Differentiation of the left- from right-side ventricular septum in acute anterior myocardial infarction by tissue Doppler imaging.
This study was to evaluate the longitudinal and radial function of the left- and right-side ventricular septum (Ls and Rs) in patients with acute anterior myocardial infarction (AMI) by tissue Doppler imaging. Thirty patients with anterior ST-elevation AMI and revascularization and 20 age-matched normal subjects were enrolled as controls. The longitudinal and radial systolic tissue velocity (TV), strain rate (SR) and strain (ɛ) of both Ls and Rs were assessed. In normal, there were no significant differences of longitudinal TV, SR and ɛ between the Ls and Rs. The radial TV was same directed, but larger in Ls than Rs (P < 0.001). The radial SR and ɛ were positive values of Ls and negative values of Rs, but the degrees were similar in both sides. In AMI, longitudinal and radial TV were significantly decreased in both sides. However, longitudinal and radial SR and ɛ were significantly decreased in Ls only (P < 0.001 in all). Fourteen patients with AMI who showed no functional recovery had more reduced radial ɛ of Ls (3.9 ± 1.5% vs. 5.5 ± 2.1%, P = 0.02), but not longitudinal ɛ of Ls than the other 16 patients with recovery. This study showed the ventricular septum can be functionally differentiated the Ls from the Rs, which can be well demonstrated by SR imaging. The impairment of radial rather than longitudinal function of the Ls was related to no functional recovery.


Collaborative study on saccharide quantification of the Haemophilus influenzae type b component in liquid vaccine presentations.
Before release onto the market, it must be demonstrated that the total and free polysaccharide (poly ribosyl-ribitol-phosphate, PRP) content of Haemophilus influenzae type b (Hib) vaccine complies with requirements. However, manufacturers use different methods to assay PRP content: a national control laboratory must establish and validate the relevant manufacturer methodology before using it to determine PRP content. An international study was organised by the World Health Organization (WHO), in collaboration with the Biological Standardisation Programme (BSP) of the Council of Europe/European Directorate for the Quality of Medicines & HealthCare (EDQM) and of the European Union Commission, to verify the suitability of a single method for determining PRP content in liquid pentavalent vaccines (DTwP-HepB-Hib) containing a whole-cell pertussis component. It consists of HCl hydrolysis followed by chromatographic separation and quantification of ribitol on a CarboPac MA1 column using high-performance anion exchange chromatography coupled with pulsed amperometric detection (HPAEC-PAD). The unconjugated, free, PRP is separated from the total PRP using C4 solid-phase extraction cartridges (SPE C4). Ten quality control laboratories performed two independent analyses applying the proposed analytical test protocol to five vaccine samples, including a vaccine lot with sub-potent PRP content and very high free PRP content. Both WHO PRP standard and ribitol reference standard were included as calibrating standards. A significant bias between WHO PRP standard and ribitol reference standard was observed. Study results showed that the proposed analytical method is, in principle, suitable for the intended use provided that a validation is performed as usually expected from quality control laboratories.


Complement activation and increased systemic and pulmonary vascular resistance indices during infusion of postoperatively drained untreated blood.
In nine healthy young patients, operated on for thoracic scoliosis, a pulmonary artery catheter was inserted for the study of haemodynamic variables and blood sampling during autologous transfusion of postoperatively drained blood. At 1-3 h after wound closure, 10 ml kg/body weight of drained untreated blood from the wound was collected and recirculated over a l-h period. The concentration of the complement activation product, C3bc, increased from a mean of 5.4 (SD 1.5) AU ml-1 before infusion to 11.1 (3.9) AU ml-1 during infusion and then returned to 7.8 (2.8) AU ml-1 after infusion. The concentration of the terminal complement complex (TCC) increased from 0.5 (0.2) to 1.3 (0.5) AU ml-1 and was reduced to 0.7 (0.3) AU ml-1 after infusion. Only TCC exceeded the reference values which are 14 AU ml-1 for C3bc and 1.0 AU ml-1 for TCC. Pulmonary vascular resistance index concomitantly increased from a mean of 130 (SD 52) to 195 (88) dyn s cm-5 m-2 and was reduced to 170 (86) dyn s cm-5 m-2 after infusion. Systemic vascular resistance index increased from a mean of 1238 (SD 403) to 1349 (473) dyn s cm-5 m-2 and returned to 1196 (401) dyn s cm-5 m-2 after infusion. White blood cell count (WCC) increased from 14.4 (4.3) x 10(9) litre-1 before infusion to 17.8 (7.2) x 10(9) litre-1 during and after infusion. No change in platelet count during infusion was observed. There were no differences in WCC or platelet count between mixed venous or peripheral arterial blood. Pulmonary and systemic vascular resistance indices may be influenced by activated complement in drained untreated blood when it is recirculated.


Isolation of Platelet-Derived Exosomes from Human Platelet-Rich Plasma: Biochemical and Morphological Characterization.
Platelet-Rich Plasma (PRP) is enriched in molecular messengers with restorative effects on altered tissue environments. Upon activation, platelets release a plethora of growth factors and cytokines, either in free form or encapsulated in exosomes, which have been proven to promote tissue repair and regeneration. Translational research on the potential of exosomes as a safe nanosystem for therapeutic cargo delivery requires standardizing exosome isolation methods along with their molecular and morphological characterization. With this aim, we isolated and characterized the exosomes released by human PRP platelets. Western blot analysis revealed that CaCl2-activated platelets (PLT-Exos-Ca2+) released more exosomes than non-activated ones (PLT-Exos). Moreover, PLT-Exos-Ca2+ exhibited a molecular signature that meets the most up-to-date biochemical criteria for platelet-derived exosomes and possessed morphological features typical of exosomes as assessed by transmission electron microscopy. Array analysis of 105 analytes including growth factors and cytokines showed that PLT-Exos-Ca2+ exhibited lower levels of most analytes compared to PLT-Exos, but relatively higher levels of those consistently validated as components of the protein cargo of platelet exosomes. In summary, the present study provides new insights into the molecular composition of human platelet-derived exosomes and validates a method for isolating highly pure platelet exosomes as a basis for future preclinical studies in regenerative medicine and drug delivery.


Differences in admission rates of children with bronchiolitis by pediatric and general emergency departments.
It is uncertain whether pediatric and general emergency departments have different admitting practices regarding children with bronchiolitis. The objective of this study was to quantify the differences in admission practices between pediatric and general emergency departments of children with bronchiolitis in 1 North American metropolitan area, controlling for various factors such as clinical severity, comorbid conditions, and socioeconomic status. Retrospective cohort review of emergency department visits from April 1992 to March 1997. Five emergency departments (1 pediatric and 4 general) serving the Calgary Health Region, which encompasses approximately 850 000 people. All children residing within the region who visited a regional emergency department and were diagnosed to have bronchiolitis (International Classification of Diseases, Ninth Revision code 466.1, primary or secondary diagnosis). Population-standardized estimates of admission rates. The medical charts of 3091 children diagnosed to have bronchiolitis during the study period were reviewed. Of this number, 2496 children were evaluated at the pediatric emergency department, and 629 (25%) were admitted. The remaining 595 (19%) were evaluated at the general emergency departments, and 221 (37%) were admitted. Controlling for age, gender, estimated family income based on postal code, medical comorbidity, and clinical severity estimated by presenting respiratory rate and room air oxygen saturation, population-standardized estimates for admission rates at the pediatric and general emergency departments were 24% (standard error: 1%) and 43% (standard error: 2%), respectively. Children diagnosed to have bronchiolitis at the Calgary Health Region's pediatric emergency department were about half as likely to be admitted to the hospital as children diagnosed at the region's general emergency departments.


Measures of satisfaction with care during labour and birth: a comparative review.
Satisfaction is the one of the most frequently reported outcome measures for quality of care. Assessment of satisfaction with maternity services is crucial, and psychometrically sound measures are needed if this is to inform health practices. This paper comparatively reviews current measures of satisfaction with care during labour and birth. A review of the literature was conducted. Studies were located through computerised databases and hand searching references of identified articles and reviews. Inclusion criteria were that the questionnaire was a multi-item scale of satisfaction with care during labour and birth, and some form of psychometric information (either information about questionnaire construction, or reliability, or validity) had to be reported. Nine questionnaires of satisfaction with care during labour and birth were identified. Instruments varied in psychometric properties and dimensions. Most described questionnaire construction and tested some form of reliability and validity. Measures were generally not based on the main theoretical models of satisfaction and varied in scope and application to different types of samples (e.g. satisfaction following caesarean section). For an in-depth measure of satisfaction with intrapartum care, the Intrapartal-Specific Quality from the Patient's Perspective questionnaire (QPP-I) is recommended. Brief measures with good reliability and validity are provided by the Six Simple Questions (SSQ) or Perceptions of Care Adjective Checklist (PCACL-R). Despite the interest in measures of satisfaction there are only a small number of validated measures of satisfaction with care during labour and birth. It is important that brief, reliable and valid measures are available for use in general and specific populations in order to assist research and inform practice.


[Immunoenzyme analysis of ovarian metastatic antigen-8].
Immunoenzymatic method for the determination of new ovarian-metastatic antigen-8 in human blood serum was worked out. OMA-8 level was studied in blood serum of 40 healthy women, 40 healthy men, 16 neonates, 33 pregnant women, 103 patients with genital tumours. It was found out that OMA-8 level in blood serum of healthy women changed between 2 to 15.4 micrograms/l, in men between 5-17.0 microgramS/l. OMA-8 concentration higher than 15.4 micrograms/ was considered elevated. The elevated OMA-8 level was marked in neonates (100%) and in pregnant (39.3%). High level was discovered in the amniotic fluid.


The effect of static neck flexion on mechanical and neuromuscular behaviors of the cervical spine.
Occupations that involve sustained or repetitive neck flexion are associated with a higher incidence of neck pain. Little in vivo information is available on the impact of static neck flexion on cervical spinal tissue. The aim of this study was to assess changes in mechanical and neuromuscular behaviors to sustained neck flexion in healthy adults. Sixty healthy subjects aged 20-35 years participated in this study. The participants were exposed to static neck flexion at a fixed angle of full flexion for 10 min. Mechanical and neuromuscular responses of the cervical spine to sudden perturbations were measured pre- and post-exposure. Magnitude of load-relaxation during flexion exposure, stiffness, peak head angular velocity, and reflexive activities of cervical muscles were recorded. Effective neck stiffness decreased significantly, especially in female participants (P = 0.0001). The reflexive response of the cervical erector spinae muscles to head perturbation delayed significantly (P = 0.0001). Peak head angular velocity was significantly increased after exposure to neck flexion for 10 min, especially in female participants (P = 0.001). In the present study, static flexion resulted in changes in mechanical and neuromuscular behavior of the cervical spine, potentially leading to decreased stiffness of the cervical spine. The results confirm the importance of maintaining a correct head and neck position during work and improving the work environment to reduce the cervical spinal load and work-related neck pain.


