Efficacy of levamisole, ivermectin and moxidectin against Capillaria spp. in European hedgehogs (Erinaceus europaeus).
This randomised study aimed to assess and compare the efficacy of treatment protocols containing levamisole, ivermectin, or moxidectin against Capillaria spp. in naturally infected European hedgehogs (Erinaceus europaeus) presented to a British wildlife rehabilitation centre. Faecal analysis, consisting of wet mount and flotation, was performed for 229 hedgehogs weighing ≥200g. Animals testing positive for Capillaria spp. (81%), excluding pregnant females, were randomly allocated a treatment protocol. Initially, hedgehogs (n = 50) received one of six 'pilot' protocols, whereas the remaining animals (n = 97) received one of three 'main' protocols. Faecal analysis was repeated on day 8 and day 12 after treatment initiation. Efficacy of each treatment was assessed based on Capillaria reduction rate (CRR), weight gain, presence of respiratory clinical signs, and outcome. Pilot protocols containing only moxidectin had a significantly lower CRR (≥28.1%) compared to those with levamisole or ivermectin (≥86.6%), whereas the main protocols containing levamisole had a significantly higher CRR (≥93.0%) compared to those containing only ivermectin (≥69.3%). Clinical parameters did not differ significantly between treatments, but animals with respiratory clinical signs at the end of the trial were significantly more likely to have lower CRR and test positive for Crenosoma striatum. C. striatum often appeared refractory to treatment, and managing these infections requires additional anthelmintic therapy. Based on the formulations and dosages trialled, moxidectin is not recommended for treating capillariosis in European hedgehogs, whereas levamisole given orally for two consecutive days at 25-35 mg/kg is suggested as the treatment of choice.


Longitudinal MRI atrophy biomarkers: relationship to conversion in the ADNI cohort.
Atrophic changes in early Alzheimer's disease (AD) and amnestic mild cognitive impairment (MCI) have been proposed as biomarkers for detection and monitoring. We analyzed magnetic resonance imaging (MRI) atrophy rate from baseline to 1 year in 4 groups of participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI): AD (n = 152), converters from MCI to probable AD (MCI-C, n = 60), stable MCI (MCI-S, n = 261), and healthy controls (HC, n = 200). Scans were analyzed using multiple methods, including voxel-based morphometry (VBM), regions of interest (ROIs), and automated parcellation, permitting comparison of annual percent change (APC) in neurodegeneration markers. Effect sizes and the sample required to detect 25% reduction in atrophy rates were calculated. The influence of APOE genotype on APC was also evaluated. AD patients and converters from MCI to probable AD demonstrated high atrophy APCs across regions compared with minimal change in healthy controls. Stable MCI subjects showed intermediate atrophy rates. APOE genotype was associated with APC in key regions. In sum, APC rates are influenced by APOE genotype, imminent MCI to AD conversion, and AD-related neurodegeneration.


MassKinetics: a theoretical model of mass spectra incorporating physical processes, reaction kinetics and mathematical descriptions.
A theoretical framework and an accompanying computer program (MassKinetics, www.chemres.hu/ms/ masskinetics) is developed for describing reaction kinetics under statistical, but non-equilibrium, conditions, i.e. those applying to mass spectrometry. In this model all the important physical processes influencing product distributions are considered: reactions, including the effects of acceleration, collisions and photon exchange. These processes occur simultaneously and are taken into account by the master equation approach. The system is described by (independent) product, kinetic energy and internal energy distributions, and the time development of these distributions is studied using transition probability functions. The product distribution at the end of the experiment corresponds to the mass spectrum. Individual elements in this scheme are mostly well known: internal energy-dependent reaction rates are calculated by transition state theory (RRK or RRKM formalisms). In the course of collisions, energy transfer and other processes may occur (the latter usually resulting in the 'loss' of ion signal). Collisions are characterized by their probability and by energy transfer in a single collision. To describe single collisions, three collision models are used: long-lived collision complexes, partially inelastic collisions and partially inelastic collisions with cooling. The latter type has been developed here, and is capable of accounting for cooling effects occurring in collision cascades. Descriptions of photon absorption and emission are well known in principle, and these are also taken into account, in addition to changes in kinetic energy due to external (electric) fields. These changes in the system occur simultaneously, and are described by master equations (a set of differential equations). The usual form of the master equation (taking into account reactions and collisional excitation) was extended to consider also radiative energy transfer, kinetic energy changes, energy partitioning and ion loss collisions. Initial results show that close to experimental accuracy can be obtained with MassKinetics, using few or no adjustable parameters. The model/program can be used to model almost all types of mass spectrometric experiments (e.g. MIKE, CID, SORI and resonant excitation). Note that it was designed for mass spectrometric applications, but can also be used to study reaction kinetics in other non-equilibrium systems.


Hypertension and endothelial dysfunction in apolipoprotein E knockout mice.
Mice lacking ApoE (Apoe(-/-)) develop initially hypercholesterolemia and lastly atherosclerosis. This study examined hemodynamics and endothelial function in 6-week-old Apoe(-/-) mice with hypercholesterolemia only, 7.5-months-old Apoe(-/-) mice with both hypercholesterolemia and atherosclerosis, and age matched controls. One day after implantation of catheters into the carotid artery, arterial pressure was measured in conscious, unrestrained mice. Compared with the respective controls, there was a significant increase in arterial pressure and the ratio of left ventricular weight to body weight in 7.5-month-old Apoe(-/-) mice but not in 6-week-old Apoe(-/-) mice. Histopathological analysis demonstrated significant renal artery disease in the form of extensive atheromatous plaques only in 7.5-month-old Apoe(-/-) mice, whereas no atherosclerotic lesions were found in 6-week-old Apoe(-/-) mice. For evaluation of endothelial function, a laser Doppler perfusion imager with a computer-controlled optical scanner was used to measure cutaneous blood perfusion on the dorsal side of one hind paw before and after topical application of mustard oil, which is known to induce nitric oxide-mediated vasodilation. The mustard oil treatment elicited a substantial increase in blood perfusion (P<0.01), which was similar between 6-week-old Apoe(-/-) mice and controls but significantly blunted in 7.5-month-old Apoe(-/-) mice versus control mice, suggesting nitric oxide-mediated vasodilation is diminished in 7.5-month-old Apoe(-/-) mice but not in 6-week-old Apoe(-/-) mice. In contrast, the increase in blood perfusion induced by topical administration of cilostazol, which induces vasodilation via cyclic adenosine monophosphate, was not different between 7.5-month-old Apoe(-/-) mice and controls. Thus hypertension and endothelial dysfunction observed in 7.5-month-old Apoe(-/-) mice may be due mainly to atherosclerosis.


Contact Ion Pairs in the Bulk Affect Anion Interactions with Poly(N-isopropylacrylamide).
Salt effects on the solubility of uncharged polymers in aqueous solutions are usually dominated by anions, while the role of the cation with which they are paired is often ignored. In this study, we examine the influence of three aqueous metal iodide salt solutions (LiI, NaI, and CsI) on the phase transition temperature of poly(N-isopropylacrylamide) (PNIPAM) by measuring the turbidity change of the solutions. Weakly hydrated anions, such as iodide, are known to interact with the polymer and thereby lead to salting-in behavior at low salt concentration followed by salting-out behavior at higher salt concentration. When varying the cation type, an unexpected salting-out trend is observed at higher salt concentrations, Cs+ > Na+ > Li+. Using molecular dynamics simulations, it is demonstrated that this originates from contact ion pair formation in the bulk solution, which introduces a competition for iodide ions between the polymer and cations. The weakly hydrated cation, Cs+, forms contact ion pairs with I- in the bulk solution, leading to depletion of CsI from the polymer-water interface. Microscopically, this is correlated with the repulsion of iodide ions from the amide moiety.


The limits of aerial and contact techniques for producing twist in reverse 1½ somersault dives.
An angle-driven computer simulation model of aerial movement was used to determine the maximum amount of twist that can be produced in a reverse 1½ somersault dive from a three-metre springboard using various aerial and contact twisting techniques. The segmental inertia parameters of an elite springboard diver were used in the simulations and lower bounds were placed on the durations of arm and hip angle changes based on recorded performances of twisting somersaults. A limiting dive was identified as that producing the largest possible odd number of half twists. Simulations of the limiting dives were found using simulated annealing optimisation to produce the required amounts of somersault, tilt and twist after a flight time of 1.5 s. Additional optimisations were then run to seek solutions with the arms less adducted during the twisting phase. It was found that the upper limits ranged from 3½ to 5½ twists with arm abduction ranges lying between 8° and 23°. Similar results were obtained when the inertia parameters of two other springboard divers were used. It may be concluded that a reverse 1½ somersault dive using aerial asymmetrical arm and hip movements to produce 5½ twists is a realistic possibility. To accomplish this limiting dive the diver needs to be able to coordinate the timing of configurational changes with the progress of the twist with a precision of 10 ms or better.


Studies of mitochondrial and nuclear DNA released from food allergen-activated neutrophils. Implications for non-IgE food allergy.
Background: Although adverse food reactions are commonly divided into immunoglobulin E (IgE) mediated food allergy (FA), and non-IgE FA, the current literature is providing support for the role of innate immune responses as an important component of non-IgE FA. Using a commercially available leukocyte activation (LA) assay, a recent quantitative study of total extracellular DNA released in cellular supernatants of human peripheral blood mononuclear cells exposed either to positive or negative tested foods demonstrated that leukocytes exposed to foods with positive LA test results showed higher DNA content than those exposed to foods with negative LA test results. In humans, the origin of DNA might be either the nucleus or the mitochondria. Analysis of emerging data from several laboratories, including our own, suggests that mitochondrial DNA induces inflammatory responses through induction of proinflammatory cytokines. Objective: This pilot study was designed primarily to convey the finding, and relevance of, mitochondrial DNA in the form of neutrophil extracellular traps (NET) as a new pathogenetic mechanism for innate immune-mediated non-IgE FA. Methods: The study population consisted of a total of six subjects, four in a major FA study group and two in a subgroup. Neutrophils were isolated and treated with food antigens that elicited positive and negative LA responses, and the released free DNA was analyzed for the cellular site of origin by using real-time polymerase chain reaction and for leukocyte calprotectin and S100 calcium-binding protein A12 (S100A12) proteins as markers of NETs. Results: We showed that cellular supernatants from neutrophils treated with foods that elicit positive LA responses can contain increased DNA levels of nuclear as well as mitochondrial origin. Supernatants from neutrophils treated with negative tested food (LA) responses did not induce the release of nuclear or mitochondrial DNA. Conclusion: Analysis of our data suggested that the induction of NETs that contain proinflammatory mitochondrial DNA may provide the critical link necessary for a better understanding of the pathogenesis of non-IgE-mediated FA. These discoveries may not only facilitate better diagnostic tests of FA but should also improve clinical management of allergic and other inflammatory diseases.


