Non-acid mechanisms of gastric and duodenal ulcer formation.
The pathophysiology of gastric and duodenal ulcer disease has two sides: the aggressive attack, principally by the highly corrosive gastric acid; and the defending forces of mucus, mucosal resistance, and other protective substances and functions. This report reviews the roles of both the attacking and defending forces in the pathophysiology of ulcer disease. It also discusses how an early notion of ulcer formation (e.g., the Schwarz dictum of "no acid, no ulcer," first published in 1910) became the slogan by which ulcer disease was understood and from which therapy took its cue. Subsequent work has since found that the Schwarz dictum holds for duodenal ulcer, but not for gastric ulcer. Non-acid mechanisms of ulcer formation--i.e., impairment of at least one of the defending or protective forces--are also described, as are treatment approaches to ulcer disease. Although suppression of acid secretion is a mainstay of treatment, agents that safely and effectively strengthen the defense are being used more frequently. There are signs that the safe limits for acid-suppressing therapy have been reached or passed. On the other hand, the search for therapy that strengthens the defensive factors has only begun.


A procedure for the measurement of infant skin conductance and its initial validation using clap induced startle.
Studies examining psychophysiologic markers of infant emotional development abound. However, few studies have used skin conductance (SC), though it measure's sympathetic activity, and none have measured SC on infants sitting up and actively engaged with another person, a significant challenge given the measures sensitivity to movement artifact. In this pilot/feasibility study, we present a procedure for measuring infant SC during active engagement with another person who executes a series of startling claps to elicit an SC response. We measured SC on the plantar surface of the foot of seventeen 5-month-old infants. We found unconditioned SC responses that were related to the intensity of physical startle reactions for each clap trial. We also found anticipatory, conditioned SC responses that occurred within 5 s before each clap that occurred when the researcher raised his clasped hands. These conditioned SC responses grew linearly in intensity over trials. We conclude that SC may be a useful addition to the infant researcher's armamentarium and may indeed be used to measure physiologic reactivity in infants even when actively engaged with another person. Addition of SC measurement to research on infant emotion and emotional communication is likely to advance our understanding of the psychophysiologic foundations of infant emotional development.


Novel variants of muscle calpain 3 identified in human melanoma cells: cisplatin-induced changes in vitro and differential expression in melanocytic lesions.
Calpains are cysteine proteases comprising members ubiquitously expressed in human tissues and other tissue-specific isoforms. Alterations of calpain 3 (p94), the muscle-specific isoform that contains three peculiar sequences (NS, IS1 and IS2), are strictly associated to the limb-girdle muscular dystrophy type 2A, in which a myonuclear apoptosis has been documented. Our recent demonstration of a proapoptotic role of ubiquitous calpains in drug-induced apoptosis of melanoma cells prompted us to investigate the expression of calpain 3 in human melanoma cell lines undergoing apoptosis and in melanocytic lesions. In melanoma cell lines, we have identified two novel splicing variants of calpain 3 (hMp78 and hMp84): they have an atypical initiation exon and a putative nuclear localization signal, the shorter one lacks IS1 inset and both proteins are extremely unstable. Virtually, both isoforms (prevalently as cleavage forms) are localized in cytoplasm and in nucleoli. In cisplatin-treated preapoptotic cells, an increase of both transcription and autoproteolytic cleavage of the novel variants is observed; the latter event is prevented by the inhibitor of ubiquitous calpains, calpeptin, which is also able to protect from apoptosis. Interestingly, among melanocytic lesions, the expression of these novel variants is significantly downregulated, compared with benign nevi, in the most aggressive ones, i.e. in vertical growth phase melanoma and, even more, in metastatic melanoma cells, characterized by invasiveness properties and usually highly resistant to apoptosis. On the whole, our observations suggest that calpain 3 variants can play a proapoptotic role in melanoma cells and its downregulation, as observed in highly aggressive lesions, could contribute to melanoma progression.


Comparative study of Mycobacterium bovis primary isolation methods.
For the definitive diagnosis of bovine tuberculosis, isolation of the etiologic agent is required. However, there is no consensus on the best methodology for isolation of Mycobacterium bovis in Brazil. This study evaluated the most used decontaminants and culture media in the country, in order to identify the best combination for the Brazilian samples. Three decontaminants - 2% sodium hydroxide (w/v), 0.75% hexadecylpiridinium chloride (w/v) and 5% sulphuric acid (v/v) and four culture media - 7H11 Middlebrook with additives and OADC supplement "A" (7H11 A), the same media with another supplement trademark (7H11 B), tuberculosis blood agar (B83) and Stonebrink's medium were compared. Regarding the isolation, there were no significant differences between the decontaminants and media combinations, except 7H11A combined to any decontaminant. However, the mean colonies score was significantly greater when the samples were decontaminated with 5% sulphuric acid and inoculated in 7H11 B or SB, without significant difference between them, although colonies appeared earlier on 7H11B than on SB. The trademark of OADC supplement influenced the isolation rate and the number of isolated colonies in Middlebrook 7H11. An incubation time of four weeks was required to detect all positive samples in 7H11 B after decontamination with 5% sulphuric acid but there was an increase in the number of colonies until the sixth week of incubation. Overall, the best strategy for the primary isolation of M. bovis from Brazilian samples was the decontamination with 5% sulphuric acid (final concentration) and inoculation in Middlebrook 7H11 medium formulated with OADC supplement "B".


Self-concept of children with intellectual disability in mainstream settings.
Positive self-concept is an important educational outcome for individuals with disability. Perceived competence and acceptance of 17 children with intellectual disability, included in mainstream classes, were assessed using the Pictorial Scale of Perceived Competence and Social Acceptance for Young Children (PSPCSA) and compared with (a) independently rated academic work samples and measures of social status, and (b) measures of perceived competence and acceptance reported for other populations of individuals with and without disability. Perceived competence and acceptance were positive and comparable to previously reported results for individuals with disability and young children without disability. The children's perceived cognitive competence was not consistent with ratings of their work samples but their perceived peer acceptance was more consistent with peer ratings of social status. Children with intellectual disability remained positive at an age when self-concept is likely to be negatively impacted by comparisons with higher performing peers.


Postural control in chronic obstructive pulmonary disease: a systematic review.
Patients with chronic obstructive pulmonary disease (COPD) fall frequently, although the risk of falls may seem less important than the respiratory consequences of the disease. Nevertheless, falls are associated to increased mortality, decreased independence and physical activity levels, and worsening of quality of life. The aims of this systematic review was to evaluate information in the literature with regard to whether impaired postural control is more prevalent in COPD patients than in healthy age-matched subjects, and to assess the main characteristics these patients present that contribute to impaired postural control. Five databases were searched with no dates or language limits. The MEDLINE, PubMed, EMBASE, Web of Science, and PEDro databases were searched using "balance", "postural control", and "COPD" as keywords. The search strategies were oriented and guided by a health science librarian and were performed on March 27, 2014. The studies included were those that evaluated postural control in COPD patients as their main outcome and scored more than five points on the PEDro scale. Studies supplied by the database search strategy were assessed independently by two blinded researchers. A total of 484 manuscripts were found using the "balance in COPD or postural control in COPD" keywords. Forty-three manuscripts appeared more than once, and 397 did not evaluate postural control in COPD patients as the primary outcome. Thus, only 14 studies had postural control as their primary outcome. Our study examiners found only seven studies that had a PEDro score higher than five points. The examiners' interrater agreement was 76.4%. Six of those studies were accomplished with a control group and one study used their patients as their own controls. The studies were published between 2004 and 2013. Patients with COPD present postural control impairment when compared with age-matched healthy controls. Associated factors contributing to impaired postural control were muscle weakness, physical inactivity, elderly age, need for supplemental oxygen, and limited mobility.


Interleukin-1 beta switches electrophysiological states of synovial fibroblasts.
The role of electro-physiological events in signal transduction of interleukin-1 beta (IL-1 beta) was investigated in rabbit synovial fibroblasts using the perforated-patch method. Aggregated synovial fibroblasts using the perforated-patch method. Aggregated synovial fibroblasts occurred in two different electrophysiological states having membrane potentials (Vm) of -63 +/- 4 (n = 71) and -27 +/- 10 mV (n = 55) (high and low Vm, respectively). IL-1 beta affected the cells with high Vm; it switched the state of the cell from high to low Vm. This effect was strongly dependent on the external potential applied to the cell membrane. Low Vm (-30 mV) alone without IL-1 beta did not switch the state of the cells. Thus a synergistic effect involving the cytokine and cell Vm in switching the electrophysiological state of the cell was shown, indicating that electrophysiological changes are involved in signal transduction. Gap junctions between aggregated cells were necessary for the cells to have a high Vm and to respond to IL-1 beta. Gap junction resistance between adjacent cells was estimated as 300 +/- 100 M omega. Our findings suggest that the electrophysiological behavior of synovial fibroblasts is tightly connected to a signaling or intracellular mediator system that is triggered by IL-1 beta.


Evaluation of Drug Treatment of Bronchopneumonia at the Pediatric Clinic in Sarajevo.
Bronchopneumonia is the most common clinical manifestation of pneumonia in pediatric population and leading infectious cause of mortality in children under 5 years. Evaluation of treatment involves diagnostic procedures, assessment of disease severity and treatment for disease with an emphasis on vulnerability of the population. To determine the most commonly used antibiotics at the Pediatric Clinic in Sarajevo and concomitant therapy in the treatment of bronchopneumonia. The study was retrospective and included a total of 104 patients, hospitalized in pulmonary department of the Pediatric Clinic in the period from July to December 2014. The treatment of bronchopneumonia at the Pediatric Clinic was empirical and it conformed to the guidelines and recommendations of British Thoracic Society. First and third generation of cephalosporins and penicillin antibiotics were the most widely used antimicrobials, with parenteral route of administration and average duration of treatment of 4.3 days. Concomitant therapy included antipyretics, corticosteroids, leukotriene antagonists, agonists of β2 adrenergic receptor. In addition to pharmacotherapy, hospitalized patients were subjected to a diet with controlled intake of sodium, which included probiotic-rich foods and adequate hydration. Recommendations for further antimicrobial treatment include oral administration of first-generation cephalosporins and penicillin antibiotics. Results of the drug treatment of bronchopneumonia at the Pediatric Clinic of the University Clinical Center of Sarajevo are comparable to the guidelines of the British Thoracic Society. It is necessary to establish a system for rational use of antimicrobial agents in order to reduce bacterial resistance.