Human T cells are highly sensitive to suppression of mitogenesis by polycyclic aromatic hydrocarbons and this effect is differentially reversed by alpha-naphthoflavone.
The immunosuppressive effects of polycyclic aromatic hydrocarbons (PAHs) on immune responses in rodents, both in vivo and in vitro, have been widely documented. However, few studies have addressed the immunotoxicity of PAHs in the human system. In this report, we examined the toxic effects of nine different PAHs on human peripheral blood T cell mitogenesis. We found that benzo(a)pyrene (BaP), 3-methylcholanthrene (3-MC), and 7,12-dimethylbenz(a)anthracene (DMBA) were highly immunotoxic in the human system, while dibenz(a,c)anthracene (DAC) and dibenz(a,h)anthracene (DAH) were of intermediate toxicity, 9,10-dimethylanthracene (DMA), benzo(e)pyrene (BeP), and benz(a)anthracene (BA) were mildly immunotoxic, and anthracene (ANTH) had no measureable toxicity at the concentrations tested. Our results using human lymphocytes differed from previous studies in rodents, in that BaP and 3-MC were the most immunotoxic PAHs in the human mitogenesis assay, while DMBA has long been regarded as the PAH that is most potently toxic to rodent T cell responses. We also showed that alpha-naphthoflavone (ANF), which functions as both an Ah receptor antagonist and an inhibitor of cytochrome P450 activity, was able to block the suppressive effects of both BaP and DMBA, but not 3-MC. This suggests that the immunotoxicity of 3-MC may be mediated through a different mechanism than BaP or DMBA. Addition of four different BaP metabolites directly to cultures of human mononuclear cells showed that the 7,8-dihydrodiol metabolite was the most toxic, and that this toxicity could be completely blocked by equimolar and 10-fold greater concentrations of ANF. The 7,8-dihydrodiol metabolite was probably further metabolized to the 7,8-diol epoxide, the toxicity of which could not be effectively reversed by ANF. The 4,5-epoxide metabolite was apparently cytotoxic at high concentrations (10 microM), while the 7-hydroxy metabolite had no overtly negative effects on proliferation.


Systemic nitric oxide production and renal function in nonazotemic human cirrhosis: a reappraisal.
Several studies in human cirrhosis have demonstrated increased nitric oxide (NO) production. In experimental animals, intracerebroventricular administration of NO donors causes a marked depression of the endogenous dopaminergic activity, a function known to be physiologically recruited and exerting a natriuretic function in patients with compensated cirrhosis. The aim of this study is to evaluate the interaction between the systemic plasma levels of NO, the endogenous dopaminergic activity and the main parameters of renal function in patients with liver cirrhosis of differing degrees of severity. A total of 21 patients (11 with preascitic and 10 with nonazotemic diuretic-free ascitic cirrhosis) and 10 healthy control subjects underwent the following tests: a) basal plasma renin activity (PRA) and aldosterone levels; b) renal clearances of sodium, potassium, inulin, para-minohippurate and lithium (the latter being a measure of the fluid delivery to the distal nephron); c) NO systemic plasma levels measured through paramagnetic resonance spectroscopy as nitrosylhemoglobin complexes; d) endogenous dopaminergic activity, evaluated by means of the incremental prolactin and aldosterone plasma levels after dopaminergic blockade with i.v. metoclopramide. NO plasma values and endogenous dopaminergic activity, although significantly increased with respect to healthy controls, were not different in the two groups of patients. The plasma NO/PRA ratio was significantly higher in the group of compensated patients with respect to ascitic cirrhotics (respectively, 18.3 +/- 11.8 vs 3.5 +/- 2.6 A.U./ng/ml/h, p < 0.001). Compared with compensated cirrhotics, patients with ascites showed significantly lower values of glomerular filtration rate (GFR) and renal plasma flow (RPF). Interestingly, GFR values were substantially the same in the ascitic patients and the control subjects. Compensated patients displayed a significant positive correlation between metoclopramide-induced incremental aldosterone plasma levels (i.e., endogenous dopaminergic tone) and fractional excretion of sodium (r = 0.58; p < 0.05). In the group of compensated patients, NO levels correlated inversely with creatinine plasma concentrations (r = -0.85; p < 0.001) and directly with inulin clearance (r = 0.65; p < 0.05). These data show that, at least in compensated cirrhotic patients, the stimulation of systemic NO production and the increased dopaminergic function may be mechanisms preventing renal perfusion, GFR, and fractional excretion of sodium from precocious reductions.


Epidural clonidine or bupivacaine as the sole analgesic agent during and after abdominal surgery: a comparative study.
The rationale of this study was to compare high-dose epidural clonidine with a more commonly used agent, such as bupivacaine. This was performed to give a more objective idea of the relative analgesic potency of epidural clonidine. Sixty patients undergoing intestinal surgery during propofol anesthesia were studied. At induction, the patients received epidurally a dose of 10 micrograms/kg [corrected] clonidine in 7 ml saline followed by an infusion of 6 micrograms [corrected] x kg(-1) x h(-1) (7 ml/h) (group 1, n = 20), a dose of 7 ml bupivacaine, 0.5%, followed by 7 ml/h bupivacaine, 0.25% (group 2, n = 20), or a dose of 7 ml bupivacaine, 0.25%, followed by 7 ml/h bupivacaine, 0.125% (group 3, n = 20). Intraoperatively, increases in arterial blood pressure or heart rate not responding to propofol (0.5 mg/kg) were treated with intravenous alfentanil (0.05 mg/kg). Additional doses of propofol were given to maintain an adequate bispectral index. The epidural infusions were maintained for 12 h. In cases of subjective visual analogue pain scores up to 5 cm at rest or up to 8 cm during coughing, the patients were given access to a patient-controlled analgesia device. During anesthesia, patients in group 1 required less propofol than those in groups 2 and 3 (78 [36-142] mg vs. 229 [184-252] mg and 362 [295-458] mg; P < 0.05) and less alfentanil than patients in group 3 (0 [0-0] mg vs. 11 [6-20] mg; P < 0.05). Analgesia lasted 380 min (range, 180-645 min) in group 1 versus 30 min (range, 25-40 min) in group 2 and 22 min (range, 12.5-42 min) in group 3 (P < 0.05). There was no suggestion of a hemodynamic difference among the three groups except for heart rates that were significantly reduced in patients in group 1. Sedation scores were significantly higher in this group during the first 2 h postoperatively. Our results show that high doses of epidural clonidine potentiate general anesthetics and provide more efficient postoperative analgesia than the two bupivacaine dosage regimens investigated.


Sonotubometry in chronic ear disease.
Aeration of the tympanic cavity was studied after 81 operations were performed on ears with cholesteatoma, in which sonometry was used preoperatively to measure the eustachian tube (ET) function. Twenty-nine of the 44 ears in which all or part of the tympanic mucosa could be preserved had positive sonometric test results, and 25 ears (86%) retained satisfactory aeration. Eight (53%) of the 15 ears with negative test results showed good postoperative aeration while adhesive changes developed in seven ears (47%). In 37 ears after the removal of all tympanic mucosa, aeration was satisfactory in eight (55%) of the 15 ears with positive sonometric test results, whereas only three (14%) of the 22 ears with negative test results developed an aerated tympanum. A positive sonometric test result can be regarded as a fair prognostic indicator of normal ET function. In extensive tympanic disease, there is a clear correlation (86%) between a negative test result and postoperative adhesion.


Fabrication, characterisation and voltammetric studies of gold amalgam nanoparticle modified electrodes.
The tabrication, characterisation, and electroanalytical application of gold and gold amalgam nanoparticles on glassy carbon electrodes is examined. Once the deposition parameters for gold nanoparticle electrodes were optimised, the analytical utility of the electrodes was examined in CrIII electroanalysis. It was found that gold nanoparticle modified (Au-NM) electrodes possess higher sensitivity than gold macroelectrodes. In addition, gold amalgam nanoparticle modified (AuHg-NM) electrodes were fabricated and characterised. The response of those electrodes was recorded in the presence of important environmental analytes (heavy metal cations). It was found AuHg-NM electrodes demonstrate a unique voltammetric behaviour and can be applied for electroanalysis when enhanced sensitivity is crucial.


Children's callous-unemotional traits moderate links between their positive relationships with parents at preschool age and externalizing behavior problems at early school age.
Growing research on children's traits as moderators of links between parenting and developmental outcomes has shown that variations in positivity, warmth, or responsiveness in parent-child relationships are particularly consequential for temperamentally difficult or biologically vulnerable children. But very few studies have addressed the moderating role of children's callous-unemotional (CU) traits, a known serious risk factor for antisocial cascades. We examined children's CU traits as moderators of links between parent-child Mutually Responsive Orientation (MRO) and shared positive affect and future externalizing behavior problems. Participants included 100 two-parent community families of normally developing children, followed longitudinally. MRO and shared positive affect in mother-child and father-child dyads were observed in lengthy, diverse naturalistic contexts when children were 38 and 52 months. Both parents rated children's CU traits at 67 months and their externalizing behavior problems (Oppositional Defiant Disorder and Conduct Disorder) at 67, 80, and 100 months. Children's CU traits moderated links between early positive parent-child relationships and children's future externalizing behavior problems, even after controlling for strong continuity of those problems. For children with elevated CU traits, higher mother-child MRO and father-child shared positive affect predicted a decrease in mother-reported future behavior problems. There were no significant associations for children with relatively lower CU scores. Positive qualities for early relationships, potentially different for mother-child and father-child dyads, can serve as potent factors that decrease probability of antisocial developmental cascades for children who are at risk due to elevated CU traits.


[The effect of nonnutritives weeteners on certain metabolic parameters].
Nonnutritive sweeteners can be found in many other foods apart from soft drinks. Producers of foodstuffs often use a combination of several sweeteners or sweetener and sugar mixes in a single product mainly to achieve a sweeter taste with a lower calorie count. According to the 2012 Scientific Statement of the American Heart and Diabetes Association, reduction of sugar intake plays an important role in establishing an optimal diet and the maintenance of an appropriate body weight. Controlled intervention studies show that during use of calorie-free sweeteners body weight did not change, moreover, in some cases weight even fell. This was also demonstrated in a recently published summary study of randomized controlled studies, according to which calorie-free sweeteners contributed to both loss and maintenance of body weight. According to the summary of the American Dietetic Association, the use of calorie-free sweeteners does not influence the glycemic response and does not increase postprandial blood glucose levels in diabetics. The results thus far, then, show that the use of nonnutritive sweeteners can reduce the consumption of carbohydrates, by which total calorie intake can also be lowered. Their use can promote weight loss and maintenance as well as can help to improve the values of other metabolic parameters (eg. blood sugar, triglycerides). In addition to this, it is important to note that these benefits will not fully materialize if consumption of nonnutritive sweeteners is accompanied by an increase in compensatory caloric intake. Orv. Hetil., 2016, 157(Suppl. 1), 8-13.