Implementation and interpretation of hydrogen breath tests.
Hydrogen breath tests are non-invasive and safe diagnostic tools used to investigate functional intestinal disorders. For the diagnosis of fructose or lactose malabsorption as well as for the detection of small intestinal bacterial overgrowth syndrome, hydrogen breath tests are even regarded as gold standard. However, standardization of the testing procedure and the interpretation of the test results are still lacking. In this paper, reliable information on the implementation of the most common hydrogen breath tests and precise guidelines for the interpretation of the test results are presented.


Full-field transmission x-ray microscopy for bio-imaging.
A full-field hard-x-ray microscope at SSRL has successfully imaged samples of biological and environmental origin at 40 nm resolution. Phase contrast imaging of trabeculae from a female mouse tibia, loaded in vivo to study the effects of weight-bearing on bone structure, revealed a complex network of osteocytes and canaliculi. Imaging of cordgrass roots exposed to mercury revealed nanoparticles with strong absorption contrast. 3D tomography of yeast cells grown in selenium rich media showed internal structure.


Expressive writing as a presurgical stress management intervention for breast cancer patients.
This study evaluated whether expressive writing (EW) was an effective stress management intervention for breast cancer patients. Women were recruited at the end of neoadjuvant chemotherapy and assigned to write about their cancer experience (EW group; n = 24) or neutral topics (neutral writing [NW] group; n = 25). Women were asked to write for 20 minutes a day for a total of four writing sessions that were completed over a 7-day period. Participants were reassessed approximately 3 days before and 2 weeks after surgery. The intervention did not significantly decrease women's distress, perceived stress, sleep disturbance, or pain. There was some evidence that the EW group used more sleep medication at the presurgical assessment than the NW group. Social constraints moderated the effect of the intervention. Among women with high social constraints, the EW group reported lower average daily pain than the NW group. Among women with low social constraints, the EW group reported higher average daily pain than the NW group. EW was not broadly effective as a stress management intervention for women with breast cancer. These data do not support the use of EW as a presurgical mind-body complementary medicine program for this population.


Parental smoking, maternal alcohol, coffee and tea consumption during pregnancy and childhood malignant central nervous system tumours: the ESCALE study (SFCE).
Parental smoking and maternal alcohol and caffeinated beverage consumption are prevalent exposures which may play a role, either directly or through their influence on metabolism, in the aetiology of childhood malignant central nervous system (CNS) tumours. The hypothesis was investigated in the Epidemiological Study on childhood Cancer and Leukemia ESCALE study, a national population-based case-control study carried out in France in 2003-2004. The study included 209 incident cases of CNS tumours and 1681 population-based controls, frequency matched with the cases by age and sex. The data were collected through a standardized telephone interview of the biological mothers. No association between maternal smoking during pregnancy and CNS tumours [odds ratio (OR): 1.1 (0.8-1.6)] was observed. Paternal smoking during the year before birth was associated with CNS tumours (P for trend=0.04), particularly astrocytomas [OR: 3.1 (1.3-7.6)]. Maternal alcohol consumption during pregnancy was not associated with CNS tumours. Associations between ependymomas and the highest consumption of coffee [OR: 2.7 (0.9-8.1)] and tea [OR: 2.5 (1.1-5.9)] were observed. A strong association between CNS tumours and the highest maternal consumption of both coffee and tea during pregnancy was observed [OR: 4.4 (1.5-13)]. The results constitute additional evidence for a role of paternal smoking and suggest that maternal coffee and tea consumption during pregnancy may also increase the risk of CNS tumours. The study does not suggest an increased risk of CNS tumours related to alcohol consumption during pregnancy.


Clinical research education: perspectives of nurses, employers, and educators.
The aim of this study was to understand the current environment around clinical research relating to nursing education and practice. This descriptive study analyzed data from 33 in-depth interviews with faculty members, nurse executives, staff development directors, and practicing nurses, as well as an online interactive brainstorming session with 28 deans of schools of nursing (or their designee). Patterns and themes that emerged within each group were identified and analyzed in relation to study objectives. Central themes emerged around participants' knowledge and attitudes about clinical research education for baccalaureate nursing students, factors enhancing or inhibiting inclusion of clinical research content in baccalaureate nursing programs, and professional roles nursing students could expect to assume after graduation. Although the participants agreed that mastery of clinical research knowledge and related skills is important, there was no agreement whether nurses should receive this education and training in baccalaureate programs or in staff development.


Biotechnology and urban agriculture: A partnership for the future sustainability.
The global population is growing rapidly, and with it, the demand for food. In the coming decades, more and more people will be living in urban areas, where land for traditional agriculture is scarce. Urban agriculture can help to meet this growing demand for food in a sustainable way. Urban agriculture is the practice of growing food in urban areas. It can be done on rooftops, balconies, vacant lots, and even in alleyways. Urban agriculture can produce a variety of crops, including fruits, vegetables, and herbs. It can also help to improve air quality, reduce stormwater runoff, and create jobs. Biotechnology can be used to improve the efficiency and sustainability of urban agriculture. Biotechnological tools can be used to develop crops that are resistant to pests and diseases, that are more tolerant of drought and heat, and that have higher yields. Biotechnology can also be used to improve the nutritional value of crops. This review article discusses the need for and importance of urban agriculture, biotechnology, and genome editing in meeting the growing demand for food in urban areas. It also discusses the potential of biotechnology to improve the sustainability of urban agriculture.


Knockdown of B7-H6 inhibits tumor progression and enhances chemosensitivity in B-cell non-Hodgkin lymphoma.
B7 homologue 6 (B7-H6) is a new member of the B7 family molecules and is selectively expressed on tumor cells, especially in hematologic malignancies. However, the role of B7-H6 in lymphoma progression and chemosensitivity remains unclear. We determined the effects of downregulating B7-H6 expression on tumorigenesis and chemosensitivity in B-cell lymphoma. Stable B7-H6 knockdown in CA46 cells was established with a lentiviral system. The expression of mRNA was measured by PCR while protein expression was detected by western blotting and flow cytometry. Cell viability, apoptosis and cell cycle distribution were analyzed using CCK-8, colony formation and flow cytometry assays, respectively. Cell migration and invasion were determined using the Transwell chamber assay. B7-H6 was widely expressed in B-cell lymphomas. Knockdown of B7-H6 inhibited cell proliferation, colony formation and migration and invasion of lymphoma cells. After B7-H6 silencing, CA46 cells were arrested in G0/G1 phase. Moreover, the silencing of B7-H6 increased cell apoptosis and sensitivity to vincristine and dexamethasone. Investigation of expression of downstream targets of STAT3 supported a theory in which B7-H6 knockdown may confer an antitumor effect via abrogation of the STAT3 pathway. This study demonstrates that B7-H6 plays an important role in the pathogenesis and chemosensitivity of lymphoma. B7-H6 is therefore a potential clinical biomarker and therapeutic target in B-cell lymphomas.


Elucidation of the sequence and the genomic organization of the human dentin matrix acidic phosphoprotein 1 (DMP1) gene: exclusion of the locus from a causative role in the pathogenesis of dentinogenesis imperfecta type II.
The dentin matrix acidic phosphoprotein 1 (DMP1) gene has been mapped to human chromosome 4q21 and shown to exhibit no recombination with the autosomal dominant disorder of dentin formation, dentinogenesis imperfecta type II. In the current study, sequencing of DMP1 cDNA and genomic clones has indicated that the human gene contains an open reading frame of 1539 bp, which predicts a highly acidic, serine-rich protein of 513 amino acids. Comparison of the human DMP1-coding sequence with that of the rat, mouse, and cow indicated that the predicted protein contains a conserved hydrophobic signal peptide sequence and an Arg-Gly-Asp cell attachment sequence. The gene is encoded by six exons, the splicing phase of which is type 0, the first exon containing solely 5' untranslated sequence. Sequencing of each of the coding exons in individuals affected by dentinogenesis imperfecta type II failed to reveal any disease-specific mutations, suggesting that mutations in DMP1 are not causative of this condition at least in the two families examined in this study.


Unravelling the fluorescence kinetics of light-harvesting proteins with simulated measurements.
The plant light-harvesting pigment-protein complex LHCII is the major antenna sub-unit of PSII and is generally (though not universally) accepted to play a role in photoprotective energy dissipation under high light conditions, a process known Non-Photochemical Quenching (NPQ). The underlying mechanisms of energy trapping and dissipation within LHCII are still debated. Various models have been proposed for the underlying molecular detail of NPQ, but they are often based on different interpretations of very similar transient absorption measurements of isolated complexes. Here we present a simulated measurement of the fluorescence decay kinetics of quenched LHCII aggregates to determine whether this relatively simple measurement can discriminate between different potential NPQ mechanisms. We simulate not just the underlying physics (excitation, energy migration, quenching and singlet-singlet annihilation) but also the signal detection and typical experimental data analysis. Comparing this to a selection of published fluorescence decay kinetics we find that: (1) Different proposed quenching mechanisms produce noticeably different fluorescence kinetics even at low (annihilation free) excitation density, though the degree of difference is dependent on pulse width. (2) Measured decay kinetics are consistent with most LHCII trimers becoming relatively slow excitation quenchers. A small sub-population of very fast quenchers produces kinetics which do not resemble any observed measurement. (3) It is necessary to consider at least two distinct quenching mechanisms in order to accurately reproduce experimental kinetics, supporting the idea that NPQ is not a simple binary switch.