Neurocognitive effects of first- and second-generation antipsychotic drugs in early-stage schizophrenia: a naturalistic 12-month follow-up study.
The study aimed to assess the cognitive effects of first- and second-generation antipsychotics on neurocognition under naturalistic treatment conditions. In a 12-month, open-label, multicenter study, 698 patients with early-stage schizophrenia (duration of illness ≤5 years) were prescribed chlorpromazine, sulpiride, clozapine, risperidone, olanzapine, quetiapine, or aripiprazole monotherapy. A neuropsychological battery including tests of attention, processing speed, learning/memory, and executive functioning was administered at baseline, 6- and 12-months. The primary outcome was change in a cognitive composite score after 12-months of treatment. At 12 months, treatment resulted in mild to moderate neurocognitive improvements of z=0.32 for chlorpromazine, 0.33 for sulpiride, 0.43 for clozapine, 0.51 for risperidone, 0.69 for olanzapine, 0.64 for quetiapine and 0.46 for aripiprazole. However, the olanzapine and quetiapine groups demonstrated greater improvement in the composite score and processing speed than did the chlorpromazine and sulpiride groups. Both first- and second-generation antipsychotics may improve cognitive function in patients with early-stage schizophrenia. Given that some neurocognitive improvement is attributable to a practice effect, any improvement is likely to be in the range of a small effect size.


A Familial Case Report of a 13;22 Chromosomal Translocation with Recurrent Intracytoplasmic Sperm Injection Failure.
The importance of cytogenetic analysis in a family with reproductive failure in two siblings is highlighted, where two siblings and their mother presented with a balanced translocation between chromosomes 13;22. The clinical evaluation had shown the female to be normal and the male to be oligoasthenoteratozoospermic despite repeated semen analysis. The couple was referred to our laboratory after three consecutive intracytoplasmic sperm injection (ICSI) failures at a local assisted reproductive technique (ART) center. Peripheral blood lymphocytes, obtained for karyotyping, were studied by a standard G-banding technique. Chromosomal analysis of the members of the pedigree, including the probands, showed the presence of the same translocation, t(13;22)(q21.2;q13.3), carried by three generations of the family. The sister and the mother of the proband had multiple spontaneous abortions in the first trimester. The spouses, when examined cytogenetically, were found to be normal. We propose the involvement of a balanced t(13;22)(q21.2;q13.3) chromosomal translocation in the pathogenesis of recurrent ART or spontaneous reproductive failures. Hence, it is suggested that all cases with structural chromosomal abnormalities be counseled prior to opting for ART and undergoing pre-implantation genetic diagnosis (PGD). This would prevent recurrent financial, physical and emotional stress in couples seeking ART.


Do Docking Sites Persist Upon Fluorination? The Diadamantyl Ether-Aromatics Challenge for Rotational Spectroscopy and Theory.
Fluorinated derivatives of biological molecules have proven to be highly efficient at modifying the biological activity of a given protein through changes in the stability and the kind of docking interactions. These interactions can be hindered or facilitated based on the hydrophilic/hydrophobic character of a particular protein region. Diadamantyl ether (C20 H30 O) possesses both kinds of docking sites, serving as a good template to model these important contacts with aromatic fluorinated counterparts. In this work, an experimental study on the structures of several complexes between diadamantyl ether and benzene as well as a series of fluorinated benzenes is reported to analyze the effect of H→F substitution on the interaction and structure of the resulting molecular clusters using rotational spectroscopy. All experimentally observed complexes are largely dominated by London dispersion interactions with the hydrogen-terminated surface areas of diadamantyl ether. Already single substitution of one hydrogen atom with fluorine changes the preferred docking site of the complexes. However, the overall contributions of the different intermolecular interactions are similar for the different complexes, contrary to previous studies focusing on the difference in interactions using fluorinated and non-fluorinated molecules.


Laryngeal histoplasmosis: an occupational hazard.
Isolated laryngeal histoplasmosis is a very rare entity. It has variable clinical presentations that might mimic both benign and malignant lesions, and is usually associated with pulmonary and other disseminated forms of histoplasmosis. Herein, we report a case of primary laryngeal histoplasmosis without the involvement of other systems in a 70-year-old Chinese man, who previously worked as a miner. He presented with a history of hoarseness for two months, with no other associated symptoms. Direct laryngoscopy revealed irregularity of the posterior one-third of both vocal folds. Histopathological examination revealed the presence of Histoplasma capsulatumon periodic acidSchiff and Grocott's methenamine silver staining. The lesion resolved after one month of oral itraconazole treatment. However, the patient had to complete six months of antifungal treatment to prevent recurrence.


Reversible control of enzyme-inhibitor interactions with light illumination using a photoresponsive surfactant.
The effects of a photoresponsive surfactant and light illumination on the complex formed between ribonuclease A (RNase A) and a protein ribonuclease inhibitor (RI) have been investigated to develop a light-based technique to reactivate an enzyme through surfactant-induced dissociation of the enzyme-inhibitor complex. The photoresponsive surfactant undergoes a photoisomerization from the relatively hydrophobic trans isomer under visible light to the relatively hydrophilic cis isomer upon UV illumination, providing a means to reversibly control protein-inhibitor interactions. In the absence of surfactant, RI binds tightly to RNase A through noncovalent interactions, which inhibits the enzyme activity. Upon addition of the surfactant under visible light, RNase A is reactivated, regaining ~75% of the native activity in the absence of RI. In the presence of the surfactant under UV light, however, the enzyme remains inhibited. Fluorescence spectroscopy, dynamic light scattering, and circular dichroism spectroscopy reveal that RI dramatically unfolds upon addition of the trans form of the surfactant, while RNase A does not undergo noticeable structural changes under the same conditions. This indicates that RNase A reactivation occurs through dissociation of the enzyme-inhibitor complex arising from surfactant-induced unfolding of the inhibitor. As a result, photoresponsive surfactant and light illumination can be used as a novel light-based technique to dissociate enzyme-inhibitor complexes and, thus, reactivate an inhibited enzyme.


Expression of monocyte chemotactic protein 3 following simulated birth trauma in a murine model of obesity.
To determine the effect of obesity on simulated birth trauma in leptin-deficient obese mice as measured by relative monocyte chemotactic protein 3 (MCP-3) expression. A total of 25 wild-type and 25 obese C57BL/6 virgin female mice underwent 1 hour of vaginal distension (VD), sham VD, or anesthesia without VD. Pelvic organ tissues were then harvested either immediately or 24-hours post VD and subsequent real-time polymerase chain reaction analysis was performed. Urethral MCP-3 levels in wild-type mice were elevated from baseline at 0 hours with a return to baseline at 24 hours in both VD and sham VD groups. In obese mice, there was a 6-fold elevation in MCP-3 levels at 0 hours after sham VD vs control (P <.05), which then returned to baseline levels at 24 hours. After undergoing VD, MCP-3 levels increased to 6-fold baseline values (P = .002) at 0 hours, with continued elevation in MCP-3 levels to 15 times control levels (P = .0003) at 24 hours. MCP-3 is significantly over-expressed in the urethral tissues of both wild-type and obese mice immediately after any urethral manipulation. At 24 hours, the MCP-3 expression patterns become divergent between VD and sham VD in obese mice. With a greater degree of trauma, MCP-3 continued to rise at 24 hours, suggesting that the underlying obesity resulted in alterations in response to tissue injury, paralleling the degree of injury. Such associations warrant further investigation into the role of MCP-3 as a chemokine for stem cell migration, with implications for subsequent tissue repair mechanisms after birth trauma.


Management of Pincer Nail Deformity by Realignment of Nailbed Using a Dermofascial Graft.
Pincer nail deformity is an uncommon entity which can be painful and cosmetically unappealing. We describe our technique of correcting this deformity by realignment of the nailbed using a dermofascial graft. Pain relief as well as a cosmetically good result have been obtained in all patients, and this has been maintained over the long term. The technique has proven to be safe, effective, and reproducible.


Future access to HIV vaccines. Report from a WHO-UNAIDS Consultation, Geneva, 2-3 October 2000.
Results from the first phase III efficacy trial of an HIV vaccine will be available within the next 2-3 years. Thus, it is imperative to start planning now to address how any effective vaccines should be used. In the absence of definitive information on the characteristics of the first generation of HIV vaccines, the following assumptions were made: the vaccine will (i) have only low to moderate efficacy (on the order of 50%); (ii) not be inexpensive (on the order of 10 to 30 US $ per dose); (iii) require multiple doses; and, (iv) at least initially, be available in limited quantities. A vaccine with that profile would not be suitable for general use in all countries, and it might have to be initially targeted to populations at higher risk of HIV infection. These populations will differ from region to region, according to the epidemiological situation. In most high and middle income countries potential target groups for an initial HIV immunization programme would include intravenous drug users, gay men, commercial sex workers, and high-risk heterosexuals, as well as healthcare workers exposed to blood. In sub-Saharan Africa, future HIV immunization programmes might include larger segments of the population. In order to plan future vaccination programmes it is important to estimate the need (size of target population) and the demand (uptake in target populations) for future HIV vaccines. In addition to the public sector demand for an HIV vaccine (to be used in public health programmes), there will also be a private sector demand driven by the willingness and ability of individuals and employers to pay for the vaccine. HIV vaccines would need to be delivered as part of comprehensive HIV prevention packages, including behavioral and health promotion interventions. This would be especially important with vaccines of moderate efficacy, in order to prevent increased risk behavior among vaccine recipients. To avoid false expectations, the vaccine message would need to be recast as part of the total prevention strategy, rather than the "magic bullet" that people have come to expect. Initial deployment of HIV vaccines could proceed through targeted vaccination campaigns, drawing from experience with other vaccines. These campaigns would be complex and expensive, and would require full participation and collaboration from all levels of the community, as well as considerable strengthening of the infrastructures required for vaccine delivery. Current candidate vaccines in phase III trials may not be appropriate for much of Africa and South Asia, two areas most in need of an HIV vaccine. Credible international efforts (''push and pull" mechanisms) are needed to create incentives for the industry to develop vaccines for these regions. Feasible financing mechanisms may have to be established to cover the cost of production and delivery of vaccines, in order to ensure equitable access to HIV vaccines around the world. In parallel to the deployment of the initial vaccine, additional bridging studies and effectiveness trials may be needed to expand vaccine use. Research should also continue at an increased pace to develop new generations of more effective vaccines, especially vaccines appropriate to Africa. Achieving these goals will require real political commitment from government and international organizations, to be materialized in specific actions and budget allocations. The daunting challenge of making future effective vaccines accessible to all populations in need will require a sustained collaborative effort on the part of all parties involved.