[Structure-activity relationships in the quinolone group: antibacterial activity of two new compounds (author's transl)].
Authors describe structure-activity relationships in quinolone group and report a study of the antibacterial activity of two new compounds: pefloxacin and its demethyl derivative, AM-715. These two products take place in the field of researches carried out for extending indications of this group of antimicrobial agents by obtaining derivatives more active, with broader spectrum, less biotransformed and susceptible to be used in general infections and not only in urinary tract infections.


Haemangiopericytoma of the adult male breast.
Haemangiopericytoma is an uncommon, usually benign, soft tissue tumour which has been rarely reported to occur in the female breast. Haemangiopericytoma of the adult male breast has been reported only once before. We report another such case.


Psychoanalysis and medication: is real integration possible?
The author first summarizes historical tensions surrounding the use of medication in psychoanalytic treatments. Next he examines the now-popular viewpoint that clinicians should consider only descriptive criteria in deciding whether to medicate. He then describes how medication use can potentially undermine patients' full integration of psychic experiences. Finally, he presents clinical material to illustrate why clinicians ought to consider patients' defensive processes as a core part of the initial decision about medication use.


Adjuvant chemotherapy for early breast cancer: optimal use of epirubicin.
Anthracyclines are central components of adjuvant combination chemotherapy regimens for early breast cancer. Epirubicin is underutilized for this indication in the United States, where it was approved by the Food and Drug Administration in 1999, compared to Europe and Canada, where it gained approval in 1980. Use of epirubicin offers advantages in specific treatment settings and patient subsets, including situations where use of dose-dense and/or dose-intense protocols may provide additional benefits and where combinations including taxanes and/or trastuzumab may provide increased efficacy. Epirubicin also has a distinct safety profile compared to doxorubicin with regard to cardiotoxicity. In order to optimize treatment benefits and safety concerns for node-positive, node-negative and HER-2-positive patients as well as patients receiving neoadjuvant therapy and elderly patients it is worthwhile to consider the potential benefits of epirubicin.


Role of Bone Marrow-Derived Stem Cells in Polyps Development in Mice with Apc(Min/+) Mutation.
We explored the hypothesis that an altered microenvironment (intestinal adenomatous polyp) could modify the differentiation program of bone marrow-derived stem cells (BMSCs), involving them in colon carcinogenesis. Sublethally irradiated 8-week-old female Apc(Min/+) mice were transplanted with bone marrow (BM) cells obtained from either male age-matched Apc(Min/+) (Apc-Tx-Apc) or wild type (WT) (WT-Tx-Apc) mice. At 4 and 7 weeks after transplantation, BM-derived colonocytes were recognized by colocalization of Y-chromosome and Cdx2 protein (specific colonocyte marker). Polyp number, volume, and grade of dysplasia were not influenced by irradiation/transplantation procedures since they were similar in both untreated female Apc(Min/+) and Apc-Tx-Apc mice. At 4 and 7 weeks after transplantation, a progressive significant reduction of polyp number and volume was observed in WT-Tx-Apc mice. Moreover, the number of WT-Tx-Apc mice with a high-grade dysplastic polyps significantly decreased as compared to Apc-Tx-Apc mice. Finally, at 4 and 7 weeks after transplantation, WT-Tx-Apc mice showed a progressive significant increase of Y+/Cdx2+ cells in "normal" mucosa, whereas, in the adenomatous tissue, Y+/Cdx2+ cells remained substantially unvaried. Our findings demonstrate that WT BMSCs do not participate in polyp development but rather inhibit their growth. The substitution of genotypically altered colonocytes with Y+/Cdx2+ cells probably contributes to this process.


Empirically corrected DFT and semi-empirical methods for non-bonding interactions.
Computational modeling of systems governed by non-bonded interactions, especially van der Waals (dispersion) interactions, is currently a difficult task, since many conventional quantum mechanical techniques neglect such interactions. For example, the popular semi-empirical and Hartree-Fock methods, as well as most DFT methods all neglect long-range dispersion. In attempt to model dispersion interactions at reduced computational expense, one approach is to add an empirical potential to one of the quantum mechanical techniques. This approach has been successfully used to model a large variety of systems that involve, or are governed by, dispersion interactions. The accuracy of empirically-corrected density functional theory (DFT-D) and empirically-corrected semiempirical (SE-D) methods are reviewed here. The analysis considers both the ability to reproduce benchmark energies and geometries.


Nonperturbative and perturbative parts of energy eigenfunctions: a three-orbital schematic shell model.
We study the division of components of energy eigenfunctions, as the expansion of perturbed states in unperturbed states, into nonperturbative and perturbative parts in a three-orbital schematic shell model possessing a chaotic classical limit, the Hamiltonian of which is composed of a Hamiltonian of noninteracting particles and a perturbation. The perturbative parts of eigenfunctions are expanded in a convergent perturbation expansion by making use of the nonperturbative parts. The division is shown to have the property that, when the underlying classical system is chaotic, the statistics of the components of the nonperturbative parts whose relative localization length are close to 1 is in agreement with the prediction of random-matrix theory. When the underlying classical system is mixed, main bodies of most of the eigenfunctions are found to occupy parts of their nonperturbative regions, with some of the rest of the eigenfunctions being "ergodic" in their nonperturbative regions due to avoided level crossings. In case of the classical system being chaotic, most of the eigenfunctions are found "ergodic" or almost "ergodic" in their nonperturbative regions. Numerical results show that the average relative localization length of nonperturbative parts of eigenfunctions is useful in characterizing the behavior of the quantum system in the process of the underlying classical system changing from a mixed system to a chaotic one.


Opioid-prescribing Patterns for Pediatric Patients in the United States.
The opioid crisis in America affects both adults and children. However, knowledge about the epidemiology of the opioid crisis, opioid prescribing patterns, and the link between opioid prescribing and problematic opioid behaviors remain limited. Thus, children are often excluded from health care policies and guidelines aimed at curbing the opioid crises. The primary aim of this topical review is to provide a brief overview of the opioid crises affecting children, followed by a synopsis of recent research on opioid prescribing patterns and data on the links between legitimate opioid use and risk for problematic opioid use behaviors. This is a narrative review. Opioid misuse is a public health crisis facing children and adolescents in the United States and serves as a key antecedent for other problematic opioid behaviors, including opioid use disorder, heroin use, and opioid overdose. Furthermore, the United States experienced a significant increase in opioid prescribing to children and adolescents as compared with prescribing rates before the year 2000. Yet, data on the associations between opioid prescribing patterns and risk for problematic opioid use remains limited. There exist an urgent need to identify adolescents at increased risk for problematic opioid use behaviors following a receipt of medically prescribed opioids. The article closes with some general guidelines that providers may follow to reduce the risk of opioids in pediatric patients.


Viscoelasticity and structure of polystyrene/fumed silica nanocomposites: filler network and hydrodynamic contributions.
We investigate the relationships between structure and linear viscoelasticity of a model polymer nanocomposite system based on a mixture of fumed silica nanoparticles and polystyrene. Alterations in the viscoelastic behavior are attributed to the structuring of primary silica aggregates. Above a critical filler volume fraction, a space-filling network builds up as the result of cluster aggregation, and the complex frequency-dependence of the moduli is simplified by splitting the viscoelasticity of the composites into the independent responses of the suspending polymer melt and the filler network. Specifically, we present a refinement of a two-component model recently proposed for attractive colloidal suspensions, in which hydrodynamic effects related to the presence of the filler are properly taken into account using the concept of shear stress equivalent deformation. Our approach, validated through the building of a master curve of the elastic modulus for samples of different composition, allows the estimation of the elasticity of samples in which the filler network is too tenuous to be appreciated through a simple frequency scan. In addition, the structure of the filler network is studied using both the percolation and fractal approaches, and the reliability of the critical parameters is discussed. We expect that our analysis may be useful for understanding the behavior of a wide variety of complex fluids where the elasticity of the components may be superimposed.


Meta-analysis of lifestyle modification interventions addressing overweight and obesity in preschool-age children.
Increased rates of pediatric obesity extend into early childhood. There have been increasing calls for intervention programs specifically designed to address obesity in preschool-age youth. A review of the literature is critical to guide intervention and future research. The objective of this study was to conduct a meta-analysis of randomized, controlled trials examining the efficacy of lifestyle modification interventions to address overweight and obesity in preschool-age children. Six electronic databases were searched for articles through December 8, 2020. After screening articles for inclusion criteria, 14 articles with 12 randomized, controlled trials (41 effect sizes, 2,525 participants) were included in this meta-analysis. Weighted-standardized mean differences for body mass index-related variables were calculated using random-effects models to estimate effect sizes. Risk of bias assessment was conducted. There was a statistically significant impact of the interventions on child weight outcomes. Cohen's d was .32 (95% CI [.09, .55]). The quality of evidence was assigned a "low" GRADE rating. Lifestyle modification interventions for overweight and obesity in preschool-age children produce small but significant changes in child weight status. However, few new trials have been published in the last 5 years and the quality of evidence in this area is low, limiting confidence in the estimates and the power to examine potential moderator effects. Additional quality, randomized, control trials that report study information consistent with consort guidelines, use intent-to-treatment procedures, assess and report health behaviors and treatment adherence to explore mechanisms of change, and examine sustained effects of interventions are needed. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


[Difficulties in diagnosis of hepatic encephalopathy in ethanol dependent patients].
As a somatic evaluation by outpatient psychotherapy service for alcoholics is being done very rarely the patients are not informed about health harm related to alcohol having the "false feeling of safety". The aim of the study was to evaluate a functional and morphological liver state of patients served by such a service for minimum 5 years who were sent do the Department of Clinical Toxicology via intervention medicine. The changes in the central nervous system were also considered. The West Haven criteria of altered mental state in hepatic encephalopathy were applied. The Number Connection Test, part A and B, and "100-7" test were used to psychometric evaluation. A significantly higher serum ammonia concentration (p<0.02), AST, ALT and GTP enzymes activity, bilirubin (p<0.02), iron (p=0.005) concentration and significantly lower prothrombin index and albumin concentration were found in the group of ethanol dependent patients as compared to the reference group. A significantly lower RBC and platelets number, lower Ht and significantly elevated MCV compared to the control group were also found. The relationship between West Haven criteria and results of laboratory testing was shown: a worse West Haven criteria a worse metabolic disorders. The pathologic changes in the liver ultrasonography and scintigraphy were significantly higher in the group of ethanol dependent patients. The presented observations indicate on necessity of close co-operation between psychologists, therapeutics and clinical toxicologists in early diagnosing and treatment the organ injury in alcohol addicted patients.