Long-acting chloramphenicol versus intravenous ampicillin for treatment of bacterial meningitis.
In most developing countries, bacterial meningitis (BM) is associated with a high case-fatality rate. The search for a simple, convenient, and inexpensive antibiotic treatment remains a priority. In this study, a non-blinded, multicentre, randomised clinical trial of 528 cases of BM was done in two hospitals in Mali and Niger, between March, 1989, and May, 1990, to see whether a double injection of long-acting chloramphenicol (on admission to hospital and 48 h later) is as effective as a course of intravenous ampicillin (8 days, 4 times a day). The cumulative case-fatality rate on day 4 (principal end-point) among the chloramphenicol (254 patients) and ampicillin (274) groups were, respectively, 28% and 24.5% (relative risk 1.14, 95% confidence interval 0.86-1.52). No outbreak occurred during the study period. The hospital case-fatality rate was 33.1%. Main risk factors for death were associated with clinical condition on admission--ie, altered consciousness, convulsions, or dehydration. The case-fatality rates were 13% (21/161) for Neisseria meningitidis, 36.1% (48/133) for Haemophilus influenzae, and 67% (77/115) for Streptococcus pneumoniae. In a multiple logistic regression model, controlling for the differential distribution of potential risk factors (including bacterial species), there was no difference between treatment groups. Our findings suggest that long-acting chloramphenicol is a useful first-line presumptive treatment for BM in high-incidence countries.


Incidence of injury in Texas girls' high school basketball.
We studied the incidence of injury in girl's varsity basketball to characterize injury demographics in high school athletics. We defined a reportable injury as one that occurred during organized practice or competition, resulted in either missed practice or game time, required physician consultation, or involved the head or face. We prospectively evaluated the athletes on team rosters during the 1993 to 1994 season from 100 randomly selected Class 4A and 5A Texas public high schools that employed full-time certified athletic trainers. The 890 student athletes from 80 schools ranged in age from 14 to 18 years. Four hundred thirty-six injuries were reported for a rate of 0.49 per athlete per season. Injury risk, calculated on the basis of exposure time, was 0.4% per hour per athlete. Although game time accounted for only 12.5% of exposure time, it represented one half of the total injuries. Sprains and strains (56%) were the most common injuries, followed by contusions (15%) and dental injuries (14%). Injuries to the ankle (31%) and knee (19%) were by far the most common. There were 34 severe injuries defined as requiring surgery or hospitalization, for a rate of 0.038 per athlete per season. Knee injuries were by far the most likely to require surgeries, and ACL injuries accounted for 69% of the severe knee injuries.


Human primary visual cortex and lateral geniculate nucleus activation during visual imagery.
The functional magnetic resonance (fMRI) technique can be robustly used to map functional activation of the visual pathway including the primary visual cortex (V1), the lateral geniculate nucleus (LGN), and other nuclei of humans during visual perception stimulation. One of the major controversies in visual neuroscience is whether lower-order visual areas involve the visual imagery process. This issue was examined using fMRI at high magnetic field. It was demonstrated for the first time that the LGN was activated during visual imagery process in the human brain together with V1 and other activation. There was a tight coupling of the activation between V1 and the LGN during visual imagery.


Sport Nutrition Knowledge, Behaviors and Beliefs of High School Soccer Players.
For adolescent athletes (14-18 years), data on sport nutrition knowledge, behaviors and beliefs are limited, especially based on sex, race/ethnicity and socioeconomic status. High school soccer players (n = 535; 55% female; 51% White, 41% Latino; 41% National School Lunch Program (NSLP) participants (80% Latino)) completed two questionnaires (demographic/health history and sport nutrition). The sport nutrition knowledge score was 45.6% with higher scores in NSLP-Whites vs. NSLP-Latinos (p < 0.01). Supplement knowledge differed by sex (16% lower in females; p = 0.047) and race/ethnicity (33% lower in Latinos; p < 0.001). Breakfast consumption was 57%; females ate breakfast less (50%) than males (60%; p < 0.001); NSLP-participants ate breakfast less (47%) than non-NSLP (62%; p < 0.001). Supplement use was 46%, with Latinos using more supplements than Whites do (p = 0.016). Overall, 30% used protein shakes, with females using less than males (p = 0.02), while use was twice as likely in Latino vs. White (p = 0.03). Overall, 45% reported their nutrient requirements were different from non-athlete peers. Latinos were less likely (p = 0.03) to report that their diet met nutritional requirements, but more than twice as likely to report that nutritional supplements were necessary for training (p < 0.001). Adolescent athletes, especially females and Latinos, would benefit from sport nutrition education that enhances food selection skills for health and sport performance.


Utilization of a mobile medical van for delivering pediatric care in the bateys of the Dominican Republic.
Bateys are impoverished areas of housing for migrant Haitian sugar cane workers in the Dominican Republic (DR). In these regions, preventative health care is almost non-existent, public service accessibility is limited, and geographic isolation prevents utilization of care even by those families with resources. Consequently, the development of a viable mobile system is vital to the delivery of acute and preventative health care in this region. This study evaluated an existing mobile medical system. The primary goal was to describe the population served, diseases treated, and resources utilized. A secondary goal was to determine qualitatively an optimal infrastructure for sustainable health care delivery within the bateys. Information on basic demographic data, diagnosis, chronicity of disease, and medications dispensed was collected on all pediatric patients seen in conjunction with an existing mobile medical system over a 3-month period in the DR. Health statistics for the region were collected and interviews were conducted with health care workers (HCWs) and community members on existing and optimal health care infrastructure. Five hundred eighty-four pediatric patients were evaluated and treated. Median age was 5 years (range 2 weeks to 20 years), and 53.7% of patients seen were 5 years of age or younger. The mean number of complaints per patient was 2.8 (range 0 to 6). Thirty-six percent (373) of all diagnoses were for acute complaints, and 64% (657) were chronic medical problems. The most common pediatric illnesses diagnosed clinically were gastrointestinal parasitic infection (56.6%), skin/fungal infection (46.2%), upper respiratory tract infections (URIs) (22.8%), previously undiagnosed asthma and allergies (8.2%), and symptomatic anemia (7.2%). Thirty HCWs and community members were interviewed, and all cited the need for similar resources: a community clinic and hospital referral site, health promoters within each community, and the initiation of pediatric training for community HCWs. A mobile medical system is a sustainable, efficient mechanism for delivering acute and preventive care in the Haitian bateys of the Dominican Republic. The majority of patients served were 8 years of age or younger with multiple presenting symptoms. A pediatric protocol for identifying the most appropriate drugs and supplies for mobile units in the DR can be created based upon diseases evaluated. Qualitative data from HCWs and community members identified the need for an integrative health care delivery infrastructure and community health promoters versed in pediatric care who can aid in education of batey members and monitor chronic and acute illnesses. We are planning follow-up visits to implement these programs.


Current and ceased users of sit stand workstations: a qualitative evaluation of ergonomics, safety and health factors within a workplace setting.
Many workplaces have implemented sit-stand workstations (SSW), which enable a worker to transition between sitting and standing as they perform their work activities. The factors which determine the initial adoption, sustainability or cessation of use for a SSW, remain largely unexamined. This study investigates the experiences of workers who had previously used or were currently using a SSW. The study setting was within an Australian university. Participants who were current or past SSW users, as well as workplace key informants, were interviewed for the study. All interviews were recorded, transcribed and analysed. Transcripts were coded by two researchers for concepts and themes regarding uptake and sustainability of SSW. Discussion and validation of themes was undertaken by the team of three researchers. A total of 24 interviews were conducted. Twenty-two interviews were with ceased and current users (16 current and six ceased users) and two interviews were with workplace key informants. Analysis of the interviews with current and ceased users identified three main themes: Personal considerations for use/sustainability; Posture; and Usability. Analysis of the interviews with key informants identified two themes: Considerations and concerns and Policies and procedures. Little information was provided to workers when first using a SSW. Workers who were able to adopt their working style to the new workstations were able to sustain ongoing use of a SSW. Key informants were concerned that employees believed using a SSW would provide a health benefit in its own right without an understanding of the possible risks that might be associated with use. Sustainable usage of this type of SSW is achievable, however, it requires some element of adaptation at the individual worker level. Participants spoke about how the use of the SSW in a standing position was typically associated with the time of day, specific task selection and musculoskeletal comfort or fatigue factors. The provision of education to new SSW users with relevant supporting information by a subject matter expert should enable the worker to obtain a more holistic understanding of the safety and health risks and benefits embedded in the use of a SSW.


The clinical importance of monitoring intra-abdominal pressure after ruptured abdominal aortic aneurysm repair.
The aim of this paper was to review the literature on the clinical importance of monitoring intra-abdominal pressure (IAP) after ruptured abdominal aortic aneurysm (rAAA) repair. The literature was searched for abdominal compartment syndrome (ACS) or intra-abdominal pressure and aortic aneurysm. Original articles were studied. Personal experiences were reported. The Consensus Documents of the World Society on the Abdominal Compartment Syndrome (wsacs.org), with their definitions and guidelines, constitute an important step forward for the possibilities to study this clinical entity. Few papers were published describing the problem specifically in the patient population operated on for ruptured abdominal aortic aneurysm (rAAA). The incidence was approximately 5% when the patients were not monitored with IAP, and above 10% when IAP was monitored. The incidence seems to be similar irrespective if open or endovascular repair is performed, though comparative prospective studies were not published. Patients with intra-abdominal hypertension (IAH) or ACS have higher mortality and more complications. If IAH is recognized early conservative treatment may be effective to prevent development of ACS. After ACS has developed, surgical decompression is usually required. A proposed algorithm on how to act on different levels of IAH is presented. IAH/ACS is an important complication after operation on patients with rAAA. Monitoring IAP may be associated with improved outcomes.


Hispanic Segregation and Poor Health: It's Not Just Black and White.
Despite the importance of understanding the fundamental determinants of Hispanic health, few studies have investigated how metropolitan segregation shapes the health of the fastest-growing population in the United States. Using 2006-2013 data from the National Health Interview Survey, we 1) examined the relationship between Hispanic metropolitan segregation and respondent-rated health for US-born and foreign-born Hispanics and 2) assessed whether neighborhood poverty mediated this relationship. Results indicated that segregation has a consistent, detrimental effect on the health of US-born Hispanics, comparable to findings for blacks and black-white segregation. In contrast, segregation was salutary (though not always significant) for foreign-born Hispanics. We also found that neighborhood poverty mediates some, but not all, of the associations between segregation and poor health. Our finding of divergent associations between health and segregation by nativity points to the wide range of experiences within the diverse Hispanic population and suggests that socioeconomic status and structural factors, such as residential segregation, come into play in determining Hispanic health for the US-born in a way that does not occur among the foreign-born.