Measurement of fibrous cap thickness in atherosclerotic plaques by spatiotemporal analysis of laser speckle images.
Necrotic-core fibroatheromas (NCFA) with thin, mechanically weak fibrous caps overlying lipid cores comprise the majority of plaques that rupture and cause acute myocardial infarction. Laser speckle imaging (LSI) has been recently demonstrated to enable atherosclerotic plaque characterization with high accuracy. We investigate spatio-temporal analysis of LSI data, in conjunction with diffusion theory and Monte Carlo modeling of light transport, to estimate fibrous cap thickness in NCFAs. Time-varying laser speckle images of 20 NCFAs are selected for analysis. Spatio-temporal intensity fluctuations are analyzed by exponential fitting of the windowed normalized cross-correlation of sequential laser speckle patterns to obtain the speckle decorrelation time constant, tau(rho), as a function of distance rho from the source entry location. The distance, rho', at which tau(rho) dropped to 65% of its maximum value is recorded. Diffusion theory and Monte Carlo models are utilized to estimate the maximum photon penetration depth, zmax(rho'), for a distance equal to rho', measured from LSI. Measurements of zmax(rho') correlate well with histological measurements of fibrous cap thickness (R=0.78, p<0.0001), and paired t-tests show no significant difference between the groups (p=0.4). These results demonstrate that spatio-temporal LSI may allow the estimation of fibrous cap thickness in NCFAs, which is an important predictor of plaque stability.


The use of new CRISPR tools in cardiovascular research and medicine.
Many novel CRISPR-based genome-editing tools, with a wide variety of applications, have been developed in the past few years. The original CRISPR-Cas9 system was developed as a tool to alter genomic sequences in living organisms in a simple way. However, the functions of new CRISPR tools are not limited to conventional genome editing mediated by non-homologous end-joining or homology-directed repair but expand into gene-expression control, epigenome editing, single-nucleotide editing, RNA editing and live-cell imaging. Furthermore, genetic perturbation screening by multiplexing guide RNAs is gaining popularity as a method to identify causative genes and pathways in an unbiased manner. New CRISPR tools can also be applied to ex vivo or in vivo therapeutic genome editing for the treatment of conditions such as hyperlipidaemia. In this Review, we first provide an overview of the diverse new CRISPR tools that have been developed to date. Second, we summarize how these new CRISPR tools are being used to study biological processes and disease mechanisms in cardiovascular research and medicine. Finally, we discuss the prospect of therapeutic genome editing by CRISPR tools to cure genetic cardiovascular diseases.


Action Spectra for Guard Cell Rb Uptake and Stomatal Opening in Vivia faba.
Abaxial epidermal strips, containing guard cells as the only viable cells, were prepared from leaves of Vicia faba following a period in darkness, and floated, under CO(2)-free air, on 2 mm RbCl + 0.1 mm CaCl(2) labeled with (86)Rb(+). Under white light (high pressure mercury vapor lamp), stomatal opening in these strips approached its maximum at less than 0.02 calorie per square centimeter per minute. Under light of different wavelengths, 20 nanometers apart, and at a low quantum flux density of 7 x 10(14) quanta per square centimeter per second, Rb(+) uptake and stomatal opening were activated only in the blue and long ultraviolet regions, with a peak at 420 to 460 nanometers. The action spectrum suggests that the underlying process is not photosynthesis. At higher quantum flux density (38 x 10(14) quanta per square centimeter per second), uptake and opening also responded to red (600-680 nanometers) and somewhat to green light, with a minimum at 540 to 560 nanometers, indicating a possible involvement of the photosynthetic process. This light-induced opening appeared not to be mediated by a lowering of CO(2) concentration, since CO(2)-free air was used in all treatments and controls. Stomatal opening paralleled Rb(+) uptake in all cases. This constitutes further evidence for the potassium transport hypothesis of stomatal movement.In the abaxial surface of leaf discs under air of normal CO(2) concentration, stomatal opening in white light approached its maximum at an intensity similar to that for epidermal strips. At both quantum flux densities, the action spectra for opening in leaf discs were very similar to those for epidermal strips. Thus, these light-linked processes for stomatal opening are likely to be the same in leaves as in epidermal strips.


Characterization of distribution of pesticide residues in crop units.
The characteristic features of distribution of pesticide residues in crop units and single sample increments were studied based on more than 19,000 residue concentrations measured in root vegetables, leafy vegetables, small-, medium- and large-size fruits representing 20 different crops and 46 pesticides. Log-normal, gamma and Weibull distributions were found to provide the best fit for the relative frequency distributions of individual residue data sets. The overall best fit was provided by lognormal distribution. The relative standard deviation of residues (CV) in various crops ranged from 15-170%. The 100-120 residue values being in one data set was too small to identify potential effects of various factors such as the chemical and physical properties of pesticides and the nature of crops. Therefore, the average of CV values, obtained from individual data sets, were calculated and considered to be the best estimate for the likely variability of unit crop residues for treated field (CV = 0.8) and market samples (CV = 1.1), respectively. The larger variation of residues in market samples was attributed to the potential mixing of lots and varying proportion of non-detects. The expectable average variability of residues in composited samples can be calculated from the typical values taking into account the sample size.


Photobiology of phytochrome-mediated growth responses in sections of stem tissue from etiolated oats and corn.
The far-red reversibility of the phytochrome-controlled stimulation of elongation of coleoptile sections by low fluence red light has been characterized in subapical coleoptile sections from dark-grown Avena sativa L., cv Lodi seedlings. The fluence dependence of the far-red reversal was the same whether or not the very low fluence response is also expressed. The capacity of far-red light to reverse the red light-induced response began to decline if the far-red light was given more than 90 minutes after the red irradiation. Escape was complete if the far red irradiation was given more than 240 minutes after the red irradiation. Sections consisting of both mesocotyl and coleoptile tissue from dark-grown Avena seedlings were found to have physiological regulation of the very low fluence response by indole 3-acetic acid and low external pH similar to that seen for sections consisting entirely of coleoptile tissue. The fluence-dependence of the red light-induced inhibition of mesocotyl elongation was studied in mesocotyl sections from dark grown Zea mays L. hybrid T-929 seedlings. Ten micromolar indole 3-acetic acid stimulates the control elongation of the sections, while at the same time increasing the sensitivity of the tissue for the light-induced inhibition of growth by a factor of 100.


Intravitreal bevacizumab in acute central/hemicentral retinal vein occlusions: three-year results of a prospective clinical study.
To prospectively evaluate the effects of intravitreal bevacizumab (IVB, Avastin; Genentech, Inc., San Francisco, CA) injections in patients with acute central/hemicentral retinal vein occlusions (C/HCRVOs) (≤1 month after the occlusion was diagnosed) over the course of 3 years. The study included 57 patients with unilateral acute C/HCRVOs. Initially, the treatment for acute C/HCRVO patients consisted of 4 consecutive IVB injections administered off-label at a dose of 2.5 mg per injection, with each injection spaced ∼45 days apart. Thereafter, IVB therapy was flexible, and subsequent injections were administered during scheduled visits whenever a best corrected visual acuity (BCVA) loss of ≥5 Early Treatment Diabetic Retinopathy Study (ETDRS) letters occurred and/or iris/angle neovascularization appeared (regardless of the intraocular pressure level). Changes in the BCVA and foveal thickness (FT), number of IVB injections administered, and incidence of neovascular glaucoma (NVG) were estimated. The increase in the BCVA score at month 36 was 17.15 (ETDRS letters) (P<0.0001) in cases of nonischemic and 26.81 (ETDRS letters) (P<0.01) in cases of ischemic occlusions. At the end of the follow-up, the proportion of BCVA score improvements greater than 15 ETDRS letters was similar in patients with both forms of occlusions (measured in 45.5% of nonischemic and 45.8% of ischemic patients) (P=0.977). There were significant reductions in FT from baseline values to 230±40.50 μm (P=0.0001) in patients with nonischemic occlusions and 270±40.50 μm (P=0.0001) in patients with ischemic forms. There was a significant difference (P<0.03) in the number of IVB injections administered in patients with nonischemic C/HCRVOs (8.7±1.58) compared to patients with ischemic occlusions (9.7±1.78). NVG occurred in 2 cases of ischemic occlusions. The 3-year IVB therapy provided sustained vision and FT gains in most phakic patients with acute C/HCRVOs, making this treatment option a rational and viable therapeutic strategy. Bevacizumab was more effective in patients with ischemic occlusions who required a significantly higher number of injections.


Over-expression of miR-193a-3p regulates the apoptosis of colorectal cancer cells by targeting PAK3.
Although dysregulated expression of microRNAs (miRNA) has been investigated in colorectal cancer (CRC), MiR-193a-3p, as a tumor inhibitor, is less studied. To investigate the function and mechanism of miR-193a-3p in CRC, the potential function of miR-193a-3p in regulating PAK3 in CRC with a series of experimental assays including western blotting, qRT-PCR, bioinformatics analysis, a luciferase reporter assay, flow cytometry, Transwell assay, CCK8 assay and immunofluorescence were performed in this study. The results showed that miR-193a-3p was down-regulated in CRC tissues and cell lines, which was also correlated with tumor progression. PAK3 was predicted as a target gene of miR-193a-3p in CRC cells by TargetScan database, which was confirmed by luciferase assays. Moreover, overexpression of miR-193a-3p suppressed the viability, cell cycle progression, migration, and invasion, and induced apoptosis of CRC cells in vitro by regulating the PAK3 signaling pathway. Therefore, miR-193a-3p may serve as a tumor suppressor and potential target for CRC treatment.