Speed of remission in elderly patients with depression: electroconvulsive therapy v. medication.
Severe depression can be a life-threatening disorder, especially in elderly patients. A fast-acting treatment is crucial for this group. Electroconvulsive therapy (ECT) may work faster than medication. To compare the speed of remission using ECT v. medication in elderly in-patients. The speed of remission in in-patients with a DSM-IV diagnosis of major depression (baseline MADRS score ≥20) was compared between 47 participants (mean age 74.0 years, s.d. = 7.4) from an ECT randomised controlled trial (RCT) and 81 participants (mean age 72.2 years, s.d. = 7.6) from a medication RCT (nortriptyline v. venlafaxine). Mean time to remission was 3.1 weeks (s.d. = 1.1) for the ECT group and 4.0 weeks (s.d. = 1.0) for the medication group; the adjusted hazard ratio for remission within 5 weeks (ECT v. medication) was 3.4 (95% CI 1.9-6.2). Considering the substantially higher speed of remission, ECT deserves a more prominent position in the treatment of elderly patients with severe depression.


The World Survey of Cardiac Pacing and Implantable Cardioverter Defibrillators: calendar year 1997--Europe.
The registry of the European Working Group on Cardiac Pacing (EWGCP) is based on the European Pacemaker Identification Card originally designed in July 1978. National registration centers collect the local data and send aggregated annual data to the EWGCP. For 1997, data were obtained from 2,887 hospitals in 20 European countries representing a population of 568 million. Across all participating countries, the median value for all implanted pacemakers was 378 per million population. For initial pacemaker implants, the median value was 290 per million population. Single chamber atrial pacing was important in Denmark, the Netherlands, Poland, Slovak Republic, Spain, and Sweden for the treatment of sick sinus syndrome. Dual chamber pacing accounted for < 50% of initial implants in only 5 of 14 countries for atrioventricular block, and in only 3 of 15 countries for sick sinus syndrome. In 7 of 15 countries, unipolar ventricular leads were used in > or = 50% of cases. In 6 of 14 countries, there was > 15% use of unipolar atrial leads. Nine of 13 countries frequently used atrial active-fixation leads. For the 1997 survey, ICD data were obtained from 16 countries. The total number of ICDs per million population was a median value of 14. Initial ICD implants per million population was 11. Only 3 of 16 countries implanted a total of 30 or more ICDs per million population. Pacing and ICD practices were dependent on the availability of medical and technical resources and influenced by economic constraints inherent in health care administration and insurance coverage patterns.


Regulation of platelet lifespan by apoptosis.
The lifespan of platelets in circulation is brief, close to 10 days in humans and 5 days in mice. Bone marrow residing megakaryocytes produce around 100 billion platelets per day. In a healthy individual, the majority of platelets are not consumed by hemostatic processes, but rather their lifespan is controlled by programmed cell death, a canonical intrinsic apoptosis program. In the last decade, insights from genetically manipulated mouse models and pharmacological developments have helped to define the components of the intrinsic, or mitochondrial, apoptosis pathway that controls platelet lifespan. This review focuses on the molecular regulation of apoptosis in platelet survival, reviews thrombocytopenic conditions linked to enhanced platelet death, examines implications of chemotherapy-induced thrombocytopenia through apoptosis-inducing drugs in cancer therapy as well as discusses ex vivo aging of platelets.


Stability of magistral phage preparations before therapeutic application in patients with chronic rhinosinusitis, sepsis, pulmonary, and musculoskeletal infections.
As antimicrobial resistance becomes more prevalent, the application of (bacterio)phage therapy as an alternative treatment for difficult-to-treat infections is (re)gaining popularity. Over the past decade, numerous promising case reports and series have been published demonstrating the therapeutic potential of phage therapy. However, important questions remain regarding the optimal treatment protocol and, unlike for medicinal products, there are currently no predefined quality standards for the stability of phage preparations. Phage titers can be influenced by several factors which could lead to reduced titers after preparation and storage and, ultimately, subtherapeutic applications. Determining the stability of different phages in different recipients according to the route of administration is therefore one of the first important steps in establishing a standardized protocol for phage therapy.


Unraveling cellular pathways contributing to drug-induced liver injury by dynamical modeling.
Drug-induced liver injury (DILI) is a significant threat to human health and a major problem in drug development. It is hard to predict due to its idiosyncratic nature and which does not show up in animal trials. Hepatic adaptive stress response pathway activation is generally observed in drug-induced liver injury. Dynamical pathway modeling has the potential to foresee adverse effects of drugs before they go in trial. Ordinary differential equation modeling can offer mechanistic insight, and allows us to study the dynamical behavior of stress pathways involved in DILI. Areas covered: This review provides an overview on the progress of the dynamical modeling of stress and death pathways pertinent to DILI, i.e. pathways relevant for oxidative stress, inflammatory stress, DNA damage, unfolded proteins, heat shock and apoptosis. We also discuss the required steps for applying such modeling to the liver. Expert opinion: Despite the strong progress made since the turn of the century, models of stress pathways have only rarely been specifically applied to describe pathway dynamics for DILI. We argue that with minor changes, in some cases only to parameter values, many of these models can be repurposed for application in DILI research. Combining both dynamical models with in vitro testing might offer novel screening methods for the harmful side-effects of drugs.


Characterization of IkappaBalpha nuclear import pathway.
IkappaBalpha controls the transcriptional activity of nuclear factor (NF)-kappaB by retaining it in the cytoplasm; but, when expressed in the nucleus, it can also inhibit the interaction of NF-kappaB with DNA and promote the export of NF-kappaB from the nucleus to the cytoplasm. Here, we report that IkappaBalpha, when not bound to NF-kappaB, is constitutively transported to the nucleus, and we confirm that the interaction of IkappaBalpha with NF-kappaB retains IkappaBalpha in the cytoplasm. Nuclear import of IkappaBalpha does not result from passive diffusion but from a specific energy-dependent transport process that requires the ankyrin repeats of IkappaBalpha. Nuclear accumulation of IkappaBalpha is dependent on importins alpha and beta as well as the small GTPase Ran, which are also responsible for the nuclear import mediated by basic nuclear localization sequences (NLS). However, these proteins are not sufficient to promote IkappaBalpha nuclear translocation. Factor(s) can be removed selectively from cell extracts with ankyrin repeats of IkappaBalpha which strongly reduce import of IkappaBalpha but not of proteins containing basic NLS. These findings indicate that IkappaBalpha is imported in the nucleus by a piggy-back mechanism that involves additional protein(s) containing a basic NLS and able to interact with ankyrin repeats of IkappaBalpha.


Cross-linguistic study of lateral misarticulation using electropalatography.
This paper reports on some preliminary aspects of a collaborative cross-linguistic study of normal and disordered Japanese and British English speech. The investigation compares lateralised productions of parallel s which are abnormal in the two languages. EPG and acoustic recordings were made of four Japanese and four British subjects. The EPG patterns were classified according to certain criteria, such as the presence or absence of complete constriction between the tongue and the hard palate, and the area and location of this contact. Findings revealed that lateralised articulations varied between individual speakers, but that Japanese and English productions were broadly similar. Acoustically, misarticulations in both languages were characterised by a lower frequency of peak energy than would be expected in normal productions.


Use of an ultra short-acting beta-blocker in patients with acute myocardial ischemia.
Esmolol is a new ultra short-acting (half-life [t1/2] beta 9 min) beta 1-adrenergic-receptor antagonist reported to have no intrinsic sympathomimetic activity. The safety and efficacy of esmolol in lowering the ventricular rate and rate-pressure product in patients with acute myocardial infarction (n = 5), postmyocardial infarction angina (n = 10), or acute unstable angina (n = 4), and without cardiogenic shock were studied. After a 30 min observation period, esmolol was titrated to a maximum dose of 300 micrograms/kg/min and infused for up to 420 min. The ventricular rate fell from 92 +/- 11 (mean +/- SD) to 77 +/- 13 beats/min (p less than .01) and the systolic arterial pressure decreased from 120 +/- 13 to 97 +/- 11 mm Hg (p less than .01) during the initial 30 min titration period. There was no significant change during the maintenance phase, and both the ventricular rate and arterial pressure returned rapidly toward baseline values within 30 min of termination of the infusion. The cardiac index fell from 2.8 +/- 0.6 to 2.2 +/- 0.6 liters/min/m2 (p less than .01) during the same period, and also returned to the baseline level 30 min after termination of the infusion. There was no significant change in the pulmonary capillary wedge pressure, respiratory rate, or PR interval. Five patients required termination of infusion because of hypotension and all recovered uneventfully within 30 min of stopping the esmolol. One patient required a brief infusion of dopamine to restore hemodynamic stability.(ABSTRACT TRUNCATED AT 250 WORDS)


Gamma-glutamyl transpeptidase (G.G.T) in leprosy.
Activity of the enzyme gamma-glutamyl transpeptidase (GGT) was measured in 21 patients of BL or LL disease and 10 age matched healthy controls. None of the patients had any systemic or hepatic diseases. Mean values in the patients (53.67 +/- 9.67 U/L) were significantly higher (p less than 0.05) compared to that of controls (34.2 +/- 5.69 U/L).


