirus disease 2019 (COVID-19) disease caused by a new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been associated with many neurological symptoms. The purpose of this article is to describe the neurological manifestations so far reported and their probable pathogenesis. We conducted a literature review on EMBASE, MEDLINE and SCIELO databases using the terms "COVID-19", "COVID", "neurological", "neurologic", "manifestations", "implications", "Guillain-Barre syndrome", "encephalopathy". A total of 33 articles including clinical series, retrospective studies, and case reports were selected and thoroughly reviewed to describe neurological manifestations of COVID-19. There are several neurological manifestations of SARS-CoV-2 infection with different clinical presentations, severity, and prevalence. The most critical ones, such as cerebrovascular disease, encephalopathy, and Guillain-Barre syndrome, were less common and usually associated with previous medical history, known risk factors for cerebrovascular disease or advanced age. The main hypotheses for the spread of the virus are through the hematogenous route or the cribriform plate of the ethmoid bone or a disseminated severe immune response by a cytokine storm. The presence of neurological disturbances associated with laboratory tests alterations is an important clue for the physicians to promptly recognize neurological manifestations of SARS-CoV-2.


New methods and applications in solid-state NMR spectroscopy of quadrupolar nuclei.
Solid-state nuclear magnetic resonance (NMR) spectroscopy has long been established as offering unique atomic-scale and element-specific insight into the structure, disorder, and dynamics of materials. NMR spectra of quadrupolar nuclei (I > (1)/2) are often perceived as being challenging to acquire and to interpret because of the presence of anisotropic broadening arising from the interaction of the electric field gradient and the nuclear electric quadrupole moment, which broadens the spectral lines, often over several megahertz. Despite the vast amount of information contained in the spectral line shapes, the problems with sensitivity and resolution have, until very recently, limited the application of NMR spectroscopy of quadrupolar nuclei in the solid state. In this Perspective, we provide a brief overview of the quadrupolar interaction, describe some of the basic experimental approaches used for acquiring high-resolution NMR spectra, and discuss the information that these spectra can provide. We then describe some interesting recent examples to showcase some of the more exciting and challenging new applications of NMR spectra of quadrupolar nuclei in the fields of energy materials, microporous materials, Earth sciences, and biomaterials. Finally, we consider the possible directions that this highly informative technique may take in the future.


Effect of use of different landmark methods on determining stifle angle and on calculated tibial tuberosity advancement.
Firstly, to investigate the effect that using different landmarks has on the measured stifle angle. Secondly, to determine whether any differences in measured stifle angle would lead to variations in the required extent of tibial tuberosity advancement (TTA). Three greyhound stifles were positioned in a total of 66 different angles. Radiographic exposures of each stifle angle were made. For each radiograph i) the stifle angle was measured using each of three sets of landmarks and ii) the extent of TTA required to obtain a patella tendon angle of 90° was measured. Each radiograph was plotted graphically according to the stifle angle and the extent of TTA required. Linear regression analysis was used to calculate the TTA required for a stifle angle of 135° measured using each of the three landmark sets. On average, the stifle angle determined by the Long Axes method differed by 18° from the stifle angle determined with the Kinematic method. The stifle angle determined using the Eminence method differed from that determined using the Kinematic method by three degrees. The use of the Long Axes of the tibia and femur as landmarks to determine a stifle angle resulted in 5 mm and 4 mm over-advancement of the tibial tuberosity compared to the use of Kinematic or Eminence landmark methods respectively. The method used to measure the stifle joint angle can influence the value of the required TTA advancement. This is an additional variable that should be considered during TTA planning and when comparing in vivo and in vitro studies.


Latent transition regression for mixed outcomes.
Health status is a complex outcome, often characterized by multiple measures. When assessing changes in health status over time, multiple measures are typically collected longitudinally. Analytic challenges posed by these multivariate longitudinal data are further complicated when the outcomes are combinations of continuous, categorical, and count data. To address these challenges, we propose a fully Bayesian latent transition regression approach for jointly analyzing a mixture of longitudinal outcomes from any distribution. Health status is assumed to be a categorical latent variable, and the multiple outcomes are treated as surrogate measures of the latent health state, observed with error. Using this approach, both baseline latent health state prevalences and the probabilities of transitioning between the health states over time are modeled as functions of covariates. The observed outcomes are related to the latent health states through regression models that include subject-specific effects to account for residual correlation among repeated measures over time, and covariate effects to account for differential measurement of the latent health states. We illustrate our approach with data from a longitudinal study of back pain.