Engineered Heart Muscle Models in Phenotypic Drug Screens.
Classical drug development is compromised by considerable clinical failure of promising drug candidates after decades of costly preclinical work. Failure can be because of previously unrecognized safety concerns or more commonly lack of clinical efficacy. Classical drug discovery and safety pharmacology programs rely heavily on well-established in vitro and preclinical animal models. The availability of human pluripotent stem cells and the possibility to direct them into any somatic cell type suggest that a paradigm shift in drug development may be possible and timely, with the opportunity to test safety and efficacy of candidate drugs on the human target cells and tissue. However, there is considerable uncertainty as to whether human models would only qualify as replacement for well-established tools or add substantially more information to the preclinical data package, to facilitate translation of more promising drug candidates into clinical practice. This chapter provides an overview of tissue-engineered macro-scale heart muscle models for applications in drug discovery and safety pharmacology.


Protein biomarkers of susceptibility and resilience to stress in a rat model of depression.
The molecular etiologies of psychological stress and major depressive disorder (MDD) are highly complex and many brain regions are involved. The prefrontal cortex (PFC) has gained attention in depression research due to its role in cognition including working memory and decision-making, which are impaired in MDD. The aim of the present study was to identify differentially regulated synaptosomal proteins from PFC in stress-exposed animals. The well-established chronic mild stress (CMS) rodent model was applied and three groups of rats were studied: unstressed controls, stress-susceptible and stress resilient. Large-scale proteomics based on relative iTRAQ quantification was applied on three synaptosomal Percoll gradient fractions and 27 proteins were found to undergo significant differential regulation. Gradient fraction two (F2) contained the highest amounts of synaptosomal proteins and is therefore recommended to be included in proteomic studies onwards, in addition to the traditionally used fractions F3 and F4. The regulated proteins corroborate previous studies on depression regulated proteins; including GFAP, HOMER1 and glutamatergic transmission (vesicular transporter 1, VGLUT1). However, additional functionalities were represented - especially in stress-resilient rats - such as oxidative stress protection (peroxiredoxins PRDX1 and PRDX2), Na/K-transporter ATP1A2 and respiratory chain subunits (UQCRC1 and UQCRFS1), which illustrate the biochemical complexity behind the stress phenotypes, but may also aid in the development of novel treatment strategies.


Echocardiogram changes following parathyroidectomy for primary hyperparathyroidism: A systematic review and meta-analysis.
The aim of the study is to systematically review the evidence on post parathyroidectomy (PTX) changes as measured by echocardiogram (ECHO) in patients with primary hyperparathyroidism (PHPT).PHPT may increase risk of cardiovascular morbidity/mortality. Conclusions of studies assessing ECHO changes, pre versus post PTX, are inconsistent.A systematic literature search was conducted to locate published and unpublished studies. Randomized control trials, nonrandomized control trials, and observational studies were included. Variables were reported as means and standard deviations. An inverse variance statistical method, with random-effects analysis model, was applied to continuous data. The effect measure was standardized mean difference, confidence interval of 95%. Primary outcome measure was left ventricular ejection fraction (LVEF). Secondary outcome measures were left ventricular mass index (LVMI), peak early over peak late diastolic velocity ratio (E/A ratio), isovolumetric relaxation time (IVRT), intraventricular septal thickness (IVST), and posterior wall thickness (PWT).Fourteen studies were included. Follow-up time ranged 3 to 67 months. No significant differences (P > .05) in primary outcome measure LVEF (SMD = -0.03, CI = -0.24, 0.19), or secondary outcome measures E/A Ratio (SMD = -0.05, CI = -0.24, 0.14), IVST (SMD = 0, CI = 0.31, 0.32), PWT (SMD = 0.01, CI = -0.38, 0.39), LVMI (SMD = -0.18, CI = -0.74, 0.38), and IVRT (SMD = -0.84, CI = -1.83, 0.14) were observed.There was no significant difference in LVEF pre to post PTX. Due to heterogeneity of current literature, we were unable to determine if other outcome measures of cardiac function are affected after PTX in patients with PHPT. We recommend a randomized control trial be conducted to make concrete conclusions.


Sodium alginate/soybean protein-epigallocatechin-3-gallate conjugate hydrogel beads: evaluation of structural, physical, and functional properties.
Sodium alginate (SA) hydrogel beads have been extensively studied as delivery systems for bioactive compounds. Key challenges include overcoming the highly porous and poor emulsifying properties of SA hydrogels. Herein, soy protein isolate (SPI) was modified by covalent and noncovalent conjugation with epigallocatechin-3-gallate (EGCG), followed by complexation with SA to change the SA structure and fabricate hydrogel beads with low porosities. Microencapsulation beads were fabricated from SA-, SA/SPI-, and SA/SPI-modified EGCG complexes with a corn oil/quercetin mixture core. After the covalent and noncovalent SPI-modified EGCG complexes were combined with SA, the OH stretching vibration shifted, indicating that hydrogen bonds formed between the protein and SA, and the crystal structure of SA was destroyed. To achieve crosslinking, the beads were injected into a CaCl2 solution, whereby Ca2+ ions replaced the Na+ ions in SA. Meanwhile, the addition of covalent and noncovalent SPI-modified EGCG complexes promoted the binding capacity of Ca2+ and SA. All hydrogel beads possessed open-cell microstructures with interconnecting pores. The SA/SPI-modified EGCG hydrogel beads exhibited smoother surfaces, thicker shells, and lower porosity than the SA hydrogel beads. Moreover, they exhibited significantly higher antioxidant activities. During digestion, all types of hydrogel bead maintained their structure, and only a small part of the encapsulated oil and quercetin was digested in the upper part of the gastrointestinal tract. In short, the formation mechanism of hydrogel beads was clarified, and hydrogel beads with low porosity and high antioxidation activities were successfully fabricated.


Antithrombin reduces reperfusion-induced liver injury in mice by enhancing sensory neuron activation.
We recently demonstrated that antithrombin (AT) reduces ischemia/reperfusion (I/R)-induced liver injury in rats by increasing hepatic tissue levels of calcitonin gene-related peptide (CGRP), a neuropeptide released from the sensory nerve endings. In the present study, we examined the effect of AT on I/R-induced liver injury in wild type mice (CGRP+/+) and congenitally alphaCGRP-deficient mice (CGRP-/-). We also investigated any effects of AT on CGRP release from dorsal root ganglion neurons (DRG) isolated from CGRP+/+. Based on results obtained in the present study, we attempted to determine if the anti-inflammatory activity of AT in vivo is dependent mainly on sensory neuron activation. AT enhanced ischemia/reperfusion-induced increases in hepatic tissue levels of CGRP and 6-keto-PGF(1alpha), a stable metabolite of PGI2, in CGRP+/+, but it did not enhance these increases in CGRP-/-. AT inhibited reperfusion-induced increases in serum alanine aminotransferase levels by increasing hepatic tissue blood flow and by attenuating increases in hepatic levels of tumor necrosis factor and myeloperoxidase in CGRP+/+, although it showed neither of these therapeutic effects in CGRP-/-. AT increased CGRP release from cultured DRGs only in the presence of anandamide, and AT-induced increase in CGRP release was not observed in the presence KT5720, an inhibitor of protein kinase A (PKA). AT markedly increased intracellular levels of cAMP in the presence of anandamide. These results strongly suggest that AT might reduce I/R-induced liver injury by enhancing activation of the sensory neurons through activation of PKA in sensory neurons.


Pressurized laboratory experiments show no stable carbon isotope fractionation of methane during gas hydrate dissolution and dissociation.
The stable carbon isotopic ratio of methane (δ(13)C-CH(4)) recovered from marine sediments containing gas hydrate is often used to infer the gas source and associated microbial processes. This is a powerful approach because of distinct isotopic fractionation patterns associated with methane production by biogenic and thermogenic pathways and microbial oxidation. However, isotope fractionations due to physical processes, such as hydrate dissolution, have not been fully evaluated. We have conducted experiments to determine if hydrate dissolution or dissociation (two distinct physical processes) results in isotopic fractionation. In a pressure chamber, hydrate was formed from a methane gas source at 2.5 MPa and 4 °C, well within the hydrate stability field. Following formation, the methane source was removed while maintaining the hydrate at the same pressure and temperature which stimulated hydrate dissolution. Over the duration of two dissolution experiments (each ~20-30 days), water and headspace samples were periodically collected and measured for methane concentrations and δ(13)C-CH(4) while the hydrate dissolved. For both experiments, the methane concentrations in the pressure chamber water and headspace increased over time, indicating that the hydrate was dissolving, but the δ(13)C-CH(4) values showed no significant trend and remained constant, within 0.5‰. This lack of isotope change over time indicates that there is no fractionation during hydrate dissolution. We also investigated previous findings that little isotopic fractionation occurs when the gas hydrate dissociates into gas bubbles and water due to the release of pressure. Over a 2.5 MPa pressure drop, the difference in the δ(13)C-CH(4) was <0.3‰. We have therefore confirmed that there is no isotope fractionation when the gas hydrate dissociates and demonstrated that there is no fractionation when the hydrate dissolves. Therefore, measured δ(13)C-CH(4) values near gas hydrates are not affected by physical processes, and can thus be interpreted to result from either the gas source or associated microbial processes.


Second malignancies after treatment of Hodgkin's disease: the influence of treatment, follow-up time, and age.
In the period 1968 through 1988, The Norwegian Radium Hospital (NRH) treated an unselected population of 1,152 patients with Hodgkin's disease (HD) that comprised more older patients (mean age, 43 years) than most other institutions. We considered it important to evaluate these patients for development of second cancers (SCs). The Norwegian Cancer Registry identified previously untreated patients with HD treated at NRH who had developed a SC more than 1 year after diagnosis of HD. The relative risk ratio (RR) (observed/expected cases) and the cumulative risk were calculated. Sixty-eight patients had developed a SC, including nine acute nonlymphocytic leukemias (ANLLs), eight non-Hodgkin's lymphomas (NHLs), and 51 solid tumors, including 11 lung cancers. The RR of SC and leukemia was 1.86 (95% confidence interval [CI], 1.4 to 2.4) and 24.3 (95% CI, 11.1 to 46.2), respectively. The RR of SC was highest in younger patients (< 41 years, RR = 3.8). No significant association between splenectomy and development of ANLL was found. The influence of treatment and follow-up time on the development of SC agrees with data from other large cancer institutions. (1) The low RR of developing a SC in this study is probably due to the number of older patients included, who have a lower RR of developing a SC due to less aggressive treatment, shorter follow-up time, and higher incidence of cancer in the expected background population. (2) The low RR and cumulative risk of developing ANLL may be due to the limited use of extensive chemotherapy (CT) in our hospital in the earlier years.