Restrictive strategy versus usual care for cholecystectomy in patients with gallstones and abdominal pain (SECURE): a multicentre, randomised, parallel-arm, non-inferiority trial.
International guidelines advise laparoscopic cholecystectomy to treat symptomatic, uncomplicated gallstones. Usual care regarding cholecystectomy is associated with practice variation and persistent post-cholecystectomy pain in 10-41% of patients. We aimed to compare the non-inferiority of a restrictive strategy with stepwise selection with usual care to assess (in)efficient use of cholecystectomy. We did a multicentre, randomised, parallel-arm, non-inferiority study in 24 academic and non-academic hospitals in the Netherlands. We enrolled patients aged 18-95 years with abdominal pain and ultrasound-proven gallstones or sludge. Patients were randomly assigned (1:1) to either usual care in which selection for cholecystectomy was left to the discretion of the surgeon, or a restrictive strategy with stepwise selection for cholecystectomy. For the restrictive strategy, cholecystectomy was advised for patients who fulfilled all five pre-specified criteria of the triage instrument: 1) severe pain attacks, 2) pain lasting 15-30 min or longer, 3) pain located in epigastrium or right upper quadrant, 4) pain radiating to the back, and 5) a positive pain response to simple analgesics. Randomisation was done with an online program, implemented into a web-based application using blocks of variable sizes, and stratified for centre (academic versus non-academic and a high vs low number of patients), sex, and body-mass index. Physicians and patients were masked for study-arm allocation until after completion of the triage instrument. The primary, non-inferiority, patient-reported endpoint was the proportion of patients who were pain-free at 12 months' follow-up, analysed by intention to treat and per protocol. A 5% non-inferiority margin was chosen, based on the estimated clinically relevant difference. Safety analyses were also done in the intention-to treat population. This trial is registered at the Netherlands National Trial Register, number NTR4022. Between Feb 5, 2014, and April 25, 2017, we included 1067 patients for analysis: 537 assigned to usual care and 530 to the restrictive strategy. At 12 months' follow-up 298 patients (56%; 95% CI, 52·0-60·4) were pain-free in the restrictive strategy group, compared with 321 patients (60%, 55·6-63·8) in usual care. Non-inferiority was not shown (difference 3·6%; one-sided 95% lower CI -8·6%; pnon-inferiority=0·316). According to a secondary endpoint analysis, the restrictive strategy resulted in significantly fewer cholecystectomies than usual care (358 [68%] of 529 vs 404 [75%] of 536; p=0·01). There were no between-group differences in trial-related gallstone complications (40 patients [8%] of 529 in usual care vs 38 [7%] of 536 in restrictive strategy; p=0·16) and surgical complications (74 [21%] of 358 vs 88 [22%] of 404, p=0·77), or in non-trial-related serious adverse events (27 [5%] of 529 vs 29 [5%] of 526). Suboptimal pain reduction in patients with gallstones and abdominal pain was noted with both usual care and following a restrictive strategy for selection for cholecystectomy. However, the restrictive strategy was associated with fewer cholecystectomies. The findings should encourage physicians involved in the care of patients with gallstones to rethink cholecystectomy, and to be more careful in advising a surgical approach in patients with gallstones and abdominal symptoms. The Netherlands Organization for Health Research and Development, and CZ healthcare insurance.


Device related infections: are we making progress?
Infection was identified early in development of mechanical circulatory support devices (MCSDs) as an important cause of morbidity and mortality. Sepsis, infection of implanted pump components, and infections of percutaneous drivelines continue to limit survival and decrease quality of life for patients with a MCSD. This review examines five questions related to whether there has been progress in preventing or managing infection complications in patients with MCSDs. Have changes in patient selection, device design, and surgical implant techniques decreased the incidence of infection? Do smaller implanted blood pumps have a lower risk for infection than larger implanted blood pumps? Will fully implanted circulatory support systems have fewer infection complications than tethered MCSDs? Can optimal design of a driveline together with improvements in surgical techniques and care of the percutaneous driveline diminish the rate and consequences of driveline infections? Have improvements in the preoperative, intraoperative, and immediate postoperative management of patients with MCSDs decreased the risk of sepsis? Although infection remains an important problem for patients with MCSDs, there is evidence that we are making progress as described in this review. It is crucial that we continue.


Blocking of L-type calcium channels protects hippocampal and nigral neurons against iron neurotoxicity. The role of L-type calcium channels in iron-induced neurotoxicity.
Iron plays an important role in maintaining normal brain function. However, iron overload and enhanced hydroxyl radical formation have been implicated as the causative factors of some neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. Calcium is also required for diverse physiological process including secretion of neurotransmitters, synaptic plasticity, gene expression and axonal growth. Iron and calcium are essential for neuronal function but, when present in excessive level, they induce neuronal damage and may even cause neuronal death. Some reports suggest that voltage gated calcium channels (VGCCs) are an alternate route for iron entry into neuronal cell lines under conditions of iron overload. The aim of the present study was to investigate the effects of L-type VGCCs on iron-induced neurotoxicity. Iron neurotoxicity was generated by intracerebroventricular FeCl₃ injection. Nicardipine treatment (10 mg/kg/d) was applied to block L-type VGCCs for 10 d. Rats were perfused intracardially under deep urethane anaesthesia after treatment period. Removed brains were processed using the standard histological techniques. The numbers of neurons in hippocampus and substantia nigra of all rats were estimated by stereological techniques. Results of present study show that nicardipine decreased hippocampal and nigral neuron loss from 43.9% to 18.4% and 41.0% to 12.1%, respectively. Outcomes of the present study propose that blocking of L-type VGCCs may reduce the neurotoxic effects of iron by inhibiting the cellular influx of excessive calcium and/or iron ions.


Effects of Zinc Glycinate on Productive and Reproductive Performance, Zinc Concentration and Antioxidant Status in Broiler Breeders.
An experiment was conducted to investigate the effects of zinc glycinate (Zn-Gly) supplementation as an alternative for zinc sulphate (ZnSO4) on productive and reproductive performance, zinc (Zn) concentration and antioxidant status in broiler breeders. Six hundred 39-week-old Lingnan Yellow broiler breeders were randomly assigned to 6 groups consisting of 4 replicates with 25 birds each. Breeders were fed a basal diet (control group, 24 mg Zn/kg diet), basal diet supplemented with 80 mg Zn/kg diet from ZnSO4 or basal diet supplemented with 20, 40, 60 and 80 mg Zn/kg diet from Zn-Gly. The experiment lasted for 8 weeks after a 4-week pre-test with the basal diet, respectively. Results showed that Zn supplementation, regardless of sources, improved (P < 0.05) the feed conversion ratio (kilogram of feed/kilogram of egg) and decreased broken egg rate, and elevated (P < 0.05) the qualified chick rate. Compared with the ZnSO4 group, the 80 mg Zn/kg Zn-Gly group significantly increased (P < 0.05) average egg weight, fertility, hatchability and qualified chick rate, whereas it decreased (P < 0.05) broken egg rate. The Zn concentrations in liver and muscle were significantly higher (P < 0.05) in 80 mg Zn/kg Zn-Gly group than that in ZnSO4 group. Compared with ZnSO4 group, 80 mg Zn/kg Zn-Gly group significantly elevated (P < 0.05) the mRNA abundances of metallothionein (MT) and copper-zinc superoxide (Cu-Zn SOD), as well as the Cu-Zn SOD activity and MT concentration in liver. Moreover, the 80 mg Zn/kg Zn-Gly group had higher (P < 0.05) serum T-SOD and Cu-Zn SOD activities than that in the ZnSO4 group. This study indicated that supplementation of Zn in basal diet improved productive and reproductive performance, Zn concentration and antioxidant status in broiler breeders, and the 80 mg Zn/kg from Zn-Gly was the optimum choice for broiler breeders compared with other levels of Zn from Zn-Gly and 80 mg/kg Zn from ZnSO4.


Guidelines for Biosafety Training Programs for Workers Assigned to BSL-3 Research Laboratories.
The Guidelines for Biosafety Training Programs for Workers Assigned to BSL-3 Research Laboratories were developed by biosafety professionals who oversee training programs for the 2 national biocontainment laboratories (NBLs) and the 13 regional biocontainment laboratories (RBLs) that participate in the National Institute of Allergy and Infectious Diseases (NIAID) NBL/RBL Network. These guidelines provide a general training framework for biosafety level 3 (BSL-3) high-containment laboratories, identify key training concepts, and outline training methodologies designed to standardize base knowledge, understanding, and technical competence of laboratory personnel working in high-containment laboratories. Emphasis is placed on building a culture of risk assessment-based safety through competency training designed to enhance understanding and recognition of potential biological hazards as well as methods for controlling these hazards. These guidelines may be of value to other institutions and academic research laboratories that are developing biosafety training programs for BSL-3 research.


Effectiveness of Prison-Based Exercise Training Programs: A Systematic Review.
The promotion of physical activity among imprisoned people is a public health strategy that could help to improve the health status of this collective. This systematic review is aimed at reviewing the scientific evidence regarding the effects of exercise training programs performed by inmates. A systematic search for randomized controlled trials aimed at identifying the characteristics and effects of prison-based exercise training programs on imprisoned people was carried through MEDLINE, SPORTDiscus, and Scopus. A total of 11 randomized controlled studies were selected, and the methodological quality of these was acceptable according to the Downs and Black scale. The proposed interventions were mainly based on the performance of aerobic or combined exercise training programs. Generally, the participants were healthy men who were imprisoned for at least 2 months and up to 15 years. Ten out of the 11 studies reported significant changes on physical and mental health-related variables, after the intervention took place. These findings suggest that prison-based exercise programs constitute a feasible and useful strategy for improving the physical and mental health status of prisoners.