Is Melatonin the "Next Vitamin D"?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements.
Melatonin has become a popular dietary supplement, most known as a chronobiotic, and for establishing healthy sleep. Research over the last decade into cancer, Alzheimer's disease, multiple sclerosis, fertility, PCOS, and many other conditions, combined with the COVID-19 pandemic, has led to greater awareness of melatonin because of its ability to act as a potent antioxidant, immune-active agent, and mitochondrial regulator. There are distinct similarities between melatonin and vitamin D in the depth and breadth of their impact on health. Both act as hormones, affect multiple systems through their immune-modulating, anti-inflammatory functions, are found in the skin, and are responsive to sunlight and darkness. In fact, there may be similarities between the widespread concern about vitamin D deficiency as a "sunlight deficiency" and reduced melatonin secretion as a result of "darkness deficiency" from overexposure to artificial blue light. The trend toward greater use of melatonin supplements has resulted in concern about its safety, especially higher doses, long-term use, and application in certain populations (e.g., children). This review aims to evaluate the recent data on melatonin's mechanisms, its clinical uses beyond sleep, safety concerns, and a thorough summary of therapeutic considerations concerning dietary supplementation, including the different formats available (animal, synthetic, and phytomelatonin), dosing, timing, contraindications, and nutrient combinations.


A comparison of methods for determining the ventilatory threshold: implications for surgical risk stratification.
The ventilatory threshold (VT) is an objective physiological marker of the capacity of aerobic endurance that has good prognostic applications in preoperative settings. Nevertheless, determining the VT can be challenging due to physiological and methodological issues, especially in evaluating surgical risk. The purpose of the current study was to compare different methods of determining VT and to highlight the implications for assessing perioperative risk. Our study entailed analysis of 445 treadmill cardiopulmonary exercise tests from 140 presurgical candidates with an aortic abdominal aneurysm (≥3.0 to ≤5.0 cm) and a mean (standard deviation [SD]) age of 72 (8) yr. We used three methods to determine the VT in 328 comparable tests, namely, self-detected metabolic system (MS), experts' visual (V) readings, and software using a log-log transformation (LLT) of ventilation vs oxygen uptake. Differences and agreement between the three methods were assessed using analysis of variance (ANOVA), coefficient of variation (CV), typical error limits of agreement (LoA), and interclass correlation coefficients (ICC). Overall, ANOVA revealed significant differences between the methods [MS = 14.1 (4.3) mLO2·kg-1·min-1; V = 14.6 (4.4) mLO2·kg-1·min-1; and LLT = 12.3 (3.3) mLO2·kg-1·min-1; P < 0.001]. The assessment of agreement between methods provided the following results: ICC = 0.85; 95% confidence interval (CI), 0.82 to 0.87; P < 0.001; typical error, 2.1-2.8 mLO2·kg-1·min-1; and, 95% LoA and CV ranged from 43 to 55% and 15.9 to 19.6%, respectively. The results show clinically significant variations between the methods and underscore the challenges of determining VT for perioperative risk stratification. The findings highlight the importance of meticulous evaluation of VT for predicting surgical outcomes. Future studies should address the prognostic perioperative utility of computed mathematical models combined with an expert's review. This trial was registered at ClinicalTrials.gov, identifier: NCT00349947.


Both subunits of the circadian RNA-binding protein CHLAMY1 can integrate temperature information.
The circadian RNA-binding protein CHLAMY1 from the green alga Chlamydomonas reinhardtii consists of two subunits named C1 and C3. Changes in the C1 level cause arrhythmicity of the phototaxis rhythm, while alterations in the level of C3 lead to acrophase shifts. Thus, CHLAMY1 is involved in maintaining period and phase of the circadian clock. Here, we analyzed the roles of the two subunits in the integration of temperature information, the basis for other key properties of circadian clocks, including entrainment by temperature cycles and temperature compensation. Applied temperatures (18 degrees C and 28 degrees C) were in the physiological range of C. reinhardtii. While C1 is hyperphosphorylated at low temperature, the C3 expression level is up-regulated at 18 degrees C. An inhibitor experiment showed that this up-regulation occurs at the transcriptional level. Promoter analysis studies along with single promoter element mutations revealed that individual replacement of two DREB1A-boxes lowered the amplitude of c3 up-regulation at 18 degrees C, while replacement of an E-box abolished it completely. Replacement of the E-box also caused arrhythmicity of circadian-controlled c3 expression. Thus, the E-box has a dual function for temperature-dependent up-regulation of c3 as well as for its circadian expression. We also found that the temperature-dependent regulation of C1 and C3 as well as temperature entrainment are altered in the clock mutant per1, indicating that a temperature-controlled network of C1, C3, and PER1 exists.