[Transplantation of spermatogonial stem cells and prospects of its application].
Spermatogonial stem cells are male germ line stem cells, whose potency of proliferation is indispensable for the permanent production of male germ cells. With the advances in the technology of cryopreservation, in vitro culture and intracytoplasmic sperm injection (ICSI), the transplantation of spermatogonial stem cells is showing a splendid vista of application in basic medical research and clinical practice. This review briefly introduces the genesis and differentiation of spermatogonial stem cells, the current situation of their transplantation and the prospects of its application in medical science.


Direct Evaluation of Rare Events in Active Matter from Variational Path Sampling.
Active matter represents a broad class of systems that evolve far from equilibrium due to the local injection of energy. Like their passive analogs, transformations between distinct metastable states in active matter proceed through rare fluctuations; however, their detailed balance violating dynamics renders these events difficult to study. Here, we present a simulation method for evaluating the rate and mechanism of rare events in generic nonequilibrium systems and apply it to study the conformational changes of a passive solute in an active fluid. The method employs a variational optimization of a control force that renders the rare event a typical one, supplying an exact estimate of its rate as a ratio of path partition functions. Using this method we find that increasing activity in the active bath can enhance the rate of conformational switching of the passive solute in a manner consistent with recent bounds from stochastic thermodynamics.


Adolescents with d-transposition of the great arteries corrected with the arterial switch procedure: neuropsychological assessment and structural brain imaging.
We report neuropsychological and structural brain imaging assessments in children 16 years of age with d-transposition of the great arteries who underwent the arterial switch operation as infants. Children were randomly assigned to a vital organ support method, deep hypothermia with either total circulatory arrest or continuous low-flow cardiopulmonary bypass. Of 159 eligible adolescents, 139 (87%) participated. Academic achievement, memory, executive functions, visual-spatial skills, attention, and social cognition were assessed. Few significant treatment group differences were found. The occurrence of seizures in the postoperative period was the medical variable most consistently related to worse outcomes. The scores of both treatment groups tended to be lower than those of the test normative populations, with substantial proportions scoring ≥1 SDs below the expected mean. Although the test scores of most adolescents in this trial cohort are in the average range, a substantial proportion have received remedial academic or behavioral services (65%). Magnetic resonance imaging abnormalities were more frequent in the d-transposition of the great arteries group (33%) than in a referent group (4%). Adolescents with d-transposition of the great arteries who have undergone the arterial switch operation are at increased neurodevelopmental risk. These data suggest that children with congenital heart disease may benefit from ongoing surveillance to identify emerging difficulties. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000470.


A Simple Density-Based Empirical Likelihood Ratio Test for Independence.
We develop a novel nonparametric likelihood ratio test for independence between two random variables using a technique that is free of the common constraints of defining a given set of specific dependence structures. Our methodology revolves around an exact density-based empirical likelihood ratio test statistic that approximates in a distribution-free fashion the corresponding most powerful parametric likelihood ratio test. We demonstrate that the proposed test is very powerful in detecting general structures of dependence between two random variables, including non-linear and/or random-effect dependence structures. An extensive Monte Carlo study confirms that the proposed test is superior to the classical nonparametric procedures across a variety of settings. The real-world applicability of the proposed test is illustrated using data from a study of biomarkers associated with myocardial infarction.


Brain granulomas in neurocysticercosis patients are associated with a Th1 and Th2 profile.
Neurocysticercosis (NCC) is a common central nervous system (CNS) infection caused by Taenia solium metacestodes. Despite the well-documented importance of the granulomatous response in the pathogenesis of this infection, there is limited information about the types of cells and cytokines involved. In fact, there has been limited characterization of human brain granulomas with any infectious agent. In the present study a detailed histological and immunohistochemical analysis of the immune response was performed on eight craniotomy specimens where a granuloma surrounded each T. solium metacestode. The results indicated that in all the specimens there was a dying parasite surrounded by a mature granuloma with associated fibrosis, angiogenesis, and an inflammatory infiltrate. The most abundant cell types were plasma cells, B and T lymphocytes, macrophages, and mast cells. Th1 cytokines were prevalent and included gamma interferon, interleukin-18 (IL-18), and the immunosuppressive, fibrosis-promoting cytokine transforming growth factor beta. The Th2 cytokines IL-4, IL-13, and IL-10 were also present. These observations indicate that a chronic immune response is elicited in the CNS environment with multiple cell types that together secrete inflammatory and anti-inflammatory cytokines. In addition, both collagen type I and type III deposits were evident and could contribute to irreversible nervous tissue damage in NCC patients.


Circulating hormone levels in menopausal women receiving different hormone replacement therapy regimens. A comparison.
To measure and compare plasma levels of sex hormones after the administration of different hormone replacement therapy (HRT) regimens. Ninety women with natural menopause were randomized into this comparative study. Eighty-five women completed one year of follow-up. Patients were randomly assigned to five groups. The first received 0.6 mg/d of conjugated equine estrogen (CEE) cyclically (n = 15). The second received 50 micrograms/d of transdermal estradiol (E2) cyclically (n = 17), and the third received 0.6 mg/d of CEE continuously (n = 17). All these groups also received 2.5 mg of medroxyprogesterone acetate (MPA) sequentially for the last 12 days of HRT, while the fourth therapy group received 0.625 mg/d of CEE and 2.5 mg/d of MPA continuously (n = 19). The fifth group constituted a treatment-free control group (n = 22). Levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), E2, estrone (E1), prolactin (PRL), testosterone (T), androstenedione (A4), dehydroepiandrosterone sulfate (DHEA-S) and sex hormone binding globulin (SHBG) were determined prior to HRT and during the last week of the 6th and 12th months of HRT, between days 21 and 24 of estrogen administration. After HRT we found decreases in FSH, LH and PRL levels, increases in E2, E1 and SHBG, and no modifications in T, A4 and DHEA-S plasma levels. There were no significant differences between the treatment groups in FSH, LH, E2, PRL, T, A4 or DHEA-S. E1 and SHBG were significantly higher in the groups with oral HRT. All the observed changes in hormone levels are to be expected after HRT except for the decrease in PRL levels. Finally, although MPA dosage was not the focus of the present study, our results suggest that the dosage of 2.5 mg/d of MPA in sequential regimens is clearly inadequate to protect the endometrium from hyperplastic changes.


Predictive Accuracy of a Perioperative Laboratory Test-Based Prediction Model for Moderate to Severe Acute Kidney Injury After Cardiac Surgery.
Effective treatment of acute kidney injury (AKI) is predicated on timely diagnosis; however, the lag in the increase in serum creatinine levels after kidney injury may delay therapy initiation. To determine the derivation and validation of predictive models for AKI after cardiac surgery. Multivariable prediction models were derived based on a retrospective observational cohort of adult patients undergoing cardiac surgery between January 2000 and December 2019 from a US academic medical center (n = 58 526) and subsequently validated on an external cohort from 3 US community hospitals (n = 4734). The date of final follow-up was January 15, 2020. Perioperative change in serum creatinine and postoperative blood urea nitrogen, serum sodium, potassium, bicarbonate, and albumin from the first metabolic panel after cardiac surgery. Area under the receiver-operating characteristic curve (AUC) and calibration measures for moderate to severe AKI, per Kidney Disease: Improving Global Outcomes (KDIGO), and AKI requiring dialysis prediction models within 72 hours and 14 days following surgery. In a derivation cohort of 58 526 patients (median [IQR] age, 66 [56-74] years; 39 173 [67%] men; 51 503 [91%] White participants), the rates of moderate to severe AKI and AKIrequiring dialysis were 2674 (4.6%) and 868 (1.48%) within 72 hours and 3156 (5.4%) and 1018 (1.74%) within 14 days after surgery. The median (IQR) interval to first metabolic panel from conclusion of the surgical procedure was 10 (7-12) hours. In the derivation cohort, the metabolic panel-based models had excellent predictive discrimination for moderate to severe AKI within 72 hours (AUC, 0.876 [95% CI, 0.869-0.883]) and 14 days (AUC, 0.854 [95% CI, 0.850-0.861]) after the surgical procedure and for AKI requiring dialysis within 72 hours (AUC, 0.916 [95% CI, 0.907-0.926]) and 14 days (AUC, 0.900 [95% CI, 0.889-0.909]) after the surgical procedure. In the validation cohort of 4734 patients (median [IQR] age, 67 (60-74) years; 3361 [71%] men; 3977 [87%] White participants), the models for moderate to severe AKI after the surgical procedure showed AUCs of 0.860 (95% CI, 0.838-0.882) within 72 hours and 0.842 (95% CI, 0.820-0.865) within 14 days and the models for AKI requiring dialysis and 14 days had an AUC of 0.879 (95% CI, 0.840-0.918) within 72 hours and 0.873 (95% CI, 0.836-0.910) within 14 days after the surgical procedure. Calibration assessed by Spiegelhalter z test showed P >.05 indicating adequate calibration for both validation and derivation models. Among patients undergoing cardiac surgery, a prediction model based on perioperative basic metabolic panel laboratory values demonstrated good predictive accuracy for moderate to severe acute kidney injury within 72 hours and 14 days after the surgical procedure. Further research is needed to determine whether use of the risk prediction tool improves clinical outcomes.


The pharmacology of immunosuppression.
In this paper, we review the pharmacological techniques by which graft rejection can be prevented from the early development of azathioprine to the current controversies surrounding FK 506. The basic chemistry of each drug is outlined, its source, mode of action, current uses and the clinical management are briefly documented. In addition to the more usual immunosuppressive agents, the current state of art of using monoclonal antibodies as immunosuppressives is addressed.


The state of the state mental hospital at the turn of the century.
There is a core of services whose specific content varies from place to place that still appears to belong to the state mental hospital.


Nonequilibrium mode-coupling theory for uniformly sheared systems.
We develop a nonequilibrium mode-coupling theory for uniformly sheared systems starting from microscopic, thermostatted Sllod equations of motion. Our theory aims at describing stationary-state properties including rheological ones of sheared systems, and this is accomplished via two steps. First, a set of self-consistent equations is formulated based on the projection-operator formalism and on the mode-coupling approach for the transient density correlators which measure the correlations between the density fluctuations in the initial equilibrium state and the ones at later times after the shearing force is turned on. The transient time-correlation function formalism is then used which, combined with the mode-coupling approximation, expresses stationary-state properties in terms of the transient density correlators. A detailed comparison of our theory is also presented with the related mode-coupling theory which is based on the Smoluchowski equation for Brownian particles under stationary shearing.