Symmetric and asymmetric solitons supported by a 𝒫𝒯-symmetric potential with saturable nonlinearity: bifurcation, stability and dynamics.
The symmetry breaking bifurcation of solitons in an optical waveguide with focusing saturable nonlinearity and parity-time (𝒫𝒯)-symmetric complex-valued external potentials is investigated. As the soliton power increases, it is found that the branches of asymmetric solitons split off from the base branches of 𝒫𝒯-symmetric fundamental soliton. The bifurcation diagrams, consisting essentially of the propagation constants of optical solitons, indicate that symmetric fundamental and multipole solitons, as well as asymmetric solitons can exist. The stabilities and the dynamics characteristics of solitons are comprehensively investigated. We find the different instability scenarios of the symmetric solitons, but the symmetry breaking bifurcation is caused only by the onset of instability of the symmetric fundamental solitons. This result is further confirmed by the numerical examples with the different saturable nonlinearity parameters. In particular, we find that the soliton power and the stability of soliton at the bifurcation points are significantly changed by varying the strength of the saturable nonlinearities. These results provide additional way to control symmetry breaking bifurcations in 𝒫𝒯-symmetric optical waveguide.


Mesenteric artery aneurysms.
In this case of atherosclerotic aneurysm involving the main superior mesenteric artery and an aberrant artery from the aorta, characteristic eggshell calcifications were visible on preoperative x-ray films of the abdomen. The aneurysm was excised. Flow through the superior mesenteric artery was maintained by lateral suture of the artery at the site of excision of the aneurysm.


Molecular cloning, expression and characterization of cDNA encoding a mouse alpha1a-adrenoceptor.
1. In this study, we have cloned, expressed, and characterized an alpha1a-adrenoceptor gene from the mouse. We designed oligonucleotide PCR primers complementary to regions of the rat alpha1a-adrenoceptor sequence and amplified cDNA fragments from total RNA of mouse cerebral cortex, liver and kidney by reverse transcription-polymerase chain reaction (RT PCR). 2. Both the nucleotide and deduced peptide sequences of the cDNA showed high sequence identity with those of cloned alpha1a-adrenoceptors from other species. The cDNA clone had an open reading frame of 1398 nucleotides encoding a 466 amino acid peptide which had 97%, 92% and 90% identity with the deduced amino acid sequences of the rat, human and bovine alpha1a-adrenoceptor, respectively. 3. The amplified mouse cDNA was inserted into a mammalian expression vector pcDNA3.1(+) and expressed in COS-1 cells. The pharmacological properties of the mouse cDNA clone were examined in radioligand binding studies and functional assays. The expressed mouse protein had a high affinity for [3H]-prazosin (Kd = 0.48 nM) and pattern of affinity for antagonists in competition studies that is similar to that of the rat alpha1a-adrenoceptor. Chloroethylclonidine (CEC) could slowly alkylate the expressed protein, with a rate similar to that of the rat alpha1a-adrenoceptor. 4. The expressed receptors were able to mediate noradrenaline (NA) stimulation of the production of inositol phosphates in COS-1 cells, consistent with coupling to phospholipase C. This response to NA could be reversed by pretreatment of the transfected cells with prazosin. 5. Based on the above evidence, we concluded that the cloned cDNA is that of the mouse alpha1a-adrenoceptor.


Towards Personal Exposures: How Technology Is Changing Air Pollution and Health Research.
We present a review of emerging technologies and how these can transform personal air pollution exposure assessment and subsequent health research. Estimating personal air pollution exposures is currently split broadly into methods for modeling exposures for large populations versus measuring exposures for small populations. Air pollution sensors, smartphones, and air pollution models capitalizing on big/new data sources offer tremendous opportunity for unifying these approaches and improving long-term personal exposure prediction at scales needed for population-based research. A multi-disciplinary approach is needed to combine these technologies to not only estimate personal exposures for epidemiological research but also determine drivers of these exposures and new prevention opportunities. While available technologies can revolutionize air pollution exposure research, ethical, privacy, logistical, and data science challenges must be met before widespread implementations occur. Available technologies and related advances in data science can improve long-term personal air pollution exposure estimates at scales needed for population-based research. This will advance our ability to evaluate the impacts of air pollution on human health and develop effective prevention strategies.


Young men's behavioral competencies and risk of alcohol use disorder in emerging adulthood: Early protective effects of parental education.
We investigate how early exposure to parental externalizing behaviors (EB) may contribute to development of alcohol use disorders (AUD) in young adulthood, testing a developmental cascade model focused on competencies in three domains (academic, conduct, and work) in adolescence and emerging adulthood, and examining whether high parental education can buffer negative effects of parental EB and other early risk factors. We use data from 451,054 Swedish-born men included in the national conscript register. Structural equation models showed parental EB was associated with academic and behavioral problems during adolescence, as well as with lower resilience, more criminal behavior, and reduced social integration during emerging adulthood. These pathways led to elevated rates of AUD in emerging and young adulthood. Multiple groups analysis showed most of the indirect pathways from parental EB to AUD were present but buffered by higher parental education, suggesting early life experiences and competencies matter more for young men from lower socioeconomic status (SES) families than from higher SES families. Developmental competencies in school, conduct, and work are important precursors to the development of AUD by young adulthood that are predicted by parental EB. Occupational success may be an overlooked source of resilience for young men from low-SES families.


[Water-borne outbreaks of rotavirus infections].
The clinico-epidemiological characteristics of group rotavirus infection observed in one settlement in March-April is presented. 173 cases of infection were registered in all age groups (children under 7 years constituted only 10.4% of the patients). In most of the apartments found to be the foci of infection only one patient was registered. The virological study of fecal samples from 24 patients showed the presence of human rotaviruses in the feces of 10 patients (41.7%). Neutralizing antibodies in titers of 1:4 to 1:64 were detected in all taken paired sera (21). THe clinical study of 53 hospitalized patients showed that in all cases the infectious process had acute beginning. In most patients the disease took mild forms. The peculiarities of the distribution of the patients in different age groups, the location of the foci of infection and its seasonal character, as well as some objective data on the presence of pollutions in the water mains, indicated that this infection could spread through water via the system of centralized water supply.


Hydrogen-rich saline ameliorates hippocampal neuron apoptosis through up-regulating the expression of cystathionine β-synthase (CBS) after cerebral ischemia- reperfusion in rats.
This study aimed to evaluate the potential role of hydrogen in rats after cerebral ischemic/reperfusion (I/R) injury. The experimental samples were composed of sham group, model group of rats that received middle cerebral artery occlusion (MCAO) for 2 hr followed by reperfusion for 24 hr, and the hydrogen saline group treated by hydro¬gen-rich saline (1 ml/kg) after MCAO. Hydrogen sulfide (H2S), S100-βprotein (S100-β), and neuron-specific enolase (NSE) levels were measured; the levels of malondialdehyde (MDA), reactive oxygen species (ROS), and superoxide dismutase (SOD) were detected; the histologic structure and apoptotic cells of hippocampus were observed; the expressions of cystathionine β-synthase (CBS), nuclear factor erythroid 2-related factor 2 (Nrf2), and hemeoxygenase-1 (HO-1) were measured. Statistical analyses were performed using one-way analysis of variance (ANOVA) followed by Fisher's least significant difference (LSD) test. Our results showed that hydrogen up-regulated H2S levels via promoting the expression of CBS in the hippocampus, and its treatment alleviated oxidative stress via activating the expression of Nrf2 and HO-1, and then cell apoptosis reduced, furthermore, brain function improved by down-regulating the levels of S100-βand NSE. This study showed that hydrogen-rich saline ameliorates cell injury through up-regulating the expression of CBS in the hippocampus after cerebral ischemia reperfusion (I/R) in rats, this provides new experimental evidence for the treatment of stroke with hydrogen saline.


Large size and high light do not lower the cost of reproduction for the Neotropical herb Goeppertia marantifolia.
• Sexual reproduction is often associated with a cost in terms of reduced survival, growth, or future reproduction. It has been proposed that plant size and the environment (availability of key resources) can sometimes lower or even nullify the cost of reproduction.• We address this issue experimentally with the Neotropical herb Goeppertia marantifolia, by manipulating sexual reproductive effort and measuring the demographic performance of plants and of their clonal offspring, in the context of natural variation in light availability.• Plants in the high-reproductive-effort treatment grew less between seasons but did not differ in their probability of flowering the second season or in inflorescence size compared with plants in the low-effort treatment. Reproductive effort of parent plants influenced the leaf area of their clonal offspring. Plants that invested less in sexual reproduction produced clonal offspring that were initially larger than those produced by plants that invested more in reproduction. The magnitude of this effect was greater in parent plants that received two seasons of the manipulated reproductive effort than in those that received a single season. The trade-off between reproductive modes dampened with time, leading to smaller differences in clonal offspring leaf area between treatments over time.• We found evidence of a cost of reproduction and trade-offs between reproductive modes, although the magnitude of these costs was small. However, we found no evidence of lower costs of reproduction for larger plants or for plants in higher-light environments over our 2-yr study period.


Craniofacial growth and functional change in oligodontia with ectodermal dysplasia: a case report.
A case of ectodermal dysplasia in a Japanese boy is presented in this report. After prosthetic treatment was performed with partial dentures in both jaws, mandibular movement, dental casts, and lateral and frontal cephalograms were taken at an initial visit (age 7 years 8 months), and at follow-up 1 year and 8 months later (age 9 years 3 months) to evaluate the developmental changes in masticatory movement, dental arch width, and craniofacial morphology. Stability of the jaw movements improved during the follow-up period both with and without dentures. The facial skeleton grew between the initial visit and follow-up. Mandibular length remained long compared with the average value for Japanese children. A possible genetic marker for mandibular growth (growth hormone receptor), which is considered to be an important factor in mandibular growth and development, was analysed for the gene variant and the result supported the characteristic mandibular growth in the reported case. These results indicate the characteristic craniofacial growth in this disease and emphasize the potential ability of functional development of jaw movements with oligodontia.