[Barium granuloma of the rectum].
The authors report a case of barium granuloma of the rectum. This complication of barium enema is exceptional. During enema, the cannula may ulcerate the mucosa which is blown up secondarily by the barium. Clinically, the granuloma presents like a hard polyp which is suggestive in certain cases of a malignant tumour. The precise diagnosis is made by careful examination of the abdominal films before administration of barium taking in the whole of the pelvis.


BLF1, the first Burkholderia pseudomallei toxin, connects inhibition of host protein synthesis with melioidosis.
Melioidosis is a disease caused by infection with Burkholderia pseudomallei. The molecular basis for the pathogenicity of B. pseudomallei is poorly understood. However, recent work has identified the first toxin from this bacterium and shown that it inhibits host protein synthesis. Here, we review the illness that is potentially associated with biological warfare, the pathogen and its deadly molecular mechanism of action, as well as therapeutic developments that may follow.


Group I p21-activated kinases (PAKs) promote tumor cell proliferation and survival through the AKT1 and Raf-MAPK pathways.
Group I p21-activated kinases (PAK) are important effectors of the small GTPases Rac and Cdc42, which regulate cell motility/migration, survival, proliferation, and gene transcription. Hyperactivation of these kinases have been reported in many tumor types, making PAKs attractive targets for therapeutic intervention. PAKs are activated by growth factor-mediated signaling and are negatively regulated by the tumor suppressor neurofibromatosis type 2 (NF2)/Merlin. Thus, tumors characterized by NF2 inactivation would be expected to show hyperactivated PAK signaling. On the basis of this rationale, we evaluated the status of PAK signaling in malignant mesothelioma, an aggressive neoplasm that is resistant to current therapies and shows frequent inactivation of NF2. We show that group I PAKs are activated in most mesotheliomas and mesothelioma cell lines and that genetic or pharmacologic inhibition of PAKs is sufficient to inhibit mesothelioma cell proliferation and survival. We also identify downstream effectors and signaling pathways that may contribute mechanistically to PAK-related tumorigenesis. Specifically, we show that inhibition of PAK results in attenuation of AKT and Raf-MAPK signaling and decreased tumor cell viability. Collectively, these data suggest that pharmacologic inhibition of group I PAKs may have therapeutic efficacy in tumors characterized by PAK activation.


Cigarette smoke-induced oxidative stress suppresses generation of dendritic cell IL-12 and IL-23 through ERK-dependent pathways.
IL-12p70, a heterodimer composed of p35 and p40 subunits, is a key polarizing cytokine produced by maturing dendritic cells (DCs). We report that cigarette smoke extract (CSE), an extract of soluble cigarette smoke components, suppresses both p35 and p40 production by LPS or CD40L-matured DCs. Suppression of IL-12p70 production from maturing DCs was not observed in the presence of nicotine concentrations achievable in CSE or in the circulation of smokers. The suppressed IL-12p70 protein production by CSE-conditioned DCs was restored by pretreatment of DCs or CSE with the antioxidants N-acetylcysteine and catalase. Inhibition of DC IL-12p70 by CSE required activation of ERK-dependent pathways, since inhibition of ERK abrogated the suppressive effect of CSE on IL-12 secretion. Oxidative stress and sustained ERK phosphorylation by CSE enhanced nuclear levels of the p40 transcriptional repressor c-fos in both immature and maturing DCs. Suppression of the p40 subunit by CSE also resulted in diminished production of IL-23 protein by maturing DCs. Using a murine model of chronic cigarette smoke exposure, we observed that systemic and lung DCs from mice "smokers" produced significantly less IL-12p70 and p40 protein upon maturation. This inhibitory effect was selective, since production of TNF-alpha during DC maturation was enhanced in the smokers. These data imply that oxidative stress generated by cigarette smoke exposure suppresses the generation of key cytokines by maturing DCs through the activation of ERK-dependent pathways. Some of the cigarette smoke-induced inhibitory effects on DC function may be mitigated by antioxidants.