Clinical use of anti-DFS70 autoantibodies.
The dense fine speckled (DFS) nuclear pattern is one of the most common indirect immunofluorescence (IIF) patterns detected during routine anti-nuclear antibody (ANA) screening. There is a negative association between anti-DFS70 status and systemic autoimmune rheumatic disease (SARD), especially in the absence of concomitant SARD-specific autoantibodies. The purpose of this study was to determine the need for confirming anti-DFS70 status when a DFS pattern is observed in IIF-ANA. The frequency of anti-DFS70 detection on Western blot and the positive rate of connective tissue disease (CTD)-related autoantibody screening with a fluorescence-based enzyme immunoassay was evaluated in DFS (n = 182) and non-DFS (n = 359) groups. Specific autoantibodies against 15 autoantigens were identified by line immunoassay. We evaluated the frequency of cases of DFS mistaken for non-DFS and non-DFS cases mistaken for DFS, as well as the clinical impacts of these misinterpretations. Among cases of IIF-ANA with an observable DFS pattern, 68.1% had only anti-DFS70 without CTD-related autoantibodies, 20.3% were false positive for IIF-ANA, and the remaining 11.5% had CTD-related autoantibodies independent of anti-DFS70 status. These results indicated that CTD-related autoantibodies may be present with or without anti-DFS70 even if a DFS pattern is observed in IIF-ANA. Among patients who are ANA negative or have a low probability of SARD, an anti-DFS70 confirmation test has no clinical benefit and cannot replace specific tests for detecting CTD-related autoantibodies. Specific tests to detect CTD-related autoantibodies should be performed instead of anti-DFS70 confirmation tests when a DFS pattern is observed in IIF-ANA.


Organ donation protocols.
Organ transplantation improves survival and quality of life in patients with end-organ failure. Waiting lists continue to grow across the world despite remarkable advances in the transplantation process, from the creation of public engagement campaigns to the development of critical pathways for the timely identification, referral, approach, and treatment of the potential organ donor. The pathophysiology of dying triggers systemic changes that are intimately related to organ viability. The intensive care management of the potential organ donor optimizes organ function and improves the donation yield, representing a significant step in reducing the mismatch between organ supply and demand. Different beliefs and cultures reflect diverse legislations and donation practices amongst different countries, creating a challenge to standardized practices. Maintaining public trust is necessary for continued progress in organ donation and transplantation, hence the urge for a joint effort in creating uniform protocols that ensure transparent practices within the medical community.


Construction of a contig of BAC clones spanning the region of the apple scab avirulence gene AvrVg.
The ascomycete Venturia inaequalis, causal pathogen of apple scab, underlies a gene-for-gene relationship with its host plant apple (Malus spp.). 'Golden Delicious', one of the most common cultivated apples in the world, carries the ephemeral resistance gene Vg. Avirulence gene AvrVg, matching resistance gene Vg has recently been mapped on the V. inaequalis genome. In this paper, we present the construction of a BAC library from a V. inaequalis AvrVg isolate. The library is composed of 7680 clones, with an average insert size of 80kb. By hybridization, it has been estimated that the library contains six haploid genome equivalents. Thus the V. inaequalis genome can be predicted to be approximately 100Mb in size. A chromosome walk, starting from the marker VirQ5 co-segregating with AvrVg, has been performed using the BAC library. Twelve BAC clones were identified during four steps of the chromosome walking. The size of the resulting contig is approximately 330kb.


[Hemodialysis Patients in Cardiovascular Surgery;Current Status and Management].
Cardiovascular surgery for renal failure patients with dialysis is challenging. According to the nationwide cardiovascular surgery database in Japan(Japan Cardiovascular Surgery Database;JCVSD), dialysis patients have occupied about 10% of whole surgery of coronary artery bypass grafting( CABG). In CABG, ratio of off-pump surgery did not change between non-dialysis (63%) and dialysis (64%) patients. Operative mortality of dialysis patients (7.8%) was 3 times higher than non-dialysis patients (2.1%). In aortic valve replacement (AVR) dialysis patients occupied about 9% of whole AVR in Japan. In dialysis patients the percentage of bioprostheses was 65% and the choice of bioprostheses steeply increased when the age was over 70, which was similar to the non-dialysis patients. For dialysis before cardiovascular surgery, it is important not to dehydrate too much in order to maintain stable hemodynamics during the surgery. It is also important not to dehydrate too much after surgery in order to prevent non-occlusive mesenteric ischemia(NOMI).


Guar Gum-Based Floating Microspheres of Repaglinide Using 32 Factorial Design: Fabrication, Optimization, Characterization, and In Vivo Buoyancy Behavior in Albino Rats.
In this present study, floating microspheres of repaglinide were successfully fabricated by the solvent evaporation technique with varying ratios of guar gum, hydroxypropyl methylcellulose, and ethylcellulose with polyvinyl alcohol. Microspheres were characterized by production yield, particle size, in vitro buoyancy, entrapment efficiency, in vitro drug release, and in vivo floating behavior in albino rats. The formulation process was optimized for stirring speed (X1) and concentration of polymer ratio (X2) on dependent variables such as percentage entrapment efficiency, percentage yield, in vitro buoyancy, and percentage of drug release by the 32 factorial Design-Expert® 12, trial version, software. The optimized formulation was characterized by Fourier transform infrared spectroscopy, powder X-ray diffraction, differential scanning calorimetry, and scanning electron microscopy and was successfully formulated with the highest percentage of cumulative drug release (94.26 ± 3.10), entrapment efficiency (74.70% ± 2.16%), and particle size (50.34 ± 3.67 μm) and remains buoyant for 24 h in simulated gastric fluid (0.1N HCL) with high in vitro buoyancy percent (84.90 ± 2.88). When the drug-polymer solution of dichloromethane and ethanol is dropped in polyvinyl alcohol solution, it leads to the formation of a shell and produces cavities, creating the buoyant nature of floating microspheres. X-ray imaging indicates the uniform distribution and buoyant nature of microspheres in the gastric fluid for a 10-h period.


BRAF Mutations Classes I, II, and III in NSCLC Patients Included in the SLLIP Trial: The Need for a New Pre-Clinical Treatment Rationale.
BRAF V600 mutations have been found in 1-2% of non-small-cell lung cancer (NSCLC) patients, with Food and Drug Administration (FDA) approved treatment of dabrafenib plus trametinib and progression free survival (PFS) of 10.9 months. However, 50-80% of BRAF mutations in lung cancer are non-V600, and can be class II, with intermediate to high kinase activity and RAS independence, or class III, with impaired kinase activity, upstream signaling dependence, and consequently, sensitivity to receptor tyrosine kinase (RTK) inhibitors. Plasma cell-free DNA (cfDNA) of 185 newly diagnosed advanced lung adenocarcinoma patients (Spanish Lung Liquid versus Invasive Biopsy Program, SLLIP, NCT03248089) was examined for BRAF and other alterations with a targeted cfDNA next-generation sequencing (NGS) assay (Guardant360®, Guardant Health Inc., CA, USA), and results were correlated with patient outcome. Cell viability with single or combined RAF, MEK, and SHP2 inhibitors was assessed in cell lines with BRAF class I, II, and III mutations. Out of 185 patients, 22 had BRAF alterations (12%) of which seven patients harbored amplifications (32%) and 17 had BRAF mutations (77%). Of the BRAF mutations, four out of 22 (18%) were V600E and 18/22 (82%) were non-V600. In vitro results confirmed sensitivity of class III and resistance of class I and II BRAF mutations, and BRAF wild type cells to SHP2 inhibition. Concomitant MEK or RAF and SHP2 inhibition showed synergistic effects, especially in the class III BRAF-mutant cell line. Our study indicates that the class of the BRAF mutation may have clinical implications and therefore should be defined in the clinical practice and used to guide therapeutic decisions.


Movement as utopia.
Opposition to utopianism on ontological and political grounds has seemingly relegated it to a potentially dangerous form of antiquated idealism. This conclusion is based on a restrictive view of utopia as excessively ordered panoptic discursive constructions. This overlooks the fact that, from its inception, movement has been central to the utopian tradition. The power of utopianism indeed resides in its ability to instantiate the tension between movement and place that has marked social transformations in the modern era. This tension continues in contemporary discussions of movement-based social processes, particularly international migration and related identity formations, such as open borders transnationalism and cosmopolitanism. Understood as such, utopia remains an ongoing and powerful, albeit problematic instrument of social and political imagination.


Gynaecomastia.
This paper reviews the development of excess breast tissue in the male. Gynaecomastia is a common problem and may have a physiological or pathological basis. It can be dealt with in most cases by reassurance or simple surgery.


Chromosomal rearrangements between tomato and Solanum chilense hamper mapping and breeding of the TYLCV resistance gene Ty-1.
Tomato yellow leaf curl disease, a devastating disease of Solanum lycopersicum (tomato), is caused by a complex of begomoviruses generally referred to as Tomato yellow leaf curl virus (TYLCV). Almost all breeding for TYLCV resistance has been based on the introgression of the Ty-1 resistance locus derived from Solanum chilense LA1969. Knowledge about the exact location of Ty-1 on tomato chromosome 6 will help in understanding the genomic organization of the Ty-1 locus. In this study, we analyze the chromosomal rearrangement and recombination behavior of the chromosomal region where Ty-1 is introgressed. Nineteen markers on tomato chromosome 6 were used in F(2) populations obtained from two commercial hybrids, and showed the presence of a large introgression in both. Fluorescence in situ hybridization (FISH) analysis revealed two chromosomal rearrangements between S. lycopersicum and S. chilense LA1969 in the Ty-1 introgression. Furthermore, a large-scale recombinant screening in the two F(2) populations was performed, and 30 recombinants in the Ty-1 introgression were identified. All recombination events were located on the long arm beyond the inversions, showing that recombination in the inverted region was absent. Disease tests on progenies of informative recombinants with TYLCV mapped Ty-1 to the long arm between markers MSc05732-4 and MSc05732-14, an interval overlapping with the reported Ty-3 region, which led to the indication that Ty-1 and Ty-3 may be allelic. With this study we prove that FISH can be used as a diagnostic tool to aid in the accurate mapping of genes that were introgressed from wild species into cultivated tomato.


Rheology of a sonofluidized granular packing.
We report experimental measurements on the rheology of a dry granular material under a weak level of vibration generated by sound injection. First, we measure the drag force exerted on a wire moving in the bulk. We show that when the driving vibration energy is increased, the effective rheology changes drastically: going from a non-linear dynamical friction behavior --weakly increasing with the velocity-- up to a linear force-velocity regime. We present a simple heuristic model to account for the vanishing of the stress dynamical threshold at a finite vibration intensity and the onset of a linear force-velocity behavior. Second, we measure the drag force on spherical intruders when the dragging velocity, the vibration energy, and the diameters are varied. We evidence a so-called "geometrical hardening" effect for smaller-size intruders and a logarithmic hardening effect for the velocity dependence. We show that this last effect is only weakly dependent on the vibration intensity.