Phytochemical characterization and anti-inflammatory potential of Egyptian Murcott mandarin cultivar waste (stem, leaves and peel).
The stem (S), leaf (L) and fruit peel (P) of Murcott mandarins were separately extracted using 80% ethanol and then fractionated into dichloromethane (DCM) and ethyl acetate (ET). Their metabolic profiles were studied via HPLC-PDA-ESI-MS/MS and afforded a tentative characterization of 98 compounds, including free organic acids, phenolic acid derivatives, flavonoid aglycones, flavonoid glycosides, flavonoids containing 3-hydroxyl-3-methylglutaroyl (HMG) units, coumarin derivatives and limonoids. Column chromatography resulted in isolation of six metabolites for the first time that were identified as nobiletin (C1), isosinensetin (C2), limonin (C3), 4'-demethylnobiletin (C4), stigmasterol-O-glucoside (C5) and hesperidin (C6). In vitro studies of the anti-inflammatory activity of DCM-L against cyclooxygenases (COXs) and 5-lipoxygenase (5-LOX) enzymes revealed that DCM-L showed higher activity than the other tested fractions. The in vivo gastroprotective effects of that fraction were evaluated using alcohol-induced gastric ulcers in rats. The obtained findings validated the gastroprotective and anti-ulcerogenic activities of DCM-L through its anxiolytic, anti-inflammatory, antioxidant and anti-apoptotic effects. Therefore, we recommend the use of Murcott mandarin leaves as a part of a protection strategy for gastric ulcer.


Negative correlation between blood cell counts and serum neopterin concentration in patients with HIV-1 infection.
Hematopoietic disturbances are common in patients with HIV-1 infection. Recent studies on immune activation markers such as neopterin demonstrate that HIV-1 infection is associated with chronic immune activation. We investigated a possible association between serum neopterin concentrations and blood cell counts (CD4+ T cells, white blood cells, platelets, red blood cells) and hemoglobin and hematocrit in 94 HIV-1-seropositive individuals [52 Walter Reed (WR) stage 1, 31 WR2, one WR5, and 10 WR6]. There were significant negative correlations between neopterin concentrations and CD4+ T cells, hemoglobin, hematocrit and platelets. These correlations were also significant if either only WR1 and WR2 patients or the entire set of data were considered for calculations. Thus, hematological abnormalities are associated with chronic immune activation in patients with HIV-1 infection. Large amounts of neopterin are released by human macrophages on stimulation with interferon-gamma (IFN gamma), and tumor necrosis factor alpha (TNF alpha) further enhances the effect of IFN gamma. Therefore, our data suggest that activated immune cells and specific cytokines such as IFN gamma and TNF alpha are involved inhibiting hematopoiesis.


Improved monomeric red, orange and yellow fluorescent proteins derived from Discosoma sp. red fluorescent protein.
Fluorescent proteins are genetically encoded, easily imaged reporters crucial in biology and biotechnology. When a protein is tagged by fusion to a fluorescent protein, interactions between fluorescent proteins can undesirably disturb targeting or function. Unfortunately, all wild-type yellow-to-red fluorescent proteins reported so far are obligately tetrameric and often toxic or disruptive. The first true monomer was mRFP1, derived from the Discosoma sp. fluorescent protein "DsRed" by directed evolution first to increase the speed of maturation, then to break each subunit interface while restoring fluorescence, which cumulatively required 33 substitutions. Although mRFP1 has already proven widely useful, several properties could bear improvement and more colors would be welcome. We report the next generation of monomers. The latest red version matures more completely, is more tolerant of N-terminal fusions and is over tenfold more photostable than mRFP1. Three monomers with distinguishable hues from yellow-orange to red-orange have higher quantum efficiencies.


Purchases Made with a Fruit and Vegetable Voucher in a Rural Mexican-Heritage Community.
Recent recommendations for US food assistance programs are intended to ensure foods provided through these programs help households consume a varied, healthful diet. From a policy viewpoint, it is important to examine the impact of economic incentives to purchase healthy foods across subpopulations, particularly low-income Latinos, who comprise 40% of the WIC program nationwide. Our aim was to determine how rural, Mexican-heritage households (N = 227) residing in California's Central Valley distributed fruit and vegetable (F/V) voucher spending among F/V subgroups and specific items over a 1-year period. Households contained at least one child who was between 3 and 8 years old at baseline and had a parent of Mexican-heritage. F/V voucher purchase data were collected via grocery store scanners. Expenditure and frequency shares of subgroups and individual items were analyzed to determine purchasing habits. Fruits were the most commonly purchased subgroup, representing 55% of spending and 45% of frequency. Households allocated low percentages of their voucher to dark green and red/orange vegetables-7 and 9% respectively. Approximately 20% of purchases were good potassium sources and 30% of purchases were good fiber sources. Many of the most frequently purchased items were of cultural significance (tomatillo, chayote, chili/jalapeño pepper, and Mexican squash). This study suggests that economic incentives can contribute important nutrients to participants' diets and targeted vouchers provided by food assistance programs should continue to include culturally important foods and be aware of the cultural values of their participants.


Antiviral options and therapeutics against influenza: history, latest developments and future prospects.
Drugs and chemotherapeutics have helped to manage devastating impacts of infectious diseases since the concept of 'magic bullet'. The World Health Organization estimates about 650,000 deaths due to respiratory diseases linked to seasonal influenza each year. Pandemic influenza, on the other hand, is the most feared health disaster and probably would have greater and immediate impact on humanity than climate change. While countermeasures, biosecurity and vaccination remain the most effective preventive strategies against this highly infectious and communicable disease, antivirals are nonetheless essential to mitigate clinical manifestations following infection and to reduce devastating complications and mortality. Continuous emergence of the novel strains of rapidly evolving influenza viruses, some of which are intractable, require new approaches towards influenza chemotherapeutics including optimization of existing anti-infectives and search for novel therapies. Effective management of influenza infections depend on the safety and efficacy of selected anti-infective in-vitro studies and their clinical applications. The outcomes of therapies are also dependent on understanding diversity in patient groups, co-morbidities, co-infections and combination therapies. In this extensive review, we have discussed the challenges of influenza epidemics and pandemics and discoursed the options for anti-viral chemotherapies for effective management of influenza virus infections.


Parental transfer of tris(1,3-dichloro-2-propyl) phosphate and transgenerational inhibition of growth of zebrafish exposed to environmentally relevant concentrations.
Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) is a re-emerging environmental contaminant that has been frequently detected at sub-ppb (<μg/L) concentrations in natural waters. The objective of this study was to evaluate effects of TDCIPP on growth in initial generation (F0) zebrafish after chronic exposure to environmentally relevant concentrations, and to examine possible parental transfer of TDCIPP and transgenerational effects on growth of first generation (F1) larvae. When zebrafish (1-month old) were exposed to 580 or 7500 ng TDCIPP/L for 240 days, bioconcentration resulted in significantly less growth as measured by body length, body mass, brain-somatic index (BSI) and hepatic-somatic index (HSI) in F0 females but not F0 males. These effects were possibly due to down-regulation of expression of genes along the growth hormone/insulin-like growth factor (GH/IGF) axis. Furthermore, residues of TDCIPP were detected in F1 eggs after exposure of parents, which resulted in less survival, body length and heart rate in F1 individuals. Down-regulation of genes in the GH/IGF axis (e.g., gh, igf1) might be responsible for transgenerational toxicity. This study provides the first known evidence that exposure of zebrafish to environmentally relevant concentrations of TDCIPP during development can inhibit growth of offspring, which were not exposed directly to TDCIPP.


Room-temperature magnetoresistance in Ni78Fe22/C8-BTBT/Ni78Fe22 nanojunctions fabricated from magnetic thin-film edges using a novel technique.
Molecular spintronic devices are gaining popularity because the organic semiconductors with long spin relaxation times are expected to have long spin diffusion lengths. A typical molecular spintronic device consists of organic molecules sandwiched between two magnetic layers, which exhibits magnetoresistance (MR) effect. Nanosized devices are also expected to have a high spin polarization, leading to a large MR effect owing to effective orbital hybridization. However, most studies on nanosized molecular spintronic devices have investigated the MR effect at low temperatures because of the difficulty in observing the MR effect at room temperature. Here we focus on high-mobility molecules expected to show long spin diffusion lengths, which lead to the observation of the MR effect in nanoscale junctions at room temperature. In this study, we fabricate magnetic nanojunctions consisting of high-mobility molecules, 2,7-dioctyl[1]benzothieno[3,2-b][1]benzothiophene (C8-BTBT), sandwiched between two Ni78Fe22 thin films with crossed edges. Transmission electron microscopy (TEM) images reveal that C8-BTBT molecular layers with smooth and clear interfaces can be deposited on the Ni78Fe22 thin-film edges. Consequently, we observe a clear positive MR effect, that is, R P < R AP, where R P and R AP are the resistances in the parallel (P) and antiparallel (AP) configurations, respectively, of two magnetic electrodes in the Ni78Fe22/C8-BTBT/Ni78Fe22 nanojunctions at room temperature. The obtained results indicate that the spin signal through the C8-BTBT molecules can be successfully observed. The study presented herein provides a novel nanofabrication technique and opens up new opportunities for research in high-mobility molecular nano-spintronics.


[Proliferation and death of thymocytes caused by phospholipase A2 activator--melittin].
The effects of mellitin, a component of bee venom activating phospholipase A2, on proliferation and death of the rat thymocytes were studied in a wide concentration range. Cell proliferation was estimated by the accumulation of colchicine metaphases, Necrosis was estimated by cell lysis and Trypan blue staining. Apoptosis was estimated by the type of DNA fragmentation, amount of fragmented DNA, and percentage of cells with hypodiploid DNA set. Low concentrations of mellitin (below 5 micrograms/ml) stimulated proliferation. At higher mellitin concentrations, the thymocytes die by the primary necrosis type. Mellitin did not induce apoptosis in the thymocytes within the concentration range used: on the contrary, at high concentrations, it inhibited apoptosis of the thymocytes in the control and after irradiation. Actinomycin D, inhibitor of RNA synthesis, exerted no effect on the thymocyte death in the presence of mellitin. It has been concluded that activation of phospholipase A2 may induce necrosis, rather than apoptosis, and consequently, activation of phospholipase A2 is not a necessary step in the signalling cascade that initiated apoptosis in the thymocytes.