The transcription factor PAX2 regulates ADAM10 expression in renal cell carcinoma.
ADAM10 is a metalloprotease that plays an important role in the progression and metastasis of various cancers. In the present study, we present compelling evidence that PAX2 can bind to the promotor of ADAM10 and regulate ADAM10 protein expression in renal cancer cells. We further show that ADAM10 is the major sheddase for the constitutive cleavage of L1-CAM and c-Met, two important proteins involved in the progression of renal cancer. The downregulation of ADAM10 led to a more scattered cell phenotype, which was accompanied by the induction of Slug and the loss of E-cadherin, which is observed during epithelial-to-mesenchymal transition (EMT). In addition, the downregulation of ADAM10 reduced the proliferation but induced the migration of renal cancer cells. Notably, the downregulation of PAX2 led to an increased L1-CAM expression, which was accompanied by a massive metalloprotease-mediated release of soluble L1-CAM. Importantly, soluble L1-CAM induced the proliferation of endothelial cells and the migration of renal cancer cells. Finally, we can demonstrate that the silencing of PAX2 led to an L1-CAM-dependent activation of the PI3K/Akt pathway, one important pathway mediating cancer cell survival. In summary, we identified PAX2 as a regulator of L1-CAM and ADAM10, which play crucial roles in the progression of various cancers including renal cell carcinoma and the downregulation of ADAM10 maybe an earlier step in renal cancer development as it seems to be involved in processes of EMT.


Altered morphology and distribution of cellular junction proteins in non-lesional psoriatic epidermis: an insight into disease severity.
Psoriasis affects 2.7% of the world's population. Keratinocyte proliferation outside the basal layer suggests alterations in cell-cell interactions in affected epidermis. Anomalous expression of proteins forming intercellular junctions has been reported in lesional skin of psoriatic patients. In contrast, little is known about possible alterations in psoriatic non-lesional skin. Ten clinically diagnosed psoriasis vulgaris patients and ten controls were studied. All patients were diagnosed with active but controlled psoriatic plates (PASI 3 to 5) and had not received any systemic treatment. The mean age was 43 years for patients and 43.5 years for controls. Four-mm2 skin samples were taken from lesional and non-lesional zones in patients and from abdomen in controls. Five-mum sections were examined for integrity and structural organization by fluorescent labeling of actin filaments and nuclei. Specific antibodies were utilized to localize occludin, E-cadherin, beta-catenin, and proliferation-specific keratins in sections and epidermal sheets. Samples were also processed for immunoblotting with occludin antibody. Lesional and non-lesional psoriatic epidermis from all patients showed keratinocyte hyperproliferation, lack of rete ridges and dermal papillae in the dermal-epidermal junction in some areas. Proteins forming tight and adherens junctions in non-lesional skin keratinocytes from two patients who during the course of the study evolved to uncontrolled disease, showed similar alterations to those observed in lesional skin of all the patients. However, the occludin isoforms expressed were apparently the same in all samples. Analysis of non-lesional skin in psoriatic patients diagnosed with controlled disease may provide clues about incipient structural abnormalities in the pathogenesis of psoriasis, providing an early diagnostic indicator for evolution to a generalized form of the disease.


Effect of some anthracycline antibiotics on the neuraminidase activity of Sendai virus and its isolated glycoproteins.
Anthracycline antibiotics violamycin BI (VBI) and adriamycin (Adr) strongly inhibited the neuraminidase (NA) activity of Sendai virus and of its isolated glycoproteins, occurring either in solution or associated in liposome-like particles. NA did not exhibit the classical Michaelis-Menten kinetics: the plot of reaction velocity versus substrate concentration was sigmoidal, while Hill's plotting indicated that the enzyme has at least two binding sites for the substrate. The reaction kinetics obtained suggested that Sendai virus NA acts as an allosteric enzyme, when its material support, the HN is located on the virus surface. The inhibitory effect of the anthracycline antibiotics in question on the NA activity seemed to be similar to that of negative effectors.


Preceptorship: a review of the literature.
Preceptorship is an important part of the United Kingdom Central Council for Nursing's (UKCC) post-registration and practice recommendations. Therefore, there is a great need for educationalists and clinical practitioners to explore the issues surrounding preceptorship and come to informed decisions on how they intend to implement preceptor programmes. There is a need to identify existing knowledge and its application to practice based on the commonly occurring themes within the theoretical and empirical literature. This paper reviews the current literature addressing these themes of role definition, preceptor selection, preceptorship programmes, the preceptorship experience and the limitations of preceptorship in clinical practice.


Evaluation of a clinical decision support system for glucose control: impact of protocol modifications on compliance and achievement of glycemic targets.
Treating hyperglycemia may improve patient outcome, but is a clinical challenge. Three variations of a computerized insulin protocol were compared with regard to protocol compliance and achievement of glucose target levels. In group 1, the existing protocol was applied, in group 2 the protocol was modified to account for decreasing glucose values; group 3 had a higher threshold for initiating insulin, wider glucose target ranges, and included instructions to regulate glucose around mealtimes. From July 28, 2008 until February 1, 2010, data from 1255 patients admitted to our Intensive Cardiac Care Unit with at least 2 glucose measurements were analyzed. Mean age was 64 +/- 15 years, 66% were male, 21% had diabetes. Groups 1 to 3 included 269, 814, and 142 patients, respectively. Protocol compliance in group 2 was lower with 44% of the glucose measurements performed on time versus 51% in group 1 (P < 0.001), and insulin was dosed correctly in 57% versus 67% (P < 0.001). In group 3, compliance increased, 52% of the measurements were done on time, and insulin was dosed correctly in 71%. Average glucose levels increased in group 3 due to a higher threshold for starting insulin and a wider target range: 70% (group 1), 66% (group 2), and 61% (group 3) had an average glucose of <8 mmol/L (P < 0.001). Also, we observed a decreasing trend in incidence of hypoglycemia and reporting of noncompliance. Further improvements in glucose measurement technology and protocols are needed to optimally treat hyperglycemia in the Intensive Cardiac Care Unit.


Severe congenital neutropenia: clinical effects and neutrophil function during treatment with granulocyte colony-stimulating factor.
We studied neutrophil function and clinical responses in seven patients with severe congenital neutropenia (SCN) after they received treatment with recombinant human granulocyte colony stimulating factor (rhG-CSF). Two subpopulations of patients with SCN were defined by their pattern of absolute neutrophil response, superoxide production, and cytochrome b559 levels. One group had an oscillating absolute neutrophil count and reduced ability to produce superoxide and cytochrome b559 (n = 4), and the second group had a relatively constant absolute neutrophil count response with normal superoxide and cytochrome levels (n = 3). Neutrophils from both groups had decreased surface expression of FcRIII and abnormal upregulation of the C3bi receptor (CR3). All patient neutrophils, however, had normal contents of the primary granule constituent, beta-glucuronidase, and the specific granule constituent, vitamin B 12 binding protein. The clinical response to rhG-CSF was evident by marked improvement in the degree of periodontitis and reduction in the number of oral ulcers in both groups of patients. Although neutrophil function is not completely normal in patients with SCN, it is likely that enough redundancy exists in neutrophil bactericidal capacity to promote normal host response to inflammation.


[Prevention of psychopathology in children: Interventions for intergenerational transmission].
Children of parents with anxiety or mood disorders have an increased risk of developing an anxiety or mood disorder themselves. A qualitative review of different components of well-studied prevention programs shows that all programs use elements of psychoeducation. Programs that primarily target children often use elements of cognitive behavioral therapy. Programs aimed at the whole family contain components focused on communication between family members and parenting skills. In general, these prevention programs are effective in preventing short- and long-term anxiety/mood disorders and reducing existing symptoms in children. Future research should pay more attention to how and for whom the prevention programs are effective. Primary health care plays an important role in identifying children at risk, underscoring the importance of training professionals in early signaling psychopathology in parents and children. Children with mild complaints could be identified earlier, possibly preventing more serious problems and intensive treatment processes.


Changes in physiology with increasing fat mass.
Obesity has reached epidemic proportions in the USA with a nearly fourfold rise in the prevalence of childhood obesity. There are many possible etiologies of obesity as the adipose tissue plays a significant, complex role in the physiology of fuel metabolism and hormone regulation. The development of obesity represents a pathophysiologic increase in fat mass in which multiple metabolic pathways are deranged. The consequences of these metabolic derangements, including insulin resistance and inflammation, are reflected in obesity-related comorbidities and can be seen in the setting of pediatric obesity. Obese adolescents demonstrate increased rates of early maturation, orthopedic growth abnormalities, diabetes mellitus, obstructive sleep apnea, hypertension, steatosis, and polycystic ovarian syndrome, placing this group of children at risk for long-term health problems and reduced quality of life. Given the negative short- and long-term impact of obesity on children, careful attention should be paid to the unique health issues of this "at-risk" population with both prevention and early intervention strategies.


A study of clinical questions posed by hospital clinicians.
This article presents the results of complementary research studies on the behaviors of hospital clinicians in asking clinical questions and the relationship between asking of questions, outcome of information searches, and success in problem solving. Triangulation in research methods--a combination of mailed questionnaires, interviews, and a randomized controlled study--was employed to provide complementary views of the research problems under study. The survey and interviews found that clinical problems (concerned mainly with therapy and equipment or technology) were expressed as statements rather than questions (average number of concepts = 1.7), that only slightly more than half (higher for doctors) of problems could be solved, and that the majority of clinical questions were not well formed. An educational workshop however improved clinicians' formulation of questions, but the use of structured prompting was found to improve building of hypotheses in the doctors' group without training. The workshop also improved satisfaction with the obtained information and success in problem solving. Nonetheless, for both the experimental and control groups, more structured and complete questions or statements did not mean higher success rates in problem solving or higher satisfaction with obtained information. The triangulation methods have gathered complementary evidence to reject the hypothesis that building well-structured clinical questions would mean higher satisfaction with obtained information and higher success in problem solving.