Eosinophilic gastroenteritis: 10 years experience.
Eight patients (five men, three women), mean age 36.9 +/- 13.5 (17-60) yr, were diagnosed to have eosinophilic gastroenteritis. The condition was proved in five patients by biopsies through endoscope, and in three, by operation. All had hypereosinophilia (absolute eosinophil count of 1,337-21,787/cm3). According to Klein classification, two had mucosal disease, three had muscle layer disease, and three, subserosal disease. The most common symptoms were abdominal pain (100%), diarrhea (62.5%), vomiting (62.5%), and nausea (50%). Four patients (50%) had symptoms for more than 1 yr before diagnosis. Barium studies revealed mucosal edema and/or thickening of the small intestinal wall in three cases (including one case with ulceration), partial gastric outlet obstruction in one case, and narrowing of lumen of the terminal ileum in one case. Hypotonic duodenogram revealed double contour in one case. Ultrasound examination revealed thickening of the intestinal wall in two cases; computer tomography revealed thickening of the intestinal wall in one case. All patients were treated with steroid (40 mg/day for initial dose and relapse; 5-10 mg/day for maintenance). The symptoms subsided and the eosinophil counts returned to normal within 2 wk in seven patients and 1 month in one. Of six patients being followed up for 2-10 yr, one had remission, four needed small maintenance dose of steroid, and one suffered from relapse with intestinal perforation.


Prostate cancer in native Japanese and Japanese-American men: effects of dietary differences on prostatic tissue.
To investigate the relationship between diet and prostate cancer (CaP) among native Japanese (NJ) and second-generation or third-generation Japanese-American (J-A) men--focusing on the effects of animal fat and soy on prostatic tissues. The subjects were 50 Japanese men undergoing radical prostatectomy, 25 NJ living in Nagoya, Japan and 25 U.S.-born J-A men, living in Los Angeles, California. A priori, the NJ men were believed to be a low-fat, high-soy group and the J-A men, a high-fat, low-soy group. The studies included postoperative measurements of diet (Block questionnaire), body fat (bioimpedance), blood, urine, and prostatic biomarkers in malignant and adjacent normal tissue, using a tissue microarray made from the original paraffin blocks. The NJ and J-A men were similar in age (65 to 70 years old; P <0.05), prostate-specific antigen level (7.1 to 8.6 ng/mL), prostate volume (35 to 38 cm3), and Gleason score (5.6 to 6.6), but their body composition differed. J-A men had more body fat (24% versus 19%), higher serum triglyceride levels (245 versus 106 mg/dL), lower estradiol levels (27 versus 31 ng/mL), and much lower urinary soy-metabolite levels (1:3) than NJ men (P <0.02). In both NJ and J-A groups, expression of numerous tissue biomarkers separated normal from CaP tissue, including markers for apoptosis (Bcl-2, caspase-3), growth factor receptors (epidermal growth factor receptor), racemase, 5-lipoxygenase, kinase inhibition (p27), and cell proliferation (Ki-67; all P <0.02). Furthermore, within both normal and CaP tissues, caspase-3 and 5-lipoxygenase were expressed more in NJ than in J-A men (P <0.01). Nuclear morphometry showed that the chromatin in each of the four groups (normal versus CaP, NJ versus J-A) was different (area under the curve 85% to 94%, P <0.01), despite fundamental genetic homogeneity. NJ and J-A men, products of similar genetics but differing environments, were shown to have differences in body composition that could influence CaP evolution. The CaP specimens from the NJ and J-A men were histologically similar, but tissue biomarker expression, especially of lipoxygenase and the caspase family, suggested differing mechanisms of carcinogenesis. Differences in nuclear morphometry suggested the additional possibility of gene-nutrient interactions.


Stereospecificity of ginsenoside Rg2 epimers in the protective response against UV-B radiation-induced oxidative stress in human epidermal keratinocytes.
Ginseng, referring to the dried roots of Panax ginseng C.A. Meyer, has been known as a famous traditional folkloric medicine in East Asian countries for a long time. In recent years, it has been gaining a worldwide popularity as a dietary herbal supplement. Ginsenosides are bioactive ingredients that are responsible for most pharmacological efficacies of ginseng. Ginsenoside Rg2 (Rg2), one of minor protopanaxatriol (PPT)-type ginsenosides, exists in two epimeric forms, 20(S)-ginsenoside Rg2 [20(S)-Rg2] and 20(R)-ginsenoside Rg2 [20(R)-Rg2]. This work was undertaken to assess and compare their skin anti-photoaging properties. When they were applied to HaCaT keratinocytes prior to the irradiation, 20(S)-Rg2 only could attenuate the UV-B-induced intracellular reactive oxygen species (ROS) elevation, which were detected using three fluorescent ROS dyes, such as 2',7'-dichlorodihydrofluorescein diacetate, dihydroethidium and dihydrorhodamine 123. 20(S)-Rg2 but not 20(R)-Rg2 significantly attenuated the UV-B-induced promatrix metalloproteinase-2 (proMMP-2) gelatinolytic activity and protein levels. Likewise, 20(S)-Rg2 only augmented the UV-B-reduced total glutathione (GSH) and superoxide dismutase (SOD) activity levels in a concentration-dependent manner. Neither of the two Rg2 epimers was cytotoxic to HaCaT keratinocytes, regardless of UV-B irradiation. Taken together, of the two Rg2 epimers, 20(S)-Rg2 only possesses the stereospecific protective properties against the UV-B-induced skin photoaging in HaCaT keratinocytes.


Relationship between nasal and bronchial responsiveness in perennial allergic rhinitic patients with asthma.
The nasal and bronchial mucosa present similarities and most patients with asthma also have rhinitis, suggesting the concept of 'one airway one disease'. Although many studies may suggest the relationship between nasal and bronchial responsiveness in patients with allergic rhinitis and asthma, few studies have been published which address this question directly. The aim of this study is to investigate whether the relationship between nonspecific nasal and bronchial responsiveness exists in perennial allergic rhinitic patients with asthma. Fifty-one perennial allergic rhinitic patients with the definitive or suspected asthma underwent methacholine bronchial provocation tests and nasal histamine challenge tests. A slope of the absolute changes in nasal symptoms score/log concentrations of histamine was calculated by linear regression analysis. A ratio of the final absolute change in nasal symptoms score to the sum of all the doses of histamine given to the subject was also calculated. The degree of bronchial responsiveness to methacholine was categorized as positive bronchial hyperresponsiveness (BHR) if PC(20) (provocative concentration of methacholine resulting in 20% fall in FEV(1)) was <4 mg/ml, borderline BHR if PC(20) was >or=4 but <or=16 mg/ml, and negative BHR if PC(20) was >16 mg/ml. Another index of bronchial responsiveness (BRindex) was calculated as the log [(% decline in FEV(1)/log final methacholine concentration as mg/dl) + 10]. The geometric means of the slope (4.47 vs. 2.95, p < 0.05) and the ratio (1.68 vs. 0.54, p < 0.01) were higher in patients with positive BHR (n = 23) than in patients with negative BHR (n = 19), respectively. The geometric means of the slope (3.50) and the ratio (1.13) in patients with borderline BHR (n = 9) were between the two groups, respectively. In all patients, the log-slope (r = 0.48, p < 0.001) and the log-ratio (r = 0.51, p < 0.001) were correlated well with the BRindex, respectively. Even in allergic rhinitic patients with definitive asthma, the log-slope was correlated with the BRindex (r = 0.39, p < 0.05) or log-PC(20) (r = -0.36, p < 0.05). The nonspecific nasal responsiveness may be related to the nonspecific bronchial responsiveness in patients with allergic rhinitis and asthma, which may support the viewpoint that allergic rhinitis and asthma represent a continuum of inflammation involving one common airway.


Contact allergy to o-cresol--a sensitizer in phenol-formaldehyde resin.
In patients hypersensitive to phenol formaldehyde resin (PFR) it is, for therapeutic and preventive reasons, important to know the identity of the primary sensitizing substances, their sensitizing capacity, as well as their cross-reaction patterns. When elucidating the issue of cross reactivity in patients with contact allergy to simple methylol phenols (MP), o-cresol was shown to be a contact sensitizer. Besides cross reactivity, contamination of one or more MP(s) in o-cresol as well as o-cresol being a sensitizer of its own in PFR were possible explanations of the simultaneous positive patch test reactions to MP and o-cresol. The aim of this study was to investigate if the simultaneous allergic reactions to PFR and o-cresol could be explained by the presence of this substance in PFR. Patch testing, high-pressure liquid chromatography (HPLC), nuclear magnetic resonance spectrometry (NMR), gas chromatography (GC), and mass spectrometry (MS) were used. o-Cresol was isolated from the specific PFR used in our standard patch test series and identified. The concentration in the resin was 0.066% wt/wt. The current study establishes o-cresol as a contact sensitizer in a PFR. The observed reactions to o-cresol could be on the basis of cross reactivity or primary sensitization.


Impact of additional chromosomal aberrations and BCR-ABL kinase domain mutations on the response to nilotinib in Philadelphia chromosome-positive chronic myeloid leukemia.
Additional chromosomal aberrations in Philadelphia chromosome-positive chronic myeloid leukemia are non-random and strongly associated with disease progression, but their prognostic impact and effect on treatment response is not clear. Point mutations in the BCR-ABL kinase domain are probably the most common mechanisms of imatinib resistance. We assessed the influence of additional chromosomal aberrations and BCR-ABL kinase domain mutations on the response to the second-generation tyrosine kinase inhibitor nilotinib after imatinib-failure. Standard cytogenetic analysis of metaphases was performed to detect additional chromosomal aberrations and the BCR-ABL kinase domain was sequenced to detect point mutations. Among 53 patients with a median follow-up of 16 months, of whom 38, 5 and 10 were in chronic phase, accelerated phase and blast crisis, respectively, 19 (36%) had additional chromosomal aberrations and 20 (38%) had BCR-ABL kinase domain mutations. The 2-year overall survival rate of all patients with-out additional chromosomal aberrations (89%) was higher than that of patients with such aberrations (54%) (P=0.0025). Among patients with chronic phase disease, overall survival at 2 years was 100% and 62% for patients without or with additional chromosomal aberrations, respectively (P=0.0024). BCR-ABL kinase domain mutations were associated with lower remission rates in response to nilotinib, with 9 of 20 (45%) of these patients achieving a major cytogenetic remission as compared to 26 of 33 (79%) patients without mutations (P<0.05). However, overall survival was not affected by BCR-ABL kinase domain mutations. Whereas BCR-ABL kinase domain mutations may confer more specific resistance to nilotinib, which will predominantly affect response rates, the presence of additional chromosomal aberrations may reflect genetic instability and, therefore, intrinsic aggressiveness of the disease which will be less amenable to subsequent alternative treatments and thus negatively affect overall survival. Conventional cytogenetic analyses remain mandatory during follow-up of patients with chronic myeloid leukemia under tyrosine kinase inhibitor therapy.