Why is it challenging to predict intestinal drug absorption and oral bioavailability in human using rat model.
To study the correlation of intestinal absorption for drugs with various absorption routes between human and rat, and to explore the underlying molecular mechanisms for the similarity in drug intestinal absorption and the differences in oral bioavailability between human and rat. The intestinal permeabilities of 14 drugs and three drug-like compounds with different absorption mechanisms in rat and human jejunum were determined by in situ intestinal perfusion. A total of 48 drugs were selected for oral bioavailability comparison. Expression profiles of transporters and metabolizing enzymes in both rat and human intestines (duodenum and colon) were measured using GeneChip analysis. No correlation (r(2) = 0.29) was found in oral drug bioavailability between rat and human, while a correlation (r(2) = 0.8) was observed for drug intestinal permeability with both carrier-mediated absorption and passive diffusion mechanisms between human and rat small intestine. Moderate correlation (with r(2) > 0.56) was also found for the expression levels of transporters in the duodenum of human and rat, which provides the molecular mechanisms for the similarity and correlation of drug absorption between two species. In contrast, no correlation was found for the expressions of metabolizing enzymes between rat and human intestine, which indicates the difference in drug metabolism and oral bioavailability in two species. Detailed analysis indicates that many transporters (such as PepT1, SGLT-1, GLUT5, MRP2, NT2, and high affinity glutamate transporter) share similar expression levels in both human and rat with regional dependent expression patterns, which have high expression in the small intestine and low expression in the colon. However, discrepancy was also observed for several other transporters (such as MDR1, MRP3, GLUT1, and GLUT3) in both the duodenum and colon of human and rat. In addition, the expressions of metabolizing enzymes (CYP3A4/CYP3A9 and UDPG) showed 12 to 193-fold difference between human and rat intestine with distinct regional dependent expression patterns. The data indicate that rat and human show similar drug intestinal absorption profiles and similar transporter expression patterns in the small intestine, while the two species exhibit distinct expression levels and patterns for metabolizing enzymes in the intestine. Therefore, a rat model can be used to predict oral drug absorption in the small intestine of human, but not to predict drug metabolism or oral bioavailability in human.


Inhibition of mechanistic target of rapamycin promotes dendritic cell activation and enhances therapeutic autologous vaccination in mice.
Dendritic cells (DCs) are potent inducers of T cell immunity, and autologous DC vaccination holds promise for the treatment of cancers and chronic infectious diseases. In practice, however, therapeutic vaccines of this type have had mixed success. In this article, we show that brief exposure to inhibitors of mechanistic target of rapamycin (mTOR) in DCs during the period that they are responding to TLR agonists makes them particularly potent activators of naive CD8+ T cells and able to enhance control of B16 melanoma in a therapeutic autologous vaccination model in the mouse. The improved performance of DCs in which mTOR has been inhibited is correlated with an extended life span after activation and prolonged, increased expression of costimulatory molecules. Therapeutic autologous vaccination with DCs treated with TLR agonists plus the mTOR inhibitor rapamycin results in improved generation of Ag-specific CD8+ T cells in vivo and improved antitumor immunity compared with that observed with DCs treated with TLR agonists alone. These findings define mTOR as a molecular target for augmenting DC survival and activation, and document a novel pharmacologic approach for enhancing the efficacy of therapeutic autologous DC vaccination.


The Role of PKM2 in Metabolic Reprogramming: Insights into the Regulatory Roles of Non-Coding RNAs.
Pyruvate kinase is a key regulator in glycolysis through the conversion of phosphoenolpyruvate (PEP) into pyruvate. Pyruvate kinase exists in various isoforms that can exhibit diverse biological functions and outcomes. The pyruvate kinase isoenzyme type M2 (PKM2) controls cell progression and survival through the regulation of key signaling pathways. In cancer cells, the dimer form of PKM2 predominates and plays an integral role in cancer metabolism. This predominance of the inactive dimeric form promotes the accumulation of phosphometabolites, allowing cancer cells to engage in high levels of synthetic processing to enhance their proliferative capacity. PKM2 has been recognized for its role in regulating gene expression and transcription factors critical for health and disease. This role enables PKM2 to exert profound regulatory effects that promote cancer cell metabolism, proliferation, and migration. In addition to its role in cancer, PKM2 regulates aspects essential to cellular homeostasis in non-cancer tissues and, in some cases, promotes tissue-specific pathways in health and diseases. In pursuit of understanding the diverse tissue-specific roles of PKM2, investigations targeting tissues such as the kidney, liver, adipose, and pancreas have been conducted. Findings from these studies enhance our understanding of PKM2 functions in various diseases beyond cancer. Therefore, there is substantial interest in PKM2 modulation as a potential therapeutic target for the treatment of multiple conditions. Indeed, a vast plethora of research has focused on identifying therapeutic strategies for targeting PKM2. Recently, targeting PKM2 through its regulatory microRNAs, long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) has gathered increasing interest. Thus, the goal of this review is to highlight recent advancements in PKM2 research, with a focus on PKM2 regulatory microRNAs and lncRNAs and their subsequent physiological significance.


Nanoparticle-Assisted Laser Desorption/Ionization Mass Spectrometry (Nano-PALDI MS) with Py-Tag for the Analysis of Small Molecules.
We compared two ionization methods, matrix assisted laser desorption/ionization (MALDI) and nanoparticle assisted laser desorption/ionization (Nano-PALDI) mass spectrometry (MS), for the analysis of amino acids derivatized with Py-Tag™ that consists pyrylium-based compound. Py-Tag is a useful stable derivatization reagent due to wide mass differences (using 13C as the sole stable labelling isotope). For Py-Tag labelled lysine, sensitive signals that showed less noise with a ten times higher sensitivity, showed a wider mass difference by Nano-PALDI MS compared to MALDI MS.


454 sequencing of pooled BAC clones on chromosome 3H of barley.
Genome sequencing of barley has been delayed due to its large genome size (ca. 5,000 Mbp). Among the fast sequencing systems, 454 liquid phase pyrosequencing provides the longest reads and is the most promising method for BAC clones. Here we report the results of pooled sequencing of BAC clones selected with ESTs genetically mapped to chromosome 3H. We sequenced pooled barley BAC clones using a 454 parallel genome sequencer. A PCR screening system based on primer sets derived from genetically mapped ESTs on chromosome 3H was used for clone selection in a BAC library developed from cultivar "Haruna Nijo". The DNA samples of 10 or 20 BAC clones were pooled and used for shotgun library development. The homology between contig sequences generated in each pooled library and mapped EST sequences was studied. The number of contigs assigned on chromosome 3H was 372. Their lengths ranged from 1,230 bp to 58,322 bp with an average 14,891 bp. Of these contigs, 240 showed homology and colinearity with the genome sequence of rice chromosome 1. A contig annotation browser supplemented with query search by unique sequence or genetic map position was developed. The identified contigs can be annotated with barley cDNAs and reference sequences on the browser. Homology analysis of these contigs with rice genes indicated that 1,239 rice genes can be assigned to barley contigs by the simple comparison of sequence lengths in both species. Of these genes, 492 are assigned to rice chromosome 1. We demonstrate the efficiency of sequencing gene rich regions from barley chromosome 3H, with special reference to syntenic relationships with rice chromosome 1.


Adenoviral transfer of murine oncostatin M elicits periosteal bone apposition in knee joints of mice, despite synovial inflammation and up-regulated expression of interleukin-6 and receptor activator of nuclear factor-kappa B ligand.
Oncostatin M (OSM) has been described as a bone-remodeling factor either stimulating osteoblast activity or osteoclast formation in vitro. To elucidate the in vivo effect of OSM on bone remodeling, we injected an adenoviral vector encoding murine OSM in knee joints of mice. OSM strongly induced interleukin (IL)-6 gene expression, a known mediator of osteoclast development. We investigated the OSM effect in wild-type and IL-6-deficient mice and found a similar degree of OSM-induced joint inflammation. Within the first week of inflammation, the periosteum along the femur and tibia increased in cell number and stained positive for the osteoblast marker alkaline phosphatase. At these sites bone apposition occurred in both strains as demonstrated by Goldner and Von Kossa staining. In vitro OSM enhanced the effect of bone morphogenetic protein-2 on osteoblast differentiation. Immunohistochemistry demonstrated expression of receptor activator of nuclear factor-kappa B ligand (RANKL) and its receptor, receptor activator of nuclear factor-kappa B (RANK), in the periosteum but osteoclasts were not detected at sites of bone apposition. Induced mRNA expression for the receptor activator of nuclear factor-kappa B ligand inhibitor osteoprotegerin probably controlled osteoclast development during OSM overexpression. Our results show that OSM favors bone apposition at periosteal sites instead of resorption in vivo. This effect was not dependent on or inhibited by IL-6.


Insect growth-regulating activity of 1-benzyl-2-methylbenzimidazole derivatives on silkworms.
Derivatives of 1-benzyl-2-methylbenzimidazoles (BMBIs) were synthesized to evaluate their biological activities against Bombyx mori, a lepidopteran model insect. Synthesized BMBIs exhibited two different biological activities: inhibition of development and acute lethality. From a structural perspective, the activity varied with the position of the substitutions on the 1-benzyl moiety; BMBIs with substitutions on the 2 and/or 4 positions had comparatively high activity in comparison with those with substitutions on the 3-position. There was more activity for the inhibition of development with low doses, and more for acute lethality with high doses. The activity was also affected by the applied stage, that is, application in the 4th instar mostly interfered the larval molting or pupation, whereas that in the 3rd instar caused more acute mortality. Taken together, these results suggest that BMBIs have multiple modes of action.


[Colorimetric and opacity percentage study of dental restorative resins].
A colorimetric and opacity percentage study was carried out to compare experimental prototypes of resin at different die and additive concentrations with commercial prototypes. A simple and reproducible method was used. Through this study the optimum die and optical brightener formulas for a new dental resin were found and compared with available commercial dental resins in the national market.


Expression of gamma-aminobutyric acid(A) receptor subunits in the vestibular system.
Profile the expression of genes encoding GABAA receptor subunits in the vestibular end organs of a rat. Using a combination of reverse transcription followed by polymerase chain reaction (PCR) with gene-specific primers, expression of mRNAs encoding 13 individual GABA(A) receptor subunits was examined. PCR amplification products representing subunit gene expression for alpha1-6, beta1-3, and gamma1-3, but not for delta, subunits were amplified, suggesting multiple molecular levels of regulation of vestibular GABA(A) receptor expression. Nucleotide sequencing confirmed the identity of rat vestibular end-organs subunit cDNAs. These results give the most direct evidence to date that GABAA receptors composed of the detected subunits are expressed in the mammalian vestibular system, giving new support to previous investigations implicating GABA as a vestibular neurotransmitter.