Advanced glycation end products in Descemet's membrane and their effect on corneal endothelial cell.
[corrected] The purpose of this study was to evaluate the effect of advanced glycation end products (AGEs) in Descemet's membrane on the attachment and spreading of the corneal endothelial cells. An anti-AGEs monoclonal antibody (6D12), which recognizes a N(epsilon)-carboxymethyl lysine (CML)-protein adduct as an epitope, was used for immunohistochemistry and enzyme-linked immunosorbent assay (ELISA). Fresh bovine Descemet's membrane was incubated for 4 weeks in the buffered solution with 500 mM of glucose-6-phosphate (G-6-P). In the incubated Descemet's membrane, the immunohistochemical localization of CML was examined. Type I collagen-, type IV collagen-, fibronectin-, or laminin-coated 96-well plates were glycated by G-6-P. The amount of CML was determined by ELISA using 6D12. Cultured bovine corneal endothelial cells were seeded onto glycated or non-glycated extracellular matrix (ECM) in 96-well plates and allowed to attach for 3 hours. The number and the surface area of the attached cells were examined. Immunoreactivity to CML was detected in Descemet's membrane incubated in the buffered solution containing G-6-P. Glycation of fibronectin and laminin decreased the number and the surface area of the attached corneal endothelial cells. Aminoguanidine in the incubation mixture inhibited CML formation of ECM components and increased the number and the surface area of the attached corneal endothelial cells in a dose-dependent manner. AGE formation on fibronectin and laminin attenuated the attachment and spreading of the corneal endothelial cells. AGEs' formation in Descemet's membrane may be responsible for the corneal endothelial cell loss with aging and corneal endothelial abnormalities in diabetic patients


Time course of diffusion weighted image and apparent diffusion coefficient in acute spinal cord infarction: A case report and review of the literature.
An 80-year-old woman was admitted to our hospital with acute onset of flaccid paraplegia and sensory and urinary disturbances that developed soon after acute pain in her lower back and leg. Neurological examination revealed, severe flaccid paraplegia, bladder and rectal disturbances and dissociated sensory loss below the level of L1 spinal cord segment. MR imaging with T2 weighted imaging (T2WI) and diffusion weighted imaging (DWI) on day 2 showed hyper signal intensity in the spinal cord at the vertebral level of L1 while initial apparent diffusion coefficient (ADC) showed decreased signal intensity in the lesion. We diagnosed spinal cord infarction, and anticoagulant and neuroprotective agents were administrated. Serial MRI findings revealed that the DWI signal of the lesion attenuated with time, and pseudo-normalization of the ADC occurred approximately 1 month after onset. These findings were similar to those seen in brain infarction. Our patient demonstrated serial MRI changes of spinal cord infarction showing anterior spinal cord syndrome.


Influence of monoclonal immunoglobulins in direct determinations of iron in serum.
I compared seven buffers and four chromogens for determining serum iron, to evaluate the frequency of falsely high or low concentrations of iron in 59 sera containing monoclonal immunoglobulins. The results for these direct assays with untreated sera were compared with those obtained by a proposed reference method (Br J Haematol 1978;38:291-4) with protein-free filtrates of the same sera. Sera with monoclonal immunoglobulins sometimes yielded erroneous results; the frequency of errors, which could be as much as 29% (17/59), depended on the composition of buffer and color reagent. Addition of thiourea or a detergent (Triton X-405) to some of the buffers lowered the frequency of errors, but did not abolish them. In only a few of the investigated buffer/chromogen combinations were no errors found. Detection of errors by analyzing the absorbance pattern after mixing sample and buffer was not always successful. Moreover, the presence and magnitude of errors bore no relationship to the type or the concentration of the monoclonal immunoglobulins. Unfortunately, the problem cannot be solved by a simple two- or threefold dilution of the sample.


Environmental effects of large impacts on Mars.
The martian valley networks formed near the end of the period of heavy bombardment of the inner solar system, about 3.5 billion years ago. The largest impacts produced global blankets of very hot ejecta, ranging in thickness from meters to hundreds of meters. Our simulations indicated that the ejecta warmed the surface, keeping it above the freezing point of water for periods ranging from decades to millennia, depending on impactor size, and caused shallow subsurface or polar ice to evaporate or melt. Large impacts also injected steam into the atmosphere from the craters or from water innate to the impactors. From all sources, a typical 100-, 200-, or 250-kilometers asteroid injected about 2, 9, or 16 meters, respectively, of precipitable water into the atmosphere, which eventually rained out at a rate of about 2 meters per year. The rains from a large impact formed rivers and contributed to recharging aquifers.


Anticipatory guidance in type 2 diabetes to improve disease management; next steps after basal insulin.
The alarming rise in the number of people living with type 2 diabetes (T2D) presents primary care physicians with increasing challenges associated with long-term chronic disease care. Studies have shown that the majority of patients are not achieving or maintaining glycemic goals, putting them at risk of a wide range of diabetes-related complications. Disease- and self-management programs have been shown to help patients improve their glycemic control, and are likely to be of particular benefit for patients with diabetes dealing with these issues. Anticipatory guidance is an individualized, proactive approach to patient education and counseling by a health-care professional to support patients in better coping with problems before they arise. It has been shown to improve disease outcomes in a variety of chronic conditions, including diabetes. While important at all stages, anticipatory guidance may be of particular importance during changes in treatment regimens, and especially during transition to, and escalation of, insulin-based regimens. The aim of this article is to provide advice to physicians on anticipatory guidance for basal-insulin dosing, focusing on appropriate basal-insulin-dose increase and prevention of potentially deleterious basal-insulin doses, so called overbasalization. It also provides an overview of new treatment options for patients with T2D who are not well controlled on basal-insulin therapy, fixed-ratio combinations of basal insulin and glucagon-like peptide-1 receptor agonists, and advice on the type of anticipatory guidance needed to ensure safe and appropriate switching to these therapies.


[General surgery and the digestive system: new program, same challenges].
On 8 may 2007, the Official Bulletin (BOE) published the new Specialist Training Program. The Post-Graduate Training Section of the Spanish Surgeons Association (AEC), conscious of the importance of this situation, has carried out a reflective analysis of this Program and proposes a series of objectives. The new plan coordinates a training program that sets out three general objectives as regards, knowledge, skills and attitudes that the resident must assimilate and develop, it strictly defines the final product, without substantially changing the previous program and emphasises two fundamental aspects: training in minimally invasive surgery and research training, although the inclusion of previously unpublished new rotations and the continuation of the current assessment model. The logic in the definition of general surgery as "a major discipline paradigm" should lead to important structural changes. Aspects such as regulating work and training times, European Directives, lack of professional motivation and changes in the vocational spectrum of new residents, will make the optimisation of the results difficult a priori. The year 2017 will be the time to judge the results after five groups of surgeon graduates have been trained by this program.


Induction of apoptosis by hemorrhagic snake venom in vascular endothelial cells.
Vascular degeneration appears to play crucial roles in producing many vascular malfunctions (1-3). In order to identify specific inducers of programmed death in vascular endothelial cells (VEC), examinations were made of the effects of substances that are known to affect the vascular system by using VEC in culture (4,5). We found that hemorrhagic snake venoms induced apoptotic cell death or programmed cell death of VEC. By contrast, neurotoxic snake venoms did not induce programmed cell death but caused necrosis at much higher doses of the venoms. No effect of hemorrhagic venom was observed with many types of cultured cells other than VEC. Thus, hemorrhagic snake venom appears to be a useful tool for studies of the molecular mechanisms of vascular apoptosis. The results also suggest a possible mechanism of action of hemorrhagic snake venom on the vascular system.


Pax6 is essential for lens fiber cell differentiation.
The developing ocular lens provides an excellent model system with which to study the intrinsic and extrinsic cues governing cell differentiation. Although the transcription factors Pax6 and Sox2 have been shown to be essential for lens induction, their later roles during lens fiber differentiation remain largely unknown. Using Cre/loxP mutagenesis, we somatically inactivated Pax6 and Sox2 in the developing mouse lens during differentiation of the secondary lens fibers and explored the regulatory interactions of these two intrinsic factors with the canonical Wnt pathway. Analysis of the Pax6-deficient lenses revealed a requirement for Pax6 in cell cycle exit and differentiation into lens fiber cells. In addition, Pax6 disruption led to apoptosis of lens epithelial cells. We show that Pax6 regulates the Wnt antagonist Sfrp2 in the lens, and that Sox2 expression is upregulated in the Pax6-deficient lenses. However, our study demonstrates that the failure of differentiation following loss of Pax6 is independent of beta-catenin signaling or Sox2 activity. This study reveals that Pax6 is pivotal for initiation of the lens fiber differentiation program in the mammalian eye.


[Epidemiology of H. pylori infection and exploration of its infection route].
To build up a preventive strategy for H. pylori related diseases including gastric cancer, infection ages and routes are important. Recently, several studies have explored them. In advanced countries, most infections occur under five years of age. Mother to child in some studies and sibling to sibling in others were dominant infection routes. As infection ages and routes depend on countries, studies in Japan are indispensable. Infection in kindergartens, nursery and elementary schools as well as in families should be explored. Based on the findings, a strategy preventing infection to children should be build up to prevention H. pylori related diseases.


[Clinical management of genital herpes: what can be done in pregnancy?].
Neonatal herpes infection is the major complication of genital herpes even if it occurs in less than 1/10,000 births. A great number of recent studies illustrates the natural history of genital herpes. The importance of viral transmission by asymptomatic shedding is now well established. The widespread use of viral diagnosis strategies is the prerequisite to efficient genital herpes prevention in order to eradicate viral mother-to-child transmission. This starts with the detection of at-risk situations such as primary infection in late pregnancy. Once the at-risk situation is known there should be concern about the adaptation of treatment strategies including antiviral therapy. The following work proposes different strategies facing each at-risk situation in order to discuss the efficiency of new diagnostic and treatment tools.