Effects of anti-inflammatory therapies on recurrent and low-grade respiratory syncytial virus infections in a murine model of asthma.
Recurrent and subclinical viral respiratory tract infections could immunologically exacerbate allergic airway inflammation. However, the most appropriate treatment for virus-induced asthma exacerbation is yet to be established. The effects of glucocorticoids in virus-induced acute asthma are controversial. To determine the effects of representative anti-inflammatory therapies for asthma--glucocorticoids and leukotriene receptor antagonists (LTRAs)--in mite allergen-sensitized and repeatedly low-grade respiratory syncytial virus (RSV)--infected mice. Dermatophagoides farinae-sensitized mice were inoculated twice with low-grade RSV and subcutaneously injected with either a glucocorticoid or an LTRA for 4 consecutive days. Lung inflammation, cytokine profiles, LT production, and viral RNA in lung tissues were compared in 5 groups of 8 mice each: controls, D farinae allergen sensitized, D farinae sensitized and RSV infected, D farinae sensitized and RSV infected with dexamethasone, and D farinae sensitized and RSV infected with pranlukast, an LTRA. Allergic airway inflammation in D farinae mice was significantly enhanced by recurrent and low-grade RSV infections (RLRIs). The glucocorticoid attenuated allergic airway inflammation, which was associated with interleukin 5 (IL-5) and interferon-gamma (IFN-gamma) suppression in lung-draining lymph nodes without affecting viral quantity. The LTRA also attenuated allergic airway inflammation in D farinae-RSV mice with concomitant inhibition of IL-5 but not IFN-gamma. Dermatophagoides farinae allergen sensitization significantly increased LTs in the airway, whereas RLRIs did not further enhance LT production. Glucocorticoids and LTRAs significantly inhibit RLRI-induced exacerbation of allergic airway inflammation by distinct pathways. Dexamethasone suppressed nonspecific cytokines, whereas viral RNA did not increase via suppression of immunity. In contrast, pranlukast specifically inhibited IL-5 but not IFN-gamma.


Promising Oral Compounds for the Treatment of Multiple Sclerosis: A Glance into the Future.
Recently, there have been major advances in the development of disease-modifying treatments for multiple sclerosis (MS) and new promising treatment compounds are on the horizon. The available drugs mainly target inflammatory components of MS; hence, there is an urgent need for new treatment approaches that focus on the neurodegenerative aspects of the disease. Innovative study designs and biomarkers such as neurofilament light chain and brain atrophy measurement could help to identify neuroprotective treatments for the progressive phase of MS.Furthermore, there is increasing knowledge on the impact of dietary factors on MS (e.g., vitamin D). Although their exact role in the pathophysiology of MS is unclear, there are first hints that they might modulate the disease course. Randomized studies are necessary to evaluate the value of substitution therapies for these dietary factors. In this review, the authors focus on promising oral compounds and dietary factors that are in the early development stages for the treatment of MS.


Respi-Care. An innovative home care program for the patient with chronic obstructive pulmonary disease.
The purpose of the present study was to evaluate the effectiveness of a hospital-based home care program for a group of patients with severe COPD. Respi-Care was a multidisciplinary home care program administered by Norwalk Hospital in cooperation with the public health nursing departments of the city of Norwalk and the town of Wilton, Conn. The overall goal of Respi-Care was to provide more comprehensive home care services to patients previously requiring frequent hospitalizations by combining the advantages of hospital resources and community agencies through a unique cooperative effort. Preprogram and on-program data were collected on the following variables for the 48 months of Respi-Care operation: hospitalizations; hospital days; emergency room visits; home care services; and the costs of these services. Costs of operating the Respi-Care program were included in on-program data. Seventeen subjects completed 320.5 months on Respi-Care. Each subject was matched to an equal length of time prior to entering the program, for a total of 641 months analyzed. There were 88 preprogram hospitalizations for the group; hospitalizations while participating in Respi-Care dropped to 53 (p = 0.022; paired t statistics). On-program hospital days showed a significant decrease, from 1,181 preprogram days to 667 on-program days (p = 0.024). Emergency room visits decreased from 105 before the program to 64 during the program (p = 0.017). Costs of care also decreased. Costs for hospitalizations, emergency room visits, and home care fell from $908,031 to $802,999, resulting in a $105,032 savings or $328 per patient per month.(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of alpha-naphthylisothiocyanate-induced liver injury on intestinal adaptation in a rat model of short bowel syndrome.
Progressive hyperbilirubinemia and end-stage liver failure are among the most serious complications of short bowel syndrome (SBS), representing the principle cause of death in a majority of fatal cases. In the current study, we examined the effects of alpha-naphthylisothiocyanate (ANIT)-induced liver injury on intestinal adaptation in a rat model of SBS. Male rats were divided into four groups: Sham rats underwent bowel transection (n = 8), Sham liver-injury rats underwent bowel transection and IP injection of ANIT (100 mg/kg, n = 8), SBS rats underwent a 75% bowel resection, and SBS-ANIT rats underwent bowel resection and liver injury similar to group sham-ANIT (n = 8). Fourteen days after intervention, liver biopsies and intestinal samples were obtained and evaluated for liver damage and measures of intestinal adaptation. Real time PCR and Western blotting were used to determine the level of bax and bcl-2 mRNA and protein, and p-ERK protein levels. Statistical analysis was performed using the one-way ANOVA test, with p < 0.05 considered statistically significant. All ANIT-treated animals exhibited histological evidence of liver damage that was associated with the expansion of atypical ductal proliferation near the periportal areas, intense neutrophil infiltration in the liver, increased mitotic activity, Kupfer cells hyperplasia and fatty liver degeneration. ANIT-induced liver damage in bowel resected animals was associated with a significant decrease in all parameters of intestinal adaptation including bowel and mucosal weight in jejunum (twofold decrease) and ileum (twofold decrease), mucosal DNA in jejunum (fourfold decrease), mucosal protein in jejunum (threefold decrease) and ileum (threefold decrease), villus height in jejunum (38%) and ileum (34%), and crypt depth in jejunum (24%) and ileum (30%) compared to SBS animals. Both Sham-ANIT and SBS-ANIT rats demonstrated decreased enterocyte proliferation rates that were accompanied by decreased p-ERK protein levels. Lower apoptotic rates in jejunum (40%) and ileum (52%) in SBS-ANIT rats (vs. SBS) coincided with decreased bax mRNA and protein levels. In a rat model of SBS, ANIT-induced liver injury was associated with decreased enterocyte proliferation and inhibited intestinal adaptation.


Transfer of Lipophilic Drugs from Nanoemulsions into Lipid-Containing Alginate Microspheres.
Knowledge about the release behavior and drug retention properties of colloidal carriers is of essential importance for quality control as well as to predict in vivo performance. When conducting release studies from such systems, the release media should preferentially contain lipophilic acceptor components in order to mimic physiological conditions. In this study, transfer from a trimyristin nanoemulsion into lipid-containing hydrogel beads was investigated for fenofibrate, cannabidiol, retinyl acetate, orlistat, and lumefantrine. To generate the acceptor system, a trimyristin nanoemulsion was incorporated into Ca-alginate microspheres (mean diameter ~40 µm) with a spraying method. Using this approach, the advantages of small lipophilic acceptor particles with a large interfacial area were combined with a single separation process from the donor via a filtration step. The method was applicable to distinguish between fast (fenofibrate) and slow drug transfer (lumefantrine) with good time resolution. Lipophilicity, estimated according to the calculated logP value of the respective drug, was a major factor influencing the transfer performance: the higher the logP value, the slower the transfer. This experimental setup is a promising technique to investigate the release of poorly water-soluble drugs from various types of nanocarriers under closer to physiological conditions than with many other methods currently applied.


High-intensity exercise training does not influence body weight but improves lipid oxidation in obese adults: a 6-week RCT.
This study examined the effects of 6 weeks of high-intensity training (HIT) on lipid oxidation (LO) rates during incremental exercises in obese adults. Twenty-four obese adults were randomised into a no-exercise control group (n=12; body mass index=33.3 (4.8) kg.m-2) and a HIT group (18 sessions of 6×6 s of supramaximal cycling and 2 min passive intervals; n=12; body mass index=33.2 (2.8)kg.m-2). The percentage of LO contribution was computed at rest and for all workloads (25, 50, 75, 100 and 125 W) in both groups before and after training via a graded maximal cycling test. After training, the HIT group showed significantly higher LO at rest and at 25, 50 and 75 W compared with baseline (p<0.01) and the control group (p<0.01). Moreover, for the training group, the homoeostasis model assessment of insulin resistance (HOMA-IR) index decreased significantly from the baseline value (p<0.01) and the control group value (p<0.01). The increases in LO observed at rest and stages 25, 50 and 75 W were positively correlated with the declines in the HOMA-IR index (r=0.87, r=0.83, r=0.91 and r=0.88; p<0.01). In obese adults, HIT increased lipid contributions to energy release at rest and in response to incremental exercise, while there were no changes in participants' aerobic capacity. This supports the hypothesis that metabolic changes rather than improved aerobic capacity are important to improve LO. ISRCTN66508384. Stage: post-results.


Organic field effect transistor using pentacene single crystals grown by a liquid-phase crystallization process.
Nearly perfect pentacene single crystals with wide terraces several micrometers in width were grown by crystallization from a pentacene-containing trichlorobenzene solution. Organic field-effect transistors (OFETs) were fabricated with the pentacene single crystals and characterized for their electrical properties. The field effect mobility was found to be in the range of 0.4-0.6 cm(2)/V x s, which is comparable to that of OFETs fabricated with pentacene single crystals prepared by a physical vapor-phase growth method. The results described in this paper clearly demonstrate that the crystallization of organic semiconductors from solution is a promising chemical method for device processing of OFETs.


Adenocarcinoma of the rete testis. Case report, ultrastructural observations, and clinicopathologic correlates.
Adenocarcinoma of the rete testis is a rare tumor that tends to occur in men over the age of 60 and is usually associated with a poor prognosis. We report such a tumor occurring in a 63-year-old male 2 years after he underwent a scrotal exploration in the management of a hydrocele, varicocele, and inguinal hernia. The postorchidectomy course was characterized by slowly advancing, painful scrotal and perineal skin recurrences, lymph node metastases, and the absence of response to Adriamycin and electron-beam therapy. We are confident that the lesion is a carcinoma of the rete testis because: 1) the tumor is situated mainly in the testicular mediastinum, 2) primary germinal and nongerminal testicular tumors and spread from distant sources have been excluded, 3) a transition from normal rete testis to atypical and neoplastic rete epithelium is demonstrable, and 4) the transmission electron-microscopic findings support our conclusion. The distinction between carcinoma of the rete testis and malignant mesothelioma may be difficult and requires consideration of the gross, light-microscopic, and ultrastructural tumor characteristics in optimally fixed tissue.