Quantitative determination of porosity: a local assessment by NMR imaging techniques.
The local determination of porosity is an extremely valuable target because of different applications in petrophysics. In fact, obtaining a reliable profile of porosity or saturations could considerably improve the evaluation of transport properties of porous media, especially if applied to multiphase flow test (i.e., for relative permeability characterisation). However, the best procedure to adopt for these kind of studies is currently under debate, involving different experimental choices both for acquisition and hardware solutions. The choice of a reliable procedure could be particularly important especially if heterogeneous samples (i.e., vugular or fractured carbonates) are approached. We have investigated selected carbonate cores, characterised by fractures and large vugs, using different instrumental solutions in order to assess usefulness of application of NMR imaging methods as a porosity measurement tool for heterogeneous samples. Local porosity data have been obtained and discussed relative to conventional measurements and petrographical aspects of rock samples.


Structural basis of the transcriptional regulation of the proline utilization regulon by multifunctional PutA.
The multifunctional Escherichia coli proline utilization A (PutA) flavoprotein functions both as a membrane-associated proline catabolic enzyme and as a transcriptional repressor of the proline utilization genes putA and putP. To better understand the mechanism of transcriptional regulation by PutA, we have mapped the put-regulatory region, determined a crystal structure of the PutA ribbon-helix-helix domain (PutA52, a polypeptide corresponding to residues 1-52 of E. coli PutA) complexed with DNA, and examined the thermodynamics of DNA binding to PutA52. Five operator sites, each containing the sequence motif 5'-GTTGCA-3', were identified using gel-shift analysis. Three of the sites are shown to be critical for repression of putA, whereas the two other sites are important for repression of putP. The 2.25-A-resolution crystal structure of PutA52 bound to one of the operators (operator 2; 21 bp) shows that the protein contacts a 9-bp fragment corresponding to the GTTGCA consensus motif plus three flanking base pairs. Since the operator sequences differ in flanking bases, the structure implies that PutA may have different affinities for the five operators. This hypothesis was explored using isothermal titration calorimetry. The binding of PutA52 to operator 2 is exothermic, with an enthalpy of -1.8 kcal/mol and a dissociation constant of 210 nM. Substitution of the flanking bases of operator 4 into operator 2 results in an unfavorable enthalpy of 0.2 kcal/mol and a 15-fold-lower affinity, showing that base pairs outside of the consensus motif impact binding. Structural and thermodynamic data suggest that hydrogen bonds between Lys9 and bases adjacent to the GTTGCA motif contribute to transcriptional regulation by fine-tuning the affinity of PutA for put control operators.


Complementary leucine zippering system for effective intracellular delivery of proteins by cell-penetrating peptides.
A heterodimeric leucine zipper composed of a pair of leucine zipper peptides containing acidic or basic amino acid residues at appropriate positions in each peptide was used as a molecular glue to connect protein cargos to a cell-penetrating peptide (CPP) carrier. To investigate the hybridization properties by fluorescence experiments, we prepared an enhanced green fluorescent protein (EGFP) fused with an acidic leucine zipper (LzK), EGFP-LzK, and a basic leucine zipper (LzE) modified with a CPP, LzE-CPP. The LzK and LzE formed a 1:1 hybrid when EGFP-LzK and LzE-CPP were mixed in phosphate buffer saline, thereby conjugating the EGFP with the CPP. The formation of the 1:1 hybrid was confirmed by fluorescence spectra and fluorescence titration curves. Results from fluorescence microscopy experiments showed that EGFP was successfully delivered into cells by conjugating with the CPP via formation of the LzK/LzE hybrid. We also fused the apoptotic protein p53 with LzK (p53-LzK) and investigated the inhibition of cell proliferation of various cell lines by incubation with the p53-LzK/LzE-CPP hybrid. This hybrid was found to localize in nuclei and successfully inhibited cell-specific proliferation. The LzE/LzK zipper system inhibited cell proliferation more efficiently than the directly fused conjugate, p53-CPP. Our method will be a useful drug delivery system for delivering bioactive proteins to treat various diseases.


High-dose chemo/radiotherapy and autologous bone marrow or stem cell transplantation for poor-risk advanced-stage Hodgkin's disease during first partial or complete remission.
Complete remission rates of 70-90% can be achieved following combination chemotherapy for patients with advanced-stage Hodgkin's disease (HD). Patients who present with unfavorable poor prognostic factors, however, have a 5-year disease-free survival of only 40-50%. In an attempt to improve the prognosis of 20 patients with poor-risk advanced-stage HD, we evaluated the role of early high-dose therapy (HDT) and autologous bone marrow/stem cell transplantation (ASCT) during the first complete or partial remission (CR/PR). Patients were eligible for ASCT if they either achieved a PR (defined as > 50% regression) (six patients), or achieved a CR (14 patients) but had presented with three or more of the following unfavorable features: stage IV disease with bone marrow involvement or > or = 2 extranodal sites of involvement; bulky mass > 10 cm or bulky mediastinal mass > 1/3 of mediastina/thoracic ratio; B symptoms; and elevated serum lactate dehydrogenase (LDH) level. The study included 11 men (55%) and 9 women (45%). The median age was 37 years (range 20-57). Seventeen patients (85%) had stage IV disease; 14 (70%) had B symptoms; 13 (65%) had bulky mass > 10 cm; 14 (70%) had > or = 2 extra nodal sites involvement; and eight patients (40%) had elevated LDH levels. All patients were treated with standard four or 7-8 drug combination chemotherapy regimens until they achieved maximal response prior to ASCT with a median of six cycles (range 4-11). Six patients also received involved field radiotherapy to residual bulky mass > 5 cm or bony lesions before ASCT. The median time from diagnosis to ASCT was 8.6 months (range 5.5-18.9). Preparative regimens consisted of fractionated total body irradiation (FTBI) 1200 cGy in combination with etoposide 60 mg/kg and cyclophosphamide 100 mg/kg in all patients except one who had borderline pulmonary function and received lomustine 15 mg/kg instead of FTBI. All patients engrafted and there was no transplant-related mortality. One patient developed congestive cardiomyopathy at 4 years post-ASCT. All patients remain alive and in remission at a median follow-up of 42.8 months (range, 13.2-149.2). These preliminary results suggest that HDT and ASCT can be performed safely during first CR/PR in selected patients with advanced-stage HD who have an unfavorable prognosis. Further randomized studies comparing HDT and ASCT during first CR with conventional chemotherapy and ASCT at relapse in poor-risk advanced-stage HD should be conducted. The prognostic factors and risk groups described recently by an international prognostic study can be used to identify high-risk patients who may be candidates for more intensive therapy.


Progressive multifocal leukoencephalopathy in two psoriasis patients treated with efalizumab.
Progressive multifocal leukoencephalopathy (PML) is a rare neurological disorder that occurs almost exclusively in immunocompromised individuals by reactivation of the John Cunningham virus (JC virus), a polyomavirus found latent in more than 80 percent of healthy adults. Efalizumab, an immunosuppressive monoclonal antibody targeting T cells, has been used for treatment of moderate-to-severe chronic psoriasis. The authors describe two cases of PML that occurred in patients < or = 70 years old treated with efalizumab for more than three years. Both presented with symptoms resembling cerebral infarction (slurred speech, reduced motor control, personality changes) and were assessed for evidence of stroke. Multiple magnetic resonance images over successive weeks demonstrated progression of cerebral abnormalities. PML was diagnosed, and the presence of JC virus was confirmed in spinal fluid samples. Both patients died shortly after diagnosis. Dermatologists treating patients with immunosuppressive agents should be alert for the symptoms of PML and seek immediate consultation with a neurologist should symptoms arise.


Dexamethasone Attenuates the Enhanced Rewarding Effects of Cocaine Following Experimental Traumatic Brain Injury.
Clinical studies have identified traumatic brain injury (TBI) as a risk factor for the development of cocaine dependence. This claim is supported by our recent preclinical studies showing enhancement of the rewarding effects of cocaine in mice sustaining moderate controlled cortical impact (CCI) injury during adolescence. Here we test the efficacy of dexamethasone, an anti-inflammatory corticosteroid, to attenuate augmentation of the behavioral response to cocaine observed in CCI-TBI animals using the conditioned place preference (CPP) assay. These studies were performed in order to determine whether proinflammatory activity in the nucleus accumbens (NAc), a key brain nucleus in the reward pathway, mediates enhanced cocaine-induced CPP in adolescent animals sustaining moderate CCI-TBI. Our data reveal robust glial activation in the NAc following CCI-TBI and a significant increase in the cocaine-induced CPP of untreated CCI-TBI mice. Furthermore, our results show that dexamethasone treatment following CCI-TBI can attenuate the cocaine place preference of injured animals without producing aversion in the CPP assay. Our studies also found that dexamethasone treatment significantly reduced the expression of select immune response genes including Monocyte chemoattractant protein-1 (MCP-1/CCL2) and intercellular adhesion molecule-1 ( ICAM-1), returning their expression to control levels, which prompted an investigation of peripheral blood monocytes in dexamethasone-treated animals. Experimental findings showed that no craniectomy/dexamethasone mice had a significant increase, while CCI-TBI/dexamethasone animals had a significant decrease in the percentage of circulating nonclassical patrolling monocytes. These results suggest that a portion of these monocytes may migrate to the brain in response to CCI-TBI, potentially sparing the development of chronic neuroinflammation in regions associated with the reward circuitry such as the NAc. Overall, our findings indicate that anti-inflammatory agents, such as dexamethasone, may be effective in normalizing the rewarding effects of cocaine following CCI-TBI.


Polo-like kinase-1 triggers histone phosphorylation by Haspin in mitosis.
Histone modifications coordinate the chromatin localization of key regulatory factors in mitosis. For example, mitotic phosphorylation of Histone H3 threonine-3 (H3T3ph) by Haspin creates a binding site for the chromosomal passenger complex (CPC). However, how these histone modifications are spatiotemporally controlled during the cell cycle is unclear. Here we show that Plk1 binds to Haspin in a Cdk1-phosphorylation-dependent manner. Reducing Plk1 activity decreases the phosphorylation of Haspin and inhibits H3T3ph, particularly in prophase, suggesting that Plk1 is required for initial activation of Haspin in early mitosis. These studies demonstrate that Plk1 can positively regulate CPC recruitment in mitosis.