Self-help cognitive behavioural therapy for anxiety in pulmonary hypertension: pilot randomised controlled trial.
People with pulmonary hypertension (PH) are at an increased risk of experiencing anxiety disorders. This study developed and tested the acceptability, feasibility and preliminary effectiveness of a cognitive behavioural self-help intervention for anxiety in adults with PH using a pilot randomised control trial design. Individuals with PH recruited from pulmonary hypertension associations were randomised to either receive a newly developed self-help intervention (n=37) or a wait-list condition (n=40). Acceptability was explored using mixed-methods questionnaires. A 2×3 repeated-measures analysis of variance was used to explore anxiety (GAD-7), depression (PHQ-9), health-related quality of life (emPHAsis-10), dyspnoea (D-12), self-mastery (Self-Mastery Scale) and mood-related cognitions and behaviours (CBP-Q) at baseline, post-intervention and 1-month follow up. A mediation analysis was performed to examine potential mechanisms of change. Dropout was low at 15.6%. All participants would recommend the intervention to another person with PH and felt it had helped with their anxiety. Participants in the intervention group reported a reduction in anxiety, depression and cognitive and behavioural processes linked with mood disorders, compared to the control group. Change in unhelpful cognitions and behaviours mediated the relationship between intervention condition and change in anxiety and depression. The intervention was found to be acceptable, feasible and safe. Anxiety at baseline was higher than previously observed, which could be associated with the additional burden caused by COVID-19 as the intervention was trialled during the pandemic. Findings add to the growing evidence supporting the use of psychological therapies, including cognitive behavioural therapy, in this clinical group.


Photoresponse Enhancement in Monolayer ReS2 Phototransistor Decorated with CdSe-CdS-ZnS Quantum Dots.
ReS2 films are considered as a promising candidate for optoelectronic applications due to their direct band gap character and optical/electrical anisotropy. However, the direct band gap in a narrow spectrum and the low absorption of atomically thin flakes weaken the prospect for light-harvesting applications. Here, we developed an efficient approach to enhance the performance of a ReS2-based phototransistor by coupling CdSe-CdS-ZnS core-shell quantum dots. Under 589 nm laser irradiation, the responsivity of the ReS2 phototransistor decorated with quantum dots could be enhanced by more than 25 times (up to ∼654 A/W) and the rising and recovery time can be also reduced to 3.2 and 2.8 s, respectively. The excellent optoelectronic performance is originated from the coupling effect of quantum dots light absorber and cross-linker ligands 1,2-ethanedithiol. Photoexcited electron-hole pairs in quantum dots can separate and transfer efficiently due to the type-II band alignment and charge exchange process at the interface. Our work shows that the simple hybrid zero- and two-dimensional hybrid system can be employed for photodetection applications.


Does schooling buffer the effects of early risk?
The data presented here come from a 20-year study conducted in a rural area of Guatemala. Data on early biological indicators, graduated parameters of social structure, and preschool cognition were combined into a risk scale and analyzed in relation to primary school grade attainment and adolescent psychoeducational test performance. Similar to empirical relations reported in industrialized countries, performance declined as the number of risk factors to which a subject was exposed increased. More important, primary education was observed to buffer the effects of early risk for a subset of subjects. Subjects at high risk who stayed in school performed significantly better than subjects with similar levels of risk who completed fewer than 4 years of primary school.


Diagnostic Imaging of Fetal and Neonatal Abdominal and Soft Tissue Tumors.
Imaging plays a key role in the diagnosis and staging of prenatal and neonatal tumors, and is essential in treatment planning. Though obstetrical ultrasound is the first choice prenatally, fetal MRI continues to play an increasing role as experience with this imaging modality increases. In the neonate, in addition to ultrasound and MRI, CT and nuclear medicine studies can also play an important role. We describe the prenatal and neonatal imaging findings of some of the most common congenital abdominal and soft tissue neoplasms including neuroblastoma, renal, liver and soft tissue tumors.


Pulmonary arterial hypertension in children: a medical update.
Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by a progressive pulmonary vasculopathy with ensuing right heart failure if left untreated. In the 1980's, prior to the current treatment era, idiopathic pulmonary arterial hypertension (IPAH) carried a poor prognosis with a 10 month median survival for children after diagnosis. However, in 1995 continuous intravenous epoprostenol was approved for the treatment of severe PAH, improving hemodynamics, quality of life, exercise capacity, functional class and survival. In the past decade there have been further advances in the treatment of PAH; however, there is still no cure. While much of the groundbreaking clinical research has been performed in adults, children have also seen the benefits of PAH novel therapies. The target population among pediatric patients is expanding with the recent recognition of pulmonary hypertension as a risk factor for sickle cell disease patients. With rapid advances, navigating the literature becomes challenging. A comprehensive review of the most recent literature over the past year on available and emerging novel therapies as well as an approach to target pediatric populations provides insights into the management of pediatric PAH patients.


Effect of calcium ions and inhibitors on internal NAD(P)H dehydrogenases in plant mitochondria.
Both the external oxidation of NADH and NADPH in intact potato (Solanum tuberosum L. cv. Bintje) tuber mitochondria and the rotenone-insensitive internal oxidation of NADPH by inside-out submitochondrial particles were dependent on Ca2+. The stimulation was not due to increased permeability of the inner mitochondrial membrane. Neither the membrane potential nor the latencies of NAD(+)-dependent and NADP(+)-dependent malate dehydrogenases were affected by the addition of Ca2+. The pH dependence and kinetics of Ca(2+)-dependent NADPH oxidation by inside-out submitochondrial particles were studied using three different electron acceptors: O2, duroquinone and ferricyanide. Ca2+ increased the activity with all acceptors with a maximum at neutral pH and an additional minor peak at pH 5.8 with O2 and duroquinone. Without Ca2+, the activity was maximal around pH 6. The Km for NADPH was decreased fourfold with ferricyanide and duroquinone, and twofold with O2 as acceptor, upon addition of Ca2+. The Vmax was not changed with ferricyanide as acceptor, but increased twofold with both duroquinone and O2. Half-maximal stimulation of the NADPH oxidation was found at 3 microM free Ca2+ with both O2 and duroquinone as acceptors. This is the first report of a membrane-bound enzyme inside the inner mitochondrial membrane which is directly dependent on micromolar concentrations of Ca2+. Mersalyl and dicumarol, two potent inhibitors of the external NADH dehydrogenase in plant mitochondria, were found to inhibit internal rotenone-insensitive NAD(P)H oxidation, at the same concentrations and in manners very similar to their effects on the external NAD(P)H oxidation.


Transient symptomatic cryoglobulinemia in gram-negative bacteria infections.
Mixed polyclonal cryoglobulinemia was observed in seven patients suffering from severe gram-negative bacterial infections and/or septicaemias and presenting with arthralgia and purpuric manifestations on admission. Cryoglobulins disappeared after recovery from infection in all of them and were never found during a longterm follow-up. In our opinion, gram-negative bacteria may induce the synthesis of cryoglobulins via a non-specific T-independent B-cell stimulation triggered by cell-wall lipopolysaccharides. This kind of infections, especially if chronic or relapsing, might play a role in the aetiology of some so-called essential mixed cryoglobulinemias.


Multi-measure assessment of adherence to antiretroviral therapy among children under five years living with HIV in Jinja, Uganda.
Adherence to Antiretroviral Therapy (ART) is required to achieve HIV viral load suppression. However, children under 5 years in Jinja, Uganda, had been shown to have low HIV suppression rates. This study aimed to determine the level of ART non-adherence among these children and the associated factors. Data for the cross-sectional study was collected from April to July 2019, from caregivers of 206 children under 5 years living with HIV who were attending health facilities in Jinja and had been on ART for at least 3 months. Non-adherence was measured using a Visual Analog Scale that assessed both dosing and timing non-adherence, and by determining the Proportion of Days Covered by the medication. A questionnaire administered to the caregivers was used to collect the data, together with medical record review. A child was only considered adherent if they had adherence greater than 95% on all the measures. The data was analysed using Modified Poisson Regression, taking a p-value less than 0.05 as statistically significant. Of the 206 children, 73.8% were older than 2 years, and 52.9% were female. Likewise, the majority of caregivers were female (93.7%). Using the combined adherence measure, 57.3% of the children were categorised as non-adherent. School/day-care attendance, Prevalence Ratio (PR) = 1.25 (p = 0.042), the caregiver having higher than a primary school education, PR = 0.72 (p = 0.044) and satisfaction with the quality of service at the health facility, PR = 0.97 (p < 0.001) were associated with non-adherence. Household food insecurity was also associated with non-adherence: PR = 1.55 (p = 0.011) for mild food insecurity, PR = 1.75 (p = 0.001) for moderate insecurity and PR = 1.48 (p = 0.015) for severe food insecurity. Children under 5 years in Jinja had a high level of ART non-adherence. It is important to engage schools to support adherence among children living with HIV. Addressing household food insecurity and improving the quality of paediatric ART services would also reduce the barriers to optimal adherence.


Mancozeb fungicide-induced genotoxic effects, metabolic alterations, and histological changes in the colon and liver of Sprague Dawley rats.
The present study was designed to evaluate genotoxic markers of mancozeb exposure and withdrawal in colon and liver tissues together with histological changes in the gastrointestinal tract of Sprague Dawley rats. Thirty rats were divided into three equal groups; group I: treatment, 250 mg/kg mancozeb dissolved in corn oil administered twice weekly for 7 weeks; group II: withdrawal, the same treatment as group I after which animals were untreated for 5 weeks; group III: control, administered corn oil on the same schedule as group I for 7 weeks. All administrations were by oral gavage. Serum samples were analyzed for biochemical parameters. The comet assay and histopathological examinations were done on liver and colon specimens. The results demonstrated that mancozeb exposure caused significant increases in triglycerides and total cholesterol accompanied by decreases in glucose levels, with extensive DNA damage in liver and colon together with pathological changes in stomach, colon, and liver. Mancozeb withdrawal for 5 weeks improved the lipid and glucose profiles and decreased the degree of DNA damage and changes in the architecture of the stomach, colon, and liver. We concluded that discontinuing exposure to mancozeb fungicide for 5 weeks could ameliorate the adverse effects induced by 7 weeks of exposure to mancozeb. A longer withdrawal time may further reduce the observed genotoxicity.


Accountable care the journey begins.
In healthcare reform legislation, the concept of accountable care organizations (ACOs) has been deliberately broad. Providers' efforts to develop ACOs are likely to proceed on different paths and at different paces in various parts of the country, and some organizations will move faster than others. In deciding which approach to use, a provider should choose a target market, a service area, and a reimbursement methodology; identify the provider structure; design, develop, enhance, and modify core support elements; and identify patient-related and organizational strategies for improvement.