Atrial and ventricular septal defects can safely be closed by percutaneous intervention.
Various transcatheter devices and methods to close congenital heart defects are currently available. Devices have been designed specifically for atrial septal defect (ASD), patent foramen ovale (PFO), and ventricular septal defect (VSD) closure. The trend in interventional treatment of intracardiac shunts shows toward defect-specific systems. The PFO is a tunnel defect requiring occluders that adapt to its length while common ASD strongly vary in their diameter, making a large scale of device sizes indispensable. VSDs are predominantly sealed by coils or tissue-adapted devices like muscular or perimembranous occluders. Since VSDs may occur with an aneurysm (VSA), a multi-perforated septum, an instable myocardial situation (postinfarction) or a high interventricular pressure gradient, closure of these defects is regarded sometimes as complicated. But during the last 30 years (since King and Mills implanted the first double-umbrella occluding system) several studies have proven procedure efficacy and safety of both ASD and VSD closure. This article reviews a large scale of studies and includes our single center data on 1,609 PFO, ASD, and VSD patients.


Cognitive, Psychiatric, and Motor Symptoms-Based Algorithmic Approach to Differentiate Among Various Types of Dementia Syndromes.
It may be difficult to distinguish among the various dementia syndromes due to the overlap in many common clinical features across the dementias. Accurate diagnosis of dementia type is increasingly important in an era when promising disease-modifying agents can be marketed soon. In this review, we outline a clinical algorithmic approach particularly tailored to the major forms of dementia in the clinic and refined from our accumulated experience of these patients. We first present an algorithmic approach for patients presenting with predominant deficits in episodic memory, executive function, language, visuospatial, and apraxia. We then consider types of dementia that mainly cause behavioral and psychiatric changes. Finally, we illustrate clinical pearls regarding motor deficits as key associations of each syndrome.


HO-1 mitigates acute kidney injury and subsequent kidney-lung cross-talk.
Ischemia-reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI), which contributes to the development of chronic kidney disease (CKD). IRI-induced AKI releases proinflammatory cytokines (e.g. IL-1β, TNF-α, IL-6) that induce a systemic inflammatory response, resulting in proinflammatory cells recruitment and remote organ damage. AKI is associated with poor outcomes, particularly when extrarenal complications or distant organ injuries occur. Acute lung injury (ALI) is a major remote organ dysfunction associated with AKI. Hence, kidney-lung cross-talk remains a clinical challenge, especially in critically ill population. The stress-responsive enzyme, heme oxygenase-1 (HO-1) is largely known to protect against renal IRI and may be preventively induced using hemin prior to renal insult. However, the use of hemin-induced HO-1 to prevent AKI-induced ALI remains poorly investigated. Mice received an intraperitoneal injection of hemin or sterile saline 1 day prior to surgery. Twenty-four hours later, mice underwent bilateral renal IRI for 26 min or sham surgery. After 4 or 24 h of reperfusion, mice were sacrificed. Hemin-induced HO-1 improved renal outcomes after IRI (i.e. fewer renal damage, renal inflammation, and oxidative stress). This protective effect was associated with a dampened systemic inflammation (i.e. IL-6 and KC). Subsequently, mitigated lung inflammation was found in hemin-treated mice (i.e. neutrophils influx and lung KC). The present study demonstrates that hemin-induced HO-1 controls the magnitude of renal IRI and the subsequent AKI-induced ALI. Therefore, targeting HO-1 represents a promising approach to prevent the impact of renal IRI on distant organs, such as lung.


Transcriptional repression of peri-implantation EMX2 expression in mammalian reproduction by HOXA10.
HOXA10 is necessary for mammalian reproduction; however, its transcriptional targets are not completely defined. EMX2, a divergent homeobox gene, is necessary for urogenital tract development. In these studies we identify and characterize the regulation of EMX2 by HOXA10. By using Northern analysis and in situ hybridization, we found that EMX2 is expressed in the adult urogenital tract in an inverse temporal pattern from HOXA10, suggestive of a negative regulatory relationship. Constitutive expression of HOXA10 diminished EMX2 mRNA, whereas blocking HOXA10 through the use of antisense resulted in high EMX2 mRNA expression. Deletional analysis of the EMX2 5' regulatory region revealed that a 150-bp element mediated transcriptional repression when cotransfected with pcDNA3.1/HOXA10 in transient-transfection assays. Binding of HOXA10 protein to this element was demonstrated by electrophoretic mobility shift assay and further localized to a consensus HOXA10 binding site within this element by DNase I footprinting. Site-directed mutagenesis abolished binding, as well as the negative transcriptional regulation. Transcriptional activation of empty spiracles, the Drosophila ortholog of EMX2, by Abdominal-B (HOXA10 ortholog) has been previously demonstrated. These findings demonstrate conservation of the transcription factor-target gene relationship, although the direction of regulation is reversed with possible evolutionary implications.


Sleep as a component of the performance triad: the importance of sleep in a military population.
Sleep habits among military populations are problematic. Poor sleep hygiene occurs in parallel with the global increase in obesity and metabolic syndrome and contributes to a decrease in performance. The extent of sleep issues needs to be quantified to provide feedback for optimizing warfighter performance and readiness. This study assessed various health behaviors and habits of US Army Soldiers and their relationship with poor sleep quality by introducing a set of new questions into the Comprehensive Soldier and Family Fitness (CSF2) Global Assessment Tool (GAT). Subjects included 14,148 US Army Active, Reserve, and National Guard members (83.4% male) who completed the GAT, a self-report questionnaire that measures 4 fitness dimensions: social, family, emotional, and spiritual. Approximately 60 new questions, including ones on sleep quality, within the fifth CSF2 dimension (physical) were also answered. A sleep score was calculated from 2 questions validated in the Pittsburgh Insomnia Rating Scale (0 to 6). Poor sleepers (5-6) were significantly (P<.001) more likely than good sleepers (0-1) to consider themselves in fair or poor health, be overweight or obese, and score in the lowest quartile of the emotional, social, family, and spiritual fitness dimensions. Additionally, poor sleepers were significantly (P<.001) less likely to have a healthy body mass index and waist circumference, eat breakfast 6 or more times a week, meet aerobic exercise and resistance training recommendations, and pass their Army Physical Fitness Test in the top quartile. This study examined sleep quality in a group of military personnel and indicated significant associations between quality of sleep and physical performance, nutritional habits, measures of obesity, lifestyle behaviors and measures of psychosocial status. Targeted educational interventions and resources are needed to improve sleep patterns based on behaviors that can be most easily modified.


The noncoding small RNA SsrA is released by Vibrio fischeri and modulates critical host responses.
The regulatory noncoding small RNAs (sRNAs) of bacteria are key elements influencing gene expression; however, there has been little evidence that beneficial bacteria use these molecules to communicate with their animal hosts. We report here that the bacterial sRNA SsrA plays an essential role in the light-organ symbiosis between Vibrio fischeri and the squid Euprymna scolopes. The symbionts load SsrA into outer membrane vesicles, which are transported specifically into the epithelial cells surrounding the symbiont population in the light organ. Although an SsrA-deletion mutant (ΔssrA) colonized the host to a normal level after 24 h, it produced only 2/10 the luminescence per bacterium, and its persistence began to decline by 48 h. The host's response to colonization by the ΔssrA strain was also abnormal: the epithelial cells underwent premature swelling, and host robustness was reduced. Most notably, when colonized by the ΔssrA strain, the light organ differentially up-regulated 10 genes, including several encoding heightened immune-function or antimicrobial activities. This study reveals the potential for a bacterial symbiont's sRNAs not only to control its own activities but also to trigger critical responses promoting homeostasis in its host. In the absence of this communication, there are dramatic fitness consequences for both partners.


The Therapeutic Effect and In Vivo Assessment of Palmitoyl-GDPH on the Wound Healing Process.
The standard treatment of open wounds via the direct usage of therapeutic agents is not without limitations with respect to healing. Small peptides can create a favorable milieu for accelerating the healing of wounds. This study presents the potential of a novel fatty acid conjugated tetrapeptide (palmitic acid-glycine-aspartic acid-proline-histidine; Palmitoyl-GDPH) in alleviating wound healing. Tetracycline was employed as a standard control drug following its significance in wound healing including biologically active and antimicrobial effects. The peptide in liquid form was applied on to a 4 cm2 full thickness wound surgically induced at the dorsum of Sprague Dawley (SD) rats. The in vivo wound treatment with Palmitoyl-GDPH for eighteen days, histologically demonstrated an almost perfect healing exhibited by increased re-epithelialization, enhanced collagen deposition, and diminished scar formation compared to the controls. In addition, the well-developed epidermal-dermal junction and ultimate stimulation of hair follicle-growth in the Palmitoyl-GDPH treated group indicated the wound to have healed as functionally viable tissues. In general, the much lower hemogram values in the Palmitoyl-GDPH group indicated that the ongoing healing is en route to an earlier recovery. Additionally, the liver, kidney, and pancreas function biomarkers being within normal limits indicated the relatively non-toxic nature of Palmitoyl-GDPH at the used dosage. These results indisputably supported the great potential of this newly synthesized Palmitoyl-GDPH to be used as an effective therapeutic agent for wound healing (this actually means creating a new wound).


Introduction of disease-related mitochondrial DNA deletions into HeLa cells lacking mitochondrial DNA results in mitochondrial dysfunction.
Mutant mitochondrial DNA with large-scale deletions (delta-mtDNA) has been frequently observed in patients with chronic progressive external ophthalmoplegia (CPEO), a subgroup of the mitochondrial encephalomyopathies. To exclude involvement of the nuclear genome in expression of the mitochondrial dysfunction characteristic of CPEO, we introduced the mtDNA of a CPEO patient into clonal mtDNA-less HeLa cells and isolated cybrid clones. Quantitation of delta-mtDNA in the cybrids revealed that delta-mtDNA was selectively propagated with higher levels of delta-mtDNA correlating with slower cellular growth rate. In these cybrid clones, translational complementation of the missing tRNAs occurred only when delta-mtDNA was less than 60% of the total mtDNA, whereas accumulation of delta-mtDNA to greater than 60% resulted in progressive inhibition of overall mitochondrial translation as well as reduction of cytochrome c oxidase activity throughout the organelle population. Because these cybrids shared the same nuclear background as HeLa cells, these results suggest that large-scale deletion mutations of mtDNA alone are sufficient for the mitochondrial dysfunction characteristic of CPEO.