[Fast identification of rifampicin-and isoniazid resistance of M. Tuberculosis strains by the "TB-biochip" test system].
A total 988 specimens were obtained from patients with pulmonary tuberculosis, which were all diagnosed according to clinical and X-ray and bacteriological studies. 940 patients were newly diagnosed without any history of treatment; 48 patients with a history of treatment one course. Mutations of rpoB, katG, inhA and ahpC gene associated with rifampicin (RIF) and isoniazid (INH) resistance were detected by "TB-Biochip" test system. Resistance was significantly higher in patients with a history of treatment compared with patients were newly diagnosed. Initial and acquired resistance were 53% (499/940) and 87% (41/48) respectively. Initial multidrug-resistance (MDR) (both to RIF and INH) was 30% (282/940) and acquired MDR was 75% (35/48). The single primary drug resistance only to RIF was 3% (29/940), to INH was 20% (188/940). The single acquired drug resistance only to RIF was 4% (2/48), to INH was 8% (4/48). The most common point mutations in rpoB gene were in codon 531 (58%), 526 (18%), 516 (9%) and 511 (6.8%). The point mutation Ser531-->Leu was at the highest frequency (59.7%). Resistance to INH was associated mostly with mutations found in katG gene-90.5%, inhA gene-9.05% and ahpC gene-0.45%. Prevalence of mutation was found in katG gene-Ser315 Thr (88.7%). The rifampicin and isoniasid resistance of M. Tb strains isolated in Kyrgyzstan is associated mostly with Ser531-->Leu mutation of rpoB gene, Ser315-->Thr mutation of katG gene. The "TB-Biochip" test system is simple and rapid for detection of rifampicin-and isoniazid resistant of M. Tuberculosis. The biochip-based analysis of RIF and INH susceptibility provides fast (less than 24 hours) and accurate identification of the mutations in gene rpoB, katG, inhA, ahpC responsible for resistance to rifampin and isoniazid.


Breast and cervical cancer screening behaviours among colorectal cancer survivors in Nova Scotia.
We analyzed patterns and factors associated with receipt of breast and cervical cancer screening in a cohort of colorectal cancer survivors. Individuals diagnosed with colorectal cancer in Nova Scotia between January 2001 and December 2005 were eligible for inclusion. Receipt of breast and cervical cancer screening was determined using administrative data. General-population age restrictions were used in the analysis (breast: 40-69 years; cervical: 21-75 years). Kaplan-Meier and Cox proportional hazards models were used to assess time to first screen. Of 318 and 443 colorectal cancer survivors eligible for the breast and cervical cancer screening analysis respectively, 30.1% [95% confidence interval (ci): 21.2% to 39.0%] never received screening mammography, and 47.9% (95% ci: 37.8% to 58.0%) never received cervical cancer screening during the study period. Receipt of screening before the colorectal cancer diagnosis was strongly associated with receipt of screening after diagnosis (hazard ratio for breast cancer screening: 4.71; 95% ci: 3.42 to 6.51; hazard ratio for cervical cancer screening: 6.83; 95% ci: 4.58 to 10.16). Many colorectal cancer survivors within general-population screening age recommendations did not receive breast and cervical cancer screening. Future research should focus on survivors who meet age recommendations for population-based cancer screening.


Retinal nerve fiber layer measurements in normal black subjects as determined with scanning laser polarimetry.
This study aimed to obtain normal nerve fiber layer (NFL) measurements by means of scanning laser polarimetry in black subjects and to compare these measurements with those in normal white subjects. Polarimetric NFL measurements were obtained in 1 eye of 133 normal black subjects and 133 age- and gender-matched white subjects. Ratios were determined for the superior and inferior NFL, each relative to the nasal value (S/N and I/N, respectively). Results of black and white subjects were compared by means of the Student's t test. The effect of age on NFL measurements was determined with linear regression analysis. The mean S/N was statistically significantly lower in black subjects (1.7) when compared with that of white subjects (2.5). Similar values were obtained for I/N. In this cross-sectionally performed study, a negative, albeit not significant relation (-0.003) was recognized between NFL measurements and age for both S/N and I/N in black subjects. In the white subjects, there was a statistically significant relation of -0.012 between age and NFL measurements. The NFL retardation is less in black than in white subjects. Compared with white subjects, the decrease in NFL measurements of black subjects over time, cross sectionally, appears less.